A Study of Efficacy and Safety of Fruquintinib (HMPL-013) in Participants With Metastatic Colorectal Cancer

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)/mismatchrepair (MMR) status for each patient must be documented, according to country levelguidelines;

• Participants must have progressed on or been intolerant to treatment with eithertrifluridine/tipiracil (TAS-102) or regorafenib. Participants are consideredintolerant to TAS-102 or regorafenib if they have received at least 1 dose of eitheragents and were discontinued from therapy for reasons other than diseaseprogression. Participants who have been treated with both TAS-102 and regorafenibare permitted. Participants must also have been previously treated with standardapproved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-basedchemotherapy, an anti-VEGF biological therapy, and, if RAS wild-type, an anti-EGFRtherapy;

• Participants with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR)tumors must have been treated with immune checkpoint inhibitors if approved andavailable in the participant's country unless the patient is ineligible fortreatment with a checkpoint inhibitor;

• Participants who received oxaliplatin in the adjuvant setting and developedmetastatic disease during or within 6 months of completing adjuvant therapy areconsidered eligible without receiving oxaliplatin in the metastatic setting.Participants who developed metastatic disease more than 6 months after completion ofoxaliplatin-containing adjuvant treatment must be treated with oxaliplatin-basedtherapy 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. Tumorsthat 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 withpartners of childbearing potential, agreement to use a highly effective form(s) ofcontraception, that results in a low failure rate (<1% per year) when usedconsistently and correctly, starting during the screening period, continuingthroughout the entire study period, and for 90 days after taking the last dose ofstudy 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), bilateraltubal ligation, vasectomized partner, or true sexual abstinence in line with thepreferred and usual lifestyle of the participant. Highly effective contraceptionshould always be combined with an additional barrier method (eg, diaphragm, withspermicide). The same criteria are applicable to male participants involved in thisclinical trial if they have a partner of childbirth potential, and male participantsmust always use a condom.

• Participants with BRAF-mutant tumors must have been treated with a BRAF inhibitor ifapproved and available in the participant's home country unless the patient isineligible 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 ofincreasing the likelihood of eligibility is not allowed;

• Serum total bilirubin >1.5 × the upper limit of normal (ULN). Participants withGilbert syndrome, bilirubin <2 X ULN, and normal AST/ALT are eligible;

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × ULN inparticipants without hepatic metastases; ALT or AST >5 × ULN in participants withhepatic metastases;

• Serum creatinine >1.5 × ULN or creatinine clearance <60 mL/min. Creatinine clearancecan either be measured in a 24-hour urine collection or estimated by theCockroft-Gault equation.

• Urine dipstick protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h. Participants withgreater than 2+ proteinuria by dipstick must undergo a 24-hour urine collection toassess urine protein level;

• Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mm Hg and/ordiastolic blood pressure ≥90 mm Hg despite optimal medical management. Participantswere required to have blood pressure values below both limits. Repeated assessmentswere permitted;

• International Normalized Ratio (INR) >1.5 x ULN or activated partial thromboplastintime (aPTT) >1.5 × ULN, unless the patient is currently receiving or intended toreceive anticoagulants for prophylactic purposes;

• History of, or active gastric/duodenal ulcer or ulcerative colitis, activehemorrhage of an unresected gastrointestinal tumor, history of perforation orfistulas; or any other condition that could, in the investigator's judgment, resultin gastrointestinal hemorrhage or perforation; within the 6 months prior toscreening;

• History or presence of hemorrhage from any other site (eg, hemoptysis orhematemesis) within 2 months prior to screening;

• History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonaryembolism (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 acutemyocardial infarction or coronary artery bypass surgery within 6 months prior toenrollment, severe or unstable angina pectoris, New York Heart Association ClassIII/IV congestive heart failure, ventricular arrhythmias requiring treatment, orleft ventricular ejection fraction (LVEF) <50% by echocardiogram;

• Mean corrected QT interval using the Fridericia method (QTcF) >480 msec or anyfactors that increase the risk of QTc prolongation or risk of arrhythmic events suchas hypokalemia, congenital long QT syndrome, family history of long QT syndrome, orunexplained sudden death under 40 years of age in a first-degree relative.

• Concomitant medications with a known risk of causing QT prolongation and/or Torsadesde Pointes.

• Systemic anti-neoplastic therapies (except for those described in Exclusion 18) orany investigational therapy within 4 weeks prior to the first dose of study drug,including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy andimmunotherapy;

• Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors) within 5half-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 theinitiation of study drug;

• Brachytherapy (i.e., implantation of radioactive seeds) within 60 days prior to thefirst 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; centralvenous catheter placement is allowed) within 60 days prior to the first dose ofstudy drug or unhealed surgical incision;

• Any unresolved toxicities from a previous antitumor treatment greater than CTCAEv5.0 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 chronichepatitis B virus (HBV) infection, the HBV viral load must be undetectable onsuppressive therapy, if indicated. Participants with HCV infection who are currentlyon 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 orinferior vena cava;

• Women who are pregnant or lactating;

• Brain metastases and/or spinal cord compression untreated with surgery and/orradiotherapy, and without clinical imaging evidence of stable disease for 14 days orlonger; participants requiring steroids within 4 weeks prior to start of studytreatment are excluded;

• Other malignancy, except for non-melanoma skin cancer, in situ cervical ca orbladder ca (Tis and T1) that have been adequately treated during the 5 years priorto screening;

• Inability to take medication orally, dysphagia or an active gastric ulcer resultingfrom previous surgery (eg, gastric bypass) or a severe gastrointestinal disease, orany other condition that investigators believe may affect absorption of theinvestigational product;

• Other disease, metabolic disorder, physical examination anomaly, abnormal laboratoryresult, or any other condition (e.g., current alcohol or drug abuse) thatinvestigators suspect may prohibit use of the investigational product, affectinterpretation of study results, or put the patient at undue risk of harm based onthe investigator's assessment;

• Known hypersensitivity to fruquintinib (or placebo) or any of its inactiveingredients 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 forinfluenza are generally inactivated vaccines and are allowed. Intranasal vaccinesare live vaccines and are not allowed.