PMID- 29059635 OWN - NLM STAT- MEDLINE DCOM- 20171121 LR - 20180207 IS - 1879-0852 (Electronic) IS - 0959-8049 (Linking) VI - 86 DP - 2017 Nov TI - Phase II randomised discontinuation trial of cabozantinib in patients with advanced solid tumours. PG - 296-304 LID - S0959-8049(17)31292-3 [pii] LID - 10.1016/j.ejca.2017.09.011 [doi] AB - BACKGROUND: Cabozantinib is an inhibitor of tyrosine kinases, including MET, vascular endothelial growth factor receptor, AXL and RET. This multi-cohort phase II randomised discontinuation trial explored anticancer activity of cabozantinib in nine tumour types. PATIENTS AND METHODS: Cabozantinib was administered (100 mg, once daily) to patients with advanced, recurrent or metastatic cancers. Those with stable disease at week 12 were randomised 1:1 to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) in the randomised phase. RESULTS: A total of 526 patients were enrolled. The highest ORR was observed in ovarian cancer (OC) (21.7%); the largest PFS benefit was observed in castration-resistant prostate cancer (CRPC) (median 5.5 versus 1.4 months for placebo; hazard ratio 0.14, 95% confidence interval: 0.04, 0.52). Disease control rates were >40% for CRPC, OC, melanoma, metastatic breast cancer (MBC), hepatocellular carcinoma (HCC) and non-small cell lung cancer. Median duration of response ranged from 3.3 (MBC) to 11.2 months (OC). Encouraging efficacy results and symptomatic improvements prompted early suspension of the randomised stage and conversion to open-label non-randomised expansion cohorts. Dose reductions to manage adverse events (AEs) occurred in 48.7% of patients. The most frequent grade III-IV AEs were fatigue (12.4%), diarrhoea (10.5%), hypertension (10.5%) and palmar-plantar erythrodysesthesia syndrome (8.7%). CONCLUSIONS: Clinical antitumour activity of cabozantinib was observed in a subset of tumour types: CRPC and OC were evaluated further in expansion cohorts. Phase III programs were initiated in CRPC and HCC. Interpretation of efficacy outcomes was limited by early termination of the randomised portion of the trial. TRIAL REGISTRATION NUMBER: NCT00940225. CI - Copyright (c) 2017 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Schoffski, Patrick AU - Schoffski P AD - Department of General Medical Oncology, Leuven Cancer Institute, University Hospital Leuven, Leuven, Belgium. Electronic address: patrick.schoffski@uzleuven.be. FAU - Gordon, Michael AU - Gordon M AD - Pinnacle Oncology Hematology, Scottsdale, AZ, USA. Electronic address: mgordon@azpoh.com. FAU - Smith, David C AU - Smith DC AD - Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA. Electronic address: dcsmith@med.umich.edu. FAU - Kurzrock, Razelle AU - Kurzrock R AD - Moores Cancer Center, University of California, San Diego, San Diego, CA, USA. Electronic address: rkurzrock@ucsd.edu. FAU - Daud, Adil AU - Daud A AD - Medical Center at Parnassus, University of California, San Francisco, San Francisco, CA, USA. Electronic address: Adil.Daud@ucsf.edu. FAU - Vogelzang, Nicholas J AU - Vogelzang NJ AD - Comprehensive Cancer Centers of Nevada, US Oncology Research, Las Vegas, NV, USA. Electronic address: Nicholas.Vogelzang@usoncology.com. FAU - Lee, Yihua AU - Lee Y AD - Exelixis, Inc., South San Francisco, CA, USA. Electronic address: ewalee@yahoo.com. FAU - Scheffold, Christian AU - Scheffold C AD - Exelixis, Inc., South San Francisco, CA, USA. Electronic address: cscheffo@exelixis.com. FAU - Shapiro, Geoffrey I AU - Shapiro GI AD - Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: geoffrey_shapiro@dfci.harvard.edu. LA - eng SI - ClinicalTrials.gov/NCT00940225 SI - ClinicalTrials.gov/NCT00940225 PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20171020 PL - England TA - Eur J Cancer JT - European journal of cancer (Oxford, England : 1990) JID - 9005373 RN - 0 (Anilides) RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridines) RN - 1C39JW444G (cabozantinib) SB - IM MH - Anilides/*administration & dosage/adverse effects MH - Antineoplastic Agents/*administration & dosage/adverse effects MH - Belgium MH - Disease Progression MH - Disease-Free Survival MH - Drug Administration Schedule MH - Early Termination of Clinical Trials MH - Female MH - Humans MH - Israel MH - Kaplan-Meier Estimate MH - Male MH - Neoplasms/*drug therapy/enzymology/mortality/pathology MH - Protein Kinase Inhibitors/*administration & dosage/adverse effects MH - Pyridines/*administration & dosage/adverse effects MH - Taiwan MH - Time Factors MH - Treatment Outcome MH - United States OTO - NOTNLM OT - Cabozantinib OT - Objective response rate OT - Progression-free survival OT - Randomised discontinuation trial OT - Solid tumour OT - Vascular endothelial growth factor receptor EDAT- 2017/10/24 06:00 MHDA- 2017/11/29 06:00 CRDT- 2017/10/24 06:00 PHST- 2017/08/18 00:00 [received] PHST- 2017/09/14 00:00 [accepted] PHST- 2017/10/24 06:00 [pubmed] PHST- 2017/11/29 06:00 [medline] PHST- 2017/10/24 06:00 [entrez] AID - S0959-8049(17)31292-3 [pii] AID - 10.1016/j.ejca.2017.09.011 [doi] PST - ppublish SO - Eur J Cancer. 2017 Nov;86:296-304. doi: 10.1016/j.ejca.2017.09.011. Epub 2017 Oct 20.