A Study Evaluating The Efficacy and Safety of Neoadjuvant Immunotherapy Combinations in Patients With Surgically Resectable Hepatocellular Carcinoma

Study Overview
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Brief Summary
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This is a Phase Ib/II, open-label, multicenter, randomized platform study to evaluate neoadjuvant immunotherapy combinations in participants with resectable HCC. The study is designed with the flexibility to open new treatment arms as new agents become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, or modify the participant population.

Official Title
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A Phase Ib/II, Open-Label, Multicenter, Randomized Platform Study Evaluating The Efficacy and Safety of Neoadjuvant Immunotherapy Combinations in Patients With Surgically Resectable Hepatocellular Carcinoma (MORPHEUS-NEO HCC)

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Bevacizumab
* Drug: Tiragolumab
* Drug: Tobemstomig


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of HCC confirmed either histologically or clinically according to AASLD criteria for patients with cirrhosis. For participants without cirrhosis, histological confirmation is mandatory. HCC that is amenable to R0 surgical resection with curative intent in the opinion of the surgeons and oncologists or hepatologists involved in the care of the participant. Patients presenting with resectable HCC within or beyond Milan criteria (without extrahepatic spread or macrovascular invasion) are eligible. Measurable disease (at least one target lesion) according to RECIST v1.1 as determined by the investigator Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 days prior to randomization Child-Pugh Class A within 7 days prior to randomization Negative HIV test at screening No prior locoregional or systemic treatment for HCC Adequate hematologic and end-organ function Documented virology status of hepatitis For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating sperm General Exclusion Criteria: Presence of extrahepatic disease or macrovascular invasion Known fibrolamellar HCC, sarcomatoid HCC, mixed cholangiocarcinoma and HCC, or other rare variants of HCC History of hepatic encephalopathy if clinically significant within one year prior to initiation of study treatment Moderate or severe ascites Active co-infection with HBV and HCV Known active co-infection with HBV and hepatitis D viral infection Prior treatment with CD137 agonists or immune checkpoint inhibitors, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies Treatment with investigational therapy within 28 days prior to initiation of study treatment Untreated or incompletely treated esophageal and/or gastric varices with bleeding or that are at high risk for bleeding A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment Inadequately controlled hypertension History of hypertensive crisis or hypertensive encephalopathy Significant vascular disease within 6 months prior to initiation of study treatment History of hemoptysis within 1 month prior to initiation of study treatment Evidence of bleeding diathesis or significant coagulopathy Current or recent (<= 10 days prior to initiation of study treatment) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes History of abdominal or tracheoesophageal fistula, GI perforation or intra-abdominal abscesses within 6 months prior to initiation of study treatment History of intestinal obstruction and/or clinical sign or symptoms of GI obstruction Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture Grade >= proteinuria Major surgical procedure, open biopsy, or significant traumatic injury, or abdominal surgery, interventions or traumatic injuries, or anticipation of need of major surgical procedure other than potentially curative liver resection Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID) Serious infection requiring oral or IV antibiotics and/or hospitalization Active tuberculosis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezo + Bev<br>Participants in the atezolizumab plus bevacizumab (Atezo + Bev) arm will receive up to three cycles of treatment until surgery or unacceptable toxicity, whichever occurs first. | Drug: Atezolizumab<br>* Atezolizumab will be administered at a dose of 1200 mg by IV infusion on Day 1.<br>* Other names: Tecentriq;Drug: Bevacizumab<br>* Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1.<br>* Other names: Avastin;|
| Experimental: Atezo + Bev +Tira<br>Participants in the atezolizumab plus bevacizumab plus tiragolumab (Atezo + Bev +Tira) arm will receive up to three cycles of treatment until surgery or unacceptable toxicity, whichever occurs first. | Drug: Atezolizumab<br>* Atezolizumab will be administered at a dose of 1200 mg by IV infusion on Day 1.<br>* Other names: Tecentriq;Drug: Bevacizumab<br>* Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1.<br>* Other names: Avastin;Drug: Tiragolumab<br>* Tiragolumab will be administered at a dose of 600 mg by IV infusion on Day 1.<br>|
| Experimental: Tobe + Bev<br>Participants in the Tobemstomig + Bev arm will receive up to three cycles of treatment until surgery or unacceptable toxicity, whichever occurs first. | Drug: Bevacizumab<br>* Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1.<br>* Other names: Avastin;Drug: Tobemstomig<br>* Tobemstomig will be administered at a dose of 600 mg by IV infusion on Day 1<br>* Other names: RO7247669;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Pathologic Response (MPR) Rate | MPR rate is defined as the proportion of participants with =<10% residual viable tumor in the tumor bed at the time of surgery, as assessed by central pathological review. | At the time of surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response (pCR) Rate | pCR rate is defined as the proportion of participants with an absence of residual tumor at the time of surgery, as assessed by central pathological review. | At the time of surgery | 
| Relapse-Free Survival (RFS) | RFS is defined as the time from surgery to the first documented recurrence of disease (intrahepatic or extrahepatic) according to EASL and/or RECIST v1.1, or death from any cause. | Surgery to the first documented recurrence of disease (up to approximately 2 years) | 
| Event-Free Survival (EFS) | EFS is defined as the time from randomization to any of the following events (whichever occurs first): disease progression that precludes surgery, as assessed by the investigator according RECIST v1.1; local regional, or distant disease recurrence as measured by EASL and/or RECIST v1.1; or death from any cause. | Randomization up to approximately 3 years | 
| Overall Survival (OS) | OS is defined as the time from randomization to death from any cause. | Randomization to death from any cause (up to approximately 3 years) | 
| OS Rate at 24 Months | OS rate at 24 months is defined as the proportion of participants who have not experience death from any cause at 24 months after randomization. | Randomization up to 24 months | 
| OS Rate at 36 Months | OS rate at 36 months is defined as the proportion of participants who have not experience death from any cause at 36 months after randomization. | Randomization up to 36 months | 
| Objective Response Rate (ORR) | ORR is defined as the proportion of participants with a radiographic Complete Response (CR) or Partial Response (PR) prior to surgery, as determined by the investigator according to RECIST v1.1 and HCC mRECIST. Responses will be assessed and determined according to RECIST v1.1 and HCC mRECIST but are not required to be confirmed by subsequent imaging assessments. | Prior to surgery | 
| Proportion of Participants Downstaged to Within Milan Criteria | Proportion of participants downstaged to within Milan criteria (for participants beyond criteria at randomization). Within Milan criteria is defined as single tumor <= 5 cm or 2 - 3 nodules all <= 3 cm. | Prior to surgery | 
| R0 Resection Rate | R0 resection rate (proportion of resected participants obtaining an R0 resection). R0 resection is defined as a microscopically margin-negative resection, in which no tumor (gross or microscopic) remains in the primary tumor bed. | At the time of surgery | 
| Percentage of Participants With Adverse Events |  | Up to approximately 3 years after first participant enrolled | 
| Proportion of Participants With Delayed or Canceled Surgery Due to Treatment-Related Adverse Events | Proportion of participants with delayed or canceled surgery due to treatment-related adverse events (defined as > 28 days from surgical restaging visit). | >28 days from surgical restaging visit, anticipated up to 56 days | 
| Post-Operative Surgical Complication Rates According to The Clavien-Dindo Surgical Classification | Post-operative surgical complication rates according to the Clavien-Dindo surgical classification. Clinically relevant complications are defined as Clavien-Dindo Grade >= IIIa. | Surgery to treatment completion/discontinuation (up to approximately 2 years) | 
| Post-Operative Mortality | Post-operative mortality is defined as death within 90 days after surgery | Within 90 days after surgery |