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CTRI Number  CTRI/2018/10/016042 [Registered on: 16/10/2018] Trial Registered Prospectively
Last Modified On: 08/09/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Placebo Controlled Trial 
Public Title of Study   Study of Osimertinib as maintenance therapy in patients with locally advanced, unresectable Non-Small Cell Lung Cancer whose disease has not progressed following platinum-based chemoradiation therapy 
Scientific Title of Study   A Phase III, randomized, double-blind, placebo-controlled, multicenter, international study of osimertinib as maintenance therapy in patients with locally advanced, unresectable EGFR mutation-positive Non-Small Cell Lung Cancer (Stage III) whose disease has not progressed following definitive platinum-based chemoradiation therapy (LAURA) 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
D5160C00048 version 1.0 dated 23 Mar 2018  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name   
Designation   
Affiliation   
Address 




 
Phone    
Fax    
Email    
 
Details of Contact Person
Scientific Query
 
Name  Mr Tapankumar M Shah  
Designation  Country Head, Site Management and Monitoring – India  
Affiliation  AstraZeneca Pharma India Ltd. 
Address  AstraZeneca Pharma India Ltd. Block N1, 12th Floor, Manyata Embassy Business Park Rachenahalli, Outer Ring Road

Bangalore
KARNATAKA
560045
India 
Phone  91-9535104975  
Fax  91-8067748857   
Email  tapankumar.shah@astrazeneca.com  
 
Details of Contact Person
Public Query
 
Name  Mr Tapankumar M Shah  
Designation  Country Head, Site Management and Monitoring – India  
Affiliation  AstraZeneca Pharma India Ltd. 
Address  AstraZeneca Pharma India Ltd. Block N1, 12th Floor, Manyata Embassy Business Park Rachenahalli, Outer Ring Road

Bangalore
KARNATAKA
560045
India 
Phone  91-9535104975  
Fax  91-8067748857   
Email  tapankumar.shah@astrazeneca.com  
 
Source of Monetary or Material Support  
AstraZeneca AB, 151 85 Södertälje, Sweden 
 
Primary Sponsor  
Name  AstraZeneca AB 
Address  151 85 Sodertalje Sweden 
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     Argentina
China
India
Japan
Republic of Korea
Spain
Taiwan
Thailand
Turkey
United States of America
Viet Nam  
Sites of Study
Modification(s)  
No of Sites = 10  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Sushant Mittal  Action Cancer Hospital  Ground floor, Dept. of Medical Oncology A4, Paschim Vihar PIN-110063
West
DELHI 
01149222222
01145024287
sushantmittal80@gmail.com 
Dr Hari Goyal  Artemis Hospitals  Basement, Dept. of Medical Oncology Sector-51, PIN-122001,
Gurgaon
HARYANA 
01246767999
01246767701
harig@artemishospitals.com 
Dr Shruti Kate  HCG Manavata Cancer Centre  Dept. of Medical Oncology Behind Shivang Auto Mumbai Naka Nashik PIN 422002
Nashik
MAHARASHTRA 
7506117343

drshruti@mcrinasik.com 
Dr Kartikeya Jain  Himalaya Cancer Hospital & Research Institute,  Third floor, Dept. of Medical Oncology #4 Vinod Baugh, Jetalpur bridge, Alkapuri - 390007
Vadodara
GUJARAT 
0265-6542151

jainkartikeya@rocketmail.com 
Dr Priyanka Srivastava   Manibhai Shivabhai Patel Cancer Centre  Ground Floor, Dept. of Medical Oncology Shree Krishna Hospital and Medical Research Centre, H M Patel Centre for Medical Care & Education Gokal Nagar, Karamsad PIN-388325
Anand
GUJARAT 
7574868577
02692223466
priyankass@charutarhealth.org 
Dr Ullas Batra  Rajiv Gandhi Cancer Institute and Research Centre (RGCI & RC)  Department of Medical Oncology Rajiv Gandhi Cancer Institute and Research Centre (RGCI & RC) Sector 5 Rohini Delhi 110085
North West
DELHI 
9711080001
01127051037
ullasbatra@gmail.com 
Dr Lokesh K N   Shettys Hospital  First floor, Dept. of Medical Oncology Plot No.11 and 12, 12th F Main, Kaveri Nagar, Kodichikkanahalli, Bommanahalli, PIN-560068
Bangalore
KARNATAKA 
08025732886
08025732887
knloki@gmail.com 
Dr Rajeev L K  Sri Venkateshwara Hospital  Dept. of Medical Oncology # 27, 29th Main Road, Rashtra Kuvempu Nagara, BTM 2nd stage, BTM layout, PIN-560076
Bangalore
KARNATAKA 
08041508702
08040416700
lkrajeev@gmail.com 
DrBivas Biswas  Tata Medical Centre Kolkata   Department of Medical Oncology 14-MAR (EW), New Town, Rajarhat
Kolkata
WEST BENGAL 
9830922005

bivasbiswas@gmail.com 
Dr Kiran Ashok Kattimani   The Karnataka Cancer Therapy & Research Institute  First floor, Dept. of Medical Oncology, Padmashree Dr. R. B. Patil Cancer Hospital Navanagar, Hubli-580025
Dharwad
KARNATAKA 
0836-2228217
0836-2323167
dr_kattimani@yahoo.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 10  
Name of Committee  Approval Status 
Action Cancer Hospital Ethics Committee, Action Cancer Hospital  Approved 
Artemis Health Sciences Institutional Ethics Committee  Approved 
Institutional Ethics Committee H. M. Patel Centre for Medical Care and Education  Approved 
Institutional Ethics Committee Shree Himalaya Cancer Hospital & Research Institute  Approved 
Institutional Ethics Committee,The Karnataka Cancer Therapy & Research Institute   Approved 
Institutional Review Board (IRB) Rajiv Gandhi Cancer Institute and Research Centre (RGCI & RC)  Approved 
Manavata Clinical Research Institute Ethics Committee  Approved 
Shetty’s Hospital Ethics Committee  Approved 
Sri Venkateshwara Hospital Ethics Committee  Approved 
Tata Medical centre-Institutional Review Board   Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied
Modification(s)  
Health Type  Condition 
Patients  C349||Malignant neoplasm of unspecifiedpart of bronchus or lung, C349||Malignant neoplasm of unspecifiedpart of bronchus or lung,  
 
Intervention / Comparator Agent
Modification(s)  
Type  Name  Details 
Intervention  Osimertinib oral once a day, until objective radiological disease progression as defined by RECIST v1.1  Patients will be in a 2:1 ratio to either Osimertinib or placebo  
Comparator Agent  Placebo oral once a day, until objective radiological disease progression as defined by RECIST v1.1   Patients will be in a 2:1 ratio to either Osimertinib or placebo 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  99.00 Year(s)
Gender  Both 
Details  1.Male and Female patient must be aged at least 18 years.
2.Provision of signed and dated written informed consent for Part I screening form prior to any mandatory provision of tumor samples for testing of EGFR mutation status.
3.Patients with histologically documented NSCLC of predominantly non-squamous pathology who present with locally advanced, unresectable (Stage III) disease (according to Version 8 of the International Association for the Study of Lung Cancer [IASLC] Staging Manual in Thoracic Oncology).
Part II Screening:
Part II screening applies to:
(i)patients that have a pre-existing local positive (Exon 19 Deletion or L858R) cobas® EGFR Mutation Test v2 (Roche Diagnostics) in a CLIA-certified (USA sites) or an accredited local laboratory (sites outside of the USA) conducted according to the cobas® EGFR Mutation Test v2 instructions for use or (ii) patients who completed Part I screening and have centrally confirmed EGFR mutation (Ex19 Deletion or L858R) positive NSCLC.
4.Provision of signed and dated, written informed consent form for the main study prior to any mandatory study specific procedures, sampling, and analyses.
5.The tumor harbours one of the two common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations, assessed by cobas® EGFR Mutation Test v2 (Roche Diagnostics) in a CLIA certified (USA sites) or an accredited local laboratory (sites outside of the USA) or by central testing.
6.Patients must not have had disease progression during or following definitive platinum based, chemoradiation therapy.
7.Patients must have received either concurrent chemoradiation or sequential chemoradiation regimens as defined below;
-CCRT- Patients must have received at least 2 cycles of platinum-based chemotherapy (or 5 doses of weekly platinum–based chemotherapy) concurrent with radiation therapy, which must be completed ≤6 weeks prior to randomization. The final chemotherapy cycle must end prior to, or concurrently with, the final dose of radiation. (A final cycle of platinum and pemetrexed doublet is permitted up to 3 days after the last dose of radiation). Consolidation chemotherapy after radiation is not permitted but administration of chemotherapy prior to CCRT is permitted
-SCRT- SCRT is defined as chemotherapy followed by radiation therapy and not radiation therapy followed by chemotherapy. Patients must have received at least 2 cycles of platinum based chemotherapy prior to radiation treatment, which must be completed ≤6 weeks prior to randomization. Consolidation chemotherapy after radiation is not permitted
8.The platinum-based chemotherapy regimen must contain one of the following agents: etoposide, vinblastine, vinorelbine, paclitaxel, docetaxel, or pemetrexed, according to the local standard of care regimens. Gemcitabine is permitted if used prior to radiation but not with radiation.
9.Patients must have received a total dose of radiation of 60 Gy ±10% (54 to 66 Gy) as part of the chemoradiation therapy in order to be randomized. It is recommended but not required that patients eligible for randomization have a
-Mean lung dose <20 Gy and/or V20 <35%
-Mean esophagus dose <34 Gy
-Heart V50 <25%, V30 <50%, and V45 <35%
10.World Health Organization (WHO) performance status of 0 or 1 at Part II screening and Day 1
11.Life expectancy >12 weeks at Day 1.
 
 
ExclusionCriteria 
Details  Part II Screening;

Patients are eligible to be included in Part II screening process only if none of the exclusion criteria apply:

Medical conditions;

1.Mixed small cell and non-small cell lung cancer histology.
2.History of interstitial lung disease (ILD) prior to chemoradiation.
3.Symptomatic pneumonitis following chemoradiation.
4.Any unresolved toxicity Common Terminology Criteria for Adverse Events (CTCAE) > Grade 2 from the prior chemoradiation therapy. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study drug may be included (e.g. hearing loss) after consultation with the AstraZeneca medical monitor.
5.Any of the following cardiac criteria:
-Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs
-Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, e.g., complete left bundle branch block, third-degree heart block, second degree heart block.
-Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval.
6.Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values.
-Absolute neutrophil count <1.5 x 109/L
-Platelet count <100 x 109/L
-Haemoglobin <90 g/L
-Alanine aminotransferase (ALT) >2.5x the upper limit of normal (ULN)
-Aspartate aminotransferase (AST) >2.5x ULN
-Total bilirubin >1.5x ULN or >3x ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia)
-Creatinine >1.5x ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5xULN
7.History of other malignancies, except: adequately treated non-melanoma skin cancer or lentigo maligna , curatively treated in-situ cancer, or other solid tumors curatively treated with no evidence of disease for > 5 years following the end of treatment and which, in the opinionof the treating physician, do not have a substantial risk of recurrence of the prior malignancy.
8.Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Active infection will include any patients receiving intravenous treatment for infection; active hepatitis B infection will, at a minimum, include all patients who are hepatitis B surface antigen positive (HbsAg positive) based on serology assessment. Screening for chronic conditions is not required.
9.Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of osimertinib.
Prior/concomitant therapy;
10.Prior treatment with any prior chemotherapy, radiation therapy, immunotherapy or investigational agents for NSCLC outside of that received in the definitive setting for Stage III disease (chemotherapy and radiotherapy in SCRT and CCRT regimens is allowed for treatment of Stage III disease). Prior surgical resection (i.e. stage I or II) is permitted.
11.Prior treatment with EGFR-TKI therapy.
12.Major surgery as defined by the investigator within 4 weeks of the first dose of study drug.
13.Patients currently receiving (unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (at least 3 weeks prior to receiving the first dose of study drug).
14.Participation in another clinical study with an investigational product during the 4 weeks prior to Day 1. Patients in the follow-up period of an interventional study are permitted.
15.Patient with involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
16.Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
17.Patient was previously randomized in the present study.
18.For female patients only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
19.Contraindication to MRI, including but not limited to, claustrophobia, pace makers, metal implants, intracranial surgical clips and metal foreign bodies.
20.History of hypersensitive to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.
21.Prior allogeneic bone marrow transplant.
22.Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection.
 
 
Method of Generating Random Sequence   Stratified block randomization 
Method of Concealment   Centralized 
Blinding/Masking   Participant and Investigator Blinded 
Primary Outcome  
Outcome  TimePoints 
To assess the efficacy of osimertinib treatment compared with placebo as measured by progression free survival (PFS)

PFS using BICR assessment according to RECIST v1.1
Sensitivity analysis of PFS using Investigator assessment according to RECIST v1.1
 
Overall Survival (OS) (Time frame-Approximately 5 years)  
 
Secondary Outcome  
Outcome  TimePoints 
Secondary objectives
To assess the efficacy of osimertinib treatment compared with placebo by
assessment of PFS in patients with:
EGFR Ex19del or L858R mutation
EGFRm plus Ex19del or L858R detectable in plasma-derived ctDNA 
Overall Survival (OS) (Time frame-Approximately 5 years) 
To assess the efficacy of osimertinib versus placebo on CNS PFS

 
Overall Survival (OS) (Time frame-Approximately 5 years) 
To assess the efficacy of osimertinib versus placebo on CNS PFS  Overall Survival (OS) (Time frame-Approximately 5 years) 
To further assess the efficacy of osimertinib compared to placebo post progression  Overall Survival (OS) (Time frame-Approximately 5 years)  
To assess disease-related symptoms and health-related QoL in patients treated with osimertinib compared with placebo  Overall Survival (OS) (Time frame-Approximately 5 years) 
To assess the safety and tolerability profile of osimertinib compared with placebo  Overall Survival (OS) (Time frame-Approximately 5 years)  
To assess the PK of osimertinib  Overall Survival (OS) (Time frame-Approximately 5 years) 
Exploratory objectives:
To assess potential treatment-related adverse effects in patients treated with osimertinib compared with placebo using PRO-CTCAE 
Overall Survival (OS) (Time frame-Approximately 5 years) 
To assess the patients’ overall impression of the severity of their cancer symptoms using PGIS  Overall Survival (OS) (Time frame-Approximately 5 years)  
To compare osimertinib treatment with placebo treatment on health state utility  Overall Survival (OS) (Time frame-Approximately 5 years) 
To compare health resource use associated with osimertinib treatment versus placebo  Overall Survival (OS) (Time frame-Approximately 5 years)  
To investigate the relationship between osimertinib (and metabolite) PK and selected endpoints (which may include efficacy, safety and/or PRO), where deemed appropriate  Overall Survival (OS) (Time frame-Approximately 5 years) 
 
Target Sample Size   Total Sample Size="200"
Sample Size from India="18" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)   22/10/2018 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  01/08/2018 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="6"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  
Open to Recruitment 
Recruitment Status of Trial (India)  Open to Recruitment 
Publication Details   not yet 
Brief Summary  

This is a Phase III, randomized, double-blind, placebo-controlled, multicenter international study assessing the efficacy and safety of osimertinib, as maintenance therapy in patients with locally advanced, unresectable epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (Stage III), whose disease has not progressed following definitive platinum based- chemoradiation therapy.Patients will be randomized in a 2:1 ratio (osimertinib to placebo). If fewer than 40 patients have been recruited in mainland China, recruitment will continue in mainland China until approximately 40 patients have been randomized. Osimertinib 80mg po QD until objective radiological disease progression per (RECIST) v1.1 which is confirmed by BICR or until another treatment discontinuation criterion is met. Matching placebo 80 mg po QD until objective radiological disease progression per (RECIST) v1.1 which is confirmed by BICR or until another treatment discontinuation criterion is met.Patients randomized will have achieved a complete response (CR), partial response (PR), or have stable disease (SD) following definitive, platinum-based, chemoradiation. Randomization will be stratified by: sequence of chemoradiation (concurrent versus sequential), disease stage prior to chemoradiation (IIIA versus IIIB/IIIC) and will also include China cohort (enrolled at a Chinese site and patient declaring themselves of Chinese ethnicity versus enrolled at Non-Chinese site or patient declaring themselves of non-Chinese ethnicity) as a stratification factor to allow separate randomization for the purposes of reporting in China.In order to reflect global clinical practice, recruitment will be monitored on an ongoing basis and will be managed to ensure that the majority (≥60%) of patients entering the study have received prior CCRT. Study entry is permitted based on detection of Exon 19 deletion and/or L858R mutation based on central tissue EGFR testing using the cobas® EGFR Mutation Test v2, or from a pre-existing local EGFR test result obtained using the cobas® EGFR MutationTest v2 from a CLIA-certified (USA sites) or an   local laboratory (sites outside of the USA).

 
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