LY3214996 +/- HCQ in Pancreatic Cancer

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed adenocarcinoma orpoorly differentiated carcinoma of the pancreas.

• Age ≥ 18 years.

• ECOG performance status ≤ 1

• Participants must have measurable disease, defined as at least one lesion that canbe accurately measured in at least one dimension (longest diameter to be recordedfor nonnodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventionaltechniques 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 ofsystemic 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 ofmetastases

• Creatinine ≤ 1.5 × institutional ULN, OR

• Creatinine Clearance ≥ 60 mL/min/1.73 m2 for participants with creatininelevels above 1.5 × institutional normal (calculated via the Cockcroft-Gaultequation)

• The effects of LY3214996 or HCQ on the developing human fetus are unknown. For thisreason and because anti-cancer agents are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal orbarrier method of birth control; abstinence) prior to study entry and for theduration of study participation. Should a woman become pregnant or suspect she ispregnant while she or her partner is participating in this study, she should informher treating physician immediately. Men treated or enrolled on this protocol mustalso agree to use adequate contraception prior to the study, for the duration ofstudy participation, and 6 months after completion of LY3214996 or HCQadministration.

• Ability to understand and the willingness to sign a written informed consentdocument.

• 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 poorlydifferentiated carcinoma, such as neuroendocrine or acinar cell carcinoma.

• Participants who have received a prior MAPK pathway inhibitor, including but notlimited to LY3214996.

• Participants who have had systemic chemotherapy, other investigational therapy, orimmunotherapy within 3 weeks prior to the first dose of study medication.

• Participants who have received oral tyrosine kinase inhibitors (TKIs) within 5half-lives of the first dose of study medication.

• Participants who have received radiation therapy within 2 weeks prior to the firstdose of study medication.

• Participants who have had major surgery within 4 weeks prior to the first dose ofstudy medication.

• Participants with known brain metastases should be excluded from this clinical trialbecause of their poor prognosis and because they often develop progressiveneurologic dysfunction that would confound the evaluation of neurologic and otheradverse events.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to LY3214996 or HCQ. Individuals with a history of a differentmalignancy are ineligible with the following exceptions: individuals who have beentreated and are disease-free for a minimum of 3 years prior to study enrollment, orindividuals who are deemed by the treating investigator to be at low risk fordisease recurrence. Additionally, individuals with the following cancers areeligible if diagnosed and curatively treated within the past 3 years: basal orsquamous cell carcinomas of the skin, and breast or cervical carcinomas in situ.

• Uncontrolled intercurrent illness including, but not limited to: ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements.

• Pregnant women are excluded from this study because LY3214996 and HCQ are agentswith the potential for teratogenic or abortifacient effects. Because there is anunknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with LY3214996 or HCQ, breastfeeding should be discontinuedif the mother is treated with LY3214996 or HCQ. A negative serum pregnancy test isrequired for women of childbearing potential prior to the first dose of studymedication.

• 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 orvenous occlusion with significant vision loss, or other retinal diseases causingvisual impairment or would likely cause visual impairment over the time period ofthe 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 concomitanttreatment with strong CYP3A4 inhibitors or inducers. Because the lists of theseagents are constantly changing, it is important to regularly consult a frequentlyupdated medical reference.