Abstract 3969: Pediatric preclinical testing program (PPTP) evaluation of BMN 673, an inhibitor of poly-adp ribose polymerase (PARP), with temozolomide (TMZ)
Authors: Smith Malcolm , Kang Min , Reynolds Patrick , Gorlick Richard , Kolb Anders , Maris John , Lock Richard , Carol Hernan , Keir Stephen , Billups Catherine , Kurmasheva Raushan , Houghton Peter 
Published: May 2015

Abstract
Introduction: BMN 673 is a potent and selective inhibitor of PARP1/2. Inhibitors of PARP such as BMN 673 show clinical activity against cancers lacking homologous repair through mutations in BRCA1 and 2. PARP inhibitors are of particular interest for Ewing sarcoma (ES) given reports of ES cell lines being preferentially sensitive to PARP inhibitors. However, BMN 673 and other PARP inhibitors have shown limited single agent activity against Ewing sarcoma xenografts.
Methods: BMN 673 (10 nM) was evaluated in combination with TMZ and topotecan against the 23 cell lines of the PPTP in vitro panel using 96 hour exposure. For in vivo combination studies, two dose levels of BMN 673 (0.25 & 0.1 mg/kg BID x 5 days) given with TMZ [12 & 30 mg/kg/day x 5 days, respectively] were evaluated against ES xenografts. The combination regimen using the lower dose (LD) of TMZ and higher dose of BMN 673 was studied against other histotypes. Standard PPTP measures of in vivo antitumor activity were employed to assess response.
Results: BMN 673 markedly potentiated TMZ activity in vitro, with the TMZ rIC50 reduced by a median of 10-fold for PPTP cell lines, with ES cell lines showing a median 50-fold reduction. BMN 673 potentiated topotecan to a lesser degree (median 2.8-fold reduction in rIC50), with no differential sensitivity by histotype.
In vivo, 10 ES xenografts showed little or no response to 5 days of treatment with single agent TMZ (30 mg/kg) or BMN 673 (0.25 mg/kg BID), but 8 of 10 showed complete responses (CR) or maintained CR (MCR) to BMN 673 and TMZ (LD), and 5 of 10 showed CR or MCR to BMN 673 and higher-dose TMZ. The 10 ES xenografts could be separated into 2 groups based on duration of response to the combinations, with 5 showing delayed growth or brief objective responses (median time to event ≤ 30 days), and with the other 5 showing prolonged time to regrowth (median &gt; 77 days). Among 5 neuroblastoma xenografts, all showed significant treatment effects to BMN 673 plus TMZ(LD), with 1 achieving CR. Among 4 osteosarcoma xenografts, each showed significant tumor growth delay, but no objective responses were noted. Among 3 glioblastoma xenografts, 2 of 3 achieved maintained CRs (MCR) to the BMN 673 plus TMZ(LD) combination. Excessive toxicity was observed for ALL xenografts in NOD-SCID mice treated with the combination.
Conclusions: While BMN 673 shows limited single agent activity against PPTP solid tumor and ALL models with responses limited to models also highly sensitive to cisplatin, the BMN 673 plus TMZ(LD) combination shows dramatic activity for a subset of Ewing sarcoma xenografts and for selected additional models. Based on these results a pediatric phase 1 trial of BMN 673 plus TMZ with a phase 2 expansion for Ewing sarcoma is proceeding. Efforts are ongoing to relate genomic alterations identified through exome sequencing to responsiveness of ES xenografts to BMN 673 plus TMZ. (Supported by NO1-CM-42216)
Citation Format: Malcolm Smith, Min Kang, Patrick Reynolds, Richard Gorlick, Anders Kolb, John Maris, Richard Lock, Hernan Carol, Stephen Keir, Catherine Billups, Raushan Kurmasheva, Peter Houghton. Pediatric preclinical testing program (PPTP) evaluation of BMN 673, an inhibitor of poly-adp ribose polymerase (PARP), with temozolomide (TMZ). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3969. doi:10.1158/1538-7445.AM2014-3969