Clinical trial NCT04524871: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Liver Cancers
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: Adagene Inc
name: Tempest Therapeutics
name: NiKang Therapeutics, Inc.
name: Immune-Onc Therapeutics
First posted: 2020-08-24
Enrollment: 518
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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 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)

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

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: From randomization until disease progression or loss of clinical benefit (up to approximately 7-9 years)
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Randomization to first occurrence of disease progression or death from any cause in Stage 1 (up to approximately 7-9 years)
measure: Overall Survival (OS)
timeFrame: Randomization to death from any cause (up to approximately 7-9 years)
measure: OS at Specific Timepoints
timeFrame: Randomization to a specific timepoint, such as Month 6
measure: Duration of Response (DOR)
timeFrame: First occurrence of a documented objective response to disease progression or death (up to approximately 7-9 years)
measure: Disease Control
timeFrame: Randomization to end of study (approximately 7-9 years)
measure: Percentage of Participants With Adverse Events During Stage 1
timeFrame: Baseline through the end of the study (approximately 7-9 years)
measure: Percentage of Participants With Adverse Events During Stage 2
timeFrame: Baseline through the end of the study (approximately 7-9 years)
Other outcomes:
Locations:
city: Costa Mesa
country: United States
facility: UC Irvine Medical Center
state: California
city: Duarte
country: United States
facility: City of Hope
state: California
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Orange
country: United States
facility: UC Irvine Medical Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Cancer Center
state: California
city: Santa Monica
country: United States
facility: UCLA Center for East
state: California
city: Aurora
country: United States
facility: Cherry Creek Medical Center
state: Colorado
city: Aurora
country: United States
facility: UCHealth Cancer Center Pharmacy - Highlands Ranch Hospital
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital - Anschutz Cancer Pavilion
state: Colorado
city: New Haven
country: United States
facility: Smilow Cancer Hospital at Yale New Haven
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Nashville
country: United States
facility: Sarah Cannon Research Institute / Tennessee Oncology
state: Tennessee
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Shanghai
country: China
facility: Zhongshan Hospital Fudan University
city: Dijon
country: France
facility: Centre Georges Francois Leclerc
city: Marseille CEDEX 05
country: France
facility: CHU Hôpitaux de Marseille
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Villejuif CEDEX
country: France
facility: Gustave Roussy
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Jerusalem
country: Israel
facility: Hadassah University Medical Center
city: Petah Tikva
country: Israel
facility: Rabin Medical Center-Beilinson Campus
city: Tel-Aviv
country: Israel
facility: Sourasky Medical Centre
city: Gyeonggi-do
country: Korea, Republic of
facility: CHA Bundang Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: