ProAgio in Pancreatic Ductal Adenocarcinoma (PDAC)

Inclusion Criteria:

1. Must be ≥ 18 years of age on day of signing informed consent.

2. Histologic or cytologic diagnosis of pancreatic adenocarcinoma with clinical stageIV.

3. In the dose escalation phase: patients must be eligible for gemcitabine and nabpaclitaxel. For dose expansion phase: patients must have received 5FU-based therapyfor metastatic disease or for neoadjuvant/adjuvant therapy in prior 12 months.

4. Presence of a lesion that can be safely biopsied for correlative assays.

5. Patient must meet the following laboratory values at the screening visit:

• Absolute Neutrophil Count ≥1.5 x 10'9/L

• Platelets ≥100 x 10'9/L

• Hemoglobin (Hgb) ≥9 g/dL

• Serum creatinine <1.5 mg/dL OR Creatinine Clearance ≥60 mL/min usingCockcroft-Gault formula

• Total bilirubin ≤1.5 x ULN

• Aspartate transaminase (AST) ≤2.5 x ULN, except for subjects with livermetastasis, who may only be included if AST ≤5.0 x ULN

• Alanine transaminase (ALT) ≤2.5 x ULN, except for subjects with livermetastasis, who may only be included if ALT ≤5.0 x ULN

6. Presence of measurable disease by RECIST 1.1 criteria

7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

8. Written informed consent must be obtained prior to any screening procedures.

9. Normal ECG defined as the following: QTcF at screening <450 ms (male subjects), <460ms (female subjects)

10. Before enrollment, a woman must be either:

11. Not of childbearing potential: postmenopausal (>45 years of age with amenorrheafor at least 12 months or any age with amenorrhea for at least 6 months and aserum follicle stimulating hormone (FSH) level >40 IU/mL); permanentlysterilized (eg, tubal occlusion, hysterectomy, bilateral salpingectomy); orotherwise be incapable of pregnancy.

12. Of childbearing potential and practicing (during the study and for 6 monthsafter receiving the last dose of study agent) a highly effective method ofbirth control consistent with local regulations regarding the use of birthcontrol methods for subjects participating in clinical studies: eg, establisheduse of oral, injected or implanted hormonal methods of contraception; placementof an intrauterine device (IUD) or intrauterine system (IUS); barrier methods;true abstinence (when this is in line with the preferred and usual lifestyle ofthe subject).

13. Note: If the childbearing potential changes after start of the study (eg, womanwho is not heterosexually active becomes active) a woman must begin a highlyeffective method of birth control, as described above.

14. A woman of childbearing potential must have a negative serum (β-human chorionicgonadotropin [β-hCG]) or urine pregnancy test at screening.

15. During the study and for 6 months after receiving the last dose of study agent, awoman must agree not to donate eggs (ova, oocytes) for the purposes of assistedreproduction.

16. A man who is sexually active with a woman of childbearing potential and has not hada vasectomy must agree to use a barrier method of birth control eg, either condomwith spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository,and all men must also not donate sperm during the study and for 3 months afterreceiving the last dose of study drug.

17. Sign an informed consent document indicating that they understand the purpose of andprocedures required for the study, are willing to participate in the study, and arewilling and able to adhere to the prohibitions and restrictions specified in thisprotocol. Informed consent must be obtained before performing any study specificprocedures.

Exclusion Criteria:

1. Prior exposure to gemcitabine and nab paclitaxel

2. Clinically significant peripheral neuropathy

3. Any untreated central nervous system (CNS) lesion. However, subjects are eligibleif: a) all known CNS lesions have been treated with radiotherapy or surgery and b)patient remained without evidence of CNS disease progression ≥4 weeks aftertreatment.

4. Use of hematopoietic colony-stimulating growth factors (eg, G-CSF, GMCSF, M-CSF),thrombopoietin mimetics or erythroid stimulating agents ≤ 2 weeks prior start ofstudy treatment. If erythroid stimulating agents were initiated more than 2 weeksprior to the first dose of study treatment and the patient is on a stable dose, theycan be maintained.

5. Active unstable autoimmune disease. Documented history of autoimmune disease that iswell controlled on stable immune suppressive therapy can be enrolled afterdiscussion with principal investigator.

6. Allogenic bone marrow or solid organ transplant.

7. Known history or current interstitial lung disease or non-infectious pneumonitis.

8. Malignant disease, other than that being treated in this study. Exceptions to thisexclusion include the following: malignancies that were treated curatively and havenot recurred within 2 years prior to study treatment; completely resected basal celland squamous cell skin cancers and any completely resected carcinoma in situ.

9. Clinically significant infection, including known HIV or hepatitis C infection, orknown hepatitis B surface antigen positivity. Testing of asymptomatic patients willnot be required.

10. Clinically significant ongoing infection.

11. Received an investigational drug (including investigational vaccines) or used aninvasive investigational medical device within 14 days or 5 half-lives beforeenrollment or is currently enrolled in the treatment stage of an investigationalstudy.

12. A woman who is pregnant or breast-feeding, or a woman who is planning to becomepregnant or a man who plans to father a child while enrolled in this study or within 30 days after the last dose of study agent.

13. Had hospitalization for infection or major surgery (eg, requiring generalanesthesia) within 2 weeks before enrollment or have not fully recovered fromsurgery. Note: subjects with surgical procedures conducted under local anesthesiamay participate.

14. History or current diagnosis of cardiac disease indicating significant risk ofsafety for subjects participating in the study such as uncontrolled or significantcardiac disease, including any of the following:

15. recent myocardial infarction (within last 6 months),

16. uncontrolled congestive heart failure,

17. unstable angina (within last 6 months),

18. clinically significant (symptomatic) cardiac arrhythmias (e.g., sustainedventricular tachycardia, and clinically significant second or third degree AVblock without a pacemaker). Following additional exclusion criteria applies only to the patients in the cohortincluding atezolizumab:

19. Active or prior documented autoimmune or inflammatory disorders (including, but notlimited to inflammatory bowel disease [e.g., colitis or Crohn's disease], systemiclupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis withpolyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).The following are exceptions to this criterion:

• Patients with vitiligo or alopecia

• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement

• Any chronic skin condition that does not require systemic therapy

• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician

• Patients with celiac disease controlled by diet alone

• Patients with type I diabetes mellitus who are on an insulin regimen areeligible for the study

16. Current or prior use of immunosuppressive medication ≤ 14 days prior toregistration. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)

• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent Steroids as premedication for hypersensitivityreactions (e.g., CT scan premedication)

17. Receipt of live attenuated vaccine ≤30 days prior to registration. Note: Patients,if enrolled, should not receive live vaccine whilst on study treatment and up to 30days after the last dose of study treatment.

18. History of pneumonitis/interstitial lung disease