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

5144 Background: There are few treatment options for mCRPC pts. Immunotherapy + adjuvant immunomodulators is a promising modality. PSA-TRICOM V is composed of poxviral vectors encoding PSA and 3 costimulatory molecules (ICAM-I, LFA-3, and B7.1) and has clinical activity in mCRPC. Ipi blocks CTLA-4, a T-cell downregulatory receptor, has clinical activity in mCRPC as monotherapy and has also been shown to enhance anti-tumor responses in combination with V in preclinical studies. Methods: Pts received V and GM-CSF q 4 weeks in 4 sequential cohorts of escalating doses of ipi at 1, 3, 5, and 10 mg/kg (DL1–4 respectively). After 6 courses of ipi, pts could receive a maintenance dose q 3 months (mo) until progression. Results: Study accrual is complete with 30 pts. There was no DLT and no > G2 adverse event (AE) attributed to V. There were 20 ≥ G2 immune-related AE (irAE): 0/3, 2/6, 5/6 and 13/15 pts on DL1–4, respectively. There was no evidence of clinical benefit in the 6 pts who had prior chemo on DL1 and 2, so subsequently we excluded pts with prior chemo. Median TTP for 9 chemo-naïve pts treated on DL2 and 3 was 6.1 mo (2.9–11.6 mo). Median PSA doubling time (DT) ↑ from 2.2 mo at baseline to 3.7 on study (p = 0.17). 5 of 9 had ≥ 50% ↓ in PSA from peak during study and 1 had a sustained ↓ PSA > 95% from baseline. 4 of these pts had stable disease (SD) for ≥ 6 mo and 2 had unconfirmed partial responses by RECIST. Of the 15 pts on DL4, to date 9 have had SD for ≥ 6 mo (2 ≥ 12 mo); 4 remain on trial. 1 had a sustained ↓ in PSA > 99% from baseline and is still on study after 12 mo. Median PSA DT ↑ > 3-fold from 2.6 mo at baseline to 8.2 on study (p = 0.01) in DL4. The 24 chemo-naïve pts had PSA DT ↑ from 2.5 to 6 mo (p = 0.003). 14 of 30 pts had a PSA ↓ from baseline or peak PSA on study. 2 of 14 had no irAE, 12 showed ≥ G2 irAE temporally associated with PSA ↓. 5 of 9 pts had > 2–5 fold ↑ in T-cell responses by ELISPOT assay and 4 of 13 had significant ↓ in their IL-6 levels. Immune responses appeared to correlate with clinical activity. Conclusions: This combination has clinical activity in pts with chemo-naïve mCRPC and seems to correlate with immune responses. It is associated with manageable side effects; however, further studies are required to see if the combination is more effective than either agent alone. No significant financial relationships to disclose.