Telotristat ethyl to promote weight stability in patients with advanced pancreatic cancer.

747 Background: Cachexia a key feature of pancreatic ductal adenocarcinoma (PDAC), affects up to 80% of patients (pts), and is associated with worse outcomes. Serotonin, due to its tumorigenic potential and effect on gut function may contribute to weight loss in PDAC. Telotristat ethyl (TE) inhibits serotonin production and improves gut motility dysfunction. We developed a phase II trial to evaluate the impact of TE on the weight of patients with metastatic PDAC (mPDAC) receiving first-line chemotherapy. Methods: Treatment-naïve pts with mPDAC who had lost at least 10% of baseline weight (Group 1) received gemcitabine and nab-paclitaxel (GnP) in combination with TE (250mg administered orally three times a day). Pts with < 10% weight-loss were recruited in Group 2 and received chemotherapy without TE. Serum serotonin was collected monthly during the study. The primary endpoint was weight stability, evaluated as % weight change at 3 months compared to baseline, with a goal of < 5% decrease. A key secondary endpoint was change in serotonin levels at 3 months compared to baseline. The groups were analyzed independently. Results: We enrolled 22 pts, 14 in group 1 (planned 40) and 8 in group 2 (planned 40). The median age was 70 years (IQR 62-75), majority were male (n = 15; 68%) and 11 (50%) were Black. Mean weight at treatment start was 77.9 kg (SD 19.16) group 1, and 90.6kg (SD 24.71) group 2. Mean serotonin level at baseline was 165.07 ng/ml (SD 60.49) group 1, and 296.9 ng/ml (SD 166.65) group 2. Mean % weight change over 3 months in group 1 was -2% (90% CI -5.2 to 1.3, P < -5% = 0.0595). Mean change in group 2 was -5.6% (90% CI -9.4 to -1.7%, P < 5% = 0.53). At 3 months, the median change in serotonin level in group 1 was -37.8% (IQR -59.1 to -13, P = 0.064) and -42.6% (IQR-57.8 to -29.9, P = 0.016) for group 2. Adverse events (AE) were consistent with known AE for GnP and TE. The median overall survival was 10.7 months (95% CI 5.4-16.9) group 1 and 12.2 (95% 6.1 to 21.4) group 2, HR 1.41 (95% CI 0.57 to 3.52 P = 0.46). Conclusions: Among pts with mPDAC and cachexia, the addition of TE to chemotherapy led to weight stabilization. These pts experienced 2% weight loss on average during the study (the upper limit of the CI just crossed -5% at -5.2%). The average weight loss was 5.6% in those who did not receive TE suggesting a signal of activity. A larger study is warranted to evaluate the role of TE in the management of cachexia in mPDAC. Funded by Lexicon Pharmaceuticals (NCT03910387). Clinical trial information: NCT03910387 .