CB-839, a glutaminase inhibitor, in combination with cabozantinib in patients with clear cell and papillary metastatic renal cell cancer (mRCC): Results of a phase I study.

Authors

null

Funda Meric-Bernstam

University of Texas MD Anderson Cancer Center, Houston, TX

Funda Meric-Bernstam , Richard J. Lee , Bradley Curtis Carthon , Othon Iliopoulos , James Walter Mier , Manish R. Patel , Nizar M. Tannir , Taofeek Kunle Owonikoko , Naomi B. Haas , Martin Henner Voss , James J. Harding , Ramaprasad Srinivasan , Geoffrey Shapiro , Melinda L. Telli , Pamela N. Munster , Richard D. Carvajal , Yonchu Jenkins , Sam H. Whiting , Johanna C. Bendell , Todd Michael Bauer

Organizations

University of Texas MD Anderson Cancer Center, Houston, TX, Massachusetts General Hospital Cancer Center, Boston, MA, Emory University Winship Cancer Institute, Atlanta, GA, Harvard Medical School, Charlestown, MA, Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA, Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, The University of Texas MD Anderson Cancer Center, Houston, TX, Emory University, Atlanta, GA, Penn Medicine Abramson Cancer Center, Philadelphia, PA, Memorial Sloan Kettering Cancer Center, New York, NY, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, National Cancer Institute at the National Institutes of Health, Bethesda, MD, Dana-Farber Cancer Institute, Boston, MA, Stanford University School of Medicine, Stanford, CA, University of California San Francisco, San Francisco, CA, Columbia University Medical Center, New York, NY, Calithera Biosciences, Inc., South San Francisco, CA, Gradalis Inc., Dallas, CA, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN

Research Funding

Pharmaceutical/Biotech Company

Background: Glutaminase (GLS) is a key enzyme that controls glutamine utilization, a metabolic pathway upregulated in RCC and important for tumor proliferation and survival. CB-839 is a first-in-clinic, small molecule, reversible, oral GLS inhibitor that synergizes with cabozantinib (Cabo), a VEGFR2/MET/AXL inhibitor, in preclinical RCC models to inhibit metabolic pathways and enhance anti-tumor activity. Cabo monotherapy is associated with a 17% overall response rate (ORR) for clear cell (cc) mRCC (Choueiri et al. Lancet Oncol. 2016). Here we present findings from a Phase 1 study cohort evaluating the safety, efficacy, and recommended Phase 2 dose (RP2D) of CB-839 + Cabo in patients (pts) with mRCC as 2L+ therapy. Methods: Eligible pts had mRCC with cc or papillary histology, ECOG 0-1, RECIST measurable disease, and, for cc pts, treatment with ≥1 prior anti-VEGF therapy. Escalating doses of CB-839 (600-800 mg PO BID) plus Cabo (60 mg PO QD) were evaluated using a 3+3 design. Tumor response was assessed per RECIST 1.1 every 8 wks. Results: The CB-Cabo cohort enrolled 13 pts with a median 3 (range, 0-7) prior lines of therapy. No maximum tolerated dose was reached; 800 mg was selected as the CB-839 RP2D. The most common treatment-related AEs (occurring in >25% of pts) were diarrhea (62%), decreased appetite (46%), ALT increased (39%), fatigue (39%), AST increased (31%), nausea (31%), and rash (31%); Gr ≥3 treatment-related AEs included diarrhea, hypertension, platelet count decreased, and hallucination (n=1 each). Among 12 evaluable pts, ORR was 42% and disease control rate (DCR = complete response + partial response [PR] + stable disease [SD]) was 100%: 42% (5/12) PR, 58% (7/12) SD. Among 10 evaluable cc mRCC pts, 50% (5/10) had PRs, 50% (5/10) SDs. As of Sept 24, 2018, 5 pts received >12 months treatment; 4 remain on study. Conclusions: CB-839 plus Cabo showed encouraging clinical activity and tolerability in heavily pretreated mRCC pts, with response rates for cc mRCC (50% ORR, 100% DCR) comparing favorably to historical Cabo monotherapy. A randomized Phase 2 study of CB-839 + Cabo vs. Cabo + placebo in cc mRCC is ongoing. (CANTATA; NCT0342821) Clinical trial information: NCT02071862

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Abstract Details

Meeting

2019 Genitourinary Cancers Symposium

Session Type

Rapid Oral Abstract Session

Session Title

Rapid Abstract Session C: Renal Cell Cancer

Track

Renal Cell Cancer

Sub Track

Renal Cell Cancer

Clinical Trial Registration Number

NCT02071862

Citation

J Clin Oncol 37, 2019 (suppl 7S; abstr 549)

DOI

10.1200/JCO.2019.37.7_suppl.549

Abstract #

549

Abstract Disclosures