Data from A Phase 1 Study of the PARP Inhibitor Veliparib in Combination with Temozolomide in Acute Myeloid Leukemia

• DOI: 10.1158/1078-0432.c.6525036.v1
• Publication Date: 2023-04-01T06:36:21Z
• Authors: Ivana Gojo; Jan H. Beumer; Keith W. Pratz; Michael A. McDevitt; Maria R. Baer; Amanda L. Blackford; B. Douglas Smith; Steven D. Gore; Hetty E. Carraway; Margaret M. Showel; Mark J. Levis; Amy E. Dezern; Douglas E. Gladstone; Jiuping Jay Ji; Lihua Wang; Robert J. Kinders; Marie Pouquet; Ismail Ali-Walbi; Michelle A. Rudek; Weijie Poh; James G. Herman; Larry M. Karnitz; Scott H. Kaufmann; Alice Chen; Judith E. Karp

<div>Abstract<p><b>Purpose:</b> In preclinical studies, the 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.</p><p><b>Experimental Design:</b> 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 ≥2)] and temozolomide [150–200 mg/m² daily on days 3–9 in cycle 1 (days 1–5 in cycle ≥2)] every 28 to 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 <i>MGMT</i> promoter, and integrity of the Fanconi anemia pathway were also examined.</p><p><b>Results:</b> Forty-eight patients were treated at seven dose levels. Dose-limiting toxicities were oral mucositis and esophagitis lasting >7 days. The MTD 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 <i>MGMT</i> promoter methylation achieved CR.</p><p><b>Conclusions:</b> Veliparib plus temozolomide is well tolerated, with activity in advanced AML. Further evaluation of this regimen and of treatment-induced phosphorylation of H2AX and <i>MGMT</i> methylation as potential response predictors appears warranted. <i>Clin Cancer Res; 23(3); 697–706. ©2016 AACR</i>.</p></div>