Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00092222
Recruitment Status : Recruiting
First Posted : September 22, 2004
Last Update Posted : November 3, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE September 21, 2004
First Posted Date  ICMJE September 22, 2004
Last Update Posted Date November 3, 2021
Actual Study Start Date  ICMJE October 28, 2004
Estimated Primary Completion Date October 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 18, 2018)
Describe natural history [ Time Frame: Study Closure ]
Response to treatment
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 2, 2021)
  • overall survival [ Time Frame: Study Closure ]
    percentage of patients alive until study closure
  • Number of flares [ Time Frame: Study closure ]
    Quantify the number of flares requiring treatment in patients enrolled in this study
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Virotherapy and Natural History Study of KHSV-Associated Multricentric Castleman s Disease With Correlates of Disease Activity
Official Title  ICMJE Targeted Oncolytic Virotherapy and Natural History Study of KSHV-Associated Multicentric Castleman's Disease With Laboratory and Clinical Correlates of Disease Activity
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 , 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.

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 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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Lymphoproliferative Disorder
  • HHV-8
  • Malignancy
  • HIV
Intervention  ICMJE
  • 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: 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: 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: 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.
  • 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
  • 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 greater than or equal to 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.
  • Drug: Sirolimus
    Maximum daily dose of 40 mg given as a single agent on 21 day cycle.
  • Other: Observation Only
    Observation of symptoms
Study Arms  ICMJE
  • Active Comparator: Active Treament 3
    Patients not responding to high- dose zidovudine and valganciclovir alone may be treated with botezomib plus high- dose zidovudine and valganciclovir
    Interventions:
    • Drug: Zidovudine
    • Drug: Bortezomib
    • Drug: Valganciclovir
  • Active Comparator: Active Treatment 1
    Single agent sirolimus for patients where targeted oncolytic virotherapy seems suboptimal
    Intervention: Drug: Sirolimus
  • Active Comparator: Active Treatment 2
    EPOCH chemotherapy with rituximab may be utilized to rescue such patients, with the intent of stabilizing suchpatients
    Interventions:
    • Drug: Etoposide
    • Drug: Rituximab
    • Drug: Doxorubicin
    • Drug: Vincristine
    • Drug: Cyclophosphamide
    • Drug: Filgrastim (G-CSF)
    • Drug: Prednisone
  • Active Comparator: Active Treatment 4
    Rituximab with liposomal doxorubicin (R-Dox) followed by consolidation or lmaintenancel therapy with dose escalating interferon-alpha
    Interventions:
    • Drug: Interferon-alpha
    • Drug: Rituximab
    • Drug: Liposomal Doxorubicin
  • Active Comparator: Active Treatment 5
    High dose zidovudin and valganciclovir
    Interventions:
    • Drug: Zidovudine
    • Drug: Valganciclovir
  • Active Comparator: Natural History
    Observation Only
    Intervention: Other: Observation Only
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 2, 2021)
80
Original Enrollment  ICMJE
 (submitted: June 23, 2005)
30
Estimated Study Completion Date  ICMJE October 1, 2025
Estimated Primary Completion Date October 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

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.

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Irene Ekwede, R.N. (240) 760-6126 ekwedeib@mail.nih.gov
Contact: Robert Yarchoan, M.D. (240) 760-6075 robert.yarchoan@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00092222
Other Study ID Numbers  ICMJE 040275
04-C-0275
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Robert Yarchoan, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date August 31, 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP