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

Autor: Harvey RD; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. donald.harvey@emory.edu, Owonikoko TK, Lewis CM, Akintayo A, Chen Z, Tighiouart M, Ramalingam SS, Fanucchi MP, Nadella P, Rogatko A, Shin DM, El-Rayes B, Khuri FR, Kauh JS
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2013 Mar 05; Vol. 108 (4), pp. 762-5. Date of Electronic Publication: 2013 Jan 15.
DOI: 10.1038/bjc.2012.604
Abstrakt: Background: 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.
Databáze: MEDLINE
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