A Phase Ib Study of Fruquintinib in 3rd Line mCRC

Study Overview
=================
Brief Summary
-----------------
Fruquintinib is a novel oral small molecule compound discovered and developed by Hutchison MediPharma that selectively inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 and has demonstrated potent inhibitory effects on multiple human tumor xenografts.Based on first-in-human study, both 4mg QD and 5mg 3wks on/1wk off are safety and efficacy, this phase Ib study is to evaluable the safety, tolerability and efficacy of these 2 regimens with mCRC failed 2nd therapy or more and to determine the recommended dose and regimen in phase II/III study.

Detailed Description
-----------------
This is a phase Ib, randomize, interventional, open-label, multicenter study to provide fruquintinib to subjects diagnosed with metastatic colorectal cancer who have failed after standard therapy and for whom no therapy alternatives exist. The primary endpoint of this study will be safety.

Official Title
-----------------
A Randomized, Open-label Phase Ib Trial of Fruquintinib 4mg Once Daily ContinuousVersus 5mg Once Daily 3wks on/1wk Off in Patients With Metastatic Colorectal Carcinoma as 3rd Therapy

Conditions
-----------------
Colorectal Cancer

Intervention / Treatment
-----------------
* Drug: fruquintinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ≥ 18 and ≤ 70 years of age , with ≥ 40Kg Histological or cytological confirmed colorectal cancer ECOG performance status of 0-1 Standard regimen failed or no standard regimen available Adequate hepatic, renal, heart, and hematologic functions At least one measurable lesion (larger than 10 mm in diameter by spiral CT scan) Signed and dated informed consent. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedure 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) Uncontrolled hemorrhage in GI 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A- 4mg QD<br>arm A- fruquintinib 4mg once daily, p.o.,continuous;given in 28-days cycles until disease progress, intolerable toxicity or patients withdrawal of consent | Drug: fruquintinib<br>* Fruquintinib is a capsule in the form of 1mg and 5mg, orally, daily<br>* Other names: HMPL-013;|
| Experimental: B- 5mg once daily, 3wks on/1wk off<br>arm B-fruquintinb 5mg once daily,p.o.,3 weeks on/1 week off, given in 28-day cycles until disease progress,intolerable toxicity or patients withdrawal of consent | Drug: fruquintinib<br>* Fruquintinib is a capsule in the form of 1mg and 5mg, orally, daily<br>* Other names: HMPL-013;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety and tolerability | The primary objective is evaluation of safety and tolerabilty with 2 regimens. The primary endpoint is the incidence of AEs, SAEs, Gr3/4 AEs and AEs led to dose interruption and dose discontinued | from day 1 of first dosing to 30days after permanent discontinuation of HMPL-013 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| objective response rate(ORR) | using RECIST version 1.1 | every 8 weeks until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 20 months | 
| pharmacokinetic profiles | At QD regimen, PK sampling will include a pre-dose and at the 1,2,4,8,24 hour time points on day 1 and day 21;a pre-dose and at the 2 hour time point on day 28,42,70,84. At 3wks on/1wk off regimen,PK sampling will include a pre-dose and at the 1,2,4,8,24 hour time points on day 1 and day 21; a pre-dose and at the 2 hour time point on day 42 and day 70; only pre-dose on day 28,56,84. | Day 1-84 steady state | 
| disease control rate (DCR) | using RECIST version 1.1 | every 8 weeks until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 20 months | 
| progression-free survival (PFS) | using RECIST version 1.1 | every 8 weeks until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 20 months | 
| overall survival (OS) | from first dosing until death due to any cause, assessed up to 2 years | every 2 months since end of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
patients with mCRC who failed 2nd therapy or more