Clinical trial NCT04035486: A Study of Osimertinib With or Without Chemotherapy as 1st Line Treatment in Patients With Mutated Epidermal Growth Factor Receptor Non-Small Cell Lung Cancer (FLAURA2)
Official title: A Phase III, Open-label, Randomized Study of Osimertinib With or Without Platinum Plus Pemetrexed Chemo, as First-line Treatment in Patients With Epidermal Growth Factor Receptor (EGFR) Mutation Positive, Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA2).
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Non-Small Cell Lung Cancer
Keywords: Locally
Advanced
Metastatic
Carcinoma
Non-Small Cell Lung Cancer
Osimertinib
Tagrisso
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2019-07-29
Enrollment: 587
Sex: ALL
Minimum age (years): 18
Maximum age (years): 110
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel Assignment
Primary purpose: TREATMENT

Brief summary: The reason for the study is to find out if an experimental combination of an oral medication called osimertinib (TAGRISSO®) when used in combination with chemotherapy is more effective than giving osimertinib alone for the treatment of locally advanced or metastatic non-small cell lung cancer. Some lung cancers are due to mutations in the Deoxyribonucleic acid (DNA) which, if known, can help physicians decide the best treatment for their patients. One type of mutation can occur in the gene that produces a protein on the surface of cells called the Epidermal Growth Factor Receptor (EGFR).

Osimertinib is an Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets Epidermal Growth Factor Receptor (EGFR) mutations. Unfortunately, despite the benefit observed for patients treated with osimertinib, the vast majority of cancers are expected to develop resistance to the drug over time. The exact reasons why resistance develops are not fully understood but based upon clinical research it is hoped that combining osimertinib with another type of anti-cancer therapy known as chemotherapy will delay the onset of resistance and the worsening of a patient's cancer.

In total the study aims to enroll approximately 586 patients, consisting of approximately 30 patients who will participate in a safety run-in component of the trial, and approximately 556 who will receive osimertinib alone or osimertinib in combination with chemotherapy in the main trial. In the main part of the trial there is a one in two chance of receiving osimertinib alone, and the treatment is decided at random by a computer.

The study involves a Screening Period, Treatment Period, and Follow up Period. Whilst receiving study medication, it is expected patients will attend, on average, approximately 15 visits over the first 12 months and then approximately 4 visits per year afterwards. Each visit will last about 2 to 6 hours depending on the arrangement of medical assessments by the study centre.


Eligibility criteria: Inclusion Criteria:

1. Male or female, at least 18 years of age; patients from Japan at least 20 years of age.
2. Pathologically confirmed non-squamous Non-Small Cell Lung Cancer (NSCLC). NSCLC of mixed histology is allowed.
3. Newly diagnosed locally advanced (clinical stage IIIB, IIIC) or metastatic Non-Small Cell Lung Cancer (NSCLC) (clinical stage IVA or IVB) or recurrent Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiotherapy.
4. The tumor harbors 1 of the 2 common epidermal growth factor receptor (EGFR) mutations known to be associated with Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) sensitivity (Ex19del or L858R), either alone or in combination with other epidermal growth factor receptor (EGFR) mutations, which may include T790M.
5. Patients must have untreated advanced Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiotherapy.
6. WHO PS of 0 to 1 at screening with no clinically significant deterioration in the previous 2 weeks.
7. Life expectancy \>12 weeks at Day 1.
8. Willing to use contraception as appropriate during the study and for a period of time after discontinuing study treatment.

Exclusion Criteria:

1. Spinal cord compression; and unstable brain metastases, with stable brain metastases who have completed definitive therapy, are not on steroids, and have a stable neurological status for at least 2 weeks after completion of the definitive therapy and steroids can be enrolled. Patients with asymptomatic brain metastases can be eligible for inclusion if in the opinion of the Investigator immediate definitive treatment is not indicated
2. Past medical history of Interstitial Lung Disease (ILD), drug-induced Interstitial Lung Disease, radiation pneumonitis that required steroid treatment, or any evidence of clinically active Interstitial Lung Disease.
3. 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 jeopardize compliance with the protocol, or active infection including Hep. B, Hep. C and HIV. Screening for chronic conditions is not required. Active infection will include any patients receiving treatment for infection.
4. QT prolongation or any clinically important abnormalities in rhythm.
5. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

   * Absolute neutrophil count below the lower limit of normal (\<LLN)
   * Platelet count below the LLN
   * Hemoglobin \<90 g/L. The use of granulocyte colony stimulating factor support, platelet transfusion and blood transfusions to meet these criteria is not permitted.
   * ALT \>2.5 x the upper limit of normal (ULN) if no demonstrable liver metastases or \>5 x ULN in the presence of liver metastases
   * AST \>2.5 x ULN if no demonstrable liver metastases or \>5 x ULN in the presence of liver metastases
   * Total bilirubin \>1.5 x ULN if no liver metastases or \>3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases
   * Creatinine clearance \<60 mL/min calculated by Cockcroft and Gault equation or 24 hour urine collection (refer to Appendix I for appropriate calculation)
6. 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.
7. Prior treatment with any systemic anti-cancer therapy for advanced Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiation including chemotherapy, biologic therapy, immunotherapy, or any investigational drug. Prior adjuvant and neo-adjuvant therapies (chemotherapy, radiotherapy, immunotherapy, biologic therapy, investigational agents), or definitive radiation/chemoradiation with or without regimens including immunotherapy, biologic therapies, investigational agents are permitted as long as treatment was completed at least 12 months prior to the development of recurrent disease.
8. Prior treatment with an Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI).
9. Major surgery within 4 weeks of the first dose of investigational product (IP). Procedures such as placement of vascular access, biopsy via mediastinoscopy or biopsy via video assisted thoracoscopic surgery are permitted.
10. Radiotherapy treatment to more than 30% of the bone marrow or( with a wide field of radiation within 4 weeks of the first dose of investigational product (IP).
11. History of hypersensitivity to active or inactive excipients of investigational product (IP) or drugs with a similar chemical structure or class to investigational product (IP).

Primary outcomes:
measure: Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only)
timeFrame: From first dose date to 28 days following last dose, up to 45 months
measure: Progression-free Survival (PFS) (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized (maximum follow up of 33.3 months)
measure: Sensitivity Analysis for Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Assessment (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized (maximum follow up of 33.2 months).
Secondary outcomes:
measure: Overall Survival (OS) (Safety Run-In Treatment Arms Only)
timeFrame: Up to 45 months (maximum follow up 44.6 months)
measure: Duration of Response (DoR) (Safety Run-In Treatment Arms Only)
timeFrame: Up to 45 months
measure: Objective Response Rate (ORR) (Safety Run-In Treatment Arms Only)
timeFrame: Up to 45 months
measure: Depth of Response (Percent Change From Baseline in Tumor Diameter) (Safety Run-In Treatment Arms Only)
timeFrame: Up to 45 months
measure: Disease Control Rate (DCR) by Investigator (Safety Run-In Treatment Arms Only)
timeFrame: Up to 45 months
measure: Overall Survival (OS) (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized (maximum follow up of 34.1 months)
measure: Landmark Overall Survival (LOS) at 1, 2, and 3 Years (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized (maximum follow up of 34.1 months)
measure: Objective Response Rate (ORR) (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Duration of Response (DoR) (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Depth of Response (Percent Change From Baseline in Tumor Diameter) (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Disease Control Rate (DCR) by Investigator (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Progression Free Survival 2 (PFS2) (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Time to First Subsequent Therapy (TFST) or Death (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Time to Second Subsequent Therapy (TSST) or Death (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: Exon 19 Deletion (Randomized Component)
timeFrame: Screening/Baseline
measure: Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: L858R (Randomized Component)
timeFrame: Screening/Baseline
measure: Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: Exon 19 Deletion - Participants With an Event (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: L858R - Participants With an Event (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component)
timeFrame: Pre-dose and 1-hour post-dose on Day 22; pre-dose, 1-, 2-, 4-, and 6-hours post-dose on Day 43; pre-dose and 1-hour post-dose on Day 106.
measure: Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component)
timeFrame: Pre-dose and 1-hour post-dose on Day 22; pre-dose, 1-, 2-, 4-, and 6-hours post-dose on Day 43; pre-dose and 1-hour post-dose on Day 106.
measure: Mean Cmin,ss and Mean Cmax,ss of Osimertinib (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Mean Cmin,ss and Mean Cmax,ss of AZ5104 (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Mean AUCss of Osimertinib (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Mean AUCss of AZ5104 (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
measure: Mean CLss/F of Osimertinib (Randomized Component)
timeFrame: Up to approximately 33 months after the first patient is randomized.
Other outcomes:
Locations:
city: Bellflower
country: United States
facility: Research Site
state: California
city: Fullerton
country: United States
facility: Research Site
state: California
city: La Jolla
country: United States
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city: Santa Monica
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state: Virginia
city: Fairfax
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state: Virginia
city: Vancouver
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state: Washington
city: Buenos Aires
country: Argentina
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city: Buenos Aires
country: Argentina
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city: Caba
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city: Caba
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city: Ciudad de Buenos Aires
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city: Cordoba
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city: Heidelberg
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city: São José do Rio Preto
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city: Vitoria
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city: Calgary
country: Canada
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state: Alberta
city: Edmonton
country: Canada
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city: Toronto
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state: Ontario
city: Santiago
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city: Santiago
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city: Temuco
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city: Viña del Mar
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country: China
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city: Changsha
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city: Chengdu
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city: Chongqing
country: China
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city: Guangzhou
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city: Haikou
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city: Hangzhou
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city: Hangzhou
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city: Harbin
country: China
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city: Hefei
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city: Jinan
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city: Nanjing
country: China
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city: Shanghai
country: China
facility: Research Site
city: Shanghai
country: China
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city: Shenyang
country: China
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city: Urumqi
country: China
facility: Research Site
city: Wuhan
country: China
facility: Research Site
city: Xi'an
country: China
facility: Research Site
city: Zhengzhou
country: China
facility: Research Site
city: Olomouc
country: Czechia
facility: Research Site
city: Ostrava - Vitkovice
country: Czechia
facility: Research Site
city: Praha 5
country: Czechia
facility: Research Site
city: Praha
country: Czechia
facility: Research Site
city: Bordeaux Cedex
country: France
facility: Research Site
city: Lyon
country: France
facility: Research Site
city: Montpellier
country: France
facility: Research Site
city: Villejuif Cedex
country: France
facility: Research Site
city: Belagavi
country: India
facility: Research Site
city: Bengaluru
country: India
facility: Research Site
city: Gurgaon
country: India
facility: Research Site
city: Kolkata
country: India
facility: Research Site
city: New Delhi
country: India
facility: Research Site
city: Pune
country: India
facility: Research Site
city: Bunkyo-ku
country: Japan
facility: Research Site
city: Bunkyo-ku
country: Japan
facility: Research Site
city: Fukuoka
country: Japan
facility: Research Site
city: Hidaka-shi
country: Japan
facility: Research Site
city: Himeji-shi
country: Japan
facility: Research Site
city: Iwakuni-shi
country: Japan
facility: Research Site
city: Kanazawa
country: Japan
facility: Research Site
city: Kashiwa
country: Japan
facility: Research Site
city: Koto-ku
country: Japan
facility: Research Site
city: Osaka-shi
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: 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: Goyang-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: Seoul
country: Korea, Republic of
facility: Research Site
city: Arequipa
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: Cebu City
country: Philippines
facility: Research Site
city: Davao City
country: Philippines
facility: Research Site
city: Iloilo City
country: Philippines
facility: Research Site
city: Las Pinas
country: Philippines
facility: Research Site
city: Legazpi City
country: Philippines
facility: Research Site
city: Quezon City
country: Philippines
facility: Research Site
city: Quezon City
country: Philippines
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Murmansk
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: Saint-Petersburg
country: Russian Federation
facility: Research Site
city: Syktyvkar
country: Russian Federation
facility: Research Site
city: Bratislava
country: Slovakia
facility: Research Site
city: Kosice
country: Slovakia
facility: Research Site
city: Poprad
country: Slovakia
facility: Research Site
city: Johannesburg
country: South Africa
facility: Research Site
city: Port Elizabeth
country: South Africa
facility: Research Site
city: Rondebosch
country: South Africa
facility: Research Site
city: Changhua
country: Taiwan
facility: Research Site
city: Hualien City
country: Taiwan
facility: Research Site
city: Kaohsiung
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
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: Hat Yai
country: Thailand
facility: Research Site
city: Khon Kaen
country: Thailand
facility: Research Site
city: Muang
country: Thailand
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Leicester
country: United Kingdom
facility: Research Site
city: Liverpool
country: United Kingdom
facility: Research Site
city: Maidstone
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Hanoi
country: Vietnam
facility: Research Site
city: Ho Chi Minh
country: Vietnam
facility: Research Site
Study officials:
affiliation: Dana Farber Cancer Institute, 450 Brookline Avenue, LC4114, Boston, MA 02215, USA
name: Pasi A. Jänne, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Respiratory Medicine, Saitama Medical University International Medical Center, Saitama, Japan
name: Kunihiko Kobayashi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Medical Oncology - Institut Gustave Roussy (IGR) - Villejuif - France
name: David Planchard, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Planchard D, Feng PH, Karaseva N, Kim SW, Kim TM, Lee CK, Poltoratskiy A, Yanagitani N, Marshall R, Huang X, Howarth P, Janne PA, Kobayashi K. Osimertinib plus platinum-pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study. ESMO Open. 2021 Oct;6(5):100271. doi: 10.1016/j.esmoop.2021.100271. Epub 2021 Sep 17.
citation: White MN, Piotrowska Z, Stirling K, Liu SV, Banwait MK, Cunanan K, Sequist LV, Wakelee HA, Hausrath D, Neal JW. Combining Osimertinib With Chemotherapy in EGFR-Mutant NSCLC at Progression. Clin Lung Cancer. 2021 May;22(3):201-209. doi: 10.1016/j.cllc.2021.01.010. Epub 2021 Jan 27.
citation: Asahina H, Tanaka K, Morita S, Maemondo M, Seike M, Okamoto I, Oizumi S, Kagamu H, Takahashi K, Kikuchi T, Isobe T, Sugio K, Kobayashi K. A Phase II Study of Osimertinib Combined With Platinum Plus Pemetrexed in Patients With EGFR-Mutated Advanced Non-Small-cell Lung Cancer: The OPAL Study (NEJ032C/LOGIK1801). Clin Lung Cancer. 2021 Mar;22(2):147-151. doi: 10.1016/j.cllc.2020.09.023. Epub 2020 Oct 16.