Phase 2 study of elraglusib (9-ING-41), a glycogen synthase kinase-3b inhibitor, in combination with gemcitabine plus nab-paclitaxel (GnP) in patients with previously untreated advanced pancreatic ductal adenocarcinoma (PDAC).

person Devalingam Mahalingam Northwestern University, Robert H Lurie Comprehensive Cancer Center, Chicago, IL info_outline Devalingam Mahalingam, Anwaar Saeed, Steven Francis Powell, Marisol Huerta Alvaro, Vaibhav Sahai, Andrew L. Coveler, Elizabeth J. Davis, Neeltje Steeghs, Mary Frances Mulcahy, Alexander G Raufi, Ludimila Cavalcante, Andres Cervantes, Jordan Berlin, Janna Afanasjeva, William Mikrut, Sheri Lynn Smith, Francis J. Giles, Benedito A. Carneiro

Authors person Devalingam Mahalingam Northwestern University, Robert H Lurie Comprehensive Cancer Center, Chicago, IL info_outline Devalingam Mahalingam, Anwaar Saeed, Steven Francis Powell, Marisol Huerta Alvaro, Vaibhav Sahai, Andrew L. Coveler, Elizabeth J. Davis, Neeltje Steeghs, Mary Frances Mulcahy, Alexander G Raufi, Ludimila Cavalcante, Andres Cervantes, Jordan Berlin, Janna Afanasjeva, William Mikrut, Sheri Lynn Smith, Francis J. Giles, Benedito A. Carneiro Organizations Northwestern University, Robert H Lurie Comprehensive Cancer Center, Chicago, IL, University of Pittsburgh Medical Center (UPMC), Department of Medicine, Division of Hematology and Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, Sanford Health, Sioux Falls, SD, Hospital Clinico Universitario, Valencia, Spain, University of Michigan, Ann Arbor, MI, Fred Hutchinson Cancer Center, Seattle, WA, Vanderbilt University Medical Center, Nashville, TN, The Netherlands Cancer Institute, Amsterdam, Netherlands, Brown University/Lifespan Cancer Institute, Providence, RI, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, INCLIVA, Biomedical Research Institute, Hospital Clínico, University of Valencia, Valencia, Spain, ApteWrite, Chicago, IL, Vantage Data Designs, Austin, TX, Courante Oncology, Excelsior, MN, DTC, Chicago, IL, Legorreta Cancer Center, Brown University, Providence, RI Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Actuate Therapeutics Background: Despite the increasing incidence and low survival rates in PDAC, treatment options remain somewhat limited. Glycogen synthase kinase-3 (GSK-3) has been known to regulate tumor cell survival and proliferation, suppress apoptosis, and counteract chemotherapy resistance through activation of NF-kB-dependent gene transcription. Elraglusib (9-ING-41), a potent small molecule inhibitor of GSK-3β, has demonstrated inhibition of tumor growth and regression of tumors in patient-derived PDAC xenograft models in combination with gemcitabine (G). This provides the rationale for evaluating the efficacy and safety of elraglusib in combination with GnP in advanced PDAC. Methods: In an open-label, non-randomized, phase 2 study (NCT03678883), pts with previously untreated advanced PDAC received elraglusib 15 mg/kg IV on Days 1 and 4 of each week and nab-paclitaxel (nP) 125 mg/m 2 plus G 1000 mg/m 2 on Days 1, 8, and 15 in a 28-day cycle. Based on the Simon’s 2-stage design, if > 50% of the first 23 efficacy evaluable (EE) pts achieved a disease control rate (DCR) ≥16 weeks in Stage 1, an additional 37 pts would be enrolled during Stage 2. The primary endpoint was DCR, defined as stable disease for ≥16 weeks, confirmed complete response, or confirmed partial response. Secondary endpoints consisted of objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and treatment-emergent adverse events (TEAEs). Results: 42 pts (ITT) with ECOG 0 to 2 were enrolled in the study (38 received elraglusib at 15 mg/kg and 4 at 9.3 mg/kg); 29 pts with complete first post-baseline tumor assessment comprised the EE population. The median duration of treatment (as of February 4, 2023, cutoff) in the EE was 5.5 months. The DCR was 51.7% (95% CI, 32.5 to 70.6), and the ORR was 37.9% (95% CI, 20.7 to 57.7). Given that Stage 1 criterium of Simon’s 2-stage design was met, the study proceeded to Stage 2. The median PFS and OS were 4.9 months (95% CI, 4.1 to 7.5) and 15.8 months (95% CI, 7.9 to not estimable), respectively, in the EE and 4.9 months (95% CI, 4.1 to 7.5) and 13.7 months (95% CI, 7.9 to 18.1) in the ITT. Grade ≥3 TEAEs occurred in 85.7% of pts in the ITT population. Two pts (4.8%) developed grade ≥3 reversible visible disturbances related to elraglusib and 8 pts (19%) developed grade ≥3 TEAEs (most common being febrile neutropenia and anemia) related to the combination of elraglusib with GnP. All of these were observed at the highest dose of elraglusib (15 mg/kg). Conclusions: Elraglusib in combination with GnP demonstrates early evidence of clinical activity against advanced PDAC and an acceptable safety profile. The study has advanced to randomized phase 2 in pts with metastatic PDAC evaluating the 9.3 mg/kg dose of elraglusib plus GnP compared to GnP alone. Clinical trial information: NCT03678883.

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