Clinical trial NCT03521154: A Global Study to Assess the Effects of Osimertinib Following Chemoradiation in Patients With Stage III Unresectable Non-small Cell Lung Cancer (LAURA)
Official title: 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).
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Non Small Cell Lung Cancer (Stage III)
Keywords: Phase III
Osimertinib
Non Small Cell Lung Cancer (Stage III)
Unresectable NSCLC
EGFR
chemoradiation therapy
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2018-05-11
Enrollment: 216
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A global study to assess the efficacy and safety of osimertinib following chemoradiation in patients with stage III unresectable Epidermal Growth Factor Receptor Mutation Positive non-small cell lung cancer

Detailed description: This is a phase 3 double-blind, randomized, placebo-controlled, study to assess the efficacy and safety of osimertinib following chemoradiation in patients with stage III unresectable EGFR mutation-positive NSCLC, including the most common EGFR sensitising mutations (Ex19Del and L858R), either alone or in combination with other EGFR mutations. Chemoradiation may have been given either given concurrently or sequentially. Patients whose disease has not progressed following chemoradiation will be randomised within 6 weeks of completion of chemoradiation to receive osimertinib or placebo in a 2:1 ratio, and treatment will be continued until disease progression, unacceptable toxicity or other discontinuation criteria are met. After progression, patients can be unblinded and may receive open-label osimertinib. After the final OS analysis, the study blind will be broken and patients still receiving open-label osimertinib will be supplied with open-label osimertinib by AstraZeneca for as long as their treating physician considers they are deriving clinical benefit.

Eligibility criteria: Inclusion Criteria

1. Male or female aged at least 18 years.
2. 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).
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

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 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 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

Primary outcomes:
measure: Progression-free Survival (PFS) by Blinded Independent Central Review (BICR)
timeFrame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Secondary outcomes:
measure: Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Ex19del or L858R Mutation
timeFrame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
measure: Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Mutations Ex19del or L858R Detectable in Plasma-derived ctDNA
timeFrame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
measure: Central Nervous System (CNS) Progression-free Survival (PFS) by Blinded Independent Central Review (BICR)
timeFrame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
measure: Overall Survival (Count)
timeFrame: Date of randomisation to date of death by any cause. Assessed up to a maximum of approximately 63 months
measure: Overall Survival (Duration)
timeFrame: Date of randomisation to date of death by any cause. Assessed up to a maximum of approximately 63 months
measure: Objective Response Rate by Blinded Independent Central Review (BICR)
timeFrame: Every 8 weeks for first 48 weeks, then every 12 weeks until radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
measure: Duration of Response, Unconfirmed by Blinded Independent Central Review (BICR)
timeFrame: Every 8 weeks for first 48 weeks, then every 12 weeks until radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
measure: Disease Control Rate by Blinded Independent Central Review (BICR)
timeFrame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
measure: Tumour Shrinkage by Blinded Independent Central Review (BICR)
timeFrame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
measure: Proportion With Tumour Shrinkage by Blinded Independent Central Review (BICR)
timeFrame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
measure: Time to Death or Distant Metastases by Blinded Independent Central Review (BICR)
timeFrame: Time from randomisation to the date of distant metastases or death. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
measure: Time to Study Treatment Discontinuation
timeFrame: Time from randomisation to the earlier of the date of study treatment discontinuation or death. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
measure: Time to First Subsequent Treatment
timeFrame: Time from randomisation to the start of first subsequent anti-cancer therapy or death. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
measure: Time to Second Subsequent Treatment
timeFrame: Time from randomisation to the start of second subsequent anti-cancer therapy or death. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
measure: Second Progression-free Survival (PFS2)
timeFrame: Every 8 weeks for first 48 weeks, then every 12 weeks. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Research Site
state: California
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Florham Park
country: United States
facility: Research Site
state: New Jersey
city: Salt Lake City
country: United States
facility: Research Site
state: Utah
city: Madison
country: United States
facility: Research Site
state: Wisconsin
city: Ciudad Autónoma de Bs. As.
country: Argentina
facility: Research Site
city: Ciudad Autónoma de Bs. As.
country: Argentina
facility: Research Site
city: Mar del Plata
country: Argentina
facility: Research Site
city: Rosario
country: Argentina
facility: Research Site
city: San Salvador de Jujuy
country: Argentina
facility: Research Site
city: Barretos
country: Brazil
facility: Research Site
city: Curitiba
country: Brazil
facility: Research Site
city: Florianópolis
country: Brazil
facility: Research Site
city: Fortaleza
country: Brazil
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Ribeirão Preto
country: Brazil
facility: Research Site
city: Sao Paulo
country: Brazil
facility: Research Site
city: São Paulo
country: Brazil
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Changchun
country: China
facility: Research Site
city: Changsha
country: China
facility: Research Site
city: Chengdu
country: China
facility: Research Site
city: Guangzhou
country: China
facility: Research Site
city: Hangzhou
country: China
facility: Research Site
city: Hangzhou
country: China
facility: Research Site
city: Hangzhou
country: China
facility: Research Site
city: Jinan
country: China
facility: Research Site
city: Linhai
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Urumqi
country: China
facility: Research Site
city: Wuhan
country: China
facility: Research Site
city: Wuhan
country: China
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Gyöngyös - Mátraháza
country: Hungary
facility: Research Site
city: Pécs
country: Hungary
facility: Research Site
city: Bangalore
country: India
facility: Research Site
city: Gurgaon
country: India
facility: Research Site
city: Hubli
country: India
facility: Research Site
city: Karamsad
country: India
facility: Research Site
city: Kolkata
country: India
facility: Research Site
city: Nashik
country: India
facility: Research Site
city: New Delhi
country: India
facility: Research Site
city: New Delhi
country: India
facility: Research Site
city: New Delhi
country: India
facility: Research Site
city: Hiroshima-shi
country: Japan
facility: Research Site
city: Kanazawa-shi
country: Japan
facility: Research Site
city: Kashiwa
country: Japan
facility: Research Site
city: Nagoya-shi
country: Japan
facility: Research Site
city: Niigata-shi
country: Japan
facility: Research Site
city: Osaka-shi
country: Japan
facility: Research Site
city: Osakasayama
country: Japan
facility: Research Site
city: Sakai-shi
country: Japan
facility: Research Site
city: Sapporo-shi
country: Japan
facility: Research Site
city: Sendai-shi
country: Japan
facility: Research Site
city: Shinjuku-ku
country: Japan
facility: Research Site
city: Sunto-gun
country: Japan
facility: Research Site
city: Yokohama-shi
country: Japan
facility: Research Site
city: Cheongju-si
country: Korea, Republic of
facility: Research Site
city: Incheon
country: Korea, Republic of
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: George Town
country: Malaysia
facility: Research Site
city: Kuala Lumpur
country: Malaysia
facility: Research Site
city: Selangor
country: Malaysia
facility: Research Site
city: Mérida
country: Mexico
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: San Isidro
country: Peru
facility: Research Site
city: Kazan
country: Russian Federation
facility: Research Site
city: Kostroma
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Novisibirsk
country: Russian Federation
facility: Research Site
city: Obninsk
country: Russian Federation
facility: Research Site
city: Saint-Petersburg
country: Russian Federation
facility: Research Site
city: Saint-Petersburg
country: Russian Federation
facility: Research Site
city: Ufa
country: Russian Federation
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Málaga
country: Spain
facility: Research Site
city: San Sebastián
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Kaohsiung
country: Taiwan
facility: Research Site
city: Taichung City
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Tainan City
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taoyuan
country: Taiwan
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Hat Yai
country: Thailand
facility: Research Site
city: Khon Kaen
country: Thailand
facility: Research Site
city: Lampang
country: Thailand
facility: Research Site
city: Mueang
country: Thailand
facility: Research Site
city: Adana
country: Turkey
facility: Research Site
city: Adapazari
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: Izmir
country: Turkey
facility: Research Site
city: Ha Noi
country: Vietnam
facility: Research Site
city: Hanoi
country: Vietnam
facility: Research Site
city: Ho Chi Minh
country: Vietnam
facility: Research Site
city: Ho Chi Minh
country: Vietnam
facility: Research Site
Study officials:
affiliation: Emory University School of Medicine, Atlanta, U.S.
name: Suresh S Ramalingam, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Shanghai Chest Hospital, Shanghai, China
name: Shun Lu, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lu S, Casarini I, Kato T, Cobo M, Ozguroglu M, Hodge R, van der Gronde T, Saggese M, Ramalingam SS. Osimertinib Maintenance After Definitive Chemoradiation in Patients With Unresectable EGFR Mutation Positive Stage III Non-small-cell Lung Cancer: LAURA Trial in Progress. Clin Lung Cancer. 2021 Jul;22(4):371-375. doi: 10.1016/j.cllc.2020.11.004. Epub 2021 Jan 6.