Is the "3+3" dose-escalation phase I clinical trial design suitable for therapeutic cancer vaccine development? A recommendation for alternative design.

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 dose-escalation 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 dose-escalation design is not suitable for cancer vaccines with few exceptions. Here, we propose an alternative design for therapeutic cancer vaccine development.

• Authors: Osama E Rahma, Emily Gammoh, Richard M Simon, Samir N Khleif
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 18 Pg. 4758-67 (Sep 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 25037736 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Intramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Cancer Vaccines

Topics

• Cancer Vaccines (administration & dosage)
• Clinical Trials, Phase I as Topic (methods, standards)
• Humans
• Neoplasms (drug therapy)
• Research Design (standards)