A global study to assess the effects of Osimertinib following chemoradiation in patients with Stage III unresectable non-small cell lung cancer (LAURA).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Astrazeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15], Analytical,Diagnostic,Therapeutic Techniques and Equipment [E]-Surgical Procedures, Operative [E04], Psychiatry and Psychology [F] - Behavior and Behavior Mechanisms [F01], Phenomena and Processes [G] - Circulatory and Respiratory Physiological Phenomena [G09], Diseases [C] - Neoplasms [C04]

Trial duration

19 Sep 2018 → ongoing

Decision date (initial)

2024-06-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2022-500860-36-00

EudraCT number

2018-001061-16

ClinicalTrials.gov

NCT03521154

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy

To assess the efficacy of osimertinib treatment compared with placebo as measured by progression free survival (PFS).

Secondary objectives 7

1. To assess the efficacy of osimertinib treatment compared with placebo by assessment of PFS in patients with: EGFR Ex19del or L858R mutation EGFRm+ Ex19del or L858R detectable in plasma-derived ctDNA
2. To assess the efficacy of osimertinib versus placebo on CNS PFS
3. To further assess the efficacy of osimertinib compared with placebo as measured by OS, ORR, DoR, DCR and tumor shrinkage, time to death or distant metastases ( TTDM) and Time to treatment discontinuation (TTD)
4. To further assess the efficacy of osimertinib compared to placebo post progression (as measured by Second progression free survival on a subsequent treatment (PFS2), Time to first subsequent therapy (TFST) and Time to second subsequent therapy (TSST)
5. To assess disease-related symptoms and health-related QoL in patients treated with osimertinib compared with placebo
6. To assess the safety and tolerability profile of osimertinib compared with placebo
7. To assess the PK of osimertinib

Conditions and MedDRA coding

Histologically documented non-small cell lung cancer of predominantly non-squamous pathology who present with locally advanced, unresectable (Stage III) disease, whose tumor tissue has EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, either alone or in combination with other EGFR mutations, as detected by cobas® EGFR Mutation Test v2 (Roche Diagnostics) and whose disease has not progressed following definitive platinum-based chemoradiation.

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Male or female aged at least 18 years
2. Patients with histologically documented NSCLC of predominantly nonsquamous 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)
3. 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) or FoundationOne® test in a CLIA certified (USA sites) or an accredited local laboratory (sites outside of the USA) or by central testing (cobas® v2 only)
4. Patients must have received either concurrent chemoradiation or sequential chemoradiation including at least 2 cycles of platinum based chemotherapy and a total dose of radiation of 60 Gy ±10% (54 to 66 Gy)
5. Chemoradiation must be completed ≤6 weeks prior to randomization
6. Patients must not have had disease progression during or following definitive platinum-based, chemoradiation therapy
7. World Health Organization (WHO) performance status of 0 or 1
8. Life expectancy >12 weeks at Day 1
9. Female patients who are not abstinent (in line with the preferred and usual lifestyle choice) must be using adequate contraceptive measures, must not be breast feeding, and must have a negative pregnancy test prior to first dose of study drug; or female patients must have an evidence of non-childbearing potential

Exclusion criteria 14

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
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 • 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 and cause Torsades de Pointes
6. Inadequate bone marrow reserve or organ function
7. History of other malignancies, except: adequately treated nonmelanoma 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 opinion of 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; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV)
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
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)
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. Contraindication to MRI, including but not limited to, claustrophobia, pace makers, metal implants, intracranial surgical clips and metal foreign bodies

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS using BICR assessment according to RECIST v1.1 Sensitivity analysis of PFS using Investigator assessment according to RECIST v1.1

Secondary endpoints 7

1. PFS in patients with EGFR Ex19del or L858R mutation and Patients with EGFRm+ Ex19del or L858R detectable in plasma-derived ctDNA using BICR assessment according to RECIST v1.1; Sensitivity analysis of PFS using Investigator assessment according to RECIST v1.1
2. Time to CNS PFS (time to the earliest of CNS progression or death) using BICR assessments according to RECIST v1.1; Cumulative incidence rate of CNS PFS by BICR at 12 and 24 months
3. OS, ORR, DoR, DCR and tumor shrinkage, TTDM using BICR assessments according to RECIST v1.1, Time to treatment discontinuation (TTD)
4. Second progression free survival on a subsequent treatment (PFS2), Time to first subsequent therapy (TFST), Time to second subsequent therapy (TSST)
5. Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 items (EORTC QLQ-C30): Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Lung Cancer 13 items (EORTC QLQ-LC13)
6. Adverse Events (graded by CTCAE v5); Clinical chemistry, hematology and urinalysis; Vital signs (pulse and blood pressure), physical examination, weight; ECG parameters; Left ventricular ejection fraction; WHO Performance Status
7. Trough plasma concentrations of osimertinib, and its metabolite AZ5104 If conducted, PK Parameters (CLss/F, Css, min and Css, max, AUCss) may be derived using population PK analysis and reported separately to the CSR. Data from this study may form part of a pooled analysis with data from other studies

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Astrazeneca AB

Sponsor organisation

Astrazeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications