A Tolerability and Pharmacokinetics Study of SHR6390 in Advanced Melanoma Patients

Study Overview
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Brief Summary
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SHR6390 is a small molecular,oral potent, selective CDK4/6 inhibitor. The purpose of this study is to investigate the safety/tolerability and the pharmacokinetic profile of SHR6390 in Chinese advanced melanoma patients by using a 3+3 dose escalation.Preliminary efficacy will be also investigated in this study.

Official Title
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A Tolerability and Pharmacokinetics Phase 1 Study of SHR6390 in Advanced Melanoma Patients

Conditions
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Melanoma

Intervention / Treatment
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* Drug: SHR6390


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed melanoma Unresectable stage III or IV melanoma patient companion with cell cycle pathway abnormal (e.g CDK4 amplify and/or CCND1 amplify and/or CDKN2A loss) Eastern Cooperative Oncology Group (ECOG) performance status:0-1 Life expectancy ≥ 3 months Adequate function of major organs, meaning the following criteria should be met within 14 days before randomization: Hemoglobin > 100g/L Neutrophils > 2.0×10^9/L Platelets > 100×10^9/L Total bilirubin < 1.5×the upper limit of normal (ULN) ALT and AST ≤ 1.5×ULN (≤ 5×ULN, if existing liver metastases) Creatinine ≤ 1 ULN Left ventricular ejection fraction (LVEF) ≥ 50% QTcF(Fridericia correction) male≤450 ms, female≤470 ms Good compliance of patient by physician's judgement Signed and dated informed consent Exclusion Criteria: Previously received therapy of anti-tumor agent targeting at CDK4/6 Less than 3 weeks from the last cell-toxicity chemotherapy, less than 6 weeks from last mitomycin or nitrosamine therapy Less than 3 weeks from any other anti-tumor therapy (including targets therapy, immunotherapy or other approved therapy) Having joined in other clinical trials within 4 weeks Uncontrolled/untreated brain metastasis (well-controlled/well-treated brain metastasis by physician's judgement is allowed) existing abnormal CTCAE≥grade 2 resulted from previous treatment uncontrollable symptomatic pleural effusion or ascites or require clinical intervention require continous treatment by steroids Factors influencing the usage of oral administration (e.g. unable to swallow, chronic diarrhea and intestinal obstruction, etc.) existing uncontrollable hypokalemia or hypomagnesemia history of serious allergy events or known being allergy constitution active HBV or HCV infection (HBV virus≥10e4 copies/ml, HCV virus≥10e3 copies/ml) History of immunodeficiency, acquired or congenital immunodeficiency, history of organ transplantation history of cardiac dysfunction, include(1)angina (2)clinical significant arrythmia or require drug intervention (3)myocardial infarction (4)heart failure (5) other cardiac dysfunction (judged by the physician); any cardiac or nephric abnormal ≥grade 2 found in screening Female patients who are pregnancy, lactation or women who are of childbearing potential tested positive in baseline pregnancy test childbearing female who refuse to accept any contraception practice determined by the physician, any coexisting disease might lead to life threatening complications or avoid the patients from accomplishing the treatment(e.g serious hypertension, diabetes, thyroid dysfunction,etc.) history of neuropathy or dysphrenia, including epilepsy and dementia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: SHR6390<br>Each subject will receive a single dose of SHR6390 and then repeat doses following a 3 week/1 week off regimen. | Drug: SHR6390<br>* SHR6390 either 50mg,75mg,100mg,125mg,150mg,175mg given orally, QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | The maximum-tolerated dose (MTD) will be defined as the maximum dose level at which no more than one out of three subjects experience a dose-limiting toxicity (DLT) within the first 3 week of the first cycle of multiple dosing. | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of pharmacokinetic parameter of SHR6390: Cmax |  | 6 weeks | 
| Evaluation of pharmacokinetic parameter of SHR6390: Tmax |  | 6 weeks | 
| Evaluation of pharmacokinetic parameter of SHR6390: t1/2 |  | 6 weeks | 
| Evaluation of pharmacokinetic parameter of SHR6390: AUC |  | 6 weeks | 
| Number of patients experience adverse events |  | 6 months | 
| objective response rate |  | every 8 weeks, up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, Cycline-Dependent Kinase