Abstract 3593: OQL051, a gut-restricted CDK4/6 inhibitor has prophylactic potency for chemotherapy-induced diarrhea

Abstract

Abstract Introduction: Chemotherapy-induced diarrhea (CID) is a common and potentially life-threatening side effect of chemotherapy and has an incidence of 50% - 80% with 5FU and irinotecan (CPT-11). For severe CID, dose reduction, interruption, or discontinuation of chemotherapy is often required, negatively impacting anticancer therapy. Cyclin-dependent kinases 4/6 (CDK4/6) regulate cell cycle G1/S transition and can induce a “pharmacological quiescence” with transient administration. Recently, trilaciclib, an IV CDK4/6 inhibitor prophylactically reduced chemotherapy-induced neutropenia without decreasing overall survival. Therefore, transient oral administration of a gut-restricted CDK4/6 inhibitor, prior to the chemotherapy may slow/inhibit intestinal stem/epithelial cell cycling and thus, be prophylactic for CID without reducing chemotherapy efficacy. Methods: PK was studied in Balb/c mice given OQL051 (OQL, 50 mg/kg) intra-gastrically. Blood samples were collected at pre- and 0.25, 0.5, 1, 2, 4, and 6 h post-dosing and centrifuged for plasma. Tissues (jejunum/colon) were collected at 0.5, 2, and 6 h after OQL (n=3/collection). Plasma and tissues were analyzed for OQL by Liquid Chromatography Mass Spectrometry. CID was studied in 5 groups of Balb/c mice (n=5/group) given OQL vehicle (OQLV)+0.9%NaCl saline (NaCl), OQLV+5FU (175 mg/kg) and OQL+5FU at 3 OQL doses (25, 50, and 100 mg/kg) orally at 8 h prior and 4 h post an IP 5FU injection. In a second CID study, Balb/c mice (controls as above, n=5/group) were given OQL+5FU at 2 OQL doses (30 and 100 mg/kg, n=5/dose) plus IP 5FU daily (70 mg/kg) for 3 consecutive days. OQLV or OQL were given orally at 8 h prior and 4 h after each daily IP 5FU injection. OQL doses were given once more on the 4th day. Results: OQL concentrations in the jejunum and colon were over 300 times greater than those in plasma (AUC 12017 and 10515 vs 32.1 ng·h/g, respectively). The 1-day in vivo CID study showed OQL decreased diarrhea grades by 67% to 83% (̄x̄ (SE): OQLV/NaCl 0.0 (0.0), OQLV/5FU 1.2 (0.3), OQL 25mg 0.2 (0.2), OQL 50mg 0.4 (0.2), OQL 100mg 0.4 (0.4)). The 3-day in vivo study showed OQL decreased the diarrhea grades by 63% (̄x̄ (SE): QOLV/NaCl 0.0 (0.0), OQLV/5FU 1.6 (0.5), OQL 30mg 0.6 (0.2), OQL 100mg 0.6 (0.7)). In the 5FU CID model, histological examination showed intestinal tissues/epithelial cells had less edema, inflammatory cell infiltration and necrosis after OQL treatment compared with OQLV+5FU. Conclusion: Oral administration of the CDK4/6 inhibitor, OQL051, was restricted to the intestinal lining and reduced 5FU intestinal cell inflammation and necrosis. This resulted in a reduction in CID in a preclinical model and supports the potential for a prophylactic CID treatment in cancer patients without reducing their chemotherapy anticancer efficacy. Citation Format: Wemqin Zeng, Wenxi Li, Liping Chen, Shilan Liu, Robert Claude Tyler, Shiyi Zhang. OQL051, a gut-restricted CDK4/6 inhibitor has prophylactic potency for chemotherapy-induced diarrhea [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3593.