Design of Clinical Trials with Molecularly Targeted Therapies. Gilberto Schwartsmann

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1 Design of Clinical Trials with Molecularly Targeted Therapies Gilberto Schwartsmann

2 What are the basics of clinical trial design? Presented By Jordan Berlin at 2016 ASCO Annual Meeting

3 Advances in molecular biology Molecularly targeted agents (MTAs) against specific oncogenic drivers. MTAs differ from cytotoxics in toxicity profiles and availability of predictive biomarkers. Early trials are evolving to adapt to MTAs!

4 The lines have become blurred Presented By Jordan Berlin at 2016 ASCO Annual Meeting

5 Example 1

6 Background

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9 Dosing schedule and toxicities

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12 Phase II IIa: Pilot to evaluate efficacy (and safety) in selected patient populations, to define dose-response, type of patients, frequency of dosing, etc. IIb: Well controlled trials for efficacy (and safety) in specific disease, most rigorous demonstration of efficacy, pivotal trials.

13 Example 2

14 Rationale Presented By Hans-Joachim Schmoll at 2016 ASCO Annual Meeting

15 PAPAGEMO : Pazopanib vs. Pazopanib+ Gemcitabine in refractory soft tissue sarcoma:<br />A randomized phase II trial of the AIO Presented By Hans-Joachim Schmoll at 2016 ASCO Annual Meeting

16 PAPAGEMO - Trial design<br />Multicenter open-label prospective randomized phase II trial Presented By Hans-Joachim Schmoll at 2016 ASCO Annual Meeting

17 Endpoints Presented By Hans-Joachim Schmoll at 2016 ASCO Annual Meeting

18 Conclusion Presented By Hans-Joachim Schmoll at 2016 ASCO Annual Meeting

19 Example 3

20 Efficacy and safety of nivolumab monotherapy in metastatic urothelial cancer: Results from the phase I/II CheckMate 032 study Presented By Padmanee Sharma at 2016 ASCO Annual Meeting

21 Study design Presented By Padmanee Sharma at 2016 ASCO Annual Meeting

22 Eligibility criteria Presented By Padmanee Sharma at 2016 ASCO Annual Meeting

23 Study endpoints Presented By Padmanee Sharma at 2016 ASCO Annual Meeting

24 Treatment-related AEs Presented By Padmanee Sharma at 2016 ASCO Annual Meeting

25 Tumor burden reduction in target lesions Presented By Padmanee Sharma at 2016 ASCO Annual Meeting

26 Time to and duration of response Presented By Padmanee Sharma at 2016 ASCO Annual Meeting

27 Progression-free survival Presented By Padmanee Sharma at 2016 ASCO Annual Meeting

28 Overall survival Presented By Padmanee Sharma at 2016 ASCO Annual Meeting

29 Phase III IIIa: Conducted after efficacy is demonstrated, but prior to regulatory submission of NDA (New Drug Application). Includes patients for which the drug is intended; or special groups (p.e., renal failure). IIIb: Conducted after regulatory submission of NDA, but prior to approval. Complete or supplement earlier trials, or directed to new type of trials (QoL, marketing).

30 Example 4

31 Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) - <br />CALGB (Alliance) Presented By Ghassan Abou-Alfa at 2016 ASCO Annual Meeting

32 CALGB Study Schema Presented By Ghassan Abou-Alfa at 2016 ASCO Annual Meeting

33 CALGB Study Objectives Presented By Ghassan Abou-Alfa at 2016 ASCO Annual Meeting

34 CALGB 80802: Overall Survival by Treatment Presented By Ghassan Abou-Alfa at 2016 ASCO Annual Meeting

35 CALGB 80802: Progression-Free Survival by Treatment Presented By Ghassan Abou-Alfa at 2016 ASCO Annual Meeting

36 Summary Presented By Ghassan Abou-Alfa at 2016 ASCO Annual Meeting

37 Overall Success at Phase II and III Presented By George Sledge at 2016 ASCO Annual Meeting

38 Low Success Rate of Drug Approvals! Likelihood of approval for drugs tested in phase I trials is 6.7%, the lowest of all diseases*! From , failure-to-success ratio of investigational agents for melanoma was 14:1, and only 10 of 177 agents for lung cancer were approved**. Drug development in oncology takes 1.5 years longer than in other diseases (slow recruitment, low PS and longer follow-up needed)***. *Hay, M. et al. Clinical development success rates for investigational drugs. Nat. Biotechnol. 32, (2014). **Pharmaceutical Research and Manufacturers of America. Researching Cancer Medicines: Setbacks and Stepping Stones, (2014). *** DiMasi, J. A. & Grabowski, H. G. Economics of new oncology drug development. J. Clin. Oncol. 25, (2007).

39 New Features in MTA Phase I trials New expedited approval to accelerate drug development requires efficacy in early phase trials! Molecular tumor profiling for matched therapy and testing of drug combinations! The shift towards multi-institutional trials and centralized management.

40 What Could Be Done to Improve Early Trials of MTAs? Safety is a key requirement Novel dose-escalation schemes? Improved patient selection? Pharmacokinetic/Pharmacodynamics?

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42 1997 Design 1 was a conventional design (similar to the commonly used modified Fibonacci method) using cohorts of 3-6 patients, with 40% dose-step increments and no intra-patient dose escalation. Designs 2-4 included only 1 patient per cohort until 1 patient experienced DLT or 2 patients experienced grade 2 toxic effects (during their first course of treatment for designs 2 and 3 or during any course of treatment for design 4). Designs 3 and 4 used 100% dose steps during this initial accelerated phase. After the initial accelerated phase, designs 2 through 4 resorted to standard cohorts of 3-6 patients, with 40% dose-step increments. Designs 2 through 4 used intra-patient dose escalation if the worst toxicity is grade 0 1 in the previous course for that patient. Conclusion: Accelerated titration (i.e., rapid intra-patient drug dose escalation) designs appear to effectively reduce the number of patients who are undertreated, speed the completion of phase I trials, and provide a substantial increase in the information obtained.

43 Methods: One hundred phase I studies were simulated by both standard and quantitative assessment phase I designs. We compared MTD, frequency of 0 leukopenia and study size in the studies simulated using the standard design with those in the studies simulated using the quantitative assessment design. Results: The median MTD determined from the 100 studies was nearly identical for the two designs: 100 and 95 mg/m2 per day for standard and quantitative assessment designs, respectively. However, the interstudy variation in the MTD was decreased in the quantitative assessment design. Moreover, the study size was significantly reduced (P<.0001), and the median percentage of patients treated at sub-toxic doses (no leukopenia) was significantly lower for the quantitative assessment design (44% versus 48%; P<.0001). Conclusion: Our results show clear evidence that a phase I study design using dose and toxicity data in a repetitive and quantitativemanner can identify the MTD with more accuracy than the standard design. 1993

44 Novel vs Classical Dose-Escalation The efficiency of novel dose-escalation designs was demonstrated in a study of 84 phase I trials published between 2000 and 2010*. Compared with traditional 3+3 strategy, newer designs explored a greater number of dose levels (median of 6 vs 8-10) and achieved > mean MTD-to-starting-dose ratio (ratios of 9 vs 22-30). *Le Tourneau, C., Gan, H. K., Razak, A. R. & Paoletti, X. Efficiency of new dose escalation designs in dose-finding phase I trials of molecularly targeted agents. PLoS ONE 7, e51039 (2012)

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46 Patient Selection In most cases, an MTA is active in a subgroup of patients who may be identified using predictive biomarkers. The selection of patients based on molecular profiling can be done by gene or protein expression or detecting gene alterations (p.e., mutation, amplification or translocation) in tumor tissue or DNA.

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49 LUX-Lung 6: Primary End Point PFS by Independent and Investigator Review PFS (probability) PFS by independent review Afatinib (n=242) Cis/Gem (n=122) Median, mo PFS in overall population HR (95% CI) P-value 47% 2% 0.28 ( ) P< Afatinib Cis/Gem 2% PFS (mo) No. at risk: Afatinib Cis/Gem PFS (probability) PFS by investigator review Afatinib (n=242) Cis/Gem (n=122) Median, mo PFS in overall population HR (95% CI) P-value 56% 4% 0.26 ( ) P< Afatinib Cis/Gem PFS (mo) No. at risk: Afatinib Cis/Gem PFS = progression-free survival; HR = hazard ratio. Wu et al. Lancet Oncol. 2014;15:

50 Recent Examples of Successful Use of Predictive Biomarkers in Phase I Phase I trials of crizotinib*, ceritinib** and alectinib*** in patients with EML4 ALK rearranged NSCLC Vemurafenib in patients with BRAF/V600Emutant melanoma**** The remarkable tumor responses in these patient subsets facilitated drug approval! * Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, (2010). ** Shaw, A. T. et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N. Engl. J. Med. 370, (2014). *** Seto, T. et al. CH (RO ) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1 2 study. Lancet Oncol. 14, (2013). **** Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, (2010).

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54 Limitations of Biomarkers Most cancers have multiple genetic aberrations and the sensitivity to an MTA is likely modulated by many factors. Identifying a reliable biomarker might be less feasible when an MTA interacts with several targets or pathways, as is the case with many tyrosine kinase inhibitors. Establishing a very strong scientific basis for the biomarker with preclinical validation is, therefore, a prerequisite to avoid negative trials.

55 Afatinib Is the First Irreversible ErbB Family Blocker F Cl Afatinib covalently binds and irreversibly blocks EGFR, HER2, and ErbB4 N N N Afatinib N O O N ErbB3 does not have a kinase domain and cannot be directly blocked by afatinib Afatinib prevents ligand-dependent ErbB3 phosphorylation in preclinical studies F O S N O Anti-phospho-immunoblotting has shown that afatinib prevents ligand (heregulin)- stimulated ErbB3 phosphorylation Cl N N N N O O S N Heregulin Afatinib (nm) Afatinib covalently bound O N O perbb3 Li et al. Oncogene. 2008;27:4702; Solca et al. J Pharmacol Exp Ther. 2012;343:

56 Inhibitory potency of afatinib, erlotinib, and gefitinib against ErbB family members in cell-free kinase assays and cell proliferation assays of various human lung cancer cell lines (nanomolar concentration causing 50 % inhibition (Solca et al. J Pharmacol Exp Ther, 2012; and Li et al. Oncogene, 2008) 56

57 Afatinib Is a Potent and Selective Inhibitor of EGFR, HER2, and ErbB4 Molecular potency and selectivity (IC 50 ) EGFR (nm) 0.5 HER2 (nm) 14 Afatinib selectively and potently blocks the ErbB family receptors EGFR, HER2, and ErbB4 ErbB4 (nm) 1 HGFR (nm) >10,000 VEGFR2 (nm) >100,000 Molecular selectivity Kinase panel 10 μm 0/50 PanLab 5 μm 3/62 CYP μm 0/6 Afatinib is highly selective and does not inhibit a range of other kinases significantly, even at 1000 times higher concentrations IC 50 = 50% inhibitory concentration; HGFR = hepatocyte growth factor receptor; VEGFR2 = vascular endothelial growth factor receptor 2. Li et al. Oncogene. 2008;27:4702; Solca et al. J Pharmacol Exp Ther. 2012;343:

58 Biomarkers Need Optimal Collection, Assay Performance, Reproducibility and Standardization! That s why a low percentage of MTAs were developed with biomarker-based patient selection. In phase I studies, predictive value of biomarkers are studied as exploratory objectives. Examples: tumor PD-L1 expression in a subset of patients in phase I trial of nivolumab or tumor genotyping for BRAF and NRAS mutations in phase I trial of MEK inhibitor trametinib.

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61 *Manji, A. et al. Evolution of clinical trial design in early drug development: systematic review of expansion cohort use in singleagent phase I cancer trials. J. Clin. Oncol. 31, (2013). **Bugano, D. et al. Impact of phase 1 expansion cohorts on probability of success in phase 2 and time-to-drugapproval: analysis of 385 new drugs in oncology [abstract 237]. Eur. J. Cancer 50, (2014). Anticancer Drug Development in 2016 Breakthrough therapy FDA designation to expedite drug development, obtaining early evidence of efficacy as a key component of phase I studies. Tumor-specific expansion cohorts in phase I trials to further characterize safety and tumor response at the recommended dose for Phase II increased. Response rate contributed to over 75% of accelerated FDA drug approvals from 2002 to For therapies with benefit across many tumor types, efficacy evaluation can lead to large phase I trials with multiple expansion cohorts.

62 Anticancer Drug Development in 2016 Phase I of immunotherapies with anti-pd-1 and anti-pd-l1 in tumor-type-specific cohorts to assess efficacy in various settings. Selected phase I trial centers and diseasespecific investigators to help enrolment in disease-based cohorts. The use of efficacy endpoints in phase I can lead to direct transition to phase III testing. Nivolumab and MEDI4736 are examples.

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64 Target Modulation as Endpoint For MTAs, target modulation and downstream molecular effects are more relevant surrogates of activity than toxicity*. Levels of protein expression in tumor tissue by IHC before and after treatment, serum proteins, peripheral blood mononuclear cells and imaging biomarkers are used. Circulating tumor cells and DNA will become essential as liquid biopsies!**. Also, PK PD and PK toxicity relationships are important, when drug concentration for maximal biological effects is known. *Postel-Vinay, S. et al. Clinical benefit in phase-i trials of novel molecularly targeted agents: does dose matter? Br. J. Cancer 100, (2009). **Diaz, L. A. Jr & Bardelli, A. Liquid biopsies: genotyping circulating tumor DNA. J. Clin. Oncol. 32, (2014).

65 Slide 17 Presented By Luis Diaz at 2016 ASCO Annual Meeting

66 Slide 22 Presented By Luis Diaz at 2016 ASCO Annual Meeting

67 Slide 23 Presented By Luis Diaz at 2016 ASCO Annual Meeting

68 Slide 27 Presented By Luis Diaz at 2016 ASCO Annual Meeting

69 Slide 36 Presented By Luis Diaz at 2016 ASCO Annual Meeting

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71 Slide 39 Presented By Luis Diaz at 2016 ASCO Annual Meeting

72 Slide 41 Presented By Luis Diaz at 2016 ASCO Annual Meeting

73 Slide 42 Presented By Luis Diaz at 2016 ASCO Annual Meeting

74 Precision Medicine Trials MTAs to target specific oncogenic drivers and advances in next-generation sequencing (NGS) to rapidly interrogate the genomic mutational profile of a tumor led to Precision Cancer Medicine*. This concept can be described as the delivery of patient-tailored therapy against actionable molecular targets in order to maximize antitumor activity while minimizing toxicity. *Meric-Bernstam, F. & Mills, G. B. Overcoming implementation challenges of personalized cancer therapy. Nat. Rev. Clin. Oncol. 9, (2012).

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76 Lancet Oncol. 15, (2014). Methods Breast cancer patients with accessible metastases for biopsy in 18 centers in France. Therapeutic targets decided on the basis of identified genomic alterations. Primary outcome to check the proportion of patients to whom a targeted therapy could be offered. Results 423 patients included and biopsy obtained from 407. Sequencing feasible in 67-70%. A targetable genomic alteration identified in 46%, most frequently in PIK3CA (25%), CCND1 (19%) and FGFR1 (13%). In 39% rare genomic alterations (<5% of the general population), such as AKT1 mutations, EGFR, MDM2, FGFR2, AKT2, IGF1R, and MET amplifications. Therapy could be personalized in 13% of patients. Of the 43 patients who were assessable and received targeted therapy, 9%) had objective response, and 21% had stable disease for more than 16 weeks. Grade 3 or higher adverse events related to biopsy in only 1% of cases.

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78 MTAs in Combination studies As most cancers are driven by multiple genes and pathways, most benefits will be derived from combinations of MTAs with other targeted therapy or standard chemotherapy. Thus, phase I trials of combination therapies are increasingly being conducted.

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80 Regulatory changes The development of a successful anticancer drug from first-in-human study to approval normally takes about 7 years! If an MTA has a well-defined mechanism based on proof-of-concept studies, unprecedented clinical responses with minimal toxicity in early clinical trials and strong predictive biomarker, the approval process is being accelerated*. *Sherman, R. E. et al. Expediting drug development the FDA s new breakthrough therapy designation. N. Engl. J. Med. 369, (2013).

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