Nelfinavir and Concurrent Radiation and Temozolomide in Patients With WHO Grade IV Glioma
Current therapy for GBM GBM is the most frequent primary malignant brain tumor in adults.
Prior to the introduction of temozolomide, the median survival was generally less than one
year from the time of diagnosis. Standard therapy had consisted of surgical resection to the
extent safely feasible, followed by radiotherapy. Adjuvant carmustine, a nitrosourea drug,
was commonly prescribed in the United States. Cooperative-group trials had investigated the
addition of various chemotherapeutic regimens to radiotherapy but no randomized phase 3
trial of nitrosourea-based adjuvant chemotherapy had demonstrated a significant survival
benefit as compared with radiotherapy alone. A metaanalysis based on randomized trials
suggested a small survival benefit of chemotherapy, as compared with Template Version: 7 May
2008 IRB APPLICATION page 1 of 8 radiotherapy alone (a 5 percent increase in survival at two
years, from 15 percent to 20 percent). To further improve on these survival rates, the
European Organization for Research and Treatment of Cancer (EORTC) Brain Tumor and
Radiotherapy Groups, and the National Cancer Institute of Canada (NCIC) Clinical Trials
Group completed a randomized, multicenter, phase III trial to compare the alkylating agent
temozolomide and radiotherapy with radiotherapy alone in patients with newly diagnosed
glioblastoma.  A total of 573 patients from 85 centers underwent randomization. At a
median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus
temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death
in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52
to 0.75; P0.001 by the log-rank test). The two-year survival rate was 26.5 percent with
radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant
treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic
effects in only 7 percent of patients.
Due to this landmark study, GBM patients who have a good performance status are now
typically treated with concurrent radiation and temozolomide followed by adjuvant
temozolomide. However, this standard therapy still only results in a median survival of
about 14.6 months and a progression-free survival of about 6.9 months. Given these low
survival rates, new approaches are needed. The addition of a molecularly-targeted therapy to
the standard treatment is an approach that merits further investigation.
GBM, Molecular Markers, and Radiosensitization In GBM, PTEN mutations occur in about a third
of patients while EGFR or EGFRvIII (truncated EGFR) amplification occurs in up to 40% of
patients. These changes have been shown to correlate with a poor prognosis. Over the past
decade EGFR and Ras have been shown to modulate tumor radiosensitivity. EGFR has a number of
downstream effectors that include Ras and PI3K. EGFR and Ras-mediated radioresistance is
mediated, at least in part by PI3K, and phosphorylated Akt (P-Akt) is a good marker for this
effect . We have previously shown in head and neck cancer that P-Akt is a good predictor of
clinical response to radiation. We and others have shown that blocking PI3K-Akt pathway
enhances radiation response in vitro and in vivo. Radiosensitization occurs in cells in
which this pathway is constitutively activated but does not occur in cells (such as normal
tissues) in which this pathway is not activated. Inhibition of this pathway, therefore, is a
promising approach for radiation sensitization. One difficulty in implementing this
therapeutic strategy has been obtaining the means to block this deregulated signaling
pathway in patients.
We have found that one class of commonly used drugs, the HIV protease inhibitors (HPIs)
interfere with PI3K-Akt signaling. These drugs given in combination with reverse
transcriptase inhibitors are the mainstay of the current therapeutic regimens for HIV
infected patients. The HPIs are peptidomimetics that inhibit the HIV aspartyl protease, a
retroviral enzyme that cleaves the viral gag-pol polyprotein and is necessary for the
production of infectious viral particles. One prominent side effect of HPI treatment is
insulin resistance. Since Akt, plays a key role in the coordinated regulation of growth and
metabolism by the insulin/IGFsignaling pathway, we explored the possibility that HPIs might
block the PI3K-Akt signaling axis in tumor cells and hence might be used clinically as
radiation sensitizers. We tested NFV and found that it inhibited Akt at concentrations that
are routinely achieved in patients. NFV also sensitized tumor cells both in vitro and in
vivo to radiation. HPIs have been used continuously in patients with well-characterized
pharmacokinetics. There are reports of HIV patients on protease inhibitors who have received
radiation therapy; no increase in side effects from the radiation have been reported and
clinical outcome may be improved.
In summary, there is clearly strong rationale to proceed with a clinical trial of NFV and
chemoradiation in GBM:
1. The prognosis in GBM patients is poor with median survival of 14.6 months with best
2. Preclinical work demonstrates NFV results in down regulation of Akt signaling in cancer
cells and results in radiation sensitization.
3. There is a high frequency of Akt activation in GBM, which has been linked to the
pathogenesis and maintenance of the tumor.
4. NFV has been shown to be distributed brain tissue while on therapy and is likely to
have increased brain penetrance during fractionated radiotherapy when disruption of the
blood-brain-barrier may occur.
5. NFV has not been shown to sensitize normal tissues to radiation.
6. NFV has been safely administered to HIV+ patients over the last decade with minimal
To determine the safety, dose-limiting toxicities, and maximally tolerated dose of NFV concurrently with radiation and temozolomide.
United States: Institutional Review Board
|Abramson Cancer Center of the University of Pennsylvania||Philadelphia, Pennsylvania 19104-4283|