Activity of Lorlatinib Based on ALK Resistance Mutations Detected on Blood in ALK Positive NSCLC Patients

NCT04127110 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: EORTC-18252019-003862-41
• Study Type: interventional
• Target: 68
• Locations: 7 countries
• Sites: 26

Brief Summary

This study includes patients diagnosed with a metastatic non small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) translocation. The standard treatment for patients with metastatic non small cell lung cancer with ALK translocation is represented by personalized treatment with drugs called ALK inhibitors. During the treatment with an ALK inhibitor, the tumour can start to grow again, because the tumour adapts to the drug and develops escape mechanisms, becoming resistant. At the tumour cells level, the mechanisms underlying resistance can include the development of other alterations, mainly mutations, including in the ALK gene. The alterations that developed depend on the drug the tumour has been exposed to. The alterations can be identified by analysing tumour tissue obtained through a biopsy, however, repeating a tumour biopsy is difficult and risky and might not be able to provide sufficient tissue for the test. Therefore in the last years, new tests have been developed to identify the mutations in the blood. Lorlatinib is a drug that inhibits ALK and has already been identified to be able to control the tumour growth when ALK mutations are identified and is already approved as standard treatment after progression to a previous treatment with ALK inhibitors. The purpose of this study is to identify which patient populations may benefit most from treatment with lorlatinib, based on the alterations found in their genes.

Conditions

Non Small Cell Lung Cancer

Keywords

Anaplastic lymphoma kinase (ALK) positive non small cell lung cancer (NSCLC)

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS)

  Progression Free Survival Rate at 12 months (PFSR-12) is defined as the proportion of patients at 12 months who are alive and non-progressing.

  12 months after enrolment of last patient

Secondary Outcomes (5)

• Overall Survival (OS)

  12 months after enrolment of last patient

• Overall Response Rate (ORR)

  12 months after enrolment of last patient

• Duration of Response (DOR)

  12 months after enrolment of last patient

• CNS Overall Response Rate (CNS-ORR)

  12 months after enrolment of last patient

• Safety profile according to NCI CTCAE v.5

  30 days after last dose

Study Arms (1)

Lorlatinib

EXPERIMENTAL

Lorlatinib is administered orally at the daily dose of 100 mg (four tablets of 25 mg). Lorlatinib will be taken continuously on a daily basis until disease progression, unacceptable toxicity, occurrence of any withdrawal criterion, whichever comes first.

Drug: Lorlatinib

Interventions

Lorlatinib DRUG

Lorlatinib is administered orally at the daily dose of 100 mg (four tablets of 25 mg).

Lorlatinib

Eligibility Criteria

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

You may qualify if:

• Age ≥18 years old
• Histologically or cytologically confirmed diagnosis of NSCLC with ALK rearrangement, assessed by fluorescence in situ hybridization (FISH) assay (Abbott Molecular Inc) or by Immunohistochemistry (IHC) (Ventana Inc) approved by food and drug administration (FDA)
• Stage IIIB (not eligible for local therapy) or stage IV (according to Union for International Cancer Control (UICC) tumor lymph node metastasis (TNM) staging v8.0)
• World health organization (WHO) performance status (WHO PS) of 0-2
• Previous treatment with at least one 2nd-generation ALK inhibitor. The 2nd-generation ALK TKI (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 Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 by computed tomography (CT) 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.
• Archival tissue from primary tumour or metastatic site, if available, and blood samples
• Note: if blood samples cannot be collected (patient's refusal or any other reason), patient will not be eligible for this study.
• 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 10E9/L;
• Platelets ≥ 100 x 10E9/L;
• Hemoglobin ≥ 9 g/dL;

You may not qualify if:

• 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 treatment.
• 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 5 half-lives 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 International Common Terminology Criteria for Adverse Events (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 HBV is defined as a known positive hepatitis B surface antigen (HBsAg) result. Active HCV is defined by a known positive Hep C antibody (Ab) result and known quantitative HCV ribonucleic acid (RNA) result greater than the lower limits of detection of the assay
• Known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related illness Note: Testing for HIV must be performed at sites where mandated locally
• 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 atrioventricular (AV) block (unless paced) or any AV block with PR \>220 msec
• Ongoing cardiac dysrhythmias of National Cancer Institute (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, etc.)

Sponsors & Collaborators

• European Organisation for Research and Treatment of Cancer - EORTC: lead

Study Sites (26)

Institut Jules Bordet-Hopital Universitaire ULB

Brussels, 1000, Belgium

Location

Cliniques Universitaires Saint-Luc

Brussels, BE 1200, Belgium

Location

Universitair Ziekenhuis Antwerpen

Edegem, BE 2650, Belgium

Location

CHU-UCL Namur - CHU Mont Godinne - UCL Namur

Yvoir, 5530, Belgium

Location

Centre Hospitalier Avignon

Avignon, 84902, France

Location

Assistance Publique Hopitaux Paris - Hopital Avicenne

Bobigny, France

Location

CHU de Brest

Brest, 29200, France

Location

Centre Hopitalier Intercommunal De Creteil

Créteil, 94010, France

Location

Gustave Roussy

Villejuif, France

Location

King Hussein Cancer Center

Amman, Jordan

Location

The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis

Amsterdam, 1066 CX, Netherlands

Location

Academisch Ziekenhuis Maastricht

Maastricht, Netherlands

Location

Erasmus MC

Rotterdam, Netherlands

Location

Oslo University Hospital - Radiumhospitalet

Oslo, Norway

Location

Institut Catala d'Oncologia - ICO L'Hospitalet - Hospital Duran i Reynals

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

Location

Hospital Clinic Universitari de Barcelona

Barcelona, Spain

Location

Hospital De La Santa Creu I Sant Pau

Barcelona, Spain

Location

Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol

Barcelona, Spain

Location

Hospital General Universitario Gregorio Maranon

Madrid, 28007, Spain

Location

Clinica Universidad de Navarra - Clinica Universitaria De Navarra

Madrid, Spain

Location

Hospital Universitario 12 De Octubre

Madrid, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, Spain

Location

Hospital Universitari Son Espases

Palma de Mallorca, Spain

Location

Clinica Universidad de Navarra - Clinica Universitaria De Navarra

Pamplona, Spain

Location

University Hospital Virgen del Rocio

Seville, Spain

Location

The Christie NHS Foundation Trust

Manchester, United Kingdom

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

lorlatinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Anne-Marie Dingemans, MD

  Erasmus MC, Rotterdam, Netherlands

  PRINCIPAL INVESTIGATOR

• Laura Mezquita, MD

  Hospital Clinic Universitari de Barcelona, Spain

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: October 14, 2019
• First Posted: October 15, 2019
• Study Start: November 17, 2020
• Primary Completion: July 31, 2024
• Study Completion: November 1, 2024
• Last Updated: November 5, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

NO (1); BE (4); JO (1); ES (11); NL (3); FR (5); GB (1)