Personalized Medicine for Advanced Biliary Cancer Patients

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.

SCREENING PHASEInclusion Criteria: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 diseaseAvailability 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 sampleAged ≥18 yearsEastern Cooperative Oncology Group (ECOG) performance status of 0 or 1Estimated life expectancy >3 monthsCandidate for standard of care first line (1L-SoC) therapy, or has initiated first cycle of 1L-SoC therapyAffiliated to a social security system or in possession of equivalent private health insurance (according to local country health provision arrangements).Exclusion Criteria:Contraindication to 1L-SoCPatients who are candidates for locoregional therapyContraindication to tumour biopsy in the absence of suitable archived sample of tumour tissuePrior anticancer therapy in the palliative setting. Adjuvant capecitabine allowed if completed ≥ 183 days prior to study entryReceived more than 1 cycle of treatment with 1L-SoCPrior treatment with any of the molecular targeted therapies (MTT) under investigation in the SAFIR-ABC10 studyCurrent malignancies (other than advanced biliary cancer), 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 trialAny 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 protocolPatients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasonsIndividuals deprived of liberty or placed under protective custody or guardianshipRANDOMISED TRIALInclusion 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 investigatorECOG performance status of 0 or 1Presence of at least one evaluable lesion according to RECIST v1.1, or complete response to 12 weeks 1L-SoCAdequate bone marrow function: absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count ≥100 × 10⁹/L, and haemoglobin ≥9 g/dLAdequate liver function: total bilirubin level ≤1.5 × the upper limit of normal (ULN) range unless 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 ≥45 mL/min according to the Cockcroft-Gault formulaAdequate 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 infectionMen, 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 randomisationWilling and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests, and other study proceduresAffiliated 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 deliveredToxicities from 1L-SoC not resolved to Grade ≤ 2 (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 alopeciaContraindication 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) cancersMajor surgery within 4 weeks of randomisationUntreated 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).Known leptomeningeal disease. If leptomeningeal disease has been reported radiographically on baseline magnetic resonance 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 trialKnown active hepatitis B virus or hepatitis C virus infection or human immunodeficiency virus (HIV) or known acquired immunodeficiency syndromeAny 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 protocolWomen who are pregnant or breast-feedingParticipation in another therapeutic trial within the 30 days prior to entering the study. Participation in an observational trial would be acceptablePatients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasonsIndividuals deprived of liberty or placed under protective custody or guardianshipADDITIONAL EXCLUSION CRITERIA FOR SPECIFIC MTTs:Patients assigned to receive oral therapies:Inability or unwillingness to swallow pillsHistory of malabsorption syndrome or other condition that would interfere with enteral absorption. For example, active intestine inflammation (e.g., Crohn's disease or ulcerative colitis) requiring immunosuppressive therapyFutibatinib:1. History and/or current evidence of any of the following disorders:Non-tumour related alteration of the calcium-phosphorus homeostasis that is considered clinically significant in the opinion of the InvestigatorEctopic mineralization/calcification, including but not limited to soft tissue, kidneys, intestine, or myocardia and lung, considered clinically significant in the opinion of the InvestigatorRetinal or corneal disorder confirmed by retinal/corneal examination and considered clinically significant in the opinion of the InvestigatorIvosidenib:Patients with history of torsade de pointesConcomitant treatment with digoxin where this cannot be substituted for another therapyPatients with a heart-rate corrected QT interval (using Fridericia's formula) (QTcF) ≥ 450 msec or other factors that increased the risk of QT prolongation or arrhythmic events (e.g. heart failure, hypokalemia, family history of long QT interval syndrome)Zanidatamab:Treatment with anthracyclines within 90 days before first dose of zanidatamab and/or total lifetime load exceeding 360 mg/m2 Adriamycin® or equivalentUse of corticosteroids administered at doses equivalent to > 15 mg per day of prednisone within 2 weeks of first zanidatamab dosing unless otherwise approved by the coordinating investigator. Topical, ocular, intra-articular, intranasal, and/or inhalational corticosteroids are permittedQTcF > 470 msHistory of myocardial infarction or unstable angina within 6 months prior to enrollment, troponin levels consistent with myocardial infarction, or clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension, or any history of symptomatic congestive heart failureAcute or chronic uncontrolled pancreatitis or Child-Pugh Class C liver diseaseClinically significant infiltrative pulmonary disease not related to lung metastasesA history of life-threatening hypersensitivity to monoclonal antibodies or recombinant proteinsNeratinib & trastuzumab:Patients with severe hepatic impairment (Child-Pugh Class C)Co-administration with the following medical products that are strong inducers of the CYP3A4/P-gp isoform of cytochrome P450, such as carbamazepine, phenytoin (antiepileptics), St John's wort (Hypericum perforatum) or rifampicin (antimycobacterial)Patients who are experiencing dyspnoea at rest due to complications of advanced malignancy or co-morbiditiesHypersensitivity to murine proteinsEncorafenib & binimetinib:Patients with a history or current evidence of retinal vein occlusion or risk factors for retinal vein occlusion (e.g., uncontrolled glaucoma or history of hyperviscosity or hypercoagulability syndrome)Patients with concurrent neuromuscular disorders associated with elevated cytokininClinically 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)Current or expected use of a strong inhibitor of CYP3A4Niraparib:Hypertension that is inadequately treated or controlledParticipants receiving corticosteroids who have not been on a stable dose for at least 4 weeks prior to niraparibHistory of Myelodysplastic Syndrome/Acute Myeloid LeukemiaHistory of Reversible Encephalopathy SyndromeCurrent active pneumonitis within 90 days of receiving niraparib or a known history of interstitial lung disease, drug-related pneumonitis or radiation pneumonitis requiring steroid treatmentIncreased bleeding risk due to concurrent conditionsReceipt of a live vaccine within 30 days of planned start of therapyRadiation encompassing >20% of bone marrow within 2 weeks ; or any radiation therapy within 1 week prior to receiving niraparib