Clinical Trials /

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

NCT00092222

Description:

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. Patients ages 12 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 patients 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 patients 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 patients disease might use more FDG because these cells burn more glucose fuel. Children younger than 18 years will not have PET scan done. 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.

Related Conditions:
  • Multicentric Angiofollicular Lymphoid Hyperplasia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Virotherapy and Natural History Study of KHSV-Associated Multricentric Castleman s Disease With Correlates of Disease Activity
  • Official Title: Targeted Oncolytic Virotherapy and Natural History Study of KSHV-Associated Multicentric Castleman's Disease With Laboratory and Clinical Correlates of Disease Activity

Clinical Trial IDs

  • ORG STUDY ID: 040275
  • SECONDARY ID: 04-C-0275
  • NCT ID: NCT00092222
  • NCT ALIAS: NCT00099073

Conditions

  • Lymphoproliferative Disorder
  • HHV-8
  • Malignancy
  • HIV

Interventions

DrugSynonymsArms
EtoposideActive Treatment 2
Interferon-alphaActive Treatment 4
RituximabActive Treatment 2
ZidovudineActive Treament 3
Liposomal DoxorubicinActive Treatment 4
BortezomibActive Treament 3
ValganciclovirActive Treament 3
DoxorubicinActive Treatment 2
VincristineActive Treatment 2
CyclophosphamideActive Treatment 2
Filgrastim (G-CSF)Active Treatment 2
PrednisoneActive Treatment 2
SirolimusActive Treatment 1

Purpose

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. Patients ages 12 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 patients 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 patients 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 patients disease might use more FDG because these cells burn more glucose fuel. Children younger than 18 years will not have PET scan done. 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.

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 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 patients 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.

        -  To assess disease activity as reflected by fever, thrombocytopenia, anemia, neutropenia,
           and lymphocytopenia, human and viral interleukin-6 levels, C-reactive protein, and KSHV
           viral loads.

        -  To describe how the laboratory pathogenesis-related parameters (especially serum levels
           of human and viral interleukin-6) are related to the clinical and hematologic parameters
           listed.

      Eligibility

        -  Age greater than or equal to 12 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
    

Trial Arms

NameTypeDescriptionInterventions
Active Treament 3Active ComparatorPatients not responding to high- dose zidovudine and valganciclovir alone may be treated with botezomib plus high- dose zidovudine and valganciclovir
  • Zidovudine
  • Bortezomib
  • Valganciclovir
Active Treatment 1Active ComparatorSingle agent sirolimus for patients where targeted oncolytic virotherapy seems suboptimal
  • Sirolimus
Active Treatment 2Active ComparatorEPOCH chemotherapy with rituximab may be utilized to rescue such patients, with the intent of stabilizing suchpatients
  • Etoposide
  • Rituximab
  • Doxorubicin
  • Vincristine
  • Cyclophosphamide
  • Filgrastim (G-CSF)
  • Prednisone
Active Treatment 4Active ComparatorRituximab with liposomal doxorubicin (R-Dox) followed by consolidation or lmaintenancel therapy with dose escalating interferon-alpha
  • Interferon-alpha
  • Rituximab
  • Liposomal Doxorubicin
Active Treatment 5Active ComparatorHigh dose zidovudin and valganciclovir
  • Zidovudine
  • Valganciclovir
Natural HistoryActive ComparatorObservation Only

    Eligibility Criteria

            -  INCLUSION CRITERIA:
    
            Age greater than or equal to 12 years.
    
            Biopsy proven KSHV-associated MCD, confirmed in the Laboratory of Pathology, CCR.
    
            Willing to give informed consent.
    
            -A parent or guardian must be available for giving consent for pediatric subjects under 18
            years of age.
    
            EXCLUSION CRITERIA:
    
            Any abnormality that would be scored as NCI CTC 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.
          
    Maximum Eligible Age:65 Years
    Minimum Eligible Age:12 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Describe natural history
    Time Frame:Study Closure
    Safety Issue:
    Description:Response to treatment

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Trial Keywords

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

    Last Updated

    June 27, 2020