Trametinib and Hydroxychloroquine in Treating Patients With Pancreatic Cancer

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of escalating doses of hydroxychloroquine (HCQ) in
combination with a fixed dose of trametinib in subjects with metastatic or locally advanced,
unresectable pancreatic ductal adenocarcinoma and determine the maximum tolerated dose (MTD)
and/or recommended phase II dose (RP2D) of the combination.

Inclusion Criteria:

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

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

- Subject must have progressed during or after first line treatment with either
gemcitabine/ nab-paclitaxel or FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin)

- 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 contrast CT 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 longer

- 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)

- 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

- 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)