A Phase II Study of Biological Response to Dasatinib Treatment in Patients with Acral Lentiginous, or Mucosal Melanoma
Kevin B. Kim
The goal of this clinical research study is to compare how the drug Sprycel (dasatinib) can help to control the tumor in patients whose tumor has a gene abnormality known as a "CKIT mutation" to patients whose tumor does not have a CKIT mutation. The safety of this drug will also be studied.
Disease Group: Melanoma
Treatment Agent: Dasatinib
Treatment Location: Only at MD Anderson
Estimatated Length of Stay in Houston: N/A
Sponsor: Bristol Myers Squibb
Return Visit: Weekly for 2 wks, 2 wks later, then every 4 wks for up to 12 cycles. Patients may continue treatment beyond 12 cycles if there is continued clinical response or disease stabilization per RECIST 1.1 guideline, in the absence of significant toxicities.
Home Care: N/A
Primary Objectives 1. To compare the biological response of tumors harboring exon 11 or 13 KIT mutations versus tumors without exon 11 or 13 KIT mutations from patients with acral, or mucosal melanomas after treatment with dasatinib. Secondary Objectives 1. To assess the safety and tolerability of dasatinib in this patient population 2. To evaluate molecular changes of tumors harboring exon 11 or 13 KIT mutations versus tumors without KIT exon 11 or 13 mutations from patients with acral or mucosal melanomas after treatment with dasatinib by assessing apoptosis, autophagy and cell proliferation markers 3. To assess the secondary mutations that may account for resistance to dasatinib therapy Completely Resectable Acral, CSD, and Mucosal Melanoma: 4. To assess the median time to recurrence and overall survival of patients with completely resectable acral, CSD, and mucosal melanoma treated with dasatinib 5. To assess whether FDG-avidity and KIT phosphorylation responses after treatment with dasatinib predicts prolonged time to recurrence and/or overall survival in patients with completely resectable acral, CSD, and mucosal melanomas 6. To assess whether exon 11 or 13 KIT mutation status predicts prolonged time to recurrence and/or overall survival in patients with completely resectable acral, CSD, and mucosal melanomas treated with dasatinib Not Completely Resectable Acral, CSD, and Mucosal Melanoma: 7. To assess the response rate, progression free survival, and overall survival of patients with acral, CSD, and mucosal melanoma treated with dasatinib 8. To assess whether FDG-avidity and KIT phosphorylation responses after treatment with dasatinib predicts response rate, progression free survival, and/or overall survival in patients with acral, CSD, and mucosal melanomas 9. To assess whether exon 11 or 13 KIT mutation status predicts response rate, progression free survival, and/or overall survival in patients with acral, CSD, and mucosal melanomas
IRB Review and Approval Date: 03/09/2011
Recruitment Status: Not Accepting
Projected Accrual: N/A
1) Patients must have primary, recurrent or metastatic melanoma with one
of the following pathology or characteristics: i) acral lentiginous
melanoma ii) mucosal melanoma iii) any known KIT mutation.
2) (Continued 1) If 20 patients without tumors harboring exon 11 or 13 KIT mutation are enrolled and treated before the completion of the patient accrual of 30, only those with tumors harboring exon 11 or 13 KIT mutation will be enrolled. Likewise, if 10 patients with tumors harboring exon 11 or 13 KIT mutation are enrolled and treated before the completion of the patient accrual of 30, only those without tumors harboring exon 11 or 13 KIT mutation will then be enrolled.
3) Patients must have measurable disease by FDG-PET (with or without CT) defined as having a SUVmax of 3 and SUVmax ofat least 2 fold greater than background.
4) Patients scheduled for FDG-PET should have uptake of the tracer in at least one lesion (tumor-to-muscle ratio >2) in the baseline PET/CT scan in order to be eligible for the follow-up FDG PET scans.
5) Patient must have surgically resectable melanoma lesion(s) or biopsiable lesion(s) which are amenable to 2 separate biopsy procedures by a core needle or excision.
6) Age >/= 18 years.
7) ECOG performance status 0 or 1.
8) Adequate Organ Function: a. Total bilirubin < 2.0 times the institutional Upper Limit of Normal (ULN), b.Hepatic enzymes (AST, ALT ) </= 2.5 times the institutional ULN, c. Serum Creatinine < 1.5 time the institutional ULN, d.Neutrophil count >/= 1500; Platelets >/= 75,000;
9) Ability to take oral medication (dasatinib must be swallowed whole)
10) Concomitant Medications: a. Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy (discontinue St. Johns Wort at least 5 days before starting dasatinib), b.Patient agrees that IV bisphophonates will be withheld for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia.
11) Women of childbearing potential (WOCBP) must have: a) A negative serum or urine pregnancy test (sensitivity 25 IU HCG/L) within 72 hours prior to the start of study drug administration b) Persons of reproductive potential must agree to use and utilize an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped. Prior to study enrollment, women of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy.
12) Signed written informed consent including a HIPAA form according to institutional guidelines
1) No other malignancy which required radiotherapy or systemic treatment
within the past 5 years.
2) Concurrent medical condition which may increase the risk of toxicity, including: a. Pleural or pericardial effusion of any grade.
3) Cardiac Symptoms; any of the following should be considered for exclusion: a. Uncontrolled angina, congestive heart failure or MI within (6 months), b. Diagnosed congenital long QT syndrome, c. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes), d. Prolonged QTc interval on pre-entry electrocardiogram (> 480 msec) [or > 500 msec for patients with a bundle branch block]), e. Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration.
4) History of significant bleeding disorder unrelated to cancer, including: a. Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease), b. Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies), c. Ongoing or recent (</= 3 months) significant gastrointestinal bleeding.
5) Concomitant Medications, any of the following should be considered for exclusion: a. Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes including: (Patients must discontinue drug 7 days prior to starting dasatinib), I. quinidine, procainamide, disopyramide, II. amiodarone, sotalol, ibutilide, dofetilide, III. erythromycin, clarithromycin, IV. chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide V. cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.
6) Women who: a. are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after cessation of study drug, or, b. have a positive pregnancy test at baseline, or, c. are pregnant or breastfeeding,
7) Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness
8) No active, untreated brain metastases. Patients with known brain metastases will be included if the brain metastases have been treated and stable for at least 3 months without the use of steroid
9) HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with dasatinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
10) Patients with melanoma harboring BRAF mutation. If BRAF mutation is not known at the time of screening, patients will still be eligible
Information and next steps
Kevin B. Kim
Melanoma Medical Oncology
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