Transcript Why Randomize in Phase II?

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
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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
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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
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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
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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?