Phase 1 dose escalation trial of CV301

Background CV301 is a poxviral‐based vaccine comprising a prime‐boost strategy with Modified Vaccinia Ankara (MVA, prime) and fowlpox (FPV, boost), which contain transgenes encoding two tumor associated antigens, CEA and MUC‐1, as well as 3 costimulatory molecules (B7.1, ICAM‐1 and LFA‐3, called TRICOM). Preclinical evidence suggests CV‐ 301 activates CEA and MUC‐1 specific T cell responses, potentially increasing the clinical benefit of immune checkpoint inhibition. An open label phase 1/1b/2 trial was initiated to evaluate safety of CV301 alone (phase 1) and in combination with PD‐1/L1 inhibition (phase 1b) to be followed by a randomized phase 2 trial evaluating the combination compared with PD‐1/L1 inhibition alone. Here, we report the phase 1 safety evaluation of CV301. Methods This open‐label, 3 +3 design dose‐escalation phase 1 trial evaluated 3 dose levels of the priming dose of CV301 (MVA): 1, 2 or 4 s.c. injections of 4 x 108 Inf.U/0.5 mL on days 1 and 29. FPV booster doses were scheduled for all subjects subcutaneously at a 1 × 109 Inf.U/0.5 mL dose on weeks 9, 11, 13, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 65, 78, 91 and 104. Results There were no dose limiting toxicities in the phase 1 evaluation of CV301 alone. The minimum required patient number was enrolled in each dose level (DL1: 3, DL2: 3, DL3: 6, total: 12). The most frequent treatment‐related AEs were temporary and self‐limiting, grade 1/2, and included injection site reactions (erythema, pruritus, pain, induration and/or swelling) and general symptoms (fever/chills, flu‐like symptoms, headache, fatigue/weakness, nausea/vomiting, myalgia and arthralgia). Seven of the 12 patients have microsatellite stable colon cancer. Of these seven, two had preliminary evidence of benefit. One patient with stable disease at first restaging has marked reduction (60% fall) in tumor markers at 10 weeks. Another patient had unconfirmed partial response at first restaging (6 weeks). When 3 month restaging scans indicated progression, a PD‐L1 inhibitor was initiated. Subsequently, tumor markers fell by 60%. Conclusions CV301 priming doses (MVA) can be safely administered to at least 4 injection sites concurrently at 4 x 108 Inf.U/0.5 mL per site for a total of 1.6 x 109 Inf.U, which is the recommended phase 1b and phase 2 dose. Booster doses (FPV) can safely be administered s.c. at 1 x 109 Inf.U/0.5mL. Subsequent analyzes will include immune response data. The trial will continue to enroll phase 1b and, subsequently, the randomized phase 2.