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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04524871




Registration number
NCT04524871
Ethics application status
Date submitted
21/08/2020
Date registered
24/08/2020
Date last updated
19/08/2024

Titles & IDs
Public title
A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver)
Scientific 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)
Secondary ID [1] 0 0
GO42216
Universal Trial Number (UTN)
Trial acronym
MORPHEUS-LIVER
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Liver Cancers 0 0
Condition category
Condition code
Cancer 0 0 0 0
Liver
Oral and Gastrointestinal 0 0 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Atezolizumab
Treatment: Drugs - Bevacizumab 15 mg/kg
Treatment: Drugs - Tiragolumab
Treatment: Drugs - Tocilizumab
Treatment: Drugs - TPST-1120
Treatment: Drugs - Tobemstomig 2100 mg
Treatment: Drugs - Bevacizumab 10 mg/kg
Treatment: Drugs - Tobemstomig 600 mg
Treatment: Drugs - Tobemstomig 1200 mg
Treatment: Drugs - ADG126
Treatment: Drugs - IO-108 1800 mg
Treatment: Drugs - NKT2152
Treatment: Drugs - IO-108 1200 mg

Active comparator: Stage 1: Atezolizumab + Bevacizumab - Participants 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.

Experimental: Stage 1: Atezolizumab + Bevacizumab + Tiragolumab - Participants 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.

Experimental: Stage 1: Atezolizumab + Bevacizumab + Tocilizumab - Participants 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.

Experimental: Stage 1: Atezolizumab + Bevacizumab + TPST-1120 - Participants will receive atezolizumab plus bevacizumab plus TPST-1120 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.

Experimental: Stage 1: Tobemstomig 2100 mg Q2W + Bevacizumab - Participants will receive Tobemstomig 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.

Experimental: Stage 1: Tobemstomig 600 mg Q3W + Bevacizumab - Participants will receive Tobemstomig 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.

Experimental: Stage 1: Tobemstomig 1200 mg Q3W + Bevacizumab - Participants will receive Tobemstomig 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.

Experimental: Stage 1: Atezolizumab + Bevacizumab + ADG126 - Participants will receive atezolizumab plus bevacizumab plus ADG126 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.

Experimental: Stage 1: Atezolizumab + Bevacizumab + IO-108 1200 mg Q3W - Participants will receive atezolizumab plus bevacizumab plus IO-108 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.

Experimental: Stage 1: Atezolizumab + Bevacizumab + NKT2152 - Participants will receive atezolizumab plus bevacizumab plus NKT2152 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.

Experimental: Stage 1: Atezolizumab + Bevacizumab+ IO-108 1800 mg Q3W - Participants will receive atezolizumab plus bevacizumab plus IO-108 until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic andbiochemical data, local biopsy results (if available), and clinical status


Treatment: Drugs: Atezolizumab
Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.

Treatment: Drugs: Bevacizumab 15 mg/kg
Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.

Treatment: Drugs: Tiragolumab
Tiragolumab will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.

Treatment: Drugs: Tocilizumab
Tocilizumab will be administered at a dose of 8 mg/kg by IV infusion on Day 1 of each 21 day cycle.

Treatment: Drugs: TPST-1120
TPST-1120 will be administered at a dose of 1200 mg by mouth on Days 1-21 of each 21 day cycle.

Treatment: Drugs: Tobemstomig 2100 mg
Tobemstomig will be administered at a dose of 2100 mg by IV infusion on Days 1 and 15 of each 28 day cycle.

Treatment: Drugs: Bevacizumab 10 mg/kg
Bevacizumab will be administered at a dose of 10 mg/kg by IV infusion on Days 1 and 15 of each 28 day cycle.

Treatment: Drugs: Tobemstomig 600 mg
Tobemstomig will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.

Treatment: Drugs: Tobemstomig 1200 mg
Tobemstomig will be administered at a dose of 1200 mg every 3 weeks.

Treatment: Drugs: ADG126
ADG126 will be administered at a dose of 6 mg/kg by IV infusion on Day 1 of every other cycle (cycle length = 21 days).

Treatment: Drugs: IO-108 1800 mg
IO-108 will be administered at a dose 1800 mg by IV infusion on Day 1 of each 21 day cycle.

Treatment: Drugs: NKT2152
NKT2152 will be administered by mouth.

Treatment: Drugs: IO-108 1200 mg
IO-108 will be administered at a dose 1200 mg by IV infusion on Day 1 of each 21 day cycle.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Objective Response Rate (ORR)
Timepoint [1] 0 0
From randomization until disease progression or loss of clinical benefit (up to approximately 7-9 years)
Secondary outcome [1] 0 0
Progression Free Survival (PFS)
Timepoint [1] 0 0
Randomization to first occurrence of disease progression or death from any cause in Stage 1 (up to approximately 7-9 years)
Secondary outcome [2] 0 0
Overall Survival (OS)
Timepoint [2] 0 0
Randomization to death from any cause (up to approximately 7-9 years)
Secondary outcome [3] 0 0
OS at Specific Timepoints
Timepoint [3] 0 0
Randomization to a specific timepoint, such as Month 6
Secondary outcome [4] 0 0
Duration of Response (DOR)
Timepoint [4] 0 0
First occurrence of a documented objective response to disease progression or death (up to approximately 7-9 years)
Secondary outcome [5] 0 0
Disease Control
Timepoint [5] 0 0
Randomization to end of study (approximately 7-9 years)
Secondary outcome [6] 0 0
Percentage of Participants With Adverse Events During Stage 1
Timepoint [6] 0 0
Baseline through the end of the study (approximately 7-9 years)
Secondary outcome [7] 0 0
Percentage of Participants With Adverse Events During Stage 2
Timepoint [7] 0 0
Baseline through the end of the study (approximately 7-9 years)

Eligibility
Key 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 RO7247669 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)

NKT2152-Containing Arm:

* Total bilirubin = 1.5 X ULN in the absence of Gilbert's disease (= 3.0 X ULN if Gilbert's disease)
* AST/ALT = 2.5 X ULN (= 5 X ULN if liver metastases present)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Stage 1

* Prior treatment with CD137 agonists or immune checkpoint blockade therapies or inhibitors targeting HIF2a
* 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 aspirin (>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 clinically significant 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
* Grade >= 3 hemorrhage or bleeding event within 8 weeks prior to initiation of study treatment
* Patients entering Stage 2: immunotherapy-related adverse events that have not resolved to Grade 1 or better or to baseline at time of consent

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
2/11/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/08/2026
Actual
Sample size
Target
518
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Connecticut
Country [3] 0 0
United States of America
State/province [3] 0 0
District of Columbia
Country [4] 0 0
United States of America
State/province [4] 0 0
Tennessee
Country [5] 0 0
United States of America
State/province [5] 0 0
Texas
Country [6] 0 0
China
State/province [6] 0 0
Beijing
Country [7] 0 0
China
State/province [7] 0 0
Shanghai
Country [8] 0 0
France
State/province [8] 0 0
Dijon
Country [9] 0 0
France
State/province [9] 0 0
Marseille CEDEX 05
Country [10] 0 0
France
State/province [10] 0 0
Rennes
Country [11] 0 0
France
State/province [11] 0 0
Villejuif
Country [12] 0 0
Israel
State/province [12] 0 0
Haifa
Country [13] 0 0
Israel
State/province [13] 0 0
Jerusalem
Country [14] 0 0
Israel
State/province [14] 0 0
Petach Tikva
Country [15] 0 0
Israel
State/province [15] 0 0
Tel-Aviv
Country [16] 0 0
Korea, Republic of
State/province [16] 0 0
Seoul
Country [17] 0 0
New Zealand
State/province [17] 0 0
Auckland
Country [18] 0 0
Taiwan
State/province [18] 0 0
Tainan
Country [19] 0 0
Taiwan
State/province [19] 0 0
Taipei

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Hoffmann-La Roche
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Adagene Inc
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/industry
Name [2] 0 0
Tempest Therapeutics
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Commercial sector/industry
Name [3] 0 0
NiKang Therapeutics, Inc.
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Commercial sector/industry
Name [4] 0 0
Immune-Onc Therapeutics
Address [4] 0 0
Country [4] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
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 website
https://clinicaltrials.gov/study/NCT04524871
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Reference Study ID Number: GO42216 https://forpatients.roche.com/
Address 0 0
Country 0 0
Phone 0 0
888-662-6728 (U.S. and Canada)
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT04524871