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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
0
5
10
15
20
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
Can
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Poin
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CSP sPoC DDP FDP 3CP SDP
Sele
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Pro
of
of
Con
cep
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Develo
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ecis
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Poin
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Develo
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Ph
ase I
IIC
heckp
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issio
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Poin
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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
-100
-80
-60
-40
-20
0
20
40
60
-100
-80
-60
-40
-20
0
20
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?