Safety Study of Nelfinavir + Cisplatin + Pelvic Radiation Therapy to Treat Cervical Cancer

Despite cisplatin chemoradiation, 40-50% of women with locally advanced cervical cancer will
die from their disease. The evaluation of new chemoradiation regimens have since included
cisplatin to further build on its current success. In one year, Nelfinavir will be off
patent and become a potential cost effective therapy. HIV Protease inhibitors are now being
explored as potential therapies in oncology. The repositioning of HIV protease inhibitors,
specifically nelfinavir in cancer therapeutics, is based on three facts. First, recent
studies show that HIV protease inhibitors are established broad-spectrum anti-cancer agents
that work through pleiotropic mechanisms such as by down-regulating activated mitogenic
signaling pathways, and activating the immune response with Nelfinavir being the most potent
[7]. Second, HIV protease inhibitors including nelfinavir can target specific viral
antigens. Nelfinavir has been shown to target Human Papilloma Virus (HPV)-transformed
cervical carcinoma cells via inhibition of E6-mediated proteosomal degradation of mutant p53
[8]. Thirdly, Nelfinavir has radiosensitizing properties through inhibiting the PI3K/Akt
signaling pathway as demonstrated in vivo and in vitro in head and neck and pancreatic
cancers models [9].

Nelfinavir is currently being evaluated as a radiosensitizer in head and neck and pancreatic
cancers in phase I/II clinical trials. Brunner et al. (2008) recently completed the first
phase I trial of nelfinavir added to chemoradiation for locally advanced pancreatic cancer
[16]. Investigators treated 12 patients with advanced pancreatic carcinoma with Nelfinavir
1250 mg orally twice daily starting 3 days before radiation therapy and continued until the
last day of radiation. They found no significant toxicity attributable to nelfinavir and
observed a response rate of 50% versus 30% in historical controls. There were 5 of 12
patients with grade 3 hematologic toxicities (4 with leukopenia and 2 with
thrombocytopenia). There were 3 of 12 patients with grade 3 GI toxicity (including abdominal
pain, nausea, vomiting). There were no grade 4 drug related toxicities [16]. There were
grade 1/ 2 toxicities including hematologic (thrombocytopenia, anemia, neutropenia),
gastrointestinal toxicities (nausea, vomiting, diarrhea, abdominal pain), and elevated
transaminases which were approximately 70%. Ten of 12 patients completed therapy. Complete
responses were observed in 5 patients and partial responses were observed in 5 of 10
patients. Overall, the addition of Nelfinavir added minimal additional toxicity.
Determination of a dose for biologic activity was not performed [14].

In summary, HIV protease inhibitors have a very broad spectrum of anti-tumor activity and
can inhibit proliferation and/or cause death in the majority of cancer cell lines tested in
a dose-dependent manner [7]. Nelfinavir has been found to be the most potent anti-tumor
agent among the HIV protease inhibitors. As a result, several clinical trials are
investigating Nelfinavir as a chemotherapeutic agent with and without concurrent radiation
therapy in varied disease sites including rectal, head & neck, glioblastomas, pancreas,
renal cell, non-small cell lung cancer, liposarcoma, and gliomas. The NCI is also
investigating Nelfinavir as single agent chemotherapy in advanced and recurrent solid tumors
[15].

As Nelfinavir has both cytotoxic and radiation sensitizing effects, it is an ideal agent to
use in combination with cisplatin-based chemoradiation in locally advanced cervical cancers.

In this study, patients with clinical stages IIA, IIB, IIIA, IIIB, IVA cervical carcinoma
limited to the pelvis will receive twice daily oral Nelfinavir (NFV) and weekly IV cisplatin
in combination as radiosensitizers with daily whole pelvic external beam (Mon-Fri) followed
by intracavitary radiation brachytherapy.

Inclusion Criteria:

- All patients with primary, previously untreated, histologically confirmed invasive
carcinoma of the uterine cervix (any cell type). Clinical stages IIA, IIB, IIIA,
IIIB, IVA.

- Patients must have adequate bone marrow, renal and hepatic function:

- ANC ≥ 1,500/μL;

- Platelet count ≥ 100,000/μL;

- Creatinine < 2.0 mg/dL;

- Total Bilirubin ≤ 1.5 times normal;

- SGOT ≤ 3 times normal.

- Patients with a GOG Performance Status of 0, 1, or 2.

- Patients with ureteral obstruction must be treated with stent or nephrostomy tube.

- Patients must be entered within eight weeks of diagnosis.

- Patients of childbearing potential must use an effective form of birth
control."Patients receiving oral contraceptives should be instructed that alternate
or additional contraceptive measures should be used during therapy with VIRACEPT. "

- Seronegative HIV status.

- Patients must be at least 18 years of age.

- Patients must have signed an approved informed consent and authorization permitting
release of personal health information.

Exclusion Criteria:

- Patients with Stage IA, IB or IVB disease.

- Patients who have known metastases to other organs outside the radiation field at the
time of the original clinical and surgical staging.

- Patients who have received previous pelvic or abdominal radiation, cytotoxic
chemotherapy, or previous therapy of any kind for this malignancy.

- Patients with septicemia or severe infection.

- Patients who have circumstances that will not permit completion of this study or the
required follow-up.

- Patients who are pregnant at the time of diagnosis and do not wish pregnancy
termination prior to initiation of treatment.

- Patients with renal abnormalities, such as pelvic kidney, horseshoe kidney, or renal
transplantation, that would require modification of radiation fields.

- Patients with other concomitant malignancies (with the exception of non-melanoma skin
cancer), who had (or have) any evidence of other cancer present within the last 5
years.

- Patients with GI tract disease resulting in an inability to take oral medication,
malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures
affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative
colitis).

- Patients with poorly controlled diabetes mellitus despite medication.

- Patients taking anti-arrhythmic agents such as amiodarone, quinidine, rifampin, ergot
derivatives such as ergotamine, St Johs Wort, HMG-CoA reductase inhibitors such as
lovastatin, neuroleptic such as pimozide, sedatives such as midazolam and triazolam
among other CYP3A4 and CYP2C19 substrates.

- Patients with Phenylketonuria.