Studio di fase II sull’ utilizzo di una dieta che simula il digiuno (Fasting-Mimicking Diet, FMD) come mezzo per ridurre la tossicità da chemioterapia in

pazienti anziani

Responsabile Scientifico: Prof. Alessio Nencioni Clinica di Medicina Interna ad Indirizzo Oncologico, Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università degli Studi di Genova, U01D, IRCCS AOU San Martino – IST Genova

Personale scientifico coinvolto: Prof. Alberto Ballestrero

Prof. Patrizio Odetti Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università degli Studi di Genova, IRCCS AOU San Martino – IST Genova Prof. Valter D. Longo Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA Dr. Vito Pistoia Laboratory of Oncology, Department of Translational Research and Laboratory Medicine, Istituto Giannina Gaslini, Genoa, Italy

Projected cases of all invasive cancers in the United States by age and sex. Nonmelanoma skin cancers were excluded from projections (adapted from Smith BD et al. J Clin Oncol 2009;27:2758-2765; American Society of Clinical Oncology).

Since we are now in the midst of a demographic revolution as a result of aging of populations worldwide and approximately 60% of cancer incidence and 70% of cancer mortality occurs in individuals older than 65 (Smith BD, et al. J Clin Oncol. 2009;27:2758-65) the issue of proper management of elderly patients and, primarily, the avoidance of treatment-related toxicities has become of central importance (Cleeland CS, et al. Nat Rev Clin Oncol. 2012;9:471-8; http://www.eortc.org/research-groups/cancer-elderly-task-force; http://www.siog.org/). Interventions that effectively reduce the side effects of CT in elders (but not only) are expected to translate into major clinical and socio-economic benefits.

Strong preclinical data and results from ongoing pilot clinical studies indicate that the lack of nutrient intake (fasting) but also diets that mimic this severe restriction in the days immediately before and after CT activate potent protection mechanisms in healthy body tissues and shield them from toxicity (Raffaghello L, et al. Proc Natl Acad Sci U S A. 2008;105:8215-20; Lee C, et al. Sci Transl Med. 2012;4:124ra27; Safdie FM, et al. Aging 2009; 1:988-1007; Couzin J, et al. Science. 2008. 29;321:1146-7; Scrable H. Sci Transl Med. 2012;4:124ps6; Laviano A, Rossi Fanelli F. N Engl J Med. 2012;366:2319-20).

Short-term starvation protects against high-dose chemotherapy in vivo

Raffaghello L et al. PNAS 2008;105:8215-8220

Short-term starvation protects against high-dose chemotherapy in vivo. (A) A/J mice were treated (i.v.) with 80 mg/kg etoposide with (STS/Eto, n = 17) or without (Eto, n = 23) a prior 48-h starvation (STS). (B) Percent weight loss (a measure of toxicity) after etoposide treatment in STS-treated (n = 17) or untreated (n = 23) A/J mice. (C) CD-1 mice were treated (i.v.) with 110 mg/kg etoposide with (STS/Eto, n = 5) or without (Eto, n = 5) a 60-h prior starvation. (D) Percent weight loss after etoposide treatment in STS-treated (n = 5) or untreated (n = 5) CD-1 mice. Asterisks indicate the day at which all mice died of toxicity. (E) Athymic (Nude-nu) mice were treated (i.v.) with 100 mg/kg etoposide with (STS/Eto, n = 6) or without (Eto, n = 9) a 48-h prior starvation. (F) Percent weight loss after etoposide treatment in the treated (STS/Eto, n = 6) or untreated (Eto, n = 9) athymic (Nude-nu) mice. (G) Comparison of survival of all of the mice that were either prestarved (STS/Eto) or not (Eto) before etoposide injection. The survival of all STS-treated (n = 28) and untreated (n = 37) mice from all genetic backgrounds above (A/J, CD1, and Nude-nu) has been averaged (***, P < 0.05).

Short-term starvation enhances the activity of chemotherapy in cancer cells in vitro

Lee C, et al. Sci Transl Med. Mar 7, 2012; 4(124): 124ra27.

Short-term starvation enhances the activity of chemotherapy in vivo

Lee C, et al. Sci Transl Med. Mar 7, 2012; 4(124): 124ra27.

In 2009, Safdie and colleagues, reported on a series of 10 patients diagnosed with a variety of malignancies who voluntarily fasted prior to (48-140 hours) and/or following (5-56 hours) CT (an average of 4 cycles of various CT drugs in combination with fasting) (Safdie FM, et al. Aging 2009; 1:988-1007). In this study, none of the patients reported significant side effects caused by fasting itself other than hunger and light-headedness and fasting during CT allowed them to pursue daily activities better than CT accompanied by a regular diet. In those patients whose cancer progression could be assessed (6), fasting did not prevent the CT-induced reduction of tumor volume or tumor markers.

Several pilot trials are currently exploring fasting in combination with CT in humans (NCT01304251, NCT01175837, NCT00936364, NCT01175837). Probably the main limitation to the use of fasting in clinical practice is that most patients dread complete fasting and refuse to refrain from eating for a long period of time. In a survey conducted at USC’s Norris Comprehensive Cancer Center, only 28% of the patients said that they would be willing to undergo 3-4 days of complete fasting as required by these protocols. However, 70% of the patients said that they would agree with a dietary intervention as long as this was in the form of a meal-replacing calorie-restricted diet formula. Based on this data and on clinical trials in humans showing the effect of protein restriction on IGF-1 levels, Longo and colleagues designed a specific low calorie/low aminoacid fasting-mimicking diet (ChemoLieve) which recreates the changes in IGF-1, IGFBP1, glucose, insulin, and ketone bodies as well as the oxidative stress resistance observed with fasting and achieves maximal protection against CT toxicity in mice. A clinical study of an fasting mimicking diet enrolling 49 healthy volunteers (aged 25-70) has recently been completed at USC. The clinical trial consisted of 3 cycles of the FMD, each of which was followed by 25 days of normal eating. Nearly 50% of the volunteers completed the 3 cycles while 75% completed at least one of them. The diet was well-tolerated with only minimal side effects reported. Serum levels of the stress hormone, cortisol, remain unchanged throughout the diet period. The FMD induced benchmark changes in blood glucose levels, which were significantly reduced, and in urine ketone bodies, which were strongly increased.

SPONSOR Fondazione Umberto Veronesi

FASE CLINICA Fase II

INDICAZIONE Pazienti di età compresa tra i 65 e gli 80 anni, affette da carcinoma

mammario metastatico HER-2 negativo ed idonee ad intraprendere

una chemioterapia sistemica (CT) di II linea

OBIETTIVI OBIETTIVI PRIMARI

Valutare profilo di sicurezza e fattibilità di una dieta simulante il

digiuno effettuata in concomitanza ad una chemioterapia

antineoplastica sistemica.

Valutare l’efficacia della FMD nel ridurre la tossicità da CT

(ematologica e non) in pazienti anziane affette da carcinoma

mammario metastatico HER2-negativo trattate mediante

chemioterapia antineoplastica.

OBIETTIVI SECONDARI

Valutare l’impatto biologico della FMD su: markers infiammatori

indotti da chemioterapia, markers di stress ossidativo, livelli di

fattori oncogenici circolanti (es. insulina, IGF-1, IGFBP1, VEGF).

NUMERO DI PAZIENTI Nello studio saranno arruolati circa 35 pazienti valutabili.

CRITERI DI INCLUSIONE Per risultare idonee a prendere parte a questo studio, le pazienti devono soddisfare TUTTI i criteri elencati di seguito:

Età compresa tra 65 e 80 anni

Pazienti con carcinoma della mammella metastatico HER2-neg

confermato istologicamente, candidate ad una chemioterapia di II

linea

ECOG performance status 0-1; Normale funzionalità d’organo (epatica e renale) BMI >23 kg/m2 [con possibilità di arruolare anche pazienti con BMI

compreso tra 20 e 23 kg/m2 se ritenuto sicuro dal medico esaminatore];

Firma del consenso informato

CRITERI DI ESCLUSIONE Anziano fragile;

Pazienti che abitino da sole o per le quali non esistano sufficienti

garanzie di un’adeguata assistenza a domicilio;

Diabete mellito;

Neuropatia periferica di grado > 1;

Precedente terapia con inibitori di IGF-1;

Allergie alimentari significative;

BMI < 20 kg/m2;

Recente perdita di peso non intenzionale >10% rispetto al peso

medio dei soggetti di pari età;

Qualsiasi disordine metabolico in grado di influenzare la

gluconeogenesi o la capacità di adattamento a periodi di digiuno;

Trattamento in atto con altre terapie sperimentali

PRODOTTO(I)

SPERIMENTALE

DOSE/VIA DI

SOMMINISTRAZIONE/SCH

EMA TERAPEUTICO

La FMD utilizzata per questo studio è ChemoLieveTM (LNI S.r.l.). Tale

dieta è costituita al 100% da alimenti considerati sicuri e contiene i

micronutrienti necessari per evitare l’insorgere di malnutrizione. La

dieta da seguire consisterà in un pasto ipocalorico ma ricco di lipidi

durante 1 dei 4 giorni previsti, mentre nei restanti 3 giorni verrà

somministrato cibo estremamente ipocalorico (per un totale di meno

di 300 Kcal/die). ChemoLieveTM contiene barrette e brodi vegetali in

grado di assicurare l’apporto adeguato quotidiano di vitamine

essenziali ed oligoelementi.

Giorno 1 della dieta: barrette energetiche (2 porzioni), brodo (2

porzioni) e bevanda vegetale (1 porzione); Giorni 2 & 3 della dieta:

zuppa (1 porzione), brodo (1 porzione) e bevanda energetica (1

litro/die); Giorno 4 della dieta: zuppa (1 porzione), brodo (1 porzione);

Giorno 5 della dieta: il paziente riprenderà la dieta abituale, iniziando

però con liquidi e riso (dieta di transizione); Giorno 6 della dieta: dieta

abituale con aggiunta di barretta energetica (1 porzione) e bevanda

vegetale (1 porzione).

……

Gli schemi di chemioterapia di II linea consentiti per questo studio

sono: AC/EC, docetaxel in monoterapia.

Irene Caffa Michele Cea Debora Soncini Inga Bauer Eva Moran Gabriele Zoppoli Denise Lasigliè Patrizia Damonte Lauretta Galeno Fiammetta Monacelli Franco Patrone Patrizio Odetti Alberto Ballestrero DIMI UNIGE Valter Longo USC Vito Pistoia Lizzia Raffaghello Istituto Giannina Gaslini

Acknowledgments