Trametinib and Hydroxychloroquine in Treating Patients With Pancreatic Cancer

Inclusion Criteria:

• Subject with histologically confirmed metastatic or locally advanced, unresectablepancreatic carcinoma

• Subject is willing to provide a baseline biopsy.

• EXPANSION COHORT ONLY: Subject must have progressed during or after two standard ofcare lines of treatment or refused standard of care options.

• Subject must have computed tomography (CT) measurable disease by Response EvaluationCriteria in Solid Tumors (RECIST) 1.1 criteria

• Subject must be able and willing to undergo disease assessment while on study andafterwards, if removed for reason other than progression

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

• Platelet count >= 100 x 10^9/L

• Hemoglobin >= 9 g/dL

• Total bilirubin level =< 1.5 x the upper limit of normal (ULN) range

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =< 3 xULN. Patients with liver metastases will be allowed to enroll with AST and ALTlevels =< 5 x ULN

• Estimated creatinine clearance >= 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)

• Negative serum or urine pregnancy test at screening for women of childbearingpotential

• Highly effective contraception for both male and female subjects throughout thestudy and for at least 4 months after last study treatment administration

• Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 from toxicities related to any prior treatments, unlessadverse event (AE)(s) are clinically nonsignificant and/or stable on supportivetherapy

• Able to provide informed consent and willing to sign an approved consent form thatconforms to federal and institutional guidelines

Exclusion Criteria:

• Subject who have received systemic antineoplastic therapy (including unconjugatedtherapeutic antibodies and toxin immunoconjugates) or any investigational therapywithin 2 weeks or within 5 half-lives of the investigational therapy prior tostarting study treatment, whichever is shorter.

• Subject who have received radiotherapy within 2 weeks prior to the first dose ofstudy treatment. Localized radiation therapy for the treatment of symptomatic bonemetastasis is allowed during that timeframe

• Subjects who have undergone major surgery =< 3 weeks prior to starting study drug orwho have not recovered from side effects of such procedure

• Patients with multiple primary malignancies may be enrolled if non-pancreatic ductaladenocarcinoma (PDAC) tumor(s) does not have the potential to interfere with thesafety or efficacy assessment of the investigational regimen as determined bytreating investigator and do not require active treatment

• Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeksbefore first dose of study treatment. Eligible subjects must be neurologicallyasymptomatic and without corticosteroid treatment at the time of first dose of studytreatment

• History or current evidence of retinal vein occlusion (RVO) or current risk factorsfor RVO (e.g. uncontrolled glaucoma or ocular hypertension, history ofhyperviscosity or hypercoagulability syndromes)

• History of active major bleeding.

• Patients whom thromboembolic prophylaxis is medically contraindicated per thetreating investigator's assessment.

• Current evidence of uncontrolled, significant intercurrent illness including, butnot limited to, the following conditions:

• Cardiovascular disorders:

• Congestive heart failure New York Heart Association class 3 or 4, unstableangina pectoris, serious cardiac arrhythmias.

• Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venousthrombosis, pulmonary embolism) within 3 months before first dose. Thepresence of an asymptomatic portal vein thrombosis will not preclude studyparticipation.

• History of glucose-6-phosphate dehydrogenase (G6PD) deficiency

• History of seizures

• Patients who are planning on embarking on a new strenuous exercise regimenafter first dose of study treatment. Muscular activities, such as strenuousexercise, that can result in significant increases in plasma creatine kinase (CK) levels should be avoided while on study treatment

• Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateralsclerosis, spinal muscular atrophy)

• Impairment of gastrointestinal function or gastrointestinal disease (e.g.,ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorptionsyndrome, or small bowel resection that under the judgment of the principalinvestigator [PI] may impair absorption of study drugs)

• Any other condition that would, in the Investigator?s judgment, contraindicatethe patient?s participation in the clinical study due to safety concerns orcompliance with clinical study procedures, e.g., infection/inflammation,intestinal obstruction, unable to swallow medication.(patients may not receivedrug through a feeding tube), social/ psychological issues, etc

• Screening corrected QT interval by Fridericia (QTcF) > 500 msec

• Known human immunodeficiency virus (HIV), unless patient is on effectiveanti-retroviral therapy with undetectable viral load within 6 months are eligiblefor this trial

• Known chronic hepatitis B virus, unless hepatitis B virus (HBV) viral load isundetectable

• Known history of hepatitis C virus (HCV) infection, unless treated and cured; forpatients with HCV infection who are currently on treatment, they are eligible ifthey have an undetectable HCV viral load

• Medical, psychiatric, cognitive or other conditions that may compromise thepatient's ability to understand the patient information, give informed consent,comply with the study protocol or complete the study

• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of afemale after conception and until the termination of gestation, confirmed by apositive human chorionic gonadotropin (hCG) laboratory test

• Sexually active males who are not willing to use a condom during intercourse whiletaking the drug and for 4 months after stopping treatment. A condom is also requiredto be used by vasectomized men in order to prevent delivery of the drug via seminalfluid

• Known prior severe hypersensitivity to investigational product or any component inits formulations, including known severe hypersensitivity reactions to monoclonalantibodies (National Cancer institute [NCI] CTCAE v5.0 grade >= 3)