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

December 18, 2023 updated by: Intergroupe Francophone de Cancerologie Thoracique

A Phase II Single-group Assignment, Multicenter Study of Efficacy and Safety of Lorlatinib Monotherapy After Failure of First-line Tyrosine Kinase Inhibitor in Patients With Advanced ROS1-positive Non-small Cell Lung Cancer (ALBATROS)

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

84

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Aix-en-Provence, France, 13616
        • Recruiting
        • Centre Hospitalier du Pays d'Aix
        • Contact:
          • Stéphanie Martinez, Dr
          • Phone Number: +33156811045
          • Email: contact@ifct.fr
      • Angers, France
        • Recruiting
        • Angers - CHU
        • Contact:
          • Marie Capucine Willemin, Dr
          • Phone Number: +33156811045
          • Email: contact@ifct.fr
      • Angers, France, 49055
        • Recruiting
        • Centre Paul Papin
        • Contact:
      • Annecy, France
        • Recruiting
        • Annecy - CH
        • Contact:
      • Antony, France
        • Recruiting
        • Antony - Hôpital privé
        • Contact:
      • Avignon, France
        • Recruiting
        • Avignon - CH
        • Contact:
      • Bayonne, France, 64100
        • Recruiting
        • Centre Hospitalier de la Côte Basque
        • Contact:
      • Bordeaux, France
        • Recruiting
        • Bordeaux - Institut Bergonié
        • Contact:
      • Bordeaux, France
        • Recruiting
        • Bordeaux - CHU
        • Contact:
      • Bordeaux, France
        • Recruiting
        • Bordeaux - Polyclinique
        • Contact:
      • Boulogne, France, 92104
        • Recruiting
        • AP-HP Hopital Ambroise Paré
        • Contact:
      • Caen, France, 14000
        • Recruiting
        • Caen - CHU Côte de Nacre
        • Contact:
      • Chauny, France
        • Recruiting
        • Chauny - CH
        • Contact:
      • Cholet, France
        • Recruiting
        • Cholet - CH
        • Contact:
      • Clermont-Ferrand, France
        • Recruiting
        • Clermont-Ferrand - CHU
        • Contact:
      • Colmar, France
        • Recruiting
        • Colmar - CH
        • Contact:
      • Créteil, France, 94000
        • Recruiting
        • Centre hospitalier intercommunal de Créteil
        • Contact:
      • Dijon, France
        • Recruiting
        • Dijon - CRLCC
        • Contact:
      • Grenoble, France
        • Recruiting
        • CHRU Grenoble
        • Contact:
      • Le Mans, France, 72000
        • Recruiting
        • Centre Hospitalier - Pneumologie
        • Contact:
      • Lille, France, 59037
        • Recruiting
        • Hopital Calmette
        • Contact:
      • Lyon, France, 69373
        • Recruiting
        • Centre Léon Bérard
        • Contact:
      • Marseille, France, 13273
        • Recruiting
        • Institut Paoli Calmettes
        • Contact:
      • Marseille, France, 13915
        • Not yet recruiting
        • Marseille Hôpital Nord
        • Contact:
      • Mulhouse, France
        • Recruiting
        • GRH Mulhouse Sud-Alsace
        • Contact:
      • Paris, France, 75020
        • Recruiting
        • AP-HP Hopital Tenon - Pneumologie
        • Contact:
          • Jacques Cadranel, Pr
          • Phone Number: +33.1.56.01.65.31
          • Email: contact@ifct.fr
        • Principal Investigator:
          • Jacques CADRANEL, Pr
      • Paris, France, 75014
        • Recruiting
        • AP-HP Hôpital Cochin
        • Contact:
      • Paris, France, 75877
        • Not yet recruiting
        • AP-HP Hôpital Bichat
        • Contact:
      • Paris, France
        • Not yet recruiting
        • Paris - Curie
        • Contact:
          • Marie-Ange MASSIANI, Dr
          • Phone Number: +33156811045
          • Email: contact@ifct.fr
      • Pierre-Bénite, France
        • Recruiting
        • Lyon - URCOT
        • Contact:
          • Michael Duruisseaux, Dr
          • Phone Number: +33156811045
          • Email: contact@ifct.fr
      • Rouen, France
        • Recruiting
        • Rouen - CHU
        • Contact:
      • Strasbourg, France, 67091
        • Recruiting
        • Nouvel Hôpital Civil - Hôpitaux Universitaires de Strasbourg
        • Contact:
      • Suresnes, France, 92151
        • Recruiting
        • Hopital FOCH
        • Contact:
      • Toulouse, France
        • Recruiting
        • CHU Toulouse - Pneumologie
        • Contact:
      • Tours, France, 37044
        • Recruiting
        • CHU Bretonneau
        • Contact:
      • Valenciennes, France
        • Recruiting
        • Valenciennes - Clinique
        • Contact:
      • Vandœuvre-lès-Nancy, France
        • Recruiting
        • Vandoeuvre-lès-Nancy - CHU
        • Contact:
      • Villejuif, France, 94805
        • Not yet recruiting
        • Gustave Roussy
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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).
  • 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 crizotinib or entrectinib 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).
  • Tumor Sample Requirement: Tumour biopsy sampling on fresh tissue (FFPE blocks required) obtained after progression on crizotinib or entrectinib. 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.
  • 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.
  • Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
  • Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedure.
  • Participant has national health insurance coverage.
  • Washout period: if previous progression on ROS1-TKI: 7 days from last dose of the drug. The washout period may be shortened to 2 days at investigator discretion.

Exclusion Criteria:

  • 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.
  • Current use or anticipated need for food or drugs prohibited (see chapter 8.8.1 for details).
  • Patients presenting with abnormal Left Ventricular Ejection Fraction (LVEF) by echocardiogram or Multi-Gated Acquisition Scan (MUGA) according to institutional lower limits.
  • Breastfeeding female patients (including patients who intend to interrupt breastfeeding).
  • Liver disease characterized by: ALT or AST level > 3 the upper normal limit (UNL) (≥ 5 x UNL for patients with liver metastases) confirmed on 2 consecutive measures OR impaired excretory function (e.g.. hyperbilirubinemia) or synthetic function or other conditions of decompensated liver disease e.g.: coagulopathy, Hepatic encephalopathy, hypoalbuminemia, ascites and bleeding from esophageal varices OR Acute viral or autoimmune or other types of hepatitis.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Lorlatinib
100 mg once daily
Drug: Lorlatinib
100 mg once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective Response Rate (ORR) at 8 weeks by investigators
Time Frame: 8 weeks
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Response Rate (ORR) at 8 weeks by Independent Reviewer Committee (IRC)
Time Frame: 8 weeks
Percentage of subjects with a confirmed at 16 weeks complete response (CR) or partial response (PR) as per RECIST v1.1 criteria.
8 weeks
Progression Free Survival (PFS)
Time Frame: Up to 24 months
Time between the date of inclusion and the first date of documented disease progression (according to RECIST v1.1) or death (from any cause)
Up to 24 months
Time to progression (TTP)
Time Frame: Up to 24 months
Time from the date of inclusion to the earliest date of disease progression (according to RECIST v1.1.)
Up to 24 months
Disease control rate (DCR) at 8 weeks weeks)
Time Frame: 8 weeks
Proportion of patients have achieved a confirmed best overall response of CR, PR or SD (Stable Disease) (according to RECIST v1.1.)
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.
Time Frame: Up to 24 months
Time from the date of the first documented response (CR or PR) to the earliest date of disease progression or death due to any cause.
Up to 24 months
Overall survival (OS) months
Time Frame: 12 months and 24 months
Time from the date of first dose of study drug to the date of death due to any cause
12 months and 24 months
Central Nervous System (CNS) Objective response rate (C-ORR)
Time Frame: Up to 24 months
ORR estimated in patients with measurable CNS metastases at baseline.
Up to 24 months
CNS duration of response (C-DOR) measurable CNS metastases at baseline.
Time Frame: Up to 24 months
DOR estimated in patients with measurable CNS metastases at baseline.
Up to 24 months
Time to CNS progression
Time Frame: Up to 24 months
In patients without brain metastases baseline.
Up to 24 months
Change from baseline of EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L)
Time Frame: Up to 24 months
At all scheduled time points
Up to 24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Intergroupe Francophone de Cancerologie Thoracique

Investigators

  • Study Chair: Michael Duruisseaux, Lyon - URCOT
  • Study Chair: Denis Moro-Sibilot, Grenoble - CHU

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 19, 2021

Primary Completion (Estimated)

March 1, 2025

Study Completion (Estimated)

January 1, 2026

Study Registration Dates

First Submitted

November 4, 2020

First Submitted That Met QC Criteria

November 4, 2020

First Posted (Actual)

November 9, 2020

Study Record Updates

Last Update Posted (Estimated)

December 19, 2023

Last Update Submitted That Met QC Criteria

December 18, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IFCT-2003

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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