Activity of Lorlatinib based on ALK resistance mutations on blood in ALK positive NSCLC patients previously treated with 2nd generation ALK inhibitor
- Conditions
- on-small cell lung cancerMedDRA version: 21.1Level: PTClassification code 10061873Term: Non-small cell lung cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2019-003862-41-NO
- Lead Sponsor
- European Organisation for Research and Treatment of Cancer
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 68
• Age = 18 years old
• Histologically or cytologically confirmed diagnosis of NSCLC with ALK rearrangement, assessed by FISH assay or by Immunohistochemistry 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 of 0-2
• Previous treatment with at least one 2nd-generation ALK inhibitor. The 2nd-generation ALK TKI (including but not limited to 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 or magnetic resonance imaging (MRI) of Chest/Abdomen/Pelvis and brain MRI performed within 28 days prior to study enrolment
Note: At least one measurable extracranial lesion is required.
• Collection of blood sample for cohort allocation.
• 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 defined as following:
• Absolute Neutrophil Count (ANC) = 1.5 x 109/L;
• Platelets = 100 x 109/L;
• Hemoglobin = 9 g/dL;
• Serum total amylase = 1.5 ULN;
• Serum lipase =1.5 ULN;
• Serum creatinine = 1.5 x ULN or estimated creatinine clearance > 30 mL/min as calculated using the MDRD formula for subject with serum creatinine levels > 1.5x institutional ULN;
• Total serum bilirubin = 1.5 x ULN or direct bilirubin = ULN for patients with total bilirubin levels > 1.5 x ULN; for patients with Gilbert's disease total bilirubin may be > 1.5 x ULN, however direct bilirubin must be normal;
• Aspartate Aminotransferase (SGOT) and Alanine Aminotransferase (SGPT) = 2.5 x ULN (=5.0 x ULN if there is liver metastases involvement);
• Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 3 days prior to enrolment.
• 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
Patient selection criteria for the optional prospective sub-study:
In the optional prospective sub-study, the patient could be enrolled during the ongoing response to second-generation ALK inhibitor if the following conditions are fulfilled:
• Age = 18 years old
• The patient has receive
• 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 reatment.
• Radiation therapy within 2 weeks of study entry. Exception are:
• Palliative radiation (=10 fractions) is allowed if completed at least 48 hours prior to study enrolment
• Stereotactic or small field brain irradiation is allowed if completed at least 2 weeks prior to study enrolment
• Whole brain radiation is allowed if completed at least 4 weeks prior to study enrolment
• 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, including haematological toxicities, greater than CTCAE v5.0 grade 2 at the time of study enrolment
• Active infection requiring therapy
• Known active hepatitis B (HBV) or hepatitis C (HCV). Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA result greater than the lower limits of detection of the assay
• 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 <3 months prior to enrolment): cerebral vascular accident/stroke, myocardial infarction, unstable angina,
congestive heart failure (New York Heart Association Classification Class = 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 longdistance 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 dministration 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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: The main aim of this trial is to assess the progression-free survival rate at 12 months (PFSR12) to lorlatinib in ALK positive advanced NSCLC patients, who progressed on second generation ALKTKI with the presence of ALK resistance mutations on blood (liquid biopsies) by Independent Central Review (ICR) assessment per RECIST v1.1;Secondary Objective: To evaluate:<br>• Activity as measured by ORR, Central nervous system response rate (CNS ORR), Duration of the response (DOR), PFS, OS<br>• Toxicity of lorlatinib in patients previously treated with 2nd generation ALK TKI<br>• 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<br>cancer.;Primary end point(s): PFS Rate at 12 months;Timepoint(s) of evaluation of this end point: disease evaluation at 52 weeks (+/- 2 weeks) is required for all patients who are still alive and without progression
- Secondary Outcome Measures
Name Time Method Secondary end point(s): Overall Survival (OS).<br>• Progression Free Survival (PFS).<br>• Overall Response Rate (ORR).<br>• Duration of Response (DOR).<br>• CNS Overall Response Rate (CNS-ORR)<br>• Patient Reported Outcomes (PROs): as assessed by EORTC QLQ- C30, EORTC QLQ-LC13 and study specific Item List.<br>• Safety profile according to NCI CTCAE v 5.0;Timepoint(s) of evaluation of this end point: Follow the primary endpoint