A Study to Assess the Dose, Adverse Events, and Change in Disease Activity of Livmoniplimab as an Intravenous (IV) Solution in Combination With Budigalimab as an IV Solution in Adult Participants With Hepatocellular Carcinoma (HCC)

Study Overview
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Brief Summary
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Hepatocellular carcinoma (HCC) is a common cancer worldwide and a leading cause of cancer-related death. The majority of participants first presenting with HCC have advanced unresectable or metastatic disease. The purpose of this study is to evaluate the optimized dose, adverse events, and efficacy of livmoniplimab in combination with budigalimab. Livmoniplimab is an investigational drug being developed for the treatment of HCC. There are 2 stages to this study. In Stage 1, there are 3 treatment arms and participants will be randomized in a 1:1:1 ratio. Participants will either receive livmoniplimab (at different doses) in combination with budigalimab (another investigational drug), atezolizumab in combination with bevacizumab, or tremelimumab in combination with durvalumab. In Stage 2, there are 2 treatments arms and participants will be randomized in a 1:1 ratio. Participants will either receive livmoniplimab (optimized dose) in combination with budigalimab or tremelimumab in combination with durvalumab. Approximately 660 adult participants will be enrolled in the study across 185 sites worldwide. Stage 1: In arm 1, participants will receive intravenously (IV) infused livmoniplimab (Dose 1) in combination with IV infused budigalimab, every 3 weeks. In arm 2, participants will receive IV infused livmoniplimab (Dose 2) in combination with IV infused budigalimab, every 3 weeks. In Arm 3 (control), participants will receive the investigator's choice: IV atezolizumab in combination with IV bevacizumab every 3 weeks or single dose IV tremelimumab in combination with IV durvalumab every 4 weeks. Stage 2: In arm 1, participants will receive IV infused livmoniplimab (optimized dose) in combination with IV infused budigalimab, every 3 weeks. In Arm 2 (control), participants will receive single dose IV tremelimumab in combination with IV durvalumab every 4 weeks. All participants will continue treatment until disease progression or discontinuation criteria are met, whichever occurs first. The estimated duration of this study is about 56 months. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic and may require frequent medical assessments, blood tests, questionnaires, and scans.

Official Title
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A Phase 2/3, Randomized Study to Evaluate the Dose Optimization, Safety, and Efficacy of Livmoniplimab in Combination With Budigalimab in Subjects With Locally Advanced or Metastatic Hepatocellular Carcinoma (HCC) Who Have Not Previously Received Systemic Treatment

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Livmoniplimab
* Drug: Budigalimab
* Drug: Durvalumab
* Drug: Atezolizumab
* Drug: Bevacizumab
* Drug: Tremelimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC) with diagnosis confirmed by histology or cytology or clinically by American Association for the Study of Liver Diseases criteria for participants with cirrhosis. Barcelona Clinic Liver Cancer (BCLC) Stage B or C. Child-Pugh A or B7 classification (i.e., total Child-Pugh score of 5, 6, or 7). Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. Exclusion Criteria: Prior systemic therapy for HCC. Symptomatic, untreated, or actively progressing CNS metastases. History of malignancy other than HCC.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1: Cohort 1<br>Participants will receive livmoniplimab Dose 1 in combination with budigalimab every 3 weeks until disease progression or until discontinuation criteria are met. | Drug: Livmoniplimab<br>* Intravenous (IV) Solution<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Intravenous (IV) Solution<br>* Other names: ABBV-181;|
| Experimental: Stage 1: Cohort 2<br>Participants will receive livmoniplimab Dose 2 in combination with budigalimab every 3 weeks until disease progression or until discontinuation criteria are met. | Drug: Livmoniplimab<br>* Intravenous (IV) Solution<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Intravenous (IV) Solution<br>* Other names: ABBV-181;|
| Active Comparator: Stage 1: Cohort 3 - Group 1 (Control)<br>Participants will receive atezolizumab in combination with bevacizumab every 3 weeks until disease progression or until discontinuation criteria are met. | Drug: Atezolizumab<br>* Intravenous (IV) Solution<br>Drug: Bevacizumab<br>* Intravenous (IV) Solution<br>|
| Active Comparator: Stage 1: Cohort 3 - Group 2 (Control)<br>Participants will receive a single dose of tremelimumab in combination with durvalumab every four weeks until disease progression or until discontinuation criteria are met. | Drug: Durvalumab<br>* Intravenous (IV) Solution<br>Drug: Tremelimumab<br>* Intravenous (IV) Solution<br>|
| Experimental: Stage 2: Arm 1<br>Participants will receive livmoniplimab (optimized dose) in combination with budigalimab every 3 weeks until disease progression or until discontinuation criteria are met. | Drug: Livmoniplimab<br>* Intravenous (IV) Solution<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Intravenous (IV) Solution<br>* Other names: ABBV-181;|
| Active Comparator: Stage 2: Arm 2 (Control)<br>Participants will receive a single dose of tremelimumab in combination with durvalumab every 4 weeks until disease progression or until discontinuation criteria are met. | Drug: Durvalumab<br>* Intravenous (IV) Solution<br>Drug: Tremelimumab<br>* Intravenous (IV) Solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1: Best Overall Response (BOR) per Investigator | BOR is defined as a participant achieving confirmed complete response (CR) or confirmed partial response (PR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as determined by investigators at any time prior to subsequent anticancer therapy. | Through Study Completion, Up to Approximately 56 Months | 
| Stage 2: Overall Survival (OS) | OS is defined as the time from randomization until death from any cause | Through Study Completion, Up to Approximately 56 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1: Number of Participants with Progression-Free Survival (PFS) | PFS is defined as the time from randomization until the first documentation of progressive disease according to RECIST 1.1 as determined by investigators or death from any cause, whichever occurs first. | Through Study Completion, Up to Approximately 56 Months | 
| Stage 1: Duration of Response (DOR) per Investigator | DOR is defined as the time from first confirmed CR or PR until the first documentation of progressive disease according to RECIST 1.1 as determined by investigators or death from any cause, whichever occurs first. | Through Study Completion, Up to Approximately 56 Months | 
| Stage 1: Overall Survival (OS) | OS is defined as the time from randomization until death from any cause. | Through Study Completion, Up to Approximately 56 Months | 
| Stage 1: Number of Participants with Adverse Events (AEs) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. | Through Study Completion, Up to Approximately 56 Months | 
| Stage 1: Maximum Plasma Concentration (Cmax) of Livmoniplimab and Budigalimab | Cmax of livmoniplimab and budigalimab. | Through Study Completion, Up to Approximately 56 Months | 
| Stage 1: Time to Cmax (Tmax) of Livmoniplimab and Budigalimab | Tmax of livmoniplimab and budigalimab. | Through Study Completion, Up to Approximately 56 Months | 
| Stage 1: Area Under the Serum Concentration Versus Time Curve (AUC) of Livmoniplimab and Budigalimab | AUC of livmoniplimab and budigalimab. | Through Study Completion, Up to Approximately 56 Months | 
| Stage 2: Number of Participants with Progression-Free Survival (PFS) | PFS is defined as the time from randomization until the first documentation of progressive disease according to RECIST 1.1 as determined blinded independent central review (BICR) or death from any cause, whichever occurs first. | Through Study Completion, Up to Approximately 56 Months | 
| Stage 2: Best Overall Response (BOR) of Complete Response (CR)/Partial Response (PR) per BICR | BOR is defined as a participant achieving confirmed CR/PR per RECIST 1.1 as determined by BICR at any time prior to subsequent anticancer therapy. | Through Study Completion, Up to Approximately 56 Months | 
| Change from Baseline in the Pain Domain of the European Organization for Research Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18-Question Module (EORTC QLQ-HCC18) | The EORTC QLQ-HCC18 is an 18-item scale that measures hepatocellular carcinoma (HCC)-specific symptoms and health-related quality of life (HRQoL). The Pain Domain contains 2 items where scores are based on a 4-point Likert scale (with 1 = 'not at all' to 4 = 'very much'); scaled scores for each domain ranged from 0-100 with a higher score indicating worse symptoms. | Baseline to Week 12 | 
| Change from Baseline in the Fatigue Domain of the EORTC QLQ-HCC18 | The EORTC QLQ-HCC18 is an 18-item scale that measures HCC-specific symptoms and HRQoL. The Fatigue Domain contains 3 items where scores are based on a 4-point Likert scale (with 1 = 'not at all' to 4 = 'very much'); scaled scores for each domain ranged from 0-100 with a higher score indicating worse symptoms. | Baseline to Week 12 | 
| Change from Baseline in Physical Function (PF) Domain of the European Organization for Research Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) | The EORTC QLQ-C30 is an 30-item patient-reported questionnaire that measures symptoms and HRQoL. The PF Domain is a functional scale where participants rate items on a 4-point scale (with 1 = 'not at all' to 4 = 'very much'). A change of 5 to 10 points is considered a small change and the lower bound (5) will be used to define the minimum important difference. A change of >= 10 to < 20 points is considered a moderate change. | Baseline to Week 12 | 
| Change from Baseline in Global Health Status (GHS)/Quality of Life (QoL) Domain as Measured by the GHS/QoL Domain of the EORTC QLQ-C30 | The EORTC QLQ-C30 is an 30-item patient-reported questionnaire that measures symptoms and HRQoL. The GHS/QoL Domain is a scale where participants rate items on a 4-point scale (with 1 = 'not at all' to 4 = 'very much'). A change of 5 to 10 points is considered a small change and the lower bound (5) will be used to define the minimum important difference. A change of ≥ 10 to < 20 points is considered a moderate change. | Baseline to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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budigalimab, ABBV-181, Hepatocellular Carcinoma, Livmoniplimab, ABBV-151