Novel Targeted Drugs and Their Introduction to the Clinic

1. Novel Targeted Drugs and Their Introduction to the Clinic Phil Bedard MD, FRCP(C) Division of Medical Oncology/Hematology Drug Development Program

2. Learning Objectives • Introduction to how new drugs are tested in the clinic • Phases of clinical trials • Objectives of Phase I and Phase II testing • Types of Study Designs • Role of biomarkers to accelerate new cancer drug development • Challenges of applying lab-developed biomarkers to clinical testing of new cancer drugs

3. High Rate of Failure in Oncology Drug Development Likelihood of success Cost of bringing a new cancer drug to clinical practice is >$1 Billion 11% 5% CNS Arthritis Oncology Metabolic disease Women’s health All Cardio- vascular Infectious diseases Opthal- mology Urology Kola Nat Rev Drug Discovery 2004

4. Even Successes Take Too Long! Humanization of an anti HER-2 MoAb = Herceptin (Carter et al.) Identification of the HER-2 neu oncogene (Schechter et al.) Pivotal phase III trial in MBC (Slamon et al.) Anti-HER-2 MoAb inhibits neu-transformed cells (Drebin et al.) Phase II trial as monotherapy in MBC (Baselga et al.) 1984 1985 1986 1987 1992 1994 1996 1998 2005 1999 Phase II trial in MBC, in combination with chemo (Pegram et al.) Correlation of HER-2/neu amplification and prognosis (Slamon et al.) NSABP B-31, NCCTG-N9831 and HERA trial results at ASCO Herceptin-enhanced chemosensitivity: impressive synergy in pre-clinical models (Pietras et al.) Cloning of HER-2 (Semba et al., Coussens et al.) Courtesy M. Piccart

5. Phases of Clinical Trials Research Early Development Full Development • Life Cycle • Management Discovery Phase Candidate Profiling Phase Pre- clinical Phase Clinical Trials Phase 1 Phase IIa Phase IIb Phase III Phase IV FDP DDP 3CP SDP sPoC CSP Full Development Point Selected for Proof of Concept Development Decision Point Candidate Selection Point Submission Decision Point Phase III Checkpoint IND – Investigational New Drug NDA – New Drug Application

6. Phase Purpose Subjects Scope Length (per phase) I Safety, ADME, bioactivity, drug-drug interaction Healthy volunteers or subj. w/ indications 20-80 6-12 mos II Short-term side effects & efficacy Subjects with indications Several hundred 1-2 yrs III Safety & efficacy Basis for labeling, new formulations Subjects with indications Hundreds-thousands 2-3 yrs IV New indications, QoL, surveillance Subjects with indications Hundreds-thousands 1-5 yrs Phases of Clinical Trials

7. Sources of Phase I Drugs • Pharmaceutical industries / biotechnology companies (big and small) • Big pharmas: often select “preferred sites” for pipeline development, often intense “test burden”, secure and well funded • Small pharmas/Biotech: 1 or 2 drugs as their “life-line”, more amenable to data sharing, less secure • Academic agencies (NCI US, EORTC, etc) • In-house development • Challenges: • Getting support for investigator-initiated trial ideas • Getting different agents from different companies for a single trial

8. Definitions of Phase I Trial • First evaluation of a new cancer therapy in humans • First-in-human, first-in-class single agent • First-in-human, non first-in-class single agent • Combination of novel agents • Combination novel agent and approved agent • Combination of approved agents • Combination of novel agent and radiation therapy Eligible patients usually have refractory solid tumors or hematological cancers

9. Prerequisites for Phase I • Unmet clinical need • Biological plausibility (target validation) • Expectation of benefit (preclinical activity) • Reasonable expectation of safety (preclinical toxicology) • Basis for selection of starting dose

10. Objectives of Phase I Trial • Primary objective: • Identify dose-limiting toxicities (DLTs) and the recommended phase II dose (RPTD) • Secondary objectives: • Describe the toxicity profile of the new therapy in the schedule under evaluation • Assess pharmacokinetics (PK) • Assess pharmacodynamic effects (PD) in tumor and/or surrogate tissues • Document any preliminary evidence of objective antitumor activity

11. Fundamental Questions • At what dose do you start? • What type of patients? • How many patients per dose level? • How quickly do you escalate? • What are the endpoints?

12. Key Principles of Phase I Trials • Start with a safe starting dose • Minimize # of pts treated at sub-toxic doses • Escalate dose rapidly in the absence of toxicity • Escalate dose slowly in the presence of toxicity • Expand patient cohort at maximum tolerated dose

13. Pre-clinical Toxicology • Typically a rodent (mouse or rat) and non-rodent (dog or non-human primate) species • Reality of animal organ specific toxicities – very few predict for human toxicity • Myelosuppression and gastrointestinal toxicity more predictable • Hepatic and renal toxicities – large false positive • Toxicologic parameters: • LD10 – lethal dose in 10% of animals • TDL (toxic dose low) – lowest dose that causes any toxicity in animals • NOAEL – no observed adverse effect level

15. Patient Population • “Conventional” eligibility criteria- examples: • Advanced solid tumors unresponsive to standard therapies or for which there is no known effective treatment • Performance status (e.g. ECOG 0 or 1) • Adequate organ functions (e.g. ANC, platelets, Creatinine, AST/ALT, bilirubin) • Specification about prior therapy allowed • Specification about time interval between prior therapy and initiation of study treatment • No serious uncontrolled medical disorder or active infection

16. Key Concepts: DLT • Dose-limiting toxicity (DLT): • Toxicity that is considered unacceptable (due to severity and/or irreversibility) and limits further dose escalation • Specified using standardized grading criteria, e.g. Common Terminology Criteria for Adverse Event (CTCAE v4.0 release in May 2009) • DLT is defined in advance prior to beginning the trial and is protocol-specific • Typically defined based on toxicity seen in the first cycle

17. Dose Escalation: 3+3 Design Many phase I trials accrue additional patients at the RPTD to obtain more safety, PK, PD data (but this expansion cohort does not equal to a phase II trial)

18. Recommended PhII dose(some call this MTD in US) DLT 3 pts + 3 pts 3 pts 3 pts Dose 3 pts 3 pts 3 pts Classical 3+3 Design MAD DLT

19. Pitfalls of Phase 1 Trials • Chronic toxicities usually cannot be assessed • Cumulative toxicities usually cannot be identified • Uncommon toxicities will be missed

20. Phase I Trials Risk/Benefit Ratio • Response Rate 4-6% (first in human) • Higher for combination studies involved approved drug (~15%) • Majority of responses occur at 75-125% of recommended phase II dose • Response is a surrogate endpoint • Direct patient benefit is difficult to measure • Risk of toxic death is low (<0.5%)

21. Definition of a Biomarker • “A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacological responses to a therapeutic intervention” • NIH Working Group, 2011 • “A molecular, cellular, tissue, or process-based alteration that provides indication of current, or more importantly, future behavior of a cancer.” • Hayes et al JNCI, 1996

22. Biomarkers in Clinical Trials • Based on pre-clinical studies • Phase I: • Pharmacokinetics • Proof-of-mechanism • Establish optimal biological dose in some trials (especially if little or no toxicity expected) • Molecular enrichment • Proof-of-concept – anti-tumor activity

23. Pharmacokinetic Biomarkers (PK) • “What the body does to the drug” • Absorption, distribution, metabolism, and excretion • PK parameters – provide information about the drug and/or its metabolites • Cmax (peak concentration) • AUC (exposure) • T1/2 (half-life) • Clearance (elimination) • Requires serial sampling to characterize fully • ie. Pre-dose, 30m, 1h, 2h, 4h, 6h, 8h, 24h • Cycle 1 Day 1 and repeat when drug is expected to have reached steady state serum concentrations

24. Serum concentration (mg/mL) AUC PK: Time x Concentration Plot

25. Pharmacodynamic Biomarkers (PD) • “What the drug does to the body (or tumor)” • Provide therapeutic information about the effect of a therapeutic intervention on the patient and/or tumor • Tumor PD biomarkers • Phosphoprotein (IHC) • Gene expression (RT-PCR, microarray) • Cell surface markers (Flow cytometry) • Functional imaging • FDG-PET, FLT-PET, DCE MRI, etc • Surrogate Normal Tissue PD biomarkers • Hair follicles • Skin biopsies • Peripheral blood mononuclear cells (PBMCs)

26. Pharmacodynamic Endpoints • Phase I PD biomarkers • Requires assessment before and during treatment • Should be correlated with PK parameters • Proof of mechanism • Is a new drug hitting its target? • Establish optimal biological dose • Especially if little of no toxicity expected (monoclonal antibodies) • Often more practical to perform in expansion cohort at recommended phase II dose

27. Key Concepts • Optimal biological dose (OBD): • Dose associated with a pre-specified desired effect on a biomarker • Examples: • Dose at which > XX% of patients have inhibition of a key target in tumor/surrogate tissues • Dose at which > XX% of patients achieve a pre-specified immunologic parameter • Challenge with defining OBD is that the “desired effect on a biomarker” is generally not known or validated before initiation of the phase I trial

28. Pharmacodynamic Endpoints • Key Questions for tissue based PD markers in Phase I trials? • Is the assay robust? • Does it accurately measure the target of interest? • Is the cutoff established? • What level of inhibition is required for anti-tumor activity in pre-clinical models? • Can the assay be performed from patient specimens collected in a multi-centre study?

29. Challenges with Development of Molecularly Targeted Agents • General requirement for long-term administration: pharmacology and formulation critical • Difficulty in determining the optimal dose in phase I: MTD versus OBD • Absent or low-level tumor regression as single agents: problematic for making go no-go decisions • Need for large randomized trials to definitively assess clinical benefit: need to maximize chance of success in phase III

30. Correlative Studies – Logistical Issues • Eligibility • Restrict to marker positive? • Prevalence, cost, turnaround time, archival vs fresh tumor material • Informed Consent • Optional vs mandatory collection • Procurement • Experience of interventional radiologist • Localization, adequate specimen size, complications • Sampling timepoints • Handling • Logistics and speed, standardized procedure (snap freezing, formalin, fixation)

31. Why do we need biomarkers? Pre-Clinical Develop-ment Phase I Phase II Phase III Scarcity of drug discovery Pre-Clinical Develop-ment Biomarker – Proof of mechanism (Pharmacodynamic Biomarkers) Phase II-III – Proof of principle (Predictive Biomarkers) Commercialization Abundance of drug discovery Adapted from Eli Lilly and Company

32. Primary Objective of a Phase II Trial • Provide an estimate of the clinical “activity” of a new treatment approach: • Examples: • To determine the objective response rate (CR + PR) of drug A in patients with advanced X cancer • To determine the 6 month progression-free survival (PFS) rate of the combination AB in patients with recurrent or metastatic Y cancer

33. Why are Phase II trials important? • Drug development is a series of “go/no go” decisions • We have lots of drugs (and fewer targets) to test • Most new cancer drugs don’t make it • Screening out ineffective agents is a critical component of drug development "For many are called, but few are chosen." Matthew 22:14 “Sometimes you have to kiss a few frogs to find your prince”Grimm

34. Oncology Drugs in Development Walker & Newell Nat Rev Drug Discovery 2009

35. Key Questions for Phase II Trial • What patient population should be targeted? • What are the appropriate endpoints of efficacy? • ORR, DCR, TTP, PFS • What is the appropriate trial design? • Single arm • Randomized

36. Biomarkers in Phase II Trials • Phase II: • Predictive markers (difficult to distinguish between sensitivity to treatment vs tumor biology [i.e. prognostic markers], as all patients receive study drug if single-arm trials) • Pharmacodynamic markers in a more homogeneous population • Limited phamacokinetic sampling • Molecular enrichment if responder population previously identified

37. Patient Selection for Phase II Trials • Selection of tumor types is straightforward when “responder” population identified in phase I trial GDC-0449 (Hedgehog inhibitor) Crizotinib (ALK inhibitor) Vemurafenib (BRAF inhibitor) Basal Cell Carcinoma EML4-ALK fusion BRAF V600 mutation

38. Patient Selection for Phase II Trials • When responder population is not identified in phase I trial • Tumor types in which objective response/prolonged stable disease seen in a small number of pts in phase I • Tumor types in which preclinical or laboratory data suggest relevance of specific target inhibition • Enrichment based on presence of “unvalidated” biomarker • “Big four” – breast, lung, colorectal, prostate • Unmet need and/or orphan tumor types

39. Essential Elements of Phase II Trial • Endpoints: • Measurable tumor mass reduction • Progression-based endpoints: TTP, PFS • Serologic response: PSA, CA125 • Survival • Disease “stabilization” • Correlative studies

40. Correlative Studies • Important, hypothesis-generating, exploratory studies • But do not definitively establish a predictive marker for clinical use • BUT during course of study: • Validation of targets and assays may occur • New markers and pathways may be identified • Consider collecting specimens to evaluate only if activity signals are seen in stage I (for 2-stage designs)

41. Design Options • Single arm, 2 stage • Randomized, phase II

42. Single-Arm, 2-Stage Design(Simon, Mini-max,..) • Treat ~12-18 patients at 1st stage • Determine the “response rate” • Less than that projected to indicate activity (p0): STOP! • Sufficiently great to indicate activity: CONTINUE • At the end of 2nd stage, declare drug / intervention worthy of further evaluation if > x number of “responses” are observed (p1)

43. Problems with Single Arm Phase II • Phase II trials are designed to screen out ineffective therapies and to identify promising ones • ‘Positive’ non-randomized phase II trials are not highly predictive of success in a phase III trial • Only 13 of 100 “positive” phase II trials subsequently evaluated in phase III RCT over 10 year period • Berthold et al JCO 2009

44. Why Randomize in Phase II? • General advantages of randomization • Balances known and unknown prognostic factors among treatment groups • Allows valid inferences concerning differential treatment effects • Standardization of patient selection • Uniformity of outcome criteria

45. Summary • Early phase clinical trials are critical for the evaluation of new therapies – translation from the lab to the clinic • Patient safety/well-being is the most important principle in phase I • Biomarker studies are essential to evaluate new cancer drugs • Phase I/II trials are increasingly complex and require good team science

46. Many of the Slides are from Dr. Lillian Siu Acknowledgements

47. Case-Based Example

48. BMS-936558: Nivolumab Topalian et al NEJM 2012

50. Adverse Events By Dose Level