Paclitaxel or Liposomal Doxorubicin for HIV-positive Persons with Kaposi Sarcoma
This phase III trial compares the effectiveness of pegylated liposomal doxorubicin (PDL) hydrochloride to paclitaxel (PTX) for the treatment of acquired immunodeficiency syndrome-associated Kaposi sarcoma (AIDS-KS) in Africa. Doxorubicin hydrochloride is a drug that interferes with deoxyribonucleic acid (DNA). It can prevent DNA replication, induce DNA repair, or cause cell death. PDL delivers doxorubicin hydrochloride in very small particles called liposomes, which may improve the penetration of the drug into the tumor, allowing it to work better and produce less side effects. PTX is a drug that prevents cell replication and induces cell death. PDL and PTX are Food and Drug Administration approved treatments for AIDS-KS, but these drugs are not easily available in low-income African nations. Giving PDL or PTX may shrink or stabilize KS tumors in patients with AIDS-KS.
Inclusion Criteria
- Human immunodeficiency virus 1 (HIV-1) infection
- Histologically confirmed Kaposi sarcoma (KS) at any time prior to study entry, confirmed by an AMC-certified pathologist. NOTE: If KS is suspected on clinical grounds but has not been histologically confirmed, a confirmatory biopsy may be performed as a screening procedure
- Current T1 KS (irrespective of prior treatment with ART) OR T0 KS that has progressed or not responded after a minimum of 12 weeks of treatment with ART. Participants with T0 KS must have either: * 20 or more skin and/or oral KS lesions, and/or * Any number of lesions on exposed body areas that have an adverse effect on quality of life (e.g., stigmatization)
- Men and women >= 18 years. Because no dosing or adverse event data are currently available on the use of PTX or PLD for acquired immunodeficiency syndrome (AIDS)-KS in persons < 18 years of age, children are excluded from this study
- Karnofsky performance status >= 60 (Eastern Cooperative Oncology Group [ECOG] =< 2)
- Echocardiogram or multiple gated acquisition scanning (MUGA) showing an ejection fraction >= 50%
- Ability and willingness of participant or legal guardian to provide informed consent
- Participants may be ART-naive or ART-experienced but must be able to receive an ART regimen considered likely to result in HIV suppression
- Measurable cutaneous KS, defined as follows: * When available, a minimum of five bi-dimensionally measurable KS cutaneous marker lesions * If fewer than five bi-dimensionally measurable marker lesions are available, the total surface area of the marker lesion(s) must be >= 700mm^2
- Absolute neutrophil count (ANC) >= 1000 cells/mm^3 (within 14 days prior to study entry)
- Hemoglobin >= 8 g/dL (may be achieved with transfusion if clinically indicated, in the opinion of the investigator) (within 14 days prior to study entry)
- Platelet count >= 75,000/mm^3 (within 14 days prior to study entry)
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) =< 5 x upper limit of normal (ULN) (within 14 days prior to study entry)
- Total bilirubin: =< 1.5 x the upper limit of normal (ULN), unless the participant is receiving an antiretroviral drug known to be associated with increased bilirubin, in which case the direct fraction should be =< 2 x the ULN (within 14 days prior to study entry)
- Creatinine =< institutional ULN OR estimated glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal. Estimated GFR must be measured using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (within 14 days prior to study entry)
- Women of reproductive potential, defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months), must have a negative pregnancy test done within 24 hours of initiating the protocol-specified chemotherapy medication
- Participants must agree to use two reliable forms of contraception simultaneously while receiving study protocol-specified medication and for 6 months after stopping the medication
- Adequate venous access
- No prior chemotherapy or use of systemic cytotoxic therapy agents
- Participant is able to understand and willing to sign a written informed consent document
Exclusion Criteria
- Current acute, chronic, 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 before study entry and/or is not clinically stable
- Serious illness necessitating hospitalization/systemic treatment within 14 days prior to study entry
- Breastfeeding or pregnant women are excluded because of potential risks of cytotoxic chemotherapy to an unborn child or infant
- Known history of congestive heart failure and/or systolic ejection fraction < 50%
- Prior radiotherapy to KS indicator lesions
- Prior or current immunotherapy
- Any immunomodulator, HIV vaccine, live attenuated vaccine, other investigational vaccine within 30 days prior to study entry, excluding vaccines against coronavirus disease 2019 (COVID-19)/severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which are permitted
- Known allergy/hypersensitivity to the study drug or its formulation
- Any condition, including the presence of laboratory abnormalities, which in the opinion of the responsible investigator places the subject at unacceptable risk if they were to participate in the study or confounds the ability to interpret data from the study
- Corticosteroid use at doses above those given for replacement therapy for adrenal insufficiency within the last 30 days prior to study entry
- Patients with psychiatric illness and/or social circumstances that would limit compliance with study requirements
- Patients with grade 3 or 4 peripheral neuropathy
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PRIMARY OBJECTIVE:
I. To evaluate whether there is sufficient evidence to conclude that PLD is non-inferior to PTX in people with severe AIDS-associated KS receiving concomitant antiretroviral therapy (ART) in resource-limited settings.
SECONDARY OBJECTIVES:
I. To describe the safety and toxicity of PLD and PTX in patients with severe AIDS-KS in resource-limited settings.
II. To estimate the objective response rate (defined as the sum of complete and partial responses) for AIDS-KS, response duration and overall survival in each treatment arm.
EXPLORATORY OBJECTIVES:
I. To describe the cost of therapy across AIDS Malignancy Consortium (AMC) sites in sub-Saharan Africa to deliver both PLD and PTX by micro-costing analysis for goods and time-in-motion analysis for services.
II. To assess quality of life across Patient Reported Outcomes Measurement Information System (PROMIS) domains (i.e., cognitive function, physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance) with the PROMIS Preference (PROPr) tool at start of therapy, mid-treatment, and after treatment with PLD and PTX.
III. To describe the incremental cost-effectiveness ratio per quality adjusted life years (QALY) gained (as assessed by PROPr) between PLD and PTX.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive pegylated liposomal doxorubicin hydrochloride intravenously (IV) over 30-60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy at screening and as clinically indicated. Patients undergo chest x-ray and computed tomography (CT) at screening, prior to cycle 4, at treatment discontinuation, and then every 12 weeks thereafter for participants with lung involvement at study entry or at the time new lung involvement is suspected. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) at screening and at the time congestive heart failure is suspected. Patients also undergo collection of blood samples at screening, within 3 days before the start of cycles 2, 3, 4, 5, and 6, at 3 weeks after the last dose of treatment, every 4 weeks after discontinuation until week 48 and then every 12 weeks until week 96.
ARM II: Patients receive PTX IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy at screening and as clinically indicated. Patients undergo chest x-ray and CT at screening, prior to cycle 4, at treatment discontinuation, and then every 12 weeks thereafter for participants with lung involvement at study entry or at the time new lung involvement is suspected. Patients undergo ECHO or MUGA at screening and at the time congestive heart failure is suspected. Patients also undergo collection of blood samples at screening, within 3 days before the start of cycles 2, 3, 4, 5, and 6, at 3 weeks after the last dose of treatment, every 4 weeks after discontinuation until week 48 and then every 12 weeks until week 96.
After completion of study treatment, patients are followed up every 4 weeks for 48 weeks and then every 12 weeks for an additional 48 weeks.
Trial PhasePhase III
Trial Typetreatment
Lead OrganizationAIDS Malignancy Consortium
Principal InvestigatorSusan E. Krown
- Primary IDAMC-114
- Secondary IDsNCI-2022-04732
- ClinicalTrials.gov IDNCT05411237