Escalating Multiple-Dose Safety and Tolerance of WR 6026 Hydrochloride in HIV-Infected Subjects

In recent animal studies, WR 6026 demonstrated inhibitory activity against Pneumocystis carinii pneumonia (PCP). This study will assess the safety and tolerance of this drug in HIV-infected patients who do not have PCP.

Escalating doses of WR 6026 will be studied in successive patient cohorts. Four patients will be randomized to active drug or placebo in a 3:1 ratio at each dose level until moderate toxicity is demonstrated. If one patient at a given dose level experiences WR 6026-related moderate or worse toxicity, the sample size for all subsequent dose levels will be doubled. If two or more patients at a given dose level experience moderate or dose-limiting toxicity, an additional four patients (randomized in the same 3:1 ratio) will be entered at that level, and sample size at all subsequent dose levels will be doubled. Dose escalation will continue until three of six patients receiving active drug at a given dose level experience dose-limiting or worse toxicity, or until two of six patients at a given dose level experience life-threatening toxicity. The MTD will be defined as the dose immediately below the highest dose studied. Eight additional patients will be studied at the presumed MTD to confirm tolerance.

Inclusion criteria

Patients must have:

• HIV antibody positive.
• CD4 cell counts less than 500/mm3.
• Adequate general health.
• No significant deterioration in performance status within the past month.
• Prior treatment with a stable regimen of antiretroviral medication for at least 4 weeks prior to study.

Prior Medication:

Required:

• Stable regimen of antiretroviral medication for at least 4 weeks prior to study entry.

Allowed:

• Aerosolized pentamidine for PCP prophylaxis.

Exclusion criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Intercurrent infection.
• Clinically significant abnormality on EKG.
• Known hypersensitivity to quinolines.
• Known hemoglobin M abnormality.
• Known NADH methemoglobin reductase deficiency.
• Positive test for G6PD deficiency.
• Fever.

Prior Medication:

Excluded:

• Other systemic medication (other than AZT, ddC, ddI, methadone, acyclovir, and NSAIDs) within 3 days prior to study entry.