Informations générales (source: ClinicalTrials.gov)
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 (ORAKLE)
Interventional
Phase 2
Intergroupe Francophone de Cancerologie Thoracique (Voir sur ClinicalTrials)
août 2020
janvier 2025
19 octobre 2024
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.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CHI DE CRETEIL | Gaelle ROUSSEAU | 29/03/2024 01:28:48 | Contacter | ||
| HOPITAL FOCH | HELENE DOUBRE | 21/10/2024 07:07:13 | Contacter | ||
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| AP-HP - Hôpital Bichat | Contact (sur clinicalTrials) | ||||
| AP-HP - Hôpital Cochin | Contact (sur clinicalTrials) | ||||
| AP-HP - Hôpital Tenon | Contact (sur clinicalTrials) | ||||
| CLCC INSTITUT CURIE | Contact (sur clinicalTrials) | ||||
| Les établissements hors Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Angers - CHU - Angers - France | Contact (sur clinicalTrials) | ||||
| Annecy - CH - Annecy - France | Contact (sur clinicalTrials) | ||||
| Besançon - CHU - Besançon - France | Contact (sur clinicalTrials) | ||||
| Bordeaux - CHU Hôpital Haut-Lévèque - Bordeaux - France | Contact (sur clinicalTrials) | ||||
| Caen - CHU Côte de Nacre - 14000 - Caen - France | Contact (sur clinicalTrials) | ||||
| Colmar - CH - Colmar - France | Contact (sur clinicalTrials) | ||||
| Dijon - CRLCC - Dijon - France | Contact (sur clinicalTrials) | ||||
| Lille - Hôpital Calmette - Lille - France | Contact (sur clinicalTrials) | ||||
| Lyon - CRLCC - Lyon - France | Contact (sur clinicalTrials) | ||||
| Lyon - URCOT - Pierre-Bénite - France | Contact (sur clinicalTrials) | ||||
| Marseille - AP-HM Hôpital Nord - Marseille - France | Contact (sur clinicalTrials) | ||||
| Montpellier - CHU - Montpellier - France | Contact (sur clinicalTrials) | ||||
| Mulhouse - GHRMSA - Mulhouse - France | Contact (sur clinicalTrials) | ||||
| Nantes - CRLCC - Nantes - France | Contact (sur clinicalTrials) | ||||
| Orléans - CHR - 45000 - Orléans - France | Contact (sur clinicalTrials) | ||||
| Saint Quentin - CH - 02100 - Saint Quentin - France | Contact (sur clinicalTrials) | ||||
| Toulon - CHI - 83000 - Toulon - France | Contact (sur clinicalTrials) | ||||
| Vandoeuvre-lès-Nancy - CRLCC - Vandoeuvre-lès-Nancy - France | Contact (sur clinicalTrials) | ||||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Bayonne - CH - Bayonne - France | Contact (sur clinicalTrials) | ||||
| Boulogne - Ambroise Paré - Boulogne-Billancourt - France | Contact (sur clinicalTrials) | ||||
| Grenoble - CHU - Grenoble - France | Contact (sur clinicalTrials) | ||||
| Le Mans - CHG - Le Mans - France | Contact (sur clinicalTrials) | ||||
| Marseille - Institut Paoli Calmette - Marseille - France | Contact (sur clinicalTrials) | ||||
| Montpellier - Clinique - Montpellier - France | Contact (sur clinicalTrials) | ||||
| Strasbourg - Nouvel Hôpital Civil - Strasbourg - France | Contact (sur clinicalTrials) | ||||
| Toulouse - CHU - Toulouse - France | Contact (sur clinicalTrials) | ||||
Critères
Tous
Inclusion Criteria:
1. 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
2. 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 .
3. 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.
4. 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).
5. 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.
6. Age ≥18 years.
7. Life expectancy of at least 12 weeks, in the opinion of the Investigator.
8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2
9. Adequate Bone Marrow Function, including:
- Absolute Neutrophil Count (ANC) ≥1.5 x 109/L;
- Platelets ≥100 x 109/L;
- Hemoglobin ≥9 g/dL.
10. Adequate Pancreatic Function, including:
- Serum lipase ≤1.5 x ULN.
11. 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.
12. 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.
13. 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.
14. Participants must have recovered from effects of any major surgery, or significant
traumatic injury, at least 35 days before the first dose of lorlatinib
15. 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.
16. 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.
17. Evidence of a personally signed and dated informed consent document indicating that
the patient has been informed of all pertinent aspects of the study.
18. Willingness and ability to comply with the study scheduled visits, treatment plans,
laboratory tests and other procedure.
19. Participant has national health insurance coverage.
20. 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.
1. 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
2. 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 .
3. 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.
4. 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).
5. 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.
6. Age ≥18 years.
7. Life expectancy of at least 12 weeks, in the opinion of the Investigator.
8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2
9. Adequate Bone Marrow Function, including:
- Absolute Neutrophil Count (ANC) ≥1.5 x 109/L;
- Platelets ≥100 x 109/L;
- Hemoglobin ≥9 g/dL.
10. Adequate Pancreatic Function, including:
- Serum lipase ≤1.5 x ULN.
11. 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.
12. 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.
13. 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.
14. Participants must have recovered from effects of any major surgery, or significant
traumatic injury, at least 35 days before the first dose of lorlatinib
15. 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.
16. 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.
17. Evidence of a personally signed and dated informed consent document indicating that
the patient has been informed of all pertinent aspects of the study.
18. Willingness and ability to comply with the study scheduled visits, treatment plans,
laboratory tests and other procedure.
19. Participant has national health insurance coverage.
20. 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.
1. Patients who experienced a clinical benefit of less than 6 months with front-line
alectinib or brigatinib.
2. 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).
3. Transdifferentiation into small cell lung cancer.
4. 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.
5. 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).
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. Active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic
diverticular disease or previous gastric resection or lap band.
17. Current use or anticipated need for food or drugs prohibited (see chapter 8.9.2 for
details).
18. Patients presenting with abnormal Left Ventricular Ejection Fraction (LVEF) by
echocardiogram or Multi-Gated Acquisition Scan (MUGA) according to institutional
lower limits.
19. Breastfeeding female patients (including patients who intend to interrupt
breastfeeding).