Is there a Cookbook for Oncology Clinical Trials?

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1 Masterclass for Masters See beyond : An Oncology Brainstorm Ghent, 16th of September 2016 Is there a Cookbook for Oncology Clinical Trials? Dimitrios Zardavas MD Associate Scientific Director, Breast International Group

2 Clinical trials Phases of Clinical Trials Phase 0: evaluate PD and/or PK properties of agents (non-therapeutic doses) DRUG APPROVAL Phase I: Identify the appropriate dose Phase II: Evaluate the clinical activity Phase III: randomized comparison of experimental approach vs. standard of care Phase IV: post marketing evaluation EXPLORATORY trials CONFIRMATORY trials D U R A T I O N

3 Transformative Study Designs in the Era of Personalised Cancer Medicine

4 Adaptive Trial Design Adapted from Richard A. Koup, Barney S. Graham & Daniel C. Douek Nature Reviews Immunology 11, (January 2011)

5 Adaptive Trial Design: Pros and Cons PROS CONS Planned Flexibility: change study parameters as trial progresses Program Efficiency: reduce overall development time Optimal Sample Size: adjust sample size Patient Outcomes: increased exposure to effective doses Quicker Decisions: stop early for safety, futility, or efficacy Regulatory Issues: need regulatory buy-in Upfront Planning: modeling and simulations needed Complicated Design: increased start-up complexity Logistical Issues: more difficut to implement

6 Umbrella trials Advanced disease setting Lung cancer Battle 1 and 2 Lung MAP Colorectal cancer FOCUS 4 Melanoma (Braf mutation) GEMM Early disease setting Lung cancer ALCHEMIST

7 Squamous Lung Cancer Master Protocol

8 Squamous Lung Cancer Master Protocol

9 Challenges to the LUNG-MAP clinical trial Anti-PD1 drug trial «positive» Need for a major protocol amendment!

10 THE ALCHEMIST TRIAL (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) Screening Treatment Research (Long-term follow-up) N = 8,000 pts NSCLC (non squamous) up to st. III A undergoing SX? EGFR mut (15%)? ALK transl. (5%) No (N 7,000) Yes (N 1,000) St. adj. CTX Unable to go on trial DNA germline analysis Whole genome seq. Epidemiology questionnaire B X at relapse Repeat whole % sequencing St. adj. CTX ± erlotinib ± crizotinib Adapted from J. Abrams, ASCO Educ book 2014

11 Basket trials One drug VE-Basket Neratinib-basket Several drugs NCI-Match Custom

12 NSCLC Cholangiocarcinoma Vemurafenib basket trial Interim results (ASCO 2014) Objective responses 6/19 2/7 Erdheim chester disease Langerhans cell histiocystosis Other Braf V600m Vemurafenib (Simon 2-stage design) 5/6 histologies + all comers cohort D.M. Hyman et al, abst 2533, ASCO 2014

13 The CUSTOM basket trial (NSCLC, SCLC, Thymic cancers) Lopez-Chavez et al, JCO 2015

14 Lessons learned from the CUSTOM trial 647 pts profiled at 2 cancer centers Heavily pretreated! Successful profiling N = % Actionable mutation N = % Received matched drug N = 45 6% Trial was conclusive only for NSCLC! and for 2 drugs Erlotinib active (60% PR) Selumetinib inactive (60% PR) 13/15 arms «unfeasible» 4/5 pts with actionable mutations never accessed one of the 15 treatment arms - Lab testing not efficient enough - or pt not enrolled for other reasons Of note : prognostic information was obtained for all the genomic aberrations A. Lopez-Chavez, JCO:33, 2015 Recruitement for rare aberrations far too slow with only 2 hospitals!

15 Phase III Studies in the Era of Personalised Cancer Medicine

16 Types of phase III clinical trials in the genomic era A) The genomic aberration is not so rare Does the biomarker have strong credential? YES Biomarker (BM) stratified design Assess BM BM+ BM- Treatment A Treatment B Treatment A Treatment B NO All comers design R Treatment A Treatment B with retrospective subgroup analysis according to BM

17 Types of phase III clinical trials in the genomic era B) The genomic aberration is rare (< 10%) Does the biomarker have strong credential? YES NO Biomarker enriched design Assess BM BM+ BM- Adaptive trial Treatment A Treatment B Off study