A Phase I Concentration-Targeted Multidose Study of Atevirdine Mesylate ( U-87201E ), AZT, and ddI or ddC
Information source: National Institute of Allergy and Infectious Diseases (NIAID)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: HIV Infections
Intervention: Atevirdine mesylate (Drug); Zidovudine (Drug); Zalcitabine (Drug); Didanosine (Drug)
Phase: Phase 1
Status: Completed
Sponsored by: Upjohn Official(s) and/or principal investigator(s):
Reichman R, Study Chair
Summary
To determine the safety, toxicity, pharmacokinetic profile, and antiretroviral activity of
atevirdine mesylate ( U-87201E ) in HIV-infected patients. Per 06/04/93 amendment, to also
evaluate the interactive effects of didanosine ( ddI ) or zalcitabine ( dideoxycytidine; ddC
) with zidovudine ( AZT ) on the pharmacokinetics of U-87201E and to assess the effects of
the triple combination therapies on immunologic and virologic parameters.
Since the use of non-nucleoside reverse transcriptase inhibitors such as U-87201E has been
associated with the rapid development of resistant HIV isolates, an initial evaluation of
this drug in patients was made in combination with AZT. Because of the inability to detect
resistance after 6 weeks of combined AZT/U-87201E therapy, this protocol will initially
investigate U-87201E administered alone and then investigate the effect of this drug with AZT
and ddI or ddC.
Clinical Details
Official title: A Phase I Concentration-Targeted Multidose Study of Atevirdine Mesylate ( U-87201E ), AZT, and ddI or ddC
Study design: Treatment, Open Label, Pharmacokinetics Study
Detailed description:
Since the use of non-nucleoside reverse transcriptase inhibitors such as U-87201E has been
associated with the rapid development of resistant HIV isolates, an initial evaluation of
this drug in patients was made in combination with AZT. Because of the inability to detect
resistance after 6 weeks of combined AZT/U-87201E therapy, this protocol will initially
investigate U-87201E administered alone and then investigate the effect of this drug with AZT
and ddI or ddC.
Ten patients are treated at each of three targeted concentration ranges of U-87201E. Patients
in the second cohort are enrolled immediately after patients in the first cohort are accrued;
patients in the third cohort are enrolled when 5 of 10 patients in the second cohort have
tolerated that dose for at least 4 weeks. The MTD will be the dose below that which produces
dose-limiting grade 3 or 4 toxicity in five out of 10 patients. At least two women and five
antiretroviral naive patients must be enrolled in each dose concentration range. Patients
receive at least 8 weeks of monotherapy with U-87201E, with possible extension to at least 24
weeks with the same dose of U-87201E alone or in combination with zidovudine plus either ddI
or ddC. Patients are followed weekly for at least 8 weeks and, if applicable, at weeks 10,
12, 16, 20, and 24 and monthly thereafter, up to 1 month following the last dose. Patients on
combination therapy will have an indwelling venous catheter inserted for the first 2 days of
combination therapy. Per 10/15/93 amendment, if no MTD is established with the first three
cohorts, then 10 additional patients will be enrolled at a fourth concentration.
Eligibility
Minimum age: 13 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria
Concurrent Medication:
Allowed:
- PCP prophylaxis with pentamidine, TMP/SMX, or dapsone (if appropriate).
- Clotrimazole troches or nystatin oral suspension for oral candidiasis.
- Acyclovir (up to 1000 mg/day) for herpes lesions.
- Supportive care as deemed necessary for toxicities .
Patients must have:
- HIV infection.
- CD4 count <= 500 cells/mm3.
- No active opportunistic infections.
- Consent of parent, guardian, or person with power of attorney, if less than 18 years
of age.
NOTE:
- Participation of women in the study is encouraged.
Exclusion Criteria
Co-existing Condition:
Patients with the following symptoms and conditions are excluded:
- Acute medical problems, including opportunistic infections (e. g., active
cryptococcosis, Pneumocystis carinii, herpes zoster, histoplasmosis, and CMV) or
nonopportunistic diseases (e. g., liver or renal disease or lymphoma).
- Current diagnosis of malignancy for which systemic therapy would be required during
the study.
- Active gastrointestinal disorders.
Concurrent Medication:
Excluded:
- Investigational drugs.
- Systemic therapy for malignancy.
- Phenobarbital, phenytoin, ketoconazole, rifampin, rifabutin, cimetidine, beta
blockers, chronic antacids, antiarrhythmic agents, or other medications known to
affect cardiac conduction or seizure threshold.
Patients with the following prior conditions are excluded:
- History of any cardiovascular disease, including conduction disturbances, arrhythmias
or atherosclerotic heart disease.
- History of CNS disease such as seizure disorder, AIDS Dementia Complex, progressive
multifocal leukoencephalopathy, or any other active neurological disorder.
- History of chronic gastrointestinal disorders such as chronic diarrhea (> 4 weeks
duration).
Prior Medication:
Excluded:
- Antiretroviral or immunomodulator agents (such as AZT, ddI, ddC, interferon, etc.)
within 15 days prior to study entry.
- Cytotoxic chemotherapy within 1 month prior to study entry.
- Prior U-87201E or other non-nucleoside reverse transcriptase inhibitors (i. e.,
nevirapine, TIBO, L697,661).
Present use of alcohol or illicit drugs.
Locations and Contacts
Los Angeles County - USC Med Ctr, Los Angeles, California 900331079, United States
Univ of Miami School of Medicine, Miami, Florida 331361013, United States
St Louis Regional Hosp / St Louis Regional Med Ctr, St. Louis, Missouri 63112, United States
Univ of Rochester Medical Center, Rochester, New York 14642, United States
Ohio State Univ Hosp Clinic, Columbus, Ohio 432101228, United States
Julio Arroyo, West Columbia, South Carolina 29169, United States
Additional Information
Click here for more information about Zidovudine Click here for more information about Zalcitabine Click here for more information about Didanosine
Related publications: Demeter LM, Meehan PM, Morse G, Fischl MA, Para M, Powderly W, Leedom J, Holden-Wiltse J, Greisberger C, Wood K, Timpone J Jr, Wathen LK, Nevin T, Resnick L, Batts DH, Reichman RC. Phase I study of atevirdine mesylate (U-87201E) monotherapy in HIV-1-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Oct 1;19(2):135-44. Morse GD, Reichman RC, Fischl MA, Para M, Leedom J, Powderly W, Demeter LM, Resnick L, Bassiakos Y, Timpone J, Cox S, Batts D. Concentration-targeted phase I trials of atevirdine mesylate in patients with HIV infection: dosage requirements and pharmacokinetic studies. The ACTG 187 and 199 study teams. Antiviral Res. 2000 Jan;45(1):47-58.
Last updated: June 23, 2005
|
