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

NCT04111705 | Completed Phase 2

• 1 other identifier: IFCT-1902
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 32

Brief Summary

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.

Conditions

Non Small Cell Lung Cancer Metastatic

Keywords

IFCT; ORAKLE; NSCLC; ALK-positive; monotherapy

Outcome Measures

Primary Outcomes (1)

• 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.

  Time from enrollment until 6 weeks after treatment.

Secondary Outcomes (11)

• Overall Response Rate (ORR) assessed by an independent review committee (IRC).

  Time from enrollment until 6 weeks after treatment

• PFS in overall population and in cohort A, B and C.

  Approximately 8 months after randomization

• Disease Control Rate (DCR) in overall population and in cohort A, B and C.

  Percentage of participants with CR, PR, or stable disease (SD) for at least twelve weeks (according to RECIST 1.1)

• Duration of Response (DOR) in overall population and in cohort A, B and C.

  Approximately 1 year

• Overall Survival .

  Approximately 1 year

Study Arms (1)

Lorlatinib

EXPERIMENTAL

100 mg once daily

Drug: Lorlatinib

Interventions

Lorlatinib DRUG

100 mg once daily

Lorlatinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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 .
• 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.
• Age ≥18 years.
• Life expectancy of at least 12 weeks, in the opinion of the Investigator.
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2
• Adequate Bone Marrow Function, including:
• Absolute Neutrophil Count (ANC) ≥1.5 x 109/L;
• Platelets ≥100 x 109/L;
• Hemoglobin ≥9 g/dL.
• Adequate Pancreatic Function, including:
• Serum lipase ≤1.5 x ULN.
• Adequate Renal Function, including:

You may not qualify if:

• Patients who experienced a clinical benefit of less than 6 months with front-line alectinib or brigatinib.
• 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).
• Transdifferentiation into small cell lung cancer.
• 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.
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Sponsors & Collaborators

• Intergroupe Francophone de Cancerologie Thoracique: lead

Study Sites (32)

Angers - CHU

Angers, France

Location

Annecy - CH

Annecy, France

Location

Bayonne - CH

Bayonne, France

Location

Besançon - CHU

Besançon, France

Location

Bordeaux - CHU Hôpital Haut-Lévèque

Bordeaux, France

Location

Boulogne - Ambroise Paré

Boulogne-Billancourt, France

Location

Caen - CHU Côte de Nacre

Caen, 14000, France

Location

Colmar - CH

Colmar, France

Location

Créteil - CHI

Créteil, France

Location

Dijon - CRLCC

Dijon, France

Location

Grenoble - CHU

Grenoble, France

Location

Le Mans - CHG

Le Mans, France

Location

Lille - Hôpital Calmette

Lille, France

Location

Lyon - CRLCC

Lyon, France

Location

Marseille - AP-HM Hôpital Nord

Marseille, France

Location

Marseille - Institut Paoli Calmette

Marseille, France

Location

Montpellier - CHU

Montpellier, France

Location

Montpellier - Clinique

Montpellier, France

Location

Mulhouse - GHRMSA

Mulhouse, France

Location

Nantes - CRLCC

Nantes, France

Location

Orléans - CHR

Orléans, 45000, France

Location

Paris - APHP - Hopital Tenon

Paris, 75020, France

Location

Paris - APHP Bichat

Paris, France

Location

Paris - Curie

Paris, France

Location

Paris - Hôpital Cochin

Paris, France

Location

Lyon - URCOT

Pierre-Bénite, France

Location

Saint Quentin - CH

Saint-Quentin, 02100, France

Location

Strasbourg - Nouvel Hôpital Civil

Strasbourg, France

Location

Suresnes - Hopital Foch

Suresnes, 92151, France

Location

Toulon - CHI

Toulon, 83000, France

Location

Toulouse - CHU

Toulouse, France

Location

Vandoeuvre-lès-Nancy - CRLCC

Vandœuvre-lès-Nancy, France

Location

Related Links

• IFCT website

MeSH Terms

Interventions

lorlatinib

Study Officials

• Michael Duruisseaux

  Lyon - URCOT

  STUDY CHAIR

• Denis Moro-Sibilot

  Grenoble - CHU

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A phase II non-randomized, single group assignment, open-label, multicenter

Study Record Dates

• First Submitted: August 30, 2019
• First Posted: October 1, 2019
• Study Start: August 5, 2020
• Primary Completion: August 11, 2022
• Study Completion: December 15, 2024
• Last Updated: April 1, 2025

Record last verified: 2025-03

Locations

FR (32)