Phase I study of Rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and Polo-like kinase 1 pathways, combined with gemcitabine in patients with solid tumors and pancreatic cancer.

PURPOSE Rigosertib, a dual non-ATP inhibitor of polo-like kinase 1 (Plk1) and phosphoinositide 3-kinase pathways (PI3K), and gemcitabine have synergistic antitumor activity when combined in preclinical studies. This phase I study aimed to determine the recommended phase II dose (RPTD) of the combination of rigosertib and gemcitabine in patients with cancer. EXPERIMENTAL DESIGN Patients with solid tumors who failed standard therapy or were candidates for gemcitabine-based therapy were eligible. Gemcitabine was administered on days 1, 8, and 15 on a 28-day cycle and rigosertib on days 1, 4, 8, 11, 15, and 18. Pharmacokinetic studies were conducted during an expansion cohort of patients with advanced pancreatic ductal adenocarcinoma (PDA). RESULTS Forty patients were treated, 19 in the dose-escalation phase and 21 in the expansion cohort. Dose levels evaluated were (gemcitabine/rigosertib mg/m(2)): 750/600 (n = 4), 750/1,200 (n = 3), 1,000/600 (n = 3), 1,000/1,200 (n = 3), and 1,000/1,800 (n = 6 + 21). One dose-limiting toxicity (death) occurred at the highest dose level (1,000/1,800) tested. Non-dose-limiting ≥grade II/III toxicities included neutropenia, lymphopenia, thrombocytopenia, fatigue, and nausea. Grade III/IV neutropenia, thrombocytopenia, and fatigue were seen in two, one, and two patients in the expansion cohort. Partial responses were observed in PDA, thymic cancer, and Hodgkin lymphoma, including gemcitabine-pretreated PDA. The pharmacokinetic profile of rigosertib was not affected by gemcitabine. CONCLUSION The RPTD established in this study is rigosertib 1,800 mg/m(2) and gemcitabine 1,000 mg/m(2). This regimen is well tolerated with a toxicity profile of the combination similar to the profile of gemcitabine alone. Antitumor efficacy was observed in patients who previously progressed on gemcitabine-based therapy.