In Vivo Angiostatin Generation Using Tissue Plasminogen Activator and Captopril in Treating Patients With Progressive Metastatic Cancer
In Vivo Angiostatin Generation Using Tissue Plasminogen Activator and Captopril in Treating Patients With Progressive Metastatic Cancer
RATIONALE: Tissue plasminogen activator and captopril may help the body generate angiostatin.
 Angiostatin may stop the growth of cancer by stopping blood flow to the tumor.

 PURPOSE: This phase I/II trial is studying the side effects and best dose of tissue
 plasminogen activator and captopril and to see how well they work in treating patients with
 progressive metastatic cancer.
OBJECTIVES:

 Primary

 -  Determine the maximum tolerated dose and toxicity of captopril and tissue plasminogen
 activator (tPA) in patients with progressive metastatic cancer.

 -  Determine the in vivo generation of angiostatin by western analysis in patients treated
 with this regimen.

 Secondary

 -  Determine the antitumor effect of this regimen in these patients.

 OUTLINE: This is a dose-escalation study.

 Patients receive tissue plasminogen activator (tPA) IV over 6 hours and oral captopril twice
 daily on days 1-5. Courses repeat every 14 days for up to 1 year in the absence of disease
 progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 2
 additional courses beyond CR.

 Cohorts of 3-6 patients receive escalating doses of tPA and captopril until the maximum
 tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
 of 3 or 2 of 6 patients experience dose-limiting toxicity.

 PROJECTED ACCRUAL: Not specified.
DISEASE CHARACTERISTICS:

 -  Diagnosis of progressive metastatic cancer, excluding hematologic malignancies (i.e.,
 leukemia or lymphoma)

 -  Measurable disease not required

 -  Must have received at least 1 prior systemic treatment for metastatic disease

 -  No known CNS involvement

 -  CNS involvement allowed provided it is successfully controlled by prior surgery
 or radiotherapy and there is no current requirement for corticosteroids

 PATIENT CHARACTERISTICS:

 Age

 -  18 and over

 Performance status

 -  ECOG 0-2

 Life expectancy

 -  At least 3 months

 Hematopoietic

 -  Granulocyte count at least 1,500/mm^3

 -  Platelet count at least 100,000/mm^3

 -  No bleeding diathesis

 Hepatic

 -  Bilirubin no greater than 1.5 mg/dL

 -  SGOT no greater than 3 times upper limit of normal

 -  Albumin normal

 -  PT and aPTT normal

 -  Fibrinogen > lower limit of normal

 Renal

 -  Creatinine no greater than 1.8 mg/dL

 Cardiovascular

 -  No myocardial infarction within the past 6 months

 -  No history of stroke, transient ischemic attack, or symptoms of cerebral ischemia

 -  No history of angioedema with captopril

 -  No severe or uncontrolled hypertension (i.e., systolic blood pressure greater than 180
 mm Hg or diastolic blood pressure greater than 110 mm Hg)

 -  No congestive heart failure requiring therapy

 -  No chronic hypotension (e.g., systolic blood pressure less than 100 mm Hg)

 Other

 -  Not pregnant or nursing

 -  Fertile patients must use effective contraception

 -  HIV negative

 -  Potassium no greater than 5.2 mmol/L

 -  No active internal bleeding

 -  No history of seizures

 -  No psychiatric disorder that would preclude the giving of informed consent or study
 follow-up

 -  No other malignancy within the past 5 years except adequately treated basal cell or
 squamous cell skin cancer or carcinoma in situ of the cervix

 -  No uncontrolled or active bacterial, viral, or invasive fungal infection

 -  No recent trauma

 -  No medical indication for anticoagulation

 -  No contraindication to captopril

 PRIOR CONCURRENT THERAPY:

 Biologic therapy

 -  At least 4 weeks since prior biologic therapy

 -  No concurrent immunomodulator therapy

 Chemotherapy

 -  At least 4 weeks since prior chemotherapy

 -  No concurrent chemotherapy

 Endocrine therapy

 -  See Disease Characteristics

 -  At least 4 weeks since prior endocrine therapy

 Radiotherapy

 -  See Disease Characteristics

 -  At least 4 weeks since prior radiotherapy

 Surgery

 -  See Disease Characteristics

 -  No recent intracranial or intraspinal surgery

 -  No concurrent surgery

 Other

 -  More than 48 hours since prior anticoagulation agents (e.g., warfarin or heparin)

 -  More than 3 weeks since prior investigational agents

 -  No concurrent anticoagulation agents, aspirin, or nonsteroidal anti-inflammatory drugs

 -  No other concurrent investigational agent

 -  No concurrent phenytoin, phenobarbital, or other antiepileptic prophylaxis

 -  Concurrent bisphosphonates allowed for metastatic bone disease