A phase I trial of veliparib (ABT-888) and temozolomide in children with recurrent CNS tumors: a pediatric brain tumor consortium report

Most cytotoxic chemotherapy drugs induce single-strand DNA breaks, and radiation treatment induces double-strand DNA breaks. Repair of single-strand DNA breaks is mediated by multiple mechanisms, including the base-excision repair pathway, while double-strand DNA breaks are repaired by the homologous recombination (HR) and nonhomologous end-joining (NHEJ) repair pathways.1,2 Poly(ADP-ribose) polymerase (PARP) recognizes single- and double-strand DNA breaks3 and recruits and activates repair proteins from the base-excision,4 NHEJ,5,6 and HR repair pathways.4,7 Elevated PARP expression and/or activity may therefore mediate chemotherapy and radiation resistance and have indeed been demonstrated in numerous human cancers, including pediatric brain tumors.8–11 Veliparib (ABT-888) is an oral PARP inhibitor that potentiates anticancer activity of chemotherapy drugs,12,13 including temozolomide (TMZ), and enhances radiation efficacy.14–17 Several adult trials of veliparib and various chemotherapy agents,18–20 including TMZ,21,22 are ongoing. To explore the potential of veliparib as a novel treatment strategy in pediatric brain tumors, we previously showed that in a nonhuman primate model, the CSF-to-plasma ratio of veliparib was 57% ± 7%.23 We also demonstrated by immunohistochemistry (IHC) that PARP is highly expressed in pediatric medulloblastoma (MB) and glioblastoma multiforme (GBM) tumors but absent in postnatal normal brains, and veliparib treatment potently inhibited PARP activity in mouse orthotopic xenografts of pediatric MB and GBM and enhanced TMZ efficacy (X-N.L. and J.M.S., unpublished data). TMZ treatment in children with recurrent brain tumors showed only modest activity,24–26 with objective response rates ranging 5%–14%; although prior clinical data suggested a high rate of TMZ resistance in pediatric brain tumors, we hypothesized that such resistance to TMZ may be partially mediated by elevated PARP activity, and veliparib treatment may therefore abrogate PARP activity and improve response to TMZ. Here we report the results of our phase I trial of veliparib and TMZ in children with recurrent brain tumors. The primary objectives of the trial were: (i) to estimate the maximum tolerated dose (MTD) of veliparib and TMZ in children with recurrent brain tumors; (ii) to study veliparib pharmacokinetic (PK) and PARP inhibition in peripheral blood mononuclear cells (PBMCs); and (iii) to describe the toxicities of this regimen in children. The secondary objectives were: (i) to study PARP and other DNA repair protein expression by IHC in formalin-fixed, paraffin-embedded (FFPE) tumors; and (ii) to document tumor response to this regimen.