ETOP 21-21 BOUNCE: A multicentre, randomised, phase II trial of brigatinib consolidation versus observation or durvalumab in patients with unresectable stage III NSCLC and ALK-rearrangement, after definitive chemo-radiotherapy.
- Trial ID
- 2022-502467-38-00
- Protocol
- ETOP 21-21 BOUNCE
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to assess the **efficacy** of brigatinib consolidation in terms of progression-free survival (PFS) compared to observation or durvalumab in patients with unresectable stage III non-small cell lung cancer (NSCLC) and ALK-rearrangement, who have completed definitive chemo-radiotherapy without disease progression. This evaluation is clinically relevant as it aims to determine the potential benefit of brigatinib in extending the period during which the disease does not worsen, which is crucial for improving patient outcomes in this specific cancer subset.
Secondary objectives include evaluating additional measures of clinical efficacy such as overall survival (OS), CNS-relapse-free survival, patterns of disease progression, and safety. These secondary endpoints provide a comprehensive understanding of the treatment's impact on patient health and disease management, offering insights into long-term benefits and potential risks associated with the therapy.
Participants
The clinical trial involves a total of **14 participants** diagnosed with **non-small cell lung cancer (NSCLC)**, specifically those with unresectable stage III NSCLC and ALK-rearrangement. The study population includes both male and female subjects, aged 18 years and older, who have completed definitive chemo-radiotherapy without disease progression. Participants were selected based on specific criteria, including a pathologically documented diagnosis of NSCLC, documented ALK-fusion, and an ECOG Performance Status of 0-1. The trial population is characterized by their ability to comply with the trial protocol and their candidacy for chemo-radiotherapy, as assessed by the investigator. Lifestyle considerations such as diet and physical activity are not specified, but participants must have adequate hematological, renal, and liver function. The trial does not exclude vulnerable populations, and the selection process ensures that participants have resolved any adverse events from previous treatments to a manageable level, except for alopecia. The trial aims to evaluate the efficacy of brigatinib consolidation compared to observation/durvalumab in terms of progression-free survival.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **brigatinib** consolidation therapy compared to observation or **durvalumab** in patients with unresectable stage III non-small cell lung cancer (NSCLC) with ALK-rearrangement, following definitive chemo-radiotherapy. This is a multicenter, randomized, phase II trial with a double-blind, controlled design. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), CNS-relapse-free survival, patterns of disease progression, and safety. The estimated duration of the trial is from October 2023 to April 2029.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as pathologically documented unresectable stage III NSCLC, documented ALK-fusion, and an ECOG Performance Status of 0-1. Randomization of eligible patients must occur within 8 weeks after the last radiotherapy fraction. Follow-up visits will be scheduled to monitor the participants' health status, adherence to the treatment protocol, and any adverse events. The end-of-study visit will conclude the trial for each participant, assessing the final outcomes and collecting data for analysis.
The expected length of participant involvement in the trial is up to 156 weeks, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or any other reason deemed necessary by the investigator. Participants will be closely monitored throughout the trial to ensure safety and adherence to the protocol.
Treatment
The clinical trial involves the administration of **BRIGATINIB**, a small molecule of chemical origin, provided in the form of a film-coated tablet. The active substance, brigatinib, is manufactured by Takeda Development Center Americas, Inc. The medication is administered orally. During the trial, two dosing regimens are employed. The first regimen involves a maximum daily dose of 90 mg, with a total dose of 630 mg over a 7-day period. The second regimen allows for a maximum daily dose of 180 mg, with a total dose of 27,900 mg over a 155-day period. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.
Additionally, the trial includes the use of **DURVALUMAB**, marketed as IMFINZI, which is a protein-based therapeutic agent. This medication is provided as a concentrate for solution for infusion, with a concentration of 50 mg/mL. Manufactured by AstraZeneca AB, durvalumab is administered via infusion. The dosing schedule permits a maximum daily dose of 1500 mg, with a cumulative dose of 60,000 mg over a 156-day period. The administration of durvalumab is carefully monitored to ensure proper infusion techniques and participant compliance.
In this trial, **BRIGATINIB** serves as the experimental treatment, while **DURVALUMAB** acts as a comparator treatment. The trial aims to evaluate the efficacy of brigatinib consolidation therapy compared to observation or durvalumab in patients with unresectable stage III non-small cell lung cancer (NSCLC) and ALK-rearrangement, following definitive chemo-radiotherapy. The primary endpoint is progression-free survival, with secondary endpoints including overall survival, CNS-relapse-free survival, patterns of disease progression, and safety. The trial does not involve the use of a placebo, and all treatments are administered according to the specified dosing schedules to ensure consistency and reliability of the trial outcomes.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**, as defined by RECIST v1.1 criteria, in the intention-to-treat (ITT) cohort. PFS will be compared between the two arms of the study: brigatinib consolidation versus observation or durvalumab. Secondary efficacy endpoints include overall survival (OS), CNS-relapse-free survival, patterns of disease progression, and safety, with toxicity evaluated according to CTCAE v5.0.
The trial will involve patients with unresectable stage III non-small cell lung cancer (NSCLC) and ALK-rearrangement, who have completed definitive chemo-radiotherapy without disease progression. The efficacy parameters will be collected and analyzed at specified intervals throughout the trial duration, which is estimated to conclude by April 2029. The trial is designed to provide a comprehensive evaluation of the clinical benefits of brigatinib consolidation therapy compared to standard observation or durvalumab treatment in this patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Most important inclusion criteria for enrolment: • Pathologically documented, treatment naïve unresectable stage III NSCLC • Documented ALK-fusion, tested locally on tumor tissue by a validated method (DNA NGS, RNA NGS, FISH, IHC, or ctDNA) • ECOG Performance Status 0-1 • Age ≥18 years • Patient is a candidate to receive chemo-radiotherapy, as per investigator’s assessment (including adequate haematological, renal and liver function as per local clinical practice). • Negative pregnancy test for women of childbearing potential. • Ability to comply with the trial protocol, in the investigator's judgment. • Written informed consent for trial participation must be signed and dated by the patient and the investigator prior to any trial-related intervention, including the submission of mandatory biomaterial. Most important inclusion criteria for randomisation: Randomisation of eligible patients must occur within 8 weeks after the last radiotherapy fraction. • Completion of thoracic radiotherapy • Non-PD at restaging • Adequate haematological, renal and liver function. • Negative pregnancy test for women of childbearing potential • No radiation pneumonitis of grade ≥2 • All other AEs from previous chemo-radiotherapy resolved to grade <2 (except for alopecia) • ECOG 0-2 • No major surgery, as defined by the investigator, within 4 weeks of the first planned dose of brigatinib. Minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed. • No systemic treatment with strong cytochrome p-450 (cyp)3a inhibitors, strong cyp3a inducers, or moderate cyp3a inducers within 14 days before randomisation.
Exclusion Criteria
- Most important exclusion criteria for enrolment: • Diagnosis of another primary malignancy other than NSCLC. • Prior treatment for NSCLC • Any evidence of stage IV NSCLC • Significant, uncontrolled, or active cardiovascular disease - History of clinically significant atrial arrhythmia (including clinically significant brady-arrhythmia), as determined by the treating physician. - Any history of clinically significant ventricular arrhythmia. - Cerebrovascular accident or transient ischemic attack within 6 months before enrolment. - Myocardial infarction within 6 months before enrolment. - Unstable angina within 6 months before enrolment. - Congestive heart failure within 6 months before enrolment. • Uncontrolled hypertension: Patients with hypertension should be under treatment on study entry to control blood pressure. • History or the presence at baseline of pulmonary interstitial disease, drug-related pneumonitis. • Ongoing or active infection, including, but not limited to, the requirement for intravenous antibiotics. • Malabsorption syndrome or other GI illness that could affect oral absorption of brigatinib. • Known or suspected hypersensitivity to brigatinib or its excipients. • Any concurrent medical condition which, in the opinion of the investigator, would compromise patient safety or interfere with the evaluations of brigatinib.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Oct 2023 | 5 |
 Italy | Not Recruiting | 01 Oct 2023 | 6 |
 Poland | Not Recruiting | 01 Oct 2023 | 18 |
 Spain | Not Recruiting | 01 Oct 2023 | 12 |
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 |
|---|---|---|---|---|---|---|
BRIGATINIB | Test | FILM-COATED TABLET | ORAL | 90 | 7 | PRD10066549 |
BRIGATINIB | Test | FILM-COATED TABLET | ORAL | 180 | 155 | PRD10069416 |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | CONCENTRATE FOR SOLUTION FOR INFUSION | 1500 | 156 | PRD6651398 |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | CONCENTRATE FOR SOLUTION FOR INFUSION | 1500 | 156 | PRD6651400 |