A phase 1 study of the PARP inhibitor veliparib in combination with temozolomide in acute myeloid leukemia
Mené sur 48 patients atteins d'une leucémie myéloïde aiguë récidivante et réfractaire, cet essai de phase I évalue la dose maximale tolérée et l'activité antitumorale du véliparib, un inhibiteur de PARP, en combinaison avec le témozolomide
PURPOSE: In preclinical studies the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arising from aggressive myeloid malignancies. EXPERIMENTAL DESIGN: Patients received veliparib (20-200 mg once a day on day 1 and twice daily on days 4-12 in cycle 1 [days 1-8 in cycle {greater than or equal to}2]) and temozolomide (150-200 mg/m2 daily on days 3-9 in cycle 1 [days 1-5 in cycle {greater than or equal to}2]) every 28-56 days. Veliparib pharmacokinetics and pharmacodynamics [ability to inhibit poly(ADP-ribose) polymer (PAR) formation and induce H2AX phosphorylation] were assessed. Pretreatment levels of MGMT and PARP1 protein, methylation of the MGMT promoter and integrity of the Fanconi Anemia pathway were also examined. RESULTS: Forty-eight patients were treated at seven dose levels. Dose-limiting toxicities were oral mucositis and esophagitis lasting >7 days. The maximum tolerated dose was veliparib 150 mg twice daily with temozolomide 200 mg/m2 daily. The complete response (CR) rate was 17% (8/48 patients). Veliparib exposure as well as inhibition of PAR polymer formation increased dose proportionately. A veliparib-induced increase in H2AX phosphorylation in CD34+ cells was observed in responders. Three of 4 patients with MGMT promoter methylation achieved CR. CONCLUSIONS: Veliparib plus temozolomide is well tolerated, with activity in advanced AML. Further evaluation of this regimen and of treatment-induced phosphorylation of H2AX and MGMT methylation as potential response predictors appears warranted.