Health Condition 1: C349- Malignant neoplasm of unspecifiedpart of bronchus or lung Health Condition 2: C349- Malignant neoplasm of unspecifiedpart of bronchus or lung
Conditions
Interventions
Intervention1: 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
Control Interve
Sponsors
AstraZeneca AB
Eligibility
Inclusion criteria
Inclusion criteria: 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 -Mean esophagus dose -Heart V50 10.World Health Organization (WHO) performance status of 0 or 1 at Part II screening and Day
Exclusion criteria
Exclusion criteria: 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 -Platelet count -Haemoglobin -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 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 the
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 Timepoint: Overall Survival (OS) (Time frame-Approximately 5 years) | — |
Secondary
| Measure | Time frame |
|---|---|
| Exploratory objectives: To assess potential treatment-related adverse effects in patients treated with osimertinib compared with placebo using PRO-CTCAETimepoint: Overall Survival (OS) (Time frame-Approximately 5 years);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 ctDNATimepoint: Overall Survival (OS) (Time frame-Approximately 5 years);To assess disease-related symptoms and health-related QoL in patients treated with osimertinib compared with placeboTimepoint: Overall Survival (OS) (Time frame-Approximately 5 years);To assess the efficacy of osimertinib versus placebo on CNS PFSTimepoint: Overall Survival (OS) (Time frame-Approximately 5 years);To assess the efficacy of osimertinib versus placebo on CNS PFS Timepoint: Overall Survival (OS) (Time frame-Approximately 5 years);To assess the patients’ overall impression of the severity of their cancer symptoms using PGISTimepoint: Overall Survival (OS) (Time frame-Approximately 5 years);To assess the PK of osimertinibTimepoint: Overall Survival (OS) (Time frame-Approximately 5 years);To assess the safety and tolerability profile of osimertinib compared with placeboTimepoint: Overall Survival (OS) (Time frame-Approximately 5 years);To compare health resource use associated with osimertinib treatment versus placeboTimepoint: Overall Survival (OS) (Time frame-Approximately 5 years);To compare osimertinib treatment with placebo treatment on health state utilityTimepoint: Overall Survival (OS) (Time frame-Approximately 5 years);To further assess the efficacy of osimertinib compared to placebo post progressionTimepoint: 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 appropriateTimepoi | — |
Countries
Argentina, China, India, Japan, Republic of Korea, Spain, Taiwan, Thailand, Turkey, United States of America, Viet Nam
Contacts
Public ContactMr Sandeep AV
AstraZeneca Pharma India Ltd.
Outcome results
None listed