A Phase Ib/2 Clinical Study of Fruquintinib Combined With Paclitaxel in the Treatment of Advanced Gastric Cancer

Study Overview
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Brief Summary
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An open-label, dose escalation and maximum tolerated dose (MTD) and/or recommended phase II dose (RPTD) study of fruquintinib combined with paclitaxel in patients with advanced gastric cancer who did not respond to first-line standard chemotherapy.

Detailed Description
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In dose escalation period, 12-24 patients with advanced gastric cancer will be enrolled. Patients meeting enrollment eligibility will receive 28-day cycles of fruquintinib 2-5 mg qd combined with paclitaxel 80 mg/m2. Safety information and pharmacokinetic data will be collected till disease progression or intolerable toxicity to determine MTD and/or RPTD of fruquintinib combined with paclitaxel in patients with advanced gastric cancer. This period will include the following 4 dose groups from low to high: A: Fruquintinib 2 mg qd for 3 weeks followed by 1-week break + paclitaxel 80 mg/m2 once a week during the first three weeks of each cycle B: Fruquintinib 3 mg qd for 3 weeks followed by 1-week break + paclitaxel 80 mg/m2 once a week during the first three weeks of each cycle C: Fruquintinib 4 mg qd for 3 weeks followed by 1-week break + paclitaxel 80 mg/m2 once a week during the first three weeks of each cycle D: Fruquintinib 5 mg qd for 3 weeks followed by 1-week break + paclitaxel 80mg/m2 once a week during the first three weeks of each cycle This study will use traditional 3+3 trial design (3 subjects will be enrolled in each dose group first. If 1 case of DLT is observed, additional 3 subjects will be enrolled in the same dose group to further evaluate toxicity) to observe DLT and evaluate MTD. If there are 2 or more cases of DLT in one dose group, the group lower than this dose group by one level is MTD dose group. At least 6 subjects are required in MTD dose group for confirmation. If MTD is not achieved at the end of dose escalation and there are 6 subjects in the highest dose group, RPTD can be determined based on obtained safety, tolerability, PK and efficacy information. Dose escalation and study in the next dose group can be initiated only after the first treatment cycle (DLT window observation period) is completed and subject safety and tolerability are confirmed in this dose group (0/3 or ≤1/6 subjects experience DLT). Subjects in the original dose group will continue to receive the next cycle of treatment at the original dose till disease progression or treatment withdrawal due to any of the following reasons: 1) death, 2) intolerable toxicity, 3) pregnancy, 4) the investigator considers the study should be terminated for the subject's best interests, 5) the subject or legal representative requests withdrawal, 6) loss to follow-up, 7) the subject has poor compliance and cannot comply with the study protocol.

Official Title
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A Phase Ib/2 Clinical Study to Evaluate the Safety, Pharmacokinetic Characteristics and Preliminary Efficacy of Fruquintinib Combined With Paclitaxel in Patients With Advanced Gastric Cancer

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: fruquintinib+paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fully understand the study and sign the informed consent form voluntarily; Patients with local advanced and/or metastatic gastric cancer confirmed by histology and/or cytology; Fail in previous first-line standard chemotherapy Aged 18-70years (inclusive); Body weight ≥40 kg; At least one measurable lesion (according to RECIST1.1); Physical status score (ECOG score) 0-1; Expected survival >12 weeks. Exclusion Criteria: Who are participating in another drug clinical trial in the past 4 weeks; or receive systemic anti-tumor chemotherapy, radiotherapy or biotherapy within 4 weeks prior to administration of the study drug; Who previously received VEGF/VEGFR inhibitors; Who have not recovered from toxicity caused by previous anti-cancer treatment (CTCAE>grade 1), or not completely recovered from previous surgery; Active brain metastasis(with clinical symptom); Other malignancies except squamous-cell or basal cell carcinoma, and cervical carcinoma in situ in the past 5 years; Uncontrolled clinical active infection, e.g. acute pneumonia, hepatitis B or active hepatitis C; Dysphagia, intractable vomiting or known drug malabsorption;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: fruquintinib+paclitaxel<br>fruquintinib combined with paclitaxel. Fruquintinib treatment: administration for 3 weeks followed by 1-week break, and administration every day for the first 21 days.Paclitaxel is administered once weekly in the first three weeks of each cycle. | Drug: fruquintinib+paclitaxel<br>* 28-day cycle of fruquintinib qd for 3 weeks followed by 1-week break combined with paclitaxel 80 mg/m2<br>* Other names: HMPL-013+paclitaxel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| incidence of DLT |  | every subject's DLT observation window is 4 weeks | 
| progression free survival of RP2D | using RECIST v1.1 progressive disease (PD), using RECIST v 1.1 | from first dose up to progressive disease or EOT due to any cause, assessed up to 1 year | 
| safety and tolerance | Safety and tolerance will be evaluated by incidence, severity and outcomes of adverse events (AEs) and categorized by severity in accordance with the NCI CTC AE Version 4.0. | From first dose to within 30 days after the last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | using RECIST v 1.1 | from first dose up to progressive disease or EOT due to any cause, assessed up to 1 year] | 
| Disease control rate (DCR) | using RECIST v 1.1 | From first dose up to progressive disease or EOT due to any cause, assessed up to 1 year] | 
| Pharmacokinetic profiles of Fruquintinib combined with Paclitaxel | PK sampling of Fruquintinibwill include a pre-dose and 1,2,4,8,24 hours time-point at Day 2 and day 15 of dosing in the first 28-day cycle; PK sampling of Paclitaxel will include a pre-dose and at 0.25,1,2,4,8, and 24 hours time-point on day 1 and day 15 of dosing in the first 28-day cycle | From first dose up to day 15 in the first 28-day cycle |