TY - JOUR
T1 - Clinical benefit in Phase-I trials of novel molecularly targeted agents
T2 - Does dose matter
AU - Postel-Vinay, S.
AU - Arkenau, H. T.
AU - Olmos, D.
AU - Ang, J.
AU - Barriuso, J.
AU - Ashley, S.
AU - Banerji, U.
AU - De-Bono, J.
AU - Judson, I.
AU - Kaye, S.
N1 - Funding Information:
The Drug Development Unit at RMH/ICR is supported by an Experimental Cancer Medicine Centre grant from Cancer Research UK and the Department of Health and by a programme grant from Cancer Research UK. It also received support from the Department of Health as part of the NIHR Biomedical Research Centre at RMH. Sophie Postel-Vinay is supported by a fellowship from Institut Gustave-Roussy, Villejuif, France.
PY - 2009/5/5
Y1 - 2009/5/5
N2 - 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, P0.9. Median duration of non-progression (17 weeks; 95% CI13-22) was not correlated with the MTD level, P0.9. 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.
AB - 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, P0.9. Median duration of non-progression (17 weeks; 95% CI13-22) was not correlated with the MTD level, P0.9. 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.
KW - Clinical benefit
KW - Maximal tolerated dose
KW - Molecularly targeted agents
KW - Non-progression rate
KW - Phase-I trial
UR - http://www.scopus.com/inward/record.url?scp=65549149873&partnerID=8YFLogxK
U2 - 10.1038/sj.bjc.6605030
DO - 10.1038/sj.bjc.6605030
M3 - Article
C2 - 19401696
AN - SCOPUS:65549149873
SN - 0007-0920
VL - 100
SP - 1373
EP - 1378
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 9
ER -