A phase 1 Bayesian dose selection study of bortezomib and sunitinib in patients with refractory solid tumor malignancies

• Type of Material: Article
• Authors: R. Harvey, Emory University; Taofeek Owonikoko, Emory University; C M Lewis, Emory University; A Akintayo, Emory University; Z Chen, Emory University; M Tighiouart, Cedars-Sinai Medical Center; Suresh Ramalingam, Emory University; MP Fanucchi, Fred B Cohen Comprehensive Cancer and Blood Disorders Center; P Nadella, Northeast Georgia Diagnostic Clinic; A Rogatko, Cedars-Sinai Medical Center; Dong Shin, Emory University; Bassel El-Rayes, Emory University; FR Khuri, Emory University; JS Kauh, Emory University
• Language: English
• Date: 2013-01-15
• Publisher: Cancer Research UK
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Cancer Research UK
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1038/bjc.2012.604
• Title of Journal or Parent Work: British Journal of Cancer
• ISSN: 0007-0920
• Volume: 108
• Issue: 4
• Start Page: 762
• End Page: 765
• Keywords: PROTEASOME INHIBITOR BORTEZOMIB; Life Sciences & Biomedicine; sunitinib; ONCOLOGY; Bayesian; EFFICACY; CLINICAL-TRIALS; OVERDOSE CONTROL; Science & Technology; Oncology; bortezomib; THERAPY; EWOC; CELL LUNG-CANCER; ESCALATION; CARCINOMA; COMBINATION; RECEPTOR; Phase 1
• Research Categories: Biology, Biostatistics; Health Sciences, Oncology

Abstract

This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination. Methods: Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m−2. Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria. Results: Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m−2 were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m−2. Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m−2 and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients. Conclusion: Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.