Dose-response relationship in phase 1 clinical trials: a European Drug Development Network (EDDN) Collaboration Study

Victor Moreno Garcia, David Olmos, Carlos Gomez-Roca, Philippe A. Cassier, Rafael Morales-Barrera, Gianluca Del Conte, Elisa Gallerani, Andre Brunetto, Patrick Schoffski, Silvia Marsoni, Jan H. M. Schellens, Nicolas Pennel, Emile Voest, Jeffrey Evans, Ruth Plummer, Richard H. Wilson, Jean Charles Soria, Josep Tabernero, Jaap Verweij, Stan B. Kaye

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12 Citations (Scopus)

Abstract

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 6 months 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)
Original languageEnglish
Pages (from-to)5663-5671
Number of pages11
JournalClinical Cancer Research
Volume20
Issue number22
Early online date24 Sep 2014
DOIs
Publication statusPublished - 15 Nov 2014

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    Garcia, V. M., Olmos, D., Gomez-Roca, C., Cassier, P. A., Morales-Barrera, R., Del Conte, G., Gallerani, E., Brunetto, A., Schoffski, P., Marsoni, S., Schellens, J. H. M., Pennel, N., Voest, E., Evans, J., Plummer, R., Wilson, R. H., Soria, J. C., Tabernero, J., Verweij, J., & Kaye, S. B. (2014). Dose-response relationship in phase 1 clinical trials: a European Drug Development Network (EDDN) Collaboration Study. Clinical Cancer Research, 20(22), 5663-5671. https://doi.org/10.1158/1078-0432.CCR-14-0719