Clinical Research Papers:
Phase I study of pemetrexed with sorafenib in advanced solid tumors
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Andrew Poklepovic1,2, Sarah Gordon2, Danielle A. Shafer1,2, John D. Roberts1,2,7, Prithviraj Bose1,2,8, Charles E. Geyer Jr.1,2, William P. McGuire1,2, Mary Beth Tombes1, Ellen Shrader1, Katie Strickler1, Maria Quigley1, Wen Wan1,3, Maciej Kmieciak1, H. Davis Massey4, Laurence Booth5, Richard G. Moran1,6, Paul Dent1,5
1Department of Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
2Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
3Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA
4Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA
5Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, USA
6Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
7Current address: Department of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USA
8Current address: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Andrew Poklepovic, email: firstname.lastname@example.org
Keywords: clinical trial, pemetrexed, solid tumors, sorafenib
Received: February 26, 2016 Accepted: April 16, 2016 Published: May 18, 2016
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/m2 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/m2 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.
Primary Contact _
Danielle A. Shafer
John D. Roberts
Charles E. Geyer Jr
William P. McGuire
Mary Beth Tombes
H. Davis Massey
Richard G. Moran
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