A PHASE III, RANDOMISED, CONTROLLED, MULTI-CENTRE, 3-ARM STUDY OF NEOADJUVANT OSIMERTINIB AS MONOTHERAPY OR IN COMBINATION WITH CHEMOTHERAPY VERSUS STANDARD OF CARE CHEMOTHERAPY ALONE FOR THE TREATMENT OF PATIENTS WITH EPIDERMAL GROWTH FACTOR RECEPTOR MUTATION POSITIVE, RESECTABLE NON-SMALL CELL LUNG CANCER (NEOADAURA)
- Conditions
- -C349 Bronchus or lung, unspecifiedBronchus or lung, unspecifiedC349
- Registration Number
- PER-091-20
- Lead Sponsor
- AstraZeneca AB,
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 0
Informed consent
1 Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
2 Provision of signed and dated written ICF 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 written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative (as allowed per local regulations).
Age and Sex
4 Male or female, at least 18 years of age.
Type of patient and disease characteristics
5 Histologically or cytologically documented non-squamous NSCLC with completely resectable (Stage II -IIIB N2) disease (according to Version 8 of the IASLC Cancer Staging Manual [IASLC Staging Manual in Thoracic Oncology 2016]).
6 Complete surgical resection of the primary NSCLC must be deemed achievable, as assessed by a MDT evaluation (which should include a thoracic surgeon, specialised in oncologic procedures).
7 Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1 at enrolment, with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.
8 Adequate organ and marrow function as defined below:
• Haemoglobin: ≥9.0 g/dL*
• Absolute neutrophil count: ≥1.5 × 109/L*
• Platelet count: ≥100 × 109/L*.
* Note: The use of granulocyte colony stimulating factor (G-CSF) support, platelet transfusion and blood transfusions to meet these criteria is not permitted.
• Serum bilirubin: ≤1.5 × the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (unconjugated hyperbilirubinemia), who will be allowed in consultation with their physician.
• ALT and AST: ≤2.5 × ULN.
• Creatinine clearance ≥50 mL/min calculated by Cockcroft and Gault equation
9 Life expectancy of >6 months prior to randomisation.
Tumour sample requirements
10 A tumour which harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations (ie, T790M, G719X, Exon20 insertions, S7681 and L861Q).
Reproduction
11 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, and must have a negative pregnancy test prior to first dose of any study treatment if they are of child-bearing potential; 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
12 Male patients must be willing to use barrier contraception
Medical conditions
1 History of allogeneic organ transplantation
2 Any evidence of severe or uncontrolled systemic diseases (as judged by the Investigator), 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). 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.
3 Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
4 History of another primary malignancy, except for the following:
• Malignancy treated with curative intent and with no known active disease ≥2 years before the first dose of investigational product (IP) and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo malignancy without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease.
5 History of active primary immunodeficiency.
6 Patients who have pre-operative radiotherapy treatment as part of their care plan.
7 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.
8 Mixed small cell and NSCLC histology.
9 Stages I, IIIB N3, IIIC, IVA, and IVB NSCLC.
10 T4 tumours infiltrating the aorta, the oesophagus and/or the heart; and/or any bulky N2 disease.
11 Patients who are candidates to undergo only segmentectomies or wedge resections.
12 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 or by manual calculation;
• Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, second-degree heart block, and third-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 Pointe
* correction of electrolyte abnormalities to within normal ranges can be performed during screening
13 Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
Prior/concomitant therapy
14 Prior treatment with any systemic anti-cancer therapy for NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug
15 Prior treatment with EGFR-TKI therapy
16 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 l
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <br>Outcome name:Determination of efficacy of osimertinib as monotherapy or in combination wit chemotherapy compared to chemotherapy alone as neoadjuvant tratment as assessed per central pathology laboratory<br>Measure:Major pathological response (MPR) (defined as ≤10% residual cancer cells in the surgical specimen post-surgery<br>Timepoints:Since randomization until post surgery<br>
- Secondary Outcome Measures
Name Time Method