Clinical Trial Design Considerations for Therapeutic Cancer Vaccines

1. Clinical Trial Design Considerations for Therapeutic Cancer Vaccines Richard Simon, D.Sc. Chief, Biometric Research Branch, NCI http://linus.nci.nih.gov/brb

2. 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

3. 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

4. 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)

5. 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

6. 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.

7. Finding The Minimum Active Dose

8. 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

9. 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

10. 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

11. 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%

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

13. 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

14. 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 it’s mean response is at least  standard deviations above the next best regimen

15. Number of Patients Per Arm for Randomized Selection DesignPCS = 90%

16. 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

17. 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

18. 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

19. 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

20. 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

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

22. 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.

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

24. References • Korn EL et al. Clinical trial designs for cytostatic agents: Are new approaches needed? JCO 19:265-272, 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 2006. • Rubinstein LV et al. Randomized phase 2 design issues and a proposal for phase 2 screening trials, JCO 23:7199-7206, 2005 • Simon R et al. Randomized phase II clinical trials. Cancer Treatment Rep 69:1375-81, 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 29:1848-54, 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 54:1183-89, 1998.