A Study of Safety, Tolerability, and Clinical Activity of Durvalumab and Tremelimumab Administered as Monotherapy, or Durvalumab in Combination With Tremelimumab or Bevacizumab in Subjects With Advanced Hepatocellular Carcinoma
Overview
- Phase
- Phase 2
- Intervention
- Tremelimumab
- Conditions
- Hepatocellular Carcinoma
- Sponsor
- MedImmune LLC
- Enrollment
- 433
- Locations
- 44
- Primary Endpoint
- Number of Participants With Abnormal Vital Signs Reported as TEAEs
- Status
- Active, not recruiting
- Last Updated
- 2 months ago
Overview
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).
Investigators
Eligibility Criteria
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
Arms & Interventions
Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
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.
Intervention: Tremelimumab
Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
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.
Intervention: Durvalumab
Parts 2 and 3: Durvalumab 1500 mg
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.
Intervention: Durvalumab
Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg
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.
Intervention: Tremelimumab
Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg
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.
Intervention: Durvalumab
Parts 2 and 3: Tremelimumab 750 mg
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.
Intervention: Tremelimumab
Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg
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.
Intervention: Tremelimumab
Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg
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.
Intervention: Durvalumab
Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg
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
Intervention: Durvalumab
Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg
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
Intervention: Bevacizumab
China Cohort: Durvalumab 20 mg/kg
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.
Intervention: Durvalumab
China Cohort: Tremelimumab 10 mg/kg
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.
Intervention: Tremelimumab
China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
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.
Intervention: Tremelimumab
China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
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.
Intervention: Durvalumab
Outcomes
Primary Outcomes
Number of Participants With Abnormal Vital Signs Reported as TEAEs
Time Frame: 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 Electrocardiogram (ECG) Abnormalities Reported as Treatment-Emergent Adverse Events
Time Frame: 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 Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
Time Frame: 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)
Time Frame: 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
Time Frame: 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 Outcomes
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))