Harvey, Donald

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 Defecatory disorders can be diagnosed by rectal balloon expulsion ( BE ) and anorectal manometry, which are traditionally evaluated in the seated and left lateral ( LL ) positions, respectively. The aims of this study were to compare BE in the LL and seated positions and to compare anorectal manometric parameters to BE performed in the seated and LL positions. Methods 220 women [healthy (62), chronic constipation (158)] had anorectal high‐resolution manometry and BE , summarized by time required (seated position, normal ≤60 s) or external traction to facilitate expulsion ( LL position, normal ≤100 g). Key Results Balloon expulsion results in both positions were either concordant [normal (141) or abnormal (32)] or discordant [only LL abnormal (30), only seated abnormal (17)]. There was modest agreement [κ = 0.44 (95% CI 0.30–0.57)] between seated and LL BE . Compared with subjects with normal BE in both positions, anal pressure during simulated evacuation ( SE ) was higher, and the rectoanal gradient (rectal‐anal pressure) during SE was more negative in the other 3 categories (i.e., abnormal LL only, abnormal seated only, and both abnormal). High anal pressure during SE ( OR = 1.02, 95% CI 1.00–1.04) and high rectal sensory threshold for desire to defecate ( OR = 1.01, 95% CI 1.00–1.02) were associated with increased risk of abnormal BE in both positions, whereas high rectal pressure during SE ( OR = 0.96, 95% CI 0.93–0.98) was associated with lower risk. Conclusions & Inferences There is modest agreement between rectal BE in LL and seated positions. In addition to abnormal seated BE , which is considered indicative of pelvic floor dysfunction, high resolution manometry findings suggest that even some patients with abnormal BE in the LL position have pelvic floor dysfunction.