Phase II Trials

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Phase II Trials
2008 AACR/ASCO Workshop

• Miguel Villalona-Calero, MD., FACP
• The Ohio State University

2
Overview

• Objectives
• Design
• Endpoints Outcomes Measures
• Sample Size Calculation
• Examples

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Objectives

• To define the spectrum of antitumor activity of
  new agents, which have completed phase I
  evaluation, in selected solid tumors and
  hematologic malignancies.
• To demonstrate that the dose and schedule chosen
  for these new agents during phase I trials can be
  given safely.
• To evaluate the antitumor activity of
  combinations of anticancer agents or between the
  agents and other treatment modalities.
• To gain new insights into the pharmacokinetics,
  pharmacodynamics and metabolism of a specific
  therapeutic agent including its mechanism of
  action and/or toxicity.
• To evaluate biologic correlates utilizing blood,
  bone marrow, tumor, normal tissue, or research
  imaging modalities, which may predict response or
  resistance to treatment and/or toxicity, or may
  allow for dosing adjustments of the drug below
  the maximal tolerated dose, while achieving the
  intended antitumor effect.

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Objectives

• To define the spectrum of antitumor activity of
  new agents, which have completed phase I
  evaluation, in selected solid tumors and
  hematologic malignancies.
• To demonstrate that the dose and schedule chosen
  for these new agents during phase I trials can be
  given safely.
• To evaluate the antitumor activity of
  combinations of anticancer agents or between the
  agents and other treatment modalities.
• To gain new insights into the pharmacokinetics,
  pharmacodynamics and metabolism of a specific
  therapeutic agent including its mechanism of
  action and/or toxicity.
• To evaluate biologic correlates utilizing blood,
  bone marrow, tumor, normal tissue, or research
  imaging modalities, which may predict response or
  resistance to treatment and/or toxicity, or may
  allow for dosing adjustments of the drug below
  the maximal tolerated dose, while achieving the
  intended antitumor effect.

5
Objectives

• To define the spectrum of antitumor activity of
  new agents, which have completed phase I
  evaluation, in selected solid tumors and
  hematologic malignancies.
• To demonstrate that the dose and schedule chosen
  for these new agents during phase I trials can be
  given safely.
• To evaluate the antitumor activity of
  combinations of anticancer agents or between the
  agents and other treatment modalities.
• To gain new insights into the pharmacokinetics,
  pharmacodynamics and metabolism of a specific
  therapeutic agent including its mechanism of
  action and/or toxicity.
• To evaluate biologic correlates utilizing blood,
  bone marrow, tumor, normal tissue, or research
  imaging modalities, which may predict response or
  resistance to treatment and/or toxicity, or may
  allow for dosing adjustments of the drug below
  the maximal tolerated dose, while achieving the
  intended antitumor effect.

6
Objectives

• To define the spectrum of antitumor activity of
  new agents, which have completed phase I
  evaluation, in selected solid tumors and
  hematologic malignancies.
• To demonstrate that the dose and schedule chosen
  for these new agents during phase I trials can be
  given safely.
• To evaluate the antitumor activity of
  combinations of anticancer agents or between the
  agents and other treatment modalities.
• To gain new insights into the pharmacokinetics,
  pharmacodynamics and metabolism of a specific
  therapeutic agent including its mechanism of
  action and/or toxicity.
• To evaluate biologic correlates utilizing blood,
  bone marrow, tumor, normal tissue, or research
  imaging modalities, which may predict response or
  resistance to treatment and/or toxicity, or may
  allow for dosing adjustments of the drug below
  the maximal tolerated dose, while achieving the
  intended antitumor effect.

7
Objectives

• To define the spectrum of antitumor activity of
  new agents, which have completed phase I
  evaluation, in selected solid tumors and
  hematologic malignancies.
• To demonstrate that the dose and schedule chosen
  for these new agents during phase I trials can be
  given safely.
• To evaluate the antitumor activity of
  combinations of anticancer agents or between the
  agents and other treatment modalities.
• To gain new insights into the pharmacokinetics,
  pharmacodynamics and metabolism of a specific
  therapeutic agent including its mechanism of
  action and/or toxicity.
• To evaluate biologic correlates utilizing blood,
  bone marrow, tumor, normal tissue, or research
  imaging modalities, which may predict response or
  resistance to treatment and/or toxicity, or may
  allow for dosing adjustments of the drug below
  the maximal tolerated dose, while achieving the
  intended antitumor effect.

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How do we go from Phase I to Phase II?

• Review your preclinical and Phase I data
• Decide on dose and schedule
• What tumor(s) to study
• Select your trial design
• Select your endpoint(s)/outcome measure(s)
• Determine the sample size

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II. Study Designs

• Frequentist
• Gehan 2-Stage
• Simon 2-Stage Optimal
• Simon 2-Stage Minimax
• Fleming 1-stage
• Gehan-Simon 3-Stage
• Randomized Phase 2
• Constant Arc-Sine
• Randomized Discontinuation

• Bayesian
• Thall-Simon-Estey
• 1-Stage Bayesian
• 2-Stage Bayesian
• Tan Machin
• Heitjan

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Two-Stage Design

• The two-stage Phase 2 design to minimize the
  number of patients treated with ineffective
  regimens was initially proposed in Gehans1
  Rule of 14 design with 14 patients accrued in
  the first stage followed by 25 patients overall
  if the first stage goal is met.
• While this design allows early termination for
  ineffectual regimens, it fails to address
  probabilities associated with the decision to
  recommend that the Phase 2 regimen be considered
  for subsequent randomized Phase 3 studies.
  Regimens with a low probability for "success"
  were recommended for subsequent large-scale
  randomized clinical trials.

1Gehan et al, J Chron Dis, 1961
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Two-stage Design

• A decision-based two-stage design was refined by
  Simon2 whose procedure minimizes the expected
  sample size given specified response rates and ?
  and ? error rates.
• While a large number of possible trials can be
  generated using his procedure, the investigator
  usually selects either the optimal solution
  which minimizes the number of patients treated if
  the regimen is truly ineffective or the minimax
  solution which minimizes the overall sample size.
  The majority of Phase 2 trials are based on
  Simons design.
• Recist Response CRPRSD is generally utilized.

2Simon et al, Cont Clin Trials, 1989
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One-stage Design

• Phase 2 trials often address time-dependent
  endpoints of progression-free or DFS translated
  to dichotomous alternatives at a given time point
  
• e.g., the proportion of patients free of
  progression at one year following initiation of
  treatment.
• Given the time period from initiation of
  treatment to the endpoint, two-stage designs
  often prove impractical and a Fleming3 one-stage
  design is used.
• Since a larger number of patients will be treated
  prior to a decision to embark on additional
  studies and due to limited information on the
  toxicity profile of a new agent, they frequently
  incorporate sequential early stopping rules for
  adverse events.

3Biometrics,1982
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One-stage Design

• Korn et al4 proposed single-arm Phase 2 designs
  with comparisons with historical control data.
  The lack of well-characterized historical data
  with which to make comparisons often limits ones
  confidence that the historical data present a
  reasonable baseline from which to detect
  therapeutic improvements.
• Mick et al5 developed a novel Phase 2 design for
  failure-time endpoints by comparing time to
  treatment failure or progression on the new
  regimen TTP2 with the individual patients
  failure time or TTP1 observed with their prior
  regimen of treatment. If the new agent
  demonstrated a TTP2/TTP1 ratio of greater than
  1.33, it would be considered effective and worthy
  of further study.

4J Clin Oncol, 2001 5Cont Clin Trials, 2000
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Randomized Phase II Trials

• Randomized Phase 2 trials provide a mechanism to
  determine which of two regimens should undergo
  further study in the Phase 3 setting.6 These
  trials usually randomize patients between one of
  two regimens differing by dose level, schedule,
  or specific agent.
• The randomized Phase 2 trial is not to be viewed
  as an inexpensive Phase 3 trial since the study
  is not powered for inferential comparisons
  between the treatment arms.7 With both arms
  incorporating two-stage designs, however, the
  randomized Phase 2 trial offers four specific
  decision points for determining regimen efficacy.
  

6Simon et al, Cancer Treat Rep,1985 7Liu et al,
Control Clin Trials,1999
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Randomized Phase II Trials

• The randomized discontinuation design,8 recently
  proposed for selection of antineoplastic agents,9
  incorporates a time-dependent endpoint such as
  time to progression with disease response.
  Patients with stable disease are randomized to
  either continuation with the agent or a placebo
  (the discontinuation). Patients subsequently
  showing progression on placebo are then retreated
  with the agent to determine if disease stability
  can be regained.
• This design allows one to demonstrate the
  effectiveness of a cytostatic agent by
  distinguishing between disease stability due to
  the agent versus due to a naturally slow tumor
  growth rate. This design is most appropriate in
  diseases where tumor growth rates are slow,
  whereas with an aggressive/rapidly progressive
  malignancy, few patients would quality for
  randomization, limiting therefore the designs
  effectiveness.

8Kopec, J Clin Epidemiol, 1993 9Rosner (J Clin
Oncol, 2002
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Bayesian

• In single and two-stage designs, Bayesian designs
  allow the investigator to determine the
  probability that the true response rate exceeds a
  pre-specified target response or to determine the
  response interval that has a 95 chance of
  containing the true response rate.
• Using prior probabilities based on the
  investigators prior beliefs about the new
  regimen, the study design re-computes posterior
  probabilities based on observed data.
• While many Bayesian designs use continuous
  monitoring, studies may be adapted to a two-stage
  model.

Staquet and Sylvester Biomedicine, 1977 Cancer
Treat Rep,1980) Thall (Biometrics, 1994, Stat
Med, 1995, Stat Med,1998), Tan and Machin (Stat
Med, 2002), Heitjan (Stat Med,1997), Mayo and
Gajewski (Cont Clin Trials, 2004).
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Possible Endpoint Outcome Measures

• RECIST/WHO Response Rate
• CR PR
• CR PR SD
• Time to Failure / Survival
• Progression-Free Rate
• Disease-Free Rate
• Biological Endpoints
• Safety Adverse Events
• Multiple Endpoints
• QOL

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Sample Size Calculation

• Prior determination of the sample size that is
  needed to show an important difference is
  essential in a well designed Phase II study.
• Two errors can be made in a test of a hypothesis
  
• rejecting the null hypothesis when it is true
  (Type I Error, ?) (false-positive)
• not rejecting the null hypothesis when it is
  false (Type II, ?) (false-negative).
• Another important consideration is Power the
  probability of rejecting the null hypothesis when
  it is false, or of concluding the alternative
  hypothesis when it is true.

From Basic Clinical Biostatistics
Dawson-Saunders and Trapp eds.
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Sample Size Calculation

• Before going to your statistician
• Single versus two proportions
• What is the desired level of significance of the
  null hypothesis (?0)?
• What chance should there be of detecting an
  actual difference (what power) associated with
  the alternative hypothesis (?1) is desired?
• How large should the difference between the
  proportions (?1- ?0) be in order for it to have
  clinical importance?
• What is a good estimate of the standard deviation
  in the population? The value of the null
  hypothesis , determines in most cases the
  standard deviation

From Basic Clinical Biostatistics
Dawson-Saunders and Trapp eds.
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• Given this complexity of design and outcome
  alternatives, the selection of a trial design
  requires close collaboration between the study
  investigator and clinical biostatisticians to
  clearly define study objectives, to select
  appropriate endpoints, to select a trial design,
  and to compute the required number of patients to
  be enrolled.
• We should individualize the trial design and
  outcome measures to the particular agent (or
  combination) and disease or subset of disease to
  be evaluated.

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Examples
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Phase II Trial of Gefitinib in Patients With
Advanced NSCLC Efficacy
P0.26
P0.51

• Median overall survival in the 250 mg/d and 500
  mg/d gefitinib groupswere 7 months and 6 months,
  respectively (P0.40)
• Projected 1-year survival rates were 27 and 24,
  respectively (P0.54)

Kris et al. JAMA. 20032902149.
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Single-Agent Nexavar in 3rd line NSCLC
Double-blind Phase II
Second Randomized patients first evaluated for
progression after another 8 weeks
B
First Patients evaluated for SD at 8 weeks
ECOG 2501, Joan Schiller, MD.
ASCO Abstr 8014.