AmrubicinAmrubicin

Francesco GrossiFrancesco Grossi

S.S. Tumori PolmonariS.S. Tumori PolmonariIstituto Nazionale per la Ricerca sul CancroIstituto Nazionale per la Ricerca sul Cancro

GenovaGenova

New Drugs in Cancer TherapyNew Drugs in Cancer TherapyMediterranean School of OncologyMediterranean School of Oncology

Roma, 13th May 2011Roma, 13th May 2011

Chemical structures of amrubicin Chemical structures of amrubicin and amrubicinoland amrubicinol

Amrubicin is an antracycline current approved in Japan since 2002 in SCLC and NSCLC produced by Sumitomo Pharmaceuticals under the brand name Calsed.Amrubicin acts by inhibiting topoisomerase II

Activity and toxicity in Activity and toxicity in preclinical modelspreclinical models

Its antitumor activity was found to be superior to that of doxorubicin in experimental therapeutic models using human tumor xenografts. Morisada S, Jpn J Cancer Res 1989

AMR showed much less cardiotoxicity than doxorubicin in chronic experimental models using rabbits and dogs.Suzuki T, Invest New Drugs 1997; Noda T, Invest New Drugs 1998

Amrubicin vs anthracyclinesAmrubicin vs anthracyclinesIn contrast to other anthracyclines, the in vitro cytotoxic activity of amrubicinol is 18–220 times more potent than that of its parent compound, amrubicin. Yamaoka T, Jpn J Cancer Res 1998

In mice experiments, Noguchi et al showed that amrubicinol has more potent antitumor activity than its parent compound, amrubicin. The levels of amrubicinol in the tumors of these mice were higher than doxorubicin levels in doxorubicin-treated mice. Noguchi T, Jpn J Cancer Res 1998

In contrast, the levels of amrubicin and amrubicinol were lower than those of doxorubicin in several non-tumor tissues, including the heart. Noda T, Invest New Drugs 1998

Canine Cardiotoxicity: Effect of AMR Canine Cardiotoxicity: Effect of AMR on DOX-Induced Cardiomyopathyon DOX-Induced Cardiomyopathy

DOX2 IV(1.75 mg/kg first

treatment, then 1.5 mg/kg

1x q 3 wks x 4 cycles)

30th Week:Sacrifice

Score lesions

>19 Heart sections/animalDOX

1.5 mg/kg q 3 wks IV; 4 cycles

AMR32.5 mg/kg q 3 wks IV; 4 cycles

Vehicle1 q 3 wks IV; 4 cycles

9-Weekinterval(no treatment)

18th Week: Sacrifice

Score lesions

Continued DOX IV

(1.5 mg/kg

1x q 3 wks)

Experimental Design

Noda T, Invest New Drugs 1998

Canine Cardiotoxicity: Effect of AMR Canine Cardiotoxicity: Effect of AMR on DOX-Induced Cardiomyopathyon DOX-Induced Cardiomyopathy

*P<0.01 DOX + DOX vs DOX + vehicle.

**P<0.01 DOX + AMR vs DOX + DOX.

Less Cardiotoxicity Observed With AMR1

0 1 2 3 4 5

3.42

0.42

0.40

1.98DOX (18 wks)

DOX + Vehicle (9 + 9 wks)

DOX + DOX (9 + 9 wks)

DOX + AMR (9 + 9 wks)

Mean Scores

**

*

Noda T, Invest New Drugs 1998

Japanese Data on Amrubicin Show Japanese Data on Amrubicin Show Minimal Signs of CardiotoxicityMinimal Signs of Cardiotoxicity

N ≥ 600 Patients

6% Of patients who received treatment with Amrubicin experienced transient

electrocardiogram (ECG) abnormalities1

Anthracycline-induced cardiomyopathy was not observed at cumulative doses

tested1,2

17 Patients from various clinical trials received greater than Amrubicin 900

mg/m2 and reported no cardiomyopathy2

Amrubicin 600 mg/m2 is the equivalent of the recommended maximum dose of

Doxorubicin (300 mg/m2)

1 Amrubicin Investigator’s Brochure, 22 Jun 07, Edition 3, p. 120.2 Amrubicin Investigator’s Brochure, 22 Jun 07, Edition 3, pp. 114-115.

Japanese Postmarketing DataJapanese Postmarketing Data

N = Approximately 6500 Patients

Rare cardiotoxic events noted

Acute heart failure: 1 reported case from a patient who

received 15 cycles of AMR; reversed after 10 days

Transient ECG changes occurred

Asymptomatic ST-T depression

Acute changes only

1Data on file (2006 periodic safety report).

AMR Is Potentially Devoid of AMR Is Potentially Devoid of CardiotoxicityCardiotoxicity

Preclinical data show that cardiotoxicity profiles are similar between AMR and control/vehicle comparators

Only background incidences of cardiac events were documented in the Japanese clinical data

Cardiac events in ongoing phase 2 trials in amrubicin-treated patients are comparable to topotecan-treated patients

Amrubicin in preclinical modelsAmrubicin in preclinical models

Synergistic effects were obtained for the simultaneous use of amrubicinol with CDDP, CPT-11, gefitinib and trastuzumab.

The combination of amrubicinol with gemcitabine was antagonistic.

Phase I trials with amrubicin Phase I trials with amrubicin monotherapymonotherapy

AMR given on day 1 of every 3-week. Myelosuppression was the dose-limitingmtoxicity (DLT) and the maximum tolerated dose (MTD) was 130 mg/m2. The recommended dose (RD) and schedule for a phase II trial was 100 mg/m2 every 3 weeks.

Infusion for three consecutive days (3 trials) every 3 weeks, the MTD was 40-50 mg/m2/day and the DLTs were leukopenia, neutropenia, thrombocytopenia, and gastrointestinal complications. The RD in these phase I study was 35-45 mg/m2 for three consecutive days every 3 weeks.

Inoue K, Invest New Drugs 1989; Sugiura T, Invest New Drugs 2005;Okamoto I, Cancer Chemother Pharmacol 2006; Igawa S, J Thorac Oncol. 2007

Amrubicin story (a Japanese story)Amrubicin story (a Japanese story)

1986-1998 Phase I-II trials

1998-99 Preclinical studies

2002 Drugs approval in Japan, preclinical Lung cancer

2005-06 Phase I SCLC and NSCLC

2007 SCLC phase II

2008 SCLC random phase II

2009-2011 SCLC-NSCLC random phase II and III (ongoing)

Overview of Clinical Studies Used for Overview of Clinical Studies Used for Approval of Amrubicin in Japan (1-12) andApproval of Amrubicin in Japan (1-12) andPost-Marketing Studies in SCLC Post-Marketing Studies in SCLC (13-15)(13-15)

Responses to Crizotinib in ALK + NSCLCResponses to Crizotinib in ALK + NSCLC

Kwak EL, NEJM 2010

Study A8081007: Crizotinib vs CT i ALK +Study A8081007: Crizotinib vs CT i ALK +Study designStudy design

ClinicalTrials.gov record

RANDOMISE

Pemetrexed 500 mg/m2

d1 q 3 weeks OR

Docetaxel 75 mg/m2

d1 q 3 weeks

Crizotinib 250 mg BIDtill PD

Primary endpoint: PFSEnrollment 318 patients ALK +

PFS for patients on pemetrexed PFS for patients on pemetrexed (ALK+ vs triple negative)(ALK+ vs triple negative)

Camidge DR, JTO 2011

Phase II studies of amrubicin Phase II studies of amrubicin monotherapy for monotherapy for recurrent SCLCrecurrent SCLC

Side effects (grade 3-4)Side effects (grade 3-4)Hematologic toxicities

Neutropenia (67-85%) - Febrile neutropenia (14-5%)

Thrombocytopenia (20-41%)

Anemia (21-42%)

Non-Hematologic toxicitiesAnorexia (7-15%)

Fatigue(15-22%)

Hyponatremia (8%)

Nausea (3-5%)

Amrubicin vs TopotecanAmrubicin vs Topotecan

Jotte R, JCO 2010 Inoue A, JCO 2008

Clinical trials with amrubicin-based Clinical trials with amrubicin-based combination therapycombination therapy

Amrubicin + carboplatin in ED- SCLCAmrubicin + carboplatin in ED- SCLCCarboplatin AUC 4 + Amrubicin 35 mg/m2 d 1-3 q 21

RR sensitive relapse (58.3%) vs refractory relapse (15.4%) p 0.03.

MST sensitive relapse (10 months) refractory relapse(5months: p = 0.004)

PFS sensitive relapse (5 months) refractoryrelapse (2 months; p = 0.01).

Neutropenia g 3-4 (88%), anemia g 3-4 (56%) thrombocyopenia g 3-4 (44%)

Hirose T, Lung Cancer 2011

Amrubicin + topotecan in ED-SCLCAmrubicin + topotecan in ED-SCLC

Amrubicin 35 mg/m2 d 3-5 q 21, topotecan 0.75 mg/m2 d 1-5 q 21

RR naive (74%) vs relapse (43%).

MST naive (14.9 months) relapse (10.2 months)

PFS naive (5.3 months) relapse (4.7 months).

Neutropenia g 3-4 (97%), febrile neutropenia (41%, 2 TD)

Nogami k, Lung Cancer 2011 (in press)

Survival for pts with LD/ED, refractory/ Survival for pts with LD/ED, refractory/ sensitive with vs w/o Amrubicinsensitive with vs w/o Amrubicin

Survival curves for pts with LD

Survival curves for pts with ED

Survival curves for LDpatients with refractory relapse

Survival curves for LDpatients with sensitive relapse

Suzuki H, Med Oncol 2010

Randomized phase II study of amrubicin as single Randomized phase II study of amrubicin as single agent or in combination with cisplatin versus agent or in combination with cisplatin versus

etoposide cisplatin as first-line treatment in patients etoposide cisplatin as first-line treatment in patients with with extensive stage SCLC (ES)extensive stage SCLC (ES)

Investigate the activity and safety of amrubicin alone versus amrubicin incombination with cisplatin versus standard treatment for extensive disease(ED) small-cell lung cancer in the first line setting.

EORTC protocol 08062: study designEORTC protocol 08062: study design

Twenty-seven eligible patients who start their treatment will be entered in each of the 3 arms.

In either of the two experimental arms, if at least 19 patients show a response (a response rate of 69% or higher), the treatment will be declared sufficiently active for taking forward to a phase III study.

Non-eligible/non-assessable patients will be replaced up to a maximum of 85 patient

Grazie per l’attenzione!Grazie per l’attenzione!

francesco.grossi@istge.itfrancesco.grossi@istge.it