Durvalumab and Tremelimumab as First Line Treatment in Participants With Advanced Hepatocellular Carcinoma (HCC)

Study Overview
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Brief Summary
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This study will assess the safety and efficacy of Single Tremelimumab Regular Interval Durvalumab (STRIDE) as first-line therapy in participants with advanced unresectable HCC.

Detailed Description
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This is a Phase IIIb, open-label, single arm, multicentre study to assess the safety and efficacy of STRIDE as first-line therapy in participants with advanced unresectable HCC who have one of the following: Child-Pugh score B7 or B8 with a World Health Organisation Eastern Cooperative Oncology Group Performance Status (WHO/ECOG PS) of 0-1 at enrolment, or Child-Pugh class A with a WHO/ECOG PS of 2 at enrolment, or Child-Pugh class A with a WHO/ECOG PS of 0-1 and with evidence of chronic main trunk portal vein thrombosis at enrolment Participants must not have received any prior systemic therapy for HCC. Participants may have previously received locoregional therapy (LRT) but must no longer be suitable for additional LRT. Any local treatment needs to have been completed at least 4 weeks prior to initiation of treatment. The study consists of 4 periods: screening (Day-28 to Day -1), Treatment period, safety follow-up and survival follow-up.

Official Title
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A Phase IIIb Single Arm, Open-label, Multicentre Study of Durvalumab and Tremelimumab as First Line Treatment in Participants With Advanced Hepatocellular Carcinoma (SIERRA)

Conditions
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Advanced Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Durvalumab
* Drug: Tremelimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed HCC based on histopathological findings from tumour tissue Must not have received prior systemic therapy for HCC Minimum life expectancy of 12 weeks At least 1 measurable lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter with CT or MRI, and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines Must not be eligible for LRT for unresectable HCC. Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional therapy LRT) or stage C Child-Pugh Score classification on liver disease and WHO/ECOG PS at enrolment complying one of the following: Child-Pugh score B7 or B8 with a WHO/ECOG PS of 0-1 at enrolment, without main trunk portal vein thrombosis. Child-Pugh class A with a WHO/ECOG PS of 2 at enrolment, without main trunk portal vein thrombosis (ie, ECOG PS 2 participants with main portal vein tumour thrombosis are excluded from this study). Child-Pugh class A with WHO/ECOG PS of 0-1 at enrolment and evidence of chronic main trunk portal vein thrombosis Participants with hepatitis B virus (HBV) infection must be treated with antiviral therapy prior to enrolment. Participants with hepatitis C virus (HCV) infection must have confirmed diagnosis of HCV characterized by the presence of detectable HCV RNA or anti-HCV upon enrolment Adequate organ and bone marrow function Negative pregnancy test (serum) for women of childbearing potential. Female participants must be 1 year post-menopausal, surgically sterile, or using one highly effective form of birth control Male and Female participants and their partners must use an acceptable method of contraception. Body weight >30 kg Exclusion Criteria: Any evidence of acute or uncontrolled diseases or history of allogeneic organ transplant or those eligible to receive a transplant which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol Refractory nausea and vomiting, chronic gastrointestinal (GI) disease, inability to swallow a formulated product, or previous significant bowel resection History of symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia History of another primary malignancy except for: Malignancy treated with curative intent with no known active disease ≥ 5 years before the first dose of study intervention and of low potential risk for recurrence, or Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or lentigo maligna that has undergone potentially curative therapy, or Adequately treated carcinoma in situ without evidence of disease Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAE] Grade > 1) caused by previous anticancer therapy Active or prior documented autoimmune or inflammatory disorders History of active primary immunodeficiency History of leptomeningeal carcinomatosis History of hepatic encephalopathy within the past 12 months or requirement for medications to prevent or control encephalopathy Active or prior documented GI bleeding (eg, esophageal varices or ulcer bleeding) within the past 6 months. Evidence of acute main trunk portal vein thrombosis History of previous, or current, brain metastases or spinal cord compression Known fibrolamellar hepatocellular carcinoma (HCC), sarcomatoid HCC, or mixed cholangiocarcinoma and HCC Clinically meaningful ascites Participants co-infected with HBV and HCV or co-infected with HBV and hepatitis D virus (HDV) Known to have tested positive for human immunodeficiency virus (HIV) or active tuberculosis infection Prior exposure to immune-mediated therapy excluding therapeutic anticancer vaccines Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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
Intervention Model: Single Group Assignment
Interventional Model Description: Phase IIIb Non-randomised and non-blinded single arm study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Durvalumab plus Tremelimumab<br>Participants will receive a single priming dose of Tremelimumab plus Durvalumab at Day 1 (Week 0), followed by Durvalumab monotherapy starting at Week 4 and continuing until clinical progression, confirmed RECIST 1.1-defined radiological progression, unacceptable toxicity, withdrawal of consent, or any intervention discontinuation criteria. | Drug: Durvalumab<br>* Participants will receive 1500 mg at Day 1 and later receive as monotherapy starting at Week 4 for every 4 weeks through IV infusion<br>Drug: Tremelimumab<br>* Participants will receive single dose of 300 mg through IV infusion at Day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of grade 3 or 4 possibly related to treatment adverse events (PRAEs) | PRAE is defined as an AE which has been assessed by the investigator to be possibly related to IMP. | From the date of first dose of IMP until 6 months after the initiation of study intervention | 
| Objective response rate (ORR) | ORR is defined as the number (%) of participants with a confirmed objective tumour response (complete response [CR] or partial response [PR]) as determined by the investigator per Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1). | From the first dose of IMP until progression, or the last evaluable assessment in the absence of progression [approx. up to 33 months] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs), serious adverse events (SAEs), adverse event of special interest (AESIs), immune-mediated AEs (imAEs) | To assess the safety and tolerability of STRIDE in participants with advanced unresectable HCC | From screening until 90 days following discontinuation of the last dose of IMP [approx. up to 33 months] | 
| Overall Survival (OS) | OS is defined as the time from the date of the first dose of IMP until death due to any cause. | From the date of the first dose of IMP until death [maximum follow-up approx. 33 months] | 
| Progression-Free Survival (PFS) | PFS is defined as the time from the first dose of IMP until the date of objective PD (per RECIST 1.1 as assessed by the investigator) or death (by any cause in the absence of progression) | From the date of the first dose of IMP until the date of objective PD or death [maximum follow-up approx. 33 months] | 
| Disease Control Rate at Week 16 (DCR-16w) | DCR-16w is defined as the percentage of participants who have a best objective response of complete response or partial response (by Week 16 + 7 days) or who have stable disease for at least 16 weeks (-7 days), following the start of study intervention as determined by the investigator per RECIST 1.1 | At Week 16 | 
| Disease Control Rate at Week 24 (DCR-24w) | DCR-24w is defined as the percentage of participants who have a best objective response of complete response or partial response (by Week 24 + 7 days) or who have stable disease for at least 24 weeks (-7 days), following the start of study intervention per RECIST 1.1 | At Week 24 | 
| Duration of Response (DOR) | DOR is defined as the time from the date of first documented response until the date of documented progression per RECIST 1.1, as assessed by the investigator or death in the absence of disease progression. | From the date of first documented response until the first date of documented progression or death in the absence of disease progression [approx. up to 33 months] | 
| Duration of Treatment (DOT) | DOT is defined as time on study intervention. | From the date of first dose of IMP to the date of last dose of IMP [approx. up to 33 months] | 
| Time to deterioration in Health-Related Quality of Life (HRQoL), assessed using the EORTC QLQ C-30. | Time to deterioration is defined as time from date of first dose of study intervention to the date of the first clinically meaningful deterioration (defined as a a decrease from baseline of at least 10 points for EORTC QLQ-C30 global HRQoL and functional scales, and an increase from baseline of at least 10 points for the EORTC QLQ-C30 symptom scales) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration. The domains/scales of the EORTC QLQ-C30 prioritized include global health status/QoL, functioning (physical), multi-term symptom (fatigue) and single item symptoms (appetite loss and nausea). Final scores range from 0 to 100, where higher scores on the global measure of health status and functional scales indicate better health status/function, but higher scores on symptom scales represent greater symptom severity. | Every 8 weeks from date of first dose of IMP for the first 48 weeks and then every 12 weeks thereafter until treatment discontinuation and 90 days after last dose during safety follow-up [approx. up to 33 months] | 
| Clinically meaningful change from baseline in HRQoL as assessed by EORTC QLQ C-30 | Clinically meaningful change from baseline in global health status/QoL, symptoms and function score (categorized as improvement, no change or deterioration) is defined as an absolute change in the score from baseline of ≥ 10 for scales from the EORTC QLQ-C30 to assess disease and treatment related symptoms and HRQoL.The domains/scales of the EORTC QLQ-C30 prioritized include global health status/QoL, functioning (physical), multi-term symptom (fatigue) and single item symptoms (appetite loss and nausea). Final scores range from 0 to 100, where higher scores on the global measure of health status and functional scales indicate better health status/function, but higher scores on symptom scales represent greater symptom severity. | Every 8 weeks from date of first dose of IMP for the first 48 weeks and then every 12 weeks thereafter until treatment discontinuation and 90 days after last dose during safety follow-up [approx. up to 33 months] | 
| Best overall response for HRQoL as assessed by EORTC QLQ C-30 | Best overall response for global health status/QoL, function and symptom (fatigue) will be derived as the best response the participant achieved, based on evaluable electronic patient-reported outcome (ePRO) data collected during the study period to assess disease and treatment related symptoms and HRQoL. The domains/scales of the EORTC QLQ-C30 prioritized include global health status/QoL, functioning(physical), multi-term symptom (fatigue) and single item symptoms (appetite loss and nausea). Final scores range from 0 to 100, where higher scores on the global measure of health status and functional scales indicate better health status/function, but higher scores on symptom scales represent greater symptom severity. | Every 8 weeks from date of first dose of IMP for the first 48 weeks and then every 12 weeks thereafter until treatment discontinuation and 90 days after last dose during safety follow-up [approx. up to 33 months] | 
| Change from baseline in HRQoL as assessed by EORTC QLQ C-30 | Change from baseline of global health status/QoL, symptom and functioning scores to assess disease and treatment related symptoms and HRQoL. The domains/scales of the EORTC QLQ-C30 prioritized include global health status/QoL, functioning(physical), multi-term symptom (fatigue) and single item symptoms(appetite loss and nausea). Final scores range from 0 to 100, where higher scores on the global measure of health status and functional scales indicate better health status/function, but higher scores on symptom scales represent greater symptom severity. | Every 8 weeks from date of first dose of IMP for the first 48 weeks and then every 12 weeks thereafter until treatment discontinuation and 90 days after last dose during safety follow-up [approx. up to 33 months] | 
| Time to deterioration in HRQoL as assessed by EORTC QLQ-HCC18 | Time to deterioration is defined as time from date of first dose of study intervention to the date of the first clinically meaningful deterioration (defined as an increase from baseline of at least 10 points for EORTC QLQ-HCC18) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration. The QLQ-HCC18 is an HCC-specific module from the EORTC comprising 18 questions to assess HCC symptoms. The module includes 6 multi-item domain scales and 2 single-item scales. Final scores range from 0 to 100 where higher scores indicate a greater level of symptom severity and a poorer HRQoL. The items prioritized are single items shoulder pain, abdominal pain and abdominal swelling. | Every 8 weeks from date of first dose of IMP for the first 48 weeks and then every 12 weeks thereafter until treatment discontinuation and 90 days after last dose during safety follow-up [approx. up to 33 months] | 
| Clinically meaningful change from baseline in HRQoL as assessed by EORTC QLQ-HCC18 | Clinically meaningful change from baseline (categorized as improvement, no change or deterioration) is defined as an absolute change in the score from baseline of ≥ 10 for scales/items from QLQ-HCC18 to assess disease-related symptoms. The single items prioritized are shoulder pain, abdominal pain and abdominal swelling. The EORTC QLQ-HCC18 module is an 18-item questionnaire. All questions have a 4-point scale: Not at all, A little, Quite a bit, and Very much. For each of the 8 domains (6 multiple-item scales and 2 single-item scales), final scores are transformed such that they range from 0 to 100, where higher scores indicate greater level of symptoms and worse symptom or a poorer HRQoL. | Every 8 weeks from date of first dose of IMP for the first 48 weeks and then every 12 weeks thereafter until treatment discontinuation and 90 days after last dose during safety follow-up [approx. up to 33 months] | 
| Best overall response for HRQoL as assessed by EORTC QLQ-HCC18 | Best overall response in single-item symptoms (shoulder pain, abdominal pain, abdominal swelling) will be derived as the best response the participant achieved, based on evaluable ePRO data collected during the study period to assess disease-related symptoms. The single items prioritized are shoulder pain, abdominal pain and abdominal swelling. The EORTC QLQ-HCC18 module is an 18-item questionnaire. All questions have a 4-point scale: Not at all, A little, Quite a bit, and Very much. For each of the 8 domains (6 multiple-item scales and 2 single-item scales), final scores are transformed such that they range from 0 to 100, where higher scores indicate greater level of symptoms and worse symptom or a poorer HRQoL. | Every 8 weeks from date of first dose of IMP for the first 48 weeks and then every 12 weeks thereafter until treatment discontinuation and 90 days after last dose during safety follow-up [approx. up to 33 months] | 
| Change from baseline in HRQoL as assessed by EORTC QLQ-HCC18 | Change from baseline assessment in EORTC QLQ-HCC18 scale/item score at each post baseline assessment. The prioritized single items scores are shoulder pain, abdominal pain and abdominal swelling. The EORTC QLQ-HCC18 module is an 18-item questionnaire. All questions have a 4-point scale: Not at all, A little, Quite a bit, and Very much. For each of the 8 domains (6 multiple-item scales and 2 single-item scales), final scores are transformed such that they range from 0 to 100, where higher scores indicate greater level of symptoms and worse symptom or a poorer HRQoL. | Every 8 weeks from date of first dose of IMP for the first 48 weeks and then every 12 weeks thereafter until treatment discontinuation and 90 days after last dose during safety follow-up [approx. up to 33 months] | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunoglobulin G1 kappa subclass, STRIDE, liver cancer, human mAb, Barcelona Clinic Liver Cancer (BCLC), Child-Pugh