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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

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Novel Targeted Drugs and Their Introduction to the Clinic

Phil Bedard


Division of Medical Oncology/Hematology

Drug Development Program

learning objectives
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
High Rate of Failure in Oncology Drug Development

Likelihood of success

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


















Kola Nat Rev Drug Discovery 2004

even successes take too long
Even Successes Take Too Long!

Humanization of an anti HER-2 MoAb = Herceptin (Carter et al.)

Identification of the HER-2 neu oncogene (Schechter et al.)

Pivotal phase III trial in MBC (Slamon et al.)

Anti-HER-2 MoAb inhibits neu-transformed cells (Drebin et al.)

Phase II trial as monotherapy in MBC (Baselga et al.)











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

Correlation of HER-2/neu amplification and prognosis (Slamon 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

phases of clinical trials
Phases of Clinical Trials






  • Life Cycle
  • Management









Clinical Trials

Phase 1

Phase IIa

Phase IIb

Phase III

Phase IV








Development Point

Selected for

Proof of Concept


Decision Point


Selection Point


Decision Point

Phase III


IND – Investigational New Drug

NDA – New Drug Application

phases of clinical trials1






(per phase)


Safety, ADME, bioactivity,

drug-drug interaction

Healthy volunteers or subj. w/ indications


6-12 mos


Short-term side

effects & efficacy

Subjects with indications

Several hundred

1-2 yrs


Safety & efficacy

Basis for labeling,

new formulations

Subjects with indications


2-3 yrs


New indications,

QoL, surveillance

Subjects with indications


1-5 yrs

Phases of Clinical Trials

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
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
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
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
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
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

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)


Recommended PhII dose(some call this MTD in US)


3 pts


3 pts

3 pts

3 pts


3 pts

3 pts

3 pts

Classical 3+3 Design




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
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
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

Serum concentration



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

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

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?

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?

Pre-Clinical Develop-ment

Phase I

Phase II

Phase III

Scarcity of drug discovery

Pre-Clinical Develop-ment

Biomarker – Proof of mechanism (Pharmacodynamic Biomarkers)

Phase II-III – Proof of principle (Predictive Biomarkers)


Abundance of drug discovery

Adapted from Eli Lilly and Company

primary objective of a phase ii trial
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
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
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
Patient Selection for Phase II Trials
  • Selection of tumor types is straightforward when “responder” population identified in phase I trial


(Hedgehog inhibitor)


(ALK inhibitor)


(BRAF inhibitor)

Basal Cell Carcinoma

EML4-ALK fusion

BRAF V600 mutation

patient selection for phase ii trials1
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
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
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
Design Options
  • Single arm, 2 stage
  • Randomized, phase II
single arm 2 stage design simon mini max
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
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
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

BMS-936558: Nivolumab

Topalian et al NEJM 2012


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?