Inclusion Criteria:
1. Stage IV pancreatic adenocarcinoma, confirmed by histology or cytology.
2. Clinical and/or radiographic progression on and/or intolerance to and/or ineligibility
for treatment with at least one of the following: a fluoropyrimidine or gemcitabine
based chemotherapy treatment regimens
3. Radiographically measurable disease by Response Evaluation Criteria in Solid Tumors
version 1.1 (RECIST 1.1). Images (MRI or CT Scan) must be completed within two weeks
prior 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 of treatment
and may be eligible pending subject meeting all other inclusion/exclusion criteria.
6. Adequate organ and marrow function, based upon meeting all of the following laboratory
criteria within 14 days before first dose of study treatment:
1. Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte colony-stimulating
factor support.
2. White blood cell count ≥ 2500/µL including Lymphocyte count ≥ 500/µL.
3. Platelets ≥ 100,000/µL without transfusion.
4. Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN) with the following
exceptions:
Patients with documented liver metastases: AST and ALT ≤ 5 x ULN Patients with
documented liver or bone metastases: ALP ≤ 5 x ULN
6. Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3 x ULN).
7. Serum albumin ≥ 2.8 g/dl
8. (PT)/INR or partial thromboplastin time (PTT) test < 1.3 x the laboratory ULN
9. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 mL/min using
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-h urine
protein ≤ 1 g
7. No clinically significant hypertension as per treating physician or if hypertension,
adequate control with anti-hypertensives
8. Negative hepatitis B surface antigen (HBsAg) test at screening
9. ECOG performance status ≤ 1
10. Recovered to baseline or to CTCAE v5.0 ≤ Grade 1 treatment-related toxicity from prior
therapies
11. At least two weeks since last dose of prior treatment
12. Sexually active fertile subjects and their partners must agree to use medically
accepted methods of contraception (e.g., barrier methods, including male condom,
female condom, or diaphragm with spermicidal gel) during the course of the study and
for 6 months after the last dose of study treatment.
13. Female subjects of childbearing potential must not be pregnant at screening. Female
subjects are considered to be of childbearing potential unless one of the following
criteria are met: documented permanent sterilization (hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined
as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other
biological or physiological causes. In addition, females < 55 years-of-age must have a
serum follicle stimulating (FSH) level > 40 mIU/mL to confirm menopause). Note:
Documentation may include review of medical records, medical examinations, or medical
history interview by study site.
14. 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 other PD-1/PDL-1 checkpoint inhibitor.
3. Receipt of any type of small molecule kinase inhibitor (including investigational
kinase inhibitor) within 2 weeks 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 therapy
within 4 weeks before first dose of study treatment. Systemic treatment with
radionuclides within 6 weeks before first dose of study treatment. Subjects with
clinically relevant ongoing complications from prior radiation therapy are not
eligible.
6. Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to
first dose of study treatment after major surgery (e.g., removal or biopsy of brain
metastasis). Subjects must have complete wound healing from major surgery or minor
surgery before first dose of study treatment. Eligible subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of first dose of study
treatment.
7. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet
inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
1. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH).
2. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who
are on a stable dose of the anticoagulant for at least 1 week before first dose
of study treatment without clinically significant hemorrhagic complications from
the anticoagulation regimen or the tumor.
8. 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 Association
Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg
systolic 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 months
are allowed if stable, asymptomatic, and treated with a stable dose of permitted
anticoagulation (see exclusion criterion #6) for at least 1 week before first dose of
study treatment.
b) Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation: i. The subject has evidence of tumor invading the GI
tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn's
disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis,
acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or
gastric outlet obstruction.
ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
within 6 months before first dose of study treatment.
iii. Note: Complete healing of an intra-abdominal abscess must be confirmed before
first dose of study treatment.
9. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5
ml) of red blood, or other history of significant bleeding (e.g., pulmonary
hemorrhage) within 12 weeks before first dose of study treatment.
10. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation.
11. Lesions invading or encasing any major blood vessels.
12. History of leptomeningeal disease
13. Uncontrolled tumor-related pain
1. Patients requiring pain medication must be on a stable regimen at study entry.
2. Symptomatic lesions (e.g., bone metastases or metastases causing nerve
impingement) amenable to palliative radiotherapy should be treated prior to
enrollment. Patients should be recovered from the effects of radiation. There is
no required minimum recovery period.
3. Asymptomatic metastatic lesions that would likely cause functional deficits or
intractable pain with further growth (e.g., epidural metastasis that is not
currently associated with spinal cord compression) should be considered for
loco-regional therapy if appropriate prior to enrollment.
14. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures
a) Patients with indwelling catheters are allowed.
15. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12
mg/dL or corrected serum calcium >ULN)
16. Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome,
or multiple sclerosis (see Appendix III for a more comprehensive list of autoimmune
diseases and immune deficiencies), with the following exceptions:
1. Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
2. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
3. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are
met:
i. Rash must cover < 10% of body surface area ii. Disease is well controlled at
baseline and requires only low-potency topical corticosteroids iii. No occurrence of
acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A
radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or
high-potency or oral corticosteroids within the previous 12 months
17. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on screening chest computed tomography (CT) scan
a) History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
18. Active infection requiring systemic treatment with the following exceptions:
1. Urinary tract infections
2. HCV on active treatment
19. Patients with SARS-COV-2 infections with the following exceptions:
a) Recovery from active symptoms 30 days prior to treatment start.
20. Known history of infection with human immunodeficiency virus (HIV) or acquired
immunodeficiency syndrome (AIDS)-related illness, or a known positive test for
tuberculosis due to tuberculosis infection.
21. Other clinically significant disorders as deemed by the investigator, that would
preclude safe study participation.
1. Serious non-healing wound/ulcer/bone fracture.
2. Uncompensated/symptomatic hypothyroidism.
3. Moderate to severe hepatic impairment.
22. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain
metastasis) within 2 weeks before first dose of study treatment. Subjects must have
complete wound healing from major surgery or minor surgery before first dose of study
treatment. Subjects with clinically relevant ongoing complications from prior surgery
are not eligible.
23. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG) within 14 days before first dose of study treatment [add
reference for Fridericia formula].
Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional
ECGs at intervals of approximately 3 min must be performed within 30 min after the
initial ECG, and the average of these three consecutive results for QTcF will be used
to determine eligibility.
24. 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
25. Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, or
anticipation of need for systemic immunosuppressive medication during study treatment,
with the following exceptions:
1. Patients who received acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
corticosteroids for a contrast allergy) are eligible for the study after
Principal Investigator confirmation has been obtained.
2. Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible
for the study.
26. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
or fusion proteins
27. Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab formulation
28. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment
of within 6 months after the final dose of study treatment. Women of childbearing
potential must have a negative serum pregnancy test result within 14 days prior to
initiation of study treatment.
29. Inability to swallow tablets.
30. Previously identified allergy or hypersensitivity to components of the study treatment
formulations.
31. Any other active malignancy at time of first dose of study treatment or diagnosis of
another malignancy within 3 years prior to first dose of study treatment that requires
active treatment, except for locally curable cancers that have been apparently cured,
such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma
in situ of the prostate, cervix, or breast.
