Clinical trial NCT02841579
Conditions: Non-Small Cell Lung Cancer
Sponsor: MedSIR
Start date: 2016-09-02; Completion date: 2020-02-14
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary goal is to evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria.

Safety and efficacy will also be measured.

Detailed description:
Naïve patients ≥ 18 years of age with histological confirmation of locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC) with an activating EGFR mutation and concomitant T790M mutation. Evidence of measurable or evaluable metastatic disease is required.

Primary objective:

* To evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria.

Secondary objectives:

* To determine the safety and tolerability profile of osimertinib (AZD9291), measured using the number and severity of AEs entered into the Case Report Form (CRF); chemistry, blood count, vital signs, physical examination, weight, ECG and performance status (S).
* To determine other efficacy parameters such as progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), duration of response (DOR), disease control rate (DCR), and tumor shrinkage (TS).
* To correlate the parameters of clinical response efficacy documented with the EGFR mutational status.
* To carry out a longitudinal analysis of EGFR mutations (including the T790M mutation) in plasma and serum.
* To determine levels of BIM mRNA as well as mRNA levels of other biomarkers related to EGFR TKI response and determine whether they are predictors of treatment response.
* To identify mechanisms of acquired resistance to osimertinib (AZD9291); mutations at the site of covalent binding to the drug (C797) or other mutations in tissue or blood.

Type of study: Multicenter, international, single-arm, open-label, non-controlled phase IIa clinical study.

Treatment: Patients will be treated with 1 tablet of osimertinib (AZD9291) 80 mg per os (p.o.) daily.

Arms: arm 1: The patients will be treated with 1 tablet of osimertinib (AZD9291) 80 mg per os (p.o.) daily. Patients will receive study treatment until disease progression or occurrence of unacceptable side effects up to 78 weeks from the time of the first administered dose.
Interventions: intervention 1: Osimertinib
Intervention descriptions: intervention 1: The patients will be treated with 1 tablet of osimertinib (AZD9291) 80 mg per os (p.o.) daily up to 78 weeks from the time of the first administered dose.

Protocol documents:
Prot_000.pdf: 
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Clinical study protocol 
 
 
A phase IIa clinical trial to evaluate the safety and efficacy of 
osimertinib (AZD9291) as first-line treatment in patients with 
locally advanced or metastatic EGFR-mutant non-small cell lung 
cancer and concomitant EGFR T790M mutation at time of 
diagnosis 
(AZENT study) 
Code: MedOPP112 
 
Study drug: 
Osimertinib (AZD9291) 
EudraCT No.: 
2015-004828-66 
ESR code: 
ESR-15-10768 
ClinicalTrials.gov No.: 
NCT02841579 
Protocol No.: 
MedOPP112 
 
Protocol date: 
May 21, 2018 
 
 
 
Protocol review history 
Initial approved version: 
v 2 June 22, 2016 
Amendment No. 1 
v 3 May 21, 2018 
Amendment No. 2: 
Amendment No. 3: 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Primary objective 
To evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate (ORR) 
in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M 
mutation at diagnosis, according to RECIST 1.1 criteria. 
 
Primary endpoint: Objective Response Rate (ORR) which is defined as the Complete Responses 
[CR] or Partial Responses [PR] to treatment in accordance with the guidelines of RECIST version 
1.1 criteria. An objective response should be confirmed at least 4-6 weeks after the initial 
response. 
 
 
2.2 
Secondary objectives 
• 
To determine the safety and tolerability profile of osimertinib (AZD9291), measured using 
the number and severity of AEs entered into the Case Report Form (CRF); chemistry, 
blood count, vital signs, physical examination, weight, ECG and performance status 
(ECOG). 
• 
To determine secondary efficacy parameters such as the progression-free survival 
(PFS), overall survival (OS), time to treatment failure (TTF), duration of response (DOR), 
disease control rate (DCR) and tumor shrinkage (TS). 
• 
To correlate the parameters of clinical response efficacy documented with the EGFR 
mutational status. 
• 
To carry out a longitudinal analysis of EGFR mutations (including the T790M mutation) in 
plasma and serum. 
• 
To determine levels of BIM mRNA as well as mRNA levels of other biomarkers related to 
EGFR TKI response and determine whether they are predictors of treatment response. 
• 
To identify mechanisms of acquired resistance to osimertinib (AZD9291); mutations at 
the site of covalent binding to the drug (C797) or other mutations in tissue or blood. 
• 
To analyze biomarkers related to mechanisms of resistance to the treatment. 
 
Secondary efficacy endpoints: Patient safety and adverse events will be assessed using the 
Common Terminology Criteria for Adverse Events (CTCAE) of the U.S. National Cancer Institute 
(NCI), version 4. Grade 3 or 4 adverse events and serious adverse events will be assessed to 
determine the safety and tolerability of the various combinations of drugs. 
 
Secondary efficacy endpoints: 
• 
The progression-free survival (PFS) is defined as the time from the start of the treatment to 
death or disease progression, assessed by the investigator in accordance with RECIST v1.1, 
regardless of whether the patient has discontinued the study treatment or is receiving 
treatment with another drug. 
• 
Overall survival (OS) is defined as the time from the start of treatment to the time of death 
due to any cause. 
• 
Time to treatment failure (TTF) is defined as the time from the start of treatment to the time at 
which the patient discontinues treatment due to any cause, including disease progression 
assessed by the investigator in accordance with RECIST v1.1, toxicity, death or at the 
patient’s request. 
• 
Duration of response (DOR) is defined as the time from the first documented response to 
documented disease progression or death, in accordance with RECIST 1.1 criteria. 


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• 
Disease control rate (DCR) is defined as the percentage of patients with CR, PR or stable 
disease for a minimum of 24 weeks, assessed in accordance with the modified Response 
Evaluation Criteria in Solid Tumors (RECIST v. 1.1), version 1.1. 
• 
Tumor shrinkage (TS) is defined as the percentage of tumor shrinkage from baseline 
(obtained from the sum of the largest diameters of the target lesions) according to RECIST 
v1.1 criteria. 
 
Molecular secondary endpoints 
• 
Correlation ratio of mutational status and documented clinical response. 
• 
A progress curve showing the EGFR mutational status (including the T790M mutation) in 
plasma and serum longitudinally. 
• 
Percentage levels of BIM mRNA as well as mRNA levels of other biomarkers related to 
EGFR TKI response. 
• 
Percentage of patients with mutations at the site of covalent binding to the drug (C797) or 
other mutations in tissue and correlation ratio of documented clinical response. 
 
 
3 
STUDY OVERVIEW 
 
3.1 
Type of study 
This is a multicenter, open-label, non-controlled phase IIa clinical trial. 
 
3.2 
Study design 
The design of this study is divided into three well-defined phases: 
 
• 
Screening phase 
 
During this phase, subject eligibility is determined, including the genotyping of the tumor and 
documentation of baseline characteristics. Considering that the study requires a sample of 73 
patients with metastatic NSCLC (preferably women, with adenocarcinoma, former smokers or 
never-smokers) with activating EGFR mutations and concomitant T790M mutation, and bearing 
in mind that the estimated frequency of the concomitant T790M mutation in patients with 
metastatic NSCLC with activating EGFR mutations is 50% based on the frequency found in 
previous studies (Costa et al. 2010; Chen et al. 2016; Stahel RA, Dafni U, Gautschi O, et al. 
September 25-29; Costa et al. 2014), we estimate that it will be necessary to screen 146 patients 
with EGRF mutation to identify 73 patients with EGFR mutation and concomitant T790M 
mutation. This phase of the study will begin once the informed consent is signed by the patient, 
and the procedures to be performed are described in section 5 of the protocol. 
 
• 
Treatment phase: 
 
When a patient harboring both mutations is identified and the study screening criteria have 
been met, the patient will receive a dose of osimertinib (AZD9291) 80 mg every 24 hours, 
in tablets for oral administration. The study treatment will continue until one of the following 
situations arises: 
• 
Disease progression is confirmed radiologically and unequivocally, except for new 
metastases in CNS or isolated progression of previously treated lesions in the CNS. 
Patients who present disease control outside of CNS, defined as confirmed PR or CR of 
any duration, or SD lasting ≥3 months, but who have developed metastases in CNS that 
can be treated with radiation therapy, will be allowed to continue receiving study 
treatment until they experience systemic progression of the disease outside CNS and/or 
additional progression in the CNS that cannot be treated with additional radiation 


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therapy. 
• 
Adverse event(s) which, according to the protocol or in the opinion of the investigator, 
can cause serious or permanent damage or which rule out further treatment with the 
study drug. 
• 
General or specific changes in the patient’s health state which, in the opinion of the 
investigator, make further treatment unacceptable. 
• 
Major protocol non-compliance. 
• 
Patient’s withdrawal from the study. 
• 
Death. 
• 
Until the end of study, after a maximum of 78 weeks from the administration of the first 
dose of treatment by the last enrolled patient (see Section 3.7). 
• 
Study is canceled by the sponsor. 
 
In the event a dose change is required during the treatment, 40 mg tablets can be 
administered as described in section 6.9. 
 
Treatment with osimertinib (AZD9291) is continuous, and every 21-day period will be 
considered one cycle. The treatment will begin on day 1 of the first cycle. 
 
Follow-up visits will take place every 6 weeks to obtain basic safety data and every 12 weeks 
to obtain complete efficacy and safety data. 
 
At the end of the study, patients may continue taking commercial osimertinib 
(TAGRISSO™) if it provides benefits in the investigator’s opinion. 
 
• 
Follow-up phase: 
 
 
Once the treatment phase is completed, a biopsy should be performed to identify acquired 
mechanisms of resistance to the drug and the follow-up phase will begin. The frequency of 
clinical assessments during this phase of the study will not differ from that performed in the 
course of standard clinical practice. Follow-up visits will take place every 12 weeks; 
information on the patient’s health state will be included in the CRF, as well as any treatment 
received until the end of study. 
 
 
3.5 
Duration of study treatment (treatment phase) 
The study treatment period is defined as the time elapsed between the first and the last dose of 
drug taken. 
 
The study treatment should be discontinued if at least one of the reasons described in Section 
3.2 occur, and the reason(s) for discontinuation will be recorded in the patient’s history and in the 
corresponding case report form. 
 
 
3.6 
Duration of post-treatment follow-up period (follow-up phase) 
The follow-up period is defined as the time elapsed from the last dose of treatment received and 
death, withdrawal of consent or end of study (EoS), whichever occurs first. 
 
 
 


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3.7 
End of study (EoS) 
The EoS is defined as the Last Patient Last Visit (LPLV) at the end of the follow-up period. This is 
the last time point for data collection. It can be a clinical visit or a laboratory sample. The EoS will 
take place in a maximum of 78 weeks after the first dose administered to the last patient enrolled 
in the study. 
 
However, the interim analysis will assess the primary objective and all the safety and efficacy 
objectives limited to a window of up to 42 weeks. After database lock at 42 weeks, patients will 
continue to be treated and controlled until the end of study date (see Section 8.6 Interim 
analysis). 
 
 
 
4 
PATIENT SCREENING 
The following eligibility criteria can be used in the screening of patients for whom the protocol 
treatment is deemed suitable. In order to determine whether this protocol is suitable for a given 
patient, all medical and non-medical criteria should be taken into consideration. 
 
4.1 
Study Population 
Patients diagnosed with stage EIIIB or IV non-small cell lung cancer harboring the EGFR 
activating mutation and concomitant T790M mutation who have not received prior treatment for 
this advanced disease will be enrolled in this study. Patients are not eligible if they are 
candidates for local curative treatment. 
 
The analysis of EGFR mutational status (del19, L858R, L861Q or G719X) may be previously 
performed at each of the participating sites, but the tumor material taken from all patients should 
be submitted to the central laboratory for supportive analysis and T790M mutation analysis. 
 
The patient’s signed informed consent should be obtained before sending the tumor tissue 
sample to the central laboratory. 
 
 
4.2 
Inclusion criteria 
Patient eligibility will be reviewed and documented by a suitable member of the investigator’s 
study team before the patients are enrolled in the study. 
 
Patients must meet all the following inclusion criteria to be enrolled in the study: 
 
 
1. Patient aged 18 years or older. 
2. Patients with histological confirmation of metastatic, non-squamous or locally advanced non-
small cell lung cancer (NSCLC) who are not candidates for local curative treatment, with an 
activating EGFR mutation and concomitant T790M mutation. 
3. Patients with an M1a stage according to the TNM version 7 including M1a (malignant 
effusion) or M1b (distant metastasis), or locally advanced disease that is not a candidate for 


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curative treatment (including patients who progress after chemoradiotherapy in stage III 
disease). 
4. Patients with an EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 
(G719X) and concomitant T790M mutation before treatment confirmed centrally. 
5. ECOG (Eastern Cooperative Oncology Group) performance status less than or equal to 2. 
6. Existence of measurable or evaluable disease (according to RECIST 1.1 criteria). Patients 
with asymptomatic and stable brain metastases are eligible for the study. 
7. Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection of the 
primary tumor or metastatic tumor tissue, if no systemic treatment has been performed for 
advanced or metastatic disease from sample collection to enrollment in the trial. 
8. Life expectancy ≥12 weeks. 
9. Adequate hematologic function: Absolute neutrophil count (ANC) >1.5 x 109/L, platelet count 
>100.0 x109/L and hemoglobin >9.0 g/dL (>6.2 mmol/L). 
10. Appropriate coagulation (INR ≤1.5). 
 
11. Adequate liver function: Total bilirubin <1.5 × ULN, ALT and/or AST <2.5 × ULN, alkaline 
phosphatase <5 ULN, except in the presence of single bone metastases and in absence of 
any liver disorders. 
12. Adequate renal function: Calculated creatinine clearance >50 mL/min (Cockcroft-Gault) and 
proteinuria <2+ (dipstick). 
13. Capacity to swallow, patient capable of completing treatment and accessible, ensuring 
proper follow-up. 
14. Patients able to complete study and within geographical proximity allowing for adequate 
follow-up. 
15. Resolution of all acute toxic effects of previous anti-cancer therapy (which can only be 
adjuvant or neoadjuvant) or surgical interventions not exceeding grade 1 according to the 
NCI CTCAE version 4.0 (except for alopecia or other side effects that the investigator does 
not consider to be a risk to patient safety). 
16. All men or women of childbearing potential must use a contraception method during the 
study treatment and for at least 12 months after the last dose of the study drug. Sexually 
active men and women of childbearing potential who are unwilling to use a contraception 
method are not eligible for the study. 
17. The written informed consent (IC) must be signed and dated by the patient and the 
investigator before any study intervention takes place. 
 
 
4.3 
Exclusion criteria 
Any patient meeting ANY of the following criteria will be excluded from the study: 
1. Locally advanced lung cancer candidate for curative treatment through radical surgery and/or 
radio(chemo)therapy. 
2. Patients diagnosed with another lung cancer subtype, patients with mixed NSCLC with 
predominantly squamous cell cancer, or with any small-cell lung cancer component . 
3. Patients with an EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 
(G719X) and T790M mutation before treatment that have not been confirmed centrally. 


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4. Patients who have received prior antineoplastic treatment for advanced disease. 
5. Second active neoplasia; e.g., patients diagnosed with a potentially lethal cancer for which 
they may be receiving treatment (but are not obliged to do so). 
6. Patients with just one measurable or evaluable tumor lesion that has been resected or 
irradiated prior to their enrollment in the study. 
7. Medical history of Interstitial Lung Disease (ILD) induced by drugs, radiation pneumonitis 
requiring steroid treatment or any evidence of clinically active ILD. 
8. Any of the following criteria: 
• 
Corrected QT Interval (QTc) >470 ms, obtained from ECG at rest, using the QTc value 
determined according to the clinical screening ECG machine. 
• 
Any clinically significant abnormality in ECG rhythm, conduction or morphology at rest. 
• 
Any factor that increases the risk of QTc prolongation or risk of irregular heartbeat or 
sudden inexplicable death under the age of 40 in first-degree relatives or any 
concomitant medications that prolong the QT interval. 
9. Uncontrolled, active or symptomatic metastases of CNS, carcinomatous meningitis or 
leptomeningeal disease indicated by known clinical symptoms, cerebral edema and/or 
progressive neoplasia. Patients with history of CNS metastasis or compression of the spinal 
cord are eligible if they have received local final treatment (e.g., radiotherapy, stereotactic 
surgery) and if they have remained clinically stable without using anticonvulsants and 
corticosteroids for a minimum of 4 weeks prior to the first day of study treatment. 
10. Refractory nauseas and vomiting, chronic gastrointestinal disease, inability to swallow study 
drug or significant intestinal resection that restricts the adequate absorption of osimertinib 
(AZD9291). 
11. Patients who have had a surgical procedure unrelated to the study within 7 days prior to the 
administration of the drug or a significant traumatic lesion during the 4 weeks prior to starting 
the administration of the study drug, patients who have not recovered from the side effects of 
any major surgery or patients who might need major surgery during the course of the study. 
12. Pregnant or breastfeeding women. Women of childbearing potential, including women who 
had their last menstrual period within the last two years, must have a negative serum or urine 
pregnancy test in the 7 days prior to the start of the treatment. 
13. Patients who are not willing to use an adequate contraception method until 12 months after 
the last dose of study treatment. 
14. Patients with a serious concomitant systemic disorder (e.g., active infection, including the 
HIV or heart disease) incompatible with the study (in the investigator’s judgment) and 
previous history of bleeding diathesis. 
15. Inability to swallow tablets. 
16. Patients with a history of cancer that has been completely treated, with no evidence of 
malignant disease currently cannot be enrolled in the study if their radiotherapy and/or 
chemotherapy was completed less than 6 months prior and/or have received a bone marrow 
transplant less than 2 years before the first day of study treatment. 
17. Prior treatment with cytotoxic radiotherapy and/or chemotherapy for advanced NSCLC; 
neoadjuvant/adjuvant radiotherapy and/or chemotherapy is permitted if at least 6 months 
have elapsed between the end of radiotherapy and/or chemotherapy and the first day of 
study treatment. 


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18. Patients who have received prior EGFR treatments for lung cancer. 
19. Patients who have received treatment with an investigational drug within 3 weeks before their 
enrollment in the study. 
20. Treatment with prohibited drugs within 14 days before the first day of study treatment. 
21. Any other reason that the investigator deems to be incompatible with the patient’s 
participation in the study. 
 
5 
STUDY ASSESSMENTS AND PROCEDURES 
 
5.1 
Screening phase: Patient enrollment procedures 
Study-specific assessments performed during the screening phase: Day 0 (patient enrollment 
pending re-confirmation of EGFR and confirmation of T790M in the central laboratory), Day 14 
maximum (to confirm T790M during days 1-14) and Day 28 (to confirm remaining screening 
criteria during Days 15-42 after Day 0 of the screening phase). 
 
Written informed consent from the patient must be signed before performing any study 
procedure. 
 
By giving their consent, patients will be informed as to the nature of the study drug and will 
receive pertinent information regarding the study objectives, possible benefits and potential 
adverse events. They will also receive information on the follow-up procedures and possible risks 
they will be exposed to. This document also informs patients about how biological samples will 
be obtained and collected and its legal implications. After receiving the document, the patient will 
read it (or receive information verbally before witnesses) and will sign the previously approved 
informed consent. The patient will receive a signed copy of the informed consent. The patient can 
withdraw their consent and discontinue the study; this will not affect any future medical treatment. 
 
Once this consent is obtained and upon confirmation that the patient meets the remaining 
screening criteria (through the available data in the medical history or by performing the 
corresponding necessary tests), the investigator staff will submit the tumor tissue samples 
(accompanied by the anatomy-pathology report) and serum/plasma to the central reference 
laboratory immediately for central evaluation of activating EGFR mutations and T790M mutation 
in exon 20. The characteristics and packaging of biological sample shipments are described in 
“Appendix 4: Instructions for shipment of biological samples to the central laboratory” of this 
protocol. 
 
Within 7 working days, the central reference laboratory will inform as to whether there is sufficient 
material that is suitable for EGFR analysis and determination of T790M mutation. 
 
A. If tissue quality and/or quantity is deemed unacceptable by the central reference laboratory, 
the study staff will be suitably informed and if a sample of tumor tissue cannot be obtained 
under better conditions, the patient will not be eligible for the study. 
 
B. If the EGFR mutation and concomitant T790M status are not confirmed, the patient will not 
be eligible for the study. The central reference laboratory will inform the study staff as to the 
results of the analyses, which will be kept on file in the study documentation file of the 
participating site. 
 


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C. If the EGFR mutation and concomitant T790M status are confirmed, the results of the 
analyses will be sent to the investigator staff, who will then proceed to confirm the remaining 
patient screening criteria and proceed to enroll the patient in the study. 
 
EGFR results of the test carried out in the local laboratory should be obtained up to 28 days prior 
to the patient’s enrollment in the study. 
 
At enrollment: 
1. The sponsor will request the patient’s demographic and clinical data related to screening 
criteria. 
 
2. Each patient will be given a Unique Patient Number (UPN) for this study, provided by the 
sponsor. All data will be recorded in the appropriate CRFs using this identification number. 
This number will be provided to the central laboratory to ensure traceability of study samples. 
 
Confirmation of patient’s eligibility for study participation will be recorded in the Case Report 
Form (CRF). The investigator is responsible for safeguarding patient information (e.g., age, 
name, address, telephone number, social security number and study identification number), 
ensuring access to said information by health authorities if necessary. These records will remain 
confidential for the period of time stipulated by current legislation. 
 
The screening period will include: 
• 
Anamnesis and symptom assessment. 
• 
Physical examination and measurement of weight, vital signs and performance status. 
• 
Basic blood test that includes blood count (hemoglobin, hematocrit, RBC count, platelet 
count and leukocyte count with differential blood count [neutrophils, lymphocytes, 
monocytes, eosinophils and basophils]) and blood chemistry (sodium, potassium, 
calcium, chloride, magnesium, uric acid, total proteins, alkaline phosphatase, gamma-
glutamyl transferase, lactate dehydrogenase and total bilirubin) with renal function 
analysis (serum creatinine and creatinine clearance according to the Cockcroft-Gault 
formula), liver function (AST, ALT, ALP and bilirubin), glucose and coagulation (INR). 
• 
Urine dipstick test for analysis of proteinuria. 
• 
Pregnancy test, when applicable. 
• 
12-lead electrocardiogram. 
• 
Tissue sample, which is then sent to central laboratory. 
• 
Blood sample for the translational study, which is then sent to central laboratory. 
• 
Antineoplastic therapy (if applicable). 
• 
Assessment of concomitant medication (as specified in Section 3.3). 
• 
CT, PET-CT and MRI of at least the chest and abdomen prior to starting the first cycle. 
Radiological study with CT, PET-CT or MRI that include at least the chest and abdomen. 
 
5.2 
Treatment phase: Assessments 
The results of the reference tests or examinations performed prior to obtaining the informed 
consent and in the 28 days prior to treatment start may be used; it will not be necessary to repeat 
these tests for the screening. 
 
All screening assessments should be performed and reviewed to confirm that the patients meet 
all the eligibility criteria prior to treatment start (Day 1). The investigator will maintain a screening 
log to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 


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Visits are organized in programmed cycles of 21 days (if there are no delays in treatment owing 
to the occurrence of a side effect). Dose reductions or delays are permitted, as described in 
section 6.9. All visits must occur within ± 3 working days from the scheduled date, unless 
otherwise stated in the schedule of assessments. All evaluations will be performed on the 
specific visit day unless a time frame is specified. Assessments scheduled on the day of study 
treatment administration should be performed prior to study treatment administration unless 
otherwise indicated. If a mandatory procedure described in the protocol falls on a bank holiday 
and/or weekend, this procedure should be performed on the day before or after the holiday (i.e. 
within a period of ± 3 working days), unless otherwise indicated. 
 
Local laboratory assessments scheduled for Day 1 (prior to treatment) every two cycles should 
be performed within 72 hours prior in order to confirm if the treatment may continue (in each 
treatment visit scheduled every 2 cycles). The results of local blood tests should be reviewed, 
and this review will be recorded before administration of the study treatment. 
Specific study assessments during treatment phase: Day 14 of 
the first treatment cycle: 
• 
Serum/blood draw for translational analysis. 
 
During basic safety visits - Day 1 of each cycle every 2 cycles (every 6 weeks). 
• 
Symptom assessment. 
• 
Physical examination and measurement of weight, vital signs and ECOG performance 
status. 
• 
Basic blood test that includes blood count (hemoglobin, hematocrit, RBC count, platelet 
count and leukocyte count with differential blood count [neutrophils, lymphocytes, 
monocytes, eosinophils and basophils]) and blood chemistry (sodium, potassium, 
calcium, chloride, magnesium, uric acid, total proteins, alkaline phosphatase, gamma-
glutamyl transferase, lactate dehydrogenase and total bilirubin) with renal function 
analysis (serum creatinine and creatinine clearance according to the Cockcroft-Gault 
formula), liver function (AST, ALT, ALP and bilirubin), glucose and coagulation (INR). 
• 
Urine dipstick test for analysis of proteinuria. 
• 
Antineoplastic therapy. 
• 
Assessment of concomitant medications. 
• 
Assessment of adverse events. 
• 
Survival. 
 
During full visits - Day 1 of each cycle every 4 cycles (every 12 weeks): 
• 
Anamnesis and symptom assessment. 
• 
Physical examination and measurement of weight, vital signs and ECOG performance 
status. 
• 
Basic blood test that includes blood count (hemoglobin, hematocrit, RBC count, platelet 
count and leukocyte count with differential blood count [neutrophils, lymphocytes, 
monocytes, eosinophils and basophils]) and blood chemistry (sodium, potassium, 
calcium, chloride, magnesium, uric acid, total proteins, alkaline phosphatase, gamma-
glutamyl transferase, lactate dehydrogenase and total bilirubin) with renal function 
analysis (serum creatinine and creatinine clearance according to the Cockcroft-Gault 
formula), liver function (AST, ALT, ALP and bilirubin), glucose and coagulation (INR). 
• 
Urine dipstick test for analysis of proteinuria. 
• 
3 12-lead electrocardiograms. 


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• 
Antineoplastic therapy. 
• 
Assessment of concomitant medications. 
• 
Assessment of adverse events. 
• 
Tumor evaluation: CT, PET-CT and MRI of at least the chest and abdomen prior to 
starting the cycle every 4 cycles and every 12 weeks until the end of the treatment phase 
(Section 3.2). 
• 
Survival. 
 
 
 
Tissue and serum/plasma assessment for translational study: 
• 
Tumor re-biopsy will be considered at the time of progression (as recommendation only) 
for analysis of possible mechanisms of resistance and future translational research at the 
reference laboratory. 
• 
Blood/plasma collection prior to starting the cycle every 4 cycles and every 12 weeks 
until the end of the treatment phase (Section 3.2). 
 
Biological sampling: Given that very little is known on how cancer develops resistance to 
pyrimidine-based EGFR inhibitors, mutations in tumor tissue or blood will be identified at the site 
of covalent binding to osimertinib (AZD9291) (C797) in addition to other mutations that can 
mediate resistance . 
The first tissue samples should be taken before starting study treatment (see Appendix 6 for 
more details on tissue sampling procedures). Tumor re-biopsy will be considered at the time of 
progression (as recommendation only) for analysis of possible mechanisms of resistance and 
future translational research at the reference laboratory. 
The first blood samples for serum and collection of plasma should be taken before starting study 
treatment (see Appendix 6 for more details on blood sampling procedures). The following 
samples should be taken at 2 weeks, and every 12 weeks thereafter (coinciding with 
assessments of responses using radiographic imaging) and at the time of progression. 
At the time of site activation, the sponsor will provide cryovials and cryoboxes for the storage and 
transport of samples, as well as labels. This material will be provided by the central laboratory. 
No other cryovials or labels should be used for this study. If more tubes and labels are required, 
these should be requested from the sponsor in writing at least 3 weeks before they are required 
(see Appendix 6). 
 
Anamnesis and demographic data: Anamnesis includes clinically significant diseases, surgical 
interventions, history of cancer (including prior antineoplastic treatments and procedures), history 
of smoking, alcoholism, drug addiction, as well as any medications (e.g., prescribed drugs, over-
the-counter drugs, medicinal plants, homeopathic remedies, or food supplements) used by the 
patient in the 21 days prior to screening visit. Demographic data will include age, gender and 
race/ethnicity reported by the patient himself/herself. 
 
Vital signs: These will include the measurement of height (only during screening), weight, 
respiratory rate, heart rate, blood pressure, and body temperature. Abnormal or significant 
changes in vital signs from baseline should be recorded as adverse events, if appropriate. 
 
Physical examination: A complete physical examination should include an examination of head, 
eyes, ears, nose, and throat as well as cardiovascular, dermatological, musculoskeletal, 
respiratory, digestive, genitourinary and neurological systems. Changes to abnormalities 
identified during the baseline period should be recorded at all subsequent physical exams. New 
or worsening abnormalities should be recorded as adverse events, if applicable. 


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Physical exams should also include, as part of tumor assessment, evaluation of presence and 
degree of increase of lymph nodes, hepatomegaly and splenomegaly. Limited physical exams 
will focus on symptoms. 
 
 
Response and tumor assessments: Tumor response will be assessed for all patients, unless they 
withdraw from the study for any reason not attributable to disease progression confirmed 
radiologically or clinically and who have not received an acceptable complete assessment of the 
disease. The measurable and non-measurable disease should be documented at screening and 
be re-assessed at every tumor assessment thereafter. The initial assessment of tumor response 
will be performed at the end of cycle 4. Thereafter, an efficacy follow-up will be carried out for all 
patients every 12 weeks during the study period, until disease progression, death, treatment 
discontinuation or study completion. In this study, response and disease progression will be 
assessed using the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) 
(Appendix 2: Response Evaluation Criteria in Solid Tumors Guidelines (RECIST criteria) (version 
1.1)). 
 
A PET-CT, CT or MRI of at least the chest and abdomen should be performed at screening. If a 
positron emission tomography (PET)/CT is used in tumor assessments, the CT portion of the 
PET/CT should meet diagnostic quality requirements. Tumor assessments should include an 
assessment of all known and/or suspected sites of the disease wherever possible. Patients 
should have a series of selected lesions that can be assessed at each tumor assessment. 
 
The same radiographic procedure employed at screening should be used throughout the study 
(e.g., the use of the same contrast protocol for CTs) The initial assessment of tumor response will 
be performed at the end of cycle 4. Thereafter, tumor response should be assessed every 12 
weeks until disease progression or the end of the study (see definition in section 3.7). Response 
assessments will be evaluated by the investigator, using physical examinations, PET-CTs, CTs 
or MRI of at least the chest and abdomen, based on RECIST v criteria. 1.1 (Appendix 2: 
Response Evaluation Criteria in Solid Tumors Guidelines (RECIST criteria) (version 1.1)). In the 
case of patients who continue with study treatment after isolated brain progression, the frequency 
of radiological tests will be left up to the discretion of the investigator. PET-CT, CT and MRI 
scans may be obtained at any time when clinically indicated or if disease progression is 
suspected. 
 
Radiographic assessments should always be performed in place of clinical examinations, 
unless lesions being monitored cannot be captured using imaging techniques, unless they are 
evaluable via clinical examination. According to the RECIST 1.1 criteria, imaging should be 
performed in color, and include a ruler to calculate lesion size. 
 
Laboratory assessments 
Laboratory tests will be performed in accordance with local standard treatment and clinical 
indications before treatment administration. These values should include: Hemoglobin, 
hematocrit, RBC count, platelet count and leukocyte count with differential blood count 
(neutrophils, lymphocytes, monocytes, eosinophils and basophils), sodium, potassium, calcium, 
chloride, 
magnesium, 
uric 
acid, 
total 
proteins, 
alkaline 
phosphatase, 
aspartate 
aminotransferase, 
alanine 
aminotransferase, 
gamma-glutamyl 
transferase, 
lactate 
dehydrogenase, total bilirubin, creatinine, blood glucose level, coagulation and proteinuria. 
 
Electrocardiograms: A 12-lead ECG will be performed at baseline, printed and kept on file along 


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with the patient’s history. Thereafter, 3 electrocardiograms will be performed every 12 weeks 
until disease progression, death, treatment discontinuation or study completion. The QT interval 
should be recorded according to Fridericia’s formula (QTcF). 
 
 
 
ECOG performance status: Performance status will be determined using the ECOG 
performance status scale. Wherever possible, the patient’s performance status should always 
be assessed by the same personnel throughout the study. 
 
 
Grade 
Scale 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50 % of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 
Adverse events and toxicity to treatment: Safety and tolerability of all patients will be closely 
monitored throughout study treatment and the follow-up period. Patients will be assessed in 
order to detect any side effects before administering new bottles of the study treatment. New 
bottles of treatment will only be administered if clinical evaluation and local laboratory test 
results are acceptable. 
 
5.3 
Follow-up phase 
Patients will be followed up until the patient dies or the study ends, whichever occurs first. The 
follow up of all patients will be performed until the last patient completes 78 weeks of treatment, 
progresses or dies, whichever occurs first. 
 
At these follow-up contacts, information will be obtained on survival status and post-study 
antineoplastic therapy assessment. Contact by telephone is permitted. 
 
Any events grade ≥2 will be followed until improvement to baseline levels is observed, complete 
recovery or resolution to grade 1, consent is withdrawn by the patient, patient death or until 
follow-up is no longer possible. 


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Assessment schedule after progression or study discontinuation for any reason: After 
progression or study discontinuation for any reason, the following assessments will be 
performed within a maximum period of 28 days: 
o 
Anamnesis and symptom assessment. 
o 
Physical examination and measurement of weight, vital signs and ECOG 
performance status. 
o 
Basic blood test that includes blood count (hemoglobin, hematocrit, RBC count, 
platelet count and leukocyte count with differential blood count [neutrophils, 
lymphocytes, monocytes, eosinophils and basophils]) and blood chemistry (sodium, 
potassium, calcium, chloride, magnesium, uric acid, total proteins, alkaline 
phosphatase, gamma-glutamyl transferase, lactate dehydrogenase and total 
bilirubin) with renal function analysis (serum creatinine and creatinine clearance 
according to the Cockcroft-Gault formula), liver function (AST, ALT, ALP and 
bilirubin), glucose and coagulation (INR). 
o 
Urine dipstick test for analysis of proteinuria. 
o 
12-lead electrocardiogram. 
o 
Blood sample, which is then sent to central laboratory. 
o 
Antineoplastic therapy. 
o 
Assessment of concomitant medications. 
o 
Assessment of adverse events. 
o 
Tumor evaluation: CT, PET-CT and MRI of at least the chest and abdomen. 
o 
Survival. 
o 
Tumor re-biopsy will be considered (as recommendation only) for analysis of 
possible mechanisms of resistance and future translational research at the 
reference laboratory. 
 
 
5.5 
Discontinuation of patient, study or site participation 
Treatment discontinuation: Patients have the right to withdraw from the study at any time and 
for any reason, without being required to state their reasons for doing so. The investigator has 
the right to discontinue a patient from study treatment or from the study for any medical 
condition that the investigator determines may jeopardize the patient’s safety if he or she 
continues in the study, for reasons of non-compliance (e.g., missed doses, visits), if the patient 
becomes pregnant, or if the investigator determines it is in the best interest of the patient. 
 
Patients should be withdrawn from the study treatment if they experience disease progression 
as defined by RECIST v1.1 criteria. An exception to this are patients who develop isolated brain 
progression as described in section 3.4, and who, in the investigator’s judgment, will clinically 
benefit from the drug. 
 
Further details regarding study discontinuation due to side effects are described in section 7. 


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Patients who withdraw from study treatment prematurely will be followed up in accordance with 
section 5.3 except for those patients who withdraw their consent and who do not wish to 
undergo a follow-up. The main reason for discontinuation should be recorded in the appropriate 
section of the case report form (CRF). 
 
Study discontinuation: Section 3.7 defines EoS and study discontinuation. 
 
Patients will be withdrawn from the study (e.g., from any subsequent study procedure) for any 
of the following reasons: 
• 
Withdrawal of consent. 
• 
Lost to follow up. 
If patient is lost to follow-up, site personnel must do their utmost to re-establish contact with the 
patient and determine the reason for their withdrawal. All measures taken to undertake follow-
up should be recorded. 
 
When a patient withdraws before the end of the study, the reason for withdrawal should be 
recorded in the CRF and in the original document. Patients who withdraw from the study will not 
be replaced. 
 
In addition, the sponsor reserves the right to terminate this study at any time. Reasons for 
terminating the study may include, but are not limited to, the following: 
− 
The incidence or severity of AEs in this or other studies indicates a potential health risk 
to patients. 
− 
Patient enrollment is unsatisfactory. 
− 
Decision of the Scientific Committee once results of interim analysis are known. 
− 
Data recording is inaccurate or incomplete. 
 
 
6 
INFORMATION ON STUDY DRUG 
 
6.1 
Study treatment 
Once enrolled in the study, the patient will receive study treatment. 
 
The treatment dose will be one tablet of osimertinib (AZD9291) 80 mg for daily oral 
administration. 
 
Tablets will be packed in child-resistant high-density polyethylene (HDPE) bottles. The bottles 
dispensed to patients will be specially prepared for the study. 
 
 
6.2 
Drug supplies 
The latest version of study document Summary of Product Characteristics for osimertinib 
(AZD9291) includes updated information on this drug. 
The drug will be supplied by AstraZeneca to the sponsor, who will be responsible for its 
distribution to participating hospitals until the end of study, which will be after 78 weeks of 
follow-up of the last patient enrolled. From this point onwards, patients may continue to 
receive the commercial drug, if your doctor considers it appropriate. 


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The sponsor will supply sites with HDPE (high-density polyethylene) bottles containing 
osimertinib (AZD9291) 80 mg tablets for oral administration and HDPE (high-density 
polyethylene) bottles containing osimertinib (AZD9291) 40 mg tablets for oral administration. 
The smaller dose tablets can be taken in cases that call for a reduction of the dose of 
osimertinib (AZD9291) under circumstances described in Section 6.9. 
 
6.3 
Formulation and packaging 
The sponsor will supply drug formulation for oral administration to sites in HDPE (high-density 
polyethylene) bottles containing 80 mg or 40 mg tablets. Tablets will be packed in bottles with 
child-resistant closures. The bottles will be dispensed to patients in packages specially prepared 
for use in this study. 
 
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines. The label text will be translated into the local language. The label will include the 
name of the sponsor, study code, text stating that the drug is for clinical trial use only and/or any 
other market-specific requirements. All study drugs should be kept in a secure place under 
appropriate storage conditions. The investigational product label on the pack will specify the 
appropriate storage. 
 
 
6.4 
Dispensation 
The unique patient number (UPN) will be recorded on the label affixed to the box in the areas 
set aside for this information when drug is assigned to the patient. Site personnel should ensure 
that the patients fully understand the instructions given to them regarding self-administration. 
Patients should be given an adequate supply of the drug that will last until the following study 
visit. Any unused and/or empty bottles should be returned to the site during the next study visit. 
Unused medication that has been returned SHOULD NOT be supplied to patient. 
 
Two doses of osimertinib (AZD9291), 40 mg and 80 mg tablets for oral administration, will be 
supplied. At each visit, sufficient osimertinib (AZD9291) for the following programmed cycles (21 
days per cycle) to last until the next visit, + 4 additional days per cycle (overage) will be 
distributed. Individual bottles will be dispensed in accordance with the medication identification 
numbers provided by the sponsor. Subjects should swallow one osimertinib (AZD9291) 80 mg 
tablet once daily, commencing on Day 1 of each cycle. 
 
At each dispensing visit, the patient will only receive tablets of one strength or the other, not 
both. In the event a dose change is required, the patient will be asked to return all previously 
supplied medication and new tablets will be supplied to them. 
 
 
6.5 
Administration 
Patients will be treated with osimertinib (AZD9291) administered orally, once a day. The initial 
dose of osimertinib (AZD9291) is of 80 mg per day. Treatment with osimertinib (AZD9291) is 
continuous. Each 21-day treatment period represents one cycle, and treatment will begin on 
day 1 of the first cycle. Routine pre-medication is not recommended for osimertinib (AZD9291). 
In the event of relevant toxicity, dose reduction is recommended to improve tolerance. 
 
At each visit, sufficient osimertinib (AZD9291) for the following programmed cycles (21 days per 


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cycle) to last until the next visit, + 4 additional days per cycle (overage) will be distributed. 
Individual bottles will be dispensed in accordance with the medication identification numbers 
provided by the sponsor. Subjects should swallow one osimertinib (AZD9291) 80 mg tablet 
once daily, commencing on Cycle 1 Day 1. 
 
Tablets will be taken once daily and may be taken with or without food. The tablet should be 
swallowed whole with water and should be crushed, split or chewed. 
 
If the patient cannot swallow the tablet, it may be diluted in 50 mL of non-carbonated water and 
immediately swallowed. Subsequently, the patient should refill the glass with water and swallow 
it again in order to take the full dose. No other liquid may be added for this purpose. 
 
In case of administration via nasogastric feeding tube, the same process described above 
should be carried out using volumes of 15 mL for the initial dilution and 15 mL to clean the 
potential medication waste. The remaining 30 mL should be administered via nasogastric 
feeding tube appropriately according to the manufacturer’s instructions. This alternative 
administration should be carried out until a maximum of 30 minutes upon dilution. 
 
The initial dose of 80 mg AZD9291 can be reduced to 40 mg AZD9291 once daily, under 
circumstances described in Section 6.9. Doses should be taken approximately 24 hours apart at 
the same time point each day. If a subject misses a scheduled dose, it is acceptable to take the 
dose within a window of 12 hours. If it is more than 12 hours after the dose time, the missed dose 
should not be taken, and subjects should be instructed to take the next dose at the next 
scheduled time. If a subject vomits after taking their osimertinib (AZD9291), they should not make 
up for this dose, but should take the next scheduled dose. Any change from dosing schedule, 
dose interruptions, and dose reductions should be recorded in the CRF. 
 
Drug treatment is to begin within 2-4 weeks of reception of the tumor sample at the central 
reference laboratory. Patients will continue receiving the assigned therapy until objective 
disease progression, symptomatic deterioration, occurrence of an unacceptable side effect, 
death, withdrawal of consent or the end of the trial (78 weeks from the first dose of the last 
enrolled patient), whichever occurs first. 
 
However, patients may continue to receive treatment with commercial osimertinib (TAGRISSO) 
according to the investigator’s judgment. In this case, the investigator should follow-up on the 
patient in an appropriate manner, according to standard clinical practice. 
 
 
6.6 
Medication errors and overdose 
Medication errors in this study may arise when the drug is administered at the wrong time or 
when the wrong dose strength is taken. Patient medication errors should be recorded in the 
relevant section in the CRF. In the event of an error in the administration of the medication, the 
sponsor should be informed immediately. 


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Medication errors must be reported irrespective of the presence of an associated AE/SAE, 
including: 
• 
Medication errors involving patient exposure to the investigational medicinal product; 
• 
Any possible medication errors or use of the medication not defined in the protocol 
which implicate the participating patient or not. 
Regardless of whether the medication error is accompanied by an AE or not, in the judgment of 
the investigator, the medication error should be recorded in the adverse event (AE) page. 
 
 
6.7 
Treatment compliance 
At the beginning of each cycle, patients will be required to return all bottles of osimertinib 
(AZD9291) for drug count. The members of the study staff are responsible for counting 
osimertinib (AZD9291). 
 
Drug accountability will be performed on Day 1 of every cycle prior to dispensing drug for the 
next cycle. The number of remaining tablets will be documented and recorded. 
 
To be considered compliant, each study patient must have received at least 80 % of the 
planned number of doses of primary treatment based on the number of days of actual dose 
administration. If a dose titration is required, see instructions provided in section 6.9. 
 
 
6.8 
Drug storage and accountability 
Investigators and site personnel are reminded to continuously observe storage temperatures 
and to verify the correct operation of thermometers, as required for the correct storage of the 
investigational product. This includes thermometers for room temperature storage and 
thermometers for fridge storage. 
At the end of the study, the sponsor will give instructions regarding the disposal of unused 
investigational products. If the sponsor authorizes the destruction of medication at the study 
site, the investigator should ensure that the materials are destroyed in accordance with the 
relevant environmental regulations, institutional policy and any special instructions given by the 
sponsor. The destruction of these materials will be recorded in an appropriate manner. 
 
 
6.9 
Dose change 
Every effort should be made to administer study treatment based on the planned dose and 
regimen. Nevertheless, in the event of a significant treatment-related side effect, an adjustment 
can be made in the administration of the study drug as described in the following sections. 
 
In case of toxicity, symptomatic treatment and dose changes should be made according to the 
following instructions. Repeated dose interruptions are allowed as required, for a maximum of 3 
weeks each time (a delay of up to 3 weeks after the planned drug administration is allowed). As 
long as the study drug administration can be continued, the patient will remain on trial 
treatment. In case of doubt, please contact the medical monitor immediately. 
 


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6.9.1 
Dose reduction 
In the event of a significant treatment-related side effect, the osimertinib (AZD9291) dose can 
be interrupted, delayed and/or reduced, as described below. In the event of multiple side 
effects, dose change should be based on the worst toxicity observed. Patients are instructed to 
notify the investigator the moment he/she notices any adverse signs or symptoms. 
 
After an interruption in administration or a delay in a cycle, a dose reduction may be necessary 
when treatment is to be resumed. No specific dose adjustments are recommended for Grade 1 
or 2 treatment-related toxicity. 
 
However, investigators should always use their judgment when treating patients, in accordance 
with the specific clinical circumstances. A reduction in osimertinib (AZD9291) dose by 1 dose 
level (Table 2) is permitted, based on the type and severity of the side effect. Patients requiring 
more than 1 dose reductions will be discontinued from the study and entered into the follow-up 
phase. All dose changes/adjustments should be clearly noted in the original patient record and 
in the CRF. 
 
Table 2. Osimertinib (AZD9291) dose reduction 
 
Dosing level 
Osimertinib (AZD9291) for 3 weeks 
Starting dose 
80 mg/day 
- 1 
40 mg/day 
Discontinue study treatment 
 
 
Table 3. Osimertinib (AZD9291) dose adjustment after adverse reactions 
 
Organ 
involved 
Adverse Reaction 
Dose change 
Lung 
ILD/Pneumonia 
Discontinue the treatment 
permanently. 
. 
Heart 
QTc interval >500 ms at least in 2 
different ECGs. 
Maintain of osimertinib (AZD9291) 
until the QTc interval <481 ms or go 
back to baseline results if they are 
≤481 ms and then, restart at a reduced 
dose (40 mg). 
QTc interval prolongation with 
signs/symptoms of severe 
arrhythmia. 
Discontinue osimertinib (AZD9291) 
permanently. 
Other 
Grade 3 or higher adverse reaction. Discontinue osimertinib (AZD9291) up 
to 3 weeks. 


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If the grade 3 adverse reaction 
improves to grade 2 or lower after 
osimertinib discontinuation up to 3 
weeks 
The administration of osimertinib 
(AZD9291) may start at a normal dose 
(80 mg) or at a reduced dose (40 mg). 
If the grade 3 adverse reaction 
improves to grade 2 or lower after 
osimertinib discontinuation up to 3 
weeks. 
Discontinue osimertinib (AZD9291) 
permanently. 
 
6.9.2 Interruption of administration 
The dose may be interrupted, when necessary, until the resolution of toxicity. Depending on 
when the adverse event is resolved, an interruption in therapy may cause the patient to miss 
subsequent doses that have been scheduled for that cycle and even delay the start of the next 
cycle. 
 
Administration of osimertinib (AZD9291) should be permanently discontinued under the 
following circumstances: 
 
- 
Interstitial pneumonitis. 
- 
Hepatic insufficiency. 
- 
Gastrointestinal perforation. 
- 
Corrected QT interval prolongation with signs/symptoms of severe arrhythmia. 
- 
Suspension of treatment lasting more than 3 weeks. 
 
If the adverse event that gave rise to the interruption of treatment is resolved within that same 
cycle, the treatment can be resumed in that cycle. Doses not administered due to toxicity will 
not be replaced in that same cycle. The need for a dose reduction when treatment is to be 
resumed should be assessed in keeping with the criteria defined above, unless otherwise 
agreed upon by the investigator and sponsor. If a dose reduction is made within the cycle, the 
patient should come to the site to receive a new supply of the drug. If the treatment is 
interrupted for reasons other than treatment-related toxicity (e.g., surgery not related to 
cancer) for a period >2 weeks, treatment can only be resumed after consultation with the 
sponsor. 
 
The appropriate follow-up assessments should be performed until adequate resolution has 
been reached, in the judgment of the investigator. If these parameters are not met within 3 
weeks after the dose interruption (including the scheduled treatment week during which the 
patient did not receive treatment), then the treatment should be considered permanently 
discontinued. Treatment can be resumed in cases where patients have recovered from a 
treatment-related side effect after a period in which treatment has been discontinued for more 
than 3 weeks or after the cycle has been delayed, but only if treatment offers a clinical benefit 
to the patient in the judgment of the investigator. In these cases, it is left to the discretion of 
the investigator after consultation with the sponsor. 
 
If a new cycle is delayed owing to a treatment-related side effect, all procedures other than 
tumor assessments that are outlined in the protocol and required on Day 1 of the cycle will be 
performed when treatment with osimertinib (AZD9291) is resumed. Note that the protocol 
schedule must be followed for tumor assessments. The procedures performed on Day 1 of a 
new cycle (i.e. physical examination, ECOG performance status, ECG, blood chemistry, 


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blood count) that were performed before awareness of the need to delay the start of the cycle 
do not need to be repeated (1) if the study staff does not need to determine whether study 
drug can be resumed and (2) if they were performed within 7 days prior to resuming the study 
drug. 
 
 
6.10 
Possible drug interactions 
In vitro data indicate that osimertinib (AZD9291) is mainly metabolized via CYP3A4. Patients 
should avoid using drugs that are strong inhibitors or inducers of cytochrome p450 (CYP)3A4 
during the study active phase. Patients should also avoid grapefruit juice and herbal remedies, 
including St John’s Wort. If their use is essential, patients who are taking them should be 
monitored closely. 
 
Drugs listed in Appendix 3: Pharmacological interactions with osimertinib (AZD9291) are not 
permitted due to their drug interaction with the study drug. 
 
Patients who use drugs that are known to prolong the QT interval should be closely monitored 
using serial electrocardiograms. 
 
 
7 
STATISTICAL CONSIDERATIONS AND STATISTICAL ANALYSIS PLAN 
 
7.1 
Sample Size 
In the Phase I/II AURA clinical trial, where osimertinib (AZD9291) was administered to patients 
with advanced EGFR-mutant NSCLC after progression to EGFR TKIs, among the 127 patients 
with centrally confirmed EGFR T790M mutation, the response rate was 61%. In contrast, 
amongst 61 patients without centrally confirmed EGFR T790M, the response rate was 21% 
(15). In the West Japan Thoracic Oncology Group 3405 (WJTOG3405) study, comparing 
gefitinib with first-line chemotherapy in patients with advanced NSCLC with activating mutations 
in EGFR, the ORR in the overall population with measurable disease was 62.1% in the gefitinib 
group and 32.2% in the chemotherapy group. In the North East Japan 002 (NEJ002) study, 
comparing gefitinib with first-line chemotherapy in patients with advanced NSCLC with EGFR 
mutations, the gefitinib group had a significantly higher ORR (73.7% vs. 30.7%). In the 
OPTIMAL study, comparing erlotinib with chemotherapy in patients with advanced NSCLC with 
EGFR mutations, ORR was 83% for erlotinib and 36% for patients receiving chemotherapy (37). 
In the LUX-Lung 3 study, comparing afatinib with first-line chemotherapy in patients with 
advanced NSCLC with EGFR mutations, ORR was significantly higher for patients treated with 
afatinib compared to chemotherapy according to both the independent evaluation committee 
(56% and 23%, respectively) and the investigator (69% and 44%, respectively) assessments. In 
the EURTAC study, comparing erlotinib with first-line chemotherapy in patients with advanced 
NSCLC with EGFR mutations, ORR was 65.1% in the erlotinib group and 16.1% in the 
chemotherapy group. A subsequent study assessed the impact of pre-treatment presence of the 
concomitant EGFR T790M mutation. Among patients treated with erlotinib, the presence of this 
concomitant mutation was evaluated in 95 patients. ORR was found to be 75% in patients 
without pre-treatment T790M, compared to 47% in patients with pre-treatment T790M. 
This data suggests that excluding an ORR ≤50% while targeting the improvement of the ORR to 
≥70% would be a conservative approach to assess the osimertinib (AZD9291) treatment effect 
in this patient population. Accordingly, this study will test the null hypothesis that the ORR is 
≤50% against the alternative hypothesis that it is ≥70%. Applying Simon’s optimum 2-stage 


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EudraCT No.: 2015-004828-66 
Protocol No.: MedOPP112 
Protocol date: May 21, 2018 
Version 3 
 
 
design [Simon 198940], a sample size of 73 patients has power >0.90 to achieve a 1-sided 
significance level of 0.025. A total of 21 patients will be recruited in the first stage. If there are 11 
or fewer responses in these 21 patients, the study will be stopped. Otherwise, 52 additional 
patients will be accrued for a total of 73 patients. The null hypothesis will be rejected if 45 or 
more responses are observed in 73 patients. This design yields a type I error rate of 0.025 and 
a power of 90% when the ORR is 70%. 
 
 
8.2 
Efficacy results 
Primary Endpoint 
We will describe number and proportion of patients with OR (Objective Response) in the first 
and second stages. We will estimate the proportion of responders with Clopper-Pearson 95% 
confidence intervals. We will estimate the uniformly minimum variance unbiased estimator 
(UMVUE), p-value and 95% confidence interval. 
 
Secondary endpoints: 
Number and percentage of patients who obtain Complete Response, Partial Response, Stable 
Disease and Disease Progression will be provided. The Objective Response Rate (ORR) and 
its 95% confidence interval (CI) will be calculated. The Disease Control Rate (DCR) and its 95% 
CI will be calculated. Progression-free Survival (PFS), Overall Survival (OS), Time to Treatment 
Failure (TTF) and Duration of Response (DOR) will be considered secondary objectives, and as 
they are time objectives, they will be analyzed using the Kaplan-Meier method. The number and 
proportion of events and median survival time with their corresponding 95% CIs will be 
calculated. The analyses will be supported by graphical presentations such as survival plots. 
 
Difference between baseline tumor measurements and those observed throughout the study will 
be analyzed using the Wilcoxon test. The average percentage of Tumor Shrinkage (TS) 
observed from baseline to study visits, with their corresponding 95% CIs, will be calculated. 
Patients with and without different types of EGFR mutation will be compared. For binary 
outcomes (ORR and DCR), the chi-square or Fisher's exact test will be used. For time 
objectives (PFS, OS, TTF and DOR), the Kaplan-Meier method and log-rank test will be used. 
For continuous objectives (percentage of Tumor Shrinkage, TS), the Mann-Whitney U test will 
be used. 
 
Baseline biomarker levels will be correlated with the clinical response. For binary and 
continuous results, the Spearman correlation will be used. For time objectives (PFS), the 
Kaplan-Meier method and log-rank test will be used. The categorization or log-transformation of 
biomarker levels will be considered. 
 
The feasibility of re-biopsies at the time of progression will be estimated with the number and 
percentage of patients with rebiopsy and 95% confidence interval. 
 
The presence of mutations and biomarker levels (tissue or blood) will be compared from 
baseline to time of progression with the Mc Nemar and Wilcoxon tests, respectively. 
 
All efficacy analyses will be exploratory. Positive results in this trial will not confirm treatment 
efficacy, however, they will indicate that osimertinib (AZD9291) might be considered in the 
supportive tests. 
 
 


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Protocol date: May 21, 2018 
Version 3 
 
 
 
8.3 
Safety results 
Analysis of safety-related data will be considered at three levels: 
 
• 
First, the degree of exposure (dose, duration, number of patients) will be assessed to 
determine the degree to which study safety can be assessed. 
 
• 
Second, clinically relevant tests, concomitant medications and reported adverse 
events for each study group will be described and compared. For adverse events, 
severity, expectedness, causality, relationship, body system, action taken, and 
outcome will be reported. 
 
• 
Third, serious adverse events, deaths and study discontinuations for each study group 
will be described and assessed. 
 
 
8.4 
Populations for analysis 
 
Full population for efficacy and safety analysis 
 
It includes all patients who have received the investigational treatment, regardless of the 
degree of compliance with the protocol. 
 
Per-protocol population (PP): 
 
Per-protocol population includes all patients of the full population for analysis that have not 
presented any protocol violations that may affect the assessment of the primary endpoint of 
the study (major protocol violations). 
 
Population for biomarker analysis 
 
All patients included in the full population for analysis whose biomarkers have been assessed. 
 
Efficacy analyses are performed on the full population for analysis and the per-protocol 
population. The full analysis set population will be the primary population for the efficacy 
analyses. 
 
The biomarker analysis will be performed on the population for biomarkers. The 
safety analysis will be performed for the full analysis population. 
 
8.5 
Missing data management 
We will report the number of missing values for each endpoint. Patients with missing values in 
the primary analysis and clinical response outcomes (ORR and DCR) will be considered non-
responders. The analysis of time-dependent secondary endpoints (progressions, treatment 
failures and deaths) will be based on a log-rank test or on Cox regression tests and therefore, 
will not be affected by the withdrawal of patients (as they would be censored), provided that 
withdrawals are not related to the prognosis. Patients with missing data regarding endpoints, 
such as objective response, will be considered patients with no response to treatment. In 
addition, we will report the reasons for withdrawal of each patient assigned to the treatment. 
 


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Protocol No.: MedOPP112 
Protocol date: May 21, 2018 
Version 3 
 
 
 
8.6 
Interim analysis 
An interim analysis will be performed when 21 patients have been assessed up to 42 weeks or 
have withdrawn from the study. The interim analysis will assess the primary endpoint and all 
the secondary safety and efficacy objectives limited to a window of up to 42 weeks. However, 
after the database lock at 42 weeks, these patients will continue to be treated and followed up 
in the study until the patient progresses, dies, discontinues the treatment or completes the 
study, whichever occurs first. 
 
 
The efficacy and safety results of the interim analysis will be evaluated by a Scientific 
Committee that will decide on the suitability of continuing with the study. The study will only be 
interrupted in case of futility or for safety reasons. For this test, significance levels with p-
values with alpha error ≤0.025 will be used. 
 
 
8.7 
Scientific Committee Review 
A Scientific Committee (SC) has been appointed for this study. Initially, the committee 
consists of the investigators, the study Medical Monitor and two physicians specialized in 
osimertinib (AZD9291) therapy. 
 
The SC will meet on demand to review, discuss and evaluate all of the collected safety data. 
In the event of a safety issue, a meeting can also be called at any time at the request of an 
investigator participating in the study. At these meetings, MedSIR and the participating 
investigators must reach a consensus on safety data. MedSIR will prepare minutes for these 
meetings and submit them to each investigator for comment prior to finalization. 
 
The study site Investigators and MedSIR will review patient data at least every four months. 
Each study site investigator will regularly review patient data to detect serious side effects. 
 
 
8 
ETHICAL CONSIDERATIONS 
 
9.1 
Regulatory and ethical compliance 
The study will be conducted and reported in accordance with the protocol, the International 
Conference on Harmonization (ICH) Guidelines, and the ethical principles laid down in the 
Declaration of Helsinki. The study will also comply with European Regulation No. 536/2014 
and any applicable local regulations. 
 
 
9.2 
Ethics Committee: 
The conduct of the study must be authorized by a duly constituted EC. Authorization is 
required for study protocol, protocol amendments, informed consent forms, patient 
information sheets and promotional materials. 
 
Wherever necessary, the investigator and/or sponsor should contact the EC to ensure that 
accurate and timely information is being provided at every phase of the study. 
The principal investigator and/or sponsor are responsible for providing, when required, 
written summaries of the study status to the EC annually or more frequently, in accordance 
with the requirements, policies and procedures set out by the EC. 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
Autores: Bernat Miguel Huguet 
MedOPP112 
 
 
 
     Miguel Sampayo Cordero 
SAP_MedOPP112 
 
SAP_AZENT_MedOPP112_Final.docx 
 Confidential 
03/05/2019 
 Page 1 of 26 
 
Statistical Analysis Plan 
1. TITLE PAGE 
Study Title: 
A phase IIa clinical trial to evaluate the safety and efficacy of 
osimertinib (AZD9291) in first-line patients with EGFR mutation-
positive locally advanced or metastatic non-small cell lung cancer and 
concomitant EGFR T790M mutation at time of diagnosis 
(AZENT study) 
Sponsor: 
Medica Scientia Innovation Research (MedSIR ARO) 
Protocol Number: 
MedOPP112 
Protocol Version: 
3 
Protocol Date: 
21 de mayo de 2018 
 
 
Project Code: 
SAP_MedOPP112 
Document Version: 
Final Version 
Document Date: 
03/05/2019 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This confidential document is the property of the Sponsor. No unpublished information contained 
herein may be disclosed without prior written approval from the Sponsor. Access to this document 
must be restricted to relevant parties. 
 
 


STATISTICAL ANALYSIS PLAN 
 
Autores: Bernat Miguel Huguet 
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TABLE OF CONTENTS 
1. 
TITLE PAGE......................................................................................................................... 1 
2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................... 5 
3. 
VERSION HISTORY ........................................................................................................... 6 
4. 
INTRODUCTION ................................................................................................................. 7 
4.1 
Preface .............................................................................................................................. 7 
4.2 
Purpose of the analyses..................................................................................................... 7 
5. 
STUDY OBJETCTIVES AND ENDPOINTS .................................................................... 7 
5.1 
Study objectives ................................................................................................................ 7 
5.2 
Endpoints .......................................................................................................................... 7 
5.2.1 
Primary endpoint ....................................................................................................... 8 
5.2.2 
Secondary endpoints ................................................................................................. 8 
5.2.3 
Exploratory endpoints ............................................................................................... 8 
5.2.4 
Safety endpoints ........................................................................................................ 9 
6. 
STUDY DESIGN ................................................................................................................... 9 
6.1 
General study design and plan .......................................................................................... 9 
6.2 
Visits schedule ................................................................................................................ 10 
6.3 
Study population ............................................................................................................. 13 
6.3.1 
Inclusion criteria ...................................................................................................... 13 
6.3.2 
Exclusion criteria ..................................................................................................... 14 
6.4 
Sample size ..................................................................................................................... 16 
6.5 
Randomization and blinding ........................................................................................... 16 
6.6 
Interim analysis............................................................................................................... 16 
6.1 
Final analysis .................................................................................................................. 17 
7. 
STATISTICAL METHODS............................................................................................... 17 
7.1 
Primary analysis ............................................................................................................. 17 
7.2 
Secondary analysis: ........................................................................................................ 18 
7.3 
Safety analysis: ............................................................................................................... 18 
7.4 
Analysis populations....................................................................................................... 18 
7.5 
Covariates and subgroups ............................................................................................... 19 
7.6 
Missing data .................................................................................................................... 19 
7.7 
Multi-centre studies ........................................................................................................ 20 
7.8 
Multiple testing ............................................................................................................... 20 
7.9 
Interim analyses and data monitoring ............................................................................. 20 
7.9.1 
Purpose of interim analyses ..................................................................................... 20 
7.9.1 
Stopping rules .......................................................................................................... 20 
7.10 
Decision rules and adjustment of alpha for primary endpoint at final analysis .......... 20 


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7.11 
Steering committee review ......................................................................................... 21 
7.11.1 Adjustment of confidence intervals and p-values ................................................... 21 
7.11.2 Practical measures to minimize bias ....................................................................... 21 
7.11.3 Documentation of interim analyses ......................................................................... 21 
7.12 
Reporting conventions ................................................................................................ 21 
7.12.1 General reporting conventions ................................................................................ 21 
7.12.2 Statistical summary conventions ............................................................................. 22 
8. 
TECHNICAL DETAILS .................................................................................................... 22 
9. 
SUMMARY OF CHANGES TO THE PROTOCOL ...................................................... 22 
10. 
REFERENCES ................................................................................................................ 22 
 
 


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LIST OF TABLES 
SAP Table. 1 Visits schedule ........................................................................................................ 11 
SAP Table. 2  Handling of missing data and time fields .............................................................. 23 
 
LIST OF APPENDICES 
Appendix 1. Handling of missing date and time fields ................................................................. 23 
Appendix 2 
List of protocol deviations ................................................................................... 25 
 
 
 


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2. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
95%CI 
95% confidence interval 
AE 
Adverse Event 
ALT 
Alanine transferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BOR 
Best overall response 
cORR 
Confirmed overall response rate 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case Report Form 
CTCAE 
Common terminology criteria for adverse events 
DCR 
Disease control rate 
DoR 
Duration of response 
ICH 
International conference of harmonisation 
ECG 
Electrocardiography 
ECOG 
Eastern cooperative oncology group 
EGFR 
Epidermal growth factor receptor 
EORTC 
European organisation for research and treatment of cancer 
HIV 
Human immunodeficiency virus 
IC 
Informed consent 
IMP 
Investigational Medical Product 
ILD 
Interstitial Lung Disease 
LNL 
Lower normal limit 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
N 
Number of patients 
NA 
Not applicable 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
OR 
Overall response 
ORR 
Overall response rate 
OS 
Overall survival  
PD 
Progressive disease 
PFS 
Progression-free survival 
PET-CT 
Positron emission tomography/computed tomography 
PMF 
Probability of mass function 
PR 
Partial response 
RECIST 
Response evaluation criteria in solid tumours 
SAP 
Statistical Analysis Plan 
SC 
Steering committee 
SD 
Stable disease 
TTF 
Time to failure 
TS 
Tumor Shrinkage 
UMVUE 
Uniformly minimum variance unbiased estimator 
UNL 
Upper normal limit 
US 
United states 
 


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SAP_MedOPP112 
 
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3. VERSION HISTORY  
(Versions before data base lock) 
Version 
Date 
Status 
Draft 1 
21/06/2018 
Pre interim database lock 
Draft 2 
28/06/2018 
Pre interim database lock 
Draft 2 
03/05/2019 
Pre interim database lock 
APPROVAL 
The signing parts declare to have seen and revised this document and approve its content. (Draft 
versions do not require signed approval). 
Name 
Function 
Date 
Signature 
Miguel Sampayo Cordero 
Statistician 
 
 
Bernat Miguel Huguet 
Statistitcian 
 
 
Sponsor 
Name 
Function 
Date 
Signature 
Noemí 
López 
Martínez 
(MedSIRI 
Project Manager 
 
 
 
Cordinator 
investigator 
 
 
 
Medical monitor 
 
 
 
 
 


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4. INTRODUCTION 
4.1 Preface 
We can state that in EGFR-mutation-positive NSCLC, in addition to the molecular diagnosis, it is 
necessary to quickly validate and implement a kit as part of clinical practice for the detection of a 
predictive biomarker panel that will allow for adequately personalized treatments using EGFR 
TKIs in monotherapy. To this end, we propose to begin a phase IIa clinical trial of osimertinib 
(AZD9291) in patients with a recent diagnosis of NSCLC with EGFR mutations and with the 
concomitant pre-treatment T790M mutation. The mutation will be detected in tumor tissue using 
a highly sensitive assay for T790M, based on laser microdissection and a peptide-nucleic acid 
clamping PCR. 
4.2 Purpose of the analyses 
These analyses will assess the efficacy and safety of osimertinib (AZD9291) in patients with 
advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at 
diagnosis. 
5. STUDY OBJECTIVES AND ENDPOINTS 
5.1 Study objectives 
To evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate (ORR) 
in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M 
mutation at diagnosis, as defined by RECIST 1.1 criteria. 
5.2 Endpoints 
(ICH E9; 2.2.2) 
The efficacy study endpoints will be deribed in accordance with Per Response Evaluation Criteria 
in Solid Tumours (RECIST v1.1) assessed by magnetic resonance imaging (MRI) or computed 
tomography scan (CT). The next endpoints has been defined:  
Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions. 
Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (TL) (compared 
to baseline) and no new lesions. 
Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to 
qualify as progression. 
Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute 
increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression 
of NTLs or a new lesion.  
Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and 
no new lesions.  
BOR is the best response (by investigator assessment) a patient has achieved where the order of 
best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer 
therapy. 
 


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Additionally censoring strategies in time to event outcomes will be defined in accordance with 
Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
from dood and drug administration.  
5.2.1 Primary endpoint 
Confirmed objective response rate (cORR) is defined as the number of patients with complete 
response (CR) and partial response (PR), confirmed at least 4-6 weeks after the initial response, 
divided by the number of patients in the analysis set. Tumor response will be defined as best 
response, based on local investigator’s assessment according to RECIST criteria guidelines 
(version 1.1). 
5.2.2 Secondary endpoints 
The following exploratory endpoints will be analysed: 
• 
Objective response rate (ORR) is defined as the number of patients with complete response 
(CR) and partial response (PR) divided by the number of patients in the analysis set. Tumor 
response will be defined as best response, based on local investigator’s assessment according to 
RECIST criteria guidelines (version 1.1).  
• 
Disease control rate (DCR) is defined as the patients with CR, PR, or SD relative to all 
participants in analysis set. Participants who do not have on-study radiographic tumor 
reevaluation, who received anti-tumor treatment, who died, progressed, or dropped out for any 
reason prior to achieving reaching a CR or PR and a best response of SD was counted as non-
responders in DCR. 
• 
The progression-free survival (PFS) as assessed by investigator is defined as the time from 
the date of randomization to the date of the first documentation of objective tumor progression as 
per RECIST v1.1 or death due to any cause in the absence of documented PD, whichever occurs 
first. If tumor progression data include more than 1 date, the first date will be used. PFS (in months) 
will be calculated as (first event date − randomization date +1)/30.4. Progression is defined using 
RECIST v1.1, as a 20% increase in the sum of diameters of target measurable lesions above the 
smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with 
a minimum absolute increase of 5 mm, or unequivocal progression of pre-existing non-target 
lesions, or the appearance of new lesions. 
• 
Overall survival (OS) is defined as the time from treatment start to the time of death due to 
any cause. 
• 
Time to treatment failure (TTF) is defined as the time from treatment start to the time at 
which the patient discontinues treatment due to any cause, including disease progression assessed 
by the investigator as per RECIST v1.1, toxicity, death or at the patient’s request. 
• 
Duration of response (DOR): is defined as the time from the date of first documented 
response (CR or PR that was subsequently confirmed) until the date of documented progression 
(PD) or death in the absence of disease progression (by investigator assessment). 
• 
Tumor shrinkage (TS) is defined as the percentage of tumor shrinkage from baseline 
(obtained from the sum of the largest diameters of the target lesions) per RECIST v1.1 criteria. 
5.2.3 Exploratory endpoints 
The following exploratory endpoints will be analyzed: 
 • 
Correlation ratio of mutational status and documented clinical response. 


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• 
A progress curve showing the EGFR mutational status (including the T790M mutation) in 
plasma and serum longitudinally. 
• 
Percentage levels of BIM mRNA as well as mRNA levels of other biomarkers related to 
EGFR TKI response. 
• 
Percentage of patients with mutations at the site of covalent binding to the drug (C797) or 
other mutations in tissue and correlation ratio of documented clinical response. 
5.2.4 Safety endpoints 
The following safety endpoints will be analyzed: 
Patient safety and adverse events will be assessed using the Common Terminology Criteria for 
Adverse Events (CTCAE) of the U.S. National Cancer Institute (NCI), version 4. Grade 3 or 4 
adverse events and serious adverse events will be assessed to determine the safety and tolerability 
of the various combinations of drugs. 
6. STUDY DESIGN 
6.1 General study design and plan 
(ICH E3;9.) 
Identify the study design, including the following: 
• This is a multicenter, open-label, single-arm non-controlled phase IIa trial. The design of 
this study is divided into three well-defined phases: 
• Screening phase 
During this phase, subject eligibility is determined, including the genotyping of the tumor and 
documentation of baseline characteristics.   
• 
Treatment phase: 
When a patient carrying both mutations is identified and the study screening criteria have been 
met, the patient will receive a dose of osimertinib (AZD9291) 80 mg every 24 hours, in tablets 
for oral administration. The study treatment will continue until one of the following situations 
arises: 
• Disease progression is confirmed radiologically and unequivocally, except for new 
metastases in CNS or isolated progression of previously-treated lesions in the CNS.  
• Adverse event(s) which, according to the protocol or in the opinion of the investigator, can 
cause serious or permanent damage or which rule out further treatment with the study drug. 
• General or specific changes in the patient’s health state which, in the opinion of the 
investigator make further treatment unacceptable. 
• Major study protocol non-compliance. 
• Patient’s withdrawal from the study. 
• Dead. 
• After a maximum of 78 weeks from the patient first study treatment dose intake. 
• Study is canceled by the Sponsor. 
 


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• 
Follow-up phase:  
Once the treatment phase is completed, a biopsy should be performed to identify acquired 
mechanisms of resistance to the drug and the follow-up phase will begin. 
 
 
 
6.2 Visits schedule 
(ICH E3; 9.5.1. ICH E9; 2.2.2) 
The following table presents the relation between visits and medical assessments planned for this 
study: 
 


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 SAP Table. 1 Visits schedule 
Assessment 
Screening 
Baseline 
Treatment 
period: 2 -weeks 
post-baseline 
evaluation 
 
Treatment 
period: 
Complete 
evaluations 
Treatment period: 
Routine evaluations 
End of treatment 
visit: 
After progression or 
at the end of 
treatment for any 
other reason 
Follow-up 
 
(2-4 weeks as 
maximum before 
baseline) 
Day 0  
(pre-
treatment) 
After 2 weeks 
After 12, 24, 
36, 48, 60, 72 
weeks from 
first dose  
After 6, 18, 30, 42, 54, 
66, 78 weeks from 
first dose  
Within 4 weeks after 
end of treatment 
(only if end of 
treatment is not 
confirmed in some of 
the scheduled full 
visits) 
After progression or 
end of treatment for 
any other reason, after 
12,24,36,48, 60, 72, 78 
weeks after first dose 
Written Informed Consent 
X 
 
 
 
 
 
 
Sample (tissue) to the central lab 
X [1] 
 
 
 
 
X (if available) 
 
Medical History 
 
X 
 
X 
 
 
 
Physical 
examination, 
ECOG 
Performance Status, Vital Signs, 
body weight  
 
X [2] 
 
X [2] 
X [2] 
X [2] 
 
Recording of symptoms  
 
X 
 
X 
X 
X 
 
Pregnancy Test  
 
X [3] 
 
 
 
 
 
Hematology 
 
X [4] 
 
X [4] 
X [4] 
X [4] 
 
Renal function 
 
X [4] 
 
X [4] 
X [4] 
X [4] 
 
Blood Chemistry 
 
X [4] 
 
X [4] 
X [4] 
X [4] 
 
Coagulation  
 
X [4] 
 
X [4] 
X [4] 
X [4] 
 
Urine dipstick test for analysis of 
proteinuria 
 
X [4] 
 
X [4] 
X [4] 
X [4] 
 
ECG  
 
X [5] 
 
X 
X (only if clinically 
required) 
X 
 
Tumor Assessment  
 
X [6] 
 
X [6] 
 
X [6] 
 


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Serum/plasma 
sample 
for 
translational research  
 
X 
X 
X 
 
X 
 
Antineoplasic therapy 
 
X 
X 
X 
X 
X 
X 
Concomitant Medication  
X 
 
X [7] 
X [7] 
X [7] 
X [7] 
 
Adverse Events 
 
 
X 
X 
X 
X  
X [8] 
Survival 
 
 
X 
X 
X 
X 
X 
1. 
EGFR results from test performed locally in the same laboratory than the central one up to 28 days before inclusion will be accepted.        
2. 
Vital signs include pulse and temperature. 
3. 
A negative serum or urine pregnancy test up to 7 days before inclusion will be accepted. 
4. 
Hematology, renal function, blood chemistry and coagulation tests performed up to 72 hours before inclusion and before the corresponding date of each visit will be accepted.  
5. 
ECG performed up to 14 days before inclusion and before the corresponding date of each visit will be accepted.  
6. 
Assessment procedures should be the same at every visit. Baseline tumor assessments should include, at least, chest and abdominal CT. If, in the opinion of the investigator it is clinically 
indicated, other radiological evaluations may be performed (PET-CT, MRI). PET-CT, MRI performed up to 28 days before inclusion and up to 14 days before every visit during treatment 
period including end of treatment visit will be accepted   
7. 
Every concomitant medication will be recorded, including analgesics. 
8. 
Every new AE identified up to 28 days after administration of last dose of study treatment or until a maximum of 78 weeks after first dose should be recorded on the corresponding CRF 
page (AE). 


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6.3 Study population 
(ICH E3;9.3. ICH E9;2.2.1) 
Patients diagnosed with stage IIIB or IV non-small cell lung cancer carrying the EGFR activating 
mutation and confirming concomitant T790M mutation during screening who have not received 
prior treatment for this advanced disease will be enrolled in this study. Patients are not eligible if 
they are candidates for local curative treatment. 
The analysis of EGFR mutational status (del19, L858R, L861Q or G719X) may be previously 
performed at each of the participating sites, but the tumor material taken from all patients should 
be submitted to the central laboratory for supportive analysis and T790M mutation analysis. 
The patient’s signed informed consent should be obtained before sending the tumor tissue sample 
to the central laboratory. 
6.3.1 Inclusion criteria 
Patient eligibility will be reviewed and documented by a suitable member of the investigator’s 
study team before the patients are enrolled in the study. 
Patients must meet all the following inclusion criteria to be enrolled in the study: 
1. Patient aged 18 years or older. 
2. Patients with histological confirmation of locally advanced or metastatic, non-squamous non-
small cell lung cancer (NSCLC) with an activating EGFR mutation and concomitant T790M 
mutation who are not candidates for local curative treatment. 
3. Patients with a M1a stage according to the TNM version 7 including M1a (malignant effusion) 
or M1b (distant metastasis), or locally advanced disease that is not a candidate for curative 
treatment (including patients who progress after chemoradiotherapy in stage III disease). 
4. Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 
(G719X) and concomitant T790M mutation before treatment confirmed centrally. 
5. ECOG (Eastern Cooperative Oncology Group) performance status less than or equal to 2. 
6. Existence of measurable or evaluable disease (as per RECIST 1.1 criteria). Patients with 
asymptomatic and stable brain metastases are eligible for the study. 
7. Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection of the 
primary tumor or metastatic tumor tissue, within the 60 days prior to study entry. 
8. Life expectancy ≥12 weeks. 
9. Adequate hematologic function: Absolute neutrophil count (ANC) > 1.5 x 109/L, platelet count 
> 100.0 x109/L and hemoglobin > 9.0 g/dL (> 6.2 mmol/L). 
10. Adequate coagulation: INR ≤ 1.5. 
11. Adequate liver function: Total bilirubin < 1.5 × ULN, ALT and/or AST < 2.5 × ULN, alkaline 
phosphatase < 5 ULN, except in the presence of single bone metastases and in absence of any 
liver disorders. 


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12. Adequate renal function: Calculated creatinine clearance > 50 mL/min (Cockroft-Gault) and 
proteinuria < 2+ (dipstick). 
13. Capacity to swallow, patient capable of completing treatment and accessible, ensuring proper 
follow-up. 
14. Patients able to complete study and within geographical proximity allowing for adequate 
follow-up. 
15. Resolution of all acute toxic effects of previous anti-cancer therapy (which can only be 
adjuvant or neoadjuvant) or surgical interventions not exceeding grade  1 according to the 
NCI CTCAE version 4.0 (except for alopecia or other side effects that the investigator does 
not consider to be a risk to patient safety). 
16. All men or women of childbearing potential must use a contraception method during the study 
treatment and for at least 12 months after the last dose of the study drug. Sexually active men 
and women of childbearing potential who are unwilling to use a contraception method are not 
eligible for the study. 
17. The written informed consent (IC) must be signed and dated by the patient and the investigator 
before any study intervention takes place. 
6.3.2 
Exclusion criteria 
Any patient meeting ANY of the following criteria will be excluded from the study: 
1. Locally advanced lung cancer candidate for curative treatment through radical surgery and/or 
radio(chemo)therapy. 
2. Patients diagnosed with another lung cancer subtype, patients with mixed NSCLC with 
predominantly squamous cell cancer, or with any small-cell lung cancer component. 
3. Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 
(G719X) and concomitant T790M mutation before treatment that have not been confirmed 
centrally. 
4. Patients who have received prior antineoplastic treatment for advanced disease. 
5. Second active neoplasia; e.g. patients diagnosed with a potentially lethal cancer for which they 
may be receiving treatment (but are not obliged to do so). 
6. Patients with just one measurable or evaluable tumor lesion that has been resected or irradiated 
prior to their enrollment in the study. 
7. Medical history of Interstitial Lung Disease (ILD) induced by drugs, radiation pneumonitis 
requiring steroid treatment or any evidence of clinically active ILD. 
8. Any of the following criteria: 
• Corrected QT Interval (QTc) >470 msec, obtained from 3 ECGs at rest, using the QTc 
value determined according to the clinical screening ECG machine. 
• Any clinically significant abnormality in ECG rhythm, conduction or morphology at rest. 


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• Any factor that increases the risk of QTc prolongation or risk of irregular heartbeat or 
sudden inexplicable death under the age of 40 in first-degree relatives or any concomitant 
medications that prolong the QT interval. 
9. Uncontrolled, active or symptomatic metastases of CNS, carcinomatous meningitis or 
leptomeningeal disease indicated by known clinical symptoms, cerebral edema and/or 
progressive neoplasia. Patients with history of CNS metastasis or compression of the spinal 
cord are eligible if they have received local final treatment (e.g., radiotherapy, stereotactic 
surgery) and if they have remained clinically stable without using anticonvulsants and 
corticosteroids for a minimum of 4 weeks prior to the first day of study treatment. 
10. Refractory nauseas and vomiting, chronic gastrointestinal disease, inability to swallow study 
drug or significant intestinal resection that restricts the adequate absorption of osimertinib 
(AZD9291). 
11. Patients who have had a surgical procedure unrelated to the study within 7 days prior to the 
administration of the drug or a significant traumatic lesion during the 4 weeks prior to starting 
the administration of the study drug, patients who have not recovered from the side effects of 
any major surgery or patients who might need major surgery during the course of the study. 
12. Pregnant or breastfeeding women. Women of childbearing potential, including women who 
had their last menstrual period within the last two years, must have a negative serum or urine 
pregnancy test in the 7 days prior to the start of the treatment. 
13. Patients who are not willing to use an adequate contraception method until 12 months after the 
last dose of study treatment. 
14. Patients with a serious concomitant systemic disorder (e.g., active infection, including HIV or 
heart disease) that is incompatible with the study (in the opinion of the investigator), history 
of bleeding diathesis or anticoagulant therapy (the use of low molecular weight heparin is 
permitted provided that it is used for prophylaxis). 
15.  Inability to swallow tablets. 
16. Patients with a history of cancer that has been completely treated, with no evidence of 
malignant disease currently cannot be enrolled in the study if their chemotherapy was 
completed less than 6 months prior and/or have received a bone marrow transplant less than 2 
years before the first day of study treatment. 
17. Prior treatment with cytotoxic chemotherapy for advanced NSCLC; neoadjuvant/adjuvant 
chemotherapy is permitted if at least 6 months have elapsed between the end of chemotherapy 
and the first day of study treatment. 
18. Patients who have received prior EGFR treatments for lung cancer. 
19. Patients who have received treatment with an investigational drug within 3 weeks before the 
first day of study treatment. 
20. Treatment with prohibited drugs within 14 days before the first day of study treatment. 
21. Any other reason that the investigator deems to be incompatible with the patient’s participation 
in the study. 


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6.4 Sample size 
(ICH E3; 9.7.2. ICH E9; 3.5) 
In the Phase I/II AURA clinical trial, where osimertinib (AZD9291) was administered to patients 
with advanced EGFR-mutant NSCLC after progression to EGFR TKIs, among the 127 patients 
with centrally confirmed EGFR T790M mutation, the response rate was 61%. In contrast, amongst 
61 patients without centrally confirmed EGFR T790M, the response rate was 21% (15). In the 
West Japan Thoracic Oncology Group 3405 (WJTOG3405) study, comparing gefitinib with first-
line chemotherapy in patients with advanced NSCLC with activating mutations in EGFR, the ORR 
in the overall population with measurable disease was 62.1% in the gefitinib group and 32.2% in 
the chemotherapy group. In the North East Japan 002 (NEJ002) study, comparing gefitinib with 
first-line chemotherapy in patients with advanced NSCLC with EGFR mutations, the gefitinib 
group had a significantly higher ORR (73.7% vs. 30.7%). In the OPTIMAL study, comparing 
erlotinib with chemotherapy in patients with advanced NSCLC with EGFR mutations, ORR was 
83% for erlotinib and 36% for patients receiving chemotherapy (C. Zhou et al. 2011). In the LUX-
Lung 3 study, comparing afatinib with first-line chemotherapy in patients with advanced NSCLC 
with EGFR mutations, ORR was significantly higher for patients treated with afatinib compared 
to chemotherapy according to both the independent evaluation committee (56% and 23%, 
respectively) and the investigator (69% and 44%, respectively) assessments. In the EURTAC 
study, comparing erlotinib with first-line chemotherapy in patients with advanced NSCLC with 
EGFR mutations, ORR was 65.1% in the erlotinib group and 16.1% in the chemotherapy group. 
A subsequent study assessed the impact of pre-treatment presence of the concomitant EGFR 
T790M mutation. Among patients treated with erlotinib, the presence of this concomitant mutation 
was evaluated in 95 patients. ORR was found to be 75% in patients without pre-treatment T790M, 
compared to 47% in patients with pre-treatment T790M. 
This data suggests that excluding an ORR ≤50% while targeting the improvement of the ORR to 
≥70% would be a conservative approach to assess the osimertinib (AZD9291) treatment effect in 
this patient population. Accordingly, this study will test the null hypothesis that the ORR is ≤50% 
against the alternative hypothesis that it is ≥70%. Applying Simon’s optimum 2-stage design 
(Simon, R 1989), a sample size of 73 patients has power > 0.90 to achieve a 1-sided significance 
level of 0.025. In the first stage, 21 patients will be accrued. If there are 11 or fewer responses in 
these 21 patients, the study will be stopped. Otherwise, 52 additional patients will be accrued for 
a total of 73 patients. The null hypothesis will be rejected if 45 or more responses are observed in 
73 patients. This design yields a type I error rate of 0.025 and a power of 90% when the ORR is 
70%. The recruitment will be competitive between sites. 
6.5 Randomization and blinding 
(ICH E3; 9.4.3, 9.4.6. ICH E9; 2.3.1, 2.3.2) 
No applicable. 
6.6 Interim analysis 
An interim analysis will be performed when 21 patients have been assessed up to 42 weeks or 
withdrawn from the study. The interim analysis will assess the primary endpoint and all the 
secondary safety and efficacy objectives limited to a window of up to 42 weeks. The first interim 
report will only include the summary of study accrual, the clinical and demographic summary, the 
primary efficacy analysis and the report of toxicity. This first report has developed to not delaying 
the go/not go decision in the first stage. The other results will be presented later. After the database 


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lock at 42 weeks, these patients will continue to be treated and monitored until progression, death 
or treatment discontinuation. The decision to stop and continue the trial should be agreed by the 
steering committe after reviewing the interim safety and efficacy data. 
6.1 Final analysis 
Upon completion of the interim analysis, and according to the evaluation of the results obtained 
during the interim analysis, recruitment of patients will resume until a total of 73 patients have 
been recruited during a 24-month recruitment period. A follow-up lasting up to 78 weeks will 
begin upon the first dose had been administered to each patient. The study will end, at latest, 78 
weeks after last patient has started the treatment.  
7. STATISTICAL METHODS 
7.1 Primary analysis 
We will describe number and proportion of patients with cOR (confirmed objective Response) in 
the first and second stages. We will estimate the proportion of responders with Clopper-Pearson 
95% confidence intervals. We will estimate the uniformly minimum variance unbiased estimator 
(UMVUE), p-value and 95% confidence interval. 
 
Point estimation according UMVUE: 
 
 
 
 
 
Probability of mass function (PMF) according UMVUE: 
 
 
 
P-value according UMVUE: 
 
             s/n1                  
 
 
 
if m=1 
𝑝 = 
 
 
 
 
 
(Equation 1) 
            
 
 𝑛1−1
𝑥1−1  𝑛2
𝑠−𝑥1 
s ∧(b1 −1)
x1 =(a1 +1) ∨(s−n2 )
 
 𝑛1
𝑥1  𝑛2
𝑠−𝑥1 
s ∧(b1 −1
x1 =(a1 +1) ∨(s−n2 )
      
 
 
if m=2 
                         ps(1-p)n1-s  𝑛1
𝑠                    
    if m=1, 0 ≤ s ≤ a1 or b1 or b=1 
f(m,s|p) =  
 
 
 
 
 
(Equation 2) 
                        ps(1-p)n1+n2-s  
 𝑛1
𝑥1  
𝑛2
𝑠−𝑥1 
s ∧(b1−1
x1=(a1+1)
  if m=2, a1+1  s ≤ b1 – 1+ n2 


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Where: 
M = study stage (1 or 2); p = effect of treatment as rate; p0 = expected effect of treatment 
considered as futility; a = maximum number of responders to accept null hypothesis at final 
analysis; a1 = maximum number of responders to accept null hypothesis at interim analysis; b1 = 
n1+1 for Simon’s two-stage designs;  s = the observed number of responding patients; n = expected 
number of patients included in the study; n1 = patients included in stage 1; n2 = patients included 
in stage 2; a ∧ b = min(a, b); a ∨ b = max(a, b); x! = x× (x ‒ 1) × … × 2 × 1. 
7.2 Secondary analysis: 
Number and percentage of patients who obtain Complete Response, Partial Response, Stable 
Disease and Disease Progression will be provided. The Objective Response Rate (ORR), 
unconfirmed and confirmed and its 95% confidence interval (CI) will be calculated. The Disease 
Control Rate (DCR) and its 95% CI will be calculated. Progression-free Survival (PFS), Overall 
Survival (OS), Time to Treatment Failure (TTF) and Duration of Response (DOR) will be 
considered secondary objectives, and as they are time objectives, they will be analyzed using the 
Kaplan-Meier method. The number and proportion of events and median survival time with their 
corresponding 95% CIs will be calculated. The analyses will be supported by graphical 
presentations such as survival plots. The average percentage of Tumor Shrinkage (TS) observed 
from baseline to study visits, with their corresponding 95% CIs, will be calculated. 
All efficacy analyses will be exploratory. Positive results in this trial will not confirm treatment 
efficacy, however, they will indicate that osimertinib (AZD9291) might be considered in the 
supportive tests.  
7.3 Safety analysis: 
Analysis of safety-related data will be considered at three levels: 
• 
First, the degree of exposure (dose, duration, number of patients) will be assessed to 
determine the degree to which study safety can be assessed. 
• 
Second, clinically relevant tests, concomitant medications and reported adverse events for 
each study group will be described and compared. For adverse events, severity, expectedness, 
causality, relationship, body system, action taken and outcome will be reported. 
• 
Third, serious adverse events, deaths and study discontinuations for each study group will 
be described and assessed. 
7.4 Analysis populations 
(ICH E3; 9.7.1, 11.4.2.5. ICH E9; 5.2) 
Full Analysis and Safety analysis set (FAS) 
Includes all included subjects who have received any study drug, independently of the degree of 
adherence to the protocol. 
                     
𝑓 1, 𝑗|𝑝0 
n1
j=s
                            
  if m = 1, s    1 
 p-value=     1-  
𝑓 1, 𝑗|𝑝0 
s−1
j=0
                         
  if m = 1, s    1            (Equation 3) 
                     
𝑓 1, 𝑗|𝑝0 +  
𝑓 2, 𝑗|𝑝0 
b1−1+n2
j=s
n1
j=b1
         if m = 2 


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Per Protocol Set (PP) 
The Per Protocol set includes all patients included in the FAS who did not violate the protocol in 
a way that might affect the evaluation of the effect of the study drug on the primary endpoint, i.e., 
without a major protocol violation. 
Major and minor protocol violations will be identified by clinically trained personnel before the 
database lock.  The definition of the major protocol violations is described in Appendix 2. 
Biomarker analysis set 
All patients included in FAS who has been evaluable for biomarker status. 
Sensitivity analysis 
Primary efficacy analysis will be performed on the full analysis (FAS) and PP sets. Secondary 
efficacy analysis will be performed on FAS. FAS will be considered the primary population for 
the efficacy analysis.  
Biomarker analysis will be performed on biomarker analysis set. 
Safety analysis will be performed on the full analysis set. 
7.5 Covariates and subgroups 
(ICH E3; 9.7.1, 11.4.2.1. ICH E9; 5.7. CPMP 2002; 4.CPMP 2003.) 
Difference between baseline tumor measurements and those observed throughout the study will 
be analyzed using the Wilcoxon test. Patients with and without different types of EGFR mutation 
will be compared. For binary outcomes (cORR, ORR and DCR), the chi-square or Fisher's exact 
test will be used. For time objectives (PFS, OS, TTF and DOR), the Kaplan-Meier method and 
log-rank test will be used. For continuous objectives (percentage of Tumor Shrinkage, TS), the 
Mann-Whitney U test will be used. 
Baseline biomarker levels will be correlated with the clinical response. For binary and continuous 
results, the Spearman correlation will be used. For time objectives (PFS), the Kaplan-Meier 
method and log-rank test will be used. The categorization or log-transformation of biomarker 
levels will be considered. 
The feasibility of re-biopsies at the time of progression will be estimated with the number and 
percentage of patients with rebiopsy and 95% confidence interval. 
The presence of mutations and biomarker levels (tissue or blood) will be compared from baseline 
to time of progression with the Mc Nemar and Wilcoxon tests, respectively. 
7.6 Missing data 
(ICH E3; 9.7.1, 11.4.2.2. ICH E9;5.3. EMA Guideline on Missing Data in Confirmatory Clinical 
Trials) 
We will report the number of missing values for each endpoint. Patients with missing values in the 
primary analysis and clinical response outcomes (cORR, ORR and DCR) will be considered non-
responders. The analysis of time-dependent secondary endpoints (progressions, treatment failures 
and deaths) will be based on a log-rank test or on Cox regression tests and therefore, will not be 
affected by the withdrawal of patients (as they would be censored), provided that withdrawals are 
not related to the prognosis. Patients with missing data regarding endpoints, such as objective 
response, will be considered patients with no response to treatment. In addition, we will also report 
the reasons for withdrawal for each allocated patient.  


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7.7 Multi-centre studies 
(ICH E3;9.7.1, 11.4.2.4. ICH E9; 3.2) 
Individual centre results will be analysed combined in a single cohort. In accordance with previous 
experiences we assume that the center will not have relevant effect on safety or the activity of the 
study treatment.   
7.8 Multiple testing 
(ICH E3; 9.7.1, 11.4.2.5. ICH E9; 2.2.5) 
All efficacy analyses will be exploratory. Positive results in this trial has not a confirmatory 
meaning, however, they will indicate that osimertinib (AZD9291) might be considered in the 
supportive tests. However the statistical design was based on a superiority binomial test of ORR. 
The statistical test has 90% power to detect a 20% increase over 50% ORR observed with other 
strategies in previous studies. The total type I error was adjusted in accordance with the stopping 
boundaries constraints in a Simon Two-stage design. The design yields a type I error rate of 0.025. 
All secondary efficacy analysis has been considered supportive of primary endpoint and we have 
not planned a formal correction of the alpha error due to multiple testing.  
Subgroup analysis has been considered exploratory, too. However, multiplicity issues derived 
from analysing multiple hypothesis will be adjusted by the Q-value index at 10% nominal level, 
based on (Storey JD, Bass AJ, Dabney A and Robinson D (2018). qvalue: Q-value estimation for 
false discovery rate control. R package version 2.14.0, http://github.com/jdstorey/qvalue). 
7.9 Interim analyses and data monitoring  
(ICH E3; 9.7.1, 11.4.2.3. ICH E9; 4.1, FDA Feb 2010 “Guidance for Industry Adaptive Design 
Clinical Trials for Drugs and Biologics”) 
7.9.1 Purpose of interim analyses 
We have planned an interim analysis to reduce the number of patients exposed if the therapeutic 
regimen investigated was inefficient or unsafe. We propose an interim analysis with a futility 
boundary, but not with efficacy boundary. The study will be only finished for primary outcome if 
the results are not promising. We do not want to stop the trial early for efficacy because we will 
recruit only a few patients at interim (21). The early discontinuation of the trial will impact 
negatively in the power of primary and secondary analysis if the combination is promising. 
However, the decision to stop and continue the trial should be agreed by the steering committee 
after reviewing the interim safety and efficacy data. 
7.9.1 Stopping rules 
The efficacy and safety results of the interim analysis will be evaluated by a Scientific Committee 
that will decide on the suitability of continuing with the study. The study will only be interrupted 
in case of futility (if there are 11 or fewer responses in these 21 patients) or safety (in case of any 
arising safety concern after steering committee review). 
7.10 
Decision rules and adjustment of alpha for primary endpoint at final 
analysis 
The study will be declared positive if the following outcome are achieved: 


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1.  Final analysis:  The  p-value  estimated  according  stochastic  ordering  of uniformly  minimum  
variance  unbiased  estimator  (UMVUE)  is  <0.025. According with these criteria, if 73 patients 
are included in the analysis we will achieve a positive finding with 45 or more responders. 
7.11 
Steering committee review 
A Scientific Committee (SC) has been appointed for this study. Initially, the committee consists 
of the investigators, the study Medical Monitor and two physicians specialized in osimertinib 
(AZD9291) therapy. 
The SC will meet on demand to review, discuss and evaluate all of the collected safety data. In the 
event of a safety issue, a meeting can also be called at any time at the request of an investigator 
participating in the study. At these meetings, MedSIR ARO and the participating investigators 
must reach a consensus on safety data. MedSIR ARO will prepare minutes for these meetings and 
submit them to each investigator for comment prior to finalization. 
The study site Investigators and MedSIR ARO will review patient data at least every four months. 
Each study site investigator will regularly review patient data to detect serious side effects. 
7.11.1 Adjustment of confidence intervals and p-values 
The total type I error was adjusted in accordance with the stopping boundaries constraints in a 
Simon Two-stage design. The design yields a type I error rate of 0.025. 
We account for the sequential nature of the design calculating the responder rate, confidence 
interval and p-values of primary endpoint in accordance with UMVUE method. The equation has 
been described in primary endpoint section.  
7.11.2 Practical measures to minimize bias 
This is an open label study with a descriptive purpose. All efficacy analyses will be exploratory. 
Positive results in this trial has not a confirmatory meaning. In accordance, the interim and final 
analysis will not be developed by different teams of statisticians. The decisions at interim analysis 
will be made by the steering committee and they will decide the information that will be publically 
available following the interim analysis.  
7.11.3 Documentation of interim analyses 
Snapshots of the data available at each interim analysis should be preserved, as should all 
documentation of analysis plans, programming code and reporting provided at each interim. It 
should be possible to recreate the decision process from the trial archive. Record what documents 
will be created and stored thus. 
7.12 
Reporting conventions 
7.12.1 General reporting conventions 
All tables, figures and data listings will be presented in portrait orientation, unless landscape 
orientation suggests that the information is easier to view. Legends will be used for all figures with 
more than one variable or item displayed. Figure lines should be wide enough to see the line after 
being copied.  
Titles of all tables, listings and figures should contain the following information:  


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• Output number.  
• Description of the data that is being summarized. 
• Type of analysis performed, covariates used (if applicable).  
• Analysis population. 
7.12.2 Statistical summary conventions 
For tables, sample sizes for each treatment group will be presented as totals in the column header 
(N=xxx), where appropriate. Sample sizes shown with summary statistics are the number (n) of 
patients with non-missing values.  
Summaries for categorical variables will include only categories that patients had a response in. 
Percentages corresponding to null categories (cells) will be suppressed. All summaries for 
continuous variables will include: N, mean, and SD. Other summaries (e.g. median, quartiles, 5%, 
95% intervals, range or interquartile range) will be used as appropriate. All percentages should be 
rounded and reported to a single decimal place (xx.x%). If percentages are reported as integers, 
percentages greater than 0% but <1% will be reported as <1%, whereas percentages greater than 
99% but <100% will be reported as >99%. A percentage of 100% will be reported as 100%. No 
value of 0% should be reported. Any computation of percent that results in 0% is to be reported as 
a blank. P-values will be reported with three decimal places with a leading zero (0.001). P-values 
<0.001 will be reported as <0.001. 
8. TECHNICAL DETAILS 
Include a brief statement of:  study-specific documents used, including version numbers; which 
software package or packages used; and the directory/file paths used to store data, code and output 
documents. 
Describe what quality assurance measures are in place to monitor the quality of any coding. 
Document who will review which pieces of code, and to what level of detail. For example: 
A second review statistician will independently reproduce the primary analyses. The reviewing 
statistician will have an overview of the entire. 
9. SUMMARY OF CHANGES TO THE PROTOCOL 
On December 17, 2018, the AZENT data monitoring committee, on review of the interim analysis, 
determined that there was evidence to support continued accrual, however the trial was closed to 
further accrual due to a funder’s decision. 
10. REFERENCES 
Provide references for any citations in the main body of the SAP.  
 
 


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APPENDICES 
Appendix 1. Handling of missing date and time fields  
All dates and times used in the analysis are supposed to be complete. Nevertheless, in certain 
situations it will be difficult or impossible to have a complete date or time, e.g., lost to follow-up 
patients. SAP Table 3 contains a list of dates/times that will be completed in case of missing 
information.  
General rules for completion of dates are the following: 
1. Dates are split in 3 parts: year, month and day. Year is the top level, month is medium level 
and day is low level. If a part expected to contain a number is numeric but the value is outside 
a valid range, the complete date is handled as missing. For example, if date = 32-NOV-2012 
the whole date is considered to be missing. 
2. If a part expected to contain a number is not numeric, i.e., contains values such as, for example, 
ND, NA, 2? it is considered as missing. 
3. If a part is missing, all other parts of a lower level are considered to be missing, e.g., ’21-ND-
2012’ is considered as ‘NK-NK-2012’. 
4. Missing parts are changed into acceptable non-missing values depending on the type of date 
to be replaced. 
In the following table, ‘lower limit’ and ‘upper limit’ refer to the minimum or maximum, 
respectively, of a possible date. For example, if the day is missing, the lowest limit is the first day 
of the given month and the upper limit is the last day of the given month. If the day and month are 
missing, the lower limit refers to the first day of the given year and the upper limit to the last day 
of the given year. The earliest and the latest of different dates refer to the first or last date, 
respectively, when ordered in sequence. 
 
SAP Table. 2  Handling of missing data and time fields 
Type of Date / 
Time 
Date /Time is incomplete 
Date / Time is missing 
Date of birth  
Day missing: 15th of the month  
Day and month missing: 30th of June 
No replacement 
AE resolution 
date 
The upper limit 
No approximation, the AE is considered 
as ongoing in the analysis. 
AE onset date 
If the end date of the AE is not before the start of 
study drug, and if the study drug start falls in the 
range of possible dates, it is the study drug start 
date. In all the other cases, it is the lower limit. 
Earliest date between the AE end date 
and the start of study drug. 
Hospitalization 
discharge date  
The upper limit 
No approximation, the hospitalization is 
considered as ongoing in the analysis. 
Hospitalization 
admission date  
If the onset date of the AE leading to 
hospitalization falls in the range of possible dates, 
it is the onset date of the AE. In all the other cases, 
it is the lower limit. 
The onset date of the AE leading to 
hospitalization 


STATISTICAL ANALYSIS PLAN 
 
Autores: Bernat Miguel Huguet 
MedOPP112 
 
 
 
     Miguel Sampayo Cordero 
SAP_MedOPP112 
 
SAP_AZENT_MedOPP112_Final.docx 
 Confidential 
03/05/2019 
 Page 24 of 26 
 
Previous/ 
concomitant 
medication start 
date 
Lower limit except when: 
Not tagged as ongoing at baseline  
AND 
Medication stop date not collected or with the 
upper limit after the study drug start 
AND 
the treatment start day falls in the range of possible 
dates. 
In which case it is the study drug start day 
No replacement, the medication is 
considered to have started before the 
study 
Previous/ 
concomitant 
medication end 
date 
Upper limit except when: 
Medication start is before study drug start or 
missing 
AND 
Upper limit is after the study drug start 
AND 
Not tagged as concomitant at baseline. 
In which case it is 1 day before study drug start 
No replacement (considered ongoing) 
 
End of 
treatment 
Use the earliest date between the: 
• 
upper limit  
• 
last contact date 
• 
date of death (if applicable)  
Use the earliest date between the: 
• 
last contact date 
• 
date of death (if applicable) 
Death date 
Use the lower limit 
No replacement 
 
 


STATISTICAL ANALYSIS PLAN 
 
Autores: Bernat Miguel Huguet 
MedOPP112 
 
 
 
     Miguel Sampayo Cordero 
SAP_MedOPP112 
 
SAP_AZENT_MedOPP112_Final.docx 
 Confidential 
03/05/2019 
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Appendix 2 List of protocol deviations 
 
 
Description 
Category 
Deviation excludes from analysis set? 
Full Analysis / 
safety set 
Per protocol 
set 
Biomarker 
analysis set 
Informed consent form not 
signed 
Inclusion/Exclusion 
criteria 
Yes 
Yes 
Yes 
Outdated versions of 
informed consent signed 
Inclusion/Exclusion 
criteria 
Case by case 
Case by case 
Case by case 
IMP no administered 
Treatment 
Yes 
Yes 
Yes 
Without histological 
confirmation of locally 
advanced or metastatic, 
non-squamous non-small 
cell lung cancer (NSCLC). 
Inclusion/Exclusion 
criteria  
No 
Yes 
No 
Without an activating EGFR 
mutation. 
Inclusion/Exclusion 
criteria 
No 
Yes 
Yes 
Without concomitant 
T790M mutation. 
Inclusion/Exclusion 
criteria  
No 
Yes 
Yes 
Patients without a M1a 
stage or M1b or locally 
advanced disease for which 
there is curative treatment 
Inclusion/Exclusion 
criteria  
No 
No 
No 
ECOG>2 
Inclusion/Exclusion 
criteria 
No 
No 
No 
No measurable or 
evaluable disease (as per 
RECIST 1.1 criteria). With 
the exception of pts with 
asymptomatic and stable 
brain metastases. 
Inclusion/Exclusion 
criteria 
No 
Yes 
No 
Patients without having a  
pre-dose  and  a  postdose  
valid  result. 
Biomarkers 
No 
No 
Yes 
Life expectancy <12 
weeks. 
Inclusion/Exclusion 
criteria 
No 
Case by case 
No 
Adequate organ function 
Inclusion/Exclusion 
criteria 
No 
Case by case 
No 
Without capacity of 
swallow or complete the 
study. 
 
Inclusion/Exclusion 
criteria 
No 
Case by case 
No 
No relevant toxicities at 
baseline  
Inclusion/Exclusion 
criteria 
No 
Case by case 
No 
Patients who have received 
prior antineoplastic 
treatment for advanced 
disease. 
Inclusion/Exclusion 
criteria 
No 
Case by case 
No 
Second active neoplasia 
Inclusion/Exclusion 
criteria 
No 
Case by case 
No 


STATISTICAL ANALYSIS PLAN 
 
Autores: Bernat Miguel Huguet 
MedOPP112 
 
 
 
     Miguel Sampayo Cordero 
SAP_MedOPP112 
 
SAP_AZENT_MedOPP112_Final.docx 
 Confidential 
03/05/2019 
 Page 26 of 26 
 
<6 months with prior 
treatment with cytotoxic 
chemotherapy for 
advanced NSCLC. 
Inclusion/Exclusion 
criteria 
No 
Case by case 
No 
Patients who have received 
prior EGFR treatments for 
lung cancer. 
Inclusion/Exclusion 
criteria 
No 
Case by case 
No 
Patients who have received 
treatment with an 
investigational drug within 
3 weeks before the first 
day of study treatment. 
Inclusion/Exclusion 
criteria 
No 
Case by case 
No 
Treatment with prohibited 
drugs within 14 days 
before the first day of 
study treatment. 
Inclusion/Exclusion 
criteria 
No 
Case by case 
No 
Prohibited conocomitant 
medication 
Efficacy and safety 
No 
Case by case 
No 
Hypersensitivity to IMP 
Investigational 
Medicinal Product  
No 
Case by case 
No 
Serious concomitant 
systemic disorder, 
including conditions that 
could interfere with 
absortion 
Investigational 
Medicinal Product 
No 
Case by case 
No 
IMP overdose 
Investigational 
Medicinal Product  
No 
 
Case by case 
No 
 
IMP underdose 
Investigational 
Medicinal Product  
No 
Case by case 
No 
IMP administration 
dosing/schedule 
Investigational 
Medicinal Product  
No 
Case by case 
No 
IMP toxicity 
Investigational 
Medicinal Product  
No 
Case by case 
No 
Tumor assessment not 
done 
Efficacy 
No 
Yes 
No 
Tumor assessment out of 
the window 
Efficacy 
No 
Case by case 
No 
No baseline tumor 
assessment 
Efficacy 
No 
Yes 
No 
No post-baseline tumor 
assessment 
Efficacy 
No 
Yes 
No 
Subject not withdrawn as 
per protocol 
Safety 
No 
Case by case 
No