Zimberelimab and Quemliclustat in Combination With Chemotherapy for the Treatment of Patients With Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma

Inclusion Criteria:

• Male or female >= 18 years of age and willing and able to provide informed consent

• Previously untreated cytologically or histologically confirmed pancreaticadenocarcinoma with one of the following:

• Borderline resectable disease. There are multiple definitions of borderlineresectable PDAC including the MD Anderson definition and the criteria developedduring the Consensus Conference sponsored by the AmericanHepato-Pancreato-Biliary Association, Society of Surgical Oncology, and Societyfor Surgery of the Alimentary Tract. Borderline resectable PDAC cases will beidentified per the definition developed in the currently running inter-grouppilot trial for borderline resectable pancreatic cancer (NCT01821612). Per thistrial, borderline resectable PDAC is defined as the presence of any one or moreof the following on CT;

• An interface between the primary tumor and the superior mesenteric vein orportal vein (SMV-PV) measuring >= 180 degrees of the circumference of thevessel wall

• Short-segment occlusion of the SMV-PV with normal vein above and below thelevel of obstruction that is amenable to resection and venousreconstruction

• Short segment interface (of any degree) between tumor and hepatic arterywith normal artery proximal and distal to the interface that is amenableto resection and reconstruction

• An interface between the tumor and SMA measuring < 180 degrees of thecircumference of the vessel wall

• Locally advanced disease. Multiple guidelines defining locally advanced PDAChave been developed, including the MD Anderson definition, the NationalComprehensive Cancer Network (NCCN) definition, as well as the criteriadeveloped during the Consensus Conference sponsored by the AmericanHepato-Pancreato-Biliary Association, Society of Surgical Oncology, and Societyfor Surgery of the Alimentary Tract. Locally advanced PDAC cases will beidentified per the definition developed by the Alliance for Clinical Trials inOncology. Per this definition, locally advanced PDAC is defined as presence ofany one or more of the following on CT;

• Occlusion of the SMV-PV that is not amenable to resection and venousreconstruction

• Interface between tumor and hepatic artery that is not amenable toresection and reconstruction

• Interface between the tumor and SMA measuring > 180 degrees of thecircumference of the vessel wall

• Interface between the tumor and celiac axis measuring > 180 degrees of thecircumference of the vessel wall

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

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

• Platelets >= 100 x 10^9/L

• Hemoglobin >= 9 g/dL

• Serum creatinine (sCr) =< 1.5 x upper limit of normal (ULN) or Creatinine clearance (Ccr) >= 40 mL/min (as calculated by Modified Cockcroft-Gault formula)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (AST/[SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvatetransaminase [SGPT]) =< 2.5 X ULN

• Women with no childbearing potential because of surgery or who are at least 1 yearpostmenopausal (ie, 12 months post last menstrual period) or with menopauseconfirmed by follicle-stimulating hormone testing

• Women of childbearing potential must use an effective nonhormonal method ofcontraception (intrauterine device or intrauterine system; condom or occlusive cap [diaphragm or cervical or vault caps] with spermicidal foam or gel or film or creamor suppository; or vasectomized male partner if he is the sole partner of thatparticipant) for the duration of the study and for up to 6 months after the lastdose of zimberelimab or quemliclustat

• Male participants must use an effective method of contraception (condom or occlusivecap [diaphragm or cervical or vault caps] with spermicidal foam or gel or film orcream or suppository, or vasectomy) throughout the study and for up to 6 monthsafter the last dose of zimberelimab or quemliclustat

• Immunosuppressive doses of systemic medications, such as corticosteroids or absorbedtopical corticosteroids (doses > 10 mg/day prednisone or equivalent) must bediscontinued at least 2 weeks (14 days) before study treatment administration.Physiologic doses of corticosteroids (=< 10 mg/day of prednisone or its equivalent)or short pulses of corticosteroids (=< 3 days) may be permitted

• Prior surgery that required general anesthesia or other major surgery as defined bythe Investigator must be completed at least 4 weeks before study treatmentadministration. Surgery requiring regional/epidural anesthesia must be completed atleast 72 hours before study treatment administration. Participants should haverecovered from the surgical procedure prior to the first dose being administered

Exclusion Criteria:

• Recurrent or metastatic pancreatic adenocarcinoma

• Peripheral neuropathy > grade 2

• Known status of human immunodeficiency virus (HIV) which is not well-controlled (CD4 <300) at the time of study eligibility. Patients with controlled and treatedHIV/Hepatitis C virus (HCV) and an undetectable viral load are allowed

• Untreated Hepatitis B infection: Patient has known active hepatitis B virus (HBV) orhepatitis C virus (HCV), or Human immunodeficiency virus (HIV) infection (testing isnot mandatory, unless required by local regulation)

• Participants with resolved or treated HCV (ie, HCV antibody positive butundetectable HCV ribonucleic acid [RNA]) will not be excluded from this study

• Underlying medical conditions that, in the Investigator's or Sponsor's opinion, willmake the administration of Investigational products (IPs) hazardous, including butnot limited to:

• Interstitial lung disease, including history of interstitial lung disease ornon-infectious pneumonitis (lymphangitic spread of non-small cell lung cancer (NSCLC) is not disqualifying)

• Active viral, bacterial, or fungal infections requiring parenteral treatmentwithin 14 days of the initiation of the IP

• Active infection or antibiotics within 48 hours prior to study screening

• Clinically significant cardiovascular disease

• A condition or unresolved adverse event (AE) from a prior investigational drugthat may obscure the interpretation of toxicity determination or AEs

• History of prior solid-organ transplantation

• Currently active second primary malignancy or history of malignancy less than 5years prior to the time of study eligibility (Patients with history of skin cancersexcluding melanoma will be eligible for participation)

• Serious medical comorbidities such as New York Heart Association Class III/IVcardiac disease, uncontrolled cardiac arrhythmias, myocardial infarction over thepast 12 months

• Known, existing uncontrolled coagulopathy. Patients who have had a venousthromboembolic event (e.g., pulmonary embolism or deep vein thrombosis) requiringanticoagulation are eligible IF: they are appropriately anticoagulated and have nothad a Grade 2 or greater bleeding episode in the 3 weeks before Day 1

• Known pregnancy, nursing women or positive pregnancy test. Requirement for women ofchild-bearing potential (WOCBP): Negative serum pregnancy test at screening andprior to dosing on Cycle 1 Day 1, within 24 hours prior to the start of treatment (minimum sensitivity 25 IU/L or equivalent units of HCG). WOCBP must also have anegative serum or urine pregnancy test every 4 weeks, within 24 hours prior to thestart of treatment

• Any condition (concurrent disease, infection, or comorbidity) that interferes withability to participate in the study, causes undue risk, or complicates theinterpretation of safety data, in the opinion of the investigator

• History of trauma or major surgery within 28 days prior to the first dose of IP

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial

• Any active or documented history of autoimmune disease, including but not limited toinflammatory bowel disease, celiac disease, Wegner syndrome, Hashimoto syndrome,systemic lupus erythematosus, scleroderma, sarcoidosis, or autoimmune hepatitis,within 3 years of the first dose of study treatment, except for the following:

• Type I diabetes mellitus, hypothyroidism only requiring hormone replacement,skin disorders such as vitiligo, or alopecia not requiring systemic therapy, orconditions not expected to recur in the absence of an external trigger

• Endocrinopathies where the participant is stable on hormone replacement therapy

• History of Hashimoto syndrome within 3 years of the first of study treatmentthat resolved to hypothyroidism alone

• History of a syndrome that required systemic steroids or immunosuppressivemedications, except for vitiligo or resolved childhood asthma/atopy. Participantswith asthma who require intermittent use of bronchodilators (such as albuterol) willnot be excluded from this study