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A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver)

NCT04524871

Description:

This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in participants with advanced liver cancers. The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, modify the participant population, or introduce additional cohorts of participants with other types of advanced primary liver cancer. Cohort 1 will enroll participants with locally advanced or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy for their disease. Eligible participants will initially be randomly assigned to one of several treatment arms (Stage 1). Participants who experience loss of clinical benefit or unacceptable toxicity during Stage 1 may be eligible to receive treatment with a different treatment combination (Stage 2). When a Stage 2 treatment combination is available, this will be introduced by amending the protocol.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver)
  • Official Title: A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver)

Clinical Trial IDs

  • ORG STUDY ID: GO42216
  • NCT ID: NCT04524871

Conditions

  • Advanced Liver Cancers

Interventions

DrugSynonymsArms
AtezolizumabTecentriqStage 1: Atezolizumab + Bevacizumab
BevacizumabAvastinStage 1: Atezolizumab + Bevacizumab
TiragolumabStage 1: Atezolizumab + Bevacizumab + Tiragolumab
TocilizumabActemraStage 1: Atezolizumab + Bevacizumab + Tocilizumab

Purpose

This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in participants with advanced liver cancers. The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, modify the participant population, or introduce additional cohorts of participants with other types of advanced primary liver cancer. Cohort 1 will enroll participants with locally advanced or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy for their disease. Eligible participants will initially be randomly assigned to one of several treatment arms (Stage 1). Participants who experience loss of clinical benefit or unacceptable toxicity during Stage 1 may be eligible to receive treatment with a different treatment combination (Stage 2). When a Stage 2 treatment combination is available, this will be introduced by amending the protocol.

Trial Arms

NameTypeDescriptionInterventions
Stage 1: Atezolizumab + BevacizumabActive ComparatorParticipants will receive atezolizumab plus bevacizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.
  • Atezolizumab
  • Bevacizumab
Stage 1: Atezolizumab + Bevacizumab + TiragolumabExperimentalParticipants will receive atezolizumab plus bevacizumab plus tiragolumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.
  • Atezolizumab
  • Bevacizumab
  • Tiragolumab
Stage 1: Atezolizumab + Bevacizumab + TocilizumabExperimentalParticipants will receive atezolizumab plus bevacizumab plus tocilizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.
  • Atezolizumab
  • Bevacizumab
  • Tocilizumab

Eligibility Criteria

        Inclusion Criteria:

        Stage 1

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 days
             prior to randomization

          -  Locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC) with
             diagnosis confirmed by histology/cytology or clinically by American Association for
             the Study of

          -  Liver Diseases criteria in cirrhotic patients

          -  Child-Pugh class A within 7 days prior to randomization

          -  Disease that is not amenable to curative surgical and/or locoregional therapies

          -  No prior systemic treatment for HCC

          -  Life expectancy >= 3 months

          -  Availability of a representative tumor specimen that is suitable for determination of
             PD-L1 and/or additional biomarker status via central testing

        Stage 1 and Stage 2

          -  Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1

          -  Adequate hematologic and end-organ function within 7 days prior to initiation of study
             treatment

          -  Documented virology status of hepatitis, as confirmed by screening tests for hepatitis
             B virus - (HBV) and hepatitis C virus (HCV)

          -  Negative HIV test at screening

          -  For women of childbearing potential: agreement to remain abstinent or use
             contraception and for men: agreement to remain abstinent or use contraception, and
             agreement to refrain from donating sperm

        Stage 2

          -  ECOG Performance Status of 0, 1, or 2

          -  Ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable
             toxicity not related to atezolizumab or loss of clinical benefit as determined by the
             investigator while receiving Stage 1 treatment

          -  Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage
             1 (if deemed clinically feasible)

        Exclusion Criteria:

        Stage 1

          -  Prior treatment with CD137 agonists or immune checkpoint inhibitors

          -  Treatment with investigational therapy within 28 days prior to initiation of study

          -  Treatment with locoregional therapy to liver within 28 days prior to initiation of
             study, or non-recovery from side effects of any such procedure

          -  Untreated or incompletely treated esophageal and/or gastric varices with bleeding or
             at high risk for bleeding

          -  Prior bleeding event due to esophageal and/or gastric varices within 6 months prior to
             initiation of study

          -  AEs from prior anti-cancer therapy that have not resolved to Grade <= 1 or better,
             with the exception of alopecia of any grade

          -  Inadequately controlled hypertension

          -  History of hypertensive crisis or hypertensive encephalopathy

          -  Significant vascular disease

          -  History of hemoptysis within 1 month prior to initiation of study

          -  Evidence of bleeding diathesis or significant coagulopathy

          -  Current or recent use of asprin (>325 mg/day) or treatment with clopidogrel,
             dipyramidole, ticlopidine, or cilostazol

          -  Current or recent use of full-dose oral or parenteral anticoagulants or thrombolytic
             agents for therapeutic (as opposed to prophylactic) purpose

          -  Core biopsy or other minor surgical procedure within 3 days prior to initiation of
             study

          -  History of abdominal or tracheoesophageal fistula, GI perforation, or intra-abdominal
             abscess, intestinal obstruction and/or clinical signs/symptoms of GI obstruction

          -  Evidence of abdominal free air not explained by paracentesis or recent surgery

          -  Serious, non-healing/dehiscing wound, active ulcer, or untreated bone fracture

          -  Grade >=2 proteinuria

          -  Metastatic disease involving major airways/blood vessels, or centrally located
             mediastinal tumor masses of large volume

          -  History of intra-abdominal inflammatory process

          -  Radiotherapy within 28 days or abdominal/pelvic radiotherapy within 60 days prior to
             initiation of study with the exception of palliative radiotherapy to bone lesions
             within 7 days prior to initiation of study

          -  Major surgery, open biopsy, or significant traumatic injury within 28 days prior to
             initiation of study; or abdominal surgery, abdominal interventions or significant
             abdominal traumatic injury within 60 days prior to initiation of study; or
             anticipation of need for major surgery during study or non-recovery from side effects
             of any such procedure

          -  Chronic daily treatment with NSAID

          -  Eligible only for control arm

        Stage 1 and 2

          -  Fibrolamellar or sarcomatoid HCC, or mixed cholangiocarcinoma and HCC

          -  History of hepatic encephalopathy

          -  Moderate or severe ascites

          -  HBV and HCV coinfection

          -  Symptomatic, untreated, or actively progressing CNS metastases

          -  History of leptomeningeal disease

          -  Uncontrolled tumor-related pain

          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures

          -  Uncontrolled or symptomatic hypercalcemia

          -  Active or history of autoimmune disease or immune deficiency

          -  History of IPF, organizing pneumonia, drug-induced or idiopathic pneumonitis, or
             evidence of active pneumonitis on screening chest CT scan

          -  Active TB

          -  Significant CV disease within 3 months prior to initiation of study, unstable
             arrhythmia, or unstable angina

          -  Major surgery, other than for diagnosis, within 4 weeks prior to initiation of study,
             or anticipated major surgery during study

          -  History of malignancy other than HCC within 5 years prior to screening

          -  Severe infection within 4 weeks prior to initiation of study

          -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
             of study

          -  Prior allogeneic stem cell or solid organ transplantation

          -  Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study,
             or anticipation of need for such a vaccine during atezolizumab treatment or within 5
             months after the final dose of atezolizumab

          -  History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
             or fusion proteins

          -  Known allergy or hypersensitivity to any of the study drugs or any of their excipients
             Treatment with systemic immunostimulatory, immunosuppressive agents within 4 weeks or
             5 drug-elimination half-lives (whichever is longer) prior to initiation of study

          -  Treatment with systemic immunosuppressive medication within 2 weeks prior to
             initiation of study

          -  Patients entering Stage 2: immunotherapy-related adverse events that have not resolved
             to Grade 1 or better or to baseline at time of consent

        Tiragolumab-Containing Arm

          -  Prior treatment with an anti-TIGIT agent

          -  Active EBV infection or known or suspected chronic active EBV infection at screening

        Tocilizumab-Containing Arm

          -  Preexisting CNS demyelinating or seizure disorders

          -  History of diverticulitis, chronic ulcerative lower GI disease, or other symptomatic
             lower GI conditions that might predispose a patient to GI perforation

          -  Active current infection or history of recurrent infection

          -  Untreated latent TB

          -  History of, or currently active, primary or secondary immunodeficiency
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:From randomization until disease progression or loss of clinical benefit (up to approximately 3-5 years)
Safety Issue:
Description:ORR, defined as the proportion of participants with a complete response or partial response on two consecutive occasions >=4 weeks apart during Stage 1, as determined by the investigator according to RECIST v1.1.

Secondary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:Randomization to first occurrence of disease progression or death from any cause in Stage 1 (up to approximately 3-5 years)
Safety Issue:
Description:PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first) in Stage 1, as determined by the investigator according to RECIST v1.1.
Measure:Overall Survival (OS)
Time Frame:Randomization to death from any cause (up to approximately 3-5 years)
Safety Issue:
Description:OS after randomization, defined as the time from randomization to death from any cause.
Measure:OS at Specific Timepoints
Time Frame:Randomization to a specific timepoint, such as Month 6
Safety Issue:
Description:OS at a specific timepoint, such as Month 6
Measure:Duration of Response (DOR)
Time Frame:First occurrence of a documented objective response to disease progression or death (up to approximately 3-5 years)
Safety Issue:
Description:DOR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first) in Stage 1, as determined by the investigator according to RECIST v1.1.
Measure:Disease Control
Time Frame:Randomization to end of study (approximately 3-5 years)
Safety Issue:
Description:Disease control, defined as stable disease for >=12 weeks or a complete or partial response, as determined by the investigator according to RECIST v1.1.
Measure:Percentage of Participants With Adverse Events During Stage 1
Time Frame:Baseline through the end of the study (approximately 3-5 years)
Safety Issue:
Description:
Measure:Percentage of Participants With Adverse Events During Stage 2
Time Frame:Baseline through the end of the study (approximately 3-5 years)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

Last Updated

August 21, 2020