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

Advanced Liver Cancers Clinical Trial

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 Details — Status: Recruiting

Administrative data

• NCT number: NCT04524871
• Other study ID #: GO42216
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: November 2, 2020
• Est. completion date: August 31, 2026

Study information

• Verified date: May 2024
• Source: Hoffmann-La Roche
• Contact: Reference Study ID Number: GO42216 https://forpatients.roche.com
• Phone: 888-662-6728 (U.S. and Canada)
• Email: global.rochegenentechtrials[@]roche.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 506
• Est. completion date: August 31, 2026
• Est. primary completion date: August 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

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 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 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

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

Related Conditions & MeSH terms

• Advanced Liver Cancers
• Liver Neoplasms

Intervention

Drug:
• Atezolizumab
Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.
• 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.
• Tiragolumab
Tiragolumab will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.
• Tocilizumab
Tocilizumab will be administered at a dose of 8 mg/kg by IV infusion on Day 1 of each 21 day cycle.
• TPST-1120
TPST-1120 will be administered at a dose of 1200 mg by mouth on Days 1-21 of each 21 day cycle.
• 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.
• 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.
• Tobemstomig 600 mg
Tobemstomig will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.
• Tobemstomig 1200 mg dose
Tobemstomig will be administered at a dose of 1200 mg every 3 weeks.
• 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).
• IO-108
IO-108 will be administered at a dose 1800 mg by IV infusion on Day 1 of each 21 day cycle.
• NKT2152
NKT2152 will be administered at a dose of 200 mg by mouth once daily x 14 days (loading) then 50 mg once daily (maintenance) on Days 15-21 during the first cycle. For all subsequent cycles, NKT2152 is administered at 50 mg once daily.

Locations

Country	Name	City	State
China	Beijing Cancer Hospital; Pharmacy room	Beijing
China	Zhongshan Hospital Fudan University	Shanghai
France	Centre Georges Francois Leclerc; Oncologie 3	Dijon
France	CHU Hôpitaux de Marseille	Marseille CEDEX 05
France	Centre Eugène Marquis	Rennes
France	Gustave Roussy	Villejuif
Israel	Rambam Medical Center	Haifa
Israel	Hadassah University Medical Center	Jerusalem
Israel	Rabin Medical Center-Beilinson Campus; Davidof Institute	Petach Tikva
Israel	Sourasky Medical Centre	Tel-Aviv
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
New Zealand	Auckland City Hospital	Auckland
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
United States	UC Irvine Medical Center	Costa Mesa	California
United States	The University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	City of Hope	Duarte	California
United States	University of California San Diego	La Jolla	California
United States	SCRI Oncology Partners	Nashville	Tennessee
United States	Smilow Cancer Hospital at Yale New Haven	New Haven	Connecticut
United States	UC Irvine Medical Center	Orange	California
United States	University of California San Francisco Cancer Center; Pharmacy	San Francisco	California
United States	UCLA Center for East; West Medicine	Santa Monica	California
United States	Georgetown University Medical Center	Washington	District of Columbia

Sponsors (5)

Lead Sponsor	Collaborator
Hoffmann-La Roche	Adagene Inc, Immune-Onc Therapeutics, NiKang Therapeutics, Inc., Tempest Therapeutics

Countries where clinical trial is conducted

United States,  China,  France,  Israel,  Korea, Republic of,  New Zealand,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR)	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.	From randomization until disease progression or loss of clinical benefit (up to approximately 7-9 years)
Secondary	Progression Free Survival (PFS)	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.	Randomization to first occurrence of disease progression or death from any cause in Stage 1 (up to approximately 7-9 years)
Secondary	Overall Survival (OS)	OS after randomization, defined as the time from randomization to death from any cause.	Randomization to death from any cause (up to approximately 7-9 years)
Secondary	OS at Specific Timepoints	OS at a specific timepoint, such as Month 6	Randomization to a specific timepoint, such as Month 6
Secondary	Duration of Response (DOR)	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.	First occurrence of a documented objective response to disease progression or death (up to approximately 7-9 years)
Secondary	Disease Control	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.	Randomization to end of study (approximately 7-9 years)
Secondary	Percentage of Participants With Adverse Events During Stage 1		Baseline through the end of the study (approximately 7-9 years)
Secondary	Percentage of Participants With Adverse Events During Stage 2		Baseline through the end of the study (approximately 7-9 years)