SIERRA: Durvalumab and Tremelimumab as First Line Treatment in Participants with Advanced Hepatocellular Carcinoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

6 Oct 2023 → ongoing

Decision date (initial)

2023-08-07

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Safety, Efficacy

To assess the safety and efficacy of tremelimumab 300 mg × 1 dose therapy plus durvalumab 1500 mg Q4W (STRIDE) in
participants with advanced unresectable HCC who have one of the following:
• Child-Pugh score B7 or B8 with a WHO/ECOG PS of 0-1, or
• 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 with chronic main trunk portal vein thrombosis

Secondary objectives 3

1. To further assess the safety and tolerability of STRIDE in participants with advanced unresectable HCC, as described above
2. To further assess the efficacy of STRIDE in participants with advanced unresectable HCC, as described above
3. To assess disease-and treatment-related symptoms and HRQoL

Conditions and MedDRA coding

Advanced Hepatocellular Carcinoma

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. 1. Participant must be ≥ 18 years (and above legal age) at the time of screening.
2. 3. Must not have received prior systemic therapy for HCC.
3. 4. Participants expected to live 12 weeks or more.
4. 5. 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.
5. 6. 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.
6. 14. Negative pregnancy test (serum) for women of childbearing potential.
7. 15. 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.
8. 7. BCLC stage B (that is not eligible for LRT) or stage C.
9. 8. 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).
10. 12. Body weight of > 30 kg.
11. 13. Male or female.
12. 9. 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.
13. 11. 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)
14. 10. 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).
15. 2. 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.
16. 16. 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.
17. 17. Capable of giving signed informed consent.
18. 18. Written informed consent from the participant has been obtained prior to any study-related procedures.

Exclusion criteria 31

1. 1. 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.
2. 26. 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.
3. 27. Participants with a known allergy or hypersensitivity to durvalumab and/or tremelimumab or any of the excipients of the product.
4. 15. 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)
5. 10. 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).
6. 20. 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.
7. 11. 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.
8. 2. 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.
9. 3. 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.
10. 4. 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.
11. 7. History of active primary immunodeficiency.
12. 28. No liver biopsy should have been performed within 2 weeks of the first dose of study intervention.
13. 29. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
14. 30. 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.
15. 16. 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).
16. 19. 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).
17. 18. 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.
18. 21. 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.
19. 23. 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.
20. 5. 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).
21. 6. 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
22. 13. 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.
23. 31. 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.
24. 12. Clinical judgement of acute main trunk portal vein thrombosis, before enrolment.
25. 14. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
26. 8. History of leptomeningeal carcinomatosis.
27. 9. 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).
28. 24. 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.
29. 25. Previous study intervention assignment in the present study or a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
30. 17. Any concomitant medication known to be associated with TdP.
31. 22. Any concurrent anticancer treatment. Concurrent use of hormonal therapy for noncancer related conditions (eg, hormone replacement therapy) is allowed.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. • Incidence of Grade 3/4 PRAEs as observed within 6 months after the initiation of study intervention. A PRAE is defined as an AE that has been assessed by the investigator to be possibly related to study intervention.
2. • ORR, defined as the proportion of participants who have a confirmed CR or PR, as determined by the investigator per RECIST 1.1.

Secondary endpoints 14

1. Incidence, severity, nature, seriousness, intervention/treatment, outcome and causality of AEs, including PRAEs, AESIs, imAEs, SAEs, AEs resulting in treatment interruption and discontinuation, and laboratory findings.
2. • Median OS, OS12, and OS24. OS is defined as the time from the date of the first dose of study intervention until death due to any cause.
3. • Median PFS, PFS12, and PFS18. PFS is defined as the time from the first dose of study intervention until the date of PD per RECIST 1.1, as assessed by the investigator, or death due to any cause
4. • DCR-16 and DCR-24, defined as the percentage of participants who have a best objective response of CR or PR by Week 16/24 or who have demonstrated SD per RECIST 1.1, as assessed by the investigator for at least 16/24 weeks following the start of study intervention.
5. • DOR, 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 due to any cause.
6. • DOT, defined as the time on study intervention.
7. EORTC QLQ-C30: • Time to deterioration in global health status/QoL, functioning (physical), multiterm symptom (fatigue), single-item symptoms (appetite loss, nausea).
8. EORTC QLQ-C30: • Clinically meaningful change from baseline in global health status/QoL, symptoms and function score (categorised as improvement, no change or deterioration) at each post-baseline assessment
9. EORTC QLQ-C30: • Best overall response for global health status/QoL, function and symptom (fatigue)
10. EORTC QLQ-C30: • Change from baseline of global health status/QoL, symptom and functioning scores at each post-baseline assessment.
11. EORTC QLQ-HCC18: • Time to deterioration in single-item symptoms (shoulder pain, abdominal pain, abdominal swelling)
12. EORTC QLQ-HCC18: • Clinically meaningful change from baseline (categorised as improvement, no change or deterioration) at each post-baseline assessment
13. EORTC QLQ-HCC18: • Best overall response in single-item symptoms (shoulder pain, abdominal pain, abdominal swelling)
14. EORTC QLQ-HCC18: • Change from baseline for each EORTC QLQ-HCC18 scale/item score at each post-baseline assessment.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Third parties 6

Locations

4 EU/EEA countries · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 67 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications