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Clinical Trials

MainTitle

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

This study is currently recruiting participants. (see Contacts and Locations)

Verified September 20, 2017 by National Cancer Institute (NCI)

Sponsor
National Cancer Institute (NCI)


Information provided by (Responsible Party)
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier
NCT00092222

First received: September 21, 2004
Last updated: October 18, 2017
Last Verified: September 20, 2017
History of Changes
Purpose

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.

Condition Intervention Phase
Lymphoproliferative Disorder
HHV-8
Malignancy
HIV

Drug : Etoposide
Drug : Interferon-alpha
Drug : Rituximab
Drug : Zidovudine
Drug : Liposomal Doxorubicin
Drug : Bortezomib
Drug : Valganciclovir
Drug : Doxorubicin
Drug : Vincristine
Drug : Cyclophosphamide
Drug : Filgrastim (G-CSF)
Drug : Prednisone
Drug : Sirolimus
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Targeted Oncolytic Virotherapy and Natural History Study of KSHV-Associated Multicentric Castleman's Disease With Laboratory and Clinical Correlates of Disease Activity

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures

  • Describe natural history [ Time Frame: Study Closure ]
Secondary Outcome Measures:
  • Therapeutic efficacy and toxicity of several rationally designed therapeutic approaches to KSHV-MCD [ Time Frame: 21 days ]

Estimated Enrollment: 55
Study Start Date: September 20, 2004
Estimated Study Completion Date: October 1, 2020
Estimated Primary Completion Date: October 1, 2018 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Active Comparator: A
Treatment with rituximab and liposomal doxorubicin for patients where targeted oncolytic virotherapy seems suboptimal
Drug: Zidovudine

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)

Drug: Valganciclovir

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 Comparator: B
Single agent sirolimus for patients where targeted oncolytic virotherapy seems suboptimal
Drug: Sirolimus

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

Active Comparator: C
EPOCH chemotherapy with rituximab may be utilized to rescue such patients, with the intent of stabilizing such patients
Drug: Etoposide

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.

Drug: Rituximab

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.

Drug: Doxorubicin

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

Drug: Vincristine

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

Drug: Cyclophosphamide

Cyclophosphamide: if CD4 < 100 cells/mm3, 187 mg/m2 IV (Day 5) if CD4 (Bullet) 100 cells/mm3, 375 mg/m2 IV (Day 5) of 21 day cycle.

Drug: Filgrastim (G-CSF)

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)

Drug: Prednisone

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

Active Comparator: D
Patients not responding to high-dose zidovudine and valganciclovir alone may be treated with botezomib plus high-dose zidovudine and valganciclovir
Drug: Zidovudine

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)

Drug: Bortezomib

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

Drug: Valganciclovir

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 Comparator: E
Rituximab with liposomal doxorubicin (R-Dox) followed by consolidation or maintenance therapy with dose escalating interferon-alpha
Drug: Interferon-alpha

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

Drug: Rituximab

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.

Drug: Liposomal Doxorubicin

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.

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
    mab with EPOCH chemotherapy

    Eligibility

    Eligibility

    Ages Eligible for Study: 12 Years to 65 Years  
    Sexes Eligible for Study: All  
    Accepts Healthy Volunteers: No  

    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.
      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.

    contacts and locations

    Contacts and Locations

    Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

    Please refer to this study by its ClinicalTrials.gov identifier: NCT00092222

    Contacts

    Contact:   Karen Aleman, R.N. (301) 435-5621 alemank@mail.nih.gov
    Contact:   Robert Yarchoan, M.D. (240) 760-6075 robert.yarchoan@nih.gov

    Locations

    United States, Maryland
    National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
    Bethesda, Maryland, United States, 20892
    Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937

    Sponsors and Collaborators

    National Cancer Institute (NCI)

    Investigators

    Principal Investigator: Robert Yarchoan, M.D. National Cancer Institute (NCI)
    More Information

    More Information

    Additional Information:

    NIH Clinical Center Detailed Web Page

    Responsible Party: National Cancer Institute (NCI)  
    ClinicalTrials.gov Identifier: NCT00092222   History of Changes  
    Other Study ID Numbers: 040275  
      04-C-0275  
    Study First Received: September 21, 2004  
    Last Updated: October 18, 2017  

    Keywords provided by National Institutes of Health Clinical Center (CC):

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

    Additional relevant MeSH terms:
    Neoplasms
    Lymphoproliferative Disorders
    Cyclophosphamide
    Sirolimus
    Everolimus
    Rituximab
    Liposomal doxorubicin
    Etoposide phosphate
    Doxorubicin
    Interferons
    Prednisone
    Bortezomib
    Etoposide
    Vincristine
    Interferon-alpha
    Lenograstim
    Zidovudine
    Valganciclovir
    Ganciclovir

    ClinicalTrials.gov processed this data on October 23, 2017
    This information is provided by ClinicalTrials.gov.