Phase I clinical trial of DNA methyltransferase inhibitor decitabine and PARP inhibitor talazoparib combination therapy in relapsed/refractory acute myeloid leukemia
Mené sur 25 patients atteints d'une leucémie myéloïde aiguë réfractaire ou récidivante, cet essai de phase I évalue la dose maximale tolérée de la décitabine (un inhibiteur des méthyltransférases de l'ADN) en combinaison avec le talazoparib (un inhibiteur de PARP), et analyse les caractéristiques pharmacodynamiques de cette combinaison
Purpose: Acute myeloid leukemia (AML) patients unfit for, or resistant to, intensive chemotherapy are often treated with DNA methyltransferase inhibitors (DNMTis). Novel combinations may increase efficacy. In addition to demethylating CpG island gene promoter regions, DNMTis enhance poly (ADP-ribose) polymerase (PARP1) recruitment and tight binding to chromatin, preventing PARP-mediated DNA repair, downregulating homologous recombination (HR) DNA repair and sensitizing cells to PARP inhibitor (PARPi). We previously demonstrated DNMTi and PARPi combination efficacy in AML in vitro and in vivo. Here we report a phase I clinical trial combining the DNMTi decitabine and the PARPi talazoparib in refractory/relapsed AML.
Experimental Design: Decitabine and talazoparib doses were escalated using a 3 + 3 design. Pharmacodynamic studies were performed on Cycle 1 Days 1 (pre-treatment), 5 and 8 blood blasts.
Results: Doses were escalated in seven cohorts [25 patients, including 22 previously treated with DNMTi(s)] to a recommended phase II dose combination of decitabine 20 mg/m2 intravenously daily for 5 or 10 days and talazoparib 1 mg orally daily for 28 days, in 28-day cycles. Grade 3-5 events included fever in 19 and lung infections in 15, attributed to AML. Responses included complete remission with incomplete count recovery in two patients (8%) hematologic improvement in three. Pharmacodynamic studies showed the expected DNA demethylation, increased PARP trapping in chromatin, increased gH2AX foci and decreased HR activity in responders. gH2AX foci increased significantly with increasing talazoparib doses combined with 20 mg/m2 decitabine.
Conclusions: Decitabine/talazoparib combination was well tolerated. Expected pharmacodynamic effects occurred, especially in responders.
Clinical Cancer Research , résumé, 2021