Phase 2 Study of Durvalumab plus Tremelimumab with Lenvatinib Versus Durvalumab plus Tremelimumab in Unresectable Intermediate/Advanced Hepatocellular Carcinoma
- Trial ID
- 2025-521608-23-00
- Protocol
- HE.2
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to compare progression‑free survival of the combination regimen (durvalumab plus tremelimumab with lenvatinib) versus durvalumab plus tremelimumab alone in patients with intermediate or advanced unresectable hepatocellular carcinoma who are not candidates for locoregional therapy, providing a direct assessment of disease control. Secondary objectives include evaluation of overall survival associated with the two regimens, assessment of the safety profile and toxicity of the combination versus the immunotherapy alone, and determination of the objective response rate for each treatment arm, thereby addressing long‑term benefit, tolerability, and tumor response metrics.
Participants
The trial enrolled 84 participants diagnosed with hepatocellular carcinoma that was unresectable and not amenable to local therapy. Adults aged 18 years or older of both sexes were included, with a minimum body weight of 30 kg and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients had a life expectancy of at least 12 weeks, Child‑Pugh class A or B7 liver function, and Barcelona Clinic Liver Cancer stage B (ineligible for locoregional treatment) or stage C. All participants required at least one measurable lesion (≥10 mm on CT or MRI, or ≥15 mm short axis for lymph nodes) and had not received prior systemic therapy for hepatocellular carcinoma. The cohort allowed individuals with active hepatitis B virus infection provided they were on antiviral therapy or demonstrated viral suppression, and participants could be classified as vulnerable. Selection was based on the defined inclusion criteria, confirming diagnosis by histopathology or AASLD imaging standards, and ensuring suitability for repeated radiologic assessment. No additional lifestyle restrictions such as specific diet or physical activity requirements were stipulated.
Plans and Procedures
The study is a phase II, randomized, multicenter, open‑label trial comparing the combination of durvalumab (1500 mg IV) plus tremelimumab (300 mg IV) with lenvatinib (12 mg oral daily) versus durvalumab plus tremelimumab alone in adults with unresectable hepatocellular carcinoma; the anticipated recruitment period extends from August 2026 to August 2029, providing an overall trial duration of approximately three years. Participants are screened during an initial visit to confirm eligibility criteria, including age ≥18 years, body weight >30 kg, Child‑Pugh class A or B7, ECOG performance status 0–1, measurable disease per RECIST 1.1, and absence of prior systemic therapy. Eligible subjects are randomized 1:1 to one of the two treatment arms and receive the assigned regimen on a 28‑day cycle; the investigational arm adds daily lenvatinib to the intravenous agents. Follow‑up visits occur at the start of each treatment cycle for safety assessments, laboratory testing, and imaging; tumor assessments are performed every 8 weeks until documented disease progression, withdrawal, or study completion. The end‑of‑study visit is scheduled 30 days after the last dose of study medication to collect final efficacy and safety data. Participant involvement is expected to continue for up to 24 months or until discontinuation due to disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision. The primary endpoint is Progression-Free Survival, with secondary endpoints including overall survival, objective response rate, safety, and toxicity. Early termination of individual participation may occur if predefined stopping criteria such as grade 4 adverse events, confirmed disease progression, or violation of protocol‑defined inclusion/exclusion criteria are met.
Treatment
Lenvatinib is supplied as hard capsules containing 4 mg of the active substance. The investigational regimen uses a total daily dose of 12 mg, administered orally in divided capsules as directed by the study protocol. Dosing is intended to be taken each day throughout the treatment period, with investigators verifying intake at each study visit.
Durvalumab and tremelimumab are provided for intravenous infusion. Durvalumab is administered at a dose of 1500 mg per infusion, while tremelimumab is given at a dose of 300 mg per infusion. Both agents are delivered by intravenous route according to the schedule defined in the protocol, and are combined as the STRIDE regimen.
All study medications are prepared and administered in a clinical setting under controlled conditions. Participants receive detailed instructions regarding timing of oral dosing and are monitored for adherence through pill counts and patient diaries. Intravenous infusions are recorded in the electronic case report form, and infusion-related observations are documented to ensure compliance with the dosing schedule. The trial focuses on patients with unresectable hepatocellular carcinoma who are not candidates for local therapy.
Efficacy
Efficacy will be evaluated primarily by measuring Progression-Free Survival (PFS). Secondary efficacy assessments will include Overall Survival (OS) and Objective Response Rate (ORR). Safety and toxicity parameters will also be recorded as part of the secondary outcomes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 4.1.1 Age ≥ 18 years. 4.1.2 Body weight > 30 kg. 4.1.3 Life expectancy of at least 12 weeks. 4.1.4 Confirmed HCC based on histopathological findings from tumour tissues or clinically by AASLD criteria [Singal 2023] in cirrhotic participants. Note: Participants diagnosed based on AASLD criteria only must have corresponding source documentation available which confirms these criteria have been met. This includes imaging documentation of at least one LI-RADS 5 lesion. 4.1.5 Must not have received prior systemic therapy for HCC. 4.1.6 Must not be eligible for locoregional therapy for unresectable HCC. For patients who progressed after locoregional therapy for HCC, locoregional therapy must have been completed ≥28 days prior to the baseline scan of the abdomen and pelvis for the current study. 4.1.7 Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional therapy) or stage C. 4.1.8 Child-Pugh Score class A or B7 based on low albumin (albumin 25-27 g/L) only. 4.1.9 Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 4.1.10 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 computerized tomography (CT) or magnetic resonance imaging (MRI), and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines. A lesion which progressed after previous ablation or TACE could be measurable if it meets these criteria. PROTOCOL DATE: 2025-MAR-17 CCTG TRIAL: HE.2 CONFIDENTIAL 14 CONFIDENTIAL 4.1.11 Participants with active HBV infection [characterized by positive hepatitis B virus surface antigen (HBsAg) and/or positive hepatitis B core antibodies (anti-HBcAb) with detectable HBV deoxyribonucleic acid (DNA) (≥10 IU/mL or above the limit of detection per local lab standard)] are eligible if: • The participant is being treated with antiviral therapy, as per institutional practice. The HBV antiviral therapy must be initiated prior to randomization, and the participant must remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication. • The participant must show evidence of HBV stabilization or signs of viral response (e.g. reduction of HBV DNA levels) prior to enrollment Participants who test positive for HBsAg or anti-hepatitis B core (HBc) with undetectable HBV DNA (< 10 IU/mL or under the limit of detection per local lab standard) are eligible and do not require antiviral therapy prior to randomization. • These participants will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥ 10 IU/mL or above the limit of detection per local lab standard). • If HBV DNA becomes detectable during study treatment, antiviral therapy must be initiated, and the participant must remain on antiviral therapy during the study treatment period and for 6 months after the last dose of study medication. See the protocol for other criteria
Exclusion Criteria
- 4.2.1 Participants with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other tumours curatively treated with no evidence of disease for ≥ 5 years. 4.2.2 Any concurrent chemotherapy, study drug, or biologic or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g. hormone replacement therapy) is acceptable. 4.2.3 Known fibrolamellar HCC, sarcomatoid HCC, infiltrative-type HCC or mixed cholangiocarcinoma and HCC. 4.2.4 Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g. paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose. Participants with ascites that has required pharmacologic intervention (e.g. diuretics) and who have been on stable doses of diuretics for ascites for ≥ 2 months are eligible. 4.2.5 Uncontrolled arterial hypertension defined by a systolic pressure ≥ 150 mm Hg or diastolic pressure ≥ 90 mm Hg or other hypertensive cardiovascular complications despite standard medical management. 4.2.6 Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab, or an anti-CTLA4, including tremelimumab. 4.2.7 History of primary immunodeficiency, history of organ transplant or prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy. 4.2.8 Known to have tested positive for human immunodeficiency virus (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). 4.2.9 Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 4.2.10 Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 4.2.11 Active or prior documented autoimmune or inflammatory disorders including inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis), diverticulitis (with the exception of diverticulosis), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc. The following are exceptions to this criterion: vitiligo; alopecia; hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement; any chronic skin condition that does not require systemic therapy; celiac disease controlled by diet alone; Graves’ disease if no treatment was required within 2 years prior to enrollment. Otherwise, patients without active disease in the last 5 years may be included but only after consultation with the study physician. See the protocol for other criteria
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Yet Recruiting | 01 Aug 2026 | 56 |
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 |
|---|---|---|---|---|---|---|
TREMELIMUMAB | Comparator | — | INTRAVENOUS USE | 300 | 1 | SUB37101 |
DURVALUMAB | Comparator | — | INTRAVENOUS USE | 1500 | 1 | SUB176342 |
LENVIMA 4 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 12 | 1 | PRD3616568 |