Kaposi Sarcoma

Ongoing and Upcoming Studies

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, Matthew Painschab)

Background: 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:  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.

Funding source: National Cancer Institute

Targeted accrual: 90

Study status: Enrolling

Rituximab for Multicentric Castleman Disease in Malawi, A Single-Arm Phase II Safety/Efficacy Trial

(PI, Matthew Painschab)

Background: 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: 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).

Funding source: Fogarty International Center, National Cancer Institute

Targeted accrual: 27

Study status: Enrolling

New Approaches for the Diagnosis of Kaposi’s Sarcoma

(PI, Dr.Bongani Kaimila and Dr.Matthew Painschab)

Background: 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.

Objectives: 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.

Collaborators: Weill Cornell Medical College, Uganda Cancer Institute, Makarere University

Funding source: Linberger Comprehensive Cancer Center, National Cancer Institute

Targeted accrual: 216

A Phase II Study of Pomalidomide Monotherapy in HIV-Positive Individuals with Kaposi Sarcoma (KS)

Summary

(Clinical leads, Dr.Bongani Kaimila and Dr.Lameck Chinula)

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.

Completed Studies

Investigating chemotherapy treatments, response and subsets of HIV-associated Kaposi sarcoma in Malawi

(PI, Dr. Sam Phiri, closed)

Background: 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: 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.

Funding source: Lineberger Comprehensive Cancer Center

Targeted accrual: 157

Study status: Closed