THERAPY WITH A TAT ANTAGONIST FOR KAPOSI'S SARCOMA

Project: Research project

Description

Kaposi's sarcoma is not an uncommon complication of HIV disease. The
treatment of Kaposi's sarcoma is complicated by bone marrow toxicity,
opportunistic infections, progressive HIV disease, including progressive
immunodeficiency, increasing viral burden increasing virulence of HIV and
eventual failure of current anti-retroviral therapies. Treatments which
enhance suppression of HIV, immune function and focuses on the
pathogenesis of Kaposi's sarcoma are needed. Several single agent and
combination chemotherapy regimens result in tumor regression. Interferon
(IFN) alpha-2a has been associated with tumor responses, and in
combination with zidovudine (ZDV) may result in greater anti-tumor
responses at lower doses of IFN alpha-2a. The HIV-1 tat gen and the TAT
protein has been implicated in the pathogenesis of Kaposi's sarcoma. A
tat gene antagonist, Ro 24-7429, inhibits HIV in acutely and chronically
infected cells and is active against zidovudine-resistant strains. Thus,
Ro 24-7429 represents a novel approach for the treatment of patients with
HIV disease and Kaposi's sarcoma. Two phase I/II studies to evaluate the
role of combination therapies for patients with HIV-related Kaposi's
sarcoma are proposed. The first study is designed to extend the
observation that IFN alpha-2a and ZDV is useful in the treatment of
patients with HIV-related Kaposi's sarcoma by including a third drug, the
tat gene antagonist (Ro 24-7429), that inhibits HIV post transcription
and may inhibit specific cytokine function implicated in the pathogenesis
of Kaposi's sarcoma. The first phase I/II study proposed will evaluate
the safety, pharmacokinetic parameters and preliminary efficacy of
combination therapy with Ro 24-7429, IFN alpha-2a and ADV in patients
with earlier stages of HIV-related Kaposi's sarcoma. Two doses of Ro 24-
7429 will be tested (50 mg TID and 100 mg TID) and two doses of IFN
alpha-2a (4.5 MIU QD and 9.0 MIU QD). Pharmacokinetic studies will be
done week 1 and 12 to determine the pharmacokinetic disposition of Ro 24-
7429 when given with IFN alpha-2a and ZDV. Tumor responses will be
monitored. To further evaluate the anti-HIV activity of this
combination, changes in CD4+ cells, serum p24 antigen levels and copy
numbers of plasma HIV RNA by PCR will be evaluated. HIV+ supernatants
and PBMCs will be stored for future studies which could include
evaluation of mRNA in cells and resistance studies. The second study
will evaluate single agent chemotherapy, vinblastine, in the treatment
of patients with non-visceral Kaposi's sarcoma when given with Ro 24-7429
and monitor safety and tumor responses.
StatusFinished
Effective start/end date9/30/938/31/97

Funding

  • National Institutes of Health: $63,175.00
  • National Institutes of Health

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Kaposi's Sarcoma
HIV
Zidovudine
Therapeutics
Pharmacokinetics
Neoplasms
Safety
Drug Therapy
Vinblastine
Opportunistic Infections
Viral Load
Genes
Virulence
Ro 24-7429
HIV-1
Bone Marrow
interferon alfa-2a
RNA
Cytokines

ASJC

  • Medicine(all)