Cabozantinib and Pembrolizumab for the First-Line Treatment of Advanced Liver Cancer
Cabozantinib and Pembrolizumab for the First-Line Treatment of Advanced Liver Cancer
This phase II trial studies how well cabozantinib and pembrolizumab work for the first-line
 treatment of patients with liver cancer who are not eligible for local therapy (i.e. advanced
 stage). Cabozantinib may stop the growth of tumor cells by blocking some cell surface
 receptors and signaling pathways inside the tumor cells. Immunotherapy with monoclonal
 antibodies, such as pembrolizumab, may help the body's immune system attack the cancer.
 Giving cabozantinib and pembrolizumab together may work better in treating patients with
 advanced liver cancer compared to cabozantinib or pembrolizumab alone.
OUTLINE:

 Patients receive cabozantinib S-malate orally (PO) once daily (QD) on days 1-21 and
 pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for up
 to 2 years in the absence of disease progression or unacceptable toxicity. Disease assessment
 by imaging will be performed every 9 weeks.
Inclusion Criteria:

 -  Must have a histologically confirmed diagnosis of HCC or a non-invasive diagnosis of
 HCC as per the American Association for the Study of Liver Diseases (AASLD) criteria

 -  If available, archival tissue must be submitted

 -  Mixed HCC-cholangiocarcinoma is not allowed

 -  Patient has Barcelona Clinic Liver Cancer (BCLC) stage C disease, or BCLC stage B
 disease that is not amenable to locoregional therapy or refractory to locoregional
 therapy, and not amenable to curative treatment

 -  Previous locoregional therapy is allowed (e.g. surgical resection, external beam
 radiation, catheter-based therapy), and patients must have evidence of disease
 progression from locoregional therapy

 -  Must have measurable disease by RECIST v1.1

 -  Lesions that were previously radiated or ablated cannot be target lesions unless
 there was subsequent radiographic progression at those sites

 -  No prior systemic therapy for HCC. Prior chemotherapy given locally into the liver
 (e.g. transarterial chemoembolization [TACE]) is allowed

 -  Must have Child-Pugh class A hepatic function within 7 days prior to first dose of
 study intervention

 -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

 -  Life expectancy of at least 12 weeks

 -  Recovery to baseline or =< grade 1 toxicities (CTCAE v5) related to any prior
 treatments, unless adverse events (AEs) are clinically nonsignificant and/or stable on
 supportive therapy

 -  Absolute neutrophil count (ANC) >= 1500/mm^3 without granulocyte colony-stimulating
 factor support (within 14 days before first dose of study treatment)

 -  Platelets >= 60,000/mm^3 without transfusion (within 14 days before first dose of
 study treatment)

 -  Hemoglobin >= 9 g/dL (>= 90 g/L) without transfusion or erythropoietin (EPO)
 dependency (within 14 days before first dose of study treatment)

 -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5 x upper limit
 of normal (ULN) (within 14 days before first dose of study treatment)

 -  Total bilirubin =< 2 mg/dL OR direct bilirubin =< ULN for participants with total
 bilirubin levels > 2 mg/dL (within 14 days before first dose of study treatment)

 -  Serum albumin >= 2.8 g/dl (>= 28 g/L) without albumin infusion (within 14 days before
 first dose of study treatment)

 -  Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin
 time (PTT) test =< 1.5 x ULN (within 14 days before first dose of study treatment)

 -  Serum creatinine =< 1.5 x ULN or calculated creatinine clearance >= 40 mL/min using
 the Cockcroft-Gault equation (within 14 days before first dose of study treatment)

 -  Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol) or 24 hour(h)
 urine protein =< 1 g (within 14 days before first dose of study treatment)

 -  Hemoglobin A1c (HbA1c) =< 8% within 28 days before randomization or fasting serum
 glucose =< 160 mg/dL (within 14 days before first dose of study treatment)

 -  Patients with positive hepatitis B surface antigen (HBsAg) and/or hepatitis B virus
 (HBV) viral load > 100 IU/mL at the time of enrollment are eligible to enroll on study
 if they meet the following criteria:

 -  Anti-HBV therapy as per institutional practice must be given at least 4 weeks and
 HBV viral load must be < 100 IU/mL prior to initiating study treatment. Patients
 on active HBV therapy with viral loads < 100 IU/mL should remain on the same
 therapy throughout study treatment

 -  Note: Patients with positive anti-hepatitis B core antibody (HBcAb), negative
 HBsAg, and negative or positive anti-hepatitis B surface antibody, and who have
 an HBV viral load < 100 IU/mL do not require anti-viral prophylaxis

 -  Patients with past or ongoing hepatitis C infection (HCV) are eligible to enroll on
 study, with or without prior anti-viral treatment, as long as the other eligibility
 criteria are met. Treated patients must have completed their anti-viral treatment at
 least 1 month prior to initiating study treatment

 -  Sexually active fertile subjects and their partners must agree to use effective
 methods of contraception during the course of the study and for at least 4 months
 after the last dose cabozantinib. They must also refrain from donating sperm during
 this time period

 -  Female subjects of childbearing potential must not be pregnant at screening and not
 breastfeeding. Females of childbearing potential are defined as premenopausal females
 capable of becoming pregnant (i.e. females who have had any evidence of menses in the
 past 12 months, with the exception of those who had prior hysterectomy)

 -  Women who have been amenorrheic for 12 or more months are still considered to be
 of childbearing potential if the amenorrhea is possibly due to prior
 chemotherapy, antiestrogens, low body weight, ovarian suppression or other
 reasons

 -  Capable of understanding and complying with the protocol requirements and must provide
 written informed consent/assent for the study

 Exclusion Criteria:

 -  Prior treatment with any systemic therapy for HCC, including anti-VEGF therapy or any
 systemic investigational agent

 -  If the patient previously received systemic treatment for reasons other than HCC:
 small molecule kinase inhibitors are not allowed within 2 weeks and
 cytotoxic/biologic agents are not allowed within 4 weeks of study treatment

 -  Prior exposure to immune checkpoint inhibitors or other immunotherapeutic agents

 -  Currently participating in or has participated in a study of an investigational agent
 or device within 4 weeks prior to the first dose of study treatment

 -  Major surgery within 6 weeks or minor surgery (e.g. dental extraction) within 10 days
 prior to first dose of study treatment

 -  Complete wound healing from major surgery must have occurred at least 1 month
 before first dose and from minor surgery (e.g. simple excision, tooth extraction)
 at least 7 days before first dose. Subjects with clinically relevant ongoing
 complications from prior surgery are not eligible

 -  Local liver-directed therapy within 4 weeks of initiating study treatment

 -  Palliative radiation for the purpose of symptomatic relief to non-liver and
 non-central nervous system (CNS) disease within 2 weeks of starting treatment. Other
 radiation treatments within 4 weeks of starting treatment

 -  Patients must have recovered from all radiation-related toxicities, not require
 corticosteroids, and have not had radiation pneumonitis

 -  Prior liver or other allogenic tissue/organ transplantation

 -  History of primary immunodeficiency

 -  Active autoimmune or inflammatory disease that has required systemic treatment in the
 past 2 years (i.e. with use of disease-modifying agents, corticosteroids or
 immunosuppressive drugs). This includes, but is not limited to, inflammatory bowel
 disease, celiac disease, systemic lupus erythematosus, rheumatoid arthritis,
 myasthenia gravis, Graves' disease, etc.

 -  The following autoimmune conditions are allowed: vitiligo or alopecia;
 hypothyroidism on stable hormone replacement therapy; psoriasis/eczema not
 requiring systemic treatment

 -  Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
 replacement therapy for adrenal or pituitary insufficiency) is not considered a
 form of systemic treatment and is allowed

 -  Chronic use of systemic steroid (in dosing exceeding 10 mg daily of prednisone
 equivalent) or immunosuppressive therapy or use within 14 days prior to enrollment

 -  The following treatments are allowed: intranasal, inhaled, topical or local
 steroid injections; systemic corticosteroids at physiologic doses equivalent to
 no more than prednisone 10 mg/day; steroids as premedication for contrast dye
 allergy

 -  History of (non-infectious) pneumonitis that required steroids or has current
 pneumonitis

 -  History of hepatic encephalopathy or treatment to prevent or control encephalopathy
 within the past 12 months. Subjects on lactulose and/or rifaximin to control hepatic
 encephalopathy are not allowed

 -  Esophageal or gastric variceal bleeding within the past 6 months. All subjects will be
 screened for esophageal varices unless performed in the last 12 months before study
 treatment. If varices are present, they should be treated according to institutional
 standards before starting study treatment

 -  Uncontrolled ascites, clinically significant or symptomatic ascites requiring
 paracenteses or increasing doses of diuretics within the past 3 months

 -  Patients who are on stable diuretic doses for at least 3 months are eligible if
 they meet other eligibility criteria

 -  Asymptomatic ascites detected on imaging are allowed

 -  Has known history or any evidence of CNS metastases and/or carcinomatous meningitis.
 Subjects with previously treated brain metastases may participate provided they are
 asymptomatic and radiologically stable (i.e. without progression for at least 4 weeks
 by repeat imaging [which must be performed during study screening], clinically stable,
 and without the need steroids for at least 4 weeks prior to first dose of study
 treatment)

 -  Concomitant anticoagulation with oral anticoagulants (e.g. warfarin, direct thrombin
 and factor Xa inhibitors) or platelet inhibitors (e.g. clopidogrel). Allowed
 anticoagulants are the following:

 -  Low-dose aspirin for cardioprotection (per local applicable guidelines) is
 permitted

 -  Low molecular weight heparin (LMWH) is permitted

 -  Anticoagulation with therapeutic doses of LMWH is allowed in subjects without
 known brain metastases who are on a stable dose of LMWH for at least 4 weeks
 before first dose of study treatment, and who have had no clinically significant
 hemorrhagic complications from the anticoagulation regimen or the tumor

 -  The subject has uncontrolled, significant intercurrent or recent illness including,
 but not limited to, the following conditions:

 -  Cardiovascular disorders:

 -  Congestive heart failure New York Heart Association class 3 or 4, unstable
 angina pectoris, serious cardiac arrhythmias with risk of hemodynamic
 instability within 12 months before the first dose of study treatment

 -  Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm
 Hg systolic or > 95 mm Hg diastolic despite optimal antihypertensive
 treatment, and/or change in antihypertensive medications within 1 week
 before starting treatment. Note: eligibility of a subject receiving 4 or
 more antihypertensive medications prior to study entry will require approval
 from the principal investigator (PI)

 -  Stroke (including transient ischemic attack [TIA]), myocardial infarction
 (MI), or other ischemic event, or arterial thromboembolic within 12 months
 before the first dose

 -  Asymptomatic venous thromboembolic event (e.g. deep venous thrombosis,
 pulmonary embolism) is allowed if the patient has been stable on
 anticoagulation with LMWH for at least 4 weeks

 -  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), GI
 malabsorption, 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

 -  Note: Complete healing of an intra-abdominal abscess must be confirmed
 before first dose

 -  Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon
 (2.5 ml) of red blood, other history of significant bleeding (e.g. pulmonary
 hemorrhage) within 12 weeks before first dose, or known thrombotic disorder

 -  Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
 manifestation

 -  Lesions invading any major blood vessels, including main portal vein, inferior
 vena cava, or cardiac involvement of HCC based on imaging

 -  Note: Branch portal vein and hepatic vein invasion is allowed

 -  Ongoing active infection requiring antibiotics. Antibiotics must be completed at
 least 7 days before initiating study treatment

 -  Known active tuberculosis

 -  Serious non-healing wound, ulcer, or bone fracture

 -  Patients with proteinuria > 1+ on urine dipstick testing will undergo 24-hour urine
 collection for quantitative assessment of proteinuria. Participants with urine protein
 >= 1 g/24 hours will be ineligible

 -  Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per
 electrocardiogram (EKG) within 28 days before first dose of study treatment

 -  Note: If a single EKG shows a QTcF with an absolute value > 500 ms, two
 additional EKGs at intervals of approximately 3 min must be performed within 30
 min after the initial EKG, and the average of these three consecutive results for
 QTcF will be used to determine eligibility

 -  Inability to swallow tablets or any other condition that might interfere with oral
 absorption of medications

 -  Previously identified allergy or hypersensitivity to study drugs and/or any of their
 excipients

 -  Ongoing secondary malignancy that is progressing and/or has required active treatment
 within the past year. Adjuvant treatment for resected breast cancer is allowed

 -  Subjects with basal cell carcinoma of the skin, squamous cell carcinoma or the
 skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that
 have undergone potentially therapy are allowed

 -  Has a known history of human immunodeficiency virus (HIV) infection. Note: HIV testing
 is not mandated for screening

 -  Co-infection with HBV (HBsAg [+] and /or detectable HBV DNA) and HCV (anti-HCV Ab [+]
 and detectable HCV ribonucleic acid [RNA]) at study entry

 -  Co-infection with HBV and hepatitis D virus (HDV) at study entry

 -  Live attenuated vaccine within 30 days prior to first dose of study treatment.
 Examples of live vaccines include, but are not limited to, the following: measles,
 mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
 Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
 are generally killed virus vaccines and are allowed; however, intranasal influenza
 vaccines (e.g. FluMist) are live attenuated vaccines and are not allowed

 -  Pregnant or lactating females

 -  Known psychiatric illness, substance abuse disorder, or other condition that would
 interfere with the ability to comply with the requirements of the study

 -  Has 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