Nelfinavir for the Treatment of Gammaherpesvirus-Related Tumors

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified March 2014 by Sidney Kimmel Comprehensive Cancer Center
Sponsor:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT02080416
First received: March 4, 2014
Last updated: NA
Last verified: March 2014
History: No changes posted
  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.


Condition Intervention Phase
Non-Hodgkin Lymphoma
Hodgkin Lymphoma
Kaposi Sarcoma
Gastric Cancer
Nasopharyngeal Cancer
EBV
Castleman Disease
Drug: Nelfinavir
Phase 0

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
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

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • Lytic activation of viral gene expression by NFV [ Time Frame: Day 4 and day 5 of Cycle 1 ] [ Designated as safety issue: No ]
    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:
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 10
Study Start Date: July 2014
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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®

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.

Nelfinair (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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02080416

Contacts
Contact: Jennifer Kanakry, MD 410-502-0882 jenkanakry@jhmi.edu

Locations
United States, Maryland
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Not yet recruiting
Baltimore, Maryland, United States, 21287
Contact: Jennifer Kanakry, MD    410-502-0882    jenkanakry@jhmi.edu   
Principal Investigator: Jennifer Kanakry, MD         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Investigators
Principal Investigator: Jennifer Kanakry, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  More Information

No publications provided

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT02080416     History of Changes
Other Study ID Numbers: J13174, NA_00092477
Study First Received: March 4, 2014
Last Updated: March 4, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
EBV
KSHV
malignancy
lymphoma
sarcoma
virus-associated

Additional relevant MeSH terms:
Giant Lymph Node Hyperplasia
Sarcoma
Lymphoma, Non-Hodgkin
Hodgkin Disease
Stomach Neoplasms
Lymphoma
Sarcoma, Kaposi
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Neoplasms, Vascular Tissue
Nelfinavir
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 30, 2014