Randomized, Phase I/II, Dose-Ranging, Open-Label Trial of the Anti-HIV Activity of Delavirdine Mesylate (DLV; U-90,152S)

PRIMARY: To study the safety and tolerance of delavirdine mesylate ( U-90152 ) monotherapy. To compare the anti-HIV activity of three blood concentration levels of this agent with nucleoside analog monotherapy, either zidovudine ( AZT ) or didanosine ( ddI ), based on the reduction of HIV viral burden.

SECONDARY: To use pharmacokinetic parameters to assess the relationship between daily drug exposure and antiviral activity and toxicity of the U-90152, AZT, and ddI monotherapy. To assess anti-HIV activity using other disease markers.

Data suggest that bisheteroarylpiperazines (BHAPs) such as delavirdine mesylate are potent and safe anti-HIV agents and may have different biological behavior than other currently available non-nucleoside RT inhibitors.

Data suggest that bisheteroarylpiperazines (BHAPs) such as delavirdine mesylate are potent and safe anti-HIV agents and may have different biological behavior than other currently available non-nucleoside RT inhibitors.

Patients are randomized to receive U-90152 at one of three doses (treatment arms I through III) or either AZT or ddI (treatment arm IV). Patients on arm IV who are AZT-naive receive AZT; those who are AZT-experienced receive ddI. Treatment continues for 24 weeks.

PER 12/22/94 AMENDMENT: All patients receiving U-90152 have the same starting dose, to attain one of three target trough levels.

• Drug: Delavirdine mesylate
• Drug: Zidovudine
• Drug: Didanosine

• Dereuddre-Bosquet N, Clayette P, Martin M, Fretier P, Jaccard P, Benveniste O, Lebeaut A, Dormont D. IL-10 and HIV-1 infection of human primary monocyte/macrophages. Int Conf AIDS. 1996 Jul 7-12;11(2):75 (abstract no WeA3107)
• Para M, Weinstock M. Retrospective analysis of protease inhibitor efficacy among patients failing a delavirdine regimen. Int Conf AIDS. 1998;12:59 (abstract no 12236)
• Morse G, Para M, Fischl M, Freimuth W. Concentration-targeted (CT) Delavirdine therapy in 82 patients in ACTG 260. Conf Retroviruses Opportunistic Infect. 1996 Jan 28-Feb 1;3rd:118
• Para M, Morse G, Fischl M. Plasma protein binding of delavirdine in HIV-infected patients in ACTG 260. Int Conf AIDS. 1996 Jul 7-12;11(2):78 (abstract no WeB3131)
• Demeter L, Shafer R, Para M, Morse G, Freimuth W, Merigan T, Reichman R. Delavirdine (DLV) susceptibility of HIV-1 isolates obtained from patients (pts) receiving DLV monotherapy (ACTG 260). Conf Retroviruses Opportunistic Infect. 1996 Jan 28-Feb 1;3rd:113
• Para MF, Fischl M, Meehan P, Morse G, Wood K, Shafer R, Freimuth W, Demeter L, Holden-Wiltse J, Nevin T. ACTG 260: Randomized phase I/II concentration-controlled trial of the anti-HIV activity of delavirdine. Conf Retroviruses Opportunistic Infect. 1996 Jan 28-Feb 1;3rd:163
• Demeter LM, Shafer RW, Meehan PM, Holden-Wiltse J, Fischl MA, Freimuth WW, Para MF, Reichman RC. Delavirdine susceptibilities and associated reverse transcriptase mutations in human immunodeficiency virus type 1 isolates from patients in a phase I/II trial of delavirdine monotherapy (ACTG 260). Antimicrob Agents Chemother. 2000 Mar;44(3):794-7.
• Para MF, Meehan P, Holden-Wiltse J, Fischl M, Morse G, Shafer R, Demeter LM, Wood K, Nevin T, Virani-Ketter N, Freimuth WW. ACTG 260: a randomized, phase I-II, dose-ranging trial of the anti-human immunodeficiency virus activity of delavirdine monotherapy. The AIDS Clinical Trials Group Protocol 260 Team. Antimicrob Agents Chemother. 1999 Jun;43(6):1373-8.

Inclusion Criteria

Concurrent Medication:

Allowed:

• PCP prophylaxis.
• Topical antifungal agents, clotrimazole troches, nystatin oral suspension, topical ketoconazole, and oral fluconazole.
• Acyclovir (<= 1000 mg/day) as maintenance therapy for herpes simplex virus.
• Recombinant erythropoietin and G-CSF.
• Antibiotics for bacterial infections, unless specifically excluded.
• Symptomatic treatment such as antipyretics, analgesics, nonsteroidal anti-inflammatory agents, and antiemetics.
• Antacids.

Patients must have:

• HIV-1 infection.
• CD4 count 200 - 500 cells/mm3.
• Either no prior antiretroviral therapy or discontinued AZT monotherapy 3 or more weeks prior to study entry.

NOTE:

• Half of patients should be antiretroviral naive.

Prior Medication:

Allowed:

• Prior AZT.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Malignancy other than minimal Kaposi's sarcoma.

Concurrent Medication:

Excluded:

• Rifabutin.
• Rifampin.
• Terfenadine.
• Astemizole.
• Loratadine.
• Trifluoperazine.
• Piperazine citrate.
• Any acute or chronic therapy for CMV, MAC, toxoplasmosis, or disseminated fungal infection.
• Non-study antiretroviral therapies, interferons, biologic response modifiers, and HIV vaccines.
• Systemic corticosteroids for more than 21 consecutive days.
• Foscarnet.
• Systemic cytotoxic chemotherapy for a malignancy.

Patients with the following prior conditions are excluded:

• History of pancreatitis (in patients who received prior AZT).
• History of grade 2 or worse peripheral neuropathy (in patients who received prior AZT).
• History of hypersensitivity to BHAP compounds (e.g., trifluoperazine - Stelazine, piperazine citrate - Antepar).

Prior Medication:

Excluded within 30 days prior to study entry:

• Any investigational medication.
• Interferon.
• Interleukin.
• Rifabutin.
• Rifampin.
• Terfenadine.
• Astemizole.
• Loratadine.
• Trifluoperazine.
• Piperazine citrate.

Excluded at any time:

• Prior ddI, ddC, d4T, or 3TC.
• Prior foscarnet.
• Prior BHAP compound or other non-nucleoside RT inhibitor.

Active substance abuse interfering with compliance.