PRODIGE 81-FFCD 2101-TRIPLET: Study evaluating the benefit of adding Ipilimumab to the combination of Atezolizumab and Bevacizumab in patients with hepatocellular carcinoma receiving first-line systemic therapy-

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondation Franc.Cancerologie Digestive, Fondation Franc.Cancerologie Digestive

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06], Phenomena and Processes [G] - Immune system processes [G12]

Trial duration

9 Mar 2023 → ongoing

Decision date (initial)

2022-10-27

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Fédération Francophone de Cancérologie Digestive

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

Phase II: To assess the percentage of patients with an objective response (complete response or partial response) according to the investigator (RECIST v1.1) within the first 24 weeks (9 cycles) for both treatment arms, in patients with hepatocellular carcinoma.

Phase III: to compare the overall survival between the triplet and doublet arms.

Secondary objectives 11

1. • Radiation progression-free survival (PFS)
2. • Objective response rate (OR) under treatment
3. • Rate of disease control (complete response or partial response or stability)
4. • Response time (DDR)
5. • Median time to progression
6. • Median time to WHO degradation>2
7. • Time to objective response
8. • Tolerance (NCI CTC v4.0 assessed treatment and non-treatment related adverse events (bevacizumab and immunotherapy)
9. • Rate of permanent discontinuation of protocol treatment due to a study treatment-related effect.
10. • Quality of life according to the EORTC QLQ-C30 and its HCC supplement EORTC QLQ-HCC18, time to deterioration of the quality of life score.
11. • Overall survival (median) - Phase II patients

Conditions and MedDRA coding

Hepatocellular carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Age ≥ 18 years
2. Advanced (BCLC-C) or intermediate (BCLC-B) HCC after failure or contraindication of the CEL
3. Normal Troponin-T
4. No clinically evident ascites or history of clinical ascites, liver failure encephalopathy
5. Adequate liver function: AST and ALT ≤ 5 x ULN (upper normal limit), total bilirubin ≤ 35 μM/L, albumin ≥ 28 g/L and Child-Pugh A score (if cirrhosis associated).
6. Adequate haematological and renal function (haemoglobin > 8.5 g/dl, platelets > 60 G/L, PNN > 1.5 G/L) and renal function (creatinine clearance ≥ 40ml/min according to MDRD formula)
7. Patients with controlled cardiovascular disease for at least 6 months
8. At least one target lesion measurable according to RECIST v1.1 criteria
9. Oesophageal endoscopy less than 6 months old. All patients with varicose veins of any grade should be treated with β-blockers prior to initiation of therapy, in the absence of contraindications.
10. Women of childbearing potential must agree to use contraception during the trial treatment and for at least 6 months after discontinuation of the experimental treatments. Men who have sex with women of childbearing potential must agree to use contraception during treatment and for at least 6 months after discontinuation of the experimental treatments
11. Ability of the patient to understand, sign and date the informed consent form before randomisation
12. Patient affiliated to a social security scheme
13. Histologically proven hepatocellular carcinoma (HCC) on biopsy less than two years old. If not histologically proven, it is necessary to perform a tumour (mandatory) and non-tumour (optional) liver biopsy.
14. WHO 0 or 1
15. HCC not amenable to curative treatment by surgery, thermo-ablation or liver transplantation, or to intra-arterial palliative treatment (IAP) for intermediate BCLC-B HCC.
16. Histologically proven hepatocellular carcinoma (HCC) on biopsy less than two years old. If no histological evidence, a tumour (mandatory) and non-tumour (optional) liver biopsy is required.

Exclusion criteria 31

1. Patients who have already received systemic therapy for HCC
2. History of severe active life-threatening autoimmune disease
3. Interstitial lung disease
4. Chronic HBV infection with HBV DNA > 500 IU/ml, infected patients, cirrhotic or not, should be treated with nucleotide/nucleoside analogues
5. Known HIV infection
6. Immunosuppression, including subjects with conditions requiring systemic corticosteroid treatment (>10 mg/day prednisone equivalent)
7. History of organ transplantation
8. Non-healing decaying wound, active ulcer or untreated bone fracture
9. Proteinuria ≥ 2+ on urine dipstick if confirmation of 24h proteinuria showing a level ≥ 2 g/24 hours
10. Medically uncontrolled hypertension (≥ 150 mm Hg and/or diastolic blood pressure superior to 90 mm Hg)
11. History of arterial aneurysm at high risk of bleeding
12. Bleeding related to portal hypertension in the last 6 months
13. Alive attenuated vaccine within 28 days prior to randomisation
14. Pregnant or breastfeeding women.
15. Person under guardianship, or person deprived of liberty.
16. Inability to undergo the medical follow-up of the trial for geographical, social or psychological reasons
17. History of abdominal or oesophageal fistula, gastrointestinal perforation or intra-abdominal abscess, diverticulitis or colitis within 6 months prior to randomisation
18. Patients on dual anti-platelet therapy
19. Patients on chronic non-steroidal anti-inflammatory drugs (except aspirin)
20. History of intra-abdominal inflammatory process within 6 months prior to initiation of treatment - including but not limited to - active peptic ulcer, diverticulitis or colitis
21. Major surgery or significant traumatic injury within 28 days prior to treatment, abdominal surgery or significant abdominal traumatic injury within 60 days prior to treatment, or the need for major surgery during the therapeutic trial
22. Hypersensitivity to any of the study drugs or their excipients
23. Allergy to any component of Chinese hamster ovary cells. Other malignancies within the last 2 years, except for carcinoma in situ of the uterus or basal cell or squamous cell skin carcinoma or any other carcinoma in situ, considered cured
24. History of pericardial abnormalities possibly immune-related (pericarditis or cardiac tamponade)
25. Patient who has received immunotherapy (including anti-CTLA-4, anti-PD-1 or anti-PD-L1 agents) or anti-VEGF antibody therapy
26. Patients who has previously received external radiotherapy up to 1 month before the start of the study treatment, or 3 months beofre the start of the study treatment in case of radio embolization
27. Central nervous system metastases
28. Active bacterial infection
29. Patients with uncontrolled cardiovascular disease
30. History of arterial thromboembolic events, including stroke, transient ischemic attack and myocardial infarction, if less than 6 months old and unresolved
31. History of venous thromboembolic disease, if less than 6 months old

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase II : objective response (complete response or partial response)within the first 24 weeks (9 cycles) for both arms treatment
2. Phase III : overall survival between the two arms

Secondary endpoints 11

1. Radiation progression-free survival (PFS)
2. Objective response rate (OR) under treatment
3. Rate of disease control (complete response or partial response or stability)
4. Response time
5. Median time to progression
6. Median time to WHO degradation>2
7. Time to objective response
8. Tolerance (NCI CTC v4.0 assessed treatment and non-treatment related adverse events (bevacizumab and immunotherapy)
9. Rate of permanent discontinuation of protocol treatment due to a study treatment-related effect.
10. Quality of life according to the EORTC QLQ-C30 and its HCC supplement EORTC QLQ-HCC18, time to deterioration of the quality of life score.
11. Overall survival (median) - Phase II patients

Investigational products

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

Test 3

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondation Franc.Cancerologie Digestive

Sponsor organisation

Fondation Franc.Cancerologie Digestive

Address

7 Boulevard Jeanne D Arc

City

Dijon Cedex

Postcode

21079

Country

France

Scientific contact point

Organisation

Fondation Franc.Cancerologie Digestive

Contact name

national coordinator

Public contact point

Organisation

Fondation Franc.Cancerologie Digestive

Contact name

national coordinator

Fondation Franc.Cancerologie Digestive

Sponsor organisation

Fondation Franc.Cancerologie Digestive

Address

7 Boulevard Jeanne D Arc

City

Dijon Cedex

Postcode

21001

Country

France

Locations

1 EU/EEA country · 63 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

Urgent safety measures 1 · Art. 54 CTR

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

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

Documents 8 files

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

Application history

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