SAFIR02_Lung - Efficacy of Targeted Drugs Guided by Genomic Profiles in Metastatic NSCLC Patients
- Conditions
- Non-small Cell Lung Cancer Metastatic
- Interventions
- Drug: Standard maintenance for squamous NSCLC
- Registration Number
- NCT02117167
- Lead Sponsor
- UNICANCER
- Brief Summary
Open label multicentric randomized phase II trial, using high throughput genome analysis as a therapeutic decision tool, aimed at comparing a targeted treatment administered according to the identified molecular anomalies of the tumor with a standard treatment (pemetrexed in Non-squamous patients and erlotinib in squamous cells, targeted substudy 1) as well as immunotherapy with maintenance therapy in patients without actionable genomic alterations or non eligible to substudy 1 (immune substudy 2).
- Detailed Description
Screening phase:
New frozen biopsy or an archived frozen sample or ctDNA sample will be sent to the genomic platforms for DNA extraction and genomic analysis (DNA microarrays and Next generation sequencing).
Patients can be considered as pre-eligible for the targeted substudy 1 randomisation phase when both following mandatory conditions have been met : stable or responding disease has been observed after 4 cycles of chemotherapy (investigator judgment) and targetable alteration has been identified by the Molecular tumor board (MTB).
If not eligible for the substudy 1 randomisation phase, patients can be considered as pre-eligible for the immune substudy 2 randomization phase when both following mandatory conditions are met: stable or responding disease (investigator judgment) is observed after 4 cycles of a platinum-based chemotherapy AND not eligible to randomization in the substudy 1 (because patient had no targetable alteration identified by the Molecular Tumor Board, or failed to have a genomic profile for the tumor \[low tumor cells percentage, technical issue during genomic analysis, etc.\], or a non-inclusion criteria that precluded entry into the substudy 1)
Randomization phase:
The mandatory post-chemotherapy 28-day wash-out period following cycle 4 of chemotherapy will provide time to achieve all the required tests and examinations.
The randomization program will allocate the following treatments with a 2:1 ratio in favor of Arm A of the considered substudy:
Substudy 1 : targeted therapies versus standard maintenance therapy
* Arm A1 / targeted arm: targeted maintenance from a list of 6 targeted drugs guided by the genomic analysis, or
* Arm B1 / standard arm : standard maintenance (pemetrexed in non-squamous and standard practice in squamous NSCLC).
Substudy 2 : immunotherapy versus standard maintenance therapy
* Arm A2 / immunotherapy maintenance arm: MEDI4736 or
* Arm B2 / standard arm : standard maintenance (pemetrexed in non-squamous and standard practice in squamous NSCLC).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 999
- histologically proven NSCLC
- Metastatic relapse or stage IV at diagnosis, or stage IIIb not amenable to surgery or radiotherapy
- No EGFR-activating mutation or ALK translocation
- primary tumor or metastases that can be biopsied, excluding bone.
- Age >18 years
- WHO Performance Status 0/1
- Chemo-naïve patients eligible to a first line platinum-based chemotherapy
- No tumor progression observed with the current line of treatment
- measurable target lesion or evaluable diseases RECIST
Exclusion criteria
- Spinal cord compression and/or symptomatic or progressive brain metastases
- Abnormal coagulation contraindicating biopsy
- Inability to swallow
- Major problem with intestinal absorption
- Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG
- Any factors increasing the risk of QTc prolongation or arrhythmic events
- Experience of any of the following in the preceding 12 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, past or current uncontrolled angina pectoris, congestive heart failure NYHA Grade ≥2, torsades de pointes, current uncontrolled hypertension, cardiomyopathy
- Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which requires steroid treatment or any evidence of clinically interstitial lung disease
- Previous or current malignancies of other histologies within the last 5 years,
- Evidence of severe or uncontrolled systemic disease (active bleeding diatheses, or active Hepatitis B, C and HIV)
- Diagnosis of diabetes mellitus type I or II
- diagnosis of acne rosacea, severe psoriasis and severe atopic eczema
- Prior exposure to anthracyclines or mitoxantrone with cumulative exposure in excess of 360 mg/m² for doxorubicin, 720 mg/m² for epirubicin, or 72 mg/m² for mitoxantrone
- History of retinal degenerative disease, eye injury or corneal surgery in the previous 3 months, past history of central serous retinopathy or retinal vein occlusion, intraocular pressure >21 mmHg, or uncontrolled glaucoma.
- History of hemorrhagic or thrombotic stroke, TIA or other CNS bleeds
- Renal disease including glomerulonephritis, nephritic syndrome, Fanconi syndrome, renal tubular acidosis
- Patients using drugs that are known potent inhibitors or potent inducers or substrates of cytochrome P450
Randomized phase:
Substudy 1:
Inclusion criteria
- Patients who received 4 cycles of an induction platinum-based chemotherapy and who have a SD or a PR at randomization
- presenting at least one genomic alteration from the predefined list
- Age > 25 years for patients planned to receive AZD4547
- 28-day washout period from chemo prior to randomization and grade ≤1 residual toxicities
Exclusion criteria
- Life expectancy <3 months
- Disease progression occuring at any time during chemotherapy and before randomization or toxicity that led to the discontinuation of the platinum-based chemotherapy before 4 full cycles have been delivered
- Less than 28 days from radiotherapy, less than 2 weeks from palliative radiation
- Patients previously treated with a targeted agent in the same class as agents tested in this study
- Toxicities of grade ≥2 from any previous anti-cancer therapy
- Altered haematopoietic or organ function
- Mean resting corrected QT interval (QTc) >480msec (or QTcF >450 msec) obtained from 3 consecutive ECGs
- Left ventricular ejection fraction (LVEF) <55% (MUGA scan or Echocardiogram),
- Altered ophthalmic conditions confirmed by an ophthalmology specialist for patients likely to be treated with AZD4547 orAZD8931 or Selumetinib
- Patients using non-substitutable drugs, that are known to prolong QT interval or induce Torsades de Pointes, when they are supposed to be treated with vandetanib, AZD5363 or AZD8931
Substudy 2:
Inclusion criteria
- Patients who received 4 cycles of an induction platinum-based chemotherapy and who have a SD or a PR at randomization
- Patients not eligible to substudy 1
- 28-day washout period from chemo prior to randomization and grade ≤1 residual toxicities
Exclusion criteria
- Life expectancy <3 months
- Disease progression occuring at any time during chemotherapy and before randomization or toxicity that led to the discontinuation of the platinum-based chemotherapy before 4 full cycles have been delivered
- Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736
- Toxicities of grade ≥2 from any previous anti-cancer therapy
- Altered haematopoietic or organ function
- Mean resting QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 consecutive ECGs using Bazett's Correction
- Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
- Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
- History of primary immunodeficiency
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Substudy 1: targeted agent AZD8931 Arm A1/ targeted arm: targeted maintenance from a list of targeted drugs guided by the genomic analysis, AZD2014 tablet per os 50 mg bd, continuous dosing, AZD4547 tablet per os 80 mg bd, 2 weeks on/1 week off, AZD5363 capsule per os 480 mg bd, 4 days on/3 days off, AZD8931 tablet per os 40 mg bd, continuous dosing, selumetinib capsule per os 75 mg bd, continuous dosing, vandetanib tablet per os 300 mg od, continuous dosing, olaparib tablet per os 300 mg bd continuous dosing savolitinib tablet per os 600 mg od continuous dosing Substudy 1: standard maintenance therapy Standard maintenance for squamous NSCLC Arm B1/ standard arm pemetrexed Intra venous 500 mg/m², every 3 weeks, standard maintenance left to the investigator's choice Substudy 2: standard maintenance therapy Standard maintenance for squamous NSCLC Arm B2/ standard arm pemetrexed Intra venous 500 mg/m², every 3 weeks, standard maintenance left to the investigator's choice Substudy 1: targeted agent AZD4547 Arm A1/ targeted arm: targeted maintenance from a list of targeted drugs guided by the genomic analysis, AZD2014 tablet per os 50 mg bd, continuous dosing, AZD4547 tablet per os 80 mg bd, 2 weeks on/1 week off, AZD5363 capsule per os 480 mg bd, 4 days on/3 days off, AZD8931 tablet per os 40 mg bd, continuous dosing, selumetinib capsule per os 75 mg bd, continuous dosing, vandetanib tablet per os 300 mg od, continuous dosing, olaparib tablet per os 300 mg bd continuous dosing savolitinib tablet per os 600 mg od continuous dosing Substudy 1: targeted agent AZD2014 Arm A1/ targeted arm: targeted maintenance from a list of targeted drugs guided by the genomic analysis, AZD2014 tablet per os 50 mg bd, continuous dosing, AZD4547 tablet per os 80 mg bd, 2 weeks on/1 week off, AZD5363 capsule per os 480 mg bd, 4 days on/3 days off, AZD8931 tablet per os 40 mg bd, continuous dosing, selumetinib capsule per os 75 mg bd, continuous dosing, vandetanib tablet per os 300 mg od, continuous dosing, olaparib tablet per os 300 mg bd continuous dosing savolitinib tablet per os 600 mg od continuous dosing Substudy 1: targeted agent AZD5363 Arm A1/ targeted arm: targeted maintenance from a list of targeted drugs guided by the genomic analysis, AZD2014 tablet per os 50 mg bd, continuous dosing, AZD4547 tablet per os 80 mg bd, 2 weeks on/1 week off, AZD5363 capsule per os 480 mg bd, 4 days on/3 days off, AZD8931 tablet per os 40 mg bd, continuous dosing, selumetinib capsule per os 75 mg bd, continuous dosing, vandetanib tablet per os 300 mg od, continuous dosing, olaparib tablet per os 300 mg bd continuous dosing savolitinib tablet per os 600 mg od continuous dosing Substudy 1: targeted agent Selumetinib Arm A1/ targeted arm: targeted maintenance from a list of targeted drugs guided by the genomic analysis, AZD2014 tablet per os 50 mg bd, continuous dosing, AZD4547 tablet per os 80 mg bd, 2 weeks on/1 week off, AZD5363 capsule per os 480 mg bd, 4 days on/3 days off, AZD8931 tablet per os 40 mg bd, continuous dosing, selumetinib capsule per os 75 mg bd, continuous dosing, vandetanib tablet per os 300 mg od, continuous dosing, olaparib tablet per os 300 mg bd continuous dosing savolitinib tablet per os 600 mg od continuous dosing Substudy 2: Immunotherapy Durvalumab Arm A2/ Immunotherapy arm: maintenance with durvalumab for patient without actionable genomic alterations or non eligible to Targeted substudy 1, durvalumab Intra-venous 10 mg/kg, Q2W Substudy 1: targeted agent Vandetanib Arm A1/ targeted arm: targeted maintenance from a list of targeted drugs guided by the genomic analysis, AZD2014 tablet per os 50 mg bd, continuous dosing, AZD4547 tablet per os 80 mg bd, 2 weeks on/1 week off, AZD5363 capsule per os 480 mg bd, 4 days on/3 days off, AZD8931 tablet per os 40 mg bd, continuous dosing, selumetinib capsule per os 75 mg bd, continuous dosing, vandetanib tablet per os 300 mg od, continuous dosing, olaparib tablet per os 300 mg bd continuous dosing savolitinib tablet per os 600 mg od continuous dosing Substudy 1: targeted agent savolitinib Arm A1/ targeted arm: targeted maintenance from a list of targeted drugs guided by the genomic analysis, AZD2014 tablet per os 50 mg bd, continuous dosing, AZD4547 tablet per os 80 mg bd, 2 weeks on/1 week off, AZD5363 capsule per os 480 mg bd, 4 days on/3 days off, AZD8931 tablet per os 40 mg bd, continuous dosing, selumetinib capsule per os 75 mg bd, continuous dosing, vandetanib tablet per os 300 mg od, continuous dosing, olaparib tablet per os 300 mg bd continuous dosing savolitinib tablet per os 600 mg od continuous dosing Substudy 1: targeted agent Olaparib Arm A1/ targeted arm: targeted maintenance from a list of targeted drugs guided by the genomic analysis, AZD2014 tablet per os 50 mg bd, continuous dosing, AZD4547 tablet per os 80 mg bd, 2 weeks on/1 week off, AZD5363 capsule per os 480 mg bd, 4 days on/3 days off, AZD8931 tablet per os 40 mg bd, continuous dosing, selumetinib capsule per os 75 mg bd, continuous dosing, vandetanib tablet per os 300 mg od, continuous dosing, olaparib tablet per os 300 mg bd continuous dosing savolitinib tablet per os 600 mg od continuous dosing Substudy 1: standard maintenance therapy Pemetrexed Arm B1/ standard arm pemetrexed Intra venous 500 mg/m², every 3 weeks, standard maintenance left to the investigator's choice Substudy 2: standard maintenance therapy Pemetrexed Arm B2/ standard arm pemetrexed Intra venous 500 mg/m², every 3 weeks, standard maintenance left to the investigator's choice
- Primary Outcome Measures
Name Time Method progression-free survival in the targeted drug arm compared to standard maintenance therapy arm from randomization to disease progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months) To evaluate whether treatment with targeted agents guided by high throughput molecular analysis (CGH array, next generation sequencing) improves progression-free survival as compared to standard maintenance therapy in patients with metastatic NSCLC
- Secondary Outcome Measures
Name Time Method correlate molecular characteristics in patients with the efficacy endpoints (response rate, progression-free and overall survival) in each substudy from randomization or treatment initiation to disease progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months) tumor response is defined as a complete or partial response, upon RECIST v1.1 criteria
overall response rates and changes in tumor size in each substudy tumor response is assessed every 21 days from treatment initiation until first progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months) tumor response is defined as a complete or partial response, upon RECIST v1.1 criteria
progression-free survival in patients treated with anti-PDL1 antibody (MEDI4736) compared to standard maintenance therapy arm from randomization to disease progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months) To evaluate whether treatment with MEDI4736 improves progression-free survival as compared to standard maintenance therapy in patients with metastatic NSCLC
overall survival in each substudy from randomization to death (any cause), up to 16 months To evaluate whether treatment with targeted agents guided by high throughput molecular analysis (CGH array, next generation sequencing) or MEDI4736 improves overall survival as compared to standard maintenance therapy in patients with metastatic NSCLC
evaluate safety, in each substudy toxicities will be assessed during the whole treatment period (4 months expected in average) followed by a 1-year post-treatment follow-up period, and reported during the visits scheduled by the study flow chart Toxicities are graded according to the CTCAE V4
efficacy (response rate, change in tumor size, progression-free survival, overall survival) and safety of each individual targeted agent (substudy 1) tumor response is assessed every 21 days from treatment initiation until first progression or death from any cause, whichever comes first, up to 16 months (estimated treatment duration average: 4 months) tumor response is defined as a complete or partial response, upon RECIST v1.1 criteria
Trial Locations
- Locations (37)
Hôpital Avicenne
🇫🇷Bobigny, France
Institut Bergonié
🇫🇷Bordeaux, France
Institut Paoli Calmettes
🇫🇷Marseille, France
AP-HP Hôpital Tenon
🇫🇷Paris, France
CHU Toulouse -Hôpital Larrey
🇫🇷Toulouse, France
Hôpital Ambroise Paré
🇫🇷Boulogne Billancourt, France
CHRU de Lille
🇫🇷Lille, France
Hôpital Bretonneau
🇫🇷Tours, France
AP-HP Hôpital Cochin
🇫🇷Paris, France
Institut de cancérologie de l'Ouest
🇫🇷Nantes, France
CHI de Toulon - Hôpital Sainte-Musse
🇫🇷Toulon, France
Centre Hospitalier Henri Duffau
🇫🇷Avignon, France
Centre Hospitalier Universitaire de Besancon - Hopital Jean Minjoz
🇫🇷Besancon, France
Hospices Civils de Lyon- Hôpital Louis Pradel
🇫🇷Bron, France
Centre François Baclesse
🇫🇷Caen, France
CHU Caen
🇫🇷Caen, France
centre Jean Perrin
🇫🇷Clermont-Ferrand, France
Chu de Caen - Hopital Cote de Nacre
🇫🇷Caen, France
Centre Georges François Leclerc
🇫🇷Dijon, France
Hôpital Louis Pasteur
🇫🇷Chartres, France
CHU Clermont Ferrand - Hôpital Gabriel Montpied
🇫🇷Clermont-Ferrand, France
CHU Grenoble
🇫🇷Grenoble, France
Hopitaux Civils de Colmar
🇫🇷Colmar, France
Centre Hopsitalier Intercommunal de Créteil
🇫🇷Créteil, France
Chd Vendee
🇫🇷La Roche Sur Yon, France
Centre Oscar Lambret
🇫🇷Lille, France
Hôpital Nord
🇫🇷Marseille, France
CH du Mans
🇫🇷Le Mans, France
Centre Antoine Lacassagne
🇫🇷Nice, France
Chr Orleans
🇫🇷Orleans, France
Centre Léon Bérard
🇫🇷Lyon, France
AH-HP Hôpital Saint Louis
🇫🇷Paris, France
Centre Hospitalier de Pau
🇫🇷PAU, France
Institut Curie
🇫🇷Paris, France
Centre Hospitalier Lyon Sud
🇫🇷Pierre Bénite, France
Chru Strasbourg - Nouvel Hopital Civil
🇫🇷Strasbourg, France
Gustave Roussy
🇫🇷Villejuif, France