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

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

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

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 considerations. 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 Immunologic Response Rate N at Dose Probability of No Immunologic Response 20% % % %5.08

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 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

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

Optimal Single Arm Two-Stage Design of Tumor Shrinkage To distinguish 5% (p 0 ) response rate from 25% (p 1 ) 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 it’s 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 development –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 it’s mean response is at least  standard deviations above the next best regimen

Number of Patients Per Arm for Randomized Selection Design PCS = 90% Number of treatment arms  = 0.5  = 0.75  =

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

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 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

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

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

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.

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

References Korn EL et al. Clinical trial designs for cytostatic agents: Are new approaches needed? JCO 19: , 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 23: , 2005 Simon R et al. Randomized phase II clinical trials. Cancer Treatment Rep 69: , 1985 Simon R. Statistical designs for clinical trials of immunomodulating agents. In Immune Modulating Agents (Kresina TF), Dekker, Simon RM et al. Clinical trial designs for the early clinical development of therapeutic cancer vaccines. JCO 29: , 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: , 1998.