Phase II Clinical Trials

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Phase II Clinical Trials
2008 AACR/ASCO Workshop

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

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Question

• What percentage of the concepts submitted by you
  are Phase 2 trials or the Phase 2 trial is its
  main component?
• 20
• 40
• 50
• 60

3
Interactive Answer
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Overview

1. Objectives Concept Development
2. Design
3. Endpoints Outcomes Measures
4. Sample Size Calculation
5. Examples

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Objectives

1. To define antitumor activity.
2. To demonstrate safety.
3. To gain new insights into the pharmacokinetics,
   pharmacodynamics and metabolism of therapeutic
   agents.
4. To evaluate biologic correlates which may predict
   response or resistance to treatment and/or
   toxicity.

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Concept Development

• The What
• The Who
• The How

Simple and fun
Moderate and exciting
Hard and frustrating
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The What

• What is your hypothesis?
• Is it sound?
• Do a background check
• What has been written?
• What is being tested at present?
• Review your preclinical and phase I data well
• Draw an illustration
• Sell it to your spouse
• Sell it to a colleage

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The Who

• Who do you want your concept tested in?
• Define your population
• Define the standard of care
• Define historical outcomes with standard of care
• Decide on dose and schedule
• Prior treatment allowed
• Discuss with your mentor and with an experienced
  faculty member

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The How

• How will you do it?
• Come to Vail?
• Select your trial design
• Select your endpoints and outcome measures
• Select your sample size

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II. Study Designs

• Single Arm
• Two or more arms

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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
• Adaptive
• Multiple Outcomes

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Two-stage Design

• Main objective is to minimize the number of
  patients treated with ineffective regimens
• A very commonly used 2 stage design is the Simon,
  which minimizes sample size based on a
  pre-specified response rate and an ? and ? error
  rates.
• Optimal minimizes the of pts treated if the
  regimen is ineffective
• Minimax minimizes the whole sample size
• Recist Response CRPRSD is generally utilized.

Simon et al, Cont Clin Trials, 1989
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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 gt x
  number of responses are observed (p1)

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One-stage Design

• When time-dependent endpoints are considered
• 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 are
  often impractical.
• Early stopping rules are usually incorporated for
  obvious lack of efficacy or unacceptable toxicity.

Biometrics,1982
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One-stage Design

• Fleming is the most commonly utilized one-stage
  design.
• You need to have a good grip on historical
  control data.
• Mick Design Compare time to treatment failure or
  progression on the new regimen TTP2 with the
  individual patients failure time or TTP1
  observed with their prior regimen.
• If the TTP2/TTP1 ratio is greater than 1.33, the
  regimen is considered effective and worthy of
  further study.

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

• Patients are randomized to receive one of two (or
  more) regimens differing by dose level, schedule,
  or specific agent.
• It is not powered to make inferential comparisons
  between the treatment arms.
• Pick the winner approach.
• If both arms incorporate two-stage designs, you
  would have four specific decision points for
  determining efficacy.

Simon et al, Cancer Treat Rep,1985 Liu et al,
Control Clin Trials,1999
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Randomized Discontinuation

• It incorporates time-dependent endpoints with
  disease response.
• Stable disease patients are randomized to
  continuation with the agent or placebo (the
  discontinuation)
• Patients subsequently showing progression on
  placebo are then retreated with the agent to
  determine if stability can be regained.
• This design is most appropriate in diseases where
  tumor growth rates are slow.

Kopec, J Clin Epidemiol, 1993 Rosner (J Clin
Oncol, 2002
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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
Population Stage IIIB and IV 2 or more prior chemotherapy regimens 18 years of age ECOG PS 01 Asymptomatic brain metastases allowed
Sample Size N330 accrued, 98 randomized
Endpoints 1st endpoint SD or response after 2 courses of treatment post randomization 2nd endpoint PFS, RR, Survival
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.
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Endpoint Outcome Measures

• RECIST/WHO Response Rate
• CR PR
• CR PR SD
• Time to Failure / Survival
• Progression-Free Rate
• Disease-Free Rate

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Endpoint Outcome Measures

• Biological Endpoints
• Safety Adverse Events
• Multiple Endpoints
• QOL

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Correlative Studies

• Important, hypothesis-generating, exploratory
  studies
• However, dont do them because everyone else
  is..
• 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)

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Sample Size Calculation

• Prior determination of the sample size that is
  needed to show an important difference is
  essential.
• 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
• 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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(No Transcript)
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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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My Examples

• Phase 2 Study of Capecitabine and Docetaxel in
  Previously Untreated advanced Non-Small Cell Lung
  Cancer Patients (OSU-0356). NCI R21 CA108157
• Phase 2 trial of Sequentially Administered CPT-11
  and Mitomycin C in Patients with Advanced
  Esophageal and Stomach Cancer (OSU-0151). NCI R21
  CA92956
• Phase 1/2 Study of Etanercept and Gemcitabine in
  Patients with Advanced Stage and
  Chemotherapy-Naïve Pancreatic Adenocarcinoma
  (OSU-0041). NCI R21 CA101360

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Phase 2 Study of Capecitabine/Docetaxel in
Previously Untreated Advanced NSCLC Patients

• Capecitabine last conversion step is mediated by
  thymidine phosphorylase (TF), which is
  preferentially expressed in tumors
• Preclinical studies suggest that
  paclitaxel/docetaxel increase expression of TF
• A previous trial in pretreated NSCLC patients
  (n31) showed a 26 RR, 25 26- wks PFS, MS 9.1
  m, 1-year survival 37

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How would you design it?

1. Simon 2-stage Minimax
2. Fleming 1-stage
3. Randomized Phase 2
4. Mick Design
5. Randomized Discontinuation

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Interactive Answer
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Our Design

• Endpoint RECIST objective response (PR/CR)
• Simon Two-stage minimax
• lt30 no interest, ? 50 interest
• If 8 or more patients show responses in the first
  28, 11 additional patients are treated for a
  total of 39. If ?15 show responses, the regimen
  will not be recommended for further study. If
  ?16 patients show responses in the 39, the
  regimen will be studied further.

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Potential Alternatives?

1. Fleming 1-stage (yes, if time dependent endpoints
   were chosen)
2. Randomized Phase 2 (yes, if multi-institutional)
3. Mick Design (no, first line treatment)
4. Randomized Discontinuation (no for aggressive
   malignancy, more appropriate to test durability
   of efficacy or significance of stability)

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Phase 2 trial of Sequentially Administered CPT-11
and Mitomycin C in Patients with Advanced
Esophageal and Stomach Cancer

• Irinotecan (CPT-11) is a topoisomerase 1 (Topo 1)
  interactive agent.
• Decreased levels of Topo 1 is a mechanism of
  resistance
• Preclinical studies showed that mitomycin C
  upregulate activity of Topo 1, thus modulation of
  Topo 1 activity by MMC may result in increased
  response to CPT-11
• Mitomycin C has many side effects, so doctors
  hate it.
• A phase I trial established 6 mg/m2 on day 1,
  followed by CPT-11 125mg/m2 days 2 and 9, every
  28 days as safe, and showed 5 responses in
  refractory esophageal cancer patients

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How would you design it?

1. Simon 2-stage Minimax
2. Fleming 1-stage
3. Randomized Phase 2
4. 2-stage Bayesian
5. Randomized Discontinuation

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Interactive Answer
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Our Design
Two Arms, randomized parallel Simon
Mini-Max MMC 6 mg/m2 on day 1 and irinotecan
125 mg/m2 on days 2 and 9, with cycles repeated
every 4 weeks. MMC, 3 mg/m2 on days 1 and day
8, prior to irinotecan 125 mg/m2 on days 2 and 9,
every 4 weeks. A cap in the dose of MMC of 36
mg/m2 was enforced.
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Potential Alternatives?

1. Simon 2-stage Minimax (yes, but historical
   controls shaky)
2. Fleming 1-stage (no since other interventions may
   follow, time dependent end-points not reliable).
3. Randomized Phase 2
4. 2-stage Bayesian (yes, if your stats support is
   active on this)
5. Randomized Discontinuation (no, as per B)

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Phase 1/2 Study of Etanercept and Gemcitabine in
Patients with Advanced Stage and
Chemotherapy-Naïve Pancreatic Adenocarcinoma

• Pancreatic cancer patients are often cacquectic,
  have very poor quality of life and a dismal
  survival
• Gemcitabine is standard of care in metastatic
  pancreatic cancer mainly due to quality of life
  improvements
• Tumor necrosis factor have been shown to play a
  role in caquexia and to stimulate cancer growth
  through NF-kB
• Etanercept is a decoy receptor of TNF and you
  wonder if adding it to gemcitabine can result in
  improvements in quality of life and disease
  progression.

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How would you design it?

1. Simon 2-stage Minimax
2. Fleming 1-stage
3. Randomized Phase 2
4. 2-stage Bayesian
5. Randomized Discontinuation

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Interactive Answer
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Our Design

• Single Stage Fleming
• Progression-Free Rate at 6 Months (gt7/25).
• Median Survival and Survival at 6 and 12 months.
• Assessment of Clinical Benefit Response
• Pain Intensity (MPAC)
• Analgesic Use
• Weight Change
• ECOG PS
• Quality of Life
• Correlation of cytokines and Clinical Benefit
  Response.

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Potential Alternatives?

1. Simon 2-stage Minimax (no, time dependent
   endpoints and QOL being considered)
2. Fleming 1-stage
3. Randomized Phase 2 (yes, if both arms fleming and
   multi-institutional)
4. 2-stage Bayesian (yes, if your stats support is
   active on this)
5. Randomized Discontinuation (too aggressive)

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Conclusions

• Phase II trials are exploratory studies and
  rarely are definitive
• Efficient to exclude inactive therapies
• Results must be interpreted cautiously, in the
  context of the availability of other therapies
• Estimate clinical activity and provide further
  safety information important in the go/no go
  decision
• Require confirmation in phase III trials