Personalized Medicine for Advanced Biliary Cancer Patients

Prior treatment

• Patients who are candidates for locoregional therapy
• 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
• 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
• 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).
• Manifestation of tinnitus and/or hearing loss since initiation of cisplatin therapy.
• Concomitant treatment with phenytoin in prophylactic use where this cannot be substituted for another therapy
• Participation in another therapeutic trial within the 30 days prior to entering the study. Participation in an observational trial would be acceptable
• Individuals deprived of liberty or placed under protective custody or guardianship
  • ADDITIONAL EXCLUSION CRITERIA FOR SPECIFIC MTTs:
  • Patients assigned to receive oral therapies:
• Concomitant treatment with strong CYP3A/P-gp inhibitors or strong or moderate CYP3A/P gp inducers where these cannot be substituted for another therapy.
  • Ivosidenib:
• Concomitant treatment with digoxin where this cannot be substituted for another therapy
• Concomitant treatment with strong CYP3A4 inducers or dabigatran where these cannot be substituted for another therapy
• Treatment with anthracyclines within 90 days before first dose of zanidatamab and/or total lifetime load exceeding 360 mg/m2 Adriamycin® or equivalent
• Use 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 permitted
• History 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 failure
• Current active pneumonitis within 90 days of receiving trastuzumab or a known history of interstitial lung disease
  • Encorafenib \& binimetinib:
• Current or expected use of a strong inhibitor of CYP3A4

Other illness

• 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
• 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
• 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
• 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
• History 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 therapy
  • Futibatinib:
• Patients with history of torsade de pointes
• Familial history of sudden death or polymorphic ventricular arrhythmia.
• Acute or chronic uncontrolled pancreatitis or Child-Pugh Class C liver disease
• Clinically significant infiltrative pulmonary disease not related to lung metastases
• A history of life-threatening hypersensitivity to monoclonal antibodies or recombinant proteins
  • Neratinib \& trastuzumab:
• Patients with severe hepatic impairment (Child-Pugh Class C)
• Patients who are experiencing dyspnoea at rest due to complications of advanced malignancy or co-morbidities
• Hypersensitivity to murine proteins
• 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)

Lab values

• 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).
• 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 Investigator
  • Ectopic mineralization/calcification, including but not limited to soft tissue, kidneys, intestine, or myocardia and lung, considered clinically significant in the opinion of the Investigator
  • Retinal or corneal disorder confirmed by retinal/corneal examination and considered clinically significant in the opinion of the Investigator
• Patients 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)
• Concomitant treatment with medicinal products known to prolong the QTc interval, or moderate or strong CYP3A4 inhibitors where these cannot be substituted for another therapy
• Patients with concurrent neuromuscular disorders associated with elevated creatine phosphokinase (\>ULN)
• Patients with hypokalemia, hypomagnesemia, or hypocalcemia (i.e. Serum potassium, magnesium or calcium \< lower normal limit)

Other

• Contraindication to 1L-SoC
• Contraindication to tumour biopsy in the absence of suitable archived sample of tumour tissue
• 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
• Cardiorespiratory pathologies where hyperhydration is contraindicated.
• 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
• Inability or unwillingness to swallow pills
• Hypokalemia, hypomagnesemia or hypocalcemia where this cannot be corrected by supplementation
  • Zanidatamab:
• QTcF \> 470 ms
• 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 with a QTcF ≥ 450 msec for men, or ≥ 470 msec for women

• 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).
• 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)

Criteria the registry did not label

• SCREENING PHASE