History of the KSHV Inflammatory Cytokine Syndrome (KICS)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01419561
First received: August 17, 2011
Last updated: March 14, 2014
Last verified: February 2014

August 17, 2011
March 14, 2014
August 2011
August 2016   (final data collection date for primary outcome measure)
Assessment of the natural history of KICS, including the spectrum of clinical, laboratory and radiographic abnormalities seen in affected patients. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT01419561 on ClinicalTrials.gov Archive Site
  • Exploration of the relationship of KICS clinical manifestations to KSHV viral loads, cytokines including viral IL-6, human IL-6, human IL-10 and other human cytokines, and KSHV lytic activation assessed by gene array. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Exploration of the pathophysiology of KICS, by assessment of affected tissue, including lymph nodes, bone marrow, effusions and sites of KS (where present), including immunohistochemical evaluation of cells with KSHV latent and lytic infection i... [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Exploratory assessment of potential stimuli of KSHV lytic activation in KICS patients, including potential stimuli such as coincident infection, uncontrolled HIV viremia, hypoxia, immune reconstitution with institution of HAART, or association o... [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Exploratory assessment of the prevalence of KICS in a cohort of KSHV infected patients with symptoms potentially attributable to KICS. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Assessment of 18[F]-Fluorodeoxyglucose positron emission tomographyfindings at KICS symptomatic time points compared with those following symptom resolution. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Estimation of clinical response rate with institution of each specific therapy (high dose zidovudine/valganciclovir or rituximab/liposomal doxorubicin). [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Estimation of rates of progression of patients to multicentric Castleman disease and other KSHV-associated diseases including KSHV-associated lymphomas. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Estimation of overall survival for the entire cohort, and of progressionfree survival and overall survival for each specific therapy (high dose zidovudine/valganciclovir or rituximab/liposomal doxorubicin). [ Time Frame: 5 years ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
History of the KSHV Inflammatory Cytokine Syndrome (KICS)
Natural History Study of the KSHV Inflammatory Cytokine Syndrome (KICS) Incorporating Pilot Evaluation of KSHV Targeted Therapies

Background:

- KSHV inflammatory cytokine syndrome (KICS) is a newly recognized disease caused by Kaposi sarcoma-associated herpesvirus (KSHV). This virus can cause cancer. People with KICS can have severe symptoms. They include fever, weight loss, and fluid in the legs or abdomen. People with KICS may also be at risk of getting other cancers associated with KSHV. These cancers include Kaposi sarcoma and lymphoma. Because KICS is a newly identified disease, more information is needed on how the disease works and what can be done to treat it.

Objectives:

- To collect genetic and medical information from people with KSHV inflammatory cytokine syndrome.

Eligibility:

- Individuals at least 18 years of age who have Kaposi sarcoma herpes virus and symptoms that resemble those caused by KICS.

Design:

  • Participants will have regular study visits. The schedule will be determined by the study researchers.
  • Participants will provide a complete medical history and have a full physical exam. Blood and urine samples will be collected as well.
  • People with KICS that requires treatment may get new experimental treatments. These treatments may include antiviral drugs and chemotherapy drugs, depending on the nature of the disease.
  • Participants will have imaging studies, such as chest x-rays and computed tomography scans, to study the tumors.
  • Bone marrow and lymph node biopsies may be done to collect tissue samples for study.
  • Participants who have Kaposi sarcoma will have photographs taken of their lesions.

BACKGROUND:

KSHV inflammatory cytokine syndrome (KICS) is a newly recognized syndrome caused by Kaposi sarcoma-associated herpesvirus (KSHV). It is characterized by severe inflammatory symptoms including fevers, wasting, cytopenias, hypoalbuminemia, and hyponatremia, associated in some cases with lymphadenopathy or effusions, without pathological evidence of MCD. Patients with KICS exhibit elevated KSHV viral loads and cytokine dysregulation, with elevations of IL-6, IL-10, and a KSHV-encoded IL-6 homolog, viral IL-6.

OBJECTIVES:

The primary study objective is to enable intensive study and description of the natural history of KICS. Secondary objectives include assessment in affected persons of KSHV viral loads and cytokine levels, evaluation of tissue pathophysiology, exploration of FDG-PET abnormalities, and pilot assessment of response to two therapies: high dose zidovudine/valganciclovir or rituximab/liposomal doxorubicin.

ELIGIBILITY:

Adults of any HIV status with:

  • At least two symptoms, laboratory or radiographic abnormalities which are at least possibly attributable to KICS (including fever, fatigue, cachexia, edema, respiratory or gastrointestinal symptoms, hematologic cytopenias, hypoalbuminemia, hyponatremia, lymphadenopathy,organomegaly, effusions)
  • C-reactive protein > 3mg/dL.
  • Evidence of KSHV infection or a risk exposure for KSHV infection
  • No evidence of KSHV-associated multicentric Castleman disease

Patients with these characteristics will be further evaluated to identify those whose clinical and laboratory features are consistent with the working KICS working case definition to be followed in the natural history phase of the study.

DESIGN:

This is a single center natural history cohort with an observation arm and two nested open label pilot treatment arms, and an accrual ceiling of 40 patients to the overall natural history arm. Natural history patients will undergo clinical, laboratory and correlative assessment every 3 months until sustained resolution. Patients with clinical and laboratory manifestations of KICS, elevated inflammatory markers and KSHV viral load will be eligible for therapy with high dose zidovudine/valganciclovir or, if they have intercurrent KS requiring cytotoxic therapy, rituximab/liposomal doxorubicin. Each treatment arm uses a two stage design, with interim analysis at 8 patients in each arm and potential accrual of 14 per arm.

Interventional
Not Provided
Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • KSHV Inflammatory Cytokine Syndrome (KICS)
  • KSHV
  • HHV-8
  • Drug: Zidovudine/Valgancyclovir
    Zidovudine 600 mg orally 4 times a day/Valgancyclovir 900 mg orally twice a day for 7 to 14 days of a 21 day cycle.
  • Drug: Rituximab/Liposoma Doxorubicin
    Rituximab 375 mg/m2 and Doxil 20 mg/m2 on Day 1 of a 21 day cycle
  • Experimental: Group A
    Treatment
    Intervention: Drug: Zidovudine/Valgancyclovir
  • Experimental: Group B
    Treatment
    Intervention: Drug: Rituximab/Liposoma Doxorubicin
  • No Intervention: Group C
    Observation

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
80
August 2016
August 2016   (final data collection date for primary outcome measure)
  • INCLUSION CRITERIA:
  • Age greater than or equal to18 Years.
  • Any HIV status.
  • At least two manifestations drawn from at least two of the categories (clinical symptoms, laboratory abnormalities and radiographic abnormalities), which are at least possibly attributable to KICS and are not readily explicable from known medical conditions in the patient:
  • Clinical symptoms (each at least grade 1 by CTCAE definitions)
  • Fever (> 38 degrees C), chills or rigors
  • Fatigue or lethargy
  • Cachexia or edema
  • Cough, dyspnea, airway hyperreactivity, or nasal inflammation
  • Nausea, anorexia, abdominal pain or altered bowel habit
  • Athralgia or myalgia
  • Altered mental state
  • Neuropathy with or without pain
  • Laboratory abnormalities
  • Anemia (hemoglobin< 12.0g/dL)
  • Thrombocytopenia (platelets< 100,000 cells/microL)
  • Leukopenia (white cell count< 4,000 cells/microL)
  • Hypoalbuminemia (albumin< 3.5g/dL)
  • Hyponatremia (sodium< 135mmol/L)
  • Coagulopathy (PT or PTT > 1.5 times upper limit of normal)
  • Pathologic lymphadenopathy (at least five discrete nodes each > 1cm in their longest dimension)
  • Splenomegaly (> 12 cm in the longest dimension)
  • Hepatomegaly (> 17cm in the longest dimension)
  • Body cavity effusions not caused by primary effusion lymphoma nor chylous effusions directly related to lymphatic infiltration by KS

    -. C-reactive protein > 3mg/dl.

  • Exposure risk for KSHV infection (including being a first or second generation immigrant from an endemic area, or male-to-male sexual activity) or evidence of KSHV infection demonstrated by one of:

    • Molecular evidence of KSHV in whole blood, confirmed by testing at Focus Laboratories, CA (HHV-8 Quantitative PCR, Focus Unit Code 45700).
    • Immunohistochemical evidence of KSHV in tissues (for example by staining for LANA or vIL-6). Confirmed in the Laboratory of Pathology, CCR, NCI.
    • Presence of KS or PEL (KSHV-associated malignancies), confirmed in the Laboratory of Pathology, CCR, NCI.

EXCLUSION CRITERIA:

  • Biopsy proven KSHV-associated MCD, confirmed in the Laboratory of Pathology, CCR, NCI.
  • Pregnancy
  • Any abnormality that would be scored as NCI CTC Grade 4 toxicity that is unrelated to HIV, its treatment, or to KICS that would preclude the use of all of the study treatments or the ability to monitor the natural history of KICS untreated.
  • Any condition or set of circumstances that in the opinion of the investigators would make participation in this study unsafe or otherwise inappropriate for a given individual.
Both
18 Years and older
No
Contact: Kathleen Wyvill, R.N. (301) 435-5622 wyvillk@mail.nih.gov
Contact: Robert Yarchoan, M.D. (301) 496-0328 robert.yarchoan@nih.gov
United States
 
NCT01419561
110220, 11-C-0220
Not Provided
Not Provided
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Robert Yarchoan, M.D. National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
February 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP