Nelfinavir for the Treatment of Gammaherpesvirus-Related Tumors

Study Overview
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Brief Summary
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The goals of this study is to determine if nelfinavir can target Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) in patients with certain cancers.

Detailed Description
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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.

Official Title
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A Pilot Trial of Nelfinavir for the Lytic Activation and Treatment of Gammaherpesvirus-Related Tumors

Conditions
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EBV, Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Kaposi Sarcoma, Gastric Cancer, Nasopharyngeal Cancer, Castleman Disease

Intervention / Treatment
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* Drug: Nelfinavir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nelfinavir<br>Nelfinavir twice daily on days 1-14 of a 14-day cycle for 4 cycles | Drug: Nelfinavir<br>* 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).<br>* Other names: Viracept®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lytic activation of viral gene expression by NFV | 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 | 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 | 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). | Day 4 of Cycle 1, at the end of cycles 1-4, 2 weeks post-treatment, and 4 weeks post-treatment | 
| Tolerability of high-dose nelfinavir | 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 | 
| Tumor regression and response | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EBV, KSHV, lymphoma, sarcoma, virus-associated, malignancy