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Tailoring early-phase clinical trial design to address multiple research objectives

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Introduction

In contemporary oncology drug development, implementation of novel early-phase designs with the ability to address multiple research objectives is needed to better refine regimens. This paper describes an adaptive design strategy for identifying a range of optimal regimens based on two endpoints within multiple cohorts. The proposed design was developed to address objectives in an early-phase trial of cancer vaccines in combination with agonistic antibodies to CD40 and CD27.

Materials and methods

We describe a model-based design strategy that was developed for a trial evaluating the safety and immunogenicity of vaccination with (1) peptides plus CD40 antibody and TLR3 ligand, (2) systemic administration of an agonistic CD27 antibody, and (3) to assess immune response from (1) and (2) compared to optimal controls in participants with stage IIB-IV melanoma.

Results and conclusions

The proposed design is a practical adaptive method for use with combined immunotherapy regimens with multiple objectives within multiple cohorts of interest. Further advances in the effectiveness of cancer immunotherapies will require new approaches that include redefining optimal strategies to take multiple regimens forward into later phases, incorporating additional endpoints in the dose selection process and testing drug combination therapies to improve efficacy and reduce toxicity. Our goal is to facilitate the acceptance and application of more novel designs in contemporary early development trials.

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Abbreviations

DLT:

Dose-limiting toxicity

FDA:

Food and drug administration

IFA:

Incomplete Freund’s adjuvant

Mel12.1:

12 Class I MHC-restricted melanoma peptides plus tetanus helper peptide

MTD:

Maximum tolerated dose

OBA:

Optimal biologic adjuvant

OBD:

Optimal biologic dose

UVA:

University of Virginia

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Acknowledgements

The authors would like to thank the Editor and two reviewers for their comments that lead to an improved paper.

Funding

Dr. Wages is supported by Grant Number K25CA181638 from the National Cancer Institute. Dr. Petroni is partially supported by Grant Number R01CA142859 from the National Cancer Institute. Drs. Slingluff and Petroni are supported by a Team Science Award from the Melanoma Research Alliance. Supported in part by the Biostatistics Shared Resource, University of Virginia Cancer Center, University of Virginia (P30CA044579).

Author information

Authors and Affiliations

  1. Division of Translational Research and Applied Statistics, Department of Public Health Sciences, University of Virginia, P.O. Box 800717, Charlottesville, VA, USA

    Nolan A. Wages & Gina R. Petroni

  2. Division of Surgical Oncology, Department of Surgery, University of Virginia, Charlottesville, VA, USA

    Craig L. Slingluff Jr.

  3. Department of Pathology, University of Virginia, Charlottesville, VA, USA

    Timothy N. Bullock

Authors
  1. Nolan A. Wages
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  2. Craig L. Slingluff Jr.
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  3. Timothy N. Bullock
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  4. Gina R. Petroni
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Contributions

All authors contributed to the study conception and design. The first draft of the manuscript was written by Nolan A. Wages and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Nolan A. Wages.

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Conflict of interest

Dr. Slingluff is an inventor on patents of peptides for use in clinical trials of cancer vaccines; these patents are held by the University of Virginia Licensing and Ventures Group. He also is on and the University receives funding for his roles as external advisory board member for Immatics, CureVac., and as PI for a clinical trial of a cell-based vaccine sponsored by Polynoma. He also receives support for investigator-sponsored cancer immunotherapy clinical trials from GlaxoSmithKline, Celldex, 3 M, and Merck. All remaining authors have declared no conflicts of interest.

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This article does not contain any studies with human participants performed by any of the authors.

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This article does not contain any studies with human participants performed by any of the authors.

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Wages, N.A., Slingluff, C.L., Bullock, T.N. et al. Tailoring early-phase clinical trial design to address multiple research objectives. Cancer Immunol Immunother 69, 95–102 (2020). https://doi.org/10.1007/s00262-019-02442-5

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