A Study of Famitinib Plus Docetaxel in Patients With Advanced Non-squamous and Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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Famitinib is a tyrosin-inhibitor agent targeting at c-Kit, VEGFR2, PDGFR, VEGFR3, Flt1 and Flt3. Phase I study has shown that the toxicity is manageable. This study assessed the safety and maximum tolerated dose of continuous daily treatment with Famitinib plus docetaxel (60 mg/m^2, every 3 weeks) in patients with Advanced Non-squamous and Non-Small Cell Lung Cancer (NSCLC) to determine the recommended dose for the Phase II trial.

Official Title
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Docetaxel Plus Famitinib Versus Docetaxel Plus Placebo in Patients With Advanced Non-squamous and Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Non-Small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Drug: famitinib L + docetaxel
* Drug: famitinib M + docetaxel
* Drug: famitinib H + docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age:18-70 years; ECOG PS (Eastern Cooperative Oncology Group Performance Status)of 0 or 1; Life expectancy of at least 12 weeks; Histologically or cytologically confirmed, locally advanced and/or metastatic NSCLC of stage IIIB or IV or recurrent NSCLC; Relapse or failure of one first line prior platinum-based chemotherapy;EGFR mutation type previously treated with platinum-based chemotherapy and EGFR inhibitors; At least one target tumour lesion that has not been irradiated within the past 3 months and that can accurately be measured ,according to RECIST 1.1; Participants have adequate organ and marrow function as defined below: Hemoglobin ≥ 90g/L ( no blood transfusion in 2 weeks) Absolute neutrophil count (ANC) ≥ 1.5×10^9/L Platelets(PLT)≥ 100×10^9/L Bilirubin < 1.25×ULN(Upper Limit Of Normal) ALT < 2.5×ULN; ALT < 5×ULN ( If have liver metastases) AST < 2.5×ULN; AST < 5×ULN ( If have liver metastases) Serum creatinine < 1.25×ULN, and endogenous Cr clearance > 45 ml/min(Cockcroft-Gault Formula) Cholesterol ≤ 1.5×ULN and triglyceride≤ 2.5×ULN Left ventricular ejection fraction(LVEF): ≥ LLN(Lower Limit Of Normal) by Color Doppler Ultrasonography Female: Child bearing potential, a negative urine or serum pregnancy test result 7 days before initiating famitinib.All subjects who are not surgically sterile or postmenopausal must agree and commit to the use of a reliable method of birth control for the duration of the study and for 8 weeks after the last dose of test article. Male: All subjects who are not surgically sterile or postmenopausal must agree and commit to the use of a reliable method of birth control for the duration of the study and for 8 weeks after the last dose of test article; Patient has given written informed consent. Exclusion Criteria: More than one chemotherapy treatment regimen (except,either neoadjuvant or adjuvant or neoadjuvant plus adjuvant) for advanced and/or metastatic or recurrent NSCLC; Previous therapy with other VEGFR inhibitors (including sunitinib,sorafenib,pazopanib,axitinib,other than bevacizumab) or docetaxel for treatment of NSCLC; Radiographical evidence of cavitary or necrotic tumours; Centrally located tumours with radiographical evidence (CT or MRI) of local invasion of major blood vessels; Pre-existing ascites and/or clinically significant pleural effusion; Pulmonary hemorrhage/ bleeding event ≥ CTCAE gr. 2 before initiating investigational drugs; History of clinically significant haemoptysis within the past 3 months（24h >half teaspoon）; Current peripheral neuropathy greater than CTCAE grade 2; Other malignancy within the past 3 years other than basal cell skin cancer, or carcinoma in situ of the cervix; Active brain metastases (such as stable time ≤ 4 weeks,no radiotherapy treatment,any symptoms,or seizures treatment needing) or leptomeningeal disease.; Treatment with other investigational drugs or other anti-cancer therapy, or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with this trial; Persistence of clinically relevant therapy related toxicities from previous chemotherapy and/or radiotherapy; Treatment with cytotoxic drugs, radiotherapy(except extremities and brain) , immunotherapy , monoclonal antibody, or TKI inhibitor therapy within the past 4 weeks, being previous anti-cancer treatment interval ≤ 4 weeks.; Patients with hypertension using combination therapy (systolic blood pressure>140 mmHg, diastolic blood pressure>90 mmHg). Patients with unstable angina, myocardial ischemia or myocardial infarction in the past 6 months, congestive heart failure>NYHA II,and arrhythmia (including QTcF interval ≥ 450ms for male and 470ms for female); Urine protein ≥ + + and confirmed the 24-hour urinary protein>1.0 g; History of major thrombotic or clinically relevant major bleeding event in the past 6 months，and known inherited predisposition to bleeding or thrombosis; PT or APTT bias from normal range≥50%; Application of anticoagulants or vitamin K antagonists such as warfarin, heparin or its analogues;If the prothrombin time international normalized ratio (INR) ≤ 1.5, with the purpose of prevention, the use of small doses of warfarin (1mg orally, once daily) ， low-dose aspirin (less than 100mg daily) is allowed; Preexisting thyroid dysfunction, even using medical therapy, thyroid function cannot maintain in the normal range; Diabetes mellitus can not controlled with hypoglycemic agent; Active or chronic hepatitis C and/or B infection with liver dysfunction; History of immunodeficiency disease, concurrent acquired or congenital immunodeficiency,or history of organ transplantation; Serious infections requiring systemic antibiotic therapy; Variety of factors that affect the oral medication (such as inability to swallow, gastrointestinal resection, chronic diarrhea and intestinal obstruction); Significant weight loss (>10 %) within the past 6 months; Pregnancy , breast feeding or child bearing potential, a positive urine or serum pregnancy test result 7 days before initiating famitinib; Active alcohol or drug abuse; Any contraindications for therapy with docetaxel；History of severe hypersensitivity reactions to docetaxel or other drugs formulated with polysorbate 80 (Tween 80)；Hypersensitivity to famitinib and/or the excipients of the trial drugs；Hypersensitivity to contrast media; Psychological, familial, sociological, or geographical factors potentially hampering compliance with the study protocol and follow-up schedule; Patients unable to comply with the protocol; Evidence of significant medical illness that in the investigator's judgment will substantially increase the risk associated with the subject's participation in and completion of the study.

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: Famitinib + docetaxel<br>Low, medium and high dose of famitinib and 60 mg/m^2 docetaxel every 3 weeks | Drug: famitinib L + docetaxel<br>* famitinib 15mg qd + docetaxel 60 mg/m^2<br>Drug: famitinib M + docetaxel<br>* famitinib 20mg qd + docetaxel 60 mg/m^2<br>Drug: famitinib H + docetaxel<br>* famitinib 25mg qd + docetaxel 60 mg/m^2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of famitinib in combination with standard-dose docetaxel(60 mg/m^2) | MTD was defined as the highest dose at which incidence of dose-limiting toxicities(DLTs) in Cyle 1 was ≤33.3%(0/3,1/6,2/6) | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidences of Adverse Events according to Common Toxicity Criteria (CTC version 4.0) associated with increasing doses of famitinib |  | 1 years | 
| Pharmacokinetics-AUC | Area under the plasma concentration-time curve (AUC) for famitinib and docetaxel | 6 weeks | 
| Pharmacokinetics-Cmax | Maximum measured plasma concentration (Cmax) for famitinib and docetaxel | 6 weeks | 
| Pharmacokinetics-Tmax | Time from dosing to the maximum plasma concentration (Tmax) for famitinib and docetaxel | 6 weeks | 
| Pharmacokinetics-t1/2 | Terminal half-life (t1/2(ss)) for famitinib and docetaxel | 6 weeks | 
| Objective Response Rate (ORR) |  | 6 weeks | 
| Progress free survival (PFS) |  | 1 years |