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History of the KSHV Inflammatory Cytokine Syndrome (KICS)

Primary Purpose

KSHV Inflammatory Cytokine Syndrome (KICS), KSHV, HHV-8

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Zidovudine

Liposomal Doxorubicin

Valganiclovir

Rituximab

Standard Therapies

About this trial

This is an interventional treatment trial for KSHV Inflammatory Cytokine Syndrome (KICS) focused on measuring KSHV, KICS, HIV, Cytokines, HHV-8

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

National Institutes of Health Clinical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

No Intervention

Experimental

Other

Arm Label

Arm Description

Evaluation for Alternative Causes of KICS Symptoms

Natural History/Observation Arm

High dose zidovudine + valganciclovir

Rituximab with or without liposomal doxorubicin

Standard and alternative rational therapies

Outcomes

Primary Outcome Measures

Natural history of KICS

Description of the natural history of KICS, including the spectrum of clinical, laboratory and radiographic abnormalities seen in affected patients

Secondary Outcome Measures

Full Information

NCT ID

NCT01419561

First Posted

August 17, 2011

Last Updated

August 23, 2023

Sponsor

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT01419561

Brief Title

History of the KSHV Inflammatory Cytokine Syndrome (KICS)

Official Title

Natural History Study of the KSHV Inflammatory Cytokine Syndrome (KICS) Incorporating Pilot Evaluation of KSHV Targeted Therapies

Study Type

Interventional

2. Study Status

Record Verification Date

July 24, 2023

Overall Recruitment Status

Recruiting

Study Start Date

September 8, 2011 (Actual)

Primary Completion Date

December 31, 2028 (Anticipated)

Study Completion Date

December 31, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief 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.

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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

KSHV Inflammatory Cytokine Syndrome (KICS), KSHV, HHV-8

Keywords

KSHV, KICS, HIV, Cytokines, HHV-8

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

No Intervention

Arm Description

Evaluation for Alternative Causes of KICS Symptoms

Arm Title

Arm Type

No Intervention

Arm Description

Natural History/Observation Arm

Arm Title

Arm Type

Experimental

Arm Description

High dose zidovudine + valganciclovir

Arm Title

Arm Type

Experimental

Arm Description

Rituximab with or without liposomal doxorubicin

Arm Title

Arm Type

Other

Arm Description

Standard and alternative rational therapies

Intervention Type

Drug

Intervention Name(s)

Zidovudine

Intervention Description

Zidovudine 600 mg will be administered orally 4 times a day or i.v. at 300 mg every 6 hours for 14 days for cycle 1 and for 7 days (up to additional 7 days if ongoing symptoms) for following cycles.

Intervention Type

Drug

Intervention Name(s)

Liposomal Doxorubicin

Intervention Description

Liposomal doxorubicin (20 mg/m2) will be administered i.v. over 1 hour at day 1 of each cycle

Intervention Type

Drug

Intervention Name(s)

Valganiclovir

Intervention Description

Valganciclovir (900mg) will be administered orally twice/day or Ganciclovir (5 mg/kg) will be administered i.v. over 1 hour for 14 days for cycle 1 and for 7 days (up to additional 7 days if ongoing symptoms) for following cycles.

Intervention Type

Drug

Intervention Name(s)

Rituximab

Intervention Description

Rituximab (375 mg/m2) will be admnistered i.v. at 50 mg/hr up to 100 mg/hr at day 1 of the first cycle and at 100mg/hr up to 400 mg /hr at day 1 of following cycles.

Intervention Type

Other

Intervention Name(s)

Standard Therapies

Intervention Description

Standard of Care drugs

Primary Outcome Measure Information:

Title

Natural history of KICS

Description

Description of the natural history of KICS, including the spectrum of clinical, laboratory and radiographic abnormalities seen in affected patients

Time Frame

one year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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) 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Anaida Widell

Phone

(240) 760-6074

anaida.widell@nih.gov

First Name & Middle Initial & Last Name or Official Title & Degree

Robert Yarchoan, M.D.

Phone

(240) 760-6075

robert.yarchoan@nih.gov

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Robert Yarchoan, M.D.

Organizational Affiliation

National Cancer Institute (NCI)

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

Individual Site Status

Recruiting

12. IPD Sharing Statement

Citations:

PubMed Identifier

7997879

Citation

Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994 Dec 16;266(5192):1865-9. doi: 10.1126/science.7997879.

Results Reference

background

PubMed Identifier

8523568

Citation

Moore PS, Gao SJ, Dominguez G, Cesarman E, Lungu O, Knowles DM, Garber R, Pellett PE, McGeoch DJ, Chang Y. Primary characterization of a herpesvirus agent associated with Kaposi's sarcomae. J Virol. 1996 Jan;70(1):549-58. doi: 10.1128/JVI.70.1.549-558.1996. Erratum In: J Virol 1996 Dec;70(12):9083.

Results Reference

background

PubMed Identifier

15012001

Citation

Viejo-Borbolla A, Schulz TF. Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8): key aspects of epidemiology and pathogenesis. AIDS Rev. 2003 Oct-Dec;5(4):222-9.

Results Reference

background

Links:

URL

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2011-C-0220.html

Description

NIH Clinical Center Detailed Web Page

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History of the KSHV Inflammatory Cytokine Syndrome (KICS)

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