Biliary Tract Cancer (BTC)
Conditions
Keywords
Adjuvant, Targeted therapy, ESCAT, Personalised medicine, Cholangiocarcinoma
Brief summary
The objective of SAFIR-IMPACT BTC is to see whether, combining or replacing the standard adjuvant chemotherapy with a targeted therapy matched to the person's cancer, is better than the standard treatment alone in delaying or preventing the return of the cancer. Three different targeted therapies will be evaluated, each of which recognises a different type of abnormality in cancer cells: * Ivosidenib - a drug which acts on a specific abnormality in a protein called IDH1. * Futibatinib - a drug which acts on abnormalities in a protein called FGFR2 * Zanidatamab - a drug which acts on cancers that produce more than the usual quantity of a protein called HER2. The trial is composed of two phases: (i) An initial screening phase to identify a suitable patient population, during which a sample of the patient's tumour will be tested to see if it has one of the target abnormalities being studied (ii) a randomised comparative phase (for selected patients only) which consists of comparing two treatment options: some patients will receive the targeted therapy specific to the abnormality identified in their tumour, while others will receive the standard treatment. Patients will be assigned to one treatment or the other by a random draw: they will have a 2 in 3 chance of receiving the targeted therapy. Randomised participants will: * Take their assigned treatment for 6 months * Visit the clinic once every 3 weeks for checkups and tests * Keep a diary of their symptoms and the treatment they take at home Follow-up information will be collected for all participants until the end of the trial.
Detailed description
This is a multicentre, randomised phase 3, open-label trial to evaluate whether a precision oncology strategy of adjuvant molecular targeted therapy (MTT) can decrease the risk of relapse in the treatment of patients with resected biliary tract cancer (BTC) whose tumour harbours target (ESCAT I) alterations. 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 tumour samples for further translational research. A genetic profile will be obtained from tumour-derived DNA and RNA samples by next-generation sequencing. The trial Molecular Tumour Board will determine whether each patient harbours a targetable molecular alteration for one or more of the trial MTTs. Patients who have sufficiently recovered from surgery, with no measurable disease on post-operative imaging (in the opinion of the investigator), and whose tumour harbours at least one targetable molecular alteration, will be invited to participate in the randomised phase of the trial in which 280 eligible patients will be randomised (2:1) to receive adjuvant therapy with either a matched MTT (combined with SoC or alone depending on the alteration) or to continue 1L-SoC treatment.
Interventions
DRUGFutibatinib
Dose 20 mg once a day (QD)
DRUGIvosidenib + Capecitabine
Ivosidenib: Dose 500 mg QD Capecitabine: 1250mg/m² BID for 14 days on, 7 days off, in 3 week cycles
DRUGZanidatamab + Capecitabine
Zanidatamab: Patients \< 70 kg: 1800 mg every 3 weeks (Q3W), Patients ≥ 70 kg: 2400 mg Q3W Capecitabine: 1250mg/m² BID for 14 days on, 7 days off, in 3 week cycles
1250mg/m² BID for 14 days on, 7 days off, in 3 week cycles
Sponsors
UNICANCER
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 cholangiocarcinoma, perihilar or distal extrahepatic cholangiocarcinoma or gallbladder carcinoma (ampullary carcinoma is excluded) 3. Macroscopically complete resection of the primary tumour (R0 or R1 surgical margin status) 4. Aged ≥18 years 5. 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 standard adjuvant therapy 2. Prior anticancer therapy in the neoadjuvant or adjuvant setting. 3. Patients with gallbladder cancer which has not extended to involve the muscle layers or lymph nodes (pT1aN0) 4. Planned post-operative radiation therapy 5. Prior treatment with any of the MTT under investigation in the trial 6. 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 7. 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 8. Women who are pregnant or breast-feeding 9. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons 10. Individuals deprived of liberty or placed under protective custody or guardianship RANDOMISED PHASE 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. 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 4. 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 5. ECOG performance status of 0 or 1 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 8. 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 9. 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. 10. Women of childbearing potential must have a negative serum pregnancy test performed within 3 days before the date of randomisation 11. 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 12. 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 |
|---|---|---|
| Relapse-free survival | From randomisation to disease or death, up to 5 years | Time from randomisation to the first documented relapse of disease, as assessed by the investigator, or death from any cause, whichever occurs first |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From randomisation to death, up to 5 years | Time from randomisation to death due to any cause |
| Post-relapse survival | From randomisation to death, up to 5 years | Time from documented relapse to death due to any cause |
| ctDNA-clearance | From randomisation to 24 weeks | The proportion of patients achieving the transition from ctDNA positivity at inclusion to ctDNA negativity at 24 weeks |
| Time-to-ctDNA recurrence | From randomisation, up to 5 years | Time from randomisation to the time of ctDNA positivation |
| Incidence of Adverse Events | From randomisation, up to 5 years | Toxicity will be evaluated according to version 6.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v6.0). NCI-CTCAE is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale, divided into 5 grades (1 = "mild", 2 = "moderate", 3 = "severe", 4 = "life-threatening", and 5 = "death") determined by the investigator, will make it possible to assess the severity of the disorders. |
| Quality of life questionnaire - Core 30 (QLQ-C30) | At Baseline, after 42 days (at Cycle 3), after 105 days (at Cycle 6) and after 168 days (end of treatment) | Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials. The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. |
| Quality of life Questionnaire - Biliary tract cancer module (QLQ-BIL21) | At Baseline, after 42 days (at Cycle 3), after 105 days (at Cycle 6) and after 168 days (end of treatment) | This EORTC cholangiocarcinoma and gallbladder cancer specific questionnaire is intended to supplement the QLQ-C30. The QLQ-BIL21 contains 21 items to assess symptoms. All items are rated on a four-point Likert-type scale (1 = "not at all", 2 = "a little", 3 = "quite a bit", and 4 = "very much"), and are linearly transformed to a 0-100 scale. |
| EuroQOL EQ-5D-5L questionnaire | At Baseline, after 42 days (at Cycle 3), after 105 days (at Cycle 6) and after 168 days (end of treatment) | Developed by the EuroQol group, the self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials consists of a descriptive system and a visual analogue scale (VAS). The EQ-5D-5L descriptive system comprises five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each dimension has 5 levels (1 = "no problems", 2 = "slight problems", 3 = "moderate problems", 4 = "severe problems", and 5 = "extreme problems"). This questionnaire provide a 5-digit score which generate a health state profile. The VAS records the patient's self-rated health on a vertical visual analogue scale where the score range from 0 (The best health you can imagine) to 100 (The worst health you can imagine). The VAS is used as a quantitative measure of health outcome that reflects the patient's own judgement. |
Contacts
CONTACTMarta Jimenez
PRINCIPAL_INVESTIGATORJulien Edeline, MD
Centre Eugène Marquis
Outcome results
None listed