- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02080416
Nelfinavir for the Treatment of Gammaherpesvirus-Related Tumors
A Pilot Trial of Nelfinavir for the Lytic Activation and Treatment of Gammaherpesvirus-Related Tumors
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) are gammaherpesviruses that are associated with a variety of human cancers, including a subset of lymphomas, carcinomas, and sarcomas. In tumors the virus typically exists in a latent state. In latently infected cells, the vast majority of viral genes are not expressed and there is little to no production of infectious virions. The virus replicates in tandem with cell division using cellular machinery. This highly restricted pattern of gene expression allows the virus to evade immune recognition and clearance.
Currently, the treatment approach to virally-associated malignancies is no different than the treatment approach to the same tumors where there is no viral association. Yet, the presence of virus within these tumors offers an opportunity to develop virus-specific, targeted therapies in these diseases. Such therapies might not only be more effective but also less toxic. EBV- and KSHV-associated cancers are more common in patients with HIV, congenital immunodeficiencies, or other immunosuppression, such as transplant recipients. These patients in particular would benefit from more targeted treatment approaches to their malignancies, potentially sparing the toxicities of cytotoxic chemotherapy in an already immunocompromised patient population.
Activation of lytic gene expression in virally-infected tumors may enhance tumor-specific cell killing through multiple mechanisms. Importantly, the cytotoxic effects of antiviral nucleoside analogues, such as acyclovir and its cogeners, depend on the activity of viral kinases which are only expressed during lytic replication. Because EBV(+) or KSHV(+) tumors are characterized by latent viral infection, these antiviral drugs as a single agent are not active in these tumors. However, if lytic gene expression could be activated in virally-associated tumors, this could render EBV(+) and KSHV(+) tumor cells susceptible to killing by antiviral nucleoside analogues.
Nelfinavir (NFV), an FDA-approved protease inhibitor for the treatment of HIV, has been shown to be a potent activator of lytic gene expression of EBV(+) and KSHV(+) cancer cell lines. Furthermore, NFV is able to activate lytic gene expression of EBV and KSHV at drug levels that are achievable in humans. There is also growing evidence that NFV has antitumor activity.
The goals of this study is to determine if NFV activates lytic gene expression in the tumors and causes tumor regression in patients with EBV(+) or KSHV(+) cancers.
Study Type
Enrollment (Actual)
Phase
- Early Phase 1
Contacts and Locations
Study Locations
-
-
Maryland
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Baltimore, Maryland, United States, 21287
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age 18 years or older
- Biopsy proven EBV(+) or KSHV(+) malignancy
- Relapsed/refractory disease failing > 2 prior therapies
- Measurable, non-bony disease (at least one lesion on radiographic or physical exam assessment measuring > 2 cm in longest axis)
- KS patients with skin-only disease must have cutaneous lesions amenable to four 3 mm punch biopsies during the course of the study
- Eastern Cooperative Oncology Group (ECOG) performance status < 2
- Life expectancy of greater than 12 weeks
- Patients must be able to lie flat for at least 60 minutes and fit on a PET-CT scanner
- Ability to comply with an oral drug regimen
- Females of childbearing potential must have a negative pregnancy test at screening
- Patients must have normal organ and marrow function as defined below within 14 days of study entry
Exclusion Criteria:
- Patients with HIV-associated primary central nervous system lymphoma
- Radiotherapy or chemotherapy ending within 14 days of study enrollment
- Patients currently on other protease inhibitors
- Chronic diarrhea
- Acute, active infection within 14 days of enrollment
- Patients on active treatment for hypo- or hyperthyroidism
- End-stage liver disease unrelated to tumor
- Hepatitis B or hepatitis C infection
- Use of any other type of investigational agent or treatment concurrently or within 28 days before the first dose of study treatment
- History of iodine hypersensitivity
- Females who are pregnant or breastfeeding
- Physical or psychiatric conditions that in the estimation of the investigator place the patient at high risk of toxicity, non-compliance, or inability to complete the study requirements
- Use of drugs to treat or prevent herpesvirus infections
- Essential medication that is known to interact with nelfinavir
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NA
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Nelfinavir
Nelfinavir twice daily on days 1-14 of a 14-day cycle for 4 cycles
|
Nelfinavir will be given 3000 mg orally twice daily on days 1-14 of a 14-day cycle.
NFV will be continued in patients tolerating therapy for 4 cycles (8 weeks).
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Lytic activation of viral gene expression by NFV
Time Frame: Day 4 and day 5 of Cycle 1
|
To determine if NFV activates lytic gene expression in the tumors of patients with EBV(+) or KSHV(+) cancers, as evidenced by the ability to image the tumor with [124I]fialuridine-PET-CT.
|
Day 4 and day 5 of Cycle 1
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Serial assessment of methylation of viral DNA
Time Frame: Day 4 of Cycle 1, at the end of cycles 1-4, 2 weeks post-treatment, and 4 weeks post-treatment
|
The methylation of viral DNA in plasma at baseline and during the course of NFV therapy and follow-up will be determined for each patient.
|
Day 4 of Cycle 1, at the end of cycles 1-4, 2 weeks post-treatment, and 4 weeks post-treatment
|
Serial assessment of viral copy number in plasma
Time Frame: Day 4 of Cycle 1, at the end of cycles 1-4, 2 weeks post-treatment, and 4 weeks post-treatment
|
Viral DNA copy number in plasma at baseline and during the course of NFV therapy and follow-up will be determined for each patient by quantitative polymerase chain reaction assay (qPCR).
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Day 4 of Cycle 1, at the end of cycles 1-4, 2 weeks post-treatment, and 4 weeks post-treatment
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Tolerability of high-dose nelfinavir
Time Frame: Every week up to 2 weeks post-treatment
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The tolerability of high-dose NFV in patients with relapsed/refractory EBV(+) or KSHV(+) tumors will be determined by evaluation of dose limiting toxicities (DLT).
|
Every week up to 2 weeks post-treatment
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Tumor regression and response
Time Frame: Within 2 weeks of ending treatment
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The responses of EBV(+) and KSHV(+) tumors after 4 cycles of NFV therapy will be assessed by CT for solid tumors, CT or PET-CT for lymphomas and lymphoproliferative disorders, and skin exam with lesion measurements for KS.
|
Within 2 weeks of ending treatment
|
Collaborators and Investigators
Investigators
- Principal Investigator: Richard Ambinder, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Virus Diseases
- Infections
- Immune System Diseases
- Neoplasms, Connective and Soft Tissue
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Immunoproliferative Disorders
- Neoplasms by Site
- Carcinoma
- Neoplasms, Glandular and Epithelial
- Pharyngeal Neoplasms
- Otorhinolaryngologic Neoplasms
- Head and Neck Neoplasms
- Nasopharyngeal Diseases
- Pharyngeal Diseases
- Stomatognathic Diseases
- Otorhinolaryngologic Diseases
- DNA Virus Infections
- Herpesviridae Infections
- Neoplasms, Vascular Tissue
- Sarcoma
- Lymphoma
- Nasopharyngeal Carcinoma
- Nasopharyngeal Neoplasms
- Castleman Disease
- Sarcoma, Kaposi
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Enzyme Inhibitors
- Anti-HIV Agents
- Anti-Retroviral Agents
- Protease Inhibitors
- HIV Protease Inhibitors
- Viral Protease Inhibitors
- Nelfinavir
Other Study ID Numbers
- J13174
- NA_00092477 (OTHER: Johns Hopkins IRB)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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