DUMELEP trial - Durvalumab (MEDI4736)/Tremelimumab in neoadjuvant and adjuvant setting in patients with HCC treated by percutaneous ablation procedure in curative intent

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02]

Trial duration

28 Mar 2024 → ongoing

Decision date (initial)

2024-10-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

AstraZeneca

External identifiers

EU CT number

2024-515768-30-01

EudraCT number

2022-003561-38

ClinicalTrials.gov

NCT06045975

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To assess local recurrence-free survival at 1-year following neoadjuvant Durvalumab/Tremelimumab and adjuvant Durvalumab therapy associated with percutaneous ablation procedure in patients with Barcelona Clinic Liver Cancer A hepatocellular carcinoma

Secondary objectives 10

1. Assess the changes of tumorous and non-tumorous perfusion parameters observed with MRI or CT scan after one months of neoadjuvant treatments
2. Assess the Per nodule rates of early response (one month) after a single procedure of PA
3. Assess the incidences of intra segmental/ extra segmental distant recurrence
4. Assess the overall survival at 1-year following PA procedure
5. Assess the respect of scheduled PA procedure as a function of neoadjuvant phase potential SAEs
6. Assess the compliance to neoadjuvant and adjuvant treatments
7. Assess the tolerance of Durvalumab/Tremelimumab in the setting of neo- and adjuvant therapy to PA
8. For biomarker studies, assess histopathological and molecular features of non-tumoral and tumor tissue after neoadjuvant phase on sequential biopsies before PA procedure
9. For biomarkers studies, assess early effects of neoadjuvant Durvalumab/Tremelimumab on the tumor before PA, judged by histology, radiology and sequential serum markers performed before PA. In particular, peripheral and histological samples will be evaluated for immunophenotyping of lymphocyte populations, circulating cytokine and chemokine assays, changes in inflammatory infiltrates and expression of immunity modulating genes.
10. For biomarkers studies, study changes in cytokine/chemokines profiling on sequential serum samples of patients before and after treatment as well as evaluation of sequential liquid biopsy on plasma samples

Conditions and MedDRA coding

Hepatocellular carcinoma

Regulatory references

Plan to share IPD

No

IPD plan description

There is no plan to share participants' data for the time being

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. Male or female patients ≥ 18 years of age. For patients aged 80 years and older, inclusion requires a systematic oncogeriatric assessment, as recommended by the Data Safety Monitoring Board (DSMB)
2. Written informed consent signed (patients must be free from tutelle, curatelle or sauvegarde de justice)
3. Histological or radiological diagnosis of HCC
4. Patients with newly diagnosed or recurrent HCC (following a previous curative procedure performed at least 6 months before inclusion) eligible for PA prcoedure as assessed by multidisciplinary board corresponding to BCLC A stage:  Uninodular HCC ≥ 2 cm and ≤ 5 cm, no macroscopic vascular invasion  Multinodular maximum 3 nodules ≤ 3 cm,  Body weight >30 kg  Liver function status Child-Pugh Class A <><
5. Adequate bone marrow, liver and renal function as assessed by the following laboratory tests:  Total bilirubin ≤ 2 mg/dL  Serum creatinine ≤ 1.5 x ULN  Lipase ≤ 2 x ULN  Prothrombine time-international normalized ratio (PT-INR) < 2.3 and PTT < 1.5  Glomerular Filtration Rate (GFR) ≥ 30 mL/min/1.73 m2
6. Life expectancy ≥ 3 months
7. Female of childbearing potential (WOCBP) or male or female patients of reproductive potential must to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab and tremelimumab combination therapy
8. Patients affiliated to a Social Security System
9. Haemoglobin ≥9.0 g/dL
10. Absolute neutrophil count (ANC ≥1.0 × 109 /L)
11. Platelet count ≥75 × 109/L
12. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). (This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
13. AST (SGOT) and ALT (SGPT) ≤5x ULN
14. Measured creatinine clearance (CL) must exceed 40 mL/min. For the estimation of glomerular filtration rate (eGFR), the Cockcroft-Gault equation was applied in patients aged ≤65 years, while the MDRD equation was used for those older than 65 years
15. Patient 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.
16. At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at preinclusion/inclusion. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to inclusion
17. Patients with HCV infection (as characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody) must be managed per local institutional practice
18. Antiviral therapy in case of HBV active infection or inactive carriage

Exclusion criteria 42

1. Patients with contraindications to PA procedure (Pacemakers or patients who have a history of cardiac arrhythmias or irregular heartbeats considered as contraindication to IRE, ascites, Coagulopathy, Ongoing infection)
2. Congestive heart failure New York Heart Association (NYHA) ≥ class 2
3. Unstable angina or myocardial infarction within the past 6 months before enrolment
4. Grade 3 (severe) hypertension ≥180 and/or ≥110 mmHG (systolic and diastolic, according to National Heart Foundation 2016)
5. Patients with phaeochromocytoma
6. Refractory ascites according to EASL guidelines definition (ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of a lack of response to sodium restriction and diuretic treatment)
7. Persistent proteinuria of NCI-CTCAE version 5.0 ≥ Grade 3
8. Ongoing infection > Grade 2 according to NCI-CTCAE version 5.0
9. Clinically significant bleeding NCI-CTCAE version 5.0 ≥ Grade 3 within 30 days before enrolment
10. Any psychological, familial, sociological, geographical or illness or medical condition that could jeopardize the safety of the patient and/or his compliance with the study protocol and follow-up procedure
11. Known history of human immunodeficiency virus (HIV) infection
12. Patients with contraindication to contrast medium intravenous injection either gadolinium or iodinate
13. Non-healing wound, ulcer or bone fracture
14. Known hypersensitivity to the study drug or excipients in the formulation
15. Any malabsorption condition
16. Breast feeding
17. Pregnancy
18. Participation in another clinical study with an investigational product during the last 6 months
19. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
20. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. - Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. - Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.
21. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non–cancer-related conditions (e.g., hormone replacement therapy) is acceptable. <>
22. Prior liver transplantation
23. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
24. History of allogenic organ transplantation
25. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], 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: - Patients with vitiligo or alopecia - Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement - Any chronic skin condition that does not require systemic therapy - Patients without active disease in the last 5 years may be included but only after consultation with the study physician - Patients with celiac disease controlled by diet alone
26. 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 consent
27. History of another primary malignancy except for - Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease - Adequately treated carcinoma in situ without evidence of disease
28. History of leptomeningeal carcinomatosis
29. Study excludes patients with brain metastases or spinal cord compression: Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry. Brain metastases will not be recorded as RECIST Target Lesions at baseline if study allows patients with brain metastases.
30. Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis identified either on the baseline brain imaging (RECIST)) for details on the imaging modality) obtained during the screening period or identified prior to signing the ICF. Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of ≤10mg/day of prednisone or its equivalent <> for at least 14 days prior to the start of treatment. Brain metastases will not be recorded as RECIST Target Lesions at baseline.
31. QT interval measurement one one ECG
32. History of active primary immunodeficiency
33. 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).
34. 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: - Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) - Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent - Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
35. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
36. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
37. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment
38. Patients who have received prior anti–PD-1, anti–PD-L1 or anti–CTLA-4: - Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy. - All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study. - Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic. - Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.
39. Prior systemic treatment for HCC, in particular agents targeting T-cell costimulation or checkpoint pathways (including those targeting PD-1, PD-L1 or PD-L2, CD137, or cytotoxic T-lymphocyte antigen [CTLA-4]).
40. Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention
41. Past or concurrent history of neoplasm other than HCC, except for in situ carcinoma of the cervix uteri and/or non-melanoma skin cancer and superficial bladder tumors. Any cancer curatively treated > 3 years prior to study entry is permitted
42. Major surgical procedure or significant traumatic injury within 28 days before enrolment (note: local surgery for isolated lesions for palliative purposes is acceptable)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. One-year local recurrence-free survival

Secondary endpoints 12

1. In neoadjuvant phase: changes of tumorous and non-tumorous perfusion parameters observed with CT scan/MRI after one months of neoadjuvant treatment (rates of nodule(s) comprising necrosis and/or hypoperfusion radiological aspect compared before and after neoadjuvant course): analyzed as qualitative variables
2. In neoadjuvant phase: changes of size of nodules following neoadjuvant course
3. Nodule rates of early response after a single procedure of PA (defined as absence of active tumor evaluated at one month following PA)
4. Incidences of intra segmental/ extra segmental distant recurrence
5. One-year Overall survival defined as patients who are alive with or without HCC recurrence 1 year after PA procedure. Causes and date of death will be specified when applicable during this timeframe.
6. Treatment-related adverse events will be monitored according to manufacturer guidelines and recommendation
7. Timeframe of PA performance defined as number of days of delay in case of safety issues encountered during neo-adjuvant phase
8. Compliance to neoadjuvant and adjuvant treatments: respect of scheduled Durvalumab/Tremelimumab infusions
9. Frequency of SAEs and discontinuations due to AEs
10. For biomarkers studies, assessment of tumour architecture and cytology from inclusion to Percutaneous Ablation procedure; assessed up to 30 days: absence of tumour cells (binary scale :0/1)
11. For biomarkers studies, assessment of tumour architecture and cytology from inclusion to Percutaneous Ablation procedure; assessed up to 30 days: assessment of intra and extra tumoral inflammatory infiltrate (semi quantitative scale: 0=non, 1=mild, 2=intense)
12. For biomarkers studies, assessment Gene expression from inclusion to Percutaneous Ablation procedure; assessed up to 30 days: change in gene expression following sequential whole exome sequencing (binary scale 0/1 with clustering analyses)

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Pierre Nahon

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Thibaut Vanrietvelde

Locations

1 EU/EEA country · 22 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 11 files

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

Application history

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