advanced ROS1-positive non-small cell lung cancer MedDRA version: 21.1 Level: PT Classification code 10029521 Term: Non-small cell lung cancer stage IIIB System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10029522 Term: Non-small cell lung cancer stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
IFCT
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Signed Written Informed Consent 2.Patients with histologically or cytologically confirmed diagnosis of locally advanced not eligible to a local treatment or metastatic NSCLC (Stage IIIB, IIIC or IV accordingly to 8th classification TNM, UICC 2015) that carries an ROS1 rearrangement, as determined by the molecular biology platform of the investigator by FISH assay or by Immunohistochemistry (IHC), or Next Generation Sequencing (NGS) or RNA sequencing approach. 3.Disease Status Requirements: Disease progression meeting RECISTv1.1 after one prior line of treatment with crizotinib or entrectinib (+ one line of chemotherapy with or without immunotherapy before TKI treatment). 4.Tumor Requirements: All Patients must have at least one measurable target lesion according to RECIST v1.1. In addition, patients with asymptomatic and neurologically stable CNS metastases (including patients controlled with stable or decreasing steroid use within the last week prior to study entry) will be eligible. The brain metastases may be newly diagnosed after disease progression with crizotinib or entrectinib or be present as progressive disease after surgery, whole brain radiotherapy or stereotactic radiosurgery (see Exclusion Criterion for the lapsed time period required between the end of radiotherapy and study entry). Patients who have leptomeningeal disease (LM) or carcinomatous meningitis (CM) will be eligible if the LM/CM is visualized on MRI or if documented baseline cerebral spinal fluid (CSF) positive cytology is available and asymptomatic and neurologically stable (including patients controlled with stable or decreasing steroid use within the last week prior to study entry). 5.Tumor Sample Requirement: Tumour biopsy sampling on fresh tissue (FFPE blocks required) obtained after progression on crizotinib or entrectinib. Tumour biopsy should be exploitable for molecular analysis. If the tumour biopsy is not exploitable, the inclusion will be allowed if two blood samples are provided for tumoral cfDNA analysis. The Sponsor will monitor a posteriori the exploitability of provided tumour biopsies and will investigate the impossibility to perform or repeat tissue tumor sampling. 6.Age =18 years. 7.Life expectancy of at least 12 weeks, in the opinion of the Investigator. 8.Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 2 9.Adequate Bone Marrow Function, including: Absolute Neutrophil Count (ANC) =1.5 x 109/L; Platelets =100 x 109/L; Hemoglobin =9 g/dL. 10.Adequate Pancreatic Function, including: Serum lipase =1.5 x ULN. 11.Adequate Renal Function, including: Serum creatinine =1.5 x ULN or estimated creatinine clearance =45 mL/min as calculated using the method standard for the institution. 12.Adequate Liver Function, including: Total serum bilirubin =1.5 x ULN; Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) =2.5 x ULN; =5.0 x ULN if there is liver metastases involvement. 13.Participants must have recovered from treatment toxicities to CTCAE Grade = 1 (for participants who have developed interstitial lung disease [ILD], they must have fully recovered) except for AEs that in the investigator’ judgment do not constitute a safety risk for the patient. 14.Participants must have recovered from effects of any major surgery, or significant traumatic injury, at least 35 days before the first dose of lorlatinib 15.For all females of childbearing potential, a negative pregnancy test must be obtained within the screening per
Exclusion criteria
Exclusion criteria: 1.Participants with disease progression on front-line treatment with TKI i.e. crizotinib or entrectinib limited to CNS or one non-CNS site (oligometastasis) and eligible to a local ablative treatment (surgery or stereotaxic radiotherapy). 2.Histological transformation with neuro-endocrine differentiation. 3.Spinal cord compression is excluded unless the patient demonstrates good pain control attained through therapy and there is stabilization or recovery of neurological function for the 4 weeks prior to study entry. 4.Patients with symptomatic and neurologically instable CNS metastases or leptomeningeal metastasis (including patients that require increasing doses of steroids within one week prior to Day 0 of screening phase and during the screening phase to manage CNS symptoms). 5.Major surgery within 35 days of study entry. Minor surgical procedures (eg, port insertion, mediastinoscopy, surgical procedure for re-sampling) are not excluded, but sufficient time at investigator discretion should have passed for wound healing. 6.Radiation therapy within 2 weeks of study entry (except palliative to relieve bone pain). Palliative radiation (=15 fractions) must have been completed at least 48 hours prior to 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. 7.Prior therapy with an antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including, but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4. 8.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. 9.Clinically significant cardiovascular disease (that is, active or 220 msec. 10.Ongoing cardiac dysrhythmias of NCI CTCAE Grade =2, uncontrolled atrial fibrillation of any grade, bradycardia defined as 470 msec, or congenital long QT syndrome. 11.Patients with predisposing characteristics for acute pancreatitis according to investigator judgment (eg, uncontrolled hyperglycemia, current gallstone disease, alcoholism [more than 4 drinks on any day or 14 drinks per week where 1 drink is defined as the alcoholic beverage containing approximately 14 grams of pure alcohol, eg, 12 fl oz/360 mL regular beer or 5 fl oz/150 mL of wine] in the last month. 12.History of bilateral or Grade 3 or 4 interstitial fibrosis or diffuse interstitial lung disease. Patients with history of prior radiation pneumonitis are not excluded. 13.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 en
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of lorlatinib in molecular subgroups of patients with advanced ROS1 positive NSCLC after molecular analysis of disease progression on first-line treatment with crizotinib or entrectinib. ;Secondary Objective: To evaluate the efficacy of lorlatinib as measured by PFS, TTP, DCR, DOR, OS (investigator-assessed) and ORR as assessed by independent reviewer. To evaluate the efficacy of lorlatinib as measured by PFS, OS (investigator-assessed) and ORR by investigator in the 3 different molecular subgroups. To evaluate the efficacy of lorlatinib on CNS (Central Nervous System) disease. To evaluate the safety and tolerability of lorlatinib. To evaluate the efficacy of lorlatinib according to the type of TKI prescribed in first line either crizotinib or entrectinib To evaluate the quality of life ;Primary end point(s): The primary endpoint is the objective response rate (ORR) at 8 weeks (confirmation needed at 16 weeks). Objective response rate will be assessed by the investigators. ORR is defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR) as per RECIST v1.1 criteria. The analysis of the primary efficacy endpoint will be conducted in FAS population. It will be presented to its associated 95% confidence interval. ;Timepoint(s) of evaluation of this end point: Time from enrollment until 8 weeks after treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Overall Response Rate (ORR) at 8 weeks, which is defined as the percentage of subjects with a confirmed at 16 weeks complete response (CR) or partial response (PR) by independent reviewer committee (IRC) as per RECIST v1.1 criteria. 2. Progression Free Survival (PFS). 3. Time to progression (TTP) 4. Disease control rate (DCR) at 8 weeks (confirmation needed at 16 weeks) 5. Duration of response (DOR) defined as the time from the date of the first documented response (CR or PR) to the earliest date of disease progression, as determined by Investigator review and by independent reviewer of radiographic disease assessments per RECIST v1.1, or death due to any cause. 6. Overall survival (OS). OS will be assessed at 12 months and at 24 months. 7. CNS Objective response rate (C-ORR) estimated in patients with measurable CNS metastases at baseline. 8. CNS duration of response (C-DOR) estimated in patients with measurable CNS metastases at baseline. 9. Time to CNS progression in patients without brain metastases at baseline. 10. Change from baseline of EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) at all scheduled time points.;Timepoint(s) of evaluation of this end point: 1. Time from enrollment until 8 weeks after treatment 2. Time between the date of inclusion and the first date of documented disease progression (according to RECIST v1.1) or death (from any cause). 3. Time from the date of inclusion to the earliest date of disease progression (according to RECIST v1.1.) 4. Proportion of patients have achieved a confirmed best overall response of CR, PR or SD (according to RECIST v1.1.) 5. Time from the date of the first documented response (CR or PR) to the earliest date of disease progression or death due to any cause. 6. Time from the date of first dose of study drug to the date of death due to any cause. 7 until 10. Approximately 1 year | — |
Countries
France
Contacts
Public ContactContact
IFCT
Outcome results
None listed