Selumetinib Sulfate in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer With KRAS G12R Mutations
Condition: KRAS NP_004976.2:p.G12R; Stage III Pancreatic Cancer AJCC v6 and v7; Stage IV Pancreatic Cancer AJCC v6 and v7
MeSH terms: Pancreatic Neoplasms
Intervention: Laboratory Biomarker Analysis; Selumetinib Sulfate
Intervention description: Correlative studies; Given by mouth (PO)
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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