• Shivaani Kummar, Jiuping Ji, Robert Morgan, Heinz-Josef Lenz, Shannon L Puhalla, Chandra P 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, and James H Doroshow.
• National Cancer Institute, Bethesda, MD, USA.
• Clin Cancer Res. 2012 Mar 15; 18 (6): 1726-34.

PurposeOral 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 DesignObjectives 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.ResultsThirty-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.ConclusionsThe 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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