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A Phase I /II Study of the Protease Inhibitor Indinavir (MK-0639) in Children With HIV Infection


Phase 1
N/A
N/A
Not Enrolling
Both
Acquired Immunodeficiency Syndrome, HIV Infections

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Trial Information

A Phase I /II Study of the Protease Inhibitor Indinavir (MK-0639) in Children With HIV Infection


This is a phase I/II study to determine the safety and tolerance of the protease inhibitor
indinavir (MK-0639), alone and then in combination with HIV reverse transcriptase inhibitor
therapy in children with HIV infection. Indinavir sulfate (the capsule formulation) has
been shown to have potent antiviral activity and an acceptable safety profile in adults.
HIV-infected children who have not received prior antiretroviral therapy, and children who
have become refractory to prior therapy, or who have experienced toxicity to prior therapy,
will be included. In addition, we will explore viral and CD4 cell kinetics before starting
therapy and following exposure to antiretroviral agents.

The study will be conducted in three parts.

1. In order to help interpret the antiviral activity of indinavir, the virologic and
immunologic profile of children will be studied within 2 weeks prior to starting the
therapeutic part. For children who have never been treated, this will be before the
initiation of any antiretroviral therapy and for children who have already received
antiretroviral therapy, this will be done during the initial "wash-out" phase that is
routinely interposed between two different treatment regimens.

2. The initial 16 weeks of therapy will then evaluate the toxicities, pharmacokinetics,
and preliminary efficacy of single drug therapy with indinavir.

3. Subsequently, all children who are able to tolerate the combination of zidovudine and
lamivudine (i.e., have no prior history of intolerance to one of these two agents) will
be treated with these two reverse transcriptase inhibitors in addition to the protease
inhibitor indinavir. Zidovudine and lamivudine will be added after 16 weeks at a fixed
dosage. Toxicity, pharmacokinetics, and preliminary efficacy of indinavir will also be
investigated after combination therapy. All patients who wish to remain in this study
after 96 weeks of therapy and who do not meet off study criteria will be permitted to
receive extended treatment with their current indinavir combination therapy for an
additional 48 weeks. The study will determine the pharmacokinetic profile of indinavir,
given as single drug or in combination with zidovudine and lamivudine. It will assess
the preliminary antiviral and clinical activity by monitoring clinical status, viral
burden in plasma, and markers of immunologic status. Based on safety and preliminary
efficacy results from studies performed in adults, we will study three dose levels
which are expected to result in drug levels above the IC95 of HIV-1 for all or most of
the dosing interval.

Inclusion Criteria


Age - six months to 18 years.

PREVIOUSLY UNTREATED OR MINIMALLY TREATED PATIENTS:

Asymptomatic HIV-infected children with an age-corrected absolute CD4 count that renders
them at possible risk for an AIDS-related opportunistic infection, or;

Children with moderate to severe symptomatic HIV infection as defined by the CDC
classification.

Absence of active opportunistic infection requiring acute intervention at the time of
entry.

Prophylaxis for PCP with trimethoprim/sulfamethoxazole or pentamidine at the time of entry
will be allowed.

Availability of a parent or legal guardian to give informed consent and who is deemed
sufficiently reliable to return for the child's follow-up visits.

PREVIOUSLY TREATED PATIENTS WITH REFRACTORY DISEASE OR INTOLERANCE TO PRIOR THERAPY:

HIV-infected patients who have been previously treated with one or more dideoxynucleosides
(zidovudine, didanosine, lamivudine, stavudine, zalcitabine) or another protease inhibitor
(will be analysed separately) and have experienced either a withdrawal grade toxicity or
refractory disease evidenced by progressive clinical immunological deterioration.

Availability of a parent or legal guardian to give informed consent and who is deemed
sufficiently reliable to return for the child's follow-up visits.

ALL CHILDREN:

Must not be critically ill or clinically unstable.

Patients receiving treatment for an acute infection must have been on stable therapy for
at least 7 days prior to entry on study.

MUST NOT HAVE ONE OR MORE OF THE FOLLOWING LABORATORY FINDINGS (WITHIN 2 WEEKS OF ENTRY
AND NOT YET RESOLVED):

Total WBC count less than 1500 cells/mm(3).

Neutrophil plus band count less than 750 cells/mm(3).

Hemoglobin less than 8.0 g/dl (history of recent transfusion is not an exclusion).

Platelet count less than 500,000/mm(3).

Creatinine greater than 2 times the upper limit of normal.

Liver transaminase greater than 3 times the upper limit of normal.

Bilirubin greater than 1.5 mg/dL.

Hematuria.

Because of the possibility for an increased risk of kidney stone formation patients must
not have severe recurrent or persistent diarrhea, or a family history of kidney stones.

Patients must not have received, within 30 days prior to entry, therapy with
immunomodulating agents (interleukin-2, interferons, growth hormone, IGF-1, or other
biological response modifier), cytolytic chemotherapeutic agents, radiation therapy.

Stable (e.g., for greater than 4 weeks prior to entry) corticosteroids therapy for the
treatment of lymphocytic interstitial pneumonitis or an autoimmune process or stable
therapy with G-CSF (Neupogen) at the same dosage for at least 4 weeks are acceptable.

Must not have an active opportunistic infection requiring acute intervention.

Women must not be pregnant or breast feeding.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Primary Purpose: Treatment

Authority:

United States: Federal Government

Study ID:

950163

NCT ID:

NCT00001443

Start Date:

July 1995

Completion Date:

October 2000

Related Keywords:

  • Acquired Immunodeficiency Syndrome
  • HIV Infections
  • AIDS
  • Bioavailability
  • Immunologic Evaluations
  • Pharmacokinetics
  • Toxicity
  • Acquired Immunodeficiency Syndrome
  • HIV Infections
  • Immunologic Deficiency Syndromes

Name

Location

National Cancer Institute (NCI)Bethesda, Maryland  20892