Clinical trial NCT05200481: Study of Safety and Efficacy of Brigatinib Plus Chemotherapy or Brigatinib Only in Advanced ALK-Positive Lung Cancer (MASTERPROTOCOL ALK)
Official title: A Phase II Randomized, Open-Labelled, Multicenter Study of Safety & Efficacy of Combination Brigatinib and Carboplatin-Pemetrexed Therapy or Brigatinib Monotherapy as First-Line Treatment in Advanced ALK-Positive Non-Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer
ALK Gene Mutation
Keywords: IFCT
NCSLC
brigatinib
chemotherapy
Lead sponsor: Intergroupe Francophone de Cancerologie Thoracique
Sponsor class: OTHER
First posted: 2022-01-20
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Interventional, phase II, randomized, open-labelled, non-comparative multicenter study with two parallel arms
Primary purpose: TREATMENT

Brief summary: This is a phase II randomized, open-labelled, non-comparative multicenter study in which ALK+ NSCLC patients who are naïve of treatment for advanced disease will be randomized to receive brigatinib monotherapy (Arm A) or brigatinib and carboplatin-pemetrexed therapy (Arm B). An estimated 110 patients (55 in Arm A, 55 in Arm B) will be enrolled at approximately 30 centers. A safety phase will evaluate the safety of brigatinib with carboplatin and pemetrexed treatment combination (Arm B). The first twenty-six patients enrolled in Arm B will represent the population of the safety phase. Patients will be treated until they experience progressive disease, intolerable toxicity, or another discontinuation criterion is met. Continuation of brigatinib beyond progression is permitted, at the investigator's discretion, if there is evidence of continued clinical benefit. The null hypothesis is progression free survival at 12 months ≤ 69% for Arm B, which is considered not sufficiently clinically meaningful to warrant further study. The alternative hypothesis is that 86% or more of patients in Arm B would achieve progression free survival at 12 months.


Eligibility criteria: Inclusion Criteria:

1. Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care. Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing.
2. Patients diagnosed with histologically or cytologically confirmed locally advanced not eligible to a local treatment or metastatic NSCLC (Stage IIIB, IIIC or IV accordingly to 8th classification TNM, UICC 2015).
3. Patients are eligible for trial entry on the basis of locally determined ALK testing. ALK Immunohistochemistry (IHC) assay (3+ only), DNA-based or RNA-based next generation sequencing (NGS) assay, nCounter Nanostring assay or ALK FISH performed locally are accepted ALK testing assays. If ALK rearrangement diagnostic is performed using IHC and the result is + or 2+, a confirmation with a second method performed locally (DNA-based or RNA-based NGS assay, nCounter Nanostring assay or ALK FISH performed) is required.
4. All Patients must have at least one measurable target lesion according to RECIST v1.1 per investigator assessment. The radiological assessment has to be done within the timelines indicated.
5. Patients with asymptomatic and neurologically stable CNS metastases (including patients controlled with less than 10mg/day of methylprednisolone within the last week prior to study entry) will be eligible.
6. Tumor Sample Requirement: sufficient tumor tissue for central analysis should be available (tumor block or a minimum of 10 unstained slides of 4 µm of analyzable tissue).
7. Age ≥18 years.
8. Life expectancy of at least 12 weeks, in the opinion of the Investigator.
9. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
10. Adequate Bone Marrow Function, including: Absolute Neutrophil Count (ANC) ≥1.5 x 109/L; Platelets ≥100 x 109/L; Hemoglobin ≥9 g/dL.
11. Adequate Pancreatic Function, including: Serum lipase ≤3.0 ULN.
12. Adequate Renal Function, including: Estimated creatinine clearance ≥45 mL/min as calculated using the standard method of the institution.
13. Adequate Liver Function, including: Total serum bilirubin ≤1.5 x ULN (\<3.0 × ULN for patients with Gilbert syndrome); Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤2.5 x ULN; ≤5.0 x ULN if there is liver metastases involvement.
14. Participants must have recovered from toxicities related to prior anticancer therapy to CTCAE Grade ≤ 1.
15. Participants must have recovered from effects of any major surgery, or significant traumatic injury, at least 35 days before the first dose of treatment.
16. Have normal QT interval on screening ECG evaluation, defined as QT interval corrected (QTc) of ≤450 milliseconds (msec) in males or ≤470 msec in females.
17. Female patients who: are postmenopausal for at least 1 year before the screening visit, OR are surgically sterile, OR if they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, one of them being nonhormonal, from the time of signing the informed consent through 6 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse.
18. Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse.
19. Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedure.
20. Participant has national health insurance coverage.

Exclusion Criteria:

1. Previously received an investigational antineoplastic agent for NSCLC.
2. Previously received any prior TKI, including ALK-targeted TKIs.
3. Known molecular co-alteration i.e. activating EGFR/BRAF/KRAS/MET mutation and ROS1/RET/NTRK fusion.
4. Previously received neo-adjuvant or adjuvant systemic chemotherapy or consolidation immunotherapy if completion of (neo) adjuvant/consolidation therapy occurred \<12 months prior to randomization.
5. Patients who have leptomeningeal disease (LM) or carcinomatous meningitis (CM) according to MRI data and/or in case of documented cerebral spinal fluid (CSF) positive cytology.
6. Spinal cord compression.
7. Patients with symptomatic or neurologically instable CNS metastases.
8. Major surgery within 30 days of study entry. Minor surgical procedures (e.g., port insertion, mediastinoscopy, surgical procedure for re-sampling) are not excluded, but sufficient time at investigator discretion should have passed for wound healing.
9. Radiation therapy within 2 weeks of study entry. Stereotactic or small field brain irradiation must have completed at least 2 weeks prior to study entry. Whole brain radiation must have completed at least 4 weeks prior to study entry.
10. Active and clinically significant bacterial, fungal, or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related illness.
11. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: a) myocardial infarction within 6 months prior to the first dose of study drug; b) unstable angina within 6 months prior to the first dose of study drug; c) congestive heart failure within 6 months prior to the first dose of study drug; d) any history of ventricular arrhythmia; e) history of clinically significant atrial arrhythmia or clinically significant bradyarrhythmia as determined by the treating physician; f) cerebrovascular accident or transient ischemic attack within 6 months prior to the first dose of study drug.
12. Have uncontrolled hypertension. Patients with hypertension should be under treatment on study entry to control blood pressure.
13. History of grade 3 or 4 of interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis and radiation pneumonitis.
14. Presence of interstitial fibrosis of any grade at baseline.
15. Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
16. Evidence of active malignancy (other than current NSCLC, non-melanoma skin cancer, in situ cervical cancer, papillary thyroid cancer, DCIS of the breast or localized and presumed cured prostate cancer) within the last 3 years.
17. Active inflammatory gastrointestinal disease, malabsorption syndrome, chronic diarrhea, symptomatic diverticular disease or previous gastric resection or lap band.
18. Current use or anticipated need for food or drugs prohibited.
19. Patients presenting with abnormal Left Ventricular Ejection Fraction (LVEF) by echocardiogram or Multi-Gated Acquisition Scan (MUGA) according to institutional lower limits.
20. Have a known or suspected hypersensitivity to brigatinib, carboplatin or pemetrexed or their excipients.
21. Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.
22. Received systemic treatment with strong cytochrome p-450 (cyp)3a inhibitors, strong cyp3a inducers, or moderate cyp3a inducers within 14 days before enrolment.

Primary outcomes:
measure: Progression Free Survival at 12 months, investigator assessment
timeFrame: 12 months
Secondary outcomes:
measure: Progression Free Survival (PFS) at 12 months, independent review
timeFrame: 12 months
measure: Overall Response Rate (ORR)
timeFrame: At progression, after an average of 2 years
measure: Incidence, nature, and severity of adverse events
timeFrame: From time of informed consent through treatment period and up to 30 days post last dose of study treatment (average of 2 years)
measure: Impact of ALK fusion detection in ctDNA on 12-months progression free survival
timeFrame: 12 months
measure: Impact of ALK fusion detection in ctDNA on overall response rate
timeFrame: At progression, after an average of 2 years
measure: Intracranial overall response rate
timeFrame: At progression, after an average of 2 years
measure: Intracranial progression free survival at 12 months
timeFrame: 12 months
measure: Time until definitive health related quality of life score deterioration
timeFrame: From enrollment to score deterioration, a period of up to 2 years
measure: Duration of response (DOR)
timeFrame: At progression, after an average of 2 years.
measure: Disease control rate (DCR)
timeFrame: At progression, after an average of 2 years.
measure: Overall survival (OS)
timeFrame: At death or lost to follow up, up to 5 years after randomisation.
measure: Duration of intracranial response (CNS DOR)
timeFrame: At progression, after an average of 2 years.
measure: Intracranial disease control rate (CNS DCR)
timeFrame: At progression, after an average of 2 years.
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU d'Angers
city: Besançon
country: France
facility: CHU Besançon - Hôpital J. MINJOZ
city: Boulogne
country: France
facility: Hôpital APHP Ambroise Paré
city: Bron
country: France
facility: Hospices Civils de Lyon - Hôpital Louis Pradel
city: Caen
country: France
facility: CHU Côte de Nacre
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal de Créteil
city: Dijon
country: France
facility: Centre Georges-François Leclerc
city: Grenoble
country: France
facility: Chu Grenoble
city: Lille
country: France
facility: Hôpital Calmette
city: Limoges
country: France
facility: CHU Dupuytren
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Marseille
country: France
facility: Hôpital Nord
city: Montpellier
country: France
facility: Hôpital Arnaud de Villeneuve
city: Mulhouse
country: France
facility: Centre Hospitalier
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Hôpital BICHAT
city: Paris
country: France
facility: Hôpital TENON
city: Pessac
country: France
facility: Hôpital Haut-Lévèque
city: Rennes
country: France
facility: CHU Rennes - Hôpital Pontchaillou
city: Rouen
country: France
facility: Hôpital Charles Nicolle
city: Saint-Herblain
country: France
facility: Institut de Cancérologie de l'Ouest - René Gauducheau
city: Saint-Quentin
country: France
facility: Centre Hospitalier
city: Strasbourg
country: France
facility: Nouvel Hôpital Civil - Hôpitaux Universitaires de Strasbourg
city: Toulon
country: France
facility: HIA Sainte-Anne
city: Toulouse
country: France
facility: Hôpital Larrey (CHU)
city: Vandœuvre-lès-Nancy
country: France
facility: Centre Alexis Vautrin
city: Villefranche-sur-Saône
country: France
facility: Centre Hospitalier de Villefranche-sur-Saône
Study officials:
affiliation: Hospices Civils de Lyon - Hôpital Louis Pradel
name: Michael DURUISSEAUX, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Leon Berard
name: Aurélie SWALDUZ, Dr
role: PRINCIPAL_INVESTIGATOR
References: