In Vivo Angiostatin Generation Using Tissue Plasminogen Activator and Captopril 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