Molecular Targeted Maintenance Therapy Versus Standard of Care in Advanced Biliary Cancer: an International, Randomised, Controlled, Open-label, Platform Phase 3 Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- UNICANCER
- 入组人数
- 800
- 试验地点
- 71
- 主要终点
- Progression-free survival (PFS)
研究概览
简要总结
The object of this trial is to evaluate whether the introduction of a targeted therapy after 4 cycles of the current standard-of-care treatment for advanced biliary cancer is superior to continuing with the standard treatment.
The trial is composed of two phases: (i) An initial screening phase to identify a suitable patient population, during which a molecular profile of the patient's tumour will be obtained, and (ii) a randomised comparative trial in which patients with disease control after 4 cycles of standard treatment, and whose tumour harbours a targetable molecular alteration, will be randomised (2:1) to receive either a matched targeted therapy or to continue with the standard treatment.
详细描述
This is a Phase 3, multicentre, randomised, open-label trial to evaluate whether the introduction of molecular targeted therapy (MTT) as maintenance after 4 cycles of standard-of-care first-line systemic therapy (1L SoC) is superior to continuation of 1L-SoC in the treatment of patients with ABC. The trial is composed of two phases: (i) An initial screening phase to identify a suitable patient population, and (ii) a randomised comparative trial.
The aim of the screening phase is to identify a medically suitable population, to obtain a molecular profile of the patient's tumour, to collect baseline data concerning patient demographics and disease characteristics and to obtain pre-treatment blood and tumour samples for further translational research.
A genetic profile will be obtained from tumour-derived DNA and RNA samples by next-generation sequencing and from circulating tumour DNA. The trial Molecular Tumour Board will determine whether each patient harbours a targetable molecular alteration for one or more of the trial MTTs.
Patients with disease control after 4 cycles of 1L-SoC, who did not experience limiting toxicity, and whose tumour harbours at least one targetable molecular alteration, will be invited to participate in the randomised phase of the trial in which 159 eligible patients will be randomised (2:1) to receive either maintenance therapy with a matched MTT or to continue 1L-SoC treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed a written informed consent form prior to any trial specific procedures (Consent #1)
- •Histologically-proven intrahepatic, perihilar or distal cholangiocarcinoma, or gallbladder carcinoma (ampullary carcinoma excluded)
- •De novo or recurrent, locally advanced (non-resectable) or metastatic disease
- •Availability of a suitable archived sample of primary or metastatic tumour tissue (frozen, or FFPE) or able to undergo a biopsy to obtain a suitable malignant tissue sample
- •Aged ≥18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Estimated life expectancy >3 months
- •Candidate for 1L-SoC therapy, or has initiated first cycle of 1L-SoC therapy
- •Affiliated to a social security system or in possession of equivalent private health insurance (according to local country health provision arrangements).
排除标准
- •Contraindication to 1L-SoC
- •Patients who are candidates for locoregional therapy
- •Contraindication to tumour biopsy in the absence of suitable archived sample of tumour tissue
- •Prior anticancer therapy in the palliative setting. Adjuvant capecitabine allowed if completed ≥ 183 days prior to study entry
- •Received more than 1 cycle of treatment with 1L-SoC
- •Prior treatment with any of the MTT under investigation in the SAFIR-ABC10 study
- •Current malignancies (other than ABC), 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
- •Any condition which in the Investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol
- •Women who are pregnant or breast-feeding
- •Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
- •Individuals deprived of liberty or placed under protective custody or guardianship
- •RANDOMISED TRIAL
- •Inclusion Criteria:
- •Signed a written informed consent form prior to any trial specific procedures (Consent #2)
- •Molecular profile showing the tumour harbours at least one targetable molecular alteration with a MTT in the study portfolio (as determined by the trial MTB)
- •Disease control (stable or responsive) after 4 cycles of 1L-SoC, compared to a pre-treatment disease evaluation, as assessed by the investigator
- •ECOG performance status of 0 or 1
- •Presence of at least one evaluable lesion according to RECIST v1.1, or complete response to 12 weeks 1L-SoC
- •Adequate bone marrow function: absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count ≥100 × 10⁹/L, and haemoglobin ≥9 g/dL
- •Adequate liver function: total bilirubin level ≤1.5 × the upper limit of normal (ULN) range (total bilirubin ≤3.0 ULN when the patient has documented Gilbert syndrome), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 × ULN (AST and ALT ≤5 ULN when documented tumour liver involvement)
- •Adequate renal function: estimated creatinine clearance ≥ 60 mL/min according to the Cockcroft-Gault formula
- •Adequate cardiac function: left ventricular ejection fraction ≥50% at baseline as determined by either echocardiogram or multigated acquisition scan (MUGA)
- •Adequate biliary drainage, with no evidence of ongoing infection
- •Men, and women of childbearing potential (WOCBP) must agree to use adequate 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.
- •Women of childbearing potential must have a negative serum pregnancy test performed within 3 days before the date of randomisation
- •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
- •Affiliated to a social security system or in possession of equivalent private health insurance (according to local country health provision arrangements)
- •Exclusion Criteria:
- •Disease progression occurring at any time prior randomisation, or toxicity that led to the discontinuation of the 1L-SoC before 4 full cycles have been delivered
- •Toxicities from 1L-SoC 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
- •Contraindication or known hypersensitivity to the MTT for the molecular alteration found in the patient, or any component in their formulation Note: For patients with multiple target alterations, contraindication to one MTT will not warrant exclusion if MTT to an alternative target is feasible.
- •Microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) cancers
- •Major surgery within 4 weeks of randomisation
- •Radiotherapy within 7 days of randomisation
- •Untreated central nervous system (CNS) metastases, symptomatic CNS metastases, or radiation treatment for CNS metastases within 4 weeks of start of study treatment. Stable, treated brain metastases are allowed (defined as subjects who are off steroids and anticonvulsants and are neurologically stable with no evidence of radiographic progression for at least 4 weeks at the time of screening).
- •Clinically significant cardiovascular disease (recent acute myocardial infarction, treated congestive heart failure [2 or above on the New York Heart Association functional classification scale], recent thromboembolic or cerebrovascular events [within 12 weeks, excepted if related to indwelling catheter], known prolonged QT syndrome).
- •Cardiorespiratory pathologies where hyperhydration is contraindicated.
- •Manifestation of tinnitus and/or hearing loss since initiation of cisplatin therapy.
- •Known leptomeningeal disease. If leptomeningeal disease has been reported radiographically on baseline magnetic responance imaging (MRI), but is not suspected clinically by the investigator, the subject must be free of neurological symptoms.
- •Concurrent malignancy (other than ABC), 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
- •Concomitant treatment with phenytoin in prophylactic use where this cannot be substituted for another therapy
- •Known active hepatitis B virus or hepatitis C virus infection or human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
- •Any condition which in the Investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol
- •Women who are pregnant or breast-feeding
- •Participation in another therapeutic trial within the 30 days prior to entering the study. Participation in an observational trial would be acceptable
- •Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
- •Individuals deprived of liberty or placed under protective custody or guardianship
- •ADDITIONAL EXCLUSION CRITERIA FOR SPECIFIC MTTs:
- •Patients assigned to receive oral therapies:
- •Inability or unwillingness to swallow pills
- 另有 35 项未显示
研究组 & 干预措施
Experimental
Molecular targeted therapy matched to genetic alteration carried by the tumour
干预措施: Futibatinib (Drug)
Experimental
Molecular targeted therapy matched to genetic alteration carried by the tumour
干预措施: Ivosidenib (Drug)
Experimental
Molecular targeted therapy matched to genetic alteration carried by the tumour
干预措施: Zanidatamab (Drug)
Experimental
Molecular targeted therapy matched to genetic alteration carried by the tumour
干预措施: Trastuzumab (Drug)
Experimental
Molecular targeted therapy matched to genetic alteration carried by the tumour
干预措施: Neratinib (Drug)
Experimental
Molecular targeted therapy matched to genetic alteration carried by the tumour
干预措施: Encorafenib (Drug)
Experimental
Molecular targeted therapy matched to genetic alteration carried by the tumour
干预措施: Binimetinib (Drug)
Experimental
Molecular targeted therapy matched to genetic alteration carried by the tumour
干预措施: Niraparib (Drug)
Control
Continued standard of care treatment for first-line biliary tract cancer
干预措施: Cisplatin (Drug)
Control
Continued standard of care treatment for first-line biliary tract cancer
干预措施: Gemcitabine (Drug)
结局指标
主要结局
Progression-free survival (PFS)
时间窗: From randomisation to disease progression or death, up to 5 years.
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.
次要结局
- Overall Survival (OS)(From randomisation to death, up to 5 years.)
- Progression-free survival after next line of treatment (PFS2)(From randomisation to second disease progression or death, up to 5 years.)
- Objective response rate(From randomisation, up to 5 years.)
- Disease control rate(From randomisation, up to 5 years.)
- Percentage change in tumour size(From randomisation, up to 5 years.)
- Time to treatment failure(From randomisation to treatment failure event, up to 5 years.)
- Duration of response(From response to disease progression or death, up to 5 years.)