Bulletin of Experimental Treatments for AIDS, No. 30; September, 1996
Leslie Hanna

For further information about individual listings, call the number provided or call the AIDS Clinical Trials Information Service (ACTIS), toll-free, at 800-874-2572 (800-TRIALS-A).

Treatment for HIV Infection

*AZT cessation and effect on viral load

ACTG 304 is a multicenter study that will evaluate the effects on viral load of temporarily suspending AZT monotherapy. As more antiretroviral drugs become treatment options, at least in clinical trials, more and more people with HIV are being required to undergo washout periods. That is, people are required to stop taking their current antiretroviral regimens for a period before beginning a new one, in order to obtain a drug-free viral load. However, the time it takes for drugs to properly wash out is not clearly known. This study will examine viral load fluctuations over a 28-day washout period. Eligible persons have 500 or fewer CD4 cells/mm3, at least 12 months of prior AZT use, 2 months of continuous AZT monotherapy before study entry, and must not have had any vaccinations within 1 month before beginning the study.

*Early infection: the Options Project

Researchers at San Francisco General Hospital (SFGH) recently began an effort to identify, recruit and treat with a 3-drug regimen (AZT, 3TC and indinavir) newly infected people with HIV. For details, see article in this issue.

*F-ddA

Sponsored by the National Cancer Institute (NCI), this 8-week Phase I study will evaluate the safety, tolerance, pharmacokinetics and antiviral potential of F-ddA. Different doses will be tried in an escalating pattern until the maximum tolerated dose is established. Eligible participants have 100-400 CD4 cells/mm3 and symptomatic HIV disease or AIDS, but have not had hepatic cirrhosis, heart disease or pancreatitis. Current use of foscarnet or ganciclovir is prohibited.

*Filgrastim (G-CSF) and stem cell harvesting

ACTG 285 is a 24-week pilot study of the safety of stem cell harvesting, after taking granulocyte colony-stimulating factor (G-CSF) to mobilize bone marrow stem cells. Participants will be randomized to receive 7 daily subcutaneous injections of 10 mcg/kg G-CSF. Doses may be raised to 20 mcg/kg. On days 5 and 6 of G-CSF administration participants will have leukapheresis (peripheral blood mononuclear cell harvesting). Participants will be stratified by CD4 cell count and clinical health. There are various requirements based on CD4 cell count, e.g., persons with greater than 500 CD4 cells/mm3 must be asymptomatic and must not have used antiretroviral therapy in the past 60 days. Prior malignancy, active alcohol or illicit substance use and central nervous system (CNS) disease or seizures within the past year are not allowed.

*Nelfinavir (Viracept) and nucleoside analogs

This study will evaluate nelfinavir, Agouron s protease inhibitor, in combination with nucleoside analogs in people with 100 or fewer CD4 cells/mm3. Participants will be randomized to either continue on the stable regimen of nuceloside analogs they are already taking, or switch to a new regimen of nuceloside analogs. Nuceloside analogs include AZT, ddI, ddC, d4T and 3TC. All participants will take 750 mg of nelfinavir, 3 times daily, and must already be on a stable nucleoside regimen. There are 9 study sites (Berkeley, Chicago, Dallas, Fort Lauderdale, Los Angeles, New York City [2], San Francisco and St. Paul); for more information, call 800-501-2474, extension 1.

*141W94, AZT and 3TC

This study will compare the safety, tolerability and efficacy of different dosing regimens of 141W94 in combination with AZT and 3TC. All participants take 3TC and AZT, and will be randomized to 4 treatment arms to receive either one of 3 doses of 141W94 or placebo. The study lasts 12 weeks, and may be extended for an additional 12 weeks. Eligibility criteria include having at least 150 CD4 cells/mm3, a viral load by PCR of at least 10,000 copies/mL, no prior treatment with 3TC or protease inhibitors and no active opportunistic infections (OI). In the San Francisco Bay Area, call ViRx at 415-353-5623.

*1592U89 and other antiretroviral therapy

This open-label study evaluates the safety, tolerability and antiretroviral activity of 1592U89 when used in combination with other antiretroviral drugs. All participants will add 300 mg 1592U89 to their current antiretroviral regimen, such as AZT, ddI, ddC, d4T or 3TC. The 24-week study is open to people with 100 or more CD4 cells/mm3, a viral load of 30,000 copies/mL or more and a history of antiretroviral use. In the San Francisco Bay Area, call ViRx at 415-353-5623.

*Ritonavir (Norvir), 3TC and AZT in moderately advanced HIV disease

ACTG 315 is a 48-week, open-label pilot study of the efficacy of a potent triple combination antiretroviral regimen in persons with moderately advanced HIV disease. Participants will first undergo a 5-week antiretroviral washout period and then will take ritonavir for 9 days, before adding 3TC and AZT. Eligible persons have 100-300 CD4 cells/mm3 and have had at least 3 months of prior AZT use. Active OIs are not allowed, nor is a history of pancreatitis within the past 2 years, nor prior use of either 3TC or protease inhibitors. Thalidomide and rifabutin, as well as other drugs contraindicated with ritonavir, are not allowed.

*Saquinavir (Invirase), hard and soft capsules, and indinavir (Crixivan)

ACTG 333 is a Phase II multicenter study of the antiviral effect in people who have been taking the original, hard-capsule formulation of saquinavir, who switch to the newer, soft-gelatin capsule formulation or switch to indinavir, Merck's protease inhibitor. Objectives of the study include learning whether switching will decrease viral load (plasma HIV RNA) and evaluating antiretroviral activity in sequential use of protease inhibitors. The study will randomize persons who have taken 1,800 mg/day of hard-capsule saquinavir for at least one year to (1) continue taking hard-capsule saquinavir, (2) switch to soft-gelatin capsule saquinavir, or (3) switch to indinavir. After 8 weeks, the people randomized to continue receiving hard caps will switch to open-label indinavir for the next 4 months. People randomized to the other 2 arms will either continue on assigned therapy or, if they have had no virologic response by week 8, will cross-over to open-label treatment with the alte! rnate drug. The study lasts 6 months.

*SPC3

This Phase I/II clinical trial is the first U.S. trial of SPC3, a multichain peptide designed to block HIV from attaching to cell receptors, thereby preventing it from entering cells. The study will evaluate the safety and efficacy of different doses of SPC3 for lowering blood levels of HIV. Laboratory studies indicate that SPC3 blocks cell infection by diverse strains of HIV, including AZT-resistant HIV. Since SPC3 binds to the cell rather than to the virus, HIV is not expected to be able to develop resistance to it. All participants receive active drug for 3 weeks, at either the 20 mg or 40 mg daily dose level. Higher doses may be tried, depending on preliminary results. Drug is administered intravenously for 1 to 2 minutes; participants are monitored after receiving the drug. Eligible participants have 100 or more CD4 cells/mm3, have been on any antiretroviral treatment regimen for at least 8 weeks (or no treatment), have a viral load by RNA PCR of at least 10,000 copies/! mL, and have no clinically active AIDS-defining OIs or tumor. Available only at Roger Williams Medical Center in Providence, RI; call Grace Accetta, RN, or Gail Skowron, MD, at 401-456-2437.

*Treatment for Opportunistic Infections

Cryptosporidiosis: BIC-C parvum

This Phase II study will randomize participants with cryptosporidiosis to receive 4 daily doses of a powder formulation of BIC-C parvum (bovine immunoglobulin concentrate-C. Parvum) or placebo for 4 weeks. Cryptosporidiosis must be diagnosed by stool or biopsy culture, and participants must have diarrhea. Par-ticipants also must have 180 CD4 cells/mm3 or fewer and must not have active CMV colitis. In Los Angeles, call Jennifer Ida at Tower Infectious Diseases at 310-358-2300, extension 228.

Cytomegalovirus (CMV) retinitis: natural history

This NIAID study, in its current incarnation, is a modification of an earlier study that would have evaluated asymptomatic CMV viremia (when CMV is present in the blood but before disease symptoms have developed) and its response to oral ganciclovir. Since enrollment began, oral ganciclovir has been dropped from the study, and now, participants will be followed with regular viral load tests for CMV, over 9 weeks, to evaluate several PCR methods of measuring CMV viral load and also to look at fluctuations.

CMV retinitis: ganciclovir and neupogen (Amgen)

This open-label Phase I study will involve increasing the dose of ganciclovir to maximum levels for each individual. Additional doses of filgrastim will be taken to protect neutrophil counts. Persons with active CMV retinitis must have finished a 2-week induction course with ganciclovir. In Los Angeles, call Connie Olsen at LAC-USC at 213-343-8279.

Treatment for Malignancies and Cancers

Kaposi's sarcoma (KS): Virulizin

In Montreal, Canada, a phase I/II trial of Virulizin for treating drug-resistant KS has begun. Laboratory studies indicate that Virulizin stimulates macrophages (immune system white blood cells) to kill tumors; data in people with KS receiving the drug through a compassionate use program indicates clinical response. The trial will evaluate the anti-tumor activity of the drug in people with HIV, KS and extreme immunosuppression, by evaluating tumor response, survival and quality of life in 16 participants. The trial is conducted by Dr. Christopher Tsoukas at the Immune Deficiency Treatment Center at Montreal General Hospital.

KS: oral thalidomide

Sponsored by the NCI, this Phase II study will evaluate the safety, pharmacokinetics and efficacy of oral thalidomide in people with KS. Since thalidomide has been shown to inhibit angiogenesis (growth of blood vessels), one of the main ways KS develops, it may inhibit KS tumor growth. Eligible participants have KS outside the lungs that has progressed over the 2 months prior to study entry but is not life-threatening. Grade 2 or worse peripheral neuropathy is not allowed. Thalidomide is taken daily, orally, at 200 mg, to be increased by 200 mg every 2 weeks to a maximum of 1,000 mg. Treatment lasts for at least 6 months, and may be continued for an additional 6.

Treatments for Wasting Syndrome and Myopathy

Nutritional supplements

This prospective, double-blind Phase IV trial will compare the effects of oral nutritional supplements with different fat contents on lean body mass, weight and quality of life in people with AIDS. The goal is to determine which type of supplement is more effective for promoting weight gain; other studies have shown that supplements containing fat in the form of medium-chain triglycerides may be better absorbed and cause less gastrointestinal distress than standard, long-chain triglyceride supplements. Participants are randomized to receive either Lipisorb (medium-chain triglycerides) or Sustacal PLUS (long-chain triglycerides). Both are liquid nutritional supplements that come in 8 oz. cans, 3 of which are used daily. Treatment duration and follow-up last 6 months each. Participants must be clinically stable, have equal to or less than 100 CD4 cells/mm3, and must not be taking ganciclovir, appetite stimulants, corticosteroids or anabolic agents. Quality of life questionnaires and bioimpedance analysis (BIA) will be used. There are several trial sites.

Immune Enhancement

Epithyme

This is a Phase I study of epithyme in severely immunocompromised people with HIV. The drug is taken by subcutaneous injections. The study is open to people with 100-250 CD4 cells/mm3. Antiretroviral use is permitted as long as the person has been on a stable regimen for at least 2 months. In Los Angeles, call Corie Castro 310-358-2429.

Gene therapy in identical twins

This Phase I/II NIAID pilot study will evaluate the safety, efficacy and immunotherapeutic effects of a gene therapy for AIDS. This treatment involves removing CD4 cells from an HIV negative identical twin and transfusing them into the HIV positive twin. Before transfusion, cells are expanded in culture and genetically altered with anti-HIV genes (antisense tar and transdominant rev) that, ideally, will provide intracellular protection against HIV. The cells are intravenously infused, then monitored through blood studies to see how long they live. A total of 4 infusions will be given during the 12-month study. The HIV negative twin must be healthy and seronegative for CMV or Epstein-Barr virus (EBV) if the other twin is, and negative for hepatitis B and C. The HIV positive twin must have greater than 50 CD4 cells/mm3, must not ever have had lymphoma and must not be undergoing systemic KS treatment.

Interleukin 2 (Aldesleukin) and standard-of-care antiviral therapy

This Phase II multicenter open-label study will evaluate the tolerability, toxicity and utility of subcutaneous interleukin 2 (IL-2) plus antiviral therapy vs antiviral therapy alone. Participants take antiviral therapy for at least 2 weeks before beginning the study, then are randomized to receive IL-2 or no IL-2 every 8 weeks. Participants are followed every 4 weeks for 14 months. Eligible persons have 200-500 CD4 cells/mm3, no history of AIDS-defining OI, no prior use of IL-2 and no use of systemic corticosteroids or chemotherapy within the month prior to entry.

Perthon/Abavca

Advanced Plant Pharmaceuticals Inc., manufacturer of Perthon/Abavca, is sponsoring a Phase II clinical trial at Albert Einstein College of Medicine. Perthon/Abavca is a "whole plant" pharmaceutical, with FDA-approved Investigational New Drug (IND) status. This study will evaluate it as an immune system booster, to see if it can delay time to AIDS and increase survival.

Children and Adolescents

Accessing experimental therapies not in pediatric trials

Although most adult studies are only open to persons over the age of 18 years, several adult studies now also include adolescents 13-17. Representatives at 1-800-TRIALS-A can identify which adult studies permit adolescents.

HIV infection: bis-POM PMEA

ACTG 310 is a Phase IA multicenter study of the safety, toxicity and pharmacokinetics of a single dose of the antiviral drug bis-POM PMEA in children. The study will determine age-related dose differences for children, and try to establish a dosage to be studied in multiple doses. Participants will be stratified by age to receive either a single 1.5 or 3.0 mg/kg dose. The lower dose is given to children aged 3 months to 17 years, first; if this dose is acceptable, the higher dose will be tried. Blood levels will be monitored for 8 hours following administration. Children aged 1 day to 17 years are eligible, with any CD4 cell count, but they must be either asymptomatic or only mildly symptomatic.

HIV infection: ritonavir (Norvir)

This is a Phase I/II study to determine the safety, tolerance and pharmacokinetics of 4 doses of a liquid formulation of Abbott s protease inhibitor, ritonavir, alone and in combination with AZT and/or ddI. Antiviral and clinical efficacy will be determined by monitoring viral load and clinical status in 2 age groups. The study has 3 parts: pre-treatment evaluation, 12 weeks of treatment at 4 dose levels, then a combination phase where AZT or ddI will be added, or ritonavir monotherapy continued, if the participant has a history of intolerance to both AZT and ddI. There is a long list of drugs that cannot be used concurrently. Call the NCI at 301-402-1391/1387.

Lymphoproliferative disorders: all-trans-retinoic acid and interferon-alpha

This study of the natural course of lymphoproliferative disorders in children with HIV has 2 parts: an observation period, without intervention, and a 6-month treatment period with all-trans-retinoic acid and interferon-alpha, as well as antiretroviral therapy. The 48-week study requires tissue biopsy at entry and after 12 weeks. Treatment can be repeated if the child declines after treatment ends. Children with rapidly growing, previously untreated malignant lymphomas are excluded. Call the NCI at 30 1-402-1391/1387.

Oral candidiasis: cyclodextrin itraconazole

This multicenter, open-label study will evaluate 2 doses of cyclodextrin itraconazole (CD-itraconazole) for treating oral candidiasis, including refractory cases. Participants take the drug for 15 days, then are on follow-up for another week. If the child benefits from the drug, she or he may continue for another 5 months, with monthly evaluations. The study is open to children aged 6 months to 18 years, with culture-proven Candida and clinical symptoms. Children with a history of azole intolerance are excluded, as is the concurrent use of several other drugs. Call the NCI at 301-402-1391/1387.

Varicella-zoster virus (VZV) disease: BV-ara-U (Sorivudine)

This Phase I study will evaluate the safety, tolerance, pharmacokinetics and efficacy of BV-ara-U in children with VZV of the skin, viscera or eyes, who have failed on or are intolerant of the standard treatments, acyclovir or foscarnet. In laboratory studies, BA-ara-U appears 1,000 times more active against VZV than acyclovir. Participants will receive 1 dose daily of oral BA-ara-U. The study is open to children under 18 years of age who weigh 15 kg or more, with documented VZV infection and a clinical history of continuous or recurrent VZV despite full-dose, standard therapy. Exclusion criteria include use of 5FC or 5FU, high-dose prednisone or probenecid. Call the NCI at 301-402-1391/1387.

Varicella vaccine (Varivax)

ACTG 265 is a Phase I/II study of the safety and immunomodulating potential of a live-attenuated vaccine against VZV in children with HIV. Infection with VZV (chickenpox) can be extremely hazardous, often involving complications, in children with HIV. Children who are VZV-naive and who have not been exposed to either chickenpox or shingles will receive Varivax vaccinations at weeks 0 and 12, with possible boosts at week 52 if they are still negative for VZV as well as CMV.

Women

Oral isotretinoin for low-grade cervical dysplasia

ACTG 293 is a Phase III multicenter trial of oral isotretinoin (Accutane) versus observation for low-grade cervical dysplasia (CIN I), to evaluate whether it may be more beneficial to wait to see if lesions resolve without treatment, or to use oral isotretinoin to prevent lesions from progressing in severity, in women with HIV. Participants will be randomized to receive oral isotretinoin for 6 months or to be observed only, with 12 additional months of follow-up. Eligible women have biopsy-proven grade I CIN; the biopsy must have been performed within the past 3 months. Participants must be at least 13 years old and not pregnant. Exclusion criteria include malignancies requiring chemotherapy within the past 3 months, hysterectomy within the past 4 months and prior treatment for grade II or higher CIN. Neither tetracycline nor vitamin A may be taken at the same time as isotretinoin.

Miscellaneous

SNX-111 for chronic pain

FDA 256A is a multicenter Phase II/III study of the safety and efficacy of different doses of SNX-111, a calcium channel blocker, for controlling severe, chronic pain. The drug is administered intrathecally, which involves inserting a catheter into the spinal canal. Participants will receive drug or placebo, both administered intrathecally. People who respond to their treatment after 5 days will continue at home for another 5; those who do not respond will be switched to the other regimen for the next 5 days. After the first 10 days, responding participants will have a permanent pump implanted under the skin for long-term administration. Eligible participants may have any CD4 cell count, but have chronic pain related to HIV or cancer which has not been satisfied by opioid treatment, either because side effects have been intolerable or pain has not been relieved.

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