Predictors for establishing recommended phase 2 doses: analysis of 320 dose-seeking oncology phase 1 trials.
BACKGROUND
For decades, determination of the recommended Phase 2 dose (RP2D) was based on the toxicity (especially the maximum tolerated dose or MTD) experienced by patients enrolled in dose-escalating Phase 1 trials investigating anti-cancer agents. Recent studies suggest that this toxicity-based strategy is not suitable for modern anti-cancer agents. We conducted a retrospective study to identify the risk factor(s) for failing to determine the RP2D according to the MTD.


METHODS
We analyzed 320 recently published (1997-2008) Phase 1 trials using the maximum tolerated dose (MTD) to define the P2RD. We analyzed the current definitions of RP2D and then identified the risk factors for not establishing the RP2D using the odds ratio and 95% confidence intervals. Interactions between these risk factors were explored using the logistic regression model and CHAID algorithm.


RESULTS
18% of contemporary dose-seeking Phase 1 trials did not identify a RP2D. The logistic regression analysis showed that the risk factors for not identifying the RP2D were: investigation of molecular targeted therapies (RR = 3.0, p = 0.0017), lack of justification of the starting dose (RR = 5.9, p = 0.0121) and lack of definition of the MTD (RR = 8.4, p = 0.0006). The CHAID algorithm confirmed the importance of the methodological parameters.


CONCLUSIONS
This study confirms the difficulty of determining the RP2D of molecular targeted therapy using conventional methods. However, it underlines the major importance of two methodological points: definition of the MTD and justification of the starting dose.
Département de Cancérologie Générale, Centre Oscar Lambret, 3 Rue F Combemale, 59020 Lille, France. n-penel@o-lambret.fr
Nicolas
N
Penel
Alain
A
Duhamel
Antoine
A
Adenis
Patrick
P
Devos
Nicolas
N
Isambert
Stéphanie
S
Clisant
Jacques
J
Bonneterre
D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D016001:Confidence Intervals; D019317:Evidence-Based Medicine; D006801:Humans; D016015:Logistic Models; D020714:Maximum Tolerated Dose; D058990:Molecular Targeted Therapy / Q000009:adverse effects; D016017:Odds Ratio; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents