Novel Targeted Drugs and Their Introduction to the Clinic

Phil BedardMD, FRCP(C)

Division of Medical Oncology/HematologyDrug 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

Kola Nat Rev Drug Discovery 2004

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ArthritisCardio-vascular

CNSInfectiousdiseases

OncologyOpthal-mology

Metabolicdisease

Urology

Women’shealth

5%

11%

All

Likelihood of success Cost of bringing a new cancer drug to clinical practice is >$1 Billion

Cloning of HER-2 (Semba et al.,

Coussens et al.)

Anti-HER-2 MoAb inhibits neu-

transformed cells (Drebin et al.)

Phase II trial as monotherapy in MBC

(Baselga et al.)

Identification of the HER-2 neu oncogene

(Schechter et al.)

Humanization of an anti HER-2 MoAb = Herceptin (Carter et

al.)

Correlation of HER-2/neu

amplification and prognosis (Slamon et al.) Herceptin -enhanced

chemosensitivity: impressive synergy in

pre-clinical models (Pietras et al.)

NSABP B-31, NCCTG-N9831 and HERA trial results at ASCO

Phase II trial in MBC, in combination with chemo (Pegram et al.)

1984 1985 1986 1987 1994 1996 200519981992

Pivotal phase III trial in MBC

(Slamon et al.)

1999

Courtesy M. Piccart

Even Successes Take Too Long!

Phases of Clinical Trials

Phase IVPhase IIIPhase IIbPhase IIaClinical Trials

Phase 1Pre-

clinical Phase

Candidate Profiling

Phase

DiscoveryPhase

Life Cycle Management

FullDevelopment

Early Development

Research

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IND – Investigational New Drug NDA – New Drug Application

Phases of Clinical Trials

1-5 yrsHundreds-thousands

Subjects with indications

New indications,

QoL, surveillanceIV

2-3 yrsHundreds-thousands

Subjects with indications

Safety & efficacy

Basis for labeling,

new formulationsIII

1-2 yrsSeveral hundred

Subjects with indications

Short-term side

effects & efficacyII

6-12 mos20-80

Healthy volunteers or subj. w/ indications

Safety, ADME, bioactivity,

drug-drug interactionI

Length(per phase)

ScopeSubjectsPurposePhase

• 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

Sources of Phase I Drugs

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

• 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?

Fundamental Questions

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

• 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

Pre-clinical Toxicology

• “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

Patient Population

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

Key Concepts: DLT

# of pts with DLT Action

0/3 Increase to next level 1/3 Accrue 3 more pts at same dose level 1/3 + 0/3 Increase to next dose level 1/3 + 1/3 Stop: recommend previous dose level 1/3 + 2/3 Stop: recommend previous dose level 1/3 + 3/3 Stop: recommend previous dose level 2/3 Stop: recommend previous dose level 3/3 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)

Dose Escalation: 3+3 Design

3 pts

Dose

3 pts

3 pts

3 pts

3 pts

3 ptsRecommended PhII dose(some call this MTD in US)

DLT 3 pts+ DLT

MAD

Classical 3+3 Design

• Chronic toxicities usually cannot be assessed

• Cumulative toxicities usually cannot be identified

• Uncommon toxicities will be missed

Pitfalls of Phase 1 Trials

• 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%)

Phase I Trials Risk/Benefit Ratio

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

AUC

Serum concentration(mg/mL)

PK: Time x Concentration Plot

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

• 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

Key Concepts

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?

• 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

Challenges with Development of Molecularly Targeted Agents

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)

Adapted from Eli Lilly and Company

Pre-Clinical Develop-ment

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

Why do we need biomarkers?

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

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EML4-ALK fusion BRAF V600 mutation Basal Cell Carcinoma

Crizotinib(ALK inhibitor)

Vemurafenib(BRAF inhibitor)

GDC-0449(Hedgehog inhibitor)

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

• 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

Summary

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?