Abstract
Recommended phase II dose (RP2D) determination for combination therapy regimens is a constrained optimization problem of maximizing antitumor activity within the constraint of clinical tolerability to provide a wide therapeutic index. A methodology for addressing this problem was developed and tested using clinical and preclinical data from combinations of the investigational drugs TAK-117, a PI3Kα inhibitor, and TAK-228, a TORC1/2 dual inhibitor. Utilizing free fraction-corrected average concentrations, [Formula: see text] and [Formula: see text], which are the primary pharmacokinetic predictors of single-agent preclinical antitumor activity, a preclinical exposure-efficacy surface was characterized, allowing for nonlinear interactions between growth rate inhibition of the agents on a MDA-MB-361 cell line xenograft model. Logistic regression was used to generate an exposure-effect surface for [Formula: see text] and [Formula: see text] versus clinical toxicity outcomes [experiencing a dose-limiting toxicity (DLT)] in single-agent and combination dose-escalation studies. A maximum tolerated exposure curve was defined at which DLT probability was 25%; predicted antitumor activity along this curve was used to determine optimal RP2D. The toxicity constraint curve determined from early clinical data predicted that any clinically tolerable combination was unlikely to result in greater antitumor activity than either single-agent TAK-117 or TAK-228 administered at their respective MTDs. Similar results were obtained with 10 other cell lines, with one agent or the other predicted to outperform the combination. This methodology represents a general, principled way of evaluating and selecting optimal RP2D combinations in oncology. The methodology will be retested upon availability of clinical data from TAK-117/TAK-228 combination phase II studies.See related commentary by Mayawala et al., p. 6564.
Highlights
Synergy hypotheses for targeted anticancer combinations, based on concepts such as synthetic lethality and compensatory pathways [1,2,3,4,5,6,7], have led to renewed interest in developing novel–novel drug combinations
The toxicity constraint curve determined from early clinical data predicted that any clinically tolerable combination was unlikely to result in greater antitumor activity than either single-agent TAK-117 or TAK-228 administered at their respective MTDs
For prediction of the RP2D as a unique dose pair with maximum therapeutic index in a novel– novel drug combination, we propose that it be defined as the tolerable dose pair predicted to provide the strongest antitumor activity
Summary
Synergy hypotheses for targeted anticancer combinations, based on concepts such as synthetic lethality and compensatory pathways [1,2,3,4,5,6,7], have led to renewed interest in developing novel–novel drug combinations. The recommended phase II dose (RP2D) of novel–standard-of-care drug combinations is commonly predicted using a one-dimensional optimization problem, being represented by a single point, assuming that the standard-of-care drug dose is fixed. Predicting the RP2D of a novel–novel drug combination is a two-dimensional optimization problem, Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Patel: Merck, Kenilworth, New Jersey; current address for E. Biogen, Inc., Cambridge, Massachusetts; and current address for A.
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