Selumetinib Sulfate in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer With KRAS G12R Mutations
Selumetinib Sulfate in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer With KRAS G12R Mutations
This phase II trial studies how well selumetinib sulfate works in treating patients with
 pancreatic cancer with Kirsten rat sarcoma (KRAS) G12R mutations that has spread from where
 it started to nearby tissue or lymph nodes or other places in the body. Selumetinib sulfate
 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:

 I. Determine the objective response rate to selumetinib sulfate (selumetinib) administered as
 75 mg orally twice daily on a continuous schedule in patients with advanced pancreas cancer
 harboring Kirsten rat sarcoma (KRAS) G12R mutations.

 SECONDARY OBJECTIVES:

 I. To determine the progression free survival of patients with locally advanced, unresectable
 and stage IV pancreas cancer treated with selumetinib monotherapy.

 II. To evaluate the safety of selumetinib in patients with advanced pancreas cancer.

 III. To determine the impact of additional genetic alterations on the response to selumetinib
 in pancreas cancer harboring KRAS G12R mutations.

 IV. To develop a clinically applicable biomarker predicting response to selumetinib in
 pancreas cancer harboring KRAS G12R mutations.

 OUTLINE:

 Patients receive selumetinib sulfate orally (PO) twice daily (BID). Treatment repeats every
 28 days for up to 27 courses in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 2 months for 52 weeks.
Inclusion Criteria:

 -  Patients must have histologically confirmed locally advanced or metastatic pancreas
 cancer

 -  Patients must have received at least 6 months fluorouracil (5-FU)- or
 gemcitabine-based treatments for pancreas cancer (fluorouracil, irinotecan
 hydrochloride, leucovorin calcium and oxaliplatin [FOLFIRINOX], fluorouracil,
 leucovorin calcium and oxaliplatin [FOLFOX], 5-FU+ nal-IRI [MM-398; nanoliposomal
 irinotecan], or 5-FU [including capecitabine], gemcitabine-based gemcitabine plus
 abraxane, gemcitabine monotherapy among others)

 -  Patients must have measurable disease, defined as at least one lesion that can be
 accurately measured in at least one dimension (longest diameter to be recorded for
 non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
 conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT)
 scan, magnetic resonance imaging (MRI), or calipers by clinical exam

 -  Patients must have Clinical Laboratory Improvement Act (CLIA) confirmed somatic
 Kirsten rat sarcoma (KRAS) G12R mutation as determined by sequence analysis of matched
 normal deoxyribonucleic acid (DNA) from any specimen obtained from the individual;
 patients must provide tumor sample for KRAS analysis or be willing to undergo
 mandatory screening biopsy

 -  Patients must not have had chemotherapy, molecular therapy with erlotinib, radiation
 therapy, or experimental biological or molecular therapy for at least 4 weeks prior to
 starting study medication; patients who received FOLFIRINOX must be 6 weeks from the
 last administration of therapy; patients must have recovered from any acute toxicity
 related to prior therapy or surgery, to a grade 1 or less unless specified

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 or Karnofsky >= 70%

 -  Leukocytes >= 3,000/mcL

 -  Absolute neutrophil count >= 1,500/mcL

 -  Platelets >= 75,000/mcL

 -  Hemoglobin (Hgb) >= 9.0 g/dL

 -  Total bilirubin within normal institutional limits

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) <
 3 x institutional upper limit of normal

 -  Creatinine =< institutional upper limit of normal OR

 -  Creatinine clearance > 60 mL/min/1.73 m^2 by either Cockcroft-Gault formula or 24-hour
 urine collection analysis

 -  Patients must be willing to return to the clinic for follow-up visits

 -  Women of child-bearing potential 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 4 weeks after dosing with selumetinib sulfate (AZD6244)
 ceases; women of child-bearing potential must have a negative pregnancy test within 14
 days prior to study treatment; should a woman become pregnant or suspect she is
 pregnant while she or her partner is participating in this study, the patient should
 inform her treating physician immediately; please note that the AZD6244 manufacturer
 recommends that adequate contraception for male patients should be used for 12 weeks
 post-last dose due to sperm life cycle; NOTE: breastfeeding should be discontinued if
 the mother is treated with selumetinib

 -  Ability to understand and the willingness to sign a written informed consent document
 or patients with Impaired Decision Making Capacity (IDMC) if they are represented by a
 Legally Authorized Representative (LAR)

 -  Patient must be able to reliably swallow oral medications

 Exclusion Criteria:

 -  Patients who have received prior treatment with tyrosine kinase inhibitors (e.g.
 erlotinib), or anti-Epidermal growth factor receptor (EGFR) agents (e.g. cetuximab,
 panitumumab)

 -  Patients currently receiving any medication known to induce central serous
 chorioretinopathy which in the opinion of the principal investigator, would make the
 administration of study drug hazardous

 -  Patients with active hepatic or biliary disease (with exception of patients with
 Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver
 disease per investigator assessment)

 -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
 or active infection, symptomatic congestive heart failure, unstable angina pectoris,
 cardiac arrhythmia, or psychiatric illness/social situations that would limit
 compliance with study requirements

 -  Any underlying medical condition which, in the opinion of the principal investigator,
 will make the administration of study drug hazardous or obscure the interpretation of
 adverse events

 -  Patients who are receiving any other investigational agents

 -  Patients with known brain metastases should be excluded from this clinical trial; no
 additional workup is needed to exclude brain metastases if the patient is asymptomatic
 or has no history of brain metastases

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to Selumetinib (AZD6244) or other agents used in study

 -  Previous Mitogen-activated protein kinase kinase (MEK), RAS, or Rapidly Accelerated
 Fibrosarcoma (RAF) inhibitor use

 -  Patients with the following cardiac conditions are excluded:

 -  Uncontrolled hypertension (blood pressure [BP] of >= 150/95 despite medical
 support/management)

 -  Acute coronary syndrome within 6 months prior to starting treatment

 -  Uncontrolled angina - Canadian Cardiovascular Society grade II-IV despite medical
 support/management

 -  Heart failure New York Heart Association (NYHA) class II or above

 -  Prior or current cardiomyopathy (within 6 months) including but not limited to
 the following:

 -  Known hypertrophic cardiomyopathy

 -  Known arrhythmogenic right ventricular cardiomyopathy

 -  Abnormal ejection fraction (echocardiogram [ECHO]) =< 53% (if a range is
 given then the upper value of the range will be used) or cardiac magnetic
 resonance imaging (MRI)

 -  Previous moderate or severe impairment of left ventricular systolic function
 (left ventricular ejection fraction [LVEF] < 45% on echocardiography or
 equivalent on multi-gated acquisition scan [MUGA]) even if full recovery has
 occurred; echocardiogram (Echo) and additional cardiac studies not indicated
 unless clinically symptomatic or patient has significant cardiac history

 -  Severe valvular heart disease

 -  Atrial fibrillation with a ventricular rate > 100 beats per minute (bpm) on
 electrocardiogram (ECG) at rest

 -  Fridericia's corrected QT interval (QTcF) >= 450 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) are
 excluded; the use of medication(s) that can prolong QTc interval is
 prohibited while treated on this study

 -  Patients with known ophthalmologic conditions, such as:

 -  Current or past history of central serous retinopathy

 -  Current or past history of retinal vein occlusion

 -  Known intraocular pressure (IOP) > 21 mmHg (or upper limit of normal [ULN]
 adjusted by age) or uncontrolled glaucoma (irrespective of IOP); patients with
 controlled glaucoma and increased IOP who do not have meaningful vision (light
 perception only or no light perception) may be eligible after discussion with the
 study chair

 -  Subjects with any other significant abnormality on ophthalmic examination
 (performed by an ophthalmologist) should be discussed with the study chair for
 potential eligibility

 -  Ophthalmological findings secondary to long-standing optic pathway glioma (such
 as visual loss, optic nerve pallor or strabismus) or long-standing
 orbito-temporal plexiform neurofibroma (PN) (such as visual loss, strabismus)
 will NOT be considered a significant abnormality for the purposes of the study

 -  Patients with refractory nausea and vomiting, chronic gastrointestinal (GI) diseases
 (e.g., inflammatory bowel disease) or significant bowel resection

 -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
 therapy are ineligible; HIV-positive patients not on antiviral therapy with
 undetectable viral loads and cluster of differentiation 4 (CD4) counts > 300, and
 after confirmation of eligibility after discussing with the study chair are eligible