E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025055 |
E.1.2 | Term | Lung cancer non-small cell stage IV |
E.1.2 | System Organ Class | 100000004864 |
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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 study the optimal time for shifting treatment with erlotinib to osimertinib, when tha patient has developed resistance mutation (T790M). |
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E.2.2 | Secondary objectives of the trial |
Study the resistance mechanisms developing during osimertinib treatment |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provision of signed and dated written informed consent by the patient or legally acceptable representative prior to any study-specific procedures 2. Age > 18 years 3. Locally advanced (stage IIIB) or metastatic (stage IV) EGFRm NSCLC, not amenable to curative surgery or radiotherapy 4. Detection of T790M in blood test verified by a quantitative stable or increase in T790M level in an additional blood test taken sequential within 7 days 5. Prior therapy with erlotinib until point of randomization as defined by positive T790M status 6. World Health Organization (WHO) performance status 0-3 7. Adequate bone marrow reserve and organ function as demonstrated by complete blood count, biochemistry in blood and urine at baseline 8. ECG recording at baseline showing absence of any cardiac abnormality as per exclusion criterion #6 9. Female patients of childbearing potential must be using adequate contraceptive measures. 10. Male patients must be willing to use barrier contraception, i.e., condoms. |
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E.4 | Principal exclusion criteria |
1. Previous (within 6 months) or current treatment with AZD9291 2. Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of AZD9291) any treatment known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A4 (Appendix C) 3. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, active infection including hepatitis B, hepatitis C and human immunodeficiency virus, or significantly impaired bone marrow reserve or organ function, including hepatic and renal impairment, which in the investigator’s opinion would significantly alter the risk/benefit balance. 4. Patient with symptomatic central nervous system (CNS) metastases who is neurologically unstable or has required increasing doses of steroids to manage CNS symptoms within the 2 weeks prior to start AZD9291 administration 5. Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD 6. Any of the following cardiac criteria: a. Mean resting corrected QT interval (QTcF) > 470 ms.
b. 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) c. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 7. Any unresolved toxicity from prior therapy CTCAE > grade 3 at the time of starting treatment 8. History of hypersensitivity to excipients of AZD9291 or to drugs with a similar chemical structure or class to AZD9291 |
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E.5 End points |
E.5.1 | Primary end point(s) |
To describe temporal changes in the levels of T790M and to explore the effect of these changes on disease progression according to RECIST 1.1. An elevated level of T790M is considered valid if it increases to 1.5 times the baseline value, which should be confirmed in a second blood sample taken approximately one week apart. The time from randomisation to elevated T790M may also be evaluated if feasible. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time from randomization to development of disease progression. |
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E.5.2 | Secondary end point(s) |
Progression-free survival (PFS1) measured from date of randomisation until the date of objective radiological disease progression (assessed via RECIST 1.1) or death (by any cause in the absence of disease progression). Time to second progression (PFS2) measured from date of randomisation to date of the progression event (assessed via RECIST 1.1) subsequent to that used for PFS1 or death. This endpoint is relevant only to the patients randomised to the erlotinib continuation arm who switch to AZD9291 treatment. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time from randomization to development of progression (RECIST 1.1). See abiove. |
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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 | No |
E.6.5 | Efficacy | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | No |
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 | Yes |
E.8.2.3.1 | Comparator description |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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After last enrolled patient has progressed or died |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |