Personalized Medicine for Advanced Biliary Cancer Patients

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, orgallbladder 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 tissuesample

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 healthinsurance (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 oftumour tissue

4. Prior anticancer therapy in the palliative setting. Adjuvant capecitabine allowed ifcompleted ≥ 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 treatedcone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cellcarcinoma of the skin. Cancer survivors, who have undergone potentially curativetherapy for a prior malignancy, have no evidence of that disease for 5 years or moreand 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 thesubject to participate in the trial or which would jeopardize compliance with theprotocol

9. Women who are pregnant or breast-feeding

10. Patients unwilling or unable to comply with the medical follow-up required by thetrial 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 molecularalteration 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 apre-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 completeresponse 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 Gilbertsyndrome), 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 theCockcroft-Gault formula

9. Adequate cardiac function: left ventricular ejection fraction ≥50% at baseline asdetermined 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 adequatecontraception for the duration of trial participation and as required aftercompleting study treatment. Men must also agree to not donate sperm and women mustagree to not donate oocytes during the specified period.

12. Women of childbearing potential must have a negative serum pregnancy test performedwithin 3 days before the date of randomisation

13. Willing and able to comply with the protocol for the duration of the study includingscheduled visits, treatment plan, laboratory tests, and other study procedures

14. Affiliated to a social security system or in possession of equivalent private healthinsurance (according to local country health provision arrangements)

Exclusion Criteria:

1. Disease progression occurring at any time prior randomisation, or toxicity that ledto 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 theNational 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 alterationfound in the patient, or any component in their formulation Note: For patients withmultiple target alterations, contraindication to one MTT will not warrant exclusionif 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, orradiation treatment for CNS metastases within 4 weeks of start of study treatment.Stable, treated brain metastases are allowed (defined as subjects who are offsteroids and anticonvulsants and are neurologically stable with no evidence ofradiographic 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 Associationfunctional classification scale], recent thromboembolic or cerebrovascular events [within 12 weeks, excepted if related to indwelling catheter], known prolonged QTsyndrome).

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 reportedradiographically on baseline magnetic responance imaging (MRI), but is not suspectedclinically by the investigator, the subject must be free of neurological symptoms.

12. Concurrent malignancy (other than ABC), with the exception of adequately treatedcone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cellcarcinoma of the skin. Cancer survivors, who have undergone potentially curativetherapy for a prior malignancy, have no evidence of that disease for 5 years or moreand are deemed at negligible risk for recurrence, are eligible for the trial

13. Concomitant treatment with phenytoin in prophylactic use where this cannot besubstituted for another therapy

14. Known active hepatitis B virus or hepatitis C virus infection or humanimmunodeficiency virus (HIV) or known acquired immunodeficiency syndrome

15. Any condition which in the Investigator's opinion makes it undesirable for thesubject to participate in the trial or which would jeopardize compliance with theprotocol

16. Women who are pregnant or breast-feeding

17. Participation in another therapeutic trial within the 30 days prior to entering thestudy. Participation in an observational trial would be acceptable

18. Patients unwilling or unable to comply with the medical follow-up required by thetrial 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 withenteral absorption. For example, active intestine inflammation (e.g., Crohn'sdisease or ulcerative colitis) requiring immunosuppressive therapy

Futibatinib:

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

2. Non-tumour related alteration of the calcium-phosphorus homeostasis that isconsidered clinically significant in the opinion of the Investigator

3. Ectopic mineralization/calcification, including but not limited to soft tissue,kidneys, intestine, or myocardia and lung, considered clinically significant inthe opinion of the Investigator

4. Retinal or corneal disorder confirmed by retinal/corneal examination andconsidered clinically significant in the opinion of the Investigator

5. Concomitant treatment with strong CYP3A/P-gp inhibitors or strong or moderateCYP3A/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 anothertherapy

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 arrhythmicevents (e.g. heart failure, hypokalemia, family history of long QT intervalsyndrome)

4. Concomitant treatment with strong CYP3A4 inducers or dabigatran where these cannotbe substituted for another therapy

5. Concomitant treatment with medicinal products known to prolong the QTc interval, ormoderate or strong CYP3A4 inhibitors where these cannot be substituted for anothertherapy

6. Familial history of sudden death or polymorphic ventricular arrhythmia.

7. Hypokalemia, hypomagnesemia or hypocalcemia where this cannot be corrected bysupplementation

Zanidatamab:

1. Treatment with anthracyclines within 90 days before first dose of zanidatamab and/ortotal lifetime load exceeding 360 mg/m2 Adriamycin® or equivalent

2. Use of corticosteroids administered at doses equivalent to > 15 mg per day ofprednisone within 2 weeks of first zanidatamab dosing unless otherwise approved bythe coordinating investigator. Topical, ocular, intra-articular, intranasal, and/orinhalational corticosteroids are permitted

3. QTcF > 470 ms

4. History of myocardial infarction or unstable angina within 6 months prior toenrollment, troponin levels consistent with myocardial infarction, or clinicallysignificant 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 orrecombinant 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 ofthe 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 advancedmalignancy or co-morbidities

4. Hypersensitivity to murine proteins

5. Current active pneumonitis within 90 days of receiving trastuzumab or a knownhistory of interstitial lung disease

Encorafenib & binimetinib:

1. Patients with a history or current evidence of retinal vein occlusion or riskfactors for retinal vein occlusion (e.g., uncontrolled glaucoma or history ofhyperviscosity or hypercoagulability syndrome)

2. Patients with concurrent neuromuscular disorders associated with elevated creatinephosphokinase (>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