Nelfinavir for the Treatment of Gammaherpesvirus-Related Tumors
Early Phase 1
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Pilot Trial of Nelfinavir for the Lytic Activation and Treatment of Gammaherpesvirus-Related Tumors|
- 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.
- 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.
- 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).
- Tolerability of high-dose nelfinavir [ Time Frame: Every week up to 2 weeks post-treatment ]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).
- Tumor regression and response [ Time Frame: Within 2 weeks of ending treatment ]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.
|Study Start Date:||July 2014|
|Study Completion Date:||February 2016|
|Primary Completion Date:||February 2016 (Final data collection date for primary outcome measure)|
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 Name: Viracept®
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02080416
|United States, Maryland|
|The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins|
|Baltimore, Maryland, United States, 21287|
|Principal Investigator:||Richard Ambinder, MD||The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins|