Background Patients with metastatic colorectal cancer who have progressed after treatment with oxaliplatin- and irinotecan-based chemotherapy, as well as anti-EGFR monoclonal antibodies (cetuximab or panitumumab) according to RAS mutation status, or anti-angiogenic agents (bevacizumab, ramucirumab, or aflibercept), have limited therapeutic options in the third-line setting. The phase III SUNLIGHT trial evaluating TAS-102 (trifluridine/tipiracil) in combination with bevacizumab demonstrated promising outcomes, with a median progression-free survival (PFS) of 5.6 months and a median overall survival (OS) of 10.8 months. However, approximately 30% of patients in that study had not previously received bevacizumab during first- or second-line treatment, indicating that a proportion of patients had not been fully exposed to current standard therapies for metastatic colorectal cancer. Therefore, there remains an unmet need to evaluate additional therapeutic strategies in patients who have received optimal prior standard treatments. This study aims to evaluate the efficacy and safety of fruquintinib as a third-line treatment in this population.

Hypothesis Proactive and comprehensive supportive care will not only help manage fruquintinib-related toxicities (e.g., hypertension, hand-foot syndrome, proteinuria, and fatigue), but also enable patients to maintain treatment, thereby potentially prolonging progression-free survival (PFS).

Study Design This is a multicenter, single-arm, investigator-initiated phase II clinical trial designed to evaluate the efficacy and safety of fruquintinib in combination with supportive care in patients with metastatic colorectal cancer who are intolerant to second-line standard chemotherapy. All subjects will receive fruquintinib treatment in combination with supportive care. Supportive care refers to medical interventions aimed at preventing and managing adverse events associated with fruquintinib, including but not limited to hypertension, proteinuria, diarrhea, fatigue, and hand-foot syndrome.

Inclusion Criteria:

• [Signed Written Informed Consent]

Subjects who voluntarily provide signed written informed consent after receiving sufficient explanation of this clinical trial prior to initiation of any study-related procedures.

[Age and Sex]

Subjects aged 19 years or older at the time of signing the informed consent.

For women of childbearing potential, a negative urine β-hCG pregnancy test within 14 days prior to the first administration of the investigational product (IP) is required.

Women will be considered not of childbearing potential if they meet any of the following criteria; women who do not meet these criteria will be considered of childbearing potential.

1. Women older than 50 years of age who have experienced amenorrhea for at least 12 months after discontinuation of all exogenous hormonal treatments.

2. Documented irreversible surgical sterilization, including hysterectomy, bilateral oophorectomy, or bilateral salpingectomy.

   (Tubal ligation is not permitted.)

3. Women 50 years of age or younger who have experienced amenorrhea for at least 12 months after discontinuation of all exogenous hormonal treatments, and whose luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels fall within the postmenopausal range according to the institutional laboratory standards.

4. Subjects with hCG-producing tumors may be enrolled at the discretion of the Principal Investigator.

   Subjects must agree to use effective contraception from the first administration of the investigational product until at least 4 weeks after the last administration.

   Female subjects of childbearing potential (or male subjects with female partners of childbearing potential) must use an effective method of contraception during the study treatment period and for at least 4 weeks after the last dose of the investigational product.

   Male subjects who have not undergone vasectomy (or female subjects with male partners) must use effective contraception during the study treatment period and for at least 4 weeks after the last dose, and must not donate sperm during this period.

   ※ Effective contraception methods include: Hormonal contraceptives (subdermal implants, injectable contraceptives, oral contraceptives, etc.), intrauterine devices (IUDs) or intrauterine hormone-releasing systems (IUSs), sterilization of the subject or partner (e.g., vasectomy or bilateral tubal ligation), or sexual abstinence, provided that abstinence is consistent with the subject's usual lifestyle.

   [Target Population]

   Metastatic colorectal cancer patients intolerant to second-line standard chemotherapy:

   Patients with histologically or cytologically confirmed metastatic or recurrent colorectal cancer who have received two prior systemic treatment regimens (first-line and second-line) including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

   Recurrence within 6 months after completion of adjuvant therapy will be considered as progression during first-line treatment.

   Subjects with an expected life expectancy of at least 3 months.

   ECOG performance status of 0 or 1.

   Evaluable disease according to RECIST version 1.1. (Measurable disease is not required.)

   Subjects must be able to swallow oral medications.

   [Clinical Laboratory Tests]

   Bone marrow function

   Hemoglobin (Hb) > 9.0 g/dL

   Absolute neutrophil count (ANC) ≥ 1.0 × 10⁹/L

   Platelet count (PLT) ≥ 75 × 10⁹/L

   Renal function

   Serum creatinine ≤ 1.5 × ULN or creatinine clearance > 30 mL/min

   Hepatic function

   Total bilirubin ≤ 2.0 × ULN (In cases of biliary obstruction, the criteria must be met after appropriate biliary drainage.)

   AST and ALT ≤ 3 × ULN (≤ 5 × ULN in patients with liver metastases)

   Cardiac function

   QTc ≤ 480 msec

   If QTc exceeds 480 msec, QTc should be measured three consecutive times, and the subject may be enrolled if the average QTc value is < 480 msec.

   Exclusion Criteria:

   • [Interventional Treatments]

   Subjects who received an investigational product in another clinical trial within 14 days prior to the first administration of the investigational product in this study.

   Subjects who received cytotoxic chemotherapy within 14 days prior to the first administration of the investigational product, or monoclonal antibody therapy within 4 weeks prior to the first administration of the investigational product.

   Subjects who received radiotherapy involving more than 30% of the bone marrow within 4 weeks prior to the first administration of the investigational product, or palliative radiotherapy to a limited field within 2 weeks prior to the first administration.

   Subjects with persistent toxicities ≥ Grade 1 according to CTCAE from prior anticancer therapy that have not resolved before the first administration of the investigational product (except for alopecia).

   [Medical History and Concurrent Diseases]

   Women who are pregnant or breastfeeding.

   Subjects with active, severe, or uncontrolled infection.

   Subjects with clinically significant cardiovascular disease, including but not limited to:

   Acute coronary syndrome within 6 months

   Congestive heart failure ≥ NYHA (New York Heart Association) Class II

   QTc prolongation or uncontrolled hypertension

   Other significant cardiovascular conditions (e.g., clinically significant arrhythmias or congenital long QT syndrome)

   Subjects with progressive brain metastases, defined as unstable or symptomatic brain lesions.

   Subjects whose lesions have been stable for at least 4 weeks following radiotherapy or surgery may be eligible for enrollment.

   (Leptomeningeal metastasis is excluded.)

   Subjects with active infections such as hepatitis B (HBV), hepatitis C (HCV), or HIV.

   However, enrollment is permitted under the following conditions:

   Subjects who are HBsAg positive may be enrolled if HBV DNA is below the lower limit of quantification according to local laboratory testing.

   Subjects with chronic HBV infection (HBsAg positive and HBV DNA positive) may be enrolled if they have received antiviral therapy for at least 3 months and are considered not to have active hepatitis at the investigator's discretion.

   Subjects with a history of previous HBV infection (IgG anti-HBc positive) may be enrolled if HBV DNA is below the lower limit of quantification.

   Subjects who are anti-HCV antibody positive may be enrolled if HCV RNA is below the lower limit of quantification.

   Subjects who underwent major surgery within 4 weeks prior to the first administration of the investigational product, or who have not adequately recovered from surgery.

   Subjects with a history of thrombosis within 6 months prior to the first administration of the investigational product.

   Subjects with a history or evidence of bleeding disorders.

   Subjects who are receiving high-dose anticoagulant therapy for therapeutic purposes.

   Subjects with non-healing wounds, active ulcers, or bone fractures.

   Subjects with a history of gastrointestinal perforation, active gastrointestinal bleeding, or abdominal fistula within the past 6 months.

   Subjects with proteinuria.

   If the urine dipstick test shows ≥2+ proteinuria, a 24-hour urine protein test or urine protein/creatinine ratio (UPCR) should be performed.

   Subjects will be excluded if:

   24-hour urine protein > 1 g, or

   UPCR > 1.0

   Subjects with a history of surgery affecting drug absorption or with severe gastrointestinal disorders that may interfere with drug absorption.

   Subjects with a history of another primary malignancy, except for:

   Adequately treated non-melanoma skin cancer, or

   Stage I cancer that has shown no recurrence for at least 36 months after curative resection

   Subjects with known hypersensitivity to the active ingredient or excipients of the investigational product, including:

   Hypersensitivity or allergy to Allura Red (relevant to Fruquintinib capsule 5 mg)

   Hypersensitivity or allergy to Tartrazine (FD&C Yellow No.5) or Sunset Yellow FCF (FD&C Yellow No.6) (relevant to Fruquintinib capsule 1 mg)

   Subjects who are scheduled to undergo major surgery during the study period.

   Subjects who have medical, psychiatric, or cognitive conditions that may interfere with the understanding of study information, performance of study procedures, or provision of written informed consent.

   Subjects who are considered inappropriate for participation in the study at the discretion of the Principal Investigator.