Clinical Trials /

Lorlatinib After Failure of First-line Second-generation ALK Kinase Inhibitor in Patients With Advanced ALK-positive Non-small Cell Lung Cancer

NCT04111705

Description:

Crizotinib is a first-generation ALK tyrosine kinase inhibitor (ITK-ALK). It is the standard first-line treatment for patients with advanced NSCLC with ALK gene rearrangement. Alectinib, ceritinib and brigatinib are second-generation ITK-ALK. They have been shown to be effective in the first line of treatment in randomized trials. Alectinib has shown superiority to crizotinib as the first line of treatment in three randomized therapeutic trials, positioning this ITK-ALK as the treatment of choice in first-line treatment. Despite the effectiveness of these new treatments, all patients will virtually experience a relapse. There is no data on second-generation TKI-ALK resistance mechanisms when given as first-line treatment and the best therapeutic strategy for progression is undefined.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Lorlatinib After Failure of First-line Second-generation ALK Kinase Inhibitor in Patients With Advanced ALK-positive Non-small Cell Lung Cancer
  • Official Title: A Phase II Non-randomized, Single Group Assignment, Open-label, Multicenter Study of Efficacy and Safety of lORlatinib (PF-06463922) Monotherapy After Failure of First-line Second-generation ALK Kinase Inhibitor in Patients With Advanced ALK-positive Non-small Cell Lung cancEr

Clinical Trial IDs

  • ORG STUDY ID: IFCT-1902
  • NCT ID: NCT04111705

Conditions

  • Non Small Cell Lung Cancer Metastatic

Interventions

DrugSynonymsArms
LorlatinibLorlatinib

Purpose

Crizotinib is a first-generation ALK tyrosine kinase inhibitor (ITK-ALK). It is the standard first-line treatment for patients with advanced NSCLC with ALK gene rearrangement. Alectinib, ceritinib and brigatinib are second-generation ITK-ALK. They have been shown to be effective in the first line of treatment in randomized trials. Alectinib has shown superiority to crizotinib as the first line of treatment in three randomized therapeutic trials, positioning this ITK-ALK as the treatment of choice in first-line treatment. Despite the effectiveness of these new treatments, all patients will virtually experience a relapse. There is no data on second-generation TKI-ALK resistance mechanisms when given as first-line treatment and the best therapeutic strategy for progression is undefined.

Trial Arms

NameTypeDescriptionInterventions
LorlatinibExperimental100 mg once daily
  • Lorlatinib

Eligibility 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 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 period. A patient is of childbearing potential if, in the opinion
             of the investigator, she is biologically capable of having children and is sexually
             active. Additionally, all females of childbearing potential must provide an agreement
             to remain abstinent or use two adequate methods of contraception, including at least
             one method with a failure rate of < 1% per year, during the treatment period and for
             at least 90 days after the last dose of study drug.

         16. For men: agreement to remain abstinent or use a barrier method of contraception (e.g.,
             condom) during the treatment period and for at least 90 days after the last dose of
             study drug and agreement to refrain from donating sperm during this same period.

         17. Evidence of a personally signed and dated informed consent document indicating that
             the patient has been informed of all pertinent aspects of the study.

         18. Willingness and ability to comply with the study scheduled visits, treatment plans,
             laboratory tests and other procedure.

         19. Participant has national health insurance coverage.

         20. Washout period: if previous progression on ALK-TKI: 7 days from last dose of the drug.
             The washout period may be shortened to 2 days at investigator discretion.

        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 <3 months prior to
             enrollment): 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.

         11. 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, athletic patients etc.), machine-read ECG with QTc >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 interpretation of
             study results and, in the judgment of the investigator, would make the patient
             inappropriate for entry into this study.

         15. 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.

         16. Active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic
             diverticular disease or previous gastric resection or lap band.

         17. Current use or anticipated need for food or drugs prohibited (see chapter 8.9.2 for
             details).

         18. Patients presenting with abnormal Left Ventricular Ejection Fraction (LVEF) by
             echocardiogram or Multi-Gated Acquisition Scan (MUGA) according to institutional lower
             limits.

         19. Breastfeeding female patients (including patients who intend to interrupt
             breastfeeding).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The primary endpoint is the Objective Response Rate (ORR) at 6 weeks.
Time Frame:Time from enrollment until 6 weeks after treatment.
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Overall Response Rate (ORR) assessed by an independent review committee (IRC).
Time Frame:Time from enrollment until 6 weeks after treatment
Safety Issue:
Description:Response according to RECIST v.1.1 as assessed by an independent review committee (IRC)
Measure:PFS in overall population and in cohort A, B and C.
Time Frame:Approximately 8 months after randomization
Safety Issue:
Description:PFS is defined as the time between the date of inclusion and the first date of documented disease progression according to RECIST 1.1 as assessed by the investigator and the IRC or death from any cause during the study, whichever occurs first.
Measure:Disease Control Rate (DCR) in overall population and in cohort A, B and C.
Time Frame:Percentage of participants with CR, PR, or stable disease (SD) for at least twelve weeks (according to RECIST 1.1)
Safety Issue:
Description:DCR is defined as the percentage of participants with CR, PR, or stable disease (SD) for at least twelve weeks, according to RECIST 1.1.
Measure:Duration of Response (DOR) in overall population and in cohort A, B and C.
Time Frame:Approximately 1 year
Safety Issue:
Description:DOR is defined as the time from the first occurrence of an objective response (CR or PR), based on RECIST 1.1 to first documented disease progression or death assessed by an IRC.
Measure:Overall Survival .
Time Frame:Approximately 1 year
Safety Issue:
Description:OS is defined as the time from the first lorlatinib dose and death from any cause during the study. OS will be assessed at 6 months, at 12 months and at 18 months.
Measure:Time to Tumor Response (TTR).
Time Frame:Approximately 1 year
Safety Issue:
Description:TTR is defined as the time from the first lorlatinib dose and the first occurrence of an objective response (CR or PR) based on RECIST 1.1 and assessed by an IRC.
Measure:Central Nervous System (CNS) ORR.
Time Frame:Approximately 1 year
Safety Issue:
Description:CNS ORR is defined as the proportion of patients achieving an objective response (complete response (CR) or partial response (PR)) of the baseline measurable and non-measurable CNS disease according to RECIST 1.1 and Revised Assessment in Neuro Oncology (RANO) criteria, as assessed by an IRC.
Measure:CNS PFS.
Time Frame:Approximately 1 year
Safety Issue:
Description:CNS PFS is defined as the proportion of patients achieving an objective response (complete response (CR) or partial response (PR)) of the baseline measurable and non-measurable CNS disease according to RECIST 1.1 and Revised Assessment in Neuro Oncology (RANO) criteria, as assessed by an IRC
Measure:CNS DOR.
Time Frame:Approximately 1 year
Safety Issue:
Description:CNS DOR is defined as the time from the first occurrence of an objective response (CR or PR) of the baseline measurable and non-measurable CNS disease for at least twelve weeks, according to RECIST 1.1. and Revised Assessment in Neuro Oncology (RANO) criteria, as assessed by an IRC.
Measure:CNS TTR.
Time Frame:Approximately 1 year
Safety Issue:
Description:CNS TTR is defined as the time from the first lorlatinib dose and the first occurrence of an objective response (CR or PR) of the baseline measurable and non-measurable CNS disease, according to RECIST 1.1. and Revised Assessment in Neuro Oncology (RANO) criteria, as assessed by an IRC.
Measure:Best ORR and PFS depending on prior brigatinib or alectinib treatment
Time Frame:Approximately 2 year
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Intergroupe Francophone de Cancerologie Thoracique

Trial Keywords

  • IFCT
  • ORAKLE
  • NSCLC
  • ALK-positive
  • monotherapy

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