Lorlatinib After Failure of First-line TKI in Patients With Advanced ROS1-positive NSCLC (ALBATROS)

NCT04621188 | Active Not Recruiting Phase 2

• 2 other identifiers: IFCT-20032024-512028-12-00
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 34

Brief Summary

ROS1 rearrangements are present in 1-2% of NSCLC cases and define a distinct molecular subgroup. Like ALK (anaplastic lymphoma kinase) rearrangements in NSCLC, ROS1 fusions confer sensitivity to the inhibitor crizotinib. Crizotinib, which is a tyrosine kinase inhibitor (TKI), has been shown to be effective in tumors in several retrospective studies. Recently the FDA approved entrectinib for the treatment of patients with ROS1-positive metastatic NSCLC. This indication is based on the results of pooled data from several trials. Together, these studies demonstrate the efficacy for entrectinib across a variety of solid tumor types including NSCLC with ROS1 fusion. However, despite the efficacy of crizotinib or entrectinib in ROS1-positive NSCLC, patients will develop resistance to these tyrosine kinase inhibitors. Lorlatinib is a new and potent ROS1 / ALK inhibitor optimized to penetrate the blood-brain barrier. A recent study has investigated the activity of lorlatinib against the crizotinib-resistant ROS1G2032R mutation. In this situation, lorlatinib effectively inhibited the catalytic activity of recombinant ROS1G2032R resulting in an antiproliferative response. Because of its potency as an ROS1 inhibitor and its ability to suppress the resistant ROS1 mutations, lorlatinib could be a treatment of choice in ROS1-positive NSCLC.

Conditions

Non Small Cell Lung Cancer Metastatic

Keywords

IFCT; ALBATROS; NSCLC; ROS1-positive; monotherapy

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR) at 8 weeks by 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.

  8 weeks

Secondary Outcomes (10)

• Overall Response Rate (ORR) at 8 weeks by Independent Reviewer Committee (IRC)

  8 weeks

• Progression Free Survival (PFS)

  Up to 24 months

• Time to progression (TTP)

  Up to 24 months

• Disease control rate (DCR) at 8 weeks weeks)

  8 weeks

• Duration of response (DOR) first documented response (CR or PR) to the earliest date of disease progression, or death due to any cause.

  Up to 24 months

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 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.
• 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).
• Note: patient with disease progression after treatment with another ROS1-TKI may still be eligible upon discussion with IFCT.
• 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: Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥45 mL/min as calculated using the method standard for the institution.
• 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.
• 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.
• Participants must have recovered from effects of any major surgery, or significant traumatic injury, at least 35 days before the first dose of lorlatinib
• 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.
• For men: agreement to remain abstinent or use an effective method of contraception (e.g., condom) during the treatment period and for at least 14 weeks after the last dose of study drug and agreement to refrain from donating sperm during this same period.

You may not qualify if:

• Participants with disease progression on front-line treatment with TKI i.e. crizotinib or entrectinib limited to CNS or one non-CNS site (oligo-metastasis) and eligible to a local ablative treatment (surgery or stereotaxic radiotherapy).
• Histological transformation with neuro-endocrine differentiation.
• 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.
• Active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease or previous gastric resection or lap band.

Sponsors & Collaborators

• Intergroupe Francophone de Cancerologie Thoracique: lead

Study Sites (34)

Centre Hospitalier du Pays d'Aix

Aix-en-Provence, 13616, France

Location

Centre Paul Papin

Angers, 49055, France

Location

Angers - CHU

Angers, France

Location

Annecy - CH

Annecy, France

Location

Antony - Hôpital privé

Antony, France

Location

Avignon - CH

Avignon, France

Location

Centre Hospitalier de la Côte Basque

Bayonne, 64100, France

Location

Bordeaux - CHU

Bordeaux, France

Location

Bordeaux - Institut Bergonie

Bordeaux, France

Location

Bordeaux - Polyclinique

Bordeaux, France

Location

AP-HP Hôpital Ambroise Paré

Boulogne, 92104, France

Location

Caen - CHU Côte de Nacre

Caen, 14000, France

Location

Chauny - CH

Chauny, France

Location

Cholet - CH

Cholet, France

Location

Clermont-Ferrand - CHU

Clermont-Ferrand, France

Location

Colmar - CH

Colmar, France

Location

Centre Hospitalier Intercommunal de Créteil

Créteil, 94000, France

Location

Dijon - CRLCC

Dijon, France

Location

CHRU Grenoble

Grenoble, France

Location

Centre Hospitalier - Pneumologie

Le Mans, 72000, France

Location

Hôpital Calmette

Lille, 59037, France

Location

Centre Léon Bérard

Lyon, 69373, France

Location

Institut Paoli Calmettes

Marseille, 13273, France

Location

GRH Mulhouse Sud-Alsace

Mulhouse, France

Location

AP-HP Hôpital Cochin

Paris, 75014, France

Location

AP-HP Hopital Tenon - Pneumologie

Paris, 75020, France

Location

Lyon - URCOT

Pierre-Bénite, France

Location

Rouen - CHU

Rouen, France

Location

Nouvel Hôpital Civil - Hôpitaux Universitaires de Strasbourg

Strasbourg, 67091, France

Location

Hôpital Foch

Suresnes, 92151, France

Location

CHU Toulouse - Pneumologie

Toulouse, France

Location

CHU Bretonneau

Tours, 37044, France

Location

Valenciennes - Clinique

Valenciennes, France

Location

Vandoeuvre-lès-Nancy - CHU

Vandœuvre-lès-Nancy, France

Location

Related Links

• Description IFCT website

MeSH Terms

Interventions

lorlatinib

Study Officials

• Denis Moro-Sibilot

  Grenoble - CHU

  STUDY CHAIR

• Michael Duruisseaux

  Lyon - URCOT

  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

Study Record Dates

• First Submitted: November 4, 2020
• First Posted: November 9, 2020
• Study Start: March 19, 2021
• Primary Completion: February 26, 2025
• Study Completion (Estimated): February 1, 2027
• Last Updated: September 24, 2025

Record last verified: 2025-09

Locations

FR (34)