PMID- 31932108 OWN - NLM STAT- MEDLINE DCOM- 20200702 LR - 20240210 IS - 1095-6859 (Electronic) IS - 0090-8258 (Linking) VI - 156 IP - 3 DP - 2020 Mar TI - Pazopanib and Fosbretabulin in recurrent ovarian cancer (PAZOFOS): A multi-centre, phase 1b and open-label, randomised phase 2 trial. PG - 545-551 LID - S0090-8258(20)30005-6 [pii] LID - 10.1016/j.ygyno.2020.01.005 [doi] AB - OBJECTIVE: Vascular co-option is a resistance mechanism to anti-angiogenic agents, but combinations of anti-vascular agents may overcome this resistance. We report a phase 1b and randomised phase 2 trial to determine the safety and efficacy of pazopanib with fosbretabulin. METHODS: Eligible patients had recurrent, epithelial ovarian cancer with a platinum-free interval (PFI) of 3 to 12 months. Patients were stratified according to PFI (>6 versus /= 2 adverse events (AEs) were hypertension (100%), neutropenia (50%), fatigue (50%), vomiting (50%). There was one DLT (grade 3 fatigue). The recommended phase 2 dose level was fosbretabulin 54 mg/m(2) on days 1, 8 and 15 and pazopanib 600 mg once daily (od), every 28 days, which was then compared to pazopanib 800 mg od in a randomised phase 2 trial. Twenty-one patients were randomised (1:1) in the phase 2 trial. In phase 1b and phase 2, four patients treated with pazopanib and fosbretabulin developed reversible, treatment-related cardiac AEs, leading to premature discontinuation of the study. In the phase 2 trial, the median PFS was 7.6 months (95% CI 4.1-not estimated) versus 3.7 months (95% CI 1.0-8.1) in favour of the experimental arm (HR 0.30, 95% CI 0.09-1.03, P = .06). CONCLUSIONS: It remains unclear whether pazopanib with with fosbretabulin is an efficacious regimen to treat epithelial ovarian cancer. Effective cardiac risk mitigation is needed to increase the tolerability and maximize patient safety in future trials. CI - Crown Copyright (c) 2020. Published by Elsevier Inc. All rights reserved. FAU - Morgan, Robert D AU - Morgan RD AD - Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. FAU - Banerjee, Susana AU - Banerjee S AD - The Royal Marsden NHS Foundation Trust, London, UK. FAU - Hall, Marcia AU - Hall M AD - Mount Vernon Cancer Centre, Northwood, Middlesex, UK. FAU - Clamp, Andrew R AU - Clamp AR AD - Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. FAU - Zhou, Cong AU - Zhou C AD - Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester, UK. FAU - Hasan, Jurjees AU - Hasan J AD - Christie NHS Foundation Trust, Manchester, UK. FAU - Orbegoso, Cecilia AU - Orbegoso C AD - The Royal Marsden NHS Foundation Trust, London, UK. FAU - Taylor, Sarah AU - Taylor S AD - Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester, UK. FAU - Tugwood, Jonathan AU - Tugwood J AD - Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester, UK. FAU - Lyon, Alexander R AU - Lyon AR AD - Royal Brompton and Harefield NHS Foundation Trust, London, UK; Faculty of Medicine, National Heart & Lung Institute, Imperial College London, London, UK. FAU - Dive, Caroline AU - Dive C AD - Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester, UK. FAU - Rustin, Gordon J S AU - Rustin GJS AD - Mount Vernon Cancer Centre, Northwood, Middlesex, UK. FAU - Jayson, Gordon C AU - Jayson GC AD - Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. Electronic address: Gordon.Jayson@christie.nhs.uk. LA - eng SI - ClinicalTrials.gov/NCT02055690 GR - 29832/CRUK_/Cancer Research UK/United Kingdom GR - CRUKE/13/022/CRUK_/Cancer Research UK/United Kingdom GR - 29569/CRUK_/Cancer Research UK/United Kingdom GR - DH_/Department of Health/United Kingdom GR - 19278/CRUK_/Cancer Research UK/United Kingdom PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20200110 PL - United States TA - Gynecol Oncol JT - Gynecologic oncology JID - 0365304 RN - 0 (Angiogenesis Inhibitors) RN - 0 (Indazoles) RN - 0 (Pyrimidines) RN - 0 (Stilbenes) RN - 0 (Sulfonamides) RN - 7RN5DR86CK (pazopanib) RN - I5590ES2QZ (fosbretabulin) SB - IM MH - Angiogenesis Inhibitors/administration & dosage/adverse effects/therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use MH - Carcinoma, Ovarian Epithelial/blood/blood supply/*drug therapy MH - Cardiotoxicity/etiology MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Indazoles MH - Neoplasm Recurrence, Local MH - Neovascularization, Pathologic/blood/drug therapy MH - Ovarian Neoplasms/blood/blood supply/*drug therapy MH - Progression-Free Survival MH - Pyrimidines/adverse effects/*therapeutic use MH - Stilbenes/administration & dosage/adverse effects MH - Sulfonamides/adverse effects/*therapeutic use MH - Survival Rate OTO - NOTNLM OT - Fosbretabulin OT - Ovarian cancer OT - Pazopanib COIS- Declaration of competing interest The authors declare no conflict of interest. EDAT- 2020/01/15 06:00 MHDA- 2020/07/03 06:00 CRDT- 2020/01/15 06:00 PHST- 2019/11/20 00:00 [received] PHST- 2019/12/30 00:00 [revised] PHST- 2020/01/02 00:00 [accepted] PHST- 2020/01/15 06:00 [pubmed] PHST- 2020/07/03 06:00 [medline] PHST- 2020/01/15 06:00 [entrez] AID - S0090-8258(20)30005-6 [pii] AID - 10.1016/j.ygyno.2020.01.005 [doi] PST - ppublish SO - Gynecol Oncol. 2020 Mar;156(3):545-551. doi: 10.1016/j.ygyno.2020.01.005. Epub 2020 Jan 10.