Thehang Luu1,2, Kyu-Pyo Kim3,4, Suzette Blanchard5,6, Bean Anyang3, Arti Hurria7, Lixin Yang8, Jan H Beumer9,10,11, George Somlo7, Yun Yen12. 1. Department of Medical Oncology, City of Hope Medical Center, Duarte, CA, 91010, USA. tluu@oncogambit.com. 2. OncoGambit, LLC, 4790 Irvine Blvd suite 105-264, Irvine, CA, 92602, USA. tluu@oncogambit.com. 3. Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Room G27E, Hillman Research Pavilion, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA. 4. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 5. Department of Biostatistics, City of Hope, Duarte, CA, 91010, USA. 6. Department of Molecular, City of Hope, Duarte, CA, 91010, USA. 7. Department of Medical Oncology, City of Hope Medical Center, Duarte, CA, 91010, USA. 8. Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA. 9. Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Room G27E, Hillman Research Pavilion, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA. beumerj@gmail.com. 10. Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, 15213, USA. beumerj@gmail.com. 11. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. beumerj@gmail.com. 12. Cancer Research and Drug Discovery Medical Technology College, Taipei Medical University, Taipei, Taiwan.
Abstract
PURPOSE: To translate promising preclinical data on the combination of vorinostat and ixabepilone for metastatic breast cancer (MBC) into clinical trials. METHODS: We conducted a randomized two-arm Phase IB clinical trial of ascending doses of vorinostat and ixabepilone in prior -treated MBC patients. To determine the maximum tolerated dose (MTD), 37 patients were randomized to schedule A: every-3-week ixabepilone + vorinostat (days 1-14), or schedule B: weekly ixabepilone + vorinostat (days 1-7; 15-21) Pharmacokinetics were assessed. Nineteen additional patients were randomized to schedule A or B and objective response rate (ORR), clinical benefit rate (CBR), toxicity, progression-free survival (PFS), and overall survival (OS) were assessed. RESULTS: The schedule A MTD was vorinostat 300 mg daily (days 1-14), ixabepilone 32 mg/m2 (day 2); 21-day cycle 27% dose-limiting toxicities (DLTs). The schedule B MTD was vorinostat 300 mg daily (days 1-7; 15-21), ixabepilone 16 mg/m2 (days 2, 9, 16); 28-day cycle; no DLTs. Vorinostat and ixabepilone clearances were 194 L/h and 21.3 L/h/m2, respectively. Grade 3 peripheral sensory neuropathy was reported in 8% (A) and 21% (B) of patients. The ORR and CBR were 22 and 22% (A); 30 and 35% (B). Median PFS was 3.9 (A) and 3.7 (B) months. OS was 14.8 (A) and 17.1 (B) months. CONCLUSIONS: We established the MTD of vorinostat and ixabepilone. This drug combination offers a novel therapy for previously treated MBC patients. The potential for lower toxicity and comparable efficacy compared to current therapies warrants further study.
RCT Entities:
PURPOSE: To translate promising preclinical data on the combination of vorinostat and ixabepilone for metastatic breast cancer (MBC) into clinical trials. METHODS: We conducted a randomized two-arm Phase IB clinical trial of ascending doses of vorinostat and ixabepilone in prior -treated MBCpatients. To determine the maximum tolerated dose (MTD), 37 patients were randomized to schedule A: every-3-week ixabepilone + vorinostat (days 1-14), or schedule B: weekly ixabepilone + vorinostat (days 1-7; 15-21) Pharmacokinetics were assessed. Nineteen additional patients were randomized to schedule A or B and objective response rate (ORR), clinical benefit rate (CBR), toxicity, progression-free survival (PFS), and overall survival (OS) were assessed. RESULTS: The schedule A MTD was vorinostat 300 mg daily (days 1-14), ixabepilone 32 mg/m2 (day 2); 21-day cycle 27% dose-limiting toxicities (DLTs). The schedule B MTD was vorinostat 300 mg daily (days 1-7; 15-21), ixabepilone 16 mg/m2 (days 2, 9, 16); 28-day cycle; no DLTs. Vorinostat and ixabepilone clearances were 194 L/h and 21.3 L/h/m2, respectively. Grade 3 peripheral sensory neuropathy was reported in 8% (A) and 21% (B) of patients. The ORR and CBR were 22 and 22% (A); 30 and 35% (B). Median PFS was 3.9 (A) and 3.7 (B) months. OS was 14.8 (A) and 17.1 (B) months. CONCLUSIONS: We established the MTD of vorinostat and ixabepilone. This drug combination offers a novel therapy for previously treated MBCpatients. The potential for lower toxicity and comparable efficacy compared to current therapies warrants further study.
Authors: Mohd Muddassir; Kunjal Soni; Chetan B Sangani; Abdullah Alarifi; Mohd Afzal; Naaser A Y Abduh; Yongtao Duan; Poonam Bhadja Journal: RSC Adv Date: 2020-12-24 Impact factor: 4.036