Dasatinib in Treating Patients With Unresectable or Metastatic Squamous Cell Skin Cancer or RAI Stage 0-I Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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This phase II trial is studying how well dasatinib works in treating patients with unresectable or metastatic squamous cell skin cancer or RAI Stage 0-I chronic lymphocytic leukemia. Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the objective response rate (complete response and partial response) in patients with unresectable or metastatic squamous cell carcinoma of the skin or RAI stage 0-I chronic lymphocytic leukemia receiving dasatinib. SECONDARY OBJECTIVES: I. Determine the progression-free survival of patients receiving this drug. II. Evaluate tumor for presence of total EphA2 and both total and active Src and FAK by immunohistochemistry (IHC) pre-treatment with dasatinib. III. Evaluate tumor for presence of cyclooxygenase-2 by IHC pre-treatment with dasatinib. OUTLINE: Patients are assigned to 1 of 2 treatment arms. ARM I: Patients receive 100 mg dasatinib orally (PO) twice daily (BID) on days 1-28. ARM II (PATIENTS ENROLLED AFTER 11/18/08): Patients receive 70 mg dasatinib PO BID on days 1-28. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre-therapy tumor biopsy specimens are collected to detect total and phosphorylated Src and FAK, total EphA2, and cyclooxygenase-2 by immunohistochemistry. After completion of study treatment, patients are followed up monthly for up to 12 weeks.

Official Title
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A Phase 2 Study of Dasatinib in Patients With Transplant and Non-Transplant Related Unresectable or Metastatic Cutaneous Squamous Cell Carcinoma and RAI Stage 0-1 Chronic Lymphocytic Leukemia

Conditions
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Recurrent Skin Cancer, Squamous Cell Carcinoma of the Skin, Stage 0 Chronic Lymphocytic Leukemia, Stage I Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: dasatinib
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of 1 of the following Histologically or cytologically confirmed squamous cell carcinoma of the skin Unresectable or metastatic disease Squamous cell histology represents ≥ 50% of the biopsy specimen May or may not be related to autologous or allogeneic organ transplantation Chronic lymphocytic leukemia (CLL) RAI stage 0-I Stable disease Patients with basalosquamous cell disease (basal cell with squamous differentiation) are eligible Measurable disease, defined as at least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan Must be willing to undergo a pre-treatment tumor biopsy Brain metastases are allowed provided the following are true: Received definitive therapy consisting of external beam radiation therapy, gamma knife therapy, or surgical resection resulting in clinically stable disease Lesions are under control for at least 4 weeks after completion of definitive therapy, as measured by repeat MRI or CT scans No requirement for dexamethasone ECOG performance status 0-1 OR Karnofsky 60-100% Life expectancy > 6 months WBC ≥ 3,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Platelets ≥ 100,000/mm^3 Total bilirubin ≤ 1.5 times upper limit of normal(ULN) AST/ALT ≤ 2.5 times ULN Potassium 3.5 - 5.1 mmol/L Calcium > lower limit of normal Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min No known HIV 1 or HIV 2 positivity No known hepatitis C or hepatitis B positivity Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No history of allergic reactions attributed to compounds of similar chemical or biological composition to dasatinib No QTc prolongation, defined as a QTc interval of ≥ 480 msecs or other significant ECG abnormality No condition that impairs the ability to swallow and retain dasatinib tablets (e.g., gastrointestinal tract disease resulting in an inability to take oral medication, requirement for IV alimentation, prior surgical procedure affecting absorption, or active peptic ulcer disease) No clinically significant cardiovascular disease including the following: Myocardial infarction within 6 months Uncontrolled angina within 3 months Diagnosed or suspected congenital long QT syndrome Any history of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or Torsades de Pointe) Any history of second or third degree heart block (may be eligible if the subject currently has a pacemaker) Heart rate consistently < 50 beats/minute on pre-entry ECG Uncontrolled hypertension Ejection fraction < 45% by transthoracic echo No uncontrolled intercurrent illness including, but not limited to, the following: Ongoing or active infection requiring intravenous antibiotics History of significant bleeding disorder, including congenital (von Willebrand's disease) or acquired (anti-factor VIII antibodies) disorders Psychiatric illness or social situations that would limit compliance with study requirements No prior malignancy except for adequately treated basal cell cancer, carcinoma in situ of the cervix, or other cancer for which the patient has been disease free for 3 years No gastro-esophageal reflux disease dependent on proton pump inhibitors, H2 blockers, or antacids Recovered from prior therapy No more than 1 prior therapy with a monoclonal antibody No more than 1 prior chemotherapy regimen No prior tyrosine kinase inhibitor therapy Prior erlotinib hydrochloride allowed More than 2 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered At least 4 weeks since prior radiotherapy Measurable disease must be outside the radiotherapy port At least 2 weeks since prior topical therapy At least 4 weeks since prior surgery requiring general anesthesia and intubation At least 120 days (4 months) since prior amiodarone At least 7 days since prior and no concurrent anti-thrombotic and/or platelet agents (e.g., warfarin, heparin, low molecular weight heparin, aspirin [full dose and 81 mg dose] and/or ibuprofen) At least 7 days since prior and no concurrent agents with pro-arrhythmic potential More than 7 days or 5 half lives, whichever is greater, since prior and no concurrent agents or substances that induce or inhibit CYP3A4 No concurrent bisphosphonate therapy for the first 8 weeks of dasatinib treatment No other concurrent investigational agents No concurrent combination antiretroviral therapy for HIV-positive patients

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (dasatinib 100 mg PO BID)<br>Patients receive 100 mg dasatinib PO BID on days 1-28 | Drug: dasatinib<br>* Given PO<br>* Other names: Sprycel;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm II (dasatinib 70 mg PO BID)<br>Patients receive 70 mg dasatinib PO BID on days 1-28 | Drug: dasatinib<br>* Given PO<br>* Other names: Sprycel;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (Complete Response and Partial Response) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Every 2 courses during treatment, assessed up to 12 weeks after completion of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | Time from start of treatment to time of progression, assessed up to 12 weeks | 
| Presence of Total EphA2 and Both Total and Active Src and FAK by Immunohistochemistry (IHC) | Performed per standard protocols by the Pathology Department. | At baseline | 
| COX-2 Presence by IHC | Performed per standard protocols by the Pathology Department. Samples will be obtained pre-therapy. Determination of the COX-2 tumor status on this trial will develop the beginnings of a data base upon which future therapy may be designed. | At baseline |