'Non-small cell lung cancer' and 'lung cancer'
Conditions
Interventions
Eligible patients will receive lorlatinib administered orally at the daily dose
of 100 mg (four tablets of 25 mg).
Sponsors
European Organisation for Research in Treatment of Cancer (EORTC)
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: • Age >=18 years old • Histologically or cytologically confirmed diagnosis of NSCLC with ALK rearrangement, assessed by FISH assay (Abbott Molecular Inc) or by Immunohistochemistry (IHC) (Ventana Inc) approved by FDA. Liquid biopsy is an acceptable method for the diagnosis of ALK rearrangement in case there is no leftover biopsy/cytological specimen. • Stage III (not eligible for local therapy) or stage IV (according to UICC TNM staging v8.0) • WHO performance status (WHO PS) of 0-2 • Previous treatment with at least one 2nd-generation ALK inhibitor. The 2nd-generation ALK TKI (including but not limited ceritinib, alectinib, brigatinib) should be the latest therapy. • Progressive disease during treatment with 2nd-generation ALK inhibitor prior to the administration of lorlatinib • Measurable disease according to RECIST version 1.1 by computed tomography (CT) or magnetic resonance imaging (MRI) of Chest/Abdomen/Pelvis and brain MRI performed within 28 days prior to study enrolment • Collection of blood sample for cohort allocation. Note: if blood sample cannot be collected (patient's refusal or any other reason), patient will not be eligible for this study • Treated and/or untreated brain or leptomeningeal metastases will be allowed if asymptomatic and/or controlled (stable dose of steroids 7 days before the beginning of lorlatinib treatment) • Adequate bone marrow and organ function • Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 3 days prior to the first dose of lorlatinib • Women of childbearing potential must use a highly effective non-hormonal method of contraception during the study treatment period and for at least 35 days after the last dose of lorlatinib. If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method. • Male patients with female partners of childbearing potential must use effective contraception, including a condom, and male patients with pregnant partners must use condoms, during the study treatment period and for at least 14 weeks after the last dose of lorlatinib. • Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 7 days after the last dose of lorlatinib • Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up • Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations Enrolment in optional prospective sub-study: • The patient has received at least 6 months of second generation ALK-TKI therapy (if crizotinib-pretreated) OR • The patient has received at least 12 months of second generation ALK-TKI therapy (if crizotinib-naïve) • Patient is willing and able to comply with the sub-study requirements including scheduled visits and examinations including follow up • Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations
Exclusion criteria
Exclusion criteria: • Spinal cord compression. Patients who received adequate treatment (surgery or radiotherapy) and has adequate control of the pain and stabilization and/or recovery of neurological symptoms/function for the 3 weeks prior to study entry are allowed • Major surgery within 4 weeks prior to study enrolment. Complete wound healing from major surgery must have occurred 3 weeks before the first dose of study treatment. • Minor surgical procedures (including port insertion, uncomplicated tooth extractions) without complete wound healing at the latest 1 week before the first dose of study treatment. • Radiation therapy within 2 weeks of study entry • Any systemic anti-cancer therapy or an investigational drug treatment completed within 7 days prior to start lorlatinib (in case of clinically meaningful risk of tumour flare according to investigator's assessment, discussion with EORTC is required before enrolment) • Any unresolved toxicities from prior systemic therapy • Active infection requiring therapy • Known active hepatitis B (HBV) or hepatitis C (HCV). • Known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related illness • Any of the following cardiac criteria: • Clinically significant cardiovascular disease (that is active or occurred = II), second-degree or third-degree AV block (unless paced) or any AV block with PR >220 msec • Ongoing cardiac dysrhythmias of NCI CTCAE Grade >=2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as long-distance runners, etc.) • Abnormal Left Ventricular Ejection Fraction (LVEF): LVEF <50% (assessed by MUGA or ECHO) • History of interstitial lung disease (ILD) or history of (non-infectious) pneumonitis that required oral or IV steroids (other than COPD exacerbation) or current pneumonitis or current evidence of interstitial lung disease. Patients with history of prior radiation pneumonitis are not excluded • Any serious or uncontrolled acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behaviour, chronic alcoholism, drug addiction, 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 not eligible for this study • Hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption • Inability to swallow and/or retain oral tablets or impaired gastrointestinal function or disease that may significantly alter the absorption of lorlatinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption) • Evidence of active hematologic or primary solid tumour malignancy (other than completely resected non-melanoma skin cancer, successfully treated in situ carcinoma for example in situ cervical cancer, completely resected and successfully treated papillary thyroid c
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Objectives of the ALKALINE phase II trial: Primary objective: to assess the progression-free survival rate at 12 months (PFSR12) to lorlatinib in ALK positive advanced NSCLC patients, who progressed on second generation ALK-TKI with the presence of ALK resistance mutations on blood (liquid biopsies) by Independent Central Review (ICR) assessment per RECIST v1.1. Objectives of the optional prospective sub-study: Primary objective: to assess the time between the emergence of ALK resistance mutation during response to second generation ALK TKI on blood (liquid biopsies) and radiological PD by investigator per RECIST v1.1 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary objectives: To evaluate: • Activity as measured by Overall Response Rate (ORR), Central nervous system response rate (CNS ORR), Duration of the response (DOR), Progression-Free Survival (PFS), Overall Survival (OS) • Toxicity of lorlatinib in patients previously treated with 2nd generation ALK TKI • Patient reported outcomes (PRO) of global health-related quality of life (HRQOL), functioning and the impact of lorlatinib on disease/treatment-related symptoms of lung cancer. Exploratory objectives: To describe: • Prevalence of ALK and other molecular alterations in blood ctDNA in patients previously treated with 2nd generation ALK TKI, and activity (as measured by PFSR12, ORR, CNS, ORR, PFS, OS) of lorlatinib in patients previously treated with 2nd generation ALK TKI • Concordance between de novo tumour tissue biopsy and blood at the same time point in patients with available tissue biopsy • In cohort B and C: to explore the PFS rate at 5 months in cohort B and PFS rate at 8 months in cohort C and established the corresponding confidence intervals Objectives of the optional prospective sub-study: Secondary objectives: To assess: • The time between the emergence of new other non-ALK resistance mutations to ALK inhibition during response to second generation ALK TKI on blood (liquid biopsies) and radiological Progressive Disease (PD) by investigator per RECIST v1.1 • The evolution of complexity of *molecular PD* before PD by RECIST v1.1 • Relevance of liquid biopsy monitoring for clinical outcomes | — |
Countries
Netherlands
Outcome results
None listed