Comments on ‘Competing designs for drug combination in phase I dose‐finding clinical trials’ by M‐K. Riviere, F. Dubois, S. Zohar

In a recent paper, Riviere, Dubois, and Zohar [1] conducted a comparative study of dose-finding methods for two-agent combination phase I oncology trials. One of the methods presented by the authors in their comparison was the partial order continual reassessment method (POCRM; [2]). Unfortunately, some of the design choices made by the authors in their implementation of POCRM hindered its performance in some scenarios. The purpose of this letter is to show how Riviere et al. [1] could have better implemented POCRM in conducting their simulation study. Specifically, the following claims are addressed and further clarification provided to ensure that accurate implementation of POCRM is followed. “As most real clinical trials begin at the lowest dose, we think that this method (POCRM) should be modified to allow initiating the trial at the lowest combination while adding ‘nonskipping’ rules or a start-up phase.” POCRM has already been modified to include a start-up phase that begins at the lowest dose combination, and work that was published by Wages, Conaway and O’Quigley [3] in 2011 evaluated the operating characteristics of this modification. POCRM was the only model-based method of those compared by Riviere et al. [1] in which the authors chose not to include a start-up phase, even though a modified version of POCRM that includes such a phase has already been published [3], and is accompanied by publically available software [4]. “Another important modification that we have added to the POCRM is the recommendation to start at the lowest dose. We have based our decision on common practice in Phase I for a single agent or a combination of agents.” As stated above, POCRM has already been modified to begin at the lowest dose combination [3]. In contrast, the modification made to POCRM by Riviere et al. [1] was not only to begin at the lowest dose of each agent (i.e. combination D1,1), but to do so within a Bayesian framework using priors and skeletons that center the prior MTD at combinations D3,3, D4,3 or D5,2, depending on the dose-toxicity ordering. After beginning the trial at D1,1, in the absence of DLT in the first cohort, this modification will cause the design to gravitate toward the prior MTD (i.e. D3,3, D4,3 or D5,2), and such behavior would not be allowed in practice, as pointed out by the authors. Therefore, the modification made by the authors does not resolve any practical issue associated with the POCRM. The authors have chosen to make a modification that is not allowable in practice within an article that is meant to inform statisticians about how best to practically conduct Phase I trials of combinations. Wages and Conaway [5] published practical guidelines for implementing POCRM, yet the comparison by Riviere et al. [1] did not follow these recommendations, especially in choosing an appropriate subset of possible dose-toxicity orderings. The guidelines in [5], combined with an R package (pocrm [4]), have led to the successful implementation of POCRM in two ongoing trials since its publication in 2011. One recently completed accrual and is in follow-up (Mel 58) and the other (Mel 60) is open to accrual at two sites, the University of Virginia Cancer Center and MD Anderson Cancer Center. Descriptions of these trials can be found at https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01585350","term_id":"NCT01585350"}}NCT01585350?term=mel58&rank=1 and https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT02126579","term_id":"NCT02126579"}}NCT02126579?term=mel60&rank=1. The use of appropriate POCRM specifications in the comparative work of Riviere et al. [1] would have resulted in a more accurate evaluation of POCRM’s design characteristics, and provided the readers of Statistics in Medicine valuable insight on how the method fares relative to existing methods. In this letter, we focus our attention on proper selection of possible dose-toxicity orderings for use in the POCRM. In the subsequent sections, we review the recommendations of Wages and Conaway [5] in choosing orderings, and discuss their impact on the operating characteristics of POCRM. This sheds a very different light on the results and conclusions of Riviere [1].