| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung cancer called "non small cell lung cancer (NSCLC)" |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the best strategy for delivering osimertinib (AZD9291) in NSCLC patients with EGFR mutation. The objective is assessed by Progression Free Survival rate at 18 months (PFSR-OSI-18). |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate PFS on osimertinib measured from randomization by RECIST criteria 1.1.
• To evaluate PFS measured from switching to osimertinib by RECIST criteria 1.1.
• To determine the proportion of patients receiving osimertinib based on the determination of cfDNA T790M mutation positive.
• To evaluate PFS-2.
• To evaluate Overall Response Rate (ORR) to osimertinib.
• To evaluate the Treatment duration.
• To evaluate Time to progression (TTP) on osimertinib (measured from switching to osimertinib).
• To evaluate Overall Survival (OS).
• To evaluate brain progression free survival (BPFS).
• Safety |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Registration
• Pathological diagnosis of adenocarcinoma of the lung carrying common EGFR activating mutations associated with EGFR-TKI sensitivity (Del19 or L858R); performed locally; no other EGFR mutations will be allowed. In case of other (than EGFR) concomitant mutations, discussion with EORTC Headquarters is mandatory;
• Stage IV NSCLC;
• Blood sample available for cfDNA EGFR T790M central testing;
• Adequate tissue sample in quantity and quality for translational research;
• Age ≥18 years;
• EGFR TKI treatment-naïve eligible to receive first-line treatment with EGFR TKI;
• Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy, investigational agents) if performed more than 12 months before registration;
• Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations.
Randomization
• Report of adequacy sample for cfDNA EGFR T790M test by central laboratory;
• Prior palliative radiotherapy or surgical procedures are allowed if completed at least 4 weeks before randomization;
• Patients with brain metastases are allowed provided they are stable (i.e. without evidence of progression by imaging for at least two weeks prior to the first dose of trial treatment and without deterioration of any neurologic symptoms), and have not received steroids for at least 7 days before randomization;
•Baseline tumor assessment scans are done within 21 days before randomization
• Evaluable disease as defined below;
• At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, 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 computed tomography (CT) or magnetic resonance imaging (MRI), and which is suitable for accurate repeated measurements.
• WHO Performance Status 0-2, with no clinically significant deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks;
• Adequate bone marrow, renal, hepatic and liver function within 21 days form randomization and defined in the protocol;
• No significant comorbidity that according to the investigator would hamper the participation on the trial;
• Female patients should be using adequate contraceptive measures, as defined by the investigator, during the treatment until 6 weeks after last dose of osimertinib. They should not be breastfeeding, and must have a negative pregnancy test (serum or urine) prior to first dose of study drug (within 72 hours); or female patients must have an evidence of non-child-bearing potential by fulfilling one of the criteria defined in the protocol at screening;
• Male patients should be willing to use barrier contraception, i.e., condoms as defined by the investigator, during the treatment until 4 months after last dose of osimertinib;
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. |
|
| E.4 | Principal exclusion criteria |
• Prior treatment with any systemic anti-cancer therapy for locally advanced/metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug;
• Prior treatment with an EGFR-TKI;
• Major surgery (excluding placement of vascular access) within 4 weeks before randomization;
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks before randomization.
• Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of study drug) medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A4; antiacids could be taken in a time-separate manner, at least 8 hours from gefitinb;
• Other anti-cancer therapies and alternative medications such as homeopathy, etc;
• Treatment with an investigational drug within five half-lives of the compound or any of its related material, if known;
• Leptomeningeal carcinomatosis; spinal cord compression;
• Any unresolved toxicities from prior systemic therapy (e.g., adjuvant chemotherapy) greater than CTCAE grade 2 at the time of randomization;
• Patients will not be eligible if they have evidence of active malignancy (other than non-melanoma skin cancer or localized cervical cancer or localised and presumed cured prostatic cancer) within 2 years before randomization and are not receiving specific treatment for these malignancies at baseline assessment;
• 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;
• 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;
• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant gastrointestinal resection that would preclude adequate absorption of osimertinib or gefitinib;
• Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs using local clinic ECG machine-derived QTcF value
• 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, PR interval >250 msec or history of episodes of bradycardia (<50 BPM);
• 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.
•Abnormal cardiac function: LVEF <50% (assessed by MUGA or ECHO)
• Past medical history of ILD (Interstitial Lung Disease), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| progression free survival rate |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. PFS measured from switching to osimertinib by RECIST criteria 1.1
2. Proportion of patients receiving osimertinib based on the determination of cfDNA T790M mutation positive.
3. Time to progression on osimertinib.
4. PFS-2.
5. Overall Response Rate (ORR) to osimertinib.
6. Treatment duration.
7. Overall Survival (OS).
8. Brain progression free survival (BPFS).
9. Safety |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.the time interval between the date of randomization and the date of disease progression or death
2.number of patients receiving at least 1 dose of osimertinib based on the determination of cfDNA T790M (positive mutation).
3.time interval between the date receiving osimertinib and the date of disease progression
4.time between randomization and the 2nd PD or death
5.overall rate including patients with documented complete response (CR) or partial response (PR)
6.from the time of randomization until the treatment stops.
7. time interval between the date of randomization and the date of death from any cause.
8.time interval between the randomization and the date of brain progression
9.from randomization until resolution or stabilization. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Jordan |
| France |
| Poland |
| Spain |
| Italy |
| Belgium |
| Slovenia |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | 25 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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