A Phase I Study of TNP-470 in the Treatment of AIDS-Associated Kaposi's Sarcoma

Since evidence shows that neovascularization is important in the development of Kaposi's sarcoma, drugs that inhibit angiogenesis, such as TNP-470, may be of benefit in patients with the disease.

Patients are entered at 7 escalating dose levels of TNP-470. (PER AMENDMENT 9/3/96: dose maximum level changed.) Four patients treated at a given dose level must receive at least 4 weeks of therapy before escalation in subsequent cohorts proceeds. If 50 percent of patients at a given dose level experience dose-limiting toxicity, the previous dose is defined as the MTD and an additional two patients are treated at the MTD. Patients receive treatment for 12 weeks, followed by 2 weeks of rest, followed by an additional 12 weeks of treatment. Patients are followed for 12 weeks post-treatment.

Inclusion criteria

Concurrent Medication:

Allowed:

• AZT, ddI, ddC, or d4T provided patients have received at least 2 weeks of this therapy prior to study entry. (Combination ddI/ddC is not permitted.)
• MAI prophylaxis.

Required in patients with CD4 count < 200 cells/mm3:

Aerosolized pentamidine, trimethoprim/sulfamethoxazole, or dapsone as PCP prophylaxis.

Patients must have:

• HIV infection.
• Cutaneous Kaposi's sarcoma.
• Life expectancy of at least 3 months.
• Consent of parent or guardian if under 18 years of age.

NOTE:

• This protocol is considered suitable for prison populations.

Exclusion criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Peripheral neuropathy (grade 2 or worse).
• Underlying severe or life-threatening infection with bacterial, viral, fungal, or protozoal pathogens.
• Known hypersensitivity to TNP-470, fumagillin, or known related compounds.

PER AMENDMENT 9/3/96:

• Cataracts.

Concurrent Medication:

Excluded:

• Combination therapy with ddI/ddC (although these drugs may be administered alone or in combination with AZT).
• Anticonvulsive medication.
• Steroids.
• Antineoplastic drugs.
• Interferons.
• Systemic or topical anti-Kaposi's sarcoma agents or regimens.
• Suramin.
• Aspirin.
• Warfarin.
• Heparin (including heparin flushes).
• Nonsteroidal anti-inflammatory drugs.
• Investigational status drugs.

Patients with the following prior conditions are excluded:

• History of substantial non-iatrogenic bleeding disorders.
• History of tumor or malignancies other than Kaposi's sarcoma, with the exception of completely resected basal cell skin carcinoma or in situ cervical carcinoma.
• History of seizures within the past 10 years.

PER AMENDMENT 9/3/96:

• History of cataracts.

Prior Medication:

Excluded within 4 weeks prior to study entry:

• Steroids.
• Antineoplastic drugs.
• Interferons.
• Systemic or topical anti-Kaposi's sarcoma agents or regimens.

Excluded within 6 months prior to study entry:

• Suramin.

Unwilling to refrain from unprotected sexual contact or other activities that may result in HIV re-infection.