Clinical trial NCT02115048
Conditions: Breast Neoplasms
Sponsor: Translational Research in Oncology
Start date: 2014-07-01; Completion date: 2018-11-01
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to compare the efficacy of treatment with afatinib plus letrozole to treatment with letrozole alone in women diagnosed with a specific type of breast cancer.

Detailed description:
This is an open-label, multicenter, international, randomized, Phase II clinical trial that will assess the efficacy and safety of letrozole in combination with afatinib(oral epidermal growth factor receptor (EGFR ) inhibitor) versus letrozole monotherapy for the first-line treatment of postmenopausal women with ER+, Human Epidermal Growth Factor Receptor 2 (HER2) negative advanced breast cancer with low ER expression.

In order to assess the level of estrogen receptor (ER) expression we will use a semi-quantitative scoring system (McClelland, 1990) defined as :

H-score = (% of cells stained at intensity category 1x1) + (% of cells stained at intensity category 2x2) + (% of cells stained at intensity category 3x3).

This formula results in an H-score in the range of 0-300 where 300 equals 100% of tumor cells stained strongly (i.e., 3+). Low ER expression will be defined as tumor sample with H-score below 160 (Finn, 2009).

All subjects who consented for the study must submit a tumor sample to the designated central laboratory for central confirmation of ER / Progesterone receptor (PR) and HER2 statuses and determination of the H-score. This will be assessed prior to randomization.

Subjects with HER2 negative, ER+ advanced breast cancer with low ER expression defined as H-score between 1 and 159 will enter screening phase and perform the required screening assessments.

Eligible subjects will be randomly assigned in a 1:1 ratio and stratified according to sites of disease (bone only disease vs. other) and prior administration of hormonal therapy in neo/adjuvant setting (Yes vs. No) to either:

Arm A : Continuous regimen of oral letrozole 2.5 mg until progression of disease or any other study treatment discontinuation criteria.

or Arm B : Continuous regimen of oral letrozole 2.5 mg daily plus oral afatinib 30 mg daily until progression of disease or any other study treatment discontinuation criteria.

IN ADDITION the following applies whichever comes first:

* If the patients treated with the combination of afatinib and letrozole (arm B) discontinue the trial treatment (whatever the reason) before 30 November 2018, the patients from the other arm (arm A, letrozole alone) still on treatment will also be discontinued from the trial at the same time. They may continue receiving letrozole using commercial drug as standard of care according to their treating physician discretion.
* If the patients treated with afatinib and letrozole (arm B) have not discontinued the trial treatment by 30 November 2018, all patients currently on treatment in the trial (including the ones only treated by letrozole alone (arm A)) will be discontinued from the trial at that time. They may continue receiving their treatment if in alignment with their treating physician judgment as follows:
* Patients in arm A: may continue receiving letrozole using commercial drug as standard of care according to their treating physician discretion.
* Patients in arm B: may continue receiving afatinib in the context of alternative drug supply outside the clinical trial as appropriate according to local legislation. Additionally, they may continue receiving letrozole using commercial drug as standard of care according to their treating physician discretion.

Once the patient is discontinued from trial treatment and has undergone the End of Treatment Visit, she will be permanently discontinued from the trial and treated as per local clinical practice.

Arms: arm 1: Continuous regimen of oral Letrozole 2.5 mg daily arm 2: Continuous regimen of oral Letrozole 2.5 mg daily plus oral Afatinib 30 mg daily
Interventions: intervention 1: Letrozole intervention 2: Afatinib
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
TRIO-020 Protocol - version 5.0- 31 July 2018 
 
 
 
 
 
A randomized open-label phase II study of  
letrozole plus afatinib versus letrozole alone  
in first-line treatment of advanced ER+, HER2-  
postmenopausal breast cancer with low ER expression 
 
CLINICAL TRIAL PROTOCOL TRIO-020  
 
 
Protocol version / Date  
Version 5.0 / 31 July  2018 
Sponsor 
 
Translational Research In Oncology (TRIO) 
EUDRACT # 
2013‐002192‐18 
IND # 
119147 
OTHER CA ID  # 
NA 
 
CONFIDENTIAL 
 
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TRIO-020 Protocol - version 5.0- 31 July 2018 
 
 
 
 
 
A randomized open-label phase II study of  
letrozole plus afatinib versus letrozole alone  
in first-line treatment of advanced ER+, HER2-  
postmenopausal breast cancer with low ER expression 
CLINICAL TRIAL PROTOCOL TRIO-020  
Protocol version / Date  
Version 5.0 / 31 July  2018 
Sponsor 
Translational Research In Oncology (TRIO) 
EUDRACT # 
2013-002192-18 
IND # 
119147 
OTHER CA ID  # 
NA 
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TRIO-020 Protocol - version 5.0- 31 July 2018 
 
Table of Contents 
CLINICAL TRIAL PROTOCOL TRIO-020 ........................................................................................................... 1 
LIST OF ABBREVIATIONS ............................................................................................................................... 9 
PROTOCOL SYNOPSIS .................................................................................................................................. 11 
1. 
BACKGROUND AND RATIONALE ......................................................................................................... 18 
1.1 
Disease Overview ........................................................................................................................ 18 
1.2 
Current Treatment Overview ...................................................................................................... 18 
1.3 
Investigational Medicinal Product Overview .............................................................................. 19 
1.3.1 
Preclinical pharmacology and toxicology ............................................................................ 20 
1.3.2 
Clinical pharmacokinetic and safety ................................................................................... 21 
1.4 
Rationale ..................................................................................................................................... 22 
2. 
OBJECTIVES ......................................................................................................................................... 25 
2.1 
Planned primary and secondary objectives ................................................................................ 25 
2.1.1 
Primary Objective ................................................................................................................ 25 
2.1.2 
Secondary Objectives .......................................................................................................... 25 
2.2 
Exploratory Objectives (Optional) ............................................................................................... 25 
3. 
TRIAL DESIGN ...................................................................................................................................... 27 
4. 
PATIENT SELECTION ............................................................................................................................ 30 
4.1 
Inclusion Criteria ......................................................................................................................... 30 
4.2 
Exclusion Criteria ......................................................................................................................... 31 
5. 
TREATMENT ........................................................................................................................................ 33 
5.1 
Protocol Treatment ..................................................................................................................... 33 
5.2 
Protocol Treatment Management .............................................................................................. 33 
5.2.1 
Packaging and Labeling ....................................................................................................... 33 
5.2.1.1 
Afatinib ............................................................................................................................ 33 
5.2.1.2 
Letrozole ......................................................................................................................... 34 
5.2.2 
Storage and Accountability ................................................................................................. 34 
5.2.2.1 
Afatinib ............................................................................................................................ 34 
5.2.2.2 
Letrozole ......................................................................................................................... 35 
5.2.3 
Return / Destruction ........................................................................................................... 36 
5.2.3.1 
Afatinib ............................................................................................................................ 36 
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5.2.3.2 
Letrozole ......................................................................................................................... 36 
5.3 
Protocol Treatment Administration ............................................................................................ 36 
5.3.1 
Premedications and special precautions ............................................................................ 36 
5.3.2 
Standard treatment schedule ............................................................................................. 36 
5.3.2.1 
Preparation ..................................................................................................................... 37 
5.3.2.2 
Treatment compliance .................................................................................................... 37 
5.3.3 
Protocol treatment discontinuation ................................................................................... 37 
5.4 
Adverse Event management and treatment schedule adjustments .......................................... 38 
5.4.1 
General rules ....................................................................................................................... 38 
5.4.2 
Management of diarrhea .................................................................................................... 39 
5.4.3 
Management of nausea and vomiting ................................................................................ 40 
5.4.4 
Management of rash ........................................................................................................... 40 
5.4.5 
Management of Interstitial Lung Disease (ILD) ................................................................... 42 
5.4.6 
Management of Protocol specified significant event: hepatic injury ................................. 42 
5.4.7 
Other Adverse events ......................................................................................................... 43 
5.5 
Concomitant Medications and Procedures ................................................................................ 44 
5.5.1 
Supportive care ................................................................................................................... 44 
5.5.2 
Precautions – Treatment interaction with P-gp.................................................................. 44 
5.5.3 
Surgery while on trial treatment ......................................................................................... 45 
5.5.4 
Prohibited Treatments and/or Procedures ......................................................................... 45 
5.5.4.1 
Local and/or systemic anticancer therapy ...................................................................... 45 
5.5.4.2 
Bone-modifying agents ................................................................................................... 45 
5.5.4.3 
Palliative radiotherapy .................................................................................................... 45 
6. 
SCHEDULE OF VISITS AND PROCEDURES ............................................................................................ 46 
6.1 
Patient Inclusion ......................................................................................................................... 46 
6.1.1 
Informed Consent ............................................................................................................... 46 
6.1.2 
Registration/ Randomization .............................................................................................. 46 
6.1.3 
Blinding/Unblinding ............................................................................................................ 47 
6.2 
Trial Participation and Discontinuation ...................................................................................... 47 
6.3 
Schedule of Procedures .............................................................................................................. 48 
6.3.1 
Safety assessments ............................................................................................................. 50 
6.3.2 
Efficacy assessments ........................................................................................................... 50 
6.3.2.1 
Schedule/details of tumor assessments ......................................................................... 50 
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6.3.2.2 
Special note for baseline determination of Bone lesions and follow-up assessments .. 51 
6.3.2.3 
Definitions of measurable/non measurable disease ...................................................... 51 
6.3.2.4 
Baseline Documentation of Target and Non-target Lesions ........................................... 53 
6.3.2.5 
Guidelines for Evaluation of Measurable Disease .......................................................... 53 
6.3.2.6 
Response criteria ............................................................................................................. 54 
7. 
SAFETY MONITORING ......................................................................................................................... 56 
7.1 
Definitions ................................................................................................................................... 56 
7.1.1 
Period of Observation ......................................................................................................... 56 
7.1.2 
Adverse Event ..................................................................................................................... 56 
7.1.3 
Protocol-specified significant event to be reported in an expedited manner .................... 57 
7.1.4 
Serious Adverse Event ......................................................................................................... 57 
7.1.4.1 
General definition ........................................................................................................... 57 
7.1.4.2 
Disease-related events .................................................................................................... 57 
7.1.4.3 
Planned or administrative hospitalization ...................................................................... 58 
7.1.4.4 
Unexpected Adverse Event ............................................................................................. 58 
7.2 
Performing Adverse Event Assessment ...................................................................................... 58 
7.2.1 
Collection of Adverse Event Information ............................................................................ 58 
7.2.2 
Assessment of Causality ...................................................................................................... 58 
7.3 
Reporting of Serious Adverse Events .......................................................................................... 59 
7.3.1 
Reporting of SAEs from the sites to TRIO ........................................................................... 59 
7.3.2 
SAE information provided by TRIO to BI ............................................................................. 59 
7.4 
Management of specific cases .................................................................................................... 59 
7.4.1 
Drug misuse......................................................................................................................... 59 
7.4.2 
Pregnancy ............................................................................................................................ 59 
7.5 
Reporting to Ethics Committees, Regulatory Authorities and other Investigators .................... 60 
8. 
STATISTICAL CONSIDERATIONS ........................................................................................................... 61 
8.1 
Populations for analyses ............................................................................................................. 61 
8.2 
Demographics and baseline characteristics ................................................................................ 61 
8.3 
Protocol Treatment ..................................................................................................................... 61 
8.4 
Safety Endpoints ......................................................................................................................... 61 
8.5 
Interim and Final Analyses .......................................................................................................... 61 
8.6 
Criteria for trial termination ....................................................................................................... 62 
9. 
ADMINISTRATIVE, ETHICAL AND REGULATORY STANDARDS ............................................................. 63 
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9.1 
Steering Committee .................................................................................................................... 63 
9.2 
Ethical Conduct of the Trial ......................................................................................................... 63 
9.3 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) ....................................... 63 
9.4 
Compliance with the protocol and protocol amendments ........................................................ 63 
9.5 
Monitoring, auditing and inspecting ........................................................................................... 64 
9.6 
Recording, processing and retention of data.............................................................................. 64 
9.7 
Data Protection ........................................................................................................................... 65 
9.8 
Confidentiality and Data Protection ........................................................................................... 65 
9.9 
Insurance of liabilities ................................................................................................................. 65 
9.10 
Use of information and publication ............................................................................................ 65 
10. 
BIBLIOGRAPHY ................................................................................................................................ 67 
 
APPENDIX 1 : EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS SCALE ..................... 69 
APPENDIX 2 : NYHA CLASSIFICATION .......................................................................................................... 70 
 
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List of tables 
Table 1 : Dose levels .................................................................................................................................... 38 
Table 2 : Management of diarrhea ............................................................................................................. 39 
Table 3: Management of nausea and vomiting .......................................................................................... 40 
Table 4 : Management of rash .................................................................................................................... 41 
Table 5 : Interstitial Lung Disease ............................................................................................................... 42 
Table 6 : Management of hepatic injury ..................................................................................................... 42 
Table 7: Treatment schedule adjustments ................................................................................................. 43 
Table 8: Treatment interacting with P-gp ................................................................................................... 44 
Table 9 : Schedule of activities .................................................................................................................... 49 
Table 10 : Efficacy assessments .................................................................................................................. 51 
Table 11 : Evaluation of the overall response (OR) in patients with target +/- non-target lesions ............ 55 
Table 12 : Evaluation of the overall response (OR) in patients with non-target lesions only .................... 55 
Table 13 : Reporting of AEs/SAEs ................................................................................................................ 56 
Table 14: Reporting of SAEs ........................................................................................................................ 59 
 
 
 
 
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TRIAL STEERING COMMITTEE 
Name 
Institution 
Contact details 
Dr Richard FINN, MD 
Trial Chair 
UCLA 
+1 (310) 203 3180 
Additional members of the Steering Committee are listed in the Steering Committee Charter. 
 
 
 
INVESTIGATORS 
26 investigators conducted the clinical trial. The list of investigators participating in the trial is 
maintained by TRIO operational team in the Clinical Trial Management System.  
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TRIO PROJECT TEAM 
TRIO – 11 rue Watt 75013 PARIS - FRANCE 
Valérie BEE-MUNTEANU 
Director Project 
Management 
 +33 1 58 10 08 81 
Hélène MANSOURI 
Global Project 
Coordinator 
+33 1 58 10 08 92 
Véronique MOINEAU 
Director Monitoring 
Resources  
+33 1 58 10 09 03 
Christopher OLIGNY 
Director, Quality 
Assurance and Regulatory 
Affairs 
+33 1 58 10 08 86 
 
TRIO – Suite 1100, 9925 – 109th Street EDMONTON, AB T5K2J8 - CANADA 
Launa ASPESLET 
Chief Executive Officer 
 
+1 (780) 702 2260 
Melissa BURTON 
Senior Data Manager 
+1 (780) 702 0228 
Helena FUNG 
Senior Biostatistician 
+1 (780) 702 0246 
Gavin LYONS 
Director Information 
Services  
+1 (780) 702 8404 
 
TRIO – Luis A. de Herrera 1248/360, 11300 MONTEVIDEO - URUGUAY 
Rodrigo FRESCO 
Medical Lead 
Trial Medical Monitor 
+598 2622 2120 ext. 1 
 
CENTRAL LABORATORY TEAM
USC/ Norris Comprehensive Cancer Center 
1441 Eastlake Avenue, STE. 5409- Los Angeles, CA 90033-0800USC 
Michael PRESS 
Central Pathologist 
+1 (323) 865 0563 
Ivonne VILLALOBOS 
Central Laboratory 
Administrator 
+1 (323) 865 0563 
 
 
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TRIO-020 Protocol - version 5.0- 31 July 2018 
 
LIST OF ABBREVIATIONS 
ABC 
Advanced Breast Cancer 
ALT 
Alanine Aminotransferase / GPT 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase / GOT 
BC 
BI 
Breast Cancer 
Boehringer Ingelheim 
BUN 
Blood Urea Nitrogen 
°C 
Degrees Celsius  
CAP 
Chest Abdomen Pelvis 
CBR 
Clinical Benefit Response 
CI 
Confidence Interval 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTA 
CTCAE 
Clinical Trial Application 
Common Terminology Criteria of Adverse Events 
CV 
Coefficient of Variation 
DCF 
Data Clarification  
DDI 
Drug-Drug interaction 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DSUR 
Developmental Safety Update Report 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture System 
ER 
Estrogen Receptor 
°F 
Degrees Fahrenheit 
FISH 
Fluorescent In Situ Hybridization 
Fmol 
FSH 
Fentomole 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practices 
HDPE 
High Density Polyethylene 
HER2 
Human Epidermal Growth Factor Receptor 2 
HR 
Hormone Receptors 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
ILD 
Interstitial Lung Disease 
INN 
International Nonproprietary Name 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IWRS 
Interactive Web Recognition System 
LDH 
Lactate dehydrogenase 
LFT 
Liver Function test 
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LPLV 
Last Patient Last Visit 
µL 
Microliter 
µM 
Micromolar 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
mL 
Milliliter 
mos 
months 
MRI 
Magnetic Resonance Imaging 
Msec 
Milliseconds 
NCBI 
National Center for Biotechnology Information 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NSCLC 
Non Small Cell Lung Cancer 
OR 
Objective Response 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
P-gp 
PICF 
P-glycoprotein 
Patient informed Consent From 
PK 
Pharmacokinetic(s) 
PR 
Partial Response 
PS 
Performance Status 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RH 
Relative Humidity 
RNA 
Ribonucleic Acid 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SNP 
Single Nucleotide Polymorphism 
SoC 
SoD 
Standard Of Care 
Sum of Diameters 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TRIO 
Translational Research In Oncology 
TTP 
Time To Progression 
Txt 
Treatment 
UCLA 
University of California Los Angeles 
UK 
United Kingdom 
UNL 
Upper Normal Limit 
WBC 
White Blood Cells 
 
 
 
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PROTOCOL SYNOPSIS 
Protocol Title 
A randomized open-label Phase II study of letrozole plus afatinib (BIBW2992) 
versus letrozole alone in the first-line treatment of advanced ER+, HER2- 
postmenopausal breast cancer with low ER expression. 
Protocol # 
TRIO-020 
Trial Duration 
Accrual = 18 months  
Total time = 44 months 
Participating Investigator 
Sites 
This is a TRIO-sponsored trial with Dr Richard FINN, as Trial chair 
26 sites worldwide. 
Background and Rationale 
The challenges in novel drug development in cancer medicine are clear: while 
many molecular targets have been identified, predicting which patients will gain 
benefit from inhibiting those targets remains critical. One of the great challenges 
in breast cancer research has been the integration of HER-family inhibitors into 
clinical practice outside of HER2 amplification (Alvarez RH, 2010).  Clearly, HER2 
amplification is a well-validated predictive marker for response to the small 
molecule dual EGFR/ HER2 inhibitor lapatinib (Geyer CE, 2006) and the 
humanized monoclonal antibody trastuzumab (Slamon DJ, 2011). However, 
outside of HER2 amplification, the role of the epidermal growth factor receptor 
(EGFR/ HER1), its ligands, and co-receptors in clinical breast cancer has been 
elusive. Of the other HER-family members, EGFR has been aggressively pursued in 
breast cancer with both small molecules (erlotinib, gefitinib, lapatinib) and 
monoclonal antibodies (cetuximab) with disappointing efficacy (Alvarez RH 2010). 
These results contribute to the following hypotheses: (1) EGFR is not an 
important therapeutic target in breast cancer, (2) the available inhibitors are 
insufficient at blocking EGFR signaling in breast cancer tissue, or (3) the 
population of breast cancer patients with EGFR driven disease is smaller than 
expected and a combination of biomarkers for patient selection is required. 
The interplay between steroid hormone signaling and peptide growth factor 
signaling through the HER-family is well described in breast cancer (Arpino G, 
2008). Both expression of EGFR and HER2 amplification have been shown to 
mediate resistance to anti-estrogen therapy in laboratory models and clinical 
studies (Massarweh S, 2008) (Osborne CK, 2005) (Rimawi MF, 2010). These data 
have been the rationale for pursuing the combination of HER family inhibition 
and anti-estrogen therapy. In patients with HER2 amplification, studies with both 
trastuzumab and lapatinib have shown an improvement in progression-free 
survival with the addition of anti-HER2 therapy in combination with anastrozole 
or letrozole respectively (Kaufman B, 2009)  (Johnston S, 2009). The latter trial, 
EGF30008, was a randomized, placebo-controlled, phase III trial of over 1200 
post-menopausal women with HR-positive disease. Two hundred and nineteen 
women were enrolled with confirmed HER2 amplification. Patients were 
randomized to receive either letrozole and placebo or letrozole and lapatinib. 
Primary endpoint of the trial was PFS. The HER2 amplified cohort had a significant 
improvement in progression-free survival (PFS) with the addition of lapatinib 
(hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; p=0.019); median PFS was 8.2 vs 
3.0 months, respectively.  However, in subjects with centrally confirmed, HR-
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positive, HER2 negative tumors (n=952) there was no improvement in PFS. A pre-
planned Cox regression analysis to try to enrich for an EGFR-dependent clinical 
phenotype, identified prior anti-estrogen therapy as a significant factor in the 
HER2 negative population. A non-significant trend toward prolonged PFS for 
lapatinib in combination with letrozole was seen in patients who experienced 
relapse less than 6 months after their prior tamoxifen discontinuation (HR = 0.78; 
95% CI, 0.57 to 1.07; p=0.117). While this trend is of interest, the identification of 
a molecular marker for response to lapatinib and letrozole in HER2 negative 
women would be of potential great value. 
Previous biomarker work by Dr Richard Finn’s group identified a correlation 
between quantitative hormone receptor measurements and response to 
lapatinib and paclitaxel in a HER2 negative cohort of women with advanced 
breast cancer (Finn RS, 2009). In addition other studies have suggested a 
relationship between peptide growth factor signaling and hormone receptor 
status  (Arpino G W. H., 2005), specifically, that progesterone receptor (PR) loss in 
estrogen receptor (ER) positive disease is associated with higher expression of 
EGFR and/or HER2. In addition, a pre-surgical trial demonstrated cell-cycle 
inhibition in ER-positive and PR-weak or PR-negative patients with breast cancer 
who were exposed to a short course of the EGFR inhibitor gefitinib (Finn RS, 
2006). 
Recently, the standard treatment of patients with ER-positive, HER2-negative ABC 
have dramatically changed with the introduction into clinical practice of cyclin-
dependent kinase (CDK) 4/6 inhibitors. Palbociclib, abemacicilib and ribociclib 
FDA-approved CDK4/6 inhibitors for the treatment of women with ER-positive, 
HER2-negative ABC. 
The benefit of CDK4/6 inhibitors in combination with aromatase inhibitors as an 
effective first‑line option was first demonstrated in the phase 2 clinical trial 
PALOMA‑1 and was later confirmed in the phase 3 trial PALOMA‑2. This trial 
randomized a total of 666 postmenopausal women in a 2:1 fashion to receive 
palbociclib plus letrozole or placebo plus letrozole. The median progression-free 
survival reported was 24.8 months (95% CI, 22.1 to not estimable) in the 
palbociclib-letrozole group, as compared with 14.5 months (95% CI, 12.9 to 17.1) 
in the placebo-letrozole group (hazard ratio for progression or death, 0.58; 95% 
CI, 0.46 to 0.72; P<0.001). Palociclib and later ribociclib and abemaciclib trials 
helped to reshape the standard approaches in ER-positive, HER2-negative ABC. 
To further test the hypothesis that semi-quantitative ER and PR measurements 
are molecular markers for EGFR dependence, we performed a blinded, 
retrospective analysis of ER and PR in HER2 negative breast cancer in the 
EGF30008 cohort (Finn RS, 2009). In this analysis that compared the activity of 
letrozole versus letrozole and lapatinib in ER+ women, it was determined that 
those women with low ER expression (defined as the lowest quartile based on 
semi-quantitative IHC, H-score) had a significant improvement in PFS with the 
combination vs letrozole alone (13.6 mos vs 6.6 mos, HR= 0.65; 95% CI 0.47 to 
0.9, p<0.005). This finding was of particular significance as the overall HER2 
negative population did not show any significant benefit from the addition of 
lapatinib. Only when a specific criterion was applied to isolate patients with low 
ER expression, was a subpopulation of breast cancers with HER dependence 
identified. Also, to note, is that the low ER expressing patients had a very poor 
natural history with letrozole alone, with a PFS of 6.6 mos. This is much less than 
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the overall population and higher ER expressing patients whose PFS was 
approximately 14 mos. 
The proposed trial with afatinib was designed to test the hypothesis that low ER 
expression as determined by semi-quantitative immuno-histochemistry (IHC) is a 
biomarker for HER-dependence in women with HER2 negative breast cancer 
 Protocol amendment 4.0 was released on 09 May 2016 and its main change was 
the enrollment closure due to insufficient efficacy data to pursue development of 
afatinib in breast cancer and low recruitment in the trial. As of the date of release 
of this new protocol amendment, there are 6 patients still on treatment in the 
trial and among those, only 2 patients are treated with the combination of 
letrozole and afatinib (Arm B). Due to the limited number of patients still on 
treatment, and especially in Arm B, TRIO and BI agreed to release this 
amendment to discontinue the trial, allowing patients receiving afatinib to 
continue with this treatment outside of the TRIO-020 trial. 
Objectives / Endpoints  
The planned objectives were  
Primary Objective : 
• 
To assess the effect of letrozole plus afatinib and of letrozole alone on 
progression-free survival (PFS) in the first line treatment of ER+, HER2 
negative postmenopausal ABC women with low ER expression. 
The Primary endpoint was PFS. 
Secondary Objectives : 
• 
To assess secondary measures of efficacy of  afatinib administered in 
combination with letrozole and of letrozole alone. 
Endpoints: Overall survival (OS), Objective Response rate (OR) and Time to 
tumor progression (TTP) 
• 
To assess the safety and tolerability of afatinib administered in combination 
with letrozole and of letrozole alone. 
Endpoint: overall safety profile  
The enrollment was closed prematurely on 05 MAR 2016 due to the small 
number of patients randomized compared to what was initially planned as per 
the statistical analysis. The data collected for all patients will be described per 
arm but no statistical comparison will be made. Therefore the primary and 
secondary objectives are not applicable.  
Population 
Inclusion Criteria 
Signed and dated informed consent. 
Postmenopausal females, 18 years of age or older. 
Histologically or cytologically proven diagnosis of adenocarcinoma of the breast 
with evidence of locally recurrent disease not amenable to resection or radiation 
therapy with curative intent, or metastatic disease.   
HER2 negative breast cancer.  
ER positive breast cancer. Central testing (required for all patients) must 
demonstrate that the tumor is ER+ with low expression (H-score [1-159]). 
Paraffin-embedded tumor block(s) or 15 to 20 unstained slides available for 
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centralized assessment of ER, PR, and HER2.   
Measurable disease according to RECIST 1.1 or bone-only non measurable 
disease.  
ECOG Performance status 0 or 1. 
Adequate hematological, hepatic and renal functions.  
Baseline LVEF ≥ 50%. 
Willingness and ability to comply with scheduled visits, treatment plan, 
laboratory tests, and other trial procedures. 
Exclusion Criteria 
Brain metastases, spinal cord compression, carcinomatous meningitis, or 
leptomeningeal disease. 
Prior treatment with any type of systemic therapy for advanced disease. 
Prior treatment with letrozole in (neo)adjuvant setting with disease-free interval  
≤ 12 months from completion of treatment until randomization. 
Prior treatment with any anti HER-family targeted therapy in (neo)adjuvant 
setting. 
Any concurrent or previous malignancy within 5 years prior to randomization, 
except for adequately and radically treated basal or squamous skin cancer, or 
carcinoma in situ of the cervix, or other non-invasive/in-situ neoplasm. 
Non-measurable disease according to RECIST 1.1, with the exception of bone-only 
non-measurable disease. 
Known pre-existing interstitial lung disease.  
Significant or recent acute gastrointestinal disorders with diarrhea as a major 
symptom.  
History or presence of clinically relevant cardiovascular abnormalities as per 
investigator assessment.  
Any other concomitant serious illness or organ system dysfunction as per 
investigator assessment  
Any contraindication to oral agents. 
Active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B DNA), 
active hepatitis C infection (defined as presence of Hep C RNA) or known HIV 
carrier. 
Known or suspected active drug or alcohol abuse. 
Known hypersensitivity to afatinib or letrozole or the excipients of any of the trial 
drugs. 
Concomitant treatment with strong inhibitor of P-gp (see section 5.5.2).  
Any ongoing acute clinically significant toxic effect of prior anticancer therapy or 
any persisting complication of prior surgery. 
Patients with known history of keratitis, ulcerative keratitis or severe dry eye. 
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Participation in the active phase of other clinical trials of investigational agents in 
which last trial treatment was administered within 2 weeks prior to 
randomization. 
Trial Design 
This is an open-label, multicenter, international, randomized, Phase II clinical trial 
that aimed to assess the efficacy and safety of letrozole in combination with 
afatinib(oral EGFR inhibitor) versus letrozole monotherapy for the first-line 
treatment of postmenopausal women with ER+, HER2 negative advanced breast 
cancer with low ER expression. 
In order to assess the level of ER expression we used a semi-quantitative scoring 
system (McClelland RA 1990) defined as: 
H-score = (% of cells stained at intensity category 1x1) + (% of cells stained at 
intensity category 2x2) + (% of cells stained at intensity category 3x3). 
This formula results in an H-score in the range of 0-300 where 300 equals 100% of 
tumor cells stained strongly (i.e., 3+). Low ER expression was defined as tumor 
sample with H-score below 160 (Finn RS, 2009). 
All patients consented on the trial submitted a tumor sample to the designated 
central laboratory for central confirmation of ER/PR and HER2 statuses and 
determination of the H-score. This was assessed prior to randomization.  
Patients with HER2 negative, ER+ advanced breast cancer with low ER expression 
defined as H-score between 1 and 159 entered screening phase and performed 
the required screening assessments.  
Eligible patients were randomly assigned in a 1:1 ratio and stratified according to 
sites of disease (bone only disease vs. other) and prior administration of 
hormonal therapy in neo/adjuvant setting (Yes vs. No) to either : 
Arm A: Continuous regimen of oral letrozole 2.5 mg until progression of disease 
or any other trial treatment discontinuation criteria. 
or  
Arm B: Continuous regimen of oral letrozole 2.5 mg daily plus oral afatinib 30 
mg daily until progression of disease or any other trial treatment discontinuation 
criteria.  
IN ADDITION the following applies whichever comes first:  
• 
If the patients treated with the combination of afatinib and letrozole (arm B) 
discontinue the trial treatment (whatever the reason) before 30 November 
2018, the patients from the other arm (arm A, letrozole alone) still on 
treatment will also be discontinued from the trial at the same time. They 
may continue receiving letrozole using commercial drug as standard of care 
according to their treating physician discretion. 
• 
If the patients treated with afatinib and letrozole (arm B) have not 
discontinued the trial treatment by 30 November 2018, all patients currently 
on treatment in the trial (including the ones only treated by letrozole alone 
(arm A)) will be discontinued from the trial at that time. They may continue 
receiving their treatment if in alignment with their treating physician 
judgment as follows: 
o Patients in arm A: may continue receiving letrozole using commercial drug 
as standard of care according to their treating physician discretion. 
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o Patients in arm B: may continue receiving afatinib in the context of 
alternative drug supply outside the clinical trial as appropriate according 
to local legislation. Additionally, they may continue receiving letrozole 
using commercial drug as standard of care according to their treating 
physician discretion. 
 
• 
Note: In case no alternative drug supply outside the clinical trial as 
appropriate according to local legislation can be put in place and the 2 
patients in Arm B are still on treatment on 30 November 2018, the protocol 
and PICF will need to be revised again. 
Once the patient is discontinued from trial treatment and has undergone the End 
of Treatment Visit, she will be permanently discontinued from the trial and 
treated as per local clinical practice. 
This trial also includes an optional exploratory research component. This optional 
portion of the trial is a molecular profiling assay aimed to assess the relationship 
of antitumor activity with the expression of a few cell cycle-related proteins and 
other markers that may be identified in the future. Patients may participate in 
this trial even if they choose not to participate in the sample banking component. 
Protocol Treatment 
Arm A: Continuous regimen of oral letrozole 2.5 mg until progression of disease 
or any other trial treatment discontinuation criteria. 
or  
Arm B: Continuous regimen of oral letrozole 2.5 mg daily plus oral afatinib 30 
mg daily until progression of disease or any other trial treatment discontinuation 
criteria. 
 
According to the decision to discontinue the patients from the trial by 30 
November 2018, the active patients will not receive their treatment  in the scope 
of the trial, but as commercial drug for letrozole and in the frame of alternative 
drug supply outside the clinical trial as appropriate according to local legislation 
for afatinib after that date. 
 
Note: In case no alternative drug supply outside the clinical trial as appropriate 
according to local legislation can be put in place and the 2 patients in Arm B are 
still on treatment on 30 November 2018, the protocol and PICF will need to be 
revised again. 
 
Efficacy Assessments 
Disease assessments every 12 weeks until documentation of progressive disease. 
This is applicable until 30 November 2018. After that date, the patients will be 
followed by their physician as per standard of care and the efficacy assessments 
will be performed as per local practice. 
 
Safety Assessments 
Physical examination, blood tests (hematology and blood chemistry) before each 
visit (every month) during the treatment period. 
LVEF every 12 weeks during the treatment period. 
This is applicable until 30 November 2018. After that date, the patients will be 
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followed by their physician as per standard of care and the safety assessments 
will be performed as per local practice. 
Additional Assessments 
None 
Statistical Methods and 
Sample Size 
N/A 
Due to the small number of patients enrolled in the trial, only a descriptive 
analysis will be conducted. 
 
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1. BACKGROUND AND RATIONALE 
1.1 
Disease Overview 
Breast cancer (BC) is the most common invasive cancer in women, with more than one million 
cases and nearly 600,000 deaths occurring worldwide annually. Although age-adjusted mortality 
from breast cancer has been decreasing since 1990, the median survival for patients with 
metastatic disease is still approximately 18 to 24 months (Ferlay J, 2010) and the medical need 
remains very high. In 2010, an estimated 209,060 newly diagnosed cases of breast cancer and 
40,230 breast cancer-related deaths occurred in the United States (Jemal A, 2010). Corresponding 
estimates in Europe for 2008 are 420,800 new cases and 129,300 deaths (Ferlay J, 2010). Although 
chemotherapy has improved outcomes, the marginal benefits achieved with cytotoxic agents 
seem to have reached a plateau, which has led to a recent, rapid increase in the development of 
molecular targeted therapeutics in breast cancer. This increase has been aided by technological 
advances in the characterization of the molecular heterogeneity of breast cancer. Consequently, 
breast cancer has been classified based on gene expression patterns into several different 
subtypes, including luminal A and B, HER2-positive, basal-like, and normal-like, although there can 
be some overlap in characteristics among the subtypes. Importantly, each of these molecular 
subtypes is associated with distinct prognoses (Sorlie T, 2001). The current trial focuses on 
addressing those women with ER+ breast cancer. Perhaps the greatest impact in the treatment of 
ER+ breast cancer has been the use of anti-estrogen agents in the adjuvant setting. However, 
there is still a number of women that relapse during or after adjuvant therapy and develop some 
degree of hormone independence. For these women, cytotoxic chemotherapy extends survival 
but is not curative. Certainly, any new agent that could improve survival and slow the progression 
to chemotherapy initiation would be of clinical importance. 
1.2 
Current Treatment Overview 
Approximately two thirds of breast cancers express estrogen receptor ER (Harvey JM, 1999) and a 
role for estrogens in breast cancer etiology and progression is well established. Modification of 
estrogen activity or synthesis represents the treatment of choice for postmenopausal women with 
hormone receptor-positive advanced breast cancer (ABC), particularly for those with slowly 
progressive disease and limited tumor-related symptoms (Hurvitz SA, 2008). Conversion of 
androgens to estrogens via aromatase enzyme action represents the main source of estrogens in 
postmenopausal women. Letrozole (Femara®) is an oral non-steroidal aromatase inhibitor that is 
approved worldwide for the first line treatment of postmenopausal women with hormone 
receptor-positive ABC. In a multicenter Phase 3 trial (Mouridsen H, 2003), 916 patients with 
hormone receptor positive or hormone receptor unknown ABC were randomized to receive either 
letrozole or tamoxifen up to disease progression. Most of the patients (91%) had received no prior 
treatment for their advanced disease. Letrozole was superior to tamoxifen for time to progression 
TTP (median, 9.4 vs 6.0 months, p<0.0001), time to treatment failure TTF (median, 9 vs 5.7 
months, p<0.0001), overall objective response rate ORR (32% vs 21%, p=.0002), and overall clinical 
benefit (50% vs 38%, p=0.0004). Median overall survival (OS) was slightly prolonged for the 
randomized letrozole arm (34 vs 30 months), however approximately 50% of the patients in the 
tamoxifen arm crossed over to letrozole at disease progression. 
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Besides letrozole or other aromatase inhibitors there are other anti-estrogen therapies available 
including direct estrogen receptor down -regulators such as fulvestrant (Faslodex) (Hurvitz SA, 
2008). 
Recently, the standard treatment of patients with ER-positive, HER2-negative ABC have 
dramatically changed with the introduction into clinical practice of cyclin-dependent kinase (CDK) 
4/6 inhibitors. Palbociclib, abemacicilib and ribociclib FDA-approved CDK4/6 inhibitors for the 
treatment of women with ER-positive, HER2-negative ABC. 
1.3 
The benefit of CDK4/6 inhibitors in combination with aromatase inhibitors as an 
effective first‑line option was first demonstrated in the phase 2 clinical trial PALOMA‑1 
and was later confirmed in the phase 3 trial PALOMA‑2. This trial randomized a total of 
666 postmenopausal women in a 2:1 fashion to receive palbociclib plus letrozole or 
placebo plus letrozole. The median progression-free survival reported was 24.8 months 
(95% CI, 22.1 to not estimable) in the palbociclib-letrozole group, as compared with 14.5 
months (95% CI, 12.9 to 17.1) in the placebo-letrozole group (hazard ratio for 
progression or death, 0.58; 95% CI, 0.46 to 0.72; P<0.001). Palociclib and later ribociclib 
and abemaciclib trials helped to reshape the standard approaches in ER-positive, HER2-
negative ABC.Investigational Medicinal Product Overview 
Afatinib is a highly potent, irreversible ErbB family blocker that displays anti-tumour efficacy 
both in vitro and in vivo. Afatinib has shown efficacy signals in clinical trials and thus may 
represent an excellent drug candidate for the treatment of a variety of cancers. 
Afatinib covalently binds to and irreversibly blocks signaling from all homo- and heterodimers 
formed by the ErbB family members: Epidermal growth factor receptor (EGFR, ErbB1), HER2 
(ErbB2), ErbB3 and ErbB4. Objective responses to treatment have been observed in afatinib 
Phase I monotherapy and combination therapy trials in patients with solid tumors, including 
NSCLC, HNSCC, urothelial carcinoma, breast cancer, esophageal cancer and cholangiocarcinoma. 
Clinical activity has been observed in Phase II trials in patients with NSCLC, HER2-positive 
trastuzumab-refractory breast cancer and urothelial carcinoma (UC). Superiority of afatinib 
monotherapy has been demonstrated in two pivotal randomized Phase III trials in patients with 
EGFR mutation positive NSCLC over standard platinum based chemotherapy, in a Phase IIb trial 
comparing head to head afatinib monotherapy to first generation EGFR TKI gefitinib, and in a 
randomised Phase III trial in patients with SCC of the lung, extending PFS progression-free survival 
and overall survival compared to erlotinib as second-line treatment. Afatinib monotherapy was 
also shown to be superior to methotrexate, in a Phase III trial in patients with recurrent or 
metastatic squamous cell carcinoma of the head and neck (HNSCC), extending PFS as second line 
treatment.  
Afatinib is approved for use: 
•  as monotherapy in patients with advanced EGFR mutation positive NSCLC in more than 70 
countries including the EU and US.  
• for the treatment of NSCLC of squamous histology after platinum based chemotherapy in 
more than 40 countries including the EU and US. 
Afatinib is currently in development in the following indications: recurrent and/or metastatic 
HNSCC; urothelial carcinoma and ErbB alteration; pediatric patients with recurrent/refractory 
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neuroectodermal tumors, rhabdomyosarcoma and/or other solid tumors with known ErbB 
pathway deregulation regardless of tumor histology; advanced NSCLC harboring HER2 mutations, 
previously treated with chemotherapy; and in combination with pembrolizumab in the second line 
treatment of patients with locally advanced or metastatic squamous cell carcinoma of the lung. 
 
1.3.1 
Preclinical pharmacology and toxicology 
In mice, afatinib reaches efficacious plasma exposure with once-daily dosing throughout the 
treatment period. afatinib displays antitumor activity, including tumor regression, against 
established subcutaneous xenografts in nude mice either as a single agent or in combination with 
a cytotoxic agent like docetaxel. The necessary maximum plasma concentrations were between 80 
to 285 nM for single agent activity. The absolute bioavailability was medium-high in rats (45%). 
The median tmax after oral administration was 4 hours and the terminal half-life was 4.5 hours. The 
terminal half-life of the radiolabelled compound was considerably longer indicating persistence of 
metabolites in the system. The exposure was dose proportional without gender-related effects. 
Some accumulation in the 13-week and 26-week toxicology trial appeared more pronounced in 
males. In minipigs there was a slight tendency towards supra-proportional increases in AUC0-24h 
with increasing doses, which was considered to be of minor relevance. A consistent effect on 
accumulation was not seen. 
In the whole body autoradiography in rats, afatinib was distributed in all organs with the 
exception of the CNS after oral administration. The highest concentrations were found in the 
kidney, liver, lung, and spleen. In general, a slow elimination of radioactivity was seen. The major 
excretion pathway is via faeces (91%). Afatinib covalently binds to plasma proteins. Whether such 
protein haptens are immunogenic and capable of inducing allergic reactions is unknown. 
Afatinib did not show relevant inhibition or induction of cytochrome P450 isoenzymes, and it 
appears unlikely that drug-drug interactions as based on this mechanism will occur. In vivo, 
afatinib was metabolized only to a minor extent and the metabolism was governed by adduct 
formation to proteins or nucleophilic small molecules. It was found that metabolism is of 
subordinate role for afatinib and that enzyme-catalyzed metabolic reactions play a negligible role 
for the metabolism of afatinib in vivo. Only approximately 2% of the dose were metabolized by 
FMO3 in vivo. The CYP3A4-dependent N-demethylation was even too low to be quantitatively 
detected in human volunteers. Therefore, intrinsic (e.g. genetic predisposition) or extrinsic (e.g. by 
comedications) effects on the activity of FMO3 or CYP3A4 in vivo are expected to be of little, if 
any, relevance for the pharmacokinetics of afatinib. 
In vitro, afatinib was found to be a P-gp substrate (estimated Km 10-30 µM) and a moderate to 
weak inhibitor of P-gp (estimated Ki of 3.4 µM). It cannot be excluded that concomitant treatment 
with other P-gp substrates or P-gp inhibitors may alter the plasma concentrations of afatinib.  
Since I/Ki of afatinib is resulting in values considerably below 0.1 which would be the defined “cut 
off” value for considerable drug-drug interactions based on P-gp (afatinib acting as a P-gp 
inhibitor) it is unlikely that afatinib may alter the plasma concentrations of other P-gp substrates. 
Safety pharmacology studies (GLP) in rats indicate no adverse effects on behavior or respiratory 
function. Afatinib in the doses tested was essentially devoid of effects on the CNS and pulmonary 
system. Lack of organ specific toxicity was also true for the cardiovascular system with the 
exception of reduced contractility at higher intravenous doses. 
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An effect on renal and liver function was seen with a very high oral dose of 300 mg/kg in rats. 
Furthermore, a dose dependent effect on gastrointestinal function was seen, leading to a 
substantial inhibition at the highest dose. In vitro data, together with the lack of effect on the ECG 
in pigs and minipigs, do not indicate a risk for QT prolongation related arrhythmias. 
A variety of single and repeated dose studies were conducted with afatinib. The main target 
organs were the skin (rat), the gastrointestinal tract (both species) and the kidneys (rat). The 
severity of the findings resulted in premature sacrifices and mortality of rats at high dose groups 
in repeat dose studies. 
In the gastrointestinal tract, increasing systemic exposure was associated with dose dependent 
atrophy of the epithelium and concomitant focal erosions/ulcerations in the stomachs of rats and 
minipigs. Clinically, this was characterized by diarrhea in both species and fecal occult blood in a 
single minipig. Other organs affected by the epithelial atrophy in the rat were the skin, prostate, 
uterus, and vagina. In minipigs, the upper respiratory tract, seminal vesicles, and the corneal 
epithelium were affected by epithelial atrophy. In the gastrointestinal and respiratory tract, 
atrophy of the mucinous glands, e.g. salivary glands, was also found. These atrophic changes were 
minimal to slight and fully reversible during the recovery periods and are most likely related to the 
pharmacodynamic mechanism of afatinib. 
Findings in rat kidneys include papillary necrosis and dilated tubules. The kidney as a target organ 
in animals is also described for the EGFR-inhibitors gefitinib (Iressa™) and erlotinib (Tarceva™). 
Afatinib is not irritating to intact skin. Afatinib is slightly mutagenic in a single bacteria strain, but it 
did not show genotoxic potential in vivo when tested up to overt toxic/lethal doses. Because of 
the pharmacodynamic mechanism, afatinib is probably embryo-/fetotoxic. 
Based on these toxicological findings and the experience with other EGFR- and HER2-inhibitors, 
the risks of anti-EGFR and anti-HER2 therapy with afatinib might primarily consist of 
gastrointestinal effects (including diarrhea) and skin rash. 
1.3.2 
Clinical pharmacokinetic and safety 
PK data available from clinical trials until now indicate that afatinib was moderately fast absorbed 
after oral administration, with median tmax values mainly between 2 and 5 hours. For afatinib there 
was no deviation from dose-proportionality detectable. However, moderate to high inter- and 
intra-individual differences in plasma concentrations were seen. Afatinib was highly distributed 
out of the blood and had a moderate to high clearance. The gMean terminal half-life was mainly in 
the range of 13-57 h. Steady state was reached no later than 8 days after the first administration. 
The major route of elimination of afatinib was via the faeces. After food intake, a decreased 
systemic exposure was observed compared to administration of afatinib under fasted conditions. 
Typically, an accumulation ratio based on AUC values between 1.8 and 4.0 has been observed. At 
doses of 40 mg and above individual Cmax,ss and AUCτ,ss values were mainly in the same range as 
those found to demonstrate anti-tumor activity in nude mouse tumor xenograft models. 
Adverse events observed with afatinib are consistent with those reported for other EGFR- and 
dual EGFR/HER2-inhibitors. These include predominantly gastrointestinal (GI) and dermatological 
adverse events which are dose-dependent. Diarrhea, including severe diarrhea, has been reported 
during treatment with afatinib. Diarrhea may result in dehydration with or without renal 
impairment, which in rare cases has resulted in fatal outcomes. Diarrhea usually occurred within 
the first 2 weeks of treatment. Patients of low body weight, females, and patients with low 
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baseline renal function appear to be at higher risk for the development of higher grades of 
diarrhea. Up to 5-7% of patients experienced dehydration and pre renal insufficiency, most likely 
secondary to gastrointestinal toxicities, particularly diarrhea. Other gastrointestinal adverse 
events include mucositis/stomatitis, nausea, and vomiting. Dermatological adverse events include 
rash, acne, paronychia, pruritus, dry skin, eczema, and folliculitis. Rash/acne occurred at a high 
frequency and half of the cases begin within 4 weeks of exposure to afatinib. Grade 3 rash is 
observed in about 17-18% of patients and those at higher risk for Grade 3 rash/acne appear to be 
the patients of low body weight/body surface area and patients with low baseline renal function. 
A higher incidence of CTCAE Grade 3 adverse events (especially diarrhea) have been observed in 
phase II trials at 50 mg.  
Interstitial lung disease (ILD) is reported in approximately 1% of patients and is a serious 
(potentially fatal) adverse event. One related case of fatal interstitial lung disease (ILD) was 
reported in a NSCLC patient. Considering reports of suspected cases of ILD on afatinib, trials 
exclude patients with known pre-existing ILD from treatment with afatinib and careful monitoring 
of pulmonary symptoms with sudden onset is warranted in all clinical trial protocols. For further 
details and regular updates on listed adverse events please refer to the current IB. 
Afatinib is metabolized only to a minor extent therefore PK-response correlations were performed 
only for the parent compound afatinib. There was no clear trend observed between afatinib 
trough plasma concentrations and objective response. A correlation was observed between 
trough plasma concentration and severity of diarrhea and rash/acne as measured by the CTCAE 
grades for these adverse events. Severity of diarrhea and rash/acne increased with increasing 
trough plasma concentration of afatinib. 
The safety profile of afatinib is characterized by a significant incidence of dose-dependent 
gastrointestinal and skin adverse events. Early, proactive, and effective management of these 
adverse events is mandated in ongoing and forthcoming clinical trials with early intervention to 
manage diarrhoea and skin toxicities.  
1.4 
Rationale 
The challenges in novel drug development in cancer medicine are clear: while many molecular 
targets have been identified, predicting which patients will gain benefit from inhibiting those 
targets remains critical. One of the great challenges in breast cancer research has been the 
integration of HER-family inhibitors into clinical practice outside of HER2 amplification (Alvarez RH, 
2010).  Clearly, HER2 amplification is a well-validated predictive marker for response to the small 
molecule dual EGFR/ HER2 inhibitor lapatinib (Geyer CE, 2006) and the humanized monoclonal 
antibody trastuzumab  (Slamon DJ, 2011). However, outside of HER2 amplification, the role of the 
epidermal growth factor receptor (EGFR/ HER1), its ligands, and co-receptors in clinical breast 
cancer has been elusive. Of the other HER-family members, EGFR has been aggressively pursued in 
breast cancer with both small molecules (erlotinib, gefitinib, lapatinib) and monoclonal antibodies 
(cetuximab) with disappointing efficacy (Alvarez RH 2010). These results contribute to the 
following hypotheses: (1) EGFR is not an important therapeutic target in breast cancer, (2) the 
available inhibitors are insufficient at blocking EGFR signaling in breast cancer tissue, or (3) the 
population of breast cancer patients with EGFR driven disease is smaller than expected and a 
combination of biomarkers for patient selection is required. 
The interplay between steroid hormone signaling and peptide growth factor signaling through the 
HER-family is well described in breast cancer (Arpino G, 2008). Both expression of EGFR and HER2 
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amplification have been shown to mediate resistance to anti-estrogen therapy in laboratory 
models and clinical studies (Massarweh S, 2008) (Osborne CK, 2005) (Rimawi MF, 2010). These 
data have been the rationale for pursuing the combination of HER family inhibition and anti-
estrogen therapy. In patients with HER2 amplification, studies with both trastuzumab and 
lapatinib have shown an improvement in progression-free survival with the addition of anti-HER2 
therapy in combination with anastrozole or letrozole respectively (Kaufman B, 2009)  (Johnston S, 
2009). The latter trial, EGF30008, was a randomized, placebo-controlled, phase III trial of over 
1200 post-menopausal women with HR-positive disease. Two hundred and nineteen women were 
enrolled with confirmed HER2 amplification. Patients were randomized to receive either letrozole 
and placebo or letrozole and lapatinib. Primary endpoint of the trial was PFS. The HER2 amplified 
cohort had a significant improvement in progression-free survival (PFS) with the addition of 
lapatinib (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; p=0.019); median PFS was 8.2 vs 3.0 
months, respectively.  However, in patients with centrally confirmed, HR-positive, HER2 negative 
tumors (n=952) there was no improvement in PFS. A pre-planned Cox regression analysis to try to 
enrich for an EGFR-dependent clinical phenotype, identified prior anti-estrogen therapy as a 
significant factor in the HER2 negative population. A non-significant trend toward prolonged PFS 
for lapatinib in combination with letrozole was seen in patients who experienced relapse less than 
6 months after their prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; p=0.117). 
While this trend is of interest, the identification of a molecular marker for response to lapatinib 
and letrozole in HER2 negative women would be of potential great value. 
Previous biomarker work by Dr Richard Finn’s group identified a correlation between quantitative 
hormone receptor measurements and response to lapatinib and paclitaxel in a HER2 negative 
cohort of women with advanced breast cancer (Finn RS, 2009). In addition other studies have 
suggested a relationship between peptide growth factor signaling and hormone receptor status  
(Arpino G W. H., 2005), specifically, that progesterone receptor (PR) loss in estrogen receptor (ER) 
positive disease is associated with higher expression of EGFR and/or HER2. In addition, a pre-
surgical trial demonstrated cell-cycle inhibition in ER-positive and PR-weak or PR-negative patients 
with breast cancer who were exposed to a short course of the EGFR inhibitor gefitinib (Finn RS, 
2006). 
To further test the hypothesis that semi-quantitative ER and PR measurements are molecular 
markers for EGFR dependence, we performed a blinded, retrospective analysis of ER and PR in 
HER2 negative breast cancer in the EGF30008 cohort (Finn RS, 2009). In this analysis that 
compared the activity of letrozole versus letrozole and lapatinib in ER+ women, it was determined   
that those women with low ER expression (defined as the lowest quartile based on semi-
quantitative IHC, H-score) had a significant improvement in PFS with the combination vs letrozole 
alone (13.6 mos vs 6.6 mos, HR= 0.65; 95% CI 0.47 to 0.9, p<0.005). This finding was of particular 
significance as the overall HER2 negative population did not show any significant benefit from the 
addition of lapatinib. Only when a specific criterion was applied to isolate patients with low ER 
expression, was a subpopulation of breast cancers with HER dependence identified. Also, to note, 
is that the low ER expressing patients had a very poor natural history with letrozole alone, with a 
PFS of 6.6 mos. This is much less than the overall population and higher ER expressing patients 
whose PFS was approximately 14 mos. 
The proposed trial with afatinib was designed to test the hypothesis that low ER expression as 
determined by semi-quantitative immuno-histochemistry (IHC) is a biomarker for HER-
dependence in women with HER2 negative breast cancer. 
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Afatinib is associated to letrozole which is one of the hormonal treatments of choice for treatment 
of advanced breast cancer in post-menopausal patients. 
This is not the first trial combining letrozole and afatinib. There was a first phase II trial conducted 
by Boehringer Ingelheim and referred to as trial 1200.5 in the afatinib IB. The trial included 28 
advanced breast cancer patients. Letrozole was used at its standard dose of 2.5 mg per day. 
Starting dose of afatinib was 50 mg (7 patients were treated at this dose) but due to toxicities 
(diarrhea and rash) afatinib dose was reduced to 40 mg (13 patients) and then 30 mg (8 patients). 
Patients on trial 1200.5 were heavily pre-treated, an amendment to the protocol allowed up to 
two prior chemo regimens in the advanced setting, 86 % of the patients had received prior 
chemotherapy and were letrozole resistant (patients were selected following progression under 
letrozole). In the proposed protocol, patients will receive letrozole + afatinib or letrozole alone as 
their first line in the advanced setting (all types of therapies confounded). They may have received 
prior chemotherapy but only in the neo-adjuvant or adjuvant setting. The two populations are 
therefore different in terms of prior treatment exposure. 
The dose initially chosen for the clinical program of afatinib was 50 mg but this dose showed a 
significant rate of grade 3 diarrhea and rash events. Afatinib dose was then reduced to 40 mg for 
the continuation of the clinical program (see afatinib Investigator Brochure). In combination with 
letrozole, the dose of 40 mg was still associated with a high incidence of grade 3/4 diarrhea 
(30.8%) and grade 3 rash (23.1 %). At the dose of 30 mg, diarrhea and rash were of lower grade 
and incidence (grade 3 diarrhea was observed in 12.5 % of patients and no grade 3 rash was 
documented). 
This, along with the relative good performance status of the patients and their light history of 
prior treatment compared to the one in the trial 1200.5, led to the choice of the dose of 30 mg for 
afatinib, to be associated with 2.5 mg of letrozole.  
In trial 1200.5 Afatinib PK parameters were within the ranges observed in afatinib monotherapy 
studies (PK meta-analysis [U10-1153]), suggesting that continuous dosing in combination with 2.5 
mg letrozole had no major influence on afatinib PK. Mean PK parameters for letrozole showed no 
trend to higher or lower values in conjunction with afatinib dosing. The observed letrozole PK 
parameters were in the ranges reported in the literature ([R10-4018] and [R10-4019]), suggesting 
that afatinib did not have a relevant effect on letrozole PK. Therefore, there was no indication of a 
DDI between letrozole and afatinib and vice versa (when compared with literature or historical 
data). Based on this data it is not planned to further evaluate PK interactions in this combination. 
A detailed section on the management of adverse events, among which diarrhea and rash, has 
been incorporated in the protocol with some proactive precautions to avoid occurrence or 
aggravation of these specific adverse events at a very early point. 
Protocol amendment 4.0 was released on 09 May 2016 and its main change was the enrollment 
closure due to insufficient efficacy data to pursue development of afatinib in breast cancer and 
low recruitment in the trial. As of the date of release of this new protocol amendment, there are 6 
patients still on treatment in the trial and among those, only 2 patients are treated with the 
combination of letrozole and afatinib (Arm B). Due to the limited number of patients still on 
treatment, and especially in Arm B, TRIO and BI agreed to release this amendment to discontinue 
the trial, allowing patients receiving afatinib to continue with this treatment outside of the TRIO-
020 trial. 
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2. OBJECTIVES 
2.1 
Planned primary and secondary objectives 
2.1.1 
Primary Objective 
To assess the effect of letrozole plus afatinib and of letrozole alone on progression-free survival 
(PFS) in the first line treatment of ER+, HER2 negative postmenopausal ABC women with low ER 
expression.  
The Primary endpoint was PFS. (Refer to section 8.4 for further details) 
2.1.2 
Secondary Objectives 
- 
To assess secondary measures of efficacy for afatinib administered in combination with 
letrozole and for letrozole alone. 
Endpoints: 
Overall survival (OS)  
Objective Response rate (OR) 
Time to tumor progression (TTP) 
- 
To assess the safety and tolerability of afatinib administered in combination with letrozole and 
of letrozole alone. 
Endpoint: overall safety profile  
The patient enrolment was closed prematurely on 05 MAR 2016 due to the small number of 
patients randomized compared to what was initially planned as per the statistical analysis The 
data collected for all the patients will be described per arm but no statistical comparison will be 
made. Therefore the primary and secondary objectives are not applicable. . 
2.2 
Exploratory Objectives (Optional) 
The area of research into the identification of tumor markers and biological processes / targets to 
aid in the identification of clinical benefit in certain subsets of populations or even in the 
identification of anticancer therapies to target the marker, is rapidly growing. 
TRIO wishes to examine the molecular profiles of tumor tissue submitted by the patients to 
identify factors that may influence biological and clinical responses to afatinib and letrozole 
including but not limited to ER and PR H-score and the EGFR related downstream pathways. 
As more development and information is revealed in the future, TRIO would like to use these 
tumor samples for measurement of the new markers. The tumor samples will be stored in the 
TRIO central laboratory until future use is required. TRIO may collaborate in the future with 
experts in the field, and the tumor material may be shared with other researchers. 
This portion of the trial was optional. The Patient Informed Consent Form (PICF) contained a 
section dedicated to this sub-trial. Refusal to grant permission for further testing does not affect 
the quality of care the participant is to receive. 
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Tumor tissue provided for central determination of ER/PR and HER2 statuses will be used to 
perform this additional research for patients having given their consent. No additional sample will 
be required. If the patient refuses to participate in the optional sub-trial then tumor tissue will 
only be assessed for determination of ER/PR and HER2 statuses to assess patient´s eligibility in the 
trial.   
Tumor tissue samples will be destroyed after 20 years unless otherwise required per local 
regulations. 
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3. TRIAL DESIGN 
This is an open-label, multicenter, international, randomized, Phase II clinical trial that aimed to 
assess the efficacy and safety of letrozole in combination with afatinib(oral EGFR inhibitor) versus 
letrozole monotherapy for the first-line treatment of postmenopausal women with ER+, HER2 
negative advanced breast cancer with low ER expression. 
Although hormone receptors (HR) are now routinely assessed by IHC, the estimate of the 
percentage of tumor cells stained or, more significantly, of staining intensity-based scoring 
systems have, necessarily, elements of patientivity within them and thus may be patient to errors 
in interpretation leading to notable variances across laboratories. In addition, the current 
reporting of hormone receptor status may be adequate for assessing patients for anti-estrogen 
therapy but not those for other targeted agents (i.e. EGFR targeted therapy).  
In order to assess the level of ER expression we used a semi-quantitative scoring system 
(McClelland RA 1990) defined as : 
H-score = (% of cells stained at intensity category 1x1) + (% of cells stained at intensity category 
2x2) + (% of cells stained at intensity category 3x3). 
This formula results in an H-score in the range of 0-300 where 300 equals 100% of tumor cells 
stained strongly (i.e., 3+).  
Low ER expression was defined as tumor sample with H-score [1-159]. 
For all patients consented  on the trial, a tumor sample was submitted to the designated central 
laboratory for central testing of ER/PR and HER2 and determination of the H-score. This was 
assessed prior to randomization.  
Patients with HER2 negative, ER+ advanced breast cancer with low ER expression defined as H-
score between 1 and 159 entered screening phase and performed the required screening 
assessments. 
Eligible patients were randomly assigned in a 1:1 ratio and stratified according to sites of disease 
(bone only disease vs. other) and prior administration of hormonal therapy in neo/adjuvant 
setting (Yes vs. No) to either: 
• 
Arm A: Continuous regimen of oral letrozole 2.5 mg until progression of disease or any 
other trial treatment discontinuation criteria as per section 5.3.3. 
Or  
• 
Arm B: Continuous regimen of oral letrozole 2.5 mg daily plus oral afatinib 30 mg daily 
until progression of disease or any other trial treatment discontinuation criteria as per 
section 5.3.3. 
IN ADDITION the following applies whichever comes first:  
• 
If the patients treated with the combination of afatinib and letrozole (arm B) discontinue 
the trial treatment (whatever the reason) before 30 November 2018, the patients from 
the other arm (arm A, letrozole alone) still on treatment will also be discontinued from 
the trial at the same time. They may continue receiving letrozole using commercial drug 
as standard of care according to their treating physician discretion. 
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• 
If the patients treated with afatinib and letrozole (arm B) have not discontinued the trial 
treatment by 30 November 2018, all patients currently on treatment in the trial (including 
the ones only treated by letrozole alone (arm A)) will be discontinued from the trial at that 
time. They may continue receiving their treatment if in alignment with their treating 
physician judgment as follows: 
o Patients in arm A: may continue receiving letrozole using commercial drug as standard 
of care according to their treating physician discretion. 
o Patients in arm B: may continue receiving afatinib in the context of an alternative drug 
supply outside the clinical trial as appropriate according to local legislation. 
Additionally, they may continue receiving letrozole using commercial drug as standard 
of care according to their treating physician discretion. 
• 
Note; In case no alternative drug supply outside the clinical trial as appropriate according 
to local legislation can be put in place and the 2 patients in Arm B are still on treatment on 
30 November 2018, the protocol and PICF will need to be revised again. 
Once the patient is discontinued from trial treatment and has undergone the End of Treatment 
visit (see section 6.3), the patient will be permanently discontinued from the trial. 
This trial also included an optional exploratory research component. This optional portion of the 
trial is a molecular profiling assay aimed to assess the relationship of antitumor activity with the 
expression of a few cell cycle-related proteins and other markers that may be identified in the 
future. (See section 2.3) 
Patients participated in this trial even if they had chosen not to participate in the sample banking 
component. 
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Figure 1 : Trial Scheme - Patient Selection and Treatment 
 
 
 
 
 
 
 
 
* As described in section 3-Trial Design (IN ADDITION) 
Central laboratory assessment of ER, PR, HER2 status 
ER+, HER2- advanced breast cancer subject 
Sign consent 
If HER2- and H-score [1-159] 
Perform Screening assessments 
Screen failure 
(HER2-) and/or (ER+ low expression) not confirmed
Subjects not eligible will be screen-failed 
Eligible subjects will be randomized using stratification factors 
Treat until disease progression or discontinuation criteria* 
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4. PATIENT SELECTION 
The following eligibility criteria were designed to select patients for whom protocol treatment was 
considered appropriate. All relevant medical and non-medical conditions were taken into 
consideration when deciding whether this protocol is suitable for a particular patient. 
4.1 
Inclusion Criteria 
Patients had to meet all of the following inclusion criteria to be eligible for enrollment into the 
trial: 
1. 
Signed and dated informed consent document indicating that the patient (or legally 
acceptable representative) has been informed of all the pertinent aspects of the trial prior to 
enrollment. 
2. 
Postmenopausal female, 18 years of age or older. 
Postmenopausal status defined as:  
o Prior bilateral surgical oophorectomy or 
o Amenorrhea and age ≥ 60 years or 
o Age < 60 years and amenorrhea for 12 or more months and FSH and estradiol in the 
postmenopausal ranges 
3. 
Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence 
of locally recurrent disease not amenable to resection or radiation therapy with curative 
intent, or metastatic disease.   
4. 
HER2 negative breast cancer. Local testing should demonstrate that the tumor is 0 or 1+ by 
immunohistochemistry (IHC) or is considered to be HER2 negative for gene amplification by 
fluorescence in-situ hybridization (FISH), chromogenic in-situ hybridization (CISH) or other in-
situ hybridization (ISH) method. Central testing (required for all patients) must demonstrate 
that the tumor is HER2 negative by FISH or IHC.  
5. 
ER positive breast cancer. Local testing should demonstrate that the tumor is ER positive. 
Central testing (required for all patients) must demonstrate that the tumor is ER+ with low 
expression (H-score[1-159]). 
6. 
Paraffin-embedded tumor block(s) available for centralized assessment of ER, PR, and HER2.  If 
no tumor block is available, 15 to 20 unstained slides of paraffin-embedded tissue from the 
tumor obtained at the initial diagnosis or prior biopsy or surgery (archived tumor tissue) will 
be accepted. Slides must be positively charged, frosted-end. Tumor biopsies may be from 
either the primary or metastatic site of disease.  
When tumor tissue from the primary tumor and from metastatic sites is available, the sample 
from the most recent biopsy/surgery/procedure will be sent to Central laboratory. 
7. 
Measurable disease according to RECIST 1.1 (E.A. Eisenhauer 2009) or bone-only non 
measurable disease according to RECIST 1.1. Previously irradiated lesions are deemed 
measurable only if progression is documented at the site after completion of radiation. 
8. 
Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1 (APPENDIX 1). 
9. 
Adequate organ function as defined by the following criteria: 
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• 
Hemoglobin ≥ 9 g/dL 
• 
Absolute neutrophils count (ANC) ≥ 1.2 x 109/L  
• 
Platelets  ≥ 100 x 109/L 
• 
Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) < 2.5 x 
upper limit of normal (ULN). 
• 
Total serum Bilirubin ≤ 1.5 mg/dL (≤  26 µ mol/L) regardless of liver involvement 
secondary to tumor. Inclusion of patients with increased serum indirect bilirubin due to 
Gilbert’s syndrome is permitted. 
• 
Serum creatinine ≤ 1.5 x ULN. For patients with serum creatinine > 1.5 x ULN then 
calculated (Cockcroft-Gault formula) or measured Creatinine clearance ≥ 60 mL/min is 
required. 
10. Baseline resting left ventricular ejection fraction (LVEF) ≥ 50% measured by multigated 
acquisition scan (MUGA scan) or echocardiogram. 
11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and 
other trial procedures. 
4.2 
Exclusion Criteria 
1. 
Brain metastases (even if treated and/or stable), spinal cord compression, carcinomatous 
meningitis, or leptomeningeal disease. 
2. 
Prior treatment with any type of systemic therapy for locally-recurrent disease not amenable 
to resection or radiation therapy with curative intent, or for metastatic disease. 
3. 
Prior treatment with letrozole in (neo)adjuvant setting with disease-free interval ≤ 12 months 
from completion of treatment until randomization. 
4. 
Prior treatment with any anti HER-family targeted therapy in (neo)adjuvant setting. 
5. 
Any concurrent or previous malignancy within 5 years prior to randomization except for 
adequately and radically treated basal or squamous skin cancer, or carcinoma in situ of the 
cervix, or other non-invasive/in-situ neoplasm. A patient with previous history of invasive 
malignancy (other than adequately and radically treated basal or squamous skin cancer) is 
eligible provided that she has been disease free for more than 5 years. 
6. 
Non-measurable disease according to RECIST 1.1 (E.A. Eisenhauer 2009), with the exception of 
bone-only non-measurable disease. 
7. 
Known pre-existing interstitial lung disease.  
8. 
Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g. 
Crohn's disease, malabsorption or CTCAE v4.0 grade ≥ 2 diarrhea of any aetiology.  
9. 
History or presence of clinically relevant cardiovascular abnormalities, as per investigator 
assessment such as uncontrolled hypertension, congestive heart failure NYHA Class ≥ III 
(APPENDIX 2) , unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 
months prior to randomization. 
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10. Any other concomitant serious illness or organ system dysfunction which in the opinion of the 
investigator would either compromise patient safety or interfere with the evaluation of the 
safety of the test drug.  
11. Any contraindication to oral agents. 
12. Active hepatitis B infection (defined as presence of Hep B sAg and/or Hep B DNA), active 
hepatitis C infection (defined as presence of Hep C RNA) or known HIV carrier. 
13. Known or suspected active drug or alcohol abuse. 
14. Known hypersensitivity to afatinib or letrozole or the excipients of any of the trial drugs. 
15. Concomitant treatment with strong inhibitor of P-gp (see section 5.5.2). 
Note: Patients having received treatment with strong P-gp inhibitors must have discontinued 
treatment at least 7 days before start of trial drugs.  
16. Any ongoing acute clinically significant toxic effect of prior anticancer therapy or any persisting 
complication of prior surgery. 
17. Patients with known history of keratitis, ulcerative keratitis or severe dry eye. 
18. Participation in the active phase of other clinical trials of investigational agents in which last 
trial treatment was administered within 2 weeks prior to randomization. 
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5. TREATMENT 
5.1 
Protocol Treatment  
Eligible patients receive either oral letrozole 2.5 mg plus oral afatinib 30 mg daily or oral letrozole 
2.5 mg daily until progression of disease or any other trial treatment discontinuation criteria as 
per section 5.3.3. 
Treatment allocation was operated centrally after patients had given their written informed 
consent and had completed the necessary baseline assessments. 
Refer to section 6.1.2 for registration and randomization process. 
If a patient was randomized but did not receive any treatment, the reason was documented in the 
case report form (CRF). Patients remained on trial, baseline data was collected and follow-up 
continued. These patients will now be discontinued from the trial once their trial treatment is 
discontinued and they will be followed and treated as per local clinical practice. 
Investigational Medicinal Product” (IMP), Non Investigational Medicinal Product” (NIMP): 
According to the ICH Good Clinical Practice and EU Directive 2001/20/EC Article 2 (d), afatinib falls 
under the definition of Investigational Medicinal Product (IMP) while letrozole which is considered 
as Standard of Care (SoC) in this treatment population falls outside of this definition and is then to 
be considered as a “Non Investigational Medicinal Product” (NIMP). 
Definition and management of IMP and NIMP are further described in a separate Trial Specific 
Guideline. 
5.2 
Protocol Treatment Management 
5.2.1 
Packaging and Labeling 
5.2.1.1 
Afatinib 
Afatinib is an oral drug. 
It is supplied by the manufacturer Boehringer Ingelheim (BI) to the sites. Initial shipment and re-
supply are described in a separate document. 
Two dose strengths of 20 and 30 mg afatinib are used in the trial to allow for any dose adjustment. 
These newly available dose strengths 20 and 30 mg film-coated immediate release tablets are 
prepared in a common blend, with higher drug load per tablet. 
A color scheme was established in order to distinguish between the doses and tablet sizes. The 20 
mg film-coated tablets are white to slightly yellowish, round, biconvex, bevel-edged shape with a 
diameter of approximately 8 mm. Film-coated 30 mg tablets are dark blue. 30 mg film-coated 
tablets are as well round, biconvex, bevel-edged shape with a diameter of approximately 9 mm. 
All doses are either one-sided embossed with the Boehringer Ingelheim Logo or double-sided 
embossed with the Boehringer Ingelheim Logo on one side and a combination of the letter“T20
”with the dose strength on the other side (example:“T20”for the 20 mg tablet). 
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The medication is provided in HDPE bottles with a desiccant at 25°C/60%RH, 30°C/75%RH and 
40°C/75%RH child-resistant, tamper-evident bottles. 
Note: In the future, instead of an HDPE bottle a PP-bottle with more desiccant will be employed 
which allows a shelf-life of 36 months with the storage statement for climatic zone III/IV “Do not 
store above 25°C” and for CZI/II “This medicinal product does not require any special temperature 
storage conditions” and for all climatic zones “Store in the original bottle in order to protect from 
moisture and light”. Respective real time stability data are available. 
Each bottle contains 30 tablets.  
Labeling of afatinib supplies is done by BI, in accordance with local regulations. 
For the purpose of this trial, the Single Reference Document to be used for afatinib is the 
Investigator’s Brochure. 
5.2.1.2 
Letrozole 
Letrozole is an oral drug.  
Letrozole is standard of care in this population. Commercial Letrozole is used.  
Commercial Letrozole contains 2.5 mg letrozole as active ingredient. 
Packaging depends on the commercial letrozole available locally. 
For the purpose of this trial, the Single Reference Document to be used for letrozole is the UK 
Summary of Product Characteristics (SPC) for Femara. 
5.2.2 
Storage and Accountability 
5.2.2.1 
Afatinib 
Afatinib tablets are shipped and stored between 8 to 25°C or as specified by label for the given 
climate zone. 
Temperature loggers shall be used. 
Alert setting of the temperature loggers are 
Climatic Zone I/II countries -20°C / +30°C (e.g. Europe, USA, Argentina, China) 
Climatic Zone III/IV countries -20°C / +25°C (e.g. Brazil, India, most Asian and African countries) 
Specific expiry date is provided on the label of each bottle. 
Medication should be kept in their original container in a secured area at the trial site in 
accordance with applicable regulatory requirements. 
Returned medication (empty containers and partially used containers) should be stored separately 
from medication that needs to be dispensed. 
To ensure adequate records, dispensations, return and accountability of afatinib tablets are 
documented in a timely manner.  
The following information are documented: 
• 
Patient’s number 
• 
Date dispensed 
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• 
Number of tabs dispensed/returned for each strength 
• 
Batch number and expiry date 
Bottles/boxes are labeled according to local regulations and include the following as 
a minimum: 
• Trial number 
• Product name (BIBW 2992) 
• Contents of the bottle (30 tablets) 
• Tablet strength 
• Batch number 
• Medication number 
• Use-by date 
• Storage information 
• Instructions for use 
• Manufacturer name and address 
• A statement that the medication is for clinical trial use only 
• A caution statement 
A new bottle of medication is dispensed on day 1 of each course, regardless of the number of 
tablets remaining in the bottle from the previous course. The patient initially receives one bottle 
of 30mg tablets and in the event that dose reduction is necessary the patient returns to the clinic 
and new medication is dispensed. 
According to the information reported in section 3-Trial Design (IN ADDITION) regarding the 
decision to discontinue the patients from the trial at the latest on 30 November 2018, the 
information reported in this section is applicable until 30 November 2018. After that date, the 
patients will not receive afatinib anymore in the scope of the trial but in the frame of an 
alternative drug supply outside the clinical trial as appropriate according to local legislation.At the 
end of the clinical trial all drug supplies unallocated or unused by the patients must be disposed of 
and accounted for according to local governing auspices and site SOPs. The documentation should 
be available.  
5.2.2.2 
Letrozole 
Letrozole is stored according to the instructions detailed in the local package insert.  
For each container of letrozole dispensed to a patient, the following information is documented in 
a specific form: 
Trade name 
Batch number 
Date of dispensation 
Patient ID 
Quantity dispensed 
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It is recommended to collect the quantity returned to assess compliance 
According to the information reported in section 3-Trial Design (IN ADDITION) regarding the 
decision to discontinue the patients from the trial at the latest on 30 November 2018, the 
information reported in this section is applicable until 30 November 2018. After that date, the 
patients will not receive letrozole anymore in the scope of the trial but as commercial drug. 
5.2.3 
Return / Destruction 
5.2.3.1 
Afatinib 
Unused/expired afatinib should be destroyed locally once accountability performed and 
reconciled. 
5.2.3.2 
Letrozole 
Unused Letrozole will be managed by the sites according to their local requirements.  
5.3 
Protocol Treatment Administration 
5.3.1 
Premedications and special precautions  
No specific pre-medication is required for afatinib. 
5.3.2 
Standard treatment schedule  
Afatinib:  
At each monthly visit, patients should be given a 30-tablet bottle.  
For administrative purposes treatment is divided into treatment cycles, which are each 4 weeks 
(28 days) in duration. However, treatment is given continuously unless treatment schedule 
adjustments are needed (as per section 5.4). Patients take a single oral dose of afatinib each day 
for the first and subsequent cycles. The medication should be taken at the same time each day (± 
2 hours) at least one hour before food intake and at least three hours after the last food intake.  
Afatinib tablets should be swallowed whole with water. If dosing of whole tablets is not possible, 
afatinib tablets can be dispersed in approximately 100 ml of noncarbonated drinking water. No 
other liquids should be used. The tablet should be dropped into the water without crushing it, and 
stirred occasionally for up to 15 min until the tablet is broken up into very small particles. The 
dispersion should be consumed immediately. The glass should be rinsed with approximately 100 
ml of water which should also be consumed. The dispersion can also be administered through a 
gastric tube. . Administration of afatinib via gastric tube has to be recorded in the CRF. 
No tablet should be ingested if it is broken, cracked, or otherwise not intact.  
Missed/Vomited/Extra Doses: 
If an entire daily dose is skipped, the patient should resume treatment the following day with her 
regular dose. No “make-up dose” or increased dosing should occur.  
If a dose is vomited at any time, the patient should resume treatment the following day with her 
regular dose. No “make-up dose” or increased dosing should occur.  
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Patients should report all vomited, missed or delayed doses to the trial staff and will be provided 
with a medication diary which should be turned in at every visit. 
If a patient inadvertently takes 1 extra dose during a day, she should not take the next day’s dose. 
Letrozole: Patients should be instructed to swallow letrozole tablet without regard to food. 
Patients should be encouraged to take their dose at approximately the same time each day.  
For patients in Arm B (letrozole + afatinib), it is recommended to take letrozole and afatinib at the 
same time to ensure compliance.  
5.3.2.1 
Preparation 
The trial medication is self administrated. There is no specific preparation. Afatinib is an oral drug 
taken daily by the patient. 
5.3.2.2 
Treatment compliance 
Treatment compliance will be assessed at the end of each visit. Patients will complete a diary to 
document their daily intakes. They will be instructed to return all unused drugs (partially used and 
empty containers) and their diary at each visit. Site staff will perform accountability of the 
returned drug and will assess compliance of the patient. Site staff must ensure that the patient 
clearly understands the directions for self-medication and follows adequately the schedule. 
5.3.3 
Protocol treatment discontinuation  
By default, patients are treated until progressive disease as per RECIST 1.1.  
Please refer to section 3-Trial Design (IN ADDITION) regarding the decision to discontinue the 
patients from the trial at the latest on 30 November 2018 and the conditions of this 
discontinuation. 
The investigator will also discontinue the treatment if any of the following conditions is met: 
 Intercurrent illness or change in patient´s condition that warrants trial treatment 
discontinuation or unacceptable toxicity, such as interstitial lung disease, rash grade 4, 
hepatic injury, left ventricular systolic dysfunction grade ≥3, ulcerative keratitis  (see 
section 5.4) 
 Any event which would warrant afatinib to be modified by > 1 dose reduction or afatinib 
to be held for > 14 days (see section 5.4.1) 
 Need for additional local and/or systemic non-protocol anticancer therapy (see 
section5.5.4) 
 Patient’s decision to withdraw 
 Lost to follow up 
 Death 
 Pregnancy (see section 7.4.2) 
 Investigator’s decision 
 Discontinuation of the trial by the sponsor 
Refer to section 6.3 for the list of assessments to be performed at the end of treatment. 
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If letrozole needs to be discontinued for any reason then afatinib must also be discontinued and 
patient must be discontinued from the trial except if patient is deriving obvious clinical benefit 
from continuing treatment with afatinib alone. Please refer to section 5.4.1 for the protocol 
definition of obvious clinical benefit. 
In this case, Medical Monitor/TRIO Medical Lead/Trial Chair should be contacted by the site prior 
to continuing with afatinib. 
If afatinib needs to be discontinued for any reason, letrozole should be discontinued within the 
frame of the trial and the patient must be discontinued from the trial.  
Last trial dose of letrozole as trial medication will be defined as last letrozole intake prior to End of 
Study Visit. 
5.4 
Adverse Event management and treatment schedule adjustments 
5.4.1 
General rules 
Regular assessment and monitoring of adverse events is required throughout trial treatment 
period and up until 30 days after last intake of trial medication (last intake of letrozole in the single 
agent arm or last intake of afatinib + letrozole or letrozole -if afatinib previously discontinued- in 
the combination arm). Recommendations regarding monitoring and adequate management of 
specific events are provided below. CTCAE version 4.0 is used to assess the severity of adverse 
events.  
Letrozole dose modification 
No dose adjustment is permitted for letrozole.  
Afatinib dose modification 
Patients are monitored closely for toxicity and the dose of afatinib may be adjusted as indicated in 
tables below. Dose reduction to 20 mg is allowed depending on the type and severity of toxicity 
encountered. Patients requiring more than one dose reduction will be discontinued from afatinib.  
Table 1 : Dose levels 
Afatinib levels 
Dose 
Starting dose level  
30 mg 
Dose reduction 
20 mg 
Dose escalation is not allowed once afatinib dose has been reduced.  
For toxicities requiring dose adjustment (see sections 5.4.2 to 5.4.7), afatinib will be held for up to 
14 days to allow patient to recover to a grade ≤ 1, and will be resumed at 20 mg. 
Dose reduction should always follow a treatment pause in order to allow recovery to grade ≤ 1 
toxicity. Nevertheless, the initial trial visits schedule should be kept unchanged (every 4 weeks 
regardless of any additional visits and treatment pauses). 
If despite optimal care and afatinib pause, patient has not recovered to grade ≤ 1 within 14 days 
and is not deriving obvious clinical benefit from trial treatment, the patient should not receive any 
further treatment with afatinib. Letrozole should be discontinued within the frame of the trial and 
the patient must be discontinued from the trial. 
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In the event that the patient is deriving obvious clinical benefit in the opinion of the investigator 
but has not recovered to grade ≤ 1 within 14 days the further treatment of the patient will be 
decided by the Medical Monitor/TRIO Medical Lead/Trial Chair in agreement with the investigator. 
Obvious clinical benefit is defined as: 
SD or PR or CR as per RECIST 1.1 in the last tumor assessment performed; AND/OR 
Improvement in cancer related symptoms from baseline as per investigator opinion, in absence of 
PD as per RECIST 1.1; AND/OR 
Improvement in cancer related laboratory abnormalities in absence of PD as per RECIST 1.1 
Additionally the following factors should be taken into consideration in order to decide about 
treatment continuation: 
Type and grade of the AE that has not resolved to grade 1 
Treatment tolerability since trial treatment start based on investigator judgment and reported 
AEs 
ECOG PS (decrease ≤ 1 point from the last PS prior to start date of the AE that has not resolved 
to grade 1) 
Absence of significant treatment related laboratory abnormalities. 
In this case, Medical Monitor/TRIO Medical Lead/Trial Chair should be contacted by the site prior 
to reintroducing afatinib. 
5.4.2 
Management of diarrhea 
Close monitoring and proactive management of diarrhea is essential for successful treatment of 
patients with afatinib. Early and appropriate intervention can prevent the development of more 
severe diarrhea. In most cases, loperamide controls diarrhea caused by afatinib. Loperamide 
should be available at the start of therapy and kept with the patient at all times; it is therefore 
advisable that patients be given a prescription at the time of initiating treatment with afatinib.  
The recommendations for management are as follows: 
Table 2 : Management of diarrhea 
CTCAE v4.0 Grade  
Recommended management  
Dose adjustment 
Diarrhea Grade 1 
Appropriate rehydration (e.g. 1.5 
L/m2/day plus equivalent of actual 
fluid loss) is essential.  
Two (2) mg loperamide tablets 
should be taken immediately, 
followed by one 2 mg tablet with 
every loose bowel movement, up 
to a maximum daily dose of 10 
tablets (20 mg). 
Patient should be advised to avoid 
lactose-containing products or any 
foods known to aggravate diarrhea. 
Trial treatment to be continued 
without dose delay/reduction  
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Diarrhea Grade 2 
Same as for grade 1. 
Electrolyte replacement has to be 
ensured. 
If diarrhea persists ≥ 2 days (48 
hours) despite adequate anti-
diarrheal treatment,  hold afatinib 
up to 14 days until patient has 
recovered to grade ≤ 1 and resume 
at a 20 mg. 
Diarrhea Grade ≥ 3 Same as for grade 1. 
Electrolyte replacement has to be 
ensured 
Hold afatinib up to 14 days until 
patient has recovered  to grade ≤ 1 
and resume at 20 mg.  
5.4.3 
Management of nausea and vomiting 
Nausea and vomiting may significantly affect patients’ adherence to the treatment and their 
quality of life. In order to reduce the occurrence and the intensity of emesis, the patients should 
be treated with an aggressive antiemetic program such as the following: 
Table 3: Management of nausea and vomiting 
CTCAE v4.0 Grade  
Recommended management 
Dose adjustment 
No event 
No prophylactic antiemetic 
treatment 
Trial treatment to be continued 
without dose delay/reduction 
Nausea Grade 1 but 
no vomiting 
No antiemetic treatment. 
Trial treatment to be continued 
without dose delay/reduction 
Nausea Grade 2 
and/or  
Vomiting Grade 1-2 
Appropriate hydration in case of 
vomiting (e.g. 1.5 L/m2/day plus 
hydration deficit). 
Implement antiemetic treatment. 
 
If vomiting grade 2 and/or 
nausea grade 2 persists for 3 or 
more consecutive days despite 
optimal supportive care, hold 
afatinib up to 14 days until 
patient has recovered from 
nausea and/or vomiting  to 
grade ≤ 1 and resume at 20 mg. 
Nausea Grade 3  
and/or  
Vomiting grade ≥ 3   
Appropriate hydration in case of 
vomiting (e.g. 1.5 L/m2/day plus 
hydration deficit). 
Implement antiemetic treatment. 
Hold afatinib up to 14 days until 
patient has recovered to grade ≤ 
1 and resume at 20 mg.  
5.4.4 
Management of rash 
A proactive and early approach to management of rash is crucial. Rash can be managed by a 
variety of treatment options to relieve symptoms and reduce the rash. The recommendations for 
management are as follows: 
 
 
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Table 4 : Management of rash 
CTCAE v4.0 Grade  
Recommended management 
Dose adjustment 
No event  
General/Prevention: strict sun 
protection; use of a sunscreen of Sun 
Protection Factor 15 (SPF 15) or higher, 
preferably containing zinc oxide; use of 
a thick, alcohol-free emollient cream; 
avoid harsh detergents, avoid using a 
solarium. 
Trial treatment to be 
continued without dose 
delay/reduction. 
Rash Grade 1 
Mild rash may not need treatment. 
However, if treatment is considered 
necessary, topical hydrocortisone (1% or 
2.5%) cream and/or clindamycin 1% gel 
can be used. 
Trial treatment to be 
continued without dose 
delay/reduction. 
Rash Grade 2  
Relief from major symptoms caused by 
grade 2 skin related adverse events 
should be achieved by a combination of 
local and systemic therapies including: 
1) Systemic antibiotics (e.g. doxycycline 
or minocycline) 
2) Topical treatment (hydrocortisone 
2.5% cream, clindamycin 1% gel, 
pimecrolimus 1% cream) 
And / or 
1) Antihistamines (e.g. 
diphenhydramine) 
2) Oral prednisone (short term i.e., <14 
days treatment) may be added at 
investigator’s discretion 
Systemic and topical treatment should 
be initiated at the start of grade2 and 
continue until resolution or 
improvement to grade ≤1. 
If grade 2 rash persists for 7 
days or more despite 
treatment and is poorly 
tolerated by the patient, the 
investigator may choose to 
hold afatinib up to 14 days 
until patient has recovered to 
grade ≤ 1 and resume at 20 
mg.  
 
Rash Grade 3 
May be treated in a manner similar to 
grade 2 rash. 
Hold afatinib up to 14 days 
until patient has recovered  
to grade ≤ 1 and resume at 
20 mg. 
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Rash Grade 4 
Same treatment as grade 2-3 is 
recommended. Additionally, use of IV 
antibiotics and/or steroids is 
recommended if clinically indicated. 
Consultation with dermatologist. 
Discontinue afatinib.  
Do not re-challenge with 
afatinib 
5.4.5 
Management of Interstitial Lung Disease (ILD) 
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnea, cough, fever) should be performed to exclude ILD. 
Table 5 : Interstitial Lung Disease 
CTCAE v4.0 Grade  
Recommended management 
Dose adjustment 
Acute onset and/or 
unexplained worsening of 
pulmonary symptoms 
(dyspnea, cough, fever), any 
grade 
Appropriate treatment 
instituted as necessary. 
Afatinib should be held 
pending investigation of these 
symptoms. 
Interstitial Lung Disease 
diagnosis (any grade) 
Appropriate treatment 
instituted as necessary. 
Discontinue afatinib. Do not 
re-challenge with afatinib. 
5.4.6 
Management of Protocol specified significant event: hepatic injury 
The following event is defined as Protocol-specified significant event: Hepatic injury defined by 
the following alterations of liver parameters:  
for patients with normal AST / ALT and bilirubin at baseline: an elevation of AST and/or ALT above 
>3 fold ULN combined with an elevation of bilirubin above >2 fold ULN measured in the same 
blood draw sample. 
for patients with abnormal AST / ALT and bilirubin at baseline : an elevation of AST and/or ALT >5 
fold ULN combined with an elevation of bilirubin >2 fold ULN measured in the same blood draw 
sample. 
Table 6 : Management of hepatic injury 
Event 
Recommended management 
Dose adjustment 
AST and/or ALT above > 3 
fold ULN combined with an 
elevation of bilirubin above 
> 2 fold ULN (patient with 
normal LFT at baseline) 
or 
AST and/or ALT above > 5 
fold ULN combined with an 
elevation of bilirubin above 
>2 fold ULN (patient with 
abnormal LFT at baseline) 
Promptly report the event to 
TRIO within 24 hours of learning 
its occurrence (see section 7.3). 
Monitor every week until liver 
chemistries resolve or return to 
within baseline values. 
A specialist or hepatology 
consultation is recommended. 
 
Discontinue afatinib. Do not 
re-challenge with afatinib. 
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5.4.7 
Other Adverse events 
Table 7: Treatment schedule adjustments 
Type and CTCAE v4.0 Grade of event 
Dose adjustment 
Any drug related AE grade ≥ 3 (except Left 
Ventricular Systolic Dysfunction which 
requires special instruction below) 
 
Hold afatinib up to 14 days until patient has 
recovered to grade ≤ 1 and resume at 20 mg. 
 
Acute kidney injury (renal dysfunction) grade 
≥ 2 
(Worsening of renal function grade ≥ 2 as 
measured by serum creatinine) 
Keratitis symptoms  (such as acute or 
worsening eye inflammation, lacrimation, 
light sensitivity, blurred vision, eye pain 
and/or red eye), any grade  
Refer promptly to an ophthalmology 
specialist. 
Hold afatinib during evaluation of suspected 
keratitis, up to 14 days until patient has 
recovered completely and resume at 20 mg.  
If keratitis is diagnosed, benefits and risks of 
continuing treatment should be carefully 
considered. Medical Monitor/TRIO Medical 
Lead/Trial Chair should be contacted. 
If diagnosis of ulcerative keratitis is 
confirmed, discontinue afatinib. Do not re-
challenge with afatinib. 
Any other drug related AE prolonged (≥ 7 
consecutive days) grade 2 poorly tolerated by 
the patient. 
Investigator may choose to hold afatinib up to 
14 days until patient has recovered to grade ≤ 
1 and resume at 20 mg. 
Any unrelated (serious or not serious) 
adverse event  
Investigator may choose to hold afatinib up to 
7 days until patient has recovered to grade ≤ 
1 and resume at the same dose. 
If the investigator chooses to pause the 
medication for more than 7 days and believes 
that the patient would derive clinical benefit 
from continuing medication, the decision to 
continue medication will be made by the trial 
medical monitor in agreement with the 
investigator. 
Left Ventricular Systolic Dysfunction grade ≥ 
3 
Discontinue afatinib. Do not re-challenge with 
afatinib. 
 
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5.5 
Concomitant Medications and Procedures 
5.5.1 
Supportive care 
Medication intended solely for supportive care (analgesics, antidiarrheals, antibiotics, 
antidepressants, etc.) may be used at the investigator’s discretion.  Erythropoietin and/or blood 
products may be used at the investigator’s discretion for the supportive treatment of anemia. 
5.5.2 
Precautions – Treatment interaction with P-gp 
There is no treatment interaction with letrozole. 
Afatinib is a substrate of P-gp and its plasma concentrations can be affected by the use of P-gp 
inhibitors and it is also likely that P-gp inducers could also influence afatinib plasma 
concentrations. The use of potent P-gp inhibitors and potent P-gp inducers has to be avoided 
during treatment with afatinib. 
For patients who require therapy with a P-gp inhibitor and who are receiving afatinib at a daily 
dose of 30 mg, afatinib dose may be reduced to 20 mg if not tolerated. If a P-gp inhibitor or 
inducer is planned to be administrated to the patient, Medical Monitor/TRIO Medical Lead/Trial 
Chair should be contacted by the site prior to initiating therapy. 
Table 8 below provides a non-exhaustive list of P-gp inhibitors or inducers to be avoided during 
trial treatment. 
Table 8: Treatment interacting with P-gp 
Strong P-gp inhibitors 
P-gp inducers 
Amiodarone 
Clarithromycin 
Cyclosporin 
Erythromycin 
Ketoconazole 
Itraconazole 
Nelfinavir 
Quinidine 
Phenobarbital salt with Quinidine 
Ritonavir 
Tacrolimus 
Saquinavir 
Valspodar 
Verapamil 
Carbamazepine 
Phenobarbital 
Phenytoin 
St John's wort 
Rifampicin 
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This list is not meant to be considered all inclusive. See website for an available current list : 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.
htm.  
It is the investigator’s responsibility to assess for potential drug interactions with afatinib and any 
P-gp inhibitor/inducer not listed above. 
5.5.3 
Surgery while on trial treatment 
Based on the EGFR blocking mode of action, the risk that afatinib may interfere with skin wound 
healing process cannot be excluded. Therefore, interruption of afatinib should be considered 
before and after surgery to allow for adequate post-operative wound healing based on individual 
benefit/risk assessment. The maximum period of interruption for afatinib is 14 days. If 
interruption of greater than 14 days is required, treatment with afatinib should be discontinued. 
5.5.4 
Prohibited Treatments and/or Procedures 
5.5.4.1 
Local and/or systemic anticancer therapy 
No additional local and/or systemic anticancer therapy will be permitted while patients are 
receiving trial therapy with the only exception of palliative radiotherapy (see section 5.5.3.3). 
5.5.4.2 
Bone-modifying agents 
Bone-modifying agents (i.e. bisphosphonates, denosumab) may be continued for patients who are 
already receiving them at the time of randomization.  However, the need to commence bone-
modifying agents after randomization will be considered indicative of disease progression unless 
disease progression can be completely ruled out and bone-modifying agents treatment initiation is 
expressly agreed by the investigator in consultation with Medical Monitor/TRIO Medical Lead/Trial 
Chair.  
Medical Monitor/TRIO Medical Lead/Trial Chair should be contacted by the site prior to initiating 
bone-modifying agents in this case. 
5.5.4.3 
Palliative radiotherapy 
Palliative radiotherapy is permitted for the treatment of painful bony lesions providing the lesions 
were known to be present at the time of randomization and the investigator clearly indicates that 
the need for palliative radiotherapy is not indicative of disease progression. In view of the current 
lack of data about the interaction of afatinib with radiotherapy, afatinib treatment should be 
interrupted during palliative radiotherapy, stopping 1 day before and resuming treatment 1 week 
after. In case of afatinib discontinuation for more than 14 days then trial treatment should be 
discontinued. 
 
 
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6. SCHEDULE OF VISITS AND PROCEDURES 
6.1 
Patient Inclusion  
6.1.1 
Informed Consent 
Prior to the screening evaluation, the patient or legally acceptable representative was informed of 
the nature of the trial treatments and was given pertinent information as to the intended 
purpose, possible benefits, and possible adverse experiences. The procedures and possible 
hazards to which the patient would be exposed were explained. A legally acceptable 
representative is an individual or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the trial. 
An approved patient informed consent form (PICF) was then read and signed by the patient, and, 
when required, a witness, and the investigator or a person designated by the investigator, as per 
local regulations. The patient was provided with a copy of the signed PICF.  
Further to this protocol amendment, the patient or legally acceptable representative will receive 
an approved addendum to the patient informed consent form that should be read and signed. 
Indeed, this PICF addendum will inform the patient or legally acceptable representative that all 
patients will be discontinued from the trial by 30 November 2018 at the latest.. The patient will be 
provided with a copy of the signed PICF addendum. 
The patient can withdraw from the trial at anytime without prejudicing future medical treatment. 
In any case, the withdrawal should be documented on the initial informed consent form, and must 
be dated and signed by patient and by the investigator.  
If a potential patient or legally acceptable representative is illiterate or visually impaired, the 
investigator must provide an impartial witness to read the PICF to the patient and must allow for 
questions. Thereafter, both the patient or legally acceptable representative and the witness must 
sign the PICF to attest that informed consent was freely given and understood. The PICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to their data, 
which will be processed according to the confidentiality regulations. In case important new 
information becomes available that may be relevant to the patient’s consent and willingness to 
continue participation in the trial, the PICF will be revised and submitted to IRB/IEC for 
approval/favorable opinion. The new information will be discussed with the patient and if she 
agrees to continue participation in the trial, the revised PICF will be signed and dated and the 
patient will receive a copy.  
This trial has an optional component described in the PICF, with a consent section dedicated to 
this optional trial. If a patient opted not to participate in the optional portion, this in no way 
affects the patient’s ability to participate in the main research trial. 
6.1.2 
Registration/ Randomization 
The treatment assigned was based on a dynamic minimization procedure using metastatic 
involvement (bone only YES or NO) and prior exposure to aromatase inhibitor (prior hormonal 
therapy YES or NO) as factors in the minimization algorithm. The ratio used was 1:1 and the 
randomization technique was using a stochastic treatment allocation algorithm based on the 
variance method. 
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The following steps for registering and randomizing a patient were chronologically performed: 
The patient had to provide written informed consent prior to performing any trial specific 
procedure not considered standard practice by the institution. 
The site registered the patient in the IWRS system (Date of ICF signed and patient year of birth 
needed). The system uniquely attributed a registration number to each patient in the trial. Each 
center was uniquely identified by a number assigned by TRIO to the investigative site. The site 
received a registration confirmation, containing patient registration number as well as 
HER2/Hormonal receptors screening form specific for the patient. 
The site prepared a tumor sample fixated in formalin and embedded in paraffin (or 15 to 20 
unstained slides) and shipped this sample along with the duly completed HER2/Hormonal 
receptors screening form to Dr Press’ Central laboratory (see contact details on Information 
Resources page - Central laboratory’s address and contact details are pre-printed on the form). 
The tumor material can be returned to the site after testing upon site’s request.  
Dr Press’ laboratory entered in the IWRS system the HER2/Hormonal receptors results in a timely 
manner after receipt of the tumor material (usual turn-around-time was within 5 working days 
after receipt of the tumor material). 
If (HER2-positive and/or H score not [1-159]) => The patient were moved to the Screen failure 
category. 
If (HER2-negative and H-score [1-159]) => Screening of the patient continued at the site.  
Upon completion of screening procedures and entry of screening data in TRIO eDC system, the 
investigator or his/her delegate checked if the patient met all eligibility criteria:  
Patients who did not meet the eligibility criteria were moved to a screen failure category in the 
IWRS.  
Patients who met all eligibility criteria were randomized in the IWRS using the following 
stratification factors:  
Bone only disease : Yes versus No 
Prior neo/adjuvant hormonal therapy : Yes versus No 
Details regarding the Registration and Randomization processes were provided in the IWRS user 
manual and in the trial specific working instruction for Registration/Randomization. 
Patients randomized in the trial had to start trial treatment within 7 days of randomization. 
6.1.3 
Blinding/Unblinding 
The trial is open-label. There is no blinding of the treatment. 
6.2 
Trial Participation and Discontinuation 
Once trial treatment is discontinued (both letrozole and afatinib) regardless of the reason, 
patients will be discontinued from the trial and will be followed and treated as per local clinical 
practice. If the patient withdraws from trial participation (consent withdrawn from trial, lost to 
follow-up, investigator’s decision), no further trial procedures are performed, and no additional 
data will be collected. Medical care of the patient is not affected if the patient chooses to leave 
the trial at anytime. 
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Please refer to section 3-Trial Design (IN ADDITION) regarding the decision to discontinue the 
patients from the trial at the latest on 30 November 2018 and the conditions of this 
discontinuation. 
 
6.3 
Schedule of Procedures 
All screening and baseline evaluations had to be completed prior to initiating trial treatments. 
Adherence to the schedule of assessments is required and visits should be planned accordingly. In 
the event a visit is missed because of an unforeseeable event, then the missed visit should be 
scheduled for the next day. 
Prior to undergoing any trial specific procedures not considered standard practice by the 
institution, patients had to read and sign the consent form. All trial procedures are detailed in the 
Schedule of Activities table presented below. 
According to the information reported in section 3-Trial Design (IN ADDITION) regarding the 
decision to discontinue the patients from the trial at the latest on 30 November 2018, the 
information reported in this section is applicable until 30 November  2018. After that date, the 
patients will be followed by their physician as per standard of care and the assessments will be 
performed as per local practice. 
 
 
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Table 9 : Schedule of activities 
Protocol Activities 
Pre-
screening 
Screening1 
28 days prior 
randomization 
Treatment 
Period2 
End of 
treatment 3 
Signed ICF4 
X 
 
 
 
Local determination of ER/HER2  
X 
 
 
 
Tumor sample to central lab. 
X 
 
 
 
Medical, surgical, disease history  
 
X 
 
 
Signs and symptoms 
 
X 
 
 
SAFETY 
 
 
q4w 
 
Physical exam / Vital signs / PS 
 
X 
X 
X 
Review of adverse events 
 
X 
X 
X 
Hematology / Blood chemistry 
 
X5, 6 
X6 
X6 
LVEF 
 
X 
within 42 days 
X7 
q12w 
X 
TREATMENT 
 
 
q4w 
 
Letrozole / Afatinib : 
Dispensation / Accountability 
 
 
X 
 
EFFICACY 
 
 
q12w 
 
Disease assessment 
 
X 
X 
 
Survival / Anticancer therapy 
 
 
 
 
 
 
 
11 Pre-screening / Screening starts once the subject has signed the PICF. 
2 Visits are scheduled every 4 weeks +/- 3 days during treatment phase.  
3 End of Treatment visit must be scheduled as close as possible to 30 days post last intake of any study drug or 
on 30 November 2018 whichever occurs first. 
4 There is no window for obtaining the signed ICF. Study specific screening assessments not considered 
standard practice by the institution may start once the PICF has been obtained. 
5 At screening only, Creatinine clearance will be assessed to check eligibility if serum creatinine ≥ 1.5 x ULN. 
6 During treatment phase, blood tests must be obtained up to 5 days prior to the visit and will assess the 
following parameters :  
Hematology: Hemoglobin, Absolute Neutrophils Count (ANC), Platelets. 
Blood chemistry: AST, ALT, Alkaline Phosphatase, Total Bilirubin and Creatinine. 
7 LVEF will be assessed every 12 weeks during treatment phase and when clinically indicated. 
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6.3.1 
Safety assessments 
The following safety assessments were performed within 28 days of randomization of the patient 
and subsequently at each visit during treatment phase and at End of trial treatment visit. There 
was no need to repeat these safety assessments at Visit 1 since screening assessments were 
available, unless deemed clinically required by the investigator.  
Physical exam: included an examination of major body systems and weight. 
Vital signs: blood pressure. 
Performance status (PS) was assessed according to ECOG scale (APPENDIX 1). 
Blood tests: 
Hematology: Hemoglobin, Absolute Neutrophils Count (ANC) and Platelets. 
Blood chemistry: AST, ALT, Alkaline Phosphatase, Total Bilirubin and Creatinine and Creatinine 
clearance (at baseline only). 
During treatment phase, blood tests may be obtained up to 5 days prior to the visit. 
LVEF: will be obtained during screening and every 12 weeks during treatment phase, and as 
required when clinically indicated. LVEF will be performed by MUGA scan or echocardiogram, 
using the same method at each assessment. 
6.3.2 
Efficacy assessments 
6.3.2.1 
Schedule/details of tumor assessments 
Screening/Baseline:  
Baseline Disease assessment were performed during screening, within 28 days of randomization 
of the patient.  
Disease assessment at screening was used to determine the nature of lesions (measurable versus 
non-measurable). Lesions must be clearly identified and documented as Target or Non-Target 
lesions as per RECIST 1.1. 
Baseline assessment included at least: 
• 
Baseline bone scan  
• 
Other bone imaging had to be performed on bone lesions if the investigator intended to 
follow bone lesions with correlative imaging (e.g. CT with bone window, MRI or plain X-
rays).   
• 
CT or MRI scan of the chest, abdomen, and pelvis (CAP) 
• 
Clinical assessment of superficial lesions (including measurement with calliper) 
• 
Any additional imaging as deemed appropriate 
Subsequent Disease assessments: 
• 
Every 12 weeks (+/- 1 week) starting from date of randomization 
• 
Whenever disease progression is suspected,  
• 
To confirm a partial or complete response (at least 4 weeks after initial documentation of 
response). For patients with bone metastases identified at baseline bone scan is required 
at the time of confirmation of complete response.  
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Disease assessments will be performed until the end of treatment.  The schedule of assessments 
should be fixed according to the calendar, regardless of treatment interruptions. 
Disease assessments will comprise evaluation of all lesions identified at baseline, with the 
exception of bone lesions in some circumstances (see 6.3.2.2).  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up imaging.  
Unless clinically required, it is not mandated to repeat imaging of an area where no lesion was 
documented at baseline.  
Table 10 : Efficacy assessments 
Baseline 
Within 28 days of randomization 
Treatment phase  until the End of  Treatment 
Bone scan  
CT or MRI of chest, abdomen and pelvis (CAP) 
Clinical assessment of superficial lesions  
Any additional imaging as deemed appropriate 
 
Every 12 weeks +/- 1 week : repeat the CT/MRI 
and/or clinical assessment and/or any 
appropriate imaging used to document baseline 
lesions 
Confirmation of PR and CR: not less than 4 
weeks after first documentation of response.  
Bone scan/bone imaging  : 
• 
when progression is suspected in bone 
• 
Bone scan for confirmation of CR (if 
bone metastases were identified at 
baseline). 
 
6.3.2.2 
Special note for baseline determination of Bone lesions and follow-up assessments 
In presence of other measurable lesions, the bone lesions are not mandatory to follow. 
Nevertheless, if followed by imaging, the technique was selected by the site at baseline and will be 
repeated until documentation of disease progression.  
In absence of any other measurable lesions, the bone lesions will be followed every 12 weeks with 
the most appropriate imaging technique selected by the site at baseline (CT with bone window or 
MRI or plain X-ray or bone scan) and repeated until documentation of disease progression. 
Bone scan/bone imaging is required when progression is suspected in bone. 
Bone scan is required at the time of confirmation of CR (if bone metastases were identified at 
baseline). 
6.3.2.3 
Definitions of measurable/non measurable disease 
At baseline, tumor lesions/lymph nodes were categorized as measurable or non-measurable 
according to RECIST 1.1 as follows: 
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Measurable Tumor lesions:  Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
10mm by CT scan for CT scan slice thickness no greater than 5 mm, 
10mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable). 
Special considerations regarding lymph nodes: lymph nodes merit special mention since they are 
normal anatomical structures which may be visible by imaging even if not involved by tumor. 
Pathological nodes which are defined as measurable and may be identified as target lesions must 
meet the criterion of a short axis of ≥ 15mm by CT scan. Only the short axis of these nodes will 
contribute to the baseline sum. The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT scan this is almost always the axial 
plane; for MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as being 20mm x 
30mm has a short axis of 20mm and qualifies as a malignant, measurable node. In this example, 
20mm should be recorded as the node measurement. All other pathological nodes (those with 
short axis ≥ 10mm but <15 mm) should be considered non-target lesions. Nodes that have a short 
axis <10mm are considered non-pathological and should not be recorded or followed.  
Non-measurable Tumor lesions: include all other lesions as follows: 
Small lesions (longest diameter < 10mm or < twice the reconstruction interval) 
Pathological lymph nodes with short axis ≥ 10 but <15 mm 
Lesions considered truly non-measurable: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.  
Special considerations regarding lesion measurability: Bone lesions, cystic lesions, and lesions 
previously treated with local therapy: 
Bone lesions: 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance of 
bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• 
Blastic bone lesions are non-measurable. 
 
 
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Cystic lesions: 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
Tumor lesions situated in a previously irradiated area, or in an area patiented to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.  
6.3.2.4 
Baseline Documentation of Target and Non-target Lesions 
When more than one measurable lesion was present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
had to be identified as target lesions and are recorded and measured at baseline. 
Target lesions were selected on the basis of their size (lesions with the longest diameter), were 
representative of all involved organs, but in addition had to be those that lend themselves to 
reproducible repeated measurements. 
A sum of diameters (SoD) (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions is calculated and reported as the baseline sum of diameters. The baseline SoD is used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
All other lesions (or sites of disease) were identified as non-target lesions and were also recorded 
at baseline. Measurements are not required and these lesions should be followed as “present”, 
“absent”, or in rare cases “unequivocal progression”.  
In addition, it is possible to record multiple non-target lesions involving the same organ as a single 
item on the CRF (e.g. “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”). 
6.3.2.5 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations had to be performed as close as possible to the treatment start and never 
more than 4 weeks before randomization. 
Method of assessment: the same method of assessment and the same technique should be used 
to characterize each identified and reported lesion at baseline and during follow-up. Imaging 
based evaluation should always be done rather than clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions are only considered measurable when they are superficial and ≥ 
10mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
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imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the trial. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. For this trial 
Chest CT is the required method of assessment of lung lesions. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. Measurability threshold of lesions on CT scan is based on the 
assumption that CT slice thickness is 5mm or less. When CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans).  
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the trial, confirmation by CT or 
MRI is advised. 
If there is concern about radiation exposure at CT, MRI may be used instead of CT. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised.  
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. 
6.3.2.6 
Response criteria 
In case target lesions are present at baseline, at each assessment the SoD is defined as the sum of 
diameters of target lesions including short axis of lymph nodes selected as target lesions, and is 
used to assess the response. 
Evaluation of target lesions: 
• 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
• 
Partial Response (PR): At least a 30% decrease in the SoD of target lesions, taking as 
reference the baseline SoD. 
• 
Progressive Disease (PD): At least a 20% increase in the SoD of target lesions, taking as 
reference the smallest SoD on trial (this includes the baseline SoD if that is the smallest on 
trial). In addition to the relative increase of 20%, the SoD must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is 
also considered progression). 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest SoD while on trial. 
Note: Target lesions that become “too small to measure” (TSM) while on trial, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2mm). However, sometimes lesions or lymph 
nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
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“too small to measure”. When this occurs it is important that a value be recorded on the case 
report form. If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0mm. If the lesion is believed to be present and is faintly 
seen but too small to measure, a default value of 5mm should be assigned. 
Evaluation of non-target lesions: 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
• 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must 
be non-pathological in size (<10mm short axis). 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s). 
• 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. The 
appearance of one or more new lesions is also considered progression. 
Overall response at each time point: 
Table 11 below provides a summary of evaluation of the overall response at each time point for 
patients with target +/- non-target lesions. Table 12 provides a summary of the evaluation of the 
overall response at each time point for patients with non-target lesions only. 
Table 11 : Evaluation of the overall response (OR) in patients with target +/- non-target lesions 
Target lesion 
Non-target lesion 
New lesion 
Overall response 
CR 
CR 
No 
CR 
CR 
Non CR / Non PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non PD or not all evaluated 
No 
PR 
SD 
Non PD or not all evaluated 
No 
SD 
Not all evaluated 
Non PD 
No 
NE (Not Evaluable) 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Table 12 : Evaluation of the overall response (OR) in patients with non-target lesions only 
Non-target lesion 
New lesion 
Overall response 
CR 
No 
CR 
Non CR / Non PD 
No 
Non CR / Non PD 
Not evaluated 
No 
NE 
Unequivocal PD* 
Yes or No 
PD 
Any 
Yes 
PD 
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*Note: The concept of progression of non-target disease requires additional explanation as 
follows: when the patient also has both measurable and non measurable disease, to achieve 
“unequivocal progression” on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to quality 
for unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
7. SAFETY MONITORING 
7.1 
Definitions 
7.1.1 
Period of Observation 
At each visit and any contact during the trial, the investigator or designee will inquire about the 
occurrence of adverse events and will document them in the patient file. 
The investigator or designee will report the adverse events in the CRF and to TRIO Safety 
department when required as per the table below  
Table 13 : Reporting of AEs/SAEs 
Trial period 
Adverse events 
Serious Adverse Events 
From ICF to first dose 
No 
Related to trial participation 
Trial treatment period* 
All (regardless of relationship) 
All (regardless of relationship) 
*All adverse events (serious or non-serious) must be followed up to 30 days after the last intake of 
trial medication (see Section 5.4 ), or 30 November 2018 whichever occurs first. 
 
7.1.2 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence, including an exacerbation 
of a pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical 
product. The event does not necessarily have to have a causal relationship with this treatment. 
Worsening of pre-existing conditions: 
A pre-existing condition present at baseline, which remains unchanged during the trial, does not 
need to be recorded as adverse event. 
Any worsening of any pre-existing baseline condition should be reported as an adverse event in 
the CRF. Examples of worsening of a preexisting condition that should be recorded as an AE are 
given below: 
Worsening of condition meets the criteria for an SAE 
Action is taken with the investigational drug (e.g. dose is reduced or treatment is discontinued) 
Treatment is required (concomitant medication is added or changed) 
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The investigator believes a patient has shown a clear deterioration from baseline symptoms 
Expected fluctuations or expected deterioration of the breast cancer (symptoms of disease 
progression) should not be recorded as an AE. 
Changes in vital signs, ECG, physical examination, and laboratory test results. 
Changes in vital signs, ECG, physical examination and laboratory test results will be recorded as an 
AE in the CRF if they are judged clinically relevant by the investigator. 
7.1.3 
Protocol-specified significant event to be reported in an expedited manner  
In addition to the cases defined above as SAE, the investigator must report the following events to 
the sponsor in an expedited manner, with the same timelines as SAEs: 
Hepatic injury defined by the following alterations of liver parameters (measured in the same 
blood draw sample):  
for patients with normal AST / ALT and bilirubin at baseline: an elevation of AST and/or ALT above 
>3 fold ULN combined with an elevation of bilirubin above >2 fold ULN measured in the same 
blood draw sample. 
for patients with abnormal AST / ALT and bilirubin at baseline : an elevation of AST and/or ALT >5 
fold ULN combined with an elevation of bilirubin >2 fold ULN measured in the same blood draw 
sample. 
Protocol-specified significant events are to be reported in an expedited manner to the sponsor 
similar to Serious Adverse Events, even if they do not meet any of the seriousness criteria. 
Patients showing these lab abnormalities need to be followed up appropriately. 
7.1.4 
Serious Adverse Event 
7.1.4.1 
General definition 
A serious adverse event (SAE) is defined as any AE which: 
• 
results in death 
• 
is immediately life-threatening 
• 
results in persistent or significant disability / incapacity 
• 
requires or prolongs patient hospitalization 
• 
is a congenital anomaly / birth defect 
• 
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. 
7.1.4.2 
Disease-related events 
An event which is part of the natural course of the disease under trial (i.e. disease progression) 
does not need to be reported as an SAE. Progression of the patient's breast cancer will be 
recorded in the appropriate pages of the CRF. Death due to progressive disease is to be recorded 
on Death Report Form of the CRF and not as an SAE.   
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However, if the progression of the underlying disease is greater than that which would normally 
be expected for the patient, or if the Investigator considers that there was a causal relationship 
between treatment with investigational product or protocol design/procedures and the disease 
progression, then this must be reported as an SAE.   
Any new primary cancer must be reported as an SAE. 
7.1.4.3 
Planned or administrative hospitalization 
Patients may be hospitalized for administrative or social reasons during the trial (e.g. days on 
which infusion takes place, long distance from home to site…). These and other hospitalizations 
planned at the beginning of or before the trial do not need to be reported as an SAE in case they 
have been reported at screening visit in the source data and have been performed as planned. 
7.1.4.4 
Unexpected Adverse Event 
Afatinib Investigator’s Brochure provides an overview of the adverse events reported across 
Afatinib clinical trial in monotherapy and in combination.   
Any serious adverse event assessed as related to Afatinib but not reported in the listed adverse 
events’ section of the Afatinib IB will be documented as a suspected unexpected serious adverse 
reaction (SUSAR) and will be carried out in accordance with applicable local regulations. 
7.2 
Performing Adverse Event Assessment 
7.2.1 
Collection of Adverse Event Information 
The following information will be collected on the CRF: 
Description of event, start date, worst grade experienced (severity), seriousness, stop date, action 
taken on trial treatments and relationship to trial treatments. 
Intensity of adverse event: 
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 in the CRF. 
7.2.2 
Assessment of Causality 
The investigator will determine the relationship of the investigational drug to all AEs as defined in 
Boehringer Ingelheim’s (BI’s) Investigator Brochure for the Product.  
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history. Assessment 
of causal relationship must be recorded for each adverse event.  
Relationship to trial drugs will be reported as either “Yes” or “No”. 
Yes: There is a reasonable causal relationship between the investigational product 
 administered and the AE.  
No: There is no reasonable causal relationship between the investigational product 
 administered and the AE. 
 
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7.3 
Reporting of Serious Adverse Events 
7.3.1 
Reporting of SAEs from the sites to TRIO 
SAEs, pregnancies, and Protocol-specified significant events will be reported promptly to TRIO 
Safety Department as described in Table 14 once the investigator determines that the event 
meets the protocol definition for that event. 
TRIO Safety Department: safety@trioncology.org 
Fax number: North America : + 1 780-702-2273 / Rest of the World: +33. 1.58.10.09.05 
Table 14: Reporting of SAEs 
 
Initial Reports 
Follow-up Information  
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
SAE form 
24 hours 
Updated SAE form 
Protocol-specified 
significant event 
24 hours 
SAE form 
24 hours 
Updated SAE form 
Pregnancy 
24 hours 
Pregnancy Form 
24 hours 
Updated Pregnancy Form 
7.3.2 
SAE information provided by TRIO to BI  
TRIO will report to BI all SAEs (and protocol-specified significant events independently from their 
seriousness) by fax or other secure method. All SAE reports will be forwarded to BI with the 
following timelines: 
• 
within five (5) calendar days upon receipt of initial and follow-up SAEs containing at least 
one (1) fatal or immediately life-threatening event, 
• 
within ten (10) calendar days upon receipt of any other initial and follow-up SAEs. 
The SAE reports will include a summary of the case, including relevant information provided by 
the investigator to TRIO and, in particular, the following information: the expectedness of the 
reported events based on BI Investigator’s Brochure for the Trial Drug, the investigator’s/TRIO’s 
causal assessment as to whether the event(s) is/are related to the use of the Trial Drug, and the 
seriousness of each AE. 
7.4 
Management of specific cases 
7.4.1 
Drug misuse 
Cases of drug abuse or dependency (per investigator’s assessment) should be reported as SAEs. 
Drug misuse and overdose of trial product(s) should be submitted as Serious Adverse Events if the 
misuse/overdose resulted in an event which the Investigator considers fulfills one or more of the 
criteria for SAE reporting. 
7.4.2 
Pregnancy 
Women of childbearing potential are not eligible for this trial. 
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Nevertheless, should a pregnancy occur, the investigator must discontinue treatment 
immediately, capture any drug exposure during pregnancy, report the pregnancy through 
Pregnancy form (see Table 13) and follow the pregnancy until outcome is known.   
A SAE report must be forwarded to the sponsor if the outcome of the pregnancy results in an 
abortion/miscarriage or the occurrence of any other SAE(s). 
TRIO will be responsible to follow-up on all information regarding a reported Drug Exposure 
during Pregnancy. TRIO will ensure that any SAEs during and after pregnancy will be reported to BI 
in accordance with the following timelines: 
• 
within five (5) calendar days upon receipt of initial and follow-up SAEs containing at least 
one (1) fatal or immediately life-threatening event, 
• 
within ten (10) calendar days upon receipt of any other initial and follow-up SAEs. 
7.5 
Reporting to Ethics Committees, Regulatory Authorities and other Investigators 
Prompt notification of SAEs by the investigator to the sponsor (TRIO) is essential so that legal 
obligations and ethical responsibilities towards the safety of patients are met. 
TRIO will comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and 
investigators. 
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and are forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE(s) or other specific 
safety information (e.g., summary or listing of SAEs) from TRIO will file it with the IB and will notify 
the IRB/IEC, if appropriate according to local requirements. 
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8. STATISTICAL CONSIDERATIONS 
Descriptive analyses will be conducted according to the Statistical Analysis Plan. 
8.1 
Populations for analyses 
The Intent-to-treat (ITT) population will consist of all patients who were randomized/registered 
to trial treatment, regardless of whether they actually received trial medication.. 
The Safety population will be used to present data relevant to clinical safety and tolerability. It 
consists of all patients who were randomized and received at least one dose of trial medication. 
This population will be based on the actual treatment received, if this differs from that to which 
the patient was randomized and will be used for the analysis of safety data. 
8.2 
Demographics and baseline characteristics 
Demographics and baseline characteristics data will be listed and summarized by treatment group 
using the ITT population. 
8.3 
Protocol Treatment 
Duration of treatment exposure, cumulative dose and dose intensity will be summarized by 
treatment group using the Safety population. The patients with dose modifications will be 
presented by treatment group, along with reasons for the dose change. 
8.4 
Safety Endpoints 
Adverse Events - The latest version of the Medical Dictionary for Regulatory Activities (MedDRA) 
will be used to code all adverse events to a preferred term and system organ class. Adverse events 
will be graded using the Common Terminology Criteria for Adverse Events (NCI CTCAE v4.0). 
Patient’s incidence of adverse events will be tabulated by system organ class, preferred term and 
toxicity grade by treatment arm. Adverse events leading to death or drug discontinuation, drug 
related and serious adverse events will also be summarized by treatment arm. 
Detailed listings for all adverse events will also be provided. 
Laboratory parameters - Laboratory parameters, graded according to the NCI CTCAE v4.0, will be 
summarized at baseline, along visits and at the end of trial treatment by treatment arm. Tables of 
shifts in toxicity will also be provided. 
Other Safety Data – Vital signs (weight and blood pressure), ECOG and LVEF will be summarized at 
baseline, along visits and at the end of trial treatment by treatment arm. Tables of shifts in toxicity 
will also be provided when applicable. 
8.5 
Interim and Final Analyses 
The following analyses are planned: 
A first analysis of safety was performed on the first 20 patients who complete 28 days of 
treatment. The steering committee reviewed this formal analysis. 
The final analysis will be performed when all patients discontinue the trial. 
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8.6 
Criteria for trial termination 
The trial will stop once the last patient reaches end of trial treatment visit (30 days post last drug 
intake or 30 November 2018 whichever occurs first). 
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9. ADMINISTRATIVE, ETHICAL AND REGULATORY STANDARDS 
9.1 
Steering Committee 
The Study Steering Committee (SSC) of the trial was set-up and operated as per TRIO SOPs. The 
SSC had the sole responsibility for the scientific conduct and integrity of the trial. Responsibilities 
included development and approval of the protocol document, monitoring of accrual, compliance 
and safety during the conduct of the trial. The SSC will be solely responsible for the analysis, 
interpretation and public disclosure of the results of the trial in accordance with the statistical 
plan. 
Note: No additional SSC has taken place since the release of the previous amendment (09 May 
2016) and no further SSC will take place after the release of this amendment. 
9.2 
Ethical Conduct of the Trial 
This clinical trial was designed and shall be implemented and reported in accordance with the 
protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directives 2001/20/EC and 2005/28/EC and the US Code of 
Federal Regulations Title 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
9.3 
Institutional Review Board/Independent Ethics Committee (IRB/IEC)  
The final approved protocol and its amendment and the informed consent statement /addendum 
will be reviewed by a properly constituted Ethics Committee/IRB. The Ethics Committee's/Board's 
decision concerning the conduct of the trial will be made in writing to the investigator and a copy 
of this decision will be provided to TRIO. 
Particular attention is drawn to the FDA's regulation regarding the IRBs. By signing the "Statement 
of Investigator" form (Form 1572), the investigator provides TRIO with the necessary assurance 
that an IRB is responsible for the initial and continuing review and approval of the proposed 
clinical trial in accordance with these regulations when applicable. 
The investigator will agree to make required progress reports to the Ethics committee/IRB, as well 
as report any serious adverse events, life-threatening problems or deaths. The Ethics 
Committee/IRB will be informed of serious adverse events in other clinical studies conducted with 
the trial drug by the investigator or the Sponsor according to the local regulations. The Ethics 
Committee/IRB must be informed by the investigator of the termination of the trial.  
9.4 
Compliance with the protocol and protocol amendments 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact TRIO or its agents, if any, monitoring the trial to 
request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the trial this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by TRIO and 
approved by the IRB/IEC it cannot be implemented. All significant protocol deviations will be 
recorded and reported in the Clinical Study Report (CSR). 
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Any modifications to the protocol which may impact on the conduct of the trial, potential benefit 
of the patient or may affect patient safety, including changes of trial objectives, trial design, 
patient population, sample sizes, trial procedures, or significant administrative aspects will require 
a formal amendment to the protocol. Such amendment will be agreed upon by TRIO, and 
approved by the Ethics Committee/IRB and Health Authorities where required, prior to 
implementation. Only amendments that are required to eliminate an immediate hazard to 
patients for patient safety can be implemented prior to IRB/IEC approval. Notwithstanding the 
need for approval of formal protocol amendments, the investigator is expected to take any 
immediate action required for the safety of any patient included in this trial, even if this action 
represents a deviation from the protocol. In such cases, TRIO should be notified of this action and 
the IRB/IEC at the trial site should be informed. 
9.5 
Monitoring, auditing and inspecting 
TRIO or its representatives must be allowed to visit all trial site locations periodically to assess the 
data, quality, and trial integrity. On site, they will notably review trial records and directly 
compare them with source documents, review regulatory documents, discuss the conduct of the 
trial with the investigator, verify trial drug accountability, and verify that the facilities remain 
acceptable. 
9.6 
Recording, processing and retention of data 
An investigator will be required to prepare and maintain adequate case histories designed to 
record all observations and other data pertinent to the trial patients. All data reported on the CRF 
must be derived from source documents and as such be consistent with the source documents, or 
the discrepancies must be explained. 
Data is entered and collected via an Electronic Data Capture System (EDC) using eCRFs (electronic 
Case Report Form). EDC is a validated system, designed for entry of data in a way that is 
attributable, secure, accurate, and in compliance with U.S. Food and Drug Administration (FDA) 
regulations for electronic records (21 CFR Part 11). Sites received training and got access to a 
manual for appropriate eCRF completion. All eCRFs should be completed by designated, trained 
site staff. The eCRFs should be reviewed and electronically signed and dated by the investigator or 
a designee. Only an identified and trained user may view the data, and their actions become part 
of the audit trial. 
Sites are responsible for data entry into the EDC system. TRIO is responsible for data management 
of this trial, including quality checks of the data.  
The eCRF must be completed shortly after the patient’s visit. All requested information must be 
entered on the eCRF. If an item is not available or is not applicable, it must be documented as 
such. The completed eCRF must be promptly reviewed, signed, and dated by the investigator or 
authorized designee. In the event of discrepant data, TRIO will request data clarification from the 
sites. The sites will resolve the discrepancy electronically in the EDC system. eCRFs and correction 
documentation will be maintained in the EDC system’s audit trail.  
At the end of the trial, the investigator will receive patient data for his or her site in a readable 
format on a compact disc that must be kept with the trial records. Acknowledgement of receipt of 
the compact disc is required. 
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The investigator will retain copies of trial documentation for a period of at least 15 years from trial 
completion. Additional considerations must be made about complying with applicable local laws, 
guidelines, etc. 
9.7 
Data Protection 
The patient’s personal data and Investigator’s personal data which may be included in the sponsor 
database shall be treated in compliance with all applicable laws and regulations. When archiving 
or processing personal data pertaining to the Investigator and/or to the patients, the sponsor shall 
take all appropriate measures to safeguard and prevent access to this data by any unauthorized 
third party. The anonymity of participating patients will be respected with strict adherence to 
professional standards of confidentiality and applicable privacy rules. 
9.8 
Confidentiality and Data Protection 
All information concerning the trial supplied by TRIO in connection with this trial and/or by any 
other party collaborating with TRIO, and not previously published, is considered confidential and 
proprietary information. This information includes the Investigator's Brochure, clinical protocol, 
workbooks (if applicable), case report forms, assay methods, TRIO technical methodology, and 
technical and scientific data. This confidential information shall remain the sole property of TRIO 
and, shall not be disclosed to others without prior written consent from TRIO and shall not be 
used except in the performance of this trial. 
9.9 
Insurance of liabilities 
If required, the investigator may forward to the Ethics Committee/IRB a copy of the insurance 
document required by TRIO, in order to cover his/her liabilities, and those of any other 
participating parties. 
9.10 Use of information and publication 
All information concerning the trial drug or in connection with this trial, supplied by TRIO and/or 
by any other party collaborating with TRIO within this trial and not previously published, is 
considered confidential and proprietary information. This information includes the Investigator's 
Brochure, clinical protocol, workbooks (if applicable), case report forms, assay methods, TRIO 
technical methodology, and basic scientific data. This confidential information shall remain the 
sole property of TRIO the respective collaborating party and, shall not be disclosed to others 
without prior written consent from TRIO and shall not be used except in the performance of this 
trial. 
To allow for the use of the information derived from this clinical trial and to insure compliance to 
current regulations, the investigator is obliged to provide TRIO with complete test results and all 
data developed in this trial. No publication, abstract or presentation of the trial will be made 
without the approval of the Steering Committee. The Steering Committee will review the 
manuscript to prevent forfeiture of patent rights to data not in the public domain. Prior to 
publication, the authorship list will be agreed upon by the Steering Committee. For the purpose of 
the efficacy and safety analyses, the names on the author list will be given according to the 
participation in the concept of the trial design as well as accrual input (number of eligible patients 
accrued) by the investigators at each center. The maximum number of authors will be determined 
by the publication policy established by the targeted journal. Abstracts and publications will be 
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submitted to the authors and to the Study Steering Committee at least 30 days prior to the 
expected date of submission to the intended publisher. 
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10. BIBLIOGRAPHY 
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Arpino G, Wiechmann L, Osborne CK, et al. «Crosstalk between the estrogen receptor and the HER 
tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine 
therapy resistance.» Endocr Rev, 2008: 29:217-33. 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H Schwartz, D. Sargent, R.Ford, J. Dancey, S. Arbuck, S. 
Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. «New 
response evaluation criteria in solid tumours : Revised RECIST guideline (version 1.1).» EJC, 2009: 
228-247. 
Ferlay J, Shin HR, Bray F, et al. «Estimates of worldwide burden of cancer in 2008.» GLOBOCAN 
2008, 2010: 127:2893-917. 
Finn RS, Dering J, et al. «Progression-free survival of patients with HER2 negative, estrogen-
receptor (ER)-low metastatic breast cancer (MBC) with the addition of lapatinib to letrozole: 
Biomarker results of EGF 30008.» J Clin Oncol, 2009: 27:Abstr 1018. 
Finn RS, Dering J, Ginther C, et al. «ER+ PR– breast cancer defines a unique subtype of breast 
cancer that is driven by growth factor signaling and may be more likely to respond to EGFR 
targeted therapies.» J Clin Oncol, 2006: 24:6s (suppl; abstr 514). 
Finn RS, Press MF, Dering J, et al. «Estrogen receptor, progesterone receptor, human epidermal 
growth factor receptor 2 (HER2), and epidermal growth factor receptor expression and benefit 
from lapatinib in a randomized trial.» J Clin Oncol, 2009: 27:3908-15. 
Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, 
Moulder S, Gauthier E, Lu DR, Randolph S, Diéras V, Slamon DJ. Palbociclib and Letrozole in 
Advanced Breast Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. 
Geyer CE, Forster J, Lindquist D, et al. «Lapatinib plus capecitabine for HER2-positive advanced 
breast cancer.» N Engl J Med, 2006: 355:2733-43. 
Harvey JM, Clark GM, Osborne CK, et al. «Estrogen receptor status by immunohistochemistry is 
superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in 
breast cancer.» J Clin Oncol, 1999: 17:1474-81. 
Hicklish T WD, Lin N, et al. «Use of BIBW 2992, a Novel Irreversible EGFR/ HER1 and HER2 Tyrosine 
Kinase Inhibitor to Treat Patients with HER2-positive Metastatic Breast Cancer after Failure of 
Treatment with Trastuzumab.» Cancer Res, 2009: 69 (abstract 5060). 
Hurvitz SA, Pietras RJ. «Rational management of endocrine resistance in breast cancer: a 
comprehensive review of estrogen receptor biology, treatment options, and future directions.» 
Cancer, 2008: 113:2385-97. 
Jemal A, Siegel R, Xu J, et al. «Cancer statistics.» CA Cancer J Clin, 2010: 60: 277-300. 
CONFIDENTIAL 
 
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TRIO-020 Protocol - version 5.0- 31 July 2018 
 
Johnston S, Pippen J, Jr., Pivot X, et al. «Lapatinib combined with letrozole versus letrozole and 
placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast 
cancer.» J Clin Oncol, 2009: 27:5538-46. 
Kaufman B, Mackey JR, Clemens MR, et al. «Trastuzumab plus anastrozole versus anastrozole 
alone for the treatment of postmenopausal women with human epidermal growth factor receptor 
2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized 
phase III TAnDEM STUDY.» J Clin Oncol, 2009: 27:5529-37. 
Li D, Ambrogio L, Shimamura T, et al. «BIBW2992, an irreversible EGFR/HER2 inhibitor highly 
effective in preclinical lung cancer models.» Oncogene, 2008: 27:4702-4711. 
Massarweh S, Osborne CK, Creighton CJ, et al. «Tamoxifen resistance in breast tumors is driven by 
growth factor receptor signaling with repression of classic estrogen receptor genomic function.» 
Cancer Res, 2008: 68:826-33. 
McClelland RA, Finlay P, Walker KJ, Nicholson D, Robertson JFR, Blamey RW, et al. «Automated 
quantitation of immunocytochemically localised oestrogen receptors.» Cancer Res, 1990: 50, 
3545-3550. 
Mouridsen H, Gershanovich M, Sun Y, et al. «Phase III study of letrozole versus tamoxifen as first-
line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update 
of efficacy from the International Letrozole Breast Cancer Group.» J Clin Oncol, 2003: 21:2101-9. 
Osborne CK, Shou J, Massarweh S, et al. «Crosstalk between estrogen receptor and growth factor 
receptor pathways as a cause for endocrine therapy resistance in breast cancer.» Clin Cancer Res, 
2005: 11:865s-70s. 
Rimawi MF, Shetty PB, Weiss HL, et al. «Epidermal growth factor receptor expression in breast 
cancer association with biologic phenotype and clinical outcomes.» Cancer, 2010: 116:1234-42. 
Slamon DJ, Leyland-Jones B, Shak S, et al. «Use of chemotherapy plus a monoclonal antibody 
against HER2 for metastatic breast cancer that overexpresses HER2.» N Engl J Med, 2011: 
344:783-92. 
Sorlie T, Perou CM, Tibshirani R, et al. «Gene expression patterns of breast carcinomas distinguish 
tumor subclasses with clinical implications.» Proc Natl Acad Sci USA, 2001: 98:10869-74. 
Yap TA, Vidal L, Adam J, et al. «Phase I trial of the irreversible EGFR and HER2 kinase inhibitor 
BIBW 2992 in patients with advanced solid tumors.» Journal of Clinical Oncology. Official Journal 
of the American Society of Clinical Oncology, 2010: 28:3965-3972. 
 
 
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TRIO-020 Protocol - version 5.0- 31 July 2018 
 
 
APPENDIX 1 : EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS SCALE 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
and sedentary nature, e.g., light housework, office work. 
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. 
3 
Capable of limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead 
 
 
 
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APPENDIX 2 : NYHA CLASSIFICATION 
 
Clinical Evaluation of Functional Capacity of Patients with Heart Disease in Relation to Ordinary Physical 
Activity 
 
NYHA 
Functional 
Class 
Description 
Objective Assessment 
I 
Mild 
No limitation of physical activity.  Ordinary 
physical activity does not cause undue 
fatigue, palpitation or dyspnoea. 
No objective evidence of 
cardiovascular disease. 
II 
Mild 
Slight 
limitation 
of 
physical 
activity.  
Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation or 
dyspnoea 
Objective 
evidence 
of 
minimal 
cardiovascular 
disease 
III 
Moderate 
Marked limitation of physical activity.  
Comfortable at rest, but less than ordinary 
activity 
causes 
fatigue, 
palpitation 
or 
dyspnoea. 
Objective 
evidence 
of 
moderately 
severe 
cardiovascular disease. 
IV 
Severe 
Unable to carry out any physical activity 
without discomfort.  Symptoms of cardiac 
insufficiency at rest.  If any physical activity 
is undertaken, discomfort is increased. 
Objective 
evidence 
of 
severe 
cardiovascular 
disease. 
The Criteria Committee of the New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256 
 
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Figure 1 : Trial Scheme - Patient Selection and Treatment 
 
 
 
 
 
 
 
 
* As described in section 3-Trial Design (IN ADDITION) 
Central laboratory assessment of ER, PR, HER2 status 
ER+, HER2- advanced breast cancer subject 
Sign consent 
If HER2- and H-score [1-159] 
Perform Screening assessments 
Screen failure 
(HER2-) and/or (ER+ low expression) not confirmed
Subjects not eligible will be screen-failed 
Eligible subjects will be randomized using stratification factors 
Treat until disease progression or discontinuation criteria* 
CONFIDENTIAL 
Page 29 
 

SAP_001.pdf: 
 
BIOSTATISTICS 
Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
 
Statistical Analysis Plan for TRIO-020 
 
 
Title 
A randomized open-label Phase II Study of Letrozole plus Afatinib 
(BIBW2992) versus Letrozole alone in first-line Treatment of 
Advanced ER+, HER2- Postmenopausal Breast Cancer with low ER 
Expression 
Study Number 
TRIO-020 
Document Number 
STAT-020-SAP 
Version Number 
2.0  
Product Name 
Afatinib (BIBW2992) 
Indication 
Advanced ER+, HER2- Postmenopausal Breast Cancer with low ER 
Expression 
Study Phase 
II 
Sponsor 
Translational Research in Oncology (TRIO) 
Suite 1100, 9925-109th Street 
Edmonton, Alberta, Canada 
Version Date 
04-Dec-2014  
 
 
Confidentiality Statement 
The information contained herein is confidential and proprietary and may not be disclosed, 
reproduced, or circulated without the prior written consent of TRIO. 
 
 
 
Document owner(s): Vincent Houé 
 
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BIOSTATISTICS 
Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
STATISTICAL ANALYSIS PLAN APPROVAL SHEET 
Protocol Number: 
TRIO-020 
Product:  
Afatinib (BIBW2992) 
Protocol Title: 
“A randomized open-label Phase II Study of Letrozole plus Afatinib (BIBW2992) versus 
Letrozole alone in first-line Treatment of Advanced ER+, HER2- Postmenopausal Breast 
Cancer with low ER Expression.” 
 
Author: 
Vincent Houé 
Version Number: 
2.0  
Version Date: 
04-Dec-2014 
The undersigned have reviewed this plan and find it to be consistent with the requirements of the 
protocol as it applies to their respective areas. 
 
Date 
Signature 
Vincent Houé 
Senior Manager of Biostatistics, TRIO 
 
 
Hélène Mansouri 
Global Project Coordinator, TRIO 
 
 
Karen Afenjar 
Global Project Coordinator, TRIO 
 
 
Richard Finn 
Steering Committee Chair 
 
 
 
 
 
 
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BIOSTATISTICS 
Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
SAP Changes From Version 1.0 to Version 2.0 
The objective of SAP version 2.0 is to update the SAP version 1.0 to match the updated 
CRF version 2.2 (dated 29-Jan-2014).  Some redefinitions were also applied..  
Other noteworthy revisions are described below: 
Section # 
Changes 
10.2 
Prior Surgery for Breast cancer and Prior Anti-Tumor Therapy are 
considered as part of Disease Characteristics rather than Medical History. 
10.3 
This section is considered as Not Applicable as data dealing with Medical 
History are not collected anymore in CRF version 2.2. 
11.1 
Baseline Demographics and Disease Characteristics will be summarized on 
ITT population only. 
Only the treatment emergent adverse events will be considered in the 
outputs. Therefore, the treatment emergent flag is removed.  
 
 
 
 
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BIOSTATISTICS 
Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
TABLE OF CONTENTS 
1. 
Introduction ..................................................................................................................................7 
2. 
Study Objectives ..........................................................................................................................7 
2.1 
Primary Objective ............................................................................................................... 7 
2.2 
Secondary Objectives ......................................................................................................... 7 
2.3 
Exploratory Objectives ....................................................................................................... 7 
3. 
Study Design ................................................................................................................................8 
4. 
Study Endpoint and Covariates ....................................................................................................9 
4.1 
Efficacy Endpoints .............................................................................................................. 9 
4.2 
Safety Endpoints ............................................................................................................... 12 
5. 
Statistical Considerations ...........................................................................................................15 
5.1 
Hypothesis for the PFS ..................................................................................................... 15 
5.2 
Sample Size....................................................................................................................... 15 
5.3 
Timing of Analyses ........................................................................................................... 16 
6. 
Definitions .................................................................................................................................16 
7. 
Study Population ........................................................................................................................18 
8. 
Interim Analysis and Early Stopping Rule ................................................................................18 
9. 
Data Screening and Acceptance .................................................................................................19 
9.1 
General Principles ............................................................................................................. 19 
9.2 
Data Handling and Electronic Data Transfer .................................................................... 20 
9.3 
Handling of Incomplete and Missing Data ....................................................................... 20 
9.4 
Outliers.............................................................................................................................. 22 
9.5 
Testing Validation Plan .................................................................................................... 22 
10. Statistical Methods of Analysis .................................................................................................22 
10.1 
Disposition of Subjects ..................................................................................................... 23 
10.2 
Demographic and Disease Characteristics ........................................................................ 23 
10.3 
Medical History ................................................................................................................ 24 
10.4 
Study Drugs Administration ............................................................................................. 24 
10.5 
Efficacy Analyses ............................................................................................................. 25 
10.5.1 
Progression Free Survival (PFS) - Primary Endpoint ................................................25 
10.5.2 
Overall Survival (OS) – Secondary Endpoint ............................................................26 
10.5.3 
Objective Response Rate (ORR) – Secondary Endpoint ...........................................26 
10.5.4 
Time to progression (TTP) – Secondary Endpoint ....................................................26 
10.6 
Safety Analyses ................................................................................................................. 26 
10.6.1 
Adverse Events ..........................................................................................................27 
10.6.2 
Performance Status, Physical Exams, Vital Signs, and Laboratory Evaluations .......27 
10.6.3 
Concomitant Medication ............................................................................................28 
11. List of Planned Tables, Figures, Listings ...................................................................................29 
11.1 
Planned tables ................................................................................................................... 29 
11.2 
Planned Listings ................................................................................................................ 33 
11.3 
Planned Figures ................................................................................................................. 35 
 
 
 
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BIOSTATISTICS 
Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
List of Abbreviations 
AE 
Adverse Event 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DM 
Data Management 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermal Growth Factor Receptor 
ER 
H- score 
Estrogen Receptor 
Immunohistochemistry staining score 
HER2 
Human Epidermal Growth Factor Receptor 2 
ITT 
Intent-to-Treat 
KM 
Kaplan-Meier 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MUGA 
Multigated Acquisition 
NE 
Not Evaluated 
OCRDC 
Oracle Clinical Remote Data Capture 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
 
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Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
PFS 
Progression Free Survival 
PgR 
Progesterone Receptor 
PR 
Partial Response 
TTP  
Time To Progression 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SC 
Steering Committee 
SD 
Stable Disease 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Tables, Listings, and Figures 
TRIO 
Translational Research in Oncology 
UE 
Un-evaluable 
URS 
User Requirement Specifications 
WHODD 
World Health Organization Drug Dictionary  
 
 
 
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BIOSTATISTICS 
Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
1. INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the detailed statistical methodology for 
executing the statistical analyses to assess the antitumor activity and safety profile of 
letrozole in combination with afatinib (BIBW2292) versus letrozole alone in the first line 
treatment of ER+, HER2 negative postmenopausal Advanced Breast Cancer women with 
low ER expression. The data will be analyzed by TRIO. It is planned that the data from all 
centers that participate in this study will be used. 
2. STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective is to compare the progression-free survival (PFS) of the drug 
combination letrozole plus afatinib (BIBW2292) to letrozole alone in the first line 
treatment of ER+, HER2 negative postmenopausal Advanced Breast Cancer women with 
low ER expression. 
2.2 Secondary Objectives 
The secondary objectives of this study are: 
• To compare the Overall Survival (OS) between the two treatment arms 
• To compare the Objective Response Rate (ORR) between the two treatment arms 
• To compare the Time to Tumor Progression (TTP) between the two treatment arms 
• To assess the safety and tolerability in the two treatment arms 
2.3 Exploratory Objectives 
TRIO plans to examine the molecular profiles of tumor tissue submitted by the subjects to 
identify factors that may influence biological and clinical responses to afatinib and 
letrozole including but not limited to Estrogen Receptor (ER) and Progesterone Receptor 
 
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BIOSTATISTICS 
Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
(PgR) statuses, H-score and the EGFR related downstream pathways. The analyses 
performed afterwards will be described in a separate document. 
3. STUDY DESIGN 
This phase II, multicenter, multinational, open-label, parallel group, randomized study will 
compare a two-drug regimen of letrozole plus afatinib (BIBW2292) to letrozole alone in 
the first line treatment of ER+, HER2 negative postmenopausal Advanced Breast Cancer 
women with low ER expression. 
Randomization is stratified by Bone only disease (Yes vs. No) and by Prior neo/adjuvant 
hormonal therapy (Yes vs. No). Eligible subjects will be randomly assigned in a 1:1 ratio to 
either: 
 Arm A: Continuous regimen of oral letrozole 2.5 mg daily until progression of 
disease or any other study treatment discontinuation criteria. 
OR 
Arm B: Continuous regimen of oral letrozole 2.5 mg daily plus oral afatinib 30 
mg daily until progression of disease or any other study treatment discontinuation 
criteria. 
Once the subject is discontinued from study treatment and has undergone the End of 
Treatment visit, the subject will enter into the follow-up phase. 
This study also includes an optional exploratory research component. This optional portion 
is a molecular profiling assay aimed to assess the relationship of antitumor activity with the 
expression of selected cell cycle-related proteins and other markers that may be identified 
in the future. Subjects may participate in this study even if they choose not to participate in 
the sample banking component. 
 
 
 
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BIOSTATISTICS 
Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
4. STUDY ENDPOINT AND COVARIATES 
4.1 Efficacy Endpoints 
Progression-Free Survival (PFS) 
Progression-free survival (PFS) is defined as the time from randomization until the first 
evidence of progression as defined by RECIST version 1.1 or death from any cause. 
Subjects who have neither progressed nor died will be censored at the day of their last 
radiographic tumor assessment, if available, or the date of randomization if no post 
initiation (i.e. post-baseline) radiographic assessment is available. Symptomatic/clinical 
disease progression (deterioration) without documented radiologic progression will not 
constitute progression for the purposes of determining PFS. 
It is defined as: PFS = Date of Progression/Death/Censor – Date of Randomization + 1. 
 
Situation 
Date of Progression or 
Censor 
Outcome 
1 
No baseline tumor assessments 
Date of Randomization 
Censored 
2 
No post-baseline assessments and 
no death 
Date of Randomization 
Censored 
3 
No documented progression and no 
death (with a post-baseline tumor 
assessment) 
Date of last tumor 
assessment 
Censored 
4 
Subject lost to follow-up (or 
withdrew consent from study 
participation) before documented 
progression or death 
Date of last tumor 
assessment 
Censored 
5 
Documented progression 
Date of documented 
progression. 
Progressed 
 
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BIOSTATISTICS 
Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
If a tumor assessment was 
done on multiple days, use 
the earliest date for that 
visit.  
6 
Death without documented 
progression 
Date of death 
Progressed 
 
Overall Survival (OS) 
Overall survival (OS) is defined as the time from randomization to the time of death from 
any cause. Subjects who are alive at the end of the follow-up period, or are lost to follow-
up during the study, will be censored at the last date known alive. 
Duration of OS is defined as the time from randomization until death (or censoring if no 
death). It is defined as: 
OS = Date of Death/Censor – Date of Randomization + 1 
Objective Response Rate (ORR) 
Objective response rate (ORR) is defined as the proportion of randomized subjects 
achieving a best overall response of CR or PR per RECIST v1.1. The overall response will 
be determined by the investigator at each scheduled assessment (every 12 weeks +/- 1 
week) based on the achievement of both measurement and confirmation criteria. The 
evaluation of the overall response is detailed in Table 11 and 12 of the protocol. 
A confirmed overall response based on the achievement and confirmation of two 
consecutive assessments is presented below: 
 
 
 
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BIOSTATISTICS 
Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
 
nfe : no further evaluation 
1 The NE assessments will not be considered as a consecutive response and will be dropped in the 
evaluation.  
The best overall response is the best confirmed overall response recorded from baseline 
until disease progression.  
Time to Progression (TTP) 
Time to progression (TTP) is defined as the time interval from date of randomization to 
date of the first documented objective tumor progression. Time to progression does not 
include deaths as events. Subjects who did not progress are censored at the last 
radiographic tumor assessment (i.e., with a cycle/visit response of CR, PR, SD, PD). If no 
post-baseline assessment is available, censoring will occur at date of randomization. The 
same censoring rules will be applied as for PFS, except that death is not considered as an 
event. 
Confirmed Overall Response Determination 
Initial Response 
(Not Yet Confirmed) 
Consecutive Response 
 (at Least 4 Weeks Later)1 
Confirmed Overall 
Response 
PD 
- 
PD 
CR/PR/SD 
PD 
SD  
CR 
CR 
CR 
CR 
PR 
PR 
CR 
nfe 
SD 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
nfe 
SD 
SD 
CR/PR/SD/nfe 
SD  
 
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BIOSTATISTICS 
Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
4.2 Safety Endpoints 
Adverse Events (AE) 
Adverse events are coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. AEs will be assessed according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. The CTCAE represents a 
comprehensive grading system for reporting the acute and late effects of cancer treatments. 
CTCAE v4.0 grading is by definition a 5-point scale generally corresponding to mild, 
moderate, severe, life threatening and death. 
Treatment Emergent Adverse Event (TEAE) 
An AE will be considered treatment emergent if: 
Its onset date occurred any time on or after the administration of the first dose of any study 
treatment up to 30 days after the last dose of study treatment (or up to any time if serious 
AE related to study treatment). 
Related Adverse Events 
Adverse events can be considered “related” and the relationship will be assessed for each 
component of the study treatment. If an AE is missing the relationship information (from 
the investigator) then this adverse event will be treated as “related” in the statistical 
analysis. 
Serious Adverse Events (SAE) 
A serious adverse event (SAE) is defined as any AE which: 
• Results in death 
• Is immediately life-threatening 
• Results in persistent or significant disability / incapacity 
• Requires or prolongs subject hospitalization 
• Is a congenital anomaly / birth defect  
 
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Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
• Is to be deemed serious for any other reason if it is an important medical event 
when based upon appropriate medical judgment which may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definitions. 
Laboratory Data 
Hematology and blood chemistry labs will be collected in the eCRF. All those labs will be 
converted using recommended units by through Oracle Clinical Remote Data Capture 
(OCRDC). 
In addition, laboratory data will be classified (by biostatistics/SAS programming) into 
grades according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.  
Vital Signs 
Vital sign assessments are performed in order to characterize basic body function. The 
parameters expected to be collected include: weight (kg) and systolic / diastolic blood 
pressure (mmHg). 
Systolic blood pressure will be categorized as <140 mmHg, 140-160 mmHg, >160 mmHg, 
and Diastolic blood pressure as <90 mmHg, 90-100 mmHg, >100 mmHg. 
Concomitant Medication 
A medication will be regarded as previous if it started within 30 days before the 
randomization and stopped before randomization (medication stop date < randomization 
date).  
A medication will be regarded as concomitant if: 
• It started on or after the date of randomization and within 30 days after the date of 
last study treatment; OR 
• It started prior to randomization but was ongoing at the time of the randomization. 
 
 
 
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Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
 
Left Ventricular Ejection Fraction (LVEF) 
Left Ventricular Ejection Fraction (LVEF) will be collected in the eCRF to assess the 
percent volume of blood that is pumped by the left ventricle with each cardiac contraction  
to detect any cardiac toxicity associated to the drugs. LVEF will be performed by MUGA 
scan or echocardiogram, using the same method at each assessment. 
ECOG Performance Status 
Performance status will be collected in the eCRF according to ECOG scale to assess how 
the disease affects the daily living abilities of the subject. 
Drug Exposure 
Exposure analyses will be based on the actual dose administered (in mg). The planned dose 
for Letrozole and Afatinib is the same for each subject regardless of their physical 
characteristics (weight). 
The following variables summarizing the overall administration (not by cycle) will be 
derived: 
Letrozole 
• Number of cycles: number of cycle having a duration of intake > 0 day 
• Duration of treatment (in weeks) = [(Date of last dose - date of first dose +1)]/7 
• Duration of exposure (days) = Sum of each sub-administration duration (Stop Date 
– Start Date +1) 
• Relative dose intensity (%) = [ Duration of exposure (days) / Duration of treatment 
(days) ] x 100 
Afatinib 
• Number of cycles: number of cycle having a duration of intake > 0 day 
• Duration of treatment (in weeks) = [(Date of last dose - date of first dose +1)] /7 
 
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Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
• Duration of exposure (days) = Sum of each sub-administration duration (Stop Date 
– Start Date +1) 
• Cumulative dose (mg) = Sum of all (each sub-administration Duration of exposure 
(days) ×  30 mg or 20 mg if dose reduced) 
• Relative dose intensity (%) = [ Cumulative Dose (mg) / (Duration of treatment 
(days) x 30 mg ] x 100 
5. STATISTICAL CONSIDERATIONS 
5.1 Hypothesis for the PFS 
The primary efficacy analysis will be the comparison of the distribution of PFS between 
the two treatment groups using a stratified logrank test at two-sided 10 % level of 
significance, i.e.: 
H0: St(t) = Sc(t) vs H1: St(t) ≠ Sc(t), t ≥ 0 
where Sc(t) is the survival distribution function of PFS in the control arm and St(t) is the 
survival distribution function of PFS in the experimental arm. 
5.2 Sample Size 
The following assumptions are made: 
• Subjects in the control arm will have a median PFS of 9 months 
• Subjects in the experimental arm will have median PFS of 14 months (PFS hazard 
ratio of 0.64) 
• Expected accrual duration will be 18 months, which leads to about 42 months of 
expected entire study duration 
• The α type I error rate is set to 10% (2-sided) 
• The β type II error rate is set to 20% (i.e. the power of the trial will be 80%) 
Under these assumptions, 150 subjects (75 per arm) will be enrolled in the trial.  
 
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Statistical Analysis Plan  
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5.3 Timing of Analyses 
The following analyses are planned: 
A first analysis of safety will be performed on the first 20 subjects who complete 28 days 
of treatment. The steering committee will review this formal analysis. 
Interim safety analyses will, then, be performed once a year until the final analysis. 
The final analysis will be performed when 127 PFS events are observed in the ITT 
population. The trial will stop once the last subject reaches end of study treatment visit (30 
days post last drug intake) and all events required for the final analysis have been observed 
and collected. 
6. DEFINITIONS 
Baseline 
The last available assessment before or at the date of start of study treatment is taken as 
‘baseline’ assessment. If subjects have no value as defined above, the baseline results will 
be missing. 
Complete Response 
The radiological assessment Complete Response is defined using the RECIST v1.1 criteria. 
Date of First Dose  
The date of first dose of study drug is derived as the first date when a nonzero dose of study 
drug is administered and recorded on the dose administration record of the eCRF. For the 
sake of simplicity, the date of first dose of study drug is also referred to as the start of the 
study drug. 
 
 
 
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Date of Last Dose  
The date of last dose of study drug is derived as the last date when a nonzero dose of study 
drug is administered and recorded on the dose administration record of the eCRF. 
Last Contact Date 
The last contact date will be derived for subjects not known to have died at the analysis cut-
off using the latest complete date among the following dates which precede the cut-off 
date: 
• All assessment dates (e.g. vital signs assessment, performance status assessment, 
tumor assessments, etc.) 
• Medication dates including concomitant medications (start or stop) 
• Adverse events dates (start or stop) 
• Date of last study drug administration 
• Randomization date 
Partial Response (PR) 
The radiological assessment Partial Response is defined using the RECIST v1.1 criteria. 
Progressive Disease (PD) 
The radiological assessment Progressive Disease is defined using the RECIST v1.1 criteria. 
RECIST 
The response to treatment will be determined according to guidelines established by the 
Response Evaluation Criteria In Solid Tumors (RECIST v1.1) criteria (or guidelines). 
Stable Disease (SD) 
The radiological assessment Stable Disease is defined using the RECIST v1.1 criteria. 
 
 
 
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Screening Phase 
The screening phase is the time between the date the subject signs the informed consent 
and the date of randomization. 
7. STUDY POPULATION 
The Intent-to-treat (ITT) population will consist of all subjects who were randomized to 
study treatment, regardless of whether they actually received study medication. All efficacy 
analyses will be evaluated based on data from this population according to the treatment 
group they were assigned to at randomization and based on the strata they were originally 
assigned to at the time of randomization. 
The Safety population will be used to assess clinical safety and tolerability and will 
consist of all subjects who were randomized and received at least one dose of study 
medication. This population will be based on the actual treatment received, if this differs 
from that to which the subject was randomized and will be used for the analysis of safety 
data. 
8. INTERIM ANALYSIS AND EARLY STOPPING RULE 
Steering Committee 
The Steering Committee (SC) will be composed of the study Co-Chairs, medical, 
operational and statistical representatives of TRIO and a non-voting representative from the 
manufacturer. 
The SC will have sole responsibility for the scientific conduct and integrity of the trial. 
Responsibilities include review and approval of the protocol document, review and 
approval of protocol amendments, monitoring of accrual, compliance and safety during the 
conduct of the trial. 
 
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Statistical Analysis Plan  
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9. DATA SCREENING AND ACCEPTANCE 
9.1 General Principles 
Data Management (DM) for this study is the responsibility of TRIO. 
For the planned analyses, data acceptance will be based on the creation and review of the 
blinded tables, listings, and figures (TLFs). In general, TLF programs will be created prior 
to a database snapshot or database lock. Extracts of the clinical study data will be made 
prior to a snapshot or lock of the database and the TLF programs will be run with the 
outputs reviewed for extreme, unusual, and missing values. These will be identified to Data 
Management and Project Management for further investigation and potential resolution 
prior to a snapshot or lock of the database. As issues are detected with the data entered in 
the database, procedures will be reviewed and programmed if necessary to ensure 
resolution in subsequent data transfers. 
For the final analysis, all procedures will be run to ensure previously identified data issues 
have been resolved. The TLF programs will be run and the outputs reviewed to ensure 
additional data issues have not evolved. Additionally, the following items will be 
specifically identified for further investigation and resolution by DM prior to acceptance of 
the data by Biostatistics: 
• Post-baseline missing disease response by radiological tumor assessment  
• Outlier lab data 
• Missing baseline data (e.g., labs, vitals, etc.) 
The clinical study team will identify the criteria for important protocol deviation criteria. 
Protocol deviations that may impact the analysis and/or the interpretation of the study 
results include, but are not limited to: 
• No disease assessments 
• Inclusion/exclusion criteria not met 
 
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• Treatment administration that is not consistent with the protocol (based on the 
randomized treatment for each subject) 
9.2 Data Handling and Electronic Data Transfer 
All clinical data will be entered directly by the sites users into the TRIO OCRDC database 
and will be transmitted electronically in the form of raw SAS® datasets. Once the final data 
queries have been generated and resolved, the database will be deemed “locked” and final 
data analysis files will be generated. 
DM will provide all data to Biostatistics as raw SAS® data sets on a regular basis. Official 
data snapshots will be extracted from the clinical database for the final and updated 
analyses. The data used for all the analyses will be archived. 
9.3 Handling of Incomplete and Missing Data 
Missing and incomplete data will be identified through a review of the tables and listings 
created within Biostatistics. Missing and incomplete data will be identified for 
investigation, and possible resolution, by DM and Project Management prior to database 
lock (or an official database snapshot). 
Missing Data: All analyses and descriptive summaries will be based on the observed data. 
Unless otherwise specified, missing data will not be imputed or “carried forward.” 
Partial or Missing Date for Adverse Events and Concomitant Medications: 
Imputation Rules for Partial or Missing Stop Dates: 
If the month and year are present, impute the last day of that month. 
If only the year is present, impute December 31 of that year. 
If the stop date is entirely missing, assume the event or medication is ongoing. 
 
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Statistical Analysis Plan  
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If a partial or complete stop date is present and the ‘ongoing’ box is checked, then it will be 
assumed that the adverse event or concomitant medication stopped and the stop date will be 
imputed if partial. 
Imputation Rules for Partial or Missing Start Dates 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
< 1st 
dose 
≥ 1st 
dose 
< 1st 
dose 
yyyymm 
≥ 1st 
dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
Partial: 
yyyymm 
= 1st dose 
yyyymm 
2 
1 
2 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose 
yyyy 
3 
1 
3 
1 
n/a 
1 
1 
≠ 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
 
1 = Impute the date of first dose 
2 = Impute the first of the month 
3 = Impute January 1 of the year 
4 = Impute January 1 of the stop year 
 
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Statistical Analysis Plan  
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9.4 Outliers 
Outliers will be identified through a review of TLFs. Procedures will be created to 
specifically look for outlier data within the laboratory and vital sign parameters. 
For laboratory parameters, vital signs and clinical parameters, extreme values will be 
identified for investigation by Data Management and Project Management, as described in 
the Procedure User Requirement Specifications (URS). 
Additional procedures may be created to assess potential outlier data for other parameters. 
All confirmed outlier data will be included in the analyses presented in this statistical 
analysis plan. 
9.5 Testing Validation Plan 
SAS® version 9.1 or higher on the Windows system will be used for all TLFs creation. The 
verification of the outputs, the analysis datasets as well as the review of all programs and 
macros created specifically for this study, will be conducted as outlined in TRIO Standard 
Operating Procedures and Standard Guidelines. 
10. STATISTICAL METHODS OF ANALYSIS 
Categorical variables will be summarized in frequency tables, with the counts and 
percentage of subjects in each category. Percentages given in the summary tables will be 
rounded and thus may not always add up to exactly 100 percent. For continuous variables, 
summary statistics will include N, mean, standard deviation, Q1, median, Q3, minimum 
and maximum values (range). 
SAS® version 9.1 or higher will be used for the statistical analyses. 
 
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10.1 Disposition of Subjects 
The disposition of subjects will be tabulated using the ITT population. Number (percent) of 
subjects who were in each analysis population (e.g. the ITT and Safety populations), 
discontinued, and ongoing as of data cut-off date will be summarized by treatment group. 
The reason for discontinuation (both from treatment and from study participation) will be 
summarized considering the categories specified in the eCRF pages. Listings of disposition 
information and analysis population will be provided as well. 
Violations of the inclusion/exclusion criteria, as well as other important protocol violations 
will be summarized and listed for the ITT population, by treatment arm. 
The stratifications factors Bone only disease (Yes vs. No) and Prior neo/adjuvant hormonal 
therapy (Yes vs. No) will also be described by treatment group. 
10.2 Demographic and Disease Characteristics 
The following demographic and baseline characteristics will be summarized and listed for 
the ITT population by treatment group: 
Demographics: 
Age, INT (Date of randomization – Date of birth) / 365.25) 
 
INT = integer part 
 
Due to the fact, only the year of birth is collected (YYYY), we assume the full date to be 31-Dec-
YYYY 
Menopausal Status 
Weight at Baseline 
ECOG Status at Baseline 
Disease Characteristics: 
Time from initial diagnosis to randomization 
Primary Tumor Side 
 
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Histopathological Type at Initial Diagnosis 
Histological Grade at Initial Diagnosis 
Stage IV Disease at Initial Diagnosis (Yes/No) 
Time from Metastatic / Locally Recurrent Disease to randomization 
Disease Status at Registration 
Prior Surgery for Breast cancer and Prior Anti-Tumor Therapy 
10.3 Medical History 
Not  Applicable.  
10.4 Study Drugs Administration 
Number of cycles, Duration of treatment, Cumulative dose (for Afatinib only) and Relative 
dose intensity (RDI) will be summarized by treatment for the safety population. 
The relative dose intensity will be additionally presented categorized (i.e., number and 
percentage of subjects with relative dose intensity of <60%, 60-<80%, 80-<90%, 90-
<110%, ≥110%). 
The number and percentage of subjects with dose interruptions/discontinuations or reduced 
(Afatinib only), along with their respective reasons will be summarized. 
For Afatinib, the compliance will be summarized by visit following this calculation : 
Compliance (%) = [ Number of tabs taken / Sum of each sub-administration 
duration in a visit] x 100 
When the total number of tabs taken does not equal the number of tabs dispensed minus the 
number of tabs returned, the reasons will also be summarized.  
 
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10.5 Efficacy Analyses 
Efficacy data for the primary endpoint and the secondary endpoints will be analyzed for the 
ITT population. Sensitivity analyses and subgroup analyses will be conducted as 
appropriate. Summaries and figures of the efficacy endpoints will be generated by 
randomization group. 
10.5.1 Progression Free Survival (PFS) - Primary Endpoint 
Progression-free survival will be summarized using Kaplan-Meier (KM) curves and 
compared between treatment arms using a stratified log-rank test, stratifying for Bone only 
disease (Yes vs. No) and by Prior neo/adjuvant hormonal therapy (Yes vs. No). The 
Kaplan-Meier estimate of the PFS survival distribution function will be computed for each 
treatment group using PROC LIFETEST with method=KM option in SAS. The results will 
also be plotted graphically (Kaplan-Meier curves) by each treatment arm. The plots will 
also display the number of subjects at risk at equidistant time points. 
For each randomization group, the Kaplan-Meier estimates for the median PFS time, the 
first and third quartiles will be presented, along with approximate 95% confidence intervals 
(CI). 
The effect of treatment on PFS will also be compared using a stratified Cox proportional 
hazards regression mode using the stratification variables at randomization as strata. This 
model will generate estimates of the stratified treatment hazard ratio, respectively. 
Additional stratified Cox regression models might be employed to explore the effects of 
additional prognostic variables (considered as covariates in the model) on PFS. The hazard 
ratio with two-sided 95% confidence interval will be derived from the stratified Cox 
proportional hazards model using PROC PHREG with ties=EXACT option in the model. 
A sensitivity analysis will be performed on Progression free survival to assess the 
robustness of the results. Therefore, subjects receiving any non-protocol anti-cancer 
therapy during the treatment period before an assessment of disease progression will be 
 
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censored on the last available assessment date prior to initiating medication or the date of 
surgery or radiotherapy. 
10.5.2 Overall Survival (OS) – Secondary Endpoint  
The treatment groups will be compared using the stratified log-rank test and the survival 
curves will be estimated, together with corresponding summary statistics. The survival 
curves for each treatment group will be generated using the Kaplan-Meier methodology. 
The effect of treatment on OS will also be compared using a stratified Cox proportional 
hazards regression mode using the stratification variables at randomization as strata. 
10.5.3 Objective Response Rate (ORR) – Secondary Endpoint 
The objective response rates observed in the treatment groups will be compared adjusting 
for the stratification variables using the Cochran-Mantel-Haenszel (CMH) test. 
A 95% CI will be calculated for each response rate. The best overall response outcome 
(CR/PR/SD/PD/Unevaluable [UE]) will be summarized and tabulated for the ITT 
population by treatment group and by the stratification variables using the Cochran-Mantel-
Haenszel test as appropriate. 
10.5.4 Time to Progression (TTP) – Secondary Endpoint 
The treatment groups will be compared using the stratified log-rank test and the survival 
curves will be estimated, together with corresponding summary statistics. The survival 
curves for each treatment group will be generated using the Kaplan-Meier methodology. 
The effect of treatment on TTP will also be compared using a stratified Cox proportional 
hazards regression mode using the stratification variables at randomization as strata. 
10.6 Safety Analyses 
Safety analyses will be performed on the safety population. 
 
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10.6.1 Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA version 16.0 or later) will be 
used to code all adverse events to a system organ class and a preferred term. 
Subject incidence of Treatment Emergent Adverse Events will be tabulated by system 
organ class, preferred term and toxicity grade for all adverse event, serious, treatment-
related, and serious treatment-related adverse events. Each of these outputs will include 
tabulation for each system organ class and preferred term as reported by the investigator 
based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. 
Summary tables will be provided separately for Treatment Emergent Adverse Events 
leading to investigational product discontinuation and Treatment Emergent Adverse Events 
leading to study withdrawal. 
All AEs leading to deaths will be summarized (not only TEAEs). An AE will be considered 
as leading to death if it has a grade 5.   
Detailed listings for all adverse events and listings and/or narratives will be provided for 
serious and significant adverse events, deaths, and treatment discontinued due to adverse 
events. A flag will be used to identify which adverse events are considered as treatment 
emergent or not. 
10.6.2 Performance Status, Physical Exams, Vital Signs, and Laboratory 
Evaluations 
Summary of ECOG Performance Status results at each scheduled time point (including 
baseline) and the change from baseline will be presented. A shift table will be provided as 
well from baseline status to the worst status of post-baseline time points. 
Vital sign measurements (only systolic and diastolic blood pressure) will be summarized at 
each visit (maximum value on day of dosing) and over the study, using descriptive 
statistics. In addition, shifts from baseline will be tabulated, by cycle (maximum value on 
 
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Statistical Analysis Plan  
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day of dosing) and over the study, with systolic blood pressure categorized as <140, 140-
160, >160 mmHg, and diastolic blood pressure as <90, 90-100, >100 mmHg. 
Body weight and change from baseline will be summarized by visit. 
LVEF and change from baseline will be summarized by visit. 
Laboratory parameters for Hematology and Blood chemistry results at each scheduled time 
point (including baseline) and the change from baseline will be presented. A shift table will 
be provided as well from baseline status to the worst status of post-baseline time points.   
10.6.3 Concomitant Medication 
The number and proportion of subjects receiving each reported medication will be 
summarized by each treatment arm as coded using World Health Organization Drug 
Dictionary (WHODD). 
A listing of all concomitant medications by subject will also be provided. 
 
 
 
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11. LIST OF PLANNED TABLES, FIGURES, LISTINGS 
11.1 Planned Tables 
Title 
Population 
Description 
Subject Disposition  
ITT 
Tabulates the disposition of all subjects, including 
the number of subjects randomized, the number 
of subjects that received investigational product 
and the number of subjects that were randomized 
and never received investigational product. The 
reason for drug discontinuation will also be 
summarized. 
The reason for study discontinuation will be 
summarized. 
Stratification Factors 
ITT 
Tabulates the stratification factors Bone only 
disease (Yes vs. No) and Prior neo/adjuvant 
hormonal therapy (Yes vs. No). 
Protocol Deviations  
ITT 
Tabulates the protocol and the eligibility 
deviations. 
Baseline 
Demographics  
ITT  
Tabulates summary statistics of the demographics 
(Age, Menopausal Status, Weight and ECOG 
Status at Baseline).  
Disease 
Characteristics  
ITT  
Tabulates the Time from Initial Diagnosis to 
Randomization, the Primary Tumor Side, the 
Histopathological Type at Initial Diagnosis, the 
Histological Grade at Initial Diagnosis, the Stage 
IV Disease at Initial Diagnosis and the Disease 
 
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Title 
Population 
Description 
Status at Registration, Prior Surgery for Breast 
cancer and Prior Anti-Tumor Therapy.  
Study Drug Exposure  
Safety 
Tabulates the Number of Cycles, the Duration of 
Treatment, the Cumulative dose, the Relative 
dose intensity, Reductions. 
The number of subjects with dose 
interruptions/discontinuation or reduction will 
also be summarized. 
Progression-Free 
Survival  
ITT 
Summary of PFS results including treatment 
comparison results. 
Progression-Free 
Survival  
ITT 
Summary of PFS results including treatment 
comparison results (sensitivity analysis). 
Overall Survival  
ITT 
Summary of OS results including treatment 
comparison results. 
Objective Response 
Rate  
ITT 
Summary of ORR results including treatment 
comparison results. 
Time to Progression 
ITT 
Summary of TTP results including treatment 
comparison results. 
TEAEs Overview 
Safety 
Tabulates the number of TEAEs, serious TEAEs, 
Grade 3-4 TEAEs, Treatment Related TEAEs, 
Serious and Treatment Related TEAEs, Fatal 
TEAEs. 
Treatment Emergent 
Adverse Events 
(TEAEs)   
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
 
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Title 
Population 
Description 
Treatment Emergent 
Adverse Events 
(TEAEs) per Grade   
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Serious Treatment 
Emergent Adverse 
Events (TEAEs)  
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Serious Treatment 
Emergent Adverse 
Events (TEAEs)  per 
Grade 
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Related Letrozole 
Treatment Emergent 
Adverse Events 
(TEAEs)  
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Related Letrozole 
Treatment Emergent 
Adverse Events 
(TEAEs) per Grade 
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Related Afatinib 
Treatment Emergent 
Adverse Events 
(TEAEs)  
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Related Afatinib 
Treatment Emergent 
Adverse Events 
(TEAEs) per Grade  
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Serious Related 
Letrozole Treatment 
Emergent Adverse 
Events (TEAEs)  
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Serious Related 
Letrozole Treatment 
Emergent Adverse 
Events (TEAEs)  per 
Grade 
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Serious Related 
Safety 
Summary by system organ class and preferred 
 
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Title 
Population 
Description 
Afatinib Treatment 
Emergent Adverse 
Events (TEAEs)  
term for each treatment group. 
Serious Related 
Afatinib Treatment 
Emergent Adverse 
Events (TEAEs)  per 
Grade 
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Grade 3-4 Treatment 
Emergent Adverse 
Events (TEAEs)  
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Grade 3-4Treatment 
Emergent Adverse 
Events (TEAEs)  per 
Grade 
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Treatment Emergent 
Adverse Events 
(TEAEs) leading to 
drug discontinuation 
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Treatment Emergent 
Adverse Events 
(TEAEs) leading to 
drug discontinuation 
per Grade 
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
Fatal Treatment 
Emergent Adverse 
Events 
Safety 
Summary by system organ class and preferred 
term for each treatment group. 
ECOG Performance 
Status  
Safety 
Summary of ECOG performance status results at 
each time point, change from baseline at each 
time point. In addition, a shift table will be 
presented. 
Blood Pressure 
Safety 
Summary of systolic and diastolic blood pressure 
results at each time point. In addition, shift tables 
 
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Title 
Population 
Description 
will be presented. 
Weight 
Safety 
Summary of weight results at each time point, 
change from baseline at each time point. 
Hematology  
Safety 
Summary of hematology parameters at each time 
point. In addition, shift tables will be presented. 
Blood Chemistry  
Safety 
Summary of blood chemistry parameters at each 
time point. In addition, shift tables will be 
presented. 
Concomitant 
Medications  
Safety 
Summary of administered concomitant 
medications by preferred name.  
11.2 Planned Listings 
Title 
Population 
Description 
Subject Accountability ITT 
Listing of all subjects population and treatment 
arms. 
Subject Withdrawal 
ITT 
Listing of all subjects who withdrew from the 
study/treatment, including the reason for 
withdrawal. 
Study Drug Exposure 
Safety 
Listing of all subjects investigational product 
administration information. 
Treatment Emergent 
Adverse Events  
Safety 
Listing of all treatment emergent adverse event.  
Listing will include subject number, system 
organ class and preferred term of adverse event, 
date of onset, date of resolution, CTCAE v4.0 
Grade, action taken, relationship and outcome.  
Serious Treatment 
Emergent Adverse 
Events 
Safety 
Listing of all serious treatment emergent adverse 
event.  Listing will include subject number, 
system organ class and preferred term of adverse 
event, date of onset, date of resolution, CTCAE 
v4.0 Grade, action taken, relationship and 
 
Document owner(s): Vincent Houé 
 
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BIOSTATISTICS 
Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
Title 
Population 
Description 
outcome.  
Treatment Emergent 
Adverse Events 
Leading to Drug 
Discontinuation 
Safety 
Listing of all treatment emergent adverse event 
leading to drug discontinuation.  Listing will 
include subject number, system organ class and 
preferred term of adverse event, date of onset, 
date of resolution, CTCAE v4.0 Grade, action 
taken, relationship and outcome.  
Fatal Treatment 
Emergent Adverse 
Events 
Safety 
Listing of all adverse event leading to death 
(grade = 5).  Listing will include subject number, 
system organ class and preferred term of adverse 
event, date of onset, date of resolution, CTCAE 
v4.0 Grade, action taken, relationship and 
outcome. 
Deaths 
ITT 
Listing of all subjects who died, including cause 
of death, study day of death. 
Vital Signs (Blood 
Pressure) 
Safety 
Listing of all vital signs results for each subject. 
ECOG Performance 
Status and Physical 
Exam (Weight) 
Safety 
Listing of ECOG PS and Weight at each 
assessment. 
Hematology 
Safety 
Listing of all hematology parameters. 
Blood Chemistry 
Safety 
Listing of all blood chemistry parameters. 
Concomitant 
Medications 
ITT 
Listing of all concomitant medications. 
Efficacy Parameters 
ITT 
Listing of all efficacy parameters for each 
subject, including Progression-Free Survival, 
Overall Survival, Objective Response Rate, Time 
to Progression. 
 
Document owner(s): Vincent Houé 
 
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Document ID: STAT-020-SAP-01 Version: 2.0– 04-Dec-2014 
Document Location: P:\020\G. STATISTICAL FILE\G1. Statistical Analysis Plan\SAP 020 v2.0 final 04DEC2014.docx 
 


 
BIOSTATISTICS 
Statistical Analysis Plan  
TRIO-020 
STAT-020-SAP 
 
11.3 Planned Figures 
Title 
Population 
Description 
Progression-Free 
Survival 
ITT 
Kaplan-Meier plot of Progression-Free Survival. 
Overall Survival 
ITT 
Kaplan-Meier plot of Overall Survival. 
Time to Progression 
ITT 
Kaplan-Meier plot of Time to Progression. 
 
 
Document owner(s): Vincent Houé 
 
Page 35 of 35 
Document ID: STAT-020-SAP-01 Version: 2.0– 04-Dec-2014 
Document Location: P:\020\G. STATISTICAL FILE\G1. Statistical Analysis Plan\SAP 020 v2.0 final 04DEC2014.docx