Phase I Clinical Trial Of Combination Imatinib And Ipilimumab In Patients With Advanced Malignancies

3054 Background: Imatinib mesylate can induce rapid tumor regression, inhibit tumor immunosuppressive mechanisms, and release large amounts of antigenic debris from tumor cell death with subsequent increase in tumor antigen presentation. CTLA-4 blockade and imatinib combination therapy in mouse models of GIST synergistically reduces size of tumors mediated by imatinib-dependent intratumoral accumulation of CD8+ T-cells and suppression of Treg-cells. We hypothesized that combination therapy with imatinib and ipilimumab immunotherapy would be tolerable and may synergistically enhance anti-tumor T-cell activation in patients (pts). Methods: Primary objective of the dose-escalation study (3+3 design) was to establish the maximum tolerated dose (MTD) and recommended phase II dose of the combination. Eligible pts had metastatic or unresectable, solid tumors. In the expansion cohort, pts were required to have a known KIT mutation. Secondary objectives included evaluation of antitumor activity of the combination based on KIT mutation status and the predictive status of tumor-associated immune biomarkers. Results: 26 pts were dosed in the escalation portion of the study. No dose limiting toxicities were encountered. The most common grade 1 and 2 related adverse events (AEs) were nausea (57%), fatigue (50%), vomiting (46%), anorexia (35%), diarrhea, skin rash, and edema (each 27%). There were 4 (16%) grade 3 related AEs including fatigue, anemia, rash, and vomiting. There were no grade 4 AEs. The MTD was the highest planned dose level of Ipilmumab at 3mg/kg and Imatinib at 400mg twice daily. An additional 10 pts were treated at MTD. Among all pts, three responses were seen: one GIST (PR) and 2 melanoma pts (CR + PR). These responses were seen at higher dose levels. Stable disease was seen in 7 pts lasting an average of 6 months. Notably, both melanoma responders had KIT mutations; the GIST responder was wild type. Immune cell activity in tumor tissue biopsy specimens and serum is under analysis. Conclusions: In this phase I trial the combination was well tolerated. Responders in this trial suggest that this combination at MTD has antitumor activity in WT GIST and KIT-mutant melanoma and merits further investigation. Clinical trial information: NCT01738139.