Investigating Precision Medicine in the Adjuvant Setting in Biliary Tract Cancer

Prior treatment

• Contraindication to standard adjuvant therapy
• Prior anticancer therapy in the neoadjuvant or adjuvant setting.
• Planned post-operative radiation therapy
• Prior treatment with any of the MTT under investigation in the trial
• Signed a written informed consent form prior to any trial specific procedures (Consent #2)
• Surgery performed at least four weeks prior to randomisation with adequate wound healing (in the Investigator's opinion) to allow adjuvant therapy to be initiated
• No measurable disease, as assessed by the investigator: normal post-operative thoracic, abdominal and pelvic CT scan or normal MRI of abdomen and pelvis + normal chest CT performed within 4 weeks prior to randomisation
• 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.
  • Note: See Section 5.8.5 for a definition of adequate contraception and required duration of contraceptive use following treatment with individual MTTs.
• Disease relapse occurring at any time prior to randomisation
• Surgery performed more than 16 weeks prior to randomisation
• Previous adjuvant treatment, including any systemic treatment, or radiotherapy
• Radiotherapy within 7 days of randomisation
• Recent or concomitant treatment with brivudine
• History of myocardial infarction or unstable angina within 6 months prior to enrolment, 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.
• Participation in another therapeutic trial within the 30 days prior to entering the study (participation in an observational trial would be acceptable)
• 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 cohort
• 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
• 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.

Other illness

• Patients with gallbladder cancer which has not extended to involve the muscle layers or lymph nodes (pT1aN0)
• Other invasive malignancies, 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 3 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
• 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
• Contraindication or known hypersensitivity to capecitabine or fluorouracil or 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.
• History of severe and unexpected reactions to fluoropyrimidine therapy
• Patients with HBV with HBV-DNA higher than 500IU/mL, active untreated HCV infection, or HIV infection with CD4 below 200. Patients with controlled HBV, HCV and HIV infections are allowed.
• 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
• 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 B or C liver disease.
• A history of life-threatening hypersensitivity to monoclonal antibodies or recombinant proteins

Lab values

• 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
• 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
• 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
• 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, hypokalaemia, family history of long QT interval 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. Blood phosphate concentration should be ≤ ULN at baseline examination.
  • 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
• 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

Other

• 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 PHASE Inclusion criteria
• 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)
• ECOG performance status of 0 or 1
• Affiliated to a social security system or in possession of equivalent private health insurance (according to local country health provision arrangements).
• Inability or unwillingness to swallow pills
• Known complete dihydropyrimidine dehydrogenase (DPD) deficiency
• 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
  • ADDITIONAL EXCLUSION CRITERIA FOR SPECIFIC MTTs:
  • Futibatinib cohort
• Hypokalaemia, hypomagnesemia or hypocalcaemia where this cannot be corrected by supplementation
  • Zanidatamab cohort
• Total lifetime anthracycline load exceeding 360 mg/m2 Adriamycin® or equivalent.

• Signed a written informed consent form prior to any trial specific procedures (Consent #1)
• Histologically-proven intrahepatic cholangiocarcinoma, perihilar or distal extrahepatic cholangiocarcinoma or gallbladder carcinoma (ampullary carcinoma is excluded)
• Macroscopically complete resection of the primary tumour (R0 or R1 surgical margin status)
• Aged ≥18 years
• 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