The PARP inhibitor veliparib can be safely added to bendamustine and rituximab and has preliminary evidence of activity in B-cell lymphoma

Jacob D. Soumerai, Andrew D. Zelenetz, Craig Moskowitz, M. Lia Palomba, Paul A. Hamlin, Ariela Noy, David J. Straus, Alison J. Moskowitz, Anas Younes, Matthew J. Matasar, Steven M. Horwitz, Carol S. Portlock, Jason A. Konner, Mrinal M. Gounder, David M. Hyman, Martin H. Voss, Matthew G. Fury, Devika Gajria, Richard D. Carvajal, Alan L. HoJan H. Beumer, Brian Kiesel, Zhigang Zhang, Alice Chen, Richard F. Little, Christine Jarjies, Thu O. Dang, Fallon France, Nishant Mishra, John F. Gerecitano

Research output: Contribution to journalArticle

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Abstract

Purpose: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase I study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas. Experimental Design: This dose-escalation study evaluated safety, pharmacokinetics, and preliminary efficacy of veliparib (20–400 mg twice a day, days 1–7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 intravenously, days 1 and 2). A cohort expansion was conducted, which combined veliparib and bendamustine at the maximum tolerated dose (MTD) with rituximab (375 mg/m2, day 1) in patients with B-cell lymphomas. Thirty-four patients were treated in seven dose-escalation cohorts and seven patients in the dose-expansion cohort. Results: The MTD was veliparib 300 mg twice daily plus bendamustine 90 mg/m2. Dose-limiting toxicities (DLT) were anemia, nausea, hypertension, and hyperhidrosis. Grade ≥3 toxicities included lymphopenia (87.8%), anemia (19.5%), neutropenia (12.2%), thrombocytopenia (9.8%), leukopenia (9.8%), nausea (7.3%), and hypophosphatemia (7.3%). Apparent veliparib clearance was slightly lower than previously reported. Of 14 patients with lymphoma evaluable for response, five of seven (71%) on VB and six of seven (86%) on VBR achieved objective response. One patient with multiple myeloma achieved partial response. Conclusions: VB and VBR were generally well-tolerated. VBR had preliminary clinical activity in patients with B-cell lymphoma, which warrants further investigation in a phase II trial. This trial was registered at www.clinicaltrials.gov as NCT01326702.

Original languageEnglish (US)
Pages (from-to)4119-4126
Number of pages8
JournalClinical Cancer Research
Volume23
Issue number15
DOIs
StatePublished - Aug 1 2017
Externally publishedYes

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B-Cell Lymphoma
Maximum Tolerated Dose
Alkylating Agents
Multiple Myeloma
Nausea
Anemia
Lymphoma
Hypophosphatemia
Hyperhidrosis
Lymphopenia
Poly(ADP-ribose) Polymerase Inhibitors
veliparib
Bendamustine Hydrochloride
Rituximab
Leukopenia
Neutropenia
Thrombocytopenia
Research Design
Pharmacokinetics
Hypertension

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The PARP inhibitor veliparib can be safely added to bendamustine and rituximab and has preliminary evidence of activity in B-cell lymphoma. / Soumerai, Jacob D.; Zelenetz, Andrew D.; Moskowitz, Craig; Palomba, M. Lia; Hamlin, Paul A.; Noy, Ariela; Straus, David J.; Moskowitz, Alison J.; Younes, Anas; Matasar, Matthew J.; Horwitz, Steven M.; Portlock, Carol S.; Konner, Jason A.; Gounder, Mrinal M.; Hyman, David M.; Voss, Martin H.; Fury, Matthew G.; Gajria, Devika; Carvajal, Richard D.; Ho, Alan L.; Beumer, Jan H.; Kiesel, Brian; Zhang, Zhigang; Chen, Alice; Little, Richard F.; Jarjies, Christine; Dang, Thu O.; France, Fallon; Mishra, Nishant; Gerecitano, John F.

In: Clinical Cancer Research, Vol. 23, No. 15, 01.08.2017, p. 4119-4126.

Research output: Contribution to journalArticle

Soumerai, JD, Zelenetz, AD, Moskowitz, C, Palomba, ML, Hamlin, PA, Noy, A, Straus, DJ, Moskowitz, AJ, Younes, A, Matasar, MJ, Horwitz, SM, Portlock, CS, Konner, JA, Gounder, MM, Hyman, DM, Voss, MH, Fury, MG, Gajria, D, Carvajal, RD, Ho, AL, Beumer, JH, Kiesel, B, Zhang, Z, Chen, A, Little, RF, Jarjies, C, Dang, TO, France, F, Mishra, N & Gerecitano, JF 2017, 'The PARP inhibitor veliparib can be safely added to bendamustine and rituximab and has preliminary evidence of activity in B-cell lymphoma', Clinical Cancer Research, vol. 23, no. 15, pp. 4119-4126. https://doi.org/10.1158/1078-0432.CCR-16-3068
Soumerai, Jacob D. ; Zelenetz, Andrew D. ; Moskowitz, Craig ; Palomba, M. Lia ; Hamlin, Paul A. ; Noy, Ariela ; Straus, David J. ; Moskowitz, Alison J. ; Younes, Anas ; Matasar, Matthew J. ; Horwitz, Steven M. ; Portlock, Carol S. ; Konner, Jason A. ; Gounder, Mrinal M. ; Hyman, David M. ; Voss, Martin H. ; Fury, Matthew G. ; Gajria, Devika ; Carvajal, Richard D. ; Ho, Alan L. ; Beumer, Jan H. ; Kiesel, Brian ; Zhang, Zhigang ; Chen, Alice ; Little, Richard F. ; Jarjies, Christine ; Dang, Thu O. ; France, Fallon ; Mishra, Nishant ; Gerecitano, John F. / The PARP inhibitor veliparib can be safely added to bendamustine and rituximab and has preliminary evidence of activity in B-cell lymphoma. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 15. pp. 4119-4126.
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abstract = "Purpose: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase I study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas. Experimental Design: This dose-escalation study evaluated safety, pharmacokinetics, and preliminary efficacy of veliparib (20–400 mg twice a day, days 1–7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 intravenously, days 1 and 2). A cohort expansion was conducted, which combined veliparib and bendamustine at the maximum tolerated dose (MTD) with rituximab (375 mg/m2, day 1) in patients with B-cell lymphomas. Thirty-four patients were treated in seven dose-escalation cohorts and seven patients in the dose-expansion cohort. Results: The MTD was veliparib 300 mg twice daily plus bendamustine 90 mg/m2. Dose-limiting toxicities (DLT) were anemia, nausea, hypertension, and hyperhidrosis. Grade ≥3 toxicities included lymphopenia (87.8{\%}), anemia (19.5{\%}), neutropenia (12.2{\%}), thrombocytopenia (9.8{\%}), leukopenia (9.8{\%}), nausea (7.3{\%}), and hypophosphatemia (7.3{\%}). Apparent veliparib clearance was slightly lower than previously reported. Of 14 patients with lymphoma evaluable for response, five of seven (71{\%}) on VB and six of seven (86{\%}) on VBR achieved objective response. One patient with multiple myeloma achieved partial response. Conclusions: VB and VBR were generally well-tolerated. VBR had preliminary clinical activity in patients with B-cell lymphoma, which warrants further investigation in a phase II trial. This trial was registered at www.clinicaltrials.gov as NCT01326702.",
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T1 - The PARP inhibitor veliparib can be safely added to bendamustine and rituximab and has preliminary evidence of activity in B-cell lymphoma

AU - Soumerai, Jacob D.

AU - Zelenetz, Andrew D.

AU - Moskowitz, Craig

AU - Palomba, M. Lia

AU - Hamlin, Paul A.

AU - Noy, Ariela

AU - Straus, David J.

AU - Moskowitz, Alison J.

AU - Younes, Anas

AU - Matasar, Matthew J.

AU - Horwitz, Steven M.

AU - Portlock, Carol S.

AU - Konner, Jason A.

AU - Gounder, Mrinal M.

AU - Hyman, David M.

AU - Voss, Martin H.

AU - Fury, Matthew G.

AU - Gajria, Devika

AU - Carvajal, Richard D.

AU - Ho, Alan L.

AU - Beumer, Jan H.

AU - Kiesel, Brian

AU - Zhang, Zhigang

AU - Chen, Alice

AU - Little, Richard F.

AU - Jarjies, Christine

AU - Dang, Thu O.

AU - France, Fallon

AU - Mishra, Nishant

AU - Gerecitano, John F.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Purpose: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase I study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas. Experimental Design: This dose-escalation study evaluated safety, pharmacokinetics, and preliminary efficacy of veliparib (20–400 mg twice a day, days 1–7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 intravenously, days 1 and 2). A cohort expansion was conducted, which combined veliparib and bendamustine at the maximum tolerated dose (MTD) with rituximab (375 mg/m2, day 1) in patients with B-cell lymphomas. Thirty-four patients were treated in seven dose-escalation cohorts and seven patients in the dose-expansion cohort. Results: The MTD was veliparib 300 mg twice daily plus bendamustine 90 mg/m2. Dose-limiting toxicities (DLT) were anemia, nausea, hypertension, and hyperhidrosis. Grade ≥3 toxicities included lymphopenia (87.8%), anemia (19.5%), neutropenia (12.2%), thrombocytopenia (9.8%), leukopenia (9.8%), nausea (7.3%), and hypophosphatemia (7.3%). Apparent veliparib clearance was slightly lower than previously reported. Of 14 patients with lymphoma evaluable for response, five of seven (71%) on VB and six of seven (86%) on VBR achieved objective response. One patient with multiple myeloma achieved partial response. Conclusions: VB and VBR were generally well-tolerated. VBR had preliminary clinical activity in patients with B-cell lymphoma, which warrants further investigation in a phase II trial. This trial was registered at www.clinicaltrials.gov as NCT01326702.

AB - Purpose: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase I study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas. Experimental Design: This dose-escalation study evaluated safety, pharmacokinetics, and preliminary efficacy of veliparib (20–400 mg twice a day, days 1–7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 intravenously, days 1 and 2). A cohort expansion was conducted, which combined veliparib and bendamustine at the maximum tolerated dose (MTD) with rituximab (375 mg/m2, day 1) in patients with B-cell lymphomas. Thirty-four patients were treated in seven dose-escalation cohorts and seven patients in the dose-expansion cohort. Results: The MTD was veliparib 300 mg twice daily plus bendamustine 90 mg/m2. Dose-limiting toxicities (DLT) were anemia, nausea, hypertension, and hyperhidrosis. Grade ≥3 toxicities included lymphopenia (87.8%), anemia (19.5%), neutropenia (12.2%), thrombocytopenia (9.8%), leukopenia (9.8%), nausea (7.3%), and hypophosphatemia (7.3%). Apparent veliparib clearance was slightly lower than previously reported. Of 14 patients with lymphoma evaluable for response, five of seven (71%) on VB and six of seven (86%) on VBR achieved objective response. One patient with multiple myeloma achieved partial response. Conclusions: VB and VBR were generally well-tolerated. VBR had preliminary clinical activity in patients with B-cell lymphoma, which warrants further investigation in a phase II trial. This trial was registered at www.clinicaltrials.gov as NCT01326702.

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