LY3214996 +/- HCQ in Pancreatic Cancer

Inclusion Criteria:

* Participants must have histologically or cytologically confirmed adenocarcinoma or poorly differentiated carcinoma of the pancreas.
* Age ≥ 18 years.
* ECOG performance status ≤ 1
* Participants 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 nonnodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan, MRI, or calipers by clinical exam.
* Participants must have received at least one but no more than two prior lines of systemic therapy for metastatic pancreatic cancer. Perioperative treatment (chemotherapy and/or radiation) is not considered a prior line of therapy.
* Participants must have adequate organ and marrow function as defined below:

  * Absolute Neutrophil Count ≥ 1,500/mcL
  * Platelet Count ≥ 100,000/mcL
  * Total Bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
  * AST (SGOT) / ALT(SGPT) ≤ 2.5 × institutional ULN, OR
  * AST (SGOT) / ALT (SGPT) ≤ 5 × institutional ULN if elevation is a result of metastases
  * Creatinine ≤ 1.5 × institutional ULN, OR
  * Creatinine Clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above 1.5 × institutional normal (calculated via the Cockcroft-Gault equation)
* The effects of LY3214996 or HCQ on the developing human fetus are unknown. For this reason and because anti-cancer agents are known to be teratogenic, women of child bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of LY3214996 or HCQ administration.
* Ability to understand and the willingness to sign a written informed consent document.
* Ability to swallow and retain oral medication
* Baseline QTcB of ≤ 470 msec on screening EKG.
* Participants must be able and willing to undergo the pre-treatment biopsy procedure, and have a cancer site amenable to biopsy.

Exclusion Criteria:

* Participants with pancreatic histologies other than adenocarcinoma or poorly differentiated carcinoma, such as neuroendocrine or acinar cell carcinoma.
* Participants who have received a prior MAPK pathway inhibitor, including but not limited to LY3214996.
* Participants who have had systemic chemotherapy, other investigational therapy, or immunotherapy within 3 weeks prior to the first dose of study medication.
* Participants who have received oral tyrosine kinase inhibitors (TKIs) within 5 half-lives of the first dose of study medication.
* Participants who have received radiation therapy within 2 weeks prior to the first dose of study medication.
* Participants who have had major surgery within 4 weeks prior to the first dose of study medication.
* Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to LY3214996 or HCQ. Individuals with a history of a different malignancy are ineligible with the following exceptions: individuals who have been treated and are disease-free for a minimum of 3 years prior to study enrollment, or individuals who are deemed by the treating investigator to be at low risk for disease recurrence. Additionally, individuals with the following cancers are eligible if diagnosed and curatively treated within the past 3 years: basal or squamous cell carcinomas of the skin, and breast or cervical carcinomas in situ.
* 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.
* Pregnant women are excluded from this study because LY3214996 and HCQ are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LY3214996 or HCQ, breastfeeding should be discontinued if the mother is treated with LY3214996 or HCQ. A negative serum pregnancy test is required for women of childbearing potential prior to the first dose of study medication.
* Participants who are known to be seropositive for human immunodeficiency virus (HIV) or hepatitis B or C.
* Participants with a history or findings of central or branch retinal artery or venous occlusion with significant vision loss, or other retinal diseases causing visual impairment or would likely cause visual impairment over the time period of the study, as assessed by an ophthalmologist.
* Participants with a known personal or family history of long QT syndrome.
* Participants with known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
* Participants who are known at the time of trial enrollment to require concomitant treatment with strong CYP3A4 inhibitors or inducers. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference.