Ezurpimtrostat autophagy inhibitor in association with Atezolizumab-Bevacizumab in first line treatment of unresectable hepatocellular carcinoma, a phase 2b randomized trial. ABE-LIVER

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Grenoble

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

15 Dec 2022 → 8 Mar 2024

Decision date (initial)

2022-11-30

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Société Genoscience Pharma

External identifiers

EU CT number

2022-502078-17-00

ClinicalTrials.gov

NCT05448677

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The primary objective of this study is to assess the efficacy of Ezurpimtrostat in association with standard of care (Atezolizumab-Bevacizumab), compared to standard of care alone, as first line treatment in patients with unresectable hepatocellular carcinoma.

Secondary objectives 13

1. To assess the tumor response under the association of Ezurpimtrostat with Atezolizumab-Bevacizumab in first line setting in unresectable hepatocellular carcinoma
2. To assess the impact of the association Ezurpimtrostat + Atezolizumab-Bevacizumab on Overall Survival (OS)
3. To assess the duration of response of the association Ezurpimtrostat + Atezolizumab-Bevacizumab
4. To assess the Alpha-fetoprotein (AFP) response at 3, 6, 12 months under the association Ezurpimtrostat + Atezolizumab-Bevacizumab
5. To assess the overall survival rate at 6, 12-months under the association Ezurpimtrostat + Atezolizumab-Bevacizumab
6. To assess the progression free survival rate at 6, 12-months under the association Ezurpimtrostat + Atezolizumab-Bevacizumab
7. To assess the safety of the association Ezurpimtrostat + Atezolizumab-Bevacizumab
8. To assess the Quality of life (by EORTC QLQ-C30 and HCC 18 score) and the time to deterioration (TTD) under the association Ezurpimtrostat + Atezolizumab-Bevacizumab
9. To assess the predictive value of CD4/CD8 intratumor infiltrate on tumor response and survival outcomes
10. To assess the predictive value of PPT1 baseline expression on tumor response and survival outcomes
11. Pharmacokinetic (PK) and pharmacodynamics (PD) study of Ezurpimtrostat in association with Atezolizumab-Bevacizumab
12. Peripheral blood mononuclear cell (PBMC) serum and plasma sample biobanking for further ancillary studies
13. 13. Socio-demographic questionnaires for ancillary study

Conditions and MedDRA coding

unresectable hepatocellular carcinoma

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 21

1. Males or females ≥ 18 years of age
2. Histologically confirmed (liver biopsy within 6 previous months) and documented non resectable or metastatic HCC
3. Patients with a BCLC C status, as per the Barcelona Clinic Liver Cancer (BCLC) staging system
4. No prior systemic therapy for advanced HCC
5. Liver tumor burden < 50% of the liver (per Investigator judgment)
6. Child-Pugh A (≤ 6) without any history of cirrhotic decompensation within the past 6 months
7. Antiviral therapy required in hepatitis B virus patients (Hepatitis B antigen positive)
8. Presence of a measurable tumor per RECIST v1.1 criteria
9. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
10. Life expectancy ≥ 12 weeks
11. In case of cirrhosis, last esophageal varices detection by esogastroduodenal endoscopy have to be performed within last the 6 months before inclusion and since macro-vascular invasion diagnosis
12. Adequate hematologic function prior to the first dose of Ezurpimtrostat, defined as: 12.1. Absolute neutrophils count ≥ 1500 cells/μL 12.2. Hemoglobin ≥ 9 g/dL with no transfusion within 4 weeks prior to first planned dose of Ezurpimtrostat 12.3. Platelet count > 50,000/μL with no transfusion within 2 weeks prior to first planned dose of Ezurpimtrostat
13. Adequate renal function prior to first dose, defined as 13.1. Serum creatinine < 1.5 × Upper limit of normal (ULN) 13.2. Creatinine clearance ≥ 30 mL/min/m2 (by Cockroft-Gault equation of 24-hour urine) if creatinine ≥ 1.5 × ULN
14. Adequate hepatic function prior to first dose, defined as AST/ALT ≤ 5 × ULN
15. Women patients of childbearing potential must have a negative serum pregnancy test at screening and baseline, and be willing to use a highly effective contraception. The patient should be advised to continue the contraception for at least 6 months following the completion of dosing. Women with cessation for > 24 months of previously occurring menses, or women of any age who have had a hysterectomy, or have had both ovaries removed will be considered to be of non-childbearing potential
16. Male patients of reproductive potential must be willing to use one acceptable method of contraception, as judged by Investigator and Sponsor, and/or to refrain from donating sperm from the time of screening through at least 6 months following the completion of dose administration
17. Amenable to computed tomography (CT) with 3 or 4 phase liver or magnetic resonance imaging (MRI) of abdomen and pelvis, and CT of chest, or MRI of whole body, for initial tumor size measurements and subsequent follow-up
18. Absence of other clinically relevant abnormalities (i.e., those which require medical intervention) for all screening laboratory test results as judged by the Investigator and Sponsor
19. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
20. Able to understand and provide written informed consent
21. Patients covered by Health Insurance System

Exclusion criteria 47

1. Any known history of encephalopathy ≤ 6 months prior to first planned dose of treatment
2. Severe or uncontrolled renal condition
3. Untreated chronic hepatitis B
4. Untreated HCV infection
5. Known history of immunodeficiency diseases (e.g., active HIV)
6. Use of any prohibited concomitant medications within 14 days of the Baseline/Day 1 visit
7. Contraindication to additional liver biopsy planned between C4 and C5
8. Contraindication to iodinated contrast agent infusion
9. Known current alcohol (> 20g/ Day in women and > 30g/ Day in men) or substance abuse
10. Malabsorption issues (e.g., gastric bypass or gastrectomy patients)
11. History of leptomeningeal disease
12. Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding
13. Active or history of autoimmune disease
14. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
15. Known active tuberculosis
16. History of malignancy other than HCC within 3 years prior to screening, with the exception of adequately treated skin basal cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, in-situ carcinoma of the uterine cervix, or prostate cancer that is controlled by hormone therapy (patients may continue hormone therapy while on study)
17. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 6 months after the last dose of treatment
18. Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
19. Uncontrolled tumor-related pain
20. Uncontrolled or symptomatic hypercalcemia
21. Treatment with systemic immunostimulatory agents
22. Prior history of hypertensive crisis or hypertensive encephalopathy
23. Known esophageal varices with recent history of bleeding (within previous 6 months)
24. Evidence of bleeding diathesis or significant coagulopathy
25. History of intestinal obstruction and/or clinical signs or symptoms of gastrointestinal (GI) obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration
26. Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
27. Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses
28. Known clinically significant or life threatening organ or systemic disease such that in the opinion of the Investigator, the significance of the disease will compromise the patient's participation in the trial
29. Known intolerance or hypersensitivity to the active ingredient or to one of the components of the study drug
30. Persistent toxicities related to prior treatment of grade greater than 1
31. Subjects with active infection
32. History of bone marrow allograft or solid organ transplant
33. Subjects requiring corticosteroid therapy at a dose equivalent to more than 10 mg of prednisone equivalent dose per day (corticosteroid administration is permitted by a route resulting in minimal systemic exposure [cutaneous, rectal, articular, ocular or inhalation] is authorized)
34. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
35. Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies
36. History of gastrointestinal perforations and fistulae
37. Uncontrolled or symptomatic proteinuria
38. Active aneurysm considered as unstable and/or at high risk of complication
39. Subject in exclusion period for another study
40. Subject who cannot be contacted in case of emergency
41. All protected persons: pregnant or parturient women, breastfeeding mothers, persons deprived of liberty by judicial or administrative decision, persons subject to a legal protection measure
42. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
43. Chronic treatment with immunosuppressive agents (like steroids) ≤ 6 weeks prior to first planned dose of treatment
44. Major surgical procedures, open biopsy or significant traumatic injury ≤ 4 weeks prior to first dose of treatment or anticipation of major surgical procedure during the course of the trial, minor surgical procedures ≤ 1 week of first planned dose (the surgical wound must be fully healed)
45. Local therapy to liver within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure
46. Any clinically significant cardiovascular condition as judged by the Investigator (such as New York Heart Association Class II or greater cardiac failure, myocardial infarction, or cerebrovascular accident within 3 months prior to Day 1 of Cycle 1, uncontrolled arterial hypertension, unstable arrhythmia, or unstable angina)
47. Patients who experienced immune-mediated pericardial disorders during previous treatment by immune checkpoint blockade therapies, including anti-CTLA4, anti-PD1, and anti-PDL1 therapeutic antibodies

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-Free Survival (PFS), defined as the time from randomization to the occurrence of disease progression or death from any cause, whichever occurs first. Progression events will be considered based on centralized tumor response assessment according to RECIST version 1.1 and PFS analyses will be performed by the CHU Grenoble Alpes Statistics department.

Secondary endpoints 12

1. To assess the tumor response under the association of Ezurpimtrostat with Atezolizumab-Bevacizumab in first line setting in unresectable hepatocellular carcinoma
2. To assess the impact of the association Ezurpimtrostat + Atezolizumab-Bevacizumab on Overall Survival (OS)
3. To assess the duration of response of the association Ezurpimtrostat + Atezolizumab-Bevacizumab
4. To assess the Alpha-fetoprotein (AFP) response at 3, 6, 12 months under the association Ezurpimtrostat + Atezolizumab-Bevacizumab
5. To assess the overall survival rate at 6, 12-months under the association Ezurpimtrostat + Atezolizumab-Bevacizumab
6. To assess the progression free survival rate at 6, 12-months under the association Ezurpimtrostat + Atezolizumab-Bevacizumab
7. To assess the safety of the association Ezurpimtrostat + Atezolizumab-Bevacizumab
8. To assess the Quality of life (by EORTC QLQ-C30 score) and the time to deterioration (TTD) under the association Ezurpimtrostat + Atezolizumab-Bevacizumab
9. To assess the predictive value of CD4/CD8 intratumor infiltrate on tumor response and survival outcomes
10. To assess the predictive value of PPT1 baseline expression on tumor response and survival outcomes
11. Pharmacokinetic (PK) and pharmacodynamics (PD) study of Ezurpimtrostat in association with Atezolizumab-Bevacizumab
12. Peripheral blood mononuclear cell (PBMC) biobanking for further ancillary studies

Investigational products

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

Test 1

Auxiliary 10

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Grenoble

Sponsor organisation

Centre Hospitalier Universitaire De Grenoble

Address

Boulevard De La Chantourne, La Tronche La Tronche

City

Grenoble Cedex 9

Postcode

38043

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire Grenoble Alpes

Contact name

Myriam COUTARD

Public contact point

Organisation

Centre Hospitalier Universitaire Grenoble Alpes

Contact name

Myriam COUTARD

Locations

1 EU/EEA country · 25 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 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