title: Bayesian Dose Finding for Combined Drugs with Discrete and Continuous Doses.
abstract: The trend of treating patients with combined drugs has grown in cancer clinical trials. Often, evaluating the synergism of multiple drugs is the primary motivation for such drug-combination studies. To enhance the patient response, a new cancer therapeutic agent is often investigated together with an existing standard of care (SOC) agent. At least a certain amount of dosage of the SOC is administered in order to maintain some therapeutic effects in patients. For clinical trials involving a continuous-dose SOC and a discrete-dose agent, we propose a two-stage Bayesian adaptive dose-finding design. The first stage takes a continual reassessment method to locate the appropriate dose for the discrete-dose agent while fixing the continuous-dose SOC at the minimal therapeutic dose. In the second stage, we make a fine dose adjustment by calibrating the continuous dose to achieve the target toxicity rate as closely as possible. Dose escalation or de-escalation is based on the posterior estimates of the joint toxicity probabilities of combined doses. As the toxicity data accumulate during the trial, we adaptively assign each cohort of patients to the most appropriate dose combination. We conduct extensive simulation studies to examine the operating characteristics of the proposed two-stage design and demonstrate the design's good performance with practical scenarios.
authors: Novartis Pharmaceuticals Corporation.
authors: Lin
authors: L
authors: Huo
authors: Ying
authors: Y
authors: Yuan
authors: Guosheng
authors: G
authors: Yin
keywords: Bayesian adaptive design; Combined drugs; Continual reassessment method; Maximum tolerated dose; Phase I trial; Toxicity probability; Two-stage design
references: Stat Med. 2008 Nov 29;27(27):5664-78
references: 18618901
references: J Clin Oncol. 1993 Apr;11(4):794-801
references: 8478673
references: Biometrics. 2005 Mar;61(1):217-22
references: 15737096
references: Biometrics. 2010 Sep;66(3):805-12
references: 19995354
references: Stat Med. 2001 Sep 15-30;20(17-18):2661-81
references: 11523075
references: Biometrics. 2007 Mar;63(1):173-9
references: 17447942
references: Biometrics. 1989 Sep;45(3):925-37
references: 2790129
references: Cancer Chemother Pharmacol. 1998;41(6):429-36
references: 9554585
references: Biometrics. 1990 Mar;46(1):33-48
references: 2350571
references: Biometrics. 2003 Sep;59(3):487-96
references: 14601749
references: Int J Clin Oncol. 2001 Dec;6(6):271-8
references: 11828945
references: Stat Med. 1995 Jun 15;14(11):1149-61
references: 7667557
references: Stat Med. 2002 Sep 30;21(18):2757-70
references: 12228889
references: Biometrics. 2011 Dec;67(4):1555-63
references: 21361888
references: Stat Med. 1999 Jul 30;18(14):1849-64
references: 10407256
references: Stat Med. 2002 Jan 15;21(1):51-63
references: 11782050
references: Stat Med. 1999 Jun 15;18(11):1307-21
references: 10399198
references: Stat Med. 1995 May 15-30;14(9-10):911-22; discussion 923
references: 7569510