Carneiro, Benedito A.

2051 Background: GSK-3β, a serine/threonine kinase, is a key regulator of metabolism and glycogen biosynthesis. GSK-3β aberrant overexpression promotes tumor progression and chemotherapy resistance through NF-κB and p53-mediated apoptotic pathways. GSK-3β inhibition impacts immunomodulation through downregulation of checkpoints, such as PD-L1 and LAG-3, and increasing NK and T-cell mediated killing of tumor cells. 9-ING-41 is a small-molecule potent selective GSK-3β inhibitor with preclinical antitumor activity against several tumor types. In chemoresistant PDX models of glioblastoma (GBM), 9-ING-41 enhanced the antitumor effect of CCNU and CPT-11. Methods: In the first-in-human study (NCT03678883), patients (pts) with refractory malignancies received 9-ING-41 monotherapy (n = 65) or in combination with one of 8 cytotoxic regimens after prior treatment with the same chemotherapy (n = 162). We report the subset of pts with recurrent gliomas treated with 9-ING-41 monotherapy IV twice a week in 21-day cycles at different dose levels (3.3, 5, 9.3, 15mg/kg), or in combination with lomustine 30 mg/m² orally once weekly in 84-day cycles. Primary objective was safety and tolerability. Results: An RP2D of 15mg/kg IV was confirmed across all 9 regimens, no accentuation of chemotherapy-related toxicity noted. Of 18 glioma patients enrolled, 13 were GBM, 2 anaplastic astrocytomas, 1 diffuse astrocytoma, and 1 anaplastic oligodendroglioma. Four patients received single agent 9-ING-41, 14 treated concurrently with lomustine. Demographics: 6 female, 12 male; median age 52 (30-69) years; median ECOG was 1 (0-2). All received first-line radiation and temozolomide (18/18), prior therapies for recurrences included nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), immune checkpoint inhibitor (4/18). Median recurrences 3 (1-6). Genomic alterations from available NGS reports included: IDH WT (11), IDH mutation (3), MGMT promoter unmethylated (11), MGMT promoter methylated (1), 1p19q co-deletion (10), EGFR amplification (6), EGFR v3 mutation (3), TERT promoter mutation (6), PTEN loss (3), NF1 rearrangement (2), ATRX loss (2), TP53 mutated (4), CDKN2A deletion (2), RB1 loss (1), PALB-2 mutation (10). No SAEs or grade 3/4 AEs attributed to 9-ING-41 were noted; AEs included G1/2 transient vision changes (9/18, 50%), infusion reactions (4/18, 22%). Side effects from lomustine included: G3/4 thrombocytopenia (3/14, 21%), and G1/2 fatigue (4/14, 28%). Best overall response: 1 minimal response (-43%) after 2 cycles of 9-ING-41 and lomustine. Median days on therapy was 55 (4-305), 4/18 (22%) were stable for 20 weeks or longer. Conclusions: These results show 9-ING-41 alone or in combination is safe and warrants further study in glioma patients. Clinical trial information: NCT03678883.

3507 Background: Overexpression of GSK-3β, a serine/threonine kinase, is associated with advanced stage malignancies, aggressive tumor growth, and chemotherapy resistance. 9-ING-41 is a GSK-3β inhibitor with significant broad spectrum pre-clinical antitumor activity, including chemotherapy-resistant models. This first-in-human study (NCT03678883) is evaluating the safety, pharmacokinetics (PK), and efficacy of 9-ING-41 monotherapy and in combination with chemotherapy in patients (pts) with refractory malignancies. Methods: 9-ING-41 is given intravenously (IV) twice-weekly as a single-agent (21-day cycle) or combined with gemcitabine, gemcitabine/nab-paclitaxel, carboplatin, carboplatin/paclitaxel, doxorubicin, lomustine or irinotecan in patients previously treated with the same chemotherapy. Results: As of Jan 2020, 101 pts were enrolled. Tumor types: 25 pancreatic (PDAC), 14 colorectal (CRC), 10 non-small cell lung cancer (NSCLC), 8 GBM and other gliomas, 7 melanoma, 5 appendiceal, 4 breast (BC), 30 others. Seven single agent dose levels (DL) completed (1, 2, 3.3, 5, 7, 9.3, 12.4 mg/kg) without any 9-ING-41-attributable SAEs. 9-ING-41 attributable AEs include: transient visual change (color perception; n = 29), starting at DL 3 (3.3mg/kg), all G1/2; infusion reactions (n = 14), all G1/2, starting at DL 5 (7mg/kg). 9-ING-41’s mean terminal half-life is 12-20 hrs. Cmax and AUC0-72, are dose proportional with no accumulation. One BRAFV600K-mutated melanoma with > 20 brain metastases, post checkpoint/BRAF/MEK failure has an ongoing CR starting at cycle 2 and sustained after 9 months on treatment. 32 (31%) pts had SD as best response (6 PDAC, 6 CRC, 3 appendiceal, 2 BC, 2 salivary gland, 2 melanoma, 1 Merkel cell, 2 GBM/glioma, 1 RCC, 1 HCC, 1 NSCLC, 1 esophageal, 1 parotid gland, 1 nasopharyngeal, 1 peritoneal, 1 T cell-ALL). 8 pts remained on study treatment > 5 months (1 melanoma, 3 PDAC, 1 appendiceal, 1 GBM, 1 peritoneal, 1 salivary gland) with median treatment duration of 198 days (range 163-261). 32 pts continue to receive 9-ING-41. Conclusions: 9-ING-41 has dose-proportional PK, is well tolerated with significant antitumor activity as monotherapy and in combination with chemotherapy in pts with refractory tumors. 1 ongoing CR was observed in a refractory BRAF-mutated melanoma. A biologically active dose has been reached, although MTD has not been determined. Enrollment is ongoing. Clinical trial information: NCT03678883 .

Abstract Background: We have previously identified Glycogen Synthase Kinase-3 beta (GSK-3β) nuclear accumulation as a hallmark of pancreatic ductal adenocarcinoma (PDAC) and demonstrated the antitumor effects of GSK-3β tool compound inhibitors in vivo (Ougolkov, Clin Cancer Res 2006). 9-ING-41 (Actuate Therapeutics Inc), a first-in-class, small-molecule potent selective GSK-3β inhibitor, has significant preclinical antitumor activity in PDAC. 9-ING-41 is synergistic with gemcitabine (GEM) in significantly reducing PDAC cell proliferation via impairment of ATR/Chk1 DNA damage response (Ding, Clin Cancer Res 2019). These data provided the rationale for inclusion of patients with PDAC in the 1801 phase 1/2 study evaluating 9-ING-41 alone and in combination with chemotherapy, including GEM and GEM plus nab-paclitaxel. Methods: Parts 1 and 2 of the 1801 phase 1/2 study evaluate the safety and tolerability of 9-ING-41 in patients with refractory malignancies. Part 1 establishes the recommended phase 2 study dose (RP2D) for 9-ING-41 monotherapy, while Part 2 assesses 9-ING-41 in combination with chemotherapies. For Part 1, patients received twice-weekly IV infusions of 9-ING-41 (21-day cycle). Based on prior treatment, Part 2 for those with PDAC consists of 9-ING-41 plus GEM (1000 to 1250 mg/m2 days 1 and 8; 21-day cycle) or 9-ING-41 plus GEM and nab-paclitaxel (125 mg/m2). Part 3 (Simon 2-stage phase 2 at the RP2D) will assess clinical benefit in patients with refractory PDAC treated with 9-ING-41-based combinations at the RP2D established in Part 2. Response is defined by response evaluation criteria in solid tumors (RECIST) criteria in evaluable lesions. The study is opening in 25 sites globally and will accrue approximately 300 patients. Results: To date, the study has accrued 34 patients with advanced solid tumors (n=33) or hematologic malignancies (n=1). Four dose levels (1, 2, 3.3, and 5 mg/kg) have been completed without dose-limiting toxicities (DLT). Part 2 of the study evaluating combination of 9-ING-41 with chemotherapy agents has been activated. Six patients with advanced PDAC have enrolled. One patient has completed 5 cycles of treatment with 9-ING-41 (1mg/kg) with stable disease (SD) as the best response. Another patient with SD as the best response has completed 6 cycles and now is joining the arm combining 9-ING-41 with GEM after disease progression. Four additional patients are awaiting first response assessment with enrollment ongoing. 9-ING-41-attributable AE to date are Grade 1 transient visual changes (color perception). Conclusions: 9-ING-41 is well tolerated. Preclinical data support the inclusion of patients with advanced PDAC on clinical studies of 9-ING-41. Citation Format: Benedito A. Carneiro, Malika Dhawan, Brittany Borden, Ludimila Cavalcante, Howard Safran, Andrey Ugolkov, Andrew P. Mazar, Daniel D. Billadeau, Francis J. Giles, Pamela Munster. GSK-3β blockade with 9-ING-41 in pancreas cancer: The 1801 phase 1/2 study [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B09.

827 Background: 9-ING-41 is a selective GSK-3β inhibitor with significant pre-clinical antitumor activity in a broad spectrum of malignancies as a single agent and in combination with cytotoxic agents. GSK-3β is a serine/threonine kinase whose overexpression is associated with advanced stage, aggressive tumor growth, and chemotherapy resistance. We report the preliminary results of patients (pts) with gastrointestinal (GI) malignancies. Methods: Phase 1b/2 study evaluating safety and efficacy of 9-ING-41 as monotherapy and combination therapy in pts with refractory cancers. 9-ING-41 is administered intravenously twice-weekly as a single agent (21-day-cycle) or combined with chemotherapy agents, including gemcitabine (GEM), nab-paclitaxel + GEM, carboplatin, or paclitaxel. Study parts 1 and 2 evaluate the safety, describe dose-limiting toxicities (DLTs), determine the maximum tolerated dose and the recommended phase 2 study dose (RP2D) for 9-ING-41 as monotherapy (Part 1) and as combination therapy (Part 2). Part 3 (Simon 2-Stage Phase 2) assess clinical benefit in pts treated with 9-ING-41-based combinations at the RP2D established in Part 2. Response is assessed by RECIST 1.1 criteria in the evaluable lesions. Results: To date, the study accrued 63 pts. Five dose levels (1, 2, 3.3, 5 and 7 mg/kg) have been completed without DLTs. Part 2 of the study evaluating 9-ING-41-based chemotherapy combinations is ongoing. Five out of nine pts with pancreas cancer (PCa) enrolled had stable disease (SD) as the best response; 2 out of 9 pts had a 40-45% decline of CA 19-9. One pt completed 6 cycles with 9-ING-41, two pts completed 4 cycles with 9-ING-41/GEM. Two active pts are receiving 9-ING-41/GEM with SD after 3 and 4 cycles. Three out of four pts with adenocarcinoma of the appendix enrolled had SD as the best response; two pts in active treatment are receiving cycles 5 and 6. One out of 13 pts with colorectal cancer had SD. 9-ING-41-attributable AE to date are reversible grade 1 transient visual changes (color perception). Conclusions: 9-ING-41 is well-tolerated with encouraging SD among heavily pretreated pts with carcinoma of the pancreas and appendix. Clinical trial information: NCT03678883.

Abstract Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, is a complex regulator of numerous cellular functions. GSK-3β is a unique kinase which is constitutively active in resting and nonstimulated cells. GSK-3β has been implicated in a wide range of diseases including neurodegeneration, inflammation and fibrosis, noninsulin-dependent diabetes mellitus, and cancer. It is a regulator of NF-κB–mediated survival of cancer cells, which provided a rationale for the development of GSK-3 inhibitors targeting malignant tumors. Recent studies, many of them reported over the past decade, have identified GSK-3β as a potential therapeutic target in more than 15 different types of cancer. Whereas only active GSK-3β is expressed in cancer cell nucleus, aberrant nuclear accumulation of GSK-3β has been identified as a hallmark of cancer cells in malignant tumors of different origin. This review focuses on the preclinical and clinical development of GSK-3 inhibitors and the potential therapeutic impact of targeting GSK-3β in human cancer. Clin Cancer Res; 23(8); 1891–7. ©2017 AACR.