Modern Dose-Finding Designs for Cancer Phase I Trials: Drug Combinations and Molecularly Targeted Agents

2018 ◽  
Author(s):  
Akihiro Hirakawa ◽  
Hiroyuki Sato ◽  
Takashi Daimon ◽  
Shigeyuki Matsui
Keyword(s):  
Phase I ◽  
Drug Combinations ◽  
Dose Finding ◽  
Phase I Trials ◽  
Targeted Agents ◽  
Molecularly Targeted Agents

scholarly journals Efficiency of New Dose Escalation Designs in Dose-Finding Phase I Trials of Molecularly Targeted Agents

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e51039 ◽  
Author(s):  
Christophe Le Tourneau ◽  
Hui K. Gan ◽  
Albiruni R. A. Razak ◽  
Xavier Paoletti
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Dose Finding ◽  
Phase I Trials ◽  
Targeted Agents ◽  
Molecularly Targeted Agents

Choice of Starting Dose for Molecularly Targeted Agents Evaluated in First-in-Human Phase I Cancer Clinical Trials

2010 ◽  
Vol 28 (8) ◽  
pp. 1401-1407 ◽  
Author(s):  
Christophe Le Tourneau ◽  
Anastasios Stathis ◽  
Laura Vidal ◽  
Malcolm J. Moore ◽  
Lillian L. Siu
Keyword(s):  
Phase I ◽  
Lethal Dose ◽  
Maximum Tolerated Dose ◽  
Cytotoxic Agents ◽  
Phase I Trials ◽  
Targeted Agents ◽  
Wide Range ◽  
Molecularly Targeted Agents ◽  
Starting Dose ◽  
Dose Levels

Purpose One tenth of the lethal dose to 10% of mice is one of the conventional parameters used to derive a safe starting dose in phase I trials of cytotoxic agents. There is no consensus on which preclinical models and parameters should define the starting dose for molecularly targeted agents. Patients and Methods Reports of 81 first-in-human phase I trials evaluating 60 different molecularly targeted agents administered as monotherapy were reviewed. The maximum-tolerated dose (MTD) was defined as the highest safe dose administered to patients, whereas the maximum-administered dose (MAD) was recorded if the MTD was not reached. Results Fifty-seven of the 81 trials specified the animal model used to determine the starting dose, with 29 (51%) of 57 based on rodent data and 28 (49%) of 57 based on non-rodent data. A wide range of toxicologic parameters was used to select the starting dose. The starting dose exceeded the human MTD in three (3.7%) of 81 trials, and in all three trials, nonhematologic toxicity was dose limiting. The median number of dose levels to reach MTD or MAD from starting dose was five (range, one to 14 dose levels), and the median ratio of MTD or MAD to starting dose was 12 (range, < 1 to 300). Hypothetical doubling of the starting dose appeared to be safe, whereas tripling of the starting dose was unsafe. Conclusion The derivation of starting dose for first-in-human phase I trials of molecularly targeted agents in patients with cancer is safe but is based on diverse practices using a variety of preclinical toxicologic parameters.

Dose-efficacy relationship for molecularly targeted agents: A literature review of monotherapy phase I cancer clinical trials.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13553-e13553
Author(s):  
Jennifer Arrondeau ◽  
Xavier Paoletti ◽  
Marie-Paule Sablin ◽  
Simona Pop ◽  
Christophe Le Tourneau
Keyword(s):  
Literature Review ◽  
Phase I ◽  
Response Rate ◽  
Statistical Significance ◽  
Maximum Tolerated Dose ◽  
Extensive Literature ◽  
Phase I Trials ◽  
Targeted Agents ◽  
Study Results ◽  
Molecularly Targeted Agents

e13553 Background: Data regarding the dose-efficacy relationship for molecularly targeted agents (MTAs) are conflicting and all based on institution data. We report the largest study evaluating this relationship based on an extensive literature review of phase I trials of MTAs administered as single agents over the last decade. Methods: Efficacy defined by the occurrence of partial or complete responses was recorded and related to the dose administered expressed as a percentage of the maximum tolerated dose (MTD) or the maximum administered dose (MAD) when the MTD was not reached. Association was estimated using logit model with random intercept to adjust for the study. Results: Hundred and sixty eight phase I trials evaluating 116 MTAs involving 5,668 patients were reviewed. Efficacy was present in 39% of trials, but in only 134 patients (2.3%). Among these 134 patients, the dose at which signs of efficacy occurred was known for 113 patients. Overall, the crude response rate slightly increased from 4% at doses <40% of the MTD/MAD to 6%, 7% and 7% at doses 40-80%, 80-120% and >120%, respectively. However, statistical significance was not reached (p=0.28), whether or not the MTD had been reached. Conclusions: Antitumor activity infrequently occurs in phase I trials of MTAs administered as single agents. Although efficacy seemed to increase with dose, statistical significance was not reached, possibly due to the low response rate and sample size.

scholarly journals Creatinine Clearance Is Associated with Toxicity from Molecularly Targeted Agents in Phase I Trials

Oncology ◽  
2012 ◽  
Vol 83 (4) ◽  
pp. 177-182
Author(s):  
B. Basu ◽  
J. Vitfell-Pedersen ◽  
V. Moreno Garcia ◽  
M. Puglisi ◽  
A. Tjokrowidjaja ◽  
...  
Keyword(s):  
Phase I ◽  
Creatinine Clearance ◽  
Phase I Trials ◽  
Targeted Agents ◽  
Molecularly Targeted Agents

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

2009 ◽  
Vol 100 (9) ◽  
pp. 1373-1378 ◽  
Author(s):  
S Postel-Vinay ◽  
H-T Arkenau ◽  
D Olmos ◽  
J Ang ◽  
J Barriuso ◽  
...  
Keyword(s):  
Phase I ◽  
Clinical Benefit ◽  
Phase I Trials ◽  
Targeted Agents ◽  
Molecularly Targeted Agents

Clinical benefit in phase I trials of novel molecularly targeted agents: Does dose matter?

2008 ◽  
Vol 26 (15_suppl) ◽  
pp. 2509-2509 ◽  
Author(s):  
S. C. Postel-Vinay ◽  
H. Arkenau ◽  
S. Ashley ◽  
J. Barriuso ◽  
D. Olmos ◽  
...  
Keyword(s):  
Phase I ◽  
Clinical Benefit ◽  
Phase I Trials ◽  
Targeted Agents ◽  
Molecularly Targeted Agents

Phase I Trials of Molecularly Targeted Agents: Should We Pay More Attention to Late Toxicities?

2011 ◽  
Vol 29 (13) ◽  
pp. 1728-1735 ◽  
Author(s):  
Sophie Postel-Vinay ◽  
Carlos Gomez-Roca ◽  
L. Rhoda Molife ◽  
Bhavesh Anghan ◽  
Antonin Levy ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trials ◽  
Targeted Agents ◽  
Conventional Chemotherapy ◽  
Treatment Interruptions ◽  
Molecularly Targeted Agents ◽  
Royal Marsden Hospital ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Dose Modifications

Purpose Phase I trials traditionally aim at determining the recommended phase II dose (RP2D) using grade ≥ 3 toxicity data from cycle 1 (C1) only. This design dates from the era of conventional chemotherapy and may not be relevant for new molecularly targeted agents (MTAs) usually administered in a chronic fashion and for which late or moderate toxicities may deserve particular attention. Patients and Methods All consecutive patients treated in phase I trials of MTAs at the Royal Marsden Hospital and Institut Gustave Roussy between January 2005 and July 2008 were included. Gastrointestinal, skin, and clinical renal toxicities of any grade and grades 3 to 4 toxic events of any type occurring at any cycle on treatment were recorded. Doses administered, treatment interruptions, dose modifications, and prescription of comedications were analyzed. Results A total of 445 patients (1,566 cycles; median treatment duration, 55 days) were included in 36 eligible trials; 790 toxicities (590, grade 1; 176, grade, 2; 24 grades, 3 to 4) and 1,819 toxicities (1,521, grade 1; 265, grade 2; 33, grades 3 to 4) were recorded during and after C1, respectively; 57% of the grades 3 to 4 toxicities occurred after C1; 50% of patients presented their worst-grade toxicity after C1. The risk of grades 3 to 4 toxicity was 3% in cycles 1 to 6 and was almost null afterwards. No cumulative toxicities were observed. Median toxicity duration was 15 days, with comedication administered in 68% of events. Conclusion Moderate and severe toxicities occur regularly after the first cycle in phase I trials of MTAs and may deserve increased attention in the RP2D process for these agents.

1232 POSTER Creatinine Clearance (CrCI) as a Predictive Marker for the Risk of Toxicity From Molecularly Targeted Agents (MTA) in Phase I Trials

2011 ◽  
Vol 47 ◽  
pp. S154
Author(s):  
J. Vitfell-Pedersen ◽  
B. Basu ◽  
V. Moreno ◽  
A. Tjokrowidjaja ◽  
M. Puglisi ◽  
...  
Keyword(s):  
Phase I ◽  
Creatinine Clearance ◽  
Predictive Marker ◽  
Phase I Trials ◽  
Targeted Agents ◽  
Molecularly Targeted Agents
Sign in / Sign up

Export Citation Format

Share Document