Is the "3+3" dose-escalation Phase i Clinical trial design suitable for therapeutic cancer vaccine development? A recommendation for alternative design

Osama E. Rahma, Emily Gammoh, Richard M. Simon, Samir N. Khleif

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Purpose: Phase I clinical trials are generally conducted to identify the maximum tolerated dose (MTD) or the biologically active dose (BAD) using a traditional dose-escalation design. This design may not be applied to cancer vaccines, given their unique mechanism of action. The FDA recently published "Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines." However, many questions about the design of cancer vaccine studies remain unanswered.

Experimental Design: We analyzed the toxicity profile in 239 phase I therapeutic cancer vaccine trials. We addressed the ability of dose escalation to determine the MTD or the BAD in trials that used a doseescalation design.

Results: The rate of grade 3/4 vaccine-related systemic toxicities was 1.25 adverse events per 100 patients and 2 per 1,000 vaccines. Only two of the 127 dose-escalation trials reported vaccine-related dose limiting toxicities, both of which used bacterial vector vaccines. Out of the 116 trials analyzed for the dose-immune response relationship, we found a statistically significant dose-immune response correlation only when the immune response was measured by antibodies (P < 0.001) or delayed type hypersensitivity (P < 0.05). However, the increase in cellular immune response did not appear further sustainable with the continued increase in dose.

Conclusions: Our analysis suggests that the risks of serious toxicities with therapeutic cancer vaccines are extremely low and that toxicities do not correlate with dose levels. Accordingly, the conventional doseescalation design is not suitable for cancer vaccines with few exceptions. Here, we propose an alternative design for therapeutic cancer vaccine development.

Original languageEnglish (US)
Pages (from-to)4758-4767
Number of pages10
JournalClinical Cancer Research
Volume20
Issue number18
DOIs
StatePublished - Sep 15 2014

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Cancer Vaccines
Clinical Trials
Vaccines
Maximum Tolerated Dose
Therapeutics
Bacterial Vaccines
Clinical Trials, Phase I
Delayed Hypersensitivity
Cellular Immunity
Industry
Research Design
Antibodies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Is the "3+3" dose-escalation Phase i Clinical trial design suitable for therapeutic cancer vaccine development? A recommendation for alternative design. / Rahma, Osama E.; Gammoh, Emily; Simon, Richard M.; Khleif, Samir N.

In: Clinical Cancer Research, Vol. 20, No. 18, 15.09.2014, p. 4758-4767.

Research output: Contribution to journalArticle

Rahma, Osama E. ; Gammoh, Emily ; Simon, Richard M. ; Khleif, Samir N. / Is the "3+3" dose-escalation Phase i Clinical trial design suitable for therapeutic cancer vaccine development? A recommendation for alternative design. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 18. pp. 4758-4767.
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