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A Phase III, Open-label, Randomized Study of Osimertinib with or without Platinum Plus Pemetrexed Chemotherapy, as First-line Treatment in Patients with Epidermal Growth Factor Receptor (EGFR) Mutation-Positive, Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA2)

PHRR200514-002656

D5169C00001

2020-CT0527

A Phase III, Open-label, Randomized Study of Osimertinib with or without Platinum Plus Pemetrexed Chemotherapy, as First-line Treatment in Patients with Epidermal Growth Factor Receptor (EGFR) Mutation-Positive, Locally Advanced or Metastatic Non-small Cell Lung Cancer 

This is a global Phase III, open-label, randomized study of osimertinib with or without platinum plus pemetrexed chemotherapy conducted in patients with locally-advanced or metastatic EGFRm (Ex19del and/or L858R) NSCLC who have not received any prior therapy for advanced disease. The proposed study will include patients with EGFRm NSCLC who have either: (1) a pre-existing positive (Ex19del or L858R) tissue test result obtained from a CLIA-certified local laboratory (for US sites) or from an accredited local laboratory (for sites outside of the US); or (2) have a positive tissue Ex19del or L858R EGFR mutation test based on the cobas® EGFR Mutation Test v2 conducted prospectively in a central laboratory.

Regime Classification Priority
2017 - 2022 Global competitiveness and innovation in health Diagnostics
Start Date Duration in Months Target Completion Date Actual Completion Date
2020-04-24 70 2026-02-24 0000-00-00

Ongoing

Institution Classification Region LTO #
AstraZeneca Pharmaceuticals (Philippines) Inc. Private Business NCR LTO-3000002234602
Institution Classification Region LTO #
None None None
Institution Region
AstraZeneca AB Sweden
Name E-Mail Institution and Institution Address
Rodgiene Garcia rodgiene.garcia@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippines
Name E-Mail Institution and Institution Address
Rodgiene Garcia rodgiene.garcia@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippines
Name Expertise Affiliation
Annielyn Beryl Ong-Cornel, MD Oncology University of Perpetual Help DALTA Medical Center
Arthur Gregory Lui, MD Oncology Metro Davao Medical and Research Center
Guia Elena Imelda R. Ladrera, MD Oncology Lung Center of the Philippines
Jandre Jomar Alipat, MD Oncology West Visayas State University Medical Center
Jennifer Sandoval-Tan, MD Oncology University of the Philippines - Philippine General Hospital
Jerry Tan Chun Bing, MD Oncology Cebu Doctors' University Hospital
May Sabando, MD Internal Medicine Bicol Regional Training and Teaching Hospital
Rubi K. Li, MD Oncology St. Luke's Medical Center - Quezon City
Project Location Institutional Ethics Review Board
University of Perpetual Help DALTA Medical Center University of Perpetual Help DALTA Medical Center Ethics Review Committee
Metro Davao Medical and Research Center Metro Davao Medical and Research Center – Ethics Review Committee
Lung Center of the Philippines Lung Center of the Philippines Ethics Review Committee
West Visayas State University Medical Center N/A
University of the Philippines - Philippine General Hospital N/A
Cebu Doctors' University Hospital Cebu Doctors' University Hospital - Institutional Ethics Review Committee
Bicol Regional Training and Teaching Hospital Bicol Regional Training and Teaching Hospital Institutional Review Board
St. Luke's Medical Center - Quezon City St. Luke's Medical Center Institutional Ethics Review Board

Non-small Cell Lung Cancer

Adverse events graded by CTCAE v5; Clinical chemistry, hematology and urinalysis; Vital signs (pulse and blood pressure); physical examination; weight; LVEF; ECG parameters; WHO Performance Status

  • ORR, DoR; depth of response; DCR by Investigator; OS;
  • Steady-state plasma concentrations and appropriate PK parameters (CLss/F, Cmax,ss Cmin,ss and AUCss) of osimertinib and its metabolite, AZ5104 will be summarized.

Pending

  • Argentina
  • Australia
  • Brazil
  • Canada
  • Chile
  • China
  • Czech Republic
  • France
  • India
  • Japan
  • Peru
  • Philippines
  • Russia
  • Slovakia
  • South Africa
  • South Korea
  • Taiwan
  • Thailand
  • United Kingdom
  • United States
  • Vietnam

Clinical Trial

D5169C00001

20200213142021

2020-04-24

0000-00-00

36

Unspecified

Unspecified

24 Apr 2020

INCLUSION CRITERIA

Informed consent
1 Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
2 Provision of signed and dated, written informed consent form prior to any mandatory study-specific procedures, sampling, and analyses.
3 For patients who agree to the optional genetic testing, provision of signed and dated genetic testing section of the written Main ICF prior to collection of a sample for genetic analysis for inclusion in the optional genetic research as allowed by local regulations.


Age
4 Male or female, at least 18 years of age; patients from Japan at least 20 years of age.

Type of patient and disease characteristics
5 Pathologically confirmed nonsquamous NSCLC
6 Newly diagnosed locally advanced (clinical stage IIIB, IIIC) or metastatic NSCLC (clinical stage IVA or IVB) or recurrent NSCLC (per Version 8 of the International Association for the Study of Lung Cancer [IASLC] Staging Manual in Thoracic Oncology), not amenable to curative surgery or radiotherapy.
7 The tumor harbors 1 of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations, which may include T790M, assessed by a CLIA-certified (US sites) or an accredited (outside of the US) local laboratory or by central prospective tissue testing.
8 Mandatory provision of a baseline plasma sample and an unstained, archival tumor tissue sample in a quantity sufficient to allow for central confirmation of the EGFR mutation status.
9 Patients must have untreated advanced NSCLC not amenable to curative surgery or radiotherapy. Prior adjuvant and neo-adjuvant therapies (chemotherapy, radiotherapy, immunotherapy, biologic therapy, investigational agents), or definitive radiation/chemoradiation with or without regimens including immunotherapy, biologic therapy, investigational agents, are permitted as long as treatment was completed at least 12 months prior to the development of recurrent disease.
10 WHO PS of 0 to 1 at screening with no clinically significant deterioration in the previous 2 weeks.
11 Life expectancy >12 weeks at Day 1.
12 At least 1 lesion, not previously irradiated that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have a short axis of ≥15 mm) with CT or MRI, and that is suitable for accurate repeated measurements. If only 1 measurable lesion exists, it is acceptable to be used (as a target lesion) as long as it has not been previously irradiated and as long as it has not been biopsied within 14 days of the baseline tumor assessment scans.

Reproduction
13 Female patients who are not abstinent (in line with the preferred and usual lifestyle choice of the patient) and intend to be sexually active with a male partner must be using highly effective contraceptive measures, must not be breast feeding, and must have a negative pregnancy test prior to first dose of IP or must have evidence of non-child-bearing potential by fulfilling 1 of the following criteria at screening:

− Post-menopausal, defined as more than 50 years of age and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
− Women under 50 years old would be considered as postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution
− Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.

14 Male patients must be willing to use barrier contraception.

EXCLUSION CRITERIA

Medical conditions
1 Spinal cord compression; symptomatic and unstable brain metastases, except for those patients 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. 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 ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD.
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 hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
4 Any of the following cardiac criteria:
• Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine-derived QTcF value;
• Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG; eg, complete left bundle branch block, third-degree heart block, second-degree heart block;
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as electrolyte abnormalities including serum/plasma potassium*, magnesium* and calcium* below the LLN, heart failure, 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. * correction of electrolyte abnormalities to within normal ranges can be performed during screening

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 *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 6 Any concurrent and/or other active malignancy that has required treatment within 2 years of first dose of IP.
7 Any unresolved toxicities from prior systemic therapy (eg, adjuvant chemotherapy) greater than CTCAE Grade 1 at the time of starting study treatment, with the exception of alopecia and Grade 2 prior platinum-therapy related neuropathy.
8 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
9 Prior treatment with any systemic anti-cancer therapy for advanced 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.

10 Prior treatment with an EGFR-TKI.
11 Major surgery within 4 weeks of the first dose of IP. Procedures such as placement of vascular access, biopsy via mediastinoscopy or biopsy via video assisted thoracoscopic surgery (VATS) are permitted.
12 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 IP.
13 Current use of (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP) 3A4 (at least 3 weeks prior).

Prior/concurrent clinical study experience
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.

Other exclusions
15 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and 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 Previous treatment allocation (safety run in) or randomization (randomization period) in the present study.
18 Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
19 History of hypersensitivity to active or inactive excipients of IP or drugs with a similar chemical structure or class to IP.
20 Contraindication for pemetrexed and cisplatin/carboplatin according to local approved label.
21 In addition, the following are considered criteria for exclusion from the exploratory genetic research:
• Prior allogeneic bone marrow transplant
• Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection.

Interventional

Osimertinib

Osimertinib is considered the preferred SoC for the first-line treatment of patients with metastatic EGFRm NSCLC given its superiority over the first-generation EGFR-TKI therapies (gefitinib/erlotinib). The tolerability profile of osimertinib when given as monotherapy is well characterized and suitable for long term dosing.

Date Amendment Classification Reason
2020-12-15 Amendments related to the protocol Informed consent

Randomized

Open Label

Unspecified

Not Applicable

To evaluate the safety and tolerability of osimertinib plus chemotherapy

Phase III

Utilization Utilization Info
Publication
Oral Presentation
Drug Literature
Posters
Others
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