Phase I study of pemetrexed with sorafenib in advanced solid tumors

// Andrew Poklepovic 1, 2 , Sarah Gordon 2 , Danielle A. Shafer 1, 2 , John D. Roberts 1, 2, 7 , Prithviraj Bose 1, 2, 8 , Charles E. Geyer Jr. 1, 2 , William P. McGuire 1, 2 , Mary Beth Tombes 1 , Ellen Shrader 1 , Katie Strickler 1 , Maria Quigley 1 , Wen Wan 1, 3 , Maciej Kmieciak 1 , H. Davis Massey 4 , Laurence Booth 5 , Richard G. Moran 1, 6 , Paul Dent 1, 5 1 Department of Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA 2 Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA 3 Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA 4 Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA 5 Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, USA 6 Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA 7 Current address: Department of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USA 8 Current address: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence to: Andrew Poklepovic, email: andrew.poklepovic@vcuhealth.org Keywords: clinical trial, pemetrexed, solid tumors, sorafenib Received: February 26, 2016      Accepted: April 16, 2016      Published: May 18, 2016 ABSTRACT Purpose: To determine if combination treatment with pemetrexed and sorafenib is safe and tolerable in patients with advanced solid tumors. Results: Thirty-seven patients were enrolled and 36 patients were treated (24 in cohort A; 12 in cohort B). The cohort A dose schedule resulted in problematic cumulative toxicity, while the cohort B dose schedule was found to be more tolerable. The maximum tolerated dose (MTD) was pemetrexed 750 mg/m 2 every 14 days with oral sorafenib 400 mg given twice daily on days 1–5. Because dosing delays and modifications were associated with the MTD, the recommended phase II dose was declared to be pemetrexed 500 mg/m 2 every 14 days with oral sorafenib 400 mg given twice daily on days 1–5. Thirty-three patients were evaluated for antitumor activity. One complete response and 4 partial responses were observed (15% overall response rate). Stable disease was seen in 15 patients (45%). Four patients had a continued response at 6 months, including 2 of 5 patients with triple-negative breast cancer. Experimental Design: A phase I trial employing a standard 3 + 3 design was conducted in patients with advanced solid tumors. Cohort A involved a novel dose escalation schema exploring doses of pemetrexed every 14 days with continuous sorafenib. Cohort B involved a modified schedule of sorafenib dosing on days 1–5 of each 14-day pemetrexed cycle. Radiographic assessments were conducted every 8 weeks. Conclusions: Pemetrexed and intermittent sorafenib therapy is a safe and tolerable combination for patients, with promising activity seen in patients with breast cancer.