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Meta-Analysis
. 2014 Sep 15;20(18):4758-67.
doi: 10.1158/1078-0432.CCR-13-2671. Epub 2014 Jul 18.

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  1 , Emily Gammoh  2 , Richard M Simon  3 , Samir N Khleif  4
Affiliations
Meta-Analysis

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 et al. Clin Cancer Res. .

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.

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Figures

Figure 1
Figure 1
The change in the percentage of immune responders on each trial measured by DTH from dose level 1 (D1) to 2 (D2) (Figure 1a); dose level 2 (D2) to 3 (D3) (Figure. 1b) and dose level 3 (D3) to 4 (D4) (Figure. 1c). Trials that showed an increase in the percentage of immune responders are marked in blue while trials that showed no change or decrease in the percentage of responders are marked in red.
Figure 2
Figure 2
The suggested alternative design for early cancer vaccine development
See this image and copyright information in PMC

References

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