Safety and Early Efficacy Analysis of a Novel Combination of the PARP Inhibitor Veliparib (ABT-888) Plus Bendamustine and Rituximab in Patients with Lymphoma

Autor: John F. Gerecitano, Paul Hamlin, Steven M. Horwitz, Matthew J Matasar, Alison J. Moskowitz, Craig H. Moskowitz, Ariela Noy, Carol S Portlock, Maria Lia Palomba, David J. Straus, Anas Younes, Andrew D. Zelenetz, Alice Chen, Richard F Little, France Fallon, Juho Whang
Rok vydání: 2014
Předmět:
Zdroj: Blood. 124:1739-1739
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.v124.21.1739.1739
Popis: Background: PARP is overexpressed in many malignancies, and can protect tumor cells from chemotherapy related genetic damage. The PARP inhibitor veliparib (V) 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 V with B in patients with solid tumors, lymphomas and multiple myeloma. The dose escalation portion of this study was reported in 2013, and established an MTD of 300 mg bid V in combination with B. We are now completing a cohort expansion of V plus B and rituximab (R) in patients with B-cell lymphomas, concluding this phase 1 trial. We present updated results from lymphoma patients included in the dose escalation portion of the study and new data on the cohort expansion in patients with B-cell lymphomas. Methods: 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 with B-Cell lymphoma (excluding Burkitt and Burkitt-like lymphomas) were treated with B 90mg/m2 IV days 1 and 2, V 300 mg PO bid x7 days and R 375 mg/m2 on day 1 of each 28 day cycle. Planned treatment duration was 6 cycles, with the option of additional cycles in cases of clinical benefit. The cohort expansion was designed to treat 6 patients at the Maximum Tolerated Dose (MTD) of V and B to assess for tolerability with the addition of R. Cohorts were planned with reduced doses of V if dose limiting toxicities (DLT) were seen in >2/6 patients in the first cohort. Results: During the dose escalation phase, 8 patients with lymphoma were treated with B + V. The median number of prior therapies was 4 (range 1-10), and 3 patients received prior B. Six out of 7 evaluable patients responded, with 4 achieving complete remission (CR) and 3 partial remission (PR). Five responding patients have progressed, while one mantle cell lymphoma patient who achieved a CR remains in remission. Median Progression Free Survival in patients with lymphoma treated in the dose escalation phase is 7 months (range 1.8 – 17.4). Five of 6 patients with B-cell lymphoma have been enrolled to the expansion cohort portion of this study (in which R is added to B+V). Toxicities reported in expansion are similar to those from the escalation portion of the study, and include nausea, vomiting and myelosuppression. No DLTs have yet been observed, although one patient did not complete cycle 1 V due to grade 1 nausea before optimal antiemetics could be instituted. All toxicities to date have been grade 1 or 2, with the exception of grade 3 lymphopenia in one patient. Efficacy and additional safety data will be updated in the final presentation. Conclusions: R 375 mg/m2 added to the MTD of V plus B is tolerable in patients with B-cell lymphoma. To date, no additional DLTs have been seen after addition of R to the regimen. This regimen has shown efficacy in lymphoma, although it is unclear if V adds benefit to R/B and a phase II trial will be needed to differentiate the benefit of V. Disclosures Hamlin: Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy; Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding. Horwitz:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Research Funding; Infinity: Research Funding; Kiowa-Kirin: Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy.
Databáze: OpenAIRE
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