PROTOCOL SAFIR 02 Lung

Transcription

1 PERSONALIZED MEDICINE GROUP PROTOCOL SAFIR 02 Lung Sponsor N : UC / IFCT-1301 EudraCT N : Evaluation of the efficacy of high throughput genome analysis as a therapeutic decision tool for patients with metastatic non small cell lung cancer Version n May 2013 CPP Approval ANSM Approval VERSION INITIAL PROTOCOL date date Version 1.0 May 2013 INVESTIGATOR COORDINATOR Prof. Jean-Charles Soria Institut Gustave Roussy, 39 rue C. Desmoulins, Villejuif Tel.: +33 (0) Fax: +33 (0) soria@igr.fr SPONSOR UNICANCER 101, rue de Tolbiac PARIS CEDEX 13 - FRANCE Tel. +33.(0) Fax: +33.(0)

2 SYNOPSIS PROTOCOL SAFIR02 Lung A) CLINICAL TRIAL IDENTIFICATION SPONSOR - PROTOCOL CODE NUMBER : UC / IFCT-1301 EUDRACT N : VERSION & DATE : Version n 1.0 May 2013 TRIAL TITLE: Evaluation of the efficacy of high throughput genome analysis as a therapeutic decision tool for patients with metastatic non small cell lung cancer. ABBREVIATED TITLE : SAFIR 02 Lung PRINCIPAL INVESTIGATOR : PR JEAN-CHARLES SORIA Institut Gustave Roussy PLANNED NUMBER OF INVESTIGATIONNAL SITES : 15 NUMBER OF PATIENTS : B) SPONSOR IDENTIFICATION NAME OF THE INSTITUTION : UNICANCER CONTACT PERSON : Marta JIMENEZ Adresse: R&D UNICANCER 101, rue de Tolbiac PARIS Cedex 13 - France Tel: + 33.(0) Fax: + 33.(0) m-jimenez@unicancer.fr 620 FOR THE SCREENING PHASE AND 220 FOR THE TREATMENT PHASE C) TRIAL GENERAL INFORMATION MEDICAL CONDITION: Patients with metastatic non small cell lung cancer (NSCLC) in 1 st line chemotherapy METHODOLOGY: This is an open-label multicentric phase II randomized trial, using high throughput genome analysis as a therapeutic decision tool, comparing a medical treatment administered according to the identified molecular anomaly of the tumour with a medical treatment administered without considering the tumour genome analysis (pemetrexed in Non-squamous patients and erlotinib in squamous cells) PRIMARY OBJECTIVE : To evaluate whether treatment with targeted agents guided by high throughput molecular analyses (CGH array, next generation sequencing) improves progression-free survival as compared to standard maintenance therapy in patients with metastatic NSCLC. 2/9

3 C) TRIAL GENERAL INFORMATION ( ) SECONDARY OBJECTIVES : To compare overall survival, To compare response rates, To evaluate safety, To explore the efficacy (reponse rate, progression-free survival, overall survival) of the individual targeted agents, To correlate molecular mechanisms in patients with the efficacy endpoints (response rate, progression-free and overall survival) ADDITIONAL RESEARCH OBJECTIVES /COMPANION STUDIES : Translational substudies involving kinome arrays, RPPA analyses, IHC analyses SCREENING INCLUSION CRITERIA: 1. Patients with histologically proven NSCLC. 2. Metastatic relapse or stage IV at diagnosis. 3. No EGFR-activating mutation or ALK translocation. 4. Patients with primary tumour or metastases that can be biopsied, excluding bone metastases. 5. Age > 18 years 6. WHO Performance Status 0/1 7. Patient chemonaïve or currently receiving a first line of platine-based chemotherapy with a maximum of 2 cycles at the time of biopsy 8. No tumour progression observed with the current line of treatment 9. Presence of a measurable target lesion according to RECIST criteria v Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses 11. Patient with social insurance coverage. EXCLUSION CRITERIA: 1. Participation to another clinical study with an investigational product (IP) during the last 30 days 2. Spinal cord compression and/or symptomatic or progressive brain metastases (unless asymptomatic or treated and stable off steroids for at least 30 days prior to start of study drug) 3. Bone metastases when this is the only site of biopsiable disease 4. Abnormal coagulation contraindicating biopsy 5. Inability to swallow 6. Major problem with intestinal absorption 7. Toxicities of grade>2 from any anti-cancer therapy, with the exception of alopecia 8. Altered haematopoietic or organ function, as indicated by the following criteria: - Polynuclear neutrophils < 1.5 x 10 9 /L - Platelets < 100 x 10 9 /L - Haemoglobin < 90 g/l - ALAT/ASAT > 2.5N in the absence or > 5 in the presence of liver metastases - bilirubin > 1.5 N 3/9

4 - creatinine clearance 50 ml/min (measured or calculated by Cockroft and Gault equation) - Calcium and Phosphate > ULN - Sodium, magnesium outside normal site range - Potassium < 4 mmol/l 9. Any of the following cardiac criteria: - Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG - Any factors increasing the risk of QTc prolongation or arrhythmic events such as heart failure, hypokalaemia, potential for torsades de pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years old or any concomitant medication known to prolong the QT interval. - Experience of any of the following procedures or conditions in the preceding 12 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestiveheart failure NYHA Grade 2. - Uncontrolled hypertension (BP 150/95 mmhg despite medical therapy) - Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy - Prior or current cardiomyopathy - Torsades de pointes within 12 months of study entry 10. Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which requires steroïd treatment or any evidence of clinically interstitial lung disease 11. Previous or current maligancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin and prostate cancer. 12. Evidence of severe or uncontrolled systemic disease (active bleeding diatheses, or active Hepatitis B, C and HIV) 13. clinically significant abnormalities of glucose metabolism as defined by any of the following: diagnosis of diabetes mellitus type I or II (irrespective of management), glycosylated haemoglobin (HbA1C) 8.0% (64 mmol/mol) at randomisation, Fasting Plasma Glucose 7.0 mmol/l(126 mg/dl) at randomisation (Fasting is defined as no calorie intake for at least 8 hours. 14. Medical diagnosis of acne rosacea, severe psoriasis and severe atopic eczema 15. 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. 16. History of ophthalmological infection or inflammation, degenerative disease, eye injury or corneal surgery in the previous 3 months, clinically significant ocular surface disease, current or past history of central serous retinopathy or retinal vein occlusion, Intraoccular pressure >21 mmhg, or uncontrolled glaucoma. 17. Women who are pregnant 4/9

5 18. History of heamorrhagic or thrombotic stroke, TIA or other CNS bleeds 19. Renal disease including glomeruloenphritis, hephritic syndrome, Fanconi syndrome, renal tubular acidosis 20. Any condition which in the Investigator s opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol 21. Individuals deprived of liberty or placed under guardianship THERAPEUTIC PHASE INCLUSION CRITERIA 1. Patients who still meet the screening phase inclusion criteria (except 4 and 7) 2. Molecular aberration as listed for the protocol 3. Age > 25 years for patients planned to receive AZD No tumour progression observed with the current line of treatment 5. Patients will have had a minimum of 28 days gap from last chemotherapy or biological therapy administration prior to randomisation. 6. Potentially reproductive patients must agree to use an effective contraceptive method, practice adequate methods of birth control while on treatment, beginning 2 weeks before the first dose of investigational product and for at least 3 months after the last dose of study drug. 7. Women of childbearing potential must have a negative serum pregnancy test within 14 days of enrollment and/or urine pregnancy test 72 hours prior to the administration of the study drug 8. Women who are breastfeeding should discontinue nursing prior to the first of study drug and until 3 months after the last dose. EXCLUSION CRITERIA 1. No targetable genomic alteration generated during the screening phase either due to the lack of alteration or due to ineligible samples for genomic analysis. 2. Life expectancy < 3 months. 3. Patients who still meet the screening phase exclusion criteria 4,7,8,9,10,11,12,15,16,17,19,20 and Major surgery within 30 days prior to entry into the study (excluding placement of vascular access) or minor surgery within 14 days of entry into the study 5. Toxicities of grade>2 from any anti-cancer therapy, with the exception of alopecia 6. Patients who have had previous treatment with a targeted agent in the same class as agents tested in this study in the last 30 days 7. History of hypersensitivity to active or inactive excipients of the study drug 8. Altered haematopoietic or organ function, as indicated by the following criteria: - Polynuclear neutrophils < 1.5 x 10 9 /L - Platelets < 100 x 10 9 /L - Haemoglobin < 90 g/l - ALAT/ASAT > 2.5N in the absence or > 5 in the presence of liver metastases 5/9

6 - bilirubin > 1.5 N - creatinine clearance 50 ml/min (measured or calculated by Cockroft and Gault equation) - Calcium and Phosphate > ULN - Sodium, magnesium outside normal site range - Potassium < 4 mmol/l 9. Any of the following additional cardiac criteria: - Mean resting corrected QT interval (QTc)>480 msec (or QTcF >450 msec)obtained from 3 consecutive ECGs - LVEF <55% (MUGA scan or Echocardiogram), 10. Potent and moderate inhibitors and inducers or substrates of cytochrome P450 taken within 14 days prior to the first dose of study drug, except those for which the minimum wash-out period is longer (Fluoxetine and Phenobarbital: 5 weeks, Rifabutin : 3 weeks and amiodarone: 27 weeks). 11. Any granulocyte growth factors (eg, G-CSF, GM-CSF) within 2 weeks prior to receiving study drug. 6/9

7 STUDY PROCEDURES: After the patient has signed an informed consent form, a biopsy will be performed on the primary tumour or a metastatic site. The consent form will be signed when the patient does not present any signs of tumour progression under the current chemotherapy treatment. The sample will be analysed by CGH array (Affymetrix 6.0 or Agilent 4*180) to detect genes amplifications or deletions. It will also be analysed by next generation sequencing (Ion Torrent PGM, AmpliSeq) using a panel of 50 genes for mutation detection. These analyses will be carried out on one of the genome platforms selected for the protocol. The patients who present with a stable disease or a tumour response at the end of chemotherapy for metastatic NSCLC will be randomized to either: Arm A genomic : targeted maintenance guided by the genomic analysis, or Arm B non-genomic : targeted maintenance not guided by the genomic analysis (pemetrexed in non-squamous and erlotinib in squamous). In Arm A, the treatment will be selected from a list of 6 targeted drugs (see appendix 5) Treatment recommendations will be made in a bimonthly staff meeting (web conference) with oncologists, biologists, and bioinformaticians. SCREENING PHASE THERAPEUTIC PHASE Tumour Biopsy (after 2 cycles max.): CGH Array Next Generation Sequencing Arm A: Targeted treatment up to progression according to the molecular abnormality Metastatic NSCLC no EGFR-activating mutation or ALK Molecular translocation Aberration chemonaive or receiving platin-based chemotherapy (1 st line, 2 cycles max.) Chemotherapy Partial response 4 cycles or Stable disease Randomisation Not eligible for randomisation Arm B: Pemetrexed in non-squamous patients and erlotinib in squamous Progression or unresolved toxicity None of the targeted molecular aberration not randomised 7/9

8 8/9 Protocol n UC0105/1305-IFCT EudraCT N D) DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCTS DRUGS : Drug Name (IDN) Commercial Name Pharmaceutical Form Administration Route Posology (bd: twice daily, od: once daily) AZD2014 NA tablet per os 50 mg bd, continuous dosing AZD4547 NA tablet per os 80 mg bd, 2 weeks on/1 week off AZD5363 NA capsule per os 480 mg bd, 4 days on/3 days off AZD8931 NA tablet per os 40 mg bd, continuous dosing Selumetinib NA capsule per os 75 mg bd, continuous dosing Vandetanib CAPRELSA tablet per os 300 mg od, continuous dosing Erlotinib TARCEVA tablet per os 150 mg od Pemetrexed ALIMTA powder IV 500 mg/m² THERAPEUTIC SCHEME : Patients will be treated either with one of the targeted therapy or with maintenance chemotherapy (pemetrexed or erlotinib) Cycles are defined in 21-day period Disease response will be assessed every 6 weeks (RECIST 1.1) Safety will be assessed every 3 weeks TREATMENT DURATION Treatment will be continued until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment, or patient refusal. E) STATISTICAL ANALYSIS SAFIR02 Lung Protocol Version n May 2013

9 9/9 Protocol n UC0105/1305-IFCT EudraCT N The primary endpoint of the SAFIR02 lung study is to demonstrate that targeted maintenance with a targeted guided by the genomic analysis (arm A) improves progression-free survival as compared to targeted maintenance therapy not guided by the genomic analysis (arm B). Assuming exponential survival, In order to detect an increase in median progression-free survival from 4 to 6 months (a hazard ratio of 0.66) with 80% power at a two-sided significance level of 0.05 using the logrank test, 191 events are required. Assuming a 36 months enrollement period with uniform accrual, and 3 months additional follow-up, a total of 220 patients need to be randomized. The stratified log-rank test will be used to compare progression-free survival between the two treatment arms. Cox proportional hazards regression models will be performed in an exploratory manner, to determine if adjustment for additional covariates will modify the conclusions from the primary analysis. The Kaplan-Meier approach will be used to estimate survival rates for each treatment arm. The stratified Cox proportional hazards model will be used to estimate the hazard ratio (HR) between the two treatment arms (ie, the magnitude of treatment effect) and its 95% confidence interval (CI). The primary analysis will be based on the intent-to-treat (ITT) population. For the combined analysis of the SAFIR02 lung and SAFIR02 breast studies, a specific protocol will be developed. F) TRIAL DURATION INCLUSION PERIOD: 3 YEARS TREATMENT PERIOD: 4 MONTHS POST- TREATMENT FOLLOW-UP PERIOD : 12 MONTHS OVERALL TRIAL DURATION : 4,5 YEARS SAFIR02 Lung Protocol Version n May 2013