Abstract A99: Phase I trial of veliparib or mitomycin C + veliparib in pts with Fanconi anemia pathway (FA) repair defects.
Authors: Villalona-Calero Miguel A. , Duan Wenrui , Zhao Weiqiang , Gao Li , Thurmond Jennifer , Leon Marino , Shilo Konstantin , De Fiore Tricia , Westman Judith A. , Ji Jay , Zhang Yiping , Marshall John , Rose Jeff , Bekaii-Saab Tanios , Chen Alice , Otterson Gregory 
Published: June 2012

Abstract
Background: The PARP inhibitors are being developed in combination with chemotherapy or radiation with the hope of inhibiting base excision repair. Homozygous deficiency of BRCA genes has been identified as a potential predictor of response to PARPi. These genes are part of the FA repair pathway, comprised of ∼20 genes, which collaborate to activate FANCD2 by ubiquitinating the protein following DNA damage. The activated protein is subsequently transported to subnuclear foci, which are the sites of DNA repair. We developed a test, which can be performed in paraffin embedded cancer tissues to identify FA deficient pts based on functionality, rather than individual gene assessment; a triple antibody immunofluorescence screening (FANCD2/DAPI/Ki-67)(FATSI) for foci formation in the nucleus of proliferating cancer cells.
Methods: Consenting pts with advanced solid malignancies had their archived tumor tissue screened for FANCD2 foci formation by FATSI, and if absent, offered participation in a two arms dose escalation trial with the PARPi veliparib, as monotherapy or in combination with MMC.
Results: 428 patients have consented. Of 390 patients with available/interpretable results, 106 (27%) had absent foci. All major solid tumors were represented. Thirty-eight pts (13 with colon, 9 breast, 5 NSCLC, 2 SCLC, 2 ovarian cancer, 1 each with anal, small bowel, cholangio, ampullary, thymoma, prostate, bladder cancer) have received veliparib, 22 as monotherapy in escalating dose cohorts (starting at 50 mg PO BID continuously), and 16 following MMC 10 mg/m2 every 4 weeks (40mg/m2 cumulative cap) at 50 mg BID at increased duration cohorts (1, 2 and 3 weeks) every 4 weeks (100 and 200 mg BID for 3 weeks in subsequent cohorts). Maximum tolerated doses have not yet been reached for either arm of the study, although grades 2/3 thrombocytopenia and emesis have been noted in the combination arm at the higher doses. Current dose levels are: veliparib 200 mg BID as monotherapy and MMC/veliparib100 mg BID three weeks duration. Analysis for germ line mutations (BRCA1 and 2 sequencing and for the 5 most common BRCA1 large rearrangements) in peripheral blood cells among 38 pts showed 5 (3 breast, 1 ampullary, 1 ovarian carcinoma) BRCA abnormalities: 4 known deleterious mutations and 1 which favors polymorphisms. Two of the pts with deleterious mutations were unaware of a presence of a germline mutation prior to participation in the study. Three RECIST criteria responses occurred (1CR, 2 PR) (1 lung, 2 breast), all in the combination arm. Two breast cancer pts on monotherapy have prolonged stability (20 and 14 months). Family history in the pt with ampullary carcinoma (newly identified deleterious mutation) showed 4 cases of breast cancer. rH2AX (n=36) and PAR (n=10) analysis in PBMC suggests veliparib dose dependency (higher rH2AX induction, lower PAR level and slower recovery for higher doses)
Conclusions: A substantial proportion of pts across several tumor histologies are FA functionally deficient. FATSI test can lead to their identification and detection of previously unknown germ line genetic abnormalities. Veliparib had few toxicities up to 200 mg BID and can be administered safely in combination with MMC. A dose dependency for its biological effect is suggested. Phase 2 studies at recommended doses should be performed to evaluate the clinical benefit potential of the approach used in this study.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A99.