Skip to content
Triangle logo TriangleGet started
← Study library

NCT03755791 · CITED IN SOURCE DOCUMENTS

Study of Cabozantinib in Combination With Atezolizumab Versus Sorafenib in Participants With Advanced Hepatocellular Carcinoma (HCC) Who Have Not Received Previous Systemic Anticancer Therapy

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
ACTIVE NOT RECRUITING
Registry last update
2025-12-11

This Phase 3 study evaluates the safety and efficacy of cabozantinib in combination with atezolizumab versus the standard of care sorafenib in adults with advanced hepatocellular carcinoma (HCC) who have not received previous systemic anticancer therapy. A single-agent cabozantinib arm will be enrolled in which participants receive single agent cabozantinib in order to determine its contribution to the overall safety and efficacy of the combination with atezolizumab.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

→

baseline

Baseline characteristics

→

outcome · POSTED

Progression Free Survival (PFS) for the Experimental Arm Versus the Control Arm in the PFS Intent to Treat (PITT) Population

→

outcome · POSTED

Overall Survival (OS) for the Experimental Arm Versus the Control Arm in the ITT Population

→

outcome · POSTED

PFS for the Single-Agent Cabozantinib Arm Versus the Control Arm in the ITT Population

→

adverse events

Adverse events

→

more info

Limitations, agreements, and source contact

→
Who could take part
eligibility Criteria
Key Inclusion Criteria: * Histological or cytological diagnosis of HCC or clinical diagnosis of HCC in cirrhotic patients by Computed Tomography (CT) or Computed Tomography (MRI) per the American Association for the Study of Liver Diseases (AASLD) 2018 or European Association for the Study of the Liver (EASL) 2018 guidelines. * The participant has disease that is not amenable to a curative treatment approach (eg, transplant, surgery, ablation therapy) or locoregional therapy (eg, TACE). * Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the Investigator. * Barcelona Clinic Liver Cancer (BCLC) stage Category B or C. * Child-Pugh Score of A. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Key Exclusion Criteria: * Known fibrolamellar carcinoma, sarcomatoid HCC or mixed hepatocellular cholangiocarcinoma. * Prior systemic anticancer therapy for advanced HCC including but not limited to chemotherapy, small molecule kinase inhibitors, and immune checkpoint inhibitors (ICIs). Participants who have received local intratumoral or arterial chemotherapy are eligible; local anticancer therapy within ≥ 28 days before randomization * Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 8 weeks prior to randomization. * 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. * Concomitant anticoagulation with oral anticoagulants Note: Other protocol defined Inclusion/Exclusion criteria may apply.
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    Participants with advanced HCC will receive cabozantinib 40 milligrams (mg) oral, once daily (qd) + atezolizumab 1200 mg infusion, once every 3 weeks (q3w)
    intervention Names
    1. Drug: Cabozantinib
    2. Drug: Atezolizumab
    label
    Experimental arm
    type
    EXPERIMENTAL
  2. description
    Participants with advanced HCC will receive sorafenib 400 mg twice a day (bid)
    intervention Names
    1. Drug: Sorafenib
    label
    Control arm
    type
    ACTIVE_COMPARATOR
  3. description
    Participants with advanced HCC will receive cabozantinib 60 mg qd
    intervention Names
    1. Drug: Cabozantinib
    label
    Single-Agent Cabozantinib arm
    type
    OTHER
interventions
  1. arm Group Labels
    1. Experimental arm
    description
    Supplied as 20-mg tablets; administered orally daily at 40 mg
    name
    Cabozantinib
    other Names
    1. XL184
    2. Cabometyx®
    type
    DRUG
  2. arm Group Labels
    1. Single-Agent Cabozantinib arm
    description
    Supplied as 60-mg tablets; administered orally once daily at 60 mg
    name
    Cabozantinib
    other Names
    1. XL184
    2. Cabometyx®
    type
    DRUG
  3. arm Group Labels
    1. Control arm
    description
    Supplied as 200-mg tablets; administered orally twice daily at 400 mg
    name
    Sorafenib
    other Names
    1. Nexavar®
    type
    DRUG
  4. arm Group Labels
    1. Experimental arm
    description
    Supplied as 1200 mg/20 mL (60 mg/mL) in sing-dose vials; administered as an intravenous (IV) infusion q3w
    name
    Atezolizumab
    other Names
    1. Tecentriq®
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
intervention Model Description
At least 740 eligible participants with advanced HCC will be randomized in a 2:1:1 ratio. Experimental arm (at least 370 participants) will receive cabozantinib plus atezolizumab. Control arm (at least 185 participants) will receive sorafenib. Single-agent cabozantinib arm (at least185 participants) will receive single-agent cabozantinib
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
837
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    PFS was defined as the time from randomization to the earlier of either the date of radiographic progression defined as a 20% increase in the sum of the longest diameters of target lesions, or the unequivocal appearance of new lesions, or progression of non-target disease per Blinded Independent Radiology Committee (BIRC) or the date of death due to any cause per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
    measure
    Progression Free Survival (PFS) for the Experimental Arm Versus the Control Arm in the PFS Intent to Treat (PITT) Population
    time Frame
    From the date of first participant randomization up to 28 months
  2. description
    OS was defined as the time from randomization to death due to any cause.
    measure
    Overall Survival (OS) for the Experimental Arm Versus the Control Arm in the ITT Population
    time Frame
    From the date of first participant randomization up to 36 months
secondary Outcomes
  1. description
    PFS was defined as the time from randomization to the earlier of either the date of radiographic progression per BIRC or the date of death due to any cause per RECIST version 1.1.
    measure
    PFS for the Single-Agent Cabozantinib Arm Versus the Control Arm in the ITT Population
    time Frame
    From the date of first participant randomization up to 28 months
Full study description
brief Summary
This Phase 3 study evaluates the safety and efficacy of cabozantinib in combination with atezolizumab versus the standard of care sorafenib in adults with advanced hepatocellular carcinoma (HCC) who have not received previous systemic anticancer therapy. A single-agent cabozantinib arm will be enrolled in which participants receive single agent cabozantinib in order to determine its contribution to the overall safety and efficacy of the combination with atezolizumab.
detailed Description
This is a multicenter, randomized, open-label, controlled Phase 3 trial of cabozantinib in combination with atezolizumab versus sorafenib in adults with advanced HCC who have not received previous systemic anticancer therapy in the advanced HCC setting. The primary objective of this study is to evaluate the effect of cabozantinib in combination with atezolizumab on the duration of progression-free survival (PFS) and duration of overall survival (OS) versus sorafenib. The secondary objective is to evaluate the activity of single-agent cabozantinib compared with sorafenib in this patient population.
Source references
references
  1. citation
    Yau T, Kaseb A, Cheng AL, Qin S, Zhu AX, Chan SL, Melkadze T, Sukeepaisarnjaroen W, Breder V, Verset G, Gane E, Borbath I, Rangel JDG, Ryoo BY, Makharadze T, Merle P, Benzaghou F, Milwee S, Wang Z, Curran D, Kelley RK, Rimassa L. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): final results of a randomised phase 3 study. Lancet Gastroenterol Hepatol. 2024 Apr;9(4):310-322. doi: 10.1016/S2468-1253(23)00454-5. Epub 2024 Feb 13.
    pmid
    38364832
    type
    DERIVED
  2. citation
    Kelley RK, Rimassa L, Cheng AL, Kaseb A, Qin S, Zhu AX, Chan SL, Melkadze T, Sukeepaisarnjaroen W, Breder V, Verset G, Gane E, Borbath I, Rangel JDG, Ryoo BY, Makharadze T, Merle P, Benzaghou F, Banerjee K, Hazra S, Fawcett J, Yau T. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):995-1008. doi: 10.1016/S1470-2045(22)00326-6. Epub 2022 Jul 4.
    pmid
    35798016
    type
    DERIVED
  3. citation
    Kelley RK, W Oliver J, Hazra S, Benzaghou F, Yau T, Cheng AL, Rimassa L. Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 Phase III study design. Future Oncol. 2020 Jul;16(21):1525-1536. doi: 10.2217/fon-2020-0283. Epub 2020 Jun 3.
    pmid
    32491932
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
    1. release id
      ctgov-registry-7ad944f6deaf1f5cd6122126
      edge id
      nct-edge-d6694bc0c88b61462f87
      requested nct id
      NCT03755791
      primary nct id
      NCT03755791
      source kind
      nci_explicit_reference_or_link
      source record id
      Source null
      source file sha256
      1235a36d17603a47ed3d80a6e33674e87daac9c8bde71462d561cc83457c5468
      payload sha256
      cf2a836359874f9c4633e1e03540880d25d9abc2e47437155ef5cc219181fca1
      payload
      clinical indication matching status
      not_inferred
      end exclusive
      true
      id
      nct-edge-d6694bc0c88b61462f87
      link basis
      explicit_NCT_identifier_in_acquired_source
      nct id
      NCT03755791
      occurrences
      1. context exact
        nce (atezolizumab and cabozantinib):</p> <div class="pdq-content-list"><ol id="_363"><li>The global, open-label, phase III <a href="/clinicaltrials/NCT03755791">COSMIC-312</a> trial (NCT03755791) included 837 patients with unresectable HCC who had not received prior systemic therapy. Patients were randomly assigned
        end
        103269
        exact text
        NCT03755791
        start
        103258
      2. context exact
        :</p> <div class="pdq-content-list"><ol id="_363"><li>The global, open-label, phase III <a href="/clinicaltrials/NCT03755791">COSMIC-312</a> trial (NCT03755791) included 837 patients with unresectable HCC who had not received prior systemic therapy. Patients were randomly assigned in a 2:1:1 ratio to receive either
        end
        103304
        exact text
        NCT03755791
        start
        103293
      offset unit
      unicode_code_points
      source file
      /tmp/cancer-full-research/nci/raw/65b6ed083cf16e30e7.html
      source file sha256
      1235a36d17603a47ed3d80a6e33674e87daac9c8bde71462d561cc83457c5468
      source json pointer
      Source null
      source kind
      nci_explicit_reference_or_link
      source record id
      Source null
      source retrieved at
      2026-09-09T23:21:57.902710+00:00
      source string basis
      UTF-8_text_with_universal_newline_translation
      source string sha256
      f65392c282090f79f9724182581fd436e649c37951fc980101dd160f5fec1c6e
      source title
      Primary Liver Cancer Treatment (PDQ®)–Health Professional Version
      source update dates
      1. context
        Updated: April 17, 2025
        datetime
        2025-04-17T12:00:00Z
        display
        April 17, 2025

    Preserved source evidence · Not medical advice