Virotherapy and Natural History Study of KHSV-Associated Multricentric Castleman s Disease With Correlates of Disease Activity
| Status: | Recruiting |
|---|---|
| Conditions: | Cancer, HIV / AIDS, Lymphoma, Hematology |
| Therapuetic Areas: | Hematology, Immunology / Infectious Diseases, Oncology |
| Healthy: | No |
| Age Range: | 12 - 65 |
| Updated: | 1/10/2019 |
| Start Date: | October 28, 2004 |
| End Date: | October 1, 2020 |
| Contact: | Matthew R Lindsley, R.N. |
| Email: | matthew.lindsley@nih.gov |
| Phone: | (240) 760-6534 |
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.
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.
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.
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
- 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
- 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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: (888) NCI-1937
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