MD Anderson Hematology/Oncology Fellowship, Houston, TX
Veronica Guerra , Courtney Denton Dinardo , Marina Konopleva , Jan Andreas Burger , Gautam Borthakur , Elias Jabbour , Naveen Pemmaraju , Kimberley Sheppard , Guillermo Garcia-Manero , Hagop M. Kantarjian
Background: Glutaminase (GLS) is an enzyme that catalyzes conversion of glutamine to glutamate, providing key metabolic fuel for tumor cells. GLS is highly expressed in AML and high-risk MDS, particularly in the setting of complex cytogenetics. Preclinical studies of primary AML cells demonstrate dependence on glutamine; glutaminase inhibition led to reduced cell growth and induced apoptosis. This study was designed to evaluate the safety and efficacy of the oral glutaminase inhibitor CB-839 in combination with azacitidine for MDS. Methods: This is a single arm Phase Ib/II trial of CB-839, evaluating the dose of 600 mg BID orally daily in combination with azacitidine (AZA) for intermediate and high-risk MDS in 28-day cycles. The primary outcome for the Phase 1 portion was to confirm the safety and recommended Phase 2 dose of CB-839 in combination with AZA. Secondary endpoints evaluate efficacy and clinical activity using IWG response criteria for MDS including hematological improvement (HI), complete response (CR), marrow CR (mCR), stable disease (SD) and no response (NR). Results: A total of 10 pts with MDS were enrolled; the Phase I portion is now complete, confirming CB-839 600 mg BID with standard AZA. Median age was 71 [47-76], 90% were men. 7 pts were treatment naïve, 3 pts had prior HMA exposure. 6 pts were intermediate-2, and 4 pts intermediate-1 by IPSS with high-risk mutations. 3 pts had complex cytogenetics. The most frequent mutations were ASXL1 (n = 5), TET2 (n = 4) and TP53 (n = 4). Median number of cycles was 3 [1-9]. The most common non-hematological AEs were grade 1-3 nausea (60%) and constipation (50%). No DLTs were identified; one pt experienced grade 3 transaminitis requiring dose reduction of CB-839 (to 400 mg BID) with resolution. Seven pts (70%) achieved mCR/CR with HI, 2 pts had SD, and 1 pt had NR. The median time to mCR was 3 months [1-3]. 4 pts proceed to hematologic stem cell transplant (HSCT) after 2-4 cycles. 1 pt progressed to AML after 3 cycles of therapy, and 3 pts remain on study. Conclusions: 600 mg BID CB-839 is safe and well tolerated in combination with azacitidine in pts with MDS. The Phase II portion is ongoing. Clinical trial information: NCT03047993
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