Abstract C49: Phase 1 study of CB-839, a first-in-class, orally administered small molecule inhibitor of glutaminase in patients with refractory solid tumors
Authors: Meric-Bernstam Funda , DeMichele Angela , Telli Melinda L. , Munster Pamela , Orford Keith W. , Demitri George D. , Schwartz Gary K. , Iliopoulos Othon , Mier James W. , Owonikoko Taofeek K. , Bennett Mark K. , Patel Manish R. , Infante Jeffery R. , Harding James J. 
Published: May 2016

Abstract
Background: CB-839 is a first-in-class highly selective inhibitor of glutaminase (GLS), a key enzyme in the utilization of glutamine by many cancer cells. Inhibition of GLS blocks the ability of tumor cells to use glutamine as a source of energy and anabolic building blocks. CB-839 has broad activity, inducing cell death or growth arrest in triple negative breast cancer (TNBC), KRAS-mutant non-small cell lung cancer (NSCLC), clear cell renal cell cancer (RCC), and mesothelioma cell lines. GLS inhibition with CB-839 has also been shown to synergistically combine with several standard of care (SOC) chemotherapies and signal transduction inhibitors.
Methods: CX-839-001 is an ongoing Phase 1 study of escalating doses of CB-839 given continuously in 21 day cycles in advanced and/or treatment-refractory solid tumor patients (pts) to evaluate safety and tolerability, and to identify the recommended Phase 2 dose (R2PD). It was initially given three times daily (TID) without food, but based on PK and safety data, the drug is now being given twice daily (BID) with meals. Pharmacokinetics (PK) is monitored on Days 1 and 15; pharmacodynamics is measured in platelets and in tumor biopsies. Pts are currently being enrolled at the RP2D, 600 mg BID, with the tumor types noted above as well as pts receiving CB-839 in combination with SOC agents, including paclitaxel in TNBC, docetaxel in KRAS-mutant NSCLC, erlotinib in EGFR-mutant NSCLC, and everolimus in RCC.
Results: Safety data from 85 pts enrolled in the trial revealed a low rate of Gr3/4 AEs, with 9.4% (8/85) of pts experiencing a Gr3/4 AE related to CB-839. One DLT occurred on study, a drug-related Gr3 creatinine elevation in a patient with diabetic nephropathy at the 250 mg TID dose level. Reversible, asymptomatic Gr3 elevations in transaminases occurred mostly on the TID schedule in 6/32 pts (18.8%), with only one Gr3 event occurring among 53 pts (1.9%) receiving the BID regimen. Clear exposure-dependent inhibition of GLS in platelets was seen 4 hr after the first dose of CB-839, with &gt;90% inhibition at PK trough for most pts at the RP2D.
A total of 93 pts have been enrolled on the monotherapy cohorts of the trial as of 24 July 2015, including 32 pts on TID dosing (100-800 mg) and 61 pts on BID dosing (600-1000 mg). Radiographic stable disease (SD) was observed in 6 (19%) of 31 efficacy-evaluable pts receiving CB-839 on the TID schedule and 17 (40%) of 43 efficacy-evaluable pts on the BID schedule. Pts with SD have been on study for a median of &gt;5 cycles (range 3-18); 15 (65%) of these pts remain on treatment. Seven of 11 (64%) evaluable RCC pts on the BID dose schedule showed SD, 5 of whom remain on study. A TNBC patient has maintained SD for more than one year and has had a 23% reduction in tumor burden. GLS expression was evaluated by IHC and found to be moderate to high in most patient tumor samples. Additional correlative studies will also be presented.
Conclusions: CB-839 has been well tolerated when administered BID with food at and above doses that produced robust inhibition of GLS in platelets and in tumors. Evidence of prolonged SD in pts receiving single agent CB-839, together with strong preclinical data in combination with SOC agents including paclitaxel, everolimus and erlotinib, provides a clear rationale for continued evaluation of CB-839 in several tumor types, as a single agent and in combination with SOC therapies.
Citation Format: Funda Meric-Bernstam, Angela DeMichele, Melinda L. Telli, Pamela Munster, Keith W. Orford, George D. Demitri, Gary K. Schwartz, Othon Iliopoulos, James W. Mier, Taofeek K. Owonikoko, Mark K. Bennett, Manish R. Patel, Jeffery R. Infante, James J. Harding. Phase 1 study of CB-839, a first-in-class, orally administered small molecule inhibitor of glutaminase in patients with refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C49.