Moving Beyond Maximum Tolerated Dose for Targeted Oncology Drugs: Use of Clinical Utility Index to Optimize Venetoclax Dosage in Multiple Myeloma Patients

• Published in: Clinical pharmacology and therapeutics Vol. 102; no. 6; p. 970
• Main Authors: Freise, K J, Jones, A K, Verdugo, M E, Menon, R M, Maciag, P C, Salem, A H
• Format: Journal Article
• Language: English
• Published: United States 01.12.2017
• Subjects: Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bortezomib - therapeutic use; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - adverse effects; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Dexamethasone - therapeutic use; Dose-Response Relationship, Drug; Drug Dosage Calculations; Humans; Logistic Models; Maximum Tolerated Dose; Multiple Myeloma - drug therapy; Neutropenia - chemically induced; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - therapeutic use
• ISSN: 1532-6535
• DOI: 10.1002/cpt.712

Exposure-response analyses of venetoclax in combination with bortezomib and dexamethasone in previously treated patients with multiple myeloma (MM) were performed on a phase Ib venetoclax dose-ranging study. Logistic regression models were utilized to determine relationships, identify subpopulations with different responses, and optimize the venetoclax dosage that balanced both efficacy and safety. Bortezomib refractory status and number of prior treatments were identified to impact the efficacy response to venetoclax treatment. Higher venetoclax exposures were estimated to increase the probability of achieving a very good partial response (VGPR) or better through venetoclax doses of 1,200 mg. However, the probability of neutropenia (grade ≥3) was estimated to increase at doses >800 mg. Using a clinical utility index, a venetoclax dosage of 800 mg daily was selected to optimally balance the VGPR or better rates and neutropenia rates in MM patients administered 1-3 prior lines of therapy and nonrefractory to bortezomib.