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Non Small Cell Lung Cancer MetastaticPhase 2ORAKLENCT04111705

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

A Phase 2 study testing Lorlatinib in people with Non Small Cell Lung Cancer Metastatic, run by Intergroupe Francophone de Cancerologie Thoracique at 32 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Non Small Cell Lung Cancer Metastatic
What is being tested?
Lorlatinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
23 participants
Where
32 sitesFrance
Study dates
5 Aug 2020to 15 Dec 2024
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
  • 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).
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  • 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.
  • 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 ≥60 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 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.
  • 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 ALK-TKI: 7 days from last dose of the drug. The washout period may be shortened to 2 days at investigator discretion.

Who cannot join

  • 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.
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  • 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 8.9.2 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).

Trial locations and contacts

32 sites in 1 country.

32 sites in 1 country

France32 sites

  • Angers - CHU

    Angers

  • Annecy - CH

    Annecy

  • Bayonne - CH

    Bayonne

  • Besançon - CHU

    Besançon

  • Bordeaux - CHU Hôpital Haut-Lévèque

    Bordeaux

  • Boulogne - Ambroise Paré

    Boulogne-Billancourt

  • Caen - CHU Côte de Nacre

    Caen, 14000

  • Colmar - CH

    Colmar

  • Créteil - CHI

    Créteil

  • Dijon - CRLCC

    Dijon

  • Grenoble - CHU

    Grenoble

  • Le Mans - CHG

    Le Mans

  • Lille - Hôpital Calmette

    Lille

  • Lyon - CRLCC

    Lyon

  • Marseille - AP-HM Hôpital Nord

    Marseille

  • Marseille - Institut Paoli Calmette

    Marseille

  • Montpellier - CHU

    Montpellier

  • Montpellier - Clinique

    Montpellier

  • Mulhouse - GHRMSA

    Mulhouse

  • Nantes - CRLCC

    Nantes

  • Orléans - CHR

    Orléans, 45000

  • Paris - APHP - Hopital Tenon

    Paris, 75020

  • Paris - APHP Bichat

    Paris

  • Paris - Curie

    Paris

  • Paris - Hôpital Cochin

    Paris

  • Lyon - URCOT

    Pierre-Bénite

  • Saint Quentin - CH

    Saint-Quentin, 02100

  • Strasbourg - Nouvel Hôpital Civil

    Strasbourg

  • Suresnes - Hopital Foch

    Suresnes, 92151

  • Toulon - CHI

    Toulon, 83000

  • Toulouse - CHU

    Toulouse

  • Vandoeuvre-lès-Nancy - CRLCC

    Vandœuvre-lès-Nancy

Other trials in France

About this study

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

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.

Being tested
Lorlatinib
Keywords
IFCT, ORAKLE, NSCLC, ALK-positive, monotherapy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LorlatinibDrug

    100 mg once daily

Study groups in NCT04111705
Study groupRoleWhat they receive
LorlatinibExperimental100 mg once daily
Receives: Drug: Lorlatinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Time from enrollment until 6 weeks after treatment.

Secondary outcomes (11)

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

    Response according to RECIST v.1.1 as assessed by an independent review committee (IRC)

    Measured: Time from enrollment until 6 weeks after treatment

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

    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.

    Measured: Approximately 8 months after randomization

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

    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.

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

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

    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.

    Measured: Approximately 1 year

  5. Overall Survival .

    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.

    Measured: Approximately 1 year

  6. Time to Tumor Response (TTR).

    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.

    Measured: Approximately 1 year

  7. Central Nervous System (CNS) ORR.

    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.

    Measured: Approximately 1 year

  8. CNS PFS.

    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

    Measured: Approximately 1 year

  9. CNS DOR.

    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.

    Measured: Approximately 1 year

  10. CNS TTR.

    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.

    Measured: Approximately 1 year

  11. Best ORR and PFS depending on prior brigatinib or alectinib treatment

    Measured: Approximately 2 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Oct 2019
  2. Study start5 Aug 2020
  3. Primary completion11 Aug 2022
  4. Study completion15 Dec 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
A phase II non-randomized, single group assignment, open-label, multicenter
Masking
None (open label)
Enrolment
23 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04111705
Sponsor's protocol ID
IFCT-1902
Acronym
ORAKLE
Status last verified
Mar 2025
First submitted
30 Aug 2019
Last updated
1 Apr 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Lorlatinib in people with Non Small Cell Lung Cancer Metastatic, run by Intergroupe Francophone de Cancerologie Thoracique at 32 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 29 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 32 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The primary endpoint is the Objective Response Rate (ORR) at 6 weeks. (time frame: Time from enrollment until 6 weeks after treatment.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04111705.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Apr 2025.

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