Clinical Trials /

Nelfinavir for the Treatment of Gammaherpesvirus-Related Tumors

NCT02080416

Description:

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.

Related Conditions:
  • Cancer
Recruiting Status:

Terminated

Phase:

Early Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Nelfinavir</span> for the Treatment of Gammaherpesvirus-Related Tumors

Title

  • Brief Title: Nelfinavir for the Treatment of Gammaherpesvirus-Related Tumors
  • Official Title: A Pilot Trial of Nelfinavir for the Lytic Activation and Treatment of Gammaherpesvirus-Related Tumors
  • Clinical Trial IDs

    NCT ID: NCT02080416

    ORG ID: J13174

    NCI ID: NA_00092477

    Trial Conditions

    Non-Hodgkin Lymphoma

    Hodgkin Lymphoma

    Kaposi Sarcoma

    Gastric Cancer

    Nasopharyngeal Cancer

    EBV

    Castleman Disease

    Trial Interventions

    Drug Synonyms Arms
    Nelfinavir Viracept Nelfinavir

    Trial Purpose

    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

    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.

    Trial Arms

    Name Type Description Interventions
    Nelfinavir Experimental Nelfinavir twice daily on days 1-14 of a 14-day cycle for 4 cycles Nelfinavir

    Eligibility Criteria

    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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Lytic activation of viral gene expression by NFV

    Secondary Outcome Measures

    Serial assessment of methylation of viral DNA

    Serial assessment of viral copy number in plasma

    Tolerability of high-dose nelfinavir

    Tumor regression and response

    Trial Keywords

    EBV

    KSHV

    malignancy

    lymphoma

    sarcoma

    virus-associated