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Nelfinavir for the Treatment of Gammaherpesvirus-Related Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02080416
Recruitment Status : Terminated (Very slow accrual; terminated to allow resources to be utilized more effectively on other studies. No data analysis completed, nor any conclusions reached.)
First Posted : March 6, 2014
Last Update Posted : June 10, 2016
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Non-Hodgkin Lymphoma Hodgkin Lymphoma Kaposi Sarcoma Gastric Cancer Nasopharyngeal Cancer EBV Castleman Disease Drug: Nelfinavir Early Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Trial of Nelfinavir for the Lytic Activation and Treatment of Gammaherpesvirus-Related Tumors
Study Start Date : July 2014
Actual Primary Completion Date : February 2016
Actual Study Completion Date : February 2016

Arm Intervention/treatment
Experimental: Nelfinavir
Nelfinavir twice daily on days 1-14 of a 14-day cycle for 4 cycles
Drug: Nelfinavir
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®

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. 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.

  2. 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).

  3. 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).

  4. 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02080416

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United States, Maryland
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
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Principal Investigator: Richard Ambinder, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Identifier: NCT02080416    
Other Study ID Numbers: J13174
NA_00092477 ( Other Identifier: Johns Hopkins IRB )
First Posted: March 6, 2014    Key Record Dates
Last Update Posted: June 10, 2016
Last Verified: June 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Study terminated; no data analysis completed
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
Additional relevant MeSH terms:
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Sarcoma, Kaposi
Nasopharyngeal Neoplasms
Nasopharyngeal Carcinoma
Castleman Disease
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Connective and Soft Tissue
Neoplasms by Site
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Neoplasms, Vascular Tissue
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Head and Neck Neoplasms
Nasopharyngeal Diseases
Pharyngeal Diseases
Stomatognathic Diseases
Otorhinolaryngologic Diseases
Neoplasms, Glandular and Epithelial
HIV Protease Inhibitors