A Phase I/II adaptive design to determine the optimal treatment regimen from a set of combination immunotherapies in high-risk melanoma

Abstract

In oncology, vaccine-based immunotherapy often investigates regimens that demonstrate minimal toxicity overall and higher doses may not correlate with greater immune response. Rather than determining the maximum tolerated dose, the goal of the study becomes locating the optimal biological dose, which is defined as a safe dose demonstrating the greatest immunogenicity, based on some predefined measure of immune response. Incorporation of adjuvants, new or optimized peptide vaccines, and combining vaccines with immune modulators may enhance immune response, with the aim of improving clinical response. Innovative dose escalation strategies are needed to establish the safety and immunogenicity of new immunologic combinations. We describe the implementation of an adaptive design for identifying the optimal treatment strategy in a multi-site, FDA-approved, phase I/II trial of a novel vaccination approach using long-peptides plus TLR agonists for resected stage IIB-IV melanoma. Operating characteristics of the design are demonstrated under various possible true scenarios via simulation studies. Overall performance indicates that the design is a practical Phase I/II adaptive method for use with combined immunotherapy agents. The simulation results demonstrate the method's ability to effectively recommend optimal regimens in a high percentage of trials with manageable sample sizes. The numerical results presented in this work include the type of simulation information that aid review boards in understanding design performance, such as average sample size and frequency of early trial termination, which we hope will augment early-phase trial design in cancer immunotherapy.

Two-Stage Design for Phase I–II Cancer Clinical Trials Using Continuous Dose Combinations of Cytotoxic Agents

“…() or Wages et al . (2016) require a short period of time to resolve the efficacy end point and may not be appropriate in the setting of the cisplatin–cabazitaxel trial. Finally, we note that our proposed method is applicable to any combination of cytotoxic and biologic agents since the models that are used in the phase I part of the study still assume monotonicity of the probability of DLT of either agent for a fixed level of the other agent.…”

“…For the cisplatin-cabazitaxel trial, a separate stopping rule using Bayesian continuous monitoring for excessive toxicity is included in the clinical protocol. We further emphasize the fact that phase I-II designs such as those described in Wages and Conaway (2014), Cai et al (2014) or Wages et al (2016) require a short period of time to resolve the efficacy end point and may not be appropriate in the setting of the cisplatin-cabazitaxel trial. Finally, we note that our proposed method is applicable to any combination of cytotoxic and biologic agents since the models that are used in the phase I part of the study still assume monotonicity of the probability of DLT of either agent for a fixed level of the other agent.…”

“…These methods are designed to identify a safe dose that maximizes the probability of treatment response or a predefined utility function. More recently, these designs have been extended to dose combination trials where the dose levels of two drugs are allowed to vary during the trial and are explored for toxicity and efficacy (Yuan and Yin, ; Wages and Conaway, ; Cai et al ., ; Riviere et al ., ) or to determine the optimal treatment regimen (Wages et al ., ). These methods accommodate cytotoxic and biologic drugs and are appropriate for short‐term efficacy end points to allow sequential updating of the probabilities of toxicity and efficacy.…”

Practical designs for Phase I combination studies in oncology

“…In addition to the trial examples described in this work, The POCRM was implemented as part of a multi-site, phase I/II trial of combination immunotherapies that is currently open to enrollment at UVA and M.D. Anderson Cancer Center (NCT02126579; Wages, Slingluff, and Petroni, 2015). The estimation procedure employed by POCRM is used in this trial to adaptively monitor safety and to identify an acceptable set of regimens in high-risk melanoma patients.…”

Polytopic vaccination with a live-attenuated dengue vaccine enhances B-cell and T-cell activation, but not neutralizing antibodies

“…Multisite or polytopic injection of different epitopes to areas of the skin with access to different lymph nodes likely reduces immunodominance and increases recognition of the four DENV serotypes [12]. Similar studies addressing multi-site vaccination for cancer [13] describes immune system dynamics that suggest polytopic vaccination leads to more robust immune responses than monotopic vaccination. In this work, strains or allele mutants were loaded into T cells located in different lymph nodes which have enough numbers of complementary T cell receptors (TCRs) to proliferate and generate an immune response to such allele.…”