Bruce S. Fischer

Discovery of Clinical Candidate BMS-906024: A Potent Pan-Notch Inhibitor for the Treatment of Leukemia and Solid Tumors.

Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.

Metabolism, Excretion, and Pharmacokinetics of Oral Brivanib in Patients with Advanced or Metastatic Solid Tumors*

The goal of this study was to evaluate the pharmacokinetics, mass balance, metabolism, routes and extent of elimination, and safety of a single oral dose of 14C-labeled brivanib alaninate and the safety and tolerability of brivanib after multiple doses in patients with advanced or metastatic solid tumors. This was a two-part, single-center, open-label, single oral-dose (part A) followed by multiple-dose (part B) study in patients with advanced or metastatic solid tumors. In part A, patients received a single dose of [14C]brivanib alaninate and in part B patients received 800 mg of nonradiolabeled brivanib alaninate every day. Four patients (two white, two black: two with non–small-cell lung cancer, one with ovarian cancer, and one with renal cell carcinoma) were treated in both parts. The median time to reach the maximal plasma concentration of brivanib was 1 h, geometric mean maximal plasma concentration was 6146 ng/ml, mean terminal half-life was 13.8 h, and geometric mean apparent oral clearance was 14.7 l/h. After a single oral dose of [14C]brivanib alaninate, 12.2 and 81.5% of administered radioactivity was recovered in urine and feces, respectively. Brivanib alaninate was completely converted to the active moiety, brivanib, and the predominant route of elimination was fecal. Renal excretion of unchanged brivanib was minimal. Brivanib was well tolerated; fatigue was the most frequent adverse event occurring in all patients and the most frequent treatment-related adverse event in three (75%). The best clinical response in one patient was stable disease; the other three had progressive disease. Brivanib alaninate was rapidly absorbed and extensively metabolized after a single 800-mg oral dose; the majority of drug-related radioactivity was excreted in feces.

Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma

Notch signaling is aberrantly activated in approximately one third of non–small cell lung cancers (NSCLC). We characterized the interaction between BMS-906024, a clinically relevant Notch gamma secretase inhibitor, and front-line chemotherapy in preclinical models of NSCLC. Chemosensitivity assays were performed on 14 human NSCLC cell lines. There was significantly greater synergy between BMS-906024 and paclitaxel than BMS-906024 and cisplatin [mean combination index (CI) value, 0.54 and 0.85, respectively, P = 0.01]. On an extended panel of 31 NSCLC cell lines, 25 of which were adenocarcinoma, the synergy between BMS-906024 and paclitaxel was significantly greater in KRAS- and BRAF-wildtype than KRAS- or BRAF-mutant cells (mean CI, 0.43 vs. 0.90, respectively; P = 0.003). Paclitaxel-induced Notch1 activation was associated with synergy between BMS-906024 and paclitaxel in the KRAS- or BRAF-mutant group. Knockdown of mutant KRAS increased the synergy between BMS-906024 and paclitaxel in heterozygous KRAS-mutant cell lines. Among KRAS- or BRAF-mutant NSCLC, there was a significant correlation between synergy and mutant or null TP53 status, as well as between synergy and a low H2O2 pathway signature. Exogenous overexpression of activated Notch1 or Notch3 had no effect on the enhanced sensitivity of NSCLC to paclitaxel by BMS-906024. In vivo studies with cell line– and patient-derived lung adenocarcinoma xenografts confirmed enhanced antitumor activity for BMS-906024 plus paclitaxel versus either drug alone via decreased cell proliferation and increased apoptosis. These results show that BMS-906024 sensitizes NSCLC to paclitaxel and that wild-type KRAS and BRAF status may predict better patient response to the combination therapy. Mol Cancer Ther; 16(12); 2759–69. ©2017 AACR.

Abstract 4834: Preclinical analysis of the Notch gamma secretase inhibitor BMS-906024 in combination with chemotherapy in the treatment of lung adenocarcinoma

Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancer (NSCLC) cases, primarily through loss of the endogenous Notch inhibitor, Numb, or via gain-of-function mutations in the Notch1 receptor. Notch activity is associated with poor overall survival among NSCLC patients whose tumors are wildtype for TP53. Here, we characterized the interaction between BMS-906024, a clinically relevant gamma secretase inhibitor (GSI) that inhibits Notch activation, and front-line chemotherapy in preclinical models of NSCLC. MTS drug synergy assays consisting of treatment with BMS-906024, cisplatin or paclitaxel, or the combination of GSI and chemotherapy were performed on a panel of human NSCLC cell lines, most of which were derived from adenocarcinomas. Analysis of the drug effects with CalcuSyn yielded significantly lower CI values for the GSI BMS-906024 combined with paclitaxel than with cisplatin (average CI = 0.54 vs 0.85, respectively; P = 0.001). The synergy between BMS-906024 and paclitaxel was significantly greater in Kras-wildtype than Kras-mutant cells (average CI = 0.39 vs 0.68, respectively; P = 0.009), while there was no correlation with EGFR or TP53 status. Treatment of lung adenocarcinoma xenografts in NOD scid gamma mice confirmed enhanced antitumor activity for the combination treatment of BMS-906024 and paclitaxel by mechanisms currently under investigation. These results are a step toward identification of the optimal combination of the GSI BMS-906024 with standard chemotherapies, as well as potential biomarkers that could be used to predict patient response to Notch-targeted therapy. Citation Format: Katherine M. Morgan, Francis Lee, Erin Michaud, Bruce S. Fischer, Sharon R. Pine. Preclinical analysis of the Notch gamma secretase inhibitor BMS-906024 in combination with chemotherapy in the treatment of lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4834.

Abstract 2535: Synergistic anti-tumor activity of the Notch gamma secretase inhibitor BMS-906024 and paclitaxel in the treatment of lung adenocarcinoma

Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancer cases, primarily through loss of the endogenous Notch inhibitor, Numb, or via gain-of-function mutations in the Notch1 receptor. Notch activity is associated with poor overall survival among non-small cell lung cancer patients whose tumors are wildtype for TP53. We set out to evaluate the combination of Notch-targeted therapy with front-line chemotherapy as an effective treatment for non-small cell lung cancer. Our study focused on lung adenocarcinoma, the most common histological subtype in lung cancer. To target Notch, we utilized the gamma secretase inhibitor (GSI) BMS-906024 which inhibits Notch activation. BMS-906024 is currently in Phase 1 clinical trials for patients with T-cell acute lymphoblastic leukemia and metastatic solid tumors, including lung cancer. Human cell lines representing the major genetic subtypes of lung cancer, most of which were derived from adenocarcinomas, underwent MTS drug synergy assays consisting of treatment with BMS-906024, cisplatin or paclitaxel, or the combination of GSI and chemotherapy. The dosing and timing for BMS-906024 administration were optimized by examination of maximal Notch1 inhibition. Analysis of the drug effects with CalcuSyn yielded Combination Index (CI) values, in which a CI of 0.5 or less was considered as strong synergism for the drug combination. We found that there were significantly lower CI values for the GSI BMS-906024 combined with paclitaxel than with cisplatin (average CI = 0.54 vs 0.85, respectively; P = 0.001). We then grouped the cell lines by major genetic subtype (wildtype versus mutant or null for EGFR, Kras or TP53). The synergy between BMS-906024 and paclitaxel was significantly greater in Kras-wildtype than Kras-mutant cells (average CI = 0.39 vs 0.68, respectively; P = 0.009), while there was no correlation with EGFR or TP53 status. These results are a step toward identification of potential biomarkers that could be used to predict patient response to Notch-targeted therapy, which could have a positive impact on the care of lung adenocarcinoma patients and be informative for treatment decisions. Citation Format: Katherine M. Morgan, Francis Lee, Erin Michaud, Joseph R. Bertino, Bruce S. Fischer, Sharon R. Pine. Synergistic anti-tumor activity of the Notch gamma secretase inhibitor BMS-906024 and paclitaxel in the treatment of lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2535. doi:10.1158/1538-7445.AM2015-2535

Abstract 1643: BMS-983970, an oral pan-Notch inhibitor for the treatment of cancer

Deregulation of the Notch pathway has been shown to be oncogenic in numerous tissue types including T-cell acute lymphoblastic leukemia (T-ALL), breast cancer, non-small cell lung cancer, and colorectal carcinoma. Notch signal activation can cause uncontrolled proliferation, restrict differentiation leading to increased self-renewal capacity, evasion of apoptosis, and enhancement of angiogenesis and metastasis. There is increasing evidence that Notch plays a role in the maintenance and survival of cancer stem cells. γ-Secretase mediates the Notch signaling pathway by releasing the Notch intracellular domain (NICD) which translocates to the nucleus and binds to the transcription factor CSL to activate transcription of various target genes. BMS-906024 is a potent pan-Notch inhibitor that demonstrated robust anti-tumor activity at tolerated doses in multiple tumor xenograft models. It is being evaluated in Phase 1 clinical studies. BMS-906024 is being administered IV (once weekly) in the clinic and the projected human efficacious dose is 4 - 6 mg. Based on the preclinical data, the projected human half-life of BMS-906024 is in the 37 h - 124 h range. This presentation will describe further structure-activity relationships in the 1,4-benzodiazepinone series that culminated in the identification of BMS-983970 as an oral-pan-Notch inhibitor. Pharmacokinetic properties and in vivo evaluation of BMS-983970 in T-ALL and solid tumor xenograft models will be presented. Citation Format: Ashvinikumar V. Gavai, Yufen Zhao, Daniel O9Malley, Brian Fink, Claude Quesnelle, Derek Norris, Libing Chen, Soong-Hoon Kim, Wen-Ching Han, Patrice Gill, Weifang Shan, Aaron Balog, Andrew Tebben, Richard Rampulla, Dauh-Rurng Wu, Yingru Zhang, Arvind Mathur, Haiqing Wang, Zheng Yang, Qian Ruan, Robin Moore, David Rodrigues, Asoka Ranasinghe, Celia D9Arienzo, Ching Kim Tye, Ching Su, Gerry Everlof, Melissa Yarde, Mary Ellen Cvijic, Krista Menard, Mei-Li Wen, George Trainor, Bruce Fischer, John Hunt, Gregory Vite, Richard Westhouse, Francis Lee. BMS-983970, an oral pan-Notch inhibitor for the treatment of cancer. [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 1643. doi:10.1158/1538-7445.AM2014-1643