Atezolizumab + Cabozantinib in Patients W/ Metastatic, Refractory Pancreatic Cancer

Inclusion Criteria:

1. Stage IV pancreatic adenocarcinoma, confirmed by histology or cytology. (Note: theprimary pancreatic adenosarcoma must be confirmed by histology or cytology. Thestage IV metastatic disease does not necessarily need to be confirmed by histologyor cytology).

2. Clinical and/or radiographic progression on and/or intolerance to and/orineligibility for treatment with at least one of the following: a fluoropyrimidineor gemcitabine based chemotherapy treatment regimens

3. Radiographically measurable disease by Response Evaluation Criteria in Solid Tumorsversion 1.1 (RECIST 1.1). Images (MRI or CT Scan) must be completed within 28 daysprior to treatment start.

4. Age ≥ 18 years

5. Patients who progress on adjuvant treatment and develop metastatic disease within < 6 months of adjuvant therapy will be considered as having one prior line oftreatment and may be eligible pending subject meeting all other inclusion/exclusioncriteria.

6. Adequate organ and marrow function, based upon meeting all of the followinglaboratory criteria within 14 days before first dose of study treatment:

7. Absolute neutrophil count (ANC) ≥ 1500/µL without granulocytecolony-stimulating factor support.

8. White blood cell count ≥ 2500/µL

9. Platelets ≥ 100,000/µL without transfusion.

10. Hemoglobin ≥ 9 g/dL (≥ 90 g/L).

11. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkalinephosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN) with the followingexceptions:Patients with documented liver metastases: AST and ALT ≤ 5 x ULN Patients withdocumented liver or bone metastases: ALP ≤ 5 x ULN

12. Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3 x ULN).

13. Serum albumin ≥ 2.8 g/dl

14. (PT)/INR or partial thromboplastin time (PTT) test < 1.3 x the laboratory ULN

15. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 mL/minusing the Cockcroft-Gault equation:Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72) Females: [(140

• age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85

10. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-hurine protein ≤ 1 g

11. For patients receiving therapeutic anticoagulation, they must have a stableanticoagulant regimen.

12. No clinically significant hypertension as per treating physician or if hypertension,adequate control with anti-hypertensives

13. Negative hepatitis B surface antigen (HBsAg) test at screening

14. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCVantibody test followed by a negative HCV RNA test at screening. The HCV RNA testmust be performed for patients who have a positive HCV antibody test.

15. ECOG performance status ≤ 1

16. Recovered to baseline or to CTCAE v5.0 ≤ Grade 1 treatment-related toxicity fromprior therapies

17. At least two weeks since last dose of prior treatment

18. Sexually active fertile subjects and their partners must agree to use medicallyaccepted methods of contraception (e.g., barrier methods, including male condom,female condom, or diaphragm with spermicidal gel) during the course of the study andfor 6 months after the last dose of study treatment.

19. Female subjects of childbearing potential must not be pregnant at screening. Femalesubjects are considered to be of childbearing potential unless one of the followingcriteria are met: documented permanent sterilization (hysterectomy, bilateralsalpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence ofother biological or physiological causes. In addition, females < 55 years-of-agemust have a serum follicle stimulating (FSH) level > 40 mIU/mL to confirmmenopause). Note: Documentation may include review of medical records, medicalexaminations, or medical history interview by study site.

20. Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

1. Prior treatment with cabozantinib.

2. Prior treatment with atezolizumab and/or CD137 agonists or immune checkpointblockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeuticantibodies.

3. Receipt of any type of small molecule kinase inhibitor (including investigationalkinase inhibitor) within 28 days before first dose of study treatment.

4. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 2 weeks before first dose of study treatment.

5. Radiation therapy for bone metastasis within 2 weeks or any other radiation therapywithin 4 weeks before first dose of study treatment. Systemic treatment withradionuclides within 6 weeks before first dose of study treatment. Subjects withclinically relevant ongoing complications from prior radiation therapy are noteligible.

6. Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeksprior to first dose of study treatment after radiotherapy or at least 4 weeks priorto first dose of study treatment after major surgery (e.g., removal or biopsy ofbrain metastasis). Subjects must have complete wound healing from major surgery orminor surgery before first dose of study treatment. Eligible subjects must beneurologically asymptomatic and without corticosteroid treatment at the time offirst dose of study treatment.

7. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombininhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or plateletinhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:

8. Prophylactic use of low-dose aspirin for cardio-protection (per localapplicable guidelines) and low-dose low molecular weight heparins (LMWH).

9. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitorsrivaroxaban, edoxaban, or apixaban in subjects without known brain metastaseswho are on a stable dose of the anticoagulant for at least 1 week before firstdose of study treatment without clinically significant hemorrhagiccomplications from the anticoagulation regimen or the tumor.

10. The subject has uncontrolled, significant intercurrent or recent illness including,but not limited to, the following conditions: a) Cardiovascular disorders: i. Congestive heart failure New York Heart AssociationClass 3 or 4, unstable angina pectoris, serious cardiac arrhythmias. ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hgsystolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment. iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI),or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis,pulmonary embolism) within 6 months before first dose of study treatment. iv. Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 monthsare allowed if stable, asymptomatic, and treated with a stable dose of permittedanticoagulation (see exclusion criterion #6) for at least 1 week before first doseof study treatment. b) Gastrointestinal (GI) disorders including those associated with a high risk ofperforation or fistula formation: i. The subject has evidence of tumor invading theGI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn'sdisease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis,acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, orgastric outlet obstruction. ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscesswithin 6 months before first dose of study treatment. iii. Note: Complete healing of an intra-abdominal abscess must be confirmed beforefirst dose of study treatment.

11. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5ml) of red blood, or other history of significant bleeding (e.g., pulmonaryhemorrhage) within 12 weeks before first dose of study treatment.

12. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial diseasemanifestation.

13. Lesions invading or encasing any major blood vessels.

14. History of leptomeningeal disease

15. Uncontrolled tumor-related pain

16. Patients requiring pain medication must be on a stable regimen at study entry.

17. Symptomatic lesions (e.g., bone metastases or metastases causing nerveimpingement) amenable to palliative radiotherapy should be treated prior toenrollment. Patients should be recovered from the effects of radiation. Thereis no required minimum recovery period.

18. Asymptomatic metastatic lesions that would likely cause functional deficits orintractable pain with further growth (e.g., epidural metastasis that is notcurrently associated with spinal cord compression) should be considered forloco-regional therapy if appropriate prior to enrollment.

19. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures a) Patients with indwelling catheters are allowed.

20. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium >ULN)

21. Active or history of autoimmune disease or immune deficiency, including, but notlimited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipidantibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barrésyndrome, or multiple sclerosis (see Appendix III for a more comprehensive list ofautoimmune diseases and immune deficiencies), with the following exceptions:

22. Patients with a history of autoimmune-related hypothyroidism who are onthyroid-replacement hormone are eligible for the study.

23. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimenare eligible for the study.

24. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis areexcluded) are eligible for the study provided all of following conditions aremet: i. Rash must cover < 10% of body surface area ii. Disease is well controlled atbaseline and requires only low-potency topical corticosteroids iii. No occurrence ofacute exacerbations of the underlying condition requiring psoralen plus ultravioletA radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors,or high-potency or oral corticosteroids within the previous 12 months

25. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis on screening chest computed tomography (CT) scan a) History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

26. Active infection requiring systemic treatment with the following exceptions:

27. Urinary tract infections

28. HCV on active treatment

29. Patients with SARS-COV-2 infections with the following exceptions: a) Recovery from active symptoms 30 days prior to treatment start.

30. Known history of infection with human immunodeficiency virus (HIV) or acquiredimmunodeficiency syndrome (AIDS)-related illness, or a known positive test fortuberculosis due to tuberculosis infection.

31. Other clinically significant disorders as deemed by the investigator, that wouldpreclude safe study participation.

32. Serious non-healing wound/ulcer/bone fracture.

33. Uncompensated/symptomatic hypothyroidism.

34. Moderate to severe hepatic impairment.

35. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy ofbrain metastasis) within 4 weeks before first dose of study treatment. Subjects musthave complete wound healing from major surgery or minor surgery before first dose ofstudy treatment. Subjects with clinically relevant ongoing complications from priorsurgery are not eligible.

36. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms perelectrocardiogram (ECG) within 14 days before first dose of study treatment [addreference for Fridericia formula]. Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additionalECGs at intervals of approximately 3 min must be performed within 30 min after theinitial ECG, and the average of these three consecutive results for QTcF will beused to determine eligibility.

37. Treatment with systemic immunostimulatory agents (including, but not limited to,interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment

38. Treatment with systemic immunosuppressive medication (including, but not limited to,corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, oranticipation of need for systemic immunosuppressive medication during studytreatment, with the following exceptions:

39. Patients who received acute, low-dose systemic immunosuppressant medication ora one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hoursof corticosteroids for a contrast allergy) are eligible for the study afterPrincipal Investigator confirmation has been obtained.

40. Patients who received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, orlow-dose corticosteroids for orthostatic hypotension or adrenal insufficiencyare eligible for the study.

41. History of severe allergic anaphylactic reactions to chimeric or humanizedantibodies or fusion proteins

42. Known hypersensitivity to Chinese hamster ovary cell products or to any component ofthe atezolizumab formulation

43. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatmentof within 6 months after the final dose of study treatment. Women of childbearingpotential must have a negative serum pregnancy test result within 14 days prior toinitiation of study treatment.

44. Inability to swallow tablets.

45. Previously identified allergy or hypersensitivity to components of the studytreatment formulations.

46. Any other active malignancy at time of first dose of study treatment or diagnosis ofanother malignancy within 3 years prior to first dose of study treatment thatrequires active treatment, except for locally curable cancers that have beenapparently cured, such as basal or squamous cell skin cancer, superficial bladdercancer, or carcinoma in situ of the prostate, cervix, or breast.

47. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation ofstudy treatment, or anticipation of need for such a vaccine during atezolizumabtreatment or within 5 months after the final dose of atezolizumab.

48. Prior allogeneic stem cell or solid organ transplantation.