First-in-human biomarker-driven phase I trial of the potent and selective glutaminase-1 (GLS1) inhibitor IACS-6274 (IPN60090) in patients (pts) with molecularly selected advanced solid tumors.
Authors: Yap Timothy A. , Dumbrava Ecaterina Elena , Rodon Ahnert Jordi , Hong David S. , Pant Shubham , Karp Daniel D. , Piha-Paul Sarina Anne Anne , Subbiah Vivek , Tsimberidou Apostolia Maria , Fu Siqing , Janku Filip , Montez Sandra , Ahmad-Taha Majd T , Guerrero Darlene , Nazarenko Natalya N. , Moore Yan , Soth Michael , Kovacs Jeff , Heffernan Timothy P. , Jones Philip 
Published: June 2021

3001 Background: Glutamine metabolism is frequently deregulated in different cancers, including tumors harboring KEAP1/ NFE2L2 mutations or those expressing low Asparagine Synthetase (ASNS) levels. IACS-6274 is a potent oral GLS1 inhibitor discovered at MD Anderson Cancer Center with excellent pharmacokinetics (PK) and antitumor activity in biomarker-defined preclinical models. Methods: Pts with advanced solid tumors received IACS-6274 BID at escalating doses using a phase 1 BOIN design. PK and pharmacodynamic (PD) studies were conducted in serial tumor and/or blood samples. Peripheral glutamine metabolism was assessed in peripheral blood mononuclear cells (PBMC) to assess glutamine metabolism via 13C-isotope labelling. Predictive biomarker studies included tumor analyses for KEAP1, NFE2L2, STK11, NF1 mutations and IHC for ASNS loss. Results: 22 pts with advanced ovarian (n=8), NSCLC (n=7), melanoma (n=2), leiomyosarcoma, gastric, anal, endometrial and HNSCC (all n=1) received IACS-6274 at 20 (n=1), 40 (n=1), 80 (n=1), 120 (n=4), 180 (n=11) or 240 (n=4) mg BID. Molecular alterations assessed included pts with ASNS loss (n=6), STK11 (n=5), KEAP1 (n=5), NFE2L2 (n=4) and NF1 (n=1). Prior lines of therapies: 2-4 (n=12); ≥5 (n=10). Common IACS-6274-related adverse events included G1-2 photopsia (n=7), photophobia (n=7), increased creatinine (n=4) and AST (n=4). Less common G3 toxicities at 180 and 240 mg included reversible nausea (n=3), vomiting and fatigue (n=2). Dose-limiting toxicities of G3 acute renal failure and PRES syndrome were seen in one patient at 240mg BID, which fully resolved. Plasma exposures showed a dose-dependent increase across doses with observed half-life ̃12 hrs. Patients at 180mg displayed steady-state exposures at C1D14 with Cmax of 45.8 μM +/- 18.6 μM and average AUC(0-12hrs) of 382.48 h*μM +/- 159.27 h*μM. Glutamate to glutamine ratios decreased in PBMC samples in pts at C1D14 vs baseline; pts at 120, 180 and 240 mg had inhibition of 82.5% (P<0.0001), 83.9% (P<0.0001) and 85.3% (P<0.0001), respectively, exceeding doses predicted to be efficacious in preclinical models. A robust PK/PD relationship was established across doses (P<0.0001). The recommended phase 2 dose was 180mg BID. Best RECISTv1.1 response was stable disease (SD) in 17 of 20 evaluable pts. Disease control rate at 12 weeks was 60%. Durable RECISTv1.1 SD ≥6 months +/- tumor regression were seen in pts with advanced ASNS-loss ovarian cancer (n=2), PD-1/L1-exposed melanoma (n=2) and NF1 mutant leiomyosarcoma (n=1). Conclusions: IACS-6274 was well tolerated at biologically active doses with good human PK, significant PD target modulation and preliminary antitumor activity observed. The clinical trial assessment of rational combinations to maximize benefit in molecularly-selected pts is initiating. Clinical trial information: NCT03894540.