Clinical trial NCT00509041: Dasatinib in Treating Patients With Previously Treated Malignant Mesothelioma
Official title: A Phase II Study of Dasatinib (NSC #732517) in Patients With Previously Treated Malignant Mesothelioma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Malignant Mesothelioma
Keywords: advanced malignant mesothelioma
epithelial mesothelioma
recurrent malignant mesothelioma
sarcomatous mesothelioma
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-07-31
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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 at least every 2 months for 1 year, then every 4 months for 1 year, then every 6 months for 1 year.

Eligibility criteria: 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
* May 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
* 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

Primary outcomes:
measure: 24 Week Progression Free Survival
timeFrame: 24 weeks
Secondary outcomes:
measure: Number of Participants With Overall Tumor Response
timeFrame: Duration of study until progression (up to 3 years)
measure: Overall Survival
timeFrame: Time from registration to death (up to 3 years)
measure: Progression Free Survival
timeFrame: Time from registration to progression or death (up to 3 years)
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Rebecca and John Moores UCSD Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Lewes
country: United States
facility: Tunnell Cancer Center at Beebe Medical Center
state: Delaware
city: Newark
country: United States
facility: CCOP - Christiana Care Health Services
state: Delaware
city: Washington
country: United States
facility: Lombardi Comprehensive Cancer Center at Georgetown University Medical Center
state: District of Columbia
city: Orlando
country: United States
facility: Florida Hospital Cancer Institute at Florida Hospital Orlando
state: Florida
city: Savannah
country: United States
facility: Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Cancer Research Center
state: Illinois
city: Elkhart
country: United States
facility: Elkhart General Hospital
state: Indiana
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology
state: Indiana
city: Kokomo
country: United States
facility: Howard Community Hospital
state: Indiana
city: La Porte
country: United States
facility: Center for Cancer Therapy at LaPorte Hospital and Health Services
state: Indiana
city: South Bend
country: United States
facility: CCOP - Northern Indiana CR Consortium
state: Indiana
city: South Bend
country: United States
facility: Memorial Hospital of South Bend
state: Indiana
city: South Bend
country: United States
facility: Saint Joseph Regional Medical Center
state: Indiana
city: South Bend
country: United States
facility: South Bend Clinic
state: Indiana
city: Baltimore
country: United States
facility: Harry & Jeanette Weinberg Cancer Institute at Franklin Square Hospital Center
state: Maryland
city: Elkton MD
country: United States
facility: Union Hospital Cancer Program at Union Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: St. Joseph
country: United States
facility: Lakeland Regional Cancer Care Center - St. Joseph
state: Michigan
city: Minneapolis
country: United States
facility: Masonic Cancer Center at University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Missouri Baptist Cancer Center
state: Missouri
city: Saint Louis
country: United States
facility: Arch Medical Services, Incorporated at Center for Cancer Care and Research
state: Missouri
city: Omaha
country: United States
facility: Methodist Estabrook Cancer Center
state: Nebraska
city: Voorhees
country: United States
facility: Cancer Institute of New Jersey at Cooper - Voorhees
state: New Jersey
city: Syracuse
country: United States
facility: SUNY Upstate Medical University Hospital
state: New York
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital, Incorporated
state: North Carolina
city: Kinston
country: United States
facility: Kinston Medical Specialists
state: North Carolina
city: Statesville
country: United States
facility: Iredell Memorial Hospital
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
state: Ohio
city: Greenville
country: United States
facility: CCOP - Greenville
state: South Carolina
city: Berlin
country: United States
facility: Mountainview Medical
state: Vermont
city: Burlington
country: United States
facility: Fletcher Allen Health Care - University Health Center Campus
state: Vermont
city: Danville
country: United States
facility: Danville Regional Medical Center
state: Virginia
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Arkadiusz Dudek, MD
role: STUDY_CHAIR
References:
citation: Dudek A, Pang H, Kratzke RA, et al.: CALGB 30601: A phase II study of dasatinib (D) in patients (pts) with previously treated malignant mesothelioma (MM). [Abstract] J Clin Oncol 28 (Suppl 15) A-7037, 2010.