Cabozantinib and Pembrolizumab for the Treatment of Metastatic Pancreatic Cancer

Inclusion Criteria

• Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of pancreatic ductal adenocarcinoma, stage IV will be enrolled in this study
• Have measurable disease based on RECIST version (v)1.1 (Response Evaluation Criteria in Solid Tumors). Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
• Evidence of progression or intolerance to previous standard of care pancreatic cancer systemic or locoregional therapies. Patients may have received prior radiation therapy and chemotherapy > 4 weeks from start of treatment. Patients may not have been on prior clinical trial with investigational drugs for this cancer
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7-14 days prior to the first dose of study intervention
• Absolute neutrophil count >= 1,500/uL (within 14 days prior to the start of study intervention)
• Platelets >= 100,000/uL (within 14 days prior to the start of study intervention)
• Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (within 14 days prior to the start of study intervention); criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• Total bilirubin =< 1.5 x upper limit of normal (ULN) or direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (within 14 days prior to the start of study intervention)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases) (within 14 days prior to the start of study intervention)
• Alkaline phosphatase =< 3 x ULN (within 14 days prior to the start of study intervention)
• International normalized ratio (INR) or prothrombin time (PT) and activated thrombo-plastin time (aPTT) =< 1.3 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (within 14 days prior to the start of study intervention)
• Serum creatinine (Cr) =< 1.5 x ULN or calculated creatinine clearance (glomerular filtration rate [GFR] can be use in place of Cr or creatinine clearance [CrCl]) >= 30 mL/min (>= 0.5 mL/sec, using Cockcroft-Gault equation) for participants with Cr >= 1.5 x ULN (within 14 days prior to the start of study intervention)
• Urine protein/creatinine ratio UPCR =< 1 mg/mg (=< 113.2 mg/mmol) (within 14 days prior to the start of study intervention)
• Patients must have a negative hepatitis screening test. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• A male participant must agree to use a contraception during the treatment period and for 4 months after the last dose of study treatment and refrain from donating sperm during this period Male participants with female partners of childbearing potential are eligible to participate if they agree to one of the following during the protocol defined time frame in section X: * Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent * Use a male condom plus partner use of a contraceptive method with a failure rate of < 1% per year when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant ** Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOBCP) or * A WOCBP who agrees to follow contraceptive guidance during the treatment period and for 4 months after the last dose of treatment
• A woman is considered fertile following menarche and until becoming post-menopausal unless permanently sterile (see below). Women in the following categories are not considered WOCBP: * Premenarchal * Premenopausal female with 1 of the following: ** Documented hysterectomy ** Documented bilateral salpingectomy ** Documented bilateral oophorectomy * Note: Documentation can come from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview * Postmenopausal female ** A postmenopausal state is defined as no menses for 12 months without an alternative medical cause *** A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with two FSH measurements in the postmenopausal range is required ** Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment
• Female participants of childbearing potential are eligible to participate if they agree to use a highly effective method of contraception that has a low user dependency consistently and correctly
• The participant (or legally acceptable representative if applicable) has the ability to understand and the willingness to provide written informed consent for the trial

Exclusion Criteria

• Chemotherapy or other locoregional anti-tumoral therapies performed within 28 days of study treatment initiation
• Has received palliative radiation therapy within 2 weeks or any other radiation therapy within 4 weeks of start of study intervention. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-CNS disease. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1), unless adverse events (AEs) are clinically non-significant and/or stable on supportive therapy. Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with =< grade 2 neuropathy may be eligible
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to allocation. Participants must have recovered from all AEs due to previous therapies to =< grade 1 or baseline. Participants with =< grade 2 neuropathy may be eligible. Participants with endocrine-related AEs grade =< 2 requiring treatment or hormone replacement may be eligible. If the participant received major surgery, the participant must have recovered adequately from the procedure and/or complications from the procedure and/or any complications from the surgery prior to starting study intervention
• Has known active CNS metastases or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention
• Has severe hypersensitivity (>= grade 3) to pembrolizumab or cabozantinib and/or any of their excipients. History of allergic reactions attributed to monoclonal antibodies (mAb), compounds of similar chemical or biologic composition to cabozantinib or pembrolizumab
• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
• Prior treatment with Cabozantinib or other receptor for MET or dual MET/HGF monoclonal antibodies or MET/HGF tyrosine kinase inhibitors
• Major surgery (e.g., laparoscopic nephrectomy, gastrointestinal [GI] surgery, removal or biopsy of brain metastasis) within 2 weeks before first dose of study treatment. Minor surgeries within 10 days 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
• Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: * 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 * Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose of study treatment * Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment
• Has a history of known additional malignancy that is progressing or has required active treatment within the past 3 years; or unless potentially curative treatment has been completed with no evidence of malignancy for 3 years. The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in-situ cancers (e.g., breast carcinoma)
• Has a diagnosis of immunodeficiency (autoimmune disease) or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to first dose of study treatment * Note: Inhaled, intranasal, intraarticular, and topical corticosteroids and mineralocorticoids are allowed. Transient short-term use of systemic corticosteroids for allergic conditions (e.g., contrast allergy) is also allowed. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
• Clinically significant cardiovascular disease, for example cerebrovascular accidents (less than 6 months, cardiovascular accident [CVA]) /stroke, myocardial infarction (also less than 6 months), unstable angina pectoris, New York Heart Association class 3 or 4 congestive heart failure, or serious cardiac arrhythmia requiring medication
• Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment
• QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment * 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 (i.e., if the average is =< 500 ms the patient is eligible)
• Concomitant anticoagulation with or plan to use oral anticoagulants (warfarin, direct thrombin and factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following: * Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH) * 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
• Pregnant, breastfeeding, and/or lactating women. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation will be excluded. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman over 45 years-of-age in the absence of other biological or physiological causes. In addition, females under 55 years-of-age must have a serum follicle stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause)
• Patients that are expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
• Patients with uncontrolled intercurrent illness
• Patients with known psychiatric illness or substance abuse disorders or other social situations that would interfere with cooperation with the requirements of the trial
• Inability to swallow tablets
• Has had an allogenic tissue/solid organ transplant
• 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
• Cavitating pulmonary lesion(s) related to bacterial infections or pneumonia or known endotracheal or endobronchial disease manifestation. Note that cavitating pulmonary lesion(s) related to malignancy, with the exception of central lesions measuring >= 4 cm, are not excluded.
• Lesions invading or encasing major blood vessels, specifically the abdominal aorta and inferior vena cava. Encasement of local vascular structure(s) is not excluded
• Other clinically significant disorders that would preclude safe study participation * Serious non-healing wound/ulcer/bone fracture * Uncompensated/symptomatic hypothyroidism
• Moderate to severe hepatic impairment (Child-Pugh B or C)
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
• Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection
• Has a known history of active TB (Bacillus tuberculosis)
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator