Abstract 32: Efficacy and tolerability of a enantiomer of Edelfosine (S-CP201) in pancreatic cancer PDX models as a single agent and in combination with approved drugs in clinical use

Abstract The anticancer alkylphospholipid Edelfosine incorporates into cell membrane lipid rafts, inducing apoptosis via CD95 and inhibiting AKT3/PI3K, phospholipase C, and protein kinase C. It disrupts cholesterol and phosphatidylcholine metabolism, and has antiangiogenic and antimetastatic effects. It's preferentially taken up by malignant cells, showed efficacy in xenografts (including metastatic breast and prostate cancer), and phase 2 trials across tumors. The main adverse events were reversible, dose-dependent gastrointestinal toxicity. Due to PK and PD advantages of Edelfosine’s S-enantiomer (S-CP201), further development has focused on S-CP201. Inter alia its efficacy was tested in patient-derived xenograft (PDX) pancreatic cancer models in immunodeficient mice. Initial testing used NSG mice with s.c. implanted PNX0001 pancreatic cancer PDX cells. Treatment groups included S-CP201, R-CP201 (20 mg/kg p.o. each; given for 5 days/week over 3 w.), Gemcitabine (Gem.;) (50 mg/kg i.p., 3 d./w. over 3 w.), and vehicle. S-CP201, R-CP201, and Gem. showed tumor growth inhibition (TGI) of 57%, 33%, and 40%, respectively, with all mice on active treatment surviving the treatment period. Treatments were well tolerated. In a similar study, Gem. and S-CP201 were combined. Three groups of mice were allocated: 5 mg/kg p.o. for S-CP201 plus i.p. Gem.; 20 mg/kg S-CP201 plus i.p. Gem.; Gem. doses see above; vehicle; 3 w. treatment. The 20 mg/kg combination group exhibited the best TGI (85%), equal to stable disease in patients. The tolerability of the active groups was comparable. The antitumor efficacy of S-CP201 (20 mg/kg p.o. over 3 w.) was assessed when given in triple combination with Gem. and albumin-bound Paclitaxel in clinically relevant doses with a TGI of 67% (matching partial response in patients), compared to 57% for Gem. and albumin-bound Paclitaxel. Additional studies with S-CP201 (20 mg/kg daily p.o. over 3 w.) and Gem. (240 mg/kg, 1x/w. over 3 w.) testing 9 pancreatic adenocarcinoma PDX models in NMRI mice showed limited efficacy for S-CP201 alone, with modest activity in PAXF2141 and PAXF2146 (tumor/control ratio [T/C] ∼57%). Gem. alone was modestly effective only in PAXF2196 (T/C ∼50%). Combination therapy achieved borderline efficacy (T/C 51%-59%) in models PAXF2141, PAXF2146, and PAXF1986, and significant TGI in PAXF1900, PAXF2196, and PAXF2116, with T/C values of 31%, 35%, and 47% (p<0.05). PAXF2141, PAXF2146, and PAXF2116 harbor Ras mutations: (G12R, G12V, G12R respectively). Weight loss was minor but rose in 4 combination groups. Survival rates stayed high across all models. These results support clinical trials of S-CP201 as an effective combination partner for Gem. and/or albumin-bound Paclitaxel in pancreatic adenocarcinoma, including in patients with tumors containing mutated Ras. An IND enabling data package is underway. Citation Format: Michael Ahrweiler, Wolfgang Meyer, Axel Zander, Daniel Perrissoud. Efficacy and tolerability of a enantiomer of Edelfosine (S-CP201) in pancreatic cancer PDX models as a single agent and in combination with approved drugs in clinical use [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 32.