Fondazione Italiana Linfomi ONLUS … · Protocollo Studio FIL_FLAZ-12 V. 1 del 23/01/2012 Page 1...

Protocollo Studio FIL_FLAZ-12 V. 1 del 23/01/2012

Fondazione Italiana LinfomiONLUS

Sede legale : piazza Turati 5, 15121 - Alessandria Segreteria: c/o S.C. Ematologia Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo,

Via Venezia 16, 15121 – AlessandriaTel. 0131-206129-6071-6066 ; Fax 0131-263455; e-mail: [email protected] ; sito web: www.filinf.it







Clinical Protocol

A PHASE III MULTICENTER, RANDOMIZED STUDY COMPARING CONSOLIDATION

WITH 90YTTRIUM-LABELED IBRITUMOMAB TIUXETAN (ZEVALIN®)

RADIOIMMUNOTHERAPY VS AUTOLOGOUS STEM CELL TRANSPLANTATION

(ASCT) IN PATIENTS WITH RELAPSED FOLLICULAR LYMPHOMA (FL)

AGED 18-65 YEARS

STUDY ID:FIL_FLAZ-12

DATE:23/01/2012 EUDRACT NUMBER: 2012-000251-14

1. STUDY CONTACT INFORMATION INVESTIGATOR SPONSOR

Fondazione Italiana Linfomi (FIL)-ONLUS Address: piazza Turati 5, 15100, Alessandria, Italy Secretary: c/o S.C. Ematologia Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo - Via Venezia 16 15121 Alessandria Italy Tel +39-0131/206071; Fax +39 0131/263455; e-mail: [email protected] UH. STUDY COORDINATORS 1. Umberto Vitolo, M.D. Division of Hematology 2, Department of Oncology and Hematology, San Giovanni Battista Hospital, Torino, Italy. e-mail: [email protected] 2. Marco Ladetto, M.D. Division of Hematology 1, Department of Oncology and Hematology, San Giovanni Battista Hospital, Torino, Italy. e-mail: [email protected] WRITING COMMITTEE AND SCIENTIFIC SUPPORT 1. Luca Arcaini, M.D. Division of Hematology, Department of Oncology-Haematology, University of Pavia, Medical School, Fondazione IRCCS Policlinico San Matteo, Italy. e-mail: [email protected]


2. Monica Balzarotti, M.D. Department of Medical Oncology-Hematology, Istituto Clinico Humanitas-Rozzano, Milano, Italy. e-mail: [email protected] 3. Massimo Federico, M.D. Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy. e-mail: [email protected] 4. Alessandro Pulsoni, M.D. Division of Hematology, Department of Cellular Biotechnologies and Hematology, La Sapienza University, Rome, Italy. e-mail: [email protected] 5. Giuseppe Rossi, M.D. Department of Haematology, Spedali Civili, Brescia, Italy. e-mail: [email protected] 6. Chiara Rusconi, M.D. Division of Hematology, Niguarda Cà Grande Hospital, Milan, Italy. e-mail: [email protected] 7. Stefano Sacchi, M.D. Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy. e-mail: [email protected] 8. Manuela Zanni, M.D. Division of Hematology 1, Department of Oncology and Hematology, San Giovanni Battista Hospital, Torino, Italy. e-mail: [email protected] 9. Pierluigi Zinzani MD, Institute of Hematology and Medical Oncology “L. e A. Seràgnoli”,Bologna, Italy, e-mail: [email protected] U FIL REFERENTS FOR MRD AND OTHER BIOLOGICAL STUDIES (FIL MRD NETWORK) 1. Marco Ladetto, M.D. Division of Hematology 1, Department of Oncology and Hematology, San Giovanni Battista Hospital, Torino, Italy. e-mail: [email protected] 2. Gianluca Gaidano, M.D. Division of Hematology, Department of clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy. e-mail: [email protected] 3. Sara Galimberti, M.D. Department of Oncology, Transplant and Advances in Medicine, Section of Hematology, University of Pisa, Pisa Italy. e-mail: [email protected] 4. Ilaria Del Giudice, M.D. Division of Hematology, Department of Cellular Biotechnologies and Hematology, La Sapienza University, Rome, Italy. e-mail: [email protected] 5. Pier Paolo Piccaluga, M.D. Hematology Section, Department of Haematology and Oncology L. and A. Seràgnoli, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. e-mail: [email protected] BIOSTATISTICS, eCRF/DATABASE 1. Giovannino Ciccone, M.D. Unit of Clinical Epidemiology, San Giovanni Battista University Hospital and CPO Piemonte, Torino, Italy. e-mail: [email protected]


2. Manuela Ceccarelli, M.D. Unit of Clinical Epidemiology, San Giovanni Battista University Hospital and CPO Piemonte, Torino, Italy. e-mail: [email protected] QUALITY OF LIFE/PHARMACOECONOMY 1. Eva Pagano, BCs MS. Unit of Clinical Epidemiology, San Giovanni Battista University Hospital and CPO Piemonte, Torino, Italy. e-mail: [email protected] HISTOPATOLOGY 1. Stefano Pileri, M.D. Department of Hematology and Oncological Sciences, S. Orsola Malpighi Hospital, University of Bologna, e-mail: [email protected] PHARMACOVIGILANCE 1. Alessandro Levis, M.D. Division of Hematology, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy. e-mail: [email protected] REFERENT FOR RADIOIMMUNOTHERAPY 1. Stefano Fanti, M.D Nuclear Medicine Division and of PET Unit at the S. Orsola Malpighi Hospital, University of Bologna, Italy. e-mail: [email protected] LOGISTIC SUPPORT 1. Elisa Cornaglia, Sonia Perticone. Segreteria Fondazione Italiana Linfomi c/o S.C. Ematologia Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo - Via Venezia 16 15121 Alessandria Tel. 0131/206071 Fax. 0131/263455. Email: [email protected] STUDY SUPPORT This non-profit study is supported by a grant application to "Agenzia Italiana Del Farmaco" (AIFA) proposal number FARM9RCP52.


2. TABLE OF CONTENTS 1 STUDY CONTACT INFORMATION .................................................................................... 1

2 TABLE OF CONTENTS .......................................................................................................... 4

3 INVESTIGATOR AGREEMENT ........................................................................................... 7

4 SYNOPSIS.................................................................................................................................. 8

5 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...................................... 17

6 BACKGROUND ...................................................................................................................... 19

6.1 Follicular Lymphoma ........................................................................................................... 19

6.2 Radioimmunotherapy........................................................................................................... 19

6.3 Autologous Stem Cell Transplantation............................................................................... 20

6.4 Maintenance .......................................................................................................................... 21

6.5 MRD....................................................................................................................................... 21

7 STUDY RATIONALE............................................................................................................. 22

8 STUDY OBJECTIVES............................................................................................................ 23

8.1 Primary Objective................................................................................................................. 23

8.2 Secondary Objectives ........................................................................................................... 23

9 STUDY ENDPOINTS.............................................................................................................. 24

9.1 Primary Endpoint ................................................................................................................. 24

9.2 Secondary Endpoints ............................................................................................................ 24

10 OVERALL STUDY DESIGN............................................................................................... 25

10.1 Study Design........................................................................................................................ 25

10.2 Screening Phase, Enrolment And Induction Chemotherapy (Step I)............................ 25

10.3 Randomization (Step II) ..................................................................................................... 26

10.4 Stem Cell Mobilization and Collection (Step III) ............................................................ 27

10.5 Consolidation (RIT vs. ASCT) (Step IV) .......................................................................... 27

10.6 Maintenance (Step V) ......................................................................................................... 28

10.7 Follow-Up Phase (Step VI)................................................................................................. 28

11 DATA SAFETY AND MONITORING COMMITTEE (DS MC).................................... 29


12 INDEPENDENT EXTERNAL PATHOLOGIC REVIEW............................................... 29

13 STUDY POPULATION ........................................................................................................ 30

13.1 Inclusion Criteria................................................................................................................ 30

13.2 Exclusion Criteria ............................................................................................................... 30

14 DESCRIPTION OF TREATMENT .................................................................................... 31

14.1 Induction.............................................................................................................................. 31

14.2 Randomization .................................................................................................................... 32

14.3 Stem Cell Mobilization ....................................................................................................... 32

14.4 Consolidation....................................................................................................................... 33

14.5 Maintenance ........................................................................................................................ 33

15 TREATMENT DELAYS AND DOSE MODIFICATION................................................. 33

16 CONCOMITANT THERAPY AND PROCEDURES ....................................................... 34

16.1 Permitted Concomitant Therapy and Procedures........................................................... 34

16.2 Prohibited Concomitant Therapy and Procedures.......................................................... 34

17 ASSESSMENT OF EFFICACY........................................................................................... 35

17.1 Methods And Timing Of Efficacy Assessments ............................................................... 35

18 ASSESSMENT OF SAFETY................................................................................................ 38

19 OTHER ASSESSMENTS ..................................................................................................... 38

19.1 MRD Analysis ..................................................................................................................... 38

19.2 Quality Of Life .................................................................................................................... 41

19.3 Cost-Effectiveness ............................................................................................................... 41

20 STATISTICAL ANALYSES ................................................................................................ 42

20.1 Sample Size Calculation ..................................................................................................... 42

20.2 Analysis Plan ....................................................................................................................... 42

20.3 Quality of life analysis ........................................................................................................ 44

20.4 Cost-Effectiveness Analysis................................................................................................ 45

20.5 Study Duration.................................................................................................................... 45

21 GOOD CLINICAL PRACTICE AND QUALITY ASSURANCE.................................... 45


21.1 Monitoring, Audit And Ispections..................................................................................... 45

21.2 Investigator’s Responsabilities .......................................................................................... 46

22 ETHICAL AND REGULATORY CONSIDERATIONS .................................................. 46

22.1 Institutional Review Board/Independent Ethics Committee Review And Approval ... 46

22.2 Protocol Amendments ........................................................................................................ 48

22.3 Informed Consent ............................................................................................................... 48

23 DATA HANDLING AND RECORDKEEPING................................................................. 49

23.1 Data/Documents .................................................................................................................. 49

23.2 Data Management............................................................................................................... 49

23.3 Retention Of Records ......................................................................................................... 49

24 PRIVACY OF PERSONAL DATA ..................................................................................... 50

24.1 Toxicity And Adverse Event Evaluation .......................................................................... 51

25 REFERENCES....................................................................................................................... 55

26 APPENDICES I-XIV


3. INVESTIGATOR AGREEMENT I have read this protocol and agree that it contains all necessary details for carrying out this study.

I will conduct the study as outlined herein and will complete the study within the time designated.

I will provide copies of the protocol and all pertinent information to all individuals responsible to me

who assist in the conduct of this study. I will discuss this material with them to ensure that they are

fully informed regarding the study drug and the conduct of the study.

Investigator’s Signature Date

Name of Investigator (Typed or Printed)

Institution, Address*

Phone Number*

Investigator-Sponsor Signature* Date

(where required)

Name of Coordinating Investigator (Typed or Printed)

Institution

* If the address or phone number of the investigator changes during the course of the study, written

notification will be provided by the investigator to the sponsor and will not require protocol

amendment(s).


4. SYNOPSIS PROTOCOL TITLE A phase III multicenter, randomized study comparing consolidation

with (90)Y Ibritumomab Tiuxetan (Zevalin®) Radioimmunotherapy vs. autologous stem cell transplantation (ASCT) in patients with relapsed follicular lymphoma (FL) aged 18-65 years.

PROTOCOL VERSION

n=1 January 23 2012

SPONSOR Fondazione Italiana Linfomi (FIL) PROTOCOL PHASE: Multicenter open label phase III Randomized trial INDICATION patients aged 18-65 years with follicular lymphoma in first or second

relapse OBJECTIVES Primary:

1. To compare RIT with (90)Y Ibritumomab Tiuxetan (Zevalin®) vs. ASCT in terms of PFS from randomization.

Secondary:

1. To compare OS; 2. To compare EFS from randomization and from enrollment and PFS

from enrollment and TFS; 3. To compare CR rate and ORR; 4. To compare toxicity in both arms during induction, consolidation

and maintenance; 5. To compare quality of life in both arms during treatment and follow-

up; 6. To compare the cost-effectiveness of RIT vs. ASCT; 7. To compare the activity of RIT vs. ASCT on MRD assessed using

the Bcl-2/IgH translocation in both nested PCR and real time quantitative PCR;

8. To assess the prognostic impact of MRD related parameters on PFS and OS;

9. To assess feasibility, toxicity and efficacy (in terms of ORR, PFS and OS) of delivering ASCT after failure of RIT.

NUMBER OF PLANNED PATIENTS

265 patients will be enrolled in order to randomize 210 patients (80%) at the end of the induction phase

NUMBER OF CENTER 60 Centers ELECTION CRITERIA

INCLUSION CRITERIA 1. Age 18-65; 2. Histologically documented diagnosis of grade I-IIIa FL defined

according to WHO guidelines 2008 (Re-biopsy required); 3. Collection of BM and PB for MRD analysis (see Appendix I); 4. Relapsed or refractory disease after ≤ 2 chemotherapy lines at least

one containing rituximab (rituximab maintenance is not considered a therapeutic line);

5. Clinical indication of systemic treatment i.e. Stage II-IV who require therapy according to SIE and GELF criteria (see Appendix II);

6. ECOG performance status 0-2 (unless disease-related) (see Appendix III);

7. Availability of histological material for centralized revision; 8. Laboratory values:

• ANC ≥ 1500/mmc and/or platelets ≥ 100000/mmc (unless due to marrow involvement by lymphoma)


• Serum creatinine ≤ 1.5 x ULN (unless disease-related) • bilirubin ≤ 1.5 x ULN (or ≤ 3.0 x ULN, if patient has Gilbert’s syndrome), AST/SGOT and/or ALT/SGPT ≤ 2.5 x ULN if not disease related or ≤ 5.0 x ULN in case of lymphoma liver involvement;

9. Adequate cardiac function: LVEF > 50% by echocardiography or MUGA scan;

10. Not pregnant or breast-feeding; 11. Willingness to use effective contraception during the study and 3

months after the end of treatment; 12. No other prior malignancies except for adequately treated non-

melanoma skin cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast, incidental histological finding of prostate cancer (TNM stage of T1a or T1b) or other cancer from which the patient has been disease-free for > 5 years;

13. Signed informed written consent. 5BEXCLUSION CRITERIA

1. Grade IIIb FL, transformed FL or histologies different from FL; 2. Previous treatment with > 2 lines of chemotherapy ± rituximab

(rituximab maintenance is not considered a treatment line); 3. Previous ASCT or RIT treatment; 4. CNS involvement by lymphoma; 5. HBV positivity (except of patients HbcAb positive and HbsAg

negative, HBV-DNA negative, provided lamivudine prophylaxis is given);

6. HCV positivity with active virus replication (HCV-RNA copies in serum), active hepatitis or impaired liver function.

7. HIV positivity; 8. Any concurrent medical condition requiring long term use (greater

than one month) of systemic corticosteroids; 9. Active bacterial, viral, or fungal infection requiring systemic

therapy; 10. Any concurrent medical or psychiatric condition which might impair

administration of therapy or preclude the ability to give informed consent;

11. Treatment within an experimental agent within 30 days prior to study entry;

12. Myelosuppressive chemotherapy or biological therapy within three weeks before study entry (use rituximab course delivered as maintenance is not an exclusion therapy);

13. Major surgery other than diagnosis within four weeks prior to study entry.

TREATMENT PLAN After signing written informed consent and checking inclusion and exclusion criteria, the patient will be enrolled with an identification numeric code. STEP I: Induction Three courses standard dose rituximab-chemotherapy including R-CHOP, R-DHAP, R-FM, R-ICE, R-IEV or R-Bendamustine (see Appendix IV).


STEP II: Randomization Patients achieving at least PR (according to Cheson et al 2007, see Appendix V) will be stratified by enrolling Center characteristics and clinical response (PR or CR) after induction and then randomized 1:1 either to RIT (arm A) or ASCT (arm B) (see below for further details). The web-based randomization procedure will be continuously accessible (24/24h a day). The treatment arm will be concealed to the treating physician until the completion of STEP III. STEP III: Stem cell mobilization All patients will receive Ara-C 2g/m2 x b.i.d day 1-2 and rituximab day 3 and at hematological recovery followed by stem cell collection (aim of collecting 6x106 CD34+ cells/kg) (see Appendix VI). A second mobilization with plerixafor will be allowed for patients that experience a mobilization failure after Ara-C (both arms). (see Appendix VI). At the end of mobilization the result of randomization will be revealed. Patients in arm B collecting less than 2x106 CD34+ cells/kg will not undergo ASCT and will proceed to rituximab maintenance. STEP IV: Consolidation UARM A RITU: infusion of 90Y Ibritumomab Tiuxetan if the patient has less than 25% BM infiltration at the pre-consolidation restaging (0.4 mCi/kg if platelets ≥150,000/mmc, 0.3 mCi/kg if platelets are between 100.000 and 150,000/mmc). Zevalin® will be delivered as per indications and should thus be provided at expenses following regular supplies procedures. Patients with platelets <100.000/mmc or more than 25% BM infiltration at the pre-consolidation restaging will directly proceed to rituximab maintenance (see Appendix VII). UARM B ASCT U: BEAM conditioning regimen (or in alternative FEAM regimen with fotemustine to replace BCNU) and reinfusion of CD34+ cells of ≥ 2x106/Kg CD34+ day 0 (optimal dose to reinfuse 4x106/Kg CD34+). G-CSF 5 mcg/Kg from day 2 until ANC>1500/mmc. Patients who failed mobilization will directly proceed to rituximab maintenance (see Appendix VIII). STEP V: Maintenance Rituximab 375mg/m2 every three months for eight courses to all patients (starting three months after consolidation). STEP VI: Follow-up Phase The follow-up phase will continue until month 36 from randomization or until study end. NB All dosage delays and modifications are described in Appendix IX

MAIN PARAMETERS OF SAFETY

• Clinical adverse events • Laboratory parameters • Instrumental parameters

An Independent Data Safety and Monitoring Board (DSMB) will be instituted


STUDY PROCEDURES

I. Procedures at baseline (within one month prior to treatment): • Written informed consent; • Tumor biopsy with CD20 immunophenotyping; • Complete medical history, physical examination, ECOG

performance status, ECG, Chest X ray; • Pregnancy test (if applicable); • Hematology (complete blood count with differential) and blood

chemistry (transaminases, serum alkaline phosphatase, GGT, LDH, total bilirubin, creatinine, uric acid, total serum proteins, albumin, beta 2-microglobulin) (within two weeks prior to treatment);

• Creatinine clearance rate; • Coagulation (PTT, PT, ATIII, D-dimer, Fibrinogen); • Immunoglobulin dosage; • HBV,HCV,HIV serology; • Echocardiography or cardiac scintigraphy; • Total body CT (TBCT) scan; • BM and PB samples for centralized MRD testing; • Bone marrow biopsy; • EORTC QLQ-C30 questionnaire (see Appendix X); • Euro-Qol (EQ-5D) (see Appendix XI); • Questionnaire on patient’s cost Q1 (see Appendix XII);

II. During treatment (induction and consolidation) at least every other week:

• Adverse events; • Physical examination, ECOG performance status, body weight; • Hematology and Blood chemistry (see point I);

III. Restaging at randomization:

• Physical examination, ECOG performance status; • Hematology and Blood chemistry (see point I); • Creatinine clearance rate; • Coagulation (PTT, PT, ATIII, D-dimer, Fibrinogen); • Immunoglobulin dosage; • TBCT scan; • BM biopsy if positive at baseline; • BM and PB samples for MRD (if marker available)(see Appendix I);

IV. During mobilization:

• Adverse events; • Physical examination, ECOG performance status, body weight; • Hematology and Blood chemistry (see point I); • Leukapheresis sample for MRD;

V. Restaging before consolidation:

• Physical examination, ECOG performance status, ECG; • Hematology and Blood chemistry (see point I); • Creatinine clearance rate; • Coagulation (PTT, PT, ATIII, D-dimer, Fibrinogen); • Immunoglobulin dosage;


• Viral markers: HBV markers (HbsAg, HbsAb, HBcAb,), HBV DNA, HCV serology and HIV serology (if positive at baseline);

• Echocardiography or cardiac scintigraphy; • PFTs (only in Arm B); • OPT (only in Arm B); • TBCT scan (if not CR at point III); • BM biopsy if positive at baseline; • BM and PB samples for MRD (if marker available)(see Appendix I); • EORTC QLQ-C30 questionnaire (See Appendix X); • Euro-Qol (EQ-5D) (See Appendix XI); • Questionnaire on patient’s cost Q2 (See Appendix XII);

VI. Restaging after consolidation:

• Physical examination, ECOG performance status; • Hematology and Blood chemistry; • Coagulation (PTT, PT, ATIII, D-dimer, Fibrinogen); • Quantitative Immunoglobulins; • TBCT scan; • BM biopsy if positive at baseline; • BM and PB samples for MRD (if marker available)(see Appendix I); • Adverse events; • EORTC QLQ-C30 questionnaire (See Appendix X); • Euro-Qol (EQ-5D) (See Appendix XI); • Questionnaire on patient’s cost Q3 (See Appendix XII);

VII. During maintenance every three months:

• Adverse events; • Physical examination, ECOG performance status, body weight; • Hematology and Blood chemistry (see point I); • Immunoglobulin dosage;

VIII. During maintenance and subsequent Follow-up (every six months up to 36 months):

• Physical examination, ECOG performance status; • Hematology and Blood chemistry (see point I); • Quantitative Immunoglobulins; • TBCT scan; • BM biopsy if positive at baseline; • BM and PB samples for MRD (if marker available)(see Appendix I); • Adverse events; • EORTC QLQ-C30 questionnaire (See Appendix X); • Euro-Qol (EQ-5D) (See Appendix XI); • Questionnaire on patient’s cost Q4 (See Appendix XII);

All study procedures are summarized in Appendix XIII

STATISTICAL CONSIDERATIONS:

Endpoints Primary endpoint

PFS from randomization will be measured from the date of randomization to the date of documented first occurrence of disease


progression or relapse or to the date of death from any cause. Secondary endpoints

1. OS will be measured from the date of randomization and from enrollment to the date of death from any cause;

2. PFS from enrolment will be measured from the date of enrolment to the date of documented first occurrence of disease progression or relapse or to the date of death from any cause;

3. EFS will be measured from the date of enrolment and from the date of randomization to the date of any treatment failure including death, disease progression or relapse, discontinuation of treatment for any reason (toxicity, patient preference, initiation of new treatment without documented progression);

4. TFS is defined for all patients who achieved a response (CR or PR) after the completion of consolidation phase as the time from the end of consolidation phase until the institution of the next chemotherapy;

5. CR Rate will be defined as the proportion of CR at the end of consolidation phase;

6. ORR will be defined as the proportion of CR or PR at the end of consolidation phase;

7. Safety will be classified according to definitions of Common Terminology Criteria for Adverse Event version 4.03 (CTCAE). It will be determined by the incidence of severe, life- threatening (CTCAE grade 3, 4 and 5) and/or serious adverse events (Infusion-related reactions) commencing during and up to 24 hours after the first drug infusion and at any time during therapy and follow-up;

8. QoL will be measured during the trial through the EORTC QLQ-C30 questionnaire;

9. ICER will be calculated by dividing the difference in mean total costs between the two arms by the difference in the mean effects. The ICER will be calculated for the primary clinical effect measures of the trial. (i.e. PFS) and for QALYs. QALYs will be calculated multiplying the amount of time a patient spent in a particular health state by the utilities estimated using the EQ-5D questionnaire;

10. Rate of MR will be defined as the proportion of patients PCR negative for Bcl-2/IgH translocation after consolidation and during follow-up;

11. Rate of conversion will be defined as the proportion of patients from baseline PCR-positivity to PCR-negativity after either ASCT and RIT.;

12. Rate of molecular relapse will be defined as the proportion of patients from PCR-negativity to PCR-positivity during maintenance and the first two years of follow-up;

Randomization The web-based randomization procedure, developed centrally by the Unit of Clinical Epidemiology (CPO Piemonte), will be done in 1:1 ratio using sequences of random blocks of variable sizes and will be continuously accessible (24/24h a day). This allocation procedure, completely concealed to researchers until the end of phase III, will be stratified by enrolling center


characteristics and clinical response (PR or CR) after induction. The randomization procedure will be performed online and implemented within the electronic CRF at the web-site (HUwww.epiclin.itUH). Sample size estimate Primary end-point for sample-size calculation is PFS from randomization. Based on data from the literature, the expected PFS at three years with RIT maintenance is about 40%. According to O'Brien and Fleming group sequential design with a maximum of two stages, a total of 210 randomized patients (105 per group) are required (including a 5% cautelative increase in sample size) to detect an increase in the 3-years PFS from 40% to 60% assessed with a two-sided log-rank test with alpha of 5% and a power of 85%. According to literature, about 80% of enrolled patients will be in clinical response (CR or PR) after induction phase. In order to randomize the estimated number of patients, 265 patients will be enrolled. Under these assumptions, an interim analysis will be performed for stopping the trial prematurely because of superiority of one regimen above the other on a statistical basis after about two years of enrollment (n=150), when one third of the 105 expected failures will be observed. To preserve the overall type I error, critical p-values for stopping are determined at p = 0.0006 for the first interim analysis and p = 0.0498 for the final analysis. Analysis plan For endpoints occurring at different times a time-to-event analysis will be performed using Kaplan-Meier. Differences between arms will be compared with logrank tests. Cox models will be used to estimate HR and 95% CIs adjusted for stratification variables and the main prognostic factors. Secondary, binary endpoints (i.e. CR, ORR, toxicity, etc.) will be compared between the two arms with a chi-square test (or Fisher's exact test). To take into account the presence of competing risks during time, cumulative incidences of the outcomes will be estimated using the method described by Gooley et al. and compared between arms by Gray's test. Decisions on early stopping will be based on wise judgments by the data monitoring committee interpreting the totality of available results and the external evidence and not only the statistical stopping rules. Quality of life Repeated QoL measurements will be collected during the trial. The pattern of missing data (which individuals, at which assessments) and the reasons for missingness will be investigated to reconstruct the missing data mechanism to some extent. Generalized linear mixed models will be applied to compare the two arms. The proportion of missing data in both arms will be analyzed. In presence of a consistent number of missing data, multiple imputation techniques will be performed to recover the information loss before comparing the two arms. Sensitivity analyses for the methods of imputation and estimation will be performed. Cost-effectiveness analysis A within trial economic analysis, with total healthcare costs and QALYs gained per patient calculated during the trial follow up, will be performed. The mean cost of care during the study period will be estimated for all


patients in each arm by including the following episodes of care: induction, stem cell mobilization, consolidation with RIT and ASCT, maintenance therapy, patient monitoring, management of side effects and relapses. Patients’ cost due to the treatment (out-of-pocket, traveling, absence from work) will also be collected with a specific questionnaire filled by the patients or their caregivers. Bootstrapping will be used for pair-wise comparison of the mean differences in total costs between the two groups. To estimate the uncertainty surrounding the ICER bootstrapping methods will be used. The bootstrapped cost-effect pairs will be used to estimate cost-effectiveness acceptability curves. Populations under study The following populations will be considered for the study

• enrolled population: all the patients who signed the informed consent

• population in induction treatment: all enrolled patients who started induction treatment

• intention to treat population: all patients randomized to either ASCT or RIT

• ASCT eligible Population: includes only patients with sufficient collection of CD34+ cells (at least 2x106 CD34+/kg) at the end of stem cell mobilization phase.

TIMING The expected duration of the study to meet the primary endpoint is 5 years: • 3 years of accrual • 2 years of follow-up after entry of the last patient

The interim analysis (on the primary endpoint) will be performed after about two years of enrollment (n=150), when one third of the 105 expected failures will be observed.


Figure 1 STUDY DESIGN A phase III multicenter, randomized study comparing consolidation with (90)Yttrium-Labeled

Ibritumomab Tiuxetan (Zevalin®) Radioimmunotherapy vs. autologous stem cell transplantation (ASCT) in patients with relapsed follicular lymphoma (FL) aged 18-65 years.


5. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS Abbreviations Explanation AE Adverse Event AIFA Agenzia Italiana del Farmaco ALT/SGPT Alanine Aminotransferase/ Serum Glutamic Pyruvic Transaminase ANC Absolute Neutrophil count Ara-C Cytarabine ASCO American Society of Clinical Oncology ASCT Autologous Stem Cell Transplantation ASH American Society of Hematology AST/SGOT Aspartate Aminotransferase/Serum Glutamic Oxalacetic Transaminase ATIII Antithrombin III BEAM BCNU, Etoposide, Ara-c, Melphalan BM Bone Marrow BUN Blood Urea Nitrogen CBC Complete Blood Count CR Complete Remission CRF Case Report Form DFS Disease Free Survival DR Duration of Response DSMC Data Safety Monitoring Committee ECOG Eastern Cooperative Oncology Group EFS Event Free Survival EMA European Medicines Agency EQ-5D Euro Qol-5 Dimensions ESG-MRD European Study Group Minimal Residual Disease FIL Fondazione Italiana Linfomi FL Follicular Lymphoma GC Germinal Center G-CSF Granulocyte Colony Stimulating Factor GELF Groupe d'Etude des Lymphomes Folliculaires GGT Gamma Glutamyl Transferase HR Hazard Ratio ICER Incremental Cost-Effectiveness Ratio IGH Immunoglobulin Heavy Chain IRB/IEC Institutional Review Board/Ethics Committee LDH Lactate Dehydrogenase LVEF Left Ventricular Ejection Fraction MAR Missing At Random MCAR Missing Completely At Random MNAR Missing Not At Random MR Molecular Remission MRD Minimal Residual Disease MUGA Multi Gated Acquisition Scan NHL Non-Hodgkin Lymphoma OPT Orthopantomography ORR Overall Response Rate OS Overall Survival PB Peripheral Blood PBSC Peripheral Blood Stem Cell PCR Polymerase Chain Reaction


PD Progression Disease PFS Progression Free Survival PFTs Pulmonary Function Tests PI Principal Investigator PPT Partial Thromboplastin Time PR Partial Response PT Prothrombin Time QALYs Quality Adjusted Life Years QoL Quality of Life R-CHOP Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone RIT Radioimmunotherapy SAE Serious Adverse Event SD Stable Disease SIE Società Italiana di Ematologia SmPC Summary of Product Characteristics TBCT Total Body Computed Tomography TFS Treatment Free Survival TTP Time To Progression ULN Upper Limit of Normal WHO World Health Organization


6. BACKGROUND 6.1 Follicular Lymphoma

FL is the second most common NHL subtype. Its natural history is characterized by an indolent clinical

course with a median survival time of approximately nine years1. FL arises from GC B-cells and retains

mRNA and protein expression patters typical of lymphocytes associated to this structure, including

CD19, CD20 and CD10, while it is usually negative for CD5. As opposed to most GC-derived cells, FL

usually express BCL-2, most often as a result of the t(14;18)(q32;q21) juxtaposing the immunoglobulin

heavy-chain gene IGH and the bcl-2 proto-oncogene.

The outcome of FL has significantly improved in recent years, mostly due to the introduction of

rituximab either alone or in combination with chemotherapy. Despite improved first line treatment, the

majority of FL patients still experience clinical relapse. A minority of relapsed FL show a transformed

histology and are usually treated as aggressive lymphomas. However, more than 80% of cases retains

classical FL histology, particularly during early relapses. Although relapsed FL is prone to respond to

second line treatment, further remissions are shorter and most patients ultimately die of their disease or

of treatment-related toxicity. There is no consensus treatment for patients with relapsed FL, particularly

those aged < 65 years. In particular, no chemotherapeutic program proved to be superior compared to

other schedules2,3. Based on empiric evidence most patients receive a rituximab-supplemented

chemotherapeutic regimen based on drugs which are not cross-resistant with those employed at

diagnosis. The most frequently used regimens include: CHOP or CHOP-like regimens, fludarabine-

containing regimens, platinum-based regimens and most recently Bendamustine4, 5, 6,7,8,9. Following R-

chemotherapy it is also common clinical practice to deliver a consolidation regimen, to target residual

disease, with the aim of increasing CR rate and prolonging disease remission, as both these parameters

seem to have a major role on long-term outcome10. Consolidation therapy consists either of intensified

chemotherapy with ASCT or RIT. Both these options proved effective in the context of phase III trials

and are recognized as appropriate treatment modalities by a number of regulatory authorities and

clinical guidelines11.

6.2 Radioimmunotherapy

The value of RIT at relapse has been proved in the context of a phase III trial which included patients

with a median age of 59 years and enrolled patients up to 80 years12. In this study RIT was used as sole

therapeutic option and not as consolidation as frequently occurs in routine clinical practice. The

regimen was compared with four consecutive infusions of rituximab once a week. Patients were

heterogeneous in the number of lines of previous chemotherapy (median 2 ranges 1-6) and most of

them were rituximab-naive. In the RIT group the CR rate was significantly higher compared to the


rituximab group (30% vs. 16%) and median TTP was 14 months. RIT has also been investigated as

consolidation regimen following first line chemotherapy and compared to a non-consolidation arm13.

The study from Morschhauser et al. demonstrated a superior outcome for RIT with a median PFS of

36.5 vs. 13.3 months (p < .0001). Considering the median PFS of 36 months observed when RIT was

delivered as consolidation of first line chemotherapy without subsequent rituximab maintenance, the

PFS of patients receiving second line treatment using the most complete non-transplantation-based

regimen (i.e. non-cross-resistant R-chemotherapy, RIT and rituximab maintenance) will probably be

around 30 months.

6.3 Autologous Stem Cell Transplantation

ASCT is commonly used in relapsed FL aged less than 65 years. The historical experience from Dana

Farber Cancer Institute was based on 153 patients. Patients from this cohort and had an eight-year PFS

of 42% in the absence of rituximab supplementation14. Rohatiner et al. treated 121 FL patients with

ASCT in second or subsequent remission, and reported that 48% of patients were alive and disease-free

at 10 years, again in a period where rituximab was still not available15. Moreover they showed a better

outcome in patients treated in second remission in term of PFS and OS at 10 years, compared to

historical controls. Also the Italian Experience from Arcaini et al, which mostly included patients

treated front-line with a doxorubicin-containing regimen, reported a five-year PFS of 59%16. Currently

there is only one phase III trial supporting the use of ASCT in relapsed FL. The CUP (Chemotherapy,

Unpurged or Purged) trial formally compared ASCT with standard chemotherapy in relapsed FL

patients. Eighty-nine patients were enrolled and those responsive after three courses of CHOP were

randomized to either three additional CHOP courses or to two separated ASCT-based arms using,

respectively, unmanipulated or ex-vivo purged stem cells collections. The results on 89 patients showed

that patients receiving any type of ASCT had a median PFS of 60 months as opposed to those treated

conventionally whose median PFS was 18 months17. Based on the CUP trial several Institutions offer

ASCT to young patients with relapsed FL. However several European and US Institutions do not

consider ASCT as standard treatment for relapsed FL, regardless of the results of the CUP trial. This is

due to a number of major limitations of this study, in particular: 1) the trial was designed and conducted

before the introduction of Rituximab; 2) the sample size was relatively modest and patients received

different ASCT schedules; 3) the study had a very prolonged enrolment time (four years for 140

patients) and had a lower than expected accrual, suggesting the presence of selection biases. Moreover,

ASCT is regarded as a potentially dangerous procedure, with non-negligible risks of both short- and

long-term toxicity, particularly secondary myelodysplasia and is thus often omitted or postponed to

later disease phases. Nevertheless more recent studies conducted in rituximab-treated patients suggest

the potential advantage of delivering ASCT over RIT also in this context. In particular, the GITMO/IIL


trial recorded a PFS at three-years of 68%, in a panel of patients with poor risk at diagnosis who

received ASCT (without subsequent rituximab maintenance) as salvage treatment after failure of first

line treatment with CHOP and Rituximab18. Such a PFS performance, if proved true in a randomized

trial, might justify the increased labor-intensiveness and toxicity of ASCT compared to RIT.

6.4 Maintenance

The role of rituximab maintenance has been shown in patients responding to induction treatment,

conferring a clear benefit to prolong the duration of remission without significantly increasing toxicity.

Rituximab maintenance proved capable of increasing PFS in FL patients, both following first line

treatment, as well as following salvage treatment. The European pivotal phase III study conducted by

Van Oers et al. (EORTC 20981) has demonstrated the advantage of maintenance with rituximab given

every three months for a maximum of two years compared to observation alone. They observed a

median PFS of 3.7 years in the maintenance arm vs. 1.3 years in the observation arm (p< .0001) and a

very favourable trend in terms of 5-year Overall Survival (OS) 74% vs. 64% (p= .07)9. Based on these

results, rituximab maintenance is now considered a mainstay for subjects achieving CR or PR,

regardless of previous induction treatment, although its benefit after RIT or ASCT has been

investigated exclusively in small non-randomized series19, 20.

6.5 MRD

FL was the first mature B cell tumor in which MRD was employed, and it is still the disease in which

MRD detection is most frequently used. The first experiences at the Dana Farber Cancer Institute date

back to the 1990s; Gribben et al. investigated the effects of immunologic purging of BM, assessed by

PCR, before ASCT. Patients autografted with PCR-negative BM had a superior outcome compared to

those whose marrow contained detectable residual lymphoma cells. This study was recently updated at

a median follow-up of 12 years21; patients receiving PCR-negative marrow had a PFS plateau at 67%,

as opposed to those who received PCR-positive cells, whose PFS was 26%, indicating that MRD status

at the time of marrow infusion has a long-term impact on the natural history of FL. Since then, several

studies have confirmed the major predictive value of MRD detection in FL22, 23, 24. When multivariate

analysis was employed, the lack of MR emerged as an independent outcome predictor in most studies21,

24,25,26,27. In a recent Italian phase III, MRD detection proved able to capture most of the beneficial

effect of intensive vs. conventional treatment: indeed the intensified arm ensured a higher number of

molecular remissions, without modifying the outcome of patients achieving or not achieving MR within

the two arms. Moreover MRD detection proved useful in identifying which patient profit most from

consolidation regimens, such as RIT, as shown by a recent report describing MRD results of patients

enrolled in the FIT trial.


Thus MRD detection has had a major impact on clinical research over the last two decades. Its

inclusion as a secondary endpoint in clinical trials is now often considered in the context of most

European multicenter clinical trials to ensure a better comprehension of disease response patterns and

treatment activity. More recently, clinical scientists have started to use it for decision-making in

selected settings.

7. STUDY RATIONALE It is thus clear that there is no “golden standard” for consolidation treatment of relapsed FL patients

aged less than 65 years. The routine clinical practice might vary considerably according to local

Institutional policies and the same patient could undergo two different therapeutic schedules with

radically different toxicity profiles in full accordance with available scientific literature and regulatory

recommendations. On one hand the patient might receive RIT which has modest short and long-term

toxicity and can be performed on an outpatient basis. On the other hand, based on evidences suggesting

superior activity of ASCT compared to non-ASCT-based procedures arising from several phase II

studies and from the CUP phase III trial, the patient might receive an intensified ASCT-containing

program, despite its superior toxicity and lack of documented evidence of outcome benefit in

comparison to current conventional schedules including rituximab and RIT. Based on these

considerations, the FIL wishes to propose a formal multicenter randomized phase III study in patients

with FL aged less than 65 years in first or second relapse: the study will compare RIT vs. ASCT as

consolidation in patients receiving rituximab-supplemented induction chemotherapy. After R-

chemotherapy, patients in PR or CR will be randomized to either RIT or ASCT. After consolidation all

patients will receive rituximab maintenance. Stem cell mobilization will be planned before

randomization in all patients to allow performing ASCT as third line treatment in case of RIT failure.

Thus, the ultimate aim of this study will be that of defining the optimal therapeutic approach in a

clinical context where there is no established "golden standard". The results of the study will be of

relevance both in case of documented superiority of ASCT or in the absence of a clear benefit for the

intensified procedure. Indeed, if ASCT will prove superior, its use will be fully justified even in the

presence of significant toxicity and superior labor-intensiveness. On the other hand, if RIT and ASCT

will prove to be comparable the use of ASCT will be no longer justified in early relapses of FL. This

finding will clearly favour the use RIT thus sparing a considerable number of patients from receiving a

highly toxic and expensive procedure, currently delivered in the absence of a clear-cut proof of

superiority. Obviously the increased toxicity of ASCT would be justified only in the presence of a

major PFS improvement (at least 20%) to compensate for the increased risks and complexity of ASCT.


The present proposal will thus compare the two strategies with the aim of detecting such a difference.

Moreover the study will include detailed evaluation of cost-effectiveness and quality of life, allowing a

comprehensive evaluation of the clinical and social benefits associated to the consolidation regimens

under investigation. The study will also allow to analyze the impact of rituximab maintenance given

after ASCT or RIT both in terms of efficacy and safety. Moreover, since patients relapsing after RIT

will receive salvage ASCT, the long term efficacy of the sequential use of RIT followed by ASCT will

be compared to an earlier use of ASCT.

8. STUDY OBJECTIVES 8.1 Primary Objective

To compare in a randomized superiority trial RIT with (90)Yttrium-Labeled Ibritumomab Tiuxetan

(Zevalin®) vs. ASCT in terms of PFS from randomization after completion of chemotherapy

additioned with rituximab in adult patients with relapsed FL. PFS is defined according to Cheson et

al.28 as the time from randomization until lymphoma relapse/progression or death as a result of any

cause (see Appendix V).

8.2 Secondary Objectives

1. To evaluate OS according to 2007 Revised Response Criteria for Malignant Lymphoma28 in

both treatment arms (see Appendix V);

2. EFS from randomization and from enrolment and PFS from enrolment and TFS according to

2007 Revised Response Criteria for Malignant Lymphoma28 in both treatments arms (see

Appendix V);

3. To evaluate CR and ORR in both treatment arms according to 2007 Revised Response Criteria

for Malignant Lymphoma28 (see Appendix V);

4. To compare toxicity in both arms during induction, consolidation and maintenance;

5. To compare quality of life in both arms during treatment and follow up with QLQ-C30

questionnaire;

6. To compare the cost-effectiveness of RIT vs. ASCT;

7. To compare the activity of RIT vs. ASCT on MRD assessed using the Bcl-2/IgH translocation

in both nested PCR and real time quantitative PCR;

8. To assess the prognostic impact of MRD related parameters on PFS and OS;

9. To assess feasibility, toxicity and efficacy (in terms of ORR, PFS and OS) of delivering ASCT

after failure of RIT.


9. STUDY ENDPOINTS 9.1 Primary Endpoint

PFS from randomization will be measured from the date of randomization to the date of

documented first occurrence of disease progression or relapse or to the date of death from any

cause. Responding patients and patients who are lost to follow up will be censored at their last

assessment date.

9.2 Secondary Endpoints

1. OS will be measured from the date of randomization and from enrollment to the date of death

from any cause. Patients who have not died at the time of the final analysis will be censored at

the date of the last contact;

PFS from enrollment will be measured from the date of enrollment to the date of documented first

occurrence of PD or relapse or to the date of death from any cause. Responding patients and patients

who are lost to follow-up will be censored at their last assessment date;

2. EFS will be measured from the date of enrolment and from the date of randomization to the date

of any treatment failure including death, disease progression or relapse, discontinuation of

treatment for any reason (toxicity, patient preference, initiation of new treatment without

documented progression). Patients without events and patients who are lost to follow up will be

censored at their last assessment date;

3. TFS is defined for all patients who achieved a response (CR or PR) after the completion of

consolidation phase as the time from the end of consolidation phase until the institution of the

next chemotherapy;

4. CR Rate will be defined as the proportion of CR at the end of consolidation phase. Patients

without a response assessment (due to any reason) will be considered as non-responders;

5. ORR will be defined as the proportion of CR or PR at the end of consolidation phase. Patients

without a response assessment (due to any reason) will be considered as non-responders;

6. Safety will be evaluated for induction, consolidation and during maintenance therapy. Toxicity

will be classified according to definitions of Common Terminology Criteria for Adverse Event

version 4.03 (CTCAE). It will be determined by the incidence of severe, life- threatening

(CTCAE grade 3, 4 and 5) and/or serious adverse events (Infusion-related reactions)

commencing during and up to 24 hours after the first drug infusion and at any time during

therapy and follow-up;

7. QoL will be measured during the trial through the EORTC QLQ-C30 questionnaire;


8. ICER will be calculated by dividing the difference in mean total costs between the two arms by

the difference in the mean effects. The ICER will be calculated for the primary clinical effect

measures of the trial. (i.e. PFS) and for QALYs. QALYs will be calculated multiplying the

amount of time a patient spent in a particular health state by the utilities estimated using the EQ-

5D questionnaire;

9. Rate of MR will be defined as the proportion of patients PCR negative for Bcl-2/IgH at different

time-points including those achieving continuous MR in two or more consecutive time-points.

Patients without a response assessment (due to any reason) will be excluded from the analysis;

10. Rate of conversion will be defined as the proportion of patients from baseline PCR-positivity to

PCR-negativity after either ASCT or RIT. Patients without a response assessment (due to any

reason) will be excluded from the analysis;

11. Rate of molecular relapse will be defined as the proportion of patients from PCR-negativity to

PCR-positivity during the first two years of follow-up. Patients without a response assessment

(due to any reason) will be excluded from the analysis. All the parameters will be assessed

using both nested-PCR and RQ-PCR. Explorative assessment of MRD kinetics (increasing vs.

decreasing vs. stable levels) by RQ-PCR will also be assessed;

10. OVERALL STUDY DESIGN

10.1 Study Design

This is a Phase III, multicenter, open-label, randomized and controlled study to compare the efficacy of

a consolidation therapy with RIT vs. ASCT in patients with FL in CR or PR after second or third line

chemotherapy supplemented with rituximab. Patients with FL will be eligible for screening at the time

of relapsed or refractory disease after two or less chemotherapy lines at least one containing rituximab.

This study will be conducted in six steps as follows.

10.2 Screening Phase, Enrolment and Induction chemotherapy (STEP I)

CBC and serum chemistry tests will be required within 15 days before the first dose of study drug. CT

of chest, abdomen and pelvis and bone marrow specimens will be performed during the screening

phase of the study as outlined in schedules of assessments and not beyond one month before the patient

has approved and signed the informed consent form. Tumor/lymph node biopsy specimen, obtained at

study enrolment is mandatory. However if the patient has a biopsy taken in the previous 12 months and

has not received anti-lymphoma treatment during this lag of time, study entry biopsy can be omitted.

Archival slides from specimen obtained at study entry with representative stained slides supporting the

diagnosis (CD20, CD10, Bcl-6, Bcl-2, MIB-1), must be sent to central pathology as soon as possible; in


parallel, 4-5 unstained slides must also be submitted. Samples for MRD detection should be sent to the

reference lab within the FIL-MRD network (see Appendix I). Upon completion of the screening phase,

eligible patients will be enrolled in the study. After registering baseline data, checking inclusion and

exclusion criteria, the patient will be enrolled with a numeric code. The web-based randomization

procedure to arm A or B will be accessible 24 h/day 7 days/week. Patients will then start Induction

treatment consisting in three rituximab-supplemented chemotherapy courses. R-chemotherapy

schedules allowed are: R-CHOP, R-FM, R-ICE, R-DHAP, R IEV and R-Bendamustine. Guidelines for

chemotherapy delivery are detailed in appendix IV.

Following Induction patients will undergo full restaging as detailed below.

Patients with stable or progressive disease will discontinue treatment and will receive any salvage

treatment.

10.3 Randomization (STEP II)

Patients achieving a CR or PR, after the completion of induction treatment phase, will be stratified into

groups according to:

1. Clinical response (CR+PCR negative vs. CR+PCR positive, PR regardless PCR status)

2. Center characteristics (Performing ASCT and RIT locally, performing exclusively ASCT

locally, not performing ASCT locally)

Then patients will be randomized with a 1:1 ratio in each stratum:

1. Arm A: RIT

2. Arm B: ASCT.

The study enrollment and the randomization will be performed centrally, using a web-based procedure,

developed by the UNIT OF CLINICAL EPIDEMIOLOGY – AZIENDA OSPEDALIERO-

UNIVERSITARIA S. GIOVANNI BATTISTA – TORINO. Dr. G. Ciccone - Tel +39-011-6336857.

The enrolment and randomization procedures will be implemented on a study specific website

( HUwww.epiclin.itUH) active during 24/24 hours for 7/7 days.

Only local study coordinators will get a specific password and instructions to access the dedicated

study area.

The random number sequence will be generated separately for each stratum, using blocks of various

lengths and in random order. The random allocation sequence is completely unpredictable by

researchers and concealed until assignment occurs. Once randomised, the patient is considered part of

the intention to treat population and included into the primary efficacy analyses.

At the moment of enrolment, an identification study number will be generated by the web-based

procedure to each patient. This study number has to be reported on all case report forms. The

randomization arm will be revealed to the physician only after the stem cell mobilization and collection


phase to prevent possible biases during the collection phase (particularly reduced commitment to PBSC

collection in the RIT arm).

10.4. Stem cell mobilization and collection (STEP III)

All patients will receive Ara-C 2g/m2 b.i.d. for two days followed by rituximab 375mg/m2 day 3 and

the first day with ANC greater that 1000/mmc. Then patients will undergo stem cell collection with the

aim of collecting 6x106 CD34+ cells/kg.

A second mobilization with plerixafor will be allowed for patients that experience a failure of

mobilization after Ara-C (both arms) (see Appendix III).

Patients in arm B (ASCT) collecting less than 2x106 CD34+ cells/kg will not undergo ASCT and will

proceed to rituximab maintenance.

After mobilization patients will undergo full restaging as detailed below.

Based on current availability of mobilization facilities, it is expected that some of the participating

Centers will not be able to deliver mobilization locally. In this case the mobilization procedure will be

delivered in a nearby Center that is able to provide the requested procedure. The procedures for patient

referral are detailed in Appendix VI.

10.5 Consolidation (RIT vs ASCT) (STEP IV)

Consolidation will be delivered according to treatment arm as follows:

1. UArm A RIT: U infusion of rituximab 250 mg/m2 on day 1 and day 8 and (90)Y Ibritumomab

Tiuxetan (0.4 mCi/Kg if platelets ≥ 150.000/mmc, 0.3 mCi/Kg if platelets are between 100.00

and 150.000/mmc) on day 8 (range days 7 to 9) immediately after the second rituximab infusion

(Zevalin® will be delivered as per indications and should thus be provided at expenses

following regular supplies procedures).

Patients with platelets <100.000/mmc or with BM infiltrated greater than 25% at the restaging

pre-consolidation will proceed to rituximab maintenance (see Appendix VII).

2. UArm B ASCTU: BEAM conditioning regimen with BCNU i.v. 300mg/m2 day - 6, etoposide 200

mg/m2 i.v. days -5, -4, -3 and -2, Ara-C 400 mg/m2 i.v., days -5, -4, -3 and -2, melphalan 140

mg/m2 i.v. day -1; reinfusion of CD34+ cells of ≥ 2x106/Kg CD34+ day 0 (optimal dose to

reinfuse 4x106/Kg CD34+). G-CSF 5 mcg/Kg from day 2 until ANC>1500/mmc. Patients, who

have experienced failure of stem cell collection, will directly proceed with rituximab

maintenance (see Appendix VIII).


Based on current availability of RIT and ASCT facilities, it is expected that some of the participating

Centers will not be able to deliver RIT or ASCT locally. In this case the consolidation procedure will

be delivered in a nearby Center that is able to provide the requested treatment. A detailed map for

patient referral to RIT Units on a geographical basis has been created. The map and the procedures for

patient referral are detailed in Appendix VII and VIII.

After consolidation, patients will undergo full restaging as detailed below.

10.6 Maintenance (STEP V)

After restaging, full haematological recovery (ANC >1.500/mmc and PLTS >75.000/mmc) and not

before day 90, patients will start maintenance treatment as follows: rituximab 375mg/m2 every three

months for 8 courses.

10.7 Follow-up Phase (STEP VI)

1. The follow-up phase will continue until month 36 from the date of randomization or until study

ends;

2. Patients who discontinue treatment due to progressive disease or relapse will be followed by

clinic visit or documented telephone contact at least every 90 days (± 14 days) for survival and

for the first subsequent anti-lymphoma therapy. In case of cross-over (i.e. following RIT failure)

patients will be followed for 24 months from salvage ASCT;

3. Patients who discontinued treatment due to reasons other than PD or relapse will be followed by

clinic visits and CT scan every 90 days (± 14 days) to assess disease status until disease

progression or relapse;

4. After disease progression or relapse has occurred, patients should be followed by clinic visit or

documented telephone contact every 90 days (± 14 days) for survival and for the first

subsequent anti-lymphoma therapy (including the time of and best response to the first anti

lymphoma treatment regimen utilized after discontinuation from this study);

5. Patients who have been treated with Arm A RIT as consolidation and subsequently experience

relapse or progression, will receive three courses of R-chemotherapy followed by ASCT. Stem

cell collections obtained in the context of the protocol as detailed in STEP III will be the

preferred stem cell source for salvage ASCT;


11. DATA SAFETY AND MONITORING COMMITTEE (DS MC)

The FIL on its own initiative and responsibility will be the sponsor of this study. The sponsor will set

up an independent external DSMC. The DSMC consists in experts independent from the sponsor.

Aims of the DSMC are: to assess, at intervals during the course of the trial, the progress of the trial,

the trial safety data and the trial outcome data with a view to recommending whether the trial should

continue, be modified or be terminated.

The DSMC will be composed by:

1. Three independent clinicians with expertise in the treatment of Follicular Lymphoma;

2. The biostatistician of the study;

3. An independent statistician with expertise in the methodology of clinical trials and data analysis.

Roles of DSMC (suggested, not exclusive)

1. Review ongoing safety data throughout the study. One efficacy interim analysis will be planned

when 33% of the total failures (progressions or deaths) have occurred. Additional safety and

efficacy reviews will be performed according to DSMC requests;

2. Monitor evidence for treatment benefit and thus decide when/whether the main trial question

has been answered;

3. Monitor evidence for treatment harm (toxicity);

4. Decide whether to recommend changes to the protocol;.

5. Decide whether to recommend that the trial continues to recruit participants or whether

recruitment should be terminated;

6. Review final analysis of the data;

7. Discuss final data with PI and the sponsor.

Planned meetings

Three face-to-face meetings that include preparation, working time during the meeting, transport time

and writing reports.

Three call conferences that include preparation, working time during the meeting, transport time and

writing reports.

12. INDEPENDENT EXTERNAL PATHOLOGICAL REVIEW

An independent pathologist panel (Stefano Pileri and colleagues) will review the lymph node/tumor

biopsy, as well as any available bone marrow biopsy or other pathology slides for retrospective

confirmation of the diagnosis of FL and relevant response assessment. The investigative site must


submit lymph node/tumor biopsy slides and any available bone marrow biopsy and aspirate slides and

other pathology slides as part of the screening phase to allow for a histological review.

13. STUDY POPULATION

13.1 Inclusion Criteria

1. Age 18-65

2. Histologically documented diagnosis of grade I-IIIa FL defined according to WHO guidelines

2008 (Re-biopsy required)

3. Availability of BM and PB for Minimal Residual Disease (MRD) analysis (see Appendix I)

4. Relapsed or refractory disease after ≤ two chemotherapy lines at least one containing Rituximab

(Rituximab maintenance is UNOTU considered a therapeutic line)

5. Clinical indication of treatment i.e. Stage II-IV who require therapy according to SIE and GELF

criteria (see Appendix II)

6. ECOG performance status 0-2 (unless disease-related) (see Appendix III)

7. Availability of histological material for centralized revision

8. Laboratory values:

a. ANC ≥ 1500/mmc unless due to marrow involvement by lymphoma and/or platelets ≥

100000/mmc unless due to marrow involvement by lymphoma

b. Serum creatinine ≤ 1.5 x ULN, unless it is disease related

c. bilirubin ≤ 1.5 x ULN (or ≤ 3.0 x ULN, if patient has Gilbert syndrome)

d. AST/SGOT and/or ALT/SGPT ≤ 2.5 x ULN if not lymphoma related or ≤ 5.0 x ULN in

case of lymphoma liver involvement

9. Adequate cardiac function: LVEF > 50% by echocardiography or MUGA scan

10. Not pregnant or breast-feeding

11. Willingness to use effective contraception during the study and 3 months after the end of

treatment

12. No other prior malignancies except for adequately treated non-melanoma skin cancer,

carcinoma in situ of the cervix, or other cancer from which the patient has been disease-free for

≥ 5 years (see Exclusion criteria 14)

13. Signed informed written consent


13.2 Exclusion Criteria

1. Grade IIIb FL, transformed FL or histologies different from FL

2. Previous treatment with > two lines of chemotherapy ± rituximab (Maintenance is UNOT U

considered a therapeutics line)

3. Previous ASCT or RIT treatment

4. CNS involvement by lymphoma

5. HBV positivity with the exception of patients who are seropositive because of hepatitis B virus

vaccination and patients HbcAb positive and HbsAg negative with undetectable serum HBV-

DNA. Occult carriers: must receive treatment with Lamivudine 100 mg for the duration of

treatment program and at least 12 months after treatment cessation; HBV-DNA levels and

HBsAg will be monitored every month

6. HCV positivity with elevated transaminases or INR or APTT or active virus replication

7. HIV positivity

8. Any concurrent medical condition requiring long term use (> one month) of systemic

corticosteroids

9. Active bacterial, viral, or fungal infection requiring systemic therapy

10. Any concurrent medical or psychiatric condition which might impair administration of therapy

or preclude the ability to give informed consent

11. Treatment with an experimental agent within 30 days prior to study entry

12. Myelosuppressive chemo or biological therapy within three weeks before study entry (use

rituximab course delivered as maintenance is not an exclusion therapy)

13. Major surgery other than diagnosis within 4 weeks prior to study entry

14. DESCRIPTION OF TREATMENT

14.1 Induction

An initial debulking with one course of vincristine and prednisone: day 1 vincristine 1.4 mg/m² (max 2

mg), day 1-5 prednisone 100 mg (total dose) p.o. is allowed but not recommended.

Three courses standard dose rituximab-supplemented chemotherapy including R-CHOP, R-DHAP, R-

FM, R-ICE, R-IEV or R-Bendamustine. Choice will be made by the treating physician according to

clinical considerations particularly the nature of previous first line treatment. Treatments schedule are

detailed in Appendix IV:

1. UR-CHOP U given every 21 days, day 1 rituximab 375 mg/m², day 1 doxorubicin 50 mg/m²,

vincristine 1.4 mg/m² (max 2 mg), day 1 cyclophosphamide iv 750 mg/m², day 1-5 prednisone


100 mg/die p.o. Patients with leukemic disease will receive the first dose of rituximab at day 8

of the first cycle (see Appendix IV).

2. UR-DHAPU given every 21 or 28 days, day 0 rituximab 375 mg/m², day 1 cisplatine 100 mg/m²,

day 2 cytarabine 2 g/m2 x 2 every 12 h (or cytarabine 2 g/m2 day 2-3 in outpatients setting), day

1-4 dexamethasone 40 mg (see Appendix IV).

3. UR-FM U given every 28 days, day 0 rituximab 375 mg/m², day 1 mitoxantrone 10 mg/m², day 1-3

fludarabine 25 g/m2 (see Appendix IV).

4. UR-ICEU given every 21 days, day 0 rituximab 375 mg/m², day 1 ifosfamide 1700 mg/m², days 2-3

ifosfamide 1650 mg/m2, days 1 –3 etoposide 100 mg/m2, day 1 carboplatin (area under the

curve = 5; maximum dose 800 mg), days 1-3 mesna 350 mg/m2 x 5 (see Appendix IV).

5. UR-IEVU given every 21 days, day 0 rituximab 375 mg/m², days 1–3 ifosfamide 2500 mg/m², day

1 epirubicin 100 mg/m2 and days 1–3 etoposide 150 mg/m2, days 1-3 mesna 500 mg/m2 x 5 (see

Appendix IV).

6. UR-BU: given every 28 days, day 1 rituximab 375 mg/m², days 1–2 Bendamustine 90 mg/m² (see

Appendix IV).

During this phase Lenograstim, Filgrastim or Peg-Filgrastim is allowed and will be given according to

responsible physician decision and local institutional and national guidelines.

14.2 Randomization (four weeks after the last chemotherapy course)

Patients achieving CR or PR (according to Cheson et al 2007, see Appendix V) will undergo a

randomization phase 1:1, between RIT (Arm A) and ASCT (Arm B). Patients will be stratified based

on Center characteristics (Performing ASCT and RIT locally, performing exclusively ASCT locally,

not performing ASCT locally), response (CR+PCR-negative vs. CR+PCR-positive, PR regardless of

PCR status). The randomization list will be developed by statisticians at The Tumor Epidemiology Unit

of University of Torino using blocks of variable length, completely concealed to researchers. The

randomization procedure will be performed online and implemented within the electronic CRF at the

web-site (HUwww.epiclin.it UH). The treatment arm will be revealed only at the end of the mobilization

procedure.

14.3 Stem cell mobilization (to be started within one or two weeks from randomization)

All patients will receive Ara-C 2g/m² b.i.d. for two days followed by rituximab 375mg/m2 day 3 and

the first day with ANC ≥ 1000/mmc. Then patients will undergo stem cell collection with the aim of

collecting 6x106 CD34+ cells/kg (see Appendix VI). Patients in Arm B collecting less than 2x106 CD34+

cells/kg will not be undergo ASCT and will proceed to rituximab maintenance.


A second mobilization with plerixafor will be allowed for patients that experience a failure of

mobilization after Ara-C (both arms) (see Appendix VI).

NB CENTERS NOT ABLE TO PERFORM STEM CELL COLLECTION SHOULD REFER

THIER PATIENTS TO NEARBY ASCT CENTERS FOLLOWING GUIDELINES DETAILED

IN APPENDIX VI.

14.4 Consolidation (to be started between 7 and 10 weeks from randomization up to 12 weeks if a

second mobilization is planned)

UARM A RITU: infusion of rituximab 250 mg/m2 on day 1 and day 8 and (90)Y Ibritumomab Tiuxetan

(0.4 mCi/kg if platelets ≥ 150.000/mmc, 0.3 mCi/kg if platelets are between 100.000 and

150.000/mmc) on day 8 (range, days 7 to 9) immediately after the second rituximab infusion

(Zevalin® will be delivered as per indications and should thus be provided at expenses following

regular supplies procedures).

Patients with platelets <100.000/mmc or with BM infiltrated greater than 25% at the restaging pre-

consolidation will proceed to rituximab maintenance (see Appendix VII).

UARM B ASCTU: BEAM conditioning regimen: BCNU i.v. 300 mg/m2 day -6, etoposide 200 mg/m2 i.v.

days -5, -4, -3 and -2, Ara-C 400 mg/m2 i.v., days -5, -4, -3 and -2, melphalan 140 mg/m2 i.v. day -1;

reinfusion of CD34+ cells of ≥ 2x106 CD34+/Kg day 0. Optimal dose 4x106 CD34+/Kg (provided that

a back up of 2x106 CD34+/Kg frozen cells is available). Start G-CSF 5 mcg/Kg from day 2 until

ANC>1500/mmc (see Appendix VIII).

NB CENTERS NOT ABLE TO DELIVER ASCT OR RIT LOCALLY SHOULD REFER

THEIR PATIENTS TO NEARBY ASCT OR RIT CENTERS FOLLOWING GUIDELINES

DETAILED IN APPENDIX VII AND VIII

14.5 Maintenance (to be started three months after consolidation)

Rituximab 375mg/m2 every three months for eight courses to all patients

15. TREATMENT DELAYS AND DOSE REDUCTIONS

Treatment delays are based on all toxicities registered before each course of study drug. Toxicities will

be evaluated according to the National Cancer Institute Common Toxicity Criteria for Adverse Events

(NCI CTCAE) Version 4.03 (see Appendix IX).


16. CONCOMITANT THERAPY AND PROCEDURES

16.1 Permitted concomitant therapy and procedures

1. Platelets and red blood cell transfusions are allowed, if needed, and will be given with filtered

and irradiated products in case of Hb <8 g/dl or Plt <10000/mmc;

2. Erytropoietin therapy is allowed according to ASH/ASCO guidelines;

3. Immunoglobulins assay is advisable during induction therapy and follow-up; immunoglobulin

replacement therapy is advisable in case of IgG level < 0.3-0.4 gr/dl and frequent infectious

events;

4. Premedication for rituximab infusion with paracetamol and diphenhydramine should be

considered before each infusion of rituximab, because it may reduce infusion reactions (see

Appendix IV);

5. Prophylaxis with levofloxacine or ciprofloxacine could be administrated in case of neutropenia

<1000/mmc according to responsible physician decision;

6. Prophylaxis for pneumocystis carinii pneumonia will be given in the form of oral cotrimoxazole

(sulphametoxazole1600mg+ trimetoprim 320 mg twice a week in consecutive days) throughout

the treatment period from beginning of chemotherapy (i.e. CHOP) up to six months after the

end of maintenance. Alternate drugs can be used in case of hypersensitivity to cotrimoxazole,

according to responsible physician decision: i.e. pentamidine 300 mg nebulised every 4 weeks;

7. Antiviral prophylaxis against Herpes Simplex and Varicella Zoster reactivation (valacyclovir

500 mg once a day, acyclovir 400 mg twice a day or acyclovir 200 mg 3 times day) should be

given throughout the treatment from the administration of mobilization regimen to at least 3

months after ASCT;

8. CMV monitoring (CMV-DNA specific PCR) should be performed every two weeks for patients

receiving consolidation with Arm B, starting after conditioning regimen and continuing until

day +90 after the ASCT. In the case of CMV reactivation acyclovir should be interrupted and

appropriate treatment should be started according to local guidelines of the ASCT unit which

performed the consolidation program;

9. Antifungal agents may be used according to Institutional guidelines;

10. 18FDG-PET is permitted, but it’s UNOTU allowed using any PET-derived information to assess

baseline staging or restaging and no therapeutic decision should be taken according to PET as

defined by Cheson criteria28 for FL (use PET for decision making will be considered Ua major

protocol violationU).


16.2 Prohibited concomitant therapy and procedures

The following medications and supportive therapies are prohibited at all times:

1. Any antineoplastic agent other than those planned by the study program

2. Any experimental agent

17. ASSESSMENT OF EFFICACY

17.1 Methods and Timing of Efficacy Assessments

Study procedures will be done before therapy as baseline assessment and at scheduled intervals

throughout the study, as assessment of efficacy (see Appendix XIII).

At baseline (within one month prior to treatment)

1. Written informed consent;

2. Tumor biopsy with CD20 immunophenotyping (if the patients has a biopsy taken in the

previous 12 months and has not received anti-lymphoma treatment during this lag of time, study

entry biopsy can be omitted);

3. Complete medical history, physical examination, ECOG performance status, ECG and Chest X

ray;

4. Pregnancy test (if applicable);

5. Haematology (CBC with differential) and blood chemistry (transaminases, serum alkaline

phosphatase, GGT, LDH, total bilirubin, BUN, creatinine, Na, K, Ca, uric acid, total protein,

albumin , beta2-microglobulin) (within two weeks prior to treatment);

6. Creatinine clearance rate;

7. Coagulation (PTT, PT, ATIII, D-dimer, Fibrinogen);

8. Quantitative Immunoglobulins;

9. Viral markers: HBV markers (HbsAg, HbsAb,HBcAb), HBV DNA, HCV serology and HIV

serology;

10. Echocardiography or cardiac scintigraphy;

11. TBCT scan;

12. BM and PB samples for centralized MRD testing (see Appendix I);

13. BM aspirate and bone marrow biopsy;

14. EORTC QLQ-C30 questionnaire (See Appendix X);

15. Euro-Qol (EQ-5D) (See Appendix XI);

16. Questionnaire on patient’s cost Q1 (See Appendix XII);

During treatment (induction, mobilization and consolidation) at least every other week:

1. Adverse events;


2. Physical examination, ECOG performance status, body weight;

3. Haematology and Blood chemistry (transaminases, serum alkaline phosphatase, GGT, LDH,

total bilirubin, creatinine);

Restaging at randomization (within four weeks after the last induction course)

1. Physical examination, ECOG performance status;






6. TBCT scan;

7. BM biopsy if positive at baseline;

8. BM and PB samples for MRD (if marker available) (see Appendix I);

During mobilization:

1. Adverse events;


3. Hematology and Blood chemistry (see point I);

4. Leukapheresis sample for MRD;

Restaging before consolidation:







6. Viral markers: HBV markers (HbsAg, HbsAb, HBcAb), HBV DNA, HCV serology and HIV

serology (if positive at baseline);

7. Echocardiography or cardiac scintigraphy;

8. PFTs (only in arm B);

9. OPT (only in arm B);

10. TBCT scan (if not CR at randomization);

11. BM biopsy if positive at the baseline;



13. EORTC QLQ-C30 questionnaire (See Appendix );



Restaging after consolidation (at two months from the beginning of consolidation)






5. TBCT scan;



8. Adverse events;




During Maintenance (every three months):

1. Adverse events;


3. Hematology and Blood chemistry;

4. Immunoglobulin dosage;

During Maintenance and subsequent Follow-up (every six months up to 36 months):


2. Hematology and Blood chemistry (transaminases, serum alkaline phosphatase, GGT, LDH, total

bilirubin, creatinine);


4. TBCT scan;



7. Adverse events;





Each patient enrolled in this study will be evaluated for long term outcomes (OS and PFS). Retire of

consent will be the only acceptable motivation for study withdrawal. An independent pathologist panel

will review the lymph node/tumor biopsy, as well as any available BM biopsy or other pathology slides

for retrospective confirmation of the diagnosis of FL and relevant response assessment.

18. ASSESSMENT OF SAFETY

The study will provide safety and tolerability data by the evaluation of Clinical Laboratory Tests and any

AE.

An AE is any noxious, unintended, or untoward medical occurrence occurring at any dose that may

appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a

worsening concomitant illness, an injury, or any concomitant impairment of the subject’s health,

including laboratory test values (as specified by the criteria below), regardless of aetiology. Any

medical condition that was present prior to study treatment and that remains unchanged or improved

should not be recorded as an AE. If there is a worsening of that medical condition, this should be

considered an AE. A diagnosis or syndrome should be recorded on the AE page of the CRF rather than

the individual signs or symptoms of the diagnosis or syndrome.

All AEs will be recorded by the Investigator(s) from the time of signing the informed consent through

the end of the designated follow-up period.

Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the

subject’s legally acceptable representative) for the duration of the study.

AE query by NCI CTCAE Version 4.03. PDF of CTCAE v 4.03 can be downloaded without charge at

HUhttp://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06.pdfUH.

19. OTHER ASSESSMENTS

19.1 MRD analysis

Molecular analysis will be performed in the context of the consolidated FIL national MRD Network:

biological samples will be sent, according to a geographical allocation, to the molecular biology

facilities of Torino, Pisa, Bologna and Roma centres, under the supervision respectively of Marco

Ladetto MD, Sara Galimberti PhD, Pierpaolo Piccaluga MD and Ilaria Del Giudice MD (see Appendix


I). The present section will briefly describe the technical background of MRD determination in the

context of the FIL FLAZ12 trial, while more practical considerations will be detailed in Appendix I.

Technical background

The molecular analysis will be performed both on PB and BM using the Bcl-2/IgH rearrangement in

Bcl-2/IgH-amplifiable t(14;18) translocation according to a modified version of the protocol originally

employed by Gribben et al at Dana Farber Cancer Institute for qualitative PCR and for RQ-PCR as

described by Ladetto et al; if technical improvement of the methodology will occur appropriative

changes will be considered29, 30, 31, 32. Expected rates of success according to data obtained from

previous studies and epidemiological data in Europe will be 60-70%. Based on these premises the

majority of patients will have a molecular marker suitable for MRD determination. MRD will be

assessed by both qualitative nested PCR and quantitative real time PCR, as previously described30, 31, to

better define the kinetics of minimal residual disease. As far as real time quantitative PCR is concerned

data reporting will be performed according to the ESG-MRD33. The laboratories of FIL national MRD

Network performing the analysis are active members of this network and perform quality control

rounds specifically targeted for NHL-MRD twice yearly.

Objectives of trial based on MRD analysis

As detailed below, two of the secondary objectives of the present protocol (see section 8.2) are

specifically focused on MRD:

1. To compare the activity of RIT vs. ASCT on MRD assessed using the Bcl-2/IgH translocation

in both nested PCR and real time quantitative PCR; assessed in terms of: a) rate of patients in

MR after consolidation during maintenance and during follow-up; b) rate of conversion from

PCR-positivity to PCR-negativity after either ASCT and RIT; c) rate of molecular relapse in the

first two years of follow-up after either ASCT or RIT;

2. To assess the prognostic impact of MRD related parameters on PFS and OS.

Molecular Time Points

A number of well defined molecular time points are planned in this study. For any time point,

excluding MRD determination on stem-cell harvests, both on PB and BM will be required. Both at

baseline and follow-up time points Uat least 7 ml of BM and 10 ml of PBU are required: lithium heparin or

citrate sodium tubes are recommended for collecting both tissues. For stem cell harvest Uat least 5 ml of

leukapheresisU product is required. In absence of BM and PB invasion at baseline, it is recommended

(though not required) to send a sample from lymph node or other diagnostic tissue biopsy for the

detection of a molecular marker. Also a pre-stored tumor invaded DNA sample (either BM or PB


or other) taken during previous treatment phases (i.e. at diagnosis) might be used to identify a

molecular marker.

Note that sample shipment will be a pre-requisite for study inclusion and randomization at some

specific time points. This means that the software will not allow to complete the required procedures if

the laboratory has not received the biological sample.

UThese are the planned MRD Molecular Time Points (see Appendix I):

1. Baseline: on PB and BM (if baseline BM have no detectable tumor invasion, additional

shipment of a diagnostic sample with documented tumor-invasion > 5% is required as described

in Appendix I). Sample is required for patient enrolment: the laboratory is committed to inform

the Center, in 60 days, on the availability of a tumor marker (expected rate of success 60%-

70%);

2. Restaging at randomization: on PB and BM after induction with three courses of R-

chemotherapy; the laboratory is committed to inform the Center on the nested PCR results in 21

days;

3. Stem cell harvest: at least 5 ml of leukapheresis are required;

4. Restaging before consolidation: on PB and BM in both arms;

5. Restaging after consolidation: on PB and BM in both arms;

6. 6 months maintenance: on PB and BM in both arms;




10. 30 months follow-up: on PB and BM in both arms;

11. 36 months follow-up: on PB and BM in both arms;

Note that all the results of molecular analyses will remain blinded for the single centers.

Further operative considerations concerning the identification of the reference lab as well as

shipment procedures are detailed in appendix I.

The form to enclose and the information concerning the courier are reported in appendix I.


19.2 QUALITY OF LIFE

The effect of chemotherapy treatment on the QoL is an important question for patients and the

collection of information on psychological distress, social disruption, emotional trauma and painful

side-effects is a routine component in many protocols. Current literature shows that additional and

useful information may be obtained from quality of life measurements.

Quality of life data allows us:

to evaluate the extent of change in the quality of life of an individual or group across time.

The main purposes of this QoL study are to describe the changes of patients' QoL following induction

and consolidation therapy and to compare QoL between patients who receive RIT with those who

receive ASCT.

In this study quality of life will be assessed using the QLQ-C30 questionnaire35.

The QLQ-C30 have been validated for self-administration and have already been used in patients with

non-Hodgkin’s lymphoma. The questionnaire is composed by 30 items and incorporates five functional

scales, three symptoms scales, a global health scale and a quality of life scale.

The information provided by the patient in the completed questionnaires is confidential and should not

be discussed with or shown to anyone who is not mentioned in the consent form signed by the patient.

Patients will be asked to complete questionnaires:

1. at baseline

2. at the restaging before the the consolidation

3. at the restaging after consolidation

4. every 6 months during maintenance and follow-up

19.3 COST-EFFECTIVENESS

The mean costs of care during the study period will be estimated for all patients in each arm in order to

verify the impact of the two different consolidation arms in terms of direct health care costs. The cost

of the following episodes of care will be estimated: induction, stem cell mobilization, consolidation

with RIT and ASCT, maintenance therapy, patient monitoring, management of side effects and

relapses. Data on health care resources utilization during treatment supply (drugs, hospital stays,

examinations, visits) will be retrieved from a sample of medical records. Use of other health care

resources after treatment will be collected through the e-CRF. Health care utilization will be valued

using hospital accounting system costs when available. If no real costs will be available, tariffs or

standard costs will be used. Patients’ cost due to the treatment (out-of-pocket, travelling, absence from

work) will also be collected with a specific questionnaire filled by the patients (See Appendix XII).


QALYs will be calculated multiplying the amount of time a patient spent in a particular health state by

the utilities estimated using the EQ-5D questionnaire (See Appendix XI). The EQ-5D, including five

self-administrated items, provides a descriptive health profile and a composite index valuing health

status.

20. STATISTICAL ANALYSES

20.1 Sample size estimate

Primary end-point for sample-size calculation is PFS from randomization. Based on data from the

literature, the expected PFS at three years with RIT maintenance is about 40%. According to O'Brien

and Fleming group sequential design with a maximum of two stages, a total of 210 randomized patients

(105 per group) are required (including a 5% cautelative increase in sample size) to detect an increase

in the three-years PFS from 40% to 60% assessed with a two-sided log-rank test with alpha of 5% and a

power of 85%. According to literature, about 80% of enrolled patients will be in clinical response (CR

or PR) after induction phase. In order to randomize the estimated number of patients, 265 patients will

be enrolled.

Under these assumptions, an interim analysis will be performed for stopping the trial prematurely

because of superiority of one regimen above the other on a statistical basis after about two years of

enrolment (n=150), when one third of the 105 expected failures will be observed. To preserve the

overall type I error, critical p-values for stopping are determined at p = 0.0006 for the first interim

analysis and p = 0.0498 for the final analysis.

20.2 Analysis plan

Analysis populations

The following analysis populations are planned:

1. Screening Population: includes all subjects who provide informed consent and provide

demographic and/or baseline screening assessments, regardless of the initiation of any

treatment;

2. Induction Phase Population: includes all enrolled patients who will start the induction phase;

3. Intent-to-Treat Population: includes all patients who are randomised to the RIT or ASCT;

4. ASCT eligible Population: includes only patients with sufficient collection of CD34+ cells (at

least 2x106 CD34+/kg) at the end of stem cell mobilization phase.

Interim analysis


A formal interim safety analysis will be performed after the first 150 randomized patients. Aim of this

analysis is to determine the feasibility of the study and the frequency of any major severe toxicity.

Decisions on early stopping will be based on wise judgments by the data monitoring committee

interpreting the totality of available results and the external evidence and not only the statistical

stopping rules.

Final analysis-efficacy

For each arm, the time-to-event function will be estimated by the Kaplan-Meier product-limit method

and difference between arms will be evaluated performing the log-rank test. Hazard Ratios (HRs) will

be estimated using the Cox proportional-hazards model, adjusted for stratification variables and the

main prognostic factors.

For each time-to-event endpoint, deviation from proportionality of hazards will be assessed on the basis

of Schoenfeld residuals36.

In case of a differential effect over time (non proportional hazards), Cox models will be applied by

dividing follow-up time into two or more periods, according to effect changes over time.

Subgroup analyses on primary efficacy parameter (PFS) will be performed to explore potential

heterogeneity of treatment by patient’s characteristics. Subgroup analyses will be carried out

irrespective of whether there is a significant effect of treatment on the primary outcome.

The following subgroup analyses will be performed:

• persistent molecular remission and molecular relapse

• induction R-chemotherapy

• center characteristics

• candidate prognostic parameters

For each subgroup, a Cox proportional-hazards model will be used for PFS and interaction will be

tested by inserting an interaction term between the treatment group and the subgroup covariate of

interest. The treatment effect (HR) and its 95%CI will be presented along with the p-value for the

interaction test.

For each arm, estimates of the TFS will be calculated according to Cheson criteria and using the

method of Gooley et al37, considering death from any cause as a competing event. Difference between

arms will be assessed using Gray's test38 and the HR and its 95% CI will be estimated using the Fine

and Gray model39, adjusted for the randomization stratum and the main prognostic factors.

Analyses will be performed on the Intent-to-Treat Population, including all randomized patients who

achieved a response (CR or PR). Secondary analyses will be performed on the ASCT eligible

population.


OS, PFS and EFS will be estimated also on the Induction Phase Population, considering all patients

who started induction phase as a single arm.

Final analysis - safety

Safety analyses will be performed including all patients receiving at least one dose of planned therapy,

both on Induction Phase Population and Intent-to-Treat Population, considering all AEs recorded and

commencing during and up to 24 hours after the first drug infusion and at any time during therapy. For

the Induction Phase Population, will be considered all AEs recorded along the Induction Phase; for the

Intent-to-Treat Population, will be considered all AEs recorded along the Consolidation and

Maintenance Phase.

Two different level units will be analyzed:

1. patient level

2. therapy cycle level

For the patient level analysis, summaries of incidence rates (frequencies and percentages) and intensity

of individual AEs by CTCAE will be reported. Each patient will be counted only once within each

preferred term during the induction phase. If a patient experiences more than one AE within a preferred

term during the induction phase, only the AE with the greatest intensity will be included in the

summaries.

For the therapy cycle level analysis, summaries of incidence rates (frequencies and percentages) and

intensity of therapy cycle AEs by CTCAE will be reported. Each therapy cycle will be counted only

once within each preferred term per the induction phase. If, during the same therapy cycle, the patient

experiences more than one AE within a preferred term during the induction phase, only the AE with the

greatest intensity will be included in the summaries.

For the Intent-to-Treat Population, summaries will be presented by ARM.

According to categorization of CTCAE ver. 4.03, the cumulative incidence of first severe, life-

threatening, fatal (CTCAE grade 3, 4 and 5) and/or serious adverse events (Infusion-related reactions)

commencing during and up to 24 hours after Rituximab infusion and at any time during therapy and

follow-up will be calculated; the cumulative incidence will be calculated using the method of Gooley et

al37, considering death from any cause as a competing event. For the Intent-to-Treat Population,

differences between arms on cumulative incidences will be assessed using Gray's test38 and the HRs

and their 95%CI will be estimated using the Fine and Gray model39.

20.3 Quality of life analysis

Repeated QoL measurements will be collected during the trial. The pattern of missing data (which

individuals, at which assessments) and the reasons for missingness will be investigated to reconstruct


the missing data mechanism to some extent. Generalized linear mixed models will be applied to

compare the two arms when a MCAR or MAR process is operating. In presence of MNAR data,

multiple imputation techniques will be performed to recover the information loss before comparing the

two arms. Sensitivity analyses for the methods of imputation and estimation will be performed.

20.4 Cost-effectiveness analysis

A within trial cost-effectiveness analysis, with total healthcare costs and QALYs gained per patient

calculated during the trial follow up, will be performed.

Mean healthcare costs during the study period will be estimated for every patient in each arm. To

account for patients lost to follow-up the mean costs of healthcare use after treatment consolidation will

be adjusted for censoring.

ICER will be calculated by dividing the difference in mean total costs between the two treatments by

the difference in the mean effects. The ICER will be calculated for the primary clinical effect measures

of the trial. (i.e. PFS) and for QALYs.

Bootstrapping will be used for pair-wise comparison of the mean differences in total costs between the

two groups. To estimate the uncertainty surrounding the ICER bootstrapping methods will be used. The

bootstrapped cost-effect pairs will be used to estimate cost-effectiveness acceptability curves.

20.5 Study Duration

This study is expected to start in May 2012. The last patient is expected to be enrolled at the end of

April 2015. After a minimum duration of follow-up of 24 months from randomization of the last patient

the study will be concluded in May 2017.

21. GOOD CLINICAL PRACTICE QUALITY CONTROL AND QUALITY ASSURANCE

21.1 Monitoring, Audits and Inspections

During the study the monitoring will be prevalently made by e-mail and telephone. The field monitor

will visit the site, when needed, mainly in presence of data incongruity, to check the completeness of

patient records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good Clinical

Practice and the progress of enrolment. Key study personnel must be available to assist the field

monitor during these visits.

The investigator must maintain source documents for each patient in the study, consisting of case and

visit notes (hospital or clinic medical records) containing demographic and medical information,

laboratory data, electrocardiograms, and the results of any other tests or assessments. All information


on CRFs must be traceable to these source documents in the patient's file. The investigator must also

keep the original informed consent form signed by the patient (a signed copy is given to the patient).

The investigator must give the monitor access to all relevant source documents to confirm their

consistency with the CRF entries. FIL Safety Monitoring standards require full verification for the

presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of SAEs,

and the recording of data that will be used for all primary and safety variables. Additional checks of the

consistency of the source data with the CRFs are performed according to the study-specific monitoring

plan. No information in source documents about the identity of the patients will be disclosed.

21.2 Investigator (s) Responsabilities

Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice. The

investigator must give the monitor access to relevant records to confirm the above.

The Investigator(s) is responsible for keeping a record of all patients who sign an Informed Consent

Form and are screened for entry into the study. For those patients who fail screening the reason(s) for

exclusion must be recorded in the patient’s source documents.

No procedure/assessment/measurement/test other than those outlined here, or in the schedule of study

assessments, has to be performed without the prior written approval of Principal Investigator, or unless

deemed by the investigator(s) as necessary for the patient’s medical care. Investigator(s) and/or

authorized designee(s) must enter study data onto CRFs supplied by FIL. The data on the CRF will be

recorded in an anonymous manner to protect the patient’s identity by using a unique identifier that will

prevent personal identifiable information.

The Investigator(s), or a designated member of the Investigators’ staff, must be available at some time

during monitoring visits to review data and resolve any queries and to allow direct access to the

patient’s records (e.g., medical records, office charts, hospital charts, and study related charts) for

source data verification. The CRFs must be completed as soon as possible after the patient’s visit, but

no later than prior to each monitoring visit and be made available to the FIL representative(s) so that

the accuracy and completeness may be checked.

22. ETHICAL AND REGULATORY CONSIDERATIONS

22.1 Institutional Review Board/Independent Ethics Committee Review and Approval

This study will be conducted according to the Declaration of Helsinki Ethical Principles for Medical

Research Involving Human Patients (see: HUhttp://www.wma.net/e/policy/b3.htmlUH for more information).

The review of this protocol by the IRB/IEC and the performance of all aspects of the study, including

the methods used for obtaining informed consent, must also be in accordance with principles


enunciated in the declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations

(CFR), Part 50 Protection of Human Patients and Part 56 Institutional Review Boards. Before

implementing this study, the protocol, the proposed informed consent form and other information to

patients, must be reviewed by a properly constituted IRB/IEC. A signed and dated statement that the

protocol and informed consent have been approved by the IRB/IEC must be given to FIL before the

study initiation. The names and occupations of the chairman and the members of the IRB/IEC must be

supplied to FIL.

The FIL as sponsor of the study, together with site Investigator(s), will be responsible for preparing

documents, where ever applicable, for submission to the relevant IRB/IEC and obtaining written

approval for this study. The approval will be obtained prior to the initiation of the study.

A copy of the IRB/IEC approval for the protocol and the Informed Consent has to be provided to FIL

and site Investigator(s). The approval for both the protocol and informed consent must specify the date

of approval, protocol number and version, or amendment number.

The Investigator(s) is responsible for notifying the FIL Safety Monitoring Office and the IRB/IEC of

any serious deviations from the protocol, or anything else that may involve added risk to patients.

Any advertisements used to recruit patients for the study must be reviewed and approved by FIL and

the IRB/IEC prior to use.

Before the start of the study, the FIL will provide the IRB/IEC with current and complete copies of the

following documents:

1. final protocol and, if applicable, amendments;

2. informed consent form (and any other written materials to be provided to the subjects);

3. Investigator’s Brochure (or equivalent information) and amendments;

4. information on compensation for study-related injuries or payment to subjects for participation

in the study, if applicable;

5. investigator’s curriculum vitae or equivalent information (unless not required, as documented by

IRB/IEC);

6. any other documents that the IRB/IEC requests to fulfil its obligation.

During the study the FIL according with site investigators will send the following documents to the

IRB/IEC for their review and approval, where appropriate:

1. protocol amendments;

2. revision(s) to informed consent form and any other written materials to be provided to subjects;

3. revisions to compensation for study-related injuries or payment to subjects for participation in

the study, if applicable;

4. Investigator’s Brochure amendments or new edition(s);


5. summaries of the status of the study (at least annually or at intervals stipulated in guidelines of

the IRB/IEC);

6. reports of adverse events that are serious, unexpected and associated with the investigational

drug;

7. new information that may affect adversely the safety of the subjects or the conduct of the study;

8. deviations from or changes to the protocol to eliminate immediate hazards to the subjects;

9. report of deaths of subjects under the investigator's care;

10. notification if a new investigator is responsible for the study at the site;

11. any other requirements of the IRB/IEC.

22.2 Protocol Amendments

Any amendment to this protocol that seems appropriate, as the study progresses will be submitted to the

IRB/IEC for written approval before the implementation of the amended version. The written signed

approval from the IRB/IEC should refer specifically to the investigator(s) and to the protocol number

and title and mention any amendment numbers that are applicable. Amendments that are administrative

in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC for information

purposes.

22.3 Informed Consent

The Investigator(s) must obtain informed consent of a patient or his/her designee prior to any study

related procedures as per Good Clinical Practices (GCP). Documentation that informed consent

occurred prior to the patient’s entry into the study and of the informed consent process should be

recorded in the patient’s source documents. Subjects will be informed that their participation is

voluntary and that they may withdraw consent to participate at any time. They will be informed that

choosing not to participate will not affect the care the subject will receive for the treatment of his/her

disease. Subjects will be told that alternative treatments are available if they refuse to take part and that

such refusal will not prejudice future treatment. The subject or legally acceptable representative will be

given sufficient time to read the informed consent form and the opportunity to ask questions. After this

explanation and before entry to the study, consent should be appropriately recorded by means of either

the subject's or his/her legally acceptable representative's dated signature. After having obtained the

consent, a copy of the informed consent form must be given to the subject. MRD detection is part of the

study and patients are required to undergo this analysis. Subjects will also be asked to consent to

participate in addictional genetic research components of the study. Refusal to participate will not result

in ineligibility for the rest of the clinical study unless participation in genetic testing is required as an

inclusion criterion. If the subject or legally acceptable representative is unable to read or write, an


impartial witness should be present for the entire informed consent process (which includes reading and

explaining all written information) and personally date and sign the informed consent form after the

oral consent of the subject or legally acceptable representative is obtained.

The original consent form signed and dated by the patient and by the person consenting the patient

prior to the patient’s entry into the study must be maintained in the Investigator’s study files and a copy

given to the patient. In addition, if a protocol is amended and it impacts on the content of the informed

consent, the informed consent must be revised. Patients participating in the study when the amended

protocol is implemented must be re-consented with the revised version of the informed consent. The

revised consent form signed and dated by the patient and by the person consenting the patient must be

maintained in the Investigator’s study files and a copy given to the patient.

23. DATA HANDLING AND RECORDKEEPING

23.1 Data/Documents

The investigator(s) must ensure that the records and documents pertaining to the conduct of the study

and the distribution of the study drug, that is copies of CRFs and source documents original documents,

data, and records (e.g., hospital records; clinical and office charts; laboratory notes; memoranda;

patient’s diaries or evaluation check-lists; pharmacy dispensing records; recorded data from automated

instruments; copies or transcriptions certified after verification as being accurate copies; microfiches;

photographic negatives, microfilm, or magnetic media; x-rays; patient files) and records kept at the

pharmacy, at the laboratories, and at medico-technical departments involved in the clinical study are

complete, accurate, filed and retained.

23.2 Data Management

Data will be entered into the clinical database as per FIL SOPs. These data will be electronically

verified through use of on-line checks during data entry, and through programmed edit checks specified

by the clinical team. Discrepancies in the data will be brought to the attention of the clinical team, and

investigational site personnel, if necessary, in the form of a Data Clarification Form (DCF). Resolutions

to these issues will be reflected in the database. An audit trail within the system will track all changes

made to the data.

23.3 Retention of Records

The investigator(s) must maintain records of all study documents and supporting information relating to

the conduct of the study. This documentation includes, but is not limited to, protocols, case report

forms, advertising for patient participation, adverse event reports, patient source data, correspondence


with health authorities and IRBs/IECs, informed consent forms, investigator(s) curricula vitae, monitor

visit logs, laboratory reference ranges, laboratory certification or quality control procedures and

laboratory director curriculum vitae. Patient files and other source data must be kept for the maximum

period of time permitted by the hospital, institution or private practice specified below. The study

monitor must be consulted if the investigator(s) wishes to assign the study files to someone else,

remove them to another location or is unable to retain them for a specified period. The investigator(s)

must retain study records for the time period according to local laws or requirements, whichever is

longer. The monitor will inform the investigator(s) of the dates for retention. All study documents

should be made available if required by relevant health authorities. The investigator(s) records must be

retained until at least 2 years after the last approval of a marketing application in an ICH region and

until there are no pending or contemplated marketing applications in an ICH region or at least 2 years

have elapsed since the formal discontinuation of clinical development of the investigational product.

These documents should be retained for a longer period if required by other applicable regulatory

requirements.

24. PRIVACY OF PERSONAL DATA

The collection and processing of personal data from subjects enrolled in this study will be limited to

those data that are necessary to investigate the efficacy, safety, quality, and utility of the investigational

product(s) used in this study. These data must be collected and processed with adequate precautions to

ensure confidentiality and compliance with applicable data privacy protection laws and regulations.

The investigator-sponsor ensures that the personal data will be:

1. processed fairly and lawfully;

2. collected for specified, explicit, and legitimate purposes and not further processed in a way

incompatible with these purposes;

3. adequate, relevant, and not excessive in relation to said purposes;

4. accurate and, where necessary, kept current.

Explicit consent for the processing of personal data will be obtained from the participating subject (or

his/her legally acceptable representative) before collection of data. Such consent should also address

the transfer of the data to other entities and to other countries. The subject has the right to request

through the investigator access to his/her personal data and the right to request rectification of any data

that are not correct or complete. Reasonable steps should be taken to respond to such a request, taking

into consideration the nature of the request, the conditions of the study, and the applicable laws and

regulations.


Patients will be registered in the study via web site at the end of their staging, before beginning the

treatment. The name of the patient will not be asked for not recorded at the Data Center. A sequential

identification number will be automatically attributed to each patient registered in the trial. This

number will identify and must be included on all case report form.

24.1 TOXICITY AND ADVERSE EVENTS EVALUATION

Timely, accurate, and complete reporting and analysis of safety information from clinical studies are

crucial.

Adverse event definitions

Adverse Event (AE): An adverse event is any untoward medical occurrence in a clinical study subject

administered a pharmaceutical product. An adverse event does not necessarily have a

causal relationship with the treatment. An adverse event can therefore be any unfavourable

and unintended sign (including an abnormal laboratory finding), symptom, or disease

temporally associated with treatment.

Serious Adverse Event (SAE): A serious adverse event is any untoward medical occurrence that meets

any of the following conditions:

1. Results in death;

2. Is life-threatening (i.e., in the opinion of the Investigator(s) the patient is at immediate

risk of death from the AE);

3. Requires inpatient hospitalization or prolongation of existing hospitalization;

4. Results in persistent or significant disability/incapacity (a substantial disruption of the

patient’s ability to conduct normal life functions);

5. Is a congenital anomaly/birth defect;

6. Constitutes an important medical event.

The cause of death of a subject in a clinical study, whether or not the event is expected or associated

with the investigational agent, is considered a serious adverse event.

Medical and scientific judgment should be exercised in deciding whether such an AE should be

considered serious.


Suspected Unexpected Serious Adverse Reaction (SUSAR): An unlisted adverse event, the nature or

severity of which is not consistent with the applicable product information. For an

investigational drug, the expectedness of an adverse event will be determined by whether

or not it is listed in the Investigator's Brochure of experimental drug. For drugs with a

marketing authorization, the expectedness of an adverse event will be determined by

whether or not it is listed in the SmPC.

Attribution Definitions

For both serious and non-serious adverse events, the Investigator must determine both the intensity of

the event and the relationship of the event to study drug administration.

Intensity: For each adverse event will be determined by using Version 4.03 of the National Cancer

Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) as a guideline,

wherever possible; a copy of the NCI-CTCAE Version 4.03 can be downloaded from the

Cancer Therapy Evaluation Program (CTEP) home page

( HUhttp://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06.pdf UH.). In those cases where the

NCI CTCAE does not apply, intensity should be defined according to the following

criteria:

Grade 1 =Mild: awareness of sign or symptom, but easily tolerated

Grade 2 =Moderate: discomfort enough to cause interference with normal daily activities

Grade 3 =Severe: inability to perform normal daily activities

Grade 4 =Life Threatening: immediate risk of death from the reaction as it occurred.

Grade 5 =Death

Classification of Relationship/Causality of adverse events (SAE/AE) to study drug will be determined

as follows:

The Investigator(s) must determine the relationship between the administration of study drug and the

occurrence of an AE/SAE as Not Suspected or Suspected as defined below:

1. UNot related: Uan adverse event which is not related to the use of the drug;

2. UUnlikely/Doubtful: Uan adverse event for which an alternative explanation is more likely, e.g.,

concomitant drug(s), concomitant disease(s), or the relationship in time suggests that a causal

relationship is unlikely;


3. UPossible: Uan adverse event which might be due to the use of the drug. An alternative

explanation, e.g., concomitant drug(s), concomitant disease(s), is inconclusive. The relationship

in time is reasonable; therefore, the causal relationship cannot be excluded;

4. UProbable: U an adverse event which might be due to the use of the drug. The relationship in time is

suggestive (e.g., confirmed by dechallenge). An alternative explanation is less likely, e.g.,

concomitant drug(s), concomitant disease(s);

5. UDefinite/Very Likely:U an adverse event which is listed as a possible adverse reaction and cannot

be reasonably explained by an alternative explanation, e.g., concomitant drug(s), concomitant

disease(s). The relationship in time is very suggestive (e.g., it is confirmed by dechallenge and

rechallenge);

6. UNot assessable:U there is insufficient or incomplete evidence to make a clinical judgement of the

causal relationship.

Administrative Procedures

All SAE and SUSAR that occur between the first study-related procedure and 30 days after the last

dose of study drug will be reported.

They must be recorded regardless of presumed relationship to study therapy, using medical terminology

( HUhttp://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06.pdfUH.) in the source document and the CRF.

Investigators must record in the CRF their opinion concerning the relationship of the adverse event to

study therapy. All measures required for adverse event management must be recorded in the source

document and reported according to Investigator-Sponsor instructions. For each SAE, the

Investigator(s) will provide information on severity, start and stop dates, relationship to study drug,

action taken regarding study drug, and outcome.

All grade 3 and 4 adverse events, considered related, must be followed until resolution of the event or

the event improves to a grade 2 or better.

The Investigator(s) is responsible for informing the IRB/IEC of the SAE and providing them with all

relevant initial and follow-up information about the event. The Investigator(s) must keep copies of all

SAE information on file. All SAEs that have not resolved upon discontinuation of the patient’s

participation in the study must be followed until either the event resolves completely, stabilizes/resolves

with sequelae, or returns to baseline (if a baseline value is available).

The SAE must be reported immediately (i.e., within 24 hours of the Investigators’ knowledge of the

event) to the FIL Safety Monitor by e-mail or fax. An e-mail has to be made to the Safety Monitor and

an initial written report (prepared by the Investigator(s) using the SAE Report Form provided by FIL)

has to be faxed to the Safety Monitor (see below for contact information).


FIL Safety Monitor Office

Address:

Haematology Division, Azienda Ospedaliera SS Antonio e Biagio Cesare Arrigo, Alessandria.

Via Venezia, 16 – 15121 – Alessandria, Italy

Telephone: +39-0131-206071

Fax: +39-0131-263455

E-mail: [email protected]

Abnormal laboratory values defined as adverse events

An abnormal laboratory value is considered to be an AE if the laboratory abnormality is characterized

by any of the following:

1. Results in discontinuation from the study;

2. Requires treatment, modification/interruption of study drug dose, or any other therapeutic

intervention;

3. Is judged by the Investigator(s) to be of significant clinical importance.

If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis or

syndrome should be recorded on the AE page of the CRF. If the abnormality was not a part of a

diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE.

Participation in the study will be determined by the Investigator(s) and the FIL Medical Monitor.


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7. Vitolo U, Boccomini C, Ladetto M, et al. A brief course of chemo-immunotherapy FND + Rituximab is effective to induce a high clinical and molecular response in elderly patients with advanced stage follicular lymphoma (FL) at diagnosis. Blood 2004;104: 371a.

8. Weide R, Hess G, Köppler H, et al High anti-lymphoma activity of bendamustine/mitoxantrone/rituximab in rituximab pretreated relapsed or refractory indolent lymphomas and mantle cell lymphomas. A multicenter phase II study of the German Low Grade Lymphoma Study Group (GLSG). Leuk Lymphoma 2007;48 :1299-306.

9. Van Oers MH,Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol.2010;28:2853-8.

10. Bachy E, Brice P, Delarue R, et al. Long-term follow-up of patients with newly diagnosed follicular lymphoma in the prerituximab era: effect of response quality on survival--A study from the groupe d'etude des lymphomes de l'adulte. J Clin Oncol. 2010;28:822-9.

11. Barosi G, Carella A, Lazzarino M, et al. Management of nodal indolent (non marginal-zone) non-Hodgkin’s lymphomas: practice guidelines from the Italian Society of Hematology, Italian Society of Experimental Hematology and Italian Group for Bone Marrow Transplantation Haematologica 2005; 90:1236-57.

12. Witzig TE, Gordon LI, Cabanillas F, et al: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2002;20:2453-63.


13. Morschhauser F, Radford J, Van Hoof A, et al: Phase III trial of consolidation therapy with

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14. Freedman AS, Neuberg D, Mauch P et al. Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 1999;94:3325–3333

15. Rohatiner AZS, Nadler L, Davies AJ et al. Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: Long-term follow-up. J Clin Oncol 2007;25:2554–9.

16. Arcaini L, Montanari F, Alessandrino P, et al. Immunochemotherapy with in vivo purging and autotransplant induces long clinical and molecular remission in advanced relapsed and refractory follicular lymphoma. Annals of Oncology 2008;19: 1331–5.

17. Schouten HC, Qian W, Kvaloy S et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma: Results from the randomized European CUP trial. J Clin Oncol 2003;21:3918–27.

18. Ladetto M, De Marco F, Benedetti F et al. Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: The superior disease control of R-HDS does not translate into an overall survival advantage. Blood 2008;111:4004–13.

19. Karmali R, Kassar M, Venugopal P, et al. Safety and Efficacy of Combination Therapy with Fludarabine, Mitoxantrone, and Rituximab Followed by Yttrium-90 Ibritumomab Tiuxetan and Maintenance Rituximab as Front-Line Therapy for Patients With Follicular or Marginal Zone Lymphoma. Clin Lymphoma Myeloma Leuk. 2011;11:467-74.

20. Pettengell R, Schmitz R, Gisselbrecht C, et al. Rituximab Purging and Maintenance Improves Progression Free Survival but Not Overall Survival In Patients with Relapsed or Resistant Follicular Lymphoma Prior Receiving An Autologous Transplant. ASH Annual Meeting Abstract 2010: 3567.

21. Brown JR, Feng Y, Gribben JG, et al. Long-term survival after autologous bone marrow transplantation for follicular lymphoma in first remission. Biol Blood Marrow Transplant 2007;13:1057-65.

22. Hardingham JE, Kotasek D, Sage RE, et al. Significance of molecular marker-positive cells after autologous peripheral-blood stem-cell transplantation for non-Hodgkin's lymphoma. J Clin Oncol 1995;13:1073-9.

23. Freedman AS, Neuberg D, Mauch P, et al. Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 1999;94:3325-33.

24. Corradini P, Ladetto M, Zallio F, et al. Long-term follow-up of indolent lymphoma patients treated with high-dose sequential chemotherapy and autografting: evidence that durable molecular and clinical remission frequently can be attained only in follicular subtypes. J Clin Oncol 2004;22:1460-8.


25. López-Guillermo A, Cabanillas F, McLaughlin P, et al. The clinical significance of molecular response in indolent follicular lymphomas. Blood 1998;91:2955-60.

26. Apostolidis J, Gupta RK, Grenzelias D, et al. High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: long-term clinical and molecular follow-up. J Clin Oncol 2000;18:527-36.

27. Rambaldi A, Lazzari M, Manzoni C, et al. Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma. Blood 2002;99:856-62.

28. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579-86.

29. HGribben JG, Freedman AS, Neuberg D, et al. Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. HN Engl J Med. 1991;325:1525-33.

30. Olsson K, Gerard CJ, Zehnder J, et al. Real-time t(11;14) and t(14;18) PCR assays provide sensitive and quantitative assessments of minimal residual disease (MRD). Leukemia. 1999;13:1833-42.

31. Ladetto M, Sametti S, Donovan JW, et al. A validated real-time quantitative PCR approach shows a correlation between tumor burden and successful ex vivo purging in follicular lymphoma patients.H HExp Hematol. 2001;29:183-93.

32. Ladetto M, De Marco F, Benedetti F, et al. Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood 2008;111:4004-13.

33. Van der Velden VH, Panzer-Grümayer ER, Cazzaniga G, et al. Optimization of PCR-based minimal residual disease diagnostics for childhood acute lymhoblastic leukemia in a multi-center setting. Leukemia. 2007;21:706-13.

34. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20:1727-36.

35. Aaronson NK, Ahmezdai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85: 365-76.

36. Schoenfeld D. Partial residuals for the proportional hazards regression model. Biometrika, 1982, 69:239-41.

37. Gooley TA, Leisenring W, Crowley J et al. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18:695-706.

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26. APPENDICES

NB In the electronic version of the protocol Appendix I, II, III, IV, V, VI, VII, VIII, IX, XIII and

XIV are included in the full text "MS Word" protocol file, while Appendix X, XI and XII are

provided as separated PDF files.

APPENDIX I MRD operative considerations

UREFERENCE LABORATORIES

MRD analysis will be conducted in the context of the FIL-MRD network which includes four MRD

laboratories. Every Center will refer to a different lab based on geographic position. In particular

assignment will be done on a provincial basis as follows:

UTORINO (BLUE LAB):

The blue lab will receive samples from: Aosta, Torino, Cuneo, Biella, Vercelli, Asti, Alessandria,

Novara, Cusio-Verbano-Ossola, Imperia, Savona, Genova, Milano, Como, Varese, Lecco, Lodi,

Sondrio, Bergamo, Monza, Pavia, Brescia, Cremona, Bolzano, Trento, Sassari, Olbia-Tempio, Nuoro,

Oristano, Ogliastra, Medio Campidano, Carbonia-Iglesias, Cagliari.

Address:

LABORATORIO BIOLOGIA MOLECOLARE DOTT. MARCO LADETTO

c/o laboratorio EMATOLOGIA UNIVERSITARIA 1 - Prof. Mario Boccadoro

Ospedale San Giovanni Battista - Molinette,

Via Genova 3, (Piano Terra)

10126 Torino

PROTOCOLLO FIL FLAZ12

Help-desk for the MRD study please contacts the following: Dott.ssa Barbara Mantoan, Dott.ssa

Luigia Monitillo or Dott.ssa Daniela Drandi, Molecular Biology Laboratory, Division of Hematology,

University of Torino; TEL: +39-011-6336884; FAX: +39-011-6963737; e-mail contacts:

[email protected], [email protected], [email protected]


UPISA (PINK LAB):

The pink lab will receive samples from: La Spezia, Piacenza, Parma, Reggio Emilia, Modena, Massa-

Carrara, Pistoia, Lucca, Prato, Pisa, Livorno, Firenze, Arezzo, Siena, Grosseto, Viterbo, Perugia, Terni,

Palermo, Trapani, Messina, Catania, Enna, Caltanissetta, Agrigento, Ragusa, Siracusa.

Address:

LABORATORIO BIOLOGIA MOLECOLARE DOTT.SSA SARA GALIMBERTI

c/o U.O Ematologia - Ospedale S.Chiara

Via Roma 67

56126 Pisa


Help-desk for the MRD study please contacts the following: Dott.ssa Sara Galimberti or Dott.ssa

Elena Ciabatti Molecular Biology Laboratory, Division of Hematology, University of Pisa; TEL: +39-

050-992815; e-mail contacts: [email protected], [email protected].

UBOLOGNA (YELLOW LAB):

The yellow lab will receive samples from: Trieste, Gorizia, Udine, Pordenone, Belluno, Treviso,

Venezia, Vicenza, Padova, Rovigo, Verona, Ferrara, Ravenna, Bologna, Forlì-Cesena, Rimini, Pesaro-

Urbino, Ancona, Macerata, Fermo, Ascoli Piceno, Pescara, Chieti.

Address:

LABORATORIO BIOLOGIA MOLECOLARE DOTT. PIERPAOLO PICCALUGA

Pad 8 L.A.Seragnoli

Ospedale Sant’Orsola Malpighi

Via Massarenti 9

40138 Bologna


Help-desk for the MRD study please contacts the following: Dott. Pierpaolo Piccaluga or Dott.ssa

Anna Gazzola, Molecular Biology Laboratory, University of Bologna; TEL: +39-051-6363047; e-mail

contacts:H [email protected], [email protected].

UROMA (GREEN LAB):

The green lab will receive samples from: L’Aquila, Rieti, Roma, Frosinone, Latina, Campobasso,

Isernia, Caserta, Benevento, Napoli, Avellino, Salerno, Foggia, Barletta-Andria-Trani, Bari, Brindisi,


Lecce, Taranto, Potenza, Matera, Maratea, Cosenza, Crotone, Catanzaro, Vibo Valentia, Reggio

Calabria.

Address:

LABORATORIO DI BIOLOGIA MOLECOLARE DOTT.SSA ILARIA DEL GIUDICE/DOTT.SSA

IRENE DELLA STARZA

C/O Ematologia

Via Benevento 6

00161 Roma


Help-desk for the MRD study please contacts the following: Dott.ssa Ilaria del Giudice or Dott.ssa

Irene della Starza, Immunology Laboratory, University of Roma; TEL: +39-06-441639822; e-mail

contacts: [email protected], [email protected] UH.

UFIG. 2: GEOGRAPHICAL ALLOCATION OF FIL MRD NETWORK LABORATORIES

Torino Pisa Bologna Roma


UOPERATIVE RULES FOR MRD COLLECTION AND SHIPMENT

Table 1: TIME POINTS FOR MRD EVALUATION. PERIPHERAL BLOOD AND BONE

MARROW ARE REQUIRED (except time point 3)

1. Baseline 2. Restaging at randomization 3. Stem cell harvest (at least 5ml of harvest product) 4. Restaging before consolidation 5. Restaging after consolidation 6. 6 months maintenance 7. 12 months maintenance 8. 18 months maintenance 9. 24 months maintenance 10. 30 months FU 11. 36 months FU

A number of well defined molecular time points are planned in this study. For any time point,

excluding MRD determination on stem-cell harvests, both BM and PB will be required. Both at

baseline and follow-up time points Uat least seven ml of BM and 10 ml of PBU are required: lithium

heparin or citrate sodium tubes are recommended for collecting both samples. For stem cell harvest Uat

least five ml of unfrozen leukapheresis materialU are required. In absence of BM invasion at baseline,

it is recommended (though not required) to send a sample from lymph node or other diagnostic

tissue biopsy for the detection of a molecular marker. Also a pre-stored tumor invaded DNA

sample (either BM or PB or other) taken during previous treatment phases (i.e. at diagnosis)

might be used to identify a molecular marker.

Note that sample shipment will be a pre-requisite for study inclusion and randomization at some

specific time points. This means that the software will not allow to complete the required procedures

if the laboratory has not received the biological sample.

UThese are the planned MRD Molecular Time Points:

1) Baseline: on PB and BM (if baseline BM and PB have no detectable tumor invasion, additional

shipment of a diagnostic sample with documented tumor-invasion > 5% is required). Sample is

required for patient enrolment: the laboratory is committed to inform the Center, in 60 days, on the

availability of a tumor marker (expected rate of success 60%-70%);

2) Restaging at randomization: on PB and BM after induction with three courses or R-chemotherapy;

3) Stem cell harvest: at least 5 ml of leukapheresis are required;


4) Restaging before consolidation: on PB and BM in both arms;

5) Restaging after consolidation: on PB and BM in both arms;

6) 6 months maintenance: on PB and BM in both arms;




10) 30 months follow-up: on PB and BM in both arms;

11) 36 months follow-up: on PB and BM in both arms;

Note that the results of molecular analyses performed (with the exception of notification of the

presence of a molecular marker) will remain blinded to clinical centers.

UOPERATIVE CONSIDERATIONS FOR SAMPLE SHIPMENT

BM, PB and leukapheresis samples will be collected according to a schedule which has been previously

described. A shipment kit containing: self-sticking labels, boxes suitable for biohazard transport,

laboratories addresses and telephone number of the courier will be provided by FIL.

Please follow carefully the following instructions:

1. UObtain PB and BM from the patientU: for any time point both BM will be required. Both at

baseline and follow-up time points at least Useven ml of BM and 10 ml of PB are requiredU:

Ulithium heparin or citrate sodium tubes U are recommended for collecting both tissues. For

stem cell harvest Uat least five ml of leukapheresisU stored at room temperature are required.

2. UIn absence of BM invasion at baseline U, it is recommended to send a frozen or paraffin-

embedded (the latter choice is sub-optimal) sample having a tumor invasion of at least 5%. Also

a tumor invaded DNA sample (either BM or other) taken during previous treatment

phases (i.e. at diagnosis) might be used to identify a molecular marker. These samples

might derive either from lymph node or extra nodal tissue. For the subsequent MRD molecular

time-points BM and leukapheresis products are required, as described before. UFor samples other

than BM or leukapheresis products, please contact your reference laboratory to discuss

shipment modalities and other related issuesU.

3. UApply adhesive labelsU specifying the kind of sample (e.g. PB, BM, leukapheresis, lymph node,

etc…), the patient code and the treatment phase (e.g. “Baseline”, “Restaging at randomization”,

“Stem cell harvest”, etc…). DO NOT write the name of the patient. Secure the biohazard box.

4. Apply the address on the external side of the box.


5. Contact FIL Secretariat by e-mail ([email protected]) or fax (+39-0131-263455)

6. UShipment is mandatory for enrollmentU, so please check after three days that the laboratory has

received the sample.

Samples should be Usent at room temperature from Monday to Thursday and should not reach

destination after 4 p.m.

It is advisable to send no samples the day before an Italian vacation day, if occurring on Friday or

Monday, because this will result in a >72 hour delay in sample processing.

For non Italian centres: be careful about Italian vacation days. The list of Italian vacation days is: 1

January, 6 January, Easter Monday (variable), 25 April, 1 May, 2 June, 15 August, 1 November, 8

December, 25 December, 26 December.

Please note that sample shipment on Friday will often cause a 48 hour delay of processing, resulting in

a sub-optimal pre-analytical procedure. UWe thus recommend sending samples on Friday only in cases

which are extremely urgent.

FOR THE PRESENT PROTOCOL WE DO NOT RECOMMEND THE SHIPMENT OF

ALREADY EXTRACTED DNA OR FROZEN CELLS (EXCEPT IN CASES DETAILED IN

POINT 2).

Samples should be sent through the DHL EXPRESS, according to the following geographical

allocation, to this address:


APPENDIX II Follicular Lymphoma Stage III or IV who require therapy based on the presence of one or more

GELF criteria or one or more SIE, SIES AND GITMO CRITERIA criteria

UGELF CRITERIA: one of these criteria*

1. High tumor bulk defined by either:

a. Any nodal or extranodal tumor mass >seven cm

b. three nodes in three distinct areas each >three cm

c. symptomatic splenic enlargement

d. organ compression

2. ascites or pleural effusion

3. Presence of systemic symptoms

4. ECOG performance status >one

5. Serum LDH or β2-Microglobulin above normal values

* (Brice P et al, J Clin Oncol. 1997)

USIE, SIES AND GITMO CRITERIA: one of these criteria*

1. Systemic symptoms

2. High tumor burden

3. Extranodal disease

4. Cytopenia due to marrow involvement

5. Spleen involvement

6. Leukemic phase

7. Serous effusion

8. Erythrocyte sedimentation rate >20mm/h

9. High LDH levels

*(Barosi G et al, Haematologica 2005)


APPENDIX III ECOG Performance Scale

6BECOG PERFORMANCE STATUS*

Grade ECOG

0 2BFully active, able to carry on all pre-disease performance without restriction

1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work

2 Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours

3 Capable of only limited self care, confined to bed or chair more than 50% of waking hours

4 Completely disabled. Cannot carry on any self care. Totally confined to bed or chair

5 Dead * Oken MM et al, Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J

Clin Oncol 5:649-655, 1982.


APPENDIX IV CHEMOTHERAPY REGIMENS

(NB: Only chemotherapy and immunotherapy are described. Use support treatment according to your Institutional

guidelines. In case of conflict between Institutional guidelines and the list of "Other Permitted Concomitant Therapies"

please contact the Study PIs)

U1 R-CHOP* U(cycle every 21 days) can be performed in an outpatient setting Rituximab 375 mg/m2 i.v.# day 0 or 1 Doxorubicin 50 mg/m2 i.v. in 100 ml saline solution in 30' day 1 Ciclofosfamide 750 mg/m2 i.v. in 100 ml saline solution in 60' day 1 Vincrstine 1.4 mg/m2 i.v. (maximum dose 2 mg) in 100 ml saline solution in 30' day 1 Prednisone 100 mg/day PO days 1–5 (*Czuczman MS et al. JCO 1999) #For first and subsequent infusions follow point 7 (see bottom of the appendix) U2. R-DHAP* U(cycle every 21 or 28 days) can be performed in an outpatient setting Rituximab 375 mg/m2 i.v. # day 0$

Cisplatin° 100 mg/m2 i.v. in 500 ml saline solution (timing of infusion is variable. In outpatients

usually six hours, in inpatients usually 24h) day 1$

Cytarabine 2 g/m2 x 2 every 12 h i.v. in 500 ml dextrose 5% solution in 180' (In outpatients every 24h) day 2 (or 2-3) Dexamethasone 40 mg i.v. (or PO) days 1-4 (* Olivieri A, et al. Eur J Haematol. 2004) #For first and subsequent infusions follow point 7 (see bottom of the appendix) $Rituximab and cisplatin may be infused on separate days or on the same day based on the logistics ° Cisplatin can be substituted with Oxaliplatin or Carboplatin U3. R- FM*U (cycle every 28 days) can be performed in an outpatient setting Rituximab 375 mg/m2 i.v. # day 0 or 1 Mitoxantrone 10 mg/m2 i.v. in 100ml saline solution in 30’ day 1 Fludarabine 25 mg/m2 i.v. in 100ml saline solution in 30’ day 1-3

(*Zinzani PL et al.JCO 2004) #For first and subsequent infusions follow point 7 (see bottom of the appendix) U4. R- ICE* U (cycle every 21 days) can be performed in an outpatient setting Rituximab 375 mg/m2 i.v. # day 0$

Etoposide 100 mg/m2 i.v. in 500 ml saline solution in 30’ min days 1-3 Carboplatin (area under the curve = 5; maximum dose 800 mg) in 60' day 1 Ifosfamide 1700 mg/m2 i.v. in 250 ml dextrose 5% solution in 120’ min days 1 Ifosfamide 1650 mg/m2 i.v in 250 ml dextrose 5% solution in 120’ min days 2-3 Mesna 350 mg/m2 x 5 i.v. bolus 2 h after ifosfamide infusion and then every 3 h days 1-3


(*Hertzber MS et al, Annals of Oncology 2003) # For first and subsequent infusions follow point 7 (see bottom of the appendix) $Rituximab and etoposide/carboplatin may be infused on separate days or on the same day based on the logistics U5. R- IEV* U (cycle every 21 days) can be performed in an outpatient setting Rituximab 375 mg/m2 i.v.# day 0$

Ifosfamide 2500 mg/m2 i.v. 250 ml dextrose 5% solution in 240’ min days 1-3 Epirubicn 100 mg/m2 i.v. in 100 ml saline solution in 30' day 1 Etoposide 150mg/ m2 i.v. 250 ml saline solution in 120’ min days 1-3 Mesna 500 mg/m2 x 5 i.v. bolus 2 h after ifosfamide infusion and then every 3 h days 1-3 (*Zinzani et al haematologica 2002) #For first and subsequent infusions follow point 7 (see bottom of the appendix) $Rituximab and Ifosfamide may be infused on separate days or on the same day based on the logistics U6. R- Bendamustine*U (cycle every 28 days) can be performed in outpatients Rituximab 375 mg/m2 i.v.# day 1 Bendamustine 90mg/m2 i.v. in 250 or 500 ml saline solution, in 30’-60’ days1-2 (*Rummel MJ et al JCO 2005) #For first and subsequent infusions follow point 7 (see bottom of the appendix) 7. ADMINISTRATION OF RITUXIMAB Caution: Do not administer rituximab as an intravenous push or bolus.

• Oral premedication (1000 mg of paracethamole and 50-100 mg diphenhydramine hydrochloride) needs to be administered 30-60 minutes prior to starting each infusion.

• Prednisone/prednisolone as part of the chemotherapy protocol will be administered in the prescribed dose before the infusion of rituximab, preferably as oral medication. A peripheral or central intravenous (iv) line will be established.

FIRST INFUSION

• 1st dose 100 mg in 100 ml saline solution • 2nd dose the remaining amount in 1000 ml saline solution

Begin infusion at the initial rate of 50 mg/hr If no infusion-related or hypersensitivity reaction occurs, increase the infusion rate in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr If an infusion reaction develops, stop or slow the infusion. Administer infusion-reaction medications and supportive care in accordance with institutional guidelines. If the reaction resolves, resume the infusion at a 50% reduction in rate

SUBSEQUENT INFUSIONS


If no adverse events occurred during first rituximab infusion, subsequent infusion will be performed as follows:

• 1st dose 100 mg in 100 ml saline solution • 2nd dose the remaining amount in 250ml or 500 ml saline solution

Hours ml/h 0-1 100 1–3 125 or 250


APPENDIX V Revised Response Criteria for Malignant Lymphoma (Cheson BD et al, JCO 2007)

Definition Lymph Nodes Spleen, Liver Bone Marrow

CR Disappearance of all evidence of disease

Regression to normal size on CT

No palpable spleen

Liver nodules disappeared

Infiltrate cleared on repeated biopsy; if indeterminate by morphology, immuno-histochemistry should be negative

PR Regression of measurable disease and no new sites

≥50% decrease in SPD of up to six largest masses; no increase in size of other nodes Regression on CT

≥50% decrease in SPD of nodules; no increase in size of liver or spleen

Irrelevant, if positive prior to therapy (cell type should be specified)

SD Failure to attain CR or PR

No new sites on CT No change in size of previous lesions on CT

Relapse or PD

Any new lesion or increase by ≥50% of previously involved sites

Appearance of a new lesion(s) > 1.5cm in any axis, ≥ 50% increase in SPD of more than one node, or ≥ 50% increase in longest diameter of a previously identified node > 1cm in short axis

Increase by ≥ 50% in the SPD of any previous lesion

New or recurrent involvement

CR: Complete Remission; CT: Computed Tomography; PR: Partial Response; SPD: Sum of the Product of Diameters; SD: Stable Disease; PD: Progressive Disease


APPENDIX VI STEM CELL MOBILIZATION

(NB Only chemotherapy, immunotherapy and Myelostimulation are described. Use support treatment

according to Your Institutional guidelines)

1. Citarabine (Ara-C) 2 g/m2 every 12 hours i.v. in 500ml saline solution in 120' days 1-2 2. Rituximab 375 mg/m2 i.v. on day 3 and on the first day with ANC >1000/mmc 3. Growth factor (Lenograstim or Filgrastim) Lenograstim or Filgrastim 5μg/kg start on day 4, until end of stem cell harvesting

4. Apheresis With the aim of collecting at least 6x106 CD34+ cells/kg (to be stored in at least two separate bags

containing > 4x106 CD34+ cells/kg for ASCT and 2x106 CD34+/Kg for back up).

In conclusion:

a) For patients collecting ≥6x106 CD34+ cells/kg, use >4x106 CD34+ cells/kg for ASCT and keep

>2x106 CD34+ cells/kg for back up;

b) For patients collecting 4-6x106 CD34+ cells/kg, use >2x106 CD34+ cells/kg for ASCT and keep


c) For patient collecting 2-4x106 CD34+ cells/kg, use all CD34+ cells for ASCT and keep no back

up;

d) For patient collecting <2x106 CD34+ cells/kg are mobilization failures.

NOTE Mobilization with plerixafor Patients with insufficient cell mobilization after the first standard mobilization with Lenograstim or

Filgrastim can undergo a second mobilization with plerixafor (Mozobil®) according to EMA and

AIFA indication and prescription schedule.

IN CASE OF ASCT AND STEM CELL COLLECTION FACILITIES ARE NOT AVAILABLE

AT THE LOCAL INSTITUTION PLEASE CONTACT THE PRINCIPAL INVESTIGATORS,

DR LADETTO AND DR VITOLO AS SOON AS INDUCTION TREATMENT IS

COMPLETED FOR REFFERING THE PATIENT TO A FIL CENTER INVOLVED IN THE

STUDY POSSESSING ADEQUATE FACILITIES. THE PATIENT WILL RETURN TO THE

ENROLLING CENTER IMMEDIATLY AFTER CONSOLIDATION OR MOBILIZATION.


APPENDIX VII RADIOIMMUNOTHERAPY

Initiate the Zevalin® therapeutic regimen if the patient has less than 25% BM infiltration at the pre-consolidation restaging and following recovery of platelet counts to ≥ 150.000/mmc at least 6 weeks, but no more than 12 weeks, following the last dose of first-line chemotherapy. If the patient doesn’t meet these two criteria will proceed directly to maintenance. If at week 11 platelets are between 100.000 and 150.000/mmc proceed with Zevalin® 0.3 mCi/kg the following week. • Rituximab 250mg/m2 i.v. Day 1 and Day 7 Administer rituximab 250 mg/m2 intravenously at an initial rate of 100 mg/hr. Increase rate by 100 mg/hr increments at 30 minute intervals, to a maximum of 400 mg/hr, as tolerated. If infusion reactions occurred during rituximab infusion on Day 1 of treatment, administer rituximab at an initial rate of 50 mg/hr and escalate the infusion rate in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. • Zevalin® i.v. Day 7 (drug will be delivered as per indications and should thus be provided at expenses

following regular supplies procedures). Administer over 10 minutes as an intravenous injection within 4 hours after completion of the rituximab infusion. • NOTE 0.4 mCi/kg if platelets ≥ 150,000/mmc, 0.3 mCi/kg if platelets are between 100.000 and

150,000/mmc). Follow Institutional rules for radioprotection after RIT Infusion. REFERENT OF RIT: Stefano Fanti, M.D Nuclear Medicine Division and of PET Unit at the S. Orsola Malpighi Hospital, University of Bologna, Italy. e-mail: [email protected] IN CASE RIT IS NOT AVAILABLE AT THE LOCAL INSTITUTION PATIENTS SHOULD REFERR TO THE NEAREST RIT CENTER, AMONG THOSE SPECIFIED IN THIS LIST CONTACTS:

1. BOLOGNA Policlinico S. Orsola-Malpighi Via Albertoni 15 40138 Bologna Direttore Prof Fanti, Referente Dott. Montini Tel +39-051-6363198

2. BOLZANO

Ospedale S. Maurizio di Bolzano Via Lorenz-Böhler 5 I-39100 Bolzano Direttore Dott. Osele, Responsabile Dott. Farsad Tel. +39-0471-908313,

3. BRESCIA

Azienda Ospedaliera Spedali Civili di Brescia P.le Spedali Civili, 1


25123 Brescia Direttore Dott. Giubbini, Referente Dott. Bertagna Tel +39-030-3995334

4. CAGLIARI

Azienda Ospedaliera "Businco" 09134 Cagliari Direttore Dott.Meleddu, Referente Dr. Meleddu Tel. +39-070-6095477

5. GENOVA

Università di Genova Ospedale San Martino Viale Benedetto XV 6 16132 Genova Direttore Prof Bagnasco, Referente Dr.ssa Schiavo Tel +39-010-3537979

6. MACERATA

Ospedale Generale Provinciale via Santa Lucia 1 62010 Macerata Direttore Dott. Brianzoni, Referente Dr.ssa Capoccetti Tel. +39-0733-2572467

7. MESSINA

A.O.U. Policlinico G. Martino Via Consolare Valeria 1 98100 Messina Direttore Prof Baldari, Referente dr. Campennì Tel +39-090-2844.2841

8. MILANO

Fondazione IRCCS Istituto Nazionale dei Tumori (INT) di Milano via Venezian, 1 20133 Milano Direttore Dott. Bombardieri, Referente dr. Seregni Tel +39-02-23903007

9. POTENZA

Centro di Riferimento Oncologico della Basilicata Strada Prov.le N.8 85028 Rionero in Vulture Direttore Dott. Storto, Referente Dr. Storto Tel. +39-0972-726400

10. REGGIO EMILIA

Arcispedale S. Maria Nuova Azienda Ospedaliera di Reggio Emilia v.le Risorgimento, 80 42123 Reggio Emilia Direttore Dott.ssa Salvo, Referente Dr. Versari


Tel. +39-0522-296284

11. SAN GIOVANNI ROTONDO Fondazione di Religione e di Culto Casa Sollievo della Sofferenza Viale Cappuccini 71013 San Giovanni Rotondo (FG) Direttore Dott. Frusciante, Referente Dr.ssa Dicembrino Tel +39-0882-410387

12. TORINO

Ospedale San Giovanni Battista – Molinette corso Bramante 10126 Torino Direttore Prof. Bisi, Referente Dott.ssa Bellò Tel. +39-011-6335546

13. TREVISO

Ospedale "S. Maria di Ca' Foncello" Piazza Ospedale 1 31100 Treviso Direttore Dott. Boccaletto, Referente Dr. Dalla Pozza Tel. +39-0422-322111

14. UDINE

Azienda Ospedaliera di Udine P.zza S. Maria della Misericordia 33100 Udine Direttore Dott Geatti, Referente Dr.ssa Englaro Tel +39-0432-552665/66

CONTACTS WITH FURTHER RIT CENTERS ARE ONGOING AND THEY WILL BE INCLUDED IN THE NEXT PROTOCOL EMENDMENT.


FIG. 3 GEOGRAPHICAL ALLOCATION OF RIT CENTERS


APPENDIX VIII STEM CELL TRANSPLANTATION

(NB: Only chemotherapy and immunotherapy and myelostimolation are described. Use support treatment according to

Your Institutional guidelines)

UNB only patients with a collection of at least 2x106 CD34+ cells/kg will proceed to ASCT.

UBEAM REGIMEN day -6 Carmustine* 300 mg/ m2 i.v. in 250ml dextrose 5% solution from day -5 to day -2 Cytarabine 200 mg/m2 i.v. every 12 hours in 250 ml dextrose 5% solution, 250 ml/hr Etoposide 100 mg/m2 i.v. every 12 hours in 250 ml dextrose 5% solution, 250 ml/hr day -1 Melphalan 140 mg/m2 i.v. in 100ml saline solution in 200 ml/hr day 0 UReinfusion of autologous stem cells following this rules:

a) Patient collecting ≥6x106 CD34+ cells/kg use >4x106 CD34+ cells/kg for ASCT and keep


b) Patient collecting 4-6x106 CD34+ cells/kg use >2x106 CD34+ cells/kg for ASCT and keep


c) Patient collecting 2-4x106 CD34+ cells/kg use all CD34+ cells for ASCT and keep no back up.

day 2 Filgrastim or Lenograstim 5μg/Kg s.c. until ANC > 1500/mmc *it is allowed in this protocol the use of Fotemustine-based conditioning (FEAM regimen), as described by Musso M. et al in Bone Marrow Transplantation, 2010. UFEAM REGIMEN The suggested schedule is as follows: days -7, -6 Fotemustine 150 mg/m2

from day -5 to day -2 Cytarabine 200 mg/m2 i.v. every 12 hours in 250 ml dextrose 5% solution, 250 ml/hr Etoposide 100 mg/m2 i.v. every 12 hours in 250 ml dextrose 5% solution, 250 ml/hr day -1 Melphalan 140 mg/m2

day 0 UReinfusion of autologous stem cells following this rules:


a) Patient collecting ≥6x106 CD34+ cells/kg use >4x106 CD34+ cells/kg for ASCT and keep


b) Patient collecting 4-6x106 CD34+ cells/kg use >2x106 CD34+ cells/kg for ASCT and keep


c) Patient collecting 2-4x106 CD34+ cells/kg use all CD34+ cells for ASCT and keep no back up.

day 2 Filgrastim or Lenograstim 5μg/Kg s.c. until ANC > 1500/mmc IN CASE OF ASCT AND STEM CELL COLLECTION FACILITIES ARE NOT AVAILABLE

AT THE LOCAL INSTITUTION PLEASE CONTACT THE PRINCIPAL INVESTIGATORS,

DR LADETTO AND DR VITOLO AS SOON AS INDUCTION TREATMENT IS

COMPLETED FOR REFFERING THE PATIENT TO A FIL CENTER INVOLVED IN THE

STUDY POSSESSING ADEQUATE FACILITIES. THE PATIENT WILL RETURN TO THE

ENROLLING CENTER IMMEDIATLY AFTER CONSOLIDATION.


APPENDIX IX Guidelines for Dose Delay or Modification

UINDUCTION

Grade 3 or 4 neutropenia and/or thrombocytopenia

• Delay R-chemotherapy for a maximum of 2 weeks until recover to ANC > 1000/mmc and Plt > 75000/mmc.

• Administer G-CSF or growth factors for neutropenia and for all subsequent cycles.

• Consider dose reduction by 25-50% of baseline according to local guidelines.

Grade 3 or 4 non-hematologic toxicity

• Delay doses of R-chemotherapy for a maximum of 2 weeks. • Consider dose reduction by 25-50% of baseline according to

local guidelines. • If recurrent Grade 4 (>1) discontinue treatment.

UMOBILIZATION

Stem cell collection

• Aim of collecting 6x106 CD34+/Kg to be stored in at least two separate bags containing > 4x106 CD34+ cells/kg for ASCT and 2x106 CD34+/Kg for back up.

• If failure after R-Ara-C + G-CSF, a second mobilization will be allowed using Plerixafor according to EMA and AIFA guidelines.

UCONSOLIDATION

RIT

• 90Y Ibritumomab Tiuxetan 0,4 mCi/kg if platelets > 150.000/mmc. • 90Y Ibritumomab Tiuxetan 0,3 mCi/kg if platelets 100.000- 150.000/mmc. • 90Y Ibritumomab Tiuxetan will be not administrated if platelets < 100.000/mmc or if there is a BM infiltration greater than 25% at the restaging pre-consolidation.

ASCT with BEAM or FEAM

• ASCT will be not delivered if collection less than 2x106 CD34+/Kg.

• ASCT will be performed if ANC > 1000/mmc and Plt > 75000/mmc. For single chemotherapeutic agent dose modification, please refer to the approved product label for instructions.

UMAINTENANCE

Rituximab

• Timing of maintenance will be as per indication in relapsed FL (375mg/m2 every three months for eight courses).

• Delay of administration should be considered if neutropenia and thrombocytopenia occur.

• If any Rituximab-related SAE occurs maintenance will be discontinued.

ENGLISH

EORTC QLQ-C30 (version 3) We are interested in some things about you and your health. Please answer all of the questions yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will remain strictly confidential.

Please fill in your initials: bbbb Your birthdate (Day, Month, Year): cececdde Today's date (Day, Month, Year): 31 cececdde __________________________________________________________________________________________

Not at A Quite Very All Little a Bit Much 1. Do you have any trouble doing strenuous activities, like carrying a heavy shopping bag or a suitcase? 1 2 3 4 2. Do you have any trouble taking a long walk? 1 2 3 4 3. Do you have any trouble taking a short walk outside of the house? 1 2 3 4 4. Do you need to stay in bed or a chair during the day? 1 2 3 4 5. Do you need help with eating, dressing, washing yourself or using the toilet? 1 2 3 4

During the past week: Not at A Quite Very All Little a Bit Much 6. Were you limited in doing either your work or other daily activities? 1 2 3 4 7. Were you limited in pursuing your hobbies or other leisure time activities? 1 2 3 4 8. Were you short of breath? 1 2 3 4 9. Have you had pain? 1 2 3 4 10. Did you need to rest? 1 2 3 4 11. Have you had trouble sleeping? 1 2 3 4 12. Have you felt weak? 1 2 3 4 13. Have you lacked appetite? 1 2 3 4 14. Have you felt nauseated? 1 2 3 4 15. Have you vomited? 1 2 3 4 16. Have you been constipated? 1 2 3 4

Please go on to the next page

ENGLISH

During the past week: Not at A Quite Very All Little a Bit Much 17. Have you had diarrhea? 1 2 3 4 18. Were you tired? 1 2 3 4 19. Did pain interfere with your daily activities? 1 2 3 4 20. Have you had difficulty in concentrating on things, like reading a newspaper or watching television? 1 2 3 4 21. Did you feel tense? 1 2 3 4 22. Did you worry? 1 2 3 4 23. Did you feel irritable? 1 2 3 4 24. Did you feel depressed? 1 2 3 4 25. Have you had difficulty remembering things? 1 2 3 4 26. Has your physical condition or medical treatment interfered with your family life? 1 2 3 4 27. Has your physical condition or medical treatment interfered with your social activities? 1 2 3 4 28. Has your physical condition or medical treatment caused you financial difficulties? 1 2 3 4 For the following questions please circle the number between 1 and 7 that best applies to you 29. How would you rate your overall health during the past week? 1 2 3 4 5 6 7 Very poor Excellent 30. How would you rate your overall quality of life during the past week? 1 2 3 4 5 6 7 Very poor Excellent © Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0

© 1990 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group

Health Questionnaire

English version for the UK

(validated for Ireland)


2

By placing a tick in one box in each group below, please indicate which statements

best describe your own health state today.

Mobility

I have no problems in walking about

I have some problems in walking about

I am confined to bed

Self-Care

I have no problems with self-care

I have some problems washing or dressing myself

I am unable to wash or dress myself

Usual Activities (e.g. work, study, housework, family or

leisure activities)

I have no problems with performing my usual activities

I have some problems with performing my usual activities

I am unable to perform my usual activities

Pain/Discomfort

I have no pain or discomfort

I have moderate pain or discomfort

I have extreme pain or discomfort

Anxiety/Depression

I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed


3

To help people say how good or bad a health state is, we have drawn a scale (rather like a thermometer) on which the best state you can imagine is marked 100 and the worst state you can imagine is marked 0. We would like you to indicate on this scale how good or bad your

own health is today, in your opinion. Please do this by drawing a

line from the box below to whichever point on the scale indicates

how good or bad your health state is today.

9 0

8 0

7 0

6 0

5 0

4 0

3 0

2 0

1 0

100

Worst

imaginable

health state

0

Best

imaginable

health state

Patient Costs Questionnaire (English version)

In this questionnaire we are trying to find out about the costs to you, the patient and also the costs to your family of the treatment you have been receiving for your disease. Your answers are important because they will give persons who make decisions about patient treatment within the NHS an idea of how much the treatment costs you.

Please answer every question even if the answer is "0". If you are not sure or cannot remember the exact details, please give the best answer you can. If you have a problem in answering any question, please write that problem beside the question.’

The information that you provide will be completely confidential. Your answers will be combined with the answers of other patients involved in the study and reported in such a way that it will not identify you or influence your pattern of treatment.

Employment

Current employment:Are you currently employed? Yes No

Is this: Paid employment Full time Part-time

If No, please: choose one or more of the following categories that best described your current status and go to the next question XXX:

Retired Housewife UnemployedRetired on medical grounds Student Other____________________

Over the last 6 months, have you had to take any time off work because of your illness?

No Yes , number of days:

Did you normally lose earning as results? Yes No

Travelling costs

Over the last 6 months, how many times have you visited the hospital where you were recruited for your disease? Please, write the number of times in the box below.(An approximate figure will be fine) Number of times

How far away from the hospital where you were recruited do you live? Please write the number of kilometres in the box below.(An approximate figure will be fine) Number of kilometres

Over the last 3 months, roughly how much have you or your family and friends had to pay directly for travelling due to your disease? (An approximate figure will be fine) €

Caregiving

Over the last 6 months, who normally went with you to the hospital where you were recruited? You may circle more than one answer if appropriate.

NobodyPatner/spouseOther relativePaid caregiverOther_____________________________________

Over the last 6 months, how long did that person normally stay with you at the hospital where you were recruited each time? (An approximate figure will be fine) Number of hours per visit

Over the last 6 months, who normally have provide you with informal nursing and other care as a result of illness?

NobodyPatner/spouseOther relativePaid caregiverOther_____________________________________

Over the last 6 months, how much time have your caregiver devoted to providing you with informal nursing and other care as a result of your disease? (An approximate figure will be fine) Number of hours per day

Health care services

Over the last 6 months, how many times have you:1. Seen your GP ? ................................................................2. Visited a hospital out-patient clinic?................................3. Visited an Emergency Department (ER)?........................4. Been admitted to hospital as day-care?............................5. Been admitted to hospital as an in-patient?.....................6. Visited at home by health care professionals (ADI)?......

Over the last 6 months, roughly how much have you or your family and friends had to pay directly for any healthcare service such as equipment, supplies, medications, drugs related to your disease. (An approximate figure will be fine) €

If you would like to make any other comments, please write them here.

.......................................................................................................................................................

.......................................................................................................................................................

Many thanks for your help.

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APPENDIX XIII Schedule of Study Assessments

3BCONSOLIDATION 4BMAINTENANCE FOLLOW-UP

(up to 36 months)

0BSCREENING

(within 1 month)

1BINDUCTION

(every other week)

RANDOMIZATION

(within four weeks after the last chemotherapy course)

MOBILIZATION

(within one week from randomization)

BEFORE AFTER (two months)

Before each corse

Every six

months

Every 12 months

Every six months

Written informed consent

7BX Diagnostic Biopsy1 X Physical examination X X X X X X X X ECOG PS X X X X X X X X ECG X X Ecocardiography or cardiac scintigraphy

X X

PFTs, OPT X Chest X-Ray X Pregnancy test (if applicable)

X

Hematology and blood chemistry2

(also within two week prior to treatment)

X Xa Xa Xa Xa Xa Xa Xa

Creatinine clearance rate3 X X X X Coagulation4 X X X X Quantitative Immunoglobulins

X X X X X X

Viral markers 5 X Xb Total body CT scan6 X X Xc Xd X X BM Biopsy and aspirate7 X Xe Xe Xe Xe Xe

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BM and PB for centralized MRD testing8

X Xf Xf Xf Xf Xf

Leukapheresis sample for PCR analysis

X

Adverse events X X X X X X QLQ-30 e EQ-5D X X X X X Questionarie on patient’s cost

X X X X X

1 - if the patients has a biopsy taken in the previous 12 months and has not received anti-lymphoma treatment during this lag of time, study entry biopsy can be omitted 2 - CBC with differential, transaminases, serum alkaline phosphatase, GGT, LDH, total bilirubin, BUN, creatinine, Na, K, Ca, uric acid, total protein, albumin , beta2-microglobulin 2a - CBC with differential, transaminases, serum alkaline phosphatase, GGT, LDH, total bilirubin, creatinine 3 - Cockcroft-Gault formula 4 - (PTT, PT, ATIII, D-dimer, Fibrinogen ) 5 - HBV markers (HbsAg, HbsAb, HBcAb), HBV DNA, HCV serology, HIV serology 5b - if positive at baseline 6c – if is not in CR at the restaging post-induction 6d - after three months 7e - If positive at baseline 8f - If marker available.

APPENDIX XIV Cronoprogram

Fondazione Italiana Linfomi ONLUS … · Protocollo Studio FIL_FLAZ-12 V. 1 del 23/01/2012 Page 1...

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