Everolimus in CDK12-Deficient Metastatic Colorectal Cancer (EVER-RECODE)

Metastatic colorectal cancer (mCRC) remains a major cause of cancer-related mortality. Patients with refractory disease who have progressed after standard systemic therapies have limited treatment options and poor clinical outcomes. Identification of molecularly defined subgroups that may benefit from targeted therapeutic strategies represents an important unmet clinical need. Cyclin-dependent kinase 12 (CDK12) plays a role in transcriptional regulation of genes involved in DNA damage response and genomic stability. CDK12 deficiency has been reported in a small subset of colorectal cancers, estimated at approximately 3-5% of cases. This molecular alteration may confer distinct biological characteristics and potential therapeutic vulnerabilities. However, the clinical efficacy of mTOR inhibition in CDK12-deficient metastatic colorectal cancer has not been prospectively evaluated. EVER-RECODE adopts a combined Phase Ib/II study design. Phase Ib Component Design: Prospective, multicenter, open-label, single-arm study utilizing a traditional 3+3 dose-escalation design. Objectives: * Evaluate the safety and tolerability of everolimus in patients with CDK12-deficient refractory mCRC. * Determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). Planned dose levels include 5 mg/day, 7.5 mg/day, and 10 mg/day administered orally once daily in continuous dosing. Although 10 mg/day has been widely used in several solid tumors, everolimus is associated with dose-dependent toxicities, particularly mucosal and dermatologic adverse events that frequently occur during early treatment. To ensure patient safety in this refractory population, the study adopts 5 mg/day as the starting dose, with stepwise escalation under close safety monitoring to identify the optimal tolerated dose. Phase II Component Design: Prospective, multicenter, open-label, single-arm expansion study. Objective: • Evaluate the preliminary antitumor activity of everolimus at the RP2D in patients with CDK12-deficient refractory mCRC. Study Procedures Eligible participants must have metastatic colorectal cancer with CDK12 deficiency confirmed by immunohistochemistry (IHC). Participants will receive continuous daily oral everolimus. Radiologic tumor assessments will be performed every 8 weeks. Participants will be followed for safety and survival for up to 24 months. Primary Endpoints Phase Ib: Incidence of dose-limiting toxicities (DLTs) and determination of MTD/RP2D. Phase II: Objective response rate (ORR) assessed according to RECIST version 1.1.