A Study Evaluating The Efficacy and Safety of Neoadjuvant Immunotherapy Combinations in Patients With Surgically Resectable Hepatocellular Carcinoma
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Atezo + Bev 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
Atezolizumab will be administered at a dose of 1200 mg by IV infusion on Day 1.
Other Names:
Drug: Bevacizumab
Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1.
Other Names:
|
| Experimental: Atezo + Bev +Tira 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
Atezolizumab will be administered at a dose of 1200 mg by IV infusion on Day 1.
Other Names:
Drug: Bevacizumab
Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1.
Other Names:
Drug: Tiragolumab
Tiragolumab will be administered at a dose of 600 mg by IV infusion on Day 1.
|
| Experimental: Tobe + Bev Participants in the Tobemstomig + Bev arm will receive up to three cycles of treatment until surgery or unacceptable toxicity, whichever occurs first. |
Drug: Bevacizumab
Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1.
Other Names:
Drug: Tobemstomig
Tobemstomig will be administered at a dose of 600 mg by IV infusion on Day 1
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Major Pathologic Response (MPR) Rate [At the time of surgery]
MPR rate is defined as the proportion of resected participants with an MPR =<10% (residual viable tumor in the tumor bed), as assessed by central review.
Secondary Outcome Measures
- Pathologic Complete Response (pCR) Rate [At the time of surgery]
pCR rate is defined as the proportion of resected participants with a pCR. pCR is defined as the absence of residual tumor in the resected tumor specimen.
- Relapse-Free Survival (RFS) [Surgery to the first documented recurrence of disease (up to approximately 2 years)]
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.
- Event-Free Survival (EFS) [Randomization up to approximately 3 years]
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 or distant disease recurrence as measured by EASL and/or RECIST v1.1; or death from any cause.
- Overall Survival (OS) [Randomization to death from any cause (up to approximately 3 years)]
OS is defined as the time from randomization to death from any cause.
- Objective Response Rate (ORR) [Prior to surgery]
ORR is defined as the proportion of participants with a Complete Response (CR) or Partial Response (PR), as determined by the investigator according to RECIST v1.1 and HCC mRECIST, prior to surgery. 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.
- Proportion of Participants Downstaged to Within Milan Criteria [Prior to surgery]
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.
- R0 Resection Rate [At the time of surgery]
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.
- 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 [>28 days from surgical restaging visit, anticipated up to 56 days]
Proportion of participants with delayed or canceled surgery due to treatment-related adverse events (defined as > 28 days from surgical restaging visit).
- Post-Operative Surgical Complication Rates According to The Clavien-Dindo Surgical Classification [Surgery to treatment completion/discontinuation (up to approximately 2 years)]
Post-operative surgical complication rates according to the Clavien-Dindo surgical classification. Clinically relevant complications are defined as Clavien-Dindo Grade >= IIIa.
- Post-Operative Mortality [Within 90 days after surgery or prior to discharge]
Post-operative mortality is defined as death within 90 days after surgery or prior to discharge.
Eligibility Criteria
Criteria
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.
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Measurable disease (at least one target lesion) according to RECIST v1.1 as determined by the investigator
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Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 days prior to randomization
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Child-Pugh Class A within 7 days prior to randomization
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Negative HIV test at screening
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No prior locoregional or systemic treatment for HCC
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Adequate hematologic and end-organ function
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Documented virology status of hepatitis
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For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception
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For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating sperm
General Exclusion Criteria:
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Presence of extrahepatic disease or macrovascular invasion
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Known fibrolamellar HCC, sarcomatoid HCC, mixed cholangiocarcinoma and HCC, or other rare variants of HCC
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History of hepatic encephalopathy if clinically significant within one year prior to initiation of study treatment
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Moderate or severe ascites
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Active co-infection with HBV and HCV
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Active co-infection with HBV and hepatitis D viral infection
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Prior treatment with CD137 agonists or immune checkpoint inhibitors, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
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Treatment with investigational therapy within 28 days prior to initiation of study treatment
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Untreated or incompletely treated esophageal and/or gastric varices with bleeding or that are at high risk for bleeding
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A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment
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Inadequately controlled hypertension
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History of hypertensive crisis or hypertensive encephalopathy
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Significant vascular disease within 6 months prior to initiation of study treatment
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History of hemoptysis within 1 month prior to initiation of study treatment
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Evidence of bleeding diathesis or significant coagulopathy
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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
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History of abdominal or tracheoesophageal fistula, GI perforation or intra-abdominal abscesses within 6 months prior to initiation of study treatment
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History of intestinal obstruction and/or clinical sign or symptoms of GI obstruction
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Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
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Grade >= proteinuria
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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
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Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID)
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Serious infection requiring oral or IV antibiotics and/or hospitalization
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Hoffmann-La Roche
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- GO44457