217 (PB097) - A preclinical toxicology and pharmacology study of OQL051, a gut-restricted CDK4/6 inhibitor for the prophylaxis of chemotherapy-induced diarrhea

Abstract

Background: Chemotherapy-induced diarrhea (CID) from fluorouracil (5FU) and irinotecan (IRI, rate 50–80%) leads to therapy interruption/discontinuation and disruption of the intestinal microbiome. Cyclin-dependent kinase 4/ 6 inhibitors (CDK4/6i) induce a “pharmacological quiescence” with transient dosing. OQL051, a gut-restricted CDK4/6i, decreases chemotherapy-induced histological damage to the intestinal wall and reduces CID. We studied OQL051’s toxicology, maintenance of the microbiome, and the impact on tumor growth. Methods: Rats, 20 female, 20 male, 6–7 weeks of age were studied for 8 days. OQL051 was orally administered once daily (100, 250, or 500 mg/kg) for 7 days. Mortality, clinical observations, body weight, and food consumption were recorded daily during treatment. Hematology, coagulation, serum chemistry, gross pathology, and histopathological examination (14 tissue/organ panel including stomach, duodenum, jejunum, and colon) was conducted at D8. Blood was collected from 3 to 5 animals on D1 and D7 at predose, 0.25, 1, 2, 4, 8, and 24 h post-dose to determine the concentration of OQL051. BALB/c mice were subcutaneously injected with 106 CT-26 cells (undifferentiated colon carcinoma cell line), given oral OQL051 (25 mg/kg) or control (CON) at a tumor vol. of 30∼50 mm3, then 6 h later, injected with irinotecan (IRI, 70 mg/kg)/IRI-CON. At a tumor vol. 200∼400 mm3 mice were injected with anti-PD-1 mAb (200 μg)/mAb-CON. Tumor vol. was determined routinely with calipers. The GI tract was sampled for microbiome analysis. Microbiome DNA library (NEBNext® Ultra™ II DNA Kit) was used for sequencing on an Illumina NovaSeq platform. Results: No drug-related mortality or adverse events (AEs) were observed across all dose levels. One female rat had an intussusception event at 250 mg/kg; however, no histopathological abnormality was observed. Compared to vehicle control OQL051 at all doses studied showed no effect on body weight, food intake, hematology, coagulation, serum chemistry, gross pathology, or histopathological examination. In particular, OQL051 being concentrated in the gut showed no histopathological changes in the stomach, duodenum, jejunum, or colon. Microbiome diversity was maintained in OQL051- vs. CON-treated mice, and tumor volume was less in OQL051+IRI+anti-PD-1 vs. CON+IRI+anti-PD-1 (p = 0.035 @ 28 days). Conclusion: OQL051 safety was confirmed as there were no drug-related AEs observed for OQL051 repeat doses up to 500 mg/kg/day for 7 days. CDK 4/6 inhibitor common AEs (neutropenia, leukopenia, thrombocytopenia, anemia, diarrhea, nausea, ALT) were absent indicating a low systemic exposure. The previously observed decrease in intestinal wall damage and CID from chemotherapy led to the maintenance of the gut microbiome and potentially enhanced the efficacy of chemotherapy plus immunotherapy antitumor efficacy at reducing tumor volume. Conflict of interest: Ownership: Shiyi Zhang, Founder, CEO Jie Lou, Co-founder, CSO Hong Tang, Co-founder, CMO Other Substantive Relationships: Wenqin Zeng, employee; Wenxi Li, employee; Shilan Liu, employee; Liping Chen, employee; Robert Tyler, employee.