Hepatocellular carcinoma

This trial aims to further understand the efficacy of durvalumab in combination with tremelimumab and lenvatinib for the treatment of local tumors, and its impact on meeting the criteria for surgical resection of tumors, referred to as "resection." We also want to better understand the disease under study and related health issues. This trial will also evaluate: • How the investigational drug affects biomarkers. Biomarkers are substances in your body that can be used to measure or predict response to treatment or disease progression.

Injection solution
Injection solution
Capsule solution

Durvalumab
Tremelimumab
Lenvatinib

279
279
130

500mg/10ml
25mg/1.25ml
4 mg

Evaluate the conversion of participants with localized HCC to radical resection using Durvalumab and Tremelimumab (STRIDE) in combination with Lenvatinib and TACE or HAIC.

Inclusion Criteria: Participants are eligible to participate in the trial only if they meet all of the following criteria:
Age
1. Participants must be 18 years of age or older, or of legal consent age in the jurisdiction where the trial is being conducted, at the time of signing the consent form.

Participant Type and Disease Characteristics
2. Newly diagnosed HCC and previously untreated participants with histologically or radiologically confirmed HCC.

3. No evidence of extrahepatic disease on any available imaging studies.

4. At the time of enrollment, the HCC was initially assessed as unresectable by a multidisciplinary team (MDT).

5. The disease must be suitable for embolization or hepatic artery infusion chemotherapy (HAIC).

6. Child-Pugh score of A (i.e., a score of 5 to 6).

7. ECOG PS (East Coast Cancer Clinical Research Collaboration) of 0 or 1, and no worsening within the first 2 weeks prior to baseline or the day of first dose at screening.

8. Minimum life expectancy of at least 12 weeks.

9. At least one measurable intrahepatic target lesion suitable for repeat evaluation according to the following mRECIST criteria:

⚫ The liver lesion shows typical features of HCC on computed tomography (CT) or magnetic resonance imaging (MRI) scans following intravenous contrast administration, i.e., rich vascularity in the arterial phase and flushing in the portal venous or delayed venous phase.

⚫ Viable, non-necrotic portions (showing contrast enhancement in the arterial phase), accurately measurable at baseline, with a maximum diameter ≥ 10 mm.

10. Participants with active HBV (hepatitis B virus) infection, characterized by a positive HBsAg (hepatitis B surface antigen) test and/or a positive anti-HBcAb (hepatitis B core antibody) test with detectable HBV DNA (≥ 10 IU/mL or exceeding the detection limit of the local laboratory standard), must receive antiviral therapy according to the trial facility's practices. Antiviral therapy for HBV must be initiated before enrollment, and participants will continue antiviral therapy during the trial and for 6 months after the last dose of the investigational drug. Before initiating trial treatment, participants must demonstrate evidence of HBV stability or a sign of viral response (e.g., decreased HBV DNA levels).

⚫ Participants who test positive for HBsAg or hepatitis B core antibody but have undetectable HBV DNA (< 10 IU/mL or below the detection limit of their local laboratory) do not require antiviral therapy before enrollment. If HBV DNA is detected (≥ 10 IU/mL or above the detection limit of their local laboratory), these participants will be tested at each cycle to monitor HBV DNA levels. Participants with detectable HBV DNA must initiate and continue antiviral therapy during the trial and for 6 months after the last dose of the investigational drug.

11. Participants with active HCV (hepatitis C virus) infection (characterized by detectable HCV RNA or anti-HCV; participants with a positive HCV antibody test are only eligible if their HCV RNA PCR [polymerase chain reaction] test is negative) must be managed according to local trial facility practices prior to trial treatment.

12. Participants must have adequate organ and bone marrow function as determined during screening. Transfusions, infusions, or growth factor support administered within 14 days of the start of the first dose of the investigational drug must not meet criteria "a", "b", "c", and "f":

(a) Heme ≥ 9.0 g/dL

(b) Absolute neutrophil count ≥ 1.5 × 10⁹/L

(c) Platelet count ≥ 75 × 10⁹/L

(d) Total bilirubin ≤ 2.0 × Upper limit of normal

(e) ALT and AST ≤ 5 × Upper limit of normal

(f) Albumin ≥ 3.5 g/dL

(g) INR ≤ 1.6

(h) 2+ proteinuria or low urine strip reading. Participants undergoing >2+ urine proteinuria strip testing will have 24-hour urine collected for quantitative assessment of proteinuria. Participants with ≥ 1 g/24-hour urine protein will be ineligible.

(i) CrCL (creatinine clearance) calculated according to the Cockcroft-Gault method (based on actual body weight) or 24-hour urine CrCL ≥ 40 mL/min.

o Male:

CrCL (mL/min) = Weight (kg) × (140 - Age) / 72 × Serum creatinine (mg/dL)

o Female:

CrCL (mL/min) = Weight (kg) × (140 - Age) / 72 × Serum creatinine (mg/dL) × 0.85

Weight
13. Weight > 30 kg.

Gender and Contraception/Barrier Requirements

14. Participants designated as male and/or female at birth, including all gender identities.

The contraceptive method used by the participant or their partner should comply with local regulations regarding contraceptive methods used in the clinical trial.

(j) Male Participants:
o Male participants intending to have sexual intercourse with a female partner of childbearing potential must prevent their partner from becoming pregnant by surgical sterilization or by using an acceptable method of contraception from screening until the entire duration of the trial and the drug clearance period (90 days after the last dose of any investigational drug, or 180 days after the last TACE/HAIC procedure, whichever is longer). Male participants must not donate or store sperm during this period.

Female participants:
o Women who are infertile;
o Women receiving HRT (hormone replacement therapy) with questionable postmenopausal status who wish to continue HRT during the trial must use one of the contraceptive methods outlined in the FOCBP guidelines. Otherwise, HRT must be discontinued to confirm postmenopausal status prior to trial enrollment;
o FOCBP participants must agree to use a highly effective contraceptive method. FOCBP participants should have consistently used their chosen contraceptive method for at least 3 months prior to trial entry, up to 90 days after any last dose of the test drug or 180 days after the last TACE/HAIC procedure (whichever is longer).

o Unsterilized male partners of FOCBP participants must use male condoms and spermicide during this period (condoms only in countries where spermicide is not permitted). Female participants must not donate or store eggs during this period.

(l) Pregnancy Test: All women of childbearing age (FOCBP) must have a negative serum pregnancy test result at their first follow-up visit.

Informed Consent
15. Must be able to sign an informed consent form, including compliance with the requirements and limitations set forth in the ICF and this CSP (Clinical Trial Proposal).

Other Inclusion Criteria
16. Participants of all races, sexes, and ethnicities are eligible to participate in this trial.

Exclusion Criteria: Participants must not participate in the trial if they meet any of the following criteria:

Medical Conditions
1. Hepatocellular carcinoma lesions confirmed by MDT occupying ≥ 50% of the liver volume, or lesions distributed in both lobes of the liver.

2. Any indication of disease that the trial administrator deems unsuitable for participation or would jeopardize trial protocol adherence (e.g., severe or uncontrolled systemic disease), active bleeding disorders, active systemic infections (excluding HBV or HCV infection), active interstitial lung disease (ILD)/pneumonia, severe chronic gastrointestinal disease associated with diarrhea, mental illness/social status, or a history of allogeneic organ transplantation.

3. Uncontrolled hypertension unresponsive to standard medical treatment, defined as systolic blood pressure ≥ 150 mm Hg or diastolic blood pressure ≥ 90 mm Hg, or other hypertension-related cardiovascular complications.

4. Intractable nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulation, or previous major bowel resection that may impair the adequate absorption, distribution, metabolism, or excretion of Lenvatinib.

5. History of other primary malignancies. Exceptions include: 1) Malignancies treated with radical methods, with no known active disease for ≥ 5 years prior to the first dose of the trial treatment, and a low potential risk of recurrence; 2) Malignancies that occurred < 5 years prior to the first dose of the trial treatment, are inactive, and are not expected to recur within the next 5 years or are clinically relevant (this may be discussed further with the trial physician before enrollment). Exceptions include fully excised non-melanoma skin cancer and in situ diseases treated with curative methods.

6. Persistent toxicity from previous anticancer treatment (CTCAE [Common Adverse Event Evaluation Criteria] ≥ 2); alopecia and vitiligo are not excluded toxicities. Participants with irreversible toxic reactions (e.g., hearing loss) may be included in the trial after consultation with the AstraZeneca trial physician, provided that the trial administrator believes the toxicity will not be reasonably expected to worsen with durvalumab or tremelimumab treatment.

7 participants were co-infected with HBV and HCV, or co-infected with HBV and hepatitis D virus (HDV). (Presence of HBsAg and/or anti-HBcAb (anti-HBcAb) and detectable HBV DNA indicates HBV infection; HCV test positive [presence of anti-HCV antibodies (anti-HCV antibodies)]. Participants with a positive HCV antibody test are eligible to participate in the trial only if the HCV RNA PCR test is negative; HDV positive [presence of anti-HDV antibodies (anti-HDV antibodies)]). 8. Known HIV positive test (HIV antibody positive) or active tuberculosis infection (clinical assessment may include clinical history, physical examination and radiological findings, or tuberculosis testing in accordance with local practice).

(Note: Because this trial requires exclusion of individuals infected with human immunodeficiency virus (HIV), you will undergo HIV testing according to local practices. Participation in this trial is only permitted if the test result is negative. If your test result is positive (including false positives), the trial hospital and physician will provide you with follow-up medical referrals or consultations and will report to the relevant authorities in accordance with the law.) 9. Active or previously documented autoimmune or inflammatory diseases (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [excluding diverticulosis], systemic lupus erythematosus, sarcoidosis, syndrome or Wegener's syndrome [granulomatous polyangiitis], Graves' syndrome, rheumatoid arthritis, pituitary inflammation, uveitis, etc.), autoimmune pneumonia, autoimmune myocarditis. The following are exceptions to this condition:
* Participants with vitiligo or alopecia
* Participants with hypothyroidism (e.g., Hashimoto's syndrome) who are stable on hormone replacement therapy
* All chronic skin diseases that do not require systemic treatment
* Participants without active disease in the past 5 years may be included, but this must be done after consultation with the trial physician
* Participants with celiac disease controlled solely by diet
* 10 History of leptomeningeal carcinoma

11 History of kidney disease or nephrotic syndrome

12 Known fibrolamellar HCC, sarcomatoid HCC, invasive HCC, or mixed cholangiocarcinoma and HCC

13 History of hepatic encephalopathy or portosystemic shunt disease in the past 12 months, or requiring medication to prevent or control encephalopathy (i.e., lactulose, rifaximin, etc., must not be used if used to prevent or control hepatic encephalopathy).

14. Clinically significant ascites, defined as ascites requiring non-pharmacological intervention (e.g., paracentesis) to maintain symptom control within 6 months prior to the first scheduled dose.

Participants with ascites requiring pharmacological intervention (e.g., diuretics) and treated with a stable dose of diuretics for ≥ 2 months are eligible.

15. Major portal vein thrombosis visible on imaging at baseline/eligibility. Participants with Vp3 and Vp4 grades were excluded.

16. Evidence of bleeding risk varices assessed by the trial administrator during screening follow-up visits or during upper gastrointestinal endoscopy performed within 6 months (24 weeks) after enrollment.

17 participants met one or more of the following criteria:

o A mean resting corrected QT interval > 470 ms (within 15 minutes, 5-minute intervals) obtained from three ECGs performed at screening

o A history of QT prolongation associated with other medications requiring discontinuation, or a history of any concomitant medication currently known to prolong the QT interval and cause TdP (torsius point de pointes)

o Congenital long QT syndrome, a family history of long QT syndrome, or unexplained sudden cardiac death in a first-degree relative under 40 years of age

o Symptomatic congestive heart failure, unstable angina, symptomatic or treatment-required (CTCAE grade 3) uncontrolled arrhythmias (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic persistent ventricular tachycardia. Participants with pharmacologically controlled atrial fibrillation or pacemaker-controlled arrhythmias may be admitted based on the trial administrator's judgment and after consultation with a recommended cardiologist.

Previous/Concomitant Treatments
18. Major surgery or severe trauma within 4 weeks prior to the first dose of trial treatment. Biopsies of any type of surgery within 28 days are not an exclusion criterion, nor are surgeries for varicose veins.

19. Prior anticancer therapy for HCC.

20. Any concomitant medications known to be associated with torsades de pointes (TdP).

21. Prior immunomodulatory therapy, including but not limited to other anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2 antibodies, and anti-VEGF (anti-vascular endothelial growth factor) antibodies, excluding therapeutic anticancer vaccines.

22. Current or prior use of immunosuppressive drugs within 14 days prior to the first dose of durvalumab, tremelimumab, or lenvatinib. The following are exceptions to this condition:

o Intranasal, inhaled, topical, or local steroid injections (e.g., intra-articular injections).

o Systemic corticosteroids such as prednisone or its equivalent at physiological doses not exceeding 10 mg/day.

o Steroids used preoperatively for hypersensitivity reactions or as antiemetics (e.g., preoperative administration for CT scans).

23. Received an active attenuated vaccine within 30 days prior to receiving the first dose of the experimental treatment.

Previous/Combined Clinical Trial Experience

24. Previous participation in this trial or previous participation in a durvalumab and/or tremelimumab clinical trial, regardless of treatment group assignment.

25. Concurrent enrollment in another clinical trial, unless it is observational (non-interventional) or the participant is in the follow-up period of an interventional trial.

26. Participants with a known history of allergic or hypersensitivity reactions to any investigational drug or any investigational drug excipient.

Other Exclusions

27. Participation in the planning and/or execution of this trial (applicable to AstraZeneca staff and/or trial unit personnel).

28. Participants should not participate in the trial if the principal investigator determines that they are unlikely to comply with the trial procedures, restrictions, and requirements.

29. Female participants who are pregnant or breastfeeding, or fertile male or female participants who do not wish to take effective contraceptive measures within 90 days after the last dose of any investigational drug or 180 days after the last TACE/HAIC procedure (whichever is longer).