Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas

Abstract

A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I-targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and levels of poly(ADP-ribose) (PAR) and the DNA damage marker γH2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to coadminister ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m²/d and ABT-888 10 mg BID on days one to five of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in γH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We show a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I-mediated DNA damage in the clinic.

Trial registration: ClinicalTrials.gov NCT00553189.

Figure 1

Days of administration of ABT-888 (ABT) and topotecan (TPT) during cycle 1 for Schedules A, B, and C.

Figure 2

Tumor growth delay with revised ABT-888 and topotecan dosing schedules in mice bearing A375 human melanoma xenografts. Topotecan (1.5 mg/kg) was administered by intraperitoneal injection once a day for 5 consecutive days (QDx5) starting on study day 9. ABT-888 (3.13 mg/kg) was administered orally starting on study day 9 as follows, relative to topotecan: 1 hour before the first dose (QDx1), first and second doses (QDx2), first, second, and third doses (QDx3), and first, second, third, fourth, and fifth doses (QDx5). The antitumor efficacies of the revised dose schedules (1, 2, or 3 days of ABT-888 administration in combination with 5 days of topotecan), measured on day 31, were not significantly different from 5 days of ABT-888 administration. Animal weight loss did not exceed 10% in any cohort. Data presented as mean ± SD.

Figure 3

A, PAR levels relative to baseline (100%) in PBMCs collected at 2, 4, 7, and 24 h after the combination of ABT-888 and topotecan. Data presented as mean ± SEM for dose level (DL) 1 (n = 5), DL –1 (n = 3), DL –2 (n = 3), DL –3 (n = 7), and DL 1A (n = 5). PAR levels in many individual samples decreased to values below the limit of detection of the assay. B, PAR levels relative to baseline (100%) in PBMCs and pre- and post-dose tumor biopsies from patients 4 (DL 1), 8 (DL –1), and 15 (DL –3). Patients 4 and 8 were on Schedule A, and patient 15 was on Schedule B. *The baseline PAR level in PBMCs for patient 4 was below the required minimum for analysis.

Figure 4

A, Levels of γH2AX measured as percent nuclear area positive (%NAP) in PBMCs from patients on dose level –2 (dashed lines) and –3 (solid lines). B,γH2AX staining in PBMCs from the same patient at baseline (0 h) and 7 h after treatment with ABT-888 and topotecan on dose level –3. %NAP was increased after treatment. Arrows indicate γH2AX signal (in red).

Figure 5

A, Total CTCs isolated from patients on dose level –3 and 1A; data on day 5 was only available from patient 24. B, Percentage of CTCs positive for γH2AX from the same patient samples.