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
  Purpose

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.

Condition Intervention
KSHV Inflammatory Cytokine Syndrome (KICS)
KSHV
HHV-8
Drug: Zidovudine/Valgancyclovir
Drug: Rituximab/Liposoma Doxorubicin

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Natural History Study of the KSHV Inflammatory Cytokine Syndrome (KICS) Incorporating Pilot Evaluation of KSHV Targeted Therapies

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 80
Study Start Date: August 2011
Estimated Study Completion Date: August 2016
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A
Treatment
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.
Experimental: Group B
Treatment
Drug: Rituximab/Liposoma Doxorubicin
Rituximab 375 mg/m2 and Doxil 20 mg/m2 on Day 1 of a 21 day cycle
No Intervention: Group C
Observation

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01419561

Contacts
Contact: Kathleen Wyvill, R.N. (301) 435-5622 wyvillk@mail.nih.gov
Contact: Robert Yarchoan, M.D. (301) 496-0328 robert.yarchoan@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Robert Yarchoan, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT01419561     History of Changes
Other Study ID Numbers: 110220, 11-C-0220
Study First Received: August 17, 2011
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
KSHV
KICS
HIV
Cytokines
HHV-8
KSHV Inflammatory Cytokine Syndrome
Kaposi Sarcoma Heres Virus

Additional relevant MeSH terms:
Syndrome
Disease
Pathologic Processes
Rituximab
Zidovudine
Valganciclovir
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Anti-HIV Agents

ClinicalTrials.gov processed this record on October 02, 2014