Abstract IA13: Phase I trial of targeted therapy with PSA-TRICOM vaccine (V) and ipilimumab (ipi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

Background: Immunotherapy is an emerging therapeutic option for mCRPC and has demonstrated improved survival. Immunologic combinations are a logical next step in the clinical development. PSA-TRICOM V, composed of poxviral vectors encoding PSA and 3 costimulatory molecules (ICAM-I, LFA-3, and B7.1), has shown evidence of clinical activity in mCRPC and is being tested in a phase III study ([NCT01322490][1]). Ipi, which blocks CTLA-4, a T-cell coinhibitory receptor, has clinical activity in mCRPC as monotherapy and has also been shown to enhance antitumor responses in combination with V in preclinical studies. Methods: We completed a phase I dose-escalation trial, with a subsequent expansion phase, to assess the safety and tolerability of escalating doses of ipi in combination with a fixed dose of PSA-TRICOM V. Pts with mCRPC received vaccinia PSA-TRICOM subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of fowlpox PSA-TRICOM starting on day 15. Intravenous ipi was given monthly x 6 starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal was to assess the safety of the combination. Results: We completed enrollment with 30 pts (24 of whom were chemotherapy-naive) and did not identify any dose-limiting toxicity. 21 pts had grade ≥ 2 immune-related adverse events, including diarrhea or colitis, rash, raised aminotransferases, endocrinopathy, and neutropenia. Only 1 of the 6 pts previously treated with chemotherapy had a PSA decline from baseline. Of the 24 pts who were chemotherapy-naive, 14 (58%) had PSA declines from baseline, of which 6 were > 50%. While the median predicted survival was about 18 months, based on a validated nomogram, actual median OS exceeded 34 months in this phase I study. A previous 32 pt study at the same institution of V alone in the same population (predicted survival 17.4 months) had an OS of 26.6 months. Conclusions: The use of a V targeting PSA that also enhances costimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipi. There is a suggestion of clinical activity for the combination; however, randomized trials are needed to further assess clinical outcomes of the combination of ipi and V in mCRPC. ClinicalTrials.gov registry number: [NCT00113984][2] Ref: Madan et al., Lancet Oncology 2012. Citation Format: James L. Gulley, Ravi A. Madan, Kwong Y. Tsang, Caroline Jochems, William L. Dahut, Jeffrey Schlom. Phase I trial of targeted therapy with PSA-TRICOM vaccine (V) and ipilimumab (ipi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA13. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01322490&atom=%2Fcanres%2F73%2F1_Supplement%2FIA13.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00113984&atom=%2Fcanres%2F73%2F1_Supplement%2FIA13.atom