| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with locally-advanced or metastatic EGFRm (Ex19del and/or L858R) Non-Small Cell Lung Cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with locally-advanced or metastatic 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 | 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 assess the efficacy of osimertinib plus chemotherapy treatment compared with osimertinib |
|
| E.2.2 | Secondary objectives of the trial |
• To further assess the efficacy of osimertinib plus chemotherapy compared with osimertinib
• To further assess the efficacy of osimertinib plus chemotherapy compared with osimertinib post progression
• To assess disease-related symptoms and health related QoL in patients treated with osimertinib plus chemotherapy compared with osimertinib
• To assess the PK of osimertinib when given with or without chemotherapy
• To compare the local EGFR mutation test result used for patient selection with the retrospective central cobas® EGFR Mutation Test v2 results from baseline tumor samples
• To determine efficacy of osimertinib monotherapy vs. osimertinib combined with chemotherapy based on the cobas® EGFR Mutation Test v2 plasma screening test result for Exon 19 deletions or L858R EGFR mutations |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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.
4. Male or female, at least 18 years of age; patients from Japan at least 20 years of age.
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.
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:
a. Post-menopausal, defined as more than 50 years of age and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
b. 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
c. 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. |
|
| E.4 | Principal exclusion criteria |
• 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
• Past medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD
• 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
• Any of the following cardiac criteria:
o Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTcF value
o 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
o 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
• Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
o Absolute neutrophil count below the lower limit of normal (<LLN)
o Platelet count below the LLN
o Hemoglobin <90 g/L
o 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
o AST >2.5 x ULN if no demonstrable liver metastases or >5 x ULN in the presence of liver metastases
o 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
o Creatinine clearance <60 mL/min calculated by Cockcroft and Gault equation
• Any concurrent and/or other active malignancy that has required treatment within 2 years of 1st dose of IP
• 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
• 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 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
• Prior treatment with an EGFR-TKI
• 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 are permitted
• 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
• 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)
• 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
• Involvement in the planning and/or conduct of the study (applies to both AZ staff and staff at the study site)
• 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
• Previous treatment allocation (safety run in) or randomization (randomization period) in the present study
• Currently pregnant (confirmed with positive pregnancy test) or breast-feeding
• History of hypersensitivity to active or inactive excipients of IP or drugs with a similar chemical structure or class to IP |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-free survival (PFS) using Investigator assessment as defined by RECIST 1.1.
Progression-free survival (PFS) is defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdraws from randomized therapy or receives another anti-cancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST assessment.
The primary efficacy analysis of progression-free survival will be performed by investigator assessment (RECIST 1.1). An additional sensitivity analysis will be performed for PFS by BICR assessment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis of PFS based on investigator assessment will occur when approximately 280 progression events have been observed in the 556 globally randomized patients (approximately 50% maturity). |
|
| E.5.2 | Secondary end point(s) |
1. OS; Landmark OS at 1, 2, and 3 years; ORR, DoR; depth of response; DCR by Investigator
2. PFS2; TFST; TSST
3. Change from baseline in EORTC QLQ-C30; Change from baseline in EORTC QLQ-LC13
4. 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.
5. Concordance of EGFR mutation status between the local EGFR mutation test and the central cobas® EGFR Mutation Test v2 results from tumor samples with evaluable results.
6. PFS by Investigator by plasma EGFR mutation status. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| OS will be tested at the PFS analysis and when the OS data are approximately 60% mature (approximately 334 death events across both arms). |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Chile |
| China |
| Czech Republic |
| France |
| India |
| Japan |
| Korea, Republic of |
| Peru |
| Philippines |
| Russian Federation |
| Slovakia |
| South Africa |
| Taiwan |
| Thailand |
| United Kingdom |
| United States |
| Vietnam |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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