Lymphoproliferative DisorderPhase 2NCT00092222
Virotherapy and Natural History Study of KHSV-Associated Multricentric Castleman s Disease With Correlates of Disease Activity
A Phase 2 study testing Etoposide, Interferon-alpha and Rituximab in people with Lymphoproliferative Disorder and HHV-8, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 120 years
- Conditions the study is for
- Lymphoproliferative Disorder, HHV-8, Malignancy
- What is being tested?
- Etoposide, Interferon-alpha and Rituximab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 75 participants
- Where
- 1 siteUnited States
- Study dates
- 28 Oct 2004to 1 Oct 2028
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 120 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Official title: Targeted Oncolytic Virotherapy and Natural History Study of KSHV-Associated Multicentric Castleman's Disease With Laboratory and Clinical Correlates of Disease Activity
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.
Read more
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.
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Read the detailed description
Background:
- Multicentric Castleman's disease (MCD) is a rare but lethal Kaposi's sarcoma-associated herpesvirus (KSHV) associated lymphoproliferative disorder with a median survival of 2 years. It occurs more often in HIV-infected individuals than those without HIV infection. The poor prognosis is not fully explained by the underlying HIV, as the HIV-negative cases appear to have no survival advantage over the HIV-positive cohort. The disease has no defined standard treatment and has not been prospectively studied in a comprehensive manner.
- KSHV-MCD may provide a model for the development of targeted oncolytic virotherapy or other pathogenesis-based approaches to viral-associated malignancies. In KSHV-MCD, viral encoded kinase genes appear to be possible targets to exploit in a virotherapy approach. Specific viral encoded genes appear to convert zidovudine and ganciclovir (or valganciclovir) into toxic phosphorylated moieties within the KSHV-infected tumor cells, to specifically target the KSHV-infected cells thus leading to specific cell death. If successful, this could have direct therapeutic benefit to participants and also provide a model for further development of this approach in other tumors.
Objectives
-To study and describe the natural history of KSHV-MCD.
Eligibility
- Age >= 18 years
- Biopsy proven KSHV-associated MCD
Design
- Natural History study
- Inclusion of treatment as needed, with guidelines for preliminary investigation of a variety of specific treatments of interest
- High-dose zidovudine and ganciclovir
- High-dose zidovudine and ganciclovir and bortezomib
- Sirolimus
- Rituximab with liposomal doxorubicin followed by interferon-alpha or high-dose AZT with valganciclovir
- Rituximab with EPOCH chemotherapy
- Conditions
- Lymphoproliferative Disorder, HHV-8, Malignancy, HIV
- Being tested
- Etoposide, Interferon-alpha, Rituximab, Zidovudine, Liposomal Doxorubicin
- Keywords
- HHV-8, HIV, Malignancy, Lymphoproliferation, Lymph Node Hyperplasia, Multicentric Castleman DIsease, MCD, KSHV-MCD, KSHV Associated MCD, HIV Infections, Herpes Viruses
- Medical subject headings
- Lymphoproliferative Disorders, Neoplasms, Lymphadenopathy, Multi-centric Castleman's Disease, Macular dystrophy, corneal type 1, HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EtoposideDrug
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.
Interferon-alphaDrug
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
RituximabDrug
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.
ZidovudineDrug
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)
Liposomal DoxorubicinDrug
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.
BortezomibDrug
1.3 mg/m2 IV days 1, 4, 8, and 11. Cycle length is 21 days.
ValganciclovirDrug
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
DoxorubicinDrug
10 mg/m2 /day CIVI over 24 hours x 4 days (days 1-4) of 21 day cycle.
VincristineDrug
0.4 mg/m2 /day CIVI over 24 hours x 4 days (days 1-4) of 21 day cycle.
CyclophosphamideDrug
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.
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)
PrednisoneDrug
Prednisone 60 mg/m2/day PO x 5 days (days 1-5)of 21 day cycle.
SirolimusDrug
Maximum daily dose of 40 mg given as a single agent on 21 day cycle.
Observation OnlyOther
Observation of symptoms
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Drug: Zidovudine; Drug: Bortezomib; Drug: Valganciclovir |
| Active Treatment 1 | Active comparator | Single agent sirolimus for patients where targeted oncolytic virotherapy seems suboptimal Receives: Drug: Sirolimus |
| Active Treatment 2 | Active comparator | EPOCH chemotherapy with rituximab may be utilized to rescue such patients, with the intent of stabilizing suchpatients Receives: 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 Receives: Drug: Interferon-alpha; Drug: Rituximab; Drug: Liposomal Doxorubicin |
| Active Treatment 5 | Active comparator | High dose zidovudin and valganciclovir Receives: Drug: Zidovudine; Drug: Valganciclovir |
| Natural History | Active comparator | Observation Only Receives: Other: Observation Only |
What is being measured
The primary outcome is the main question the study is designed to answer.
Describe natural history
Response to treatment
Measured: Study Closure
Secondary outcomes (2)
overall survival
percentage of patients alive until study closure
Measured: Study Closure
Number of flares
Quantify the number of flares requiring treatment in patients enrolled in this study
Measured: Study closure
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Sep 2004 (estimated)
- Study start28 Oct 2004
- Primary completion1 Oct 2028 (estimated)
- Study completion1 Oct 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for Lymphoproliferative DisorderStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 75 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Robert Yarchoan, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00092222
- Sponsor's protocol ID
- 040275
- Other IDs
- 04-C-0275
- Status last verified
- 15 Oct 2026
- First submitted
- 21 Sep 2004
- Last updated
- 23 Oct 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 10979949Gaidano 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.
PubMed 9129084Oksenhendler 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.
PubMed 8924253Mercado Matos J, Marshall VA, Cornejo Castro EM, Miley WJ, Labo N, Roshan R, Ekwede I, Widell A, Agwu I, Namubiru M, Witterholt M, Yarchoan R, Lurain K, Whitby D, Ramaswami R. Kaposi Sarcoma Herpesvirus (KSHV) Subtypes and Impact on Outcomes in KSHV-Associated Diseases. J Infect Dis. 2026 Sep 23;234(3):e572-e582. doi: 10.1093/infdis/jiag168.
PubMed 41845569Lage 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.
PubMed 38941593Ramaswami 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.
PubMed 33720337Uldrick 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.
PubMed 25331113Polizzotto 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.
PubMed 24174627Uldrick 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.
PubMed 21487108