A Study of Durvalumab or Tremelimumab Monotherapy, or Durvalumab in Combination With Tremelimumab or Bevacizumab in Advanced Hepatocellular Carcinoma

Phase 2

Active, not recruiting

Conditions: Hepatocellular Carcinoma

Interventions: Biological: Tremelimumab
Biological: Durvalumab
Biological: Bevacizumab

Registration Number: NCT02519348

Lead Sponsor: MedImmune LLC

Brief Summary: This is a multicenter, open-label, stratified, randomized study to evaluate the safety, tolerability, antitumor activity, pharmacokinetics, pharmacodynamics, and immunogenicity of durvalumab or tremelimumab monotherapy, or durvalumab in combination with tremelimumab or bevacizumab in advanced hepatocellular carcinoma.

Detailed Description: The study will comprise of 6 parts. Participants in Part 1A (safety run-in cohort), Part 1B (efficacy-gating cohort), Part 2A, and Part 4 will receive weight-based dosing regimens; and participants in Part 2B and Part 3 will receive fixed dosing regimens. Part 1A Stage 2 of the study may start after the first 3 participants in Stage 1 have been observed on study for at least 4 weeks. In addition, a separate cohort of participants will be enrolled in mainland China (China cohort) once global recruitment in Part 2A will be closed.

* In Part 1 (both 1A and 1B), participants will receive tremelimumab 1 mg/kg intravenous (IV) every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W.

* In Part 2A, participants will be randomized in a 1:1:1 ratio to receive:

* Durvalumab 20 mg/kg Q4W

* Tremelimumab 10 mg/kg Q4W × 7 doses followed by every 12 weeks (Q12W)

* Tremelimumab 1 mg/kg Q4W × 4 doses + durvalumab 20 mg/kg Q4W, followed by durvalumab 20 mg/kg Q4W

* In China cohort, Part 2A study design will be followed.

* In Part 2B, participants will receive tremelimumab 300 mg × 1 dose + durvalumab 1500 mg Q4W.

* In Part 3, participants will be randomized in a 2:2:1:2 ratio to receive:

* Durvalumab 1500 mg Q4W

* Tremelimumab 300 mg × 1 dose + durvalumab 1500 mg Q4W

* Tremelimumab 750 mg Q4W for 7 doses followed by Q12W

* Tremelimumab 75 mg Q4W × 4 doses + durvalumab 1500 mg Q4W, followed by durvalumab 1500 mg Q4W.

Following protocol amendment 5, enrollment into 'Tremelimumab 75 mg Q4W × 4 doses + durvalumab 1500 mg' arm will close. Participants will be randomized at a ratio of 2:1:2 in 'Durvalumab 1500 mg Q4W', 'Tremelimumab 750 mg Q4W for 7 doses followed by Q12W', and 'Tremelimumab 300 mg × 1 dose + durvalumab 1500 mg Q4W' arms, respectively.

• In Part 4, participants will receive durvalumab 1120 mg (15 mg/kg) + bevacizumab 15 mg/kg every 3 weeks (Q3W).

Participants will receive the treatment until confirm progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

All participants will be followed for survival until the end of study visit (last participant discontinues the study treatment).

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 433

Inclusion Criteria

Male or female participants
18 years and older (Japan-20 years and older)
Confirmed hepatocellular carcinoma (HCC) based on histopathological findings from tumor tissues. Advanced HCC with diagnosis confirmed pathologically or with noninvasive methods.
Immunotherapy-naïve
Have either progressed on, are intolerant to, or refused treatment with sorafenib or another approved TKI. For arm 5 only: Have not received any prior systemic therapy for HCC.

Exclusion Criteria

Prior exposure to immune-mediated therapy
Hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy
Gastrointestinal bleeding (eg, esophageal varices or ulcer bleeding) within 12 months
Ascites requiring non-pharmacologic intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose.
Main portal vein thrombosis (Vp4) as documented on imaging
Any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment
Active or prior documented autoimmune or inflammatory disease with some exceptions
Current or prior use of immunosuppressive medication within 14 days with some exceptions

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg	Tremelimumab	Participants will receive tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first. Participant recruitment to this arm was closed following protocol amendment 5.
China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg	Durvalumab	Participants will receive tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.
Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg	Durvalumab	Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) will receive tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.
Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg	Tremelimumab	Participants will receive tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurs first.
Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg	Durvalumab	Participants will receive tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurs first.
Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg	Bevacizumab	Participants will receive durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first
China Cohort: Durvalumab 20 mg/kg	Durvalumab	Participants will receive durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.
China Cohort: Tremelimumab 10 mg/kg	Tremelimumab	Participants will receive tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.
China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg	Tremelimumab	Participants will receive tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.
Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg	Tremelimumab	Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) will receive tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.
Parts 2 and 3: Durvalumab 1500 mg	Durvalumab	Participants will receive durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.
Parts 2 and 3: Tremelimumab 750 mg	Tremelimumab	Participants will receive tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.
Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg	Durvalumab	Participants will receive tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first. Participant recruitment to this arm was closed following protocol amendment 5.
Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg	Durvalumab	Participants will receive durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first

Primary Outcome Measures

Name	Time	Method
Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment-Emergent Adverse Events	From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)	Number of participants with ECG abnormalities recorded as TEAEs are reported. There will be no updated results for this outcome measure at the time of end of study.
Number of Participants With Abnormal Vital Signs Reported as TEAEs	From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)	Vital sign assessment included pulse rate, blood pressure, temperature, weight, and respiratory rate. Vital signs abnormalities recorded as TEAEs are reported. There will be no updated results for this outcome measure at the time of end of study.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)	An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. There will be no updated results for this outcome measure at the time of end of study.
Number of Participants With Dose Limiting Toxicities (DLTs)	From Day 1 to Day 28 after first dose of study drug	A DLT was defined as treatment-related toxicity that occurred during DLT evaluation period including: any Grade 4 immune-related adverse event (irAE), any Grade 3 colitis or any Grade 3 noninfectious pneumonitis irrespective of duration, any \>= Grade 2 pneumonitis that does not resolve to \<= Grade 1 within 7 days of initiation of maximal supportive care, any other Grade 3 irAE (excluding colitis or pneumonitis) that does not downgrade to Grade 2 within 7 days after onset of the event despite optimal medical management including systemic corticosteroids or does not downgrade to \<= Grade 1 or baseline within 14 days, liver transaminase elevation \> 8 × upper limit of normal (ULN) or total bilirubin \> 5 × ULN, aspartate aminotransferase or alanine aminotransferase \> 3 × ULN with concurrent increase in total bilirubin \> 2 × ULN without evidence of cholestasis or alternative explanations, and any \>= Grade 3 non-irAE (except for the protocol stated conditions).
Number of Participants With Clinically Important Changes in Hematology and Clinical Chemistry Parameters	From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)	Participants with clinically important Common Terminology Criteria for Adverse Events (CTCAE) grade changes to 3 or 4 in hematology and chemistry parameters are reported. There will be no updated results for this outcome measure at the time of end of study.

Secondary Outcome Measures

Name	Time	Method
Duration of Response (DoR) Based on Investigator Assessments and BICR	From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)	The DoR is defined as the time from the date of first documented OR (confirmed CR or confirmed PR) until date of documented progression (PD) based on investigator assessments and BICR review by using RECIST v1.1 or death in absence of disease progression. A confirmed CR is defined in above outcome measures. The PD is defined at least 20% increase in sum of diameters of target lesions (compared with nadir at 2 consecutive visits with an absolute increase of 5 mm), unequivocal progression of existing non-target lesions or new lesion. For participants who were alive and no documented PD at the time of data cutoff for analysis, DoR was censored at the last evaluable disease assessment date. The DoR was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.
Overall Survival (OS)	From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)	The OS is defined as the time from randomization for Parts 2A and 3, and time from first dose for Parts 1, 2B, and 4 until death due to any cause. If there was no death reported for a participant by the data cut-off date for overall survival analysis, OS was censored at the last known alive date. The OS was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.
Disease Control Rate (DCR) Based on Investigator Assessments and BICR	From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)	Disease assessments based on investigator assessments and BICR review were determined by using RECIST v1.1 guidelines. The DCR is defined as a BOR of confirmed CR, confirmed PR, or stable disease (SD). A confirmed CR is defined as two CRs (disappearance of all target and non-target lesions and no new lesions) that were separated by at least 4 weeks with no evidence of progression in-between. A confirmed PR is defined as two PRs (\>= 30% decrease in the sum of diameters of target lesions compared to baseline and no new non-target lesion) that were separated by at least 4 weeks with no evidence of progression in-between. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. There will be no updated results for this outcome measure at the time of end of study.
Time to Progression (TTP) Based on Investigator Assessments and BICR	From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)	Disease assessments based on investigator assessments and BICR review were determined by using RECIST v1.1 guidelines. The TTP was defined as the time from randomization for Parts 2A and 3, and time from first dose for Parts 1, 2B, and 4 to the first documentation of radiographic disease progression. However, if the participant died without tumor progression, they were censored at the time of death. Participants with no documented PD by the data cutoff date for TTP analysis were censored at the date of their last evaluable disease assessment. The TTP was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.
Overall Objective Response Rate (ORR) Based on Investigator Assessments and Blinded Independent Central Review (BICR)	From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)	Disease assessments based on investigator assessments and BICR review were determined by using Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) guidelines. The ORR is defined as best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR). The CR is defined as disappearance of all target and non-target lesions and no new lesions. The PR is defined as \>= 30% decrease in the sum of diameters of target lesions (compared to baseline) and no new non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between. There will be no updated results for this outcome measure at the time of end of study.
Time to Response (TTR) Based on Investigator Assessments and BICR	From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)	Disease assessments based on investigator assessments and BICR review were determined by using RECIST v1.1 guidelines. The TTR is defined as the time from randomization for Parts 2A and 3, and time from first dose for Parts 1, 2B, and 4 until the first documentation of a subsequently confirmed OR (confirmed CR or confirmed PR). A confirmed CR is defined as two CRs (disappearance of all target and non-target lesions and no new lesions) that were separated by at least 4 weeks with no evidence of progression in-between. A confirmed PR is defined as two PRs (\>= 30% decrease in the sum of diameters of target lesions compared to baseline and no new non-target lesion) that were separated by at least 4 weeks with no evidence of progression in-between. The TTR was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.
Progression Free Survival (PFS) Based on Investigator Assessments and BICR	From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)	Disease assessments based on investigator assessments and BICR review were determined by using RECIST v1.1 guidelines. The PFS is defined as the time from randomization for Parts 2A and 3, and time from first dose for Parts 1, 2B, and 4 until the first documentation of radiographic disease progression or death due to any cause, whichever occurs first. The PD is defined at least 20% increase in the sum of diameters of target lesions (compared with the nadir at 2 consecutive visits with an absolute increase of 5 mm), unequivocal progression of existing non-target lesions or new lesion. Participants who were alive with no documented PD by the data cutoff date for PFS analysis were censored at the date of their last evaluable disease assessment. The PFS was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.