Trial Information

A Prospective Randomized Trial Comparing the Response of HIV Kaposi's Sarcoma (KS) to HAART Versus the Combination of HAART and Chemotherapy (CXT)

DETAILED METHODOLOGY

PRIMARY OBJECTIVES:

1.To compare the clinical response of HIV KS at month 12 in patients treated with HAART
alone with those treated with the combination of HAART and chemotherapy (CXT).

SECONDARY OBJECTIVES

1. To monitor safety, tolerance and adverse events associated with each regimen.

2. To compare the impact of each regimen at baseline and months 12 on:

1. CD4 count

2. HIV1 viral load in blood

3. HIV disease progression

3. To compare the impact of each regimen on the patients Quality of life (QOL).

4. To compare the impact of each regimen on the patients adherence to HAART. 5 To measure
and compare HHV8 viral load and HHV8 specific CTL responses at baseline and month 12 to
each regimen.(in blood and tissue specimens )

DESIGN Prospective, randomized, open- labeled trial

RANDOMISATION Patients first staged into GOOD risk and POOR risk groups according to ACTG
criteria. Thereafter 4 digit computer generated numbers after staging which assign patients
to HAART alone or HAART plus CXT to ensure that equal numbers of GOOD and POOR risk patients
are assigned to each group.

INCLUSION CRITERIA

- Signed informed consent

- Adults > 18 years

- Documented HIV positive status (Confirmed by two ELISAs and HIV-1 RNA testing)

- Willingness to use a barrier method of birth control throughout the course of the
study, because of potential drug interactions that make oral contraceptives less
effective (for women of childbearing potential) and sexually active males

- Histologically proven

- At least five measurable, previously unirradiated cutaneous lesions must be present
which can be used as indicator lesions.

- ECOG performance status 0-2

EXCLUSION CRITERIA

- Pregnancy or breastfeeding

- Fungating tumors of KS

- Symptomatic pulmonary KS

- Symptomatic GI tract KS

- Clinical evidence of peripheral neuropathy

- Clinical evidence of heart disease

- Total neutrophil count of < 1,000u/L, Hemoglobin < 9.0gm/dl or platelet count of <
75,000u/L; serum creatinine > 1.5mgh/dl, direct serum bilirubin > 85 umol/l, AST or ALT
> 2.5 time ULN.

- Prior HAART ( to fairly evaluate antiretroviral response and KS response to HAART,
patients should be antiretroviral naïve)

- Prior radiation therapy for KS to sites of indicator lesions.

- Prior cytotoxic chemotherapy for KS.

- Concurrent neoplasia requiring cytotoxic therapy.

- Life expectancy of < 3 months.

- Circumstances, which in the opinion of the investigator make it unlikely the patient,
can comply with the safety monitoring required for participation in this trial.

INTERVENTION Arm 1. HAART These patients will be given one tablet twice daily of Triomune®
(Cipla, Mumbai) Stavudine 40mg b.d > 60 kg , 30mg bd <60kg Lamivudine 150mg b.d >
50 kg 2mg/kg < 50 kg Nevirapine 200mg b.d ( 200mg daily for first 2 weeks)

Arm 2. CTX PLUS HAART HAART will be given as above. In addition, CTX will be administered at
2 weekly intervals in the Oncology Dept at KEH VIII Hospital and will consist of:-
Intramuscular Bleomycin 10 U/m2 ; Intravenous Vincristine 1.4mg/m2 maximum 2mg and
Intravenous Doxorubicin 20mg/m2.

This regimen will be given at 2 weekly intervals. This will be supplied by the Department of
Oncology, KwaZulu Natal Province.

PRIMARY ENDPOINTS

1. Clinical response of KS

- Clinical photographs taken of marker lesions (5 according to AMC criteria) will be
taken at baseline, month 6 and 12.

- Lesion measurement of 5 marker lesions (as per AMC RKS 02 )(www.amc.uab.edu) will
be done at baseline, month 3, month 6, month 9 and month 12. Responses will be
categorized as complete response(only with biopsy confirmation), complete clinical
response, partial response, stable disease and disease progression according to
ACTG criteria.

- The patients will be assessed by a specialist dermatologist, trained to use the
above instruments, and will be the same individual so as to decrease bias
introduced with inter-observer variability. We recognize that there is the
potential for bias as the study is not blinded and dermatologist will know patient
assignment. For that reason, we are using established objective criteria to
evaluate response.

- Biopsies will be performed at baseline, month 6 and month 12 to assist in
confirming response and to evaluate HIV and HHV8 tissue viral loads

2. Safety and toxicity by DAIDS Toxicity criteria

3. QOL by EORTC QLQ C30

4. Adherence by 7 day adherence questionnaire Adherence will be measured using a
standardized validated self administered questionnaire, which enables review of each
medication during previous 7 days and a medication specific and overall adherence
score.