Clinical Trial Design Considerations for Therapeutic Cancer Vaccines

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Clinical Trial Design Considerations for
Therapeutic Cancer Vaccines

• Richard Simon, D.Sc.
• Chief, Biometric Research Branch, NCI
• http//linus.nci.nih.gov/brb

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Why focus on early clinical development?

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

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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
  trial
• Optimize regimen
• Generally using non-clinical endpoint
• Identify the right population of patients to
  include in phase III trial

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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)

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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

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Immunogenicity Studies

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

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Finding The Minimum Active Dose
Immunologic Response Rate N at Dose Probability of No Immunologic Response
20 11 .09
25 9 .08
30 7 .08
40 5 .08
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• 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

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Phase II Endpoint

• Immunologic
• Inappropriate to expect it to be validated
• Appropriate for optimizing components of vaccine
  regimen
• 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
  disease
• Time till tumor progression
• Requires control group for interpretation

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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
  vaccine
• Objective response comparing different vaccine
  regimens
• Progression free survival of vaccine alone or
  vaccine plus standard therapy

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Optimal Single Arm Two-Stage Design of Tumor
Shrinkage

• 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

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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

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Randomized Phase II Designs

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

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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

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Number of Patients Per Arm for Randomized
Selection DesignPCS 90
Number of treatment arms ? 0.5 ? 0.75 ? 1.0
2 13 6 4
3 21 9 6
4 24 11 6
5 27 13 7
6 30 14 8
7 31 14 8
8 35 15 9
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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
  group

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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

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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

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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
  endpoint
• Perform interim analysis using PFS when
  approximately half the patients are accrued
• If results are not significant for PFS, terminate
  accrual
• If results are significant for PFS, continue
  accrual and do analysis of survival at end of
  trial
• Seek accelerated approval of vaccine regimen
  based on significant PFS result

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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
  response
• 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

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Summary

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

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Summary

• 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
  variability.
• 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.

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Summary

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

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References

• 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
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  Strategies for Discovery and Clinical Testing
  (Buolamwini JK and Adjei AA), Academic Press
  2006.
• 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.