| Conditions: |
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Breast Cancer - Gastrointestinal Stromal Tumor - Intraocular Melanoma - Kidney Cancer - Lung Cancer - Melanoma (Skin) - Ovarian Cancer - Prostate Cancer - Unspecified Adult Solid Tumor, Protocol Specific |
| Purpose: |
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RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes
needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth
in different ways. Some block the ability of tumor cells to grow and spread. Others find
tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may
also stop the growth of solid tumors by blocking blood flow to the tumor. Giving dasatinib
together with bevacizumab may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of dasatinib given
together with bevacizumab in treating patients with solid tumor that is metastatic or cannot
be removed by surgery.
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| Study Summary: |
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OBJECTIVES:
Primary
- To describe the safety and toxicity of the combination of dasatinib and bevacizumab in
patients with advanced solid tumors that have progressed on standard therapy.
- To find the maximum tolerated dose or recommended phase II dose of this combination.
- To describe the biochemical changes in the Src-FAK, Src-PLC-γ, and VEGF signal
transduction pathways in tumor and stromal cells in response to treatment. (Group 2)
Secondary
- To determine, preliminarily, the efficacy of this regimen.
- To evaluate correlations between pathway alteration and clinical events.
- To evaluate correlations between clinical outcomes and changes in VEGF and other
angiogenic cytokines in plasma and circulating endothelial cells.
- To evaluate the application of dynamic contrast-enhanced MRI in determining early
changes in tumor vascularity during treatment.
OUTLINE: This is a dose-escalation study of dasatinib and bevacizumab (group 1) followed by
a randomized study (group 2).
- Group 1: Patients receive oral dasatinib once daily on days 1-28 and bevacizumab IV
over 30-90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.
- Group 2: Patients receive dasatinib and bevacizumab at the maximum tolerated dose
determined in group 1. Patients are randomized to 1 of 2 treatment arms.
- Arm I: In course 1, patients receive oral dasatinib alone once daily on days 1-28.
Beginning in course 2 and for all subsequent courses, patients receive oral
dasatinib once daily on days 1-28 and bevacizumab IV over 30-90 minutes on days 1
and 15. Treatment repeats every 28 days in the absence of disease progression or
unacceptable toxicity.
- Arm II: In course 1, patients receive bevacizumab IV over 30-90 minutes on days 1
and 15. Beginning in course 2 and for all subsequent courses, patients receive
oral dasatinib once daily on days 1-28 and bevacizumab IV over 30-90 minutes on
days 1 and 15. Treatment repeats every 28 days in the absence of disease
progression or unacceptable toxicity.
Patients in group 2 undergo tumor biopsies and dynamic contrast-enhanced MRI at baseline,
after 2 weeks of single-agent therapy, and after ≥ 2 weeks of combined therapy to examine
biochemical effects of treatment and to evaluate changes in vascularity and quality of index
lesions. Blood samples are also collected from these patients and archived for future
studies, including cytokine and invasion marker analysis and circulating endothelial cell
analysis.
After completion of study therapy, patients are followed for 4 weeks.
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| Criteria: |
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DISEASE CHARACTERISTICS:
- Histologically confirmed metastatic or unresectable malignant solid tumors, including
but not limited to, any of the following:
- Renal cell carcinoma
- Ovarian cancer
- Gastrointestinal stromal tumors
- Melanoma
- Measurable (≥ 1 cm) or evaluable disease
- Standard curative therapies do not exist or are no longer effective
- Patients enrolling in group 2 must have at least one lesion deemed safe to biopsy and
be willing to undergo the three mandatory biopsies
- This determination will be made by a member of the interventional radiology team
or surgical associate investigator and an associate investigator
- Patients with active pleural effusion are eligible provided it was tapped prior to
study
- Patients with a grade 2 asymptomatic pericardial effusion found incidentally on
imaging studies are considered on a case-by-case basis
- Patients with pleural effusions that are too small to be removed may be
considered on a case-by-case basis
- No brain metastases
- Patients who have a history of remote CNS metastases that have undergone
curative therapy by radiotherapy, gamma-knife therapy, or surgery and have
remained without recurrence for ≥ 6 months are eligible
- CNS imaging consisting of a contrast CT scan or MRI is only required for
patients with certain tumor types with relatively high risk of CNS metastases
(including, but not limited to, melanoma, renal cell carcinoma, breast cancer,
and lung cancer)
- No squamous cell carcinoma of the lungs or a history of any type of lung cancer and
hemoptysis
PATIENT CHARACTERISTICS:
- ECOG performance status (PS) 0-1 (PS of 2 is considered on a case-by-case basis with
a focused assessment on risk of perforation)
- Life expectancy > 3 months
- Leukocytes > 3,000/μL
- ANC > 1,200/μL
- Platelet count > 100,000/μL
- Hemoglobin ≥ 10 g/dL
- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (in the absence of Gilbert's
syndrome)
- AST and ALT ≤ 2.5 times ULN
- Creatinine ≤ 1.5 mg/dL OR creatinine clearance > 45 mL/min
- Activated partial thromboplastin time ≤ 1.25 times ULN (in the absence of lupus
anticoagulant)
- Prothrombin time OR international normalized ratio ≤ 1.25 times ULN
- Spot urine protein:creatinine ratio ≤ 0.5 OR 24-hour urine for protein excretion ≤
1,000 mg
- No proteinuria defined as a spot urine protein-creatinine ratio of > 1.0 g
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for ≥ 3 months after
completion of study therapy
- No thrombotic or embolic events within the past 6 months, including any of the
following:
- Cerebrovascular accident (including transient ischemic attacks)
- Pulmonary embolism
- Unstable angina pectoris
- Myocardial infarction
- Patients with recent (i.e., within the past 3 months) venous thrombotic events are
considered on a case-by-case basis
- No concurrent uncontrolled illness including, but not limited to, any of the
following:
- Ongoing or active infection
- Patients with evidence of active infection must have completed antibiotic
therapy and be without clinical or laboratory evidence of infection for
seven days after treatment has concluded
- Symptomatic congestive heart failure AHA class II-IV disease
- Cardiac arrhythmia
- Psychiatric illness or social situations that would limit compliance with study
requirements
- No QTc prolongation (QTc interval ≥ 480 msec [Fridericia correction]) or other
clinically significant EKG abnormalities
- No clinically significant cardiovascular disease including any of the following:
- Ventricular tachyarrhythmia within the past 6 months
- Ejection fraction less than institutional normal (should be done if clinically
indicated and for patients with congestive heart failure on medication)
- Major conduction abnormality (unless a cardiac pacemaker is present)
- No hypertension defined as systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg despite
optimal medical management
- No serious non-healing wounds (including wounds healing by secondary intention),
acute or non-healing ulcers, or bone fractures within 3 months of fracture
- No abdominal fistula, bowel obstruction, or intra-abdominal abscesses within the past
28 days
- No hemoptysis within the past 28 days
- No history of gastrointestinal perforation
- No history of high-grade varices
- No evidence of bleeding diathesis
- No swallowing impairment that would preclude administration of dasatinib
- No known hypersensitivity to Chinese hamster ovary cell products or recombinant human
antibodies
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- Recovered from toxicity related to prior therapy
- No prior dasatinib or any other Src-family kinase inhibitors
- At least 4 weeks since prior chemotherapy, radiotherapy, hormonal therapy, or
biological therapy
- At least 6 weeks since prior mitomycin C, nitrosoureas, bevacizumab, or
carboplatin
- At least 4 weeks since prior therapy with a monoclonal antibody
- At least 28 days since prior major surgery
- At least 7 days since prior and no concurrent herbal supplements
- No concurrent use of potent inhibitors of CYP3A4
- No concurrent use of known (i.e., Class I) QT-prolonging agents
- No other concurrent investigational agents or anticancer agents including hormonal
therapy (except for bisphosphonates or erythropoietin analogs)
- Patients with prostate cancer must continue to receive leuteinizing-hormone
releasing-hormone agonist unless orchiectomy has been performed
- No concurrent anti-retroviral therapy for HIV-positive patients
- No concurrent complementary or alternative therapy
- No therapeutic anticoagulation with coumadin, heparins, or heparinoids (prophylaxis
doses are permitted)
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| NCT ID: |
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NCT00792545 |
| Primary Contact: |
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Principal Investigator
Elise C. Kohn, MD
National Cancer Institute (NCI)
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| Backup Contact: |
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N/A |
| Location Contact: |
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Bethesda, Maryland 20892
United States
Clinical Trials Office - Warren Grant Magnusen Clinical Center
Phone: 888-NCI-1937
Site Status: Recruiting |