A randomized, double-blind phase 3 study of gemcitabine plus AG-013736 versus gemcitabine plus placebo for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer

Pancreatic cancer is diagnosed in over 30,000 people in the United States each
year and ranks as the fourth leading cause of cancer death in the United States
with an overall survival (OS) rate of <4%. The highest cure rate occurs if
the tumor is truly localized to the pancreas; however, this stage of disease
accounts for fewer than 20% of cases. For those patients with localized
disease and small tumors (<2 cm) with no lymph node metastases and no extension
beyond the capsule of the pancreas, complete surgical resection can yield
actuarial 5 year survival rates of 18 24%. For patients with advanced
cancers, the OS rate of all stages is <1% at 5 years with most patients dying
within 1 year. Compare the overall survival of patients receiving gemcitabine
plus AG 013736 versus gemcitabine plus placebo is the main objective in this
clincial trial.


On 21 January 2009 the safety and efficacy data were reviewed by an external,
independent Data Monitoring Committee (DMC) and recommended stopping the study
because adding AG-013736 to gemcitabine did not offer any advantage over
gemcitabine alone.The DMC concluded that it was futile to continue the study.
Amendment 5 contains a revised schedule of activities, instructions to
investigators regardin unblinding patients, a description of how patients may
continue to access AG-013736 (in an unblinded fashion and if deemed
appropriate) and patient follow-up (including safety reporting).

Primary Objective: Compare the overall survival (OS) of patients receiving
gemcitabine plus AG-013736 versus gemcitabine plus placebo.
Secondary Objectives: 1. Compare the progression free survival (PFS) of
patients in each arm;2. Compare the objective response rate (ORR) of patients
in each arm;3. Estimate the duration of response (DR) of patients in each arm;
4. Evaluate the safety and tolerability of AG-013736 plus gemcitabine;
5.Compare the health-related quality of life (HRQOL), pain ratings, and health
status of patients in each arm; 6. Conduct population pharmacokinetic analysis
using AG-013736 plasma concentrations.

This is a 2-arm, randomized, double-blind, multi-center Phase 3 study of
gemcitabine plus AG-013736 versus gemcitabine plus placebo in patients with
chemotherapy-naïve advanced pancreatic cancer. Five hundred and ninety-six
(596) patients will be randomized in a 1:1 ration between gemcitabine plus
AG-013736 versus gemcitabine plus placebo. Randomization will be stratified by
extent of disease (metastatic vs locally advanced). Overall survival will be
the primary endpoint. Patients will have tumor assessments performed
approximately every 8. Crossover of patients from one arom to the other will
not be allowed.

No additional invasive interventions are needed as archived tumor samples,
taken in pre-study period, will be used.

Weekly visits to hospital

- Efficacy assessments (baseline tumor assessment followed by 8-weekly tumor
assessments)
- Physical exam
- Blood pressure assessments (daily home BP measurements)
- Urinalysis (monthly)
- Hematology
- Clinical Chemistry (bi-weekly)
- AG-013736/Placebo population pharmacokinetics assessments - monthly
- Pharmacogenomics for Drug metabolizing Enzymes including UGT1A1 (whole-blood)
- once at baseline
- Patient reported outcomes (monthly - 4 Quesionnaires: EORTC QLQ-C30;
QLQ-PAN26; Brief Pain Inventory-Short Form; EQ-5D)

Dose interruption and reductions schedules are foreseen in protocol for adverse
events with specific dose reductions rules provided for hypertension,
hemoptysis and proteinuria.(protocol p 33)