Selumetinib and Erlotinib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer
Selumetinib and Erlotinib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer
This phase II trial studies how well giving selumetinib and erlotinib hydrochloride together
 works in treating patients with locally advanced or metastatic pancreatic cancer that is
 refractory to chemotherapy. Selumetinib and erlotinib hydrochloride may stop the growth of
 cancer cells by blocking some of the enzymes needed for cell growth.
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 (selumetinib) and
 erlotinib (erlotinib hydrochloride).

 SECONDARY OBJECTIVES:

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

 II. Cancer antigen (CA)19-9 biomarker response (defined as a 50% decline in serum CA19-9
 level from baseline in patients with > 2 x upper limit of normal [ULN] CA19-9 measurement).

 III. Objective radiographic response by Response Evaluation Criteria in Solid Tumors (RECIST)
 criteria.

 IV. Safety and toxicity profile of the combination of AZ6244 and erlotinib.

 OUTLINE:

 Patients receive selumetinib orally (PO) once daily (QD) and erlotinib hydrochloride PO QD on
 days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable
 toxicity.

 After completion of study treatment, patients are followed up 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 EITHER 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 computed tomography [CT] scan) AND/OR a serum
 CA19-9 measurement > 2 x ULN

 -  One prior line of systemic therapy 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) leucovorin
 calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin
 (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

 -  Life expectancy of greater than 8 weeks

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

 -  Absolute neutrophil count (ANC) >= 1500/uL

 -  Platelet count >= 100,000/uL

 -  International normalized ratio (INR) =< 1.5 (except those subjects who are receiving
 full-dose warfarin)

 -  Total bilirubin =< 2.0 mg/dL

 -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 times the
 upper limit of normal for subjects

 -  Serum creatinine of =< 2.0 mg/dL

 -  Pregnancy test for women of childbearing potential (serum or urine beta-human
 chorionic gonadotropin [HCG])

 -  All patients must be informed of the investigational nature of this study and must
 sign and give written informed consent in accordance with institutional and federal
 guidelines

 -  Women of child-bearing potential and men must agree to use adequate contraception
 (hormonal or barrier method of birth control; abstinence) prior to study entry, for
 the duration of study participation, and for four weeks after dosing with AZD6244
 ceases; women of child-bearing potential must have a negative pregnancy test prior to
 entry; should a woman become pregnant or suspect she is pregnant while participating
 in this study, she should inform her treating physician immediately; please note that
 the AZD6244 manufacturer recommends that adequate contraception for male patients
 should be used for 16 weeks post-last dose due to sperm life cycle

 -  Ability to understand and the willingness to sign a written informed consent document

 Exclusion Criteria:

 -  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

 -  Patients may not be receiving any other investigational agents

 -  Patients with known brain metastases should be excluded from this clinical trial

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to AZD6244 (or its excipient Captisol) or erlotinib

 -  Previous mitogen-activated protein kinase kinase (MEK) or epidermal growth factor
 receptor (EGFR) inhibitor use

 -  Patients with corrected QT (QTc) interval > 480 msecs 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 left ventricular (LV) ejection fraction < 55% on baseline echocardiogram, are
 excluded

 -  Required use of a concomitant medication that can prolong the QT interval

 -  There are potential interactions between erlotinib and cytochrome P450, family 3,
 subfamily A, polypeptide 4 (CYP3A4) inhibitors and CYP3A4 promoters; although caution
 and careful monitoring are recommended when use of these compounds is necessary, use
 of these compounds does not exclude patients from participating in this trial

 -  Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory
 bowel disease), or significant bowel resection that would preclude adequate absorption

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection or psychiatric illness/social situations that would limit compliance with
 study requirements

 -  Pregnant women are excluded from this study; therefore, a negative pregnancy test is
 required for women of childbearing potential; breastfeeding should be discontinued if
 the mother is treated with AZD6244

 -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
 therapy are ineligible