Dasatinib in Treating Patients With Previously Treated Malignant Mesothelioma

Alliance for Clinical Trials in Oncology

Status and phase

Completed

Phase 2

Conditions

Malignant Mesothelioma

Treatments

Drug: dasatinib

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00509041

CDR0000558362 (Registry Identifier)

U10CA031946 (U.S. NIH Grant/Contract)

CALGB-30601

Details and patient eligibility

About

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.

Full 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.

Enrollment

46 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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