Biliary Tract Neoplasms
Conditions
Keywords
Biliary Tract Neoplasms, Targeted therapy, Personalised medicine
Brief summary
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.
Detailed description
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.
Interventions
DRUGFutibatinib
Dose 20 mg once a day (QD)
DRUGIvosidenib
Dose 500 mg QD
DRUGZanidatamab
Dose: Patients \< 70 kg: 1800 mg every 3 weeks (Q3W), Patients ≥ 70 kg: 2400 mg Q3W
DRUGTrastuzumab
Loading dose 8 mg/kg, then 6 mg/kg Q3W (Combination with neratinib)
DRUGNeratinib
Dose: 240 mg QD (combination with trastuzumab)
DRUGEncorafenib
Dose: 450 mg QD (Combination with binimetinib)
DRUGBinimetinib
Dose: 45 mg twice a day (BID) (Combination with encorafenib)
DRUGNiraparib
Dose: 200 mg QD or 300 mg QD
DRUGCisplatin
Dose: 25 mg/m2 IV on days 1 and 8 Q3W (CISGEM)
DRUGGemcitabine
Dose: 1000 mg/m2 IV on days 1 and 8 Q3W (CISGEM)
Sponsors
UNICANCER
Cancer Research UK & UCL Cancer Trials Centre
Belgian Group of Digestive Oncology
National Cancer Institute, France
Cancer Research UK
Taiho Oncology, Inc.
Servier
Zymeworks BC Inc.
Accord Healthcare, Inc.
Pierre Fabre Medicament
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | From randomisation to disease progression or death, up to 5 years. | Time from randomisation to the first documented progression of disease (PD) as assessed by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomisation to death, up to 5 years. | The overall survival is the length of time from randomization that patients enrolled in the study are still alive. |
| Objective response rate | From randomisation, up to 5 years. | Objective response rate is defined as the proportion of patients achieving complete response (CR) or partial response (PR) (according to RECIST v1.1). Objective response rate will be presented as the best response achieved compared to the disease assessment performed at randomisation. |
| Time to treatment failure | From randomisation to treatment failure event, up to 5 years. | Time from patient starting their allocated treatment to the date at which a patient first experiences a treatment failure event. The following will be considered as treatment failure events: early treatment discontinuation (regardless of reason), disease progression, death, starting a new treatment after completing scheduled treatment, withdrawal from the study due to any reason or loss to follow-up. |
| Progression-free survival after next line of treatment (PFS2) | From randomisation to second disease progression or death, up to 5 years. | Time from randomisation to the date of second disease progression or death, whichever occurs first. |
| Duration of response | From response to disease progression or death, up to 5 years. | Duration of response is defined as the time from first documented response (compared to baseline measurement taken at randomisation) until the date of disease progression, as assessed by the investigator according to RECIST v1.1, or death from any cause whichever occurs first. |
| Disease control rate | From randomisation, up to 5 years. | Disease control rate is defined as the proportion of randomised patients achieving CR, PR, stable disease (SD)/no evidence of disease (NED) as assessed by the investigator according to RECIST v1.1. |
| Percentage change in tumour size | From randomisation, up to 5 years. | Taking the measurements at randomisation as the reference. |
Countries
Belgium, France, United Kingdom
Contacts
CONTACTMarta Jimenez
PRINCIPAL_INVESTIGATORMalka David, MD
Institut Mutualiste Montsouris
PRINCIPAL_INVESTIGATORJulien Edeline, MD
Centre Eugène Marquis
PRINCIPAL_INVESTIGATORIvan Borbath, MD
Cliniques universitaires Saint-Luc- Université Catholique de Louvain
PRINCIPAL_INVESTIGATORJohn Bridgewater, MD
University College London Cancer Institute
PRINCIPAL_INVESTIGATORJuan W Valle
University of Manchester and The Christie NHS Foundation Trust
Outcome results
None listed