A Phase 2 Study of Tremelimumab (Day 1 only), Durvalumab (MEDI4736) and Trans-arterial catheter chemoembolization (TACE)in patients with advanced Hepatocellular Carcinoma (HCC)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University College Dublin

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

completed 6 May 2025

Decision date (initial)

2024-05-31

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

AstraZeneca

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

To determine the 6-month progression-free survival (PFS) of tremelimumab (Day 1 only) and durvalumab in patients with advanced, metastatic HCC following treatment with TACE

Secondary objectives 2

1. To assess the safety of combining single-dose tremelimumab, durvalumab and TACE in patients with advanced HCC
2. To determine the response rate (RR) and overall survival (OS) of tremelimumab (Day 1 only), durvalumab and TACE in patients with advanced, metastatic HCC

Conditions and MedDRA coding

Advanced Hepatocellular Carcinoma (HCC)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Patients must have histopathological confirmation of hepatocellular carcinoma (HCC) prior to entering this study OR histopathological confirmation of carcinoma in the setting of clinical and radiological characteristics which, together with the pathology, are highly suggestive of a diagnosis of HCC. Fibrolamellar variant is also allowed. No prior systemic therapy for advanced HCC is permitted, though investigator discretion is allowed for patients who discontinued sorafenib/lenvatinib for tolerability reasons
2. ● Patients must not have other invasive malignancies within the past 5 years (with the exception of non-melanoma skin cancers, non-invasive bladder cancer or localized prostate cancer for whom systemic therapy is not required).
3. Patient must be able to understand and willing to sign a written informed consent document
4. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: - Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). - Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
5. Patients must have HCC with evidence of extrahepatic disease that is not amenable to potentially curative resection, transplantation or ablation. Staging as per BCLC group C.
6. Disease must be technically amenable to transhepatic arterial chemoembolization (TACE) and the provision of TACE must be considered to be a reasonable intervention as decided at the GI MDT at the Mater Misericordiae University Hospital (MMUH). Each prospective case will be discussed at this tumor board with interventional radiology and a unanimous consensus across the disciplines of medical oncology, hepatology and interventional radiology must be reached as to the suitability of each patient for this protocol based on the distribution of their disease.
7. If liver cirrhosis is present, patient must have a Child-Pugh A/B7 classification.
8. Age >18 years
9. ECOG performance status 0-1 with a life expectancy of at least 12 weeks
10. Body weight >30kg
11. Patients must have normal organ and marrow function as defined below: o Haemoglobin ≥9.0 g/dL o Absolute neutrophil count (ANC ≥1.0 × 109 /L) o Platelet count ≥75 × 109/L o Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). <> o AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN o Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine clearance CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
12. ● Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be ≤ grade 1 or returned to baseline.
13. 13. Men and women of all races and ethnic groups are eligible for this trial.

Exclusion criteria 17

1. Patients who have had standard of care chemotherapy, large field radiotherapy, or major surgery must wait 4 weeks prior to entering the study.
2. Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent
3. ● Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)Patients should not be vaccinated with live attenuated vaccines within 30 days of starting durvalumab or tremelimumab treatment.
4. Has a known history of Human Immunodeficiency Virus (HIV). HIV-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between antiretroviral medications and tremelimumab. HIV positive patients not receiving antiretroviral therapy are excluded due to the possibility that tremelimumab may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined as the presence of anti‑HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Adjust wording as necessary and consider evaluating at screening for studies with known hepatotoxicity or other relevant requirements.
5. History of hypersensitivity reaction to human or mouse antibody products.
6. Pregnancy and breast feeding are exclusion factors. The effects of tremelimumab on the developing human fetus are unknown. Enrolled patients must agree to use adequate contraception (see section 4.1 and 4.2) prior to study entry, the duration of study participation and 6 months after the end of the treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or180 days after the last dose of durvalumab and tremelimumab combination therapy
7. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
8. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
9. Patients with unhealed surgical wounds for more than 30 days.
10. Patients who have undergone prior liver transplantation are ineligible.
11. Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
12. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consentHistory of chronic autoimmune disease (e.g., Addison’s disease, multiple sclerosis, Graves’ disease, Hashimoto’s thyroiditis, rheumatoid arthritis, hypophysitis, etc.) with symptomatic disease within the 3 years before randomization. Note: Active vitiligo or a history of vitiligo will not be a basis for exclusion.
13. Dementia or significantly altered mental status that would prohibit the understanding or rendering of Information and Consent and compliance with the requirements of the protocol.
14. Diverticulitis either active or history of within the past 2 years. Note that diverticulosis is permitted.
15. Active or history of inflammatory bowel disease (colitis, Crohn’s). Active or history of systemic lupus erythematosus or Wegener’s granulomatosis.
16. 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:
17. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 6-month Progression-free survival (PFS) with median PFS included in statistical analysis

Secondary endpoints 4

1. Safety
2. Overall survival time
3. Best overall response rate
4. EXPLORATORY ENDPOINT: Changes in immune parameters in the peripheral blood over time

Investigational products

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

Test 2

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University College Dublin

Sponsor organisation

University College Dublin

Address

Catherine Mcauley Centre, 21 Nelson Street, Phibsborough 21 Nelson Street Phibsborough

City

Dublin 7

Postcode

DUB LIN7

Country

Ireland

Scientific contact point

Organisation

University College Dublin

Contact name

Austin Duffy

Public contact point

Organisation

University College Dublin

Contact name

Faye Regan

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 13 files

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

Application history

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