Novel Targeted Drugs and Their Introduction to the Clinic Phil Bedard MD, FRCP(C) Division of Medical Oncology/Hematology Drug Development Program 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 High Rate of Failure in Oncology Drug Development Likelihood of success Cost of bringing a new cancer drug to clinical practice is >$1 Billion 20 15 11% 10 5% 5 0 CNS Arthritis Cardiovascular Oncology Metabolic Women’s Infectious Opthal- disease health Urology diseases mology All Kola Nat Rev Drug Discovery 2004 Even Successes Take Too Long! Identification of the HER-2 neu oncogene (Schechter et al.) Humanization of an anti HER-2 MoAb = Herceptin (Carter et al.) Anti-HER-2 MoAb inhibits neutransformed cells (Drebin et al.) 1984 1985 1986 1987 Correlation of HER-2/neu amplification and prognosis (Slamon et al.) Cloning of HER-2 (Semba et al., Coussens et al.) Phase II trial as monotherapy in MBC (Baselga et al.) 1992 1994 1996 1998 Pivotal phase III trial in MBC (Slamon et al.) 1999 Phase II trial in MBC, in combination with chemo (Pegram et al.) Herceptin -enhanced chemosensitivity: impressive synergy in pre-clinical models (Pietras et al.) 2005 NSABP B-31, NCCTG-N9831 and HERA trial results at ASCO Courtesy M. Piccart Phases of Clinical Trials sPoC DDP IND – Investigational New Drug Phase IIa FDP Phase IIb 3CP Life Cycle Management Phase III Phase IV SDP Submission Decision Point Clinical Trials Phase 1 Full Development Phase III Checkpoint Preclinical Phase Development Decision Point Candidate Selection Point CSP Candidate Profiling Phase Selected for Proof of Concept Discovery Phase Early Development Full Development Point Research NDA – New Drug Application Phases of Clinical Trials Length Phase Purpose Subjects Scope 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 Hundredsthousands 2-3 yrs IV New indications, QoL, surveillance Subjects with indications Hundredsthousands 1-5 yrs (per phase) 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 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 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 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 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? 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 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 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 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 Dose Escalation: 3+3 Design # of pts with DLT 0/3 1/3 1/3 + 0/3 1/3 + 1/3 1/3 + 2/3 1/3 + 3/3 2/3 3/3 Action Increase to next level Accrue 3 more pts at same dose level Increase to next dose level Stop: recommend previous dose level Stop: recommend previous dose level Stop: recommend previous dose level Stop: recommend previous dose level Stop: recommend previous dose level 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) Classical 3+3 Design MAD Dose DLT Recommended PhII dose (some call this MTD in US) 3 pts 3 pts 3 pts 3 pts 3 pts + 3 pts DLT 3 pts Pitfalls of Phase 1 Trials • Chronic toxicities usually cannot be assessed • Cumulative toxicities usually cannot be identified • Uncommon toxicities will be missed 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%) 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 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 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 PK: Time x Concentration Plot Serum concentration (mg/mL) AUC 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) 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 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 prespecified 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 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 antitumor activity in pre-clinical models? – Can the assay be performed from patient specimens collected in a multi-centre study? 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 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) Why do we need biomarkers? PreClinical Development Phase I Phase II Phase III Scarcity of drug discovery PreClinical Development Abundance of drug discovery Biomarker – Proof of mechanism (Pharmacodynamic Biomarkers) Phase II-III – Proof of principle (Predictive Biomarkers) Commercialization Adapted from Eli Lilly and Company 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 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 Oncology Drugs in Development Walker & Newell Nat Rev Drug Discovery 2009 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 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 Patient Selection for Phase II Trials • Selection of tumor types is straightforward when “responder” population identified in phase I trial Crizotinib (ALK inhibitor) Vemurafenib (BRAF inhibitor) GDC-0449 (Hedgehog inhibitor) BRAF V600 mutation Basal Cell Carcinoma 20 60 40 0 20 -20 0 -20 -40 -40 -60 -60 -80 -80 -100 -100 EML4-ALK fusion 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 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 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) Design Options • Single arm, 2 stage • Randomized, phase II 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) 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 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 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 Acknowledgements Many of the Slides are from Dr. Lillian Siu Case-Based Example BMS-936558: Nivolumab Topalian et al NEJM 2012 Adverse Events By Dose Level PD Biomarker: PD-1 Receptor Occupancy in T-Cells Predictive Biomarker: PD-L1 expression by IHC in tumor Bristol-Myers-Squibb has asked you to develop a phase II clinical trial to better understand the activity of BMS-936558 and explore its biomarker effects … To Think About . . . • What dose level would you choose? • Which tumor types? • Would you allow only PD-L1 +ve to enroll? • Considerations when setting up your screening PD-L1 assay • Single arm or randomized design? • Stratify for PD-L1 expression? • Do you want to include any additional correlative studies?