A Clinical Trial of Fruquintinib in Patients With Advanced Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, multi-center Phase II clinical trial to evaluate the efficacy and safety of Fruquintinib plus best supportive care in patients with advanced non-squamous non-small cell lung cancer who failed to second-line standard chemotherapy.

Detailed Description
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Approximately 90 subjects will be randomized to Fruquintinib plus best supportive care or placebo plus best supportive care at a 2:1 ratio. Randomization will be stratified by EGFR (epidermal growth factor receptor) gene status: mutant vs. wild type vs. unknown. All subjects will receive Fruquintinib/placebo for consecutive 3 weeks, followed by one-week rest. A treatment cycle consists of 4 weeks. Tumor assessment will be performed every 4 weeks in the first 3 cycles, and every 8 weeks since the 4th cycle, until disease progression. Further treatment and survival follow-up after progression will be recorded.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multi-center Phase II Clinical Trial to Evaluate the Efficacy and Safety of Fruquintinib Plus Best Supportive Care in Patients With Advanced Non-squamous Non-small Cell Lung Cancer

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Fruquintinib
* Drug: Placebo


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; Histologically and/or cytologically diagnosed with local advanced and/or metastatic stage IIIB/IV non-squamous NSCLC; Previously failed to two chemotherapy regimens(treatment failure is defined as disease progression or intolerable toxicity), patients with positive EGFR mutation permitted to treated by EGFR-TKI previously; patients with EGFR wild type or unknown whether or not treated by EGFR-TKI previously; Aged 18-75 years (inclusive); Body weight ≥40 kg; Evident measurable lesion(s) (according to RECIST1.1); ECOG Performance Status 0-1; Expected survival >12 weeks Exclusion Criteria: Treatment in another clinical trials in the past 3 weeks; or treatment with systemic anti-tumor chemotherapy, radiotherapy or biotherapy within 3 weeks prior to administration of the study drug; Previous therapy with VEGF/VEGFR inhibitors; Unrecovered from toxicity caused by previous anti-cancer treatment (CTCAE >grade 1), or not completely recovered from previous surgery; Previous active brain metastasis (without radiotherapy previously, or symptoms stable < 4 weeks, or with clinical symptoms, or with medication to control symptoms); Other malignancies except basal cell carcinoma or cervical carcinoma in situ in the past 5 years; Uncontrolled clinical active infection, e.g. acute pneumonia and active hepatitis B; Dysphagia or known drug malabsorption; Present active duodenal ulcer, ulcerative colitis, intestinal obstruction and other gastrointestinal diseases or other conditions that may lead to gastrointestinal bleeding or perforation according to the investigators' judgment; or with a history of intestinal perforation or intestinal fistula; Have evidence or a history of thrombosis or bleeding tendency, regardless of seriousness; Stroke and/or transient ischemic attack within 12 months prior to enrollment; Appropriate organ function. Patients with any of the following conditions will be excluded: Absolute neutrophil count (ANC) <1.5×109/L, platelet <100×109/L or hemoglobin <9 g/dL within 1 week prior to enrollment; Serum total bilirubin >1.5 upper limit of normal (ULN), alanine transaminase and aspartate transferase >1.5×ULN; ALT and AST > 3×ULN in patients with liver metastasis; Electrolyte abnormality of clinical significance; Blood creatinine >ULN and creatinine clearance <60 ml/min; Urine protein 2+ or above, or 24 h urine protein quantification ≥1.0 g/24 h; Activated partial thromboplastin time (APTT) or/and INR and prothrombin time (PT) >1.5×ULN (according to reference range in each clinical study center); Uncontrolled hypertension, systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg with medication; or heart failure NYHA classification ≥ grade 2; Heart function evaluation: left ventricular ejection fraction <50% (echocardiography); Acute myocardial infarction, severe/unstable angina or coronary bypass surgery within 6 months prior to enrollment; history of arterial thrombosis or deep venous thrombosis; Skin wound, surgical site, wound site, severe mucosal ulcer or fracture without complete healing; Female subjects who are pregnant or lactating or of child bearing potential with positive pregnancy test result before the first dose; Patients with child bearing potential who or whose sexual partners are not willing to take contraceptive measures; Any clinical or laboratory abnormalities unfit to participate in this clinical trial according to the investigator's judgment; Serious psychological or psychiatric disorders which may affect subject compliance in this clinical study; Allergy to Fruquintinib and/or excipient contained in trial drugs.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control Group<br>Placebo is a capsule in the form of 1mg and 5 mg, orally, once daily, 3 weeks on/1week off with best supportive care. | Drug: Placebo<br>* Placebo is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/1 week off<br>* Other names: HMPL-013-placebo;|
| Experimental: Treatment Group<br>The subjects will receive oral Fruquintinib at fasting state 5mg+best supportive care, once daily for the first 3 consecutive weeks and dose holiday for 1 week according to their dose regimens until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent | Drug: Fruquintinib<br>* After checking eligibility criteria, subjects will be randomized into Fruquintinib plus best supportive care group (treatment group) or placebo plus best supportive care group (control group) in a ration of 2:1.<br>* Other names: HMPL-013;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progressive free survival (PFS) | To compare the Progressive Free Survival (PFS) of Fruquintinib plus best supportive care (BSC) versus placebo plus BSC in patients advanced non-squamous NSCLC patients who failed to standard second-line chemotherapy according to RECIST 1.1 | measured every 4 weeks at first 2 cycles and every 8 weeks since the third cycle from randomization to disease progression, assessed up to one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | To evaluate objective response rate (ORR) in the two groups according to RECIST 1.1 | measured every 4 weeks at first 2 cycles and every 8 weeks since the third cycle from randomization to disease progression, assessed up to one year | 
| Disease control rate (DCR) | To evaluate disease control rate (DCR) in the two groups according to RECIST 1.1 | measured every 4 weeks at first 2 cycles and every 8 weeks since the third cycle from randomization to disease progression, assessed up to one year | 
| Overall survival (OS) | To evaluate overall survival (OS) in the two groups | every 2 months from randomization to death, assessed up to one year | 
| safety and tolerability by incidence, severity and outcome of adverse events | To evaluate the safety and tolerability in the two groups by incidence, severity and outcomes of AEs and categorized by severity in accordance with the NCI CTC AE Version 4.0. | From randomization to 30 days after last dose |