A Phase I Study of Subutinib Maleate Capsules on Toleration and Pharmacokinetics

Study Overview
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Brief Summary
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purpose: to explore the maximum tolerated dose, dose-limiting toxicity of oral Subutinib Maleate capsules and rational dosage regimen for phase Ⅱ study Experimental Design： A phase Ⅰ study of single-center Test drug: Subutinib Maleate capsules Sample size≥20

Detailed Description
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The primary objective of this study is to explore the maximum tolerated dose, dose-limiting toxicity of oral Subutinib Maleate capsules and rational dosage regimen for phase Ⅱ study, to investigate the pharmacokinetics of single and multiple oral doses of Subutinib Maleate capsules.

Official Title
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A Phase I Study of Subutinib Maleate Capsules on Toleration and Pharmacokinetics

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: Subutinib Maleate capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who have histologically or cytologically confirmed solid tumors Subjects who have failed standard effective therapy or have a diagnosis for which no standard effective treatment is available; Aged 18 to 70 years old; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2; Life expectancy greater than 3 months; If the subject has been given other chemotherapy drugs, it's necessary to discontinue them more than 4 weeks. If the chemotherapy drugs are Nitrosoureas and Mitomycin C, it's necessary to discontinue them more than 6 weeks. If the subject has accepted major surgery, it's necessary to wait more than 4 weeks before the subject participating in this study. Blood test: Hb≥100g/L(no blood transfusion within 14 days); ANC≥1.5×109/L, PLT≥100×109/L Biochemistry: TBIL and ALT and AST and Cr are in normal range, or creatinine clearance ≥60ml/min; Triglyceride≤3.0mmol/L; Cholesterol ≤7.75mmol/L. Doppler ultrasound measurement: LVEF ≥ LLN Female subjects should agree to take contraceptives during the study and within 6 months after the study (such as intrauterine device [IUD], contraceptive drugs or condoms); within 7 days before they enter the study, their serum or human chorionic gonadotropin should be negative, and must be in the non-lactation period; male subjects should agree to take contraceptives during the study and within 6 months after the study. The subject is willing to participate in this study, and he/she has signed the Informed Consent Form, with good compliance. Exclusion Criteria: The subject has participated in other drug clinical research in the past 4 weeks. The subject is accompanied with several factors which will influence the investigational drug administration orally, such as inability to swallow or after gastrointestinal resection or chronic diarrhea or intestinal obstruction. Central nervous system metastasis definitely. The subject is suffering from hypertension or myocardial ischemia or myocardial infarction or arrhythmia (including QT interval≥440ms) or Grade I heart failure. If the subject's systolic BP is over 140mmhg, with diastolic BP over 90mmhg, or the subject's blood pressure is well-controlled, he/she is not permitted to enroll in this study as well. The subject's urinalysis displays that urinary protein ≥ ++ , combined with 24-hour urinary protein > 1.0g. The subject's is suffering from wounds or fractures which can not be cured for long time. Abnormal coagulation: The subject has bleeding tendency such as active peptic ulcer or the subject is receiving thrombolytic or anticoagulant therapy. There are pre-dosing arterial/venous thrombotic events on this subject, such as cerebrovascular accident (including TIA) or deep vein thrombosis or pulmonary embolism. The subject is accepting anticoagulants or vitamin K antagonists such as warfarin or heparin or analogue therapy; If the subject's INR ≤ 1.5, he/she is allowed to use small doses of warfarin (1mg oral q d) or small doses of aspirin(less than 100mg each day), and the purpose of the treatment should be prevention. Abnormal thyroid function. There is history of mental drug abuse occurred in the subject, or the subject is suffering from mental disorders. There is history of immunodeficiency occurred in the subject, including HIV positive or other acquired or congenital immunodeficiency diseases, or the subject has accepted organ transplant before. Lung squamous cell carcinoma. The subject has received small molecule targeted drug therapy of inhibition of VEGFR-2 and PDGFRβ According to the investigator's judgment, there are concomitant diseases which will seriously do harm to the subject's safety or obstruct the subject to complete 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: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subutinib Maleate capsules<br>Dose escalation will be dependent on any dose limiting toxicities | Drug: Subutinib Maleate capsules<br>* Dose escalation will be dependent on any dose limiting toxicities<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity， maximum tolerated dose. |  | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics | Subutinib Maleate pharmacokinetic parameters , include AUC, Cmax, Tmax, and t1/2 | 2 months | 
| Pharmacodynamics | The response of Subutinib Maleate on tumor. | 2 months |