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. 2009 May 5;100(9):1373-8.
doi: 10.1038/sj.bjc.6605030.

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

S Postel-Vinay  1 , H-T Arkenau, D Olmos, J Ang, J Barriuso, S Ashley, U Banerji, J De-Bono, I Judson, S Kaye
Affiliations

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

S Postel-Vinay et al. Br J Cancer. .

Abstract

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.

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Figures

Figure 1
Figure 1
Overview of trial/patient database.
Figure 2
Figure 2
Best response at 3 months (Cohort A, B, and C). This waterfall plot represents the patients remaining progression free during the first 3 months on treatment; the column's colour corresponds to the dose-level cohort.
Figure 3
Figure 3
(A) Progression-free survival (PFS) of cohort A, B, and C. (B) Overall survival (OS) of cohort A, B, and C.
See this image and copyright information in PMC

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