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 1 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 1 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 event per 100 patients and 2 per 1000 vaccines. Only 2 out 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.

Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases

“…Imiquimod is not approved for use in topical treatment of melanoma metastases, but its off-label use has been reported in that setting (18, 28, 29), with beneficial control of treated lesions in some patients. Cancer vaccines have a very favorable safety profile (30) so the present study is consistent with prior work supporting safety of vaccines plus imiquimod in combination.…”

The FDA Guidance on Therapeutic Cancer Vaccines: The Need for Revision to Include Preventive Cancer Vaccines or for a New Guidance Dedicated to Them

“…Most have a safety profile that is better than that of traditional cancer chemotherapies, with clinically significant adverse events being either not observed or only mild (18–20) (21). This of course is predicated on the ability to elicit a strong immune response in the setting of cancer.…”

“…Accordingly, testing for acute toxicity in a phase 1 safety trial would be needed in the following categories: 1) any vaccine with substantial toxicity observed in preclinical toxicity studies; 2) classes of vaccine platforms with toxicity demonstrated in previously conducted clinical trials and 3) new vaccine platforms or other vaccine components (e.g. adjuvant) with potential vital organ toxicity (21). Since induction of autoimmunity is one of the safety issues that have been associated with some cancer vaccines, assessment of this issue in the earliest stage or NED patients with greater immune competence, is much more likely to be informative.…”

“…Since phase 1 dose escalation studies of cancer vaccines do not determine toxicity or biologically active dose in the vast majority of the vaccines tested, another feasible goal of a phase 1 study in the premalignant setting, where individuals are expected to respond, could be to find a dose and a schedule that induces high levels of T helper 1 cell (TH1) and cytotoxic T lymphocytes (CTL) against tumor antigens while avoiding, to the extent possible, induction of immune suppressor cells (21). Therefore, in contrast to early phase trials with chemotherapy drugs, the most appropriate disease setting should involve patients who are not immunosuppressed and are capable of mounting a strong immune response to the vaccine.…”

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

“…The Food and Drug Administration (FDA) recently published a “Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines,” which acknowledged the need for alternative dose-escalation methods in cancer vaccines [10, 11]. In contrast to chemotherapeutic agents, dose-finding in immunotherapy often investigates treatments that demonstrate minimal toxicity overall, where higher doses may not induce greater immunologic effect.…”