Advanced liver cancer Cancer Malignant neoplasm of liver and intrahepatic bile ducts
Conditions
Interventions
Current interventions as of 08/04/2025:
Patients will be identified from Oncology or Hepatology Clinics as per local practice. AZD5069 will be administered orally, twice daily, on a continuous adminis
Sponsors
NHS Greater Glasgow and Clyde
University of Glasgow
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Current inclusion criteria as of 08/04/2025: 1. Histologically or cytologically confirmed hepatocellular carcinoma that is not suitable for surgery (with or without transplantation) or locoregional therapies 2. Patients with evidence of background liver disease or without evidence of underlying liver disease will be eligible 3. Patients who have either (a) not received prior systemic anti-cancer therapy; or (b) who have progressed on, or who are intolerant to, no more than one line or prior therapy with either sorafenib or lenvatinib (patients who change 1st-line tyrosine kinase therapy from sorafenib to lenvatinib, and vice versa, within 2 months of starting treatment because of toxicity, and without evidence of disease progression, will be considered as having had one line of therapy), or an anti-PD(L)-1 antibody either as monotherapy or in combination with bevacizumab, a CTLA-4 antibody, or lenvatinib. Patients who developed > grade 2 immune-mediated toxicity, or who discontinued treatment due to immune-mediated toxicity, or who progressed within the first 12 weeks of previous immunotherapy treatment will be excluded. However, patients who developed immune-mediated endocrinopathy that has resolved and are on hormone replacement therapy are eligible. Patients who have received pre-operative (neo-adjuvant) systemic therapy followed by surgery with curative intent, with no macroscopic or microscopic residual disease, and in whom recurrent disease occurs >12 months after surgical resection, will be considered to be treatment-naïve for unresectable HCC 4. Able to undergo a pre-treatment and on-treatment biopsy of a liver tumour and of non-tumour liver for pharmacodynamic and predictive biomarker studies 5. ECOG performance status =1 (Appendix II) 6. Age =18 years 7. Measurable disease by RECIST 1.1. Patients who have previously been treated with TACE or ablation will be eligible provided there is either a new measurable lesion (that has not been treated with ablation/TACE) or a new, reproducibly measurable, hyper-vascular area with washout within a previously treated lesion or area 8. Estimated life expectancy greater than 3 months 9. Adequate haematological function as defined by: 9.1. Haemoglobin (Hb) =90 g/l 9.2. Neutrophil Count =1.5 x 109 /l 9.3. Platelets =75 x 10e9 /l 10. Child–Pugh Score A (=6) [Appendix VIII] 11. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 50 ml/min as calculated by local standard practice 14. Ability to swallow oral medication 15. Written informed consent prior to performing any study-related procedures 16. Patients with past or ongoing HCV infection will be eligible for the study. Patients who have been treated for HCV infection must have completed their treatment at least 1 month prior to starting trial therapy 17. Patients with controlled hepatitis B will be eligible as long as they meet the following criteria: 17.1. Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral load must be less than 500 IU/ml prior to the first dose of the study drug. Patients on active HBV therapy with viral loads under 500 IU/ml should stay on the same therapy throughout the study treatment. 17.2. Patients who are positive for anti-hepatitis B core antibody HBc, negative for hepatitis B surface antigen (HBsAg), and negative or positive for anti-hepatitis B surface anti
Exclusion criteria
Exclusion criteria: Current exclusion criteria as of 08/04/2025: 1. Pregnant or breastfeeding women 2. Women of childbearing potential* and men with female partners of childbearing potential who are not willing to use two forms of contraception, including one highly effective method. Men with pregnant or breastfeeding partners should be advised to use barrier method contraception to prevent exposure to the foetus or neonate during treatment. *A woman is considered of childbearing potential (WOCBP) i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. 3. Cardiovascular disease defined as Stage II to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system, or history of myocardial infarction (MI), or cardiac arrhythmia associated with haemodynamic instability, or unstable angina, or cerebral vascular accident, or transient ischemia, if any have occurred within the previous 12 months prior to study treatment. 4. Any other serious medical or psychiatric disorder that would be, in the opinion of the investigator, a contraindication to either the trial procedures or to therapy with AZD5069 or durvalumab 5. Patients with a lack of physical integrity of the GI tract leading to a malabsorption syndrome or intestinal obstruction that would impair the administration and absorption of oral therapy 6. Any previous > grade 2 toxicity or discontinuation of therapy due to immune-mediated toxicity with an immune checkpoint inhibitor. Patients who developed immune-mediated endocrinopathy that has resolved and are on hormone replacement therapy will be considered eligible. 7. Major surgery within 14 days of starting study treatment and patients must have recovered from any effects of major surgery 8. Patients with a known hypersensitivity to AZD5069 or durvalumab or any of the excipients of the products 9. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: 9.1. Intranasal, inhaled, or topical steroids; or local steroid injections (e.g., intra-articular injection) 9.2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisolone or equivalent 9.3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) and chemotherapy-induced nausea and vomiting 10. History of allogenic organ transplant 11. Active autoimmune disorders, or prior documented severe autoimmune or inflammatory disorders requiring immunosuppressive treatment (including inflammatory bowel disease [e.g., colitis, Crohn’s disease], diverticulitis with the exception of diverticulosis, coeliac disease, irritable bowel syndrome, or other serious gastrointestinal chronic conditions associated with diarrhoea); systemic lupus erythematosus; Wegener syndrome (granulomatosis with polyangiitis), Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis, etc. The following are exceptions to this criterion: 11.1. Patients with vitiligo or alopecia 11.2. Diabetes mellitus type I or resolved childhood asthma/atopy 11.3. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement 11.4. Any chronic skin condition that does not require systemi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Dose Escalation/Phase I: The recommended dose of AZD5069 when administered in combination with durvalumab in patients with advanced hepatocellular cancer (liver cancer). This will be defined by the maximum tolerated dose (MTD), determined by dose-limiting toxicities as measured by clinical and laboratory toxicities (NCI-CTC AE version 5) during the first 4-week cycle of treatment. Dose Expansion/Phase II: The overall objective response rate as determined by Response Evaluation Criteria in Solid Tumours (RECIST)1.1 in patients with advanced hepatoceullar cancer. CT scans will be performed every 8 weeks (every 12 weeks after year 1) until disease progression. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. The safety and tolerability of AZD5069 and durvalumab, measured by NCI-CTC AE version 5. Toxicity is assessed prior to treatment and throughout treatment, up to 90 days after continuation of trial medication. 2. Time to radiological progression, measured by RECIST 1.1 CT scans will be performed every 8 weeks (every 12 weeks after year 1) until disease progression. 3. Progression-free survival, determined as the time from patient registration to subsequent radiological disease progression or death). CT scans will be performed every 8 weeks (every 12 weeks after year 1) until disease progression. 4. Overall survival (time from registration to death) will be summarised at varying timepoints, along with medians using Kaplan-Meier survival curves on completion of the study. Patients are followed-up from time of registration to death, withdrawal of consent or the end of the trial, whichever occurs first. | — |
Countries
England, Scotland, United Kingdom
Outcome results
None listed