Souza, André Luiz de

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 .

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.