Evaluation of Molecular Targeted Maintenance Therapy with Binimetinib, Futibatinib, and Drug Combination in Advanced Biliary Cancer: A Phase 3 Randomized Trial
- Trial ID
- 2023-508100-38-00
- Sponsor
- Unicancer
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate whether maintenance treatment with **molecular targeted therapies** (MTTs) directed at "actionable" targets (ESCAT I-III) after four cycles of first-line standard of care (1L-SoC) is superior to the continuation of 1L-SoC in terms of progression-free survival (PFS) in patients with **Advanced Biliary Cancer** (ABC). This is clinically relevant as it aims to determine the potential benefits of personalized medicine in extending the time patients remain free from disease progression, which is a critical factor in improving patient outcomes in ABC.
The secondary objectives include:
- Assessing the efficacy of precision oncology versus 1L-SoC in ABC patients with "actionable" tumor molecular alterations (ESCAT I-III).
- Evaluating the efficacy of each MTT or MTT combination.
- Assessing the feasibility of molecular screening in a multinational, academic trial.
- Comparing the health-related quality of life (HRQoL) of patients treated with MTTs versus 1L-SoC.
- Assessing the safety of the MTTs.
- Studying the prognostic value of molecular alterations, regardless of the randomization.
Participants
The clinical trial involves a total of **400 participants** diagnosed with **Advanced Biliary Cancer (ABC)**. The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who are candidates for first-line standard of care (1L-SoC) therapy. Participants were selected based on their ability to provide informed consent and their molecular profile, which must show at least one targetable molecular alteration. The trial includes individuals with stable or responsive disease after four cycles of 1L-SoC, as assessed by the investigator. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population is characterized by adequate bone marrow, liver, renal, and cardiac function, and participants must have adequate biliary drainage with no evidence of ongoing infection. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use adequate contraception and comply with the study protocol. The trial also includes a vulnerable population, ensuring comprehensive representation of the disease's impact across different demographics.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of molecular targeted maintenance therapy (MTT) compared to the standard of care (SoC) in patients with **advanced biliary cancer**. This is a randomized, controlled, open-label, phase III trial. The primary objective is to assess progression-free survival (PFS) following four cycles of first-line SoC treatment. The trial is expected to commence recruitment on December 15, 2023, and conclude by December 15, 2028.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as histologically-proven intrahepatic, perihilar, or distal cholangiocarcinoma, or gallbladder carcinoma. The screening phase will also ensure adequate organ function and performance status. Following successful screening, participants will be randomized to receive either MTT or continue with SoC. The trial includes regular follow-up visits to monitor disease progression, treatment response, and any adverse events. The end-of-study visit will occur upon completion of the treatment period or earlier if disease progression or unacceptable toxicity is observed.
The expected duration of participant involvement is up to four months, corresponding to the maximum treatment period. However, participants may be withdrawn from the study early due to disease progression, adverse events, or withdrawal of consent. The trial will utilize a variety of investigational products, including **binimetinib**, **gemcitabine**, **futibatinib**, **niraparib**, **ivosidenib**, **zanidatamab**, **cisplatin**, **trastuzumab**, **encorafenib**, **neratinib**, and **durvalumab**, administered either orally or via intravenous infusion, depending on the specific treatment arm. The trial's primary endpoint is progression-free survival, with secondary endpoints including overall survival, objective response rate, and duration of response.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Mektovi** (binimetinib) is provided as 15 mg film-coated tablets, administered orally. The maximum daily dose is 90 mg, with a total dose of 1890 mg over a treatment period of up to 3 months. This medication is used as a test treatment in the trial.
**GEMCITABINE** is administered as a solution for infusion, with a maximum daily dose of 1000 mg/m² and a total dose of 2000 mg/m². It is delivered intravenously and serves as a comparator treatment in the study. The treatment period is up to 3 months.
**Futibatinib** is provided in the form of film-coated tablets, with a maximum daily dose of 20 mg. The administration route is oral, and the treatment period extends up to 4 months. This medication is designated as an orphan drug and is used as a test treatment.
**Zejula** (niraparib) is available as 100 mg hard capsules, administered orally. The maximum daily dose is 300 mg, with a total dose of 6300 mg over a 3-month period. It is used as a test treatment and is also designated as an orphan drug.
**IVOSIDENIB** is administered as film-coated tablets, with a maximum daily dose of 500 mg and a total dose of 10500 mg. The route of administration is oral, and the treatment period is up to 3 months. It is used as a test treatment and has orphan drug designation.
**JZP598** (zanidatamab) is provided as a powder for concentrate for solution for infusion, with a maximum daily dose of 2400 mg. It is administered intravenously over a treatment period of up to 3 months. This medication is used as a test treatment.
**CISPLATIN** is administered as a solution for infusion, with a maximum daily dose of 25 mg/m² and a total dose of 50 mg/m². The route of administration is intravenous, and it serves as a comparator treatment in the study. The treatment period is up to 3 months.
**Zercepac** (trastuzumab) is provided as a powder for concentrate for solution for infusion, with a maximum daily dose of 8 mg/kg. It is administered via intravenous infusion over a treatment period of up to 3 months. This medication is used as a test treatment.
**Braftovi** (encorafenib) is available as 75 mg hard capsules, administered orally. The maximum daily dose is 450 mg, with a total dose of 9450 mg over a 3-month period. It is used as a comparator treatment in the study.
**Nerlynx** (neratinib) is provided as 40 mg film-coated tablets, with a maximum daily dose of 240 mg and a total dose of 5040 mg. The administration route is oral, and the treatment period is up to 3 months. This medication is used as a test treatment.
**IMFINZI** (durvalumab) is administered as a concentrate for solution for infusion, with a maximum daily dose of 1500 mg. It is delivered via intravenous infusion over a treatment period of up to 3 months. This medication serves as a comparator treatment in the study.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of these treatments in comparison to standard-of-care therapy in advanced biliary cancer.
Efficacy
Efficacy in this clinical trial will be assessed using several key endpoints. The primary endpoint is **progression-free survival (PFS)**, defined as the time from randomization to the first documented progression of disease or death from any cause, whichever occurs first. This will be assessed by the investigator according to RECIST v1.1 criteria. Patients who are alive and free of progression at the cut-off date will be censored at the last assessment date.
Secondary endpoints include overall survival (OS), objective response rate, time to treatment failure, progression-free survival after the next line of treatment (PFS2), and duration of response. Overall survival is defined as the time from randomization to death due to any cause, with patients alive at the cut-off date being censored on the last date they were known to be alive. The objective response rate is the proportion of patients achieving complete response (CR) or partial response (PR) as assessed by the investigator, presented as the best response achieved compared to the disease assessment at randomization. Time to treatment failure is the time from the start of allocated treatment to the first experience of a treatment failure event. PFS2 is the time from randomization to the date of second progression or death, whichever occurs first. Duration of response is the time from first documented PR or CR until the date of progression or death, with patients who are alive and have not progressed being censored at their last evaluable tumor assessment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Screening phase - Signed a written informed consent form prior to any trial specific procedures (Consent #1)
- Screening phase - Histologically-proven intrahepatic, perihilar or distal cholangiocarcinoma, or gallbladder carcinoma (ampullary carcinoma excluded)
- Screening phase - De novo or recurrent, locally advanced (non-resectable) or metastatic disease
- Screening phase - 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
- Screening phase - Aged ≥18 years
- Screening phase - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Screening phase - Estimated life expectancy >3 months
- Screening phase - Candidate for 1L-SoC therapy, or has initiated first cycle of 1L-SoC therapy
- Screening phase - Affiliated to a social security system or in possession of equivalent private health insurance (according to local country health provision arrangements).
- Randomised trial - Signed a written informed consent form prior to any trial specific procedures (Consent #2)
- Randomised trial - 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)
- Randomised trial - Disease control (stable or responsive) after 4 cycles of 1L-SoC, compared to a pretreatment disease evaluation, as assessed by the investigator
- Randomised trial - ECOG performance status of 0 or 1
- Randomised trial - Presence of at least one evaluable lesion according to RECIST v1.1, or complete response to 12 weeks 1L-SoC
- Randomised trial - Adequate bone marrow function: absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count ≥100 × 10⁹/L, and haemoglobin ≥9 g/dL
- Randomised trial - Adequate liver function: total bilirubin level ≤1.5 × the upper limit of normal (ULN) range unless 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)
- Randomised trial - Adequate renal function: estimated creatinine clearance ≥45 mL/min according to the Cockcroft-Gault formula
- Randomised trial - Adequate cardiac function: left ventricular ejection fraction ≥50% at baseline as determined by either echocardiogram or multigated acquisition scan (MUGA)
- Randomised trial - Adequate biliary drainage, with no evidence of ongoing infection
- Randomised trial - 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.
- Randomised trial - Women of childbearing potential must have a negative serum pregnancy test performed within 3 days before the date of randomisation
- Randomised trial - 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
- Randomised trial - Affiliated to a social security system or in possession of equivalent private health insurance (according to local country health provision arrangements)
Exclusion Criteria
- Screening phase - Contraindication to 1L-SoC
- Screening phase - Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
- Randomised trial - 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
- Randomised trial - Toxicities from 1L-SoC not resolved to Grade ≤ 2 (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
- Randomised trial - Contraindication or known hypersensitivity to the MTT for the molecular alteration found in the patient, or any component in their formulation
- Randomised trial - (MSI-H) or (dMMR) cancers
- Randomised trial - Major surgery within 4 weeks of randomisation
- Randomised trial - 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
- Randomised trial - 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.
- Randomised trial - Concurrent malignancy (other than ABC), with the exception of adequately treated conebiopsied 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
- Randomised trial - Known active hepatitis B virus or hepatitis C virus infection or human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
- Screening phase - Individuals deprived of liberty or placed under protective custody or guardianship
- Randomised 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
- Randomised trial - Women who are pregnant or breast-feeding
- Randomised trial - Participation in another therapeutic trial within the 30 days prior to entering the study. Participation in an observational trial would be acceptable
- Randomised trial - Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
- Randomised trial - Individuals deprived of liberty or placed under protective custody or guardianship
- For patients assigned to receive oral therapies - Inability or unwillingness to swallow pills
- For patients assigned to receive oral therapies - History of malabsorption syndrome or other condition that would interfere with enteral absorption.
- Screening phase - Patients who are candidates for locoregional therapy
- Screening phase - Contraindication to tumour biopsy in the absence of suitable archived sample of tumour tissue
- Screening phase - Prior anticancer therapy in the palliative setting. Adjuvant capecitabine allowed if completed ≥ 183 days prior to study entry
- Screening phase - Received more than 1 cycle of treatment with 1L-SoC
- Screening phase - Prior treatment with any of the MTT under investigation in the SAFIR-ABC10 study
- Screening phase - Current malignancies (other than ABC), with the exception of adequately treated conebiopsied 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
- Screening phase - 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
- Screening phase_Known microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) cancer at study entry
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 15 Dec 2023 | 100 |
 France | Recruiting | 15 Dec 2023 | 600 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Zercepac 150 mg powder for concentrate for solution for infusion. | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 8 | 3 | PRD8242235 |
CISPLATIN | Comparator | — | INTRAVENOUS | 25 | 3 | SUB07483MIG |
GEMCITABINE | Comparator | — | INTRAVENOUS | 1000 | 3 | SUB07892MIG |
Braftovi 75 mg hard capsules | Test | HARD CAPSULES | ORAL | 450 | 3 | PRD6728382 |
IVOSIDENIB | Test | — | ORAL | 500 | 3 | SUB189254 |
Futibatinib | Test | FILM-COATED TABLET | ORAL | 20 | 4 | PRD9585495 |
JZP598 | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 2400 | 3 | PRD10444188 |
Mektovi 15 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 90 | 3 | PRD6744227 |
PEMBROLIZUMAB | Comparator | — | INTRAVENOUS INFUSION | 200 | 3 | SUB167136 |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 1500 | 3 | PRD6651398 |