A global, randomized, placebo-controlled phase 3 study of fruquintinib in patients with refractory metastatic colorectal cancer

JRCT ID: jRCT2041200099

Registered date:09/02/2021

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: Refractory metastatic colorectal cancer
• Date of first enrollment: 27/11/2020
• Target sample size: 56
• Countries of recruitment: Austria,Japan,Belgium,,Japan,France,Japan,Germany,Japan,Republic of Hungary,Japan,Italy,Japan,Spain,Japan,UK,Japan,USA,Japan
• Study type: Interventional

Intervention(s)

Safety Lead-in Cohort: Fruquintinib will be administered 5 mg orally QD 3 weeks on/1 week off for every 4-
week treatment cycle

Main study: Fruquintinib (or Placebo) capsule 5 mg will be administered PO, QD, 3 weeks on, 1 week off (4-week cycles).

Outcome(s)

Primary Outcome

Safety Lead-in Cohort: evaluation of the safety and tolerability of fruquintinib in Japanese patients with mCRC by assessing treatmentemergent adverse events, serious adverse events (SAEs), dose-limiting toxicities (DLTs), deaths, laboratory abnormalities, and other safety data.

Main study: OS, defined as the time (months) from date of randomization to death from any cause.

• Secondary Outcome: PFS, ORR, DCR, and DoR.

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. Provide written informed consent;
2. Age >=20 years;
3. Histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS, BRAF, and microsatellite instability (MSI)/MMR status must be documented, according to country guidelines;
4. Subjects must have progressed on or been intolerant to treatment with either trifluridine/tipiracil (TAS-102) or regorafenib. Subjects are considered intolerant to TAS-102 or regorafenib if they have received at least one dose of either agent and were discontinued from therapy for reasons other than disease progression. Subjects who have been treated with both TAS-102 and regorafenib are permitted. Subjects 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.
5. Subjects with microsatellite-high (MSH-H) or mismtch repair deficient (dMMR) tumors must have been treated with immune chackpoint inhibitors if approved and available in the subject's country unless the patient is ineligible for treatment with a checkpoint inhibitor.
6. Subjects 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. Subjects 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.
7. Body weight >=40kg;
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1;
9. Have measurable disease according to RECIST Version 1.1 (RECIST v1.1), assessed locally. Tumors that were treated with radiotherapy are not measurable per RECIST v1.1, unless there has been documented progression of those lesions.
10. Expected survival > 12 weeks.
11. For female subjects of childbearing potential and male subjects 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 subject. Highly effective contraception should always be combined with an additional barrier method (eg, diaphragm, with a spermicide). The same criteria are applicable to male subjects involved in this clinical trial if they have a partner of childbirth potential, and male subjects must always use a condom.
12. Subjects with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available in the subject's country unless the patient is ineligible for treatment with a BRAF inhibitor.

Exclude criteria

1. Absolute neutrophil count (ANC) < 1.5 x 109/L, platelet count < 100 x 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;
2. Serum total bilirubin > 1.5 x the upper limit of normal (ULN). Subjects with Gilbert syndrome, bilirubin < 2 x ULN, and normal aspartate aminotransferase (AST)/alanine aminotransferase (ALT) are eligible;
3. ALT or AST > 2.5 x ULN in subjects without hepatic metastases; ALT or AST > 5 x ULN in subjects with hepatic metastases;
4. Serum creatinine > 1.5 x ULN or creatinine clearance < 60 mL/min. Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockcroft-Gault equation.
5. Urine dipstick protein >= 2+ or 24 hour urine protein >= 1.0 g/24 h. Subjects with greater than 2+ proteinuria by dipstick must undergo a 24 hour urine collection to assess urine protein level.
6. Uncontrolled hypertension, defined as: systolic blood pressure >= 140 mm Hg and/or diastolic blood pressure >= 90 mm Hg despite optimal medical management;
7. International Normalized Ratio (INR) > 1.5 x ULN or activated partial thromboplastin time (aPTT) > 1.5 x ULN, unless the subject is currently receiving or intended to receive anticoagulants for prophylactic purposes;
8. 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;
9. History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to screening;
10. History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary embolism (PE), or arterial embolism within 6 months prior to screening.
11. Stroke and/or transient ischemic attack within 12 months prior to screening;
12. 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;
13. 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.
14. Concomitant medications with a known risk of causing QT prolongation and/or torsades de pointes (See list in Appendix 4 source list is continuously updated online at www.crediblemeds.org).
15. Systemic anti-neoplastic therapies (except for those described in Exclusion Criterion 18) or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy;
16. 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;
17. Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of study drug;
18. Brachytherapy (ie, implantation of radioactive seeds) within 60 days prior to the first dose of study drug.
19. 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;
20. Surgery or invasive procedure (ie, 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;
21. Any unresolved toxicities from a previous antitumor treatment greater than National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) v5.0 grade 1 (except for alopecia or neurotoxicity grade =< 2).
22. Known human immunodeficiency virus (HIV) infection;
23. Known history of active viral hepatitis. For subjects with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Subjects with hepatitis C virus (HCV) infection who are currently on treatment are eligible if they have an undetectable HCV viral load. Subjects with an unknown history of viral hepatitis must be screened for HBV with HBs antigen (HBsAg) and HBV DNA, if indicated, and for HCV with HCV antibody.
- Patients with detectable HBsAg or detectable HBV DNA should be managed per treatment guidelines. Patients receiving antivirals at screening should have been treated for > 2 weeks before the first dose of study drug.
- Patients with a negative HCV antibody test at Screening or positive HCV antibody test followed by a negative HCV RNA test at Screening are eligible. The HCV RNA test will be performed only for patients testing positive for HCV antibody.
24. Clinically uncontrolled active infection requiring IV antibiotics;
25. Tumor invasion of a large vascular structure (eg, pulmonary artery, superior or inferior vena cava);
26. Women who are pregnant or lactating; Women who temporarily stop lactating will not be permitted and will remain excluded.
27. 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; subjects requiring steroids within 4 weeks prior to start of study treatment are excluded;
28. 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;
29. 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;
30. Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition (eg, current alcohol or drug abuse) that investigators suspect may prohibit use of the investigational product, affect interpretation of study results, or put the subject at undue risk of harm based on the investigator's assessment;
31. Known hypersensitivity to fruquintinib or any of its (or placebo) inactive ingredients including the azo dyes Tartrazine - FD&C Yellow 5 and Sunset yellow FCF - FD&C Yellow 6;
32. Subjects who have received prior fruquintinib
33. Live vaccine =< 28 days 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.

Related Information

• Primary Sponsor: Schelman William