Nelfinavir for the Treatment of Gammaherpesvirus-Related Tumors

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

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

1

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Maryland
      • Baltimore, Maryland, United States, 21287
        • The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Nelfinavir
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 Names:
  • Viracept®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Day 4 and day 5 of Cycle 1

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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
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).
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
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).
Every week up to 2 weeks post-treatment
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.
Within 2 weeks of ending treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Richard Ambinder, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2014

Primary Completion (ACTUAL)

February 1, 2016

Study Completion (ACTUAL)

February 1, 2016

Study Registration Dates

First Submitted

March 4, 2014

First Submitted That Met QC Criteria

March 4, 2014

First Posted (ESTIMATE)

March 6, 2014

Study Record Updates

Last Update Posted (ESTIMATE)

June 10, 2016

Last Update Submitted That Met QC Criteria

June 8, 2016

Last Verified

June 1, 2016

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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