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Clinical Trial Design Considerations for Therapeutic Cancer Vaccines


... and components (adjuvants, cytokines, costimulatory ... In evaluating adjuvant, pool over antigens. Trial is sized as two-arm trial, not 4-arm trial ... – PowerPoint PPT presentation

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Title: Clinical Trial Design Considerations for Therapeutic Cancer Vaccines

Clinical Trial Design Considerations for
Therapeutic Cancer Vaccines
  • Richard Simon, D.Sc.
  • Chief, Biometric Research Branch, NCI
  • http//

Why focus on early clinical development?
  • Principles for phase III trials apply equally to
  • Randomized control group
  • Endpoint reflecting clinical benefit
  • Differences between vaccines and chemotherapeutic
    agents have important implications for early
    clinical trials

Objectives of Phase II Trials
  • Determine whether regimen is sufficiently
    promising to warrant phase III trial
  • Determine whether regimen has biologic activity
    that is likely to translate into patient benefit
  • It may be better just to do a phase III trial
    than to base decision on unreliable phase II
  • Optimize regimen
  • Generally using non-clinical endpoint
  • Identify the right population of patients to
    include in phase III trial

Differences Between Therapeutic Vaccines and
Chemotherapeutic Agents
  • Many vaccines are incapable of causing immediate
    serious or life threatening toxicity at doses
    feasible to manufacture
  • Phase I dose escalation starting from low dose
    may not be necessary
  • May not wish to escalate to DLT
  • Appropriate target population may not have
    measurable tumor
  • Vaccination strategies often combine multiple
    agents and components (adjuvants, cytokines,
    costimulatory molecules)

Vaccine Safety
  • Tumor vaccines are often based on DNA constructs,
    viral vectors and cytokines that have been
    determined as safe from previous clinical trials
  • Peptide vaccines are generally safe so long as
    the cytokine adjuvants are used in combinations
    and doses previously determined to be safe

Immunogenicity Studies
  • Feasibility issues limit the maximum doses of
    certain vaccines. The dose selected may be based
    on pre-clinical findings or on practical
  • Dose ranging to find the minimal active dose will
    generally require many more than the conventional
    3-6 patients per dose level.

Finding The Minimum Active Dose
  • Finding an optimum biological dose is generally
    not feasible or necessary
  • Requires large sample sizes
  • Little evidence that immunogenicity decreases
    after maximum
  • Uncertain relevance of immunogenicity measures

Phase II Endpoint
  • Immunologic
  • Inappropriate to expect it to be validated
  • Appropriate for optimizing components of vaccine
  • Is a phase II trial of patients with measurable
    disease really promising if only immunologic
    effects are seen?
  • Tumor shrinkage
  • Appropriate if the target population for the
    phase III trial are patients with measurable
  • Time till tumor progression
  • Requires control group for interpretation

Phase II Endpoints and Need for Randomization
  • Single arm evaluation adequate
  • Objective response of vaccine alone
  • Immunologic change pre vs post treatment of
    vaccine alone
  • Randomization needed
  • Objective response of standard therapy plus
  • Objective response comparing different vaccine
  • Progression free survival of vaccine alone or
    vaccine plus standard therapy

Optimal Single Arm Two-Stage Design of Tumor
  • To distinguish 5 (p0) response rate from 25
    (p1) response rate with 10 false positive and
    false negative error rates
  • Accrue 9 patients. Stop if no responses
  • If at least 1 response in first 9, continue
    accrual to 24 patients total
  • Accept treatment if at least 3/24 responses
  • For regimens with 5 true response rate, the
    probability of stopping after 9 patients is 63

Optimal Single Arm Two-Stage Phase II Designs
  • Can be used with binary immunologic endpoints but
    its better not to reduce immunologic assay
    results to a binary response value
  • Analyze change in endpoint directly

Randomized Phase II Designs
  • N vaccine regimens
  • No non-vaccine control arm
  • Objective is to select a regimen for further
  • If one regimen is superior, want to select it
  • If regimens are equivalent, indifferent about
    which regimen is selected

Randomized Phase II Multiple-Arm Designs Using
Immunological Response
  • Randomized selection design to select most
    promising regimen for further evaluation. 90
    probability of selecting best regimen if its
    mean response is at least ? standard deviations
    above the next best regimen

Number of Patients Per Arm for Randomized
Selection Design PCS 90
Time to Progression Endpoint
  • Vaccines may slow progression or delay recurrence
    in patients with lower tumor burden
  • It is difficult to reliably evaluate time to
    progression endpoint without a randomized control

Randomized Phase II Design Comparing Vaccine
Regimen to Control
  • ? 0.10 type 1 error rate
  • Endpoint PFS
  • Detect large treatment effect
  • E.g. Power 0.8 for detecting 40 reduction in 12
    month median time to recurrence with ?0.10
    requires 44 patients per arm with all patients
    followed to progression
  • Two vaccine regimens can share one control group
    in a 3 arm randomized trial

Randomized Factorial Phase II Design Using PFS
  • vaccine antigen A
  • vaccine antigen B
  • vaccine A adjuvant
  • vaccine B adjuvant
  • In comparing antigens, pool over adjuvant
  • In evaluating adjuvant, pool over antigens
  • Trial is sized as two-arm trial, not 4-arm trial

Seamless Phase II/III Trial (a)
  • Randomized comparison of vaccine based regimen to
    non-vaccine based control
  • Size trial as phase III study with survival
  • Perform interim analysis using PFS when
    approximately half the patients are accrued
  • If results are not significant for PFS, terminate
  • If results are significant for PFS, continue
    accrual and do analysis of survival at end of
  • Seek accelerated approval of vaccine regimen
    based on significant PFS result

Seamless Phase II/III Trial (b)
  • Randomized comparison of 2 vaccine based regimens
    to non-vaccine based control
  • Size trial as phase III study with PFS endpoint
  • Perform interim analysis using immunologic
  • select vaccine arm with most promising
    immunologic response data
  • Continue accrual as 2-arm phase III trial of the
    selected vaccine arm and the control arm
  • Do analysis of PFS at end of trial using .025
    level of significance

  • Dose ranging safety trials are often not
  • Dose ranging trials to establish an optimal dose
    are often not realistic

  • Optimization of vaccine regimen by comparing
    results of single arm studies using immunological
    response is problematic
  • Randomized screening studies can be used to
    efficiently optimize immunogenicity.
  • Efficiency depends on having low assay
  • Efficient regimen selection for further study is
    different than full evaluation of each regimen
    and may involve many fewer patients per regimen
    than is conventional.

  • Phase II studies of time to progression should
    have randomized controls.

  • Korn EL et al. Clinical trial designs for
    cytostatic agents Are new approaches needed? JCO
    19265-272, 2001
  • Korn EL et al. Clinical trial designs for
    cytostatic agents and agents directed at novel
    molecular targets. In Novel Anticancer Agents
    Strategies for Discovery and Clinical Testing
    (Buolamwini JK and Adjei AA), Academic Press
  • Rubinstein LV et al. Randomized phase 2 design
    issues and a proposal for phase 2 screening
    trials, JCO 237199-7206, 2005
  • Simon R et al. Randomized phase II clinical
    trials. Cancer Treatment Rep 691375-81, 1985
  • Simon R. Statistical designs for clinical trials
    of immunomodulating agents. In Immune Modulating
    Agents (Kresina TF), Dekker, 1998.
  • Simon RM et al. Clinical trial designs for the
    early clinical development of therapeutic cancer
    vaccines. JCO 291848-54, 2001.
  • Simon R. Clinical trial designs for therapeutic
    vaccine studies. In Handbook of Cancer Vaccines
    (Morse MA et al), Humana Press, 2004
  • Yao TJ et al. Optimal two-stage design for a
    series of pilot trials of new agents, Biometrics
    541183-89, 1998.