Nelfinavir for the Treatment of Gammaherpesvirus-Related Tumors

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.

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