A Phase III Study of Fruquintinib in Combination With Paclitaxel in Second Line Gastric Cancer(FRUTIGA)

Study Overview
=================
Brief Summary
-----------------
Fruquintinib once daily in 4 weeks treatment cycle (three weeks on and one week off) in combination with Paclitaxel 80mg/㎡（day1, 8, 15 of 4 weeks cycle) was well tolerated and demonstrated encouraging preliminary clinical antitumor activity in patients with advanced GC in ph1b/2 study. This study is aimed to evaluate the efficacy and safety of Fruquintinib in combination with Paclitaxel in the treatment of patients with aGC who have progressed after first line standard chemotherapy.

Detailed Description
-----------------
This is a randomized, double-blind, placebo-controlled, multicenter Phase III clinical trial to compare the efficacy and safety of Fruquintinib combined with Paclitaxel versus Paclitaxel alone in patients with advanced gastric cancer who have progressed after first-line standard chemotherapy. After checking eligibility criteria, subjects will be randomized into Fruquintinib combined with Paclitaxel group (treatment group) or placebo combined with Paclitaxel group (control group) in a ratio of 1:1. Primary Efficacy Endpoint: Overall Survival (OS), Progression free survival (PFS) (According to RECIST Version 1.1). Secondary Efficacy Endpoints: Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DOR), EORTC QLQ-C30 (V3) .Safety and tolerance will be evaluated by incidence, severity and outcomes of AEs and categorized by severity in accordance with the NCI CTC AE Version 4.03.

Official Title
-----------------
A Phase III Study to Evaluate the Efficacy and Safety of Fruquintinib in Combination With Paclitaxel Versus Paclitaxel Alone in Second Line Gastric Cancer

Conditions
-----------------
Advanced Gastric Cancer

Intervention / Treatment
-----------------
* Combination Product: fruquintinib +paclitaxel
* Combination Product: fruquintinib placebo + paclitaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent Histologically or cytologically confirmed gastric or gastroesophageal junction adenocarcinoma Metastatic disease or locally advanced, unresectable disease Disease progression during or within 4 months after the last dose of the first-line therapy (with platinum/fluoropyrimidine ) Adequate hepatic, renal, heart, and hematologic functions At least one measurable lesion (larger than 10 mm in diameter by spiral CT scan) Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedure Good performance status Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 to 1 Exclusion Criteria: Pregnant or lactating women Any factors that influence the usage of oral administration Evidence of CNS metastasis Intercurrence with one of the following: non-controlled hypertension, coronary artery disease, arrhythmia and heart failure Abuse of alcohol or drugs Less than 4 weeks from the last clinical trial Previous treatment with VEGFR inhibition Disability of serious uncontrolled intercurrence infection Proteinuria ≥ 2+ (1.0g/24hr) Have evidence or a history of bleeding tendency within two months of the enrollment randomization, regardless of seriousness Within 12 months before the first treatment occurs artery/venous thromboembolic events, such as cerebral vascular accident (including transient ischemic attack) etc. Within 6 months before the first treatment occurs acute myocardial infarction, acute coronary syndrome or CABG Bone fracture or wounds that was not cured for a long time Coagulation dysfunction, hemorrhagic tendency or receiving anticoagulant Therapy The tumor invades a large vessel structure, such as the pulmonary artery, superior vena cava, or inferior vena cava

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: fruquintinib+paclitaxel<br>treatment arm (fruquintinib+paclitaxel) : Fruquintinib once daily, 3 weeks on/1week off combined with Paclitaxel 80mg/㎡ day1, 8, 15 of 4 weeks cycle. | Combination Product: fruquintinib +paclitaxel<br>* treatment arm(fruquintinib +paclitaxel)- subjects will receive Fruquintinib orally, once daily for 3 wks on/ 1 wk off combined with paclitaxel 80mg/㎡ at day 1,8,15 of 4-week cycle. Patients will receive a cycles of 4 weeks of study treatment or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment cretieria<br>* Other names: HMPL-013+paclitaxel;|
| Placebo Comparator: placebo+paclitaxel<br>control arm (placebo+paclitaxel): Fruquintinib placebo once daily, 3 weeks on/1week off combined with Paclitaxel 80mg/㎡ day1, 8, 15 of 4 weeks cycle. | Combination Product: fruquintinib placebo + paclitaxel<br>* control arm(fruquintinib placebo + paclitaxel)- subjects will receive Fruquintinib placebo orally, once daily for 3 wks on/ 1 wk off combined with paclitaxel 80mg/㎡ at day 1,8,15 of 4-week cycle. Patients will receive a cycles of 4 weeks of study treatment or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment cretieria<br>* Other names: HMPL-013 placebo+paclitaxel;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | every two months follow up after EOT observation period at 30 days after the last medication | from randomization until death due to any cause, assessed up to 3 year | 
| Progression free survival (PFS) | PFS defined as the time from the date of randomization to the first evidence of disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. | from the date of randomization to the date of the first documented progressive disease or date of death due to any cause, assessed up to 1 year] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Tumor assessment will be performed using radiography method every 8 weeks until the occurrence of progressive disease (PD), using RECIST v 1.1 | from randomization up to progressive disease or EOT due to any cause, assessed up to 1 year | 
| Disease control rate (DCR) | Tumor assessment will be performed using radiography method every 8 weeks until the occurrence of progressive disease (PD), using RECIST v 1.1 | from randomization up to progressive disease or EOT due to any cause, assessed up to 1 year | 
| Safety and tolerance evaluated by incidence, severity and outcomes of AEs | Safety and tolerance will be evaluated by incidence, severity and outcomes of AEs and categorized by severity in accordance with the NCI CTC AE Version 4.03 | from first dose to 30 days post the last dose | 
| Duration of response, DOR | DOR was the time from the date of first evidence of complete response or partial response to the date of objective progression or the date of death due to any cause, whichever is earlier. CR and PR were defined using the RECIST v1.1. | : From the first documented PR or CR until the first documented PD or death，assessed up to 2 years | 
| The European Organization for Reasearch and Treatment of Cancer（EORTC ） Quality of Life Questionnaire-Core 30 V3.0 (QLQ-C30 v3.0) | EORTC QLQ-C30 v3.0 was a self-administered questionnaire with multidimensional scales that measures global health status. There are 30 items in total, which can be divided into 15 fields. Five functional scales: physical function, role function, cognitive function, emotional function, social function; Three symptom scales: fatigue, pain, nausea and vomiting; Six individual measures: dyspnea, insomnia, loss of appetite, constipation, diarrhea, financial difficulties, and a global quality of life scale. The five functional scales and the global quality of life scale were scored independently. After linear transformation, the scores of all items ranged from 1 to 100, and the higher score, the higher functional level. The symptom scale was also scored independently and linearly transformed into a score from 1 to 100, with higher scores indicating more serious problems or symptoms. | Evaluation before the beginning of each treatment cycle, at the end of treatment, and at the 30 days post the last dose，up to 2 years |