Trial of 5-Fluorouracil (5FU)-Based Therapy in Combination With Fruquintinib in Patients With Locally Advanced Unresectable or Metastatic Colorectal Cancer

Prior treatment

• Receiving chronic treatment with corticosteroids ≥5 mg of prednisone per day (or equivalent) or other systemic immunosuppressive agents. Topical or nasal corticosteroids are allowed.
• Receipt of live, attenuated vaccine (e.g., intranasal influenza, measles, mumps, rubella, varicella) or close contact with someone who has received a live, attenuated vaccine within the past 1 month from consent. Note: Influenza vaccine will be allowed if administered \>21 days.
• Receipt of any investigational agent or study treatment within the past 30 days from consent for a condition other than CRC.

Other illness

• Any clinically significant and/or uncontrolled cardiac-related abnormality that would compromise patient safety or the outcome of the study including, but not limited to:
  • Arrhythmia
  • Bradycardia
  • Tachycardia
  • Symptomatic valvular disease
  • Symptomatic congestive heart failure is classified by the New York Heart Association as Class III or IV
  • Unstable angina pectoris.
• Myocardial infarction within the past 6 months from consent.
• Active bleeding diathesis.
• Current complaints of persistent constipation or history of chronic constipation, untreatable bowel obstruction, or fecaloma within the past 6 months from consent.
• Known history and/or uncontrolled hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV)-1 or HIV-2.
• History of malignancy or active treatment for malignancy other than CRC (i.e., radiation or chemotherapy, including monoclonal antibodies) within 5 years. Note: Patients with squamous or basal cell carcinomas of the skin, carcinomas in situ of the cervix or uterus, ductal breast cancer in situ, resected low-grade prostate cancer, or other malignancies that in the opinion of the investigator are considered cured may participate.
• Receipt of any protein or antibody-based therapeutic agents (e.g., growth hormones or monoclonal antibodies) within the past 3 months from consent for a condition other than CRC.
• Uncontrolled hypertension
• Active infection requiring treatment
• Recent history of major surgery

Lab values

• Hematology laboratory values of:
  • Absolute neutrophil count ≤1500 cells/mm3
  • Platelets ≤100,000 cells/mm3
  • Hemoglobin ≤9 g/dL
  • White blood count ≤3000 cells/mm3.
• Hepatic laboratory values of aspartate transaminase (AST) or alanine aminotransferase (ALT):
  • \>5 × upper limits of normal (ULN) if the documented history of hepatic metastases; or
  • \>2.5 × ULN if no liver metastases are present.
• Serum albumin \<2.8 g/dL.
• Total bilirubin \>1.7 mg/dL × ULN.
• Prothrombin time (PT) or international normalized ratio (INR) \>1.5 × ULN. Note: Patients receiving therapeutic doses of anticoagulant therapy may be considered eligible if PT and INR are within the acceptable institutional therapeutic limits.
• Serum creatinine or serum urea \>1.5 × ULN.
• Per treating physician's assessment, any other clinically significant laboratory abnormality that would compromise patient safety or the outcome of the study.
• History of galactose intolerance, deficiency of Lapp lactase, or glucose-galactose malabsorption.

Other

• Estimated glomerular filtration rate \<50 mL/min.
• Urine dipstick or urinalysis with protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h. Subjects with 1+ proteinuria must undergo a 24-hour urine collection to assess urine protein level.
• Positive pregnancy test, pregnant, or breastfeeding for all women of child-bearing potential.
• Thromboembolic events during the past 6 months
• Adults unable to consent
• Prisoners

• Male or female ≥18 years of age.
• Written informed consent is required before performing any trial-specific tests or procedures. Signing of the informed consent form can occur outside the 28-day screening period.
• Histopathologically or cytologically confirmed locally advanced unresectable or metastatic colorectal cancer. The study will include an all-comer population, meaning that patients will not be excluded based on specific molecular markers such as microsatellite instability-high (MSI-H) or B-Raf proto-oncogene mutations (BRAF mutations). However, as part of the Standard of Care, comprehensive molecular testing will be performed to assess MSI status, and other relevant biomarkers. For patients with MSI-H or BRAF mutations confirmed, treatment may be adjusted per Standard of Care practices.
• Measurable disease per RECISTv1.1.
• No prior systemic treatment. Patients with resected disease who later develop unresectable recurrence without prior systemic therapy remain eligible.
• ECOG performance status of 0 or 1.
• Life expectancy ≥6 months per treating physician's assessment.
• Patients of childbearing potential must agree to use an adequate method of contraception during the study and for 30 days after the last dose of study treatment.
• Patients must be able to swallow oral tablets.