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

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:

1. 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

2. Child-Pugh class A with a WHO/ECOG PS of 2 at enrolment, or

3. 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.

Primary Outcome Measures

1. 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.
2. 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).

Secondary Outcome Measures

1. 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
2. Overall Survival (OS)
   OS is defined as the time from the date of the first dose of IMP until death due to any cause.
3. 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)
4. 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
5. 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
6. 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.
7. Duration of Treatment (DOT)
   DOT is defined as time on study intervention.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.