Clinical trial NCT05883644: Durvalumab and Tremelimumab as First Line Treatment in Participants With Advanced Hepatocellular Carcinoma (HCC)
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Advanced Hepatocellular Carcinoma
Keywords: liver cancer
human mAb
immunoglobulin G1 kappa subclass
STRIDE
Barcelona Clinic Liver Cancer (BCLC)
Child-Pugh
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2023-06-01
Enrollment: 111
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Phase IIIb Non-randomised and non-blinded single arm study
Primary purpose: TREATMENT

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.

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:

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.

Eligibility criteria: Inclusion Criteria:

* Confirmed unresectable HCC based on histopathological findings (prior histological verification confirming HCC is acceptable), or radiological findings in participants with cirrhosis where histopathological confirmation is not clinically feasible
* Must not have received prior systemic therapy for HCC
* Participants expected to live 12 weeks or more
* 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:

  1. Child-Pugh score B7 or B8 with a WHO/ECOG PS of 0-1 at enrolment, without main trunk portal vein thrombosis.
  2. 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).
  3. Child-Pugh class A with WHO/ECOG PS of 0-1 at enrolment and with 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, chronic diverticulitis or previous complicated diverticulitis, or history of allogeneic organ 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:

  1. Malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence, or
  2. Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or lentigo maligna that has undergone potentially curative therapy, or
  3. 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, autoimmune pneumonitis, and autoimmune myocarditis
* History of active primary immunodeficiency
* History of leptomeningeal carcinomatosis
* History of hepatic encephalopathy within the past 6 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.
* Clinical judgement 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
* Any concomitant medication known to be associated with Torsades de Pointes
* 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
* Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention" and "Major surgical procedure (as defined by the investigator) or significant traumatic injury within 4 weeks of the first dose of study intervention.

Primary outcomes:
measure: Incidence of grade 3 or 4 possibly related to treatment adverse events (PRAEs)
timeFrame: From the date of first dose of IMP until 6 months after the initiation of study intervention
measure: Objective response rate (ORR)
timeFrame: From the first dose of IMP until progression, or the last evaluable assessment in the absence of progression [approx. up to 33 months]
Secondary outcomes:
measure: Number of participants with adverse events (AEs), serious adverse events (SAEs), adverse event of special interest (AESIs), immune-mediated AEs (imAEs)
timeFrame: From screening until 90 days following discontinuation of the last dose of IMP [approx. up to 33 months]
measure: Overall Survival (OS)
timeFrame: From the date of the first dose of IMP until death [maximum follow-up approx. 33 months]
measure: Progression-Free Survival (PFS)
timeFrame: From the date of the first dose of IMP until the date of objective PD or death [maximum follow-up approx. 33 months]
measure: Disease Control Rate at Week 16 (DCR-16w)
timeFrame: At Week 16
measure: Disease Control Rate at Week 24 (DCR-24w)
timeFrame: At Week 24
measure: Duration of Response (DOR)
timeFrame: 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]
measure: Duration of Treatment (DOT)
timeFrame: From the date of first dose of IMP to the date of last dose of IMP [approx. up to 33 months]
measure: Time to deterioration in Health-Related Quality of Life (HRQoL), assessed using the EORTC QLQ C-30.
timeFrame: 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]
measure: Clinically meaningful change from baseline in HRQoL as assessed by EORTC QLQ C-30
timeFrame: 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]
measure: Best overall response for HRQoL as assessed by EORTC QLQ C-30
timeFrame: 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]
measure: Change from baseline in HRQoL as assessed by EORTC QLQ C-30
timeFrame: 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]
measure: Time to deterioration in HRQoL as assessed by EORTC QLQ-HCC18
timeFrame: 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]
measure: Clinically meaningful change from baseline in HRQoL as assessed by EORTC QLQ-HCC18
timeFrame: 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]
measure: Best overall response for HRQoL as assessed by EORTC QLQ-HCC18
timeFrame: 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]
measure: Change from baseline in HRQoL as assessed by EORTC QLQ-HCC18
timeFrame: 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]
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Research Site
state: California
city: Shreveport
country: United States
facility: Research Site
state: Louisiana
city: Detroit
country: United States
facility: Research Site
state: Michigan
city: Bobigny
country: France
facility: Research Site
city: Clichy
country: France
facility: Research Site
city: Creteil
country: France
facility: Research Site
city: Marseille
country: France
facility: Research Site
city: Rennes
country: France
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Frankfurt
country: Germany
facility: Research Site
city: Köln
country: Germany
facility: Research Site
city: Lübeck
country: Germany
facility: Research Site
city: Hong Kong
country: Hong Kong
facility: Research Site
city: Shatin
country: Hong Kong
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Pisa
country: Italy
facility: Research Site
city: Rozzano
country: Italy
facility: Research Site
city: Turin
country: Italy
facility: Research Site
city: Kanazawa-shi
country: Japan
facility: Research Site
city: Kashiwa
country: Japan
facility: Research Site
city: Matsuyama-city
country: Japan
facility: Research Site
city: Musashino-shi
country: Japan
facility: Research Site
city: Osakasayama-shi
country: Japan
facility: Research Site
city: Yokohama-shi
country: Japan
facility: Research Site
city: Gyeonggi-do
country: Korea, Republic of
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Cordoba
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Pamplona
country: Spain
facility: Research Site
city: Hanoi
country: Vietnam
facility: Research Site
Study officials:
affiliation: Department of Clinical Oncology, Chinese University of Hong Kong
name: Stephen Chan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Humanitas Cancer Centre, IRCCS Humanitas Research Hospital
name: Lorenza Rimassa, MD
role: PRINCIPAL_INVESTIGATOR
References: