AZD6244 and Erlotinib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer

PRIMARY OBJECTIVES:

l. To assess overall survival (as measured by median survival and proportion of patients
alive at 24 weeks) in patients with advanced pancreatic cancer who have received one prior
line of systemic therapy when treated with the combination of AZD6244 and erlotinib.

SECONDARY OBJECTIVES:

I. Progression-free survival (median PFS and proportion of patients with PFS at 12 and 24
weeks).

II. CA19-9 biomarker response (defined as a 50% decline in serum CA19-9 level from baseline
in patients with > 2 x ULN CA19-9 measurement).

III. Objective radiographic response by RECIST criteria. IV. Safety and toxicity profile of
the combination of AZ6244 and erlotinib.

OUTLINE: This is a multicenter study.

Patients receive oral MEK inhibitor AZD6244 and oral erlotinib hydrochloride once daily on
days 1-21. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity. Tumor tissue and blood samples may be collected periodically for
correlative studies.

After completion of study treatment, patients are followed up by telephone every 2-3 months.

Inclusion Criteria:

- Histologically or cytologically proven adenocarcinoma of the pancreas

- Patients must have locally advanced unresectable disease not amenable to curative
resection or extrapancreatic metastases

- Patients must have radiographically measurable disease (defined as at least one
lesion that can be accurately measured in at least one dimension [longest diameter to
be recorded] as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT
scan) AND/OR a serum CA19-9 measurement > 2x ULN

- 1 prior systemic regimen for advanced disease (locally advanced or metastatic)

- The following represent acceptable examples meeting the definition of one prior
line of therapy:

- Gemcitabine as a single agent or in combination with other agents; patients
receiving (a) gemcitabine initially alone, with the eventual addition of a
second agent; or (b) gemcitabine as part of a combination regimen, followed
by gemcitabine alone; are eligible

- A non-gemcitabine-based regimen, including (but not limited to) FOLFIRINOX
or any combination of components therein

- Treatment as part of a clinical trial involving cytotoxic agents, small
molecule inhibitors, monoclonal antibodies, and/or immunomodulatory agents

- For patients with locally advanced disease, prior radiation to the primary tumor
is allowable as long as there is clear evidence of disease progression (either
radiographic locoregional disease progression and/or a rising CA19-9 level)

- Patients may have received chemotherapy both concurrently and/or
sequentially with (either before or after) the radiation and still be
eligible for the study, as this would be considered all part of the same
course of treatment

- Treatment given in the adjuvant setting (radiation and/or chemotherapy, given
either concurrently or sequentially) does not count as prior therapy as long as
progressive disease occurs > 6 months following completion of treatment

- No patients with known brain metastases

- ECOG performance status of 0 or 1

- Life expectancy of greater than 8 weeks

- ANC ≥ 1500/μL

- Platelet count ≥ 100,000/μL

- INR ≤ 1.5 (except those subjects who are receiving full-dose warfarin)

- Total bilirubin ≤ 2.0 mg/dL

- AST or ALT ≤ 2.5 times the upper limit of normal

- Serum creatinine ≤ 2.0 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception (hormonal or barrier method of
birth control; abstinence) before study entry, during study participation, and for 4
(female) or 16 (male) weeks after completion of treatment with MEK inhibitor AZD6244

- No patients with QTc interval > 480 msec or other factors that increase the risk of
QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family
history of long QT interval syndrome) including heart failure that (I) meets New York
Heart Association (NYHA) class III and IV definitions or (ii) is demonstrated by an
LV ejection fraction < 55% on baseline echocardiogram

- No refractory nausea and vomiting, chronic gastrointestinal diseases (e.g.,
inflammatory bowel disease), or significant bowel resection that would preclude
adequate absorption

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements

- No HIV-positive patients on combination antiretroviral therapy

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to AZD6244 (or its excipient Captisol®) or erlotinib

- No investigational or commercial agents or therapies may be administered with the
intent to treat the patient's malignancy

- No previous MEK or EGFR inhibitor use

- No patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- No required use of a concomitant medication that can prolong the QT interval

- Patients may not be receiving any other investigational agents