ABT-888 Plus Bendamustine Is Safe and Has Shown Preliminary Efficacy In Patients With Lymphoma

PARP is overexpressed in many malignancies, and can protect tumor cells from genetic damage. The PARP inhibitor ABT-888 (A) enhances the cytotoxicity of several alkylating agents. Since bendamustine (B) is an alkylator with promising clinical activity in a variety of lymphoid malignancies and some solid tumors, we have executed a phase 1b trial combining ABT-888 with bendamustine in patients with solid tumors, lymphomas and multiple myeloma. The primary aim of this study is to determine the safety and MTD of ABT-888 in combination with bendamustine, with secondary aims of establishing response rates and pharmacokinetic parameters of ABT-888 in this combination. We report here the results of the dose escalation portion of this study.

Patients with relapsed solid tumors, lymphoma and multiple myeloma with no standard curative options were eligible for enrollment to the dose escalation portion of this trial. Patients were treated with escalating doses of bendamustine (70 to 90mg/m² IV days 1 and 2) and ABT-888 (30 to 400 mg PO bid x7) over 7 days each 28 day cycle. Planned treatment duration was 6 cycles, with the option of additional cycles in cases of clinical benefit.

29 patients are evaluable for study endpoints to date, including 21 with solid tumors and 8 with lymphoma. 4 DLTs were seen: one grade 4 anemia (at A=100/B=90), one grade 3 nausea (at A=300/B=90), one grade 3 hypertension and one grade 3 hyperhidrosis. The latter 2 DLTs were seen at the Maximum Administered Dose (MAD : A=400/B=90), and the Maximum Tolerated Dose (MTD) was therefore A=300mg/B=90mg/m². Grade 3/4 toxicities to date that have occurred in more than one patient and are possibly related to treatment include anemia (n=3), thrombocytopenia (n=3), neutropenia (n=2), hematuria (n=2), nausea (n=2), abdominal pain (n=2), hypertension (n=2), pneumonia (n=2) and sepsis (n=2). There was one death due to sepsis on trial that was deemed possibly related to treatment due to its development during a possible neutropenic period after cycle 4 of treatment. There were no objective responses seen in patients with solid tumors. Of the 8 patients with relapsed/refractory lymphoma, best responses were: 3 HL (1CR, 2PR), 1 DLBCL (PD), 1 transformed FL (SD), 2 FL (1 CR, 1 pending), 1 MCL (CR). The one patient with multiple myeloma studied on trial achieved a PR. Pharmacokinetic analysis has shown no significant affect of bendamustine on Cmax, Tmax, AUC or volume of distribution of ABT-888 compared with historical single-agent analyses. Data will be updated in the final presentation, as the last patients enrolled have not yet completed their full safety and efficacy assessments.

ABT-888 plus bendamustine is tolerable in patients with solid tumors, myeloma and lymphoma, with an MTD of ABT-888 300mg bid days 1-7 plus bendamustine 90mg/m² days 1 and 2 of each 28-day cycle. This regimen has shown efficacy in lymphoma and myeloma, although it is unclear if ABT-888 adds benefit to bendamustine alone. A cohort expansion is planned to assess the safety and preliminary efficacy of this regimen at the MTD in combination with rituximab in patients with B-cell non-Hodgkin Lymphomas.

Off Label Use: novel drug combination.