Virotherapy and Natural History Study of KHSV-Associated Multricentric Castleman s Disease With Correlates of Disease Activity
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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 Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: 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 |
- Describe natural history [ Time Frame: Study Closure ] [ Designated as safety issue: No ]
- Therapeutic efficacy and toxicity of several rationally designed therapeutic approaches to KSHV-MCD [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
| Estimated Enrollment: | 55 |
| Study Start Date: | September 2004 |
| Estimated Study Completion Date: | October 2020 |
| Estimated Primary Completion Date: | October 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
- Rituximab with EPOCH chemotherapy
Eligibility| Ages Eligible for Study: | 12 Years to 65 Years (Child, Adult) |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
- 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 LocationsPlease refer to this study by its ClinicalTrials.gov identifier: NCT00092222
| Contact: Karen Aleman, R.N. | (301) 435-5621 | alemank@mail.nih.gov | |
| Contact: Robert Yarchoan, M.D. | (301) 496-0328 | robert.yarchoan@nih.gov |
| 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 | |
| Principal Investigator: | Robert Yarchoan, M.D. | National Cancer Institute (NCI) |
More Information
Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT00092222 History of Changes |
| Obsolete Identifiers: | NCT00099073 |
| Other Study ID Numbers: | 040275 04-C-0275 |
| Study First Received: | September 21, 2004 |
| Last Updated: | September 27, 2016 |
| Health Authority: | United States: Federal Government |
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 Giant Lymph Node Hyperplasia Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Cyclophosphamide Sirolimus Everolimus Rituximab Liposomal doxorubicin Etoposide phosphate Doxorubicin Interferons Prednisone |
Bortezomib Etoposide Vincristine Interferon-alpha Lenograstim Zidovudine Valganciclovir Ganciclovir Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action |
ClinicalTrials.gov processed this record on September 28, 2016