- Have histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma
based on pathology report with radiologically identified metastases that meet Response
Evaluation Criteria in Solid Tumors (RECIST) criteria.
- Be willing and able to provide written informed consent for the trial.
- Have at least one measurable lesion by RECIST criteria.
- Have had prior treatment with at least one line of therapy for metastatic disease.
- Have had tumor mutation profiling from any Clinical Laboratory Improvement Act (CLIA)
certified laboratory demonstrating a KRAS mutation. Liquid biopsy demonstrating KRAS
mutation will be considered acceptable.
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
- Absolute neutrophil count (ANC) >= 1500/uL (specimens must be collected within 10 days
prior to the start of trial treatment).
- Platelets >= 100,000/uL (specimens must be collected within 10 days prior to the start
of trial treatment).
- Hemoglobin >= 9.0 g/dL (specimens must be collected within 10 days prior to the start
of trial treatment).
- Creatinine OR measured or calculated creatinine clearance (glomerular filtration rate
[GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x
upper limit of normal (ULN) OR >= 50 mL/min for subjects with creatinine level > 1.5 x
ULN (specimens must be collected within 10 days prior to the start of trial
- Total bilirubin =< 1.5 x ULN (specimens must be collected within 10 days prior to the
start of trial treatment).
- Indirect bilirubin =< ULN (specimens must be collected within 10 days prior to the
start of trial treatment).
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]), and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN (=< 5 x ULN for subjects with liver metastases) (specimens must be collected
within 10 days prior to the start of trial treatment).
- Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for subjects with liver metastases)
(specimens must be collected within 10 days prior to the start of trial treatment).
- Serum albumin > 3.3 mg/dl (specimens must be collected within 10 days prior to the
start of trial treatment).
- International normalized ratio (INR) OR prothrombin time (PT), activated partial
thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant
therapy as long as PT or aPTT is within therapeutic range of intended use of
anticoagulants (specimens must be collected within 10 days prior to the start of trial
- Female subjects of childbearing potential must have a negative urine or serum
pregnancy test prior to the start of treatment.
- The participant is deemed by the investigator to have the ability to be compliant with
scheduled visits, treatment plan, and study procedures.
- Male and female subjects of childbearing potential must agree to use an adequate
method of contraception starting with the first dose of trial therapy through 30 days
after the last dose of trial therapy. Note: Abstinence is acceptable if this is the
usual lifestyle and preferred contraception for the subject. Acceptable methods of
contraception are listed in the protocol text.
- Has pancreatic tumor other than adenocarcinoma, including: acinar cell carcinoma,
pancreaticoblastoma, malignant cystic neoplasms, endocrine neoplasms, squamous cell
carcinoma, ampulla of Vater, periampullary, duodenal, or common bile duct
malignancies. Poorly differentiated carcinoma may be included at the discretion of the
investigator if histologic features suggest the possibility of adenocarcinoma.
- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational treatment within 2 weeks prior to the anticipated
first dose of study treatment.
- Received anticancer therapy including chemotherapy, immunotherapy, or antineoplastic
biologic drugs (e.g. erlotinib) within 14 days of the anticipated start of study
- Have undergone major surgery (e.g. inpatient procedures) =< 6 weeks prior to the start
of study treatment or who have not recovered from side effects of earlier such
- Have undergone radiation within 7 days prior to the start of treatment.
- Patient has not recovered to =< grade 1 from toxic effects of prior therapy before
starting study treatment. Note that alopecia, neuropathy, myalgias, and endocrinopathy
are exceptions to this criteria.
- Impaired cardiovascular function or clinically significant cardiovascular disease
including, but not limited to, any of the following:
- History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6
months prior to screening;
- Congestive heart failure requiring treatment (New York Heart Association grade >=
- Left ventricular ejection fraction (LVEF) < 50% as determined by multigated
acquisition scan (MUGA) or echocardiography (ECHO);
- Uncontrolled hypertension defined as persistent systolic blood pressure >= 150
mmHg or diastolic blood pressure >= 100 mmHg despite current therapy;
- History or presence of clinically significant cardiac arrhythmias (including
resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal
- Triplicate average baseline corrected QT (QTc) interval >= 480 ms.
- Impairment of gastrointestinal function or disease which may significantly alter the
absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or
diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal
absorption), or recent (=< 3 months) history of a partial or complete bowel
obstruction, or other conditions that will interfere significantly with the absorption
of oral drugs.
- Had a solid organ or hematologic transplant.
- Concurrent neuromuscular disorder that is associated with elevated creatine kinase
(CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral
sclerosis, spinal muscular atrophy).
- Has required treatment for other malignancies within 1 year prior to first dose of
study treatment, with the exception of curatively treated basal cell carcinoma of the
skin, squamous cell carcinoma of the skin and/or curatively resected tumors of low
invasive potential (e.g., in situ cervical and/or breast cancers).
- Has a history of central nervous system (CNS) metastases and/or carcinomatous
- History or current evidence of retinal vein occlusion (RVO) or current risk factors
for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
or hypercoagulability syndromes); history of retinal degenerative disease.
- Has an active infection requiring systemic therapy.
- Chronic use of steroids for pain or emesis management.
- Has known ophthalmologic disease that, in the opinion of investigators, would pose an
increased risk of visual disturbances during the study. This includes a history or
current evidence of retinal vein occlusion (RVO) or current risk factors for RVO
(e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or
hypercoagulability syndromes); history of retinal degenerative disease. The routine
use of eyeglasses does not in itself disqualify patient participation.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit through 30 days
after the last dose of trial treatment.
- Has a known history of human immunodeficiency virus (HIV) infection (HIV 1/2
antibodies) (No HIV screening is required for patients with no known diagnosis).
- Has a history of the following liver diseases:
- Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive),
- Hepatitis C (defined as detectable hepatitis C virus [HCV] ribonucleic acid
- Primary biliary cholangitis,
- Primary sclerosing cholangitis,
- History of immune mediated cholangitis.
- Of note, patients with a history of bacterial cholangitis are eligible if the
infection has been fully resolved prior to the screening visit. An exception is
made for hepatitis C patients who have undergone treatment and who have negative
serologic testing for at least one year.
- Has a known history of active TB (Mycobacterium Tuberculosis).
- Is unable to tolerate a contrast enhanced computed tomography (CT) or magnetic
resonance imaging (MRI) for staging/restaging purposes.
- In the estimation of the treating physician or primary investigator, have had a
clinical deterioration of their ECOG performance within the month prior to enrollment.
Evidence for such deterioration shall be documented in the patient's medical record.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator. Evidence for
such abnormalities/conditions will be documented in the patient's medical record.
- Has a history of thromboembolic or cerebrovascular events =< 12 weeks prior to the
first dose of study treatment. Examples include transient ischemic attacks,
cerebrovascular accidents, hemodynamically significant (i.e. massive or sub-massive)
deep vein thrombosis or pulmonary emboli. Note: Patients with either deep vein
thrombosis or pulmonary emboli that does not result in hemodynamic instability are
allowed to enroll as long as they are on a stable dose of anticoagulants for at least
4 weeks. Also note: Patients with thromboembolic events related to indwelling
catheters or other procedures may be enrolled. Finally: patients with stable
mesenteric thrombosis that predate study assessment (eg portal vein thrombus) may be
- Has a history of active bleeding requiring transfusion within a 3 month period prior
to screening. (Transfusions attributed to chemotherapy related anemia do not meet this
- Known cases of drug-induced hepatobiliary toxicities (other than a radiological
finding of fatty liver).
- Has had prior treatment with a MEK or ERK inhibitor.
- Partial or complete bowel obstruction.
- Impaired gastrointestinal function that may significantly alter the absorption of
binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome,
small bowel resection with decreased intestinal absorption) or baseline diarrhea >=
- Use of digoxin, mefloquine, cyclosporine, methotrexate, fexofenadine, quinidine,
talinolol, vinblastine, coumestrol, daidzein, dantrolene, estrone-3-sulfate,
genistein, prazosin, sulfasalazine, or antiepileptics if used for seizures (ok to use
the latter if part of a pain regimen). Prior loperamide use for diarrhea is permitted
at enrollment but should be changed to diphenoxylate / atropine before initiation of
- Has a history of psoriatic arthritis requiring systemic treatment.
- Has a history of porphyria.
- (Expansion phase only) Inability to safely undergo tumor biopsies (e.g. requirement
for antiplatelet therapy).