TY - JOUR
T1 - Dose-response relationship in phase I clinical trials
T2 - A European Drug Development Network (EDDN) collaboration study
AU - García, Victor Moreno
AU - Olmos, David
AU - Gomez-Roca, Carlos
AU - Cassier, Philippe A.
AU - Morales-Barrera, Rafael
AU - Del Conte, Gianluca
AU - Gallerani, Elisa
AU - Brunetto, Andre T.
AU - Schöoffski, Patrick
AU - Marsoni, Silvia
AU - Schellens, Jan H M
AU - Penel, Nicolas
AU - Voest, Emile
AU - Evans, Jeffrey
AU - Plummer, Ruth
AU - Wilson, Richard H.
AU - Soria, Jean Charles
AU - Tabernero, Josep
AU - Verweij, Jaap
AU - Kaye, Stan B.
PY - 2014/11/15
Y1 - 2014/11/15
N2 - Introduction: Because a dose-response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors. Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005-2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available. Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX ( N = 328). The objective response (OR) rate was 3% and disease control at 6months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%-80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003). Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%-80% of MTD).
AB - Introduction: Because a dose-response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors. Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005-2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available. Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX ( N = 328). The objective response (OR) rate was 3% and disease control at 6months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%-80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003). Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%-80% of MTD).
UR - http://www.scopus.com/inward/record.url?scp=84918595093&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84918595093&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-14-0719
DO - 10.1158/1078-0432.CCR-14-0719
M3 - Article
C2 - 25252757
AN - SCOPUS:84918595093
VL - 20
SP - 5663
EP - 5671
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 22
ER -