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. Poly(ADP-ribose) polymerase (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; measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMCs); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTCs). 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; 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 to single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma.

Sulfur and nitrogen mustards induce characteristic poly(ADP-ribosyl)ation responses in HaCaT keratinocytes with distinctive cellular consequences

“…Interestingly, some studies indeed support such a scenario. For example PARP inhibitors potentiated the effect of cyclophospha mide in preclinical tumor models (Donawho et al, 2007;Norris et al, 2014), and clinical trials have been set up to further examine the tolerability and effectiveness of this drug combination (Kummar et al, 2012) (www.clinicaltrials.gov). Our results with chlorambucil and HN2 suggest that it may be worthwhile to consider also other combinations of PARP inhibitors with mustard based chemotherapeutics as treatment options.…”

ABCB1, ABCG2, and PTEN Determine the Response of Glioblastoma to Temozolomide and ABT-888 Therapy

“…Recent clinical trials report a peak plasma level of 500 ng/mL with an AUC of 3,500 ng/mL Ã h (35). Previous preclinical studies have been using much higher doses of up to 50 mg/kg.…”

Predictive biomarkers for cancer therapy with PARP inhibitors

“…162 However, the association of olaparib with metronomic cyclophosphamide or TMZ is rather well tolerated, allowing full-dose administration of chemotherapy. 163,164 In chemonaïve metastatic melanoma, the combination therapy with TMZ seems of real interest. In a phase I trial, one patient benefited from a complete response that has been lasting for 45 years post therapy.…”