Official Title: “A Phase II Study of Dasatinib (NSC #732517) in Patients With Previously Treated Malignant Mesothelioma”

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 previously treated malignant mesothelioma.

Study Type: Interventional

Study Design: Treatment, Open Label

OBJECTIVES:

Primary - To determine the rate of progression-free survival (PFS) at 24 weeks (or 5.5 months) in patients with malignant mesothelioma treated with dasatinib.

Secondary - To determine the response rate (partial response [PR] and complete response [CR]) in patients with malignant mesothelioma treated with dasatinib. - To determine the response duration in patients with malignant mesothelioma treated with dasatinib. - To describe the overall survival (OS) of patients with malignant mesothelioma treated with dasatinib. - To describe the toxicity profile of dasatinib in patients with malignant mesothelioma. - To determine whether the amount of expression of EphA2 and PDGFRβ, as measured by immunohistochemistry from tumor specimens, correlates with PFS in patients with malignant mesothelioma. - To determine whether plasma levels of VEGF and PDGFRβ, serum levels of CSF-1, and soluble mesothelin-related protein correlate with PFS in patients with malignant mesothelioma. - To determine whether inhibition of Src phosphorylation in PBMC correlates with PFS. - To assess inhibition of phosphorylation of Src, EphA2, and PDGFRβ in tumor tissue by dasatinib.

OUTLINE: Patients receive oral dasatinib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo tumor tissue and blood sample collection periodically for correlative studies. Tumor tissue samples are analyzed for EphA2 and PDGFRβ expression by immunohistochemistry. Tumor tissue samples may also be analyzed for phosphorylation of Src, EphA2, and PDGFRβ by western blot. Blood samples are analyzed for concentration of VEGF and PDGF by quantitative sandwich enzyme immunoassay technique; mesothelin-related protein level by Mesomark® assay; CSF-1 level by ELISA assay; and phosphorylation of Src by phospho-Src (pTyr418) human ELISA.

After completion of study treatment, patients are followed periodically.

Primary:

• Progression-free survival (PFS) at 24 weeks (or 5.5 months) No

Secondary:

• Response rate (complete and partial response) as measured by RECIST criteria No
• Response duration No
• Overall survival No
• Toxicity profile Yes
• Correlation of expression levels of EphA2 and PDGFRβ with response, PFS, and overall survival No
• Correlation of plasma levels of VEGF and PDGFRβ, serum levels of CSF-1, and soluble mesothelin-related protein with response, PFS, and overall survival No
• Correlation of a decrease in Src phosphorylation in PBMC with response, PFS, and overall survival No
• Correlation of a decrease in the phosphorylation of Src, EphA2, and PDGFRβ in tumor tissue with response No

DISEASE CHARACTERISTICS:

• Histologically confirmed malignant mesothelioma of any of the following subtypes:
• Epithelial
• Sarcomatoid
• Mixed
• Any site of origin of malignant mesothelioma allowed including, but not limited to, any of the following:
• Pleura
• Peritoneum
• Pericardium
• Tunica vaginalis
• Pathology blocks or slides from a core surgical biopsy must be available
• Not amenable to curative surgery
• Measurable disease, defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques (CT scan , MRI, or x-ray) or as ≥ 10 mm with spiral CT scan
• Patients with pleural rind only disease must have at least one level with one rind measurement ≥ 1.5 cm
• Lesions that are considered nonmeasurable include the following:
• Bone lesions
• Leptomeningeal disease
• Ascites
• Pleural/pericardial effusion
• Lymphangitis cutis/pulmonis
• Abdominal masses that are not confirmed and followed by imaging techniques
• Cystic lesions
• Prior treatment with one and only one systemic chemotherapy regimen, which must have included pemetrexed disodium required
• Treatment may have been with pemetrexed disodium alone or in combination with any other agent
• No symptomatic pleural effusions, unless the patient undergoes a therapeutic thoracentesis
• Patients with pleural effusions who have had a pleurodesis are eligible
• No known brain metastases
• Must be registered on CALGB-150707 companion study

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1
• Granulocytes ≥ 1,500/μL
• Platelet count ≥ 100,000/μL
• Total bilirubin ≤ 2 x upper limit of normal (ULN)
• AST (SGOT) ≤ 2.5 x ULN
• Creatinine clearance ≥ 60 mL/min
• INR < 1.5
• PTT < 40 seconds
• QTc < 450 msec
• Not pregnant or nursing
• Fertile patients must use effective contraception
• No significant cardiac disease, including any of the following:
• New York Heart Association (NYHA) class III-IV congestive heart failure (CHF)
• Unstable angina
• Myocardial infarction or ventricular tachyarrhythmia within 6 months of study entry
• Ejection fraction less than institutional normal (in patients with a history of CHF or currently with NYHA class I or II CHF)
• Prolonged QTc > 450 msec (Fridericia correction)
• Major conduction abnormality, unless a cardiac pacemaker is present
• Hypokalemia or hypomagnesemia that cannot be corrected
• No history of significant bleeding disorder unrelated to cancer, including any of the following:
• Congenital bleeding disorder (e.g., von Willebrand disease)
• Acquired bleeding disorder within the past year (e.g., acquired anti-factor VIII antibodies)
• Ongoing or recent (≤ 3 months) significant GI bleeding or hemoptysis
• No requirement for supplemental oxygen (i.e., pulse oximetry < 89% at rest)

PRIOR CONCURRENT THERAPY:

• At least 4 weeks since prior pemetrexed disodium-containing chemotherapy
• At least 4 weeks since prior major surgery
• At least 4 weeks since prior radiation therapy
• Measurable disease must be outside the radiation port
• Prior intracavitary cytotoxic or sclerosing therapy (including bleomycin) allowed
• Intrapleural cytotoxic chemotherapy will not be considered systemic chemotherapy
• No prior tyrosine kinase, signal transduction, or angiogenesis inhibitor therapy
• At least 7 days since prior and no concurrent antithrombotic or anti-platelet agents, including any of the following:
• Aspirin or aspirin-containing combinations
• Clopidogrel
• Dipyridamole
• Tirofiban
• Epoprostenol
• Eptifibatide
• Cilostazol
• Abciximab
• Ticlopidine
• Warfarin
• Low-dose warfarin for prophylaxis to prevent catheter thrombosis allowed
• Heparin or low molecular weight heparin
• Heparin for IV line flush allowed
• At least 7 days since prior and no concurrent use of the following drugs:
• Itraconazole
• Ketoconazole (at doses > 200 mg/day)
• Miconazole
• Voriconazole
• Telithromycin
• Primidone
• Rifabutin
• Rifampin
• St. John's wort
• Carbamazepine
• Oxcarbazepine
• Rifapentine
• Phenobarbital
• Phenytoin
• Quinidine
• Procainamide
• Disopyramide
• Amiodarone
• Sotalol
• Ibutilide
• Dofetilide
• Erythromycin
• Clarithromycin
• Chlorpromazine
• Haloperidol
• Mesoridazine
• Thioridazine
• Pimozide
• Bepridil
• Droperidol
• Halofantrine
• Levomethadyl
• Sparfloxacin
• No concurrent H2 blockers or proton pump inhibitors
• No bisphosphonate therapy during the first 8 weeks of study treatment
• No concurrent hormones or other chemotherapeutic agents except for steroids administered for dasatinib-related pleural effusion or hormones administered for non-disease-related conditions (e.g., insulin for diabetes)
• No concurrent palliative radiation therapy

Lead Sponsor: Cancer and Leukemia Group B

CCOP - Christiana Care Health Services

Newark Delaware 19713 United States

Tunnell Cancer Center at Beebe Medical Center

Lewes Delaware 19958 United States

Lombardi Comprehensive Cancer Center at Georgetown University Medical Center

Washington District of Columbia 20007 United States

Florida Hospital Cancer Institute at Florida Hospital Orlando

Orlando Florida 32803-1273 United States

University of Chicago Cancer Research Center

Chicago Illinois 60637-1470 United States

Fort Wayne Medical Oncology and Hematology

Fort Wayne Indiana 46815 United States

Harry & Jeanette Weinberg Cancer Institute at Franklin Square Hospital Center

Baltimore Maryland 21237 United States

Union Hospital Cancer Program at Union Hospital

Elkton MD Maryland 21921 United States

Masonic Cancer Center at University of Minnesota

Minneapolis Minnesota 55455 United States

Arch Medical Services, Incorporated at Center for Cancer Care and Research

Saint Louis Missouri 63141 United States

Missouri Baptist Cancer Center

Saint Louis Missouri 63131 United States

Methodist Estabrook Cancer Center

Omaha Nebraska 68114 United States

Cancer Institute of New Jersey at Cooper - Voorhees

Voorhees New Jersey 08043 United States

SUNY Upstate Medical University Hospital

Syracuse New York 13210 United States

Kinston Medical Specialists

Kinston North Carolina 28501 United States

Wayne Memorial Hospital, Incorporated

Goldsboro North Carolina 27534 United States

Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center

Columbus Ohio 43210-1240 United States

Danville Regional Medical Center

Danville Virginia 24541 United States

Overall Clinical Trial Officials and Contacts

Arkadiusz Dudek, MD Study Chair Masonic Cancer Center, University of Minnesota  

Information obtained from ClinicalTrials.gov on July 23, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00509041

Study ID Number: CDR0000558362

ClinicalTrials.gov Identifier: NCT00509041

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database