Takeshi Suzuki1, Yasutaka Sukawa2, Chiyo K Imamura3, Toshiki Masuishi4, Hironaga Satake5, Yosuke Kumekawa6, Shinsuke Funakoshi7, Masahito Kotaka8, Yoshiki Horie9, Sadayuki Kawai10, Hiroyuki Okuda11, Tetsuji Terazawa12, Chihiro Kondoh13, Ken Kato14, Kenichi Yoshimura15, Hideki Ishikawa16, Yasuo Hamamoto17, Narikazu Boku14, Hiromasa Takaishi17, Takanori Kanai1. 1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Keio, Japan. 2. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Keio, Japan. Electronic address: sukawa@keio.jp. 3. Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, Keio, Japan. 4. Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, Japan. 5. Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe City, Japan. 6. Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan. 7. Division of Medical Oncology, Department of Internal Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan. 8. Gastrointestinal Cancer Center, Sano Hospital, Kobe, Japan. 9. Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan. 10. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan. 11. Department of Medical Oncology, Keiyukai Sapporo Hospital, Sapporo, Japan. 12. Cancer Chemotherapy Center, Osaka Medical College, Osaka, Japan. 13. Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan. 14. Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. 15. Department of Biostatistics, Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan. 16. Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan. 17. Keio Cancer Center, Keio University School of Medicine, Keio, Japan.
Abstract
BACKGROUND: Regorafenib demonstrated survival benefits as salvage therapy for patients with metastatic colorectal cancer. However, severe toxicities frequently occurred early in the treatment with the standard dose (160 mg/day), resulting in a dose reduction or interruption. To improve the tolerability and maintain sufficient efficacy, we conducted a phase II study of regorafenib with a lower starting dose (120 mg/day). PATIENTS AND METHODS: Regorafenib was initiated at 120 mg/day, and the dosage was increased to 160 mg/day on day 15 of the first cycle for patients who had met the dose escalation criteria. The primary endpoint was the disease control rate (DCR). The pharmacokinetics of the total and unbound regorafenib and its active metabolites (M2, M5) were assessed. RESULTS: A total of 70 patients were enrolled from September 2016 to December 2017. Only 6 patients achieved dose escalation to 160 mg on day 15 as planned. For the 68 evaluable patients, the DCR was 32.4% (95% confidence interval, 21.5%-44.8%), which was less than the threshold (30%) of our statistical hypothesis. The serum concentrations of total regorafenib for patients whose dose was escalated to 160 mg/day were significantly lower than those of the patients whose dose was not escalated (median, 3978 vs. 7244 nM; P = .027). The serum unbound concentrations of the sum of regorafenib and the active metabolites correlated significantly with the maximum grade of regorafenib-related symptomatic adverse events in the first cycle (11,138 vs. 19,096 pM; P = .035). CONCLUSION: Regorafenib with a low starting dose of 120 mg/day did not achieve the expected DCR. A relationship of unbound exposure with toxicity was found.
BACKGROUND:Regorafenib demonstrated survival benefits as salvage therapy for patients with metastatic colorectal cancer. However, severe toxicities frequently occurred early in the treatment with the standard dose (160 mg/day), resulting in a dose reduction or interruption. To improve the tolerability and maintain sufficient efficacy, we conducted a phase II study of regorafenib with a lower starting dose (120 mg/day). PATIENTS AND METHODS: Regorafenib was initiated at 120 mg/day, and the dosage was increased to 160 mg/day on day 15 of the first cycle for patients who had met the dose escalation criteria. The primary endpoint was the disease control rate (DCR). The pharmacokinetics of the total and unbound regorafenib and its active metabolites (M2, M5) were assessed. RESULTS: A total of 70 patients were enrolled from September 2016 to December 2017. Only 6 patients achieved dose escalation to 160 mg on day 15 as planned. For the 68 evaluable patients, the DCR was 32.4% (95% confidence interval, 21.5%-44.8%), which was less than the threshold (30%) of our statistical hypothesis. The serum concentrations of total regorafenib for patients whose dose was escalated to 160 mg/day were significantly lower than those of the patients whose dose was not escalated (median, 3978 vs. 7244 nM; P = .027). The serum unbound concentrations of the sum of regorafenib and the active metabolites correlated significantly with the maximum grade of regorafenib-related symptomatic adverse events in the first cycle (11,138 vs. 19,096 pM; P = .035). CONCLUSION:Regorafenib with a low starting dose of 120 mg/day did not achieve the expected DCR. A relationship of unbound exposure with toxicity was found.
Authors: Anna Mueller-Schoell; Stefanie L Groenland; Oliver Scherf-Clavel; Madelé van Dyk; Wilhelm Huisinga; Robin Michelet; Ulrich Jaehde; Neeltje Steeghs; Alwin D R Huitema; Charlotte Kloft Journal: Eur J Clin Pharmacol Date: 2020-11-09 Impact factor: 2.953