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

Sponsor

AstraZeneca (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05883644

Collaborator

(none)

140

Enrollment

Locations

Arm

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Hepatocellular Carcinoma	Drug: Durvalumab Drug: Tremelimumab	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

140 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Phase IIIb Non-randomised and non-blinded single arm studyPhase IIIb Non-randomised and non-blinded single arm study

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jul 14, 2023

Anticipated Primary Completion Date :

Apr 10, 2026

Anticipated Study Completion Date :

Apr 13, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Durvalumab plus Tremelimumab 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 Participants will receive 1500 mg at Day 1 and later receive as monotherapy starting at Week 4 for every 4 weeks through IV infusion Drug: Tremelimumab Participants will receive single dose of 300 mg through IV infusion at Day 1

Arm

Intervention/Treatment

Experimental: Durvalumab plus Tremelimumab

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

Participants will receive 1500 mg at Day 1 and later receive as monotherapy starting at Week 4 for every 4 weeks through IV infusion

Drug: Tremelimumab

Participants will receive single dose of 300 mg through IV infusion at Day 1

Outcome Measures

Primary Outcome Measures

Incidence of grade 3 or 4 possibly related to treatment adverse events (PRAEs) [From the date of first dose of IMP until 6 months after the initiation of study intervention]
PRAE is defined as an AE which has been assessed by the investigator to be possibly related to IMP.
Objective response rate (ORR) [From the first dose of IMP until progression, or the last evaluable assessment in the absence of progression [approx. up to 33 months]]
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

Number of participants with adverse events (AEs), serious adverse events (SAEs), adverse event of special interest (AESIs), immune-mediated AEs (imAEs) [From screening until 90 days following discontinuation of the last dose of IMP [approx. up to 33 months]]
To assess the safety and tolerability of STRIDE in participants with advanced unresectable HCC
Overall Survival (OS) [From the date of the first dose of IMP until death [maximum follow-up approx. 33 months]]
OS is defined as the time from the date of the first dose of IMP until death due to any cause.
Progression-Free Survival (PFS) [From the date of the first dose of IMP until the date of objective PD or death [maximum follow-up approx. 33 months]]
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)
Disease Control Rate at Week 16 (DCR-16w) [At Week 16]
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
Disease Control Rate at Week 24 (DCR-24w) [At Week 24]
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
Duration of Response (DOR) [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]]
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.
Duration of Treatment (DOT) [From the date of first dose of IMP to the date of last dose of IMP [approx. up to 33 months]]
DOT is defined as time on study intervention.
Time to deterioration in Health-Related Quality of Life (HRQoL), assessed using the EORTC QLQ C-30. [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 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.
Clinically meaningful change from baseline in HRQoL as assessed by EORTC QLQ C-30 [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 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.
Best overall response for HRQoL as assessed by EORTC QLQ C-30 [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 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.
Change from baseline in HRQoL as assessed by EORTC QLQ C-30 [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 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.
Time to deterioration in HRQoL as assessed by EORTC QLQ-HCC18 [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 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.
Clinically meaningful change from baseline in HRQoL as assessed by EORTC QLQ-HCC18 [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 (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.
Best overall response for HRQoL as assessed by EORTC QLQ-HCC18 [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 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.
Change from baseline in HRQoL as assessed by EORTC QLQ-HCC18 [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 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 130 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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
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 >

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	La Jolla	California	United States	92093
2	Research Site	Shreveport	Louisiana	United States	71103
3	Research Site	Bobigny		France	93009
4	Research Site	Clichy		France	92110
5	Research Site	Creteil		France	94010
6	Research Site	Lyon		France	69004
7	Research Site	Marseille		France	13385
8	Research Site	Rennes		France	35042
9	Research Site	Berlin		Germany	D-13353
10	Research Site	Frankfurt		Germany	60488
11	Research Site	Kiel		Germany	24105
12	Research Site	Köln		Germany	50937
13	Research Site	Magdeburg		Germany	39120
14	Research Site	Mainz		Germany	55131
15	Research Site	Hong Kong		Hong Kong
16	Research Site	Shatin		Hong Kong	00000
17	Research Site	Milano		Italy	20132
18	Research Site	Napoli		Italy	80147
19	Research Site	Padova		Italy	35128
20	Research Site	Pisa		Italy	56126
21	Research Site	Rozzano		Italy	20089
22	Research Site	Turin		Italy	10128
23	Research Site	Chiba-shi		Japan	260-8677
24	Research Site	Chuo-ku		Japan	104-0045
25	Research Site	Kanazawa-shi		Japan	920-8641
26	Research Site	Kashiwa		Japan	277-8577
27	Research Site	Matsuyama-city		Japan	790-0024
28	Research Site	Musashino-shi		Japan	180-8610
29	Research Site	Osakasayama-shi		Japan	589-8511
30	Research Site	Yokohama-shi		Japan	241-8515
31	Research Site	Gyeonggi-do		Korea, Republic of	13620
32	Research Site	Seongnam-si		Korea, Republic of	13496
33	Research Site	Seoul		Korea, Republic of	03080
34	Research Site	Seoul		Korea, Republic of	03722
35	Research Site	Seoul		Korea, Republic of	05505
36	Research Site	Seoul		Korea, Republic of	6351
37	Research Site	Singapore		Singapore	119228
38	Research Site	Singapore		Singapore	169610
39	Research Site	Singapore		Singapore	308433
40	Research Site	Barcelona		Spain	08035
41	Research Site	Barcelona		Spain	08036
42	Research Site	Cordoba		Spain	14004
43	Research Site	Madrid		Spain	28007
44	Research Site	Madrid		Spain	28040
45	Research Site	Pamplona		Spain	31008
46	Research Site	Hanoi		Vietnam	100000
47	Research Site	Ho Chi Minh		Vietnam	700000

Sponsors and Collaborators

AstraZeneca

Investigators

Principal Investigator: Stephen Chan, MD, Department of Clinical Oncology, Chinese University of Hong Kong
Principal Investigator: Lorenza Rimassa, MD, Humanitas Cancer Centre, IRCCS Humanitas Research Hospital