A Phase IIIb Single Arm, Open-label, Multicentre Study of Durvalumab and Tremelimumab as First Line Treatment in Participants with Advanced Hepatocellular Carcinoma (SIERRA)
- Trial ID
- 2022-502012-37-00
- Protocol
- D419CR00030
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **safety** and **efficacy** of a combination therapy consisting of tremelimumab 300 mg administered as a single dose and durvalumab 1500 mg every four weeks (STRIDE) in participants with advanced unresectable hepatocellular carcinoma (HCC). This evaluation is clinically relevant as it aims to provide a potential first-line treatment option for patients with specific clinical profiles, including those with a Child-Pugh score B7 or B8 and a WHO/ECOG performance status (PS) of 0-1, Child-Pugh class A with a WHO/ECOG PS of 2, or Child-Pugh class A with a WHO/ECOG PS of 0-1 and chronic main trunk portal vein thrombosis.
The secondary objectives include:
- Further assessment of the safety and tolerability of STRIDE in participants with advanced unresectable HCC.
- Further assessment of the efficacy of STRIDE in the same patient population.
- Evaluation of disease- and treatment-related symptoms and health-related quality of life (HRQoL).
Participants
The clinical trial involves a total of **101 participants** diagnosed with **Advanced Hepatocellular Carcinoma**. The study population includes both male and female subjects aged 18 years and older, with a body weight exceeding 30 kg. Participants were selected based on specific health criteria, including adequate organ and marrow function, and must not have received prior systemic therapy for hepatocellular carcinoma. The trial includes individuals with a Child-Pugh score classification on liver disease and WHO/ECOG performance status, ensuring a diverse representation of liver function and physical health status. Participants with HBV or HCV infections are included, provided they meet the necessary treatment and monitoring requirements. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to contraceptive guidelines if applicable. The trial population is characterized by a vulnerable group, reflecting the advanced nature of the disease and the specific health conditions required for participation.
Plans and Procedures
The clinical trial is designed as a **Phase IIIb**, single-arm, open-label, multicenter study to evaluate the safety and efficacy of **tremelimumab** and **durvalumab** as a first-line treatment in participants with advanced hepatocellular carcinoma. The trial will involve the administration of tremelimumab at a dose of 300 mg for one dose and durvalumab at 1500 mg every four weeks. The study aims to assess the incidence of Grade 3/4 possibly related adverse events (PRAEs) within six months of initiating the study intervention and the overall response rate (ORR) as determined by the investigator per RECIST 1.1 criteria.
The trial is expected to commence recruitment on July 7, 2023, and conclude by April 11, 2026. Participants will be involved in the study for a maximum treatment period of 10 months. The study will include several visits, starting with a screening visit to confirm eligibility based on criteria such as age, body weight, and liver function. Participants must have a confirmed diagnosis of unresectable hepatocellular carcinoma and meet specific organ and marrow function requirements. Follow-up visits will occur regularly to monitor the safety and efficacy of the treatment, with assessments of adverse events, overall survival, and progression-free survival. The end-of-study visit will evaluate the final outcomes and any long-term effects of the treatment.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The study will also monitor secondary endpoints, including the incidence and nature of adverse events, median overall survival, and quality of life assessments using the EORTC QLQ-C30 and QLQ-HCC18 questionnaires. The trial will adhere to strict eligibility criteria, including the requirement for participants to be 18 years or older, have a body weight of over 30 kg, and not have received prior systemic therapy for hepatocellular carcinoma. The study will ensure that participants with HBV or HCV infections are managed according to local institutional practices to maintain viral suppression throughout the trial duration.
Treatment
The clinical trial involves the administration of several treatments, including **MYCOPHENOLATE MOFETIL**, which is utilized as an auxiliary treatment. This medication is provided in the form of a hard capsule and is administered orally. The maximum daily dose is 2 grams, with a total maximum dose of 168 grams over a treatment period of up to 12 months. **MYCOPHENOLATE MOFETIL** is classified as an immunosuppressive agent and is not a pediatric formulation.
**DURVALUMAB**, marketed as IMFINZI, is a test treatment in this study. It is supplied as a 50 mg/mL concentrate for solution for infusion and is administered via intravenous infusion. The maximum daily and total dose is 1500 mg, with a treatment period of up to 10 months. DURVALUMAB is a protein-based therapeutic agent, specifically a monoclonal antibody, and is not formulated for pediatric use. The investigational product may differ from the commercial product, as detailed in the sponsor's response document.
**TREMELIMUMAB**, known commercially as IMJUDO, is also a test treatment. It is provided as a 20 mg/mL concentrate for solution for infusion and is administered through intravenous infusion. The maximum daily and total dose is 300 mg, with a treatment period limited to 1 month. TREMELIMUMAB is a protein-based monoclonal antibody and is not intended for pediatric use.
**INFLIXIMAB**, marketed as Inflectra, serves as an auxiliary treatment in the trial. It is available as a 100 mg powder for concentrate for solution for infusion and is administered via intravenous infusion. The maximum daily dose is 350 mg, with a total maximum dose of 1050 mg over a treatment period of up to 6 months. INFLIXIMAB is a protein-based therapeutic agent and is not a pediatric formulation.
Efficacy
The efficacy of the investigational treatment in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the incidence of Grade 3/4 **PRAEs** (possibly related adverse events) observed within six months after the initiation of the study intervention, and the overall response rate (ORR), defined as the proportion of participants who achieve a confirmed complete response (CR) or partial response (PR) as determined by the investigator per RECIST 1.1 criteria.
Secondary endpoints will encompass a range of measures, including the incidence, severity, and nature of adverse events (AEs), as well as specific outcomes such as median overall survival (OS), progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), and duration of treatment (DOT). Patient-reported outcomes will be evaluated using the EORTC QLQ-C30 and EORTC QLQ-HCC18 questionnaires, focusing on global health status, quality of life, and specific symptoms such as fatigue, appetite loss, and pain. These assessments will be conducted at various post-baseline timepoints to monitor changes from baseline and determine clinically meaningful changes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be ≥ 18 years (and above legal age) at the time of screening.
- 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 (except lymph nodes, which must have a short axis ≥ 15 mm) with CT or MRI, and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines. A lesion which progressed after previous ablation or transarterial embolisation procedures with or without radiation or chemotherapy could be measurable if it meets these criteria.
- Must not be eligible for LRT for unresectable HCC. For participants who progressed after LRT for HCC, LRT must have been completed ≥ 28 days prior to the baseline scan for the current study.
- Negative pregnancy test (serum) for women of childbearing potential.
- Female participants must be 1 year post-menopausal (amenorrhoeic for 12 months without an alternative medical cause), surgically sterile, or using one highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly). Women of childbearing potential must agree to use one highly effective method of birth control. They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study and from the time of screening throughout the total duration of the study and the drug washout period (90 days after the last dose of durvalumab and tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy). Females receiving HRT and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for FOCBP if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued to allow confirmation of postmenopausal status prior to randomization. (a) Non sterilised male partners of a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period. Cessation of birth control after this point should be discussed with a responsible physician. Periodic abstinence, as well as the rhythm and withdrawal methods are not acceptable methods of birth control.
- BCLC stage B (that is not eligible for LRT) or stage C.
- Child-Pugh Score classification on liver disease (refer to Section 8.2.7 of the protocol) and WHO/ECOG PS (refer to Section 8.2.6 of the protocol) at enrolment must comply with one of the following criteria, not cumulatively: (a) Child-Pugh score B7 or B8 with a WHO/ECOG PS of 0-1 at enrolment, without main trunk portal vein thrombosis. (b) 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). (c) Child-Pugh class A with WHO/ECOG PS of 0-1 at enrolment and with chronic main trunk portal vein thrombosis, based on investigators’ clinical judgement (participants with acute main trunk portal vein thrombosis are excluded from this study).
- Body weight of > 30 kg.
- Male or female.
- Participants with HBV infection (as characterised by positive HbsAg and/or anti-HBcAb with detectable HBV DNA, as per local laboratory standards) must be treated with antiviral therapy, as per institutional practice, to ensure adequate viral suppression (as per local laboratory standards) prior to enrolment. Participants must remain on antiviral therapy for the study duration and for 6 months after the last dose of study intervention. Participants who test positive for anti-HBc with undetectable HBV DNA (as per local laboratory standards) do not require antiviral therapy prior to enrolment. These participants will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (as per local laboratory standards). HBV DNA detectable participants must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study intervention.
- Adequate organ and marrow function, as defined below. Criteria “a”, “b”, “c”, and “f” cannot be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose. (a) Haemoglobin ≥ 7.5 g/dL. Participants with 7.5 g/dL < haemoglobin < 9.0 g/dL having active or chronic bleeding to be excluded. (b) Absolute neutrophil count ≥ 1000/μL. (c) Platelet count ≥ 60000/μL. Participants with 60000 μL < platelets count < 75000 μL having active or chronic bleeding to be excluded. (d) TBL ≤ 3 × the ULN. (e) ALT and AST ≤ 5 × ULN. (f) Albumin ≥ 2.6 g/dL. (g) INR < 2.3. (h) Calculated CrCL > 40 mL/min as determined by Cockcroft-Gault (using actual body weight) or creatinine clearance assessed by the method used as per institutional guidance. Males: CrCL (mL/min) = Weight (kg) × (140 - Age) / 72 × serum creatinine (mg/dL) Females: CrCL (mL/min) = Weight (kg) × (140 - Age) × 0.85 / 72 × serum creatinine (mg/dL)
- Participants with HCV infection must have confirmed diagnosis of HCV characterised by the presence of detectable HCV RNA or anti-HCV upon enrolment (management of this disease is per local institutional practice).
- 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. - In participants with cirrhosis, HCC radiological diagnosis following the American Association for the Study of the Liver Diseases guidance may be used if histological confirmation is not clinically feasible by fresh or archival tissue: o CT is preferred over MRI in participants with large ascites or those with difficulty holding breath. o In participants with renal disease or iodine allergy, MRI may be preferred. o In participants with hepatic decompensation (TBL > 2 to 3 mg/dL), hepatobiliary contrast agents uptake by the liver tends to be reduced, in which case, extracellular contrast agents may be preferred.
- Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception from the time of screening throughout the total duration of the study and the drug washout period (90 days after the last dose of durvalumab and tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy) to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period. (a) Female partners (of childbearing potential) of male participants must also use a highly effective method of contraception throughout this period.
- Capable of giving signed informed consent.
- Written informed consent from the participant has been obtained prior to any study-related procedures.
Exclusion Criteria
- As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active COVID-19, uncontrolled hypertension, active bleeding diseases, active infection, active interstitial lung disease/pneumonitis, serious chronic GI conditions associated with diarrhoea, psychiatric illness/social situations) chronic diverticulitis or previous complicated diverticulitis, or history of allogeneic organ transplant (eg, liver 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.
- Participation in another clinical study with a study intervention or investigational medicinal device administered within 28 days prior to first dose of study intervention or concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study.
- Participants with a known allergy or hypersensitivity to durvalumab and/or tremelimumab or any of the excipients of the product.
- Participants co-infected with HBV (presence of HbsAg and/or anti-HBcAb with detectable HBV DNA, as per local laboratory standards) and HCV (presence of anti-HCV antibodies), or co-infected with HBV and HDV (presence of anti-HDV antibodies). When not available per institutional standards, HDV serology may be replaced by RNA testing. (a) HCV positive (presence of anti-HCV antibodies); OR (b) HDV positive (presence of anti-HDV antibodies)
- Clinically meaningful ascites, defined as ascites requiring repeated paracentesis to maintain symptomatic control within 2 months prior to screening. Participants on stable doses of diuretics for ascites are eligible. Also uncontrolled pleural effusion, pericardial effusion requiring recurrent drainage procedures (once monthly or more frequently).
- Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Participants, if enrolled, should not receive live vaccine while receiving study intervention and up to 30 days after the last dose.
- Active or prior documented GI bleeding (eg, oesophageal varices or ulcer bleeding) within the past 6 months. Note: For participants with a history of GI bleeding greater than 6 months or assessed as high risk for oesophageal varices by the investigator, including main trunk portal vein thrombosis, a recent endoscopy within 3 months of enrolment and adequate endoscopic therapy according to institutional standards is required.
- Refractory nausea and vomiting, chronic GI disease, inability to swallow a formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of medication(s) needed to control participant’s symptoms.
- History of symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted.
- History of another primary malignancy except for: (a) 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. (b) Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or lentigo maligna that has undergone potentially curative therapy. (c) Adequately treated carcinoma in situ without evidence of disease.
- History of active primary immunodeficiency.
- No liver biopsy should have been performed within 2 weeks of the first dose of study intervention.
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
- Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
- Known to have tested positive for HIV (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion: (a) Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular injection). (b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent. (c) Steroids as premedication for hypersensitivity reactions or as an anti-emetic (eg, CT scan premedication).
- Prior exposure to immune-mediated therapy including, but not limited to, other antiCTLA-4, anti-PD-1, anti-PD-L1 and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.
- Receipt of the last dose of anticancer therapy (tumour embolisation) 28 days prior to the first dose of study intervention or 5 half-lives of anticancer therapy, whichever is longer.
- Palliative radiotherapy with a limited field of radiation within 2 weeks or radiotherapy with a wide field of radiation or to more than 30% of the bone marrow within 4 weeks before the first dose of study intervention.
- Persistent toxicities (CTCAE Grade > 1) caused by previous anticancer therapy; alopecia and vitiligo are excluded toxicities. (a) Participants with Grade ≥ 1 neuropathy will be evaluated on a case by-case basis. (b) Participants with irreversible toxicity that is not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included (eg, hearing loss).
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc), autoimmune pneumonitis, and autoimmune myocarditis. The following are exceptions to this criterion: (a) Participants with vitiligo or alopecia (b) Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement (c) Any chronic skin condition that does not require systemic therapy (d) Participants without active disease in the last 5 years may be included but only after consultation with the study clinical lead (e) Participants with coeliac disease controlled by diet alone
- History of previous, or current, brain metastases or spinal cord compression. Participants with suspected brain metastases at screening should have an MRI (preferred) or CT, each preferable with IV contrast of the brain prior to study entry.
- Female participants who are pregnant or breastfeeding or male or female participants of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 90 days after the last dose of durvalumab and tremelimumab combination therapy.
- Clinical judgement of acute main trunk portal vein thrombosis, before enrolment.
- Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
- History of leptomeningeal carcinomatosis.
- History of hepatic encephalopathy within the past 6 months or requirement for medications to prevent or control encephalopathy (eg, no lactulose, rifaximin, etc if used for purposes of hepatic encephalopathy).
- Major surgical procedure (as defined by the investigator) or significant traumatic injury within 4 weeks of the first dose of study intervention. Note: Local surgery of isolated lesions for palliative intent is acceptable.
- Previous study intervention assignment in the present study or a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
- Any concomitant medication known to be associated with TdP.
- Any concurrent anticancer treatment. Concurrent use of hormonal therapy for noncancer related conditions (eg, hormone replacement therapy) is allowed.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 07 Jul 2023 | 21 |
 Germany | Not Recruiting | 07 Jul 2023 | 22 |
 Italy | Not Recruiting | 07 Jul 2023 | 21 |
 Spain | Not Recruiting | 07 Jul 2023 | 25 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
MYCOPHENOLATE MOFETIL | Other | — | ORAL | 2 | 12 | SUB03360MIG |
IMJUDO 20 mg/ml concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION (STERILE CONCENTRATE). | INTRAVENOUS INFUSION | 300 | 1 | PRD10239824 |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1500 | 10 | PRD6651398 |
Inflectra 100 mg powder for concentrate for solution for infusion | Other | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 350 | 6 | PRD6483369 |