A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas

Shivaani Kummar, Jiuping Ji, Robert Morgan, Heinz Josef Lenz, Shannon L. Puhalla, Chandra Belani, David R. Gandara, Deborah Allen, Brian Kiesel, Jan H. Beumer, Edward M. Newman, Larry Rubinstein, Alice Chen, Yiping Zhang, Lihua Wang, Robert J. Kinders, Ralph E. Parchment, Joseph E. Tomaszewski, James H. Doroshow

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Abstract

Purpose: Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies. Experimental Design: Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics (PK); measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMC); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTC). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days. Results: Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels (DL); γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration. Conclusions: The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared with single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma.

Original languageEnglish (US)
Pages (from-to)1726-1734
Number of pages9
JournalClinical Cancer Research
Volume18
Issue number6
DOIs
StatePublished - Mar 15 2012

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Cyclophosphamide
Lymphoma
Neoplasms
Maximum Tolerated Dose
Triple Negative Breast Neoplasms
Poly Adenosine Diphosphate Ribose
Circulating Neoplastic Cells
Biopsy
Alkylating Agents
veliparib
Genetic Markers
Ovarian Neoplasms
Non-Hodgkin's Lymphoma
DNA Damage
Oral Administration
Blood Cells
Research Design
Pharmacokinetics
Safety
Mutation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kummar, Shivaani ; Ji, Jiuping ; Morgan, Robert ; Lenz, Heinz Josef ; Puhalla, Shannon L. ; Belani, Chandra ; Gandara, David R. ; Allen, Deborah ; Kiesel, Brian ; Beumer, Jan H. ; Newman, Edward M. ; Rubinstein, Larry ; Chen, Alice ; Zhang, Yiping ; Wang, Lihua ; Kinders, Robert J. ; Parchment, Ralph E. ; Tomaszewski, Joseph E. ; Doroshow, James H. / A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 6. pp. 1726-1734.
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title = "A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas",
abstract = "Purpose: Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies. Experimental Design: Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics (PK); measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMC); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTC). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days. Results: Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50{\%}) and tumor biopsies (by at least 80{\%}) across dose levels (DL); γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration. Conclusions: The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared with single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma.",
author = "Shivaani Kummar and Jiuping Ji and Robert Morgan and Lenz, {Heinz Josef} and Puhalla, {Shannon L.} and Chandra Belani and Gandara, {David R.} and Deborah Allen and Brian Kiesel and Beumer, {Jan H.} and Newman, {Edward M.} and Larry Rubinstein and Alice Chen and Yiping Zhang and Lihua Wang and Kinders, {Robert J.} and Parchment, {Ralph E.} and Tomaszewski, {Joseph E.} and Doroshow, {James H.}",
year = "2012",
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pages = "1726--1734",
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Kummar, S, Ji, J, Morgan, R, Lenz, HJ, Puhalla, SL, Belani, C, Gandara, DR, Allen, D, Kiesel, B, Beumer, JH, Newman, EM, Rubinstein, L, Chen, A, Zhang, Y, Wang, L, Kinders, RJ, Parchment, RE, Tomaszewski, JE & Doroshow, JH 2012, 'A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas', Clinical Cancer Research, vol. 18, no. 6, pp. 1726-1734. https://doi.org/10.1158/1078-0432.CCR-11-2821

A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. / Kummar, Shivaani; Ji, Jiuping; Morgan, Robert; Lenz, Heinz Josef; Puhalla, Shannon L.; Belani, Chandra; Gandara, David R.; Allen, Deborah; Kiesel, Brian; Beumer, Jan H.; Newman, Edward M.; Rubinstein, Larry; Chen, Alice; Zhang, Yiping; Wang, Lihua; Kinders, Robert J.; Parchment, Ralph E.; Tomaszewski, Joseph E.; Doroshow, James H.

In: Clinical Cancer Research, Vol. 18, No. 6, 15.03.2012, p. 1726-1734.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas

AU - Kummar, Shivaani

AU - Ji, Jiuping

AU - Morgan, Robert

AU - Lenz, Heinz Josef

AU - Puhalla, Shannon L.

AU - Belani, Chandra

AU - Gandara, David R.

AU - Allen, Deborah

AU - Kiesel, Brian

AU - Beumer, Jan H.

AU - Newman, Edward M.

AU - Rubinstein, Larry

AU - Chen, Alice

AU - Zhang, Yiping

AU - Wang, Lihua

AU - Kinders, Robert J.

AU - Parchment, Ralph E.

AU - Tomaszewski, Joseph E.

AU - Doroshow, James H.

PY - 2012/3/15

Y1 - 2012/3/15

N2 - Purpose: Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies. Experimental Design: Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics (PK); measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMC); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTC). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days. Results: Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels (DL); γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration. Conclusions: The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared with single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma.

AB - Purpose: Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies. Experimental Design: Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics (PK); measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMC); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTC). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days. Results: Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels (DL); γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration. Conclusions: The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared with single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma.

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U2 - 10.1158/1078-0432.CCR-11-2821

DO - 10.1158/1078-0432.CCR-11-2821

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SP - 1726

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JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

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