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.

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.

SCREENING PHASE

Inclusion Criteria:

1. Signed a written informed consent form prior to any trial specific procedures (Consent #1)
2. Histologically-proven intrahepatic, perihilar or distal cholangiocarcinoma, or gallbladder carcinoma (ampullary carcinoma excluded)
3. De novo or recurrent, locally advanced (non-resectable) or metastatic disease
4. 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
5. Aged ≥18 years
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Estimated life expectancy >3 months
8. Candidate for 1L-SoC therapy, or has initiated first cycle of 1L-SoC therapy
9. Affiliated to a social security system or in possession of equivalent private health insurance (according to local country health provision arrangements).

Exclusion Criteria:

1. Contraindication to 1L-SoC
2. Patients who are candidates for locoregional therapy
3. Contraindication to tumour biopsy in the absence of suitable archived sample of tumour tissue
4. Prior anticancer therapy in the palliative setting. Adjuvant capecitabine allowed if completed ≥ 183 days prior to study entry
5. Received more than 1 cycle of treatment with 1L-SoC
6. Prior treatment with any of the MTT under investigation in the SAFIR-ABC10 study
7. 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
8. 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
9. Women who are pregnant or breast-feeding
10. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
11. Individuals deprived of liberty or placed under protective custody or guardianship

RANDOMISED TRIAL

Inclusion Criteria:

1. Signed a written informed consent form prior to any trial specific procedures (Consent #2)
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)
3. Disease control (stable or responsive) after 4 cycles of 1L-SoC, compared to a pre-treatment disease evaluation, as assessed by the investigator
4. ECOG performance status of 0 or 1
5. Presence of at least one evaluable lesion according to RECIST v1.1, or complete response to 12 weeks 1L-SoC
6. Adequate bone marrow function: absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count ≥100 × 10⁹/L, and haemoglobin ≥9 g/dL
7. 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)
8. Adequate renal function: estimated creatinine clearance ≥ 60 mL/min according to the Cockcroft-Gault formula
9. Adequate cardiac function: left ventricular ejection fraction ≥50% at baseline as determined by either echocardiogram or multigated acquisition scan (MUGA)
10. Adequate biliary drainage, with no evidence of ongoing infection
11. 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.
12. Women of childbearing potential must have a negative serum pregnancy test performed within 3 days before the date of randomisation
13. 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
14. Affiliated to a social security system or in possession of equivalent private health insurance (according to local country health provision arrangements)

Exclusion Criteria:

1. 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
2. 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
3. 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.
4. Microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) cancers
5. Major surgery within 4 weeks of randomisation
6. Radiotherapy within 7 days of randomisation
7. 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).
8. 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).
9. Cardiorespiratory pathologies where hyperhydration is contraindicated.
10. Manifestation of tinnitus and/or hearing loss since initiation of cisplatin therapy.
11. 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.
12. 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
13. Concomitant treatment with phenytoin in prophylactic use where this cannot be substituted for another therapy
14. Known active hepatitis B virus or hepatitis C virus infection or human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
15. 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
16. Women who are pregnant or breast-feeding
17. Participation in another therapeutic trial within the 30 days prior to entering the study. Participation in an observational trial would be acceptable
18. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
19. Individuals deprived of liberty or placed under protective custody or guardianship

ADDITIONAL EXCLUSION CRITERIA FOR SPECIFIC MTTs:

Patients assigned to receive oral therapies:

1. Inability or unwillingness to swallow pills
2. 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:

1. History and/or current evidence of any of the following disorders:

   1. Non-tumour related alteration of the calcium-phosphorus homeostasis that is considered clinically significant in the opinion of the Investigator
   2. 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
   3. Retinal or corneal disorder confirmed by retinal/corneal examination and considered clinically significant in the opinion of the Investigator

2. 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:

1. Patients with history of torsade de pointes
2. Concomitant treatment with digoxin where this cannot be substituted for another therapy
3. 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)
4. Concomitant treatment with strong CYP3A4 inducers or dabigatran where these cannot be substituted for another therapy
5. 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
6. Familial history of sudden death or polymorphic ventricular arrhythmia.
7. Hypokalemia, hypomagnesemia or hypocalcemia where this cannot be corrected by supplementation

Zanidatamab:

1. Treatment with anthracyclines within 90 days before first dose of zanidatamab and/or total lifetime load exceeding 360 mg/m2 Adriamycin® or equivalent
2. 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
3. QTcF > 470 ms
4. 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
5. Acute or chronic uncontrolled pancreatitis or Child-Pugh Class C liver disease
6. Clinically significant infiltrative pulmonary disease not related to lung metastases
7. A history of life-threatening hypersensitivity to monoclonal antibodies or recombinant proteins

Neratinib & trastuzumab:

1. Patients with severe hepatic impairment (Child-Pugh Class C)
2. 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)
3. Patients who are experiencing dyspnoea at rest due to complications of advanced malignancy or co-morbidities
4. Hypersensitivity to murine proteins
5. Current active pneumonitis within 90 days of receiving trastuzumab or a known history of interstitial lung disease

Encorafenib & binimetinib:

1. 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)
2. Patients with concurrent neuromuscular disorders associated with elevated creatine phosphokinase (>ULN)
3. Patients with hypokalemia, hypomagnesemia, or hypocalcemia (i.e. Serum potassium, magnesium or calcium < lower normal limit)
4. Patients with a QTcF ≥ 450 msec for men, or ≥ 470 msec for women
5. Current or expected use of a strong inhibitor of CYP3A4

Unicancer will share de-identified individual data that underlie the results reported. A decision concerning the sharing of other study documents, including protocol and statistical analysis plan will be examined upon request.

Unicancer will consider access to study data upon written detailed request sent to Unicancer, from 6 months until 5 years after publication of summary data.

The data shared will be limit to that required for independent mandated verification of the published results, the applicant will need authorization from Unicancer for personal access, and data will only be transferred after signing of a data access agreement.