Clinical benefit in Phase-I trials of novel molecularly targeted agents: does dose matter?

• Published in: British journal of cancer Vol. 100; no. 9; pp. 1373 - 1378
• Main Authors: Postel-Vinay, S, Arkenau, H-T, Olmos, D, Ang, J, Barriuso, J, Ashley, S, Banerji, U, De-Bono, J, Judson, I, Kaye, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-05-2009; Nature Publishing Group
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - toxicity; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Cell division; Chemotherapy; Clinical Study; Clinical Trials, Phase I as Topic - standards; Clinical Trials, Phase I as Topic - statistics & numerical data; Cytotoxicity; Disease Progression; Drug dosages; Drug Resistance; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Epidemiology; Female; Humans; Male; Medical research; Medical sciences; Middle Aged; Molecular Medicine; Neoplasms - drug therapy; Oncology; Patient Selection; Toxicity; Tumors; Young Adult; United Kingdom > UK; molecularly targeted agents; non-progression rate; clinical benefit; Phase-I trial; maximal tolerated dose; Cancerology; Maximal dose; Targeted therapy; Phase I trial; Clinical trial
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605030

Phase-I trials traditionally involve dose-escalation to determine the maximal tolerated dose (MTD). With conventional chemotherapy, efficacy is generally deemed to be dose-dependent, but the same may not be applicable to molecularly targeted agents (MTAs). We analysed consecutive patients included in Phase-I trials at the Royal Marsden Hospital from 5 January 2005 to 6 June 2006. We considered only trials of monotherapy MTAs in which the MTD was defined. Three patient cohorts (A, B, and C) were identified according to the dose received as a percentage of the final trial MTD (0–33%, 34–65%, >66%). Potential efficacy was assessed using the non-progression rate (NPR), that is, complete/partial response or stable disease for at least 3 months by RECIST. A total of 135 patients having progressive disease before enrolment were analysed from 15 eligible trials. Median age was 57 years (20–86); male : female ratio was 1.8 : 1. Cohort A, B, and C included 28 (21%), 22 (16%), and 85 (63%) patients; NPR at 3 and 6 months was 21% and 11% (A), 50% and 27% (B), 31% and 14% (C), respectively,
P
=0.9. Median duration of non-progression (17 weeks; 95% CI=13–22) was not correlated with the MTD level,
P
=0.9. Our analysis suggests that the potential for clinical benefit is not confined to patients treated at doses close to the MTD in Phase-I trials of MTAs.