IVONESCIMAB for Advanced biliary tract cancer

Inclusion criteria

• {"criterion_text":"- Signed a written informed consent form prior to any trial specific procedures. Note: If the patient is physically unable to provide their written consent, a trusted person of their choice, independent of the Investigator or the Sponsor, can confirm the patients consent in writing.\n- Adequate biliary drainage, with no evidence of ongoing infection.\n- Women of childbearing potential (WOCBP) having sex with an unsterilized male partner and unsterilized males having sex with a female partner of childbearing potential, must agree to use an effective method of contraception for the duration of trial participation and as required after completing study treatment. Men must also agree to not donate sperm and women must agree to not donate oocytes during the specified period.\n- Histologically-proven intrahepatic cholangiocarcinoma, perihilar / distal cholangiocarcinoma, or gallbladder carcinoma (ampullary carcinoma excluded).\n- WOCBP must have a negative serum pregnancy test performed before randomisation and a negative urine pregnancy test on the day of first dose, prior to treatment administration.\n- Willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests, and other study procedures\n- Affiliated to a social security system or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials).\n- Locally advanced (non-resectable) or metastatic disease.\n- Participated in the Screening phase of the SAFIR-ABC10 trial.\n- Progression after standard first-line treatment (CISGEM ± immunotherapy) as assessed by the investigator.\n- Eligible for second-line treatment with FOLFOX.\n- Adequate bone marrow function: absolute neutrophil count (ANC) ≥2 × 10⁹/L, platelet count ≥100 × 10⁹/L, and haemoglobin ≥9 g/dL. Note: Blood transfusion or growth factor therapy should not be performed within 7 days prior to the screening haematology analysis\n- Adequate liver function: total bilirubin level ≤1.5 × the upper limit of normal (ULN) range (≤3 x ULN for patients with liver metastases or confirmed/suspected Gilbert syndrome), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 × ULN (AST and ALT ≤5 x ULN when documented liver metastasis).\n- Adequate renal function: estimated creatinine clearance ≥50 mL/min according to the Cockcroft-Gault formula, or estimated glomerular filtration rate (eGFR) value ≥50 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, and urine protein < 2+ or 24 hour urine protein quantification < 1.0 g.\n- Coagulation: prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5 x ULN, and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (unless abnormalities are unrelated to coagulopathy or prophylactic coagulation).\n- Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥50% at baseline as determined by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan.\n- Documented virology status of hepatitis, as confirmed by screening hepatitis B virus (HBV) and hepatitis B virus (HCV) tests: fFor patients with active HBV: HBV DNA <500 IU/ml during screening, initiation of anti-HBV treatment at least 14 days prior to randomization and willingness to continue anti-HBV treatment during the study (per local standard of care; e.g., entecavir). For patients with HCV, either with resolved infection (as evidenced by detectable antibody) or chronic infection (as evidence by detectable HCV RNA), are eligible.\n- For patients with evidence of cirrhosis, performance of an esophagogastroduodenoscopy within 6 months of inclusion and assessment and treatment of varices of all sizes per local standard of care prior to randomisation.\n- Biliary tract obstruction has been relieved.\n- Age ≥18 years.\n- Blood chemistry: potassium, magnesium and calcium levels ≥ lower limit of normal (LLN)\n- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n- Presence of at least one evaluable lesion according to RECIST v1.1."}

Exclusion criteria

• {"criterion_text":"- Microsatellite instability positive disease\n- Treatment with brivudine, sorivudine or their chemical analogues in the 4 weeks prior to randomisation.\n- Major surgical procedures or serious trauma within 4 weeks prior to randomisation, or plans for major surgery within 4 weeks after the first dose (as determined by the investigator). Minor local procedures (excluding central venous catheterisation and port implantation) within 3 days prior to randomisation.\n- History of major diseases before randomisation, specifically: a.\tUnstable angina, myocardial infarction, congestive heart failure (New York Heart Association classification ≥ grade 2) or vascular disease (eg, aortic aneurysm at risk of rupture) that required hospitalization within 12 months prior to randomisation, or other cardiac impairment that may affect the safety evaluation of the study drug (eg, poorly controlled arrhythmias, myocardial ischemia), b.\tHistory of untreated oesophageal gastric varices, severe ulcers, wounds that do not heal, abdominal fistula, intra-abdominal abscesses, or acute gastrointestinal bleeding within 6 months before randomisation, c.\tHistory of arterial thromboembolic event, venous thromboembolic event of Grade 3 and above as specified in NCI-CTCAE v5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 6 months prior to randomisation, d.\tAcute exacerbation of chronic obstructive pulmonary disease within 4 weeks before randomisation, e.\tHistory of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection) within 6 months prior to randomisation.\n- History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to randomisation, including but not limited to: a.\tGastrointestinal bleeding, b.\tHaemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots), Note: transient haemoptysis associated with diagnostic bronchoscopy is allowed. c.\tNasal bleeding /epistaxis (bloody nasal discharge is allowed), d.\tNeed for therapeutic anticoagulant therapy within 14 days prior to randomisation. Note: Prophylactic anticoagulation for deep vein thrombosis or pulmonary embolism or to maintain venous patency is allowed.\n- Current hypertension with systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy.\n- Tumours harbouring a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement or an IDH1 R132 mutation.\n- Imaging during the screening period shows that the patient has: a.Radiologically documented evidence of major blood vessel invasion or encasement by cancer, b.Radiographic evidence of intra-tumour cavitation.\n- Concurrent malignancy (other than BTC), with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for 5 years or more and are deemed at negligible risk for recurrence, are eligible for the trial.\n- HIV positive (HIV 1/2 antibodies patients), or a known history of active Tuberculosis bacillus\n- Any systemic immunosuppressive therapy (i.e. corticosteroids >10mg of hydrocortisone or equivalent dose) within 14 days before the planned start of study therapy.\n- Pregnant or breast-feeding females.\n- Active autoimmune disease that has required a systemic treatment in past 2 years (i.e. corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin) is allowed active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: a.\tPatients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study, b.\tPatients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study, c.\tPatients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: i.\tRash must cover < 10% of body surface area, ii.\tDisease is well controlled at baseline and requires only low-potency topical corticosteroids, iii.\tNo occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months.\n- Prior allogeneic bone marrow transplantation or prior solid organ transplantation.\n- Any condition which in the Investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol.\n- A heart-rate corrected QT interval (using Fridericia’s formula) (QTcF) > 450 msec for men and > 470 msec for women.\n- Ongoing peripheral sensory neuropathy with functional impairment\n- Has received a live attenuated vaccine within 30 days prior to the first dose of study drug.\n- Active infection requiring systemic therapy.\n- Patients with poor nutritional status.\n- Participation in another therapeutic trial (other than SAFIR-ABC10) within the 30 days prior to entering the study. Participation in an observational trial would be acceptable.\n- Toxicities from first-line treatment not resolved to Grade ≤ 1 (according to version 5.0 the National Cancer Institute - Common terminology criteria for adverse events [NCI-CTCAE v5.0]) before randomisation with the exception of alopecia.\n- Patient unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons.\n- Individual deprived of liberty or placed under protective custody or guardianship.\n- Received first-line maintenance therapy with a matched target therapy proposed in SAFIR ABC10, or any second-line treatment.\n- Known history of hypersensitivity or other contraindication to ivonescimab or to fluorouracil, oxaliplatin and folinic acid, or to any of, or their excipients according to the SmPCs of these products.\n- Proven complete deficiency of dihydropyrimidine dehydrogenase (DPD)."}

Primary endpoints

• {"endpoint_text":"- Progression-free survival, defined as the time from randomisation to the first documented progression of disease (PD) as assessed by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. Patients who are alive and have not progressed at the time of the analysis will be censored at their last evaluable tumour assessment","definition_or_measurement_approach":"Time from randomisation to first documented disease progression per investigator assessment using RECIST v1.1, or death from any cause; censoring at last evaluable tumour assessment for patients alive without progression."}

Secondary endpoints

• {"endpoint_text":"- Overall survival (OS), defined as the time from randomisation to death due to any cause. Patients still alive at the cut-off time (including lost to follow-up) will be censored at the last date they are known to be alive.","definition_or_measurement_approach":"Time from randomisation to death from any cause; censoring at last known alive date."}
• {"endpoint_text":"- Disease control rate, defined as the proportion of randomised patients achieving CR, PR, or stable disease (SD) as assessed by the investigator according to RECIST v1.1.","definition_or_measurement_approach":"Proportion of randomised patients with complete response (CR), partial response (PR) or stable disease (SD) per investigator assessment using RECIST v1.1."}
• {"endpoint_text":"- Objective response rate, defined as the proportion of randomised patients achieving complete response (CR) or partial response (PR) as assessed by the investigator according to RECIST v1.1.","definition_or_measurement_approach":"Proportion of randomised patients with CR or PR per investigator assessment using RECIST v1.1."}
• {"endpoint_text":"- Duration of response, defined as the time from first documented PR or CR (compared to baseline measurement taken at randomisation) until the date of PD, as assessed by the investigator according to RECIST v1.1, or death from any cause whichever occurs first. Patients who are alive and have not progressed at the time of the analysis will be censored at their last evaluable tumour assessment.","definition_or_measurement_approach":"Time from first documented CR/PR (vs baseline at randomisation) until PD per RECIST v1.1 or death; censoring at last evaluable tumour assessment if alive without progression."}
• {"endpoint_text":"- Toxicity / adverse events, evaluated according to NCI-CTCAE v5.0.","definition_or_measurement_approach":"Adverse events graded per NCI CTCAE version 5.0."}
• {"endpoint_text":"- Treatment compliance will be reported by presenting reasons for reasons for treatment delays, dose omissions, dose reductions and treatment discontinuation.","definition_or_measurement_approach":"Descriptive reporting of reasons for treatment delays, omissions, dose reductions and discontinuations."}
• {"endpoint_text":"- Health-Related quality of life assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaires QLQ-C30 and QLQ-BIL21","definition_or_measurement_approach":"HRQoL measured using EORTC QLQ-C30 and QLQ-BIL21 questionnaires."}
• {"endpoint_text":"- Time until definitive deterioration of quality of life (TTUD), defined as the time from randomisation to the first observation of a definitive deterioration of EORTC QLQ-C30 score.","definition_or_measurement_approach":"Time from randomisation to first observation of definitive deterioration in EORTC QLQ-C30 score."}
• {"endpoint_text":"- Quality of life adjusted- survival (QAS), derived from responses to the EORTC QLQ C30 questionnaire and OS data.","definition_or_measurement_approach":"Derived metric combining EORTC QLQ-C30 responses with overall survival data."}

France

Earliest CTIS Part Ii Submission Date

24-01-2025

Latest Decision Or Authorization Date

17-02-2026

Processing Time Days

389

Number Of Sites

40

Number Of Participants

42

Primary sponsor

Full Name

Unicancer

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France