Haeseong Park1,2, Kerry Williams1,3, Nikolaos A Trikalinos1,2, Sarah Larson1,2, Benjamin Tan1,2, Saiama Waqar1,2, Rama Suresh1,2, Daniel Morgensztern1,2, Brian A Van Tine1,2, Ramaswamy Govindan1,2, Jingqin Luo2,4, A Craig Lockhart1,5, Andrea Wang-Gillam6,7. 1. Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA. 2. Siteman Cancer Center, St. Louis, MO, USA. 3. Veterans Health System of Ozarks, Fayetteville, AR, USA. 4. Division of Public Health Sciences, Washington University School of Medicine, St. Louis, MO, USA. 5. Division of Medical Oncology, Department of Internal Medicine, Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, Miami, FL, USA. 6. Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA. awang-gillam@wustl.edu. 7. Siteman Cancer Center, St. Louis, MO, USA. awang-gillam@wustl.edu.
Abstract
PURPOSE: Resistance to treatment with inhibitors of mammalian target of rapamycin (mTOR) is partially mediated by activation of epidermal growth factor receptor (EGFR). We conducted a phase I study to determine the recommended phase II dose (RP2D) and dose-limiting toxicities (DLT) of temsirolimus (mTOR inhibitor) combined with erlotinib (EGFR inhibitor) in patients with refractory solid tumors. METHODS: Standard "3 + 3" design was used for dose escalation. An expansion cohort at RP2D included only patients with squamous histology or mutations relevant to PI3K or EGFR pathway activation. Patients started daily erlotinib 7 days prior to starting temsirolimus on cycle 1. Intravenous temsirolimus was then administered weekly. Starting dose levels were 15 mg for temsirolimus and 100 mg for erlotinib. RESULTS: Forty-four patients received treatment on this study (28 in dose escalation and 16 in the expansion cohort). The RP2D was temsirolimus 25 mg IV weekly and erlotinib 100 mg orally daily. Two patients experienced DLTs (G3 dehydration and G4 renal failure). The most common drug-related adverse events (all grades) were rash, mucositis/stomatitis, diarrhea, nausea and fatigue. No complete or partial responses were observed. The median duration on this study was 69 days (range 3-770) for escalation and 88 days (range 25-243) for expansion cohorts. Among 11 response-evaluable patients in the expansion cohort, 9 (82%) had stable disease and 2 (18%) had progressive disease. CONCLUSION: The combination of temsirolimus and erlotinib at the RP2D was well tolerated, and the regimen resulted in prolonged disease stabilization in selected patients (NCT00770263).
PURPOSE: Resistance to treatment with inhibitors of mammalian target of rapamycin (mTOR) is partially mediated by activation of epidermal growth factor receptor (EGFR). We conducted a phase I study to determine the recommended phase II dose (RP2D) and dose-limiting toxicities (DLT) of temsirolimus (mTOR inhibitor) combined with erlotinib (EGFR inhibitor) in patients with refractory solid tumors. METHODS: Standard "3 + 3" design was used for dose escalation. An expansion cohort at RP2D included only patients with squamous histology or mutations relevant to PI3K or EGFR pathway activation. Patients started daily erlotinib 7 days prior to starting temsirolimus on cycle 1. Intravenous temsirolimus was then administered weekly. Starting dose levels were 15 mg for temsirolimus and 100 mg for erlotinib. RESULTS: Forty-four patients received treatment on this study (28 in dose escalation and 16 in the expansion cohort). The RP2D was temsirolimus 25 mg IV weekly and erlotinib 100 mg orally daily. Two patients experienced DLTs (G3 dehydration and G4 renal failure). The most common drug-related adverse events (all grades) were rash, mucositis/stomatitis, diarrhea, nausea and fatigue. No complete or partial responses were observed. The median duration on this study was 69 days (range 3-770) for escalation and 88 days (range 25-243) for expansion cohorts. Among 11 response-evaluable patients in the expansion cohort, 9 (82%) had stable disease and 2 (18%) had progressive disease. CONCLUSION: The combination of temsirolimus and erlotinib at the RP2D was well tolerated, and the regimen resulted in prolonged disease stabilization in selected patients (NCT00770263).
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Authors: Yi-Long Wu; Ying Cheng; Xiangdong Zhou; Ki Hyeong Lee; Kazuhiko Nakagawa; Seiji Niho; Fumito Tsuji; Rolf Linke; Rafael Rosell; Jesus Corral; Maria Rita Migliorino; Adam Pluzanski; Eric I Sbar; Tao Wang; Jane Liang White; Sashi Nadanaciva; Rickard Sandin; Tony S Mok Journal: Lancet Oncol Date: 2017-09-25 Impact factor: 41.316
Authors: James Chih-Hsin Yang; Yi-Long Wu; Martin Schuler; Martin Sebastian; Sanjay Popat; Nobuyuki Yamamoto; Caicun Zhou; Cheng-Ping Hu; Kenneth O'Byrne; Jifeng Feng; Shun Lu; Yunchao Huang; Sarayut L Geater; Kye Young Lee; Chun-Ming Tsai; Vera Gorbunova; Vera Hirsh; Jaafar Bennouna; Sergey Orlov; Tony Mok; Michael Boyer; Wu-Chou Su; Ki Hyeong Lee; Terufumi Kato; Dan Massey; Mehdi Shahidi; Victoria Zazulina; Lecia V Sequist Journal: Lancet Oncol Date: 2015-01-12 Impact factor: 41.316
Authors: James C Yao; Marianne Pavel; Catherine Lombard-Bohas; Eric Van Cutsem; Maurizio Voi; Ulrike Brandt; Wei He; David Chen; Jaume Capdevila; Elisabeth G E de Vries; Paola Tomassetti; Timothy Hobday; Rodney Pommier; Kjell Öberg Journal: J Clin Oncol Date: 2016-09-30 Impact factor: 44.544
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