Clinical trial NCT02080416: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: EARLY_PHASE1
Conditions: Non-Hodgkin Lymphoma
Hodgkin Lymphoma
Kaposi Sarcoma
Gastric Cancer
Nasopharyngeal Cancer
EBV
Castleman Disease
Keywords: EBV
KSHV
malignancy
lymphoma
sarcoma
virus-associated
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
First posted: 2014-03-06
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

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

Primary outcomes:
measure: Lytic activation of viral gene expression by NFV
timeFrame: Day 4 and day 5 of Cycle 1
Secondary outcomes:
measure: Serial assessment of methylation of viral DNA
timeFrame: Day 4 of Cycle 1, at the end of cycles 1-4, 2 weeks post-treatment, and 4 weeks post-treatment
measure: Serial assessment of viral copy number in plasma
timeFrame: Day 4 of Cycle 1, at the end of cycles 1-4, 2 weeks post-treatment, and 4 weeks post-treatment
measure: Tolerability of high-dose nelfinavir
timeFrame: Every week up to 2 weeks post-treatment
measure: Tumor regression and response
timeFrame: Within 2 weeks of ending treatment
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
Study officials:
affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Richard Ambinder, MD
role: PRINCIPAL_INVESTIGATOR
References: