advanced ALK-positive non-small cell Lung cancer MedDRA version: 20.0 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: 20.0 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: ? 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 with histologically or cytologically confirmed locally advanced not eligible to a local treatment or metastatic NSCLC (Stage IIIB or IV accordingly to 8th classification TNM, UICC 2015) that carries an ALK 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 first-line alectinib or brigatinib only. No prior chemotherapy is allowed in the metastatic disease setting. 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 alectinib or brigatinib 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) at time of progression on first-line TKI is mandatory. 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 =60 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 inv
Exclusion criteria
Exclusion criteria: 1. Patients who experienced a clinical benefit of less than 6 months with front-line alectinib or brigatinib. 2. Participants with disease progression on front-line treatment with 2G ALK-TKI i.e. brigatinib or alectinib limited to CNS or one non-CNS site (oligometastasis) and eligible to a local ablative treatment (surgery or stereotaxic radiotherapy). 3. Transdifferentiation into small cell lung cancer. 4. 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. 5. 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). 6. 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. 7. 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. 8. 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. 9. 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. 10. Clinically significant cardiovascular disease (that is, active or 220 msec. 11. Ongoing cardiac dysrhythmias of NCI CTCAE Grade =2, uncontrolled atrial fibrillation of any grade, bradycardia defined as 470 msec, or congenital long QT syndrome. 12. 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. 13. 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. 14. 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 inte
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of lorlatinib in patients with advanced ALK-positive NSCLC after disease progression on first-line treatment with brigatinib or alectinib.;Secondary Objective: To evaluate molecular mechanisms of resistance to front-line brigatinib or alectinib using NGS testing and RNA sequencing in tumoral biopsy and liquid biopsy sampling. To evaluate the efficacy of lorlatinib according to molecular mechanisms of resistance to front-line brigatinib or alectinib. To evaluate the efficacy of lorlatinib on CNS disease. To evaluate the safety and tolerability of lorlatinib.;Primary end point(s): The primary endpoint is the Objective Response Rate (ORR) at 6 weeks. ORR is defined as the proportion of patients achieving an objective response (complete response (CR) or partial response (PR)) according to Response Evaluation Criteria in Solid Tumors (RECIST), v.1.1 (RECIST 1.1), as assessed by the investigators.;Timepoint(s) of evaluation of this end point: Time from enrollment until 6 weeks after treatment. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Overall Response Rate (ORR) at 6 weeks according to RECIST v.1.1 as assessed by an independent review committee (IRC). 2. Overall Response Rate (ORR) at 6 weeks according to RECIST v.1.1 as assessed by an independent review committee (IRC) in the cohort A, B and C 3. PFS in overall population and in cohort A, B and C. 4. Disease Control Rate (DCR) in overall population and in cohort A, B and C. 5. Duration of Response (DOR) in overall population and in cohort A, B and C. 6. Overall Survival 7. Time to Tumor Response (TTR). 8. Central Nervous System (CNS) ORR. 9. CNS PFS. 10. CNS DOR. 11. CNS TTR. 12. Best ORR and PFS depending on prior brigatinib or alectinib treatment 13. Description of post-discontinuation treatments;Timepoint(s) of evaluation of this end point: 1&2: Time from enrollment until 6 weeks after treatment 3: Time between the date of inclusion and the first date of documented disease progression (according to RECIST 1.1) or date of death (from any cause). Patients who did not progress or not die will be censored on the date of their last tumor assessment, i.e. on the last date that we really know that the patient was progression free. 4: % of participants with CR, PR, or stable disease (SD) for at least twelve weeks (according to RECIST 1.1) 5: Time from the first occurrence of an objective response (CR or PR) 6: Time from the first lorlatinib dose and death (any cause) 7 until 13: : Approximately 1 year | — |
Countries
France
Contacts
Public ContactContact
IFCT
Outcome results
None listed