A Phase I Study of ERY974 in Patients With Hepatocellular Carcinoma

Study Overview
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Brief Summary
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This is a multicenter, open-label, dose-escalation study designed to determine the maximum tolerated dose (MTD) by evaluating dose-limiting toxicities (DLTs) and to evaluate the safety, tolerability, pharmacokinetics, anti-tumor effect, and biomarkers of ERY974 in combination with atezolizumab and bevacizumab following premedication with tocilizumab in patients with locally advanced or metastatic HCC.

Official Title
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A Phase I Study of ERY974 in Combination With ATEZOLIZUMAB and BEVACIZUMAB in Patients With Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma (HCC)

Intervention / Treatment
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* Drug: ERY974
* Drug: Tocilicumab
* Drug: Atezolizumab
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥18 years at time of informed consent Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 HCC that has been histologically confirmed Exclusion Criteria: Previous or concomitant autoimmune disease Uncontrolled diabetes mellitus and hypertension Concurrent New York Heart Association (NYHA) Class ≥II congestive heart failure, myocardial infarction, arrhythmia, or unstable angina, or a history thereof within 6 months before enrollment. Concurrent symptomatic cerebrovascular disorder (e.g., subarachnoid hemorrhage, cerebral infarction, or transient ischemic attack), or a history thereof within 6 months before enrollment. Symptomatic, untreated, or actively progressing CNS metastases

Ages Eligible for Study
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Minimum Age: 20 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation part<br>Patients will receive ERY974 in combination with atezolizumab and bevacizumab after administering ERY974 as a single agent and to determine the MTD by evaluating DLTs of in patients with locally advanced or metastatic HCC. | Drug: ERY974<br>* ERY974 vial<br>Drug: Tocilicumab<br>* Tocilizumab vial<br>Drug: Atezolizumab<br>* Atezolizumab vial<br>Drug: Bevacizumab<br>* Bevacizumab vial<br>|
| Experimental: Expansion part<br>Patients will receive ERY974 in combination with atezolizumab and bevacizumab after administering ERY974 as a single agent To evaluate the anti-tumor effect. | Drug: ERY974<br>* ERY974 vial<br>Drug: Tocilicumab<br>* Tocilizumab vial<br>Drug: Atezolizumab<br>* Atezolizumab vial<br>Drug: Bevacizumab<br>* Bevacizumab vial<br>|
| Experimental: Concomitant use part<br>Patients will receive ERY974 in combination with atezolizumab and bevacizumab and to determine the MTD. | Drug: ERY974<br>* ERY974 vial<br>Drug: Tocilicumab<br>* Tocilizumab vial<br>Drug: Atezolizumab<br>* Atezolizumab vial<br>Drug: Bevacizumab<br>* Bevacizumab vial<br>|
| Experimental: Biomarker part<br>Patients will receive ERY974 in combination with atezolizumab and bevacizumab after administering ERY974 as a single agent and to evaluate the biomarkers. | Drug: ERY974<br>* ERY974 vial<br>Drug: Tocilicumab<br>* Tocilizumab vial<br>Drug: Atezolizumab<br>* Atezolizumab vial<br>Drug: Bevacizumab<br>* Bevacizumab vial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of ERY974 in combination with atezolizumab and bevacizumab (Dose limiting toxicities) [Dose escalation part] | Incidence and nature of DLTs | At the end of Cycle 2 (Cycle 1 is 14day, Cycle 2 or later is 21days) | 
| Safety and tolerability of ERY974 in combination with atezolizumab and bevacizumab (Electrocardiograms in triplicate) [Dose escalation part] | Incidence, nature, and severity of adverse events (AEs) as assessed by the NCI CTCAE v5.0 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Safety and tolerability of ERY974 in combination with atezolizumab and bevacizumab (Electrocardiograms in triplicate) [Dose escalation part] | Uncorrected QT interval, QTcF, PR duration, QRS interval and RR interval | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Safety and tolerability of ERY974 in combination with atezolizumab and bevacizumab (Electrocardiograms in triplicate) [Dose escalation part] | Heart Rate | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab [Dose escalation part] | Maximum plasma concentration (Cmax) of ERY974 Maximum plasma concentration (Cmax) of ERY974 Maximum plasma concentration (Cmax) of ERY974 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab [Dose escalation part] | Time to reach maximum plasma drug concentration (Tmax) of ERY974 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab [Dose escalation part] | Area under the concentration versus time curve (AUC) of ERY974 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Anti-tumor activity of ERY974 in combination with atezolizumab and bevacizumab [Expansion part] | Objective Response Rate (ORR) is defined as proportion of patients who had a confirmed complete response (CR) or partial response (PR), as determined by the investigator with use of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Safety and tolerability of ERY974 in combination with atezolizumab and bevacizumab from initiation (Dose limiting toxicities) [Concomitant use part] | Incidence and nature of DLTs | At the end of Cycle 1 (each Cycle is 21days) | 
| Safety and tolerability of ERY974 in combination with atezolizumab and bevacizumab (Adverse Events) [Expansion part] | Incidence, nature, and severity of adverse events (AEs) as assessed by the NCI CTCAE v5.0 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab from initiation [Concomitant use part] | Uncorrected QT interval, QTcF, PR duration, QRS interval and RR interval | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab from initiation [Concomitant use part] | Heart Rate | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab from initiation [Concomitant use part] | Maximum plasma concentration (Cmax) of ERY974 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab from initiation [Concomitant use part] | Time to reach maximum plasma drug concentration (Tmax) of ERY974 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab from initiation [Concomitant use part] | Area under the concentration versus time curve (AUC) of ERY974 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Biomarkers of ERY974 in combination with atezolizumab and bevacizumab [Biomarker part] | GPC3 and PD-L1 IHC staining | From screening to 6weeks | 
| Biomarkers of ERY974 in combination with atezolizumab and bevacizumab [Biomarker part] | Immune-related molecule IHC | From screening to 6weeks | 
| Biomarkers of ERY974 in combination with atezolizumab and bevacizumab [Biomarker part] | Gene expression | From screening to 6weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor activity of ERY974 in combination with atezolizumab and bevacizumab [Dose escalation part] | Objective Response Rate (ORR) is defined as proportion of patients who had a confirmed complete response (CR) or partial response (PR), as determined by the investigator with use of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) | From screening until disease progression, study discontinuation, withdrawal or death, whichever occurs first, assessed up to about 52 weeks. | 
| Safety and tolerability of ERY974 in combination with atezolizumab and bevacizumab (Adverse Events) [Expansion part] | Incidence, nature, and severity of adverse events (AEs) as assessed by the NCI CTCAE v5.0 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Safety, tolerability and pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab (Adverse Events) [Expansion part] | Uncorrected QT interval, QTcF, PR duration, QRS interval and RR interval | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Safety, tolerability and pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab (Adverse Events) [Expansion part] | Heart Rate | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab [Expansion part] | Maximum plasma concentration (Cmax) of ERY974 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab [Expansion part] | Time to reach maximum plasma drug concentration (Tmax) of ERY974 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab [Expansion part] | Area under the concentration versus time curve (AUC) of ERY974 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Anti-tumor activity of ERY974 in combination with atezolizumab and bevacizumab from initiation [Concomitant use part] | Objective Response Rate (ORR) is defined as proportion of patients who had a confirmed complete response (CR) or partial response (PR), as determined by the investigator with use of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) | From screening until disease progression, study discontinuation, withdrawal or death, whichever occurs first, assessed up to about 52 weeks. | 
| Safety of ERY974 in combination with atezolizumab and bevacizumab (Adverse Events) [Expansion part] | Incidence, nature, and severity of adverse events (AEs) as assessed by the NCI CTCAE v5.0 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Safety, tolerability and pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab (Adverse Events) [Biomarker part] | Uncorrected QT interval, QTcF, PR duration, QRS interval and RR interval | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | Heart Rate | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab [Biomarker part] | Maximum plasma concentration (Cmax) of ERY974 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab [Biomarker part] | Time to reach maximum plasma drug concentration (Tmax) of ERY974 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. | 
| Pharmacokinetics of ERY974 in combination with atezolizumab and bevacizumab [Biomarker part] | Area under the concentration versus time curve (AUC) of ERY974 | From first dose until 28 days after the last dose of study treatment, assessed up to about 52 weeks. |