A phase II randomized, double-blind study of sipuleucel-T followed by IDO pathway inhibitor, indoximod, or placebo in the treatment of patients with metastatic castration resistant prostate cancer (mCRPC).

3066 Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism exploited by tumors in order to prevent and defeat anti-tumor immunity. Sipuleucel-T has overcome this tumor mediated anergy only in part by its ex-vivo sensitization. Small-molecule inhibitors of the IDO pathway, such as indoximod, are an increasingly validated class of potential cancer therapeutics. We tested the hypothesis whether targeting the IDO pathway by indoximod will inhibit Treg and abrogate tumor-mediated immunosuppression permitting a robust and sustained immune response to sipuleucel-T. Methods: Patient (pts) with mCRPC received either indoximod or placebo orally for 10 weeks after completion of sipuleucel-T therapy. In the absence of radiographic or clinical progression, pts were continued on study drug for 3 more months. Immune monitoring was done similar to IMPACT study (NEJM 2010; 363:411-422) starting prior to sipuleucel-T therapy. The primary endpoint was augmentation of immune response to PA2024 measured at 14 weeks. Secondary endpoints include safety, clinical efficacy (PFS, OS) and HR-QOL Results: Of the 63 pts with CRPC screened, 46 eligible pts were randomized to indoximod (n = 22) or placebo (n = 24). Pts tolerated therapy with indoximod with no significant difference in adverse events between two arms. There was no difference in PSA progression nor difference in the primary endpoint of immune response to PA2024 for 35 pts who have completed study and have samples analyzed. Median OS has not yet been reached in the study. Median radiographic PFS was 10.3 months in the treatment arm vs 4.1 months in placebo arm (p = 0.011), 4.1 months being similar to PFS in the pivotal ‘IMPACT’ study. More Pts continued to complete maximum treatment on indoximod arm (40.9% vs 25%). Conclusions: Treatment with indoximod post sipuleucel-T therapy is well tolerated and led to a significant improvement in radiographic and clinical progression. Augmentation of immune response to PA2024 by ELISPOT or ELISA might not be right biomarker for augmented response assessment while studying inhibition of IDO pathway. Clinical trial information: NCT01560923.