Veliparib (ABT-888), Bendamustine, and Rituximab (VBR) Is Well Tolerated and Efficacious in Patients with Lymphoma: Final Analysis of a Phase 1b Clinical Trial of VB and a Cohort Expansion of Vbr in Patients with B-Cell Lymphoma

Background:

PARP is overexpressed in many malignancies and protects against chemotherapy-induced genetic damage. The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. Bendamustine is an alkylator with activity in several lymphoid malignancies, multiple myeloma, and solid tumors. Bendamustine plus rituximab (BR) is highly active in indolent B-cell lymphomas, with overall (ORR) and complete response rates (CRR) of 90-92% and 41-60%, respectively. We therefore completed a phase 1b trial of veliparib plus bendamustine (VB) in patients with solid tumors, lymphoma and myeloma, as well as a cohort expansion of veliparib, bendamustine and rituximab (VBR) in patients with CD20+ B-cell lymphomas. We report here final response data with 10.5 months (median) of follow up for all patients with lymphoma included in this trial.

Methods:

Patients with relapsed solid tumors, lymphoma and multiple myeloma with no standard curative options were eligible for the dose escalation portion of this trial. We have previously reported the results of the dose escalation portion, wherein MTD was established at level 6 (veliparib 300mg PO BID plus bendamustine 90 mg/m²). In the cohort expansion, patients with CD20+ B-cell lymphoma (excluding Burkitt and Burkitt-like lymphoma) were treated with bendamustine 90mg/m² IV days 1 and 2, veliparib 300 mg PO bid on days 1-7 and rituximab 375 mg/m² on day 1 of each 28-day cycle, for a total 6 cycles.

Results:

Lymphoma histologies (n=15) were FL (7), DLBCL, transformed FL, or Richter's transformation (4), classical Hodgkin lymphoma (3) and MCL (1). Eight patients received VB in the dose escalation portion and 7 received VBR in the cohort expansion (all CD20+ NHL). Fourteen patients were evaluable for response. One patient with FL in the dose escalation cohort was withdrawn for inability to swallow study drug. Median age was 66 (26-82), median number of prior therapies was 3 (1-10), 7 were refractory to prior therapy, 3 received prior bendamustine, and all patients with CD20+ disease received prior rituximab.

Among 7 patients who received VB in the dose escalation cohort, ORR and CRR were 5/7 (71%) and 4/7 (57%). Median PFS is 6.9 months (range 1.6 - 31.3), and 4 of 5 responding patients have progressed. Among 7 patients who received VBR in the cohort expansion, ORR and CRR were 6/7 (86%) and 5/7 (71%). Median PFS is not yet reached at 12.4 months (range 2.0-17.1), and 2 of 6 responding patients have progressed. All patients with FL achieved CR (including 1 VB, 5 VBR).

Toxicities in the cohort expansion are similar to those from the dose escalation study. DLTs were grade 4 anemia and grade 3 nausea, hypertension and hyperhidrosis. No DLTs were seen in the cohort expansion. Among all 42 patients treated on study with either VB or VBR, grade ≥3 toxicities were lymphopenia (85.7%), anemia (19%), neutropenia (11.9%), thrombocytopenia (9.5%), leukopenia (7.1%), fatigue (4.8%), nausea (4.8%), sepsis (4.8%), anorexia (2.4%), transaminitis (2.4%), duodenal hemorrhage (2.4%) and hyperhidrosis (2.4%).

Conclusions:

VBR is tolerated and efficacious in patients with B-cell lymphoma, particularly among patients with follicular lymphoma. These data warrant further investigation of VBR in a phase II clinical trial.