A Randomized, Controlled Phase 3 Study of Cabozantinib (XL184) in Combination with Atezolizumab versus Sorafenib in Subjects with Advanced Hepatocellular Carcinoma Who Have Not Received Previous Systemic Anticancer Therapy
- Conditions
- advanced hepatocellular carcinoma / liver cancer10019815
- Registration Number
- NL-OMON56004
- Lead Sponsor
- Exelixis, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 30
Inclusion Criteria 1. Histological or cytological diagnosis of HCC or clinical
diagnosis of HCC in cirrhotic patients by multiphase imaging using CT or MRI
per the American Association for the Study of Liver Diseases (AASLD) (Marrero
et al 2018) or European Association for the Study of the Liver (EASL 2018)
guidelines. Note: Sites must receive Sponsor accreditation for imaging-based
diagnosis of HCC prior to implementing this methodology. In addition, subjects
who do not meet the AASLD or EASL guidelines for imaging diagnosis of HCC or
who do not have cirrhosis must have histological or cytological diagnosis of
HCC. 2. The subject has disease that is not amenable to a curative treatment
approach (eg, transplant, surgery, ablation therapy) or locoregional therapy
(eg, TACE). 3. The subject is receiving antiviral therapy per local standard of
care if the subject has active HBV infection (defined by HBsAg positive); the
subject must have HBV DNA < 500 IU/mL. 4. Measurable disease per RECIST 1.1
as determined by the Investigator. 5. Barcelona Clinic Liver Cancer (BCLC)
stage Category B or C. 6. Child-Pugh Score of A. 7. Recovery to baseline or <=
Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v5 from
toxicities related to any prior treatments, unless AE(s) are clinically
nonsignificant and/or stable on supportive therapy as determined by the
Investigator. 8. Age eighteen years or older on the day of consent. 9. Eastern
Cooperative Oncology Group (ECOG) performance status of 0 or 1. 10. Adequate
organ and marrow function, based upon meeting all of the following laboratory
criteria within 14 days prior to randomization: a. Absolute neutrophil count
(ANC) >= 1500/µL (>= 1.5 × 10 9/L) without granulocyte colony-stimulating factor
support within 2 weeks before screening laboratory sample collection. b. White
blood cell (WBC) count >= 2000/µL (>= 2.0 × 10 9/L). c. Platelets >= 60,000/µL (>=
60 × 10 9/L) without transfusion within 2 weeks before screening laboratory
sample collection. d. Hemoglobin >= 9 g/dL (>= 90 g/L) without transfusion within
2 weeks before screening laboratory sample collection. e. Hemoglobin A1c
(HbA1c) <= 8% within 28 days before randomization (if HbA1c results are
unavailable [eg, hemoglobin variant], a fasting serum glucose <= 160 mg/dL) f.
Alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) <= 5 × upper
limit of normal (ULN). g. Total bilirubin <= 2 mg/dL (<= 34.2 µmol/L). h. Serum
albumin >= 2.8 g/dL (>= 28 g/L). i. Serum creatinine <= 1.5 × ULN or calculated
creatinine clearance >= 40 mL/min (>= 0.67 mL/sec) using the Cockcroft-Gault
equation. j. Urine protein/creatinine ratio (UPCR) <= 1 mg/mg (<= 113.2 mg/mmol),
or 24-h protein <= 1 g. 11. Capable of understanding and complying with the
protocol requirements and must have signed the informed consent document prior
to any screening assessment except those procedures performed as standard of
care within the screening window. 12. Sexually active fertile subjects and
their partners must agree to use highly effective methods of contraception that
alone or in combination result in a failure rate of less than 1% per year when
used consistently and correctly (see Appendix I) during the course of the study
and for 5 months after the last dose of study treatment. A barri
Exclusion Criteria 1. Known fibrolamellar carcinoma, sarcomatoid HCC or mixed
hepatocellular cholangiocarcinoma. 2. Prior systemic anticancer therapy for
advanced HCC including but not limited to chemotherapy, small molecule kinase
inhibitors, and ICIs. Subjects who have received local intratumoral or arterial
chemotherapy are eligible. 3. Documented hepatic encephalopathy (HE) within 6
months before randomization. 4. Clinically meaningful ascites (ie, ascites
requiring paracentesis or escalation in diuretics) within 6 months before
randomization. 5. Subjects who have received any local anticancer therapy
including surgery, PEI, RFA, MWA, transarterial chemoembolization (TACE), or
transarterial radioembolization (TARE)within 28 days prior to randomization 6.
Radiation therapy for bone metastasis within 2 weeks, any other external beam
radiation therapy within 8 weeks prior to randomization. Subjects with
clinically relevant ongoing complications from prior radiation therapy are not
eligible. 7. Known brain metastases or cranial epidural disease unless
adequately treated with radiotherapy and/or surgery (including radiosurgery)
and stable for at least 8 weeks prior to randomization. Subjects who are
neurologically symptomatic or are receiving systemic corticosteroid treatment
at the planned time of randomization are not eligible. 8. Concomitant
anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and
Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel), except for the
following allowed anticoagulants: • Low-dose aspirin for cardioprotection (per
local applicable guidelines) and low-dose low molecular weight heparins (LMWH)
9. Administration of a live, attenuated vaccine within 30 days prior to
randomization. 10. Any subject who cannot be evaluated by either triphasic
liver computed tomography (CT) or triphasic liver magnetic resonance imaging
(MRI) because of allergy or other contraindication to both CT and MRI contrast
agents. 11. The subject has uncontrolled, significant intercurrent or recent
(within the last 3 months before randomization [unless otherwise specified
below]) illness including, but not limited to, the following conditions: a.
Cardiovascular and cardiac disorders: i. Congestive heart failure (CHF) class
III or IV as defined by the New York Heart Association, 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 (eg, deep vein thrombosis [DVT], pulmonary
embolism) within 6 months before randomization. iv. History of risk factors for
torsades de pointes (eg, long QT syndrome). b. Gastrointestinal (GI) disorders
including those associated with a high risk of perforation or fistula
formation: i. Tumors invading the GI-tract, active peptic ulcer disease,
inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic
cholangitis or appendicitis, acute pancreatitis or acute obstruction of the
pancreatic or biliary duct, or gastric outlet obstruction. ii. Abdominal
fistula, GI perforation, bowel obstruction, or intra-abdominal
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary Efficacy Endpoints:<br /><br>• Duration of PFS per RECIST 1.1, by BIRC for the experimental arm<br /><br>(cabozantinib + atezolizumab) vs the control arm (sorafenib)<br /><br>• Duration of OS for the experimental arm (cabozantinib + atezolizumab) vs the<br /><br>control arm (sorafenib)</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary efficacy endpoint:<br /><br>• PFS per RECIST 1.1 by BIRC for the single-agent cabozantinib arm vs the<br /><br>control arm (sorafenib)<br /><br><br /><br>Additional endpoints:<br /><br>• ORR, time to progression (TTP), and DOR per RECIST 1.1 by BIRC and<br /><br>Investigator<br /><br>• Evaluation of radiographic response per modified RECIST (mRECIST)<br /><br>• Safety through the evaluation of AEs, including irAEs and other AESIs.<br /><br>• Characterization of the pharmacokinetics (PK) of cabozantinib in subjects<br /><br>with previously untreated HCC<br /><br>• Immunogenicity of atezolizumab given in combination with cabozantinib<br /><br>• Change in serum AFP from baseline<br /><br>• Correlation of biomarker analyses with clinical outcomes<br /><br>• Health-related quality of life (HRQOL) as assessed by the EuroQol Health<br /><br>questionnaire instrument (EQ-5D-5L)<br /><br>• Healthcare resource utilization</p><br>