Trial Information

A Phase I Study of Nab-paclitaxel (Abraxane), Gemcitabine, and Capecitabine (Xeloda) (AGX) in Patients With Previously Untreated, Metastatic Pancreatic Adenocarcinoma

Pancreatic adenocarcinoma (PDAC) represents the fourth leading cause of cancer-related
mortality in the United States, with an estimated 35,240 deaths attributable to PDAC in 2009
(1). Over 90% of patients have inoperable disease at presentation, at which point systemic
therapy becomes the primary form of treatment. Single agent gemcitabine became the standard
of care for advanced pancreatic cancer a decade ago since demonstrating improved survival
when compared with fluorouracil. Since then, a number of phase III trials have evaluated the
benefit of adding additional cytotoxic or targeted agents to gemcitabine (2-17).

The PA.3 trial (15), which led to the approval of erlotinib in advanced pancreatic cancer,
was a landmark study in that it represented the first positive phase III study of a
combination regimen for this disease indication; however, while erlotinib represents both an
important proof of principle and a welcome addition to our therapeutic armamentarium, it has
failed to gain significant traction in this disease, as many in the oncology community
consider the marginal absolute improvement in median overall survival to be of questionable
clinical significance.

While these studies individually have failed to consistently demonstrate a survival
advantage for gemcitabine-based combination therapy, a recent meta-analysis did show that
the addition of either a platinum analog or a fluoropyrimidine to gemcitabine does result in
a significant improvement in overall survival compared to gemcitabine alone, particularly in
patients with a preserved performance status (18). As described in the following section,
the combination of gemcitabine and capecitabine may be a particularly attractive cytotoxic
doublet to build upon.

Gemcitabine/capecitabine for pancreatic cancer

Gemcitabine and capecitabine have demonstrated synergy in pre-clinical studies, thought to
be due to several mechanisms. Capecitabine is converted to fluorouracil in tissues by
pyrimidine nucleoside phosphorylase (PyNPase), which is over-expressed in many tumors (19).
In breast cancer xenograft models, gemcitabine has been shown to cause increased expression
of PyNPase, which may in turn enhance the conversion of capecitabine to 5-FU (20). An
intermediate of gemcitabine also leads to enhanced binding of the active metabolite of 5-FU
to thymidylate synthase, further augmenting the action of capecitabine (21).

Preliminary analysis of one of these studies did show a significant survival benefit with
the combination arm (overall survival 7.4 months versus 6 months; 1 year survival 26% versus
19%); however, final data from this trial have not yet been published (3). A subsequent
phase III Swiss trial did not demonstrate a significant improvement in overall survival with
the combination of gemcitabine/capecitabine as compared to gemcitabine alone; however, a
subset analysis in patients with good performance status (KPS 90-100) did show a significant
survival improvement from 7.4 months to 10.1 months in those who received the combination
regimen (4).

Several strategies may further optimize the dose, schedule, and administration of both
gemcitabine and capecitabine. First, delivery of gemcitabine at a fixed-dose rate infusion
(FDR) (10 mg/m2/min) maximizes the intracellular accumulation of the triphosphate form of
this drug. This approach has been evaluated in both a randomized phase II and a phase III
cooperative group trial (ECOG 6201), with some suggestion of benefit compared to
standard-infusion gemcitabine given over 30 minutes (9, 22). Second, administering
capecitabine in a biweekly fashion (7 days on followed by 7 days off) rather than in the
standard 2-week on, 1-week off fashion may allow for dose intensification without increasing
toxicity (23, 24) (see also Part E. below).

The GTX Regimen

The addition of a taxane to gemcitabine/capecitabine has previously been evaluated in the
so-called GTX regimen (fixed-dose rate gemcitabine, docetaxel, capecitabine) (26). Studies
of GTX in advanced pancreatic cancer patients (26, 27) and locally advanced unresectable
disease (28) have revealed encouraging efficacy data.

Abraxane (nab-paclitaxel)

Abraxane (nab-paclitaxel, nanoparticle albumin-bound paclitaxel; formerly ABI-007) is a
Cremophor® EL-free, albumin-bound form of paclitaxel with a mean particle size of
approximately 130 nanometers. This composition provides a novel approach of increasing
intra-tumoral concentrations of the drug by a receptor-mediated transport process allowing
transcytosis across the endothelial cell.

Preclinical studies comparing Abraxane to Taxol (paclitaxel Cremophor EL solvent-based, BMS)
demonstrated lower toxicities, with an MTD approximately 50% higher for Abraxane compared to
Taxol. At equal doses there was less myelosuppression and improved efficacy in a xenograft
tumor model of human mammary adenocarcinoma. At equitoxic doses of paclitaxel, Abraxane was
found to be markedly more efficacious than Taxol (29).

The current FDA-approved indication of Abraxane is for the treatment of breast cancer after
failure of combination chemotherapy for metastatic disease or relapse within 6 months of
adjuvant chemotherapy (prior therapy should have included an anthracycline unless clinically
contraindicated).

Our choice of nab-paclitaxel for this proposal is based on provocative preclinical and
clinical data suggesting efficacy of the agent in pancreatic cancer. Specifically, binding
of nab-paclitaxel by an albumin specific receptor (gp60) leads to subsequent activation of a
protein caveolin-1, which mediates internalization of the compound into the endothelial cell
and transport through the bloodstream to the tumor interstitium. SPARC (Secreted Protein And
Rich in Cysteine), a tumor-secreted protein, binds albumin, releasing the active drug at the
tumor cell membrane, thereby increasing its concentration at the target site of action.
SPARC is known to be over-expressed in pancreatic cancers, leading to an interest in
studying nab-paclitaxel in this disease.

The combination of nab-paclitaxel and gemcitabine in advanced pancreatic cancer demonstrated
very promising results in a phase I/II study (31). In that study, the maximum tolerated dose
of nab-paclitaxel when given concurrently with gemcitabine was 125 mg/m2, both agents
administered weekly x 3 of 4. This same combination of nab-paclitaxel (125 mg/m2) and
gemcitabine (1000 mg/m2) was also shown to be well tolerated in a phase II trial in
metastatic breast cancer (32), with both agents administered on a 2-week-on, 1-week-off
schedule. Of note, the pivotal study upon which nab-paclitaxel was approved for use in
breast cancer used a dose of 260 mg/m2, as a single agent, on an every 3 week schedule.

The doses of nab-paclitaxel to be tested in our proposed dose-escalation trial, when
combined with gemcitabine and capecitabine using an alternating-week dose schedule, will
range between 75 and 150 mg/m2.