Targeted Pathway Inhibition in Patients With Pancreatic Cancer

Inclusion Criteria:

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

• Age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

• Clinically-confirmed diagnosis of resectable, borderline resectable,locally-advanced or metastatic adenocarcinoma of the pancreas.

• Patients with disease that is eligible for curative surgery may not be eligiblefor all study arms.

• Participants may be treatment naïve or have received prior therapy for thetreatment of their pancreatic ductal adenocarcinoma (PDAC). A minimum washoutperiod of 10-days after completing the most recent line of therapy is requiredbefore a participant can initiate treatment with study agent(s)

• Based on available imaging, participant must have at least one disease lesion thatcan be biopsied in accordance with institutional standards

• Hemoglobin >= 9.0 g/dL with no blood transfusion within 28 days of startingtreatment (within 4 weeks prior to initiating window treatment). Note: laboratorytests performed after initial screening (but still within the screening window) willbe evaluated by the investigator; should any of these values fall outsideeligibility parameters, the patient may still be eligible per investigatordiscretion

• White blood cells (WBC) > 3 x 10^9/L (within 4 weeks prior to initiating windowtreatment). Note: laboratory tests performed after initial screening (but stillwithin the screening window) will be evaluated by the investigator; should any ofthese values fall outside eligibility parameters, the patient may still be eligibleper investigator discretion

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (> 1500 per mm^3) (within 4 weeksprior to initiating window treatment). Note: laboratory tests performed afterinitial screening (but still within the screening window) will be evaluated by theinvestigator; should any of these values fall outside eligibility parameters, thepatient may still be eligible per investigator discretion.

• May be waived on a case-by-case basis for patient populations recognized tohave normal baseline values below this level

• Platelet count >= 100 x 10^9/L (> 100,000 per mm^3) (within 4 weeks prior toinitiating window treatment). Note: laboratory tests performed after initialscreening (but still within the screening window) will be evaluated by theinvestigator; should any of these values fall outside eligibility parameters, thepatient may still be eligible per investigator discretion

• Creatinine =< 1.5 x upper limit of normal (ULN), OR measured or calculatedcreatinine clearance (glomerular filtration rate [GFR] can also be used in place ofcreatinine or creatinine clearance [CrCl]) >= 60 mL/min/1.73m^2 for participantswith creatinine levels > 1.5 x institutional ULN (within 4 weeks prior to initiatingwindow treatment). Note: laboratory tests performed after initial screening (butstill within the screening window) will be evaluated by the investigator; should anyof these values fall outside eligibility parameters, the patient may still beeligible per investigator discretion.

• Creatinine clearance should be calculated per institutional standard. Forparticipants with a baseline calculated creatinine clearance below normalinstitutional laboratory values, a measured baseline creatinine clearanceshould be determined. Individuals with higher values felt to be consistent withinborn errors of metabolism will be considered on a case-by-case basis

• Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 4 weeksprior to initiating window treatment). Note: laboratory tests performed afterinitial screening (but still within the screening window) will be evaluated by theinvestigator; should any of these values fall outside eligibility parameters, thepatient may still be eligible per investigator discretion

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (within 4 weeks prior to initiating window treatment). Note: laboratorytests performed after initial screening (but still within the screening window) willbe evaluated by the investigator; should any of these values fall outsideeligibility parameters, the patient may still be eligible per investigatordiscretion

• Participants must be willing to undergo mandatory on-study tumor biopsies

• Participant is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up

• Participant must be able to swallow tablets or capsules. A participant with anygastrointestinal disease that would impair ability to swallow, retain, or absorbdrug is not eligible

• Participants of childbearing potential must have a negative urine or serum pregnancytest within 72 hours prior to receiving the first dose of study medication. If theurine test is positive or cannot be confirmed as negative, a serum pregnancy testwill be required

• Participants must agree to use an adequate method of contraception starting with thefirst dose of study therapy and for the required length of time ascribed to theassigned study drug assignment

• No other prior invasive malignancy is allowed except for the following: adequatelytreated basal (or squamous cell) skin cancer, in situ breast or cervical cancer, anymalignancy treated with a curative intent without evidence of disease recurrence forat least 6 months

• Individuals must not have known active hepatitis B virus (HBV). Those who havecompleted curative therapy for hepatitis C virus (HCV) are eligible. HCV infectionpermitted but patient must be Child's Pugh A. Patients with known humanimmunodeficiency virus (HIV) infection are eligible if they meet all of thefollowing 3 criteria:

• CD4 counts >= 350 mm^3

• Serum HIV viral load of < 25,000 IU/ml and

• Treated on a stable antiretroviral regimen

• Note: HIV testing is not required at screening, unless if required by localregulations, where the testing will be done by local laboratory

• AZENOSERTIB SPECIFIC CRITERIA: Those with prior treatment with a WEE1 inhibitor arenot eligible

• AZENOSERTIB SPECIFIC CRITERIA: Patients are not eligible if any of the followingtreatment interventions have occurred within the specified time frame(s) prior tostarting study intervention:

• Major surgery within 28 days (the surgical incision should be fully healedprior to study drug administration)

• Radiation therapy within 21 days; however, if the radiation portal covered ≤ 5%of the bone marrow reserve, the subject is eligible irrespective of the enddate of radiotherapy

• Autologous or allogeneic stem cell transplant within 3 months

• Current use of an investigational agent that is not expected to be cleared bythe first dosing of study drug or that has demonstrated to have prolonged sideeffects

• Prescription, non-prescription drugs or food known as moderate to stronginducers of CYP3A within 2 weeks

• AZENOSERTIB SPECIFIC CRITERIA: Patients are not eligible if there is a seriousillness or medical condition(s) including, but not limited to, the following:

• Symptomatic brain metastases

• Leptomeningeal disease that requires or is anticipated to require immediatetreatment.

• Other severe acute or chronic medical or psychiatric condition or laboratoryabnormality that may increase the risk associated with study participation orstudy drug administration, or may interfere with the interpretation of studyresults, and in the judgment of the Investigator would make the subjectinappropriate for entry into this study

• Significant gastrointestinal abnormalities, including an inability to take oralmedication, requirement for IV alimentation, active peptic ulcer, chronicdiarrhea or vomiting considered to be clinically significant in the judgment ofthe Investigator, or prior surgical procedures affecting absorption

• Active or uncontrolled infection. Subjects with an infection receivingtreatment (antibiotic, antifungal or antiviral treatment) may be entered intothe study but must be afebrile and hemodynamically stable for ≥ 72 hours

• AZENOSERTIB SPECIFIC CRITERIA: 12-lead ECG demonstrating a corrected QT intervalusing Fridericia's formula (QTcF) of >480 ms, except for subjects withatrioventricular pacemakers or other conditions (e.g., right bundle branch block)that render the QT measurement invalid

• AZENOSERTIB SPECIFIC CRITERIA: History or current evidence of congenital or familyhistory of long QT syndrome or Torsade de Pointes

• AZENOSERTIB SPECIFIC CRITERIA: Patients are not eligible in cases of unresolvedtoxicity of grade > 1 attributed to any prior therapies (excluding grade 2neuropathy, alopecia or skin pigmentation)

• AZENOSERTIB SPECIFIC CRITERIA: Patients are not eligible if there is knownhypersensitivity to any drugs similar to ZN-c3 in class

• AZENOSERTIB SPECIFIC CRITERIA: Individuals that are pregnant or breast-feeding arenot eligible

• AZENOSERTIB SPECIFIC CRITERIA: Participants must agree to use an adequate method ofcontraception as follows:

• Participants of childbearing potential agree to use adequate methods ofcontraception for the duration of study participation.

• Sperm-producing participants must agree to refrain from sperm donation duringthe study and for 30 days after the last dose of study drug

• AZENOSERTIB SPECIFIC CRITERIA: Participant requiring any medications that can leadto significant QT prolongation are not eligible

• AZENOSERTIB SPECIFIC CRITERIA: Participant requires administration of strong andmoderate CYP3A4 inhibitors and inducers as well as strong and moderateP-glycoprotein (P-gp) inhibitors are not eligible

• AZENOSERTIB SPECIFIC CRITERIA: Due to potential CYP3A4 interaction with the studymedication, participants are asked to refrain from consumption of seville oranges,grapefruit or grapefruit juice, ppomelos, exotic citrus fruits, grapefruit hybrids,or fruit juices) from 7 days prior to the initiating study agent and during theentire study. NOTE: Orange juice is permitted

• AZD5305 SPECIFIC CRITERIA: Participants must agree to use an adequate method ofcontraception as follows:

• Participants of childbearing potential must agree to use adequate methods ofcontraception starting with the first dose of study therapy through at least 6months after the last dose of study therapy

• Sperm-producing participants must use a condom during treatment and for 6months after the last dose of AZD5305 when having sexual intercourse with anindividual that is pregnant or of childbearing potential. Individuals that arepartners of sperm-producing participants should also use a highly effectiveform of contraception if they are of childbearing potential

• TREMELIMUMAB SPECIFIC CRITERIA: Participants of childbearing potential must agree touse adequate methods of contraception starting with the first dose of study therapythrough at least 3 months after the last dose of study therapy

Exclusion Criteria:

• Tumor not accessible for core biopsy

• Medical co-morbidities that are deemed to make risk of surgery unacceptably high asdetermined by institutional standards

• Recent major surgery within 4 weeks prior to starting study treatment. Minor surgerywithin 2 weeks of starting study treatment. Patients must be recovered from effectsof surgery

• Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin,rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort) ormoderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil)

• Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin,clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.,ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil)

• Concomitant use of other anti-cancer therapy (chemotherapy, immunotherapy, hormonaltherapy (hormone replacement therapy is acceptable), radiotherapy (except forpalliative), biological therapy or other novel agent) or live virus and livebacterial vaccines while the patient is receiving study medication. Strong ormoderate CYP3A inhibitors and inducers should not be taken with study treatment;however, if no other suitable alternative concomitant medication is available, dosereductions may be allowed under careful monitoring

• Known severe hypersensitivity to the study agent(s) (or equivalent agents,respectively), or any excipient of these medicinal products, or history of allergicreactions attributed to compounds of similar chemical or biologic composition to thestudy agent(s)

• Clinically significant cardiac disease or impaired cardiac function, including anyof the following:

• Clinically significant and/or uncontrolled heart disease such as congestiveheart failure (New York Heart Association grade >= 2) uncontrolledhypertension, or clinically significant arrhythmia currently requiring medicaltreatment

• Corrected QT using Fridericia's formula (QTcF) > 470 msec for females, or > 450msec for males, on screening electrocardiogram (ECG) or congenital long QTsyndrome

• Acute myocardial infarction or unstable angina pectoris < 6 months prior toscreening

• Clinically significant cardiac disease or impaired cardiac function

• Female participant who is pregnant or lactating

• Participant is known to have dysphagia, short-gut syndrome, gastroparesis, or otherconditions that limit the ingestion or gastrointestinal absorption of drugsadministered orally

• Participant has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvementdespite appropriate antibiotics, antiviral therapy, and/or other treatment)

• Psychiatric illness/social situations that would limit compliance with studyrequirements

• Participants with a history of hypersensitivity reactions to study agents or theirexcipients

• Participant is pregnant or breastfeeding, or expecting to conceive or fatherchildren within the projected duration of the trial, starting with the screeningvisit through at least 120 days after the last dose of trial treatment

• AZD5305 SPECIFIC CRITERIA: Known allergy or hypersensitivity to AZD5305 or any ofits excipients

• AZD5305 SPECIFIC CRITERIA: Patients with myelodysplastic syndrome (MDS)/acutemyeloid leukemia (AML) or with features suggestive of MDS/AML

• AZD5305 SPECIFIC CRITERIA: Cardiovascular disease, QTc > 450 ms, or any factors thatincrease the risk of QTc prolongation or risk of arrhythmic events

• AZD5305 SPECIFIC CRITERIA: History of persisting (> 2 weeks) severe pancytopenia dueto any cause (ANC < 0.5 x 10^9/L or platelets < 50 x 10^9/L)

• TREMELIMUMAB SPECIFIC CRITERIA: Medical co-morbidities that are deemed to make riskof surgery unacceptably high as determined by institutional standards

• TREMELIMUMAB SPECIFIC CRITERIA: Participants have received prior immunotherapy forthe treatment of their PDAC

• TREMELIMUMAB SPECIFIC CRITERIA: Any unresolved toxicity Common Terminology Criteriafor Adverse Events (CTCAE) > grade 2 from prior neoadjuvant therapy

• TREMELIMUMAB SPECIFIC CRITERIA: History of idiopathic pulmonary fibrosis, organizingpneumonia, drug induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis, interstitial lung disease (ILD), pleural effusion, or pulmonaryfibrosis diagnosed in the past 6 months prior to randomization

• TREMELIMUMAB SPECIFIC CRITERIA: Active or prior documented autoimmune orinflammatory disorders