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Novel Targeted Drugs and Their Introduction to the Clinic

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Presentation on theme: "Novel Targeted Drugs and Their Introduction to the Clinic"— Presentation transcript:

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% Arthritis CNS Oncology Metabolic disease Women’s health All Cardio- vascular Infectious diseases Opthal- mology Urology Kola Nat Rev Drug Discovery 2004 3

4 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 neu-transformed cells (Drebin et al.) Pivotal phase III trial in MBC (Slamon et al.) Phase II trial as monotherapy in MBC (Baselga et al.) 1984 1985 1986 1987 1992 1994 1996 1998 1999 2005 Correlation of HER-2/neu amplification and prognosis (Slamon et al.) Phase II trial in MBC, in combination with chemo (Pegram 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 CSP sPoC DDP FDP 3CP SDP Development Point Full Proof of Concept Selected for Selection Point Candidate Development Decision Point Decision Point Submission Checkpoint Phase III IND – Investigational New Drug NDA – New Drug Application

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

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

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

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 Biomarker – Proof of mechanism (Pharmacodynamic Biomarkers) Phase II-III – Proof of principle (Predictive Biomarkers) Commercialization Scarcity of drug discovery 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
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 Crizotinib (ALK inhibitor) Vemurafenib (BRAF inhibitor) GDC-0449 (Hedgehog inhibitor) EML4-ALK fusion BRAF V600 mutation Basal Cell Carcinoma

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 Acknowledgements Many of the Slides are from Dr. Lillian Siu

47 Case-Based Example

48 BMS : Nivolumab Topalian et al NEJM 2012


50 Adverse Events By Dose Level



53 PD Biomarker: PD-1 Receptor Occupancy in T-Cells

54 Predictive Biomarker:
PD-L1 expression by IHC in tumor

55 Bristol-Myers-Squibb has asked you to develop a phase II clinical trial to better understand the activity of BMS and explore its biomarker effects …

56 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?

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