Dasatinib in Treating Patients With Locally Advanced or Metastatic Mucosal Melanoma, Acral Melanoma, or Vulvovaginal Melanoma That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase II trial is studying how well dasatinib works in treating patients with locally advanced or metastatic mucosal melanoma or acral melanoma.

Detailed Description
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OBJECTIVES: Primary To estimate the objective tumor response rate in patients with KIT-positive, unresectable, locally advanced or metastatic acral or mucosal melanoma treated with dasatinib monotherapy. Secondary To estimate the response duration in patients treated with this drug. To estimate the progression-free survival of patients treated with this drug. To evaluate the safety profile of this drug in these patients. To evaluate the PDGFR expression and activation of Src family kinases in tumor samples and correlate these parameters with response to treatment. OUTLINE: This is a multicenter study. Patients receive oral dasatinib twice daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Tissue samples may be collected from some patients for correlative studies. After completion of study therapy, patients are followed up periodically for up to 5 years.

Official Title
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A Phase II Trial of Dasatinib in KIT-Positive Patients With Unresectable Locally Advanced or Stage IV Mucosal, Acral and Vulvovaginal Melanomas

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Drug: dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Pre-Registration (Step 0): Histologically or cytologically confirmed melanoma of 1 of the following subtypes: Acral melanoma (defined as occurring on the palms, soles, or subungual sites) Melanoma arising from the vagina and/or vulva Melanoma arising on other mucosal surface (not vagina or vulva) Unresectable locally advanced or metastatic disease c-KIT mutation identified by polymerase chain reaction (PCR) and sequencing meeting 1 of the following criteria: At least 1 mutation in exon 9, 11, 13, 17, or 18 At least 1 mutation in an exon not listed above and approved by central reviewer Metastatic tumor blocks are required for the evaluation of KIT mutations or amplifications Prior radiotherapy to a measurable lesion allowed provided there is radiographic evidence of progression of that lesion No other concurrent malignancies except basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, ductal or lobular carcinoma in situ of the breast, or other malignancies from which the patient has been continuously disease-free for ≥ 5 years ECOG performance status 0-1 Exclusion Criteria for Pre-Registration (Step 0): Prior treatment with targeted therapies directed to c-KIT/PDGFR (e.g., imatinib or sunitinib) Ocular melanoma Evidence of bleeding diathesis Clinically significant psychiatric illness or social situations that would limit compliance with study requirements Clinically significant cardiovascular disease including the following: Myocardial infarction or ventricular tachyarrhythmia within 6 months Prolonged QTc >480 msec (Fridericia correction) Ejection fraction less than institutional normal Major conduction abnormality (unless a cardiac pacemaker is present) Patients with any cardiopulmonary symptoms of unknown cause (e.g., shortness of breath, chest pain, etc.) are to be evaluated by a baseline echocardiogram with or without stress test as needed in addition to electrocardiogram (EKG) to rule out QTc prolongation Patients with underlying cardiopulmonary dysfunction are excluded from the study Inclusion Criteria for Registration (Step 1): Meeting the eligibility criteria for pre-registration (Step 0) The melanoma must harbor a c-KIT mutation determined by PCR and sequencing as defined in the protocol either by local assessment or Massachusetts General Hospital (MGH) Measurable disease, defined as at least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) criteria At least 4 weeks since prior chemotherapy, radiotherapy or immunotherapy and the beginning of protocol therapy and the patient must have recovered from toxicity due to the previous therapy History or clinical evidence of brain metastasis allowed provided the following criteria are met: Completed radiotherapy or surgical treatment of brain lesions and there is no evidence of central nervous system (CNS) progression for ≥ 8 weeks Must not require corticosteroids for treatment of cerebral edema from brain metastases Negative pregnancy test Fertile patients must use effective contraception Patients must have the following within 4 weeks of registration: computed tomography (CT) chest with intravenous (IV) and oral agent CT pelvis/abdomen with IV and oral agent MRI brain with gadolinium Baseline bone scan required for patients with known bone metastases, elevated alkaline phosphatase, or symptoms raising suspicion of bone metastases White blood count (WBC) ≥ 3,000/mm³ Absolute granulocyte count (AGC) ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Creatinine ≤ 2.0 times upper limit of normal (ULN) OR creatinine clearance (CrCl) ≥ 40 mL/min Total bilirubin ≤ 1.5 times ULN (< 3.0 times ULN in the presence of Gilbert disease) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN (≤ 5.0 times ULN in the presence of liver metastases) Serum potassium and magnesium normal (repletion allowed) Total serum calcium or ionized calcium ≥ institutional lower limit of normal International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) wtihin normal limits Therapeutic anticoagulation with warfarin allowed provided INR ≤ 1.5 or PTT normal prior to initiating anticoagulation therapy Exclusion Criteria for Registration (Step 1): Pregnant or nursing Concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (i.e., phenytoin, carbamazepine, or phenobarbital), rifampin, or Hypericum perforatum (St. John wort) Uncontrolled hypertension, defined as systolic blood pressure ≥ 150 mm Hg or diastolic blood pressure ≥ 90 mm Hg Hypertension that is adequately controlled with medication allowed QTc prolongation, defined as a QTc interval ≥ 450 msecs Serious intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics

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: Dasatinib<br>Patients receive oral dasatinib at 70 mg twice daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: dasatinib<br>* Patients receive oral dasatinib at 70 mg twice daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.<br>* Other names: BMS-354825;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate Among KIT-positive Patients | Objective response is defined as complete response (CR) or partial response (PR) per Solid Tumor Response Criteria (RECIST). Complete response is defined as disappearance of all target and non-target lesions. Partial response is defined as at least 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter. | Every 6 weeks; up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response for Dasatinib Monotherapy in This Patient Population | Duration of response is defined as the period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the first date that progressive disease is objectively documented, taking as reference the smallest measurements recorded since treatment started. Progressive disease is defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s). | Every 6 weeks; up to 5 years | 
| Progression-free Survival | Progression-free survival is defined as the time from registration to development of progressive disease. Patients without documented progressive disease are censored at the date of last disease assessment. Progressive disease is defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s). | Every 6 weeks; up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV melanoma, acral melanoma, mucosal melanoma, vulvovaginal melanoma, stage III melanoma