Response-Based Dosing for Ponatinib: Model-Based Analyses of the Dose-Ranging OPTIC Study.

ABSTRACT

Optimizing Ponatinib Treatment in CP-CML (OPTIC) was a randomized, phase II dose-optimization trial of ponatinib in chronic phase-chronic myeloid leukemia (CP-CML) resistant to ≥ 2 tyrosine kinase inhibitors or with T315I mutation. Patients were randomized to starting doses of 45-, 30-, or 15-mg ponatinib once daily. Patients receiving 45- or 30-mg reduced to 15-mg upon achievement of ≤ 1% BCRABL1IS (≥ molecular response with 2-log reduction (MR2)). The exposure-molecular response relationship was described using a four-state, discrete-time Markov model. Time-to-event models were used to characterize the relationship between exposure and arterial occlusive events (AOEs), grade ≥ 3 neutropenia, and thrombocytopenia. Increasing systemic exposures were associated with increasing probability of transitioning from no response to ≥ MR1, and from MR1 to ≥ MR1, with odds ratios of 1.63 (95% confidence interval (CI), 1.06-2.73) and 2.05 (95% CI, 1.53-2.89) for a 15-mg dose increase, respectively. Ponatinib exposure was a significant predictor of AOEs (hazard ratio (HR) 2.05, 95% CI, 1.43-2.93, for a 15-mg dose increase). In the exposure-safety models for neutropenia and thrombocytopenia, exposure was a significant predictor of grade ≥ 3 thrombocytopenia (HR 1.31, 95% CI, 1.05-1.64, for a 15-mg dose increase). Model-based simulations predicted a clinically meaningful higher rate of ≥ MR2 response at 12 months for the 45-mg starting dose (40.4%) vs. 30-mg (34%) and 15-mg (25.2%). The exposure-response analyses supported a ponatinib starting dose of 45 mg with reduction to 15 mg at response for patients with CP-CML.