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

Prior treatment

• Receipt of systemic antitumor therapy within 4 weeks prior to initiation of study treatment.
  • For prior small-molecule targeted therapy: the interval between the end of prior therapy and first study dose must be ≥5 half-lives of the drug or ≥7 days, whichever is longer.
  • For prior traditional Chinese antitumor medicines: ≥2 weeks washout is required.
• Palliative radiotherapy to non-target lesions, radioactive seed implantation, radiofrequency ablation, or similar local therapy within 28 days prior to first study dose.
• Toxicities or complications from prior therapies that have not recovered to NCI-CTCAE grade ≤1 or to eligibility-specified levels.
  • o Patients with stable grade ≤2 toxicities may be enrolled at investigator discretion if no safety risk exists (e.g., immune checkpoint inhibitor-related type 1 diabetes or hypothyroidism controlled with hormone replacement therapy).
• Within 28 days prior to first study dose: inability to swallow oral medication, chronic diarrhea, active gastroenteritis, gastrointestinal perforation, prior major gastrointestinal resection, colitis, or other conditions that may impair drug administration or absorption.
• Clinically symptomatic moderate or severe ascites requiring therapeutic paracentesis or drainage within 2 weeks prior to study treatment.
  • Small asymptomatic ascites detected by imaging is allowed.
  • Uncontrolled or moderate-to-large pleural effusion or pericardial effusion.
• Evidence of intestinal obstruction or signs/symptoms of obstruction at baseline.
  • Patients who underwent surgery with complete resolution of obstruction may be screened.
  • Presence of an indwelling intestinal stent at screening.
• Uncontrolled or severe cardiovascular disease, including:
  • Severe or unstable congestive heart failure (NYHA class II-IV)
  • Myocardial infarction within 6 months prior to first dose
  • Unstable angina within 1 month prior to treatment
  • Unstable arrhythmia
• History of or concurrent malignancies other than colorectal cancer, unless in complete remission for ≥5 years prior to screening and not requiring ongoing therapy, except:
  • Basal cell carcinoma of the skin
  • Superficial bladder cancer
  • Cutaneous squamous cell carcinoma
  • Cervical carcinoma in situ
  • Localized prostate cancer
  • Ductal carcinoma in situ after curative surgery
  • Non-metastatic prostate or breast cancer receiving hormone therapy
• Severe infection within 28 days prior to first dose, including infections requiring hospitalization, bacteremia, or severe pneumonia.
  • Active infection requiring therapeutic intravenous antibiotics within 2 weeks prior to treatment.
  • Prophylactic antibiotics (e.g., for urinary tract infection prevention) are permitted.
• Active pulmonary tuberculosis within 1 year prior to enrollment, or history of active tuberculosis \>1 year prior without appropriate standard treatment.
• Concomitant use of strong CYP3A4 inhibitors or inducers that cannot be discontinued ≥7 days prior to first dose (e.g., ketoconazole, itraconazole, clarithromycin, rifampin, carbamazepine, phenobarbital).
• Active dermatologic disorders (e.g., psoriasis, severe eczema, chronic pruritus) or prior ≥grade 2 drug-related skin reactions not fully resolved.
• Prior treatment with everolimus and:
  • Development of ≥grade 3 drug-related toxicity, OR
  • Discontinuation due to resistance or lack of efficacy.

Other illness

• Untreated or active central nervous system (CNS) metastases. Patients with a history of leptomeningeal metastases or current leptomeningeal disease.
• Active hepatitis B infection defined as:
  • o Positive HBsAg AND HBV DNA ≥10,000 copies/mL (≥2,000 IU/mL).
  • Active hepatitis C defined as:
  • o Positive HCV antibody AND detectable HCV RNA.
• Known immunodeficiency, including HIV positivity, congenital or acquired immunodeficiency disorders, or history of organ transplantation.
• Active autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, myasthenia gravis, or requirement for long-term systemic immunosuppressive therapy.
• Active severe oral mucosal disease or recurrent oral ulceration.
  • o History of ≥grade 2 stomatitis that has not recovered to CTCAE grade ≤1.
• Known hypersensitivity to everolimus or any of its metabolites.
• Uncontrolled psychiatric illness, known alcohol or drug abuse, incarceration, or other conditions that may interfere with study compliance.
• Any other condition that, in the investigator's judgment, may increase study risk, interfere with study outcomes, or make the participant unsuitable.
• Inability to understand study conditions and objectives or refusal to sign informed consent.

Other

• Participants meeting any of the following criteria will be excluded:
• Pregnant or breastfeeding women, or women planning pregnancy during the study period.

• Ability to understand and voluntarily sign an ethics committee-approved informed consent form and willingness to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
• Age 18 to 80 years (inclusive) at the time of signing informed consent; male or female.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Estimated life expectancy ≥12 weeks.
• CDK12 deficiency confirmed by immunohistochemistry (IHC).
• Histologically confirmed metastatic colorectal cancer with documented disease progression after prior standard systemic antitumor therapies, including but not limited to oxaliplatin, fluoropyrimidine, and irinotecan.
  • o Patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) tumors must have experienced disease progression following anti-PD-1/PD-L1 therapy.
• At least one measurable lesion according to RECIST version 1.1, defined as:
  • Non-nodal lesions ≥10 mm in longest diameter by CT scan (slice thickness ≤5 mm);
  • Malignant lymph nodes with short axis ≥15 mm by CT scan (slice thickness ≤5 mm recommended).
• Adequate organ function meeting all of the following criteria:
  • Hematologic (without growth factor support or transfusion within 7 days prior to testing):
  • Absolute neutrophil count ≥1.5 × 10⁹/L
  • Platelet count ≥75 × 10⁹/L
  • Hemoglobin ≥90 g/L
  • Biochemical:
  • Total bilirubin ≤1.5 × upper limit of normal (ULN)
  • AST and ALT ≤2.5 × ULN
  • Serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min (calculated using Cockcroft-Gault formula)
  • Coagulation:
  • International normalized ratio (INR) ≤1.5
  • Activated partial thromboplastin time (aPTT or PTT) ≤1.5 × ULN
• Absence of high-risk conditions, including:
  • Active or major cardiovascular events within 6 months (e.g., myocardial infarction, severe heart failure, stroke);
  • Severe pulmonary dysfunction requiring long-term oxygen therapy or interstitial lung disease/pulmonary fibrosis;
  • Active uncontrolled infection (including uncontrolled HBV, HCV, HIV, or tuberculosis);
  • Other active malignancies within 5 years, except those treated with curative local therapy.
• For participants of childbearing potential:
  • Must agree to use effective contraception during the study and for 120 days after completion;
  • Negative serum pregnancy test within 7 days prior to enrollment;
  • Not breastfeeding.