Trial Information

Phase 1 Study of Nelfinavir Added to Cisplatin Chemotherapy Concurrent With Pelvic Radiation for Locally Advanced Cervical Cancer (II-IVA)

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.