A phase 1 study of the PARP inhibitor veliparib in combination with temozolomide in acute myeloid leukemia.

A phase 1 study of the PARP inhibitor veliparib in combination with temozolomide in acute myeloid leukemia.

Clin Cancer Res. 2016 Aug 8;

Authors: Gojo I, Beumer JH, Pratz KW, McDevitt MA, Baer MR, Blackford AL, Smith BD, Gore SD, Carraway H, Showel MM, Levis MJ, Dezern A, Gladstone DE, Ji JJ, Wang L, Kinders R, Pouquet M, Ali-Walbi I, Rudek MA, Poh W, Herman JG, Karnitz L, Kaufmann SH, Chen A, Karp J

Abstract
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/m(2) 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/m(2) 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.

PMID: 27503200 [PubMed - as supplied by publisher]

from #ENT via xlomafota13 on Inoreader http://ift.tt/2b5S8uq
via IFTTT