Safety of TKI258 in Advanced/Metastatic Melanoma Subjects

Study Overview
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Brief Summary
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This study is an open-label, dose-escalating study to delineate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TKI258. Pharmacokinetics and pharmacodynamics will be performed on all subjects. The eligible subject population consists of subjects who have been diagnosed with locally advanced or metastatic melanoma that is refractory to standard therapy or for which no curative standard therapy exists.

Official Title
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A Phase I/II Dose Escalating Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of TKI258 (CHIR-258) in Patients With Locally Advanced or Metastatic Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: TKI258


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of locally advanced or metastatic melanoma (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC or IV) that is refractory to standard therapy or for which no curative standard therapy exists. Measurable disease Must be eighteen years of age or older Must meet baseline laboratory requirements ECOG performance status 0 or 1 Adults of reproductive potential must agree to use effective contraception or be sterile Exclusion Criteria: Concurrent therapy with any other investigational agent Uncontrolled central nervous system metastases Impaired cardiac function or clinically significant cardiac disease Received chemotherapy, targeted therapy or monoclonal antibody therapy ≤4 weeks biological therapy or immunotherapy (therapeutic or diagnostic) ≤2 weeks an investigational agent (therapeutic or diagnostic) ≤4 weeks prior to starting study drug or has not recovered from side effects of such therapy Received any hematopoietic colony-stimulating factor (e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin is allowed. Has undergone major surgery ≤ 2 weeks prior to starting study drug or has not recovered from side effects of such surgery. Malabsorption syndrome or uncontrolled gastrointestinal symptoms such as nausea, diarrhea, vomiting Pregnant or breast feeding women History of another primary malignancy that is currently clinically significant or currently requires active intervention. Chronic anticoagulation therapy with full strength aspirin, Coumadin, or heparin. History of thromboembolic or cerebrovascular events within the last 12 months. History of rectal bleeding, bloody vomit, or spitting up blood within the last 3 months. Known diagnosis of HIV infection (HIV testing is not mandatory) Use of ketoconazole, erythromycin, carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort and quinidine is prohibited. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study-drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, make the patient inappropriate for this study

Ages Eligible for Study
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Minimum Age: 18 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: TKI258<br> | Drug: TKI258<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Expansion: Determine the maximum tolerated dose based on dose limiting toxicity of TKI258 |  | end of dose escalation | 
| Dose Expansion: Determine the plasma and whole blood pharmacokinetics of orally administered TKI258 |  | PK run-in days 1 & 2, cycle 1 days 1, 8, 15, 16, 28, cycle 2 day 15, cycle 2+ day 28 | 
| Dose Escalation: Assess tumor response according to RECIST as measured by response rate and lack of early progressive disease (<=2 months) |  | every 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the safety profile of TKI258 in this patient population |  | PK run in day 1 & 2, cycle 1 day 8, 15, 28, cycle 2+ day 15 & 28, end of study | 
| Assess the effect of TKI258 on biomarkers in the blood |  | PK run day 1 & 2, cycle 1 day 2, 15, 28, cycle 2+ day 28, end of study | 
| Assess biomarker changes in tumor/nevi biopsies and archival tumor tissues where accessible, pre- and post-treatment |  | baseline, cycle 1 day 15, end of study | 
| Assess changes in tumor glucose metabolism/cell viability between pre- and post-treatment using [18F]-FDG-PET |  | baseline, cycle 1 day 15, cycle 2 day 28 | 
| Assess anti-angiogenic effects of TKI258 using DCE-MRI pre- and post-treatment |  | baseline, cycle 1 day 2 and cycle 2 day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally Advanced or Metastatic Melanoma