Virotherapy and Natural History Study of KHSV-Associated Multricentric Castleman s Disease With Correlates of Disease Activity

NCT00092222 | Active Not Recruiting Phase 2

• 2 other identifiers: 04027504-C-0275
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

Brief Summary

This study will gain information about a rare disorder called KSHV-associated multicentric Castleman's disease (MCD). KSHV, a virus, causes several kinds of cancer, including some forms of MCD. KSHV stands for the Kaposi's sarcoma herpes virus, also called human herpes virus-8, or HHV-8. Researchers want to understand the biology of KSHV-MCD to identify how this disease causes illness and to find ways to treat it. There is no standard therapy effective for all cases of KSHV-MCD. The disease is often fatal, and about half the people who have it die within 2 years of diagnosis. Participants ages 18 and older may be eligible for this study. Participation entails more drawing of blood and having repeated tumor biopsies than if patients received treatment in a non-research setting. Researchers would like to learn more about the relationship of KSHV and Castleman's disease symptoms, and they want to obtain at least three biopsies in this study. There are some side effects of experimental therapy that participants may take for KSHV-MCD. Zidovudine, or Retrovir(R), is used at a high dose. It is given orally or through a vein, four times daily, for 7 days or longer. Zidovudine can cause nausea, vomiting, decreased bone marrow function, and decreased blood counts. Combined with valganciclovir, or Valcyte(TM), it is likely to be more toxic to bone marrow. Valganciclovir can cause problems with bone marrow function, leading to low blood counts, sterility, and defects in a fetus. Combined with zidovudine, valganciclovir may cause more toxicity to the bone marrow. It is given twice daily for 7 days or longer. Bortezomib, or Velcade(TM), is given for a few seconds by a rapid push through a needle into the vein. It is given twice weekly for four doses and then stopped for 1 week. Bortezomib can sometimes cause low blood pressure; it also can cause gastrointestinal problems and a low blood platelet count. Rituximab and liposomal doxorubicin are drugs given by a catheter into a vein. Interferon-alpha is given by injection into the skin. Those drugs are not experimental, but their use in Castleman's disease is experimental. Some participants may be treated with a combination of chemotherapy followed by interferon-alpha. Interferon-alpha is infected into the skin by a needle. The natural form of interferon is produced by the body and helps to control viral infections. KSHV decreases the effect of the body's interferon, and the researchers want to see if giving higher doses of interferon will help to control KSHV infection. A positron emission tomography (PET) scan, for research purposes only, may be done up to three times a year. A radioactive sugar molecule called fluorodeoxyglucose, or FDG, is used. It is believed that activated lymphocytes that may be found in participants' disease might use more FDG because these cells burn more glucose fuel. This study may or may not have a direct benefit for participants. However, detailed assessments made throughout the study may provide information to help the doctors treat KSHV-MCD better. ...

Conditions

HHV-8; Malignancy; HIV; Lymphoproliferative Disorder

Keywords

HHV-8; HIV; Malignancy; Lymphoproliferation; Lymph Node Hyperplasia; Multicentric Castleman DIsease; MCD; KSHV-MCD; KSHV Associated MCD; HIV Infections; Herpes Viruses

Outcome Measures

Primary Outcomes (1)

• Describe natural history

  Response to treatment

  Study Closure

Secondary Outcomes (2)

• overall survival

  Study Closure

• Number of flares

  Study closure

Study Arms (6)

Active Treament 3

ACTIVE COMPARATOR

Patients not responding to high- dose zidovudine and valganciclovir alone may be treated with botezomib plus high- dose zidovudine and valganciclovir

Drug: Zidovudine; Drug: Bortezomib; Drug: Valganciclovir

Active Treatment 1

ACTIVE COMPARATOR

Single agent sirolimus for patients where targeted oncolytic virotherapy seems suboptimal

Drug: Sirolimus

Active Treatment 2

ACTIVE COMPARATOR

EPOCH chemotherapy with rituximab may be utilized to rescue such patients, with the intent of stabilizing suchpatients

Drug: Etoposide; Drug: Rituximab; Drug: Doxorubicin; Drug: Vincristine; Drug: Cyclophosphamide; Drug: Filgrastim (G-CSF); Drug: Prednisone

Active Treatment 4

ACTIVE COMPARATOR

Rituximab with liposomal doxorubicin (R-Dox) followed by consolidation or lmaintenancel therapy with dose escalating interferon-alpha

Drug: Interferon-alpha; Drug: Rituximab; Drug: Liposomal Doxorubicin

Active Treatment 5

ACTIVE COMPARATOR

High dose zidovudin and valganciclovir

Drug: Zidovudine; Drug: Valganciclovir

Natural History

ACTIVE COMPARATOR

Observation Only

Other: Observation Only

Interventions

Etoposide DRUG

Etoposide 50 mg/m2 /day continuous intravenous infusion (CIVI) over 24 hours x 4 days (days 1-4) of 21 day cycle. A maximum of 6 cycles of R-EPOCH-R will be administered except in exceptional circumstances.

Active Treatment 2

Interferon-alpha DRUG

Ages 18 and over: Initial dose of 7.5 million units subcutaneous, three times weekly x 14 days; subsequent dosesincrease dose as tolerated each 14 days to a maximum of 45 million units subcutaneous three times weekly; Ages 12-17: Initial dose of 5 million units/m2 subcutaneous, three times weekly x 14 days Subsequent doses: Increase dose as tolerated each 14 days to a maximum of 30 million units/m2 subcutaneous, three times weekly

Active Treatment 4

Rituximab DRUG

Rituximab 375 mg/m2 IV day 1, shall be administered prior to Doxil injection. When combined with EPOCH chemotherapy, Rituximab will be given on days 1 and 5.

Active Treatment 2; Active Treatment 4

Zidovudine DRUG

Cycle 1: Zidovudine 600 mg PO QID x 7-21 days in outpatient setting;600 mg PO q6hours x 7-21 (Intravenous zidovudine 300 mg q 6 hours may be substituted) days for inpatients; Cycle 2 and beyond: 600 mg PO QID x 7 days in outpatient setting; 600 mg PO q 6 hours x 7 days (300 mg q 6 hours may be substituted)

Active Treament 3; Active Treatment 5

Liposomal Doxorubicin DRUG

21 day cycle; 20 mg/m2 Liposomal Doxorubicin given on day 1 and shall be administered after completion of Rituximab infusion from 2 to 6 cycles.

Active Treatment 4

Bortezomib DRUG

1.3 mg/m2 IV days 1, 4, 8, and 11. Cycle length is 21 days.

Active Treament 3

Valganciclovir DRUG

Cycle 1: Valganciclovir 900 mg PO BID x 7-21 days in outpatient setting; 900 mg PO q 12 hours x 7-21 days for inpatients; Cycle 2 and beyond: 900 mg PO BID x 7 days for outpatients; 900 mg PO q 12 hours x 7 days (Intravenous ganciclovir 5 mg/kg may be substituted) for inpatients

Active Treament 3; Active Treatment 5

Doxorubicin DRUG

10 mg/m2 /day CIVI over 24 hours x 4 days (days 1-4) of 21 day cycle.

Active Treatment 2

Vincristine DRUG

0.4 mg/m2 /day CIVI over 24 hours x 4 days (days 1-4) of 21 day cycle.

Active Treatment 2

Cyclophosphamide DRUG

Cyclophosphamide: if CD4 \< 100 cells/mm3, 187 mg/m2 IV (Day 5) if CD4 greater than or equal to 100 cells/mm3, 375 mg/m2 IV (Day 5) of 21 day cycle.

Active Treatment 2

Prednisone DRUG

Prednisone 60 mg/m2/day PO x 5 days (days 1-5)of 21 day cycle.

Active Treatment 2

Sirolimus DRUG

Maximum daily dose of 40 mg given as a single agent on 21 day cycle.

Active Treatment 1

Observation Only OTHER

Observation of symptoms

Natural History

Filgrastim (G-CSF) DRUG

Filgrastim 300 micrograms subcutaneous daily beginning day 6 until absolute neutrophil count recovery 5000 cells/mm3 (Pegfilgrastim may be substituted with PI approval, at the recommended dose of one 6mg syringe)

Active Treatment 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age greater than or equal to 18 years.
• Biopsy proven KSHV-associated MCD, confirmed in the Laboratory of Pathology, CCR.
• Willing to give informed consent.

You may not qualify if:

• Any abnormality that would be scored as NCI CTCAE v 3.0 Grade IV toxicity that is unrelated to HIV, its treatment, or to MCD that would preclude protocol treatment and/or observation only.
• Presence of another malignancy requiring current treatment that would preclude the use of all of the study treatments or the ability to monitor the natural history of MCD untreated.
• Pregnant women are excluded from this study as certain of the study agents have the potential for teratogenic effects
• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (8)

• Oksenhendler E, Carcelain G, Aoki Y, Boulanger E, Maillard A, Clauvel JP, Agbalika F. High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric castleman disease in HIV-infected patients. Blood. 2000 Sep 15;96(6):2069-73.

  PMID: 10979949 BACKGROUND

• Gaidano G, Capello D, Pastore C, Antinori A, Gloghini A, Carbone A, Larocca LM, Saglio G. Analysis of human herpesvirus type 8 infection in AIDS-related and AIDS-unrelated primary central nervous system lymphoma. J Infect Dis. 1997 May;175(5):1193-7. doi: 10.1086/593456.

  PMID: 9129084 BACKGROUND

• Oksenhendler E, Duarte M, Soulier J, Cacoub P, Welker Y, Cadranel J, Cazals-Hatem D, Autran B, Clauvel JP, Raphael M. Multicentric Castleman's disease in HIV infection: a clinical and pathological study of 20 patients. AIDS. 1996 Jan;10(1):61-7.

  PMID: 8924253 BACKGROUND

• Lage SL, Ramaswami R, Rocco JM, Rupert A, Davis DA, Lurain K, Manion M, Whitby D, Yarchoan R, Sereti I. Inflammasome activation in patients with Kaposi sarcoma herpesvirus-associated diseases. Blood. 2024 Oct 3;144(14):1496-1507. doi: 10.1182/blood.2024024144.

  PMID: 38941593 DERIVED

• Ramaswami R, Lurain K, Polizzotto MN, Ekwede I, Waldon K, Steinberg SM, Mangusan R, Widell A, Rupert A, George J, Goncalves PH, Marshall VA, Whitby D, Wang HW, Pittaluga S, Jaffe ES, Little RF, Uldrick TS, Yarchoan R. Characteristics and outcomes of KSHV-associated multicentric Castleman disease with or without other KSHV diseases. Blood Adv. 2021 Mar 23;5(6):1660-1670. doi: 10.1182/bloodadvances.2020004058.

  PMID: 33720337 DERIVED

• Uldrick TS, Polizzotto MN, Aleman K, Wyvill KM, Marshall V, Whitby D, Wang V, Pittaluga S, O'Mahony D, Steinberg SM, Little RF, Yarchoan R. Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease. Blood. 2014 Dec 4;124(24):3544-52. doi: 10.1182/blood-2014-07-586800. Epub 2014 Oct 20.

  PMID: 25331113 DERIVED

• Polizzotto MN, Uldrick TS, Wang V, Aleman K, Wyvill KM, Marshall V, Pittaluga S, O'Mahony D, Whitby D, Tosato G, Steinberg SM, Little RF, Yarchoan R. Human and viral interleukin-6 and other cytokines in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. Blood. 2013 Dec 19;122(26):4189-98. doi: 10.1182/blood-2013-08-519959. Epub 2013 Oct 30.

  PMID: 24174627 DERIVED

• Uldrick TS, Polizzotto MN, Aleman K, O'Mahony D, Wyvill KM, Wang V, Marshall V, Pittaluga S, Steinberg SM, Tosato G, Whitby D, Little RF, Yarchoan R. High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy. Blood. 2011 Jun 30;117(26):6977-86. doi: 10.1182/blood-2010-11-317610. Epub 2011 Apr 12.

  PMID: 21487108 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphoproliferative Disorders; Neoplasms; Lymphadenopathy; Multi-centric Castleman's Disease; Macular dystrophy, corneal type 1; HIV Infections

Interventions

Etoposide; Interferon-alpha; Rituximab; Zidovudine; liposomal doxorubicin; Bortezomib; Valganciclovir; Doxorubicin; Vincristine; Cyclophosphamide; Filgrastim; Granulocyte Colony-Stimulating Factor; Prednisone; Sirolimus

Condition Hierarchy (Ancestors)

Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes

Intervention Hierarchy (Ancestors)

Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Interferon Type I; Interferons; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dideoxynucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Ganciclovir; Acyclovir; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Daunorubicin; Anthracyclines; Naphthacenes; Aminoglycosides; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Indolizidines; Indolizines; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Hematopoietic Cell Growth Factors; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Macrolides; Lactones

Study Officials

• Robert Yarchoan, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 21, 2004
• First Posted: September 22, 2004
• Study Start: October 28, 2004
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026
• Last Updated: April 14, 2026

Record last verified: 2026-02-23

Locations

US (1)