The Safety and Effectiveness of Interferon Alfa-2B Plus Didanosine in Patients With Kaposi's Sarcoma

A Randomized Phase II Trial to Determine the Safety, Tolerance, and Efficacy of Two Doses of Interferon Alfa-2b Combined With Didanosine in Patients With Kaposi's Sarcoma

Primary: To evaluate the safety, toxicity, and antitumor activity of two doses of interferon alfa-2b (IFN-alpha) combined with a fixed dose of didanosine (ddI) in patients with Kaposi's sarcoma associated with HIV infection.

Secondary: To evaluate the effects of combined IFN-alpha and ddI treatment on HIV expression and markers of immune function.

Previous studies have shown that IFN-alpha can induce regression of Kaposi's sarcoma and suppression of HIV in some patients. Although various trials using IFN-alpha in combination with the nucleoside analogue zidovudine have demonstrated a high degree of antitumor activity and evidence of HIV suppression, the overlapping toxicity (primarily neutropenia) of these two agents has proven dose-limiting. The toxicity profile of ddI suggests that this drug may be better tolerated than zidovudine when combined with IFN-alpha.

Previous studies have shown that IFN-alpha can induce regression of Kaposi's sarcoma and suppression of HIV in some patients. Although various trials using IFN-alpha in combination with the nucleoside analogue zidovudine have demonstrated a high degree of antitumor activity and evidence of HIV suppression, the overlapping toxicity (primarily neutropenia) of these two agents has proven dose-limiting. The toxicity profile of ddI suggests that this drug may be better tolerated than zidovudine when combined with IFN-alpha.

Up to 90 patients are randomized to receive either low or high doses of IFN-alpha (1 or 10 million Units/day) in combination with a fixed dose of ddI. Fourteen patients are initially entered at each dose level. If no objective antitumor responses are observed among the first 14 patients at a given dose, no further patients are entered on that treatment arm. If one or more antitumor responses are seen at a given dose, up to 45 patients may be entered on that treatment arm. Patients must complete at least 4 weeks of study therapy to be considered evaluable for tumor response. Treatment is continued until tumor progression or unacceptable toxicity occurs. PER AMENDMENT 9/19/96: NOTE - After 16 weeks of treatment subjects may receive any FDA approved antiretroviral drug regimen in addition to or in place of ddI.

Inclusion Criteria

Concurrent Medication:

Allowed:

• Chemoprophylaxis for candidiasis and herpes simplex.
• Up to 14 days of metronidazole.
• Recombinant erythropoietin.
• G-CSF (for severe cases of neutropenia).
• Isoniazid for treatment of TB if given in conjunction with pyridoxine.

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

• Prophylaxis for PCP.

PER AMENDMENT 9/19/96:

• After the first 16 weeks of combined IFN alpha-2b and ddI treatment subjects may at the discretion of the investigator receive any FDA approved antiretroviral drug regimen in addition to or in place of ddI.

Patients must have:

• Positive antibody to HIV.
• Biopsy-proven Kaposi's sarcoma (at least 5 measurable lesions, with at least 1 measurable cutaneous lesion) involving the skin, lymph nodes, oral cavity, or asymptomatic lesions of the GI tract not requiring systemic chemotherapy. Lung involvement with Kaposi's sarcoma excludes.
• Consent of parent or guardian if less than 18 years of age.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms and conditions are excluded:

• Concurrent opportunistic infection or B symptoms including unexplained fever, night sweats, weight loss > 10 percent, and diarrhea lasting more than 2 weeks.
• Visceral (non-nodal) Kaposi's sarcoma requiring cytotoxic chemotherapy.
• Severe (> 2+) tumor-associated edema.
• Concurrent neoplasia other than basal cell carcinoma, or anogenital intraepithelial neoplasia.
• Current clinical evidence of peripheral neuropathy (= or > grade 1), pancreatitis, intractable diarrhea, or active seizure disorder not well controlled by anti-seizure medications.
• Significant symptomatic cardiac disease.
• Medical contraindication.

Concurrent Medication:

Excluded:

• Other investigational, antiviral, immunomodulating, or antitumor agents.
• Drugs associated with peripheral neuropathy (other than ddI).

PER AMENDMENT 9/19/96:

• Other antiretroviral agents may not be taken during the first 16 weeks of combined IFN alpha-2b and ddI treatment.

Concurrent Treatment:

Excluded:

• Radiation therapy.

Patients with the following prior conditions are excluded:

• Opportunistic infection or B symptoms including unexplained fever, night sweats, weight loss > 10 percent, and diarrhea lasting more than 2 weeks.
• Prior grade 3 or 4 toxicity attributed to ddI therapy.
• Prior history of peripheral neuropathy (= or > grade 1), pancreatitis, intractable diarrhea, or active seizure disorder not well controlled by anti-seizure medications.
• History of myocardial infarction or ventricular arrhythmias.

Prior Medication:

Excluded:

• Prior IFN-alpha.
• Corticosteroids, biological response modifiers, cytotoxic chemotherapy, or known neurotoxic drugs (other than ddI or ddC) within 30 days prior to study entry.
• Therapy with antiretroviral drugs (other than ddI) within 7 days prior to study entry.

Prior Treatment:

Excluded:

• Radiation therapy within 30 days prior to study entry.

Risk Behavior:

• Alcohol consumption is strongly discouraged.
• Patients considered to be noncompliant should be excluded.