09,00 13,40. I Sessione. Moderatori: Giordano Beretta, Roberto Labianca

Transcription

1 09,00 13,40 I Sessione Moderatori: Giordano Beretta, Roberto Labianca

2 11,20-11,40 Gli aspetti metodologici in ambito di ricerca Valter Torri

3 Gli aspetti metodologici in ambito di ricerca Valter Torri valter torri Lab. Metodologia per la Ricerca Clinica Istituto di Ricerche Farmacologiche IRCCS Mario Negri, Milano mario negri institute - milan

4 The background Nature 2009; 458

5 Issues Heterogeneity Intra-patient (primary and metastatic) Inter-patients Success likely requires Inhibiting pathways deregulated by early oncogenic mutations Using combinations of molecularly targeted drugs Treating early Before mutational meltdown

6 Precision medicine diseases are defined by underlyingmolecular mechanisms rather than traditional signs and symptoms. Lancet 378 : 1678, 2011 Toward precision medicine

7 Personalized Medicine in a Phase I Clinical Trial Program The MD Anderson Cancer Center Initiative matched unmatched

8 Platform trials Exploratory Platform: BATTLE, I-SPY Expansion Platform type I NCI-MATCH, FOCUS, MODUL Expansion Platform type II PANGEA D. Catenacci, Mol Oncol 9 (2015)

9 Exploratory platform Usually, histology dependent Patients are randomised to receive a Rx independent of BM (BM stratified) The trial can have a control (SoC) arm (I-SPY) or not (BATTLE) Adaptive design consists in dropping ineffective drug (in any BM cohort) and randomising patient to most promising After trial completion BM enriched trial to give specific definitive response on the BM-RX pair.

10 Expansion platform I: (umbrella of basket trials) HistologyAgnostic Patients are randomised to receive a Rx matched to BM Compartimentalised: Each cohort can be randomised (ideally) or not

11 Expansion platform I: (umbrella of BM enrichment trials) Histologydependent Patients are randomised to receive a Rx matched to BM Compartimentalised: Each cohort can be randomised (ideally) or not

12 MODUL trial design

13 Expansion platform II Histologydependent Patients are randomised to receive a Rx matched to BM or control Non-Compartimentalised: all-one trial

14 Expansion platform Master Protocol Each cohort can be designed as a single phase II trial Need a strong top-down organisation central moleculartesting= local appropriate treatment Multiple enrolling centres to deal with rare molecular types ideal for cooperative groups) Close collaboration with Pharma(s): many targets= many drugs needed

15 Limitation - Early EP: how is the surrogacy?

16 Limitation - Early EP: how is the surrogacy?

17 PH Immunotherapy Model vs. type of disease for NSCLC vs. type of treatment Typical survival curves (Kaplan-Meier) observed in clinical trials YES NO NO Correlation with late benefit

18 Selecting more effective drug for a specific patient Compare the new drug to the control overall for all patients ignoring the classifier If power 0.03 claim effectiveness for the eligible population as a whole Otherwise perform a single subset analysis evaluating the new drug in the classifier + patients If in the classifier + patients p 0.02 claim effectiveness

19 New trial designs Conclusion allow fit-for-purpose drug development overcoming the rigid traditional distinction in phases representthe key to rational drugdevelopment if well integrated with biomarker data also non randomised evidence might lead to general availability warning: reliabily of endpoints in early trials