A Study of Efficacy and Safety of Fruquintinib (HMPL-013) in Participants With Metastatic Colorectal Cancer
Condition: Metastatic Colorectal Cancer; Metastatic Colon Cancer
MeSH terms: Colorectal Neoplasms
Intervention: Fruquintinib; Placebo
Intervention description: Oral VEGFR inhibitor; Placebo capsule
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 691.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: colon; colorectal; mcrc; crc; metastatic colon; metastatic colorectal; VEGF; VEGFR

Summary:

      This is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical
      trial to compare the efficacy and safety of fruquintinib plus best supportive care (BSC)
      versus placebo plus BSC in participants with refractory metastatic colorectal cancer (mCRC).
      691 participants were randomized to one of the following treatment arms in a 2:1 ratio,
      fruquintinib plus BSC or placebo plus BSC.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Provide written informed consent;

          -  Age ≥18 years;

          -  Histologically and/or cytologically documented metastatic colorectal adenocarcinoma.
             RAS, BRAF, and microsatellite instability microsatellite instability (MSI)/mismatch
             repair (MMR) status for each patient must be documented, according to country level
             guidelines;

          -  Participants must have progressed on or been intolerant to treatment with either
             trifluridine/tipiracil (TAS-102) or regorafenib. Participants are considered
             intolerant to TAS-102 or regorafenib if they have received at least 1 dose of either
             agents and were discontinued from therapy for reasons other than disease progression.
             Participants who have been treated with both TAS-102 and regorafenib are permitted.
             Participants must also have been previously treated with standard approved therapies:
             fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF
             biological therapy, and, if RAS wild-type, an anti-EGFR therapy;

          -  Participants with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR)
             tumors must have been treated with immune checkpoint inhibitors if approved and
             available in the participant's country unless the patient is ineligible for treatment
             with a checkpoint inhibitor;

          -  Participants who received oxaliplatin in the adjuvant setting and developed metastatic
             disease during or within 6 months of completing adjuvant therapy are considered
             eligible without receiving oxaliplatin in the metastatic setting. Participants who
             developed metastatic disease more than 6 months after completion of
             oxaliplatin-containing adjuvant treatment must be treated with oxaliplatin-based
             therapy in the metastatic setting to be eligible;

          -  Body weight ≥40kg;

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;

          -  Have measurable disease according to RECIST Version 1.1, assessed locally. Tumors that
             were treated with radiotherapy are not measurable per RECIST Version 1.1, unless there
             has been documented progression of those lesions;

          -  Expected survival >12 weeks.

          -  For female participants of childbearing potential and male participants with partners
             of childbearing potential, agreement to use a highly effective form(s) of
             contraception, that results in a low failure rate (<1% per year) when used
             consistently and correctly, starting during the screening period, continuing
             throughout the entire study period, and for 90 days after taking the last dose of
             study drug. Such methods include: oral hormonal contraception (combined estrogen/
             progestogen, or progestogen-only) associated with inhibition of ovulation,
             intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral
             tubal ligation, vasectomized partner, or true sexual abstinence in line with the
             preferred and usual lifestyle of the participant. Highly effective contraception
             should always be combined with an additional barrier method (eg, diaphragm, with
             spermicide). The same criteria are applicable to male participants involved in this
             clinical trial if they have a partner of childbirth potential, and male participants
             must always use a condom.

          -  Participants with BRAF-mutant tumors must have been treated with a BRAF inhibitor if
             approved and available in the participant's home country unless the patient is
             ineligible for treatment with a BRAF inhibitor.

        Exclusion Criteria:

          -  Absolute neutrophil count (ANC) <1.5×109/L, platelet count <100×109/L, or hemoglobin
             <9.0 g/dL. Blood transfusion within 1 week prior to enrollment for the purpose of
             increasing the likelihood of eligibility is not allowed;

          -  Serum total bilirubin >1.5 × the upper limit of normal (ULN). Participants with
             Gilbert syndrome, bilirubin <2 X ULN, and normal AST/ALT are eligible;

          -  Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × ULN in
             participants without hepatic metastases; ALT or AST >5 × ULN in participants with
             hepatic metastases;

          -  Serum creatinine >1.5 × ULN or creatinine clearance <60 mL/min. Creatinine clearance
             can either be measured in a 24-hour urine collection or estimated by the
             Cockroft-Gault equation.

          -  Urine dipstick protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h. Participants with
             greater than 2+ proteinuria by dipstick must undergo a 24-hour urine collection to
             assess urine protein level;

          -  Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mm Hg and/or
             diastolic blood pressure ≥90 mm Hg despite optimal medical management. Participants
             were required to have blood pressure values below both limits. Repeated assessments
             were permitted;

          -  International Normalized Ratio (INR) >1.5 x ULN or activated partial thromboplastin
             time (aPTT) >1.5 × ULN, unless the patient is currently receiving or intended to
             receive anticoagulants for prophylactic purposes;

          -  History of, or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage
             of an unresected gastrointestinal tumor, history of perforation or fistulas; or any
             other condition that could, in the investigator's judgment, result in gastrointestinal
             hemorrhage or perforation; within the 6 months prior to screening;

          -  History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis)
             within 2 months prior to screening;

          -  History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary
             embolism (PE), or arterial embolism within 6 months prior to screening.

          -  Stroke and/or transient ischemic attack within 12 months prior to screening;

          -  Clinically significant cardiovascular disease, including but not limited to acute
             myocardial infarction or coronary artery bypass surgery within 6 months prior to
             enrollment, severe or unstable angina pectoris, New York Heart Association Class
             III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left
             ventricular ejection fraction (LVEF) <50% by echocardiogram;

          -  Mean corrected QT interval using the Fridericia method (QTcF) >480 msec or any factors
             that increase the risk of QTc prolongation or risk of arrhythmic events such as
             hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or
             unexplained sudden death under 40 years of age in a first-degree relative.

          -  Concomitant medications with a known risk of causing QT prolongation and/or Torsades
             de Pointes.

          -  Systemic anti-neoplastic therapies (except for those described in Exclusion 18) or any
             investigational therapy within 4 weeks prior to the first dose of study drug,
             including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and
             immunotherapy;

          -  Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors) within 5
             half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug;

          -  Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the
             initiation of study drug;

          -  Brachytherapy (i.e., implantation of radioactive seeds) within 60 days prior to the
             first dose of study drug.

          -  Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives,
             whichever is longer) before the first dose of study drug;

          -  Surgery or invasive procedure (i.e., a procedure that includes a biopsy; central
             venous catheter placement is allowed) within 60 days prior to the first dose of study
             drug or unhealed surgical incision;

          -  Any unresolved toxicities from a previous antitumor treatment greater than CTCAE v5.0
             Grade 1 (except for alopecia or neurotoxicity grade≤2);

          -  Known human immunodeficiency virus (HIV) infection;

          -  Known history of active viral hepatitis. For participants with evidence of chronic
             hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on
             suppressive therapy, if indicated. Participants with HCV infection who are currently
             on treatment are eligible if they have an undetectable HCV viral load.

          -  Clinically uncontrolled active infection requiring IV antibiotics;

          -  Tumor invasion of a large vascular structure, eg, pulmonary artery, superior or
             inferior vena cava;

          -  Women who are pregnant or lactating;

          -  Brain metastases and/or spinal cord compression untreated with surgery and/or
             radiotherapy, and without clinical imaging evidence of stable disease for 14 days or
             longer; participants requiring steroids within 4 weeks prior to start of study
             treatment are excluded;

          -  Other malignancy, except for non-melanoma skin cancer, in situ cervical ca or bladder
             ca (Tis and T1) that have been adequately treated during the 5 years prior to
             screening;

          -  Inability to take medication orally, dysphagia or an active gastric ulcer resulting
             from previous surgery (eg, gastric bypass) or a severe gastrointestinal disease, or
             any other condition that investigators believe may affect absorption of the
             investigational product;

          -  Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory
             result, or any other condition (e.g., current alcohol or drug abuse) that
             investigators suspect may prohibit use of the investigational product, affect
             interpretation of study results, or put the patient at undue risk of harm based on the
             investigator's assessment;

          -  Known hypersensitivity to fruquintinib (or placebo) or any of its inactive ingredients
             including the azo dyes Tartrazine - FD&C Yellow 5 and Sunset yellow FCF - FD&C Yellow
             6;

          -  Participants who have received prior fruquintinib;

          -  Live vaccine <28days before the first dose of study drug(s). Seasonal vaccines for
             influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are
             live vaccines and are not allowed.