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Unicentric Castleman Disease

Multicentric Castleman Disease

Antineoplastic Agents

All Drugs and Chemicals

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Anti-Infective Agents

Etoposide

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

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Vincristine

Lenograstim

Bortezomib

Sirolimus

Etoposide phosphate

Valganciclovir

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Ganciclovir

Ganciclovir triphosphate

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Alkylating Agents

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Clotrimazole

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Reverse Transcriptase Inhibitors

Anti-HIV Agents

Anti-Retroviral Agents

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

Single agent sirolimus for patients where targeted oncolytic virotherapy seems suboptimal

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

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

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.

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

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.

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)

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.

Liposomal Doxorubicin

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

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

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

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

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 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)

Filgrastim (G-CSF)

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

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

Observation Only

Robert Yarchoan, M.D.

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 , 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 , 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 , 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.

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 tyrosine 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 greater than or equal to 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
  * Rituximab with EPOCH chemotherapy

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

Targeted Oncolytic Virotherapy and Natural History Study of KSHV-Associated Multicentric Castleman's Disease With Laboratory and Clinical Correlates of Disease Activity

percentage of patients alive until study closure

Quantify the number of flares requiring treatment in patients enrolled in this study

National Cancer Institute (NCI)

Musculoskeletal Diseases

Nervous System Diseases

Syndrome

Fatigue

Epstein-Barr Virus Infections

Fatigue Syndrome, Chronic

Muscular Diseases

Encephalomyelitis

Neuroinflammatory Diseases

Neuromuscular Diseases

Chronic Disease

Disease Attributes

Herpesviridae Infections

DNA Virus Infections

Tumor Virus Infections

Chronic Graft Versus Host Disease

Antibodies

Immunoglobulins

valganciclovir

Jose G Montoya, MD

The purpose of this study determine whether the drug valganciclovir has a significant and real benefit on the central core of symptoms experienced by patients who have high titers to EBV and HHV-6 and are experiencing long-standing fatigue and cognitive impairment (CFS).

In addition, to characterize a quantifiable biological marker in these patients that will facilitate the identification of those likely to respond to valganciclovir and will make it possible to assess response to treatment.

Chronic fatigue syndrome (CFS) is a clinically defined condition characterized by severe disabling fatigue and a combination of symptoms that prominently features self-reported impairment of concentration and short-term memory, sleep disturbances, and musculoskeletal pain. Prevalence of CFS in the adult population is estimated to be 0.007% to 2.8%. No pathognomonic signs or diagnostic tests for this condition have been yet validated in scientific studies; in addition, no definitive treatments are clinically available. Suggested etiologies of CFS include, but are not limited to: viral or bacterial infections, endocrine-metabolic dysfunction, immunological imbalance, neurally-mediated hypotension and depressioN. EBV and HHV-6 are among the viruses frequently thought as associated with CFS.

We recently encountered a group of patients at Stanford who were chronically infected with human herpes virus 6 (HHV-6) and Epstein-Barr virus (EBV), were suffering from debilitating fatigue for at least one year and experienced a significant improvement in their fatigue and cognitive symptoms following the administration of valganciclovir. Their antibody titers to both viruses were high (median antibody titer for EBV viral capsid antigen was 1:2560 and for HHV-6 IgG was 1:1280) despite the fact that some of them were known to have been infected with EBV and HHV-6 for several years. We suspected that their symptoms could be the result of an immune dysregulation triggered by high levels of replication of both EBV and HHV-6 (alterations in the immune system such as an aberrant cytokine profiles have been proposed as the central abnormality in patients with CFS associated with other viruses such as parvovirus B19. At the same time, we were familiar using valganciclovir in the context of several clinical settings including its known indications for reactivation of viral infections in immunocompromised patients. We were comfortable using valganciclovir (900 mg bid for three weeks followed by 900 mg qd to complete 3 to 12 months of treatment) in patients with solid and bone marrow transplants, cancer or other immunosuppressive disorders who had developed CMV, EBV, or HHV-6 disease.

We hypothesized that a long course (i.e. 6 months) of valganciclovir could effectively decrease or stop ongoing viral replication of both EBV and HHV-6 and that this virological effect could be translated in a clinical and laboratory benefit (i.e. decrease or resolution of lymphadenopathy, reversion of the CD4/CD8 ratio abnormalities). We were surprised to see that a dramatic recovery on the level of physical activity was also observed in the Stanford patients (from a median of 10% of energy level for daily activities at baseline to 90% after valganciclovir use). Of note, the drug has also been tried in patients in whom an improvement on their level of physical activity has not been observed. The total number of patients treated today is 30, 26 had "elevated titers" and 4 had "low titers". Of the 26 patients with "elevated titers", 25 have had a dramatic recovery. Of the 4 patients with "low titers", none have responded.

We believe that our successful experience with valganciclovir in a subset of patients with CFS at Stanford calls for a prospective study to exclude a placebo effect. We propose to measure viral, immunologic, and genomic endpoints to assess whether there are objective and measurable changes in these parameters and whether they correlate with clinical improvement. Clinical improvement will be assessed by objective measurements of daily physical and psychological activities. This will help to elucidate the possible role of HHV-6, EBV (or a yet to be known virus) and/or an altered immune system as triggers for the symptoms experienced by patients suffering CFS and to establish whether the drug valganciclovir does reverse these abnormalities. This study may also shed light on a biomarker or profile of biomarkers associated with (or diagnostic of) CFS.

We will be executing a randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of valganciclovir in patients experiencing chronic fatigue syndrome with elevated antibody titres against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV)

Objectives

1. To determine whether the drug valganciclovir has a significant and real benefit on the central core of symptoms experienced by patients who have high titers to EBV and HHV-6 and are experiencing long-standing fatigue and cognitive impairment (CFS).
2. To characterize a quantifiable biological marker in these patients that will facilitate the identification of those likely to respond to valganciclovir and will make it possible to assess response to treatment.

Design of the study A double-blind, placebo-controlled, randomized clinical trial. All patients will be given the active drug (20 patients) or placebo (10 patients) for 6 months and followed for an additional 3 months. Patients on the placebo arm will take a valganciclovir look-alike tablet that does not contain the active drug for the initial six month period. Subsequently these patients will be offered a 6 month trial of valganciclovir if at the end of the study (when the last enrolled patient reaches 9 months from initiating therapy) it is clear that there is a benefit of valganciclovir therapy and patients have not spontaneously improved.

Kogelnik A, Rosso F, Hoegh-Petersen M and Montoya JG. Use of Valganciclovir in Patients Chronically Co-infected with Human Herpes Virus 6 (HHV-6) and Epstein-Barr Virus (EBV) who were Experiencing Long-standing Fatigue. J Clin Virol 2006 Volume 37, Supplement 1 S33-S38

Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM and Bruce IN. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome. Clin Infect Dis 2003;36:e100-6

Valganciclovir (Valcyte) for Chronic Fatigue Syndrome Patients Who Have Elevated Antibody Titers Against Human Herpes Virus 6 (HHV-6)and Epstein-Barr Virus (EBV)

A Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Efficacy and Safety of Valganciclovir (Valcyte) in Patients Experiencing Chronic Fatigue Syndrome With Elevated Antibody Titers Against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV)

Stanford University

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 , 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 , 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 , 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.

...

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Virotherapy and Natural History Study of KHSV-Associated Multricentric Castleman s Disease With Correlates of Disease Activity	NCT00092222	Lymphoprolifera... HHV-8 Malignancy HIV	Etoposide Interferon-alph... Rituximab Zidovudine Liposomal Doxor... Bortezomib Valganciclovir Doxorubicin Vincristine Cyclophosphamid... Filgrastim (G-C... Prednisone Sirolimus Observation Onl...	18 Years -	National Institutes of Health Clinical Center (CC)
Valganciclovir (Valcyte) for Chronic Fatigue Syndrome Patients Who Have Elevated Antibody Titers Against Human Herpes Virus 6 (HHV-6)and Epstein-Barr Virus (EBV)	NCT00478465	Chronic Fatigue...	valganciclovir	18 Years -	Stanford University
Virotherapy and Natural History Study of KHSV-Associated Multricentric Castleman s Disease With Correlates of Disease Activity	NCT00092222	Lymphoprolifera... HHV-8 Malignancy HIV	Etoposide Interferon-alph... Rituximab Zidovudine Liposomal Doxor... Bortezomib Valganciclovir Doxorubicin Vincristine Cyclophosphamid... Filgrastim (G-C... Prednisone Sirolimus Observation Onl...	18 Years -	National Institutes of Health Clinical Center (CC)

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