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Design and Analysis of Phase I Clinical Trials in Cancer Therapy


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Title: Design and Analysis of Phase I Clinical Trials in Cancer Therapy

Design and Analysis of Phase I Clinical Trials in
Cancer Therapy
Alex A. AdjeiKatherine Anne Gioia Chair in
Cancer Medicine Roswell Park Cancer
Institute Buffalo, NY
  • First evaluation of a new cancer therapy in
  • First-in-human single agent study
  • Combination of novel agents
  • Combination novel agent and approved agent
  • Combination of approved standard agents ? (pilot
    study ?)
  • Combination of novel agent and radiation therapy
  • Eligible patients usually have refractory solid
    tumors of any type

Phase I 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

Phase I Patient Population
  • Agent-specific eligibility criteria - examples
  • Restriction to certain patient populations must
    have strong scientific rationale
  • Specific organ functions
  • For example cardiac function restrictions (e.g.
    QTc 45, etc) if preclinical
    data or prior clinical data of similar agents
    suggest cardiac risks
  • For example no recent (6-12 months) history of
    acute MI/unstable angina, cerebrovascular events,
    venous thromboembolism no uncontrolled
    hypertension no significant proteinuria, for
    antiangiogenic agents
  • Prohibited medications if significant risk of
    interaction with study drug

A New Agent Merits Clinical Study if
  • It is biologically plausible that the agent may
    have activity in cancer (target seems valid and
    agent affects it)
  • There is reason to expect benefit for patients
    (preclinical or other evidence of efficacy)
  • There is reasonable expectation of safety
  • Sufficient data on which to base starting dose
  • Hirschfeld S, 2004

The 3 Basic Tenets Of Phase I Studies
  • Define a recommended dose
  • SAFELY (minimum of serious toxicities)
  • EFFICIENTLY (smallest possible of pts)
  • RELIABLY (high statistical confidence)

Phase I Study Basic Design Principles
  • 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 recommended phase II dose

Phase I Trials Fundamental Questions
  • At what dose do you start?
  • What are the endpoints?
  • How many patients per cohort?
  • How quickly do you escalate?

At what dose do you start ?
Preclinical 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
  • Toxicologic parameters
  • LD10 lethal dose in 10 of animals
  • TDL (toxic dose low) lowest dose that causes
    any toxicity in animals

Phase I Trials Starting Dose
  • 1/10th of the LD10 in rodents,
  • or
  • 1/3rd of the minimal toxic dose in large animals
  • Expressed as mg/m2
  • These have historically been safe doses

Freireich EJ, et al, Cancer Chemother Rep
50219-244, 1966
What are the endpoints / objectives ?
Phase I Study Endpoints
  • Dose, toxicity, pharmacology (efficacy ? )
  • Classical goals
  • Identify dose-limiting toxicities (DLTs)
  • Identify the maximally tolerated dose (MTD)
  • Assess pharmacokinetics (drug metabolism and
  • Evaluate target modulation

Defining Toxicities NCI Common Toxicity
  • Grade 1 mild
  • Grade 2 moderate
  • Grade 3 severe
  • Grade 4 life-threatening
  • Grade 5 fatal

Dose-Limiting Toxicities (DLT)
  • Toxicities that, due to their severity or
    duration, are considered unacceptable, and limit
    further dose escalation
  • Defined in advance of beginning trial
  • Classically based on cycle 1 toxicity
  • Examples
  • ANC
  • ANC
  • PLT
  • Grade 3 or greater non-hematologic toxicity
  • Inability to re-treat patient within 2 wks of
    scheduled treatment

Definition of DLT is Dynamic
  • Examples DLTs in 2008
  • Diarrhea grade 3 in spite of adequate
    antidiarrheal therapy (loperamide)
  • Nausea and vomiting grade 3 in spite of
    adequate anti-emetic prophylaxis and therapy
    (steroids, 5HT3 antagonists)
  • Hypertension grade 3 in spite of adequate
    anti-hypertensive therapy
  • Inability to take at least 90 of drug doses in a
    cycle (continuous oral meds)
  • Grade 2 chronic unremitting toxicity

Maximally Tolerated Dose (MTD)
  • Inconsistently defined as either
  • Dose at which ? 33 of pts experience
    unacceptable toxicity (DLT in ? 2 of 3 or ? 2 of
  • OR
  • 1 dose level below that
  • MTD level _at_ DLT (in Europe or Japan)
  • MTD level below DLT (in US)
  • 6-10 pts treated at the recommended Phase II dose
    (MTD or 1 dose level below)

Recap Trans-AtlanticDifferences in Terminology
  • Important to note that
  • Maximum tolerated dose (MTD)
  • Usually means recommended dose in US
  • Usually means dose level above recommended dose
    in Europe and some other jurisdictions

How many patients per cohort?
Patients per Cohort Guiding Principles
  • Minimum needed to provide adequate toxicity
  • Classically 3 patients per cohort
  • In some designs 1 patient per cohort until
    toxicity seen
  • If correlative studies are a major aim, may
    increase up to 6 patients per cohort

Phase I Standard 3 3 Design
Eisenhauer et al.
How quickly do you escalate?
Phase I Trial Design Dose Escalation
  • Escalation in decreasing steps (Hansen HH et
    al. Cancer Res. 1975)
  • Attributed to a merchant from Pisa in the 13th
    century (Leonardo Bonacci, 1170-1240 aka
  • Outlined a number of problems including how many
    pairs of rabbits can be produced from a single
    pair under specified conditions? (1, 1, 2, 3, 5,
    8, 13, 21, 34, 55, 89, 144..) in a book, Liber

Phase I Trials Dose Escalation
The Modified Fibonacci Schedule
Cohort Dose Escalation
Problems and Pitfalls
Phase I Study Assumptions
  • The higher the dose, the greater the likelihood
    of efficacy
  • Dose-related acute toxicity is regarded as a
    surrogate for efficacy
  • The highest safe dose is the dose most likely to
    be efficacious

Dose-response Efficacy and Toxicity
Modified Fibonacci Dose Escalation
  • Problems
  • Requires many patients
  • Takes a long time
  • May expose a substantial proportion of patients
    to low, ineffective doses

Classic Phase I Trials Design Limitations
  • Wide confidence intervals
  • Patients treated at ineffective doses in first
  • High risk of severe toxicities at late cohorts

Classic Phase I Trials Design Limitations
  • Chronic toxicities usually cannot be assessed
  • Cumulative toxicities usually cannot be
  • Uncommon toxicities will be missed

Phase I Studies and Infrequent Toxicities
Probability of overlooking a toxicity
POT(p) (1-p)n n sample size, p
true toxicity rate
Alternate Designs
  • Starting dose
  • Number of patients per dose level
  • Method/rapidity of dose escalation

Selection of Starting Dose for Phase I Trials
Retrospective analysis of 21 trials using
modified Fibonacci dose escalation
Unsafe defined as reaching MTD in ? 3 dose
levels Eisenhauer et al JCO (18), 2000
Intra-patient dose escalation
  • Treat patients at dose level 1
  • Dose level 2 is well tolerated and patients at
    dose level 1 have no toxicities
  • Patients at level 1 are escalated to level 2
  • Makes evaluation of chronic toxicities difficult
  • The proverbial 1 responder at dose level 1

Phase I Trial DesignAccelerated Titrated Design
  • First proposed by Simon et al (J Natl Cancer Inst
  • Several variations exist
  • usual is doubling dose in single-patient cohorts
    till Grade 2 toxicity
  • then revert to standard 33 design using a 40
    dose escalation
  • intrapatient dose escalation allowed in some
  • More rapid initial escalation

Accelerated Titrated Design
Accelerated Titrated Design Phase I Study of
Lonafarnib (SCH66336)
Adjei AA et al, Cancer Research, 2000
Phase I Trial DesignModified Continual
Assessment Method (MCRM Model-based)
  • Bayesian method
  • Pre-study probabilities based on preclinical or
    clinical data of similar agents
  • At each dose level, add clinical data to better
    estimate the probability of MTD being reached
  • Fixed dose levels, so that increments of
    escalation are still conservative

Modified Continual Assessment Method (MCRM
  • Example Pre-set dose levels of 10, 20, 40, 80,
    160, 250, 400
  • If after each dose level, the statistical model
    predicts a MTD higher than the next pre-set dose
    level, then dose escalation is allowed to the
    next pre-set dose level
  • Advantages
  • Allows more dose levels to be evaluated with a
    smaller number of patients
  • More patients treated at or closer to
    therapeutic dose
  • Disadvantages
  • Does not save time, not easily implemented if
    without access to biostatistician support

Phase I Trial DesignDose Escalation with
Overdose Control (EWOC Model-based)
  • Bayesian method
  • After each cohort of patients, the posterior
    distribution is updated with DLT data to obtain
    ?d (probability of DLT at dose d). The
    recommended dose is the one with the highest
    posterior probability of DLT in the ideal
    dosing category
  • The overdose control mandates that any dose that
    has 25 chance of being in the over-dosing or
    excessive over-dosing categories, or 5
    chance of being in the excess-overdosing
    category, is not considered for dosing

Estimated MTD Based on Bayesian Logistic Method
(2-parameter evaluation with over-dose
EXAMPLE of Probability of DLTs (Bayesian design)
Phase I trial design Bayesian EWOC model
exampleScenario 0/3 DLTs
  • Posterior summaries for probabilities of DLT (in
  • __________________________________________________
  • Dose 0-0.16 0.16-0.33 0.33-0.6 0.6-1
    Median Overdose
  • mg Under- Targeted Over- Excessive DLT
    rate Control
  • /day dosing Toxicity dosing toxicity
  • __________________________________________________
  • 2.5 95.7 3.3 0.5 0.4
    0.0 ok
  • 5 91.1 5.5 3.1 0.4
    0.2 ok
  • 10 82.9 9.1 6.7 1.3
    1.9 no3
  • 17.5 62.5 17.7 12.5 7.2
    8.8 no2,3
  • 25 40.0 21.2 19.3 19.5
    22.3 no1-3
  • 35 15.6 19.7 20.4 44.3
    53.7 no1-3
  • 45 9.9 12.5 19.9 57.7
    73.0 no1-3
  • 60 5.6 10.9 12.0 71.5
    86.5 no1-3
  • 75 3.2 7.7 12.7 76.4
    92.8 no1-3
  • 100 2.4 3.3 13.3 80.9
    96.6 no1-3
  • __________________________________________________
  • 1 Escalation to this dose not possible, overdose
    control criterion
  • (P(overdosing or excessive tox)25) violated
  • 0/3
  • No first cycle DLTs
  • Bayesian model supports dose escalation in cohort
    2 (100 dose increment)

Phase I trial design Bayesian EWOC model
exampleScenario 1/4 DLTs
  • Posterior summaries for probabilities of DLT (in
  • __________________________________________________
  • Dose 0-0.16 0.16-0.33 0.33-0.6 0.6-1
    Median Overdose
  • mg Under- Targeted Over- Excessive DLT
    rate Control
  • /day dosing Toxicity dosing toxicity
  • __________________________________________________
  • 2.5 48.1 28.4 16.4 7.1
    16.5 no2
  • 5 30.5 31.5 27.5 10.5
    26.4 no1,2
  • 10 16.5 23.7 37.3 22.4
    38.3 no1-3
  • 17.5 8.8 14.7 41.6 34.9
    50.3 no1-3
  • 25 6.1 9.9 37.6 46.4
    58.3 no1-3
  • 35 5.6 7.7 29.6 57.1
    65.6 no1-3
  • 45 3.7 7.6 24.5 64.1
    69.6 no1-3
  • 60 3.3 6.5 18.9 71.2
    75.1 no1-3
  • 75 2.4 6.1 15.3 76.1
    78.1 no1-3
  • 100 2.4 4.9 13.6 79.1
    82.3 no1-3
  • __________________________________________________
  • 1 Escalation to this dose not possible, overdose
    control criterion
  • 1/4
  • First cycle DLT in first cohort
  • Bayesian model does not support dose escalation
    in cohort 2

Challenges to developing novel non-classical
cytotoxic 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

Phase I Trial Design Non-Cytotoxic Agents
  • MTD may not be the goal of Phase I since
    specificity of effect may be lost at MTD
  • Pharmacologic effect may not equal biologic
  • Goal identify optimal biologically effective
    dose (OBED)
  • Paradox requires early development and
    integration of (usually unvalidated) measures of
    biologic effect into Phase I

Do we need correlative studies ?
  • Conventional cytotoxic drugs have led to
    predictable effects on proliferating tissues
    (neutropenia, mucositis, diarrhea), thus enabling
    dose selection and confirming mechanisms of
  • Targeted biological agents may or may not have
    predictable effects on normal tissues and often
    enter the clinic needing evidence/proof of
    mechanisms in patients

Do we need correlative studies ?
  • Therefore, biological correlative studies may be
    used to derive the best dose and schedule of an
    agent, and
  • To determine whether the drug is inducing the
    intended biological effect in the patient, and
  • To predict clinical benefit, although this
    generally requires testing in large randomized

Alternative Endpoints
  • Minimum blood levels/AUC or other PK measure
  • Inhibition of target
  • In normal tissue
  • In tumor tissue
  • Need enough preclinical evidence to suggest that
    the above are reasonable endpoints with
    sufficient clinical promise
  • Must also pay attention to toxicity

Phase I Trial Design Non-Cytotoxic Agents -
  • Pre-clinically define target drug exposure
    Matrix Metalloproteinase Inhibitors
  • Define pharmacodynamic endpoint Bortezomib (70
    of 26S proteasome inhibition in PBMCs)
  • Use functional imaging as endpoint Vatalanib
  • Use cumulative toxicities CI-1040 MEK
    Inhibitor, 800mg TID intolerable after 3 cycles
    of therapy
  • Problem If drug works, youre a genius. If it
    doesnt, youre a goat

Vatalanib (PTK/ZK) VEGF Receptor Tyrosine
Kinase Inhibitor
Adapted from Dvorak H. J Clin Oncol.
PTK/ZK Induced Significant Reduction in Tumor
Blood Flow in Metastatic Colorectal Cancer by
Reduction in tumor blood flow through liver
metastases secondary to colorectal cancer at day
2 is significantly correlated with improved early
clinical outcome
Thomas AL, et al. Semin Oncol. 20033032-38. Morg
an B, et al. J Clin Oncol. 2003213955-3964.
Using DCE-MRI to Establish the Optimal
Therapeutic Dose for Vatalanib
Morgan B, et al. J Clin Oncol. 2003213955-3964.
The Conundrum of Optimal Biologic Dose Phase
PTK787 1250 mg QD
Phase I Trials of Agent Combinations
  • Initial dose-finding component often needed if
    you are planning a new combination for a phase II
  • Patients for dose-finding phase
  • Advanced solid tumors (all comers)
  • Advantage fast accrual
  • Disadvantage may not be representative of your
    patient population of interest
  • Specific patient population (e.g. same as phase
    II cohort)
  • Advantage population of interest, and early
    glimpse at antitumor activity in disease of
  • Disadvantage slow down accrual especially if
    rare/uncommon tumors

Phase I Trials of Agent Combinations
  • Dose escalation
  • New drug A Standard combination BC
  • Ideally keep standard combo doses and escalate
    the new drug (e.g. 1/3, 2/3, full dose)
  • Need to provide rationale why add A to BC?
  • Need to think about overlapping toxicity in your
    definition of DLT
  • Do you need PK assessment to determine if A, B
    and C interact with each other?

How are Phase I Studies Designed Now ?
  • 31 targeted agents representative of most common
  • Reports (papers or abstracts) of completed single
    agent phase I trials in non-hematologic
  • 57 phase I reports identified
  • Parulekar and Eisenhauer JNCI July 2004

  • Parulekar and Eisenhauer JNCI July 2004

Results Reason for Halting Dose Escalation
Parulekar and Eisenhauer JNCI July 2004
Basis for Recommending Phase II Dose
Parulekar and Eisenhauer JNCI July 2004
Secondary Information to Support Dose
Other includes clinical effects, results other
trials, convenience, etc.
Laboratory and Imaging Studies
Parulekar and Eisenhauer JNCI July 2004
Summary ReviewPhase I Trials Targeted Agents
  • Toxicity
  • Most common reason to halt escalation and primary
    basis for dose recommendation (35/50 trials)
  • PK (Blood levels)
  • Second most common basis for dose recommendation
    (9/50 trials)
  • Laboratory studies
  • May provide information to support dose

Parulekar and Eisenhauer JNCI July 2004
  • Phase I Study - Ethics

Phase I Study - Ethics
  • Patient benefit or antitumor activity is not a
    primary goal of the study, but therapeutic
    intent is an important feature
  • Desperate patients cannot make a truly informed
  • Historically low probability of response in Phase
    I trials
  • Majority of responses occur within 80-120 of
    the recommended phase II dose

Response Rates and Toxic Deaths in Phase I
Oncology Trials (Horstman et al, NEJM 352 2005)
Phase I Study - Ethics
  • Investigators have an inherent conflict of
  • Funding
  • Academic promotion
  • Publicity

Phase I Study Ethics Partial Solutions to the
  • Youre the patients physician 1st and a scientist
  • Scientific goals should never take precedence
    over the patients best interest
  • Only pts for whom no life-prolonging or curative
    therapy exists are eligible for Phase I trials
  • Informed consent is obtained from every patient
  • No new agent can hit the pharmacy shelves without
    going through Phase I clinical evaluation

Phase I Clinical Trials - Summary
  • Most drugs tend to follow the MTD/DLT paradigm
  • Alternative designs continue to be explored. Most
    times they are more complex.
  • Correlative studies are increasingly important in
    the comprehensive evaluation of new agents
  • Patient benefit/wellbeing trumps all the science
  • Being a good phase I trialist is not as simple as
    you may think