Small, Phase I combo trial suggests 3-year overall survival in men with mCRPC


A media release issued earlier today by Barvarian Nordic (the developer of Prostvac®) gives us an inkling of where we may be headed in the development of combination therapies for the management of late stage (and maybe even earlier stage) forms of prostate cancer.

The media release comments briefly on research published on line by Madan et al. in The Lancet Oncology.

Madan et al. report data from a small, Phase I, dose-escalation trial designed to test the safety and the tolerability of a fixed dose of Barvarian Nordic’s poxvirus-based Prostvac immunotherapeutic vaccine in combination with gradually escalating doses of  ipilimumab, another immunotherapeutic agent. Both agents are currently in pivotal Phase III trials as single agents for the treatment of metastatic castration-resistant prostate cancer (mCRPC), and ipilimumab (Yervoy®) has already been approved in the US as a treatment for metastatic melanoma.

In the current trial, men with mCRPC were given a subcutaneous injection with  2 × 108 plaque-forming units of Prostvac on day 1 of cycle 1 and then with monthly injections of 1 × 109 plaque-forming units of Prostvac, starting on day 15. They were also treated with escalating doses of ipilimumab, given intravenously, once monthly, starting at day 15, using doses of 1, 3, 5, and 10 mg/kg. Additional details about the trial are available on the ClinicalTrials.gov web site.

Here are the core findings from this study to date:

  • The trial enrolled 30 men with mCRPC
  • 24/30 patients (80 percent) were chemotherapy-naive.
  • No dose-limiting toxic effects were evident.
  • Vaccination-site reactions were the most common toxic effects.
    • 3/30 patients (10 percent) had grade 1 vaccination reactions.
    • 26/30 patients (87 percent) had grade 2 vaccination reactions.
  • 21 patients had grade 2 or greater immune-related adverse events.
  • Grade 3 or 4 immune-related adverse events included
    • Diarrhea or colitis (in 4 patients)
    • Grade 3 rash (in 2 patients)
    • Grade 3 raised aminotransferase levels (2 patients)
    • Grade 3 endocrine immune-related adverse events (2 patients)
    • Grade 4 neutropenia (1 patient).
  • Among the patients previously treated with chemotherapy, 1/6 (17 percent) had a PSA decline from baseline.
  • Among the patients who were chemotherapy-naive, 14/24 (58 percent) had PSA declines from baseline
    • 6/24 chemotherapy-naive patients (25 percent) had PSA declines from baseline that were > 50 percent.

However, even though this trial was not intended to assess effectiveness of therapy, the median overall survival of the patients in this study was 34.4 months (nearly 3 years). We have no way yet of knowing the implications of this overall survival period of these patients in this small study. What we do know, however, is that median overall survival of men with mCRPC in other Phase III studies of late-stage disease have been more like 15 to 25 months (depending on the study and the precise patient enrollment criteria).

It is much too early to know whether Prostvac alone, ipilimumab alone, or the combination of these two agents can really demonstrate a median overall survival of about 3 years in men with chemotherapy-naive mCRPC, but these data are certainly enough to stimulate the imagination.

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