Phase 1 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
Mené sur 40 patients atteints d'une tumeur solide, cet essai de phase I évalue l'activité antitumorale du rigosertib en combinaison avec la gemcitabine
Purpose: Rigosertib (R), a dual non-ATP inhibitor of polo-like kinase and phosphatidylinositol 3-kinase pathways, and gemcitabine (G) have synergistic anti-tumor activity when combined in preclinical studies. This phase 1 study aimed to determine the recommended phase 2 dose (RPTD) of the combination of rigosertib and gemcitabine in cancer patients. Methods: 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; rigosertib on days 1, 4, 8, 11, 15 and 18. Pharmacokinetic studies were performed during an expansion cohort of advanced pancreatic ductal adenocarcinoma (PDA) patients. Results: Forty patients were treated, 19 in the dose escalation phase and 21 in the expansion cohort. Dose levels evaluated were (G/R mg/m2): 750/600 (n=4), 750/1200 (3), 1000/600 (3), 1000/1200 (3) and 1000/1800 (6+21). One dose limiting toxicity (death) occurred at the highest dose level (1000/1800) tested. Non-dose limiting ≥grade 2-3 toxicities included neutropenia, lymphopenia, thrombocytopenia, fatigue, and nausea. Grade 3/4 neutropenia, thrombocytopenia and fatigue were seen in 2, 1, and 2 patients in the expansion cohort. Partial responses were observed in PDA, thymic cancer and Hodgkin's lymphoma, including gemcitabine-pretreated PDA. Rigosertib's pharmacokinetic profile was not affected by gemcitabine. Conclusion: The RPTD established in this study is rigosertib 1800 mg/m2 and gemcitabine 1000 mg/m2. 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.