Abstract P6-11-05: Phase 1 study of CB-839, a small molecule inhibitor of glutaminase (GLS), in combination with paclitaxel (Pac) in patients (its) with triple negative breast cancer (TNBC)
Authors: AM DeMichele, JJ Harding, ML Telli, P Münster, RR McKay, O Iliopoulos, S Whiting, KW Orford, MK Bennett, JW Mier, TK Owonikoko, MR Patel, K Kalinsky, RD Carvajal, JR Infante, F Merit-Bernstam
Journal: Cancer Research (2017)

Abstract Background: CB-839 is a first-in-class highly selective inhibitor of GLS, a key enzyme in the utilization of glutamine by cancer cells. TNBC has high GLS expression and is very dependent upon GLS-mediated conversion of glutamine to glutamate for tumor cell growth. CB-839 has antitumor activity in vitro and in vivo in preclinical models of TNBC. Recent studies demonstrate that glutamine utilization can contribute to resistance to paclitaxel, a therapy frequently used to treat TNBC patients. Paclitaxel sensitivity is dependent on down-regulation of the glutamine transporter, SLC1A5, and over-expression of SLC1A5 causes paclitaxel resistance. Consistent with these observations, inhibition of glutamine metabolism with CB-839 has demonstrated strong antitumor activity in combination with paclitaxel. CX-839-001 is an ongoing Phase 1 trial of CB-839 as monotherapy and in combination with approved agents. We previously reported pharmacodynamic studies demonstrating robust inhibition of GLS in pt blood and tumors and excellent tolerability of CB-839 monotherapy in a variety of tumor types including TNBC. In light of the preclinical rationale and monotherapy tolerability a combination arm was opened testing CB-839 with paclitaxel (Pac-CB) in patients with advanced TNBC. We report here updated results on the Pac-CB dose escalation and expansion cohorts. Methods: Patients with refractory advanced/metastatic TNBC (prior taxane therapy allowed) received escalating doses of CB-839 (400-800 mg BID) in combination with a fixed weekly Pac dose of 80 mg/m2 Days 1, 8, 15 of a 28 day cycle. Upon demonstration of safety and tolerability, an expansion cohort of TNBC pts was opened. Results: To date, 15 pts have received Pac-CB at three dose levels of CB-839: 7 pts at 400 mg BID, 5 at 600 mg BID and 3 at 800 mg BID with the latter dose level not completed. 40% of enrolled patients have received &amp;gt;5 prior lines of systemic therapy for adv/met disease, and 10 pts have received prior taxane therapy including 5 in the adv/met setting. The Pac-CB combination has been well tolerated with one DLT during dose escalation (G4 neutropenia at 400 mg BID) and a low rate of dose reductions (2 for Pac and 1 for CB-839). Of 15 pts, the best overall response rate (BORR, see Table) has been PR in 20% (3 pts), SD in 47% (7 pts) and PD in 33% (5 pts) with 5 patients remaining on study. At doses ≥600 mg BID (n=8) the BORR is 38% (3 pts), and disease control rate (CR + PR + SD) is 88% (7 pts). All 3 pts with PRs have received prior Pac, including 2 pts with disease that was refractory to Pac in the advanced/metastatic setting. Conclusions: The Pac-CB combination has been well tolerated and has demonstrated clinical activity in heavily pre-treated pts with TNBC. At doses ≥600 mg BID, BORR has been 38% and DCR 88%. Notably, PRs have occurred in pts with prior Pac therapy, including 2 pts with Pac-refractory disease in the adv/met setting. Updated data on the escalation and expansion cohorts will be presented. Dose LevelTotal400 mg BID600 mg BID800 mg BIDRECIST Response Evaluable (N)15753PR3 (20%)02 (40%)1 (33%)SD7 (47%)3 (43%)2 (40%)2 (67%)DCR (CR+PR+SD)10 (67%)3 (43%)4 (80%)3 (100%)PD5 (33%)4 (57%)1 (20%)0 Citation Format: DeMichele AM, Harding JJ, Telli ML, Münster P, McKay RR, Iliopoulos O, Whiting S, Orford KW, Bennett MK, Mier JW, Owonikoko TK, Patel MR, Kalinsky K, Carvajal RD, Infante JR, Merit-Bernstam F. Phase 1 study of CB-839, a small molecule inhibitor of glutaminase (GLS), in combination with paclitaxel (Pac) in patients (its) with triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-05.