Trametinib and Hydroxychloroquine in Treating Patients With Pancreatic Cancer
Trametinib and Hydroxychloroquine in Treating Patients With Pancreatic Cancer
This phase I trial studies the sides effects and best dose of hydroxychloroquine when given
 together with trametinib in treating patients with pancreatic cancer that has spread to
 nearby tissue, lymph nodes or other places in the body and cannot be removed by surgery.
 Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell
 growth. Drugs used in chemotherapy, such as hydroxychloroquine, work in different ways to
 stop the growth of tumor cells, either by killing the cells, by stopping them from dividing,
 or by stopping them from spreading. Giving trametinib together with hydroxychloroquine may
 work better in treating patients with pancreatic cancer.
PRIMARY OBJECTIVES:

 I. To determine the recommended phase II dose of hydroxychloroquine in combination with
 trametinib as assessed by the occurrence of dose-limiting toxicities (DLTs).
Inclusion Criteria:

 -  Subject with histologically confirmed metastatic or locally advanced, unresectable
 pancreatic carcinoma

 -  Subject must have sufficient available archival tissue OR be willing to provide a
 baseline biopsy

 -  Subject must have progressed during or after first line treatment.

 -  Subject must have computed tomography (CT) measurable disease by Response Evaluation
 Criteria in Solid Tumors (RECIST) 1.1 criteria

 -  Subject must be able and willing to undergo disease assessment while on study and
 afterwards, 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 x ULN.
 Patients with liver metastases will be allowed to enroll with AST and ALT levels =< 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 childbearing
 potential

 -  Highly effective contraception for both male and female subjects throughout the study
 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, unless adverse
 event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy

 -  Able to provide informed consent and willing to sign an approved consent form that
 conforms to federal and institutional guidelines

 Exclusion Criteria:

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

 -  Subject who have received radiotherapy within 2 weeks prior to the first dose of study
 treatment. Localized radiation therapy for the treatment of symptomatic bone
 metastasis is allowed during that timeframe

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

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

 -  Known brain metastases or cranial epidural disease unless adequately treated with
 radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
 before first dose of study treatment. Eligible subjects must be neurologically
 asymptomatic and without corticosteroid treatment at the time of first dose of study
 treatment

 -  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 active major bleeding.

 -  Patients whom thromboembolic prophylaxis is medically contraindicated per the treating
 investigator's assessment.

 -  Current evidence of uncontrolled, significant intercurrent illness including, but not
 limited to, the following conditions:

 -  Cardiovascular disorders:

 -  Congestive heart failure New York Heart Association class 3 or 4, unstable
 angina pectoris, serious cardiac arrhythmias.

 -  Stroke (including transient ischemic attack [TIA]), myocardial infarction
 (MI), or other ischemic event, or thromboembolic event (eg, deep venous
 thrombosis, pulmonary embolism) within 3 months before first dose. The
 presence of an asymptomatic portal vein thrombosis will not preclude study
 participation.

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

 -  History of seizures

 -  Patients who are planning on embarking on a new strenuous exercise regimen after
 first dose of study treatment. Muscular activities, such as strenuous exercise,
 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 lateral
 sclerosis, spinal muscular atrophy)

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

 -  Any other condition that would, in the Investigator?s judgment, contraindicate
 the patient?s participation in the clinical study due to safety concerns or
 compliance with clinical study procedures, e.g., infection/inflammation,
 intestinal obstruction, unable to swallow medication.(patients may not receive
 drug 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 effective
 anti-retroviral therapy with undetectable viral load within 6 months are eligible for
 this trial

 -  Known chronic hepatitis B virus, unless hepatitis B virus (HBV) viral load is
 undetectable

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

 -  Medical, psychiatric, cognitive or other conditions that may compromise the patient'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 a
 female after conception and until the termination of gestation, confirmed by a
 positive human chorionic gonadotropin (hCG) laboratory test

 -  Sexually active males who are not willing to use a condom during intercourse while
 taking the drug and for 4 months after stopping treatment. A condom is also required
 to be used by vasectomized men in order to prevent delivery of the drug via seminal
 fluid

 -  Known prior severe hypersensitivity to investigational product or any component in its
 formulations, including known severe hypersensitivity reactions to monoclonal
 antibodies (National Cancer institute [NCI] CTCAE v5.0 grade >= 3)