Cabozantinib and Pembrolizumab for the First-Line Treatment of Advanced Liver Cancer
Condition: Advanced Hepatocellular Carcinoma; BCLC Stage B Hepatocellular Carcinoma; BCLC Stage C Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Cabozantinib S-malate; Pembrolizumab
Intervention description: Given PO; Given IV
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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 6 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: Main and 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