History of the KSHV Inflammatory Cytokine Syndrome (KICS)

  • STATUS
    Recruiting
  • End date
    Dec 31, 2025
  • participants needed
    80
  • sponsor
    National Cancer Institute (NCI)
Updated on 22 September 2021
fever
cancer
edema
lymphoma
doxorubicin
zidovudine
herpes
imaging procedure

Summary

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.

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.

OBJECTIVE

The primary study objective is to enable intensive study and description of the natural history of KICS.

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/L
  • 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 a cohort of up to 80 patients. Of these, up to 40 who meet the criteria for KICS will then go onto a natural history arm, with two nested open label pilot treatment arms. Natural history patients will undergo clinical, laboratory and correlative assessment every 3 months until sustained resolution and two nested open label pilot treatment arms. 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 Kaposi sarcoma (KS) requiring cytotoxic with rituximab/liposomal doxorubicin on the 2 nested open label pilot treatment arms. Each treatment arm uses a two-stage design, with interim analysis at 8 patients in each arm and potential accrual of 14 per arm. Patients on the treatment arm who have not responded to the pilot treatments or for whom such treatment would not be suitable may also be treated with best available therapy. Participants who require KS and/or primary effusion lymphoma (PEL) treatment following a KICS diagnosis will receive therapies within the appropriate arm of the study or be treated for their KS and/or PEL on a separate protocol while still followed on this study.

Details
Condition Kaposi's Sarcoma, human herpesvirus 8, KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), kaposi sarcoma, KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS), KSHV Inflammatory Cytokine Syndrome (KICS)
Treatment Rituximab, Standard of Care, Zidovudine, Liposomal Doxorubicin, Valganiclovir, Standard Therapies
Clinical Study IdentifierNCT01419561
SponsorNational Cancer Institute (NCI)
Last Modified on22 September 2021

Eligibility

Yes No Not Sure

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)
Radiographic Abnormalities
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/L
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) or KSHV viral load levels within circulating peripheral blood mononuclear cells (PBMCs) as determined by the Whitby laboratory
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
Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after the study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

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
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