Conditions: HIV-1 Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 334
Healthy volunteers: no

Brief summary:
This study was done to compare the safety and efficacy of three combination treatments for Kaposi's Sarcoma (KS) and AIDS:

1. Etoposide (ET) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) (ET+ART),
2. Bleomycin and Vincristine (BV) plus co-formulated EFV/FTC/TDF (BV+ART),
3. Paclitaxel (PTX) plus co-formulated EFV/FTC/TDF (PTX+ART).

Detailed description:
The study consisted of four steps. Study duration was up to 240 weeks.

At the study Step 1 entry, participants were randomized with equal probability to each of the three regimens (ET+ART, BV+ART, PTX+ART). The original target sample size was 706. Randomization was stratified by:

1. Screening CD4 lymphocyte cell count (\<100, \>=100 cells/mm³), and
2. Country.

For participants who had an initial Independent Endpoint Review Committee (IERC) confirmed KS response and subsequent IERC-confirmed KS progression, and who, in the opinion of the investigator and with concurrence of the protocol Clinical Management Committee (CMC), could potentially have benefitted from another course of the same chemotherapy utilized in Step 1, entered Step 2. (Please see details on Step 2 eligibility.)

In Step 3, participants were randomized with equal probability to one of the two chemotherapy arms not utilized in Step 1. (Please see details on Step 3 eligibility.)

In Step 4, participants were assigned to the remaining study-provided chemotherapy not given in Step 1, Step 2 or Step 3. (Please see details on Step 4 eligibility.)

Step 1 visits occurred at screening, entry and weeks 3, 6, 9, 12, 15, 18, 21,24, 27, 30, 33, 36, 39, 42, 45, 48, 60, 72, 84 and 96 from study entry. Visits for Steps 2, 3 and 4 were scheduled at entry and weeks 3, 6, 9, 12, 15, 18, 21,24, 27, 30, 33, 36, 39, 42, 45, 48, 60, 72, 84 and 96 from the corresponding step entry date. Key evaluations included targeted physical examination, clinical assessment, KS examination, hematology, chemistry, pregnancy testing (for women of reproductive potential), and pulse oximetry for participants on BV+ART. CD4 count and HIV viral load were obtained every 12 weeks. Assessment of peripheral neuropathy was done at screening, weeks 9 and 21, and for those on BV+ART or PTX+ART, additionally at weeks 3, 6, 15 and 18. KS tumor punch biopsy, serum, plasma and peripheral blood mononuclear cells (PBMCs) were obtained and stored for use in future analyses. Participants also completed ET and ART adherence evaluations and quality of life questionnaires.

Enrollment to ET+ART and initiation of ET+ART in subsequent steps were discontinued in March 2016, based on the recommendation of the Data and Safety Monitoring Board (DSMB) due to ET+ART being less effective than PTX+ART. No safety concerns were identified. ET+ART participants in Step 1 or Step 2, in discussion with the local investigator and in consultation with the protocol CMC, could discontinue ET and enter Step 3. ET+ART participants in Step 3 could discontinue ET and start the remaining chemotherapy regimen in Step 4 in discussion with the local investigator and in consultation with the protocol CMC. Unless otherwise indicated, comparison between ET+ART and PTX+ART was based on the March 2016 data. The study remained open to enrollment and the remaining participants were randomized at Step 1 entry between BV+ART and PTX+ART. The target total sample size was revised to 446.

The DSMB recommended stopping the study in March 2018 due to BV+ART being inferior to PTX+ART. No safety concerns were identified. Study accrual was stopped. Eligible Step 1 PTX+ART participants entered Step 2 to receive PTX+ART; Step 1 and Step 2 BV+ART participants eligible to receive PTX+ART moved to Step 3 to receive PTX+ART. Otherwise, participants permanently transitioned to local care upon arrangement of appropriate oncology and ART, and then went off study. Participants who received ET while on study were followed for 144 weeks after beginning the last cycle of ET.

Comparison between BV+ART and PTX+ART was based on the March 2018 data.

Arms:
arm 1: Etoposide (ET) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) arm 2: Bleomycin and Vincristine (BV) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) arm 3: Paclitaxel (PTX) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)

Interventions: intervention 1: Etoposide (ET) intervention 2: Bleomycin and Vincristine (BV) intervention 3: Paclitaxel (PTX) intervention 4: Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)
Intervention descriptions: intervention 1: Beginning on day one of the chemotherapy cycle, ET was given orally in a dose of 50 mg twice daily for 7 consecutive days for the first cycle. If there was no Grade \>= 2 toxicity attributable to ET after the first cycle, the dose was escalated to 150 mg daily for 7 days in divided doses of 100 mg/50 mg for the second cycle. After the second cycle, if there was no Grade \>= 2 toxicity attributable to ET, the dose was escalated to 100 mg twice daily for 7 days for the third and subsequent cycles.

Treatment with ET was continued for six cycles at the maximum dose achieved or until toxicity requiring discontinuation of study chemotherapy, or the site investigator, after consulting with the protocol CMC, had determined that alternative therapy is required, whichever occurs first. intervention 2: BV was administered on day one of each chemotherapy cycle.

Vincristine sulfate was administered at a dose of 2 mg (fixed dose) in a volume of 2 mL over 1 minute into the sidearm of a rapidly flowing intravenous infusion every 3 weeks. The vincristine infusion was followed by bleomycin as detailed below.

Bleomycin sulfate was administered at a dose of 15 units/m\^2 over 10 minutes every 3 weeks.

Treatment with BV was continued for six cycles, or until toxicity requiring discontinuation of study chemotherapy, or the site investigator, after consulting with the protocol CMC, had determined that alternative therapy is required, whichever occurs first. intervention 3: Paclitaxel was administered by IV infusion in 200 mL, 250 mL, or 500 mL of 5% dextrose or 0.9%Sodium Chloride for injection at a dose of 100 mg/m\^2 body surface area (BSA) every 3 weeks. intervention 4: The following ART regimens were used:

1. EFV/FTC/TDF (Atripla) 200 mg/300 mg/600 mg orally once daily at bedtime or
2. FTC/TDF 200 mg/300 mg (Truvada) orally once daily at bedtime plus EFV (Stocrin) 600 mg orally once daily at bedtime or
3. FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus nevirapine (NVP) 200 mg orally twice daily or
4. FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus PI/r at standard dosing or
5. FTC/TDF 200 mg/300 mg (Truvada) orally once daily plus integrase inhibitor at standard dosing

Protocol document:
Prot_ICF_000.pdf: 
 
 
A5263/AMC066 
 
Randomized Comparison of Three Regimens of 
Chemotherapy with Compatible Antiretroviral 
Therapy for Treatment of Advanced AIDS-KS in 
Resource-Limited Settings 
 
A Multicenter Trial of the AIDS Clinical Trials 
Group (ACTG) 
 
And 
 
AIDS Malignancy Consortium (AMC) 
 
 
DAIDS ES # 10724 
 
 
This file contains the current ACTG A5263/AMC066 
protocol, which includes the following documents:  
 
 Letter of Amendment #2, dated 11 June 2018 
 Letter of Amendment #1, date 8 February 2018 
 Protocol Version 3.0, dated 7 December 2016 
 


 
Letter of Amendment #2 
Page 1 of 13 
11 June 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
 
Letter of Amendment #2 for: 
 
A5263/AMC066 
 
Randomized Comparison of Three Regimens of Chemotherapy with Compatible 
Antiretroviral Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings 
 
A Limited Center Trial of the AIDS Clinical Trials Group (ACTG) 
 
And 
 
AIDS Malignancy Consortium (AMC) 
 
DAIDS ES # 10724 
 
Letter of Amendment Date: 11 June 2018 
 
 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc.  
 
 
 
Phone: (301) 628-3000 
8757 Georgia Avenue, 12th Floor 
 
 
 
 
Fax: 
(301) 628-3302 
Silver Spring, MD  20910 
 
 
LETTER OF AMENDMENT 
 
 
DATE:  
June 11, 2018 
 
TO: 
 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
 
FROM: 
A5263/AMC066 Protocol Team  
 
SUBJECT: 
Letter of Amendment #2 for Protocol A5263/AMC066, Version 3.0, 12/07/16, 
entitled, “Randomized Comparison of Three Regimens of Chemotherapy with 
Compatible Antiretroviral Therapy for Treatment of Advanced AIDS-KS in 
Resource-Limited Settings” 
 
The following information affects the A5263/AMC066 study and must be forwarded to 
your institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This Letter of Amendment (LOA) must be approved by your 
IRB/EC before implementation.  
 
The following information may also affect the Sample Informed Consent. Your IRB/EC is 
responsible for determining the process of informing participants of the contents of this 
LOA. 
 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this 
LOA, sites should implement the LOA immediately. Sites are still required to submit an 


 
Letter of Amendment #2 
Page 2 of 13 
11 June 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
LOA registration packet to the DAIDS Protocol Registration Office (PRO) at the 
Regulatory Support Center. Sites will receive a registration notification for the LOA once 
the DAIDS PRO verifies that all required LOA registration documents have been received 
and are complete. An LOA registration notification from the DAIDS PRO is not required 
prior to implementing the LOA. A copy of the LOA registration notification, along with 
this letter and any IRB/EC correspondence, should be retained in the site’s regulatory 
files. 
 
The following are changes to A5263/AMC066, Version 3.0, 01/05/16 (changes are noted in bold 
or strikethrough). 
 
The NIAID DAIDS Co-Infections and Complications Data and Safety Monitoring Board (DSMB) 
met on March 13, 2018 to review safety and efficacy data from the A5263/AMC066 study. The 
DSMB recommended that A5263/AMC066 be stopped because the bleomycin/vincristine arm 
was inferior to the paclitaxel arm when the primary composite endpoint was evaluated. No 
safety concerns were identified. The DSMB made the following recommendations: 
1. The DSMB recommends stopping the study. The information at this interim analysis show 
that conclusions that can be made from this study at the current time will change little even if 
the study were continued to the end. The current statements that can be made about the 
two treatment arms are scientifically solid and important, and it is important to disseminate 
the results as soon as possible.  
2. The study team should develop a plan to offer paclitaxel to patients who are currently on the 
study.  
 
To achieve recommendation #2, the team has developed a table that describes options for 
participants currently on study treatment in A5263/AMC066. This table is attached for reference 
as Appendix I. The protocol has been minimally changed to implement this table; therefore, only 
minimal edits are included in this LOA.  
 
The following are changes (noted in bold font and strikethrough) to A5263/AMC066, Version 
3.0, 12/07/16: 
 
1. SCHEMA, DURATION 
 
Participants randomized to receive paclitaxel (PTX) in Step 1  
 
Participants who have not already done so should complete their current course 
(up to 6 cycles) of study-provided PTX chemotherapy and study-provided ART. 
 
Once participants have completed step 1 chemotherapy, they must permanently 
transition to local ART care as soon as it can be arranged, but not later than 90 
days after completion of Step 1 chemotherapy.  
o Participants on study at a site where PTX is not available for free to the 
participant should be followed on study to determine if they are eligible to 
receive PTX (up to 6 cycles) in Step 2. If participants become ineligible for 
Step 2, participants must permanently transition to locally provided 
oncology care as soon as it can be arranged, but not later than 90 days, 
and then go off study.  
o Participants on study at a site where PTX is available for free to the 
participant must permanently transition to locally provided oncology care 
as soon as it can be arranged, but not later than 90 days, and then go off 
study.  
  


 
Letter of Amendment #2 
Page 3 of 13 
11 June 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
Participants randomized to receive paclitaxel (PTX) in Step 2 or Step 3  
 Participants should complete their current course (up to 6 cycles) of 
chemotherapy and study-provided ART then permanently transition to local care 
as soon as appropriate oncology and ART care can be arranged, but not later than 
90 days, and then go off study. 
 
Participants randomized to receive bleomycin plus vincristine (BV) in Step 1 or Step 2 
who choose to switch to PTX 
 
Participants on study at a site where PTX is not available for free to the participant 
may receive study-provided PTX (up to 6 cycles) and ART on Step 3, as long as 
eligibility criteria for PTX are met. After completion of all cycles of PTX, 
participants must permanently transition to local care as soon as appropriate 
oncology and ART care can be arranged, but not later than 90 days, and then go 
off study. 
 
Participants on study at a site where PTX is available for free to the participant 
must permanently transition to locally provided PTX as soon as it can be arranged 
along with appropriate ART care, but not later than 90 days, and then go off study.  
 
Participants randomized to receive BV in Step 1 or Step 2 who choose not to switch 
to PTX at this time 
 
Participants who have not already done so should complete their current course 
(up to 6 cycles) of study-provided BV chemotherapy and study provided ART. 
 
Once study-provided BV is complete, participants must permanently transition to 
local ART care as soon as it can be arranged, but not later than 90 days after 
completion of study-provided BV.  
 
Participants may continue to be followed up to week 72 (or R+48, whichever 
comes first) or until the decision is made to switch their chemotherapy to PTX 
(this decision can be made up to week 72). At this time: 
o Participants on study at a site where PTX is not available for free to the 
participant may receive study-provided PTX (up to 6 cycles) on Step 3. After 
completion of all cycles of PTX, participants must permanently transition to 
locally provided oncology care as soon as it can be arranged, but not later 
than 90 days, and then go off study.  
o Participants on study at a site where PTX is available for free to the participant 
must permanently transition to locally provided oncology care as soon as it 
can be arranged, but not later than 90 days, and then go off study.   
 
Participants no longer eligible to receive study-provided chemotherapy  
 Permanently transition to local care as soon as appropriate oncology and ART 
care can be arranged, but not later than 90 days, and then go off study. 
 
 
 Participants who received etoposide (ET) while on study  
 
Participants will be followed for 144 weeks after beginning the last cycle of ET. All other 
participants will be followed for 96 weeks after randomization or assignment to the last step 
they enter. 
 


 
Letter of Amendment #2 
Page 4 of 13 
11 June 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
For participants who did not receive ET while on study, the duration of follow-up will 
be as follows: 
 
Participants who are randomized ONLY to Step 1 and who do not enter Step 2 or 
3 will be followed for 96 weeks from Step 1 entry;  
 
Participants who are randomized to Step 2 and/or 3 will be followed for 48 weeks 
after entry into the last step that they enter. 
 
2. Section 3.0, STUDY DESIGN 
 
Participants who received etoposide (ET) while on study will be followed for 144 weeks after 
beginning the last cycle of ET. All other participants will be followed for 96 weeks after 
randomization or assignment to the last step they enter. 
 
For participants who did not receive ET while on study, the duration of follow-up will 
be as follows: 
 
Participants who are randomized ONLY to Step 1 and who do not enter Step 2 or 
3 will be followed for 96 weeks from Step 1 entry;  
 
Participants who are randomized to Step 2 and/or 3 will be followed for 48 weeks 
after entry into the last step that they enter. 
 
3. Section 4.3, Inclusion Criteria Step 2 
 
4.3.1 IERC-Confirmed complete response (CR) or partial response (PR) to the PTX in 
Step 1. 
 
4.3.2 IERC-confirmed KS progression at least 12 weeks after the last dose of Step 1 
PTX. 
4. Section 4.4, Exclusion Criteria Step 2 
 
 
4.4.10  Receipt of BV in Step 1.  
 
5. Section 4.5, Inclusion Criteria Step 3 
 
 
4.5.1 IERC-confirmed KS progression at any time during Step 1 chemotherapy OR  
 
IERC-confirmed KS progression fewer than 12 weeks after the last 
chemotherapy dose in Step 1 in participants who have had an IERC-confirmed 
CR or PR OR 
 
IERC-confirmed KS progression following Step 1 chemotherapy, without any 
prior response OR 
 
IERC-confirmed KS progression in Step 2 OR  
 
With concurrence of the CMC, there is dose-limiting toxicity after receiving fewer 
than four cycles of chemotherapy in Step 1 or Step 2, in the absence of a CR or 
PR OR 
 
Participants otherwise eligible for Step 2 who, in the opinion of the investigator 
and with concurrence of the CMC, are unlikely to benefit from another course of 
the same chemotherapy received in Step 1. 
 
Receipt of BV in Step 1 or Step 2. 
 


 
Letter of Amendment #2 
Page 5 of 13 
11 June 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
6. Section 4.6, Exclusion Criteria Step 3 
 
 
4.6.9 Receipt of PTX in Step 1 and/or Step 2. 
 
7. Section 5.0, STUDY TREATMENT 
 
Participants will have access to local standard of care ART and chemotherapy through local 
treatment programs available at the sites following discontinuation of study-provided 
treatment study week 96. As part of their site implementation plan (SIP), sites are required 
to demonstrate that they have developed the appropriate relationship with local treatment 
programs to provide the local standard of care for ART and chemotherapy. Please refer to 
the A5263/AMC066 PSWP for the detailed SIP. 
 
8. Section 5.1.1.5, Antiretroviral Therapy 
 
The study will provide ART while participants are receiving study-provided 
chemotherapy, unless they have already transitioned to local ART care. Once 
participants have completed study-provided chemotherapy, they must permanently 
transition to local ART care as soon as it can be arranged, but not later than 90 days 
after completion of study-provided chemotherapy.  
 
Alternatively, sites may choose at any time to transfer a participant’s ART to 
locally provided drugs. until week 96 after Step 1 Randomization. 
 
 


 
Letter of Amendment #2 
Page 6 of 13 
11 June 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
9. Section 6.1.1, CLOSEOUT Schedule of Evaluations, Step 1 – Screening to Week 24 
 
Evaluation 
Step 1 Post-Entry Evaluations (Weeks) 
Virologic 
Failure 
KS-IRIS 
33,4 
24–48 Hours 
after Second 
Chemotherap
y Cycle 
Begins 
63,4 93,4 
123,
4 
153,4 183,4 
213,4 
243,4 
Concomitant Medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Complete Physical Exam 
 
 
 
 
 
 
 
 
 
 
 
Body Surface Area 
Calculation 
Recalculate if a participant’s weight has changed by 10% or more 
after Step 1 entry for re-calculation of bleomycin and PTX doses 
 
 
Targeted Physical Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Clinical Assessment 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
KS Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
CD4+/CD8+ 
(for participants on study-
provided ART) 
 
 
 
 
X 
 
 
 
X 
 
X 
HIV-1 RNA 
(for participants on study-
provided ART) 
 
 
 
 
X 
 
 
 
X 
X 
X 
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Chemistries 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Lactate 
 
Lipase & Triglycerides 
 
Creatine Kinase 
 
Pregnancy Testing 
Perform prior to a new chemotherapy cycle and whenever pregnancy is suspected 
CXR 
 
X 
Pulse Oximetry 
X2 
 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
 
 
2 Complete only if the participant is receiving bleomycin. 
3 Evaluations are required every 3 weeks if participants are receiving study-provided 
chemotherapy. 
4 Evaluations are required every 6 weeks if participants are not receiving study-provided 
chemotherapy. Q6 week visits should commence at the next even-numbered study week 
after completing chemotherapy. 
 
 


 
Letter of Amendment #2 
Page 7 of 13 
11 June 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
10. Section 6.1.2, CLOSEOUT Schedule of Evaluations, Step 1 – Week 27 to 
Discontinuation Evaluations 
 
Evaluation 
Step 1 Post-Entry Evaluations (Weeks) 
Discontinuation 
Evaluations 
Virologic Failure 
275,
6 
305,6 
335,
6 
365,
6 
395,
6 
425,
6 
455,
6 
485,
6 
60-96 
(Follow-
up  
Every 
12 
Weeks)2 
E  
+ 
1443 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Targeted Physical 
Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Clinical Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
KS Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
CD4+/CD8+ 
(for participants on 
study-provided ART) 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
HIV-1 RNA 
(for participants on 
study-provided ART) 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
Hematology 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Chemistries 
X 
 
 
X 
 
 
 
X 
X 
 
X 
 
Lactate 
Perform for symptoms suggestive of lactic acidosis 
Lipase & Triglycerides 
Perform for symptoms suggestive of pancreatitis 
Creatine Kinase 
Perform for symptoms suggestive of myopathy 
Pregnancy Testing 
Perform prior to a new chemotherapy cycle and whenever 
pregnancy is suspected 
X 
 
CXR 
Repeat at the time of suspected or IERC-confirmed KS progression or entry into the 
next step. For participants with known pulmonary KS at entry, a CXR will be repeated 
on every third cycle. 
Pulse Oximetry 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
 
2 If conducted on Step 1, week 96 is the last visit for participants in Arm 1B or 1C.  
3 E=week the last cycle of ET was started. The E+144 visit will only be conducted for 
participants in Arm 1A who are still on Step 1. 
4 Complete only if the participant is receiving bleomycin. 
5 Evaluations are required every 3 weeks if participants are receiving study-provided 
chemotherapy. 
6 Evaluations are required every 6 weeks if participants are not receiving study-provided 
chemotherapy. Q6 week visits should commence at the next even-numbered study week 
after completing chemotherapy. 


 
Letter of Amendment #2 
Page 8 of 13 
11 June 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
11. Section 6.1.3, CLOSEOUT Schedule of Evaluations, Step 2, Step 3, and Step 4 – 
Randomization to Week 27 
 
Evaluation 
Entr
y (R) 
Step 2 Post-Entry Evaluations (Weeks) 
R 
+ 
34,5 
24–48 Hours 
after Second 
Chemothera
py Cycle 
Begins 
R 
+ 
64,
5 
R 
+ 
94,5 
R 
+ 
124,
5 
R 
+ 
154,
5 
R 
+ 
184,
5 
R 
+ 
214,
5 
R 
+ 
244,
5 
R 
+ 
274,
5 
Virologic  
Failure
Concomitant Medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Targeted Physical Exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body Surface Area Calculation 
Recalculate if a participant’s weight has changed by 10% or more after Step 1 
entry for re-calculation of bleomycin and PTX doses 
Clinical Assessment 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
KS Exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
CD4+/CD8+ 
(for participants on study-
provided ART) 
X 
 
 
 
 
X 
 
 
 
X 
 
 
HIV-1 RNA  
(for participants on study-
provided ART) 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistries 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lactate 
Perform for symptoms suggestive of lactic acidosis 
 
Lipase & Triglycerides 
Perform for symptoms suggestive of pancreatitis 
 
Creatine Kinase  
Perform for symptoms suggestive of myopathy 
 
Pregnancy Testing 
Perform prior to a new chemotherapy cycle and whenever pregnancy is 
suspected 
 
CXR 
Repeat at the time of suspected or IERC-confirmed KS progression or entry into 
the next step. For participants with known pulmonary KS at entry or at the time of 
entry into Step 2 or Step 3, a CXR will be repeated on every third cycle. 
Pulse Oximetry 
X3 
X3 
 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
 
3 Complete only if the participant is receiving bleomycin. 
4 Evaluations are required every 3 weeks if participants are receiving study-provided 
chemotherapy. 
5 Evaluations are required every 6 weeks if participants are not receiving study-provided 
chemotherapy. Q6 week visits should commence at the next even-numbered R+visit 
week after completing chemotherapy. 


 
Letter of Amendment #2 
Page 9 of 13 
11 June 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
12. Section 6.1.4, CLOSEOUT Schedule of Evaluations, Step 2, Step 3, and Step 4 – Week 
30 to Discontinuation Evaluations 
 
Evaluation 
Step 2, 3, and 4 Post-Entry Evaluations (Weeks) 
Discontinuation 
Evaluations  
Virologic Failure 
R 
+ 
304,5 
R 
+ 
334,
5 
R 
+ 
364,
5 
R 
+ 
394,5 
R 
+ 
424,
5 
R 
+ 
454,5 
R 
+ 
484,5 
For Participants 
Who Received ET 
During Any Step 
R+60 
— 
R+96 
(Follow-up  
Every 12 Weeks) 
E 
+ 
1442 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Targeted Physical 
Exam 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Clinical Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
KS Exam 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
CD4+/CD8+ 
(for participants on 
study-provided ART) 
 
 
X 
 
 
 
X 
X 
 
X 
 
HIV-1 RNA  
(for participants on 
study-provided ART) 
 
 
X 
 
 
 
X 
X 
 
X 
X 
Hematology 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Chemistries 
 
 
X 
 
 
 
X 
X 
 
X 
 
Lactate 
Perform for symptoms suggestive of lactic acidosis 
Lipase & Triglycerides 
Perform for symptoms suggestive of pancreatitis 
Creatine Kinase  
Perform for symptoms suggestive of myopathy 
Pregnancy Testing 
Perform prior to a new chemotherapy cycle and whenever pregnancy is 
suspected 
X 
 
CXR  
Repeat at the time of suspected or IERC-confirmed KS progression or entry into the next 
step. For participants with known pulmonary KS at entry or at the time of entry into Step 2 or 
Step 3, a CXR will be repeated on every third cycle. 
Pulse Oximetry 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
 
2 E=week the last cycle of ET was started. E+144 visit is only for participants who received ET 
while on study and have already completed the week R+96 visit on the last step entered. 
3 Complete only if the participant is receiving bleomycin. 
4 Evaluations are required every 3 weeks if participants are receiving study-provided 
chemotherapy. 
5 Evaluations are required every 6 weeks if participants are not receiving study-provided 
chemotherapy. Q6 week visits should commence at the next even-numbered R+visit 
week after completing chemotherapy. 
 
 


 
Letter of Amendment #2 
Page 10 of 13 
11 June 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
13. Section 6.3, Instructions for Evaluations (new first paragraph) 
 
Upon implementation of this LOA, only evaluations noted in the CLOSEOUT 
Schedules of Evaluations are required.  
 
14. Section 7.1, KS Progression 
 
Please refer to the A5263/AMC066 MOPS for detailed information on calculating response 
categories and for the definition and instructions on evaluating non-measurable (evaluable) 
disease. 
 
For purposes of this study, IERC-confirmed KS progression is defined as KS progression 
that has been verified by the IERC. It is required that all KS progression be confirmed by the 
IERC. Changes in chemotherapy cannot occur until the site has received confirmation from 
the IERC. Please refer to the A5263/AMC066 MOPS for detailed instructions on contacting 
the IERC. 
 
15. Appendix VI, SAMPLE INFORMED CONSENT, WHAT DO I HAVE TO DO IF I AM IN 
THIS STUDY? 
 
Anti-HIV and anti-cancer drugs after the study: 
 
If you are not receiving study-provided chemotherapy, study visits to 96 72 weeks after 
Step 1 entry, the study will no longer provide you with anti-HIV or anti-cancer drugs. At that 
time, you may have to stop a drug combination that has worked well for you, either because 
you cannot afford the treatment or because those drugs are not available in your country. 
The doctors at your site will make sure that you have appropriate local cancer and 
HIV care before you are taken off study. Efforts will be made by your doctor to find a way 
to continue anti-HIV and anti-cancer drugs after the study is over. 
 
16. Protocol Signature Page 
 
A Protocol Signature Page (PSP) is appended for submission to DAIDS Protocol 
Registration System (DPRS) as part of the LOA registration packet. 
 
The information above will be incorporated into the next protocol version as necessary if the 
protocol is amended. 


 
Letter of Amendment #2 
Page 11 of 13 
11 June 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
APPENDIX 1: CHEMOTHERAPY OPTIONS FOR PARTICIPANTS CURRENTLY ON STUDY 
TREATMENT  
 
CURRENT 
STEP 1 
TREATMENT 
STEP 1 OPTION 
STEP 2 OPTION* 
STEP 3 OPTION* 
Receiving 
paclitaxel or 
completed 6 
cycles 
 
Complete 6 cycles of 
paclitaxel (if not already 
complete) 
1) If PR or CR and then 
progresses for up to week 
72 of the protocol, may 
move to Step 2 for up to 6 
more cycles 
2) If criteria for PR or CR 
are not met during Step 1, 
no additional study 
treatment 
NONE 
Receiving BV 
or completed 6 
cycles 
If deriving some benefit 
(which could be having 
stable disease when KS 
was previously 
progressing) may 
continue with BV or 
have option to 
immediately enter Step 
3 to receive paclitaxel 
NONE 
1) If choice is made to 
continue BV, option to 
receive paclitaxel later should 
be available up to study week 
72. May then move to Step 3 
with paclitaxel for up to 6 
additional cycles, then no 
more study treatment. 
2) If choice is made to 
immediately receive 
paclitaxel,  may move to Step 
3 with paclitaxel for up to 6 
additional cycles, then no 
more study treatment 
If not deriving benefit, 
must discontinue BV 
and have option to enter 
Step 3  to receive 
paclitaxel 
NONE 
May receive 6 cycles of 
paclitaxel, then no additional 
study treatment 
* Any move to Step 2 or Step 3 must be made by week 72 after entry onto the protocol. 
 
CURRENT 
STEP 2 
TREATMENT 
STEP 2 OPTION 
STEP 3 OPTION* 
Paclitaxel 
Complete 6 cycles, then no 
additional study treatment 
NONE 


 
Letter of Amendment #2 
Page 12 of 13 
11 June 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
Receiving BV 
or completed 6 
cycles 
 
If deriving some benefit (which 
could be having stable disease 
when KS was previously 
progressing) may continue with 
BV or have option to immediately 
enter Step 3 to receive paclitaxel 
1) If choice is made to continue BV, 
option to receive paclitaxel later should 
be available up to study week 72 (or 48 
weeks after randomization to Step 2 (i.e., 
study week R+48), whichever comes 
first). May then move to Step 3 with 
paclitaxel for up to 6 additional cycles, 
then no more study treatment. 
2) If choice is made to immediately 
receive paclitaxel,  may move to Step 3 
with paclitaxel for up to 6 additional 
cycles, then no more study treatment 
If not deriving benefit, must 
discontinue BV and have option 
to enter Step 3  to receive 
paclitaxel 
May receive 6 cycles of paclitaxel, then 
no additional study treatment  
* Any move to Step 2 or Step 3 must be made by week 72 after entry onto the protocol. 
 
CURRENT STEP 
3 TREATMENT 
STEP 3 OPTION* 
STEP 4 OPTION* 
Paclitaxel 
Complete 6 cycles, then no additional 
study treatment 
No additional options 
BV 
If deriving some benefit (which could be 
having stable disease when KS was 
previously progressing) may continue 
with BV 
No additional options 
Otherwise, discontinue treatment and 
return to SOC 
* Any move to Step 2 or Step 3 must be made by week 72 after entry onto the protocol. 
 
 


 
Letter of Amendment #2 
Page 13 of 13 
11 June 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
 
Randomized Comparison of Three Regimens of Chemotherapy with Compatible Antiretroviral 
Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings 
 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable US Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _____________________________________________________ 
 
Print/Type 
 
 
 
 
 
Signed: _______________________________________________Date: _____________ 
 
Name/Title 


 
Letter of Amendment #1 
Page 1 of 9  
8 February 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
 
Letter of Amendment #1 for: 
 
A5263/AMC066 
 
Randomized Comparison of Three Regimens of Chemotherapy with Compatible 
Antiretroviral Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings 
 
A Limited Center Trial of the AIDS Clinical Trials Group (ACTG) 
 
And  
 
AIDS Malignancy Consortium (AMC) 
 
DAIDS ES # 10724 
 
Letter of Amendment Date: 8 February 2018 
 
 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc.  
 
 
 
Phone: (301) 628-3000 
8757 Georgia Avenue, 12th Floor 
 
 
 
 
Fax: 
(301) 628-3302 
Silver Spring, MD  20910 
 
 
LETTER OF AMENDMENT 
 
 
DATE:  
February 8, 2018 
 
TO: 
 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
 
FROM: 
A5263/AMC066 Protocol Team  
 
SUBJECT: 
Letter of Amendment #1 for Protocol A5263/AMC066, Version 3.0, 12/07/16, 
entitled, “Randomized Comparison of Three Regimens of Chemotherapy with 
Compatible Antiretroviral Therapy for Treatment of Advanced AIDS-KS in 
Resource-Limited Settings” 
 
 
The following information affects the A5263/AMC066 study and must be forwarded to 
your institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This Letter of Amendment (LOA) must be approved by your 
IRB/EC before implementation.  
 
The following information may also affect the Sample Informed Consent. Your IRB/EC is 
responsible for determining the process of informing participants of the contents of this 
LOA. 
 


 
Letter of Amendment #1 
Page 2 of 9  
8 February 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this 
LOA, sites should implement the LOA immediately. Sites are still required to submit an 
LOA registration packet to the DAIDS Protocol Registration Office (PRO) at the 
Regulatory Support Center. Sites will receive a registration notification for the LOA once 
the DAIDS PRO verifies that all required LOA registration documents have been received 
and are complete. An LOA registration notification from the DAIDS PRO is not required 
prior to implementing the LOA. A copy of the LOA registration notification, along with 
this letter and any IRB/EC correspondence, should be retained in the site’s regulatory 
files. 
 
The following are changes to A5263/AMC066, Version 3.0, 12/07/16: 
 
1.  
Schema, Title 
 
 
The protocol title in the Schema has been revised to read: 
 
A Randomized Comparison of Three Regimens of Chemotherapy with Compatible 
Antiretroviral Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings 
 
2.  
Schema, Duration 
 
This section has been revised to read:  
 
Participants who received etoposide (ET) while on study will be followed for 144 weeks after 
beginning the last cycle of ET. All other participants will be followed for 96 weeks after 
randomization or assignment to the last step they enter. 
 
For participants who did not receive ET while on study, the duration of follow-up will 
be as follows: 
 
Participants who are randomized ONLY to Step 1 and who do not enter Step 2 or 
3 will be followed for 96 weeks from Step 1 entry;  
 
Participants who are randomized to Step 2 and/or 3 will be followed for 48 weeks 
after entry into the last step that they enter. 
 
3. 
Schema, Population  
 
This section has been revised to read: 
 
HIV-infected men and women with the following characteristics: 
 
Biopsy diagnostic of KS  
 
Naïve to ART (as defined in section 4.2.7), chemotherapy, and radiation therapy 
 
KS stage T1, (see section 4.1.3)   
 
Persons with chronic, acute, or recurrent infections that are serious, in the opinion of the 
site investigator, must have completed at least 14 consecutive days of appropriate anti-
infective treatment prior to study entry and be clinically stable 
 
4. 
Section 3, Study Design 
 
The final paragraph has been revised to read: 
 


 
Letter of Amendment #1 
Page 3 of 9  
8 February 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
Participants who received etoposide (ET) while on study will be followed for 144 weeks after 
beginning the last cycle of ET. All other participants will be followed for 96 weeks after 
randomization or assignment to the last step they enter. 
 
For participants who did not receive ET while on study, the duration of follow-up will 
be as follows: 
 
Participants who are randomized ONLY to Step 1 and who do not enter Step 2 or 
3 will be followed for 96 weeks from Step 1 entry;  
 
Participants who are randomized to Step 2 and/or 3 will be followed for 48 weeks 
after entry into the last step that they enter. 
 
5. 
 Section 4.1, Inclusion Criteria Step 1 
 
The following inclusion criterion has been added: 
 
4.1.14  If currently on ART for ≥24 weeks prior to study entry, plasma HIV-1 RNA <400 
copies/mL within 30 days prior to entry. 
 
NOTE: Viral load suppression is not needed if participant is not currently on ART or 
has been on ART for less than 24 weeks prior to study entry. There is no limit on 
length of time of prior ART use. 
 
6. 
Section 4.2, Exclusion Criteria Step 1 
 
The following exclusion criterion has been removed: 
 
4.2.7 Receipt of ART for more than 42 days immediately prior to entry. ART is allowed 
within the 42-day window prior to study entry. 
 
NOTE: The use of single-dose nevirapine (NVP) or zidovudine (ZDV) for any period of time 
during pregnancy to prevent mother to child transmission (MTCT) of HIV is allowed.  
 
NOTE: Successful post-exposure prophylaxis is allowed. Unsuccessful post-exposure 
prophylaxis is not allowed. 
 
7. 
 Section 4.2, Exclusion Criteria Step 1 
 
Exclusion criteria 4.2.8-4.2.16 have been renumbered to 4.2.7-4.2.15. 
 
8. 
Section 5.1.1, Step 1 
 
At entry, participants will be randomized in a 1:1 ratio to receive ART with 
either EFV/FTC/TDF (Atripla®) or their current, effective, non-study-supplied ART 
regimen plus either treatment regimen 1B or 1C as listed below. 
 
9. 
Section 5.1.1.5, Antiretroviral Therapy 
 
The study will provide ART until week 96 after Step 1 Randomization.  
 


 
Letter of Amendment #1 
Page 4 of 9  
8 February 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
The study will provide EFV/FTC/TDF (Atripla®), which is the preferred ART regimen. If there 
is a contraindication to EFV, participants must have access to an alternative NNRTI or 
protease inhibitor/ritonavir (PI/r) provided from outside of the study.  
 
The following ART regimens may be used:  
 EFV/FTC/TDF (Atripla®) 200 mg/300 mg/600 mg orally once daily on an empty stomach, 
preferably at bedtime OR 
 
FTC/TDF 200 mg/300 mg (Truvada®) orally once daily at bedtime plus EFV (Stocrin®) 
600 mg orally once daily at bedtime OR 
 
FTC/TDF 200 mg/300 mg (Truvada®) orally once daily plus NVP 200 mg orally twice 
daily OR 
 
FTC/TDF 200 mg/300 mg (Truvada®) orally once daily plus PI/r at standard dosing OR 
 
FTC/TDF 200 mg/300 mg (Truvada®) orally once daily plus integrase inhibitor at 
standard dosing 
 
10.  
Section 5.4.1.3, Study Product Supply 
 
Vincristine sulfate injection manufactured by Hospira is supplied through the study with 
funding support from the ACTG.  
 
In the event that vincristine is not available through the study, locally sourced 
vincristine may be used until study provided vincristine is available. Locally sourced 
vincristine must first be approved by the A5263 CMC prior to administering it to any 
study participant in A5263. Any study product not provided by the study must comply 
with the NIAID (DAIDS) policy that outlines the process for authorizing the use of 
study products not marketed in the US in NIAID (DAIDS)-supported and/or sponsored 
clinical trials. This policy is available on the NIAID (DAIDS) website at: 
https://www.niaid.nih.gov/sites/default/files/NonFDAapprovedProducts.pdf. 
 
Vincristine locally sourced by the site must be at a concentration of 1 mg/mL 
injectable solution in a vial for single use. The product must be prepared per protocol 
and stored as directed by the manufacturer in the package insert. 
 
When a site switches from locally obtained vincristine (approved by the A5263 CMC) 
to vincristine provided through the study, the site must notify the A5263 CMC per 
instructions in the Study Management section of the protocol and document the date 
that use of vincristine provided through the study via the CRPMC is implemented at 
the site. 
 
Site pharmacists are required to maintain complete records of study products 
received from the CRPMC and all other sources. 
 
 


 
Letter of Amendment #1 
Page 5 of 9  
8 February 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
11 
 Section 6.1.4, Step 2, Step 3, and Step 4–Week 30 to Discontinuation Evaluations 
 
This section has been revised as follows: 
 
Evaluation 
Step 2, 3, and 4 Post-Entry Evaluations (Weeks) 
Discontinuation 
Evaluations  
Virologic Failure 
R 
+ 
30 
R 
+ 
3
3 
R 
+ 
3
6 
R 
+ 
3
9 
R 
+ 
4
2 
R 
+ 
45 
R 
+ 
48 
For Participants Who 
Received ET During 
Any Step 
R+60 
— 
R+96 
(Follow-up  
Every 12 Weeks) 
E 
+ 
144
2 
Biopsy Diagnostic of KS  
(Fixed in Formalin) 
Repeat a diagnostic biopsy for 
KS to confirm a complete KS 
response1 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Targeted Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Clinical Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
KS Exam 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Photographic Record 
Complete for a change in KS response category 
X 
 
CD4+/CD8+ 
 
 
X 
 
 
 
X 
X 
 
X 
 
HIV-1 RNA 
 
 
X 
 
 
 
X 
X 
 
X 
X 
Stored Serum, Plasma, 
PBMC for Protocol-
Related Research 
 
 
 
 
 
 
X 
 
 
X 
 
Hematology 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Chemistries 
 
 
X 
 
 
 
X 
X 
 
X 
 
Lactate 
Perform for symptoms suggestive of lactic acidosis 
Lipase & Triglycerides 
Perform for symptoms suggestive of pancreatitis 
Creatine Kinase  
Perform for symptoms suggestive of myopathy 
Urinalysis 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy Testing 
Perform prior to a new chemotherapy cycle and whenever 
pregnancy is suspected 
X 
 
CXR  
Repeat at the time of suspected or IERC-confirmed KS progression or entry 
into the next step. For participants with known pulmonary KS at entry or at the 
time of entry into Step 2 or Step 3, a CXR will be repeated on every third cycle. 
Pulse Oximetry 
X3 
X3 X3 X3 X3 
X3 
X3 
X3 
X3 
X3 
 
ART Adherence 
Assessment 
X 
 
 
 
 
 
X 
X 
 
X 
 
Quality of Life 
Assessment 
 
 
 
 
 
 
X 
 
 
X 
 
1 A confirmatory biopsy is required only for participants in whom hyperpigmented macular skin 
lesions persist after apparent CR. 
2 E=week the last cycle of ET was started. E+144 visit is only for participants who received ET 
while on study and have already completed the week R+96 visit on the last step entered. 
3 Complete only if the participant is receiving bleomycin. 
 
 


 
Letter of Amendment #1 
Page 6 of 9  
8 February 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
12. 
Section 6.2.2.2, Post-Entry, Steps 2, 3, and 4 
 
This section has been revised to read: 
 
Steps 2, 3, and 4 
Study visits must be scheduled on the weeks indicated in the SOE +7 days for the step 
randomization visit to week R+48.  
 
For participants who received ET during any Step: Study visits must be scheduled on 
the weeks indicated in the SOE, +14 days for the week R+60 visit to week R+96.  
 
Study visits must be scheduled on the weeks indicated in the SOE +12 weeks for the E+144 
visit. 
 
13. 
Section 6.2.2.3.5, Long-Term Safety Follow-Up  
 
This section has been revised to read: 
 
Participants who received etoposide (ET) while on study will be followed for 144 weeks after 
beginning the last cycle of ET. All other participants will be followed for 96 weeks after 
randomization or assignment to the last step they enter. 
 
For participants who did not receive ET while on study, the duration of follow-up will 
be as follows: 
 
Participants who are randomized ONLY to Step 1 and who do not enter Step 2 or 
3 will be followed for 96 weeks from Step 1 entry;  
 
Participants who are randomized to Step 2 and/or 3 will be followed for 48 weeks 
after entry into the last step that they enter. 
 
14. 
Section 6.3, Instructions for Evaluations 
 
This section has been revised to read: 
 
All clinical and laboratory information required by this protocol is to be present in the source 
documents. Sites must refer to the Source Document Guidelines on the DAIDS website for 
information about what must be included in the source documents: 
https://www.niaid.nih.gov/sites/default/files/sourcedocappndx.pdf. 
 
15. 
Section 6.3.6, Concomitant Medications 
 
The fourth paragraph of this section has been revised to read: 
 
After week 96 (or R+9648 for participants who enter step 2, 3, or 4), only chemotherapy or 
radiation should be recorded in the CRF and source documents.  
 
16. 
Section 9.1, General Design Issues 
 
The last paragraph of this section has been revised to read: 
 


 
Letter of Amendment #1 
Page 7 of 9  
8 February 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
Participants who received ET while on study (see protocol version 2.0) will be followed for 
144 weeks after beginning the last cycle of ET. All other participants will be followed for 96 
weeks after randomization or assignment to the last step they enter. 
 
For participants who did not receive ET while on study, the duration of follow-up will 
be as follows: 
 
Participants who are randomized ONLY to Step 1 and who do not enter Step 2 or 
3 will be followed for 96 weeks from Step 1 entry;  
 
Participants who are randomized to Step 2 and/or 3 will be followed for 48 weeks 
after entry into the last step that they enter. 
 
17. 
Section 11.3, Clinical Site Monitoring and Record Availability 
 
The second paragraph of this section has been revised to read: 
 
The site investigator will make study documents (e.g., consent forms, drug distribution 
forms, CRFs) and pertinent hospital or clinic records readily available for inspection by the 
local IRB, the site monitors, the NIAID, the OHRP, other local, US, and international 
regulatory entities government agencies, and the pharmaceutical industry supporters or 
designee for confirmation of the study data.  
 
18. 
Section 12.2, Participant Confidentiality 
 
This section has been revised to read: 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will 
be identified by coded number only to maintain participant confidentiality. All records will be 
kept locked. All computer entry and networking programs will be done with coded numbers 
only. Clinical information will not be released without written permission of the participant, 
except as necessary for monitoring by the ACTG, IRB/EC, the NIAID, the OHRP, other 
local, US, or international regulatory entities as part of their duties, government 
agencies, or the pharmaceutical industry supporters or designee.  
 
19. Appendix VI, Sample Informed Consent, Title 
 
 
The protocol title in Appendix VI has been revised to read: 
 
A Randomized Comparison of Three Regimens of Chemotherapy with Compatible 
Antiretroviral Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings 
 
20. 
Appendix VI, Sample Informed Consent, WHAT DO I HAVE TO DO IF I AM IN THIS 
STUDY? 
 
The first paragraph, second sentence, of this section has been revised to read: 
 
If you join this study and do NOT take ET while you are on the study, you will be in the study 
for about up to two and a half years after you start your last step on the study. 
 


 
Letter of Amendment #1 
Page 8 of 9  
8 February 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
21. 
Appendix VI, Sample Informed Consent, WHAT ABOUT CONFIDENTIALITY? 
 
The second paragraph of this section has been revised to read: 
 
Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, 
the US Office for Human Research Protections (OHRP), or other local, US, and 
international regulatory entities as part of their duties (insert name of site) institutional 
review board (IRB) or Ethics Committee (a committee that protects the rights and safety of 
participants in research), National Institutes of Health (NIH), study staff, study monitors, 
drug companies supporting this study, and their designees.  
 
22. 
Protocol Signature Page 
 
Per a new regulatory requirement by the Division of AIDS (DAIDS), a Protocol Signature 
Page (PSP) is appended for submission to DAIDS Protocol Registration System (DPRS) as 
part of the LOA registration packet. 
 
The information above will be incorporated into the next protocol version as necessary if the 
protocol is amended. 
 
 


 
Letter of Amendment #1 
Page 9 of 9  
8 February 2018 
ACTG 5263/AMC066 Protocol Version 3.0 
Randomized Comparison of Three Regimens of Chemotherapy with Compatible Antiretroviral 
Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings 
 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable US Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _____________________________________________________ 
 
Print/Type 
 
 
 
 
 
Signed: _______________________________________________Date: _____________ 
 
Name/Title 


 
A5263/AMC066 
 
 Randomized Comparison of Three Regimens of Chemotherapy with Compatible 
Antiretroviral Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
and  
AIDS Malignancy Consortium (AMC) 
 
Sponsored by: 
National Institute of Allergy and Infectious Diseases (NIAID) 
National Cancer Institute (NCI) 
National Institute of Dental and Craniofacial Research (NIDCR) 
 
Pharmaceutical Support Provided by: 
Bristol-Myers Squibb, Inc. 
Gilead Sciences, Inc. 
Merck & Co., Inc. 
 
 
Non-IND study 
 
 
Co-Infections and Malignancies  
Working Group of the ACTG Scientific  
Agenda Steering Committee: 
 
 
Timothy Wilkin, MD, MPH, Chair 
 
AMC Kaposi's Sarcoma Working Group: 
Corey Casper, MD, MPH, Chair 
 
Protocol Co-Chairs:  
 
 
 
Margaret Borok-Williams, MD 
 
 
 
 
 
 
 
Susan Krown, MD 
 
Protocol Vice Chairs:  
 
 
 
Thomas Campbell, MD 
 
 
 
 
 
 
 
Patrick MacPhail, MD, PhD 
 
 
 
 
 
 
 
William Wachsman, MD, PhD 
 
DAIDS Clinical Representative: 
Catherine Godfrey, MD 
Clinical Trials Specialists: 
 
Lara Hosey, MA, CCRP 
 
 
Jennifer Rothenberg, MS 
 
FINAL Version 3.0 
December 7, 2016 


 
 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
 
12/7/16 
 
 
CONTENTS 
 
 
Page 
SITES PARTICIPATING IN THE STUDY .................................................................................. 14 
PROTOCOL TEAM ROSTER ................................................................................................... 15 
STUDY MANAGEMENT ........................................................................................................... 19 
GLOSSARY OF TERMS ........................................................................................................... 22 
SCHEMA .................................................................................................................................. 25 
1.0 
STUDY OBJECTIVES .....................................................................................................28 
1.1 
Primary Objective ............................................................................................ 28 
1.2 
Secondary Objectives ...................................................................................... 28 
2.0 
INTRODUCTION .............................................................................................................29 
2.1 
Background ..................................................................................................... 29 
2.2 
Rationale ......................................................................................................... 42 
3.0 
STUDY DESIGN ..............................................................................................................43 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ..................................................44 
4.1 
Inclusion Criteria Step 1 ................................................................................... 44 
4.2 
Exclusion Criteria Step 1 ................................................................................. 46 
4.3 
Inclusion Criteria Step 2 ................................................................................... 48 
4.4 
Exclusion Criteria Step 2 ................................................................................. 49 
4.5 
Inclusion Criteria Step 3 ................................................................................... 50 
4.6 
Exclusion Criteria Step 3 ................................................................................. 51 
4.7 
Inclusion Criteria Step 4 ................................................................................... 52 
4.8 
Exclusion Criteria Step 4 ................................................................................. 53 
4.9 
Study Enrollment Procedures .......................................................................... 54 
4.10 
Co-enrollment Guidelines ................................................................................ 54 
5.0 
STUDY TREATMENT ......................................................................................................55 
5.1 
Regimens, Administration, and Duration .......................................................... 55 
5.2 
Study Product Preparation ............................................................................... 60 
5.3 
Study Product Formulation and Storage .......................................................... 64 
5.4 
Study Product Supply, Acquisition, and Accountability ..................................... 65 
5.5 
Concomitant Medications ................................................................................ 67 
5.6 
Adherence Assessment ................................................................................... 67 
6.0 
CLINICAL AND LABORATORY EVALUATIONS .............................................................68 
6.1 
Schedule of Events .......................................................................................... 68 
6.2 
Timing of Evaluations ...................................................................................... 76 
6.3 
Instructions for Evaluations .............................................................................. 78 
7.0 
CLINICAL MANAGEMENT ISSUES ................................................................................87 
7.1 
KS Response .................................................................................................. 88 
7.2 
IRIS Management ............................................................................................ 91 
7.3 
Toxicity ............................................................................................................ 92 
7.4 
Anemia/Neutropenia/Thrombocytopenia .......................................................... 93 
7.5 
Peripheral Neuropathy (PN) ............................................................................. 95 
7.6 
Hyperbilirubinemia ........................................................................................... 96 
7.7 
Lipase Elevations and Pancreatitis .................................................................. 96 
7.8 
AST and ALT Elevation ................................................................................... 97 


 
 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
 
12/7/16 
CONTENTS (Cont'd) 
Page 
 
 
7.9 
Myopathy ......................................................................................................... 98 
7.10 
Lactic Acidosis ................................................................................................. 98 
7.11 
CNS Symptoms with EFV ................................................................................ 99 
7.12 
Diarrhea........................................................................................................... 99 
7.13 
Hypophosphatemia .......................................................................................... 99 
7.14 
Renal Insufficiency ........................................................................................ 100 
7.15 
Cardiac Toxicity (PTX) ................................................................................... 100 
7.16 
Pulmonary Toxicity ........................................................................................ 101 
7.17 
Management of Active Tuberculosis (TB) or Cryptococcal Meningitis (CM) ... 101 
7.18 
Allergic Reaction/Hypersensitivity (PTX) ........................................................ 101 
7.19 
Chemotherapy Extravasation ......................................................................... 101 
7.20 
Symptomatic Therapy for Toxicities ............................................................... 101 
7.21 
Virologic Failure ............................................................................................. 102 
7.22 
Procedures in the Event of Contraceptive Failure, On-Study Pregnancy, or 
Breastfeeding ................................................................................................ 102 
8.0 
CRITERIA FOR DISCONTINUATION ............................................................................ 103 
8.1 
Permanent Treatment Discontinuation ........................................................... 103 
8.2 
Temporary Treatment Discontinuation ........................................................... 103 
8.3 
Premature Study Discontinuation................................................................... 103 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................... 104 
9.1 
General Design Issues .................................................................................. 104 
9.2 
Endpoints ...................................................................................................... 106 
9.3 
Randomization and Stratification ................................................................... 107 
9.4 
Sample Size and Accrual ............................................................................... 107 
9.5 
Monitoring ...................................................................................................... 108 
9.6 
Statistical Analyses ........................................................................................ 109 
10.0 PHARMACOLOGY PLAN .............................................................................................. 110 
11.0 DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 110 
11.1 
Records to Be Kept ....................................................................................... 110 
11.2 
Role of Data Management ............................................................................. 110 
11.3 
Clinical Site Monitoring and Record Availability ............................................. 110 
11.4  
Expedited Adverse Event Reporting .............................................................. 111 
12.0 PARTICIPANTS ............................................................................................................. 112 
12.1 
Institutional Review Board (IRB) Review and Informed Consent .................... 112 
12.2 
Participant Confidentiality .............................................................................. 112 
12.3 
Study Discontinuation .................................................................................... 113 
13.0 PUBLICATION OF RESEARCH FINDINGS .................................................................. 113 
14.0 BIOHAZARD CONTAINMENT ....................................................................................... 113 
15.0 REFERENCES .............................................................................................................. 114 


 
 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
 
12/7/16 
CONTENTS (Cont'd) 
Page 
 
 
APPENDIX I: ACCEPTABLE CONTRACEPTION METHODS AND DOCUMENTATION OF 
STERILIZATION, MENOPAUSE, AND CHILD’S OR ADOLESCENT’S  REPRODUCTIVE 
POTENTIAL ................................................................................................................... 120 
APPENDIX II: ASSESSMENT OF CIRCULATING LEVELS OF PRO-INFLAMMATORY AND 
ANGIOGENESIS-ASSOCIATED MOLECULES ............................................................. 122 
APPENDIX III: IMMUNE RESPONSE TO HHV8 IN AIDS-ASSOCIATED KS ......................... 128 
APPENDIX IV: ASSESSMENT OF TISSUE MICROARRAYS TO CHARACTERIZE PATTERNS 
OF VIRAL AND CELLULAR PROTEIN EXPRESSION IN RELATION TO OUTCOMES 133 
APPENDIX V: KAPOSI’S SARCOMA GENE EXPRESSION PROFILING: DETECTION OF 
KSHV RNA LEVELS IN KAPOSI’S SARCOMA (KS) TISSUES ..................................... 135 
 
APPENDIX VI: SAMPLE INFORMED CONSENT


 
14 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
 
12/7/16 
 
 
SITES PARTICIPATING IN THE STUDY 
 
A5263/AMC066 is a multicenter study open to all non-US clinical research sites (CRSs). 
 


 
15 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
 
12/7/16 
 
PROTOCOL TEAM ROSTER 
 
Co-Chairs 
Margaret Borok-Williams, MD 
College of Health Sciences  
Department of Medicine  
University of Zimbabwe 
Mazowe Street  
P.O. Box A178  
Harare  
ZIMBABWE 
Phone: 0112634884238 
Fax: 0112634251017 
E-mail: mborok@mweb.co.zw 
  
Susan E. Krown, MD  
AIDS Malignancy Consortium 
P.O. Box 1051 
Planetarium Station 
127 West 83rd Street 
New York, NY 10024  
E-mail: krowns@mskcc.org 
 
Vice Chairs 
Thomas B. Campbell, MD  
University of Colorado  
Infectious Diseases  
Box B-168  
12700 E. 19th Avenue 
Aurora, CO  80045 
Phone: 303-724-4929 
Fax: 303-724-4926 
E-mail: Thomas.Campbell@ucdenver.edu 
 
Patrick MacPhail, M.D., PhD 
Clinical HIV Research Unit  
Department of Medicine  
University of Witwatersrand  
Themba Lethu Clinic, Helen Joseph 
Hospital  
Perth Road, Westdene, Postnet Suite 176  
Private Bag X26000  
Houghton  2041 
SOUTH AFRICA 
Phone: 271 12678850 
Fax: 271 14822130 
E-mail: pmacphail@witshealth.co.za 
Vice Chairs (cont’d) 
William Wachsman, MD, PhD 
AIDS Malignancy Consortium 
University of California, San Diego 
Hematology-Oncology (111E) 
3350 La Jolla Village Drive 
San Diego, CA 92161 
Phone: 858-552-8585 x2628 
Fax: 858-552-7416 
E-mail: wwachsman@ucsd.edu 
 
DAIDS Clinical Representative 
Catherine Godfrey, MD 
HIV Research Branch 
TRP, DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 9E49 
Rockville MD 20852 
Phone: 240-627-3074 
Fax: 301-425-9282 
E-mail: cgodfrey@niaid.nih.gov 
 
Clinical Trials Specialists 
Lara Hosey, MA, CCRP 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3395 
Fax: 301-628-3302 
E-mail: LHosey@s-3.com 
 
Jennifer Rothenberg, MS 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3344 
Fax: 301-628-3302 
E-mail: JRothenberg@s-3.com 


 
16 
A5263/AMC066 
FINAL VERSION 3.0 
 
PROTOCOL TEAM ROSTER (Cont’d) 
12/7/16 
 
 
Statisticians 
Roy Matining, MS 
Statistical and Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 519 
651 Huntington Avenue 
Boston, MA 02115 
Phone: 617-432-3025 
Fax: 617-432-3163 
E-mail: rmatining@sdac.harvard.edu 
 
Carlee Moser, PhD 
Statistical & Data Analysis Center  
Harvard School of Public Health  
FXB Building, Room 529A 
651 Huntington Avenue  
Boston, MA  02115 
Phone: 617-432-2526 
Fax: 617-432-3163 
E-mail: cmoser@sdac.harvard.edu 
 
AMC Consulting Statistician  
Jeannette Lee, PhD 
Department of Biostatistics  
University of Arkansas for Medical 
Sciences  
4301 West Markham Street, #781  
Little Rock, AR  72205 
Phone: 501-526-6712 
Fax: 501-526-6729 
E-mail: jylee@uams.edu  
 
Data Manager 
Stephanie Caruso, MBA 
Frontier Science & Technology Research 
Foundation, Inc.  
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7322 
Fax: 716-834-8432 
E-mail: scaruso@fstrf.org 
 
 
 
 
 
 
 
 
 
DAIDS Pharmacist 
Katherine Shin, PharmD 
Pharmaceutical Affairs Branch 
DAIDS/NIAID/NIH 
5601 Fishers Lane 
Room 9D30A, MSC 9829 
Bethesda, MD  20892 
Phone: 240-627-3047 
E-mail: kashin@niaid.nih.gov 
 
Immunologists 
Otoniel Martinez-Maza, PhD 
Department of Obstetrics and Gynecology 
David Geffen School of Medicine at UCLA 
Los Angeles, CA 90095-1740 
Phone: 310-825 2542 
Fax: 310-206 5387  
E-mail: omartinez@medenet.ucla.edu 
 
Charles Rinaldo, PhD 
Infectious Diseases & Microbiology  
University of Pittsburgh  
A419 Crabtree Hall  
130 DeSoto Street  
Pittsburgh, PA  15261 
Phone: 412-624-3928 
Fax: 412-624-4953 
E-mail: rinaldo@pitt.edu 
 
Virologists  
Richard F. Ambinder MD, PhD 
Johns Hopkins School of Medicine 
1650 Orleans 
CRB1, Room 389 
Baltimore, MD 21287 
Phone: 410-955-8839 
Fax: 410-955-0960 
E-mail: ambinri@jhmi.edu 
 
Dirk Dittmer, PhD 
Microbiology and Immunology 
University of North Carolina, Chapel Hill  
715 Mary Ellen Jones Building  
P.O. Box CB#7290  
Chapel Hill, NC  27599-7290 
Phone: 919-966-7960 
Fax: 919-962-7962 


 
17 
A5263/AMC066 
FINAL VERSION 3.0 
 
PROTOCOL TEAM ROSTER (Cont’d) 
12/7/16 
 
 
E-mail: ddittmer@med.unc.edu 
 
 
Neurologist 
Taylor Harrison, MD 
Department of Neurology 
Neuromuscular Division  
Emory University  
Grady Memorial Hospital 11C Neurology 
83 Jesse Hill Jr. Drive PO Box 036 
Atlanta, GA 30303 
Phone: 404-616-4020 
Fax: 404-659-0849 
E-mail: tharri4@emory.edu 
 
Pharmacologists 
Courtney Fletcher, PharmD 
College of Pharmacy  
University of Nebraska Medical Center  
986000 Nebraska Medical Center  
Omaha, NE  68198-6000 
Phone: 402-559-4333 
Fax: 402-449-5060 
E-mail: cfletcher@unmc.edu 
 
Michelle A. Rudek, PharmD, PhD 
Johns Hopkins Bunting-Blaustein Cancer 
Research Building 
1650 Orleans Street Room 1M90 
Baltimore, MD 21231-1000 
Phone: 410-614-6321 
Fax: 410-502-0895 
E-mail: mrudek2@jhmi.edu 
 
Investigators  
Naftali Busakhala, MB, ChB, MMED 
Pharmacology/Oncology  
MOI University  
Nandi Road  
P.O. Box 4606  
Eldoret  30100  
KENYA 
Phone: 254-053-722496933 
Fax: 254-053-2030786 
E-mail: nbusakhala@yahoo.com  
 
 
 
 
 
 
 
 
Investigators (cont’d) 
Fredrick K. Kirui, MBBS, MMED 
Kenya Medical Research Institute/Walter 
Reed Project HIV Program 
Hospital Road  
P.O. Box 1357  
Kericho 20200 
KENYA 
Phone: 254 52 31686 
E-mail: FKKirui@wrp-kch.org 
 
Agnes Moses, MD 
University of North Carolina Project  
Kamuza Central Hospital  
Tidziwe Centre  
100 Mzimba Road, Private Bag A-104 
Lilongwe 
MALAWI 
Phone: 265-175-5056 
Fax: 265-175-5954  
E-mail: amoses@unclilongwe.org.mw 
 
Jeffrey T. Schouten, MD, JD 
University of Washington  
1100 Fairview Avenue N., LE-500 
Seattle, WA 98109-1024 
Phone: 206-667-5980 
Fax: 206-667-6366 
E-mail: schouten@u.washington.edu 
 
Field Representatives 
Aida Asmelash, MD, MPH 
Botswana-Harvard School of Public Health 
AIDS Initiative Partnership 
Attn: CTU/Gabarone CRS 
Private Bag B0320  
Gaborone, 320  
BOTSWANA  
Phone: 267-237-3902671 x2128  
Fax: 267-271-07819  
E-mail: aasmelash@bhp.org.bw 
 
Valery Hughes, FNP 
Cornell Clinical Trials Unit Site 7804 
525 East 68th Street, Box 566 
New York, NY 10065 
Phone: 212-746-4393  


 
18 
A5263/AMC066 
FINAL VERSION 3.0 
 
PROTOCOL TEAM ROSTER (Cont’d) 
12/7/16 
 
 
Fax: 212-746-8852  
E-mail: vah9001@med.cornell.edu 
 
Laboratory Technologist 
David L. Shugarts, MA 
Medicine-Infectious Diseases  
University of Colorado, Denver 
Mail Stop #B168 
Building P15 Research 2  
Room #11450C 
12700 E. 19th Avenue 
Aurora, CO 80045 
Phone: 303-724-2981 
Fax: 303-724-2987 
E-mail: david.shugarts@ucdenver.edu 
 
CSS Representative 
Tapiwanashe Kujinga 
372 Oak Avenue 
Ferndale, Randburg 
Johannesburg 
SOUTH AFRICA 
Phone: +27 11 781 1765 
Fax: +27 11 789 6525 
E-mail: tapiwa@satamo.co.za 
 
Industry Representatives 
Debora Robertson  
CSO Drug Supply Management  
Bristol-Myers Squibb  
Research Parkway  
Mail Stop 4CD-312  
Wallingford, CT 06492  
Phone: 203-677-6167 
E-mail: debora.robertson@bms.com 
 
James F. Rooney, MD 
Gilead Sciences, Inc.  
333 Lakeside Drive  
Foster City, CA  94404 
Phone: 650-522-5708 
Fax: 650-522-5854 
E-mail: jrooney@gilead.com  
 
Krishna Sewal 
Gilead Sciences, Inc 
333 Lakeside Drive, Building 300 
Foster City, CA 94404 
Phone: 650-356-2042 
E-mail: krishna.sewal@gilead.com 
 
 
 
Industry Representatives (cont’d) 
Brian Gottshall 
Merck & Co. Inc.  
351 North Sumneytown Pike, UG2CD-30  
North Wales, PA  19454 
Phone: 267-305-0814 
Fax: 267-305-6534 
E-mail: brian_gottshall@merck.com 
 
Laboratory Data Manager 
Amanda Zadzilka 
Frontier Science & Technology Research 
Foundation  
4033 Maple Road  
Amherst, NY  14226 
Phone: 716-834-0900 x7282 
Fax: 716-833-0655 
E-mail: zadzilka@strf.org 
 


 
19 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
 
12/7/16 
 
STUDY MANAGEMENT 
 
All questions concerning this protocol should be sent via e-mail to the A5263/AMC066 Clinical 
Management Committee (CMC) at actg.cmca5263@fstrf.org. In the e-mail include “A5263” in 
the participant line and the name of your site in the message area. The appropriate member of 
the CMC will respond via e-mail with a "cc" to the CMC. A response should generally be 
received within 48 hours (Monday-Friday) excluding major US holidays. 
 
The CMC consists of the protocol co-chairs, statisticians, DAIDS clinical representative and 
pharmacist, data manager, clinical trials specialists, and other protocol team members identified 
by the A5263/AMC066 team leadership.  
 
Protocol E-mail Group 
Sites registering to this study must contact the User Support Group at the Data Management 
Center (DMC) to have the relevant personnel at the site added to the actg.protA5263 e-mail 
group. Include the protocol number in the e-mail subject line.  
 
Send an e-mail message to actg.user.support@fstrf.org 
 
Clinical Management  
For questions concerning entry criteria, toxicity management, concomitant medications, 
and co-enrollment, contact the CMC.  
 
Send an e-mail message to actg.cmca5263@fstrf.org  
 
Include the protocol number, patient identification number (PID), and a brief relevant history 
 
Sites must contact the CMC to request permission to make changes in antiretroviral drug 
regimens and chemotherapy regimens. 
 
Sites are encouraged to contact the CMC with eligibility or any other questions. 
 
Independent Endpoint Review Committee (IERC) 
For questions concerning disease progression and moving a participant to a successive study 
step, sites must contact the IERC. 
 
Send an e-mail to ACTG.IERCA526364@fstrf.org 
 
Please refer to the A5263/AMC066 Manual of Operations for detailed instructions 
 
Laboratory 
For questions specifically related to virologic or pharmacologic laboratory tests, contact the 
protocol virologist or pharmacologists.  
 
Send an e-mail message to actg.teamA5263@fstrf.org (ATTN: Richard Ambinder and Dirk 
Dittmer, virologists; Courtney Fletcher and Michelle Rudek, pharmacologists) 
 
Data Management 
For nonclinical questions about transfers, inclusion/exclusion criteria, case report forms (CRF), 
the CRF schedule of events, randomization/registration, delinquencies, and other data 
management issues, contact the Data Manager.  
 
For transfers, reference the Study Participant Transfer SOP 119, and contact Stephanie 
Caruso directly 


 
20 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
STUDY MANAGEMENT (Cont’d) 
12/7/16 
 
 
 
For other questions, send an e-mail message to actg.teamA5263@fstrf.org (ATTN: 
Stephanie Caruso)  
 
Include the protocol number, PID, and a detailed question 
 
Randomization  
For randomization questions or problems and study identification number (SID) lists.  
 
Send an e-mail message to actg.support@fstrf.org 
 
Computer and Screen Problems  
Contact the SDAC/DMC programmers. 
 
Send an e-mail message to rando.support@fstrf.org 
 
Protocol Document Questions 
 
For questions concerning the protocol document, contact the Clinical Trials Specialists.  
 
Send an e-mail message to actg.teamA5263@fstrf.org (ATTN: Lara Hosey and Jennifer 
Rothenberg) 
 
Copies of the Protocol 
To request a hard copy of the protocol, send a message to ACTGOpsCenter@s-3.com (ATTN: 
Diane Delgado) via e-mail. Electronic copies can be downloaded from the ACTG website.  
 
Product Package Inserts or Investigator Brochures 
To request copies of product package inserts or investigator brochures contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call (301) 897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to protocol@tech-res.com or call 
(301) 897-1707. 
 
Protocol Activation 
For questions related to protocol activation, contact the clinical trials specialists or 
ACTG Site Coordination group at actgsitecoordination@s-3.com.  
 
Study Drug 
For questions or problems regarding study drug, dose, supplies, records, and returns, 
call Katherine Shin, Protocol Pharmacist, at 240-627-3047. 
 
Study Drug Orders 
Call the Clinical Research Products Management Center at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
Contact the DAIDS RSC at Regulatory@tech-res.com or call 301-897-1706. 


 
21 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
STUDY MANAGEMENT (Cont’d) 
12/7/16 
 
 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com 
or call 1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 
Telephone Calls 
Sites are responsible for documenting any telephone calls made to A5263/AMC066 team 
members. 
 
Send an e-mail to actg.teamA5263@fstrf.org 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 


 
22 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
 
12/7/16 
 
GLOSSARY OF TERMS 
 
ABC 
abacavir 
ABV 
doxorubicin (adriamycin)/bleomycin/vincristine 
AE  
adverse event  
AIDS-KS  
AIDS-related Kaposi’s sarcoma  
ALT 
alanine aminotransferase 
ANC  
absolute neutrophil count  
ART   
antiretroviral therapy  
ARV 
antiretroviral  
AST 
aspartate aminotransferase 
ATV 
atazanavir 
BID 
twice daily 
BPNS 
brief peripheral neuropathy screen 
BV 
bleomycin and vincristine 
CCDSMB 
DAIDS Co-infections and Complications Data Safety Monitoring Board 
CI 
confidence interval 
CM 
cryptococcal meningitis 
CMC 
Clinical Management Committee 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
CR  
complete response  
CRF   
case report form 
CRPMC 
Clinical Research Products Management Center  
CT scan 
computed axial tomography  
CXR 
chest X-ray 
ddI 
didanosine  
d4T 
stavudine 
DAIDS  
Division of AIDS  
DMC  
Data Management Center  
EAE  
expedited adverse event  
E/CIA 
enzyme/chemiluminescence 
EFV 
efavirenz 
ET 
etoposide 
FDA 
Food and Drug Administration  
FDC 
fixed dose combination 
FTC 
emtricitabine  
G-CSF 
granulocyte-colony-stimulating factor 
HAART  
highly active antiretroviral therapy  
HBM  
human biological materials  
HBsAg 
hepatitis B surface antigen  


 
23 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
GLOSSARY OF TERMS (Cont'd) 
12/7/16 
 
 
HBV 
hepatitis B virus 
HHV-8  
human herpesvirus 8 
ICF 
informed consent form  
IERC 
Independent Endpoint Review Committee 
IRB 
Institutional Review Board  
IQA  
Immunology Quality Assurance  
ITT 
intention to treat 
IV 
intravenous  
KS 
Kaposi’s sarcoma  
KSHV 
Kaposi’s sarcoma herpesvirus 
KS-IRIS 
Kaposi's sarcoma-associated immune reconstitution inflammatory 
syndrome 
LDMS 
Laboratory Data Management System  
3TC 
lamivudine  
LFT 
liver function test 
LPC  
lab processing chart  
LPV 
lopinavir 
MOPS 
Manual of Operations 
MTCT 
mother-to-child transmission 
NIAID 
National Institute of Allergy and Infectious Diseases  
NRTI 
nucleoside reverse transcriptase inhibitor 
NVP  
nevirapine 
OHRP 
Office for Human Research Protections  
PBMC 
peripheral blood mononuclear cell 
PCP 
pneumocystis jiroveci pneumonia 
PI/r 
protease inhibitor/ritonavir  
PD  
progressive disease  
PFS 
progression-free survival 
PID 
Patient Identification Number  
PIP 
predicted interval plots 
PK 
pharmacokinetics  
PLD 
pegylated liposomal doxorubicin 
PN 
peripheral neuropathy 
PR  
partial response  
PSWP 
PTX 
protocol-specific web page 
paclitaxel 
QD 
once daily 
RSC  
Regulatory Support Center  
RLS 
resource-limited settings 
RTV 
ritonavir  
SDAC 
Statistical and Data Analysis Center  


 
24 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
GLOSSARY OF TERMS (Cont'd) 
12/7/16 
 
 
SID  
study identification number  
SIP 
site implementation plan 
SOE 
schedule of events 
SPN 
symptomatic peripheral neuropathy 
TB 
tuberculosis   
TDF 
tenofovir disoproxil fumarate 
TMA 
tissue microarray 
ULN 
upper limit of normal 
VQA  
Virology Quality Assurance  
WBC 
white blood cell 
ZDV  
zidovudine 
 
 
 


 
25 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
 
12/7/16 
 
SCHEMA 
A5263/AMC066 
 
A Randomized Comparison of Three Regimens of Chemotherapy with Compatible 
Antiretroviral Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings 
 
DESIGN:  
This is a prospective, randomized, active-controlled, two-arm clinical trial. 
 
DURATION: 
Participants who received etoposide (ET) while on study will be 
followed for 144 weeks after beginning the last cycle of ET. All other 
participants will be followed for 96 weeks after randomization or assignment 
to the last step they enter. 
 
SAMPLE SIZE: 
 446 participants ≥18 years of age (386 randomized to Arm 1B or Arm 1C, 
plus 60 who were previously randomized to Arm 1A in an earlier version 
of the protocol)  
 
POPULATION:  
HIV-infected men and women with the following characteristics: 
 
Biopsy diagnostic of KS  
 
Naïve to ART (as defined in section 4.2.7), chemotherapy, and radiation 
therapy 
 
KS stage T1, (see section 4.1.3)   
 
Persons with chronic, acute, or recurrent infections that are serious, in the 
opinion of the site investigator, must have completed at least 14 
consecutive days of appropriate anti-infective treatment prior to study 
entry and be clinically stable 
 
STRATIFICATION: Randomization will be stratified by CD4+ lymphocyte cell count (<100 or ≥100 
cells/mm3) and by country 
 
REGIMEN:  
Step 1: 
 
Arm 1A: ET 50 mg plus coformulated efavirenz, tenofovir, and emtricitabine 
(EFV/FTC/TDF) twice a day. 
 
At an interim review in March 2016, the DAIDS Co-infections and 
Complications Data Safety Monitoring Board (CCDSMB) found that the 
ET plus ART arm was less effective than the paclitaxel (PTX) plus ART 
arm. Per the CCDSMB recommendation, enrollment into this arm and all 
initiation of ET in subsequent steps were discontinued in March 2016.  
 
Arm 1B: Bleomycin 15 units/m² IV (intravenous) plus vincristine 2mg IV plus 
coformulated EFV/FTC/TDF every 3 weeks. Treatment with BV may continue 
for a maximum of six cycles, or until toxicity requiring discontinuation of study 
chemotherapy, or until the site investigator and the CMC have determined 
that alternative therapy is required, whichever occurs first. 
 
Arm 1C: PTX 100 mg/m2 IV plus coformulated EFV/FTC/TDF every 3 weeks. 
Treatment with PTX will continue for a maximum of six cycles, or until toxicity 


 
26 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
SCHEMA (Cont'd) 
12/7/16 
 
 
requiring discontinuation of study chemotherapy, or until the site investigator 
and the CMC have determined that alternative therapy is required, whichever 
occurs first. 
 
Step 2:  
A second course of up to six cycles of the same chemotherapy utilized in 
Step 1 plus coformulated EFV/FTC/TDF. Participants who completed one 
course of ET will not receive a second course of ET. These participants 
will be entered into Step 3. 
 
Step 3:  
The remaining study-provided chemotherapy regimen (BV or PTX) plus 
coformulated EFV/FTC/TDF. For those who received ET in Step 1 and/or 
Step 2, BV or PTX will be randomly assigned. 
 
Step 4:  
Please note that Step 4 applies only to those who received ET in Step 1, 
Step 2, or Step 3. The remaining study-provided chemotherapy regimen (BV 
or PTX) plus coformulated EFV/FTC/TDF.  
 
 


 
27 
A5263/AMC066 
 
 
FINAL VERSION 3.0 
 
SCHEMA (Cont'd) 
12/7/16 
 
 
*Participants currently receiving ET in Step 
1 or Step 2 may continue and complete ET 
or discontinue ET and enter Step 3 in 
discussion with the local investigator and 
in consultation with the CMC 
 
**Participants currently receiving ET in 
Step 3 may continue and complete ET or 
discontinue ET and start the remaining 
chemotherapy regimen in Step 4 in 
discussion with the local investigator and 
in consultation with the CMC 
 
IERC-confirmed KS progression at any time during Step 
1 chemotherapy OR 
 
IERC-confirmed KS progression fewer than 12 weeks 
after the last chemotherapy dose in Step 1 in participants 
who have had an IERC-confirmed CR or PR OR 
 
IERC-confirmed KS progression following Step 1 
chemotherapy, without any prior response OR 
 
With concurrence of the CMC, dose-limiting toxicity after 
receiving fewer than four cycles of chemotherapy in Step 
1, in the absence of a CR or PR OR 
 
Participants otherwise eligible for Step 2 who, in the 
opinion of the investigator and with concurrence of 
the CMC, are unlikely to benefit from another course 
of the same chemotherapy received in Step 1 
*Step 2: 
A second course of up to six cycles of the 
same chemotherapy utilized in Step 1  
+ 
EFV/FTC/TDF  
 
**Step 3: 
Remaining study-provided chemotherapy regimen  
+ 
EFV/FTC/TDF  
 
IERC-confirmed KS progression in 
Step 2 OR 
 
With concurrence of the CMC, dose-
limiting toxicity after receiving fewer 
than four cycles of chemotherapy in 
Step 2, in the absence of a CR or PR 
 
IERC-confirmed KS progression on Step 3 OR 
 
With concurrence of the CMC, dose-limiting toxicity after 
receiving fewer than four cycles of chemotherapy in Step 
3, in the absence of a CR or PR OR 
 
Currently receiving ET in Step 3 
Step 4: 
Remaining study-provided 
chemotherapy  
+ 
EFV/FTC/TDF  
Alternative care available 
locally outside of the 
study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IERC-confirmed CR or PR lasting at 
least 12 weeks followed by IERC-
confirmed KS progression prior to 
week 72 where the PI believes a 
second course of the same 
chemotherapy would be beneficial 
*Step 1: 
 
Arm 1A: NEW ENROLLMENT DISCONTINUED 
Arm 1B: BV + EFV/FTC/TDF 
Arm 1C: PTX + EFV/FTC/TDF 


 
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1.0 
STUDY OBJECTIVES 
 
1.1 
Primary Objective 
 
To compare the clinical efficacy of two regimens, etoposide (ET) plus ART and 
bleomycin plus vincristine (BV) plus ART, to paclitaxel (PTX) plus ART for initial 
treatment of advanced stage AIDS-related Kaposi’s sarcoma (AIDS-KS). 
 
1.2 
Secondary Objectives 
 
1.2.1 Compare Kaposi’s sarcoma (KS) tumor response in persons randomized to ET 
plus ART, BV plus ART, and PTX plus ART. 
 
1.2.2 Compare measures of quality of life in persons randomized to ET plus ART, BV 
plus ART, and PTX plus ART. 
 
1.2.3 Compare the safety and toxicity in persons randomized to ET plus ART, BV plus 
ART, and PTX plus ART. 
 
1.2.4 Compare suppression of plasma HIV-1 RNA and changes in CD4+ lymphocyte 
cell count in persons randomized to ET plus ART, BV plus ART, and PTX plus 
ART. 
 
1.2.5 Compare adherence to ART in persons randomized to ET plus ART, BV plus 
ART, and PTX plus ART. 
 
1.2.6 Compare the incidence of peripheral neuropathy (PN) and symptomatic 
peripheral neuropathy (SPN) in persons randomized to ET plus ART, BV plus 
ART, and PTX plus ART. 
 
1.2.7 Evaluate clinical efficacy of the remaining regimen after failure of the initial 
regimen. 
 
1.2.8 Evaluate the relationship between response of KS to therapy and development of 
KS-associated immune reconstitution inflammatory syndrome (KS-IRIS) with: 
 
1.2.8.1 Baseline immunohistochemical markers of viral and cellular gene 
expression in KS tumors. 
 
1.2.8.2 RNA levels for Kaposi’s sarcoma herpesvirus (KSHV) genes in tumor 
biopsies at baseline and during therapy. 
 
1.2.8.3 Suppression of KSHV viral load. 
 
1.2.8.4 Cellular and humoral markers of immune function and immune 
activation. 
 


 
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1.2.9 Investigate the relationship between plasma and peripheral blood mononuclear 
cell (PBMC) KSHV viral load. 
 
1.2.10 Encourage donation of excess biopsy materials to the AIDS and Cancer 
Specimen Resource. 
 
1.2.11 To assess the risk of secondary leukemia and myelodysplasia after ET. 
 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
AIDS-KS occurs in persons who are coinfected with HIV-1 and human herpesvirus 8 
(HHV-8 or KSHV). The availability of potent ART has coincided with a substantial 
decrease in AIDS-KS incidence in the United States and Europe since the mid-1990s. 
Nonetheless, AIDS-KS remains the most commonly diagnosed AIDS-associated 
malignancy in developed countries [1], and may occur even among people who have 
apparently effective HIV control [2,3]. In areas of the world where access to ART and 
chemotherapy is limited, and where rates of HIV and KSHV coinfection are much higher 
than in developed countries [4-7], AIDS-KS is an even more significant contributor to 
morbidity and mortality in HIV-1 infected persons. 
 
2.1.1 Treatment of AIDS-KS with ART 
 
In developed countries, standard treatment for persons who are ART-naïve 
consists of three-drug combinations of two nucleoside reverse transcriptase 
inhibitors (NRTIs) with either an HIV-1 protease inhibitor with ritonavir boosting 
(PI/r) or a non-NNRTI. These regimens provide effective inhibition of HIV-1 
replication that results in functional immune reconstitution, decreased risk of 
AIDS-related events, and improved survival [8-12]. 
 
A dramatic decrease in the incidence of KS in HIV-1-infected populations in 
developed countries has coincided with the widespread use of antiretroviral 
(ARV) agents to manage HIV-1 infection [12,13]. In many cases the use of highly 
active antiretroviral therapy (HAART) alone results in regression of KS lesions. 
KS improvement or complete resolution of lesions has been reported in up to 55-
60% of patients [14-16] even though ARV agents do not affect KSHV replication 
in cultured cell lines. Pilot studies have demonstrated that treatment of AIDS-KS 
with ART is safe and provides effective suppression of HIV-1 and increased 
lymphocyte cell counts in South Africa [17] and is associated with improved 
retention in care in Malawi [18] and improved survival in Zimbabwe [19] 
compared to chemotherapy alone. Although some data suggest that ART alone 
is often adequate treatment for newly diagnosed limited-stage AIDS-KS, 
response to ART alone does not invariably occur or is sometimes incomplete. 
Given that ART alone often improves or stabilizes AIDS-KS disease, it is possible 


 
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that combining ART with chemotherapy might provide improved clinical 
responses. Data from prospective randomized studies of chemotherapy in 
combination with ART are limited, and the optimal approach to treatment of more 
advanced-stage (T1) AIDS-KS in the ART era, particularly in resource-limited 
settings, has not been defined. 
 
2.1.1.1 Emtricitabine and Tenofovir Disoproxil Fumarate (Truvada, FTC/TDF) 
Fixed Dose Combination (FDC) Tablet 
 
Truvada (Gilead Sciences), a product containing FTC 200 mg and TDF 
300 mg in an FDC tablet formulation was approved by the United States 
Food and Drug Administration (US FDA) on August 2, 2004.  
 
Study GS-US-104-172 was a phase I, 28-day, randomized, four-way 
crossover, pharmacokinetic (PK) study in healthy volunteers designed to 
evaluate the bioequivalence of the FTC/TDF combination tablet 
compared with the FTC capsule and TDF tablet administered 
concurrently and also the effect of food (high-fat meal and light meal) on 
PK [20]. The results demonstrated bioequivalence between the 
FTC/TDF combination tablet and the FTC capsule and TDF tablet 
formulations when administered separately. Administration of the 
FTC/TDF combination tablet with either a high-fat meal or light meal 
increased TDF exposure by approximately 30% compared with fasted-
state administration. Clinical experience with TDF indicates that the 
effect of food on TDF exposure is not of clinical relevance. FTC and 
TDF, either administered as an FDC tablet (containing FTC 200-mg/TDF 
300-mg) or co-administered as FTC 200 mg capsule and TDF 300-mg 
tablet separately, were well tolerated.  
 
Several studies have assessed the safety and efficacy of FTC with TDF, 
although none using FDC. Study M02-418 was a phase III, randomized, 
open-label, multicenter study designed to compare lopinavir (LPV) 800 
mg/ritonavir (RTV) 200 mg QD (once daily) versus LPV 400 mg/RTV 
100 mg BID (twice daily) with the background regimen of FTC 200 mg 
QD and TDF 300 mg QD in ART-naïve patients with HIV-1 RNA >1000 
copies/mL [21-23]. A total of 190 patients between the ages of 19-75 
years were enrolled; 115 to the QD arm and 75 to the BID arm. At week 
48, based on the intention to treat (ITT) (NC=F) analysis, 70% of 
participants in the QD regimen demonstrated HIV-1 RNA <50 copies/mL 
compared with 64% of those in the BID group (95% CI: -7%; 20%). 
Gastrointestinal adverse events (AEs) were the most common cause for 
discontinuation. Overall, the most common AEs (>3%) reported were 
diarrhea, nausea, and vomiting, with diarrhea being reported 
significantly higher in the QD group (16% versus 5%; p=0.04). The most 
common Grade 3/4 laboratory abnormalities (>3%) reported were 
increased alanine aminotransferase (ALT) (>5upper limit of normal 
[ULN]), aspartate aminotransferase (AST) (>5ULN), triglyceride (>750 


 
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mg/dL), and amylase (>2ULN) levels; no significant differences 
between the two groups were observed [23]. 
 
Study 934 is a phase III, randomized, open-label, noninferiority, 
multicenter study designed to compare a regimen of TDF 300 mg + FTC 
200 mg + EFV (efavirenz) QD with a regimen of ZDV (zidovudine) 300 
mg/3TC (lamivudine) 150 mg BID (as FDC Combivir) + EFV QD in ARV-
naïve, HIV-1-infected participants [24]. The 48-week data demonstrated 
that using the time to loss of virologic response as the primary analysis 
(where missing, switch, or early termination is counted as a failure), the 
proportion of participants with plasma HIV-1 RNA levels <400 copies/mL 
in an ITT population (n=487) was 84% in the TDF+FTC group compared 
with 73% in the ZDV/3TC group (p=0.002). The proportion of 
participants with plasma HIV-1 RNA levels <50 copies/mL was 80% in 
the TDF+FTC group versus 70% in the ZDV/3TC group (p=0.020). 
Significant differences were also seen between the TDF+FTC and the 
ZDV/3TC groups in the proportion of participants with increases in CD4+ 
cell counts (190 and 158 cells/mm3, respectively; p=0.002) 
 
Safety analysis, based on 511 participants who received any study 
medication, showed that discontinuation due to AEs occurred more 
frequently in the ZDV/3TC group (9%) than in the TDF+FTC group (4%) 
(p=0.02). The most common AE resulting in discontinuation related to 
study drug for the ZDV/3TC group was anemia (14/254) and NNRTI-
associated rash (2/257) for the TDF+FTC group. Renal safety was 
similar in the two groups, and no participant discontinued study 
medication because of renal events. A significantly (p<0.001) greater 
percentage of participants in the TDF+FTC arm had a lower mean 
increase from baseline in fasting total cholesterol levels (21 mg/dL) 
compared with participants in the ZDV/3TC arm (35 mg/dL). At week 48, 
total limb fat was significantly less in a subset of participants receiving 
ZDV/3TC (mean of 6.9 kg or 15.2 pounds; n=49) compared with a 
subset of participants receiving TDF+FTC (mean 8.9 kg or 19.6 pounds; 
n=51; p=0.03). All participants with confirmed >400 copies/mL of HIV-1 
RNA at week 48 or early discontinuation were analyzed for genotypic 
resistance. Genotype data were limited to 23 participants on ZDV/3TC 
and 12 participants on TDF+FTC and showed mostly M184V/I (3% in 
ZDV/3TC participants versus 1% in TDF+FTC  
participants) and/or EFV-resistance mutations (7% in ZDV/3TC versus 
4% in TDF+FTC participants), with no participants developing the K65R 
mutation. 
 
Lactic acidosis and severe hepatomegaly with steatosis, including fatal 
cases, have been reported with the use of nucleoside analogues alone 
or in combination, including FTC, TDF, and other ART. 
 


 
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FTC/TDF is designated as US FDA use-in-pregnancy Category B. More 
information concerning FTC/TDF coformulation is available in the most 
recent Truvada package insert. 
 
2.1.1.2 Efavirenz (Stocrin, EFV)  
 
EFV is a once daily NNRTI that has been shown to be effective in the 
treatment of HIV disease [25].  
 
The most notable side effects associated with EFV are central nervous 
system (CNS) symptoms and rash. Fifty-three percent of those receiving 
EFV reported CNS symptoms. These symptoms included, but were not 
limited to, dizziness, impaired concentration, somnolence, abnormal 
dreams, and insomnia. Symptoms usually begin during the first or 
second day of therapy and generally resolve after the first 2 to 4 weeks 
of therapy. Symptoms may also be less noticeable if EFV is taken at 
bedtime. Potential for additive symptoms may occur if used 
concomitantly with alcohol or psychoactive drugs. Nervous system 
symptoms were severe in 2.0% of patients receiving EFV 600 mg QD 
and in 1.3% of patients receiving control regimens; and, 2.1% of EFV-
treated patients discontinued therapy because of nervous system 
symptoms.  
 
In multi-study comparisons of EFV-treated versus controls, severe acute 
depression (1.6% versus 0.6%) and suicidal ideation (0.6% versus 
0.3%) were reported. Participants with a history of psychiatric disorder 
are at greater risk. There have been occasional post-marketing reports 
of delusions and aberrant behavior, predominantly in those with a 
history of mental illness or substance abuse. Participants who 
experience psychiatric symptoms should contact their doctor 
immediately to assess the possibility that the symptoms may be related 
to EFV. 
 
Among approximately 2200 treated individuals in studies and expanded 
access programs, the incidence of Grade 4 rash (e.g., erythema 
multiforme and Stevens-Johnson syndrome) was 0.14%. The median 
time to onset of rash in adults was 11 days, and the median duration 
was 16 days. EFV should be discontinued in persons developing severe 
rash associated with blistering, desquamation, mucosal involvement, or 
fever. Appropriate antihistamines and/or corticosteroids may improve 
the tolerability and hasten the resolution of rash. 
 
Other side effects associated with EFV include upset stomach, diarrhea, 
anorexia, headache, tiredness, pancreatitis, elevated cholesterol 
(including high-density lipoprotein), elevated triglycerides, and elevated 
transaminase.  
 


 
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Teratogenicity/Developmental Toxicity 
The US FDA use-in-pregnancy category for EFV has been changed 
from Category C (Risk of Fetal Harm Cannot Be Ruled Out) to Category 
D (Positive Evidence of Fetal Risk). This change is a result of four 
retrospective reports of neural tube defects in infants born to women 
with first trimester exposure to EFV, including three cases of 
meningomyelocele and one of Dandy Walker syndrome. As EFV may 
cause fetal harm when administered during the first trimester to a 
pregnant woman, pregnancy should be avoided in women receiving 
EFV. Women of reproductive potential and women with bilateral tubal 
ligation should be counseled on the possible risks associated with 
pregnancy. Women should be instructed not to breastfeed while taking 
EFV. If a woman becomes pregnant while taking EFV during the first 
trimester of pregnancy, she should be apprised of the potential harm to 
the fetus.  
 
Additional information regarding EFV is available in the most recent 
Stocrin package insert. 
 
2.1.1.3 Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate FDC Tablet 
(Atripla, EFV/FTC/TDF) 
 
Merck and Company has developed Atripla, a product containing EFV 
600 mg, FTC 200 mg, and TDF 300 mg in a white color, FDC tablet for 
distribution outside of the United States.  
 
Clinical study 934 supports the use of EFV/FTC/TDF in ART-naïve HIV-
1-infected patients. Additional data supporting the use of EFV/FTC/TDF 
is found in the package insert for tenofovir (Viread). In ART-experienced 
patients, the use of EFV/FTC/TDF may be considered for patients with 
HIV-1 strains that are expected to be susceptible to the components of 
Atripla as assessed by treatment history or by genotypic or phenotypic 
testing.  
 
2.1.2 Treatment of AIDS-KS with Chemotherapy 
 
Although HAART alone may lead to regression of limited-stage (T0) AIDS-KS 
[26], the morbidity and mortality associated with advanced or rapidly progressive 
AIDS-KS usually mandates concomitant treatment with ART and chemotherapy. 
While a number of single chemotherapeutic agents and drug combinations may 
induce regression of AIDS-KS, the most effective regimen(s) to use in 
combination with ART have not been well defined, because many of the 
commonly-used regimens were tested prior to the introduction of highly active 
ART. In addition, relatively few studies have compared the efficacy of different 
chemotherapeutic regimens in randomized, phase III trials.  
 


 
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In the 1980s, a number of drugs previously approved for other cancer indications, 
including doxorubicin, bleomycin, ET, vincristine, and vinblastine, were shown to 
have single-agent activity against AIDS-KS. Intravenously administered ET was 
one of the first agents shown to have activity against AIDS-KS in the United 
States [27], and later studies conducted by the ACTG documented the activity of 
oral ET, yielding identical objective response rates of 36% using two different ET 
dosing regimens [28,29]. In addition, oral ET was shown to be superior to 
supportive care with respect to tumor response, and was superior to a 
combination of actinomycin D, bleomycin, and vincristine with respect to toxicity 
and quality of life in a randomized trial conducted in Zimbabwe prior to the 
availability of ART [30]. In the latter study, although combination chemotherapy 
was superior to ET with respect to tumor response, survival in both arms was 
similar. 
 
Although single-agent ET has activity against AIDS-KS, combination 
chemotherapy regimens were more commonly used to treat AIDS-KS in the 
1980s and early 1990s. Among the more widely used regimens were alternating 
weekly doses of vincristine and vinblastine [31], and combinations of bleomycin 
(B) and vincristine (V), with or without doxorubicin (A), so-called ABV or BV 
regimens. Estimates of the response rates induced by these regimens have 
varied from study to study, and it is not clear whether these differences reflect 
different patient characteristics, different response definitions and assessment 
methods, or both. For example, BV reportedly induced major (defined as either 
complete response, i.e., complete disappearance of all lesions, or partial 
response, i.e., ≥50%, tumor size reduction) objective responses in 57% of 
patients in a study by Gompels et al. [32], but in only 23% of patients in a large 
randomized comparison with pegylated liposomal doxorubicin (PLD) [33]. A 
review of several studies conducted at the University of Southern California 
(USC) [34] reported that BV and ABV induced major responses in 76-81% of 
patients. Other studies from USC and multicenter trials conducted by the ACTG 
reported major response rates as high as 88% for ABV [35-37]. However, two 
large, randomized, multicenter trials in which ABV was compared with liposomal 
daunomycin [38] or PLD [39] yielded response rates of only 28% and 25%, 
respectively, in the ABV arms. 
 
Although the aforementioned drugs and drug combinations were widely used to 
treat AIDS-KS from the very early days of the AIDS epidemic in the US, until the 
mid-1990s no drugs (with the exception of recombinant interferon alfa which, by 
virtue of its high cost, side effect profile, inconsistent activity in advanced 
disease, and need for parenteral self-administration, is unsuited for use in 
resource-limited settings) had received the type of rigorous testing required for 
US FDA approval for an AIDS-KS indication. Then, in the mid- to late-1990s, 
three drugs – two newly-introduced liposomal anthracyclines, PLD (Doxil; 
Caelyx) and liposomal daunorubicin (DaunoXome), and an older, established 
drug, paclitaxel (PTX; Taxol), originally approved in 1992 for treatment of 
metastatic breast and ovarian cancers and available in generic form for more 
than a decade – received US FDA approval for treatment of advanced, 


 
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symptomatic AIDS-KS. Although PTX induced high objective response rates in 
AIDS-KS, including responses in patients who had previously been treated with 
liposomal anthracyclines [40-42], until recently PLD was the agent most 
commonly selected as first-line chemotherapy for advanced, symptomatic AIDS-
KS in high-resource countries. The preference for PLD was based on its adverse 
event profile and acceptability to patients, in particular the infrequency of PLD-
induced alopecia, despite substantially higher cost. In 2011, however, because of 
manufacturing problems at its only worldwide production facility, PLD became 
unavailable, and the timing of its future availability is uncertain. This has led to a 
re-examination of alternatives for treatment of AIDS-KS and a renewed interest in 
the role of PTX as first-line therapy for patients with advanced, potentially life-
threatening KS. 
 
PTX was approved by the US FDA in 1997 as second-line therapy for AIDS-KS 
on the basis of two phase II open-label studies each of which evaluated a 
different treatment regimen: 135 mg/m2 as a 3-hour infusion every 3 weeks, and 
100 mg/m2 as a 3-hour infusion every 2 weeks [40,41,43]. Of 85 patients 
analyzed at the time of FDA review, 59 had received prior systemic therapy for 
KS, including anthracyclines in 64%, and 93% had T1 (poor risk) disease. A 
major objective response, as documented in 59% of patients (95% CI, 46-72%), 
and treatment was associated with clinical benefits that included improved 
pulmonary function in patients with pulmonary KS; improved ambulation, 
resolution of ulcers, and decreased analgesic requirements in patients with KS of 
the feet; and resolution of facial lesions and edema in patients with KS involving 
the face, extremities, and genitalia. The median time to response was 8.1 weeks 
and the median duration of response, measured from the first day of treatment, 
was 10.4 months (95% CI, 7.0-11.0 months) for patients who previously had 
received chemotherapy. The median time to progression was 6.2 months (95% 
CI, 4.6-8.7 months). Although both treatment regimens induced KS regression, 
the regimen of 100 mg/m2 every 2 weeks was better tolerated than 135 mg/m2 
every 3 weeks, with substantially lower frequencies of severe neutropenia (35% 
versus 76%), febrile neutropenia (9% versus 55%), and opportunistic infections 
(54% versus 76%) among patients in the former group. Notably, only a minority 
of patients were receiving combination ART and 88% had a CD4+ count <200 
cells/µL, reflective of the era in which these studies were conducted. Subsequent 
studies have confirmed the earlier findings. For example, Tulpule et al [41] 
reported the results in 107 previously treated patients, 85% of whom had 
received one or more prior anthracyclines including doxorubicin (49%), PLD 
(37%), and liposomal daunorubicin (46%) but had developed progressive KS or 
treatment intolerance. Complete or partial response was documented in 60 
patients (56%) treated at a PTX dose of 100 mg/m2 as a 3-hour infusion every 2 
weeks, with a median response duration of 8.9 months. Similar findings were 
noted in a British study reported by Stebbing et al. [42] that used the same PTX 
dose and schedule. Amongst 17 patients whose KS had progressed within 6 
months of receiving a liposomal anthracycline, 71% (95% CI, 60-81%) showed a 
major objective response. 
 


 
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Only one clinical trial has attempted to assess PTX’s efficacy as first-line 
chemotherapy for advanced AIDS-KS and to compare its efficacy to that of PLD 
[44]. Although the study, a joint effort of the AIDS Malignancy Consortium (AMC) 
and the Eastern Cooperative Oncology Group (ECOG) that enrolled patients 
from 1998 to 2002, was terminated because of slow accrual, there were sufficient 
numbers of evaluable patients (n=73, 36 on PTX, 37 on PLD) to estimate 
antitumor efficacy and toxicity for each of the treatment arms. At baseline, 73% of 
the patients were receiving a combination ART regimen that included a protease 
inhibitor, an NNRTI, or both. Response and progression-free survival (PFS) were 
not significantly different in the PTX and PLD arms, but favored the PTX arm. 
Using an ITT analysis, the overall complete and partial response rate was 56% 
(95% CI, 39%-75%) for PTX and 46% (95% CI, 30%-62%) for PLD, and median 
PFS was 17.5 months (95% CI, 12.8-21) for PTX and 12.2 months (95% CI, 8.2-
13.9) for PLD. PFS was marginally (p=0.0582) longer for patients receiving 
HAART (17 months) than for those not on HAART (9 months) at study entry. 
 
The toxicity profiles of the agents to be used in this study, although overlapping 
in some cases, are distinct. Bleomycin treatment is often complicated by infusion-
related fever and chills, generally requiring pre-medication with dexamethasone 
and diphenhydramine for control, and is also associated with cutaneous 
toxicities. With higher cumulative doses, pulmonary fibrosis may occur, and 
reduced but asymptomatic decreases in carbon monoxide diffusing capacity 
have been reported after lower doses. Vincristine frequently causes PN, and may 
cause jaw pain and constipation. Neither vincristine nor bleomycin is associated 
with significant hematologic toxicity. Serious or life-threatening toxicities 
associated with oral ET in AIDS-KS have mainly been confined to neutropenia, 
which occurred in about one-third of patients with chemotherapy-refractory 
disease who were entered into a trial of oral ET that used the same schedule 
proposed for the current study [29]. However, only 5 of 36 patients in this study 
were receiving a HAART regimen at the time of study enrollment. At the doses 
proposed for this study, the most commonly reported Grade 3 or 4 toxicity 
associated with PTX is neutropenia. Although PN is commonly reported with 
PTX, most cases are grade 1 or 2, and higher grades occur rarely. PTX 
preparations formulated with Cremophor EL (polyoxyethylated castor oil) may be 
associated with anaphylaxis and severe hypersensitivity reactions characterized 
by dyspnea and hypotension requiring treatment, angioedema, and generalized 
urticaria. These reactions are rarely fatal. Premedication to prevent 
hypersensitivity reactions is required. The drugs are also quite different in their 
emetogenic potential: oral ET is considered to be associated with a moderate 
risk, PTX with a low risk, and bleomycin and vincristine with minimal risk of 
emesis. Oral ET carries no risk of local skin reactions; PTX has a low vesicant 
potential if extravasated; bleomycin is classified as an irritant, and vincristine has 
a high vesicant potential. Although these latter factors may not directly influence 
response to therapy, they can have a significant influence on treatment 
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Because of their relatively low cost and widespread availability, either ABV or BV 
is the current standard of care for chemotherapy of AIDS-KS in many resource-
limited settings. PTX is available in some low-resource settings, but has been 
used there primarily as second-line therapy in patients who have failed on ABV 
or BV [M. Borok, personal communication]. In some resource-limited settings, 
oral ET is also used for chemotherapy of AIDS-KS. Additionally, ET, unlike the 
other regimens discussed above, which require intravenous administration and 
can cause local tissue injury if extravasated, can be administered orally, which 
can provide significant logistic and cost advantages in resource-limited settings. 
Relatively little relevant data exist on which to base comparisons of the cost-
effectiveness of the different available chemotherapeutic agents for AIDS-KS. 
Except for PLD, for which there is no generic form and cost is uniformly high 
(when available), all the other agents are available from multiple generic 
pharmaceutical manufacturers. Costs may vary significantly, however, from 
country to country, and it is not possible to compare costs across sites. In 
addition, the quality and potency of drugs obtained from unregulated generic 
manufacturers cannot be assured. 
  
As noted above, the most effective regimens to use in combination with ART 
have not been well defined, because many of the drugs used to treat KS were 
tested prior to the introduction of HAART. There is, however, preliminary 
evidence that suggests that chemotherapy in combination with effective ART 
may provide benefit for individuals with AIDS-KS. Although 10-30% early 
mortality has been observed in AIDS-KS patients initiating ART in several African 
settings [45,46], in one pilot study treatment with combined chemotherapy and 
ART was associated with a decreased risk of early death for Zimbabweans with 
advanced AIDS-KS [47]. Data from randomized, controlled studies of systemic 
chemotherapy plus ART are limited [48]. In a randomized study of 28 advanced 
AIDS-KS cases in Spain, patients assigned to PLD plus ART had better tumor 
response rates than patients assigned to ART alone [49].  
 
In a randomized comparison of ART alone versus ART plus a chemotherapy 
regimen of ABV in 33 South Africans, participants in the ART plus ABV arm had 
greater reductions in HHV-8/KSHV viral load and tended to have better tumor 
regression and less tumor progression [50].  
 
2.1.3 Justification of A5263/AMC066 Regimens 
 
As discussed above, there is relatively little available data on the relative 
performance of any of the chemotherapy regimens to be included in this study 
when used in combination with currently available ART, and there is no 
evidence-based standard of care for advanced KS in resource-limited settings. 
Each of the chemotherapy regimens we propose to test has induced responses 
in HIV-infected individuals with KS, but the populations studied and the response 
criteria used to evaluate efficacy were non-uniform. Thus, we consider that 
clinical equipoise exists between the three regimens, and that if one regimen in 


 
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this study is proven superior to the others, it will inform clinical practice 
worldwide.  
 
2.1.3.1 Bleomycin plus Vincristine (BV) 
 
The selection of BV, and its choice over ABV in this study was based on 
several considerations. First, the large, randomized, controlled trials of 
liposomal anthracyclines versus BV or ABV were all conducted pre-
HAART. For example, in the randomized trial that compared PLD and 
BV reported by Stewart et al. [33], only half of the patients in each arm 
of the study were receiving any ART, and ART was confined to single or 
combination NRTIs. Little is known about the performance of “standard” 
non-liposomal chemotherapy in combination with ART regimens that 
conform to current standards of care and which have resulted in 
improved overall outcomes for people with AIDS-associated KS. 
 
Second, in their 1998 paper, Stewart et al. [33] commented on the long-
held perception that ABV offered a higher response rate, whereas BV 
offered a better toxicity profile. They noted that ABV and BV had never 
been directly compared in a clinical trial. Although reports had appeared 
in the literature citing response rates of 50% to 80% for these 
combinations, these studies did not use rigorous ACTG KS response 
criteria. In those studies that did use rigorous response criteria, such as 
the studies by Stewart et al. [33], Northfelt et al. [39] and Gill et al. [37], 
the response rates for both BV and ABV were much lower than had 
previously been reported in uncontrolled phase II studies, and were 
comparable to each other. Thus, in studies that used rigorous response 
criteria, there was no evidence that BV was inferior to ABV with respect 
to objective, strictly defined response rates. On the other hand, there 
was good evidence that BV had a superior toxicity profile compared to 
ABV, which was associated with a higher rate of hematologic toxicity 
and treatment delays for neutropenia and infection and also presents 
the risk of serious cardiotoxicity. In addition, as noted by Stewart et al. 
[33], BV was also associated with considerably less myelosuppression 
than liposomal doxorubicin, which may be particularly important in 
locales where hematopoietic growth factors like granulocyte-colony 
stimulating factor (G-CSF) are not available and where access to blood 
component transfusion is limited. 
 
Finally, as part of the development of this study, we polled prospective 
sites about their standard of care for KS and whether they had concerns 
about using either regimen as part of this trial. Of the 14 sites 
responding to the survey, 4 listed BV as their standard of care, 6 listed 
ABV, 2 stated that they were able to administer liposomal anthracyclines 
but often used either BV or ABV because of their lower cost, and 2 
stated that they did not routinely give KS treatment. Eleven sites had no 
concerns about using BV, one site was concerned about drug 


 
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availability after the trial, one site was concerned about interactions with 
ART, and one site felt that ABV was superior to BV. Ten sites had no 
concerns about using ABV, one site was concerned about drug 
availability after the trial, and three sites had other concerns that 
included toxicities of the regimen and issues with doxorubicin 
administration. Thus, there was no clear consensus “favorite,” but there 
were somewhat more concerns about ABV tolerance.  
 
Thus, for all of the above reasons, the study team believes that inclusion 
of BV as a treatment arm in this study is justified and ethical, and that 
the results of this study will provide important information that will inform 
future treatment decisions for AIDS/KS in resource-limited settings. 
 
Vincristine Interactions with Ritonavir 
Vinca alkaloids, including vincristine and vinblastine, are primarily 
metabolized by CYP3A isoenzymes. Several case reports and small 
series have suggested that co-administration of Vinca alkaloids with the 
potent CYP3A inhibitor, ritonavir, may be associated with increased 
hematologic and neurotoxicity. In one small series of HIV-infected 
individuals with Hodgkin’s disease, severe neutropenia was observed 
more commonly among patients receiving ritonavir-boosted PI regimens 
than among those on non-boosted PIs or regimens that did not contain 
a PI [51], and two deaths from neutropenic sepsis were described. 
Severe, prolonged neutropenia (in one case associated with peripheral 
neuropathy and constipation) has also been reported in a patient with 
Hodgkin’s disease [52] and another with multicentric Castleman’s 
disease [53] who received vinblastine with ritonavir-containing ART. The 
patient with Castleman’s disease had multiple episodes when ritonavir 
and vinblastine were co-administered, but tolerated vinblastine well 
when not receiving ritonavir concomitantly. Another single case report 
described severe and prolonged paralytic ileus requiring parenteral 
feeding after co-administration of vincristine and lopinavir/ritonavir, an 
event that did not recur when ET replaced vincristine in the 
chemotherapy regimen. Although none of these studies included 
measurement of Vinca alkaloid pharmacokinetics, and further study is 
required, they suggest that alternatives to ritonavir should be used in 
HIV-infected patients with cancer who require Vinca alkaloid-containing 
chemotherapy regimens together with ART. 
 
2.1.3.2 Etoposide (ET)   
 
At an interim review in March 2016, the DAIDS Co-infections and 
Complications Data Safety Monitoring Board (CCDSMB) found that 
the ET plus ART arm was less effective than the PTX plus ART arm. 
Per the CCDSMB recommendation, enrollment into this arm and all 
initiation of ET in subsequent steps were discontinued in March 
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ET is a chemotherapeutic agent that has demonstrated efficacy for 
treatment of AIDS-KS. ET has potential advantages over the other 
regimens used in this study, particularly in resource-limited settings, 
including intermittent oral dosing without the need for the intensive 
clinical and pharmacy resources associated with the preparation and 
administration of intravenous chemotherapy, a favorable acute toxicity 
profile at low doses, and availability as a relatively inexpensive generic 
formulation. These advantages of ET need to be weighed against the 
long-term risk of myelodysplasia and acute leukemia associated with ET 
administration.  
 
The Cancer Therapeutics Evaluation Program of the National Cancer 
Institute performed a combined analysis of 12 NCI-sponsored 
cooperative group protocols in which ET was administered [54]. They 
divided ET exposure into low (<1.5 g/m2 ET), moderate (1.5-3.0 g/m2) 
and high (>3 g/m2) exposure. They calculated the 6-year risk of 
secondary leukemia/myelodysplasia for the low, moderate, and higher 
cumulative dose groups as 3.3% (95% upper confidence bound of 
5.9%), 0.7% (95% upper confidence bound of 1.6%), and 2.2%, (95% 
upper confidence bound of 4.6%), respectively. Overall there were 17 
cases of leukemia with 5450 person-years of follow-up. These cases 
were not clustered near the time of chemotherapy and incidence rate 
appeared uniform over the 6 years of follow-up. All of these clinical trials 
gave ET in combination with other chemotherapy agents. The 
relationship of ET to leukemia in the absence of other chemotherapeutic 
agents is unknown.  
 
Given the high risk of serious morbidity and mortality from advanced KS, 
the generally good safety and tolerance of oral ET, and the relatively low 
risk of these late complications, the use of ET in this study is justified. 
 
2.1.3.3 Paclitaxel (PTX) 
 
Only two chemotherapeutic agents, PLD and PTX, have received the 
rigorous evaluation required for US FDA approval for treatment of 
advanced AIDS-KS. Although long considered the standard initial 
treatment for advanced KS in developed countries, PLD is currently not 
available and its cost has prevented its widespread use in resource-
limited settings. The data summarized above suggest that PTX, which, 
despite its availability as an affordable, generic product, is not generally 
used as first-line therapy in resource-limited settings, shows antitumor 
activity against KS that is similar to or better than that with PLD. At the 
doses used to treat AIDS-KS, PTX is generally well-tolerated, and can 
be considered an appropriate standard against which other treatments 
for advanced AIDS-KS in resource-limited settings should be compared. 
If this trial shows that therapy with currently available standard agents 


 
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(i.e., ET or BV) with ART are similar to those obtained with PTX with 
ART, this would favor the use of the less-expensive or better-tolerated 
regimen. On the other hand, if we find that PTX is clearly superior to the 
alternatives, this could provide important information that could influence 
policy concerning the availability and use of first-line chemotherapy in 
resource-limited settings. 
 
Although in the previously cited clinical trials, PTX was administered 
over a 3-hour infusion, subsequent studies have shown that PTX can be 
safely administered over 1-hour, and many practitioners routinely use a 
1-hour infusion for treatment of AIDS-KS and other malignancies [55]. In 
addition, 1-hour infusion times have been associated with less 
myelosuppression, presumably as a result of reduced exposure to 
unbound drug [56]. In addition to using the better-tolerated PTX dose of 
100 mg/m2 (as opposed to 135 mg/m2) to mitigate toxicity, we will also 
use an every 3 week administration schedule to permit sufficient 
recovery of blood counts under circumstances where hematopoietic 
growth factor support is not routinely available.  
 
Based on the above considerations, we believe that the evaluation of 
PTX at the proposed dose, schedule, and infusion time in this study is 
justified. 
 
PTX Interactions with Antiretroviral Therapy 
PTX is metabolized in the liver predominantly by cytochromes P450 2C8 
and 3A4 via saturable elimination to less potent metabolites, indicating 
that modest changes in dose or metabolizing enzyme activity could 
result in disproportionately large alterations in systemic exposure, 
potentially influencing toxicity and response. In addition, PTX is a 
substrate for several drug transporters including ABCB1, ABCC1, 
ABCC2 and ABCG2. Pharmacodynamic analyses have shown 
hematologic and non-hematologic toxicity to correlate better with 
parameters of PTX exposure (e.g., area under the plasma 
concentration-time curve (AUC) and duration of plasma concentrations 
exceeding 0.1 mmol/L) than with the administered dosage. 
 
Although PTX has, for the most part, been well tolerated in combination 
with ART, rare reports of severe PTX toxicity have been attributed to 
concomitant ART, including protease inhibitors [57,58]. To address 
potential drug-drug interactions, a pilot study conducted jointly by the 
ECOG and AMC (AMC014/E1D95) evaluated the interactions between 
PTX and ART in patients with AIDS-KS [59]. Thirty-three patients 
received PTX as a 100 mg/m2 IV infusion over 3 hours every 14 days, of 
whom 27 underwent PK studies. There was a trend for PTX maximum 
concentration (Cmax) to be elevated in the 16 patients taking protease 
inhibitors (nelfinavir, indinavir, or multiple inhibitors) compared to the 11 
patients not taking protease inhibitors (1.47±0.68 µM versus 1.01±0.34 


 
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µM; p=0.11; Wilcoxon t-test). However, the PTX AUCinf, which was 
evaluable in only 21 patients, was significantly higher in the 15 patients 
taking protease inhibitors compared to the 6 patients not taking protease 
inhibitors (5.5±2.2 µM hour versus 2.9±0.7 µM hour; p=0.016; Wilcoxon 
t-test). Yet, there was no difference in the duration spent at a PTX 
concentration >0.05 μM (19.0 (3.0–27.8) hour versus 6.7 (3.0–22.7) 
hour; p=0.97). Patients with higher PTX exposure did not experience 
more significant granulocytopenia (Cmax p=0.96; AUCinf p=0.83; 
Time>C0.5 μM p=0.09; Wilcoxon t-test), and grade 3 or higher 
neurotoxicity occurred in only 5%.  
 
EFV induces CYP3A4 and the transporter ABCC1 inhibits several drug 
transporters (ABCB1, ABCC1, ABCC2, and ABCG2). Based on the 
metabolic profiles of PTX and EFV, there is potential for interaction. 
However, there are no clinical data to support decreased efficacy or 
increased toxicity and currently no basis for changing the doses of either 
PTX or ART. The A5278 substudy will investigate these potential PK 
interactions. 
  
2.2 
Rationale 
 
Most comparative clinical trials of different chemotherapy regimens for AIDS-KS 
were conducted prior to the availability of HAART, so scant data are available to 
guide the optimal use of chemotherapy in combination with ART. The need for 
such data is particularly acute in resource-limited settings where rates of HIV and 
KSHV co-infection are high, and where significant morbidity and mortality are 
associated with KS. In addition, despite evidence cited above that adjunctive 
chemotherapy might be beneficial for treatment of AIDS-KS, HIV-1 treatment 
programs often do not provide funding for chemotherapy in resource-limited 
countries. Thus, a well-designed clinical study to define the potential benefits of 
adjunctive chemotherapy in the treatment of advanced AIDS-KS in the era of 
HAART is needed to inform treatment guidelines. Such a study needs to take 
into account the ability of different treatments to induce KS regression, the impact 
of therapy on quality of life (including relief of KS-associated signs and 
symptoms, drug-related toxicities, and effects on HIV control), ease of 
administration of therapy (which may have an impact on adherence), and cost. 
Because there is no single chemotherapeutic agent that has proven superior to 
others in combination with ART, and because the availability of 
chemotherapeutic agents and the current standards for treatment of AIDS-KS 
differ in different resource-limited settings, a randomized comparison of PTX with 
either BV or ET is justified. 
 
 


 
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3.0 
STUDY DESIGN 
 
Step 1:  
Participants will be randomized 1:1 to bleomycin and vincristine (BV) plus antiretroviral 
therapy (ART) or paclitaxel (PTX) plus (ART). 
 
At an interim review in March 2016, the CCDSMB found that the ET plus ART arm 
was less effective than the PTX plus ART arm. Per the CCDSMB recommendation, 
enrollment into this arm and all initiation of ET in subsequent steps were 
discontinued in March 2016.  
 
Step 2:  
Participants who originally have an Independent Endpoint Review Committee (IERC)-
confirmed (complete or partial [CR or PR]) Kaposi’s sarcoma (KS) response to Step 1 
chemotherapy and subsequent IERC-confirmed KS progression at least 12 weeks after 
the last dose of Step 1 chemotherapy, but prior to week 72, and who, in the opinion of 
the investigator, could potentially benefit from another course of the same 
chemotherapy, may be provided a second course of up to six cycles of the same 
chemotherapy utilized in Step 1.  
 
Participants who completed one course of ET will not receive a second course of 
ET. These participants will be entered into Step 3. 
 
Step 3:  
Participants will move to Step 3 when (1) there is IERC-confirmed KS progression at any 
time during Step 1 chemotherapy; or (2) there is IERC-confirmed KS progression fewer 
than 12 weeks after the last chemotherapy dose in Step 1 in participants who have had 
an IERC-confirmed CR or PR; or (3) there is IERC-confirmed KS progression following 
Step 1 chemotherapy, without any prior response; or (4) there is IERC-confirmed KS 
progression in Step 2; or (5) with concurrence of the CMC, there is dose-limiting 
toxicity after receiving fewer than four cycles of chemotherapy in Step 1 or Step 2, in the 
absence of a CR or PR. Participants otherwise eligible for Step 2 who, in the opinion of 
the investigator and with concurrence of the CMC, are unlikely to benefit from another 
course of the same chemotherapy received in Step 1 will also be eligible for 
randomization in Step 3.  
 
Participants must enter Step 3 within the 72 weeks following Step 1 randomization.  
 
Participants will receive the chemotherapy not utilized in Step 1 (BV recipients will 
receive PTX; PTX recipients will receive BV).  
 
If participants completed ET in Step 1 and/or Step 2, then the choice of BV or PTX 
will be randomly assigned (1:1).  
 
Participants currently receiving ET in Step 1 or Step 2 may continue and complete 
ET or discontinue ET and enter Step 3 in discussion with the local investigator 


 
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and in consultation with the CMC. These participants will be randomized (1:1) to 
receive BV or PTX. 
 
Step 4:  
Please note that Step 4 applies only to those who received ET in Step 1, Step 2, or 
Step 3. 
 
If there is IERC-confirmed KS progression in Step 3 or, with concurrence of the 
CMC, if there is dose-limiting toxicity after receiving fewer than four cycles of 
chemotherapy in Step 3, in the absence of a CR or PR, participants may enter Step 4 
or be offered alternative care available locally outside of the study, whichever the 
investigator deems most appropriate. If an investigator offers locally-available 
alternative care, the participants will be followed according to their original Step 3 
schedule. 
 
Participants must enter Step 4 within 72 weeks following Step 1 randomization.  
 
Participants will be assigned to the remaining study-provided chemotherapy not given 
in Step 1, Step 2, or Step 3.  
 
Participants who are currently receiving ET in Step 3 may continue ET or 
discontinue ET and start the remaining chemotherapy regimen in Step 4 in 
discussion with the local investigator and in consultation with the CMC. 
 
If there is IERC-confirmed KS progression in Step 4, participants may be offered 
alternative care available locally, outside of the study. If an investigator offers locally 
available alternative care, the participants will be followed according to their original Step 
4 schedule.  
 
Participants who receive ET while on study will be followed for 144 weeks after 
beginning the last cycle of ET. All other participants will be followed for 96 weeks 
after randomization or assignment to the last step they enter. 
 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria Step 1 
 
4.1.1 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 
RNA viral load. 
 


 
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NOTE: The term “licensed” refers to a U.S FDA-approved kit or for sites located 
in countries other than the United States, a kit that has been certified or licensed 
by an oversight body within that country and validated internally.  
 
WHO (World Health Organization) and CDC (Centers for Disease Control and 
Prevention) guidelines mandate that confirmation of the initial test result must 
use a test that is different from the one used for the initial assessment. A reactive 
initial rapid test should be confirmed by either another type of rapid assay or an 
E/CIA that is based on a different antigen preparation and/or different test 
principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 
RNA viral load. 
 
4.1.2 Biopsy diagnostic of KS at any time prior to study entry. 
 
4.1.3  Current KS stage T1 using ACTG criteria [29]. 
 
KS stage T1 is KS with any of the following: 
 
symptomatic tumor-associated edema 
 
tumor ulceration 
 
extensive oral KS (other than flat KS confined to the hard palate) 
 
gastrointestinal KS 
 
KS in any other non-nodal visceral organ (e.g., lung) 
 
4.1.4 A minimum of five indicator KS cutaneous marker lesions (or if fewer than five 
marker lesions are available, the total surface area of the marker lesion(s) 
must be 700 mm2) plus an additional two lesions greater or equal to 4x4 mm 
that are accessible for punch biopsy. 
 
Please refer to the A5263/AMC066 Manual of Operations (MOPS) located on the 
PSWP for instructions on determining cutaneous marker lesions. 
 
4.1.5 CD4+ lymphocyte cell count obtained within 28 days prior to study entry at a 
DAIDS-approved laboratory. 
 
4.1.6 The following laboratory values obtained within 14 days prior to study entry: 
 
Absolute neutrophil count (ANC) 1000 cells/mm3 
 
Hemoglobin 8.0 g/dL 
 
Platelet count 100,000/mm3 
 
Estimated creatinine clearance of ≥60 mL/min using the formula: 
CrCl = {[140 – age (years)]  [weight (kg)]} ÷ [72  serum Cr (mg/dL)] 
(multiply the result x 0.85 for female participants) 
 
NOTE: The Cockroft-Gault calculation program can be found on DMC 
website (http://www.fstrf.org/ACTG/index.html). 
 


 
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 
AST (SGOT), ALT (SGPT), and alkaline phosphatase <5ULN  
 
Total bilirubin of <1.5ULN 
 
4.1.7 Female study participants of reproductive potential (defined as girls who have 
reached menarche, women who have not been post-menopausal for at least 24 
consecutive months, i.e., who have had menses within the preceding 24 months, 
or women who have not undergone surgical sterilization, specifically 
hysterectomy and/or bilateral oophorectomy) must have a negative serum or 
urine pregnancy test with a sensitivity of 15–25 mIU/mL performed within 48 
hours before initiating the protocol-specified medications.  
 
4.1.8 All participants must agree not to participate in a conception process (active 
attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization). 
 
4.1.9 If participating in sexual activity that could lead to pregnancy, the study 
participant must agree that two reliable forms of contraceptives will be used 
simultaneously while receiving protocol-specified medications, and for 12 weeks 
after stopping the medications. 
 
Male participants must agree to use condoms while receiving protocol-
specified medications and for 12 weeks after stopping the medications. 
Documentation of the second form of contraception, used by the female 
partner, is by report of the study participant. 
 
Study participants who are not of reproductive potential (women who have been 
post-menopausal for at least 24 consecutive months or have undergone 
hysterectomy and/or bilateral oophorectomy or men who have documented 
azoospermia) are eligible without the use of contraceptives. Acceptable 
documentation of sterilization and menopause is specified in Appendix I and 
includes physician report. 
 
4.1.10 Men and women age 18 years. 
 
4.1.11 Ability to swallow oral medications and adequate venous access. 
 
4.1.12 Karnofsky performance status ≥60 within 28 days prior to entry. 
 
4.1.13 Ability and willingness of participant or legal guardian/representative to provide 
informed consent. 
 
4.2 
Exclusion Criteria Step 1 
 
4.2.1 Current chronic, acute, or recurrent infections that are serious, in the opinion of 
the site investigator, for which the participant has not completed at least 14 days 
of therapy prior to study entry and/or is not clinically stable.  
 


 
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4.2.2 Serious illness requiring systemic treatment and/or hospitalization within 14 days 
prior to entry. 
 
4.2.3 Current or history of known pulmonary fibrosis, chronic obstructive pulmonary 
disease (COPD), emphysema, bronchiectasis, or diffuse or significant local 
radiographic interstitial infiltrates on chest x-ray (CXR) or computed axial 
tomography (CT) scan, that, in the opinion of the investigator, would exclude 
bleomycin use. 
 
NOTE: Participants with an abnormal CXR or CT scan (which may indicate 
pulmonary KS) should undergo screening evaluations to rule out an infectious 
cause, per standard of care. If available, other diagnostic procedures such 
as bronchoscopy should be considered to confirm the presence or 
absence of pulmonary KS and/or an infectious agent. These procedures 
should be completed outside the study. These participants should be 
excluded if, in the opinion of the site investigator, use of bleomycin would be 
detrimental. 
 
4.2.4 Oxygen saturation less than 90% and/or exercise desaturation greater than 4% 
within 14 days prior to study enrollment.  
 
NOTE: Exercise is defined as any activity that will increase a participant’s resting 
heart rate by at least 20 beats/minute. 
 
4.2.5 Grade ≥3 peripheral neuropathy (PN). 
 
NOTE: Severity of PN will be determined by the symptom severity scores from 
the Brief Peripheral Neuropathy Screen (BPNS), discussed in section 6.3.20.  
4.2.6 Breastfeeding. 
 
4.2.7 Receipt of ART for more than 42 days immediately prior to entry. ART is allowed 
within the 42-day window prior to study entry. 
 
NOTE: The use of single-dose nevirapine (NVP) or zidovudine (ZDV) for any 
period of time during pregnancy to prevent mother to child transmission (MTCT) 
of HIV is allowed.  
 
NOTE: Successful post-exposure prophylaxis is allowed. Unsuccessful post-
exposure prophylaxis is not allowed. 
 
4.2.8 Prior or current systemic or locally administered chemotherapy. 
 
4.2.9 Prior or current radiation therapy. 
 
4.2.10 Prior or current immunotherapy, e.g., interferon alfa. 
 


 
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4.2.11 Corticosteroid use at doses above those given as replacement therapy for 
adrenal insufficiency within the last 30 days prior to study entry. A tapering 
course of corticosteroids as acute therapy for Pneumocystis carinii pneumonia 
(PCP) or other conditions is an exception and is allowed. 
 
4.2.12 Any immunomodulator, HIV vaccine, live attenuated vaccines, or other 
investigational therapy or investigational vaccine within 30 days prior to study 
entry.  
 
NOTE: Using G-CSF to increase neutrophil count prior to study entry is not 
permitted under this exclusion criterion.  
 
4.2.13 Known allergy/sensitivity or any hypersensitivity to components of study drugs or 
their formulation. 
 
4.2.14 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.2.15 Current or anticipated receipt of any of the prohibited medications listed in 
section 5.5.2. 
 
4.2.16 In the opinion of the investigator, any psychological or social condition, or 
addictive disorder that would preclude compliance with the protocol. 
 
4.3 
Inclusion Criteria Step 2  
 
4.3.1 IERC-confirmed CR or PR to the chemotherapy regimen used in Step 1. 
 
4.3.2 IERC-confirmed KS progression at least 12 weeks after the last dose of Step 1 
chemotherapy. 
4.3.3 Fewer than 72 weeks after Step 1 entry. 
 
4.3.4 The following laboratory values obtained within 14 days prior to Step 2 entry: 
 
ANC ≥1,000 cells/mm3 
 
Hemoglobin ≥8.0 g/dL 
 
Platelet count ≥100,000/mm3 
 
Estimated creatinine clearance of ≥60 mL/min using the formula: 
CrCl = {[140 – age (years)]  [weight (kg)]} ÷ [72  serum Cr (mg/dL)]  
(multiply the result x 0.85 for female participants) 
 
NOTE: The Cockroft-Gault calculation program can be found on DMC 
website (http://www.fstrf.org/ACTG/index.html). 
 
 
AST (SGOT), ALT (SGPT), and alkaline phosphatase <5ULN 
 
Total bilirubin of <1.5ULN 
 


 
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4.3.5 For females of reproductive potential, negative serum or urine pregnancy test 
within 7 days prior to Step 2 entry. The urine test must have a sensitivity of 15-25 
mIU/mL. 
 
NOTE: Females not of reproductive potential who do not have required 
documentation must also undergo pregnancy testing.  Acceptable 
documentation of sterilization and menopause is specified in Appendix I 
and includes physician report.  
 
4.3.6 Karnofsky performance status ≥50 within 28 days prior to Step 2. 
 
4.3.7 All participants must agree not to participate in a conception process (active 
attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization). 
4.4 
Exclusion Criteria Step 2 
 
4.4.1 Current chronic, acute, or recurrent infections that are serious, in the opinion of 
the site investigator, for which the participant has not completed at least 14 days 
of therapy prior to Step 2 entry and/or is not clinically stable.  
 
4.4.2 Severe toxicity to the chemotherapy regimen used in Step 1 requiring 
discontinuation of study chemotherapy. 
 
4.4.3 Serious illness, other than progressive KS, requiring systemic treatment and/or 
hospitalization within 14 days prior to Step 2 entry. 
 
4.4.4 For participants who received bleomycin in Step 1: 
 
Development of pulmonary fibrosis, COPD, emphysema, bronchiectasis, and 
diffuse or significant local radiographic interstitial infiltrates on CXR or CT 
scan that in the opinion of the site investigator would exclude bleomycin use. 
 
Participants with an abnormal CXR or CT scan (which may indicate 
pulmonary KS) should undergo screening evaluations to rule out an infectious 
cause, per standard of care. If available, other diagnostic procedures such as 
bronchoscopy should be considered to confirm the presence or absence of 
pulmonary KS and/or an infectious agent. These procedures should be 
completed outside the study. These participants should be excluded if, in the 
opinion of the investigator, use of bleomycin in Step 2 would be detrimental. 
 
Oxygen saturation less than 90% or exercise desaturation greater than 4% 
within the last 30 days prior to Step 2 entry.  
 
NOTE: Individuals meeting any of the above exclusion criteria should be 
evaluated for eligibility to receive PTX in Step 3. 
 
NOTE: Exercise is defined as any activity that will increase a participant’s resting 
heart rate by 20 beats/minute. 
 
4.4.5 For participants who received vincristine or PTX in Step 1, Grade ≥3 PN at Step 
2 entry. 


 
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NOTE: Severity of PN will be determined by the symptom severity scores from 
the BPNS, discussed in section 6.3.20.  
 
4.4.6 Breastfeeding. 
 
4.4.7 Other concurrent chemotherapy, immunotherapy, or radiotherapy. 
 
4.4.8 Systemic corticosteroid use at doses above those given as replacement therapy 
for adrenal insufficiency within 30 days of Step 2 entry. 
 
NOTE: A tapering course of corticosteroids as acute therapy for PCP or if 
required for management of IRIS is an exception.  
 
4.4.9 Receipt of ET in Step 1. 
 
4.5 
Inclusion Criteria Step 3 
 
4.5.1 IERC-confirmed KS progression at any time during Step 1 chemotherapy OR  
 
IERC-confirmed KS progression fewer than 12 weeks after the last 
chemotherapy dose in Step 1 in participants who have had an IERC-
confirmed CR or PR OR 
 
IERC-confirmed KS progression following Step 1 chemotherapy, without any 
prior response OR 
 
IERC-confirmed KS progression in Step 2 OR  
 
With concurrence of the CMC, there is dose-limiting toxicity after receiving 
fewer than four cycles of chemotherapy in Step 1 or Step 2, in the absence 
of a CR or PR OR 
 
Participants otherwise eligible for Step 2 who, in the opinion of the 
investigator and with concurrence of the CMC, are unlikely to benefit from 
another course of the same chemotherapy received in Step 1. 
 
4.5.2 Fewer than 72 weeks after Step 1 entry. 
 
4.5.3 The following laboratory values obtained within 14 days prior to Step 3 entry: 
 
ANC ≥1,000 cells/mm3 
 
Hemoglobin ≥8.0 g/dL 
 
Platelet count ≥100,000/mm3 
 
Estimated creatinine clearance of ≥60 mL/min using the formula:  
CrCl = {[140 – age (years)]  [weight (kg)]} ÷ [72  serum Cr (mg/dL)] 
(multiply the result x 0.85 for female participants) 
 
NOTE: The Cockroft-Gault calculation program can be found on DMC 
website (http://www.fstrf.org/ACTG/index.html). 
 


 
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 
AST (SGOT), ALT (SGPT), and alkaline phosphatase <5ULN  
 
Total bilirubin of <1.5ULN 
 
4.5.4 For females of reproductive potential, negative serum or urine pregnancy test 
within 7 days prior to Step 3 entry. The urine test must have a sensitivity of 15-25 
mIU/mL. 
 
NOTE: Females not of reproductive potential who do not have required 
documentation must also undergo pregnancy testing.  Acceptable 
documentation of sterilization and menopause is specified in Appendix I 
and includes physician report.  
 
4.5.5 Karnofsky performance status ≥50 within 28 days prior to Step 3 entry. 
 
4.5.6 All participants must agree not to participate in a conception process (active 
attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization). 
 
4.6 
Exclusion Criteria Step 3 
 
4.6.1 Current chronic, acute, or recurrent infections that are serious, in the opinion of 
the site investigator, for which the participant has not completed at least 14 days 
of therapy prior to Step 3 entry and/or is not clinically stable.  
 
4.6.2 Serious illness, other than progressive KS, requiring systemic treatment and/or 
hospitalization within 14 days prior to Step 3 entry. 
 
4.6.3 Eligible for Step 2 entry. 
 
4.6.4 For participants who did NOT receive bleomycin in Step 1 or Step 2: 
 
Development of pulmonary fibrosis, COPD, emphysema, bronchiectasis, and 
diffuse or significant local radiographic interstitial infiltrates on CXR or CT 
scan that in the opinion of the site investigator would exclude bleomycin use. 
 
Participants with an abnormal CXR or CT scan (which may indicate 
pulmonary KS) should undergo screening evaluations to rule out an infectious 
cause, per standard of care. If available, other diagnostic procedures such as 
bronchoscopy should be considered to confirm the presence or absence of 
pulmonary KS and/or an infectious agent. These procedures should be 
completed outside the study. These participants should be excluded if, in the 
opinion of the investigator, use of bleomycin in Step 3 would be detrimental. 
 
Oxygen saturation less than 90% or exercise desaturation greater than 4% 
within the last 30 days prior to Step 3 entry.  
 
NOTE: Exercise is defined as any activity that will increase a participant’s resting 
heart rate by 20 beats/minute. 
 


 
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4.6.5 Grade ≥3 PN at Step 3 entry. 
 
NOTE: Severity of PN will be determined by the symptom severity scores from 
the BPNS, discussed in section 6.3.20.  
 
4.6.6 Breastfeeding. 
 
4.6.7 Other concurrent chemotherapy, immunotherapy, or radiotherapy. 
 
4.6.8 Systemic corticosteroid use at doses above those given as replacement therapy 
for adrenal insufficiency within 30 days of Step 3 entry. 
 
NOTE: A tapering course of corticosteroids as acute therapy for PCP or if 
required for management of IRIS is an exception.  
 
4.7 
Inclusion Criteria Step 4 
 
4.7.1  
 
IERC-confirmed KS progression in Step 3 OR  
 
With concurrence of the CMC, dose-limiting toxicity after receiving fewer 
than four cycles of chemotherapy in Step 3, in the absence of a CR or PR 
OR  
 
Current receipt of ET in Step 3 
 
4.7.2 Fewer than 72 weeks after Step 1 entry. 
 
4.7.3 The following laboratory values obtained within 14 days prior to Step 4 entry: 
 
ANC ≥1,000 cells/mm3. 
 
Hemoglobin ≥8.0 g/dL. 
 
Platelet count ≥100,000/mm3. 
 
Estimated creatinine clearance of ≥60 mL/min using the formula:  
CrCl = {[140 – age (years)]  [weight (kg)]} ÷ [72  serum Cr (mg/dL)] 
(multiply the result x 0.85 for female participants) 
 
NOTE: The Cockroft-Gault calculation program can be found on DMC 
website (http://www.fstrf.org/ACTG/index.html). 
 
AST (SGOT), ALT (SGPT), and alkaline phosphatase <5ULN.  
 
Total bilirubin of <1.5ULN. 
 
4.7.4 For females of reproductive potential, negative serum or urine pregnancy test 
within 7 days prior to Step 4 entry. The urine test must have a sensitivity of 15-25 
mIU/mL. 
 
NOTE: Females not of reproductive potential who do not have required 
documentation must also undergo pregnancy testing.  Acceptable 


 
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documentation of sterilization and menopause is specified in Appendix I 
and includes physician report.  
 
4.7.5 Karnofsky performance status ≥50 within 28 days prior to Step 4 entry. 
 
4.7.6 All participants must agree not to participate in a conception process (active 
attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization). 
 
4.7.7 Receipt of ET in Step 1, Step 2, or Step 3. 
 
4.8 
Exclusion Criteria Step 4 
 
4.8.1 Current chronic, acute, or recurrent infections that are serious, in the opinion of 
the site investigator, for which the participant has not completed at least 14 days 
of therapy prior to Step 4 entry and/or is not clinically stable.  
 
4.8.2 Serious illness, other than progressive KS, requiring systemic treatment and/or 
hospitalization within 14 days prior to Step 4 entry. 
 
4.8.3 For participants who did NOT receive bleomycin in Step 1, Step 2, or Step 3: 
 
Development of pulmonary fibrosis, COPD, emphysema, bronchiectasis, and 
diffuse or significant local radiographic interstitial infiltrates on CXR or CT 
scan that in the opinion of the site investigator would exclude bleomycin use. 
 
Participants with an abnormal CXR or CT scan (which may indicate 
pulmonary KS) should undergo screening evaluations to rule out an infectious 
cause, per standard of care. If available, other diagnostic procedures such as 
bronchoscopy should be considered to confirm the presence or absence of 
pulmonary KS and/or an infectious agent. These procedures should be 
completed outside the study. These participants should be excluded if, in the 
opinion of the investigator, use of bleomycin in Step 4 would be detrimental. 
 
Oxygen saturation less than 90% or exercise desaturation greater than 4% 
within the last 30 days prior to Step 4 entry.  
 
NOTE: Exercise is defined as any activity that will increase a participant’s resting 
heart rate by 20 beats/minute. 
 
4.8.4 Grade ≥3 PN at Step 4 entry. 
 
NOTE: Severity of PN will be determined by the symptom severity scores from 
the BPNS, discussed in section 6.3.20.  
 
4.8.5 Breastfeeding. 
 
4.8.6 Other concurrent chemotherapy, immunotherapy, or radiotherapy. 
 
4.8.7 Systemic corticosteroid use at doses above those given as replacement therapy 
for adrenal insufficiency within 30 days of Step 4 entry. 


 
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NOTE: A tapering course of corticosteroids as acute therapy for PCP or if 
required for management of IRIS is an exception.  
 
4.9 
Study Enrollment Procedures 
 
4.9.1 Site-specific informed consent forms (ICFs) WILL be reviewed and approved by 
the DAIDS Protocol Registration Office (DAIDS PRO) and sites will receive an 
Initial Registration Notification from the DAIDS PRO that indicates successful 
completion of the protocol registration process. A copy of the Initial Registration 
Notification should be retained in the site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable regulatory entities (RE) 
approval(s) for an amendment, sites should implement the amendment 
immediately. Sites are required to submit an amendment registration packet to 
the DAIDS PRO at the Regulatory Support Center (RSC). The DAIDS PRO will 
review the submitted protocol registration packet to ensure that all the required 
documents have been received. Site-specific ICFs WILL NOT be reviewed and 
approved by the DAIDS PRO and sites will receive an Amendment Registration 
Notification when the DAIDS PRO receives a complete registration packet. A 
copy of the Amendment Registration Notification should be retained in the site's 
regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual. 
 
4.9.2 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist 
found on the ACTG Member website. This checklist must be approved prior 
to any screening of participants for enrollment.  
 
4.9.3 Randomization 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database. 
 
Participants who meet eligibility criteria for A5263/AMC066 will be registered to 
the study according to standard ACTG Data Management Center procedures. 
 
4.10 
Co-enrollment Guidelines 
 
 
Sites are strongly encouraged to co-enroll participants in stand-alone substudy 
A5278s, “Pharmacology Substudies of A5263 and A5264.” Co-enrollment in A5278s 
does not require permission from the A5263/AMC066 protocol chairs.  


 
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 
Sites are strongly encouraged to co-enroll participants in A5243, “Plan for Obtaining 
Human Biological Samples at Non-US Clinical Research Sites for Currently 
Unspecified Genetic Analyses.” Co-enrollment in A5243 does not require permission 
from the A5263/AMC066 protocol chairs.  
 
For specific questions and approval for co-enrollment in other studies, sites must 
contact the protocol chairs via e-mail as described in the Study Management section. 
 
5.0 
STUDY TREATMENT  
 
Study-provided medications are ET, bleomycin sulfate, vincristine sulfate, PTX, 
FTC/TDF (Truvada®), EFV (Stocrin®), and EFV/FTC/TDF (Atripla®). 
 
ET, bleomycin sulfate, vincristine sulfate, and PTX are FDA Pregnancy Category 
D. 
 
Study treatment is considered any of the premedications for chemotherapy, any of 
the chemotherapy regimens plus study-provided ART or an approved, non-study-
provided ART regimen.  
 
Participants will have access to local standard of care ART and chemotherapy through 
local treatment programs available at the sites following study week 96. As part of their 
site implementation plan (SIP), sites are required to demonstrate that they have 
developed the appropriate relationship with local treatment programs to provide the local 
standard of care for ART and chemotherapy. Please refer to the A5263/AMC066 PSWP 
for the detailed SIP. 
 
5.1 
Regimens, Administration, and Duration 
 
Detailed instructions for administration of the chemotherapeutic study products used in 
this study and premedication and antiemetic guidelines are given in the A5263/AMC066 
MOPS. 
 
5.1.1  Step 1 
 
At entry, participants will be randomized in a 1:1 ratio to receive ART with 
EFV/FTC/TDF (Atripla®) plus either treatment regimen 1B or 1C as listed 
below. 
 
5.1.1.1 Chemotherapeutic Agents 
 
Treatment 
Arm 
Study 
Product 
Dosage 
Route/Time 
Frequency/Duration 
1A 
Etoposide 
(ET) 
Initiation of ET in all steps was discontinued as of March, 2016. 
The following treatment instructions are provided for 


 
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Treatment 
Arm 
Study 
Product 
Dosage 
Route/Time 
Frequency/Duration 
participants currently receiving ET in any step who elect to 
complete their current course of ET: 
50 mg orally twice daily (with escalation on subsequent cycles up to 
a maximum of 100 mg twice daily, depending on toxicity) for 7 
consecutive days of every 3-week cycle for maximum of six cycles at 
the highest dose achieved. 
1B 
Vincristine 
sulfate (V) 
2 mg/2mL 
solution 
IV over 1 minute 
(maximum 5 minutes)4 
Every 3 weeks for up 
to six cycles 
Bleomycin 
sulfate (B) 
15 units/m2 in 50 
mL 0.9% sodium 
chloride for 
injection1 
IV over 10 minutes 
(maximum 60 minutes) 4 
Every 3 weeks for up 
to six cycles 
1C 
Paclitaxel 
(PTX) 
100 mg/m2 in 
200 mL, 250 
mL, or 500 mL 
of 5% dextrose 
or 0.9% sodium 
chloride for 
injection1,2,3 
IV over 1 hour 
(maximum 3 hours) 
using  non-PVC  
administration set and 
≤0.22 micron inline-filter4 
Every 3 weeks for up 
to six cycles 
1  The dose of bleomycin and PTX to be administered will be calculated based on body 
surface area expressed in square meters (m2). See the PSWP for further instructions 
2 
The final concentration of prepared PTX injection in 5% dextrose or 0.9% sodium chloride 
for IV administration must be between 0.3 to 1.2 mg/mL. 
3 
Premedication MUST be given prior to administration of each dose of PTX. Please refer to 
the A5263/AMC066 MOPS for instructions on the drugs, dosages, and timing of 
premedication. 
4 
The preferred time for IV infusions is as shown, but may, if necessary, be prolonged 
up to the maximum duration as noted in parentheses under the “Route/Time” column 
for each IV study product. Deviations from these lower and upper ranges must be 
reported and explained.  
 
5.1.1.2 Etoposide (ET) 
 
Initiation of ET in all steps was discontinued in March 2016. The 
following treatment instructions are provided for participants 
currently receiving ET in any step who elect to complete their 
current course of ET: 
 
Beginning on day one of the chemotherapy cycle, ET will be given orally 
in a dose of 50 mg twice daily for 7 consecutive days for the first cycle. If 
there is no Grade ≥2 toxicity attributable to ET after the first cycle, the 
dose will be escalated to 150 mg daily for 7 days in divided doses of 100 
mg/50 mg for the second cycle. After the second cycle, if there is no 


 
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Grade ≥2 toxicity attributable to ET, the dose will be escalated to 100 
mg twice daily for 7 days for the third and subsequent cycles. 
ET should be taken on an empty stomach. Because there is no 
information concerning the administration of ET and didanosine (DDI), if 
a participant is also taking DDI, it is preferable that ET and DDI not be 
given within 2 hours of each other.  
  
Each cycle of ET should begin 21 days (+2 days) after the first day 
of the previous cycle. A new cycle of ET must not be started earlier 
than 19 days after the first dose of the previous cycle.  
  
Treatment with ET will continue for six cycles at the maximum tolerated 
dose or until toxicity requiring discontinuation of study chemotherapy, or 
the site investigator, after consulting with the CMC, has determined that 
alternative therapy is required, whichever occurs first.  
 
If ET dose reduction is required after dose escalation, any cycles 
administered at a higher dose will be counted as part of the six 
cycles at the maximum tolerated dose. Under no circumstances 
should participants receive a total of more than eight cycles of ET. 
No ET will be administered after week 96. Any unused ET returned by 
the participant should be returned to the pharmacy. 
 
See section 7.0 for ET dosage modifications.  
 
5.1.1.3 Bleomycin and Vincristine (BV) 
 
BV will be administered on day one of each chemotherapy cycle. 
 
5.1.1.3.1 Vincristine sulfate will be administered at a dose of 2 mg 
(fixed dose) in a volume of 2 mL over 1 minute (see section 
5.1.1 for note regarding acceptable IV infusion times) into 
the sidearm of a rapidly flowing intravenous infusion every 3 
weeks (+2 days) (see section 7.0 for specific instructions 
regarding dosage reduction for participants with elevated 
bilirubin or AST). The vincristine infusion will be followed by 
bleomycin as detailed below. 
 
5.1.1.3.2 Bleomycin sulfate will be administered at a dose of 15 
units/m2 over 10 minutes (see section 5.1.1 for note 
regarding acceptable IV infusion times) every 3 weeks (+2 
days) (see section 7.0 for specific instructions regarding 
dosage reduction for participants whose creatinine clearance 
falls below 60 mL/min). 
 
Maximum cumulative lifetime total dose of bleomycin is 400 
units. 


 
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See section 7.0 for specific instructions regarding bleomycin 
dosage modification for participants with reduced creatinine 
clearance. 
 
5.1.1.3.3 BV will be administered on day one of each 3-week cycle. 
 
Each cycle of BV should be administered 21 days (+2 
days) after the first day of the previous cycle. BV must 
not be administered earlier than 19 days after the 
previous cycle.  
 
Treatment with BV will continue for six cycles, or until toxicity 
requiring discontinuation of study chemotherapy, or the site 
investigator, after consulting with the CMC, has determined 
that alternative therapy is required, whichever occurs first.  
 
5.1.1.4 Paclitaxel Injection (PTX) 
 
PTX will be administered by IV infusion in 200 mL, 250 mL, or 500 mL of 
5% dextrose or 0.9% sodium chloride for injection at a dose of 100 
mg/m2 every 3 weeks (+2 days).  
 
The concentrated PTX solution in vial must be diluted prior to use in 5% 
dextrose or 0.9% sodium chloride to a final concentration of 0.3 to 1.2 
mg/mL prior to infusion. 
 
Avoid excessive agitation, vibration, or shaking of the IV solution for 
infusion. 
 
Flush the infusion sets thoroughly before use. 
 
Regularly inspect the appearance of the infusion and stop the infusion if 
precipitation is present. 
 
PTX injection for infusion must be administered through an appropriate 
in-line filter with microporous membrane of ≤0.2 micrometers. DEHP-
free infusion containers and administration sets must be used. Use of 
filter devices which incorporate short inlet and/or outlet plasticized 
tubing has not resulted in significant leaching of DEHP. 
 
The entire dose should be infused in one hour (see section 5.1.1.1 for 
note regarding acceptable IV infusion times). 
 
Each cycle of PTX should be administered 21 days (+2 days) after 
the first day of the previous cycle. PTX must not be administered 
earlier than 19 days after the previous cycle.  


 
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Treatment with PTX will continue for six cycles, or until toxicity requiring 
discontinuation of study chemotherapy, or the site investigator, after 
consulting with the CMC, has determined that alternative therapy is 
required whichever occurs first. 
 
See section 7.0 for specific instructions regarding PTX dosage 
modifications. 
 
NOTE: Do not administer as a bolus injection or an undiluted solution.  
 
5.1.1.5 Antiretroviral Therapy  
 
The study will provide ART until week 96 after Step 1 Randomization.  
 
The study will provide EFV/FTC/TDF (Atripla®) which is the preferred 
ART regimen. If there is a contraindication to EFV, participants must 
have access to an alternative NNRTI or protease inhibitor/ritonavir (PI/r) 
provided from outside of the study.  
 
The following ART regimens may be used:  
 
EFV/FTC/TDF (Atripla®) 200 mg/300 mg/600 mg orally once daily 
on an empty stomach, preferably at bedtime OR 
 
FTC/TDF 200 mg/300 mg (Truvada®) orally once daily at bedtime 
plus EFV (Stocrin®) 600 mg orally once daily at bedtime OR 
 
FTC/TDF 200 mg/300 mg (Truvada®) orally once daily plus NVP 
200 mg orally twice daily OR 
 
FTC/TDF 200 mg/300 mg (Truvada®) orally once daily plus PI/r at 
standard dosing 
 
See section 7.0 for ART dosage modifications.  
 
NOTE A: For participants taking EFV it is recommended that the ART 
regimen be taken at bedtime, although this is not required.  
 
NOTE B: Women taking EFV and who are of reproductive potential are 
required to use two methods of acceptable birth control, and they will be 
asked if they are using two methods of birth control at every visit, 
starting at the week 3 visit. If a woman reports she is not using two 
acceptable methods of birth control, EFV will be replaced with NVP or 
PI/r. Record the drug substitution and reason in the source documents 
and record the drug substitution on the case report form (CRF). 
 
NOTE C: NVP should be started with the lead-in of 200 mg orally once 
daily for 14 days; then 200 mg orally twice daily. Health care providers 
must review signs and symptoms of NVP-related hypersensitivity and 
hepatitis with the participant prior to dispensing NVP. Participants 


 
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should contact their site physician if they develop rash or signs and 
symptoms of hypersensitivity or hepatitis. If rash occurs during lead-in, 
do not increase dose until the rash has resolved. The lead-in dosing 
period should not exceed 28 days. After reaching full dose, if NVP 
dosing is interrupted for >7 days, then NVP should be started with the 
lead-in of 200 mg orally once daily for 14 days, followed by 200 mg 
orally twice daily. The risk of hepatotoxicity in women with CD4+ 
lymphocyte cell counts >250 cells/mm3, including pregnant women 
receiving chronic treatment for HIV infection, is considerably higher (12-
fold) compared with women with CD4+ lymphocyte cell counts ≤250 
cells/mm3 (11% versus 0.9%). Men with higher CD4+ lymphocyte cell 
counts (>400 cells/mm³) also have a higher risk of hepatotoxicity than 
men with lower CD4+ cell counts (6.3% versus 1.2%). 
 
NOTE D: Please be advised that didanosine (ddI)- and stavudine (d4T)-
associated neuropathy may be worsened by co-administration of 
vincristine. 
 
NOTE E: Chemotherapy-associated anemia and neutropenia may be 
worsened by co-administration of ZDV.  
 
NOTE F: Participants who have suspected or confirmed resistance to 
NNRTI, including female participants who have previously received 
single-dose NVP for prevention of MTCT of HIV, should receive:  
 
TDF/FTC + PI/r if they are randomized to receive either ET or PTX.  
 
Either ABC/3TC/ZDV, or TDF/FTC+ZDV, or a non-ritonavir-boosted 
PI + two NRTIs if they are randomized to receive BV.  
 
5.1.2 Steps 2, 3, and 4  
 
A new prescription must be written for the site pharmacist to dispense study-
products. The site pharmacist must receive a new Study Identification number 
(SID) when registering participants to each step. 
 
5.2 
Study Product Preparation  
 
5.2.1 Bleomycin 
 
5.2.1.1 Reconstitution of Lyophilized Product 
 
Hospira product: Hospira’s formulation of bleomycin is packaged 
as 30 Units of lyophilized powder per vial. Using aseptic technique, 
reconstitute each vial with 10 mL of 0.9% sodium chloride for injection to 
yield 3 Units/mL (30 Units/ 10 mL) solution. 
 
Amneal product: Amneal’s formulation of bleomycin is packaged 
as 15 Units of lyophilized powder per vial. Using aseptic technique, 


 
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reconstitute each vial with 5 mL of 0.9% sodium chloride for 
injection to yield 3 Units/mL (15 Units/ 5 mL) solution.  
 
Locally-sourced formulations of bleomycin: The locally-available 
formulations of bleomycin are packaged as 15 Units of lyophilized 
powder per vial. Instructions for reconstitution described for the 
Amneal product above should be followed. If these reconstitution 
and preparation instructions are not in accordance with the 
package insert of the locally-sourced bleomycin, then the site 
should submit the package insert and proposed preparation 
instructions to the protocol team for review and approval prior to 
use.  
 
5.2.1.2 Withdraw study participant’s calculated dose of bleomycin in mL from 
the reconstituted bleomycin vial(s) into a syringe and inject it into a 50 
mL 0.9% sodium chloride for injection IV bag. 
 
5.2.1.3 Administer the prepared bleomycin in 50 mL 0.9% sodium chloride for 
injection IV bag by IV infusion over 10 minutes (see section 5.1.1.1 for 
note regarding acceptable IV infusion times). 
 
5.2.1.4 Hospira’s bleomycin prepared in 50 mL 0.9% sodium chloride IV 
bag for infusion is stable for up to 24 hours at room temperature, 15-
30 °C (59-86°F). 
 
Amneal’s bleomycin prepared in 50 mL 0.9% sodium chloride IV 
bag for infusion is stable for up to 24 hours when stored in the 
dark at refrigerated temperature, 2-8°C (36-46°F).  
 
Locally-sourced bleomycin prepared in 50 mL 0.9% sodium 
chloride IV bag for infusion should be stored up to the duration in 
time and within specified storage temperature range as directed by 
the manufacturer in the package insert. 
 
5.2.1.5 Do not use if a precipitate, foreign matter, or discoloration is present. 
 
5.2.1.6 Bleomycin for injection should not be reconstituted or diluted with 5% 
dextrose for injection or other dextrose-containing diluents, as loss of 
potency can occur. 
 
5.2.1.7 Do not mix bleomycin with other drugs or solutions, as compatibility is 
unknown. 
 
5.2.1.8 Caution should be exercised in handling bleomycin. The use of gloves 
and gown is recommended. If bleomycin comes in contact with the skin 
or mucosa, immediately wash thoroughly with soap and water.  
 


 
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5.2.1.9 Discard any unused solution according to proper handling and disposal 
procedures for anti-cancer drugs. 
 
5.2.2 Vincristine 
 
5.2.2.1 Using aseptic technique, withdraw 2 mL from a vial of vincristine 
containing 2mg/2mL into a syringe and cap.  
 
5.2.2.2 Vincristine prepared in a syringe should be administered as soon as 
prepared. 
 
5.2.2.3 Do not use if a precipitate, foreign matter or discoloration is present. 
 
5.2.2.4 Caution should be exercised in handling vincristine. The use of gloves 
and gown is recommended. If vincristine comes in contact with the skin 
or mucosa, immediately wash thoroughly with soap and water.  
 
5.2.2.5 Do not mix vincristine with other drugs or solutions, as compatibility is 
unknown. 
 
5.2.2.6 Discard any unused solution according to proper handling and disposal 
procedures for anti-cancer drugs. 
 
5.2.2.7 Include on the prepared vincristine study product label “FATAL IF 
GIVEN INTRATHECALLY. FOR INTRAVENOUS USE ONLY”. 
 
5.2.2.8 Administer IV over 1 minute (see section 5.1.1.1 for note regarding 
acceptable IV infusion times). 
 
Vincristine must be administered via an intact free-flowing intravenous 
needle or into the tubing of a running intravenous infusion and then 
flushed with the IV fluid being administered. Care should be taken that 
no leakage or swelling occurs during administration. If any leakage or 
swelling occurs during administration, the injection should be 
discontinued immediately and any remaining portion of the dose should 
then be introduced into another vein. Please refer to the 
A5263/AMC066 MOPS for additional recommendations on the 
management of chemotherapy extravasation. 
 
5.2.2.9 Vincristine should be administered before bleomycin if given in the same 
IV line. 
 
5.2.3 PTX Injection 
 
5.2.3.1 Premedication MUST be given prior to administration of each dose of 
PTX. Please refer to the A5263/AMC066 MOPS for instructions on the 
drugs, dosages and timing of premedication.  


 
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5.2.3.2 PTX is dosed 100 mg/m2 IV over 1 hour (see section 5.1.1.1 for note 
regarding acceptable IV infusion times) every 3 weeks. Do not 
administer as a bolus injection. 
5.2.3.3  Using aseptic technique, withdraw study participant’s calculated dose in 
mL from PTX injectable vial.  
 
5.2.3.4  Do not use the Chemo-Dispensing Pin device or similar device with 
spikes since they can cause the vial stopper to collapse, resulting in loss 
of sterile integrity. 
 
5.2.3.5 PTX must be diluted in 200 mL, 250 mL, or 500 mL of 5% dextrose for 
injection or 0.9% sodium chloride for injection in polypropylene or 
polyolefin plastic bag (DEHP-free infusion containers) or a glass bottle.  
 
5.2.3.6 The final concentration of prepared PTX injection in 5% dextrose or 
0.9% sodium chloride for IV administration must be between 0.3 to 1.2 
mg/mL. 
 
5.2.3.7 Solutions for infusion prepared as above should be used immediately. If 
not used immediately, the solution for infusion can be stored in a 
refrigerator between 2-8C (36-46F) for up to 24 hours.  
 
5.2.3.8 Do not use if the prepared solution for infusion is cloudy or an insoluble 
precipitate is present. 
 
5.2.3.9 Caution should be exercised in handling PTX solution. The use of 
gloves and gown is recommended. If PTX comes in contact with the skin 
or mucosa, immediately wash thoroughly with soap and water. 
 
5.2.3.10 Do not mix PTX with other drugs or solutions, as compatibility is 
unknown. 
 
5.2.3.11 Discard any unused solution according to proper handling and disposal 
procedures for chemotherapeutic products. 
 
5.2.3.12 To avoid participant exposure to plasticizer leached from polyvinyl 
chloride (PVC), PTX must be prepared in polypropylene or polyolefin 
plastic bag (DEHP-free infusion containers) or a glass bottle and infused 
through a non-PVC containing administration set with an inline filter with 
a micro porous membrane not greater than 0.2 microns. 
 
5.2.3.13 PTX is considered an irritant with vesicant potential. Care should be 
taken that no leakage or swelling occurs during administration. If any 
leakage or swelling occurs during administration, the injection should be 
discontinued immediately and any remaining portion of the dose should 
then be introduced into another vein. Please refer to the 


 
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A5263/AMC066 MOPS for additional recommendations on the 
management of chemotherapy extravasation. 
 
5.3 
Study Product Formulation and Storage 
 
Study Product 
Formulation 
Storage 
Etoposide (ET) 
50 mg soft gelatin 
capsule 
Do not store above 25°C (77°F) 
Bleomycin sulfate 
injection (B) 
manufactured by 
Hospira 
30 units powder per 
single use vial 
Store between 2-8°C (36-46°F) 
Protect from light. Store vials upright. 
Bleomycin sulfate 
injection (B) 
manufactured by 
Amneal 
15 units powder 
per single use vial 
(15,000 IU powder 
per single use vial, 
1,000 IU = 1 unit) 
Store between 2-8°C (36-46°F) 
(Refrigerate. Do not freeze.) 
Bleomycin sulfate 
injection (B) 
locally-sourced 
15 units powder 
per single use vial 
Store within the specified storage 
temperature range as directed by the 
manufacturer in the package insert 
Vincristine sulfate 
injection (V) 
2 mg/ 2 mL solution 
per single use vial 
(1 mg/mL) 
Store between 2-8°C (36-46°F) 
Protect from light. Store vials upright. 
Paclitaxel injection 
(PTX) 
6 mg/mL solution 
per vial (for single 
use only in this 
study). The other 
ingredients 
contained in PTX 
solution are 
polyoxyl castor oil 
and ethanol. 
Do not store above 25°C (77°F).  
Store the vial in the original, outer carton 
to protect from light. 
Emtricitabine/ 
Tenofovir Disoproxil 
Fumarate (FTC/TDF) 
(Truvada®) 
200 mg/300 mg 
tablet 
Store at 25C (77F); excursions 
permitted between 15-30C (59-86F). 
Keep container tightly closed. Dispense 
only in original container. 
EFV (Stocrin®) 
600 mg tablet 
Store at 15-30°C (59-86°F).  
Each bottle contains a silica gel 
desiccant canister that should remain in 
the original container to protect the 
product from humidity. 
EFV/FTC/TDF 
(Atripla®) 
600 mg/200 mg/300 
mg tablet 
Store up to 30°C (86°F). 
 


 
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5.4 
Study Product Supply, Acquisition, and Accountability  
 
5.4.1 Study Product Supply 
 
5.4.1.1 Etoposide soft gelatin capsules are supplied by Bristol-Myers Squibb. 
 
5.4.1.2 Bleomycin sulfate injection manufactured by either Hospira or Amneal 
Biosciences is supplied through the study with funding support from the 
ACTG.  
In the event that bleomycin sulfate injection manufactured by 
either Hospira or Amneal Biosciences is not available from the 
CRPMC, study sites may source bleomycin locally until either 
Hospira’s or Amneal’s bleomycin can be provided through the 
study. Available local sources of bleomycin at each of the study 
sites are shown in the following table:  
 
CRS Number 
CRS Name 
Country 
Locally-Available Bleomycin Injection 
Formulations 
11101 
Wits Helen Joseph Hospital CRS 
South Africa     
Bleolem, by Teva  Pharmaceuticals, 15 
units/vial 
11201 
Durban International CRS 
South Africa 
Teva Bleomycin, by Teva Pharmaceuticals, 
15 units/vial 
Bleolem, by Lemery, 15 units/vial 
12001 
Malawi CRS 
Malawi 
Bleomycin Injection, by Celon Labs and 
United Biotech Limited, 15 units/vial 
12101 
Instituto De Pesquisa Clinica Evandro 
Chagas CRS 
Brazil 
Bleomycin Sulfate, by Meizler Biopharma, 
15 units/vial 
12501 
KEMRI/WRP CRS 
Kenya 
Bleochem, by Biochem Ltd, 15 units/vial, 
lyophilized 
12601 
Moi University CRS 
Kenya 
Bleochem, by Biochem Ltd, 15 units/vial 
Lyoble, by United Biotech, 15 units/vial 
30301 
Blantyre CRS 
Malawi 
Bleomycin Sulfate Injection, by Angel 
Biogenics, 15 units/vial 
30313 
Parirenyatwa CRS 
Zimbabwe 
Bleomycin Injection, by Celon Labs, 15 
units/vial 


 
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CRS Number 
CRS Name 
Country 
Locally-Available Bleomycin Injection 
Formulations 
31460 
Kisumu CRS 
Kenya 
Bemocin, by Fresenius, 15 units/vial 
31713 
Uganda Cancer Institute CRS 
Uganda 
Bleomycine-Bellon, by Sanofi-Aventis, 15 
units/vial  
Bloicin-S, by Korea United Pharm. Inc, 15 
units/vial 
8950 
FAM-CRU CRS 
South Africa 
Bleolem, by Key Oncologies, 15 units/vial 
Blenamax, by Pharmachemie, 15 units/vial 
 
5.4.1.3 Vincristine sulfate injection manufactured by Hospira is supplied through 
the study with funding support from the ACTG.  
5.4.1.4 Paclitaxel injection manufactured by Accord Healthcare Limited is 
supplied through the study with funding support from the ACTG. 
5.4.1.5  FTC/TDF (Truvada®) tablets are provided by Gilead Sciences. 
5.4.1.6 Efavirenz (Stocrin®) tablets are provided by Merck. 
5.4.1.7 EFV/FTC/TDF (Atripla®) tablets are provided by Merck. 
5.4.1.8 If bleomycin and vincristine supplied through the study are not 
manufactured by Hospira (bleomycin and vincristine) or Amneal 
(bleomycin only), then the study product that will be provided 
through the study must comply with the NIAID (DAIDS) policy for 
the use of study products not marketed in the US in NIAID (DAIDS)-
supported and/or sponsored clinical trials. This policy is available 
on the NIAID (DAIDS) website at: 
https://www.niaid.nih.gov/sites/default/files/NonFDAapprovedProd
ucts.pdf. 
 
5.4.2 Study Product Acquisition 
 
ET, bleomycin sulfate, vincristine sulfate, PTX, FTC/TDF (Truvada®), EFV 
(Stocrin®), and EFV/FTC/TDF (Atripla®) are available through the NIAID Clinical 
Research Products Management Center (CRPMC). The ACTG site pharmacists 
can obtain study products for this protocol by following the instructions in the 
manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks 
in the section Study Product Management Responsibilities. 
 
In the event that bleomycin is not available from the CRPMC, sites should 
source drug locally as described in 5.4.1.2. 


 
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5.4.3 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. The site 
pharmacist at non-US clinical research sites must follow the instructions in the 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks DAIDS 
Pharmaceutical Affairs for the destruction of unused study products. 
 
5.5 
Concomitant Medications 
 
Below is the list of selected concomitant medications. These lists are only current as of 
the date of this protocol. Therefore, whenever a concomitant medication or study agent 
is initiated or a dose changed, investigators must review the concomitant medications’ 
and study agents' most recent package inserts, Investigator’s Brochures, or updated 
information from DAIDS to obtain the most current information on drug interactions, 
contraindications, and precautions. 
 
5.5.1 Required Medications 
 
All study participants are required to take ART, see section 5.1 for details. 
 
5.5.2 Prohibited and Precautionary Medications 
 
For the list of prohibited and precautionary medications, please refer to the 
A5263/AMC066 PSWP: (https://member.actgnetwork.org/study/51726#profile=3).  
 
Click on the A5263 PSWP tab and then go to the Current Study-Specific Support 
Documents folder. 
 
5.6 
Adherence Assessment 
 
See sections 6.3.21 and 6.3.22. 
 


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Events  
 
6.1.1 Step 1–Screening to Week 24 
Evaluation 
Screen 
Entry 
Step 1 Post-Entry Evaluations (Weeks) 
Virologic 
Failure 
KS-IRIS 
3 
24–48 Hours 
after Second 
Chemotherapy 
Cycle Begins 
6 
9 
12 
15 
18 
21 
24 
Documentation of HIV-1 
X 
 
 
 
 
Biopsy Diagnostic of KS (Fixed 
in Formalin) 
X 
 
Repeat a diagnostic biopsy for KS to confirm a complete KS 
response1 
 
 
Documentation of KS Stage T1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of KS 
Cutaneous Marker Lesions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/ Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Complete Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body Surface Area Calculation 
 
X 
Recalculate if a participant’s weight has changed by 10% or 
more after Step 1 entry for re-calculation of bleomycin and PTX 
doses 
 
 
Targeted Physical Exam 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Clinical Assessment 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
KS Exam 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Photographic Record 
 
X 
Obtain for a change in KS response category 
 
 
KS Tumor Punch Biopsy for 
Storage in RNAlater 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
CD4+/CD8+ 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
HIV-1 RNA 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Stored Serum for Protocol-
Related Research 
 
X 
X 
X 
 
 
X 
 
 
 
X 
 
X 


 
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Evaluation 
Screen 
Entry 
Step 1 Post-Entry Evaluations (Weeks) 
Virologic 
Failure 
KS-IRIS 
3 
24–48 Hours 
after Second 
Chemotherapy 
Cycle Begins 
6 
9 
12 
15 
18 
21 
24 
Stored Plasma for Protocol-
Related Research 
 
X 
X 
X 
 
 
X 
 
 
 
X 
 
X 
Stored PBMC for Protocol-
Related Research 
 
X 
X 
X 
 
 
X 
 
 
 
X 
 
X 
Hematology 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Chemistries 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
HBsAg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Lactate 
Perform for symptoms suggestive of lactic acidosis 
Lipase & Triglycerides 
Perform for symptoms suggestive of pancreatitis 
Creatine Kinase 
Perform for symptoms suggestive of myopathy 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing 
X 
X 
Perform prior to a new chemotherapy cycle and whenever pregnancy is 
suspected 
CXR 
X 
Repeat at the time of suspected or IERC-confirmed KS progression or entry into the 
next step. For participants with known pulmonary KS at entry, a CXR will be 
repeated every third cycle. 
X 
Pulse Oximetry 
X 
X2 
X2 
 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
 
 
Peripheral Neuropathy 
Assessment 
X 
 
X3 
 
X3 
X 
X3 
X3 
X3 
X 
 
 
 
ART Adherence Assessment 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
ET Adherence Assessment 
 
 
X4 
 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
 
X4 
Quality of Life Assessment 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
1 A confirmatory biopsy is required only for participants in whom hyperpigmented macular skin lesions persist after apparent CR. 
2 Complete only if the participant is receiving bleomycin. 
³ Complete only if the participant is receiving vincristine or PTX. 
4 Only complete if a participant is receiving ET.


 
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6.1.2 Step 1–Week 27 to Discontinuation Evaluations 
Evaluation 
Step 1 Post-Entry Evaluations (Weeks) 
Discontinuation 
Evaluations
Virologic Failure 
27 
30 
33 
36 
39 
42 
45 
48 
60-96 
(Follow-
up  
Every 
12 
Weeks)2  
E  
+ 
1443 
 
Biopsy Diagnostic of 
KS (Fixed in Formalin) 
Repeat a diagnostic biopsy for KS to confirm 
a complete KS response1 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Targeted Physical 
Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Clinical Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
KS Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Photographic Record 
Obtain for a change in KS response category 
X 
 
CD4+/CD8+ 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
HIV-1 RNA 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
Stored Serum, 
Plasma, PBMC for 
Protocol-Related 
Research 
 
 
 
 
 
 
 
X 
 
 
X 
 
Hematology 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Chemistries 
X 
 
 
X 
 
 
 
X 
X 
 
X 
 
Lactate 
Perform for symptoms suggestive of lactic acidosis 
Lipase & Triglycerides 
Perform for symptoms suggestive of pancreatitis 
Creatine Kinase 
Perform for symptoms suggestive of myopathy 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy Testing 
Perform prior to a new chemotherapy cycle and whenever 
pregnancy is suspected 
X 
 


 
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Evaluation 
Step 1 Post-Entry Evaluations (Weeks) 
Discontinuation 
Evaluations
Virologic Failure 
27 
30 
33 
36 
39 
42 
45 
48 
60-96 
(Follow-
up  
Every 
12 
Weeks)2  
E  
+ 
1443 
 
CXR 
Repeat at the time of suspected or IERC-confirmed KS progression or entry 
into the next step. For participants with known pulmonary KS at entry, a 
CXR will be repeated on every third cycle. 
Pulse Oximetry 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
 
ART Adherence 
Assessment 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
Quality of Life 
Assessment 
 
 
 
 
 
 
 
X 
 
 
X 
 
1 A confirmatory biopsy is required only for participants in whom hyperpigmented macular skin lesions persist after 
apparent CR. 
2 If conducted on Step 1, week 96 is the last visit for participants in Arm 1B or 1C.  
3 E=week the last cycle of ET was started. The E+144 visit will only be conducted for participants in Arm 1A 
who are still on Step 1. 
4 Complete only if the participant is receiving bleomycin. 


 
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6.1.3 Step 2, Step 3, and Step 4–Randomization to Week 27 
Evaluation 
Entry 
(R) 
Step 2 Post-Entry Evaluations (Weeks) 
R 
+ 
3 
24–48 Hours 
after Second 
Chemotherapy 
Cycle Begins 
R 
+ 
6 
R 
+ 
9 
R 
+ 
12 
R 
+ 
15 
R 
+ 
18 
R 
+ 
21 
R 
+ 
24 
R 
+ 
27 
Virologic  
Failure 
Biopsy Diagnostic of KS  
(Fixed in Formalin) 
 
Repeat a diagnostic biopsy for KS to confirm a complete KS response1 
 
Concomitant Medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Targeted Physical Exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body Surface Area Calculation 
Recalculate if a participant’s weight has changed by 10% or more after Step 1 entry for re-calculation 
of bleomycin and PTX doses 
Clinical Assessment 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
KS Exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Photographic Record 
X 
Complete for a change in KS response category 
KS Tumor Punch Biopsy for 
Storage in RNAlater 
X2 
 
X2 
 
 
 
 
 
 
 
 
 
CD4+/CD8+ 
X 
 
 
 
 
X 
 
 
 
X 
 
 
HIV-1 RNA 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
Stored Serum for Protocol-Related 
Research 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
Stored Plasma for Protocol-Related 
Research 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
Stored PBMC for Protocol-Related 
Research 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistries 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lactate 
Perform for symptoms suggestive of lactic acidosis 
 
Lipase & Triglycerides 
Perform for symptoms suggestive of pancreatitis 
 
Creatine Kinase  
Perform for symptoms suggestive of myopathy 
 


 
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Evaluation 
Entry 
(R) 
Step 2 Post-Entry Evaluations (Weeks) 
R 
+ 
3 
24–48 Hours 
after Second 
Chemotherapy 
Cycle Begins 
R 
+ 
6 
R 
+ 
9 
R 
+ 
12 
R 
+ 
15 
R 
+ 
18 
R 
+ 
21 
R 
+ 
24 
R 
+ 
27 
Virologic  
Failure 
Pregnancy Testing 
Perform prior to a new chemotherapy cycle and whenever pregnancy is suspected 
 
CXR 
Repeat at the time of suspected or IERC-confirmed KS progression or entry into the next step. For 
participants with known pulmonary KS at entry or at the time of entry into Step 2 or Step 3, a CXR will 
be repeated on every third cycle. 
Pulse Oximetry 
X3 
X3 
 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
 
Peripheral Neuropathy Assessment 
X 
X4 
 
X4 
X 
X4 
X4 
X4 
X 
 
 
 
ART Adherence Assessment 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
ET Adherence Assessment 
 
X5 
 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
 
 
Quality of Life Assessment 
X 
 
 
 
 
X 
 
 
 
X 
 
 
1 A confirmatory biopsy is required only for participants in whom hyperpigmented macular skin lesions persist after apparent CR. 
2 These biopsies are strongly encouraged. 
3 Complete only if the participant is receiving bleomycin. 
4 Complete only if the participant is receiving vincristine or PTX. 
5 Only complete if a participant is receiving ET. 


 
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6.1.4 Step 2, Step 3, and Step 4–Week 30 to Discontinuation Evaluations 
Evaluation 
Step 2 Post-Entry Evaluations (Weeks) 
Discontinuation 
Evaluations  
Virologic Failure 
R 
+ 
30 
R 
+ 
33 
R 
+ 
36 
R 
+ 
39 
R 
+ 
42 
R 
+ 
45 
R 
+ 
48 
R+60 
— 
R+96 
(Follow-up  
Every 12 
Weeks) 
E 
+ 
1442 
Biopsy Diagnostic of KS  
(Fixed in Formalin) 
Repeat a diagnostic biopsy for KS to 
confirm a complete KS response1 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Targeted Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Clinical Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
KS Exam 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Photographic Record 
Complete for a change in KS response category 
X 
 
CD4+/CD8+ 
 
 
X 
 
 
 
X 
X 
 
X 
 
HIV-1 RNA 
 
 
X 
 
 
 
X 
X 
 
X 
X 
Stored Serum, Plasma, PBMC for 
Protocol-Related Research 
 
 
 
 
 
 
X 
 
 
X 
 
Hematology 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Chemistries 
 
 
X 
 
 
 
X 
X 
 
X 
 
Lactate 
Perform for symptoms suggestive of lactic acidosis 
Lipase & Triglycerides 
Perform for symptoms suggestive of pancreatitis 
Creatine Kinase  
Perform for symptoms suggestive of myopathy 
Urinalysis 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy Testing 
Perform prior to a new chemotherapy cycle and whenever 
pregnancy is suspected 
X 
 
CXR 
Repeat at the time of suspected or IERC-confirmed KS progression or entry into the next step. 
For participants with known pulmonary KS at entry or at the time of entry into Step 2 or Step 3, a 
CXR will be repeated on every third cycle. 


 
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Evaluation 
Step 2 Post-Entry Evaluations (Weeks) 
Discontinuation 
Evaluations  
Virologic Failure 
R 
+ 
30 
R 
+ 
33 
R 
+ 
36 
R 
+ 
39 
R 
+ 
42 
R 
+ 
45 
R 
+ 
48 
R+60 
— 
R+96 
(Follow-up  
Every 12 
Weeks) 
E 
+ 
1442 
Pulse Oximetry 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
 
ART Adherence Assessment 
X 
 
 
 
 
 
X 
X 
 
X 
 
Quality of Life Assessment 
 
 
 
 
 
 
X 
 
 
X 
 
1 A confirmatory biopsy is required only for participants in whom hyperpigmented macular skin lesions persist after apparent CR. 
2 E=week the last cycle of ET was started. E+144 visit is only for participants who received ET while on study and have 
already completed the week R+96 visit on the last step entered. 
3 Complete only if the participant is receiving bleomycin. 


 
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6.2 
Timing of Evaluations 
 
All evaluations will be performed following the Schedule of Events. 
 
6.2.1 Screening Evaluations 
 
Screening evaluations must occur prior to entry. 
 
Screening evaluations to determine eligibility must be completed within 30 days 
prior to study entry unless otherwise specified in section 4.1.  
 
Stratification will be based on the screening CD4+ lymphocyte cell count and 
country. 
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in a screening failure results form and entered into the ACTG database.  
 
6.2.2 On-Study Evaluations 
 
6.2.2.1 Entry  
 
Evaluations must be done prior to the participant taking any study 
treatment. Participants must begin treatment after randomization and 
within 72 hours after entry. 
 
6.2.2.2 Post-Entry  
 
In the interest of participant safety, evaluations required to ensure 
safe and timely treatment may be conducted within three days 
prior to administration of chemotherapy.  
 
The results of a complete blood count and creatinine drawn no 
more than three days earlier must be available prior to 
administration of each cycle of chemotherapy. 
 
Even if delayed, all chemotherapy cycles should be completed unless 
there is a dose-limiting toxicity, a study endpoint is met, or there is 
IERC-confirmed KS progression. 
 
Step 1 
Study visits must be scheduled on the weeks indicated in section 6.1, 
the SOE, +7 days for the baseline visit to week 48.  
 
Study visits must be scheduled on the weeks indicated in section 6.1, 
the SOE, +14 days for the week 60 visit to week 96.  
 


 
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Study visits must be scheduled on the weeks indicated in section 6.1, 
the SOE, +12 weeks for the week E+144 visit. 
 
Steps 2, 3, and 4 
Study visits must be scheduled on the weeks indicated in the SOE 
+7 days for the step randomization visit to week R+48.  
 
Study visits must be scheduled on the weeks indicated in the SOE, 
+14 days for the week R+60 visit to week R+96.  
 
Study visits must be scheduled on the weeks indicated in the SOE 
+12 weeks for the E+144 visit. 
 
6.2.2.3 Event-Driven Evaluations  
 
6.2.2.3.1 Participants who Enter Step 2  
 
These participants will be provided a second course of up to 
six additional cycles of the same chemotherapy utilized in 
Step 1. After Step 2 entry, the participant will follow the Step 2 
SOE. 
 
Entry into Step 2 can only occur fewer than 72 weeks after 
Step 1 entry. 
 
6.2.2.3.2 Participants who Enter Step 3 
 
Participants who move to Step 3 will follow the Step 3 SOE. 
 
Entry into Step 3 can only occur fewer than 72 weeks after 
Step 1 entry. 
 
6.2.2.3.3 Participants who Enter Step 4 
 
Participants who enter Step 4 will follow the Step 4 SOE. 
 
Entry into Step 4 can only occur fewer than 72 weeks after 
Step 1 entry. 
 
6.2.2.3.4 KS-IRIS Evaluation 
 
At the time of suspected KS-IRIS (see section 7.2.1 for the 
definition of suspected KS-IRIS), the assessments indicated 
in the SOE must be obtained if not already required for the 
scheduled visit. 
 


 
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6.2.2.3.5 Long-Term Safety Follow-Up 
 
Participants who received ET while on study will be 
followed for at least 144 weeks after after beginning the 
last cycle of ET. All other participants will be followed for 
96 weeks after randomization or assignment to the last step 
they enter. 
 
6.2.3 Evaluations for Randomized or Registered Participants Who Do Not Start Study 
Treatment (Chemotherapy and ART) 
 
There will be no further evaluations for randomized participants who do not start 
study treatment. All CRFs including study entry and off-study forms must be 
completed and keyed. 
 
6.2.4 Premature Treatment Discontinuation Evaluations  
 
Participants who permanently discontinue study treatment will be asked to 
continue in the study in an off-study treatment/on-study status. The participant 
will receive all study evaluations per the participant’s current Step SOE to 
completion of the study. No extra evaluations are required at the time of the 
treatment discontinuation. For treatment discontinuation due to pregnancy, see 
section 7.22. 
 
6.2.5 Premature Study Discontinuation Evaluations  
 
Participants who prematurely discontinue from the study will have the 
discontinuation evaluations per the SOE performed prior to being taken off the 
study. These evaluations should only be performed if the participant is leaving 
the study prior to week 48 on Step 1 or prior to week R+48 on Steps 2, 3, or 4. 
 
6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source documents: 
https://www.niaid.nih.gov/sites/default/files/documents/sourcedocappndx.pdf 
 
All stated evaluations are to be recorded on the CRF and keyed into the database 
unless otherwise specified. This includes events that meet the International Council for 
Harmonization (ICH) definitions for a serious adverse event: 
 
Results in death 
 
Life-threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity  
 
Congenital anomaly/birth defect 


 
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 
Other important medical event (may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the events listed above.  
 
To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), Version 1.0, December 2004 (Clarification, August 2009), which can be 
found on the DAIDS RSC website: http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/daids-grading-tables. 
 
6.3.1 Documentation of HIV-1 
 
Please refer to section 4.1.1 regarding assay requirements for HIV-1 
documentation. HIV-1 documentation is not recorded on the CRF. 
 
6.3.2 Biopsy Diagnostic of KS (fixed in formalin) 
 
Histologically-confirmed KS based on review by a pathologist at a DAIDS-
approved pathology laboratory of a biopsy of a suspected KS lesion. If a 
diagnostic biopsy specimen is not available for review, it must be performed at 
screening. Please refer to the A5263/AMC066 MOPS for instructions. 
 
In participants in whom hyperpigmented macular skin lesions persist after 
apparent CR, biopsy of at least one representative lesion is required in order to 
document the absence of malignant cells. 
 
If a diagnostic biopsy is performed as part of screening and a residual tissue 
block is available for further study, the remainder will be used to generate a 
study-specific tissue microarray (TMA). Study-specific TMAs will be used to 
characterize patterns of viral and cellular gene expression in relation to study 
outcomes as described in Appendix IV. 
 
6.3.3 Documentation of Current KS stage T1 using ACTG criteria [29]. 
 
KS stage T1 must be documented on the CRF at screening. 
 
KS stage T1 (ACTG criteria; [29]) is KS with any of the following:  
 
symptomatic tumor-associated edema 
 
tumor ulceration 
 
extensive oral KS (other than flat KS confined to the hard palate) 
 
gastrointestinal KS 
 
KS in any other non-nodal visceral organ (e.g., lung) 
 
6.3.4 Documentation of KS Cutaneous Marker Lesions 
 


 
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Please refer to the A5263/AMC066 MOPS for detailed instructions on 
assessment and documentation of cutaneous marker lesions. 
 
The presence of cutaneous marker lesions at screening does not require the 
completion of a CRF. 
 
6.3.5 Medical/Medication History 
 
Medical History 
A medical history, including allergies to any medications and their formulations, 
will be collected. All diagnoses identified by the ACTG criteria for clinical events 
and other diseases must be recorded. Refer to the study CRF for the appropriate 
appendix used for the current ACTG criteria.  
In addition to the diagnoses identified by the ACTG criteria for clinical events and 
other diagnoses, the medical history should include any previously diagnosed, 
pathologically proven malignancy, including squamous cell carcinoma of the skin 
and basal cell carcinoma. 
 
Medication History 
All previous ART medication and corticosteroids taken at any time prior to entry 
and all current medications, with start and stop dates (estimated if the exact 
dates cannot be obtained), should be recorded in source documents and on the 
CRFs. All previous use of topical and systemic steroids should be recorded on 
the source documents and on the CRFs.  
 
6.3.6 Concomitant Medications 
 
After entry and up to week 96, all prescription, non-prescription, alternative, and 
traditional concomitant medications taken since the last visit will be recorded in 
the source documents. Include all start and stop dates for concomitant 
medications.  
 
All concomitant medications, whether or not they are prescription or 
nonprescription, will be recorded on the CRF. Only start and stop dates must be 
recorded on the CRF.  
 
Alternative and traditional medications will be reported as Yes/No on the CRF. 
Vitamins DO NOT need to be recorded as alternative and traditional medications. 
 
After week 96 (or R+96 for participants who enter step 2, 3, or 4), only 
chemotherapy or radiation should be recorded in the CRF and source 
documents. 
 
6.3.7 Complete Physical Exam 
 
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 
measurement of weight and height 
 
examination of the skin, head, mouth, and neck 
 
auscultation of the chest  
 
cardiac exam  
 
abdominal exam  
 
examination for tumor associated edema  
 
Karnofsky performance status. Please refer to the A5263/AMC066 MOPS for 
Karnofsky performance status instructions. 
 
signs and symptoms 
 
diagnoses 
 
vital signs (temperature, pulse, respiration rate, and blood pressure) 
 
6.3.8 Body Surface Area Calculation 
 
Body surface area will be calculated at study entry for participants receiving 
bleomycin or PTX in order to calculate the appropriate initial chemotherapy 
doses.  
 
Body surface area may be recalculated and the appropriate chemotherapy 
doses recalculated at each treatment visit.  
 
Body surface area must be recalculated and the dose of bleomycin or PTX 
recalculated any time the participant’s weight has changed by 10% or more 
from the step entry measurement.  
 
The calculator can be found under “calculators” on the Data Management 
Center’s website, 
https://www.fstrf.org/apps/cfmx/apps/common/Portal/index.cfm.  
 
Body surface area should be recorded on the CRF. 
 
6.3.9 Targeted Physical Exam 
 
A targeted physical examination is to include weight, vital signs (temperature, 
pulse, respiration rate, and blood pressure), and is to be driven by any previously 
identified or new signs or symptoms including diagnoses that the participant has 
experienced since the last visit. This examination will be performed at entry and 
at every subsequent visit.  
 
6.3.10 Clinical Assessments 
 
Signs and Symptoms 
At entry, all signs and symptoms of any grade that occurred within 30 days 
before entry must be recorded. After study entry, all grade 3 and 4 signs and 
symptoms must be recorded. In addition, all signs and symptoms that led to a 
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If an expedited adverse event (EAE) or pregnancy occurs between scheduled 
visits, complete and key all CRFs related to that EAE or pregnancy at the time 
the EAE is reported or the pregnancy is determined. 
 
Diagnoses 
Report diagnoses identified by the ACTG Criteria for Clinical Events and Other 
Events at study entry and since the last visit. Refer to the study CRF for the 
appropriate appendix used for the current ACTG criteria.  
 
All related signs, symptoms, laboratory results, or diagnostic test results 
observed or performed as part of establishing a diagnosis are also reportable on 
the CRF, regardless of grade. 
 
The following diagnoses: death, malignancy, AIDS-defining illnesses, or 
severe/life-threatening events will be recorded on the CRF. Please refer to 
section 11.4 for SAE event reporting. 
 
Study Treatment Modifications, ART 
All modifications to ART including initial doses, participant-initiated and/or 
protocol-mandated interruptions, modifications, and permanent discontinuation of 
ART will be recorded. Participant-initiated and protocol-mandated interruptions 
include both inadvertent and deliberate interruptions of any ART. Treatment 
interruption is failure for any cause to take ART for more than 48 hours. 
 
Study Treatment Modifications, Chemotherapy 
All modifications to chemotherapy including initial doses, participant-initiated 
and/or protocol-mandated interruptions, modifications, and permanent 
discontinuations will be recorded. Participant-initiated and protocol-mandated 
interruptions include both inadvertent and deliberate interruptions of any 
chemotherapy. 
 
If a study participant is identified by the site as having progressive KS, using the 
definitions in section 7.0, the site must have the KS progression confirmed 
by the IERC in order to change the participant’s chemotherapy. Details and 
requirements for this request can be found in the A5263/AMC066 MOPS. 
 
6.3.11 KS Exam 
 
The KS exam will be performed according to the section 6.1. The entry KS tumor 
assessment must be conducted prior to receiving study medication but may be 
performed no earlier than 2 weeks before initiating treatment. Please refer to the 
A5263/AMC066 MOPS for instructions on KS exam. 
 
If a participant begins a new chemotherapy regimen, a new baseline tumor 
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All subsequent assessments of KS response to new chemotherapy and 
decisions about discontinuation of therapy for KS progression will be made with 
respect to the new baseline. 
 
6.3.12 Photographic Record 
 
Photographs will be taken to assist in documentation of diagnosis of KS and for 
clinical monitoring purposes. Photographic documentation of KS progression is 
required. This documentation will not be collected on the CRF. Please refer to 
the A5263/AMC066 MOPS for instructions. 
 
6.3.13 KS Tumor Punch Biopsy for Storage in RNAlater 
 
KS tumor punch biopsies will be performed according to the SOE. Please refer to 
the A5263/AMC066 MOPS for detailed instructions on tumor biopsy procedures. 
Lesions used as cutaneous marker lesions for measuring response to treatment 
should NOT be the lesions chosen for biopsies for Tumor Marker Assessments. 
 
If safe and feasible, KS tumor punch biopsies must be obtained when KS-IRIS is 
suspected. 
 
KS tumor punch biopsies are strongly encouraged in Step 2, Step 3, and Step 4. 
 
KSHV transcriptional virus profiling will be completed on these KS tumor punch 
biopsies as described in Appendix V. 
 
6.3.14 CD4+/CD8+ 
 
Absolute CD4+ lymphocyte cell counts and percentages will be obtained from a 
DAIDS-approved laboratory at screening and throughout the study. CD8+ 
lymphocyte cell counts and percentages are also required if they are measured 
in a DAIDS-approved laboratory as part of the CD4+ lymphocyte cell count 
measurement. All results will be recorded in the source documents and on the 
CRFs and should be obtained from the same laboratory, if possible. 
  
During the study, all laboratories must be certified for protocol testing by the 
DAIDS Immunology Quality Assurance (IQA) Program. 
 
6.3.15 Plasma HIV-1 RNA 
 
HIV-1 RNA must be performed by a laboratory certified by the DAIDS Virology 
Quality Assurance (VQA) Program. HIV-1 RNA data will be reported on the CRF 
when they are not reported through the Laboratory Data Management System 
(LDMS).  
 
6.3.16 Stored Serum, Plasma, and PBMC for Protocol-Related Research 


 
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Serum, plasma, and PBMC will be collected and stored according to the SOE.  
 
Plasma and PBMC will be collected and stored for KSHV viral load assays.  
 
Serum will be collected and stored for measuring levels of cytokines and 
inflammation- and angiogenesis-associated molecules as outlined in Appendix II. 
 
PBMCs will be collected and stored for ELISPOT and polyfunctional intracellular 
cytokine staining (ICS) as outlined in Appendix III. 
 
Please refer to the A5263/AMC006 MOPS and laboratory processing chart (LPC) 
for additional information on sample collection. 
 
6.3.17 Laboratory Evaluations 
 
At screening and entry all laboratory values must be recorded. For post-entry 
assessments, record all Grade 2 laboratory values. All laboratory toxicities that 
led to a change in treatment, regardless of grade, must be recorded.  
 
Hematology 
Hemoglobin, hematocrit, white blood cell count (WBC) with differential, ANC, and 
platelets required. 
 
Chemistries  
Sodium, potassium, chloride, CO2, phosphate, glucose, creatinine, albumin, AST, 
ALT, alkaline phosphatase, and total bilirubin.  
 
Calculated creatinine clearance will be used to determine study eligibility and to 
dose adjust renally excreted ART medication. Please refer to the A5263/AMC006 
MOPS for calculation procedure. The calculated creatinine clearance results 
should be recorded on the CRF after entry regardless of grade. 
 
Hepatitis B Surface Antigen 
HbsAg reactivity will be determined at study entry. 
 
Lactate 
Lactate is recommended for evaluation of participants with suspected lactic 
acidosis. Please refer to the A5263/AMC006 MOPS for lactate collection and 
storage guidelines. 
 
Lipase and Triglycerides  
Lipase and triglycerides will be measured whenever needed for evaluation of 
suspected pancreatitis. A triglyceride level should be drawn with the lipase, 
whether fasting or not. Pancreatic amylase is also acceptable. If a baseline 
measurement is needed, it will be obtained from stored samples. 


 
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Creatinine Kinase  
Measure creatinine kinase whenever needed for evaluation of suspected 
myopathy. 
 
Urinalysis 
Urine reagent strip will be performed. Results will be recorded on the CRF. If 
abnormalities greater than trace are found, a specimen for complete urinalysis 
must be done at the local laboratory.  
 
Pregnancy Testing 
Study participants of reproductive potential (defined in 4.1.7) must have a 
negative -HCG serum or urine pregnancy test within 48 hours prior to starting 
study treatment and at every visit prior to a new chemotherapy cycle. The urine 
test must have a sensitivity of 15-25 mIU/mL. 
 
All pregnancy test results must be recorded. Obtain a pregnancy test at any other 
time pregnancy is suspected.  
 
If a participant becomes pregnant after study entry, she may elect to continue on 
study but off study-provided chemotherapy. If a participant becomes pregnant, 
refer to section 7.22 for clinical management details. If pregnancy occurs 
between scheduled visits, complete and key all CRFs related to that pregnancy 
at the time the pregnancy is determined. If the participant elects to continue on 
study, pregnancy-related information will be reported on a CRF and she will not 
have pregnancy tests at her follow-up visits.  
 
6.3.18 CXR 
 
A CXR will be conducted and read locally at screening to assess the presence of 
pulmonary KS and will be repeated at the time of suspected or IERC-confirmed 
KS progression and/or entry into an additional step. 
 
For participants with known pulmonary KS at study entry or at the time of entry 
into the next step, a CXR will be repeated every third cycle. 
When available, and if clinically indicated, CXRs may be supplemented by 
CT scans to better define the presence of pulmonary KS, its extent, and 
its response to treatment.  
 
6.3.19 Pulse Oximetry 
 
Pulse oximetry will be conducted at rest and after exercise.  
 
NOTE: Rest is defined as sitting for 5 minutes. 
 


 
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NOTE: Exercise is defined as any activity that will increase a participant’s 
resting heart rate by 20 beats/minute. 
 
6.3.20 Peripheral Neuropathy Assessment 
 
Neuropathy Assessment 
Neuropathy assessments will be performed as indicated in the SOE. Neuropathy 
assessments should be performed by the same site personnel at each 
evaluation, if possible. The A5263/AMC066 team recommends that neuropathy 
assessments be performed by a physician investigator, but this is not a 
requirement, and neuropathy assessments may be performed by trained non-
physician site investigators or site personnel. To ensure that the neuropathy 
assessments are performed consistently across different sites, all study 
personnel assigned to complete the neuropathy exams must receive appropriate 
training. Relevant neuropathy training material will be available on the 
A5263/AMC066 PSWP. Detailed instructions will also be on the A5263/AMC066 
neuropathy examination CRF.  
 
For a detailed case definition of neuropathy as well as a case definition for 
chemotherapy-associated toxic neuropathy, refer to the A5263/AMC066 MOPS.  
 
Final determination of a neuropathy diagnosis that requires modification of study 
treatment must be confirmed by the site investigator.  
 
Brief Peripheral Neuropathy Screening (BPNS) 
The BPNS will be completed as part of the neuropathy assessment. The BPNS is 
a validated PN screening tool [60,61] which assesses common PN symptoms 
and signs. Common PN symptoms (pain, numbness, paresthesias or ‘pins and 
needles’ sensations) are documented on a numerical rating scale graded from 0 
to 10. Vibratory sensation at the distal interphalangeal joint of the great toe with a 
128 Hz tuning fork and lower extremity reflexes constitute the focused 
neuromuscular examination. 
 
NOTE: PN severity grades will be determined by the BPNS symptom severity 
score rather than the DAIDS AE Grading table. 
  
6.3.21 ART Adherence Assessment 
 
Trained site personnel will conduct the adherence assessment. Trained site 
personnel are defined as site pharmacist, nursing staff, clinician, or other trained 
clinical personnel (e.g., adherence counselors, social workers).  
 
See the CRF for specific instructions. 
 
6.3.22 ET Adherence Assessment 
 


 
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Initiation of ET in all steps was discontinued as of March, 2016. The 
following instructions are provided for participants currently receiving ET 
in any step who elect to complete their current course of ET: 
 
Trained site personnel will conduct the adherence assessment. Trained site 
personnel are defined as site pharmacist, nursing staff, clinician, or other trained 
clinical personnel (e.g., adherence counselors, social workers).  
 
See the CRF for specific instructions. 
 
6.3.23 Quality of Life Assessments 
 
Trained site personnel will administer the Quality of Life questionnaire and 
Clinical Benefit form and record results on the CRFs. Trained site personnel are 
defined as site pharmacist, nursing staff, clinician, or other trained clinical 
personnel (e.g., adherence counselors, social workers). It is estimated that this 
assessment will take 10-15 minutes to complete. See the CRFs for specific 
instructions. 
 
 
7.0 
CLINICAL MANAGEMENT ISSUES 
 
ANTIRETROVIRAL AND CHEMOTHERAPY MANAGEMENT: TOXICITIES, DRUG 
SUBSTITUTIONS, PREGNANCY, OPPORTUNISTIC INFECTIONS, AND OTHER 
CONDITIONS 
 
This section provides guidelines for management of toxicities related to chemotherapy 
and commonly used ART that may be provided either through A5263/AMC066 or 
obtained outside of the study. When one ART is held for resolution of toxicity, all ART in 
the regimen should be held concurrently unless otherwise specified. 
 
Every attempt should be made to continue to follow participants who discontinue study 
treatment because of a Grade 3 or 4 AE until resolution of the AE can be documented.  
 
Toxicity management may require reliance on clinical symptoms, clinician judgment, and 
available laboratory markers, since alternatives to study-provided ART may be very 
limited and baseline levels of certain laboratory parameters (e.g., hemoglobin) may be 
different than in other settings. The CMC is available to discuss toxicity management of 
both study and non-study ART with investigators. Sites must contact the CMC to request 
permission to make any changes in ART and chemotherapy. 
 
It is recommended that NRTIs be continued for 7 days past NNRTI (e.g., EFV, NVP) 
discontinuation unless they are suspected in a given toxicity. If available, a PI/r may be 
substituted for the 7 days that the NNRTI has been discontinued and then also stopped 
when the NRTIs are discontinued at the discretion of the site investigator. 


 
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FTC and TDF may have activity against hepatitis B virus (HBV). Permanent 
discontinuation of FTC or TDF may result in re-activation of HBV. Participants who 
discontinue FTC and/or TDF should be followed carefully for up to 16 weeks to monitor 
for a flare of HBV, according to local standard of care. 
 
A5263/AMC066 will use the DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Version 1.0, December 2004 (Clarification August 2009), as a guideline 
for grading toxicities related to study drugs unless otherwise noted. The table is located 
at the RSC website: http://rsc.tech-res.com/clinical-research-sites/safety-
reporting/daids-grading-tables. 
  
Except where noted below, study-prescribed chemotherapy should be held if a Grade ≥3 
AE develops that is considered to be related to the chemotherapeutic agent. Treatment 
may resume when the toxicity improves to Grade ≤1.  
 
If necessary for medical or administrative reasons (e.g., adverse event, 
intercurrent illness, missed appointment), the start of a new treatment cycle may 
be delayed for up to 42 days after the first day of the previous cycle. If a new 
treatment cycle is delayed more than 42 days after the start of the previous cycle 
for any reason, study-provided chemotherapy should be discontinued. 
 
7.1 
KS Response 
 
Please refer to the A5263/AMC066 MOPS for detailed information on calculating 
response categories and for the definition and instructions on evaluating non-
measurable (evaluable) disease. 
 
For purposes of this study, IERC-confirmed KS progression is defined as KS 
progression that has been verified by the IERC. It is required that all KS progression be 
confirmed by the IERC. Changes in chemotherapy cannot occur until the site has 
received confirmation from the IERC. Please refer to the A5263/AMC066 MOPS for 
detailed instructions on contacting the IERC. 
 
Once a participant has shown an objective CR or PR, subsequent assessments of KS 
progression will be made with respect to the “best response”. In participants who have 
shown an objective, measured response, subsequent progression will be assessed with 
respect to the smallest measurements recorded since the treatment started using the 
criteria in sections 7.1.1-7.1.4 (for measurable cutaneous disease) and 7.1.5 (for non-
cutaneous disease). 
  
7.1.1 Complete Response (CR) 
 
CR is defined as the absence of any detectable residual disease, including 
tumor-associated edema, persisting for at least 4 weeks. In some individuals, 
residual skin color changes may remain visible at one or more site(s) of lesions 


 
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that were previously raised and/or red or violaceous. Suspected CR in those 
lesions refers only to residual macules (flat, non-palpable lesions) that are slightly 
darker than the surrounding normal skin. In the event such lesions are present in 
a participant otherwise believed to have a CR, biopsy of at least one such lesion 
is required in order to document the absence of malignant cells and to confirm 
CR. In the event that such a confirmatory biopsy is not performed and residual 
pigment persists, the response will be considered partial (PR). In participants in 
whom all detectable cutaneous disease has resolved and in whom there are no 
visible pigmented macules as described above, a confirmatory skin biopsy is not 
required. In participants known to have had visceral disease, an attempt at 
restaging with appropriate endoscopic or radiographic procedures should be 
made. 
 
NOTE: To classify a response as a CR, the participant must have a CR in both 
the cutaneous and noncutaneous (if applicable) sites of disease and no evidence 
of progression as defined by the above criteria. 
 
7.1.2 Partial Response (PR) 
 
PR is defined as no new oral lesions or new or progressive visceral sites of 
involvement, or the appearance or worsening of tumor-associated edema (as 
defined in section 8 of the A5263/AMC066 MOPS) or effusions or the 
development of five or more new cutaneous lesions in anatomic sites which were 
previously documented as having no evidence of cutaneous disease; AND 
 
A 50% or greater decrease in the number of all lesions present at entry 
(either total body or in the representative areas) lasting for at least 4 weeks; 
OR 
 
Complete flattening of at least 50% of all previously raised lesions (i.e., 50% 
of all nodular or plaque-like lesions become macules, either total body or in 
the representative areas) present at entry lasting for at least 4 weeks; OR 
 
A 50% or greater decrease in the area of the cutaneous marker lesions 
compared with entry lasting for at least 4 weeks; OR 
 
A 50% or greater decrease in the number or size of all measurable oral 
or visceral lesions lasting for at least 4 weeks, without evidence for 
progression of cutaneous lesions; OR 
 
Complete disappearance of non-measurable oral or visceral lesions 
lasting for at least 4 weeks, without evidence for progression of 
cutaneous lesions. 
 
NOTE: To classify a response as PR, the participant must have at least a PR in 
either the cutaneous or noncutaneous sites of disease and no evidence of 
progression as defined in the above criteria. 
 
NOTE: Participants with residual tumor-associated edema or effusion who 
otherwise meet the criteria for CR will be classified as having a PR. 
 


 
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7.1.3 Stable Disease 
 
Stable disease is defined as any response not meeting the criteria for CR, PR, or 
progressive disease. 
 
7.1.4 Progressive Disease (PD) 
 
For participants with ≤50 cutaneous lesions 
PD is defined as any one or more of the following: 
 
≥25% increase in the area of the cutaneous marker lesions compared to 
entry or best response; 
 
≥25% increase in the total lesion count, or a minimum of five new lesions, 
whichever is greater, compared with entry or best response; 
 
≥25% increase in the number of raised lesions, or a minimum of five new 
raised lesions, whichever is greater, compared with entry or best response. 
NOTE: There are body sites where disease is particularly difficult to evaluate, 
and a few new lesions may be counted in spite of the fact that a participant is not 
actually progressing. For example, lesions of the foot, particularly those that are 
flat, are difficult to evaluate because their intensity may vary based on how much 
edema is present, how much the person walked the day before, how long his/her 
feet have been in a dependent position prior to the physical exam. 
 
For participants with >50 cutaneous lesions 
PD is defined as any one or more of the following: 
 
≥25% increase in the area of the cutaneous marker lesions compared to 
entry or best response; 
 
≥25% increase in the total number of lesions in the prospectively defined 
anatomic sites containing representative lesions; 
 
a total of five new lesions in anatomic sites that were previously documented 
as having no evidence of cutaneous disease, 
 
≥25% increase in the number of raised lesions in the prospectively defined 
anatomic sites containing representative lesions (minimum of five raised 
lesions if there are very few raised lesions, for example <8) whichever is 
greater. Photographic documentation of “gross” or significant progression, 
particularly in areas that were not being followed, will be of particular value. 
 
7.1.5 Noncutaneous PD  
 
Noncutaneous PD includes new oral or visceral sites of involvement or 
progression of oral or visceral disease or the development of new or increasing 
tumor-associated edema or effusion that interferes with the participant’s normal 
activities lasting for at least two consecutive evaluations. Progressive oral or 
visceral disease, for measurable and evaluable disease, should be analogous to 
cutaneous KS response criteria. 
 
Progressive edema is defined as the following: 


 
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 
an increase in non-pitting/woody edema in an upper or lower extremity 
associated with an increase in limb circumference of at least 3 cm from entry 
or best response, sustained for at least two consecutive evaluations, and 
measured at a fixed point on the extremity with respect to a bony landmark 
(e.g., 10 cm below the lower border of the patella); AND/OR 
 
new appearance of non-pitting/woody edema in an extremity where none was 
previously present, sustained for at least two consecutive evaluations; 
AND/OR 
 
new or worsening edema in a non-extremity site (e.g., periorbital, genital) that 
interferes with function and is sustained for at least two consecutive 
evaluations. 
 
7.2 
IRIS Management 
 
7.2.1 KS-IRIS 
 
For purposes of this study, a suspected case of KS-IRIS is defined as any 
progression of KS, as defined above, that occurs within 12 weeks of initiation of 
ART that is associated with an increase in CD4+ count of at least 50 cells/µL 
above the study entry value and/or a decrease in the HIV RNA level by at least 
0.5 log below the study entry value prior to, or at the time of documented KS 
progression. 
 
Participants who develop symptoms consistent with KS-IRIS during the study 
should have the evaluations listed in the KS-IRIS column of the SOE, as soon as 
possible after presentation.  
 
When KS-associated IRIS is suspected, the CMC should be consulted. This 
syndrome should be considered for all worsening of KS lesions within the first 12 
weeks of ART. Worsening may include enlargement of existing lesions, 
development of new skin lesions, or edema, or the development of 
signs/symptoms suggestive of new visceral disease. See the SOE for procedures 
to be conducted.  
 
The following management plan should be followed: 
 
Continue ART 
 
Evaluate for alternative opportunistic infections to explain the syndrome 
 
Continue chemotherapy, if participant is currently receiving chemotherapy 
 
Any modification or initiation of chemotherapy because of disease 
progression requires confirmation of disease progression by the IERC. 
 
Initiate anti-inflammatory agents, such as non-steroid agents at the discretion 
of the site investigator.  
 
The use of corticosteroids for KS-IRIS management is left to the discretion of the 
site investigator. However, corticosteroid use should be avoided whenever 
possible. 


 
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If there is a case of suspected KS-IRIS and KS progression that persisted or 
worsened after 2 weeks of non-steroid agents or other interventions, the 
participant should be moved to an alternative chemotherapy regimen on the next 
study step. 
 
KS-IRIS events should be recorded in the CRFs, however, no EAE reporting is 
required, unless events are considered serious. 
 
7.2.2 Non-KS IRIS 
 
IRIS events are not caused by a specific or individual drug, but rather are the 
result of being on a successful ART treatment regimen. Management of events 
judged by the site investigator to be non-KS IRIS may be managed at the 
discretion of the site investigator.  
 
The use of corticosteroids for non-KS IRIS management is left to the discretion of 
the site investigator. However, corticosteroid use should be avoided whenever 
possible.  
Non-KS IRIS events should be recorded in the CRFs; however, no EAE reporting 
is required, unless events are considered serious. 
 
7.3 
Toxicity 
 
Except as noted below, if an adverse event requiring a delay in chemotherapy 
does not recover to the level required for continued chemotherapy treatment 
within 3 weeks of the scheduled date of the next cycle (i.e., within 42 days after 
the start of the previous cycle), study chemotherapy should be discontinued. 
 
In any case in which the dose of study-prescribed chemotherapy is reduced due 
to toxicity, any future dosing (for that cycle and all subsequent cycles) should be 
at the reduced dose.  
 
7.3.1 Grade 1 or 2 Toxicity 
 
Participants who develop a Grade 1 or 2 AE or toxicity may continue study drugs 
without alteration of the dosage except as stated in sections 7.4-7.22, Specific 
Management of Laboratory Abnormalities and Clinical Syndromes. Participants 
experiencing Grade 1 or 2 toxicities will be managed at the discretion of the site 
investigator.  
 
7.3.2 Grade 3 Toxicity 
 
If there is compelling evidence that the AE has NOT been caused by the study 
drugs, dosing may continue. Except as stated above, participants who develop a 
Grade 3 AE or toxicity thought secondary to study medications or of unknown 


 
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etiology may have all of their study drugs withheld at the site investigator’s 
discretion. Dose reductions are not permitted. 
 
Investigators are encouraged to discuss toxicity management with the CMC. The 
participant should be re-evaluated weekly if possible until the AE returns to 
Grade <2, at which time the study drugs may be reintroduced at the discretion of 
the site investigator. 
 
7.3.3 Grade 4 Toxicity 
 
Participants who develop a symptomatic Grade 4 AE or toxicity, not specifically 
addressed below, will have all study drugs withheld until resolution of the AE to a 
Grade <2. Under certain circumstances the study drug thought most likely to be 
related to the AE may be resumed at the discretion of the site investigator after 
discussion with the CMC. Alternative study-provided or non-study-provided drugs 
should be considered. 
 
Participants with Grade 4 asymptomatic laboratory abnormalities, not specifically 
addressed below, may continue study drug therapy if the site investigator has 
compelling evidence that the toxicity is NOT related to the study drugs, or if 
benefit of the study drugs outweighs the potential risk. 
 
7.4 
Anemia/Neutropenia/Thrombocytopenia 
 
Clinicians should be alert to clinical signs of anemia, neutropenia and thrombocytopenia 
and participants should receive education or counseling about the associated symptoms. 
Participants who develop anemia, neutropenia, and/or thrombocytopenia on study 
should be evaluated for causes of anemia and/or neutropenia, such as concurrent 
bacterial, mycobacterial or fungal infection, malaria, helminthiasis, malignancy and/or 
malnutrition. Transfusion or treatment with recombinant G-CSF or recombinant 
erythropoietin should be considered if clinically appropriate and available at the site. 
 
7.4.1 Anemia  
 
NOTE: Management rules assume that erythropoietin will NOT be available. 
 
For hemoglobin >8.0, no dose modification for any chemotherapeutic agent is 
required. Transfusion is not required. 
 
For any hemoglobin <10.0, if the participant is receiving ZDV, stopping ZDV and 
switching to another NRTI, where available, is recommended. 
 
For hemoglobin <8.0 – 6.5, red blood cell transfusion is recommended to 
increase the hemoglobin level to >8.0. Chemotherapy can continue for 
hemoglobin <8.0 – 6.5. 
 


 
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For hemoglobin <6.5, chemotherapy should be held and the participant 
transfused with red blood cells until the hemoglobin level has returned to >8.0. 
Study medication may then be resumed at full dose. 
 
If hemoglobin <6.5 recurs after resumption of chemotherapy, the participant 
should again be transfused as above. Chemotherapy may then be resumed as 
follows:  
 
Participants receiving PTX: 25% dose reduction 
 
Participants receiving BV: 25% reduction in the dose of both drugs 
 
Participants receiving ET: If the participant’s dose has already been 
escalated from the starting dose, then resume dosing at the next lowest dose 
level. If the participant’s dose has not been escalated above the initial dose 
(50 mg BID for 7 days), then reduce duration of dosing on the next cycle from 
7 days to 4 days. 
 
7.4.2 Neutropenia  
 
NOTE: Management rules assume that G-CSF will NOT be available. 
 
For any grade neutropenia, if the participant is receiving ZDV, stopping ZDV and 
switching to another NRTI, where available, is recommended. 
 
For any ANC >1000, no modification in chemotherapy doses is required. 
 
For ANC <1000 at the beginning of any scheduled treatment cycle, 
chemotherapy will be withheld until the ANC is >1000. Chemotherapy may then 
be resumed as follows: 
 
Participants receiving PTX: 25% dose reduction 
 
Participants receiving BV: 25% reduction in the dose of vincristine only, no 
reduction in bleomycin 
 
Participants receiving ET: If the participant’s dose has already been 
escalated from the starting dose (50 mg BID for 7 days), then resume dosing 
at the next lowest dose level. If the participant’s dose has not been escalated 
above the initial dose, then reduce duration of dosing on the next cycle from 7 
days to 4 days. 
 
If the neutrophil count does not recover to the level required for continued 
chemotherapy treatment within 3 weeks, study chemotherapy will be 
discontinued. 
 
If ANC <1000 recurs after the first chemotherapy drug dose reduction, 
chemotherapy should again be withheld until the ANC is >1000. A second dose 
reduction may be instituted as follows: 
 
Participants receiving PTX: 50% reduction from the original dose. 
 
Participants receiving BV: Discontinue BV. 


 
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 
Participants receiving ET: Reduce the dose to the next lowest dose level. If 
the study participant is already on the lowest dose level (i.e., 4 days only at 
100 mg per day), ET will be discontinued. 
 
7.4.3 Thrombocytopenia 
 
For platelets >50,000, no change in the dose of any chemotherapeutic agent is 
required. 
 
For platelets <50,000, chemotherapeutic agents will be held until the platelet 
count increases to >50,000. Chemotherapy may then be resumed as follows: 
 
Participants receiving PTX: 25% dose reduction 
 
Participants receiving BV: 50% reduction in the dose of vincristine only, no 
reduction in bleomycin 
 
Participants receiving ET: If the participant’s dose has already been 
escalated from the starting dose, then resume dosing at the next lowest dose 
level. If the participant’s dose has not been escalated above the initial dose 
(50 mg BID for 7 days), then reduce duration of dosing on the next cycle from 
7 days to 4 days. 
 
If the platelet count again falls to <50,000 after dose reduction of vincristine or 
ET, chemotherapy will be discontinued. 
 
If the platelet count again falls to <50,000 after the first dose reduction of PTX, 
PTX will be held until the platelet count increases to >50,000. PTX treatment may 
then be resumed at a 50% reduction from the original dose. 
 
If the platelet count again falls to <50,000 after the second dose reduction of 
PTX, PTX chemotherapy will be discontinued. 
   
7.5 
Peripheral Neuropathy (PN)  
 
[After entry, for participants receiving vincristine or PTX only] 
 
NOTE: PN severity grades will be determined by the BPNS symptom severity 
score rather than the DAIDS AE Grading table. 
 
For Grade 1-2 symptomatic PN, BV or PTX may be continued. Treatment of 
neuropathy symptoms may be offered as available in line with local standard of 
care. If a participant is receiving an ART drug associated with PN, stopping that 
particular drug and switching to an alternative NRTI is recommended, where 
available. 
 
For Grade ≥3 PN when on BV, BV will be permanently discontinued. 
Symptomatic treatments to treat neuropathy symptoms may be offered as 
available in line with local standard of care.  


 
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For Grade >3 PN when on PTX, PTX treatment should be held for a maximum of 
3 weeks. If PN has not recovered to grade 1 or less within 3 weeks, PTX will be 
permanently discontinued. If Grade >3 PN has recovered to Grade 1 or less 
within 3 weeks, PTX should be reduced by 25%. Recurrence of >3 PN after dose 
reduction will require permanent discontinuation of PTX.  
 
7.6 
Hyperbilirubinemia 
 
NOTE: Grading of hyperbilirubinemia does not apply to participants who are receiving 
atazanavir (ATV). 
 
For Grade 1 hyperbilirubinemia, no change in the dose of any chemotherapeutic agent is 
required. 
 
For Grade 2 hyperbilirubinemia, the dose of chemotherapeutic agents will be modified as 
follows: 
 
Participants receiving PTX: 50% dose reduction 
 
Participants receiving BV: Discontinue BV. 
 
Participants receiving ET: If the participant’s dose has already been escalated from 
the starting dose, then resume dosing at the next lowest dose level. If the 
participant’s dose has not been escalated above the initial dose, then reduce 
duration of dosing on the next cycle from 7 days to 4 days. 
 
If Grade 2 hyperbilirubinemia recurs after modification of the dose of PTX or ET, or if 
Grade 3 or 4 hyperbilirubinemia occurs at any time, chemotherapy will be discontinued, 
except as noted below. 
 
For isolated Grade >3 unconjugated hyperbilirubinemia attributed to ATV, ATV should 
be continued unless associated with jaundice or scleral icterus that presents an 
intolerable cosmetic concern to the participant. 
 
For Grade >3 that cannot be attributed to ATV or a non-study drug related cause, all 
study medications should be held pending evaluation of etiology. 
 
7.7 
Lipase Elevations and Pancreatitis 
 
Pancreatitis will be reported as a clinical finding (i.e., symptomatic pancreatitis). The 
primary enzyme abnormality used for making the diagnosis is the lipase level. When 
obtained, lipase determinations will be recorded in the CRF. A triglyceride level should 
be drawn with the lipase. 
 
Lipase will be obtained for participants if development of clinical symptoms suggests 
pancreatitis. If a baseline measurement is needed, it will be performed from stored entry 
samples. (Pancreatic amylase is also acceptable.) 
 


 
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For symptomatic gastrointestinal symptoms (particularly abdominal pain) with elevations 
in lipase: 
 
Grade 1: Search for other causes of symptoms. If none is found and symptoms 
persist, repeat lipase within 2 weeks. 
 
Grade ≥2: Follow participants and repeat lipase as soon as possible. If lipase is 
persistently elevated and accompanied by symptoms, then participants should be 
considered to have clinical pancreatitis. CT scan of the abdomen, if available, may 
also be helpful in determining whether clinical pancreatitis is present. Exclude other 
possible diagnoses (e.g., renal insufficiency causing false elevations in lipase). If 
none is found, diagnose as clinical pancreatitis. 
 
For a diagnosis of pancreatitis (clinical), ALL study medications should be held. After 
complete resolution of the episode in a setting in which other concomitant illness might 
have reasonably contributed to the development of pancreatitis, rechallenge with study 
medications may be performed in consultation with the CMC.  
 
Upon rechallenge, lipase determinations should be performed monthly. Any elevation of 
lipase of Grade ≥2 or any recurrence of symptoms during this period will lead to a 
reevaluation and permanent discontinuation of the suspected study drugs. 
 
7.8 
AST and ALT Elevation 
 
Nearly all the study drugs, isoniazid (INH), and concomitant illness can cause alterations 
in liver function tests (LFTs). Therefore, changes in AST or ALT should be evaluated 
within the clinical context of the participant. Initiation of treatment and INH has been 
staggered to facilitate the interpretation of LFTs. Because INH and the NNRTIs have 
been most associated with serious, life-threatening hepatitis, evaluation of LFTs in the 
setting of these drugs is discussed separately.  
 
General Considerations: For asymptomatic elevation in AST or ALT of 5-10ULN (Grade 
3), medications other than NNRTIs and INH may be continued at the discretion of the 
site investigator. Careful assessments should be done to rule out alcohol use, non-study 
medication-related drug toxicity, the lactic acidosis syndrome, and viral hepatitis as the 
cause of the transaminase elevation. If the AST/ALT elevation is considered most likely 
to be due to concomitant illness or medication, standard management, including 
discontinuation of the likely causative agent, should be undertaken. 
 
For asymptomatic elevation 5-10ULN (Grade 3) believed secondary to study 
medications, all agents must be held until levels are Grade 2, at which time therapy 
may be reintroduced with the substitution of a PI for EFV or NVP, if applicable. 
 
For asymptomatic or symptomatic elevation of AST or ALT >10ULN (Grade 4), all 
medications must be discontinued and held until levels are Grade 2, at which time 
therapy may be reintroduced with the substitution of a PI for EFV or NVP, if applicable. 
All medications may be restarted if the laboratory abnormalities were thought secondary 
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of these medications should be considered the most likely cause of the elevations. 
Substitutions should be made, and the NRTI medications can be resumed. If elevations 
>10ULN (Grade 4) recur in the absence of an NNRTI drug, all current treatment and 
INH (if participant is receiving INH) must be discontinued. Alternative treatment and TB 
prophylactic regimens may be considered, at the discretion of the site investigator. 
 
INH Prophylaxis: Participants will not start INH if AST/ALT are >3ULN. At one month 
following initiation of INH, if AST/ALT are >3 times the baseline value, INH will be 
discontinued. In the event of AST or ALT >5ULN (Grade 3) at any point thereafter, 
INH should be discontinued. 
 
Clinical (Symptomatic) Hepatitis with NVP or EFV: Participants taking EFV or NVP 
should be monitored for the development of signs and symptoms of hepatitis, which may 
include fatigue, malaise, anorexia, nausea, acholic stools, bilirubinuria, jaundice, liver 
tenderness, or hepatomegaly, with or without initially abnormal serum transaminase 
levels. Anyone with these signs and symptoms must seek medical attention immediately 
and have LFTs performed. If the study clinician determines that the participant has 
clinical hepatitis with or without LFT abnormality or regardless of the degree of LFT 
abnormality, and NVP cannot be excluded as the cause, NVP should be permanently 
discontinued and not restarted after recovery. For asymptomatic elevation in AST or ALT 
>5ULN (Grade 3), NVP should be discontinued. 
 
HBV or HCV Coinfection: At study entry, hepatitis B surface antigen (HBsAg) will be 
obtained to facilitate management of HBV-coinfected participants in the event FTC, or 
TDF need to be discontinued, which would potentially worsen HBV disease.  
 
For isolated Grade >3 unconjugated hyperbilirubinemia attributed to ATV, ATV should 
be continued unless associated with jaundice or scleral icterus that presents an 
intolerable cosmetic concern to the participant. For Grade >3 that cannot be attributed to 
ATV or a non-study drug-related cause, all study medications should be held pending 
evaluation of etiology. 
 
7.9 
Myopathy 
 
CK measurements will not be performed routinely as part of the protocol. CK will be 
measured only if participants develop clinical symptoms consistent with a diagnosis of 
myopathy. If a baseline measurement is needed, it will be performed from stored 
samples. 
 
For persistent CK elevations >3000 mg/dL (about 20ULN) in symptomatic participants 
(before treatment modifications are made) CK should be redrawn after participants 
abstain from exercise for 24 hours. If CK is still >3000 mg/dL and the participant is 
receiving ZDV, ZDV should be discontinued and replaced with another NRTI as 
appropriate. 
 
7.10 
Lactic Acidosis 


 
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The following definition will be used. 
 
Symptomatic Hyperlactatemia  
New, otherwise unexplained and persistent (2 weeks) occurrence of one or more of the 
following symptoms: 
 
Nausea and vomiting 
 
Abdominal pain or gastric discomfort 
 
Abdominal distention 
 
Increased LFTs 
 
Unexplained fatigue 
 
Dyspnea 
 
And 
 
Lactate level (if available) >2ULN confirmed by repeat lactate level analysis. In the 
absence of lactate levels, serum bicarbonate levels and anion gap should be assessed. 
The presence of depressed bicarbonate levels or an increased anion gap would suggest 
the possibility of lactic acidosis. 
 
All lactates >2ULN should be repeated as soon as possible, generally within 1 week. If 
the second result confirms hyperlactatemia (>2ULN), participants should immediately 
discontinue their current study regimen, both chemotherapy and ART. 
 
7.11 
CNS Symptoms with EFV 
 
There have been reports of delusions and inappropriate behavior, predominantly in 
individuals with a history of mental illness or substance abuse. Severe acute depression 
has also been infrequently reported in both EFV-treated and control-treated individuals. 
Discontinuation of EFV may be required and substitution of NVP implemented. 
 
7.12 
Diarrhea 
 
Diarrhea can be caused by both infection and medication toxicity. If no infectious cause 
of diarrhea is found and onset is temporally related to new medication, symptomatic 
management with antidiarrheal agents is appropriate. 
 
7.13 
Hypophosphatemia 
 
For Grades 1 and 2 hypophosphatemia, phosphate should be repeated as soon as 
possible (within two weeks is optimal), and TDF may be continued if there are no other 
signs of renal tubular acidosis at the discretion of the site investigator. Please refer to the 
A5263/AMC066 MOPS for instructions. 
 
For Grades 3 and 4 hypophosphatemia, the phosphate should be repeated, preferably 
within one week. Supplemental phosphate or foods high in phosphates should be given 


 
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and other causes of low phosphate should be investigated. If Grade 3 or 4 
hypophosphatemia persists discontinue TDF permanently. 
 
7.14 
Renal Insufficiency 
 
Dose modifications are recommended for TDF, FTC, ddI-EC, d4T, and 3TC in 
participants with reduced creatinine clearance (see the most recent package inserts). 
TDF should be held for a confirmed calculated creatinine clearance <50 mL/min until an 
underlying etiology for the renal insufficiency is determined. If no other etiology is 
determined or the renal insufficiency improves with holding TDF, permanently stop TDF 
and substitute an alternative ARV. 
 
Dose modifications are recommended for bleomycin and ET in participants with reduced 
creatinine clearance. A 25% reduction in bleomycin dose is recommended if the 
calculated creatinine clearance is between 15 and 50 ml/min, and a 50% reduction is 
recommended if the calculated creatinine clearance is below 15 mL/min. For ET, the 
does will be reduced to the previous tolerated ET dose. If the participant is already at the 
lowest dose of ET, the ET should be discontinued. 
 
Baseline serum creatinine will be the mean of the screening and entry values. If at any 
time serum creatinine is increased >1.5-fold above baseline, the serum creatinine should 
be repeated as soon as possible (preferably within 1 week). Participants with confirmed 
serum creatinine increases >1.5-fold above baseline should undergo an evaluation for 
potential causes of decreased renal function. Participants with confirmed increased 
serum creatinine >1.5-fold above baseline should have serum creatinine monitored more 
frequently, at the discretion of the site investigator, until serum creatinine either stabilizes 
or decreases to ≤1.5-fold above baseline. Drug dosing adjustments should be done 
based on the calculated creatinine clearance. Please refer to the A5263/AMC066 
MOPS.  
 
7.15 
Cardiac Toxicity (PTX) 
 
No treatment is required for asymptomatic bradycardia.  
 
The PTX infusion should be stopped for symptomatic arrhythmias and the arrhythmia 
should be managed according to standard practice. Permanently discontinue PTX for 
symptomatic cardiac events. 
 
The PTX infusion should also be stopped if the participant develops any chest pain 
and/or symptomatic hypotension (<90/60 mm Hg and requires fluid replacement). An 
ECG should be performed and intravenous diphenhydramine and dexamethasone, or 
other appropriate therapy as per institutional guidelines, should be administered if 
hypersensitivity is considered. Bronchodilators may be used if chest pain is not 
considered cardiac. PTX will be permanently discontinued for symptomatic cardiac 
events. 
 


 
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7.16 
Pulmonary Toxicity 
 
Participants receiving bleomycin who develop Grade ≥3 pulmonary toxicity (other than 
reversible toxicity attributed to intercurrent infection) will have BV permanently 
discontinued. 
 
If a greater than 4% decrease in oxygen saturation develops or persists after treatment 
of an intercurrent infection, such as PCP, then BV will be permanently discontinued. 
 
7.17 
Management of Active Tuberculosis (TB) or Cryptococcal Meningitis (CM) 
 
The management of active tuberculosis (TB) or cryptococcal meningitis (CM) for 
participants in A5263/AMC066 will be per the local standard of care at the respective 
sites where the study is being carried out. In cases where a participant needs treatment 
for TB or CM, the preferred ART regimen is the study-provided regimen of 
TDF/FTC/EFV. PIs are not recommended during TB treatment with rifampicin because 
of their interactions with rifampicin. If therapy with a PI is required during TB treatment, 
rifabutin should be used instead of rifampicin. Because of the potential for rifampicin to 
increase metabolism of ET and vincristine, it is recommended that rifabutin, if available, 
be substituted for rifampicin if participants are receiving either ET or vincristine. 
 
7.18 
Allergic Reaction/Hypersensitivity (PTX) 
 
Any participants who experience severe or life-threatening symptoms of hypersensitivity 
will discontinue PTX permanently. For moderate symptoms, the PTX infusion should be 
stopped. Intravenous diphenhydramine 20 to 50 mg and intravenous dexamethasone 10 
mg, or other appropriate therapy as per institutional guidelines, should be administered. 
The PTX infusion may be resumed after recovery of symptoms at a low rate (20 mL/hour 
for 15 minutes, then 40 mL/hour for 15 minutes, and then, if no further symptoms, at a 
full dose until the infusion is complete). If the symptoms recur the infusion must be 
stopped. For severe, life-threatening symptoms of hypersensitivity, the PTX infusion 
should be stopped. Intravenous diphenhydramine 20 to 50 mg and intravenous 
dexamethasone 10 mg, or other appropriate therapy as per institutional guidelines, 
should be administered. The addition of epinephrine or bronchodilators may be used if 
indicated. 
 
7.19 
Chemotherapy Extravasation 
 
If there is evidence of chemotherapy leakage or swelling during or following intravenous 
administration of vincristine or PTX, local care should be provided as described in the 
A5263/AMC066 MOPS. For extravasation, surgical consultation could be considered.  
 
7.20 
Symptomatic Therapy for Toxicities 
 


 
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Symptomatic therapy including, but not limited to, analgesics, antihistamines, 
antiemetics, antidiarrheal agents, may be administered as deemed necessary by the 
investigator, unless specifically prohibited by the protocol. 
 
7.21 
Virologic Failure 
 
Virologic failure is defined as two successive measurements of plasma HIV-1 RNA 
≥1000 copies/mL at week 12 to week 24 or RNA ≥400 copies/mL at week 24 or later. 
Participants who have virologic failure during Step 1, 2, or 3 should have confirmatory 
samples drawn as soon as possible after the initial plasma HIV-1 RNA result but no later 
than the next scheduled study visit. 
 
If a participant’s viral load rises above 10,000 copies/mL, an ART change is required. 
The participant will be offered the best locally provided ART. Sites must contact the 
CMC to request permission to make any changes in ART. 
 
7.22 
Procedures in the Event of Contraceptive Failure, On-Study Pregnancy, or 
Breastfeeding 
 
Contraceptive Failure 
In the event of contraceptive failure, the use of an emergency contraceptive is an option. 
A levonorgestrel-only emergency contraceptive (i.e., Plan B) is preferred to minimize the 
occurrence of nausea, which may interfere with adherence to protocol medications. The 
use of EFV with an emergency contraceptive containing both ethinyl estradiol and 
levonorgestrel may cause significantly increased ethinyl estradiol levels (Stocrin 
package insert, 2006), thereby increasing the incidence of nausea and vomiting. 
Combined ethinyl estradiol/levonorgestrel emergency contraceptive is, however, an 
acceptable option if a levonorgestrel-only emergency contraceptive is unavailable. 
 
On-Study Pregnancy 
A5263/AMC066 will not provide perinatal care for women. Women who become 
pregnant will be referred to local clinics and/or other research studies for prenatal and 
postpartum care and sites are encouraged to add the participant to The Antiretroviral 
Pregnancy Registry. More information is available at www.apregistry.com. Phone: +1-
910-679-1598; Fax: +1-910-256-0637. 
 
Monitoring for toxicity related to ART will continue during and after pregnancy. ART 
during pregnancy will follow the local standard of care. 
 
Women who become pregnant on study should follow local standard of care but 
may continue to receive study-provided ART.  
 
Women who are taking chemotherapy and become pregnant will immediately stop 
study-provided chemotherapy. Women who become pregnant and who continue to be 
followed in the study will be considered “on-study/off study-provided chemotherapy” 
during the time they are pregnant or breastfeeding. After pregnancy and/or breast-


 
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feeding are/is completed, consult the CMC to discuss resumption of study-provided 
chemotherapy. 
 
Pregnancy outcomes will be documented by completion of the appropriate CRF after the 
pregnancy has ended.  
 
Breastfeeding 
Breastfeeding is permitted in areas where formula feeding is not a viable option per 
WHO guidelines. Women who breastfeed will not receive chemotherapy. Breastfeeding 
participants receiving study-provided ART will be allowed to continue their use while 
breastfeeding at the discretion of the site investigator. Changes in ART for women who 
are breastfeeding will be at the discretion of the site investigator. EFV is used in HIV-
exposed infants and HIV-infected children. Data on the use of TDF and other ART 
agents during breastfeeding are limited. Please refer to WHO guidelines in the 
A5263/AMC066 MOPS for women who breastfeed. 
 
 
8.0 
CRITERIA FOR DISCONTINUATION 
 
8.1 
Permanent Treatment Discontinuation 
 
 
Specified drug-related toxicity (see section 7.0). 
 
Requirement for prohibited concomitant medications (see section 5.5). 
 
Completion of treatment as defined in the protocol. 
 
Request by participant to terminate treatment. 
 
Clinical reasons believed life threatening by the site investigator, even if not 
addressed in the toxicity section of the protocol. 
 
8.2 
Temporary Treatment Discontinuation 
 
 
Chemotherapy will be discontinued during pregnancy and breastfeeding 
 
8.3 
Premature Study Discontinuation 
 
 
Request by the participant to withdraw. 
 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the participant. 
 
Participant judged by the investigator to be at significant risk of failing to comply with 
the provisions of the protocol as to cause harm to self. 
 
At the discretion of the ACTG, IRB, Office for Human Research Protections (OHRP), 
NIAID, local government agencies, investigator, or pharmaceutical supporters.  
 
 


 
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9.0 
STATISTICAL CONSIDERATIONS  
 
At an interim review in March 2016, the CCDSMB found that the ET plus ART arm 
was less effective than the PTX plus ART arm. Per the CCDSMB recommendation, 
enrollment into this arm and all initiation of ET in subsequent steps were 
discontinued in March 2016.  
 
The following statistical considerations apply only to the revised study as a two-
arm trial, which includes the experimental arm (BV plus ART) and the active 
control arm (PTX plus ART). Refer to Version 2.0 of the protocol for the statistical 
considerations for the original three-arm trial. 
 
9.1 
General Design Issues 
 
A5263/AMC066 is a prospective, randomized, active-controlled, two-arm clinical trial 
designed to estimate the difference in event (KS progression, death, entry into an 
additional step, or loss to follow-up, prior to week 48) rates between an “experimental” 
regimen (BV plus ART initiation, which is considered standard of care therapy in 
resource-limited settings) and an active control (PTX plus ART initiation, a standard 
treatment in the United States that is sometimes used as salvage therapy for 
relapsed/refractory KS in resource-limited settings) for the treatment of HIV-infected, 
ART-naive participants presenting with advanced KS. After confirmation of eligibility, 
study participants are randomized in 1:1 fashion to one of the two arms. Randomization 
is stratified by CD4+ lymphocyte cell count (<100 versus ≥100 cells/mm3) and country.  
 
The trial is designed to evaluate whether there is sufficient evidence to conclude BV plus 
ART is noninferior to PTX plus ART (i.e., the active control). Noninferiority is defined as 
demonstrating that the clinical 48-week PFS rate in the investigational arm is within 15% 
of the PFS rate of the PTX arm. The selection of the 15% noninferiority margin was a 
combination of clinical judgment and statistical reasoning. A poll of the sites was 
conducted to derive the “maximum treatment difference that is considered clinically 
irrelevant” (i.e., largest acceptable difference in order to gain the advantage (cost) of the 
experimental chemotherapy). However, the team realizes that this margin and thus the 
resulting interpretation of the estimates of between-arm differences is subjective and 
may be country/site-specific. The team further acknowledges that event rates could differ 
from assumed rates and that this could influence the interpretation of the results. For 
example, if the event rate in the active control turns out to be substantially smaller, then 
a 15 percentage point increase might be substantial (e.g., if the control rate is only 30%, 
a 15 percentage point increase is a 50% relative increase). The team discussed the 
possibility of defining a “sliding” noninferiority margin as a function of the control group 
response rate but concluded that this was overly complex. The team realizes that the 
interpretation of trial results must be taken in context of many things including the 
observed control group response rate. The reporting of trial results will clearly 
incorporate and elaborate on these issues. 
 


 
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The experimental regimen has advantages relative to the active control. These include 
reduced costs and increased drug access. The BV regimen is not associated with 
cardiotoxicity, whereas PTX has been associated with arrhythmias. The BV combination 
is minimally myelotoxic, whereas PTX more frequently is associated with neutropenia. If 
the experimental regimen displays efficacy that is “not too much worse” than the active 
control, then this regimen may be suitable as a substitute for the active control, given 
the advantages of the experimental regimen.  
 
Considerable deliberation was given to the endpoint selection issues in this trial. 
Selected endpoints should be clinically relevant (i.e., address the scientific question), 
easy to interpret, easy and affordable to obtain, measured in an unbiased manner, 
sensitive to changes induced by treatment, measured as objectively as possible, 
measured as consistently as possible to reduce variation (via standardization and 
centralized labs), and result in a reasonable sample size. Composite endpoints, 
combining component endpoints associated with KS and HIV-disease, were considered 
since this trial can be viewed as investigating treatment of participants with multiple 
diseases and interest lies in the totality of participant outcome (rather than the trial being 
viewed as an investigation of treatment for KS within HIV-infected participants). Thus 
composite endpoints can provide a more complete characterization of the treatment 
effect. They can also reduce bias due to competing risks and potentially improve power. 
KS progression, death, entry into an additional step, or loss to follow-up, prior to week 48 
has been selected as the primary endpoint. Secondary composite endpoints have been 
constructed by sequentially adding the next most “severe” component of interest in KS-
AIDS (AIDS-defining event, HIV-1 RNA virologic failure, KS-IRIS, and KS response).  
 
Participants who originally have an IERC-confirmed CR or PR to Step 1 chemotherapy, 
but then progress at least 12 weeks after the last dose of Step 1 chemotherapy, will 
have the opportunity to enter Step 2 and be provided a second course of up to six cycles 
of the same chemotherapy utilized in Step 1 if, in the opinion of the investigator, the 
participant could potentially benefit from another course of the same chemotherapy.  
 
Participants will have the opportunity to enter Step 3 (assignment to the chemotherapy 
arm not utilized in Step 1) when:  (1) there is IERC-confirmed KS progression at any 
time during Step 1 chemotherapy; or (2) there is IERC-confirmed KS progression fewer 
than 12 weeks after the last chemotherapy dose in Step 1 in participants who have had 
an IERC-confirmed CR or PR; or (3) there is IERC-confirmed KS progression following 
Step 1 chemotherapy, without any prior response; or (4) there is IERC-confirmed KS 
progression in Step 2; or (5) with concurrence of the CMC, there is dose-limiting 
toxicity after receiving fewer than four cycles of chemotherapy in Step 1 or Step 2, in the 
absence of a CR or PR. Participants otherwise eligible for Step 2 who, in the opinion of 
the investigator and with concurrence of the CMC, are unlikely to benefit from another 
course of the same chemotherapy received in Step 1 will also be eligible for 
randomization in Step 3.  
 
Participants who fail Step 3 will be offered alternative care available locally, outside 
of the study.  


 
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Participants who received ET while on study (see protocol version 2.0) will be 
followed for 144 weeks after beginning the last cycle of ET. All other participants 
will be followed for 96 weeks after randomization or assignment to the last step they 
enter. 
 
9.2 
Endpoints 
 
9.2.1 Primary Endpoints  
 
PFS defined as a lack of KS progression, death, entry into an additional step, or 
loss to follow-up, prior to week 48. 
 
9.2.2 Secondary Endpoints  
 
9.2.2.1 Death by week 48; KS progression by week 48 
 
9.2.2.2 AIDS-defining event by week 48 
 
9.2.2.3 HIV-1 RNA virologic failure by week 48 
 
Virologic failure is defined as two successive measurements of plasma 
HIV-1 RNA ≥1000 copies/mL at week 12 to week 24 or RNA ≥400 
copies/mL at week 24 or later. 
 
9.2.2.4 KS-IRIS by week 48 
 
9.2.2.5 KS tumor response 
 
9.2.2.6 Duration of response 
 
9.2.2.7 KS progression, death, or AIDS defining event by week 48 
 
9.2.2.8 KS progression, death, AIDS defining event, or virologic failure by week 
48 
 
9.2.2.9 KS progression, death, AIDS defining event, virologic failure, or KS-IRIS 
by week 48 
 
9.2.2.10 Time to KS progression or death 
 
9.2.2.11 Time to death  
 
9.2.2.12 Change in KS treatment by week 48 
 
9.2.2.13 Chemotherapy-related toxicities and AEs (e.g., PN) 


 
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9.2.2.14 Changes in CD4+ lymphocyte cell count 
 
9.2.2.15 Adherence to therapy 
 
9.2.2.16 Plasma KSHV 
 
9.2.2.17 PBMC KSHV 
 
9.2.2.18 Presence of oral KS 
 
9.2.2.19 RNA levels for KSHV genes 
 
9.2.2.20 PN and SPN 
 
9.2.2.21 Similar endpoints as above on other later steps 
 
9.2.2.22 Immunohistochemical evaluations of viral and cellular gene expression 
 
9.2.2.23 Quality of life measures 
 
9.2.2.24 Cellular and humoral markers of immune function and activation 
 
9.3 
Randomization and Stratification 
 
Step 1: After confirming eligibility, participants will be randomized in a 1:1 ratio to the 
two regimens. Randomization will be stratified by CD4+ lymphocyte cell count (<100 or 
≥100 cells/mm3) and by country. 
 
Step 2: There is no randomization in Step 2. 
 
Step 3: Participants in Step 3 will be assigned to the remaining regimen not utilized in 
Step 1, using the same stratification factors as in Step 1. 
 
Step 4:  There is no randomization in Step 4. 
 
9.4 
Sample Size and Accrual 
 
A5263/AMC066 is designed to evaluate if there is sufficient evidence to conclude BV 
plus ART is noninferior to PTX plus ART. Noninferiority is defined as demonstrating that 
that the 48-week PFS rate in the investigational arm is within 15% of the PTX arm.  
 
The primary analysis will consist of constructing a 95% confidence interval (CI) for the 
difference between event rates of the experimental arm (BV) with the active control 
(PTX) and noting whether the CI rules out more than a 15% increase in event rate of the 
experimental arm compared with PTX. In the three-arm trial (protocol Version 2.0) 
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to control error rates at the contrast level (with two primary contrasts comparing each 
experimental regimen versus PTX) rather than controlling the trial-wise error rate. 
Therefore, in the revised two-arm trial, the same approach will be used (i.e., 
controlling the error rate at the contrast level for the remaining treatment 
comparison). 
 
With 386 participants in the two-arm trial, the study has 80% power to demonstrate 
noninferiority assuming the true event rates in both arms are 65% (the sample size for 
the entire study, including those already randomized to ET in Step 1A under 
protocol version 2.0, is 446). 
 
This is based on the following assumptions: 
 
15% noninferiority margin. The selection of the 15% noninferiority margin was a 
combination of clinical judgment and statistical reasoning. A poll of the sites was 
conducted to derive the “maximum treatment difference that is considered clinically 
irrelevant (i.e., largest acceptable difference in order to gain the advantages (e.g., 
cost) of the experimental chemotherapy”). However, the team realizes that this 
margin and thus the resulting interpretation of the estimates of between-arm 
differences is subjective and may be country/site-specific.  
 
Two interim analyses and one final analysis are planned: The two interim evaluations 
will occur after approximately 33.3% and 66.7% of the planned enrollment has 
completed week 48 (thus having primary endpoint results, i.e., at 33% and 67% 
information). A Lan-DeMets spending function was used corresponding to the 
O’Brien-Fleming boundary. During the interim analyses, evaluation of efficacy and 
futility can be conducted (i.e., either hypotheses, H0 or H1 can be rejected but is 
nonbinding in terms of trial alteration). 
 
One-sided significance level α=0.025  
 
1:1 assigned fraction  
 
Inflation rate of 10% for loss-to-follow-up for a known reason 
 
The point estimate of primary endpoint rate at week 48 for PTX is 65-70% (though it is 
not significantly different from PLD with a 50% PFS rate) according to Cianfrocca et al 
[44]. Sensitivity analyses were conducted to evaluate the power as a function of 
assumed primary endpoint (PFS) rate when the noninferiority margin is 15%. 
 
9.5 
Monitoring 
 
The study statisticians and data manager will prepare biannual administrative reports. 
Administrative reports will include baseline summaries (combined by treatment arms) 
including demographics and will address issues concerning the viability and appropriate 
execution of the protocol such as accrual and endpoint evaluability. 
 
Quarterly toxicity reports listing individual participant toxicity information (combined by 
treatment arms) will be prepared by the statisticians and data manager and will be 
forwarded to the DAIDS Clinical Representative and protocol co-chairs.  
 


 
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The CCDSMB will monitor A5263/AMC066 annually or twice annually. The study 
statisticians will prepare reports for the CCDSMB. CCDSMB reports will include all of the 
information in the Administrative Reports and the Toxicity Reports by randomized 
treatment. CCDSMB reports will also contain summaries of endpoint data by randomized 
treatment.  
 
Moving forward, formal between-arm comparisons will occur at each interim 
CCDSMB review; corresponding CIs, based on percentage information, will be 
constructed for the difference in proportions between the experimental therapy and the 
active control. Predicted interval plots (PIP) [62,63] will be constructed to aid the 
CCDSMB in decision-making. The PIPs provide the CCDSMB with a prediction of the 
trial results were the trial to continue as planned under varying assumptions regarding 
future data. Event rates will be evaluated to determine whether sample size adjustments 
are warranted. The sample size will not be adjusted based on the effect size (e.g., 
between-group difference) but will be adjusted based only on the pooled response rate. 
If the rate is very different than anticipated, then the sample size could be adjusted at the 
discretion of the CCDSMB. Since sample size recalculation is based on a pooled 
response rate there is no concern for an inflation of Type I error. Possible 
recommendations of the CCDSMB include continuation of the trial as planned, the 
discontinuation of a specific arm(s) due to inferiority or safety concerns, discontinuation 
of the study, or a sample size adjustment.  
 
“Noninferiority has not been demonstrated” does not necessarily imply inferiority, and in 
some cases more data may still be able to demonstrate noninferiority. Similarly “not 
superior or inferior” does not imply similarity or noninferiority. 
 
For interim data monitoring, it is important that both the ITT and Per Protocol analyses 
qualitatively agree with respect to conclusions particularly if noninferiority claims are 
likely to be made. If the ITT and per protocol analyses are qualitatively different, then 
consideration of trial continuation is warranted so that more definitive conclusions can be 
reached. Consideration of the composite nature of the endpoint is also important (e.g., 
evaluation of the components of the composite is important) since one arm could have a 
lower event rate but the events could be more severe (e.g., deaths).  
 
9.6 
Statistical Analyses 
 
The primary analyses will consist of the construction of a CI for the difference (adjusted 
using the Lan-DeMets approach to account for the multiple interim analyses to 
provide 95% simultaneous coverage over the multiple analyses) in the proportion of 
48-week event rates between the experimental regimen and the active control (ART 
initiation with PTX). These analyses will utilize all randomized participants as per ITT 
principles and will be model adjusted for the stratification factors (country and CD4+ 
lymphocyte cell count). Missing data will be treated as failures since: (1) recent data 
reported at the ACTG meeting (2008) suggest that most missing data from international 
sites are due to participant deaths, and (2) the study participants have advanced stage 


 
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disease. Per-protocol analyses will be conducted as co-primary analyses given the 
noninferiority nature of the trial design.  
 
The difference in 48-week event rates for secondary endpoints will be similarly 
constructed to compare the experimental regimen with the active control but without 
adjustment for the interim analyses. Regression analyses will examine treatment-by-
stratum interactions to investigate if global estimates or stratum-specific estimates are 
appropriate. Analyses of the time-to-event endpoints will be conducted using 
proportional hazards regression controlling for the stratification factors in the model. A 
quality-of-life adjusted survival analysis will also be conducted using Q-TWIST 
methodology.  
 
Additional analyses will be described in a statistical analysis plan that will be reviewed by 
the protocol team prior to any analyses of the trial data. 
 
 
10.0 
PHARMACOLOGY PLAN 
 
Please refer to stand alone sub-study A5278s, "Pharmacology Substudies of A5263 and 
A5264", for the pharmacology plan. Sites are strongly encouraged to coenroll 
participants in A5278s.  
 
 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
Case report forms (CRF) are provided for each participant. Participants must not be 
identified by name on any CRFs. Participants are identified by the patient identification 
number (PID) and study identification number (SID) provided by the ACTG Data 
Management Center upon randomization. 
 
11.2 
Role of Data Management 
 
11.2.1 
Instructions concerning the recording of study data on CRFs are provided by 
the ACTG Data Management Center. Each CRS is responsible for keying the 
data in a timely fashion. 
 
11.2.2 
It is the responsibility of the ACTG Data Management Center to assure the 
quality of computerized data for each ACTG study. This role extends from 
protocol development to generation of the final study databases. 
 
11.3 
Clinical Site Monitoring and Record Availability 
 


 
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Site monitors under contract to the National Institute of Allergy and Infectious Diseases 
(NIAID) will visit participating clinical research sites to review the individual participant 
records, including consent forms, CRFs, supporting data, laboratory specimen records, 
and medical records (physicians’ progress notes, nurses’ notes, individuals’ hospital 
charts), to ensure protection of study participants, compliance with the protocol, and 
accuracy and completeness of records. The monitors also will inspect sites’ regulatory 
files to ensure that regulatory requirements are being followed and sites’ pharmacies to 
review product storage and management. 
 
The site investigator will make study documents (e.g., consent forms, drug distribution 
forms, CRFs) and pertinent hospital or clinic records readily available for inspection by 
the local IRB, the site monitors, the NIAID, the OHRP, local government agencies, and 
the pharmaceutical supporters or designee for confirmation of the study data.  
 
11.4  Expedited Adverse Event Reporting   
 
11.4.1 Adverse Event Reporting to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website: http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/manual. 
 
The DAIDS Adverse Events Reporting System (DAERS) internet-based reporting 
system must be used for expedited AE reporting to DAIDS. In the event of 
system outages or technical difficulties, expedited AEs may be submitted via the 
DAIDS EAE Form. For questions about DAERS, please contact NIAID CRMS 
Support at CRMSSupport@niaid.nih.gov or from within the DAERS application 
itself. 
 
Sites where DAERS has not been implemented will submit expedited AEs by 
documenting the information on the current DAIDS EAE Form. This form is 
available on the RSC website: http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/manual.  
 
For questions about EAE reporting, please contact the RSC 
(RSCSafetyOffice@tech-res.com). 
 
11.4.2 Reporting Requirements for this Study 
 
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, is used for this study. 
 
The study products for which expedited reporting is required are ET, 
bleomycin sulfate, vincristine sulfate, PTX, and any study-provided ART. 
 
In addition to the EAE Reporting Category identified above, other AEs that 
must be reported in an expedited manner are all grade 4 laboratory results 


 
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and any malignancy or myelodysplastic syndrome, serious IRIS events, and 
fetal losses. “Fetal loss” is defined on the PSWP. 
 
Overdoses of Atripla and EFV do not require expedited reporting, but will be 
reported to Merck every 3 months by the SDAC/DMC. Overdoses of Atripla 
and EFV should be recorded on the CRF and keyed in the database in a 
timely manner. “Overdose” is defined on the PSWP. 
 
11.4.3 Grading Severity of Events 
 
The DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, 
August 2009), must be used and is available on the DAIDS RSC website: 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-
grading-tables. 
 
11.4.4 Expedited AE Reporting Period 
 
 
The expedited AE reporting period for this study is from enrollment of a trial 
participant to the end of trial follow-up for that participant. 
 
After the protocol-defined AE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions SUSARs, as defined in 
Version 2.0 of the EAE Manual, will be reported to DAIDS if the study staff 
become aware of the events on a passive basis (from publicly available 
information). 
 
 
12.0 
PARTICIPANTS 
 
12.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix VI) and any subsequent 
modifications will be reviewed and approved by the IRB or ethics committee responsible 
for oversight of the study. A signed consent form will be obtained from the participant (or 
legal guardian or person with power of attorney for participants who cannot consent for 
themselves). The consent form will describe the purpose of the study, the procedures to 
be followed, and the risks and benefits of participation. A copy of the consent form will 
be given to the participant or legal guardian, and this fact will be documented in the 
participant’s record. 
 
12.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 


 
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participant, except as necessary for monitoring by IRB, the NIAID, the OHRP, local 
government agencies, or the pharmaceutical supporters or designee.  
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB, the NIAID, the 
pharmaceutical supporters, the OHRP, or other government agencies as part of their 
duties to ensure that research participants are protected.  
 
 
13.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial is governed by ACTG policies. Any presentation, 
abstract, or manuscript will be made available for review by the pharmaceutical 
supporters prior to submission.  
 
 
14.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the Centers for 
Disease Control and Prevention and the National Institutes of Health. 
 
All dangerous goods materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association Dangerous 
Goods Regulations.  


 
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15.0 
REFERENCES 
 
1. Engels EA, Pfeiffer RM, Goedert JJ, et al. for the HIV/AIDS Cancer Match Study. Trends 
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2. Maurer T, Ponte M, Leslie K. HIV-associated Kaposi's sarcoma with a high CD4 count 
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3. Krown SE, Lee JY, Dittmer DP, for the AIDS Malignancy Consortium. More on HIV-
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4. Newton R, Ziegler J, Bourboulia D, et al. Infection with Kaposi's sarcoma-associated 
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6. Sitas F, Carrara H, Beral V, et al. Antibodies against human herpesvirus 8 in black South 
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7. Makombe SD, Harries AD, Yu JK, et al. Outcomes of patients with Kaposi's sarcoma 
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8. D'Aquila RT, Hughes MD, Johnson VA, et al. Nevirapine, zidovudine, and didanosine 
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9. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside 
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10. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and 
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11. Autran B, Carcelain G, Li TS, et al. Positive effects of combined antiretroviral therapy on 
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12. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among 
patients with advanced human immunodeficiency virus infection. HIV Outpatient Study 
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13. Hermans P., Lundgren J, Sommereijns B, et al. Epidemiology of AIDS-related Kaposi's 
sarcoma in Europe over 10 years. AIDS in Europe Study Group. AIDS 1996;10:911-917. 
 
14. Jones JL, Hanson DL, Dworkin MS, Kaplan JE, Ward JW. Trends in AIDS-related 
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15. Lebbe C, Blum L, Pellet C, et al. Clinical and biological impact of antiretroviral therapy 
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16. Cattelan AM, Calabro ML, Aversa SM, Zanchetta M, Meneghetti F, De Rossi A, Chieco-
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17. Mosam A, Cassol E, Page T, et al. Generic antiretroviral efficacy in AIDS-associated 
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21. Molina JM, Gathe J, Lim PL, et al. Comprehensive resistance testing in antiretroviral-
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22. Podzamczer D, Consiglio E, Ferrer E, Gudiol F. Efavirenz associated with 
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23. Gathe J, Podzamczer D, Johnson M, et al. Once-daily versus twice-daily 
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24. Gallant JE, DeJesus E, Arribas JR, et al. for the Study 934 Group. Tenofovir DF, 
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Engl J Med 2006;354(3):251-60. 
 
25. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and 
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treatment of HIV-1 infection in adults. N Engl J Med 1999;341:1865-73. 
 
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Muggia FM. Treatment of epidemic Kaposi’s sarcoma with etoposide or a combination of 
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33. Stewart S, Jablonowski H, Goebel FD, et al. Randomized comparative trial of pegylated 
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REFERENCES (Cont'd) 
 
12/7/16 
 
 
34. Ireland-Gill A, Espina BM, Akil B, Gill PS. Treatment of acquired immunodeficiency 
syndrome-related Kaposi's sarcoma using bleomycin-containing combination 
chemotherapy regimens. Semin Oncol 1992;19(2 Suppl 5):32-6; discussion 36-7. 
 
35. Gill PS, Rarick M, McCutchan JA, et al. Systemic treatment of AIDS-related Kaposi's 
sarcoma: Results of a randomized trial. Am J Med 1991;90:427-33. 
 
36. Gill PS, Bernstein-Singer M, et al. Adriamycin, bleomycin and vincristine chemotherapy 
with recombinant granulocyte-macrophage colony-stimulating factor in the treatment of 
AIDS-related Kaposi's sarcoma. AIDS 1992;6:1477-81. 
 
37. Gill PS, Miles SA, Mitsuyasu RT, et al. Phase I AIDS Clinical Trials Group (075) study of 
adriamycin, bleomycin and vincristine chemotherapy with zidovudine in the treatment of 
AIDS-related Kaposi's sarcoma. AIDS 1994;8:1695-9. 
 
38. Gill PS, Wernz J, Scadden DT, et al. Randomized phase III trial of liposomal 
daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's 
sarcoma. J Clin Oncol 1996;14:2353-64. 
 
39. Northfelt DW, Dezube BJ, Thommes JA, et al. Pegylated-PLD versus doxorubicin, 
bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of 
a randomized phase III clinical trial. J Clin Oncol 1998;16:2445-51. 
 
40. Welles L, Saville MW, Lietzau J, et al. Phase II trial with dose titration of paclitaxel for the 
therapy of human immunodeficiency virus-associated Kaposi's sarcoma. J Clin Oncol 
1998;16:1112-21. 
 
41. Tulpule A, Groopman J, Saville MW, et al. Multicenter trial of low-dose paclitaxel in 
patients with advanced AIDS-related Kaposi sarcoma. Cancer 2002; 95:147-154. 
 
42. Stebbing J, Wildfire A, Portsmouth S, et al. Paclitaxel for anthracycline-resistant AIDS-
related Kaposi's sarcoma: clinical and angiogenic correlations. Ann Oncol 2003; 
14:1660-1666. 
 
43. Paclitaxel package insert, accessed on line 2/12/12 at 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf. 
 
44. Cianfrocca M, Lee S, Von Roenn J, et al. Randomized trial of paclitaxel versus 
pegylated liposomal doxorubicin for advanced human immunodeficiency virus-
associated Kaposi’s sarcoma: Evidence for symptom palliation from chemotherapy. 
Cancer 2010;116(16):3969-77. 
 
45. Mosam A, Cassol E, Page T, et al. Generic antiretroviral efficacy in AIDS-associated 
Kaposi’s sarcoma in sub-Saharan Africa. AIDS 2005;19:8-10. 
 


 
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46. Asiimwe F, Moore D, Nakityo R, Were W, Mermin J, Kaharuza F. Clinical outcomes of 
HIV-infected patients with Kaposi’s sarcoma disease receiving ART in rural Uganda. 
14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, 2007, 
Abstract 880. 
 
47. Borok M, Gudza I, Fiorillo S, et al. Improved survival of AIDS/KS treated with co-
formulated abacavir/lamivudine/zidovudine in Zimbabwe. 14th Conference on 
Retroviruses and Opportunistic Infections, Los Angeles, 2007, Abstract 879. 
 
48. Dedicoat M, Vaithilingum M, Newton R. Treatment of Kaposi's sarcoma in HIV-1 infected 
individuals with emphasis on resource poor settings. Cochrane Database Syst Rev 
2003;(3):CD003256.  
 
49. Martin-Carbonero L, Barrios A, Saballs P, et al. Caelyx/KS Spanish Group. Pegylated 
liposomal doxorubicin plus highly active antiretroviral therapy versus highly active 
antiretroviral therapy alone in HIV patients with Kaposi’s sarcoma. AIDS 2004;18:1737-
40. 
 
50. Bihl F, Mosam A, Henry LN, et al. Kaposi’s sarcoma-associated herpesvirus-specific 
immune reconstitution and antiviral effect of combined HAART/chemotherapy in HIV 
clade C-infected individuals with Kaposi’s sarcoma. AIDS 2007;21:1245-52. 
 
51. Cingolani A, Torti L, Pinnetti C, et al. Detrimental clinical interaction between ritonavir-
boosted protease inhibitors and vinblastine in HIV-infected patients with Hodgkin's 
lymphoma. AIDS 2010;24(15):2408-12. 
 
52. Makinson A, Martelli N, Peyrière H, et al. Profound neutropenia resulting from interaction 
between antiretroviral therapy and vinblastine in a patient with HIV-associated Hodgkin's 
disease. Eur J Haematol 2007;78(4):358-60. 
 
53. Kotb R, Vincent I, Dulioust A, et al. Life-threatening interaction between antiretroviral 
therapy and vinblastine in HIV-associated multicentric Castleman's disease. Eur J 
Haematol 2006;76(3):269-71. 
 
54. Smith MA, Rubinstein L, Anderson JR et al. Secondary Leukemia or myelodysplastic 
syndrome after treatment with epipodophyllotoxins. J Clin Oncol 1999;17:569-577. 
 
55. Greco FA, Thomas M, Hainsworth JD. One-hour paclitaxel infusions: review of safety 
and efficacy. Cancer J Sci Am 1999; 5:179-191.  
 
56. Gelderblom H, Mross K, ten Tije AJ, et al. Comparative pharmacokinetics of unbound 
paclitaxel during 1- and 3-hur infusions. J Clin Oncol 2002;15:574-581. 
 
57. Schwartz JD, Howard W, Scadden DT. Potential interaction of antiretroviral therapy with 
paclitaxel in patients with AIDS-related Kaposi sarcoma. AIDS 1999;13:283-4. 
 


 
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58. Bundow D and Aboulafia DM. Potential drug interaction with paclitaxel and highly active 
antiretroviral therapy in two patients with AIDS-associated Kaposi sarcoma. Am J Clin 
Oncol 2004;27:81-4. 
 
59. Cianfrocca ME, Lee S, Von Roenn J, Rudek MA, Dezube BJ, Krown SE, Sparano JA. 
Pilot study evaluating the interaction between paclitaxel and protease inhibitors in 
patients with human immunodeficiency virus-associated Kaposi’s sarcoma: An Eastern 
Cooperative Oncology Group (ECOG) and AIDS Malignancy Consortium (AMC) trial. 
Cancer Chemother Pharmacol 2011;68:827-33. 
 
60. Cherry CL, Wesselingh SL, Lal L, McArthur JC. Evaluation of a clinical screening tool for 
HIV-associated sensory neuropathies. Neurology 2005; 65(11):1778-1781. 
 
61. Ellis RJ, Evans SR, Clifford DB, et al. Neurological AIDS Research Consortium; AIDS 
Clinical Trials Group Study Teams A5001 and A362. Clinical validation of the 
NeuroScreen. J Neurovirol 2005;(6):503-11. 
 
62. Li L, Evans SR, Uno H, Wei LJ. Predicted interval plots: A graphical tool for data 
monitoring in clinical trials. Stat Biopharm Res 2009;1(4):348-355. 
 
63. Evans SR, Li L, Wei LJ. Data monitoring in clinical trials using prediction. Drug Inform J 
2007;41:733-742. 


 
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APPENDIX I: ACCEPTABLE CONTRACEPTION METHODS AND DOCUMENTATION OF 
STERILIZATION, MENOPAUSE, AND CHILD’S OR ADOLESCENT’S  
REPRODUCTIVE POTENTIAL 
 
1. Acceptable Contraception Methods; Please also refer to the FDA Birth Control Guide found 
at: 
http://www.fda.gov/ForConsumers/ByAudience/ForWomen/WomensHealthTopics/ucm
117971.htm 
 
Category X Medications 
Category D Medications1 
Category C Medications 
Contraception 
requirements as directed 
by drug package insert, 
medical alert, or 
investigator’s brochure.  
A Combination of TWO of the 
following methods: 
 Condoms (male or female) 
with or without a spermicidal 
agent. 
 Diaphragm or cervical cap 
with spermicide 
 IUD 
 Tubal ligation2 
 Hormone-based 
contraceptive 
At least one of the following 
methods MUST be used 
appropriately: 
 Condoms (male or female) 
with or without a spermicidal 
agent 
 Diaphragm or cervical cap 
with spermicide 
 IUD Hormone-based 
contraceptive 
1Exceptions for Some Drugs: Additional or specific requirements may be found in the package 
insert, medical alert, or investigator’s brochure, e.g., the labeling for EFV, a class D drug, 
specifies that only the female study participant must use two contraception methods, one of 
which must be a barrier method. In such cases, all the relevant instructions must be included in 
the protocol. 
 
NOTE: Some protocol-specified medications (e.g., PIs, NNRTIs) alter the metabolism of 
hormonal-based methods. This interaction may make hormone-based methods less effective. 
Therefore, alternative or an additional contraceptive method may be required. 
 
2Tubal Ligation is considered a form of sterilization for class C drugs. For classes D and X if not 
otherwise specified in the package insert or IB, it is considered a form of contraceptive. 
 
2. Acceptable Documentation of Hysterectomy and Bilateral Oophorectomy, Tubal Ligation, 
Tubal Micro-inserts, Vasectomy, and Menopause 
 
For participants receiving protocol-specified Category C medications  
 
Participant-reported history 
 
For participants receiving protocol-specified Category X and D medications 
 
Confirmation of the lack of reproductive potential is REQUIRED 
 
Written documentation or verbal communication from a clinician or clinician’s staff 
documented in source documents of one of the following:  


 
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121 
o Physician report/letter   
o Operative report or other source documentation in the participant record (a 
laboratory report of azoospermia is required to document successful vasectomy)  
o Discharge summary 
o Laboratory report of azoospermia for males only 
o FSH measurement elevated into the menopausal range as established by the 
reporting laboratory. 
 
NOTE 1: The female study participant cannot provide written proof of a male partner’s 
vasectomy status since he is not usually enrolled in the same study to provide consent for 
release of this information. This criterion, the “laboratory report of azoospermia” should be 
removed from the list of acceptable documentation that female study participants can provide.  
 
NOTE 2, for EFV only: If the female study participant reports a history of infertility based on 
one of the above categories but written documentation is not obtainable, or she states that her 
partner has had a vasectomy, the female study participant must agree to use at least one 
barrier method of contraception with a possible second method required at the discretion of the 
site study physician. Documentation of the study participant's statement should be entered into 
the source document. 


 
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APPENDIX II: ASSESSMENT OF CIRCULATING LEVELS OF PRO-INFLAMMATORY AND 
ANGIOGENESIS-ASSOCIATED MOLECULES 
 
 
1.0 
OBJECTIVES 
 
1.1 
To compare the effects of randomized treatment on serum levels of inflammatory 
cytokines and/or molecules associated with angiogenesis. 
 
1.2 
To determine whether serum levels of cytokines and angiogenesis-associated molecules 
are associated with clinical response, immunological response (assessed by measuring 
CD4+ lymphocyte cell count), virological responses (assessed by measurement of HIV-1 
and HHV8 viral load), and the development of IRIS. 
 
2.0 
BACKGROUND 
 
The risk of developing several cancers, including Kaposi’s sarcoma (KS), non-Hodgkin’s 
lymphoma (NHL), and cervical cancer is greatly increased in HIV infection. Effective 
ART has resulted in a decrease in most AIDS-associated cancers, as well as in other 
AIDS-defining conditions; HAART has been seen to result in a pronounced decrease in 
the incidence of KS, as well as those forms of NHL that are associated with Epstein-Barr 
virus (EBV) infection, such as primary central nervous system (CNS) lymphoma (1-6).  
 
Angiogenesis related to tumor growth, in concert with other tumor supporting factors, 
has been associated with the development and progression of many cancers, including 
KS. Angiogenic factors can be released into the systemic circulation as a result of 
cancer and numerous studies have demonstrated that several angiogenesis regulator 
substances circulate in the blood and may function as tumor growth factors in cancer 
patients (7). Vascular endothelial growth factor (VEGF) levels appear to be increased in 
HIV-infected patients (8-10). Several studies have assessed VEGF levels in AIDS-
associated KS (7, 9-11), with conflicting results, although published studies have 
typically involved small numbers of participants. Additionally, constitutive over-
expression of matrix metalloproteinases (MMP) MMP-2 and MMP-9 has been seen in 
AIDS-KS (12), with treatment of AIDS-KS using the matrix MMP inhibitor COL-3 
resulting in decreased serum levels of MMP-2 and MMP-9 (13). MMPs are a family of 
zinc-dependent endopeptidases that facilitate tumor invasion and metastasis by 
mediating the destruction of extracellular matrix proteins (14-17). MMP-2 (gelatinase A) 
and MMP-9 (gelatinase B) degrade collagen IV, the major component of basement 
membranes. In addition to VEGF and MMPs, several other factors have been shown to 
have angiogenesis-promoting properties, or to be associated with angiogenesis. These 
include chemokines (IL8 [CXCL8], MCP1 [CCL2]), cytokines (IL6, leptin), and other 
growth and angiogenesis-promoting factors (bFGF, PDGF, EGF, MMPs).  
 


 
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3.0 
RATIONALE 
 
The recent availability of multiplexed immunometric assays has made possible the 
simultaneous assessment of several of these angiogenic factors, using small volumes 
(<500 l) of serum/plasma. Interestingly, some agents used in HAART, especially PIs, 
have been seen to have anti-angiogenic and anti-inflammatory effects, which have the 
potential to inhibit tumor development and/or growth. These effects are independent of 
the ART properties of these drugs (18, 19). Therefore, ART drug use may result in 
decreased expression of circulating angiogenic factors and inflammatory cytokines. 
Additionally, infection with EBV and KSHV may contribute to angiogenesis and 
invasiveness directly or through paracrine mechanisms. EBV Latent Membrane Protein 
1 (LMP-1) induces expression of MMP-9, COX-2, VEGF, FGF-2, and HIF-1 alpha (20, 
21). HHV8 induces such molecules as well. Early events in viral infection, as well as 
expression of specific viral genes (K1) induce expression of MMP-9 and VEGF (22-24). 
 
Pro-inflammatory cytokines also have been seen to be associated with the pathogenesis 
of AIDS-KS (25-27). For example, IL6 has been reported to contribute to the growth of 
AIDS-KS cells (25), and elevated levels of this and other inflammatory cytokines are 
seen in HIV infection (27). Therefore, HIV-driven inflammatory cytokine production has 
the potential to contribute to the growth of KS, and enhanced production of these and 
other KS-stimulatory molecules is believed to contribute to the development of KS-IRIS 
(28). However, there is little information available on levels of angiogenesis-associated 
or inflammatory cytokines in AIDS-KS IRIS. In fact, little is known about circulating levels 
of key inflammatory cytokines, such as IL17, in KS. Additionally, the effect of HAART on 
these inflammatory cytokines has not been clearly defined.  
 
4.0 
EVALUATIONS 
 
Serum levels of cytokines and inflammation- and angiogenesis-associated molecules will 
be determined at the following study visits: pre-treatment (entry), and at 3, 24, and 48 
weeks post treatment initiation. Initially, this will be done retrospectively for specimens 
from 20 participants that: 1) respond to treatment, 2) develop IRIS, or 3) progress 
without IRIS. If this initial analysis suggests a relationship between cytokines, 
inflammatory markers and/or angiogenesis molecules and KS response status, 
additional samples from a larger number of participants will be tested to confirm and 
extend the initial results. Subsequent studies could include the assessment of markers 
of microbial translocation, in addition to inflammation- and angiogenesis-associated 
molecules. 
 
5.0 
ANALYSES 
 
The working hypotheses that will be tested are that: 1) the development of IRIS will be 
preceded/accompanied by increased levels of angiogenesis/inflammation-associated 
serum molecules, when compared to clinically defined non-responders or responders 
without IRIS, and 2) those who respond to treatment and do not develop IRIS will show 
relatively lower levels of angiogenesis/inflammation-associated molecules than either 
those who developed IRIS or did not show a clinical response to treatment. 


 
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APPENDIX II (Cont'd) 
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Levels of angiogenesis-associated molecules (VEGF, bFGF, IL6, IL8, MCP1, MMP-2, 
MMP-9), as well as of inflammatory (IL1), Th1 (IFN), Th17 (IL17, IL6, TNF) and TH2 
(IL10, IL4) cytokines will be assessed, using two custom multiplexed (Luminex platform) 
panels in this study (Table 1). The use of these assays (R&D Systems) will allow the 
simultaneous determination of serum levels of thirteen molecules associated with 
angiogenesis/inflammation by multiplex immunometric assay, minimizing sample volume 
and maximizing the information generated, both financially and in terms of serum volume 
utilized. This work will be done in the Martinez-Maza lab at UCLA, using a BioPlex 200 
Luminex system. In addition to this, we will also quantify serum levels of neopterin (IBL 
International) and CRP (high sensitivity, Hemagen), two inflammation-associated 
biomarkers, by ELISA. Serum neopterin has been seen to be a good prognostic marker 
in AIDS-KS (29). A minimum of 500 l of serum is required for assessment of these 
inflammation- and angiogenesis-associated molecules and cytokines, using these 
assays. 
 
Table 1. Cytokine and angiogenesis multiplex assay analytes, assay range and 
sensitivity (from R&D Systems) 
Analyte 
%CV* 
Sensitivity ** 
xMAP Region 
Panel (Base Kit) 
VEGF 
8.6 
3.7 pg/mL 
52 
A 
bFGF 
6 
6.3 pg/mL 
54 
A 
IL6 
0.2 
4.9 pg/mL 
32 
A 
IL8 
(CXCL8) 
3.2 
3.6 pg/mL 
36 
A 
MCP1 
(CCL2)  
8.3 
2.9 pg/mL 
78 
A 
TNFa 
- 
0.6 pg/mL*** 
77 
A 
IL17 
6.1 
3.4 pg/mL 
20 
A 
IFNg 
5.2 
4.5 pg/mL 
75 
A 
IL4 
- 
1.8 pg/mL*** 
21 
A 
IL1b 
5.5 
2.7 pg/mL 
6 
A 
IL10 
6.5 
3.0 pg/mL 
50 
A 
MMP-2 
- 
25 pg/mL*** 
13 
MMP 
MMP-9 
- 
7 pg/mL*** 
47 
MMP 
* intra-assay variability (% CV), middle of detection range, for a typical assay 
(plate 5, SMART/INSIGHT study) carried out in the Martinez-Maza lab 
** lowest routinely detectable standard, from work in the Martinez-Maza lab 
*** lower limit of detection, as indicated by manufacturer 
 


 
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LABORATORY CONTACT INFORMATION FOR THE ABOVE TESTING 
Martinez–Maza Laboratory  
UCLA AIDS Institute 
BSRB Room 173     
615 Charles Young Dr. South 
Los Angeles, CA 90095-7563 
Attn: Otto Martinez-Maza and Larry Magpantay 
Phone: 310-206-6846  
Fax: 310-206-5387 
E-mail: omartinez@mednet.ucla.edu & LMagpantay@mednet.ucla.edu  


 
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6.0 
REFERENCES 
 
1. Biggar RJ. AIDS-related cancers in the era of highly active antiretroviral therapy. Oncology 
2001;15:439-48. 
2. Hessol NA, Seaberg EC, Preston-Martin S, et al. Cancer risk among participants in the 
women's interagency HIV study. J Acquir Immune Defic Syndr 2004;36:978-85. 
3. Seaberg EC, Hessol N, Jacobson L, Martínez-Maza O, Sutcliffe C, Levine A. 2005. Cancer 
incidence before and during the era of HAART. In 9th International Workshop on HIV 
Observational Databases, 2005; Budapest, Hungary. 
4. Grulich AE, Li Y, McDonald AM, Correll PK, Law MG, Kaldor JM. Decreasing rates of 
Kaposi's sarcoma and non-Hodgkin's lymphoma in the era of potent combination anti-
retroviral therapy. AIDS 2001;15:629-33. 
5. International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and 
incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst 
2000; 92:1823-30. 
6. Biggar RJ, Chaturvedi AK, Goedert JJ, Engels EA. AIDS-related cancer and severity of 
immunosuppression in persons with AIDS. J Natl Cancer Inst 2007;99:962-72. 
7. Poon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer 
patients. J Clin Oncol 2001;19:1207-25. 
8. Sachdeva N, Yoon HS, Oshima K, Garcia D, Goodkin K, Asthana D. Biochip array-based 
analysis of plasma cytokines in HIV patients with immunological and virological discordance. 
Scan J Immunol 2007;65:549-54. 
9. Mercie P, Devianne I, Viallard JF, et al. Vascular endothelial growth factor (VEGF165) 
plasma level increase with immunodepression in AIDS patients with Kaposi's sarcoma. 
Microvascular Res 1999;57:208-210. 
10. Ascherl G, Hohenadl C, Schatz O, et al. Infection with human immunodeficiency virus-1 
increases expression of vascular endothelial cell growth factor in T cells: Implications for 
acquired immunodeficiency syndrome-associated vasculopathy. Blood 1999;93:4232-4241. 
11. Renwick N, Weverling GJ, Brouwer J, Bakker M, Schulz TF, Goudsmit J. Vascular 
endothelial growth factor levels in serum do not increase following HIV type 1 and KSHV 
seroconversion and lack correlation with AIDS-related Kaposi's sarcoma. AIDS Res Hum 
Retroviruses 2002;18:695-8. 
12. Meade-Tollin LC, Way D, Witte MH. Expression of multiple matrix metalloproteinases and 
urokinase type plasminogen activator in cultured Kaposi sarcoma cells. Acta Histochem 
1999;101:305-16. 
13. Dezube BJ, Krown SE, Lee JY, Bauer KS, Aboulafia DM. Randomized phase II trial of 
matrix metalloproteinase inhibitor COL-3 in AIDS-related Kaposi's sarcoma: an AIDS 
Malignancy Consortium Study. J Clin Oncol 2006;24:1389-94. 
14. Matrisian LM. The matrix-degrading metalloproteinases. Bioassays 1992;14:455-63. 


 
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15. Bernhard EJ, Gruber SB, Muschel RJ. Direct evidence linking expression of matrix 
metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in 
transformed rat embryo cells. PNAS USA 1994;91:4293-97. 
16. Kawamata H, Kameyama S, Kawai K, Johnson MD, Stetler-Stevenson WG, Oyasu R. 
Marked acceleration of the metastatic phenotype of a rat bladder carcinoma cell line by the 
expression of human gelatinase. A. Int’l J Cancer 1995;63:568-57. 
17. Ray JM, Stetler-Stevenson WG. Gelatinase A activity directly modulates melanoma cell 
adhesion and spreading. Embo J 1995;14:908-17. 
18. Monini P, Sgadari C, Toschi E, Barillari G, Ensoli B. Antitumour effects of antiretroviral 
therapy. Nat Rev Cancer 2004;4:861-75. 
 
19. Monini P, Toschi E, Sgadari C, et al. The use of HAART for biological tumour therapy. J HIV 
Ther 2006;11:53-56. 
20. Wakisaka N, Pagano JS. Epstein-Barr virus induces invasion and metastasis factors. 
Anticancer Res 2003;23:2133-38. 
21. Stevenson D, Charalambous C, Wilson JB. Epstein-Barr virus latent membrane protein 1 
(CAO) up-regulates VEGF and TGFa concomitant with hyperlasia, with subsequent up-
regulation of p16 and MMP9. Cancer Res 2005;65(19):8826-35. 
22. Wang L, Wakisaka N, Tomlinson CC, et al. The Kaposi's sarcoma-associated herpesvirus 
(KSHV/KSHV) K1 protein induces expression of angiogenic and invasion factors. Cancer 
Res 2004;64:2774-81. 
23. Efklidou S, Bailey R, Field N, Noursadeghi M, Collins MK. vFLIP from KSHV inhibits anoikis 
of primary endothelial cells. J Cell Sci 2008;121:450-7. 
24. Sivakumar R, Sharma-Walia N, Raghu H, et al. Kaposi's sarcoma-associated herpesvirus 
induces sustained levels of vascular endothelial growth factors A and C early during in vitro 
infection of human microvascular dermal endothelial cells: Biological implications? J Virol 
2008;82:1759-76. 
25. Miles SA, Rezai AR, Salazar-Gonzalez JF, et al. AIDS Kaposi's sarcoma-derived cells 
produce and respond to interleukin-6. PNAS USA 1990;87:4068-72. 
26. Miles SA, Martínez-Maza O, Rezai A, et al. Oncostatin-M is a potent mitogen for AIDS-
Kaposi sarcoma derived cells. Science 1992;255:1432-34. 
27. Ensoli B, Sgadari C, Barillari G, Sirianni MC, Stürzl M, Monini P. Biology of Kaposi's 
sarcoma. Eur J Cancer 2001;37:1251-1269. 
28. Feller L, Lemmer J. Insights into pathogenic events of HIV-associated Kaposi sarcoma and 
immune reconstitution syndrome related Kaposi sarcoma. Infect Agent Cancer 2008;3:1. 
29. Krown SE, Niedzwiecki D, Bhalla RB, Flomenberg N, Bundow D, Chapman D. Relationship 
and prognostic value of endogenous interferon-, 2-microglobulin, and neopterin serum 
levels in patients with Kaposi sarcoma and AIDS. J Acquir Immune Defic Syndr 1991;4:871-
880. 


 
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APPENDIX III: IMMUNE RESPONSE TO HHV8 IN AIDS-ASSOCIATED KS  
 
1.0 
OBJECTIVES 
 
1.1  
Primary 
 
1.1.1 To determine anti-HHV8 specific T cell immune response in participants with 
AIDS-associated KS before and after ART.  
 
1.1.2 To follow the trajectory of the anti-HHV8 T cell response at various time points 
after ART is started. 
 
1.1.3 To correlate changes in the anti-HHV8 T cell response with both HIV and HHV-8 
viremia at specific time points.  
 
1.1.4 To correlate the magnitude of the anti-HHV-8 T cell immune response with 
clinical outcome. 
 
1.2 
Secondary 
 
1.2.1 To explore changes in regulatory T cell frequency in participants developing KS-
IRIS. 
 
1.2.2 To evaluate CD8 T cell exhaustion before and after antiretroviral treatment and 
during the development of KS-IRIS.  
 
2.0 
BACKGROUND 
 
KS is the most common malignancy in persons with AIDS. HIV co-infection is a strong 
predictor of development of KS in HHV-8 infected patients with a 10-year probability of 
49.6% (1). It is posited that control of HHV-8 infection is largely mediated by T cell 
responses (2-4). Indeed, HHV-8-specific CD8 cells are rare in patients who progress to 
KS whereas this anti-HHV-8 immune response is frequent and diverse in patients who 
control the infection (5). HAART is recommended for all patients with AIDS- associated 
KS and has significantly lowered the rate of KS (6). Of interest is that KSHV- associated 
immune responses after HAART show a trend for increased CD8+ T cell production of 
IFNγ by ELISPOT (7). Recent studies, however, indicate that polyfunctional responses 
to HIV and other chronic virus infections including CMV and EBV are more indicative of 
host control of these viral infections (8). We have shown that HHV8 seropositive, HIV 
seronegative, normal donors have polyfunctional CD8+ T cell reactivity to 
immunodominant HHV8 peptides (9). Moreover, we have also found that CD4 regulatory 
T cells (Treg) can suppress anti-HIV polyfunctional T cell responses in HIV-infected 
persons (10). Thus, it is possible that HHV-8 specific immunity, particularly CD8+ T cell 
polyfunctional responses to HHV8, in HIV/HHV8 co-infected patients before and after 
antiretroviral treatment could correlate with HHV-8 viremia and clinical outcome. These 


 
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responses could be at least partly under control of Treg (11, 12). Similarly, these HHV8-
specific immunologic parameters could be central to the pathology of KS-IRIS.  
ACTG trials A5263/AMC066 and A5264/AMC067 will both enroll study HIV-infected 
participants not receiving ART, who are diagnosed with KS. A5263/AMC066 will 
investigate three different chemotherapeutic regimens plus ART for participants with 
advanced KS, while A5264/AMC067 will study ART alone or with delayed chemotherapy 
versus ART with immediate chemotherapy. The populations that will be studied in these 
two trials will be ideal for assessing HHV-8 specific T cell immune responses and how 
control of HIV viremia through ART can affect this response. Moreover, as some of 
these participants may develop KS-IRIS, we will be able to investigate HHV8-specific 
immune markers that could be important in IRIS pathogenesis. 
 
3.0 
RATIONALE 
 
Since KS is a major form of AIDS and is postulated to be under the control of T cell 
immunity, it is important to fully understand the immunologic response to HHV8 in HIV-
infected participants. This knowledge is important in understanding the pathogenesis 
and oncogenesis of HHV8, and in developing immune-based therapies for HHV8 
infection and KS. Moreover, as KS-IRIS can present with significant morbidity in these 
participants, defining a role for HHV8-specific immunity behind this phenomenon is 
important not only in developing potential therapies, but in identifying immune markers 
that can predict increased risk in the development of IRIS. 
 
4.0 
EVALUATIONS 
 
Anticoagulated blood for obtaining PBMC will be collected from a maximum of 50 
participants at entry, and weeks 3, 12, 24, and 48 after ART initiation, and at KS-IRIS 
diagnosis for polyfunctional intracellular staining (ICS) and determining regulatory T cell 
frequency and CD8+ T cell exhaustion using flow cytometry. Blood will be processed for 
isolation of PBMC and cryopreserved at the clinical sites for later shipping to the 
University of Pittsburgh Immunology Specialty Laboratory (Pitt ISL).  
 
5.0 
ANALYSES 
 
The working hypotheses that will be tested are that: 1) HHV-8 specific CD8+ T cell 
immune response, as measured by a polyfunctional ICS assay, will initially increase after 
starting ART leading to a decrease in HHV-8 viremia, but will decrease once HHV8 
viremia is suppressed, and 2) KS-IRIS is associated with a decrease in the frequency of 
regulatory T cells and increased down-regulation in markers of CD8+ T cell exhaustion. 
  
PBMC will be cocultured in the Pitt ISL with HHV-8 peptides and/or vaccinia or lentivirus 
vectors expressing HHV8 proteins in antigen presenting cells using autologous B cells 
(CD40L-IL4 stimulated) (9, 11-13). The HHV8 proteins are 15mers overlapping by 11aa 
for gB, LANA, K8.1 and K12; the vaccinia and lentivirus vectors express each of these, 
plus additional, KSHV proteins. Controls are mock-treated or vaccinia virus or lentivirus 
empty vector-infected B cells. CD107a, MIP-1β, IL2, IFNγ, and TNFα immune mediators 
will be evaluated using intracellular staining (ICS) and flow cytometry (5). Plasma HHV-8 


 
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APPENDIX III (Cont'd) 
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DNAemia (real time PCR) will be assessed at similar time points and will be correlated 
with the magnitude of the immune response. HHV-8 specific CD8 T cell exhaustion will 
also be evaluated by expression of inhibitory receptors PD-1, LAG-3, and 2B4 at 
baseline, at a specific time point after antiretroviral treatment is started, and when a 
study participant is diagnosed as having KS-IRIS. Regulatory T cell frequencies  
(CD4+CD25hiFoxP3+ cells) will be obtained only at baseline and when KS-IRIS is 
diagnosed. The subset of participants for these immunologic assays will be determined 
after the KS outcome results are available in order to better correlate the immune 
responses with the varying KS outcomes. 
 
Table 1 
Variability of CD8+ and CD4+ T cell intracellular cytokine secretion of TNFα, IL-2, IFNγ, MIP1β, 
and CD107α after stimulation with different HIV antigens, with and without the presence of 
dendritic cells or with positive control (Staphylococcal Enterotoxin B and CEF – 
CMV/EBV/Influenza) 
 
Immune 
Mediator 
TNFα 
IL2 
Mean 
Median 
SD 
Variance 
Mean 
Median 
SD 
Variance 
CD8 
Control 
16.93 
10.32 
17.38 
301.99 
6.10 
3.00 
7.20 
51.82 
HIV Ag* 
3.44 
0.42 
14.98 
224.26 
3.14 
0.25 
14.30 
204.38 
CD4 
Control 
19.14 
13.25 
19.27 
371.50 
8.46 
3.03 
9.84 
96.79 
HIV Ag* 
5.01 
1.57 
13.35 
178.28 
3.29 
0.26 
15.29 
233.86 
 
 
 
 
 
 
 
 
 
 
 
 
Values are % of CD8+ or CD4+ T cells secreting the immune mediator 
Immune 
Mediator 
MIP1β 
CD107α 
Mean 
Median 
SD 
Variance 
Mean 
Median 
SD 
Variance 
CD8 
Control 
4.89 
1.04 
5.91 
34.91 
17.85 
10.36 
18.84 
354.76 
HIV Ag* 
0.12 
0.09 
0.09 
0.01 
0.820 
0.840 
0.320 
0.103 
CD4 
Control 
0.68 
0.16 
0.81 
0.66 
3.93 
1.510 
4.703 
22.12 
HIV Ag* 
0.05 
0.04 
0.08 
0.01 
0.316 
0.300 
0.112 
0.013 
Immune Mediator 
IFNγ 
Mean 
Median 
SD 
Variance 
CD8 
Control 
14.40 
9.09 
14.42 
207.97 
HIV Ag* 
2.98 
0.26 
13.65 
186.19 
CD4 
Control 
6.15 
3.63 
6.56 
43.01 
HIV Ag* 
1.84 
0.35 
8.80 
77.44 


 
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APPENDIX III (Cont'd) 
12/7/16 
 
 
*Values under HIV Antigen include T-cell immune mediator secretion under 
different conditions (e.g., with and without the presence of dendritic cells) 
 
LABORATORY CONTACT INFORMATION FOR THE ABOVE TESTING 
Department of Infectious Diseases and Microbiology 
University of Pittsburgh Graduate School of Public Health 
525 Parran Hall, 130 DeSoto Street 
Pittsburgh, PA 15261 
Attn: Ms. LuAnn Borowski 
Phone: 412-624-0582 
Fax: 412-624-4953 
E-mail: luann@pitt.edu 


 
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APPENDIX III (Cont'd) 
12/7/16 
 
 
6.0 
REFERENCES 
 
1. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells 
during chronic viral infection. Nature 2006;439:682-7. 
 
2. Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by 
multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009;10:29-37. 
 
3. Boshoff C, Weiss R. AIDS-related malignancies. Nat Rev Cancer 2002;2:373-82. 
 
4. Bourboulia D, Aldam D, Lagos D, et al. Short- and long-term effects of highly active ART on 
Kaposi sarcoma-associated herpesvirus immune responses and viraemia. AIDS 
2004;18:485-93. 
 
5. Colleton BA, Huang XL, Melhem NM, et al. Primary HIV-1 specific CD8+ T cell responses 
induced by myeloid dendritic cells. J Virol 2009;83(12):6288-99. 
 
6. Gallafent JH, Buskin SE, De Turk PB, Aboulafia DM. Profile of patients with Kaposi's 
sarcoma in the era of highly active antiretroviral therapy. J Clin Oncol 2005;23:1253-60. 
 
7. Harari A, Dutoit V, Cellerai C, Bart PA, Du Pasquier RA, Pantaleo G. Functional signatures 
of protective antiviral T-cell immunity in human virus infections. Immunol Rev 2006;211:236-
54. 
 
8. Lambert M, Gannage M, Karras A, et al. Differences in the frequency and function of HHV8-
specific CD8 T cells between asymptomatic HHV8 infection and Kaposi sarcoma. Blood 
2006;108:3871-80. 
 
9. Lepone L, Rappocciolo G, Knowlton E, Jais M, and Rinaldo CR. CD8 T lymphocyte 
reactivity to KSHV/HHV8 lytic and latency proteins. MBio 2014;5(5):1277-14. 
 
10. Macatangay BJ, Szajnik ME, Whiteside TL, Riddler SA, Rinaldo CR. Regulatory T cell 
suppression of Gag-specific CD8 T cell polyfunctional response after therapeutic 
vaccination of HIV-1-infected patients on ART. PLoS One 2010;5(3):e9852. 
 
11. Wang QJ, Huang XL, Rappocciolo G, et al. Identification of an HLA A*0201-restricted 
CD8(+) T-cell epitope for the glycoprotein B homolog of human herpesvirus 8. Blood 
2002;99:3360-6. 
 
12. Wang, QJ, Jenkins FJ, Jacobson LP, et al. Primary human herpesvirus 8 infection generates 
a broadly specific CD8(+) T-cell response to viral lytic cycle proteins. Blood 2001 97:2366-
73. 
 
13. Wang, QJ, Jenkins FJ, Jacobson LP, et al. CD8+ cytotoxic T lymphocyte responses to lytic 
proteins of human herpes virus 8 in human immunodeficiency virus type 1-infected and -
uninfected individuals. J Infect Dis 2000;182:928-32. 
 


 
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APPENDIX IV: ASSESSMENT OF TISSUE MICROARRAYS TO CHARACTERIZE 
PATTERNS OF VIRAL AND CELLULAR PROTEIN EXPRESSION IN RELATION TO 
OUTCOMES  
 
1.0 
OBJECTIVE 
 
To determine the effects of randomized treatment on KS as a function of patterns of 
KSHV viral protein expression. 
 
2.0 
BACKGROUND 
 
Patterns of KSHV viral proteins expression vary among KS tumors. The role of particular 
viral proteins in determining tumor behavior remains poorly understood. Some may 
contribute to proliferation, some may protect from activation of apoptotic pathways, and 
some may play a role in angiogenesis and invasiveness. Some KSHV viral proteins are 
coordinately regulated and thus some tumors show high levels of viral lytic protein 
expression and others show only viral latent gene expression.  
 
3.0 
RATIONALE 
 
It seems possible that participants who respond to antiviral therapy alone may have a 
very different protein expression profile than participants who respond to cytotoxic 
chemotherapy. Tissue micro arrays make it possible to assess viral protein expression 
across diagnostic tumor specimens.  
 
4.0 
EVALUATIONS 
 
Viral protein expression will be assessed on tissue microarrays prepared from initial 
diagnostic specimens. This will be done for 4 viral genes (LANA, vIL6, ORF8.1, ORF59). 
The array will be evaluated by pathologist and level of expression graded 
semiquantitatively (3+, 2+, 1+, no expression). These antigens have been selected 
because reagents which work are available and have been evaluated in prior studies. 
The tissue microarray will make it possible to evaluate other markers of interest as they 
arise. 
 
5.0 
ANALYSES 
 
The working hypothesis that will be tested is that tumor response to therapies will be 
predicted by the presence of lytic viral protein expression markers (vIL6, ORF8.1, 
ORF59). Levels of lytic viral expression markers will be assessed relative to latent viral 
expression (LANA). The results will be assessed separately for each treatment. Several 
outcomes might be envisioned that would have considerable importance. For example, if 
30% of participants respond to PTX and 30% respond ET, but participants with strong 
lytic infection consistently (75%) respond to ET and rarely (10%) respond to PTX, then 
participants with lytic infection might be treated with ET so as to maximize resources (ET 
is cheaper) and maximize response rate (ET is better in this subset). Alternatively, if 
participants with strong lytic infection consistently fail to respond to ET and only respond  


 
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APPENDIX IV (Cont'd) 
12/7/16 
 
 
134 
to PTX (which is likely to be less expensive than oral ET), the use of PTX would 
maximize both the response rate and maximize the use of resources in participants with 
lytic infection. 
 
 
LABORATORY CONTACT INFORMATION FOR THE ABOVE TESTING 
Ambinder Laboratory  
Johns Hopkins Oncology 
1650 Orleans Street, CRB1-384 
Baltimore, MD  21287 
Phone: 410-955-8721 
Fax: 443-287-3217 


 
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APPENDIX V: KAPOSI’S SARCOMA GENE EXPRESSION PROFILING: DETECTION OF 
KSHV RNA LEVELS IN KAPOSI’S SARCOMA (KS) TISSUES 
 
1.0 
OBJECTIVE 
 
To determine the effect of the treatment on KSHV viral RNA levels in tumors we will be 
utilizing a RT-QPCR for KSHV  
 
2.0 
DESCRIPTION OF THE ASSAY 
 
Changes in transcription are a fundamental hallmark of cancer progression and 
invaluable tools for characterizing cancer. In the case of KS, KSHV/HHV-8 has been 
identified as the etiological agent and this assay is designed to identify KSHV genes that 
might change in response to therapy. We will use reverse-transcription (RT) coupled to 
amplification using PCR to measure the RNA levels of all KSHV/HHV-8 RNAs in the 
tumor. This assay is a research test only and should not be used to make clinical 
decisions. The purpose of including this assay as part of this trial is to determine its 
usefulness as a prognostic marker. 
 
RT coupled to amplification using PCR is widely recognized as the most sensitive 
method to detect the presence of specific RNAs. We will use RT-QPCR. This assay 
measures the amount of PCR product based on hybridization to a sequence-specific 
dual-labeled fluorogenic oligonucleotide (TaqMan) or intercalation of a fluorescent dye. 
Fluorescence is recorded at each cycle. So-called Ct-values indicate the cycle at which 
the fluorescence crosses a particular threshold (5 times standard deviation (SD) of the 
non-template control (NTC)). Hence, Ct-values indicate the abundance of a given RNA 
on a log scale. A low Ct value represents a highly abundant target RNA. We have 
experience doing these assays at the University of North Carolina and are currently 
performing similar assays for other AMC trials.  
 
Specifically, total RNA will be isolated from each biopsy using RNAzol (Tel-Test, Inc., 
Friendswood, Texas) according to the supplier's protocol and reverse-transcribed using 
Mo-MuLV reverse transcriptase and 120 pmol random hexanucleotide primers (TaqMan, 
Applied Biosystems Inc., Foster City, CA). After incubation at 42°C for 35 min, the 
reaction will be stopped by heating to 95°C for 5 min, the cDNA pool diluted, and the 
resulting sample analyzed by RT-QPCR. We will use commercial SYBRgreen-based 
PCR (Roche Inc., Foster City, CA) as a uniform detection method. 
 
3.0 SAMPLE SIZE 
 
We have calculated the sample size based on expected differences in KSHV mRNA 
levels between responders and non-responders. This results in 138 participants (46 for 
each arm), which will be analyzed at baseline and 24-48 hours post-therapy. This yields 
276 assays on trial. 
 


 
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APPENDIX V (Cont'd) 
12/7/16 
 
 
 
4.0 ENDPOINTS AND CONTRASTS 
 
Baseline gene expression (log2 (mRNA levels)) will be compared between responders 
and non-responders for each of 96 genes. It is believed that there may be a 
gene*treatment interaction and thus it is envisioned that analyses will investigate the 
relationship between gene expression and response within treatment arm. Thus Type I 
error control for multiplicity is conducted within-arm. 
 
Assumptions (within-arm) 
1. Type I error = 5% (using Bonferroni adjustment for 96 tests) 
2. Power = 90% 
3. Equal number of responders and non-responders will be randomly selected  
 
Minimally Relevant 
Between-Group 
Difference* 
 
 
SD* 
 
 
N/arm 
 
 
Total N 
5 
3.5 
46 
138 
*log2 scale 
 
 
LABORATORY CONTACT INFORMATION FOR THE ABOVE TESTING 
Vironomics Core Laboratory/ Department of Microbiology 
University of North Carolina, Chapel Hill 
CB# 7290, 715 Mary Ellen Jones Building 
Chapel Hill, NC  27599-7290 
Attention: Rebecca Hines-Boykin 
Phone: 919-966-7962              
 
E-mail: rebecca_hines-boykin@med.unc.edu 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
 
Page 1 of 17 
 
 
APPENDIX VI 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT 
For protocol: A5263/AMC066 
 
 
A Randomized Comparison of Three Regimens of Chemotherapy with Compatible Antiretroviral 
Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings, A5263/AMC066, 
FINAL VERSION 3.0, dated 12/7/16 
 
SHORT TITLE: Treatment of Advanced AIDS-KS in Resource-Limited Settings 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are infected with HIV, the 
virus that causes AIDS. It also appears that you have Kaposi's sarcoma (KS), a type of cancer 
associated with AIDS.  
 
 
WHY IS THIS STUDY BEING DONE? 
 
This study is being done to compare the safety and efficacy of two combination treatments for 
KS and AIDS. All of the drugs that are used in this study are approved by the US Food and 
Drug Administration (FDA) for the treatment of either KS or AIDS.  
 
Approximately 446 participants will partake in this study. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you join this study and take etoposide (ET) while you are on the study, you will be in 
the study for about three years after you start the last cycle of ET. If you join this study 
and do NOT take ET while you are on the study, you will be in the study for about two years 
after you start your last step on the study. During this time, you will need to be seen in the 
clinic about 18 times in the first 12 months. After this time, the number and frequency of your 
visits will depend on how well your treatment is working for you. The required evaluations at 
each visit will take (enter site’s estimation of the study visit duration) hours; the study staff will 
be able to estimate how long each visit will take. Details of the study procedures are in 
Attachment A (A5263/AMC066 STUDY VISITS). 
 
If you decide not to take part in this study or if you do not meet the eligibility requirements, 
we will still use some of your information. As part of this screening visit, demographic (for 
example, age, gender, race), clinical (for example, disease condition, diagnosis), and laboratory 
(for example, HIV viral load) information is being collected from you so that ACTG researchers 
may determine whether there are patterns or common reasons why people do not join a study. 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 2 of 17 
 
 
The information may also help ACTG researchers understand more about HIV and KS 
treatment. 
 
When this study first started, the three KS treatments being studied were 1) paclitaxel (PTX), 
2) bleomycin and vincristine given together (BV), and 3) etoposide (ET). These KS treatments 
are being studied in combination with anti-HIV medications. In March 2016, the DAIDS Co-
Infections and Complications Data Safety Monitoring Board (CCDSMB) for 
A5263/AMC066 reviewed how participants were doing on the study. The CCDSMB is a 
group of people who are experts in the fields of medicine and statistics, none of whom 
are directly involved with the study. Their role is to review the conduct of the study and 
ensure the safety of participants. The CCDSMB found that participants receiving ET did 
not do as well as those receiving PTX. Therefore, participants starting the study are no 
longer offered ET as a study treatment.  
 
If you are just starting this study, you may be assigned to either 1) PTX or 2) BV. If you 
have already started the study and are receiving ET, the investigator at the site will 
discuss with you whether or not you should change to a different KS treatment. He or 
she will also discuss this with investigators running the study. If you decide to change 
KS treatment, you will be able to stay on the study and receive another treatment that 
you have not had before (PTX or BV). 
 
PTX plus antiretroviral therapy (ART) is a standard of care used in developed countries for 
treatment of KS and HIV infection. The standard of care at this site is (Insert the standard of 
care for your site). 
 
At the study entry visit, you will be assigned to one of the two remaining treatment groups: 
 
 
 
 
 
 
 
 
 
 
 
 
Because your assignment is random, like the flip of a coin, you will have an equal chance of 
being in each group. You will not be able to choose your group, but you and your doctor, as 
well as the study staff, will know which group you are in. 
 
Study Entry 
Group A: 
Anti-HIV treatment and 
oral etoposide 
 
THIS GROUP IS NO 
LONGER OPEN TO 
ENROLLMENT 
Group B: 
Anti-HIV treatment and 
bleomycin and 
vincristine 
Group C: 
Anti-HIV treatment and 
paclitaxel 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 3 of 17 
 
 
Group A 
Participants starting the study will no longer be offered ET as a study treatment. This 
information will apply to you only if you have already started the study and are receiving 
ET and you decide to continue this treatment: 
 
If you are in group A, you will take one capsule containing 50 mg of ET twice a day for a week 
and then take no capsules for the next 2 weeks. A week of taking ET plus 2 weeks of not taking 
ET is a cycle. If you are not having any problems from the ET, the dose will be increased to 100 
mg (2 capsules) in the morning and 50 mg (1 capsule in the evening) for 1 week during the 
second cycle, followed by 2 weeks with no ET. If you are not having any problems from ET after 
the second cycle, in the third cycle the ET dose will be increased to 100 mg (2 capsules) of ET 
twice a day for a week followed by 2 weeks of not taking ET. You will receive a total of six 
cycles of treatment. 
 
Group B 
If you are in group B, you will get BV by injection into a vein in your arm. An intravenous 
catheter is inserted into an arm vein before each treatment. Vincristine is given first by a short 
(1 minute) injection. Then bleomycin is given over about 10 minutes. BV is given once every 3 
weeks for a total of 6 doses.  
 
Group C 
If you are in group C, you will get PTX by injection into a vein in your arm. An intravenous 
catheter is inserted into an arm vein before each treatment. PTX is given once every 3 weeks 
for a total of 6 doses. The treatment takes about one hour.  
 
You and your doctor will decide which anti-HIV drugs you should take. The drugs provided by 
the study are: 
 
Efavirenz (EFV, Stocrin) once a day  
 
Emtricitabine (FTC, Emtriva) once a day 
 
Tenofovir (TDF, Viread) once a day   
 
You may use different drugs from the ones above, but they will not be provided through this 
study. If you cannot tolerate EFV, the study recommends that you take nevirapine (NVP, or 
Viramune) instead, but NVP will not be provided through the study. 
 
Anti-HIV and anti-cancer drugs after the study 
After you complete your study visits to 96 weeks after Step 1 entry, the study will no longer 
provide you with anti-HIV or anti-cancer drugs. At that time, you may have to stop a drug 
combination that has worked well for you, either because you cannot afford the treatment or 
because those drugs are not available in your country. Efforts will be made by your doctor to 
find a way to continue anti-HIV and anti-cancer drugs after the study is over.  
 
Other 
If you agree, some of your blood and KS biopsy specimens that are left over after all required 
study testing is done may be stored (with usual protectors of your identity) and used for US 
National Institutes of Health (NIH)-approved HIV-related research. 
 


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APPENDIX VI (Cont’d) 
Page 4 of 17 
 
 
Please initial one of the following boxes to indicate whether or not you wish to have your 
specimens stored for research in the future: 
 
 Yes, I agree to have my specimens stored for future research  
 
 No, I do not want to have my specimens stored for future research  
 
You can decide to withdraw your permission for the storage and use of your samples for 
future research whenever you want and we will destroy your samples. If you decide to 
withdraw your permission, contact the research staff at your site. Researchers will not be 
able to destroy samples or information from research that is already underway.  
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
the study is stopped or canceled 
 
you are not able to attend the study visits as required by the study 
 
your primary care doctor thinks that participating in this study is no longer in your 
best interest 
 
The study doctor may also need to take you off anti-HIV drugs or anti-cancer drugs without your 
permission if: 
 
continuing one or more of these drugs may be harmful to you 
 
you need a treatment that you may not take while taking these drugs  
 
you are not able to take these drugs as required 
 
It is possible that your doctor may take you off study drugs, but not off the study if: 
 
you become pregnant 
 
you breastfeed 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Risk of Study Medications 
Anti-HIV drugs and anti-cancer drugs may have side effects, some of which are listed in 
Attachment B (A5263/AMC066 – RISKS AND BENEFITS). Please note that these lists include 
only the more serious or common side effects with a known or possible relationship. If you have 
questions concerning additional drug side effects, please ask the medical staff at your site. 
 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 5 of 17 
 
 
Risk of Blood Draw and Having an Intravenous Catheter    
Taking blood, inserting an intravenous catheter, and having an intravenous catheter in your arm 
may cause some discomfort, bleeding, bruising or swelling where the needle enters the body. In 
rare cases it may cause fainting or infection. 
 
Risk of Participating in This Study 
It is possible that participating in this study will make it difficult for you to keep your HIV status 
secret from people close to you. This may lead to unwelcome discussions about or reactions to 
your HIV status. Please talk with the clinic staff if you have any concerns in this regard. 
 
Risk of Non-Study Medications 
There is a risk of serious and/or life-threatening side effects when certain medications are taken 
with anti-HIV drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before you take any medications. 
You must also tell the study doctor or nurse before taking any non-study therapies while you are 
on the study. Deaths have occurred when HIV-infected people have taken therapies such as 
herbs with anti-HIV drugs. In addition, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
Pregnancy 
The drug or drug combinations in this study may be unsafe for unborn babies. The risks to 
unborn babies for each drug are listed in Attachment B. If you are having sex that could lead to 
pregnancy, you must agree not to become pregnant or make a woman pregnant. 
 
When you are taking EFV and/or anti-cancer drugs, you must use two methods of birth 
control that you discuss with the study staff. One method must be a barrier method. You 
must continue to use both methods of birth control until 12 weeks after stopping EFV or 
the anti-cancer drug.  
 
If you are a man, you must agree to use condoms. Your female partner must use at least 
one additional birth control method. 
 
If you are a woman, you may choose from any of the following birth control methods: 
 
Birth control drugs that prevent pregnancy given by pills, shots, or placed on or under the 
skin  
 
Male or female condoms with or without a cream or gel that kills sperm 
 
Diaphragm or cervical cap with a cream or gel that kills sperm 
 
Intrauterine device (IUD) 
 
If you are a woman and are unable to use two methods, your doctor will talk with you about your 
options. 
 
If you do become pregnant, you will be taken off chemotherapy, but will remain on study. You 
may also need to change the type of HIV medicine you are taking. 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 6 of 17 
 
 
 
If you are taking anti-HIV drugs when you become pregnant, your pregnancy may be 
reported to an international database that collects information about pregnancies in 
women taking anti-HIV drugs. This report will not use your name or other information 
that could be used to identify you. 
 
 
WHAT ARE THE POSSIBLE BENEFITS OF THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can be 
made. It is also possible that you may receive no benefit from being in this study. Information 
learned from this study may help others who have HIV or KS. 
 
Your health will be followed more closely than usual while you are on the study, which may help 
you to feel better. Laboratory tests to monitor the effects of the study drugs will be provided by 
the study.  
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
[Insert general information about HIV/AIDS and KS treatment availability in your country or 
locale.] 
 
Anti-HIV and anti-cancer drugs, laboratory tests to monitor how well these drugs are working, 
and quality medical care may or may not be available to you outside the study. The clinic staff 
will discuss with you other treatment choices in your area and the risks and the benefits of all 
the choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
The study team will provide you with an identification number. This identification number (not 
your name or other information that could be used to identify you) will be used for laboratory 
tests or blood work stored for testing in future studies. Your medical records and the list of 
names, addresses, and identification numbers will be kept in a locked room. Only the study staff 
will have access. Any publication of this study will not use your name or identify you personally. 
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. Your 
records may also be reviewed by (insert name of site IRB), ethics committee, NIH, the Office for 
Human Research Protections (OHRP), your country’s national health agency, study staff, study 
monitors, and the drug companies supporting this study. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required 
by U.S. law. This website will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this website at any time.  
 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 7 of 17 
 
 
 
WHAT ARE THE COSTS TO ME? 
 
There is no cost to you for study-related visits, physical examinations, laboratory tests or other 
procedures. You, your insurance company, or your health care system may need to assume the 
cost of anti-HIV drugs not provided by the study. [delete references to insurance company or 
health care system if not applicable at site]. In some cases, it is possible that your insurance 
company or health care system will not pay for these costs because you are participating in a 
research study. [Insert site/country policy] 
 
 
WHAT HAPPENS IF I AM INJURED OR, IF I BECOME PREGNANT, MY BABY IS INJURED? 
 
If you or your baby is injured as a result of your being in this study, you or your baby will be 
given immediate treatment for injuries, and be referred for further treatment, if necessary. 
However, you may/may not (per site/country policy) have to pay for this care. There is no 
program for compensation either through [this institution] or the NIH. You will not be giving up 
any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A VOLUNTEER IN A RESEARCH STUDY? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. You will still be able to receive drugs to treat your HIV and your KS 
outside this study. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
Name and telephone number for the investigator or other study staff 
 
For questions about your rights as a participant in a research study contact: 
 
(Name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
 
Telephone number of above) 
 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 8 of 17 
 
 
SIGNATURE FOR A5263/AMC066 INFORMED CONSENT 
If you have read this consent form (or had it explained to you), all your questions have been 
answered, and you agree to take part in this study, please sign your name below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
 
 
________________________________ 
___________________________________ 
Participant’s Legally Authorized  
 
Participant’s Legally Authorized 
Representative (print)  
 
 
Representative’s Signature and Date 
(As appropriate) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting Consent 
 
Study Staff Signature and Date Discussion (print)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness’s Name (print) 
 
 
Witness’s Signature and Date 
 
(As appropriate) 
 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 9 of 17 
 
 
ATTACHMENT A: A5263/AMC066 STUDY VISITS 
 
The study staff can answer any questions you have about individual study visits or about the 
evaluations that will occur. The table below can be used as a quick reference for you, along with 
the explanations that follow. 
 
I.  Study Schedule 
 
Evaluation or Procedure 
Screening1 
Entry2 
24-48 Hours 
After Second 
Chemotherapy 
Cycle Begins 
Most Other 
Visits3 
Special Visit4 
Discontinuation5 
Consent  
 
 
 
 
 
 
Contact Info Collected 
 
 
 
 
 
 
Clinical Assessment 
 
 
 
 
 
 
KS Exam 
 
 
 
 
 
 
Skin Biopsy 
 
 
 
 
 
 
Laboratory Tests 
 
 
 
 
 
 
Urinalysis  
 
 
 
 
 
 
Pregnancy Test 
 
 
 
 
 
 
Chest X-Ray 
 
 
 
 
 
 
Blood Oxygen Level 
 
 
 
 
 
 
Photographs of Your Skin 
 
 
 
 
 
 
Neuropathy Exam 
 
 
 
 
 
 
Questionnaires 
 
 
 
 
 
 
  
1 Screening Visit: After you have read and signed the consent form, you will have several 
evaluations done to make sure that you meet the requirements for joining the study.  
2 Entry Visit: If you are eligible to join the study, you will come to the clinic to enter the study and 
receive your treatment assignment. At this visit you will find out what anti-cancer drug you will 
take. 
3 Most Other Visits: Most people will return to the clinic every three weeks for the first 12 
months and then every 12 weeks for the next 12 months. Most people will then return to the 
clinic one more time the next year. 
4 If at any point during the study you are found to have Immune Reconstitution Inflammatory 
Syndrome (IRIS), you will have the evaluations listed on the table under the heading of 
“Special Visit”. Your study staff can provide further information on IRIS. 
5 Discontinuation: If, for any reason, you or your doctors decide you cannot complete all of the 
study visits, you will be asked to come in for an extra visit. 
 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 10 of 17 
 
 
II. Explanation of Evaluations  
 
Consent and Contact Information Collected 
 
After you read the consent and have had a chance to ask questions about the study, you 
will sign the consent form if you want to continue to be evaluated for study participation. 
 
You will also be asked how to be contacted in case you miss a visit or there are 
problems with your tests, and whether you give the study team permission to contact 
you. 
 
Clinical Assessments 
 
At all visits you will be asked about your health and any medicine you have taken 
in the last 60 days. 
 
At the screening visit, you will have a complete physical exam that will include 
measurement of weight and height, examination of the skin, head, mouth, and 
neck, listening to the chest, heart exam, belly exam, and examination of your legs 
and feet for swelling. The complete physical exam will also include signs and 
symptoms of diseases, diagnoses, and vital signs (temperature, pulse, respiration 
rate, and blood pressure). 
 
At all follow-up visits you will have a brief physical exam as needed. The clinic staff 
will check your vital signs such as weight, temperature, blood pressure, breathing, 
and pulse. 
 
KS Exam 
The study doctor or nurse will thoroughly examine your skin, lymph nodes (bumps in your 
neck, underarms and groin), and mouth for KS lesions. He or she will measure some of the 
KS lesions, count them, and may take photographs of the lesions to document their 
appearance.  
 
Skin Biopsy 
A biopsy is the process of cutting out a small piece of skin. The area of the skin where 
the sample will be removed is numbed with a local anesthetic. These biopsies are 
done to look at the amount of KS herpesvirus (KSHV), the virus that causes KS in the 
skin. A total of up to 3 skin biopsies are required. If your KS gets worse during or after 
the first chemotherapy treatment or if your KS appears to have healed completely, site 
staff will ask you to have more skin biopsies. 
 
Laboratory Tests 
Blood will be collected from you for various tests during the study. These include: safety lab 
tests, HIV viral load (a test that shows how much HIV is in your blood), and CD4 count (a 
test that shows how many infection-fighting cells you have in your blood). In addition, some 
of the blood that is collected will be stored for future study-related testing, including 
measuring the amount of KSHV and certain proteins in your blood. Some of the future 
testing has not been determined yet. Between 15 and 65 mL (1 to 4.5 tablespoons) of blood 
may be collected at any one visit. 
 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 11 of 17 
 
 
Urinalysis 
You will be asked to give a urine sample so that the appearance, concentration, 
and content of your urine can be tested. 
 
Pregnancy Test 
 
If you are a woman able to become pregnant, a urine or blood pregnancy test will 
be done at these visits to make sure that you are not pregnant and at any visit if 
pregnancy is suspected.  
 
You will be given the results of this test as soon as it becomes available. 
 
Chest X-Ray 
 
A chest X-ray is a picture of the chest that shows your heart, lungs, airway, blood 
vessels, and lymph nodes. A chest X-ray also shows the bones of your spine and chest, 
including your breastbone, ribs, collarbone, and the upper part of your spine. A chest X-
ray is the most common imaging test or X-ray used to find problems inside the chest. 
 
A chest X-ray will be repeated if you enter a new step of the study or if your KS 
gets worse. 
 
Blood Oxygen Level (if you are receiving bleomycin during the study) 
This is a simple measurement of the amount of oxygen in the blood. It involves putting 
a plastic device on a finger and takes less than a minute. The oxygen level is checked 
when you are at rest. You will then need to exercise for a short while (either walk 
around or walk up some stairs) to make your heart beat faster before doing the test 
again.  
 
Photographs of Your Skin 
Photographs are taken during the study to show how the KS is changing. If your KS 
gets better or gets worse, more photos will be taken. At no time will your entire face 
appear, and any distinguishing features will be removed from the photo so that you 
cannot be identified. Only your patient identification number will be used to identify the 
photo. 
 
Neuropathy Exam 
You will have two neuropathy exams. If you receive vincristine or PTX, you will have up to 5 
additional neuropathy exams. Neuropathy is a condition that can cause pain, numbness, 
and/or pins and needles in your feet and/or hands. You will be asked about how your hands 
and feet feel. You will also have your reflexes checked and will be checked to see how well 
you feel vibrations 
 
Questionnaires 
 
You will be asked about how well you have taken your HIV medicine over the past 
few days. 
 
If you have already started the study and are receiving ET and you decide to 
continue this treatment, you will be asked about how well you are taking that medicine.  
 
At some visits you will also be asked about how you are feeling and how your daily 
activities are going. This will take an additional 10 minutes. 
 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 12 of 17 
 
 
 
III. Disease Progression 
 
Step 2 
If your KS gets better but then worsens within 12 weeks or longer after you have completed 
your cycles of chemotherapy, your doctor may choose to treat you a second time with the 
same chemotherapy. If this happens, you will need to have the evaluations listed under 
entry on the table above done again. You will then follow the same schedule as listed in the 
table above. You will then receive another six cycles of chemotherapy. If you completed 
one course of ET in Step 1, you will not receive a second course of ET. Instead you 
will enter into Step 3. 
 
Step 3 
If your doctor does not choose to treat you with the same chemotherapy or if your KS gets 
worse after you are treated with the first chemotherapy regimen a second time, you will be 
given the other chemotherapy regimen. If this happens, you will need to have the 
evaluations listed under entry done again. You will then follow the same schedule as listed 
in the table below. If you received ET in Step 1 or Step 2, you will be randomly 
assigned (like flipping a coin) to receive BV or PTX. 
 
Step 4 
If you received ET prior to the decision to stop using ET in this study, it is possible that 
your KS will get worse after receiving a second regimen of chemotherapy. If this happens, 
you doctor can choose to give you the third study-provided chemotherapy or start you on 
chemotherapy not provided by the study. If you are taking ET now, you may want to 
switch to a different chemotherapy, even if your KS is not getting worse. You can 
make this decision along with your doctor, and you will be given the third study-
provided chemotherapy. 
 
If you are started on chemotherapy not provided by the study, your schedule will remain the 
same as it was on the previous chemotherapy. If you start the third study-provided 
chemotherapy, you will need to have the evaluations listed under entry done again. You will 
then follow the same schedule as listed in the study schedule above to week 24. After week 
24, you will only have to come to the clinic every 12 weeks for follow-up. 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 13 of 17 
 
 
ATTACHMENT-B: A5263/AMC066 RISKS & BENEFITS 
 
Risks from Anti-HIV Drugs 
Anti-HIV Drug or 
Class 
Possible Side Effects 
Any 
Changes in body shape, such as: 
 
Increase in fat around the waist and stomach  
 
Increase in fat on the back of the neck 
 
Thinning of the face, legs, and arms 
 
Breast enlargement 
 
Immune Reconstitution Syndrome: In some people with advanced HIV infection, signs and 
symptoms of inflammation from other infections may occur soon after anti-HIV treatment is 
started.  
Efavirenz (EFV, 
Stocrin) 
 
A small number of people may experience the following serious psychiatric problems: 
 
Depression, which may be severe 
 
Suicidal thoughts or attempts (rarely) 
 
Aggressive behavior 
 
Psychosis-like symptoms, such as abnormal thinking, paranoia, and delusions. People 
with a history of psychiatric problems may be at greater risk for these serious psychiatric 
problems. 
 
Side effects associated with the central nervous system may include the following: 
 
Dizziness 
 
Trouble sleeping  
 
Abnormal dreams  
 
Drowsiness 
 
Confusion 
 
Difficulty concentrating 
 
Hallucinations  
 
A feeling of strangeness and losing touch with reality 
 
An exaggerated feeling of well-being  
 
Agitation or anxiety 
 
If alcohol or mind- or mood-altering drugs are used with EFV, it is possible that the central 
nervous system side effects could become worse. 
 
Serious liver problems and worsening liver disease can occur. These problems can be life-
threatening. People with these conditions may have abnormal liver function tests. If you are 
developing liver problems, you may have one or more of the following: yellowing of the skin 
or whites of your eyes, dark urine, pain on the right side of your stomach, loss of appetite, 
upset stomach or vomiting, pale colored stools, itchy skin. 
 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 14 of 17 
 
 
Anti-HIV Drug or 
Class 
Possible Side Effects 
Additional side effects include: 
 
Rash, which in rare cases may be severe 
 
Upset stomach  
 
Loose or watery stools  
 
Headache 
 
Pancreatitis (inflammation of the pancreas),with one or more of the following: stomach 
pain, nausea or vomiting 
 
Hepatitis (inflammation of the liver) 
 
Abnormal increases in pancreatic and liver enzyme levels in the blood 
 Abnormal increases in the amount of triglycerides and cholesterol in the blood 
 
Abnormal vision 
 
Fever  
 
A false-positive urine-screening test for marijuana has been seen with one particular test 
brand and has not been seen when using other screening tests or with tests used to confirm 
results for marijuana. 
 
Efavirenz and Pregnancy 
The use of this drug during pregnancy and especially early pregnancy should be avoided. 
Efavirenz may cause fetal harm when taken during the first three months of pregnancy. 
Serious birth defects, including those of the central nervous system, have been seen in the 
offspring of animals and women on efavirenz. 
Nucleoside and 
Nucleotide 
Analogues 
(Emtricitabine and 
Tenofovir Disoproxil 
Fumarate are 
nucleoside 
analogues or 
closely related 
drugs) 
Lactic acidosis and severe hepatomegaly (enlarged liver) with steatosis (fatty liver) that may 
result in liver failure, other complications, and death have been reported with the use of 
antiretroviral nucleoside and nucleotide analogues alone or in combination. The liver 
complications and death have been seen more often in women on these drug regimens. 
Some nonspecific symptoms that might indicate lactic acidosis include unexplained weight 
loss, stomach discomfort, nausea, vomiting, fatigue, cramps, muscle pain, weakness, 
dizziness, and shortness of breath. 
Emtricitabine/ 
Tenofovir Disoproxil 
Fumarate 
(FTC/TDF, 
Truvada) 
 
No new or unexpected side effects are observed with the FTC 200 mg/TDF 300 mg 
combination tablet than those observed when each drug is given separately (see below). 
 
Headache 
 
Dizziness 
 
Generalized weakness 
 
Depression 
 
Worsening or new kidney damage or failure 
 
Shortness of breath 
 
Tiredness 
 
Inability to sleep, unusual dreams 
 
Loose or watery stools 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 15 of 17 
 
 
Anti-HIV Drug or 
Class 
Possible Side Effects 
 
Upset stomach (nausea) or vomiting  
 
Abdominal pain 
 
Rash, itching, which sometimes can be a sign of an allergic reaction 
 
Skin darkening of the palms and/or soles of the feet 
 
Increased cough 
 
Runny nose 
 
Allergic reaction: symptoms may include fever, rash, upset stomach, vomiting, loose or 
watery stools, abdominal pain, achiness, shortness of breath, a general feeling of illness 
or a potentially serious swelling of the face, lips, and/or tongue 
 
Abnormal liver function tests, which could mean liver damage. If you are developing 
liver problems, you may have one or more of the following symptoms: 
 
Yellowing of the skin or whites of your eyes 
 
Dark urine  
 
Pain on the right side of your stomach 
 
Loss of appetite, upset stomach or vomiting  
 
Pale colored stools 
 
Itchy skin 
 
Increases in pancreatic enzyme (substances in the blood), which could mean a problem 
with the pancreas  
 
Increased triglycerides  
 
Bone pain and bone changes such as thinning and softening which may increase the risk 
of breakage  
 
Muscle pain and muscle weakness 
 
Increased creatine phosphokinase (CPK), which could mean muscle damage 
 
NOTE: If you are infected with both Hepatitis B and HIV, you should be aware that your liver 
function tests may increase, and symptoms associated with hepatitis (an acute inflammation 
of the liver) may worsen if emtricitabine is stopped. 
 
NOTE: Because there is only a small amount of information on tenofovir in pregnant women, 
tenofovir should be used during pregnancy only if clearly needed. 
 
 
 
Risks from Anti-Cancer Drugs 
Anti-Cancer Drug 
Possible Side Effects 
Any Anti-Cancer 
Drug 
 
Chemotherapy drugs are harmful to the unborn and should not be used 
 


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 16 of 17 
 
 
Anti-Cancer Drug 
Possible Side Effects 
Etoposide 
(Etopophos, 
Vepesid) 
 
Participants starting the study will no longer be offered etoposide as a study 
treatment. This information will apply to you only if you have already started the study 
and are receiving etoposide and you decide to continue this treatment: 
 
Lowering of blood counts, such as lowered white blood count which may make you more 
susceptible to infection 
 
Lowered red blood counts which may result in fatigue, weakness or light-headedness  
 
Lowered platelet counts which may result in increased risk of bleeding.  
 
Serious allergic reactions. Symptoms may include: trouble breathing, fever, nausea, 
vomiting, chills, shakes, skin rash, blood in your urine, swelling in your hands and feet.  
 
Some cancer drugs, including ET, appear to cause a small number of people to later 
develop blood disorders including acute leukemia after treatment.  
 
Hair loss, sometimes as much as complete baldness. This may lead to others knowing 
that you are sick.  
 
Nausea and vomiting, abdominal pain, diarrhea, decreased appetite, and weight loss 
 
Mouth sores 
 
Potential harm to unborn children when it is given to a pregnant woman 
 
Do not break or open an etoposide capsule. The medicine from a broken capsule can be 
dangerous if it gets in your eyes, mouth, or nose, or on your skin. If skin contact occurs, 
wash the area with soap and water or rinse your eyes thoroughly with plain water.  
 
Avoid eating grapefruit or drinking grapefruit juice while being treated with this medication 
unless your doctor instructs you otherwise.  
Bleomycin 
(Blenoxane) and 
Vincristine 
(Oncovin) 
 
 
If vincristine leaks from the vein, it can cause serious burning and ulcers in the skin. We 
will take care to prevent this from happening, but even with care sometimes the drugs 
leak into the skin. If this happens, we will treat you to try to prevent serious injury. 
 
Scarring of the lung from bleomycin 
 
Peripheral neuropathy (numbness, tingling, and pain usually in the fingers or toes)  
 
Pain or discomfort at the site where the drug is given into the vein. 
 
Mouth sores 
 
Hair loss  
 
Nausea and/or vomiting 
 
Chills, body aches and shaking (usually from bleomycin) 
 
Skin rashes and rarely scarring   


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 17 of 17 
 
 
Anti-Cancer Drug 
Possible Side Effects 
Paclitaxel 
 
IMPORTANT WARNING ABOUT PACLITAXEL 
 
  Paclitaxel can cause serious side effects including death 
 
Serious allergic reactions (anaphylaxis) can happen in people who receive paclitaxel 
 
Anaphylaxis is a rare, but serious medical emergency that can lead to death and must be 
treated right away. Everyone will be given medicine to lessen your chance of anaphylaxis. 
This medication is effective for most people, but anaphylaxis can still happen.  
 
Tell your healthcare provider right away if you have any of these signs of an allergic 
reaction: 
 
Trouble breathing 
 
Sudden swelling of your face, lips, tongue, throat, or trouble swallowing 
 Hives (raised bumps) or rash 
 
Additional side effects include:  
 
Lowering of your blood cell counts that could cause infection, easy bruising and bleeding, 
or anemia 
 Tiredness 
 Bruising or bleeding 
 Nausea and vomiting 
 Slow or irregular heartbeat or fainting 
 Hair loss  
 Numbness, burning, or tingling in the hands or feet 
 Mouth or lip sores (mucositis) 
 Stomach pain, which can be severe 
 Diarrhea, which can be severe 
 Irritation at the  injection site 
 Low blood pressure (hypotension) 
 
Other Risk Information 
 
Immune Reconstitution Inflammatory Syndrome (IRIS) 
While being treated with anti-HIV drugs, your immune system's strong response to an 
opportunistic infection (OI) (an infection that you get because the HIV has lowered the strength 
of your immune system), may cause illness. This is called immune reconstitution inflammatory 
syndrome (IRIS). Usually, it causes a return or worsening of at least some of the symptoms you 
may have had before starting anti-HIV drugs. 
 
Some examples of what could happen are: 
 
your lymph nodes (small organs in your body that help filter disease germs from the blood) 
could swell up  


A5263/AMC066 (12/7/16) 
FINAL VERSION 3.0 
 
APPENDIX VI (Cont’d) 
Page 18 of 17 
 
 
 
you could get a high fever 
 
if you are being treated for a lung infection, you might have worsened cough and shortness 
of breath  
 
While some of these reactions can be serious, they usually last for a short time and can be 
treated without stopping the anti-HIV drugs. If any of these reactions happen to you, you will be 
treated for the problem and asked to have some additional blood drawn for testing of your 
immune system at that time. 
 
Pregnancy & Breastfeeding 
It is not known if some of the drug combinations in this study would harm unborn babies. Tests 
in pregnant animals do show some risks for some drugs. If you are having sex that could lead to 
pregnancy, you must agree not to become pregnant, or, if you are a man, you must agree not to 
attempt to make a woman pregnant or participate in sperm donation. Pregnancy tests will occur 
at study entry and prior to all chemotherapy. 
 
If you think you may be pregnant at any time during the study, tell your study staff right away. 
The study staff will talk to you about your choices and refer you to a provider of prenatal care if 
you do not have one. If you decide to continue in A5263/AMC066, you will continue to have 
study evaluations as described above. However, you will no longer receive study chemotherapy. 
If you are taking efavirenz (a medicine for your HIV) and become pregnant, you must 
immediately stop efavirenz and take a different HIV medicine. Your study doctor will decide 
which HIV drug you should take instead efavirenz and whether you should start efavirenz again 
after the pregnancy. The A5263/AMC066 study will not provide or pay for care related to your 
pregnancy or the delivery of your baby.  
 
Biopsy 
The potential risks of having a punch biopsy are: 
 
discomfort and/or pain at the site 
 
bleeding at the site 
 
infection at the site (this is rare) 
 
a small scar at the site  
 
Benefits 
Information learned from this study may help others who have KS and are infected with HIV. 
Information learned from this study may also help improve the ability of people to get anti-HIV 
drugs, by identifying drug combinations that cost less but are as effective as more expensive 
drug combinations. 
 
 
 

SAP_001.pdf: 
 
 
                                     
 
 
 
This is ACTG A5263/AMC 066 SAP Version 2.0 with names of authors, names 
 
of publication writing team members and analysis timeline redacted. 
 
 
 
 
 
ACTG A5263/AMC 066 
 
 
 
A Randomized Comparison of Three Regimens of Chemotherapy with 
Compatible Antiretroviral Therapy for Treatment of AIDS-KS in Resource 
Limited Settings  
 
 
ClinicalTrials.Gov ID: NCT01435018 
 
 
 
 
 
Statistical Analysis Plan 
 
Version 2.0 
 
 
 
 
 
 
 
 
September 26, 2018 
 
 
 
 
 
 


 
 
Page 2 of 17 
 
 
 
 
Table of Contents 
1 
Introduction ...................................................................................................................................................... 3 
1.1 
Key Updates to the SAP .......................................................................................................................... 3 
2 
Study Overview ............................................................................................................................................... 4 
2.1 
Design ..................................................................................................................................................... 4 
2.2 
Power and Sample Size .......................................................................................................................... 5 
2.3 
Hypotheses .............................................................................................................................................. 5 
2.4 
Objectives ................................................................................................................................................ 6 
2.4.1 
Primary Objective ................................................................................................................................ 6 
2.4.2 
Secondary Objectives ......................................................................................................................... 6 
2.5 
Outcome Measures ................................................................................................................................. 7 
2.5.1 
Primary Outcome Measure ................................................................................................................. 7 
2.5.2 
Secondary Outcome Measures ........................................................................................................... 7 
2.6 
Interim Monitoring .................................................................................................................................... 9 
3 
General Analysis Considerations .................................................................................................................. 10 
4 
Statistical Methods ........................................................................................................................................ 12 
4.1 
Analyses of the Primary Outcome ......................................................................................................... 12 
4.1.1 
Analysis Considerations .................................................................................................................... 12 
4.1.2 
Primary Outcome Methods ................................................................................................................ 12 
4.2 
Analysis of Secondary Outcomes ......................................................................................................... 14 
4.2.1 
Analysis Considerations .................................................................................................................... 14 
4.2.2 
Secondary Outcome Methods ........................................................................................................... 14 
 
 
 


 
 
Page 3 of 17 
 
 
1 
Introduction 
 
The Primary Statistical Analysis Plan (SAP) describes the proposed content for the primary statistical 
analysis report of ACTG A5263, which addresses the primary and secondary objectives of the study.  
This document also describes the primary and secondary outcome measures for which results will be 
posted on ClinicalTrials.gov.  The Primary SAP outlines the general statistical approaches that will be 
used in the analysis of the study and has been developed to facilitate discussion of the statistical 
analysis components amongst the study team, and to provide agreement between the study team and 
statisticians regarding the statistical analyses to be performed and presented in the primary analysis 
report. 
   
Because the study was closed prematurely (triggered by a DSMB review and recommendation), 
analyses for the primary analysis report will be initiated as soon as possible; no analysis timeline was 
generated.  In addition, all primary and secondary outcomes outlined in this SAP will be submitted to 
ClinicalTrials.gov within 1 year of the primary completion date (PCD).  The PCD has been adjusted to 
be the date of the last interim review, which occurred on March 13, 2018; only data as of this date will 
be included in the primary analysis. 
 
Additional specifications and details on other key elements of the primary analysis report are provided in 
a separate document, the Analysis Implementation Plan (AIP). 
 
 
 
1.1 
Key Updates to the SAP 
 
Version 1.0 of the SAP (finalized on February 16, 2016) included details on interim analysis methods 
and planned analyses for the primary outcome.  The SAP was updated after the final interim review, but 
prior to the final analysis, and includes the following changes: 
 
o 
Reformat to be compliant with new SOP requirements 
o 
Add details on study history related to interim analysis methods  
o 
Move specifics on basic report elements to the AIP 
o 
Modify approach for primary analysis to address statistical issues related to premature 
study closure 
o 
Add sections on secondary outcomes (not previously discussed in prior SAP). 
 
 
 
 


 
 
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2 
Study Overview 
 
Version 1.0 of the study protocol was finalized on October 14, 2010.  Due to a world-wide shortage of 
the active-control drug, doxorubicin HCL liposome, the protocol was amended to include a different 
active-control, paclitaxel.  Participants began enrollment under version 2.0 of the study protocol 
(finalized on August 7, 2012). 
 
2.1 
Design 
 
A5263/AMC066 is a randomized, prospective, active-controlled, clinical trial designed to compare three 
regimens of chemotherapy with compatible antiretroviral therapy for the treatment of advanced AIDS-KS 
in resource-limited settings.  Randomization (in each study step) is stratified by CD4+ cell count (<100 
or ≥ 100 cells/mm3) and country.  The trial was designed to evaluate whether there is sufficient evidence 
to conclude if bleomycin and vincristine (BV) plus ART is noninferior to paclitaxel (PTX) plus ART, or if 
oral etoposide (ET) plus ART is non inferior to PTX plus ART. 
 
The study was designed as a four-step study with participants randomized in the following manner: 
 
Step 1: Participants were randomized 1:1:1 to ET+ART, BV+ART, or PTX+ART 
 
Step 2: Repeat of treatment received in Step 1 if conditions outlined in protocol were met 
 
Step 3: Participants were randomized 1:1 to the two remaining treatment arms not utilized in 
Step 1 (or Step 1 and 2) if certain conditions outlined in the protocol were met 
 
Step 4:  Participants were assigned to the remaining treatment not utilized in prior steps if 
conditions outlined in the protocol were met 
 
Under protocol version 2.0, the study planned to enroll a total of 706 HIV-infected men and women at 
least 18 years of age with the following characteristics:  
  
- 
Biopsy-confirmed diagnosis of KS 
- 
Naïve to ART (allowed within 42-day window prior to study entry), chemotherapy, and 
radiation therapy 
- 
KS stage T1 
- 
Persons with chronic, acute, or recurrent infections that are serious, in the opinion of the 
site investigator, must have completed at least 14 days of therapy prior to study entry and 
must be clinically stable 
 
All participants were to be followed for 5 years after randomization or assignment to the last step of 
entry, with total follow up ranging from 5 to 7 years based on planned enrollment. 
 
The protocol was substantially modified after the March 2016 interim review.  At this review the DSMB 
recommended that enrollment to the ET+ART arm be stopped on all steps.  Protocol version 3.0 was 
finalized on December 7, 2016, and incorporated all prior amendments, edits necessary to implement 
the closure of the ET+ART arm, and a modified sample size.  The modified sample size was based not 
only on the closure of the ET+ART arm, but also on the ACTG SASC recommendations to reduce study 
power from 88% to 80% for feasibility reasons (i.e., to reduce sample size and decrease the time 
needed to complete accrual). 
 
Under protocol version 3.0, the study planned to enroll a total of 446 participants (386 randomized to 
BV+ART or PTX+ART, 60 participants previously randomized to ET+ART). 
 
 
 


 
 
Page 5 of 17 
 
Duration of follow-up was also modified with version 3.0 based on recommendations from the ACTG 
SASC.  With this change, all participants who ever received ET on study would be followed for 144 
weeks after the start of their last cycle of ET; all other participants would be followed for 96 weeks after 
randomization or assignment to their last study step of entry.   
 
Study visit schedules follow the same format on each step and remained unchanged with the protocol 
modifications.  Visits occurred every 3 weeks through week 48, and then occurred every 12 weeks until 
week 96.  Study week windows occurred ± 7 days for all visits through week 48, and then ± 14 days for 
visits through week 96.  For those who received ET, all additional visits through end of follow-up 
occurred ± 12 weeks. 
 
 
2.2 
Power and Sample Size 
 
The study planned to enroll 706 participants under version 2.0 of the protocol.  With this sample size 
there was 88% power to demonstrate non-inferiority assuming the progression-free survival (PFS) rate 
in each arm was 65%; each experimental arm (ET+ART, BV+ART) is to be contrasted separately with 
PTX+ART with Type-I error rate control at the contrast level (trial-wise Type I error will be larger than 
5%).   
 
This sample size was determined based on the following assumptions: 
- 
15% non-inferiority margin 
- 
Two interim analyses and one final analysis would be conducted 
o 
Interim analyses would occur after 33% and 67% information 
o 
Lan-DeMets spending function was used corresponding to the O’Brien-Fleming 
boundary 
- 
One-sided significance level α=0.025 
- 
1:1:1 assignment fraction 
- 
Inflation rate of 10% for loss-to-follow-up 
 
The sample size was modified in version 3.0 of the protocol and reflects the changes associated with 
the closure of the ET+ART arm and reduced power.  With the same above-stated assumptions the 
targeted sample size for the BV+ART and PTX+ART arms was 386 total participants.  With 60 
participants already enrolled to the ET+ART arm, the total planned sample size for the study under 
version 3.0 was 446.  
 
 
 
2.3 
Hypotheses 
 
1. ET plus ART is non-inferior to PTX plus ART for initial treatment of advanced stage AIDS-related 
Kaposi’s Sarcoma (AIDS-KS). 
 
2. BV plus ART is non-inferior to PTX plus ART for initial treatment of advanced stage AIDS-KS. 
  
 
 
 


 
 
Page 6 of 17 
 
 
2.4 
Objectives 
 
The Primary SAP addresses the following primary and secondary objectives listed in the study protocol.  
Secondary objectives addressing quality of life [Protocol Objective 1.2.2] will be analyzed outside of 
SDAC and those analyses will be outlined in a separate SAP.  The remaining study objectives in the 
protocol will be addressed in subsequent analysis plans [Protocol Objectives:  1.2.8, 1.2.9, and 1.2.11]; 
these are related to long-term safety follow-up (which is ongoing) and laboratory-based objectives that 
are pending sample mobilization and testing.  No statistical analysis will be conducted to address 
Protocol Objective 1.2.10, which was to encourage donations of excess biopsy materials. 
 
 
2.4.1 Primary Objective 
 
1. To compare the clinical efficacy of two regimens, etoposide (ET) plus ART and bleomycin plus 
vincristine (BV) plus ART, to paclitaxel (PTX) plus ART for initial treatment of advanced stage 
AIDS-related Kaposi’s sarcoma (AIDS-KS). [Protocol Objective 1.1] 
 
 
2.4.2 Secondary Objectives 
 
1. Compare Kaposi’s sarcoma (KS) tumor response in persons randomized to ET plus ART, BV 
plus ART, and PTX plus ART. [Protocol Objective 1.2.1] 
 
2. Compare the safety and toxicity in persons randomized to ET plus ART, BV plus ART, and PTX 
plus ART. [Protocol Objective 1.2.3] 
 
3. Compare suppression of plasma HIV-1 RNA and changes in CD4+ lymphocyte cell count in 
persons randomized to ET plus ART, BV plus ART, and PTX plus ART. [Protocol Objective 
1.2.4] 
 
4. Compare adherence to ART in persons randomized to ET plus ART, BV plus ART, and PTX 
plus ART. [Protocol Objective 1.2.5] 
 
5. Compare incidence of peripheral neuropathy (PN) and symptomatic peripheral neuropathy 
(SPN) in persons randomized to ET plus ART, BV plus ART, and PTX plus ART. [Protocol 
Objective 1.2.6] 
 
6. Evaluate clinical efficacy of the remaining regiment after failure of the initial regimen. [Protocol 
Objective 1.2.7] 
 
 
 
 


 
 
Page 7 of 17 
 
 
2.5 
Outcome Measures 
 
2.5.1 Primary Outcome Measure 
 
1. Progression free survival (PFS) defined as a lack of IERC-confirmed KS progression, death, 
entry to an additional step, or loss to follow-up prior to week 48. 
 
All potential KS disease progressions were reviewed by an independent endpoint review 
committee (IERC), which consisted of experienced investigators who were not members of the 
protocol team and were blinded to treatment assignment.  Sites submitted a request for the 
IERC to review a potential KS progression by entering CRF EVW0232 (KS Evaluation) and 
EVW0233 (KS Follow-Up Evaluation) and using the IERC Real-Time Clinical Review interface 
to submit clinical findings and photographic record; the IERC responded within 48 hours.   
 
2.5.2 Secondary Outcome Measures 
 
1. Death by week 48 
 
2. IERC-confirmed KS progression by week 48 
 
3. AIDS-defining event by week 48 
 
4. HIV-1 RNA virologic failure by week 48 
 
Virologic failure (VF) is defined as two-successive measurements of plasma HIV-1 RNA ≥ 1000 
copies/mL at week 12 to 24 or, HIV-1 RNA ≥ 400 copies/mL at week 24 or later.  The date of VF 
will correspond to the timing of the first of the two measures; if there is not a confirmatory viral 
load result then the conservative approach of classifying the single measure has a VF will be 
used 
 
5. KS-IRIS by week 48 
 
KS-IRIS is defined as any IERC-confirmed KS progression that occurs within 12 weeks of 
initiation of ART that is associated with an increase in CD4+ cells of at least 50 cells/mm3 above 
the study entry value and/or decrease in the HIV-RNA level by at least 0.5 log below the study 
entry value prior to or at the time of documented IERC-confirmed KS progression. 
 
6. Objective Response (OR) during Step 1 
 
Objective Response is defined as either a complete response (CR) or partial response (PR). 
 
7. Duration of Objective Response (OR) during Step 1 
 
Duration of OR is defined as time from initial Objective Response to time of IERC-confirmed KS 
progression among those with an OR 
 
8. IERC-confirmed KS progression, death, or AIDS-defining event by week 48 
 
9. IERC-confirmed KS progression, death, AIDS-defining event, or VF by week 48 
 
10. IERC-confirmed KS progression, death, AIDS-defining event, VF, or KS-IRIS by week 48 
 
11. Time to IERC-confirmed KS-progression or death, whichever is earlier 
 
12. Time to death 
 


 
 
Page 8 of 17 
 
 
 
 
 
 
13. Change in KS treatment by week 48 
 
Change in KS treatment is defined as stopping randomized chemotherapy and initiating a 
different chemotherapy, regardless of the reason. 
 
14. Occurrence of post-entry Grade 3 or higher  signs and symptoms and laboratory toxicities  
 
15. Occurrence of treatment-related toxicities and adverse events (AEs) 
 
16. Occurrence of peripheral neuropathy (PN) 
 
17. Occurrence of symptomatic PN (SPN)  
 
18. Change in CD4+ lymphocyte cell count from entry to weeks 12, 24, and 48 
 
19. Adherence to ART 
 
ART adherence is based on participant recall and is defined as not missing ART for the month 
prior to the current visit 
 
20. Presence of oral KS at entry 
 
21. IERC-confirmed KS progression, dose-limiting toxicity, VF, AIDS-defining events, objective 
response, or death during Step 2 
 
22. IERC-confirmed KS progression, dose-limiting toxicity, VF, AIDS-defining events, objective 
response, or death during Step 3 
 
23. IERC-confirmed KS progression, dose-limiting toxicity, VF, AIDS-defining events, objective 
response, or death during Step 4 
 
 


 
 
Page 9 of 17 
 
 
2.6 
Interim Monitoring  
 
The NIAID/DAIDS Co-infections and Complications Data and Safety Monitoring Board (CC-DSMB) was 
responsible for the interim reviews of A5263/AMC066, which occurred either annually or biannually and 
consisted of administrative, safety, and efficacy summaries.  Summary reports were prepared for each 
review and included details on study conduct, baseline characteristics, safety and tolerability, and 
endpoint data by randomized treatment arm.  Prior to the start of enrollment, the CC-DSMB requested 
that a summary of primary endpoint data by randomized treatment arm be provided in all DSMB reports.  
Although not pre-stated in the protocol, Kaplan-Meier methods with Greenwood’s formula for the 
variance were used to obtain PFS rates by calculating the survival probabilities for each treatment arm 
at week 48.  This approach was used to account for differential follow-up time by censoring 
observations at the most recent reported dates of contact if they had not experienced an event. 
 
The study planned to have two interim analyses and one final analysis, the timing of which were 
determined using a Lan-DeMets spending function corresponding to the O’Brien-Fleming boundary.  
The final analysis would consist of constructing a 95.37% CI for primary endpoint (reported as a 95% to 
account for 95% simultaneous coverage probability given the interim analyses) and interim analyses 
were planned after 33.3% and 66.7% of the planned enrollment had reached week 48 (33% and 67% 
information), which corresponded to constructing 99.98% and 98.80% confidence intervals for the 
primary endpoint. 
 
At the second interim review (September 2015), with consultation with ACTG SDAC leadership, the 
decision was made to provide formal treatment arm comparisons at an earlier-than-planned time point 
(i.e. before 33% information) because of observed differences between treatment arms; 99.98% CIs 
were used for this review.  Henceforth, the CC-DSMB requested all future reviews contain formal 
between-arm comparisons, and confidence intervals were planned to be based on the available 
statistical information at the given review.  This change in strategy for interim reviews was incorporated 
into the statistical section of protocol version 3.0.  Specifically, it noted that formal between-arm 
comparison would occur at each interim CC-DSMB review with corresponding CIs being based on the 
estimated percent information available at that review. And, that the primary analysis would consist of 
constructing a CI for the primary endpoint that is adjusted using the Lan-DeMets approach to account 
for the multiple interim analyses in order to provide 95% simultaneous coverage over the multiple 
analyses. 
 
However, because there was still limited % information at the 2016 reviews (see Table below) and 
O’Brien-Fleming stopping guidelines require a very extreme p-value (and CI coverage) before stopping 
is considered, 99.9% confidence intervals were used at these reviews.  This approach is analogous to 
capping p-values at 0.001 and is similar to the use of Haybittle-Peto guidance for analyses conducted at 
an early information time.  All subsequent reviews based the confidence intervals on % information.  
 
A summary of the alpha-spending from each DSMB reviews is provided for reference.   
 
 
Review 
Estimated 
% Info 
CI 
Alpha Spent 
Total Alpha Spent 
ET v PTX 
BV v PTX 
Sept 2015 
7% 
99.98% 
0.0002 
0.0012 
0.0104 
March 2016 
13% 
99.9% 
0.001 
Sept 2016 
22% 
99.9% 
0.001 
 
Sept 2017 
35% 
99.98% 
0.0002 
March 2018 
60% 
99.2% 
0.008 
 
 
 
 


 
 
Page 10 of 17 
 
 
3 
General Analysis Considerations 
 
Study (Step 1) entry, denoted as Week 0, is defined as the date of the entry visit recorded on Study 
Initiation Case Report Form (CRF).  Entry to other study steps is defined as the date of randomization to 
the respective step and is denoted as Week R.  
 
For summaries that occur at specific study weeks (e.g. CD4 cell count, HIV-1 RNA levels), the following 
week windows are used:  
 
 
Week 0: 
Days [0, 1] 
Week 12: 
Weeks [10, 14] 
Week 24: 
Weeks [22, 26] 
Week 36: 
Weeks [34, 38] 
Week 48: 
Weeks [46, 50] 
Week 60: 
Weeks [58, 62] 
Week 72: 
Weeks [70, 74] 
Week 84: 
Weeks [82, 86] 
Week 96: 
Weeks [94, 98] 
 
 
Loss-to-follow-up, as stated in the primary outcome, is defined as being off-study for an unknown 
reason. This was not explicitly defined in the protocol, but was decided prior to the first interim review 
with consultation with the team.  As stated in the protocol, missing data (i.e., loss to follow up) was 
included in the primary outcome because of the advanced disease state of most enrolled participants 
and most missing data from international sites is due to participant death (ACTG meeting 2008 
presentation).  
 
All data listings will use CBAR PUBLICID and will have calendar date information redacted and will 
instead be summarized in terms of study week. 
 
Descriptive summaries of continuous baseline characteristics will include number of observations, 
number of observations missing, median, IQR, and min/max; descriptive summaries of other continuous 
variables will use mean and standard deviation, or median and IQR depending upon the corresponding 
analysis method. The frequency and percentage will be used for all categorical variables. 
 
Two different freeze dates will be used to construct the final analysis database.  The first date, March 
10th 2016, corresponds to the DSMB review date at which the decision was made to close enrollment to 
the ET+ART arm; this will be the freeze date for the ET+ART data.  The second date, March 13th 2018, 
corresponds to the DSMB review date at which the decision was made to close enrollment to the 
remaining two arms (BV+ART and PTX+ART); this will be the freeze date for the BV+ART and 
PTX+ART data.  All descriptive by arm summaries will include all available data as of the relevant 
freeze dates; the ET+ART data will be from a different freeze date than the other two arms.  Formal 
treatment group comparisons are slightly more nuanced.  Comparisons of BV+ART versus PTX+ART 
will use all data as of the March 13th 2018 freeze date. Formal treatment group comparison of ET+ART 
versus PTX+ART will use all data as of the March 10th 2016 freeze date; this will require that the 
PTX+ART data be further restricted to only include data from the same time period as the ET+ART arm.  
 
 
 
 
 


 
 
Page 11 of 17 
 
 
 
The analysis population for the final analysis will include all randomized participants who were eligible 
for the study and who started their randomized chemotherapy; only a handful of participants were 
ineligible or did not initiate their assigned chemotherapy.  All analyses will be conducted among this 
population; treatment arm comparisons will contrast initially randomized treatment arms, regardless if 
chemotherapy was stopped or modified.  A second censored analysis will also be conducted, which 
censors participants if they initiate different study chemotherapy; this analysis restricts follow-up to time 
on the initially randomized treatment arm.  For the censored analysis, participants will be censored at 
the time they start a different study chemotherapy (Step 3 randomization), as appropriate for the specific 
outcome measure. Censoring will not occur if treatment is stopped prematurely without starting a new 
chemotherapy. 
 
All primary and secondary analyses outlined in this SAP will use a 5% alpha.  Each experimental arm 
(ET+ART and BV+ART) will be contrasted separately with PTX+ART, with each contrast using a 5% 
alpha.  This decision, to control the Type-I error rate at the contrast level (instead of at the trial level) 
was based on team input at the time of protocol design.  Additional details are discussed in the 
statistical methods section. 
 
 


 
 
Page 12 of 17 
 
 
4 
Statistical Methods 
 
4.1 
Analyses of the Primary Outcome 
 
4.1.1 Analysis Considerations 
 
As noted in previous sections, the original plan for interim monitoring was modified during the course of 
the study, with formal treatment arm comparisons occurring earlier than planned.  In addition, the 
ET+ART arm was prematurely closed at an early interim review and the overall study was terminated 
prior to the study fully enrolling.  Both study modifications were due to inferiority of the experimental 
arms relative to PTX+ART.  Taking into consideration this and the fact that only a small amount of alpha 
was spent at the interim reviews, the decision was made to use a 5% alpha for the primary analysis 
implemented by 95% nominal confidence intervals.    
 
Along with the nominal 95% CIs calculated for the analyses outlined in this SAP, the results (CIs) 
included in the reports that led the DSMB to recommend action (i.e., closing the ET+ART arm and 
closing the study) will also be provided in the analysis report.  These results will be taken directly from 
the prior interim reports; no additional analysis will be conducted to generate these intervals.  
 
Per NIH policy for Phase III and pivotal Phase II and IV studies, NIH requires primary analyses of 
treatment comparisons to be summarized by sex and by race and treatment interactions with sex and 
race to be tested.  These analyses are required and do not represent multiple comparisons and will be 
presented in the primary study analysis regardless of power issues.  The majority of participants 
enrolled into the study are black and therefore only analyses by sex and treatment interactions with sex 
will be examined.  
 
4.1.2 Primary Outcome Methods  
 
Within arm estimates of the PFS rate at week 48 will be obtained using Kaplan-Meier methods with 
Greenwood’s formula for the variance (see below), and are determined by calculating the survival 
probabilities at week 48.  Events are defined as the first occurrence of any component of the primary 
endpoint within the first 48 weeks.  Primary endpoint components include IERC-confirmed KS 
progression, death, entry to another step, or loss-to-follow-up for an unknown reason.  Participants 
could experience more than one component of the primary endpoint, but only the timing of the first 
component determines if they are classified as an event.  Participants who have not experienced an 
event in the first 48 weeks will be censored at their date of last reported contact (if their total follow up 
time is less than 48 weeks) or at week 48 (for those with more than 48 weeks of follow up).  Time is 
calculated as the difference from week 0 (step 1 entry) to either the event or censor date. 
Summary tables describing the frequency and percentage of each component will be provided overall 
and by treatment arm, as well as a summary of endpoint status (i.e. frequency and percent of 
participants with an event, without an event and follow-up < 48 weeks, and without an event and follow-
up > 48 weeks). Additional details will be provided in the AIP. 
 
The absolute difference in 48-week PFS rates between ET+ART and PTX+ART, and BV+ART and 
PTX+ART will be calculated separately.  The 48-week survival probabilities and two-sided 95% CIs for 
each difference will be determined overall (not adjusting for stratification factors) and with adjustment 
(weighted) for randomized stratification factors; the inverse of the stratum-specific variance will be used 
for the stratum weights.  Adjustments will be done separately for each stratification factor (CD4+ cell 
count and country); an analysis that simultaneously adjusts for both stratification factors will be 
examined, however, this may not be possible due to the limited number of participants in some strata.  
The differences and corresponding CIs will be plotted in a forest plot with a reference line for the NI 
margin (15%).   
 
 
 
 


 
 
Page 13 of 17 
 
 
Subgroup analyses will examine the difference in PFS rates within post-hoc identified subgroups. The 
subgroups considered include those with visceral disease versus those without visceral disease at 
entry, and those with screening CD4 cell counts <100 versus ≥ 100 cells/mm3 (stratification factor). 
 
Two sensitivity analyses will also be conducted.  The first sensitivity analysis will analyze the primary 
outcome among all randomized participants regardless if they started their randomized chemotherapy or 
were ineligible for the study.  The second sensitivity analysis will consider an expanded definition of 
loss-to-follow-up for the primary endpoint.  This modified definition will include all non-administrative off-
study reasons (i.e., will not include site or study closure as loss-to-follow-up).  
 
Because participants are classified as an event if they enter another study step, the censored analysis 
will not be done for the primary analysis.  
 
 


 
 
Page 14 of 17 
 
 
4.2 
Analysis of Secondary Outcomes  
 
4.2.1 Analysis Considerations 
 
All analyses of secondary outcomes will use a Type-I error rate of 5%; no secondary outcomes were 
examined during interim monitoring so prior alpha-spending considerations are not necessary for 
secondary outcomes.  As previously mentioned in the general analysis considerations section, all 
analysis will be among the defined analysis population.  A censored analysis will also be done for most 
secondary outcomes, which censors participants at the time they start different study chemotherapy 
(Step 3 randomization date or other); details on exceptions are denoted in this section. For those who 
started different study chemotherapy due to entering Step 3, the Step 3 randomization date will be used 
for the censor date, for those who initiated a different study chemotherapy while on Step 1, the start 
date of the chemotherapy will be used as the censor date (as recorded on the concomitant medications 
case report form). 
 
Prior to analysis, the team identified a list of conditions that are classified as AIDS-defining events from 
a list of diagnoses from Appendix 60, the Diagnoses Appendix used for this study.  The list of diagnosis 
codes and corresponding conditions are located in the AIP. 
 
Virologic failure (VF) is defined as two-successive measurements of plasma HIV-1 RNA ≥ 1000 
copies/mL at week 12 to 24 or, HIV-1 RNA ≥ 400 copies/mL at week 24 or later.  The date of VF will 
correspond to the timing of the first of the two measures.  The date of the HIV-1 RNA virologic failure 
event will be the first of the two measures; if there is not a confirmatory viral load result then the 
conservative approach of classifying the single measure has a VF will be used. 
 
KS-IRIS is defined as any IERC-confirmed KS progression that occurs within 12 weeks of initiation of 
ART that is associated with an increase in CD4+ cell of at least 50 cells/mm3 above the study entry 
value and/or decrease in the HIV-1 RNA level by at least 0.5 log below the study entry value prior to or 
at the time of documented IERC-confirmed KS progression. 
 
Change in KS treatment by week 48 is defined as stopping randomized chemotherapy and initiating a 
different chemotherapy, regardless of the reason; censored analysis of this outcome will not be done. 
 
4.2.2 Secondary Outcome Methods 
 
Analysis of Events by Week 48 
 
Analyses of events by week 48 will be done in a similar manner to the primary analysis.  Kaplan-Meier 
methods with Greenwood’s formula for the variance (see below) will be used to estimate the survival 
probability at week 48.  Participants will be classified as having had an event if they experience the 
specific component(s) of the secondary outcome within the first 48 weeks on study; for composite 
secondary outcomes the timing of the first occurrence of the component will be used. Participants who 
are not classified as an event will be censored at their date of last reported contact (if their total follow 
up time is less than 48 weeks) or at week 48 (for those with more than 48 weeks of follow up).  Time is 
calculated as the difference from week 0 (step 1 entry) to either event or censor date.  The censored 
analysis will also censor participant follow-up time at the time they start another study chemotherapy 
(censoring will occur as defined in the previous section). 
 
The absolute difference in 48-week rates between ET+ART and PTX+ART, and BV+ART and 
PTX+ART will be calculated separately.  The 48-week survival probabilities and two-sided 95% CIs for 
each difference will be determined overall (not adjusted for stratification factors) and with adjustment 
(weighted) for stratification factors; the inverse of the stratum-specific variance will be used for the 
stratum weights.  Adjustments for stratification factors will be done in a similar manner as the primary 
analysis.  Difference will be calculated for the rates generated from the whole analysis population, and 
for the censored analysis.  
 


 
 
Page 15 of 17 
 
 
Analysis of KS-IRIS 
 
The analysis of KS-IRIS will be different from the other secondary outcomes of events by week 48.  
Because there were only a limited number of KS-IRIS events during the course of the study (observed 
during interim reviews), there will be no formal statistical analyses comparing treatment arms.  Instead, 
descriptive summary listings of all KS-IRIS events will be included in the final analysis report.  The date 
of KS-IRIS will be the date of KS progression reported by the site. 
 
Analyses of Objective Response (OR) 
 
The best overall response on Step 1 for each participant will be determined. The possible categories 
include: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease 
(PD), or Not Evaluable (NE).   Participants will be classified as NE if they do not have enough follow-up 
data to determine their KS response.  Objective Response is defined as experiencing either a CR or PR 
(OR = CR+PR).  The number and % of participants in each category will be summarized in a table by 
treatment arm.  Logistic regression analysis will be used to compare OR between arms, adjusting for 
stratification factors (in a similar manner as the primary analysis).  The treatment effect from this model 
will determine if there are higher odds of an OR in ET+ART versus PTX+ART, and in BV+ART versus 
PTX+ART. 
 
Among those classified with their best response as an OR, the duration of this response will be 
calculated.  Duration will be calculated as the difference in time from first documented response to 
IERC-confirmed KS progression, death, or change in step.  Participants with OR, but without a 
documented IERC-confirmed KS progression, death, or change in step, will be censored at their last 
reported date of contact. Kaplan-Meier methods with Greenwood’s formula for the variance will be used 
to determine the median duration of OR for each treatment arm; no formal comparisons between arms 
will be done. 
 
Time to Event Analysis 
 
Kaplan-Meier methods with Greenwood’s formula for the variance will be used to visually display 
survival curves and estimate median time for each treatment arm.  Log-rank test will be used to 
compare the survival curves between arms; comparisons will be done separately for ET+ART versus 
PTX+ART and BV+ART versus PTX+ART.  Cox-proportional hazards regression models will be 
adjusted for stratification factors in a similar manner as the primary analysis; hazard ratios (HR), 95% CI 
for the HR, and p-values will be provided.   
 
Participants will be censored at the time of their last reported date of contact if they did not experience 
an event.  An additional censored analysis will also censor those at the time they start different study 
chemotherapy (defined in previous section). 
 
 
 


 
 
Page 16 of 17 
 
 
Safety Summaries 
 
All safety events will be presented according to MedDRA coding and will be grouped by the most 
appropriate MedDRA hierarchy at the time of analysis.   No formal treatment group comparisons are 
planned. 
 
Descriptive analysis with tabular summaries will be provided for post-entry Grade 3 or higher signs and 
symptoms and laboratory toxicities overall and by treatment arm.  This will include frequencies and 
percentages of participants who experienced a post-entry Grade 3 or higher AE; if more than one grade 
of the same event is reported for a participant then the highest grade will be reported.  This summary 
will be provided for the entire analysis population and will include events with onset dates after 
randomization to Step 1.  A separate summary will also be provided that restricts AEs to the time prior to 
starting different study chemotherapy (exclude events with onset dates after starting different study 
chemotherapy). 
 
Descriptive analysis with tabular summaries will be provided in a similar manner for all post-entry 
treatment-related toxicities and AEs; this analysis will be restricted to the time while on their initial 
chemotherapy (i.e., will excluded AEs with onset dates after initiate different study chemotherapy). The 
relationship to treatment for each toxicity or AE is determined by site investigators and is indicated on 
the CRF as:  definitely related, probably related, possibly related, probably not related, or not related.  
Events that are classified as definitely, probably or possibly related will be considered treatment-related 
events. 
 
Peripheral Neuropathy Summaries 
 
Assessments of peripheral neuropathy (PN) were recorded on a peripheral neuropathy screening form 
collected for everyone at screening, week 9, and week 21, and for those on BV or PTX also at weeks 3, 
6, 15, and 18.  PN is determined by the presence and severity of three components: symptoms, 
perception of vibrations, and deep tendon reflexes.  Each component of PN will be summarized 
separately and will pool results reported from the right and left side by taking the highest recorded result 
of the right and left side.  Summaries of PN will be by study week and treatment arm and will be done 
among participants while they were on their initially randomized chemotherapy; frequencies and 
percentages will be used for this analysis. 
 
Symptomatic PN (SPN) consists of three assessments:  (1) pain, aching or burning feet, legs, (2) “pins 
and needles” in feet, legs, and (3) numbness (lack of feeling) in the feet, legs.  SPN that is present is 
graded on a severity scale from 1 (mild) to 10 (severe).  The highest reported severity between the right 
and left sides across the three assessments will be determined.  The presence of symptomatic PN and 
the severity of the SPN for those with symptoms will be summarized. 
 
Perception of vibration will be summarized as normal or abnormal (mild, moderate, or severe loss).  The 
highest score between the right and left side will be determined.  Deep tendon reflexes will be 
summarized as either: absent/hypoactive, normal, or hyperactive/clonus.  The highest reported ankle 
reflex between the right and left side will be summarized.  
 
Presence of PN is defined as having the all of following results for the three components:  (1) presence 
of symptomatic PN, (2) abnormal perception of vibrations, and (3) absent or hypoactive deep tendon 
reflexes.  The frequency and percent of participants meeting these criteria will also be summarized.  
 
 
 
 
 


 
 
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CD4 Count Analysis 
 
Descriptive summaries of change in CD4 cell count will be provided by treatment arm and study week 
for the analysis population, regardless if treatment was changed.  The median and IQR change in CD4 
count will be calculated at each study week (12, 24, and 48) and the change will be shown visually in a 
longitudinal change plot.  Sign-ranked tests will be used to determine if CD4 counts changed over time 
within each treatment group.  Formal treatment group comparison will occur at weeks 12 and 48 
comparing ET+ART with PTX+ART and BV+ART with PTX+ART using Wilcoxon tests; no adjustment 
for multiple testing will occur. 
 
 
ART Adherence and Oral KS 
 
Questionnaires collecting details on ART adherence were administered at multiple study weeks.  
Summaries of adherence will occur at study weeks 6, 12, 18, 30, and 48.  Descriptive summaries of 
adherence will consist of the frequency and percentage of participants who were adherent, which is 
defined as either perfect or non-perfect adherence in the last month (defined in a similar manner to 
A5175 based on participant recall).  These summaries will be provided by treatment arm and study 
week.  
 
The analysis of the prevalence of oral KS at entry will be descriptive and consist of summarizing the 
frequency and percentage of participant with oral KS lesions at study entry.  
 
Summaries of Study Steps 2-4 
 
Descriptive summaries of secondary outcomes 21-23 will be provided by concurrent treatment arm.  
The proportion of participants on the given study step who experienced each of the components of the 
endpoint will be summarized, regardless of prior or subsequent occurrences on other steps.  Definitions 
of each event in the endpoint follow definitions previously noted in prior outcomes.  No formal treatment 
arm comparisons are planned.