Informations générales (source: ClinicalTrials.gov)
A Phase I-III, Multicenter Study Evaluating the Efficacy and Safety of Multiple Therapies in Cohorts of Patients Selected According to Biomarker Status, With Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer
Interventional
Phase 3
Hoffmann-La Roche (Voir sur ClinicalTrials)
novembre 2022
septembre 2033
29 avril 2025
This study will evaluate the efficacy and safety of multiple therapies in participants
with locally advanced, unresectable, Stage III NSCLC with eligible biomarker status as
determined by Version 8 of the American Joint Committee on Cancer/Union for International
Cancer Control NSCLC staging system.
Etablissements
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| HIA BEGIN | 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 | |||||
| Centre Francois Baclesse - 14000 - Caen - France | Contact (sur clinicalTrials) | ||||
| Centre Leon Berard - 69008 - Lyon - France | Contact (sur clinicalTrials) | ||||
| CHU Angers,Service de Pneumologie - 49933 - Angers - France | Contact (sur clinicalTrials) | ||||
| CHU de Toulouse - Hôpital Larrey - 31059 - Toulouse - France | Contact (sur clinicalTrials) | ||||
| CHU Strasbourg - Nouvel Hopital Civil - 67091 - Strasbourg - France | Contact (sur clinicalTrials) | ||||
| Hia Sainte Anne - 83041 - Toulon - France | Contact (sur clinicalTrials) | ||||
| Hôpital Ambroise Paré - Boulogne-Billancourt - 92100 - Boulogne Billancourt - France | Contact (sur clinicalTrials) | ||||
| Hopital Nord - 13915 - Marseille cedex 20 - France | Contact (sur clinicalTrials) | ||||
| Polyclinique Bordeaux Nord Aquitaine - 33300 - Bordeaux - France | Contact (sur clinicalTrials) | ||||
Critères
Tous
Inclusion Criteria (All Cohorts):
- Body weight >/= 30 kg at screening
- Willingness and ability to use the electronic device(s) or application(s) for the
electronic patient-reported outcome (PRO)
- Whole-body positron emission tomography/computed tomography scan (PET/CT) (from the
base of skull to mid-thighs) for the purposes of staging, performed prior and within
42 days of the first dose of cCRT or sCRT
- Histologically or cytologically documented locally advanced, unresectable Stage III
NSCLC of either squamous or non-squamous histology
- Prior receipt of at least two prior cycles of platinum-based chemotherapy given
concurrently with radiotherapy (cCRT); or at least two prior cycles of
platinum-based chemotherapy given prior to radiotherapy (sCRT)
- The RT component in the cCRT or sCRT must have been at a total dose of radiation of
60 (+/-10%) Gy (54 Gy to 66 Gy) administered by intensity-modulated radiotherapy
(preferred) or three dimension (3D)-conforming technique
- No disease progression during or following platinum-based cCRT or sCRT
- Life expectancy >/= 12 weeks
- Confirmed availability of a representative formalin-fixed, paraffin-embedded (FFPE)
tumor specimen
- Documented tumor PD-L1 status (TC score < 1% vs. >/= 1% vs. unknown) as determined:
centrally with the SP263 IHC assay on the confirmed available FFPE tumor specimen;
locally, with the SP263 (preferred) or 22C3 IHC assays
- Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2
- Adequate hematologic and end-organ function
- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraception, and agreement to refrain from
donating eggs, as defined by the protocol
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or
use contraceptive methods, and agreement to refrain from donating sperm, as defined
by the protocol
Inclusion criteria specific to Cohort A1:
- Documented ALK fusion positivity by an eligible result from: centralized multiplex
molecular testing of tumor tissue at the Sponsor's designated central laboratory
under Study BX43361 or available results from a Sponsor pre-approved local,
appropriately validated ALK fusion test on tumor tissue performed in a Clinical
Laboratory Improvement Amendments certified or equivalent laboratory
Inclusion criteria specific to Cohort A2:
- Documented ROS1 fusion positivity by an eligible result from: centralized multiplex
molecular testing of tumor tissue at the Sponsor's designated central laboratory
under Study BX43361 or available results from a Sponsor pre-approved local,
appropriately validated ROS1 fusion test on tumor tissue performed in a Clinical
Laboratory Improvement Amendments certified or equivalent laboratory
- Ability to swallow entrectinib intact, without chewing, crushing, or opening the
capsules
Exclusion Criteria (All Cohorts):
- Any history of previous NSCLC and/or any history of prior treatment for NSCLC
(patients must be newly diagnosed with unresectable Stage III disease)
- Any evidence of Stage IV disease, including, but not limited to, the following:
pleural effusion, pericardial effusion, brain metastases, history of intracranial
hemorrhage or spinal cord hemorrhage, bone metastases, distant metastases
- If a pleural effusion is present, the following criteria must be met to exclude
malignant involvement (T4 disease): when pleural fluid is visible on both the CT
scan and chest X-ray, a pleuracentesis is required to confirm that the pleural fluid
is cytologically negative; participants with exudative pleural effusions are
excluded regardless of cytology; participants with effusions that are minimal (i.e.,
not visible on chest X-ray) that are too small to safely tap are eligible
- NSCLC known to have a known or likely oncogenic-driver mutation in the EGFR gene, as
identified by site local testing or Sponsor central testing
- Liver disease, characterized by any of the following: impaired excretory function
(e.g., hyperbilirubinemia), synthetic function, or other conditions of decompensated
liver disease, such as coagulopathy, hepatic encephalopathy, hypoalbuminemia,
ascites, and bleeding from esophageal varices or active viral or active autoimmune,
alcoholic, or other types of acute hepatitis
- Positive hepatitis B surface antigen (HBsAg) test at screening
- Participants known to be positive for hepatitis C virus (HCV) antibody (Ab) are
excluded with the following exception: participants who are HCV Ab positive but HCV
RNA negative due to prior treatment or natural resolution are eligible
- HIV infection: participants are excluded if not well-controlled as defined by the
protocol
- Known active tuberculosis
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on the screening chest CT scan
- Grade >/= 2 pneumonitis from prior cCRT or sCRT
- Any Grade > 2 unresolved toxicity from prior cCRT or sCRT
- Any gastrointestinal (GI) disorder that may affect absorption of oral medications,
such as malabsorption syndrome or status post-major bowel resection
- Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that contraindicates the use of an investigational drug, may
affect the interpretation of the results, or may render the patient at high risk
from treatment complications
- Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré
syndrome, or multiple sclerosis, with the following exceptions: participants with a
history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone
are eligible for the study; participants with controlled Type 1 diabetes mellitus
who are on an insulin regimen are eligible for the study
- History of malignancy other than NSCLC within 5 years prior to screening, with the
exception of malignancies with a negligible risk of metastasis or death (e.g.,
5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix,
non-melanoma skin carcinoma, localized prostate cancer, ductal breast carcinoma in
situ, or Stage I uterine cancer
- Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer
- Major surgical procedure, within 4 weeks prior to initiation of study treatment, or
anticipation of need for a major surgical procedure during the study
- Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon and interleukin-2) within 4 weeks or 5 drug-elimination half-lives
(whichever is longer) prior to initiation of study treatment
- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of
study treatment, or anticipation of need for such a vaccine during study treatment
or within 5 months after the final dose of study treatment
- Treatment with investigational therapy within 28 days prior to initiation of study
treatment
- Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-tumor necrosis factor-alpha agents) within 2 weeks prior to initiation of study
treatment, or anticipation of need for systemic immunosuppressive medication during
study treatment, with exceptions defined by the protocol
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
including anti-cytotoxic T lymphocyte-associated protein 4, anti-TIGIT, anti-PD-1,
and anti-PD-L1 therapeutic antibodies
- Prior allogeneic stem cell or solid organ transplantation
- Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or the follow-up period of an interventional
study
- Any condition that, in the opinion of the investigator, would interfere with the
evaluation of the study drug or interpretation of patient safety or study results
- Any prior Grade >/= 3 immune-mediated adverse event or any unresolved Grade > 1
immune-mediated adverse event while receiving any previous immunotherapy agent other
than immune checkpoint blockade agents
Exclusion criteria specific to Cohort A1:
- Presence of clinically symptomatic interstitial lung disease or interstitial
pneumonitis, including radiation pneumonitis (i.e., affecting activities of daily
living or requiring therapeutic intervention)
- NSCLC known to have one or more of the following ALK point mutations, as identified
by site local testing or Sponsor central testing: I1171X (where X is any other amino
acid), V1180L, G1202R
- Symptomatic bradycardia
- Significant cardiovascular disease (such as New York Heart Association Class II or
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within
3 months prior to initiation of study treatment, unstable arrhythmia, or unstable
angina; participants with known coronary artery disease, congestive heart failure
not meeting the above criteria, or left ventricular ejection fraction < 50% must be
on a stable medical regimen that is optimized in the opinion of the treating
physician, in consultation with a cardiologist if appropriate
- Severe infection within 4 weeks prior to initiation of study treatment, including,
but not limited to, hospitalization for complications of infection, bacteremia, or
severe pneumonia
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment
- Prior treatment with ALK inhibitors
- History of hypersensitivity to alectinib, durvalumab, or any of their excipients
- Inability to swallow oral study drug
- Known hereditary problems of galactose intolerance, a congenital lactase deficiency,
or glucose-galactose malabsorption
- Pregnancy or breastfeeding, or intending to become pregnant during the study
treatment or within 90 days after the final dose of alectinib or durvalumab
Exclusion criteria specific to Cohort A2:
- Symptomatic bradycardia
- Significant cardiovascular disease (such as New York Heart Association Class II or
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within
3 months prior to initiation of study treatment, unstable arrhythmia, or unstable
angina; participants with known coronary artery disease, congestive heart failure
not meeting the above criteria, or left ventricular ejection fraction < 50% must be
on a stable medical regimen that is optimized in the opinion of the treating
physician, in consultation with a cardiologist if appropriate
- Left ventricular ejection fraction less than or equal to 50% observed during the
screening for the study
- History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval >
450 ms from ECGs performed at least 24 hours apart)
- History of additional risk factors for torsade de pointes (e.g., family history of
long QT syndrome)
- Familial or personal history of congenital bone disorders or bone metabolism
alterations
- Incomplete recovery from any surgery prior to the start of study treatment that
would interfere with the determination of safety or efficacy of the treatment
- Severe infection within 4 weeks prior to initiation of study treatment, including,
but not limited to, hospitalization for complications of infection, bacteremia, or
severe pneumonia
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment
- Prior treatment with ROS1 inhibitors
- History of hypersensitivity to entrectinib, durvalumab, and their excipients
- Grade >/= 3 toxicities due to any prior therapy (e.g., RT) (excluding alopecia) that
have not shown improvement or are not stable and are considered to interfere with
current study drug
- Known hereditary problems of galactose intolerance, total lactase deficiency or
glucose-galactose malabsorption
- Grade >/= 2 peripheral neuropathy
- Pregnancy or intention of becoming pregnant during study treatment, within 35 days
after the final dose of entrectinib, or within 90 days after the final dose of
durvalumab
- Body weight >/= 30 kg at screening
- Willingness and ability to use the electronic device(s) or application(s) for the
electronic patient-reported outcome (PRO)
- Whole-body positron emission tomography/computed tomography scan (PET/CT) (from the
base of skull to mid-thighs) for the purposes of staging, performed prior and within
42 days of the first dose of cCRT or sCRT
- Histologically or cytologically documented locally advanced, unresectable Stage III
NSCLC of either squamous or non-squamous histology
- Prior receipt of at least two prior cycles of platinum-based chemotherapy given
concurrently with radiotherapy (cCRT); or at least two prior cycles of
platinum-based chemotherapy given prior to radiotherapy (sCRT)
- The RT component in the cCRT or sCRT must have been at a total dose of radiation of
60 (+/-10%) Gy (54 Gy to 66 Gy) administered by intensity-modulated radiotherapy
(preferred) or three dimension (3D)-conforming technique
- No disease progression during or following platinum-based cCRT or sCRT
- Life expectancy >/= 12 weeks
- Confirmed availability of a representative formalin-fixed, paraffin-embedded (FFPE)
tumor specimen
- Documented tumor PD-L1 status (TC score < 1% vs. >/= 1% vs. unknown) as determined:
centrally with the SP263 IHC assay on the confirmed available FFPE tumor specimen;
locally, with the SP263 (preferred) or 22C3 IHC assays
- Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2
- Adequate hematologic and end-organ function
- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraception, and agreement to refrain from
donating eggs, as defined by the protocol
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or
use contraceptive methods, and agreement to refrain from donating sperm, as defined
by the protocol
Inclusion criteria specific to Cohort A1:
- Documented ALK fusion positivity by an eligible result from: centralized multiplex
molecular testing of tumor tissue at the Sponsor's designated central laboratory
under Study BX43361 or available results from a Sponsor pre-approved local,
appropriately validated ALK fusion test on tumor tissue performed in a Clinical
Laboratory Improvement Amendments certified or equivalent laboratory
Inclusion criteria specific to Cohort A2:
- Documented ROS1 fusion positivity by an eligible result from: centralized multiplex
molecular testing of tumor tissue at the Sponsor's designated central laboratory
under Study BX43361 or available results from a Sponsor pre-approved local,
appropriately validated ROS1 fusion test on tumor tissue performed in a Clinical
Laboratory Improvement Amendments certified or equivalent laboratory
- Ability to swallow entrectinib intact, without chewing, crushing, or opening the
capsules
Exclusion Criteria (All Cohorts):
- Any history of previous NSCLC and/or any history of prior treatment for NSCLC
(patients must be newly diagnosed with unresectable Stage III disease)
- Any evidence of Stage IV disease, including, but not limited to, the following:
pleural effusion, pericardial effusion, brain metastases, history of intracranial
hemorrhage or spinal cord hemorrhage, bone metastases, distant metastases
- If a pleural effusion is present, the following criteria must be met to exclude
malignant involvement (T4 disease): when pleural fluid is visible on both the CT
scan and chest X-ray, a pleuracentesis is required to confirm that the pleural fluid
is cytologically negative; participants with exudative pleural effusions are
excluded regardless of cytology; participants with effusions that are minimal (i.e.,
not visible on chest X-ray) that are too small to safely tap are eligible
- NSCLC known to have a known or likely oncogenic-driver mutation in the EGFR gene, as
identified by site local testing or Sponsor central testing
- Liver disease, characterized by any of the following: impaired excretory function
(e.g., hyperbilirubinemia), synthetic function, or other conditions of decompensated
liver disease, such as coagulopathy, hepatic encephalopathy, hypoalbuminemia,
ascites, and bleeding from esophageal varices or active viral or active autoimmune,
alcoholic, or other types of acute hepatitis
- Positive hepatitis B surface antigen (HBsAg) test at screening
- Participants known to be positive for hepatitis C virus (HCV) antibody (Ab) are
excluded with the following exception: participants who are HCV Ab positive but HCV
RNA negative due to prior treatment or natural resolution are eligible
- HIV infection: participants are excluded if not well-controlled as defined by the
protocol
- Known active tuberculosis
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on the screening chest CT scan
- Grade >/= 2 pneumonitis from prior cCRT or sCRT
- Any Grade > 2 unresolved toxicity from prior cCRT or sCRT
- Any gastrointestinal (GI) disorder that may affect absorption of oral medications,
such as malabsorption syndrome or status post-major bowel resection
- Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that contraindicates the use of an investigational drug, may
affect the interpretation of the results, or may render the patient at high risk
from treatment complications
- Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré
syndrome, or multiple sclerosis, with the following exceptions: participants with a
history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone
are eligible for the study; participants with controlled Type 1 diabetes mellitus
who are on an insulin regimen are eligible for the study
- History of malignancy other than NSCLC within 5 years prior to screening, with the
exception of malignancies with a negligible risk of metastasis or death (e.g.,
5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix,
non-melanoma skin carcinoma, localized prostate cancer, ductal breast carcinoma in
situ, or Stage I uterine cancer
- Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer
- Major surgical procedure, within 4 weeks prior to initiation of study treatment, or
anticipation of need for a major surgical procedure during the study
- Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon and interleukin-2) within 4 weeks or 5 drug-elimination half-lives
(whichever is longer) prior to initiation of study treatment
- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of
study treatment, or anticipation of need for such a vaccine during study treatment
or within 5 months after the final dose of study treatment
- Treatment with investigational therapy within 28 days prior to initiation of study
treatment
- Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-tumor necrosis factor-alpha agents) within 2 weeks prior to initiation of study
treatment, or anticipation of need for systemic immunosuppressive medication during
study treatment, with exceptions defined by the protocol
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
including anti-cytotoxic T lymphocyte-associated protein 4, anti-TIGIT, anti-PD-1,
and anti-PD-L1 therapeutic antibodies
- Prior allogeneic stem cell or solid organ transplantation
- Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or the follow-up period of an interventional
study
- Any condition that, in the opinion of the investigator, would interfere with the
evaluation of the study drug or interpretation of patient safety or study results
- Any prior Grade >/= 3 immune-mediated adverse event or any unresolved Grade > 1
immune-mediated adverse event while receiving any previous immunotherapy agent other
than immune checkpoint blockade agents
Exclusion criteria specific to Cohort A1:
- Presence of clinically symptomatic interstitial lung disease or interstitial
pneumonitis, including radiation pneumonitis (i.e., affecting activities of daily
living or requiring therapeutic intervention)
- NSCLC known to have one or more of the following ALK point mutations, as identified
by site local testing or Sponsor central testing: I1171X (where X is any other amino
acid), V1180L, G1202R
- Symptomatic bradycardia
- Significant cardiovascular disease (such as New York Heart Association Class II or
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within
3 months prior to initiation of study treatment, unstable arrhythmia, or unstable
angina; participants with known coronary artery disease, congestive heart failure
not meeting the above criteria, or left ventricular ejection fraction < 50% must be
on a stable medical regimen that is optimized in the opinion of the treating
physician, in consultation with a cardiologist if appropriate
- Severe infection within 4 weeks prior to initiation of study treatment, including,
but not limited to, hospitalization for complications of infection, bacteremia, or
severe pneumonia
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment
- Prior treatment with ALK inhibitors
- History of hypersensitivity to alectinib, durvalumab, or any of their excipients
- Inability to swallow oral study drug
- Known hereditary problems of galactose intolerance, a congenital lactase deficiency,
or glucose-galactose malabsorption
- Pregnancy or breastfeeding, or intending to become pregnant during the study
treatment or within 90 days after the final dose of alectinib or durvalumab
Exclusion criteria specific to Cohort A2:
- Symptomatic bradycardia
- Significant cardiovascular disease (such as New York Heart Association Class II or
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within
3 months prior to initiation of study treatment, unstable arrhythmia, or unstable
angina; participants with known coronary artery disease, congestive heart failure
not meeting the above criteria, or left ventricular ejection fraction < 50% must be
on a stable medical regimen that is optimized in the opinion of the treating
physician, in consultation with a cardiologist if appropriate
- Left ventricular ejection fraction less than or equal to 50% observed during the
screening for the study
- History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval >
450 ms from ECGs performed at least 24 hours apart)
- History of additional risk factors for torsade de pointes (e.g., family history of
long QT syndrome)
- Familial or personal history of congenital bone disorders or bone metabolism
alterations
- Incomplete recovery from any surgery prior to the start of study treatment that
would interfere with the determination of safety or efficacy of the treatment
- Severe infection within 4 weeks prior to initiation of study treatment, including,
but not limited to, hospitalization for complications of infection, bacteremia, or
severe pneumonia
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment
- Prior treatment with ROS1 inhibitors
- History of hypersensitivity to entrectinib, durvalumab, and their excipients
- Grade >/= 3 toxicities due to any prior therapy (e.g., RT) (excluding alopecia) that
have not shown improvement or are not stable and are considered to interfere with
current study drug
- Known hereditary problems of galactose intolerance, total lactase deficiency or
glucose-galactose malabsorption
- Grade >/= 2 peripheral neuropathy
- Pregnancy or intention of becoming pregnant during study treatment, within 35 days
after the final dose of entrectinib, or within 90 days after the final dose of
durvalumab