A Multi-Center, Open-Label Study of Fruquintinib in Solid Tumors and Colorectal, and Breast Cancers

The study was an open-label, dose escalation and expansion clinical trial to evaluate the safety, tolerability, and PK of fruquintinib in patients with advanced solid tumors. The study consisted of two phases:

• A dose escalation phase - Two dose cohorts were evaluated including 3 mg orally QD 3 weeks on/1 week off and 5 mg orally QD 3 weeks on/1 week off. A 3+3 design was used for this portion of the study.
• A dose expansion phase - Five cohorts were evaluated in Dose Expansion phase. Cohort A evaluated the MTD/RP2D in patients with advanced solid tumors of any type. Cohort B and Cohort C evaluated the MTD/RP2D in metastatic colorectal cancer patients. Cohort D and Cohort E evaluated the MTD/RP2D in metastatic breast cancer patients.

Study was conducted at 9 sites in the United States.

Key Inclusion Criteria:

• Fully understand the study and voluntarily sign the ICF;
• ≥18years of age;
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;

Dose Escalation Phase:

• Histologically or cytologically documented, locally advanced or metastatic solid malignancy of any type (except squamous NSCLC) that has progressed on approved systemic therapy, and for whom no effective therapy or standard of care exists. This cohort is closed to enrollment.

Dose Expansion Phase:

• Cohort A: Histologically or cytologically documented, locally advanced or metastatic solid malignancy of any type (except squamous NSCLC), that has progressed on approved systemic therapy, and for whom no effective therapy or standard of care exists. This cohort is closed to enrollment.
• Cohort B: Histologically or cytologically documented mCRC in patients that have progressed on, or had intolerable toxicity with at least 1 FDA-approved third-line systemic therapy (trifluridine/tipiracil or regorafenib). Patients must also have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and an anti-EGFR therapy for patients who had RAS wild-type tumors. This cohort is currently enrolling.
• Cohort C: Histologically or cytologically documented adenocarcinoma of the colon or rectum. Patients must have progressed on, or had intolerable toxicity to, at least 2 prior regimens of standard chemotherapy, but must not have received prior TAS-102 or regorafenib. Prior therapy could have included adjuvant chemotherapy if a tumor had recurred within 6 months after the last administration of treatment. Patients must have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy and, if RAS wild-type, an anti-EGFR therapy
• Cohort D only: Histologically- or cytologically-confirmed Her2-negative, hormone receptor positive (ER+ and/or PR+) breast cancer
• Cohort E only: Histologically- or cytologically- confirmed triple negative breast cancer

Key Exclusion Criteria:

Patients will be excluded from the study, if any of the following criteria is met:

• Severe anemia, neutropenia, thrombocytopenia
• Moderate to severe renal or hepatic impairment
• Uncontrolled hypertension
• Risk of, or active hemorrhage: history or presence of active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation of fistulas; or any other condition that could possibly result in gastrointestinal tract hemorrhage or perforation within 6 months prior to screening;
• History of a thromboembolic event (including deep vein thrombosis [DVT], pulmonary embolism, stroke and/or transient ischemic attack) within 6 months prior to screening;
• Patients with squamous NSCLC;
• 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%;
• Patients who have ever received a VEGFR inhibitor, except for patients with mCRC enrolled in the dose expansion phase;
• Systemic anti-neoplastic therapies 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 (e.g., 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 (ie, implantation of radioactive seeds) within 60 days prior to the first dose of study drug;
• Known human immunodeficiency virus (HIV) infection;
• Known clinically significant history of liver disease, including cirrhosis, current alcohol abuse or active viral hepatitis. For patients with evidence of chronic hepatitis B (HBV), the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV who are currently on treatment, they are eligible if they have an undetectable HCV viral load;
• 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; patients requiring steroids within 4 weeks prior to start of study treatment will be excluded;
• No other malignancy, except for non-melanoma skin cancer, 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 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 any of its excipients.
• For Cohort C only: patients who have been previously treated with TAS-102 or regorafenib