Kaposi Sarcoma
A Phase III, Randomized, Open-Label, Non-Inferiority Study of Paclitaxel and Pegylated Liposomal Doxorubicin for Treatment of HIV-related Kaposi Sarcoma in Resource-Limited Settings
(PI, Dr. Lameck Chinula, Upcoming)
This is an open-label, prospective, randomized, two-arm, multicenter non-inferiority study comparing the efficacy of intravenously administered PLD or PTX in participants with severe AIDS-related Kaposi’s sarcoma (AIDS/KS) based on WHO guidelines [6]. The study aims to enroll a maximum of 130 participants eligible for progression-free survival (PFS) evaluation. Participants will be randomly assigned in a 1:1 ratio to receive either PLD or PTX as their treatment regimen. Stratification for randomization will be based on the duration of prior antiretroviral therapy (ART) (< or ≥ 12 weeks) and country. Historically, the widespread use of PLD has been limited due to its high cost. However, the recent availability of more affordable generic formulations of PLD has allowed for sporadic utilization in resource-limited settings, depending on the financial capabilities of governments or individual patients. Objectives are: 1) 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. 2) To describe the safety and toxicity of PLD and PTX in patients with severe AIDS-KS in resource-limited settings. To estimate the objective AIDS-KS response rate (Complete and Partial), response duration and overall survival in each treatment arm. 3) Some exploratory objectives: to describe the cost of therapy across 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. To assess quality of life across PROMIS domains with the PROPr tool at start of therapy, mid-treatment, and after treatment with PLD and PTX. These domains are cognitive function, physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance. To describe the incremental cost-effectiveness ratio per quality-adjusted life years (QALY) gained (as assessed by PROPr) between PLD and PTX.
New approaches for the diagnosis of lymphoma and multicentric Castleman disease
(PI, Dr. Matthew Painschab, Enrollment Paused)
In persons living with HIV (PLWH) in sub-Saharan Africa (SSA), lymphadenopathy often portends one of a number of life-threatening diseases including tuberculosis, lymphoma, and multicentric Castleman disease (MCD). However, ready and safe access to definitive diagnosis by biopsy and histopathology are often limited. Less invasive and point of care diagnostics would provide significant value in this setting if they are shown to be sufficiently discriminatory by speeding diagnosis and referral to cancer care. In fact, point-of-care nucleic acid-based diagnosis has already become popularized in SSA in the tuberculosis field in the form of the commercial test called GeneXpert®.1,2
In sub-Saharan Africa (SSA), Kaposi sarcoma herpesvirus (KSHV)-related cancers account for 10-35% of malignancies3-5 and >10% of cancer-related deaths.5 Multicentric Castleman disease (MCD) is a life-threatening lymphoproliferative disorder characterized by systemic inflammation and lymphadenopathy. MCD is strongly associated with KSHV and human immunodeficiency virus (HIV). KSHV seroprevalence in SSA is >40%,6,7 the highest of any region in the world; likewise, the prevalence of HIV is high.8
Hodgkin (HL) and non-Hodgkin lymphoma (NHL) occur at increased rates in PLWH, however, delays in diagnosis in SSA lead to high mortality. Lymphoma constitutes the third most common cancer diagnosis among PLWH at Kamuzu Central Hospital (KCH) in Lilongwe, Malawi where this study will take place and the third most common cancer type across Malawi.3,9 In PLWH, both HL and many sub-types of NHL are frequently associated with Epstein-Barr virus (EBV), another herpesvirus closely related to KSHV.
Overcoming these delays and missed diagnoses requires new approaches to identify lymphoma and MCD. Our research team has developed assays based on nucleic acid measurement that have the potential to not only diagnose lymphoma and MCD but also be delivered at the point of clinical care. Nucleic acid quantification will be performed via loop-mediated isothermal amplification (LAMP) in a portable, low-cost and easy-to-operate device called “TINY” (Tiny Isothermal Nucleic acid Amplification System).
We will evaluate TINY to validate its diagnostic performance against gold-standard histology for the diagnosis of lymphoma and MCD in a resource-poor setting. Primary Objective: To understand the etiology of lymphadenopathy in patients living with HIV in Malawi. Secondary Objectives: 1) To characterize patients with HIV and lymphadenopathy including baseline clinical and laboratory characteristics. 2) To assess the diagnostic performance of KSHV DNA quantification from lymph node fine needle aspiration (FNA) and tissue biopsy using TINY for the diagnosis of MCD among HIV-infected adults in Malawi compared to gold standard histopathology and immunohistochemistry from tissue biopsy (hereafter referred to as “gold standard”). 3) To assess the diagnostic performance of EBV DNA quantification from lymph node fine needle aspiration (FNA) and tissue biopsy using TINY for the diagnosis of lymphoma among HIV-infected adults in Malawi compared to gold standard. 4) To assess the performance of KSHV DNA quantification from a peripheral blood sample using TINY for the diagnosis of MCD among HIV-infected adults in Malawi compared to gold standard. 5) To assess the performance of EBV DNA quantification from a peripheral blood sample using TINY for the diagnosis of lymphoma among HIV-infected adults in Malawi compared to gold standard
Kaposi Sarcoma chemotherapy and research (KS-CARE): Clinical and molecular determinants of HIV-associated Kaposi Sarcoma progression under local standard-of-care therapy in Malawi
(PI, Dr. Dirk Dittmer, Data Analsysis)
This is a prospective, non-interventional, nonrandomized, open-label, single-arm, cohort study of patients with pathologically confirmed HIV-associated Kaposi Sarcoma (HIV-KS) initiating chemotherapy in Lilongwe, Malawi. We plan to accrue KS patients at a rate of approximately 30 patients per year for 3 years. Patients will receive chemotherapy according to local site treatment guidelines and standard of care. The planned cohort size of this study compares or exceeds the size of previous important HIV-KS cohort studies. These studies demonstrated significant variability in clinical outcomes based on differences in gender or baseline KSHV DNA levels in patients with HIV-KS.[1, 2] In addition, all comers with histologically proven HIV-KS will be enrolled, irrespective of their prior length of combination anti-retroviral treatment (cART). This enrolment strategy will reflect a more realistic picture of HIV-KS management in SSA. Objectives are 1) to estimate the PFS rate at 48 weeks of patients overall and by chemotherapy group. 2) to estimate the PFS rate at 96 weeks of patients overall and by chemotherapy group, estimate the disease control rate, including SD, PR, and CR, of patients overall and by chemotherapy group four weeks after the completion of chemotherapy, estimate OS of patients overall and by chemotherapy group at 48 and 96 weeks, and evaluate changes in HR-QOL over time.
Rituximab for Multicentric Castleman Disease in Malawi, A Single-Arm Phase II Safety/Efficacy Trial
(PI, Matthew Painschab, Enrollment Complete)
In sub-Saharan Africa (SSA), Kaposi sarcoma herpesvirus (KSHV)-related cancers account for 10-35% of malignancies and >10% of cancer-related deaths. Multicentric Castleman disease (MCD) is a life-threatening lymphoproliferative disorder characterized by systemic inflammation and lymphadenopathy. MCD is strongly associated with KSHV and human immunodeficiency virus (HIV). KSHV seroprevalence in SSA is >40%, the highest of any region in the world; likewise, the prevalence of HIV is high. Substantial knowledge gaps remain regarding treatment for MCD, including outcomes, safety, and cost-effectiveness, particularly in SSA. MCD can be controlled with chemotherapy. When chemotherapy is discontinued, however, rapid relapses or development of non-Hodgkin lymphoma (NHL) occur with high mortality. Long-term remission is achieved in most patients with rituximab, an anti-CD20 monoclonal antibody, as described in small clinical trials in high-income countries (HIC). However, rituximab has not been evaluated for MCD in SSA, nor are there published safety data for rituximab from the region.
In this study, we aim to determine the safety and efficacy of first-line, risk-stratified rituximab-based MCD treatment in Malawi in a single-arm, phase II clinical trial. We will enroll 27 subjects with newly diagnosed or previously treated MCD (who have not previously received rituximab) requiring treatment (B symptoms or hemoglobin <10 g/dL). Subjects will be treated with four weekly doses of rituximab. High-risk subjects (defined as patients with Eastern Cooperative Oncology Group (ECOG) performance status >2 or hemoglobin <8 g/dL) will also receive etoposide chemotherapy. Subjects will be followed for one year for toxicity and two years for survival. Objectives are 1) Safety, defined as the frequency of ≥Grade 3 treatment-related Common Terminology Criteria for Adverse Events (AEs). 2) Event-free survival (death, progression, or development of NHL) and 1- and 2-year overall survival (OS). 3) To compare the cost-effectiveness of first-line rituximab treatment for MCD in Malawi to chemotherapy (using our historical controls).
New Approaches for the Diagnosis of Kaposi’s Sarcoma
(PI, Dr.Bongani Kaimila and Dr.Matthew Painschab, Enrollment Paused)
AIDS-related Kaposi sarcoma (KS) is one of the most common HIV-associated cancers in sub-Saharan Africa, with an incidence amongst HIV-infected persons of 164-334 per 100,000 person-years. In resource-rich settings, skin punch biopsy of lesions suspected to be KS followed by histopathologic interpretation is the standard means of diagnosis for KS. In resource-poor settings, histologic diagnosis of KS has been hampered by the lack of necessary resources, including sufficiently equipped pathology labs and pathologists trained in KS diagnosis. In resource-poor settings, histologic diagnosis of KS has been hampered by the lack of necessary resources, including sufficiently equipped pathology labs and pathologists trained in KS diagnosis. To address the need for new approaches to diagnose KS, investigators from our research team have developed an assay based on nucleic acid measurement that has the potential to be delivered at the point of clinical care. This approach uses nucleic acid amplification in attempt to diagnose KS without the need for histologic examination, taking advantage of the now well-established finding that the virus known as Kaposi’s sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8) is a necessary, albeit not sufficient, cause of KS. We have engineered an assay called loop-mediated isothermal amplification (LAMP) into a portable, low-cost and easy-to-operate device called “TINY” (Tiny Isothermal Nucleic acid Amplification System) for point-of-care nucleic acid-based diagnosis. We will evaluate TINY to validate its diagnostic performance in the real-world clinical settings in Africa in which it is ultimately intended to be used. In addition to determining performance characteristics, we also seek to evaluate the adoption and acceptability of TINY amongst clinicians and laboratory personnel.
A Phase II Study of Pomalidomide Monotherapy in HIV-Positive Individuals with Kaposi Sarcoma (KS)
Summary
(Clinical leads, Dr.Bongani Kaimila, Dr. Matthew Painschab, Dr.Lameck Chinula, Enrollment Complete)
In recent years, a class of medications called IMiDs (immunomodulatory imide drugs) has gained traction in the management of several malignancies, including KS, based on their anti-inflammatory, anti-angiogenic, and immunomodulatory properties. Case reports describing improvement in KS lesions and HHV-8 viral titers in KS patients treated with thalidomide, set the stage for further research into this class of medications in KS treatment. Additionally, their oral bioavailability and limited side effect profile, particularly with the next generation IMiD, pomalidomide, are important factors supporting their attractiveness for KS treatment in resource-limited settings, including SSA.
Pomalidomide, was designed to increase the anti-angiogenic and immunomodulatory effects compared to the prior IMiD compounds. Pomalidomide promotes T helper cell (Th)-1differentiation in vitro and increased Th-1 cytokine production in animal models. In pre-clinical studies, pomalidomide was shown to be effective against myeloma and B-cell lymphoma cell lines and have significant anti-angiogenic properties . It was initially postulated that the anti-angiogenic mechanism of action for both the parent compound thalidomide, and the subsequent IMiD derivatives was closely linked to their teratogenic potential. With the discovery of cereblon (CRBN) as the primary target of thalidomide teratogenicity, the interaction between pomalidomide and CRBN has been further investigated. Not only does pomalidomide bind CRBN in vitro, but resistance to pomalidomide in myeloma cell lines is associated with a decrease in CRBN protein expression . Upon binding to CRBN, the IMiD-CRBN complex results in ubiquination and proteasome-dependent degradation of the transcription factors Ikaros and Ailos, which in turn are responsible for the downregulation of c-Myc and IRF4. These in vitro findings highlight the importance of the interaction of pomalidomide with CRBN, but the dynamics of this interaction and mechanism of resistance with clinical correlation require further investigation.
Individuals with HIV-associated KS in Africa often have a spectrum of co-morbidities (e.g., anemia, infections, and nutritional deficiencies) that differ from those of HIV-infected individuals in the U.S., and which may affect drug tolerance. Thus, it will be important to determine whether the same dose and schedule of pomalidomide tolerated in a study of KS patients in the U.S. will be equally well tolerated in SSA.
Investigating chemotherapy treatments, response and subsets of HIV-associated Kaposi sarcoma in Malawi
(PI, Dr. Sam Phiri, Closed)
Kaposi Sarcoma KS is the most common cancer in Malawi. Of 18,946 new cancers in the Malawi National Cancer Registry (MNCR) between 2007 and 2010, KS accounted for 6,438 (34%) of cases. Despite large numbers of KS patients, and noted variability in clinical presentations and response to treatment, KS heterogeneity is insufficiently understood, even as it relates to key clinical issues like treatment response. All newly diagnosed patients requiring chemotherapy are treated more or less the same, using standard algorithms driven by the local availability of agents. Additionally, the burden of other diseases caused by KS-associated herpesvirus (KSHV) is unknown in Malawi, as are effects on clinical outcomes. Despite substantial geographic overlap between KSHV and HIV, lymphoproliferative diseases associated with KSHV [multicentric Castleman disease (MCD), KSHV inflammatory cytokine syndrome (KICS), and primary effusion lymphoma (PEL)] are infrequently described in SSA. The central hypothesis is that there are definable biologic and clinical subsets within the HIV+ KS population, and that identifying these subsets has direct relevance to treatment strategies. Objectives are 1) To estimate the complete response rate (or CR by ACTG criteria) at 48 weeks of HIV-associated KS patients overall and by BV treatment group. 2) To estimate progression free survival and overall survival in HIV-associated KS patients overall and by BV treatment group.