Clinical trial NCT02954055
Conditions: Breast Cancer
Keywords: locally advanced metastatic breast cancer ER-positive HER2-negative Stage IV
Sponsor: ETOP IBCSG Partners Foundation
Start date: 2017-09-13; Completion date: 2022-11-23
Enrollment: 140 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, randomized phase II trial that will randomise women with ER-positive, HER2-negative (Human Epidermal Growth factor Receptor 2-negative) metastatic or locally relapsed breast cancer in a ratio of 1:1 to receive a metronomic regimen of vinorelbine plus cyclophosphamide and capecitabine, or the conventional paclitaxel monotherapy.

Detailed description:
The prognosis for patients with locally advanced or metastatic disease (ABC) remains poor, with a median survival of 2-4 years. About 10% of newly diagnosed BC patients present with ABC, and 30% to 50% of patients diagnosed at earlier stages will subsequently develop metastatic disease.

In the first-line treatment of HER2 (Human Epidermal Growth factor Receptor 2) negative ABC patients, various chemotherapy regimens can be used including taxanes, which are among the most active agents in BC. Single agent response rates range from 20 to 50%. However, eventually all patients will progress with a median time to progression of 5 to 7 months. A weekly (qw) over a three-weekly (q3w) administration schedule of paclitaxel has been shown to be more effective in the metastatic as well as in the adjuvant setting after standard chemotherapy

The VEX regimen was recently investigated within a phase II trial currently ongoing at the European Institute of Oncology (IEO) (IEO number IEOS582/111; EudraCT Number: 2010-024266-21; title: "A phase II study of metronomic oral chemotherapy with cyclophosphamide plus capecitabine and vinorelbine in metastatic breast cancer patients"). Patients received vinorelbine 40 mg orally on days 1, 3 and 5 every week, cyclophosphamide 50 mg daily and capecitabine 500 mg 3 times a day.

Given the promising activity of the VEX regimen in a pre-treated population of advanced breast cancer patients and the good tolerability, the aim of the present trial is to investigate whether the VEX schedule may improve efficacy and tolerability as compared to standard paclitaxel treatment in advanced or metastatic ER-positive/HER2-negative breast cancer patients.

The concept of the VEX metronomic treatment is to administer the combination for as long as the patient has the possibility of deriving a benefit from it. The time to treatment failure (TTF) has been chosen as primary endpoint for this trial. TTF is defined as time from the date of randomization to the date when the final dose of trial treatment is administered. Chemotherapy may need to be stopped due to lack of tolerability, lack of efficacy or patient preference through subjective symptom assessment. TTF is a composite endpoint combining all these feasibility aspects of a treatment. It is therefore uniquely suited to the research question of the current trial. The secondary endpoints progression-free survival, disease control and safety will allow further assessment of the feasibility of the VEX metronomic treatment versus the paclitaxel monotherapy regimen.

Arms: arm 1: Paclitaxel 90 mg/m2 days 1, 8, 15 q4w. Patients will continue to receive assigned treatment until progression or lack of tolerability. arm 2: Metronomic VEX:

Cyclophosphamide 50 mg orally once daily continuously, Capecitabine 500 mg, orally 3 times a day (1500 mg/day) continuously, Vinorelbine 40 mg orally days 1, 3, 5 each week continuously. Patients will continue to receive assigned treatment until progression or lack of tolerability.
Interventions: intervention 1: Paclitaxel intervention 2: Cyclophosphamide intervention 3: Capecitabine intervention 4: Vinorelbine
Intervention descriptions: intervention 1: Arm A intervention 2: Arm B intervention 3: Arm B intervention 4: Arm B

Protocol documents:
Prot_SAP_000.pdf: 
IBCSG 54-16 METEORA-II 
 
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A randomized phase II trial of metronomic oral vinorelbine plus 
cyclophosphamide and capecitabine (VEX) versus weekly 
paclitaxel as first-line or second-line treatment in patients with 
ER-positive/HER2-negative advanced or metastatic breast 
cancer 
 
MEtronomic TrEatment Option in advanced bReast cAncer: 
 the METEORA-II trial 
 
 
 
EudraCT number: 
2016-002200-39 
 
Sponsor:   
International Breast Cancer Study 
Group (IBCSG) 
 
 
IBCSG Coordinating Center, Effingerstrasse 40, CH- 3008 Bern 
Phone: +41 31 511 94 00 
Fax: +41 31 511 94 01 
 
 
Version 1.0 
 
 
 
  
 
 
 
 
 
 
 
 
 
INTERNATIONAL BREAST 
CANCER STUDY GROUP 
IBCSG 54-16  
 
METEORA-II 
 
 
 
 
 


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Trial-Specific Contacts 
 
Trial Chair 
Elisabetta Munzone, MD 
Email: elisabetta.munzone@ieo.it 
Tel: +39 025 748 9970 
Fax: +39 029 437 9205 
Trial Statistician 
Zhuoxin Sun, PhD 
Email: zhuoxin@jimmy.harvard.edu  
 
 
 
Trial Data Manager 
 
Lead Trial Coordinator 
 
Colleen King 
 
Holly Shaw 
Email: ibcsg54_METEORA@fstrf.org 
Tel: +1 716-834-0900 (general) 
Fax:  +1 716-833-3990 
Trial Contact in Italy 
Raffaella Ghisini, MSc 
Email: raffaella.ghisini@ieo.it 
Tel: +39 029 437 2733 
Fax: +39 025 521 0169 
 
 
 
In collaboration with Pierre Fabre Pharma s.r.l.  
 
 
 
 




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Principal Investigator Protocol Signature Page 
 
IBCSG 54-16 
METEORA-II 
 
I have read the protocol and agree that it contains all necessary details for conducting this 
trial. I will conduct the trial as outlined in the following protocol and in compliance with GCP, 
and will apply due diligence to avoid protocol deviations. I will provide a copy of the protocol 
furnished to me by IBCSG, to all physicians responsible to me who participate in this trial. 
I will discuss this material with them to assure that they are fully informed regarding the 
drugs and the conduct of the trial. I agree to keep records on all patient information (Case 
Report Forms and patient's Informed Consent statement), and all other information collected 
during the trial for a minimum period of 15 years. 
 
Name of Principal Investigator:___________________________________________ 
 
 
_____________________________________________________ ______________ 
 
 
Signature 
Date 
 


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TABLE OF CONTENTS 
 
Section 
Page 
1. 
Protocol Summary and Schema ............................................................................ 7 
2. 
Trial schedule ...................................................................................................... 13 
3. 
List of abbreviations............................................................................................ 14 
4. 
Background and scientific rationale .................................................................... 15 
4.1. 
Breast cancer ........................................................................................................ 15 
4.2. 
Treatment of advanced breast cancer .................................................................. 15 
4.3. 
Metronomic chemotherapy .................................................................................. 16 
4.4. 
The VEX regimen ................................................................................................ 18 
4.5. 
Trial hypothesis ................................................................................................... 19 
4.6. 
Overall risk-benefit assessment ........................................................................... 19 
4.7. 
Rationale for the trial design ............................................................................... 19 
5. 
Trial objectives and endpoints ............................................................................ 20 
5.1. 
Primary objective ................................................................................................. 20 
5.2. 
Primary endpoint ................................................................................................. 20 
5.3. 
Secondary objectives ........................................................................................... 20 
6. 
Trial design, duration and termination ................................................................ 20 
6.1. 
Trial design .......................................................................................................... 20 
6.2. 
Trial schema ........................................................................................................ 20 
6.3. 
Sample size and trial duration ............................................................................. 21 
7. 
Patient selection .................................................................................................. 21 
7.1. 
Inclusion criteria .................................................................................................. 21 
7.2. 
Exclusion criteria ................................................................................................. 22 
8. 
Randomization and stratification ........................................................................ 23 
8.1. 
Patient randomization procedure ......................................................................... 23 
8.2. 
Randomization Help Desk ................................................................................... 24 
8.3. 
Stratification ........................................................................................................ 24 
8.4. 
Randomized Treatment Assignment ................................................................... 24 
9. 
Treatment ............................................................................................................ 24 
9.1. 
Trial treatments .................................................................................................... 25 
9.2. 
Treatment Administration .................................................................................... 25 
9.3. 
Dose modifications and delays for paclitaxel ...................................................... 25 
9.4. 
Dose modifications and delays for VEX ............................................................. 26 
9.5. 
End of trial treatment ........................................................................................... 27 
9.6. 
Removal from the trial ......................................................................................... 28 
10. 
Safety .................................................................................................................. 29 
10.1. 
Adverse event profiles ......................................................................................... 29 
10.2. 
Contraception, pregnancy, lactation .................................................................... 29 
11. 
Adverse event and serious adverse event reporting ............................................ 29 
11.1. 
Adverse event reporting ....................................................................................... 29 
11.2. 
Targeted adverse events ....................................................................................... 31 
11.3. 
Otherwise reportable events ................................................................................ 32 
11.4. 
Serious adverse event (SAE) ............................................................................... 32 
11.5. 
Reporting SAEs ................................................................................................... 34 
12. 
Disease assessment, response and progression (RECIST 1.1) ............................ 35 
12.1. 
Introduction ......................................................................................................... 35 
12.2. 
Methods of assessment ........................................................................................ 35 
12.3. 
Measurability of tumor at baseline ...................................................................... 36 


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12.4. 
Selection of target lesions .................................................................................... 37 
12.5. 
Selection of non-target lesions ............................................................................ 37 
12.6. 
Evaluation of target lesions (measurable disease) ............................................... 37 
12.7. 
Evaluation of non-target lesions .......................................................................... 38 
12.8. 
Determination of new lesions .............................................................................. 38 
12.9. 
Additional considerations .................................................................................... 39 
12.10. Determination of time point response ................................................................. 39 
12.11. Determination of best overall response ............................................................... 40 
12.12. Progression-free Survival .................................................................................... 40 
13. 
Clinical and laboratory evaluations and follow-up ............................................. 40 
13.1. 
Screening ............................................................................................................. 40 
13.2. 
Day 1 of every treatment cycle ............................................................................ 41 
13.3. 
Tumor assessments .............................................................................................. 41 
13.4. 
After end of trial treatment .................................................................................. 41 
13.5. 
Follow-up prior to documented disease progression ........................................... 42 
13.6. 
Survival follow-up ............................................................................................... 42 
14. 
Data submission .................................................................................................. 42 
14.1. 
Case report forms schedule .................................................................................. 43 
14.2. 
Signing and submitting forms.............................................................................. 43 
14.3. 
Data management ................................................................................................ 44 
14.4. 
Investigator Site File ............................................................................................ 44 
14.5. 
Authorization log ................................................................................................. 45 
14.6. 
Patient identification log ...................................................................................... 45 
15. 
Statistical considerations ..................................................................................... 45 
15.1. 
Primary Objective ................................................................................................ 46 
15.2. 
Secondary objectives ........................................................................................... 46 
15.3. 
Definitions of Trial Populations .......................................................................... 47 
15.4. 
Interim Analyses .................................................................................................. 47 
15.5. 
Accrual ................................................................................................................. 47 
15.6. 
Data and Safety Monitoring ................................................................................ 48 
16. 
Ethical aspects, regulatory approval, and patient informed consent ................... 48 
16.1. 
Ethical Review Board/Ethics Committee ............................................................ 48 
16.2. 
Regulatory approval procedures .......................................................................... 48 
16.3. 
Protection of human patients ............................................................................... 48 
16.4. 
Informed Consent ................................................................................................ 49 
16.5. 
Premature withdrawal .......................................................................................... 49 
17. 
Governance and Administrative Considerations ................................................. 50 
17.1. 
Insurance .............................................................................................................. 50 
17.2. 
Governance .......................................................................................................... 50 
17.3. 
Data and Safety Monitoring Committee (DSMC) ............................................... 50 
17.4. 
Publication of trial results .................................................................................... 50 
17.5. 
Premature discontinuation of the trial ................................................................. 50 
17.6. 
Quality Assurance................................................................................................ 51 
17.7. 
Protocol adherence .............................................................................................. 51 
17.8. 
Data protection .................................................................................................... 51 
17.9. 
Record Retention ................................................................................................. 52 
18. 
Confidentiality .................................................................................................... 52 
19. 
References ........................................................................................................... 52 
Appendices  
1. 
Informed Consent  


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1. 
Protocol Summary and Schema 
 
Title 
A randomized phase II trial of metronomic oral vinorelbine  plus 
cyclophosphamide and capecitabine (VEX) versus weekly 
paclitaxel as first- or second-line treatment in patients with ER-
positive/HER2-negative advanced or metastatic breast cancer 
Sponsor  
IBCSG 
Clinical Phase 
Randomized Phase II 
Patient population 
Patients 
with 
ER-positive/HER2-negative 
advanced 
or 
metastatic breast cancer 
Treatment 
Patients will be randomized in a 1:1 fashion to 
Arm A: 
Paclitaxel 90 mg/m2 days 1, 8, 15 q4w 
Arm B:  
Cyclophosphamide 50 mg orally once daily  
 
Capecitabine 500 mg, orally 3 times a day 
 
(1500 mg/day) 
 
Vinorelbine 40 mg orally days 1, 3, 5 each 
 
week 
Patients will continue to receive assigned treatment until 
objective progressive disease (PD), symptomatic deterioration, 
unacceptable toxicity, death, or refusal to continue treatment, 
whichever occurs first.  
Patients showing RECIST 1.1 - defined PD can continue with 
trial treatment at the discretion of the Investigator as long as that 
is considered to be in the best interest of the patient and no new 
anticancer treatment is initiated.  
Patients discontinuing the active treatment will enter a follow-up 
phase to document first progression and survival. 
Trial Schema 
 
Background and 
rationale 
Breast cancer (BC) is the most common form of malignant tumor 
in women worldwide and incidence rates are as high as 99.4 per 
100,000 women. Prognosis for patients with locally advanced or 
metastatic disease (ABC) remains poor, with a median survival 
Advanced or
metastatic
ER+ HER2-
Breast Cancer 
Diagnostic CT
Trial treatment
Screening, eligibility
and enrollment
Survival update
Paclitaxel 90 mg/m2 days 1, 8, 15  q4w
until progression or lack of tolerability
CT every 12 weeks until progression
R
Metronomic VEX until progression or lack of tolerability:
Vinorelbine
40 mg p.o. day 1, 3, 5 every week
Cyclophosphamide
50 mg/day p.o. continuous
Capecitabine 
500 mg x 3/day p.o. continuous
12 months after 
last patient randomized
12 months after 
last patient randomized


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of 2–4 years. About 10% of newly diagnosed BC patients present 
with ABC, and 30% to 50% of patients diagnosed at earlier 
stages will subsequently develop metastatic disease. 
In the first-line treatment of HER2 negative ABC patients, 
various chemotherapy regimens can be used including taxanes, 
which are among the most active agents in BC. Single agent 
response rates range from 20 to 50% [Eniu A, 2005]. However, 
eventually all patients will progress with a median time to 
progression of 5 to 7 months. As an example of the single agent 
response rates, in the recent E2100 [Miller K, 2007] and 
AVADO [Miles DW, 2010] randomized phase III trials in first-
line HER2-negative ABC, the response rates were 22% and 46% 
and median progression free survival (PFS) was 5.8 and 8.1 
months, respectively for the paclitaxel and docetaxel control 
arms. A weekly (qw) over a three-weekly (q3w) administration 
schedule of paclitaxel has been shown to be more effective in the 
metastatic as well as in the adjuvant setting after standard 
chemotherapy [Seidman AD, 2008; Sparano JA, 2008]. 
The median time to treatment failure (TTF) for docetaxel was 
investigated in patients previously treated with anthracyclines 
(47.6% pretreated) and ranged between 2.9 months and 5.2 
months [Ando M, 2001]. Weekly docetaxel showed 4.1 months 
of TTF in a subsequent trial [Tabernero J, 2004].  
Results from a multicenter phase II trial showed that median time 
to progression (TTP) for weekly paclitaxel in metastatic breast 
cancer patients was 4.7 months [Perez PA, 2001]. The median 
TTP for patients who had received no prior chemotherapy for 
metastatic disease, one prior regimen, and two prior regimens 
were 5.7 months, 4.6 months, and 2.7 months, respectively. 
Similarly, metastatic breast cancer patients treated with weekly 
paclitaxel (60-90 mg/m2/1 hour iv infusion weekly) until disease 
progression or prohibitive toxicity had a median TTP of 4.86 
months (range, 1.4-12.4) [Gori S, 2002]. Finally, a group of 74 
Japanese ABC patients (48.7% were pre-treated with one line of 
chemotherapy) received paclitaxel by 1 h intravenous infusion at 
a dose of 80 mg/m2 every week. Administration was continued 
for 3 weeks followed by a 1 week rest. The median time to 
progression was 4.8 months [Sato K, 2003]. 
The VEX regimen was recently investigated within a phase II 
trial currently ongoing in Istituto Europeo di Oncologia (IEO) 
(IEO number IEOS582/111; EudraCT Number: 2010-024266-
21; title: “A phase II study of metronomic oral chemotherapy 
with cyclophosphamide plus capecitabine and vinorelbine in 
metastatic breast cancer patients”). Patients received vinorelbine 
40 mg orally on days 1, 3 and 5 every week, cyclophosphamide 
50 mg daily and capecitabine 500 mg 3 times a day. 
Among the 88 patients evaluable for efficacy, 42 were not pre-
treated and 46 were pre-treated for metastatic disease. Median 
age was 54.4 years, 39% of patients had liver involvement. 


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Median time to progression was 26.5 months and 9.6 months for 
untreated and pre-treated patients respectively. The proportion of 
patients free of progression at one year was 73% in the not pre-
treated and 38% in the pre-treated group.  As of January 2016, 
24 patients were still on treatment. A total of 88 patients (42 
untreated and 46 pre-treated) were analyzed for safety. One 
serious adverse event (ischemic heart attack) was reported. In the 
not pre-treated and pre-treated groups, grade 1-2 toxicities 
included nausea (50% and 17%), leucopenia (43% and 30%) 
increased liver enzymes (36% and 41%), hand and foot 
syndrome (26% and 11%). Grade 3 toxicities (hand and foot 
syndrome, hematologic and liver toxicities) were reported in 
17% and 13% not pre-treated and pre-treated patients, 
respectively. No patient experienced grade 4 toxicities.  The trial 
is still ongoing with a target accrual of 100 patients.  
Given the promising activity of the VEX regimen in a pre-treated 
population of advanced breast cancer patients and the good 
tolerability, the aim of the present trial is to investigate whether 
the VEX schedule may improve efficacy and tolerability as 
compared to standard paclitaxel treatment in advanced or 
metastatic ER-positive/HER-2 negative breast cancer patients.  
The concept of the VEX metronomic treatment is to administer 
the combination for as long as the patient has the possibility of 
deriving a benefit from it. The time to treatment failure (TTF) 
has been chosen as primary endpoint for this trial. TTF is defined 
as time from the date of randomization to the date when the final 
dose of trial treatment is administered. Chemotherapy may need 
to be stopped due to lack of tolerability, lack of efficacy or 
patient preference through subjective symptom assessment. TTF 
is a composite endpoint combining all these feasibility aspects of 
a treatment. It is therefore uniquely suited to the research 
question of the current trial. The secondary endpoints 
progression-free survival, disease control and safety will allow 
further assessment of the feasibility of the VEX metronomic 
treatment versus the paclitaxel monotherapy regimen. 
References: 
Eniu A, Palmieri FM, Perez EA. Weekly administration of docetaxel and 
paclitaxel in metastatic or advanced breast cancer. Oncologist 2005; 10: 665-
685. 
Miller K, Wang M, Gralow J et al. Paclitaxel plus bevacizumab versus 
paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357: 2666-
2676. 
Miles DW, Chan A, Dirix LY et al. Phase III study of bevacizumab plus 
docetaxel compared with placebo plus docetaxel for the first-line treatment of 
human epidermal growth factor receptor 2-negative metastatic breast cancer. 
J Clin Oncol 2010; 28: 3239-3247. 
Seidman AD, Berry D, Cirrincione C et al. Randomized phase III trial of 
weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, 
with trastuzumab for all HER-2 overexpressors and random assignment to 


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trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and 
Leukemia Group B protocol 9840. J Clin Oncol 2008; 26: 1642-1649. 
Sparano JA, Wang M, Martino S et al. Weekly paclitaxel in the adjuvant 
treatment of breast cancer. N Engl J Med 2008; 358: 1663-1671. 
Ando M, Watanabe T, Nagata K et al. Efficacy of docetaxel 60 mg/m2 in 
patients with metastatic breast cancer according to the status of anthracycline 
resistance. J Clin Oncol 2001; 19: 336-342. 
Tabernero J, Climent MA, Lluch A et al. A multicentre, randomised phase II 
study of weekly or 3-weekly docetaxel in patients with metastatic breast 
cancer. Ann Oncol 2004; 15: 1358-1365. 
Perez EA, Vogel CL, Irwin DH et al. Multicenter phase II trial of weekly 
paclitaxel in women with metastatic breast cancer. J Clin Oncol 2001; 19: 
4216-4223. 
Gori S, Mosconi AM, Basurtol C et al. Weekly paclitaxel in metastatic breast 
cancer patients: a phase II study. Tumori 2002; 88: 470-473. 
Sato K, Inoue K, Saito T et al. Multicenter phase II trial of weekly paclitaxel 
for advanced or metastatic breast cancer: the Saitama Breast Cancer Clinical 
Study Group (SBCCSG-01). Jpn J Clin Oncol 2003; 33: 371-376. 
Primary Objective 
 
To determine time to treatment failure (TTF) defined as the time 
from the date of randomization to the date when the final dose of 
trial treatment was administered. 
Secondary Objectives 
 Progression free survival (PFS) based on local Investigator 
assessment by RECIST 1.1. 
 Tolerability: adverse events according to CTCAE v4 
 Disease control: best overall response of CR or PR, or SD (or 
non-CR/non-PD in the case of non-measurable disease only) 
lasting for at least 24 weeks, measured from randomization 
until first documentation of progressive disease 
 Overall survival (OS) 
Number of patients 
Randomization of 160 patients during approximately 24 months, 
with an additional 12 months of follow up after randomization of 
the last patient.  
Inclusion criteria 
 Histologically or cytologically confirmed HER2‐negative 
locally advanced or metastatic (stage IV) breast cancer. 
 Maximum one prior line of chemotherapy for advanced or 
metastatic breast cancer. 
 Measurable or non‐measurable, but radiologically evaluable 
(except for skin lesions), disease according to RECIST 1.1 
criteria. 
 Female aged 18 years or older. 
 Life expectancy > 3 months. 
 Eastern Cooperative Oncology Group (ECOG) performance 
status 0 or 1. 
 ER‐positive disease by local laboratory, determined on most 
recent available tissue (latest biopsy of metastatic lesion, 
otherwise prior biopsy or surgical specimen). 
 If previously treated with a taxane in the neoadjuvant or 
adjuvant setting, the period from end of treatment to disease 
recurrence must have been > 12 months (> 365 days). 


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 Radiation therapy, if given and regardless of site, must be 
completed at least 2 weeks prior to randomization. 
 Normal hematologic status,  
- 
Absolute neutrophil count ≥1000/mm3  
(1.0 × 109/L) 
- 
Platelets ≥ 100 × 109/L 
- 
Hemoglobin ≥ 9 g/dL (≥ 90 g/L)). 
 Normal renal function: serum creatinine ≤ 1.5 ULN or 
calculated creatinine clearance ≥ 50mL/min according to the 
Cockcroft-Gault formula. 
 Normal liver function:  
- 
Serum total bilirubin ≤ 1.5 × upper limit of normal 
(ULN). In the case of known Gilbert’s syndrome, a 
higher serum total bilirubin (< 3 × ULN) is allowed 
- 
AST and ALT ≤ 3 × ULN; if the patient has liver 
metastases, ALT and AST must be ≤ 5 × ULN. 
 Women of child bearing potential must have documented 
negative pregnancy test within 2 weeks prior to 
randomization and agree to acceptable (non-hormonal) birth 
control during and up to 6 months after trial therapy.  
 Written Informed Consent (IC) must be signed and dated by 
the patient and the Investigator prior to starting screening 
procedures and randomization. 
 The patient has been informed of and agrees to data transfer 
and handling, in accordance with national data protection 
guidelines. 
Exclusion criteria 
 More than one prior line of chemotherapy for advanced or 
metastatic breast cancer. 
 Previous treatment for advanced or metastatic disease with 
taxanes, 
or 
capecitabine 
or 
vinorelbine 
or 
oral 
cyclophosphamide. 
 More than 2 lines of previous endocrine therapy for locally 
advanced or metastatic breast cancer. 
 Known active central nervous system metastases, as 
indicated by clinical symptoms, cerebral edema, and/or 
progressive growth (patients with history of CNS metastases 
or spinal cord compression are eligible if they are clinically 
and radiologically stable for at least 4 weeks before first dose 
of trial treatment and have not required high-dose steroid 
treatment in the last 4 weeks). 
 Peripheral neuropathy grade 2 or higher (CTCAE version 
4.0). 
 Significant uncontrolled cardiac disease (i.e., unstable 
angina, myocardial infarction within prior 6 months), 
patients classified as having a New York Heart Association 
(NYHA) class III or IV congestive heart failure. 
 Pregnant or lactating. 
 Prior history of non‐breast malignancy (except for 
adequately controlled basal cell carcinoma of the skin, 


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carcinoma in situ of the cervix, in situ carcinoma of the 
bladder). 
 Any concurrent condition which in the Investigator’s opinion 
makes it inappropriate for the patient to participate in the trial 
or which would jeopardize compliance with the protocol. 
 Contraindications or known hypersensitivity to the trial 
medication or excipients. 
 The use of any anti‐cancer investigational agents within 30 
days prior to expected start of trial treatment. 
Assessments 
Efficacy: 
 Tumor assessments according to RECIST v1.1. every 12 
weeks (+2 weeks) until first documented progression. 
 Evaluation of tumor response and progression will be the task 
of the Investigator. Scans will not be centrally reviewed. 
 Follow-up will cease approximately 12 months after 
randomization of the last patient. 
Safety:  
 Laboratory evaluations should be done according to local 
standard of care. 
 Worst grade of adverse events will be recorded at beginning 
of next cycle. 
 All Serious Adverse Events must be notified to IBCSG 
within 24h of Investigator awareness. 
Statistical 
considerations 
Assuming the median TTF of paclitaxel is 4.5 months in this 
population and the median TTF of the VEX regimen is 7.5 
months, with accrual averages of 3 per month for the first 6 
months, 6 per month for the next 6 months, and 9 per month 
steady state for the next 12 months, we will complete recruitment 
of 160 patients within 24 months total accrual period, and we 
anticipate the required 123 TTF events to be available 6 months 
later. The final analysis will thus be based on data collected 
during 36 months from enrollment of the first patient, and results 
will be available within 42 months after enrollment of the first 
patient. The trial will have 80% power to detect the 
aforementioned difference in TTF using a two-sided, 0.05 
significance level for the log-rank test. 
There will be one interim efficacy analysis performed to test for 
futility when 74 TTF events have been observed. 
Randomized patients who received at least one dose of the trial 
treatment will be included in the TTF analysis. For each arm 
separately, TTF distributions will be summarized using the 
method of Kaplan‐Meier and the two‐sided 95% confidence 
interval (CI) for the median TTF will be provided. TTF will be 
compared between groups by a stratified log-rank test using 
stratification factors defined for randomization. 
The toxicities and feasibility of each of the treatment arms will 
be assessed. PFS, OS, disease control rate and other measures of 
disease response will be evaluated for each treatment arm 
separately. 


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2. 
Trial schedule 
(See section 13 for detailed examinations schedule) 
 
 
Screening 
period 28 days 
(35 days for 
imaging) 
At randomi-
zation 
Day 1 of 
every cycle 
(4 weeks) 
≤30 days 
after 
treatment 
stop 
Every  
12 (± 2) 
weeks from 
random. 
until first PD 
- 1st progression 
- Death 
- Status 12 
months after 
last pt 
randomized 
Informed 
consent 
(may be ob-
tained prior to 
28 days scree-
ning period) 
 
 
 
 
 
Eligibility 
X 
Record on 
54-A Form  
 
 
 
 
Clinical 
history 
X 
Record on 
54-A Form 
 
 
 
 
Cardiac eva-
luation: ECG 
X 
 
 
 
 
 
Physical exam 
and vital signs 
X 
 
X *) 
X 
 
 
Hematology: 
NC, TC, Hb 
X 
 
X 
X 
 
 
Biochemistry: 
creatinine, 
bilirubin, 
AST, ALT 
***) 
X 
 
X 
X 
 
 
Pregnancy test 
X 
 
 
 
 
 
Trial 
treatment 
 
 
Record on 
54-Tx A or B 
Form 
 
 
 
Adverse 
events 
 
Record 
baseline 
symptoms on 
54-AE Form 
Record 
worst grade 
on 
54-AE Form 
Record 
worst grade 
on 
54-AE Form 
 
 
Tumor 
measurements 
for RECIST 
1.1 
X  
 
 
 
 
During trial 
treatment 
**), record 
response on 
54-TR Form 
 
1st progression 
 
 
  
 
 
Record on 
54-PD Form, if 
not recorded on 
54-TR Form 
Survival or 
death 
 
 
 
 
 
Record survival 
on 54-E or 
death on 54-
Death Form 
 
X = examination/assessment to be done 
 
  *) Arm B, VEX treatment: in Cycle 1, repeat hematology on Day 15  
**) Report as long as the patient is on:  
Arm A: paclitaxel 
Arm B: all three drugs of the VEX treatment 
***) ALT not mandatory on Day 1 of every cycle 
 
 
 


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3. 
List of abbreviations 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
AST  
Aspartate transaminase 
CI 
Confidence interval 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed tomography 
CTCAE 
Common toxicity criteria for adverse events 
DMC 
Data Management Center 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EoT 
End of Treatment 
ER 
Estrogen receptor 
ERB 
Ethical Review Board 
FSTRF 
Frontier Science and Technology Research Foundation 
GCP 
Good clinical practice 
HER2 
human epidermal growth factor receptor 2 
HR 
Hazard Ratio 
IBCSG 
International Breast Cancer Study Group 
IC 
Informed consent 
ICH 
International Conference on Harmonization 
iDF 
iDataFax 
IRB 
Institutional Review Board 
MBC 
Metastatic breast cancer 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NYHA 
New York Heart Association 
OHRP 
Office for Human Research Protection 
ORR 
Overall response rate 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression free survival 
PI 
Principal Investigator 
PIS/IC 
Patient information sheet / informed consent 
PR 
Partial response 
PS 
Performance status 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SD 
Stable disease 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
ULN 
Upper limit of normal 
VEX 
vinorelbine, cyclophosphamide, capecitabine 
 
 


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4. 
Background and scientific rationale 
4.1. 
Breast cancer 
Breast cancer (BC) is the most common form of malignant tumor in women worldwide, and 
incidence rates are as high as 99.4 per 100,000 women (World Health Organization 2011). 
Prognosis for patients with locally advanced or metastatic disease (ABC) remains poor, with 
a median survival of 2–4 years. About 10% of newly diagnosed BC patients present with 
ABC, and 30% to 50% of patients diagnosed at earlier stages will subsequently develop 
metastatic disease. Although many cytotoxic agents are active in breast cancer, advanced 
disease remains incurable and new treatment strategies are urgently needed. A large number 
of targeted anticancer agents are currently emerging, and some of these could be applicable 
to the treatment of advanced breast cancer. At the same time, breast cancer subtypes are being 
defined in far greater detail by molecular profiling [1]. As breast cancer is a heterogeneous 
disease, biological characteristics should be taken into account when deciding the most 
appropriate treatment strategy. 
Luminal HER2-negative BC represents 60–65% of all newly diagnosed patients. Although 
prognosis in this subtype is generally good, still many women will relapse and luminal HER2-
negative BC remains the most common subtype among metastatic breast cancer (MBC) 
patients [2]. 
Because of the chemosensitivity of this disease, the large majority of patients are, or 
eventually become, candidates for chemotherapy, either upfront or after failure of hormone 
therapy in endocrine‐sensitive disease. 
In this disease setting, where palliation is the primary goal of treatment and life expectancy is 
limited, toxicity and quality of life become important factors when deciding on therapeutic 
agents and schedules. In particular, in an attempt to improve the tolerability of prolonged 
chemotherapy administration, while maintaining and possibly improving treatment efficacy, 
alternative chemotherapy schedules and modalities, even with lower dosages, could be 
explored in this disease setting. 
4.2. 
Treatment of advanced breast cancer 
Classic cytotoxic chemotherapy still plays a major role in the management of MBC. A change 
in the paradigm of MBC chemotherapy has led, in the majority of patients, to replacement of 
aggressive, multidrug regimens by sequential single-agent therapies. 
In the first-line treatment of HER2-negative ABC patients, various chemotherapy regimens 
can be used including taxanes, which are among the most active agents in BC. Single agent 
response rates range from 20% to 50% [3]. However, eventually all patients will progress 
with a median time to progression of 5 to 7 months. As an example of the single agent 
response rates, in the recent E2100 [4] and AVADO [5] randomized phase III trials in first-
line HER2-negative ABC, the response rates were 22% and 46% and median progression free 
survival (PFS) was 5.8 and 8.1 months, respectively for the paclitaxel and docetaxel control 
arms. A weekly (qw) over a three-weekly (q3w) administration schedule of paclitaxel has 
been shown to be more effective in the metastatic as well as in the adjuvant setting after 
standard chemotherapy [6, 7]. 


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The median time to treatment failure (TTF) for docetaxel was investigated in patients 
previously treated with anthracyclines and ranged between 2.9 months and 5.2 months [8]. 
Weekly docetaxel showed 4.1 months of TTF in a subsequent trial [9]. In this trial, 52.4% of 
the patients were not pretreated, and the remaining were pretreated with at least one line of 
chemotherapy. 
Results from a multicenter phase II trial showed that median time to progression (TTP) for 
weekly paclitaxel in metastatic breast cancer patients was 4.7 months [10]. Specifically, the 
median TTP for patients who had received no prior chemotherapy for metastatic disease, one 
prior regimen, and two prior regimens were 5.7 months, 4.6 months, and 2.7 months, 
respectively. Similarly, metastatic breast cancer patients treated with weekly paclitaxel (60-
90 mg/m2/1 hour iv infusion/weekly) until disease progression or prohibitive toxicity had a 
median TTP of 4.86 months (range, 1.4-12.4) [11]. Finally, a group of 74 Japanese ABC 
patients received paclitaxel by 1 h intravenous infusion at a dose of 80 mg/m2 every week. 
Administration was continued for 3 weeks followed by a 1 week rest. The median time to 
progression was 4.8 months [12]. In this trial, 21.6% of the patients were not pretreated and 
48.7% were pre-treated with only one line of chemotherapy. 
4.3. 
Metronomic chemotherapy 
Metronomic chemotherapy is a dosing-schedule strategy that includes a frequent, even daily, 
administration of chemotherapeutics at doses significantly below the maximum tolerated dose 
(MTD). No prolonged drug-free breaks are planned [13]. The metronomic approach 
significantly reduces toxicities and the need for growth-factor support to accelerate recovery 
from myelosuppression. Unlike dose-dense chemotherapy, which mainly targets proliferating 
tumor cells, the main targets of continuous metronomic chemotherapy are the endothelial cells 
of the growing vasculature of a tumor [14]. 
Another potential mechanism of action of agents included in a metronomic schedule is the 
DNA damage induced by continuous exposure. Therapies producing continuous DNA 
damage may significantly improve response rate and reduce the burden of chemotherapy 
related toxicity. Moreover the protracted exposure to low doses of chemotherapeutics has an 
antiangiogenic activity if compared with their cyclic administration at the maximum-tolerated 
dose [15]. 
The restoration of the anticancer effect of the immune system is among the new mechanisms 
identified for metronomic chemotherapy. There is growing evidence that anticancer immune 
responses can be crucial for the long-term control of cancer treated with chemotherapy [16]. 
In fact, some chemotherapeutic drugs (such as cyclophosphamide) may exert a beneficial 
effect by increasing antitumor immunity [17], and ultra-low noncytotoxic concentrations of 
selected antineoplastic agents might modulate the immune system [18]. 
4.3.1. 
Metronomic Cyclophosphamide and Capecitabine 
The first trial using metronomic chemotherapy, conducted at the European Institute of 
Oncology, involved the administration of oral cyclophosphamide 50 mg daily and oral 
methotrexate 2.5 mg twice daily two days per week (CM regimen). Among 63 evaluable 
patients previously treated for metastatic breast cancer, this regimen yielded a response rate 


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of 19% and a clinical benefit (CB), defined as either objective response or stable disease 
longer than 24 weeks, of 32%, in the absence of serious toxicity, with a marked drop in 
circulating VEGF [19]. In a subsequent study at the same institution, 171 patients with ABC, 
either pre-treated or not with chemotherapy, were randomized to CM alone or CM + 
thalidomide. In this less heavily pretreated group of patients, CM alone yielded an objective 
response rate of 20.9% (95% CI 12.9-31.0%) and an overall CB of 41.5% (95% CI 34.0-
49.3%) [20]. 
Capecitabine is an orally administered prodrug of fluorouracil and it is metabolically activated 
preferentially at the tumor site. Capecitabine shows antineoplastic activity and synergy with 
other cytotoxic agents including cyclophosphamide or docetaxel in animal models. 
Bioavailability after oral administration is close to 100%. 
Its daily administration mimics the activity of a continuous intravenous infusion of 
fluorouracil, which has been shown to exert antiangiogenic activity in preclinical models. For 
its pharmacokinetic and toxicological features, capecitabine seems particularly suitable for 
metronomic administration. 
Metronomic capecitabine has also proven antiangiogenic effects in tumor models of breast 
cancer [21]. 
In two small randomized trials, continuous use of low dose capecitabine (650 or 800 mg/m2 
b.i.d. with no drug-free breaks) proved to be just as effective in MBC patients as intermittent 
use of higher doses (1000 or 1250 mg/m2 b.i.d. days 1–14 every 21 days) [22, 23].  
Taguchi et al used a low dose schedule of capecitabine (852 mg/m2 twice daily on days 1-21 
of a 28-day cycle) as first-line therapy for 33 MBC patients. The authors reported a median 
progression free survival (PFS) of 6.9 months, with an overall survival (OS) of 24.8 months. 
Grade 3 toxicities included hand and foot syndrome (15%) and neutropenia (6%) [24]. 
The metronomic schedule of capecitabine was also evaluated in heavily pretreated patients 
with MBC. Sixty patients received oral capecitabine in a single daily dose of 1500 mg. The 
CB was 62% and the OS was 17 months. Grade 3–4 adverse events were uncommon [25]. 
Other studies evaluated the efficacy and safety of an all-oral doublet combination of 
cyclophosphamide and capecitabine. In the study of Wang et al, 68 anthracycline- and taxane-
pretreated MBC patients received 21-day cycles of oral cyclophosphamide (65 mg/m2 daily) 
and oral capecitabine (1,000 mg/m2 twice daily on days 1–14 followed by a 7-day rest period). 
The median time to progression was 5.2 months and the OS was 16.9 months. The overall 
response rate (ORR) and CB were 30.3% and 53.0%, respectively. Treatment was well 
tolerated, and grade 3 hand–foot syndrome was reported by 4.4% of patients [26].  
The same combination of metronomic chemotherapy with different dosages was evaluated in 
the study of Yoshimoto M et al. Fifty-one patients received capecitabine 828 mg/m2 twice 
daily with cyclophosphamide 33 mg/m2 twice daily, days 1–14 every 3 weeks. ORR was 
44.4% and the CB was 57.8%. Hematologic toxicity included grade 3 leucopenia (26%) and 
neutropenia (16%). No grade 3 hand-foot syndrome was reported [27]. 
 
 


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4.3.2. 
Oral Vinorelbine and the Metronomic Schedule 
Vinorelbine (VRL), 5’nor-anhydrovinblastine, is a semi-synthetic vinca-alkaloid, which 
differs from other vinca-alkaloids by a modification of the catharanthine moiety [28, 29]. 
The mechanism of action of VRL is similar to that of other vinca-alkaloids, i.e., disruption of 
microtubules by their reversible binding to tubulin resulting in mitotic spindle dissolution and 
metaphase arrest in dividing cells. The inhibition of tubulin polymerisation with VRL is equal 
to or greater than with vindesine. The new oral formulation of vinorelbine (VRL) was 
introduced in clinical studies in 1994. The metronomic schedule of oral vinorelbine was tested 
in patients with metastatic cancer [30] at a dose of 50 mg three times a week as the tested 
metronomic schedule [31-33]. 
Oral vinorelbine at 70 mg/m2, on days 1, 3, and 5, for 3 weeks on and 1 week off, every 4 
weeks, was assessed in 34 elderly patients with metastatic breast cancer (median age 74 years) 
[34]. The ORR in 13 patients was 38%, and median PFS and overall survival were 7.7 months 
(95% CI 6.9–9.05 months) and 15.9 months (95% CI 13.1–15.91 months), respectively.  
Escalating doses of oral metronomic vinorelbine (starting dose 30 mg every other day) and 
capecitabine (starting dose 800 mg/m2 twice daily on days 1–14) were investigated in 36 
patients. The recommended doses were 60 mg vinorelbine and 1,250 mg/m2 capecitabine. 
[35].  The main toxicities were grade 2–3 neutropenia, anaemia, and nausea/vomiting, which 
were reported in fewer than 16.5% of patients. 
4.4. 
The VEX regimen 
The VEX regimen was recently investigated within a phase II trial currently ongoing in 
Istituto Europeo di Oncologia (IEO) (IEO number IEOS582/111; EudraCT Number: 2010-
024266-21; title: “A phase II study of metronomic oral chemotherapy with cyclophosphamide 
plus capecitabine and vinorelbine in metastatic breast cancer patients”). Patients received 
vinorelbine 40 mg orally on days 1, 3 and 5 every week, cyclophosphamide 50 mg daily and 
capecitabine 500 mg 3 times a day. 
Among the 88 patients evaluable for efficacy, 42 were not pre-treated and 46 were pre-treated 
for metastatic disease. Median age was 54.4 years, 39% of patients had liver involvement. 
Median time to progression was 26.5 months and 9.6 months for untreated and pre-treated 
patients respectively. The proportion of patients free of progression at one year was 73% in 
the not pre-treated and 38% in the pre-treated group.  As of January 2016, 24 patients were 
still on treatment. A total of 88 patients (42 untreated and 46 pre-treated) were analyzed for 
safety. One serious adverse event (ischemic heart attack) was reported. The following table 
(presented at the IBCSG Annual Meeting on March 12, 2016) gives an overview of toxicities 
in 42 not pre-treated and 46 pre-treated patients: 
Untreated 
N=42 
Pretreated 
N=46 
G1 
G2 
G3 
G4 
G1 
G2 
G3 
G4 
Nausea 
21 
- 
- 
- 
8 
- 
1 
- 
Diarrhea 
19 
- 
- 
- 
14 
- 
- 
- 
Neutropenia 
- 
- 
2 
- 
- 
- 
1 
- 


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Leucopenia 
2 
16 
- 
- 
8 
6 
1 
- 
Anemia 
- 
- 
1 
- 
- 
- 
- 
Hand-foot syndrome 
5 
6 
2 
- 
- 
5 
2 
- 
increased AST/ALT 
9 
6 
2 
- 
17 
2 
- 
- 
Alopecia 
- 
- 
- 
- 
- 
- 
- 
- 
Astenia 
- 
- 
- 
- 
14 
- 
- 
- 
Mucositis 
- 
- 
- 
- 
- 
- 
1 
- 
No alopecia was observed. No patients experienced grade 4 toxicities.  The trial is still 
ongoing with a target accrual of 100 patients.  
4.5. 
Trial hypothesis 
Based on the above mentioned efficacy data for the VEX regimen, we hypothesize that this 
regimen will be better tolerated and will result in longer time on treatment for women with 
ER-positive, HER2-negative, metastatic or locally advanced breast cancer, as compared to 
the standard paclitaxel monotherapy. 
4.6. 
Overall risk-benefit assessment 
The metastatic or advanced setting was chosen to evaluate this new therapy combination. The 
setting of incurable disease is acceptable to justify the evaluation of a potential new 
combination in breast cancer. Preliminary results from the pilot trial provide evidence of good 
tolerability and promising activity for the delivery of metronomic therapy with vinorelbine, 
cyclophosphamide and capecitabine in this patient population. 
4.7. 
Rationale for the trial design 
A 1:1 randomization will be performed to compare the metronomic VEX regimen with the 
conventional paclitaxel monotherapy. The presence of a randomized control arm will allow 
to assess the efficacy and tolerability of the metronomic regimen in a controlled fashion. The 
trial uses an open label design without blinding of treatments, as one treatment arm is 
administered orally, while the other is administered intravenously. 
The concept of the VEX metronomic treatment is to administer the combination for as long 
as the patient has the possibility of deriving a benefit from it. The time to treatment failure 
(TTF) has been chosen as primary endpoint for this trial. TTF is defined as time from the date 
of randomization to the date when the final dose of trial treatment is administered. 
Chemotherapy may need to be stopped due to lack of tolerability, lack of efficacy or patient 
preference through subjective symptom assessment. TTF is a composite endpoint combining 
all these feasibility aspects of a treatment. It is therefore uniquely suited to the research 
question of the current trial. The secondary endpoints progression-free survival, disease 
control and safety will allow further assessment of the feasibility of the VEX metronomic 
treatment versus the paclitaxel monotherapy regimen. 


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5. 
Trial objectives and endpoints 
5.1. 
Primary objective 
The primary objective of the trial is to assess the combination of efficacy and tolerability, as 
measured by the time to treatment failure (TTF), of the first- or second-line combination 
treatment with vinorelbine, cyclophosphamide and capecitabine in comparison with paclitaxel 
monotherapy in estrogen receptor positive (ER+) and human epidermal growth factor receptor 
2 negative (HER2–), metastatic or locally advanced breast cancer patients, who need first- or 
second-line chemotherapy. 
5.2. 
Primary endpoint 
Time to treatment failure (TTF) is defined as the time from the date of randomization to the 
date when the final dose of trial treatment was administered. 
5.3. 
Secondary objectives 
To evaluate: 
 
Progression-free survival (PFS) based on local Investigator assessment by RECIST 1.1 
 
Safety and tolerability, as documented according to NCI CTCAE v4.0 
 
Disease control, based on RECIST 1.1 criteria 
 
Overall survival (OS) 
Secondary endpoints are defined in section 15.2. 
6. 
Trial design, duration and termination 
6.1. 
Trial design 
This is a multi-center, randomized phase II trial that will randomize women with ER-positive, 
HER2-negative, advanced or metastatic breast cancer in a ratio of 1:1 to receive a metronomic 
regimen of vinorelbine, cyclophosphamide and capecitabine or the conventional paclitaxel 
monotherapy. 
6.2. 
Trial schema 
 
Advanced or
metastatic
ER+ HER2-
Breast Cancer 
Diagnostic CT
Trial treatment
Screening, eligibility
and enrollment
Survival update
Paclitaxel 90 mg/m2 days 1, 8, 15  q4w
until progression or lack of tolerability
CT every 12 weeks until progression
R
Metronomic VEX until progression or lack of tolerability:
Vinorelbine
40 mg p.o. day 1, 3, 5 every week
Cyclophosphamide
50 mg/day p.o. continuous
Capecitabine 
500 mg x 3/day p.o. continuous
12 months after 
last patient randomized
12 months after 
last patient randomized


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6.3. 
Sample size and trial duration 
The trial will randomize a total of 160 patients. 
Patients will be enrolled at approximately 20 sites in Italy. 
The enrollment is expected to occur over a period of 24 months with accrual averages of 3 
per month for the first 6 months, 6 per month for the next 6 months, and 9 per month steady 
state for the next 12 months. Individual patients’ trial participation ends with the final 
documentation of survival status 12 months after the randomization of the last patient. Clinical 
visits are expected to span approximately 36 months after enrollment of the first patient. The 
final trial analysis is expected 42 months after the randomization of the first patient. 
7. 
Patient selection 
7.1. 
Inclusion criteria  
7.1.1. 
Histologically or cytologically confirmed HER2‐negative locally advanced or 
metastatic (stage IV) breast cancer. 
7.1.2. 
Maximum of one prior line of chemotherapy for advanced or metastatic breast 
cancer. 
7.1.3. 
Measurable or non‐measurable, but radiologically evaluable (except for skin 
lesions), disease according to RECIST 1.1 criteria. 
7.1.4. 
Female aged 18 years or older. 
7.1.5. 
Life expectancy > 3 months. 
7.1.6. 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (see Table 
1 below). 
7.1.7. 
ER‐positive disease by local laboratory, determined on most recent available tissue 
(latest biopsy of metastatic lesion, otherwise prior biopsy or surgical specimen). 
7.1.8. 
If previously treated with a taxane in the neoadjuvant or adjuvant setting, the period 
from end of treatment to disease recurrence must have been > 12 months (> 365 
days). 
7.1.9. 
Radiation therapy, if given and regardless of site, must be completed at least 2 weeks 
prior to randomization. 
7.1.10. Normal hematologic status:  
- 
Absolute neutrophil count ≥1000/mm3 (1.0 × 109/L) 
- 
Platelets ≥ 100 × 109/L 
- 
Hemoglobin ≥ 9 g/dL (≥ 90 g/L)). 
7.1.11. Normal renal function: serum creatinine ≤ 1.5 ULN or calculated creatinine 
clearance ≥ 50mL/min according to the Cockcroft-Gault formula. 
7.1.12. Normal liver function:  


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- 
Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). In the case of 
known Gilbert’s syndrome, a higher serum total bilirubin (< 3 × ULN) is 
allowed 
- 
AST and ALT ≤ 3 × ULN; if the patient has liver metastases, ALT and AST 
must be ≤ 5 × ULN. 
7.1.13. Women of child bearing potential must have a documented negative pregnancy test 
within 2 weeks prior to randomization and agree to acceptable birth control (non-
hormonal, see section 10.2) during and up to 6 months after trial therapy.  
7.1.14. Written Informed Consent (IC) must be signed and dated by the patient and the 
Investigator prior to starting screening procedures and randomization. 
7.1.15. The patient has been informed of and agrees to data transfer and handling, in 
accordance with national data protection guidelines. 
7.2. 
Exclusion criteria 
7.2.1. 
More than one prior line of chemotherapy for advanced or metastatic breast cancer. 
7.2.2. 
Previous treatment for advanced or metastatic disease with taxanes, or capecitabine 
or vinorelbine or oral cyclophosphamide. 
7.2.3. 
More than 2 lines of previous endocrine therapy for locally advanced or metastatic 
breast cancer. 
7.2.4. 
Known active central nervous system metastases, as indicated by clinical symptoms, 
cerebral edema, and/or progressive growth (patients with history of CNS metastases 
or spinal cord compression are eligible if they are clinically and radiologically stable 
for at least 4 weeks before first dose of trial treatment and have not required high-
dose steroid treatment in the last 4 weeks). 
7.2.5. 
Peripheral neuropathy grade 2 or higher (CTCAE version 4.0). 
7.2.6. 
Significant uncontrolled cardiac disease (i.e., unstable angina, myocardial infarction 
within prior 6 months), patients classified as having a New York Heart Association 
(NYHA) class III or IV congestive heart failure (see Table 2 below). 
7.2.7. 
Pregnant or lactating. 
7.2.8. 
Prior history of non‐breast malignancy (except for adequately controlled basal cell 
carcinoma of the skin, carcinoma in situ of the cervix, in situ carcinoma of the 
bladder). 
7.2.9. 
Any concurrent condition which in the Investigator’s opinion makes it inappropriate 
for the patient to participate in the trial or which would jeopardize compliance with 
the protocol. 
7.2.10. Contraindications or known hypersensitivity to the trial medication or excipients. 
7.2.11. The use of any anti‐cancer investigational agents within 30 days prior to expected 
start of trial treatment. 


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Table 1. 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction. 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light housework, office work. 
PS 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. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
Table 2. 
NYHA functional classification 
Class 
Functional Capacity: How a patient with cardiac disease feels during physical activity 
I 
Patients with cardiac disease but resulting in no limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or 
anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea or 
anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be present 
even at rest. If any physical activity is undertaken, discomfort increases. 
8. 
Randomization and stratification 
This trial will use a web-based randomization system. Specific details for randomization are 
in the “IBCSG Registration/Randomization Procedures Manual” which is available on the 
IBCSG website (www.ibcsg.org). 
 
8.1. 
Patient randomization procedure 
8.1.1. 
Patient must sign informed consent to trial participation prior to screening 
procedures. 
8.1.2. 
Screening procedures need to be done within 28 days before randomization (35 days 
for imaging) in order to verify eligibility (see section 7).  
8.1.3. 
Access the IBCSG Registration/Randomization System (Step 1: Randomization) and 
provide the requested information as indicated on the Confirmation of Registration 
(54-A) Form. The date the Informed Consent Form was signed by the patient and the 
date signed by the Investigator are both required to complete randomization. 
The Randomization System will provide the following information via email: 
 Patient ID (randomization number)  
 Treatment assignment 


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 Date of randomization  
8.1.4. 
Submit the Confirmation of Registration (54-A) electronic case report form (eCRF) 
via iDataFax. The patient binder of eCRFs will be available in iDataFax within 24 
hours of successful randomization.    
8.2. 
Randomization Help Desk 
The IBCSG Data Management Center (located at Frontier Science and Technology Research 
Foundation (FSTRF)) is responsible for developing and maintaining the IBCSG 
Registration/Randomization System. The Help Desk includes technical personnel and 
administrators of the registration programs at the Data Management Center in Amherst, NY, 
USA. 
The Help Desk is available round the clock 7 days per week, except for New Year's Eve, 
Memorial Day, Independence Day, Thanksgiving Day, Christmas Day.  
FSTRF Randomization Help Desk 
Frontier Science & Technology Research Foundation (FSTRF) 
4033 Maple Rd, Amherst, NY 14226 USA 
Phone: +1 716 834 0900 Extension 7301 
Fax: +1 716 832-8437 
Email: bc.helpdesk@fstrf.org  
8.3. 
Stratification 
For randomization, patients will be stratified by 
 Prior treatment for locally advanced or metastatic disease (no prior endocrine therapy or 
chemotherapy; prior endocrine therapy only; prior chemotherapy ± prior endocrine 
therapy) 
 ECOG performance status 0 vs 1 
Dynamic institution balancing will be done in order to balance randomized assignments 
within institutions. 
8.4. 
Randomized Treatment Assignment  
Patients will be randomized in a ratio of 1:1 to receive 
 Arm A: conventional paclitaxel monotherapy 
 Arm B: metronomic regimen of vinorelbine, cyclophosphamide and capecitabine 
9. 
Treatment 
Paclitaxel, vinorelbine, cyclophosphamide and capecitabine will be administered in this trial. 
All drugs are commercially available and are used in clinical practice to treat advanced breast 
cancer. They will be locally sourced. No drugs will be supplied by the Sponsor. Labelling 
should be done following the local procedures and guidelines, if applicable. 
Storage and handling will be according to local pharmacy standards; please consult also the 
respective SPCs at https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/ 


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9.1. 
Trial treatments 
Trial treatment should start within one week after randomization. Trial treatments will be 
administered in 4-week (28-day) cycles until progression, lack of tolerability, or until further 
trial treatment is declined (see section 9.5).  
Treatment administration should comply with the protocol; compliance will be monitored by 
the Monitoring Team and/or Data Management Center. Details of dispensation and dosing are 
recorded on the eCRF. Patients on the experimental arm (Arm B) will be handed a patient 
diary on which they should be reminded to record all doses taken during one cycle. The patient 
should return the completed diary at the next visit. 
9.2. 
Treatment Administration 
Paclitaxel will be administered according to standard local practice. 
Arm A  Paclitaxel 90 mg/m2 i.v. days 1, 8, 15 every 4 weeks, according to standard local 
practice 
Treatment with the combination vinorelbine, cyclophosphamide and capecitabine is referred 
to as “VEX treatment” and will be administered as follows 
Arm B Cyclophosphamide 50 mg orally once daily around 9am 
Capecitabine 500 mg, orally 3 times a day (total 1500 mg/day) within 30 minutes 
after meals (breakfast, lunch, dinner)  
Vinorelbine 40 mg orally days 1, 3, 5 each week (Monday, Wednesday, Friday) after 
lunch 
9.3. 
Dose modifications and delays for paclitaxel 
Refer to standard of care guidance or current clinical practice or currently approved Italian 
SPC for patients receiving paclitaxel, see also 
https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/ 
For re-dosing with weekly paclitaxel, courses of paclitaxel should not be repeated until the 
neutrophil count is at least 1000 cells/mm3 and the platelet count is at least 100,000 cells/mm3 
and in the absence of active infection. Patients who experience CTCAE Grade 4 
thrombocytopenia (platelets <25,000/mm3) or CTCAE Grade 3 peripheral neuropathy lasting 
< 7 days during paclitaxel therapy, should have dosage reduced by 20% for the subsequent 
course.  
In the event that elevated liver function tests (LFT) (greater than three times the baseline 
values of AST/ ALT or greater than twice the baseline values ALP) are determined on a day 
that the patient is scheduled to receive treatment, paclitaxel therapy will be held and the values 
repeated weekly. If LFT elevation is persistent > 21 days and not due to progressive disease, 
the patient should permanently discontinue paclitaxel. 
If values decrease within 14 days to grade ≤1, the patient may be retreated at the same 
paclitaxel dose. If within 1 week the patient again has an increase in LFTs (greater than three 
times the baseline values of AST/ ALT or greater than twice the baseline values of ALP), 
paclitaxel therapy will be held and the values assessed weekly. The patient may subsequently 
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should not be reduced to less than 80% of 90 mg/m2, otherwise treatment should be stopped 
permanently. 
Paclitaxel dosing can be delayed by a maximum of 3 weeks (maximum 5 weeks from last 
dose of previous cycle). 
9.4. 
Dose modifications and delays for VEX 
Refer to standard of care guidance or current clinical practice or currently approved Italian 
Summary of Product Characteristics (SPC) for patients receiving vinorelbine, 
cyclophosphamide 
and 
capecitabine 
(VEX) 
treatment, 
see 
also 
https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/ 
9.4.1. 
Hematological toxicity 
Complete blood count must be repeated every 4 weeks during the treatment. 
Vinorelbine (V), cyclophosphamide (E) and capecitabine (X) will be administered at full dose 
if neutrophils are equal to or greater than 1500/mm3 and platelets are equal to or greater than 
100.000/mm3. If granulocytes and/or platelets are lower than these values, treatment will be 
administered according to the following criteria: 
 
Neutrophils 
 
Grade 0 or 1: 
>1.5 × 109/L 
Grade 2: 
1.0 – 1.5 × 109/L 
Grade ≥3 
<1.0 × 109/L 
Platelets 
Percentage of dose to be administered 
≥100 × 109/L 
Continue V, E and 
X at 100% dose 
Continue X at 
67%**, and V and E 
at 50%* dose 
Hold until resolved 
to Grade ≤1, then 
continue X at 
67%**, and V and E 
at 50%* dose 
Grade 1: 
75 - 99 × 109/L 
Continue X at 
67%**, and V and E 
at 50%* dose 
Hold until resolved 
to Grade ≤1, then 
continue with 100% 
dose 
Hold until resolved 
to Grade ≤1, then 
continue X at 
67%**, and V and E 
at 50%* dose 
Grade ≥2: 
<75 × 109/L 
Hold until resolved 
to Grade ≤1, then 
continue X at 
67%**, and V and E 
at 50%* dose 
Hold until resolved 
to Grade ≤1, then 
continue X at 
67%**, and V and E 
at 50%* dose 
Hold until resolved 
to Grade ≤1, then 
continue X at 
67%**, and V and E 
at 50%* dose 
* To achieve a 50% reduction of vinorelbine (V), patients will take 1 capsule of 20 mg 3 
times a week 
* To achieve a 50% dose reduction of cyclophosphamide (E), patients will take a tablet 
every other day; 
** To achieve a 33% dose reduction of capecitabine (X), patients will take 1 tablet twice 
daily 
 


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If the hematological toxicity resolves to a grade of 1 or less, the dose may be escalated to the 
previous level at the Investigator’s discretion. 
Any platelets toxicity of grade ≥2 and granulocytes toxicity of grade ≥3 should be managed 
with temporary interruption of all chemotherapeutic agents until recovery at least to a grade 
1, when treatment may be resumed with a 50% dose reduction. Re-escalation of drug doses 
should only be attempted if close monitoring is possible. 
9.4.2. 
Non-hematological toxicity 
Renal dysfunction: Cyclophosphamide, vinorelbine and capecitabine should be administered 
only in presence of normal renal function or grade 1 renal toxicity (serum creatinine < 1.5 
upper normal limits and/or creatinine clearance ≥50 mL/min/1.73 m2). 
Cystitis: All patients should be instructed as to the importance of maintaining high fluid 
intake during cyclophosphamide therapy. If grade ≤2 cystitis occurs despite hydration, 
cyclophosphamide treatment should be stopped until recovery, and therapy with 
acetylcysteine, 1 tablet of 600 mg daily, should be administered until recovery, with the 
addition of antibiotic therapy in presence of fever. In case of repeated episodes of grade 2 
cystitis, cyclophosphamide should be restarted, after resolution to at least grade 1, at 50% of 
dose. In case of grade ≥3 cystitis, cyclophosphamide should be permanently stopped. 
Hepatic toxicity: If grade >2 hepatic toxicity occurs, vinorelbine (V), cyclophosphamide (E), 
and capecitabine (X) should be withheld until recovery to at least grade 1, and treatment with 
ademetionine may be administered. 
Gastrointestinal toxicity: In case of grade ≥2 vomiting, stomatitis, or diarrhea, vinorelbine 
(V), cyclophosphamide (E), and capecitabine (X) should be stopped. Treatment may be 
resumed after recovery at least to grade 1 toxicity, starting with 50% dosage for E and V and 
67% for X, with subsequent re-escalation to full dosage if tolerated. 
Hand-foot syndrome: In case of grade 1 hand-foot syndrome, hydrating topic therapy should 
be started and capecitabine will be continued. In case of no benefit, as well as in case of grade 
2 toxicity, the dose of capecitabine will be reduced to 67% (1 tablet twice daily) until recovery 
to at least grade 1. In case of grade 3 toxicity, capecitabine will be temporarily interrupted 
and resumed at 67% dose only after recovery to at least grade 1 toxicity, with subsequent re-
escalation if tolerated. 
Other toxicity: If deemed necessary, dosage may be reduced for other toxicities. 
VEX treatment can be delayed by a maximum of 3 weeks (21 days) from the date of the last 
dose; in case of a longer delay, trial treatment has to stop (refer to note in section 9.5). 
9.5. 
End of trial treatment  
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance.  
The treatment of the individual patient will be discontinued in case of: 
 Disease progression according to RECIST 1.1. as defined in section 12. 
 Unacceptable adverse event(s). 


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 Delay of trial treatment by more than 3 weeks.  
 Intercurrent illness that prevents further administration of trial treatment. 
 Patient demonstrates an inability or unwillingness to comply with the treatment 
regimen and/or trial requirements. 
 General or specific changes in the patient’s condition which render her 
unacceptable for further trial treatment in the opinion of the treating Investigator. 
 Patient withdraws consent to continue trial treatment. 
Note: In Arm B (VEX), trial treatment is considered stopped as soon as one of the three drugs 
is stopped permanently. However, treatment with one or two of the VEX medications may be 
continued. 
For patients who discontinue treatment for any reason other than objective disease 
progression, the date of first progression needs to be documented on the 54-PD Form. If the 
patient has not progressed yet, the date of the last visit will be reported on the 54-E Form, 12 
months after the last patient was randomized. 
After the trial treatment is stopped, future therapeutic decisions are at the discretion of the 
Investigator, with no restrictions. Patients showing RECIST 1.1 - defined PD can continue 
with trial treatment at the discretion of the Investigator as long as that is considered to be in 
the best interest of the patient and no new anticancer treatment is initiated. 
The End of Treatment (EoT) is defined as the date of  
 Arm A: the last dose of paclitaxel 
 Arm B:  the date when at least one of the three VEX drugs was administered for 
the last time  
An end of treatment visit will be conducted within 30 days after EoT to report on any adverse 
events during this period (safety data). 
In the absence of tumor progression, the patient will continue to be followed for SAE reporting 
according to a section 11.5 and for documented disease progression or a maximum of 12 
months after randomization of the last patient, see section 13.5.  
9.6. 
Removal from the trial 
After a patient has been randomized, she becomes part of the clinical trial population and 
cannot be removed from the trial for any reason. If the patient decides to withdraw consent 
and declines any further participation with the trial requirements and/or declines further 
collection of data (see Section 16.5), the data recorded up to the time point of withdrawal will 
continue to be evaluated in the trial. If the patient discontinues treatment for any of the reasons 
listed in the prior subsection other than disease progression, she should continue to be 
followed according to the protocol (see Section 9.5) and eCRFs should be completed as 
described in Section 14.1. 
Patients who have been randomized but never received any trial treatment for whatever reason 
(refusal, medical condition etc.) will have to be documented with a treatment form 54-TX A 
or 54-TX B (see section 13.4) stating this fact, but will not be followed further. 


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10. 
Safety 
10.1. 
Adverse event profiles 
The safety and adverse event profiles of the four drugs which constitute the trial treatment are 
well known. For details please refer to 
https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/ 
10.2. 
Contraception, pregnancy, lactation 
Trial treatment may have adverse effects on a fetus in utero. Non-pregnant, non-breast-
feeding women of childbearing potential may be enrolled if they are willing to use effective 
contraception, defined as: intrauterine devices (without hormones), bilateral tubal occlusion, 
vasectomized partner or total abstinence. Oral, injectable, or implant hormonal contraceptives 
should not be used. Patients should start using or continue birth control from the start of trial 
treatment throughout the trial treatment.  
Patients should be informed that taking the trial medication may involve unknown risks to the 
fetus if pregnancy were to occur during the trial. In order to participate in the trial they must 
adhere to the contraception requirement (described above) for the duration of the trial 
treatment and 6 months thereafter. If there is any doubt whether a patient will reliably comply 
with the requirements for contraception, that patient should not be entered into the trial. 
If a patient inadvertently becomes pregnant while on trial treatment, the event will be reported 
immediately, see Section 11.5. The site will contact the patient at least monthly and document 
the patient’s status until the pregnancy has been completed or terminated. The outcome of the 
pregnancy will be reported to IBCSG without delay and within 24 hours of awareness if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn). The Investigator will 
make every effort to obtain permission to follow the outcome of the pregnancy and report the 
condition of the fetus or newborn to IBCSG.  
Since many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, patients who are breast-feeding are not eligible for enrollment. 
11. 
Adverse event and serious adverse event reporting 
11.1. 
Adverse event reporting 
The main criterion for tolerability is the occurrence of toxicities and adverse events. The 
severity and causality will be classified according to the NCI CTCAE Version 4.0. The 
CTCAE 
is 
available 
for 
downloading 
on 
the 
internet 
at 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html. A quick reference can be found at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf  
An adverse event is defined as any untoward medical occurrence that occurs from the first 
dose of trial medication until 28 days after all treatment discontinuation, regardless of whether 
it is considered related to a medication. 


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Any grade of any observed adverse event should be reported on the Adverse Event Form (54-
AE) in iDataFax. Symptoms of the targeted cancer (if applicable) should not be reported as 
adverse events. 
11.1.1. Severity / intensity 
The adverse event severity grade provides a qualitative assessment of the extent or intensity 
of an adverse event, as determined by the Investigator or as reported by the patient. The 
severity grade does not reflect the clinical seriousness of the event, only the degree or extent 
of the affliction or occurrence (e.g., severe nausea, mild seizure), and does not reflect the 
relationship to trial drug. 
Severity grade for other adverse events not covered in the toxicity grading scale: 
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention/therapy required 
Grade 3 = Severe – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible 
Grade 4 = Life threatening – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable 
Grade 5 = Death – the event results in death 
The term “severe” is often used to describe the intensity of a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache). This criterion is not the same as 
“serious” which is based on patient/event outcome or action criteria associated with events 
that pose a threat to a patient’s life or functioning.   
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
Note: 
 Report the highest grade observed until resolution of the adverse event.  
 Baseline symptoms and highest grade of adverse events will be recorded on the Form 54-
AE. 
 AEs should not be reported in a narrative description, but rather by using the applicable 
CTCAE v4.0 term. 
11.1.2. Causality 
The Investigator must determine the relationship between the administration of trial drug(s) 
and the occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 
Not Suspected 
The temporal relationship of the adverse event to trial drug(s) 
administration makes a causal relationship unlikely or remote, or 
other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed 
event. 


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Suspected 
The temporal relationship of the adverse event to trial drug(s) 
administration makes a causal relationship possible, and other 
medications, therapeutic interventions, or underlying conditions 
do not provide a sufficient explanation for the observed event. 
11.1.3. Action taken 
The Investigator will report the action taken with trial drug(s) as a result of an AE or SAE, as 
applicable (e.g., discontinuation of trial drug(s)) and in case of a SAE Report if concomitant 
and/or additional treatments were given for the event. 
11.2. 
Targeted adverse events 
The presence or absence of the following AEs must be reported for every cycle on the Adverse 
Event Form (Form 54-AE). In addition, any other medically important AE should also be 
reported on Form 54-AE. 
The AEs are listed by System Organ Class and Preferred Term: 
11.2.1. Blood and lymphatic system disorders 
 Neutropenia 
 Thrombocytopenia 
 Anemia 
11.2.2. Skin and subcutaneous disorders 
 Alopecia 
 Palmar-plantar erythrodysesthesia syndrome 
11.2.3. Immune system disorders 
 Allergic reaction 
 Anaphylaxis 
 Aspartate aminotransferase increased 
11.2.4. Metabolism and nutrition disorders 
 Anorexia 
11.2.5. Gastrointestinal disorders 
 Diarrhea 
 Vomiting 
 Nausea 
 Mucositis 
 Constipation  
11.2.6. Nervous system disorders 
 Peripheral sensory neuropathy 
 Optic nerve disorder (scotomata) 


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11.2.7. Infections and infestations 
 Infection, specify 
11.2.8. Musculoskeletal and connective tissue disorders 
 Arthralgia or myalgia 
11.2.9. General disorders and administration site conditions  
 Injection site reactions 
 Fatigue 
11.2.10. Cardiac disorders 
 Heart failure 
 Acute coronary syndrome 
 Sinus bradycardia 
 Ventricular arrhythmia 
 Supraventricular tachycardia 
11.3. 
Otherwise reportable events 
Certain types of events, as identified below, are reportable to IBCSG under the reporting 
processes and requirements for SAEs, even if there is no associated adverse event. These are 
considered “otherwise reportable events” and generally reflect circumstances that could lead 
to an increased risk of an adverse event. Like a SAE, an otherwise reportable event is to be 
reported to IBCSG within 24 hours of awareness and followed up to determine outcome, 
including the later occurrence of an associated SAE. 
11.3.1. Pregnancy and lactation 
Pregnancy will be reported within 24h of awareness on the Serious Adverse Event Form 
(54-SAE-A) in all cases.  
Exposure during lactation will be reported within 24h on the 54–SAE-A Form.  
In the event of pregnancy or lactation, all trial treatment must be discontinued.  
Follow-up of the pregnancy is mandatory until the outcome has been determined. Outcome 
will be reported on the 54–SAE-B Form. 
11.3.2. Relevant overdose of trial treatment  
An overdose (accidental or intentional) of one of the trial treatment drugs is an event suspected 
by the Investigator or spontaneously notified by the patient. 
The overdose has to be reported within 24h on the 54–SAE–A Form. 
11.4. 
Serious adverse event (SAE)  
11.4.1. Definition 


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A SAE is defined in general as any undesirable medical occurrence/adverse drug experience 
that occurs from signature of informed consent until 28 days after stopping all trial treatment 
that, at any dose, results in any of the following:  
 fatal (any cause except progression of disease) 
 life-threatening 
 requires or prolongs inpatient hospitalization 
 persistent or significant disability/incapacity 
 secondary (non-breast) malignancy 
 congenital anomaly or birth defect (including neonatal deaths) 
 constitutes an important medical event 
 pregnancy or lactation 
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the patient or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should 
be considered serious. 
After completion of trial treatments, report all SAEs beyond 28 days that are considered at 
least possibly related to previous trial treatment. Cases of second (non-breast) malignancies 
and congenital abnormalities are to be regarded as SAEs, regardless of whether they occur 
during or after trial treatment. These events should be reported during the whole trial duration 
on the Serious Adverse Event eCRFs (54–SAE–A and 54–SAE–B). 
A suspected unexpected serious adverse reaction (SUSAR) is an adverse event that is serious, 
related to any of the trial treatment drugs and not listed as a known toxicity of the drug in the 
respective Italian SPC. All suspected unexpected serious adverse reactions judged by either 
the Investigator or IBCSG as the sponsor will be reported in accordance with applicable local 
regulations. IBCSG will report any SUSAR to EudraVigilance. 
11.4.2. Exceptions to the definition 
Hospitalizations occurring under the following circumstances are not considered to be serious 
adverse events:  
 elective surgery 
 those that occur on an outpatient basis and do not result in admission (hospitalization 
<24h) 
 those that are part of the normal treatment or monitoring of the studied treatment 
 progression of disease (by convention, clinical events related to the primary cancer 
being studied or to the primary cancer progression are not to be reported as SAEs, even 
if they meet any of the seriousness criteria from the standard SAE definition, unless the 
event is more severe than expected and therefore the Investigator considers that their 
clinical significance deserves reporting). Progression of disease is to be reported on 
Form 54-TR or Form 54-E and not as an SAE. 
11.4.3. Causality assessment 


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The Investigator needs to assess the relationship between trial treatment and the occurrence 
of each SAE following the definitions in this table: 
 
Relationship to the 
trial treatment  
Description 
Suspected 
The possibility that the trial treatment caused the event is 
deemed definite or probable or possible 
Not suspected 
The possibility that the trial treatment caused the event is 
deemed unlikely or unrelated 
 
The Investigator will use clinical judgment to determine the relationship. Alternative causes, 
such as natural history of the underlying diseases, medical history, concurrent conditions, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the trial 
treatment will be considered and investigated. 
The decision will be recorded on the SAE Form and if necessary the reason for the decision 
will also be recorded. 
11.4.4. Expectedness assessment 
The expectedness assessment is the responsibility of the sponsor of the trial. The expectedness 
assessment will be performed against the SPC of the respective trial treatment drugs. 
11.5. 
Reporting SAEs 
Any SAE or other reportable event (section 11.3) occurring in a patient after providing 
informed consent must be reported, including death due to any cause other than progression 
of breast cancer, which occurs within 28 days following cessation of treatment or the initiation 
of a new anticancer therapy, whichever is earlier, whether or not related to one of the trial 
treatment drugs. Information about all such events will be collected and recorded on the 
IBCSG Serious Adverse Event eCRFs (54–SAE–A and 54–SAE–B). 
To ensure patient safety, the IBCSG must be informed of each SAE using the procedures 
described below: 
 The Investigator/MD responsible for the patient must complete a Serious Adverse Event 
(SAE-A) eCRF in English within 24 hours of awareness via iDataFax. A copy is 
automatically forwarded to the IBCSG Safety Office for medical review. 
 Queries may be issued by the IBCSG Safety Office; a timely response by the 
Investigator to all SAE-related queries is crucial. 
 Follow-up information should be completed via iDataFax on the Serious Adverse Event 
(SAE-B) eCRF as soon as available but within 15 days of the initial report, even if the 
event reported in the SAE-A eCRF is not yet resolved. If the event is not resolved within 
15 days, revise the original Serious Adverse Event (SAE-B) eCRF in iDataFax to report 
the final resolution. 
 All SAEs that have not resolved upon discontinuation of the patient’s participation in 
the trial must be followed until recovered, recovered with sequelae, not recovered (death 
due to another cause) or death (due to the SAE). 


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 If a non-serious adverse event becomes serious, this and other relevant follow-up 
information must also be provided within 24 hours. 
 Photocopies of all examinations carried out with the dates on which they were 
performed should be sent by fax or DFSend into the DataFax system. Care should be 
taken to ensure that the patient's identity is protected and the Patient ID number is 
properly included on ALL pages of any reports. For laboratory results, include the 
laboratory normal ranges. Please also note on each page that the information is “SAE 
related” so it can be properly categorized in iDF. 
 In the event the eCRF system is not working, the SAE Forms can be found in the trial 
site file or downloaded from the IBCSG trial webpage and sent via fax or DFSend into 
the DataFax system within 24 hours of awareness. 
If an SAE (SAE-A and SAE-B Forms) was submitted by fax or DFSend, the original forms 
and the fax confirmation sheet(s) must be kept at the Participating Center. 
The IBCSG will inform Pierre Fabre Pharmacovigilance and other appropriate persons about 
all SAEs within 48 hours of receipt at the IBCSG. 
The IBCSG will record the SAE and prepare a monthly SAE report. Principal Investigators 
will receive the summary report on a monthly basis, and these reports can be found on the 
IBCSG web site (www.ibcsg.org). 
12. 
Disease assessment, response and progression (RECIST 1.1) 
12.1. 
Introduction 
All enrolled patients will be assessed for disease response and progression according to the 
revised Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) [36]. In this trial, 
patients may have measurable or non-measurable disease (see definitions below). Patients 
will be re-evaluated every 12 weeks until documented progression. 
Response and progression-free survival will be assessed using RECIST 1.1 criteria. Please 
consult the “RECIST 1.1 Training Workbook” available on www.ibcsg.org . 
12.2. 
Methods 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 treatment and follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been 
used to assess the antitumor effect of a treatment. 
CT scan is the best currently available and reproducible method to measure lesions selected 
for response assessment. CT scan should generally be performed using a ≤ 5 mm contiguous 
reconstruction algorithm. MRI is acceptable for certain situations (e.g., body scans). 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules) and ≥10 mm. In the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is recommended. 


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Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT scan is preferable. 
Ultrasound is not useful in assessment of lesion size and is not accepted as a method of 
assessment. 
FDG-PET is not foreseen for regular response assessments. It may, however, be used to detect 
or confirm the appearance of new lesions. Attenuation correction CT scans performed as part 
of a PET/CT scan frequently show lower resolution; therefore, dedicated CT scans are 
preferred. However, if the site can demonstrate that the CT scan performed as part of a 
PET/CT is of the same diagnostic quality as a diagnostic CT scan (with i.v. and oral contrast), 
then the CT scan portion of the PET/CT can be used for RECIST measurements. 
12.3. 
Measurability of tumor at baseline 
12.3.1. Measurable disease 
Measurable disease is defined as the presence of at least one measurable lesion. 
Measurable lesions: 
 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: 
o 10 mm by CT scan (CT scan slice thickness no greater than 5mm). 
o 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
o 20 mm by chest X-ray. 
Reminder: A lesion in a previously irradiated area is not eligible for measurable disease. 
 Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan, assuming the slice 
thickness is ≤ 5 mm. At baseline and in follow-up, only the short axis will be measured. 
12.3.2. Non-measurable disease 
Non-measurable disease is defined as lesions or sites of disease that cannot be measured.  
Non-measurable lesions/sites of disease and special considerations:  
 Small non-nodal lesions (longest diameter < 10 mm in CT scan). 
 Small lymph nodes (short axis ≥ 10 and < 15 mm). Lymph nodes that have a short axis 
< 10 mm are considered non-pathological and should not be recorded or followed as 
measurable or non-measurable disease. 
 Bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. Blastic bone lesions are non-
measurable. 
 Leptomeningeal disease 
 Ascites 


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 Pleural or pericardial effusion 
 Inflammatory breast disease 
 Lymphangitic involvement of skin or lung 
 Cystic lesions. Cystic lesions thought to represent cystic metastases may be considered 
as measurable lesions. However, if non-cystic lesions are present, these are preferred as 
target lesions. 
 Tumor lesions situated in a previously irradiated area, or subjected to other locoregional 
therapy. Such lesions may be considered measurable if there has been demonstrated 
progression in the lesion. 
 Abdominal masses/abdominal organomegaly identified by physical exam that are not 
measurable by reproducible imaging techniques. 
12.4. 
Selection of target lesions 
Target lesions should be identified, measured and recorded. At baseline, there can be up to a 
maximum of 5 lesions representative of all involved organs, and up to 2 per organ. Target 
lesions should be selected on the basis of their size and their suitability for accurate repetitive 
measurements. A sum of diameters for all target lesions will be calculated and recorded as the 
baseline sum of diameters. Lymph nodes selected as target lesions should always have the 
short axis recorded. All other lesions should always have their longest diameters recorded. 
The sum of diameters will be used as reference to further characterize the objective tumor 
response of the measurable dimension of the disease. 
12.5. 
Selection of non-target lesions  
Non-target lesions should be identified. All other lesions (or sites of disease) not identified as 
target lesions should also be recorded as non-target lesions at baseline.  
For non-target lesions, measurements are not required, but the presence or absence of each 
should be noted throughout follow-up. 
12.6. 
Evaluation of target lesions (measurable disease) 
All target lesions will be measured at each tumor assessment, and the sum of their diameters 
will be compared to previous assessments in order to assign the response status as specified 
below. 
 Complete Response (CR): Disappearance of all target lesions. Lymph nodes selected as 
target lesions must each have reduction in the short axis to <10 mm in order for the 
response to be considered complete. In this case, the sum of diameters may be >0. 
 Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions 
taking as reference the baseline sum of diameters. 
 Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum recorded on trial. In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. The 
appearance of one or more new lesions (see section 12.8) denotes disease progression. 


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 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD taking as reference the smallest sum of diameters recorded on trial. 
Note: All target lesions, including lymph nodes, should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm). If the radiologist 
does not feel comfortable assigning an exact measure and reports a lesion as "too small to 
measure", a default value of 5 mm should be recorded. If a target lesion is thought likely to 
have disappeared, use "0 mm." 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case of 
PD. 
12.7. 
Evaluation of non-target lesions  
All non-target lesions will be assessed at each tumor assessment, and compared to previous 
assessments in order to assign the response status as specified below. 
 Complete Response (CR): Disappearance of all non-target lesions; lymph nodes selected 
as non-target lesions must be non-pathological in size (< 10 mm). 
 Non-CR/non-PD: Persistence of one or more non-target lesions (non-CR). 
 Progression (PD): unequivocal progression of existing non-target lesions. Unequivocal 
means: comparable in magnitude to the increase that would be required to declare PD for 
measurable disease, or an overall substantial increase in tumor burden that merits 
treatment discontinuation. 
When no imaging is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point. If only a subset of lesions are evaluated at an assessment, usually the case is 
also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point 
response. This would be most likely to happen in the case of PD. 
12.8. 
Determination of new lesions 
The appearance of any new malignant lesions denotes disease progression. The finding of a 
new lesion should be unequivocal (i.e., not attributable to differences in scanning technique 
or findings thought to represent something other than tumor). If a new lesion is equivocal, 
(e.g., because of its small size) the patient will stay on treatment (if the decision on PD is 
based on this lesion only). If the repeat scan documents that there is definitely a new lesion, 
then progression should be declared using the date of the previous scan when the lesion was 
discovered. 
Lesions or sites of disease found in a new location not included in the baseline scan (e.g., 
brain metastases) are considered new lesions. 


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Note: The "re-appearance" of a previously "disappeared" target or non-target lesion does not 
in itself necessarily qualify as PD; this is the case only if the overall evaluation meets the PD 
criteria, or if the patient was previously in CR. 
12.9. 
Additional considerations 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
12.10. Determination of time point response 
Based on the responses of target lesions, non-target lesions, and the presence or absence of 
new lesions, the overall response will be determined at each tumor evaluation time point, 
according to Table 3 or Table 4 below. 
12.10.1. For patients with measurable disease 
Table 3. 
Measurable Disease - Overall Response 
Target lesions 
Non-target lesions 
New lesions 
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 
PD 
Any  
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes  
PD 
*Non-CR/non-PD should be used rather than SD for categorizing non-target lesions.  
12.10.2. For patients with non-measurable disease only 
Table 4. 
 
Non-Measurable Disease - Overall Response 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD* 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*Non-CR/non-PD should be used rather than SD for categorizing non-target lesions.  
 


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12.11. Determination of best overall response  
Best overall response is defined as best response recorded from randomization across all 
time points until disease progression. Confirmation of partial or complete response by an 
additional scan is not requested in this trial.  
12.12. Progression-free Survival 
The date of progression is the date that objective progression was first documented. 
Progression-free survival (PFS) is defined as time from randomization until documented 
disease progression according to RECIST 1.1 criteria or death, whichever occurs first. For 
patients without progression, follow-up will be censored at the date of the survival update 12 
months after the randomization of the last patient, unless death occurs within a short period 
of time (12 weeks, corresponding to the interval of tumor re-evaluation) following the date 
last known progression-free, in which case the death will be counted as a PFS event.  
Patients who discontinue treatment prior to documented disease progression (see Section 9.5), 
including those who initiate non-protocol therapy prior to progression, will be followed for 
disease progression, for a maximum of 12 months after the randomization of the last patient. 
A new (non-breast) cancer malignancy has to be reported on the 54-SAE Forms; such patients 
must continue to be followed for progression of the original breast cancer. 
13. 
Clinical and laboratory evaluations and follow-up 
13.1. 
Screening  
The following examinations should be done within a maximum of 28 days before 
randomization. The clock for the screening period starts when the first procedure is 
performed. If examinations were done prior to 28 days before randomization, they have to be 
repeated. The diagnostic imaging must be done within 35 days before randomization. 
13.1.1. Obtain informed consent for screening evaluations and trial participation (informed 
consent may be obtained earlier than within 28 days before randomization.). 
13.1.2. Medical history including ER status, HER2 status, prior endocrine treatment and 
chemotherapy in the locally advanced or metastatic setting. 
13.1.3. Clinical and radiological (by CT scan or MRI) tumor assessments of 
chest/abdomen/pelvis, within 35 days before randomization.  
13.1.4. Bone scan and FDG-PET if medically indicated. 
13.1.5. Cardiac evaluation: Electrocardiogram (ECG). 
13.1.6. Physical examination according to local standards including vital signs, ECOG 
Performance Status, height, weight. 
13.1.7. Hematology: Hemoglobin, platelet count, white blood cell count including 
differential (absolute neutrophil count). 
13.1.8. Biochemistry: 


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Liver function tests: total bilirubin, ALT, AST; 
Kidney function test: creatinine. 
13.1.9. For patient of childbearing potential: pregnancy test within 2 weeks prior to 
randomization. 
13.1.10. Baseline symptoms and adverse events graded according to CTCAE v4.0 (record on 
baseline adverse events form, 54-AE). Baseline symptoms and adverse events should 
be recorded from signature of informed consent to prior to start of treatment. 
13.2. 
Day 1 of every treatment cycle 
The following evaluations have to be done on Day 1 of every treatment cycle (or within 3 days 
before these dates): 
13.2.1. Physical examination according to local standards including vital signs, ECOG 
Performance Status and weight. 
13.2.2. Hematology: Hemoglobin, platelet count, white blood cell count including 
differential (absolute neutrophil count). 
Arm B, VEX treatment: in cycle 1, repeat hematology on Day 15 
13.2.3. Biochemistry:  
Liver function tests: total bilirubin, AST; 
Kidney function test: creatinine. 
13.2.4. Collection of any adverse event observed in the previous cycle and assignment of 
appropriate adverse events grade according to the NCI CTCAE Version 4.0. 
13.2.5. Arm B, VEX treatment: Compliance assessment (check patient diary, file in patient 
records as source data; hand out new patient diary for next cycle). 
13.3. 
Tumor assessments 
Tumor measurements according to RECIST 1.1 criteria (see section 12) have to be done at 
baseline, and every 12 weeks (± 2 weeks) from randomization until first disease progression.  
13.3.1. Clinical and radiological (by CT scan or MRI) tumor assessments.  
13.3.2. Bone scan and FDG-PET will be done if clinically indicated at the same time points. 
13.4. 
After end of trial treatment 
Within 30 days after end of trial treatment (or at the time of decision to stop the trial treatment 
if the decision is taken >30 days after last dose): 
13.4.1. Physical examination according to local standards including vital signs, ECOG 
Performance Status and weight. 
13.4.2. Hematology: Hemoglobin, platelet count, white blood cell count including 
differential (absolute neutrophil count). 
13.4.3. Biochemistry:  


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Liver function tests: total bilirubin, AST; 
Kidney function test: creatinine. 
13.4.4. Collection of any adverse event and assignment of appropriate adverse events grade 
according to the NCI CTCAE Version 4.0. 
13.4.5. Arm B, VEX treatment: Compliance assessment (check patient diary). 
13.5. 
Follow-up prior to documented disease progression 
In case trial treatment was stopped prior to documented disease progression, the information 
below should be documented for patients until first progression, or for a maximum of 12 
months after randomization of the last patient. Visits should take place every 12 weeks (± 2 
weeks). 
13.5.1. Tumor evaluation according to RECIST 1.1 for determination of disease progression. 
Report disease progression on the 54-PD Form. 
13.5.2. Serious adverse events up to 28 days after stop of all trial treatment:  
 Arm A: stop of paclitaxel 
 Arm B: stop of all three VEX drugs. 
13.6. 
Survival follow-up 
If a patient dies, this is to be recorded on the 54-Death Form at the time of death. 
12 months after the randomization of the last patient into the trial, survival status needs to be 
documented for all alive patients on the 54-E Form. 
14. 
Data submission 
We will conduct the trial according to the ICH Good Clinical Practice (GCP) guidelines.  
Keeping accurate and consistent records is essential to a cooperative trial. The following 
forms are to be submitted at the indicated times by the participating institutions for each 
patient: 


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14.1. 
Case report forms schedule 
Forms 
Description/Name 
Forms Submission  
ALL data should be completed in iDataFax 
(iDF) (unless otherwise specified) 
Informed 
Consent Form 
Consent to participation in clinical 
trial 
Obtain before randomization and prior to 
screening procedure and keep with patient 
records as documentation (hard copy only). 
Registration and Randomization 
54-A 
Confirmation of Registration Form 
Complete in iDF after you have randomized the 
patient in the IBCSG Registration/ 
Randomization System.  
Patient will be available in iDF within 24 hours 
of successful registration. 
Baseline  
54-AE 
Adverse Events Form 
To record any symptoms present at 
randomization and prior to start of trial 
treatment, complete in iDF within 1 week of 
randomization.   
During trial treatment 
54-TX-A 
Protocol Therapy Form, Arm A 
Complete in iDF at the end of each cycle until 
treatment stops. 
54-TX-B 
Protocol Therapy Form, Arm B 
Complete in iDF at the end of each cycle until 
treatment stops. Note for Arm B:  Stopping of at 
least one trial medication denotes stopping 
VEX treatment. 
54-AE 
Adverse Events Form 
Complete in iDF at the end of each treatment 
cycle to report highest grade for all events 
during this cycle 
 
54-TR 
Tumor Response Form 
Complete in iDF every 12 weeks up to end of 
trial treatment. 
Event-driven forms to be submitted after end of treatment (EoT) 
54-AE 
Adverse Events Form 
Complete one month after stop of trial treatment, 
to report highest grade for all events observed up 
to 30 days after treatment stops. 
54-PD 
First Progression Form 
Complete in iDF at first progression 
54-Death 
Death form 
Complete in iDF at time of death 
54-E 
Survival Follow-up Form 
Complete in iDF 12 months after randomization 
of the last patient for survival and disease status.   
Event-driven forms 
 
54-SAE-A 
Serious Adverse Event Form A - 
Initial report 
Complete in iDF within 24 hours of the SAE 
awareness. If iDF is not available, fax the form 
within 24 hours to DataFax. 
54-SAE-B 
Serious Adverse Event Form B - 
Follow-up report 
Complete in iDF as soon as follow-up available, 
at the latest within 15 days of the initial report 
(54-SAE-A). If event is not resolved in 15 days, 
update 54-SAE-B again at the time of resolution. 
54-COC 
Change of Consent Form 
Complete in iDF if there is any change in 
patient's consent to participate in the trial, see 
Section 16.5.2. 
The iDF User Manual and the Data Managers’ Manual for this trial contain instructions for 
completing and submitting forms using the iDataFax system.  
14.2. 
Signing and submitting forms 
An Authorization Log (see section 14.5) should be completed at each Participating Center to 
identify the persons who are authorized to complete CRFs. 


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CRFs should be completed on-line in iDataFax. Reports (lab, etc.) and any other non-CRF 
data will need to be sent to the DataFax system via fax or DFSend. Full instructions on 
submitting forms are available on the IBCSG website (www.ibcsg.org). Also available on the 
website is a list of fax numbers that are available for faxing CRFs. 
14.3. 
Data management 
Data collected in this trial will be submitted to the IBCSG Data Management Center in 
Amherst, NY, USA. The Data Management Center will process the data and will generate 
queries and forms requests. The Data Quality Control Office will oversee overall data 
submission and query resolution. The IBCSG Coordinating Center in Bern, Switzerland will 
provide medical review and summary of SAEs. The IBCSG Statistical Center in Boston, MA, 
USA will perform the data analysis. 
14.4. 
Investigator Site File 
Each Participating Center should keep documentation about this trial in an Investigator Site 
File (ISF). Please arrange the documentation in the order foreseen in the ISF index which will 
be provided by IBCSG. The following documents should be included (list is not complete): 
 Protocol and appendices  
 Activation letter 
 Accrual reports 
 Amendments 
 Copy of signed Protocol Signature Pages 
 Sample CRFs including blank SAE Forms 
 Patient Diary template 
 Data Managers’ Manual 
 Obvious Corrections Document and Signature Page 
 Randomization Manual 
 iDataFax (iDF) Manual 
 Patient information and Informed Consent templates approved by Ethics Committee 
 Ethics Committee and Health Authority approval of protocol, hospital management 
approval (=Delibera), Patient Information Sheet and Informed Consent, amendments 
 Ethics Committee review of SAE, Investigators' alert, and other documents 
 Correspondence with Ethics Committee and Health Authority (if applicable) 
 Certificate of clinical trial insurance 
 Agreement with IBCSG 
 Center activation email(s) from IBCSG Data Management Center (protocol and 
amendments, if any) 
 Correspondence with / Information issued by IBCSG Coordinating Center, Data 
Management Center 


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 SAE Reports sent from IBCSG Data Management Center 
 Normal laboratory values/reference ranges 
 Laboratory Certifications 
 CV of Principal Investigator and Co-Investigators, GCP certificates  
 Trial Training Certificates issued by IBCSG Center Training Office 
 Documentation of any training done internally (e.g., by use of IBCSG Training 
Confirmation Log) 
 Authorization Log 
 Center Information Sheet 
 Patient identification log (see section 14.6) 
 Weblink to ICH GCP guidelines/Declaration of Helsinki and updates 
 Audit certificates / monitoring follow-up letters 
14.5. 
Authorization log 
The Principal Investigator (PI) should identify the other members of the Clinical Trial Team 
who are supervised by the PI, appropriately qualified and approved to provide information in 
CRFs, queries, etc. Instructions for completing the Authorization Log can be found in the 
Authorization Log Manual, posted on the IBCSG website.  All changes need to be 
communicated to IBCSG by updating and emailing the Authorization Log. 
14.6. 
Patient identification log 
No patients’ names should be used in CRFs or any other documentation transmitted to IBCSG 
central offices. The only item used to identify a patient is the Patient ID (Randomization 
Number). It is therefore imperative that the local data manager keep an identification log for 
all patients entered in this trial including: 
 Patient's name 
 Patient ID issued by the IBCSG Registration/Randomization System 
 Date of birth 
 Date of randomization 
15. 
Statistical considerations 
The primary objective of the trial is to assess the combination of efficacy and tolerability, as 
measured by the time to treatment failure (TTF), of the combination treatment by vinorelbine, 
cyclophosphamide and capecitabine in comparison with paclitaxel monotherapy in estrogen 
receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2–), 
metastatic or locally advanced breast cancer patients, who need first- or second-line 
chemotherapy. A total of 160 patients will be stratified (Section 8.3) and randomized in a 1:1 
allocation (80: 80 patients) to the experimental and control groups. 


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15.1. 
Primary Objective 
15.1.1. Primary endpoint 
The primary efficacy endpoint of TTF (defined in Section 5.2) will be compared between 
treatment groups, using an intention-to-treat analysis approach. 
15.1.2. Design and Sample Size Determination 
160 patients will be stratified and randomized using 1:1 allocation of 80 patients to treatment 
with VEX and 80 patients to treatment with paclitaxel. Enrollment is expected to proceed with 
an accrual rate of 3 patients per month over the first 6 months, 6 patients per month over the 
next 6 months, and 9 patients per month over the subsequent 12 months, and the final analysis 
after an additional 12 months of follow-up. The final analysis will thus be based on data 
collected during 36 months from enrollment of the first patient, and results will be available 
within 42 months after enrollment of the first patient (allowing 6 months for data cleaning 
and statistical analysis).   
The sample size was determined in consideration of the primary objective. The median TTF 
of patients in this population treated with paclitaxel is assumed to be 4.5 months. When 123 
TTF events are observed, there is 80% power to detect an improvement in median TTF from 
4.5 with paclitaxel to 7.5 months with VEX (40% reduction in hazard, HR=0.60; two-sided 
α=0.05). If the above assumptions hold, we anticipate 123 TTF events to be observed between 
30 and 36 months from enrollment of the first patient. Exponential failures and a 1% per 
month dropout rate were assumed for the sample size calculation, which was carried out using 
East 5.4 (Cytel Inc., Cambridge, MA, USA). One interim efficacy analysis to assess for 
futility is planned (see Section 15.4).  
15.1.3. Analysis of Primary Endpoint 
TTF will be compared between groups by a stratified log-rank test using stratification factors 
defined for randomization. The hazard ratio with two-sided 95% CI will be estimated using a 
stratified Cox proportional hazards model. The distribution of TTF will be summarized for 
each treatment group using the method of Kaplan-Meier; median TTF with two-sided 95% 
confidence interval (CI) will be summarized. TTF will also be summarized separately 
according to previous chemotherapy yes vs no. 
15.2. 
Secondary objectives 
15.2.1. Safety and tolerability  
Adverse events (AE) will be collected using CTCAE v4.0. The maximum grade of each 
targeted AE while on treatment will be determined, and the frequencies summarized and 
tabulated according to grade and treatment assignment, with two-sided exact binomial 95% 
CIs, and compared between the two randomized arms. 
15.2.2. Disease Control 
Disease control is defined as best overall response of CR or PR, or SD (or non-CR/non-PD in 
the case of non-measurable disease only) lasting for at least 24 weeks, measured from 


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randomization until first documentation of progressive disease. Disease control will be 
summarized according to treatment assignment as proportion with two-sided exact binomial 
95% CI, and compared between the two randomized arms. Disease control will also be 
summarized separately according to line of chemotherapy received. 
15.2.3. Progression free survival (PFS) 
PFS (defined in Section 12.12) will be compared between groups by a stratified log-rank test 
using stratification factors defined for randomization. The statistical power of this comparison 
at the final analysis is likely to be less than 80%. The hazard ratio with two-sided 95% CI will 
be estimated using a stratified Cox proportional hazards model. The distribution of PFS will 
be summarized for each treatment group using the method of Kaplan-Meier; median PFS with 
two-sided 95% confidence interval (CI) will be summarized. PFS will also be summarized 
separately according to line of chemotherapy received. 
15.2.4. Overall survival (OS) 
Overall survival is defined as the time from the date of randomization to death from any cause. 
For patients who are lost to follow-up or who have no documentation of death at the time of 
final analysis, follow-up will be censored at the date of last assessment of vital status. The 
distribution of OS will be summarized for each treatment group using the method of Kaplan-
Meier; median OS with two-sided 95% CI will be calculated. OS will also be summarized 
separately according to line of chemotherapy received. 
15.3. 
Definitions of Trial Populations 
Efficacy analysis population: All randomized patients, who receive at least one dose of trial 
treatment. 
Safety population: All patients receiving at least one dose of trial treatment will be included 
in assessments of safety and tolerability. 
15.4. 
Interim Analyses 
One interim analysis will be performed for futility when 74 TTF events have been observed.  
It is anticipated that this number of TTF events will be observed approximately 22 months 
after first patient is enrolled. Results will be presented to the Data and Safety Monitoring 
Committee (DSMC), which may recommend discontinuation of the trial if it is clear at that 
point that the alternative hypothesis of an improved TTF associated with VEX compared with 
paclitaxel is unlikely to be shown. A one-sided boundary based on the O’Brien-Fleming 
criteria will be used to guide the DSMC deliberations.  
15.5. 
Accrual 
The overall accrual goal of this trial is 160 patients. We anticipate that the accrual rate will be 
approximately 3 patients per month during the first 6 months and 6 patients per month during 
the next 6 months as Participating Centers activate the trial. A steady state of 9 patients per 
month is anticipated during the subsequent 12 months, for a total accrual duration of 24 
months.  


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15.6. 
Data and Safety Monitoring 
The trial will be presented for review to the IBCSG DSMC at each of their semi-annual 
meetings. Accrual, safety and accumulation of TTF events will be monitored. The interim 
futility analysis will also be presented after 74 TTF events have been observed. 
16. 
Ethical aspects, regulatory approval, and patient informed consent 
The Investigator will ensure that this trial is conducted in full conformance with the principles 
of the “Declaration of Helsinki” or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the individual. The trial 
must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” ICH 
Tripartite Guideline (January 1997) or with local law if it affords greater protection to the 
patient. The Investigator will ensure compliance with the EU Clinical Trial Directive 
(2001/20/EC). 
16.1. 
Ethical Review Board/Ethics Committee 
All protocols and the patient Informed Consent Forms must have the approval of a properly 
constituted committee or committees responsible for approving clinical trials. The Ethics 
Review Board (ERB) / Institution Review Board (IRB) written, signed approval letter/form 
must contain approval of the designated Investigator, the protocol (identifying protocol title 
and version number), and of the patient Informed Consent. Documentation of Ethics 
Committee approval(s) must be sent to the IBCSG Data Management Center prior to 
enrollment of the first patient. The IBCSG Ethics Committee also approves the protocol and 
reviews it annually. 
Any modifications made to the protocol will be reviewed by the IBCSG Ethics Committee 
and must also be submitted to the appropriate ERB/IRB for information or approval in 
accordance with local procedures and regulatory requirements and to Health Authorities if 
required.  
Once approved or acknowledged by the appropriate ERB/IRB and by the Health Authorities 
(if required), the Investigator shall implement the protocol modifications. Protocol 
modifications for urgent safety matters may be directly implemented following the 
instructions of IBCSG. 
16.2. 
Regulatory approval procedures 
If applicable, in addition to the approval of the Ethics Committee according to national 
legislation, the protocol, other protocol-related documents including patient information and 
Informed Consent and other documents as required locally must be submitted to and be 
approved by the health authority. Documentation of health authority approval must be sent to 
the IBCSG Data Management Center prior to Participating Center activation. 
16.3. 
Protection of human patients 
The IBCSG has an Office for Human Research Protection (OHRP) Federal Wide Assurance 
(FWA00009439) and follows all of the policies and procedures that are part of that assurance. 


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All potential patients for this trial will receive a full explanation of the trial, its purpose, 
treatments, risks, benefits, and all of the other items listed in section 16.4. Additional 
institution-specific sections should be added to Appendix I as needed. 
The medical record must be available for review by the IBCSG monitors and audit team and 
regulatory authorities as described in section 17.6. 
Serious Adverse Event (SAE) Reports are distributed monthly. In addition they are available 
on the IBCSG website (www.ibcsg.org) for participating Centers. 
16.4. 
Informed Consent 
Informed Consent for each patient will be obtained prior to initiating any trial procedures in 
accordance with the “IBCSG Patient Information Sheet and Informed Consent" (See 
Appendix I). One signed and dated copy of the Informed Consent must be given to each 
patient and the original copy must be retained in the Investigator's trial records. The Informed 
Consent Form must be available in the case of data audits. Verification of signed Informed 
Consent and the date signed are required for randomization to this trial.   
The "Declaration of Helsinki" recommends that consent be obtained from each potential 
patient in biomedical research trials after the aims, methods, anticipated benefits, and potential 
hazards of the trial, and discomfort it may entail, are explained to the individual by the 
physician (http://www.wma.net/en/30publications/10policies/b3/index.html). The potential 
patient should also be informed of her right to not participate or to withdraw from the trial at 
any time.  
If the patient is in a dependent relationship to the physician or gives consent under duress, the 
Informed Consent should be obtained by an independent physician. By signing this protocol, 
the Investigator agrees to conduct the trial in accordance with the “Guideline for Good 
Clinical Practice” E6(R1) ICH Tripartite Guideline and the "Declaration of Helsinki."  
The IBCSG recognizes that each institution has its own local, national, and international 
guidelines to follow with regard to Informed Consent. Therefore, we provide a template 
information sheet and Informed Consent Form (Appendix I), which can be downloaded and 
edited to incorporate information specific to your institution (see www.ibcsg.org). The 
template Patient Information Sheet and Informed Consent (PIS/IC) has been written according 
to ICH guidelines which state the Informed Consent should adhere to GCP and to the ethical 
principles that have origin in the “Declaration of Helsinki”. The final version should receive 
the Institutional Review Board/ Local Ethics Committee approval in advance of its use. 
Centers should send their locally modified PIS/IC to the IBCSG Data Management Center for 
review and approval before submitting to their Ethics Committee.  
16.5. 
Premature withdrawal 
16.5.1. Cessation of trial treatment 
Patients have the right to refuse further trial treatment at any time during the trial. Patients 
may also be withdrawn from trial treatment at any time at the discretion of the Investigator 
due to an adverse event, or based on any other relevant medical condition. Such patients will 
remain in the trial and data collection will continue according to protocol. 


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16.5.2. Withdrawal of consent 
Patients have the right to withdraw consent for further trial participation at any time without 
having to specify the reason. The data recorded up to the time point of withdrawal will 
continue to be evaluated in the trial.  
Withdrawal of consent should be documented in both the medical records and in the eCRF 
(Form 54-COC). For the patient’s safety, an end of treatment visit should be performed. 
17. 
Governance and Administrative Considerations  
17.1. 
Insurance 
IBCSG will contract the appropriate liability insurance for this trial. Patients who suffer 
injuries due to the trial should report them immediately to their physician. The local Center 
should report all alleged claims immediately to the IBCSG. 
17.2. 
Governance 
The Trial Committee consisting of the Chairman of the IBCSG Scientific Committee, the 
Trial Chair, the Trial Statistician, The Director of Statistics and Data Management and the 
IBCSG Director is responsible for maintaining the scientific integrity of the trial, for example, 
by recommending changes to the protocol in light of emerging clinical or scientific data from 
other trials. The Trial Committee is also responsible for the translation of recommendations 
of the IBCSG Data and Safety Monitoring Committee into decisions.  
General partition of responsibilities: 
The Trial Committee has the authority to make and implement any final decisions, and may 
recommend the termination/early termination of the trial. 
The IBCSG Foundation Council decides on the termination/early termination of the trial. 
17.3. 
Data and Safety Monitoring Committee (DSMC) 
The trial will be presented for review to the IBCSG Data and Safety Monitoring Committee 
(DSMC) at each of their semi-annual meetings. Accrual, safety and accumulation of TTF 
events will be monitored.  
17.4. 
Publication of trial results 
IBCSG will publish the results of the trial based on the final trial report. 
17.5. 
Premature discontinuation of the trial 
The trial may be discontinued early in parts or completely if the information on the trial 
treatment leads to doubt as to the benefit/risk ratio. 
The trial can be terminated at any time if the authorization and approval to conduct the Study 
is withdrawn by ethics committee or regulatory authority decision, insufficient accrual, 
emerging new data impacting the scientific value of the trial or ethical grounds. 


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17.6. 
Quality Assurance 
The IBCSG conducts trials according to the “Guideline for Good Clinical Practice” ICH 
Tripartite Guideline (January 1997). The Trial IBCSG Data Manager reviews each CRF. In 
addition, the IBCSG Medical Reviewer reviews each case at specific timepoints. The IBCSG 
may conduct periodic audit visits to ensure proper trial conduct, verify compliance with GCP, 
and may perform source data verification. 
The Investigator should ensure that source documents are made available to appropriately 
qualified personnel from IBCSG or its designees, or to health authority inspectors after 
appropriate notification. 
At regular intervals during the clinical trial, the Center will be contacted, through monitoring 
visits, letters or telephone calls, by a representative of the Monitoring Team to review trial 
progress, Investigator and patient compliance with clinical trial protocol requirements and any 
emergent problems. These monitoring visits/phone calls will include but not be limited to 
review of the following aspects: patient Informed Consent, patient recruitment and follow-up, 
SAE documentation and reporting, AEs with pre-specified monitoring documentation and 
reporting, AE documentation, trial treatment administration, patient compliance with the 
regimens, concomitant therapy use and quality of data. 
17.7. 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the Investigator contact IBCSG or personnel monitoring the trial to 
request approval of a protocol deviation, as no deviations are permitted. The Investigator 
should document and explain any deviations from the approved protocol and promptly report 
them to IBCSG and to the EC concerned in accordance with the applicable EC policies and 
procedures. 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 
developed and activated by IBCSG and approved by the IRB/IEC/REB it cannot be 
implemented. All protocol deviations will be documented. 
17.8. 
Data protection 
A unique Patient Identification (ID)/Randomization Number will be assigned by the IBCSG 
Registration/ Randomization System to each patient registered into the trial. The names of the 
patients will not be disclosed to IBCSG.  
Only the Patient ID will be used to identify a patient on the eCRF. Identification of patients 
must be guaranteed at the Participating Center. In order to avoid identification errors, Centers 
should keep a Patient Identification Log containing the patients’ name, year of birth, and the 
Patient ID allocated by IBCSG. 
Regulatory authorities and the pertinent Ethics Committee (ERB/IRB) may have access to 
patient data on-site. IBCSG audit or monitoring personnel will also have access to such data 
on-site. 


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17.9. 
Record Retention 
The Center must retain all essential documents according to ICH GCP. This includes copies 
of the patient trial records, which are considered as source data, patient Informed Consent 
statement, laboratory printouts, and all other information collected during the trial. These 
documents are to be stored until at least 15 years after the termination of the trial. IBCSG 
guarantees access and availability of the data entered into iDataFax for at least 15 years after 
the termination of the trial. 
In the event that the Principal Investigator retires or changes employment, custody of the 
records may be transferred to another competent person who will accept responsibility for 
those records. Written notice of such transfer has to be given to IBCSG and the local Ethics 
Committee at least one month in advance. 
18. 
Confidentiality 
The protocol, CRFs and other protocol-related documents are confidential and are the 
property of IBCSG. 
19. 
References 
1. 
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2004; 15: 1358-1365. 
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women with metastatic breast cancer. J Clin Oncol 2001; 19: 4216-4223. 
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Gori S, Mosconi AM, Basurtol C et al. Weekly paclitaxel in metastatic breast cancer 
patients: a phase II study. Tumori 2002; 88: 470-473. 
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Sato K, Inoue K, Saito T et al. Multicenter phase II trial of weekly paclitaxel for 
advanced or metastatic breast cancer: the Saitama Breast Cancer Clinical Study Group 
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Bocci G, Nicolaou KC, Kerbel RS. Protracted low-dose effects on human endothelial 
cell proliferation and survival in vitro reveal a selective antiangiogenic window for 
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Andre N, Carre M, Pasquier E. Metronomics: towards personalized chemotherapy? Nat 
Rev Clin Oncol 2014; 11: 413-431. 
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Radojcic V, Bezak KB, Skarica M et al. Cyclophosphamide resets dendritic cell 
homeostasis and enhances antitumor immunity through effects that extend beyond 
regulatory T cell elimination. Cancer Immunol Immunother 2010; 59: 137-148. 
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Lake RA, Robinson BW. Immunotherapy and chemotherapy--a practical partnership. 
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Colleoni M, Rocca A, Sandri MT et al. Low-dose oral methotrexate and 
cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with 
vascular endothelial growth factor levels. Ann Oncol 2002; 13: 73-80. 
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Colleoni M, Orlando L, Sanna G et al. Metronomic low-dose oral cyclophosphamide 
and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor 
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Zhang Q, Kang X, Yang B et al. Antiangiogenic effect of capecitabine combined with 
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Martín M, Calvo L, Martínez N et al. Randomized, phase II trial comparing continuous 
versus intermittent capecitabine monotherapy for metastatic breast cancer. Journal of 
Clinical Oncology 2009; 27: 1086. 
23. 
Stockler M, Sourjina T, Grimison P et al. A randomized trial of capecitabine (C) given 
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line chemotherapy for advanced breast cancer (ABC). ASCO Annual Meeting 
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Wang Z, Lu J, Leaw S et al. An all-oral combination of metronomic cyclophosphamide 
plus capecitabine in patients with anthracycline- and taxane-pretreated metastatic breast 
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Yoshimoto M, Takao S, Hirata M et al. Metronomic oral combination chemotherapy 
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negative metastatic breast cancer. Cancer Chemother Pharmacol 2012; 70: 331-338. 
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Class of Oncolytic Agents. Cancer Res 1963; 23: 1390-1427. 
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Mangeney P, Andriamialisoa RZ, Langlois N et al. A new class of antitumor 
compounds: 5'-nor and 5',6'-seco derivatives of vinblastine-type alkaloids. J Org Chem 
1979; 44: 3765-3768. 
30. 
Ohashi Y, Watanabe T, Sano M et al. Efficacy of oral tegafur-uracil (UFT) as adjuvant 
therapy as compared with classical cyclophosphamide, methotrexate, and 5-fluorouracil 
(CMF) in early breast cancer: a pooled analysis of two randomized controlled trials 
(N.SAS-BC 01 trial and CUBC trial). Breast Cancer Res Treat 2010; 119: 633-641. 
31. 
Briasoulis E, Aravantinos G, Kouvatseas G et al. Dose selection trial of metronomic 
oral vinorelbine monotherapy in patients with metastatic cancer: a hellenic cooperative 
oncology group clinical translational study. BMC Cancer 2013; 13: 263. 
32. 
Briasoulis E, Pappas P, Puozzo C et al. Dose-ranging study of metronomic oral 
vinorelbine in patients with advanced refractory cancer. Clin Cancer Res 2009; 15: 
6454-6461. 
33. 
Rajdev L, Negassa A, Dai Q et al. Phase I trial of metronomic oral vinorelbine in 
patients with advanced cancer. Cancer Chemother Pharmacol 2011; 68: 1119-1124. 
34. 
Addeo R, Sgambato A, Cennamo G et al. Low-dose metronomic oral administration of 
vinorelbine in the first-line treatment of elderly patients with metastatic breast cancer. 
Clin Breast Cancer 2010; 10: 301-306. 
35. 
Saridaki Z, Malamos N, Kourakos P et al. A phase I trial of oral metronomic vinorelbine 
plus capecitabine in patients with metastatic breast cancer. Cancer Chemother 
Pharmacol 2012; 69: 35-42. 
36. 
Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-247. 
 


 
International Breast Cancer Study Group Statistical Center 
 
 
A randomized phase II trial of metronomic oral vinorelbine plus 
cyclophosphamide and capecitabine (VEX) versus weekly paclitaxel 
as first-line or second-line treatment in patients with ER-
positive/HER2-negative advanced or metastatic breast cancer 
 
 
MEtronomic TrEatment Option in advanced bReast cAncer:  
the METEORA-II trial (IBCSG 54-16) 
 
 
 
Statistical Analysis Plan 
 
 
 
 
Version 
Author 
Date 
Status 
1 
Subrina Farah, MS 
May 2020 
Primary endpoint definition and 
analysis for interim analysis. 
2 
Meredith Regan, ScD 
Nov 2021 
Full SAP for primary analysis 
 
 
 
 
 
 
 


METEORA-II SAP: November 2021 
 
 
Trial 54-16 -- 2 
 
1 
INTRODUCTION 
 
BACKGROUND AND RATIONALE 
Prognosis for patients with locally advanced or metastatic breast cancer (ABC) remains poor, with 
a median survival of 2–4 years. About 10% of newly-diagnosed breast cancer patients present with 
ABC, and 30% to 50% of patients diagnosed at earlier stages will subsequently develop metastatic 
disease. 
In the first-line treatment of patients with HER2-negative ABC, various chemotherapy regimens 
can be used including taxanes, which are among the most active agents in breast cancer. Single-
agent response rates range from 20 to 50%. However, eventually all patients’ disease will progress 
with a median time to progression of 5 to 7 months.  
The VEX regimen was recently investigated within a phase II trial in Istituto Europeo di Oncologia 
(IEO). Patients received vinorelbine 40 mg orally on days 1, 3 and 5 every week, 
cyclophosphamide 50 mg daily and capecitabine 500 mg 3 times a day. Among the 88 patients 
evaluable for efficacy, 42 were not pre-treated and 46 were pre-treated for metastatic disease. 
Median time to progression was 26.5 months and 9.6 months for untreated and pre-treated patients 
respectively. The proportion of patients free of progression at one year was 73% in the not pre-
treated and 38% in the pre-treated group.  As of January 2016, 24 patients were still on treatment. 
A total of 88 patients (42 untreated and 46 pre-treated) were analyzed for safety. One serious 
adverse event (ischemic heart attack) was reported. In the not pre-treated and pre-treated groups, 
grade 1-2 toxicities included nausea (50% and 17%), leucopenia (43% and 30%) increased liver 
enzymes (36% and 41%), hand and foot syndrome (26% and 11%). Grade 3 toxicities (hand and 
foot syndrome, hematologic and liver toxicities) were reported in 17% and 13% not pre-treated 
and pre-treated patients, respectively. No patient experienced grade 4 toxicities.   
Given the promising activity of the VEX regimen in a pre-treated population of patients with ABC 
and the good tolerability, the aim of the METEORA-II trial is to investigate whether the VEX 
schedule may improve efficacy and tolerability as compared to standard paclitaxel treatment in 
patients with ER-positive/HER-2 negative ABC. 
The concept of the VEX metronomic treatment is to administer the combination for as long as the 
patient has the possibility of deriving a benefit from it. The time to treatment failure (TTF) is 
chosen as primary endpoint for this trial, defined as time from the date of randomization to the 
date when the final dose of trial treatment is administered. Chemotherapy may need to be stopped 
due to lack of tolerability, lack of efficacy or patient preference through subjective symptom 
assessment. TTF is a composite endpoint combining all these feasibility aspects of a treatment. It 
is therefore uniquely suited to the research question of the current trial. The secondary endpoints 
progression-free survival, disease control and safety will allow further assessment of the feasibility 
of the VEX metronomic treatment versus the paclitaxel monotherapy regimen. 
 
 


METEORA-II SAP: November 2021 
 
 
Trial 54-16 -- 3 
 
 
TRIAL DESIGN 
IBCSG TRIAL 54-16 METEORA II 
Project Title: 
A randomized phase II trial of metronomic oral vinorelbine plus 
cyclophosphamide and capecitabine (VEX) versus weekly paclitaxel as first-
line or second-line treatment in patients with ER-positive/HER2-negative 
advanced or metastatic breast cancer 
Study Chair: Elisabetta Munzone, MD (EIO, Milan) 
Patient Population: 
Patients with ER-positive/HER2-negative advanced or metastatic breast cancer 
(stage IV), measurable or non‐measurable, but radiologically evaluable (except 
for skin lesions). 
Patient Entry: 
Maximum of one prior line of chemotherapy for advanced or metastatic breast 
cancer. If patients were previously treated with a taxane in the neoadjuvant or 
adjuvant setting, the period from end of treatment to disease recurrence must 
have been > 12 months. 
Activation Date: 
13 February 2017 (first patient randomized 13 September 2017) 
Closure Date: 
31 January 2021 (last patient entered 14 January 2021) 
Final Accrual: 
140 patients (Target 160 patients) 
 
Schema 
 
Patients were randomized in a 1:11 ratio, stratified by: 
• Prior treatment for locally advanced or metastatic disease (no prior ET or CT, prior ET only, 
prior CT±ET) 
• ECOG performance status (0 vs 1). 
Treatment Schedules 
• Arm A: Paclitaxel 90 mg/m2 days 1, 8, 15 q4 weeks; 
• Arm B: Cyclophosphamide 50 mg orally once daily, capecitabine 500 mg, orally 3 times a 
day (1500 mg/day), vinorelbine 40 mg orally days 1, 3, 5 each week. 
Patients continue to receive assigned treatment until objective progressive disease (PD), 
symptomatic deterioration, unacceptable toxicity, death, or refusal to continue treatment, 
whichever occurs first. 
 
Advanced or
metastatic
ER+ HER2-
Breast Cancer 
Diagnostic CT
Trial treatment
Screening, eligibility
and enrollment
Survival update
Paclitaxel 90 mg/m2 days 1, 8, 15  q4w
until progression or lack of tolerability
CT every 12 weeks until progression
R
Metronomic VEX until progression or lack of tolerability:
Vinorelbine
40 mg p.o. day 1, 3, 5 every week
Cyclophosphamide
50 mg/day p.o. continuous
Capecitabine 
500 mg x 3/day p.o. continuous
12 months after 
last patient randomized
12 months after 
last patient randomized


METEORA-II SAP: November 2021 
 
 
Trial 54-16 -- 4 
 
1.2.1 
Statistical Design 
160 patients will be stratified and randomized using 1:1 allocation of 80 patients to treatment with 
VEX and 80 patients to treatment with paclitaxel. Enrollment is expected to proceed with an 
accrual rate of 3 patients per month over the first 6 months, 6 patients per month over the next 6 
months, and 9 patients per month over the subsequent 12 months, and the final analysis after an 
additional 12 months of follow-up. The final analysis will thus be based on data collected during 
36 months from enrollment of the first patient, and results will be available within 42 months after 
enrollment of the first patient (allowing 6 months for data cleaning and statistical analysis).   
The sample size was determined in consideration of the primary objective. The median TTF of 
patients treated with paclitaxel is assumed to be 4.5 months. When 123 TTF events are observed, 
there is 80% power to detect an improvement in median TTF from 4.5 with paclitaxel to 7.5 months 
with VEX (40% reduction in hazard, HR=0.60; two-sided α=0.05). If the above assumptions hold, 
we anticipate 123 TTF events to be observed between 30 and 36 months from enrollment of the 
first patient. Exponential failures and a 1% per month dropout rate were assumed for the sample 
size calculation, which was carried out using East 5.4 (Cytel Inc., Cambridge, MA, USA). One 
interim efficacy analysis to assess for futility is planned.  
One interim analysis will be performed for futility when 74 TTF events have been observed.  It is 
anticipated that this number of TTF events will be observed approximately 22 months after first 
patient is enrolled. Results will be presented to the Data and Safety Monitoring Committee 
(DSMC), which may recommend discontinuation of the trial if it is clear at that point that the 
alternative hypothesis of an improved TTF associated with VEX compared with paclitaxel is 
unlikely to be shown. A one-sided boundary based on the O’Brien-Fleming criteria will be used 
to guide the DSMC deliberations.  
1.2.2 
Summary of interim analyses 
The IBCSG DSMC regularly reviews the trial at its twice-yearly meetings. One interim efficacy 
analysis to assess for futility was planned when 74 TTF events had been observed. This was 
conducted at the meeting in July 2020 (based on 122 patients enrolled as of 31 March 2020 and 
data retrieval 27 May 2020; 75 TTF events had been observed). The DSMC recommended the trial 
continue as planned.  
 
TRIAL CONDUCT 
The submission of METEORA (activated August 2016) was rejected by the Italian regulatory 
agency (AIFA) because the protocol referred to the trial as a Phase III study, but the primary 
endpoint was time to treatment failure, which AIFA would not accept as a phase III primary 
endpoint. The trial was re-written as phase II trial, renamed as METEORA-II, and resubmitted to 
AIFA and IEO ethics committee. Activities for METEORA activation ceased. The METEORA-II 
study was activated on 13 February 2017. 
The accrual goal was 160 patients for this trial, anticipated to be enrolled over 24 months with 12 
months additional follow-up for primary analysis, which would have completed enrollment before 


METEORA-II SAP: November 2021 
 
 
Trial 54-16 -- 5 
 
the end of 2019. With slow but steady enrollment, a revised completion date of 31 December 2020 
was targeted. After discussions with the IBCSG DSMC at its December 2020 meeting, the IBCSG 
leadership decided to proceed with closure of enrollment on 31 January 2021, even though the 
enrollment goal had not been reached. The decision considered that the enrollment had been 
ongoing for more than 3 years and the enrollment rate had slowed, 1 to 2 patients per month over 
the past 6 months, suggesting approximately 12 more months to reach 160 patients enrolled. The 
other consideration was that enrollment of at least 138 patients would still allow the trial to report 
results with adequate statistical power. The statistical design targeted 123 primary endpoint events 
(time to treatment failure), defined based upon discontinuation of trial treatment, and could be 
reached based upon enrolled patients well prior to anticipated enrollment of 160 patients. Thus the 
enrollment closure would allow more timely reporting of the results without any compromise of 
trial integrity. 
 
TRIAL REGISTRATION 
The trial is registered in ClinicalTrials.gov: NCT02954055 and in the European Medicines 
Agency’s (EMA) European Clinical Trials database: EudraCT 2016-002200-39. 
 
2 
EFFICACY ANALYSIS PLANS 
 
OBJECTIVES 
2.1.1 
Primary objective  
To assess efficacy, as measured by the time to treatment failure (TTF), of the first-line combination 
treatment with vinorelbine, cyclophosphamide and capecitabine (VEX) in comparison with 
paclitaxel monotherapy in ER+/HER2–, metastatic or locally advanced breast cancer patients, who 
have progressed under previous endocrine therapy. 
2.1.2 
Secondary objectives  
To evaluate: 
• 
Progression-free survival (PFS) based on local Investigator assessment by RECIST 1.1 
• 
Safety and tolerability, as documented according to NCI CTCAE v4.0 
• 
Disease control, based on RECIST 1.1 criteria 
• 
Overall survival (OS) 
 
 
ANALYSIS POPULATIONS 
Efficacy analysis population: All randomized patients who receive at least one dose of trial 
treatment. 
Safety population: All randomized patients who receive at least one dose of trial treatment. 
(thus the two populations are the same) 


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ENDPOINT DEFINITIONS 
2.3.1 
Primary Endpoint 
Time to treatment failure (TTF) is defined as the time from the date of randomization to the date 
when the final dose of trial treatment was administered. [sic; protocol §5.2] 
In implementation: The above endpoint definition from protocol §5.2 but is incorrect, as it would 
bias in favor of Arm B (VEX) which includes 3 agents vs. Arm A (paclitaxel). The protocol had 
addressed this issue by clearly defining End of Treatment (EoT), per protocol §9.5: 
“The End of Treatment (EoT) is defined as the date of  
• Arm A: the last dose of paclitaxel 
• Arm B:  the date when at least one of the three VEX drugs was administered for the last time”  
but the correction erroneously was not followed through to the endpoint definition.  
It is also stated in protocol §9.5: “After the trial treatment is stopped, future therapeutic decisions 
are at the discretion of the Investigator, with no restrictions. Patients showing RECIST 1.1 - 
defined PD can continue with trial treatment at the discretion of the Investigator as long as that is 
considered to be in the best interest of the patient and no new anticancer treatment is initiated.” 
Which is in direct conflict with the primary endpoint for VEX. 
Thus time to treatment failure (TTF) is defined as: the duration of time between the date of 
randomization to the end of treatment date (from protocol §9.5), 
• Arm A: the last dose of [iv] paclitaxel; and to account for the time of active IV drug +7 days 
is added to the date of last dose.  
• Arm B: the date when at least one of the three [oral] VEX drugs was administered for the last 
time. (the CRF records the date first medication permanently discontinued) 
The eCRF also captures date decision to (A) stop trial treatment; or (B) discontinue at least one 
trial medication. This is not used for the endpoint; this was for determining that end-of-treatment 
visit occurred within appropriate time interval. 
Cycles are 28 days. Regarding delays for toxicity that would result in discontinuation: 
• Paclitaxel dosing can be delayed by a maximum of 3 weeks (maximum 5 weeks from last 
dose of previous cycle); 
• VEX treatment can be delayed by a maximum of 3 weeks (21 days) from the date of the 
last dose; in case of a longer delay, trial treatment has to stop (refer to note in protocol 
§9.5).  Note: In Arm B (VEX), trial treatment is considered stopped as soon as one of the 
three drugs is stopped permanently. However, treatment with one or two of the VEX 
medications may be continued.).  
Indications of dose not taken, and the intervals between cycles were reviewed to ensure within the 
appropriate periods as specified above, as part of checking the permanent discontinuation dates. 
Those cycles that were not within the appropriate time interval were queried by the DMC to 


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confirm whether there was a delay exceeding protocol guidelines. Note specifically for VEX arm, 
because of pandemic the medications were sometimes provided for 2 cycles and an in-person visit 
skipped to minimize visits and these could appear as if delays between cycles; these were all 
queried to confirm that medications continued, and the database queries and correspondence 
documents this. 
If delay was beyond protocol specification, then: 
• End of treatment date was redefined (adjusted) based upon last dose prior to extended delay 
beyond protocol specification; 
• The reason for end of treatment was redefined based upon reason for delay (mostly 
recorded on eCRF as reason off schedule); 
• Subsequent cycles were marked as ones that should not have occurred and were not 
counted toward other variables describing treatment administration; the AEs will be 
reported both with and without those cycles (see subsequent sections).  
• All such cases and cycles will be listed in the report. 
2.3.2 
Secondary Endpoints 
Progression-free survival (PFS): [Protocol §12.12] The date of progression is the date that 
objective progression was first documented. Progression-free survival (PFS) is defined as time 
from randomization until documented disease progression according to RECIST 1.1 criteria or 
death, whichever occurs first.  For patients without progression, follow-up will be censored at the 
date of the survival update 12 months after the randomization of the last patient[*], unless death 
occurs within a short period of time (12 weeks, corresponding to the interval of tumor re-
evaluation) following the date last known progression-free, in which case the death will be counted 
as a PFS event.  
Patients who discontinue treatment prior to documented disease progression (see [protocol] §9.5), 
including those who initiate non-protocol therapy prior to progression, will be followed for disease 
progression, for a maximum of 12 months after the randomization of the last patient*. [In case of] 
A new (non-breast) cancer malignancy … such patients must continue to be followed for 
progression of the original breast cancer. 
*See note in next subsection regarding follow-up update, which was requested prior to 12 months 
after randomization of the last patient. 
In implementation: the interval for death as event is 14 weeks for the first (week 12) scan, allowing 
that scan window is 12 ± 2 weeks; and thereafter it was 16 weeks as 6/8 patients died within 16 
weeks of their last scan and the 2/8 that did not had much larger intervals of 30 and 60 weeks, 
providing a clear natural division (and determined without regard to treatment assignment). 
Patients without imaging after randomization who did not die within 12 weeks from randomization 
had PFS censored at date of randomization (1 day). 


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Note for those who discontinued treatment prior to documented disease progression, it cannot be 
determined whether progression is prior to or after subsequent therapy (which could include 
protocol-assigned therapy received after EOT outside of the protocol). Whether disease 
progression was documented prior to or after TTF date will be determined. 
A final note, TTF duration may be slightly greater than PFS duration, because PFS date is the date 
first suspicion of progression and sometimes additional tests or imaging were conducted to confirm 
progression, at which point treatment was permanently discontinued. 
Disease Control is defined as best overall response of CR or PR, or SD (or non-CR/non-PD in the 
case of non-measurable disease only) lasting for at least 24 weeks, measured from randomization 
until first documentation of progressive disease. [Protocol §15.2.2] Best overall response is 
defined as best response recorded from randomization across all time points until disease 
progression. Confirmation of partial or complete response by an additional scan is not requested 
in this trial. [Protocol §12.11] 
In implementation: BOR is across all time points until reported EOT, as the post-treatment PD 
eCRF captured only PD date after EOT; and the follow-up (E) eCRF captured date last adequate 
disease assessment if patient still without PD. However because disease control is non-PD for ≥24 
weeks, this endpoint can be updated using the subsequent post-treatment PD date and follow-up 
form. 
Overall survival is defined as the time from the date of randomization to death from any cause. 
For patients who are lost to follow-up or who have no documentation of death at the time of final 
analysis, follow-up will be censored at the date of last assessment of vital status. [Protocol §15.2.4] 
2.3.3 
Relevant Study Procedures 
Trial treatment should start within one week after randomization.  
Patients who have been randomized but never received any trial treatment for whatever reason 
(refusal, medical condition etc.) will have to be documented with a treatment form, but will not be 
followed further. 
Trial treatments will be administered in 4-week (28-day) cycles until progression, lack of 
tolerability, or until further trial treatment is declined. The treatment of the individual patient will 
be discontinued in case of: 
• Disease progression according to RECIST 1.1. as defined in section 12. 
• Unacceptable adverse event(s). 
• Delay of trial treatment by more than 3 weeks  
• Intercurrent illness that prevents further administration of trial treatment. 
• Patient demonstrates an inability or unwillingness to comply with the treatment regimen 
and/or trial requirements. 
• General or specific changes in the patient’s condition which render her unacceptable for 
further trial treatment in the opinion of the treating Investigator. 


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• Patient withdraws consent to continue trial treatment. 
Note: In Arm B (VEX), trial treatment is considered stopped as soon as one of the three drugs is 
stopped permanently. However, treatment with one or two of the VEX medications may be 
continued (data were not collected after first medication was discontinued). 
After the trial treatment is stopped, future therapeutic decisions are at the discretion of the 
Investigator, with no restrictions. Patients showing RECIST 1.1 - defined PD can continue with 
trial treatment at the discretion of the Investigator as long as that is considered to be in the best 
interest of the patient and no new anticancer treatment is initiated. (data were not collected) 
• Paclitaxel dosing can be delayed by a maximum of 3 weeks (maximum 5 weeks from last 
dose of previous cycle). 
• VEX treatment can be delayed by a maximum of 3 weeks (21 days) from the date of the 
last dose; in case of a longer delay, trial treatment has to stop (refer to note in [protocol] 
§9.5). 
End of treatment visit: Within 30 days after end of trial treatment (or at the time of decision to 
stop the trial treatment if the decision is taken >30 days after last dose) to report on any AEs during 
this period. 
Imaging: Tumor measurements according to RECIST 1.1 criteria have to be done at baseline, and 
every 12 weeks (± 2 weeks) from randomization until first disease progression. Tumor assessments 
include: clinical and radiological (by CT scan or MRI) tumor assessments and bone scan and FDG-
PET will be done if clinically indicated at the same time points. 
For patients who discontinue treatment for any reason other than objective disease progression, 
the date of first progression needs to be documented (54-PD Form). In the absence of tumor 
progression, the patient will continue to be followed for SAE reporting according and for 
documented disease progression or a maximum of 12 months after treatment stop [protocol §13.5] 
Visits should take place every 12 weeks (± 2 weeks). If the patient had not yet experienced disease 
progression, the date of the last adequate disease assessment (and PD, if applicable) will be 
reported on the 54-E Form, ~12 months after the last patient* was randomized. 
*Survival follow-up: 12 months after the randomization of the last patient, survival status needs 
to be documented for all alive patients on the 54-E Form.  
In implementation: The request for 54-E forms was distributed in Q3’2021 which was less than 12 
months after the last patient enrolled, in preparation for the Q4’2021 database lock. This form also 
asked for confirmation of, and allowed update of, the date objective progression first documented. 
Adverse events: from the first dose of trial medication until 28 days after all treatment 
discontinuation, regardless of whether it is considered related to a medication. The main criterion 
for tolerability is the occurrence of toxicities and adverse events. The severity and causality 
classified according to the NCI CTCAE Version 4.0. The presence or absence of the following 25 


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AEs were systematically queried for every cycle; in addition, any other medically important AE 
should also be reported: 
• Blood and lymphatic system disorders (neutropenia, thrombocytopenia, anemia), 
• Skin and subcutaneous disorders (alopecia, palmar-plantar erythrodysesthesia syndrome) 
• Immune system disorders (allergic reaction, anaphylaxis, aspartate aminotransferase 
increased) 
• Metabolism and nutrition disorders (anorexia) 
• Gastrointestinal disorders (diarrhea, vomiting, nausea, mucositis, constipation) 
• Nervous system disorders (peripheral sensory neuropathy, optic nerve disorder (scotomata)) 
• Infections and infestations 
• Musculoskeletal and connective tissue disorders (arthralgia or myalgia) 
• General disorders and administration site conditions (injection site reactions, fatigue) 
• Cardiac disorders (heart failure, acute coronary syndrome, sinus bradycardia, ventricular 
arrhythmia, supraventricular tachycardia) 
Serious adverse events up to 28 days after stop of all trial treatment: Arm A: stop of paclitaxel, 
Arm B: stop of all three VEX drugs.  
 
 
FOLLOW-UP 
As described above, study participation ended with EOT visit for patients who discontinued 
treatment for objective disease progression. Patients who discontinued treatment for other reasons 
were to continue imaging for progression for up to 12 months. Updated survival follow-up was 
sought prior to database lock for patients who were last known alive when they had completed 
trial participation. 
The median and IQR follow-up for survival will be calculated, overall and by treatment 
assignment. If a majority (at least 50%) of the patients have died, then it may be calculated as the 
median OS of surviving patients. Otherwise, the median follow-up will be estimated from the OS 
censoring distribution (i.e., by reversing the event/censoring indicator for OS).  
 
 
TESTS AND ESTIMATES 
The efficacy analysis approach is intention-to-treat (ITT) in the defined efficacy analysis 
population. 
The primary objective will be investigated by comparing TTF distribution between two treatment 
groups using two-sided stratified logrank test (H0: TTF1=TTF2; Ha: TTF1≠TTF2), with α=0.05. 
The test statistic and p-value will be taken from the stratified Cox PH model score test; Efron 
method for handling ties. Hazard ratios (VEX / paclitaxel, so that HR<1 indicates reduced hazard 


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of event with VEX and HR>1 indicates increased hazard of an event with VEX) will be estimated 
from a stratified Cox PH model, with two-sided Wald 95% CIs.  
Kaplan-Meier estimates of the TTF distributions will be calculated for each of the treatment 
groups, with reporting of the median, 6- and 12-month TTF; the SEs will use Greenwood’s formula 
and the pointwise 95% CIs will be obtained using complementary log-log transformation of the 
SDF.  
We will check the proportional hazards assumption by visually assessing the plot of 
log(-log(survival)) versus log of survival time for parallelism. This will be done overall, and 
according to strata. 
The protocol specified a subgroup analysis in which TTF was summarized separately according to 
previous chemotherapy yes vs no; estimates and CIs will be reported, with HRs and CIs estimated 
from a model with covariate-by-treatment interaction. 
2.5.1 
Stratification and Randomization 
Randomization was stratified according to 
• Prior treatment for locally advanced or metastatic disease (no prior endocrine therapy or 
chemotherapy; prior endocrine therapy only; prior chemotherapy ± prior endocrine therapy) 
• ECOG performance status 0 vs 1. 
Dynamic institution balancing was done in order to balance randomized assignments within 
institutions. 
In implementation: We had concern about (3 x 2=) 6 strata with 140 patients. The distribution of 
prior treatment was roughly (25%, 60%, 15%) and of ECOG PS (80%, 20%). Thus stratification 
for modeling will be reduced to 4 categories:  
• PS 1 regardless of prior treatment;  
• PS 0 according to prior treatment {no prior ET/CT; prior ET only; prior CT±ET}  
Sensitivity analysis for the primary endpoint will be performed, changing the strata to be each of 
the two factors individually and reported for the original combined factors (i.e., for full 6 strata).  
 
 
ANALYSIS COMPONENTS 
2.6.1 
CONSORT 
In order to complete the CONSORT flow diagram, the following will be tabulated, overall and 
according to treatment assignment: 
• First and last dates patients enrolled, number of centers that enrolled patients (overall only) 
• Number of patients randomized 
• Number of patients who started (included in efficacy analysis population) vs never started 
(excluded from efficacy analysis population) treatment, with reasons never started; there 


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will also be a listing of these patients (patid, center code, rando date, treatment assignment, 
reason) 
• Number of patients who discontinue treatment & number not discontinued at db lock 
• Number in efficacy analysis population who WC/LFU; listing all such patients also (patid, 
center code, randomization date (mon/yy), treatment assignment, number cycles, reason 
treatment discontinuation, WC/LFU status and date) 
2.6.2 
Enrollment, Follow-up Compliance 
Accrual figures/tables: 
• Monthly accrual: bar chart of numbers of patients enrolled by month, from Sep’17 to 
Jan’21, with horizontal lines indicating expected monthly accrual; 
• Cumulative accrual: bar chart of cumulative number of patients enrolled, from Sep’17 to 
Jan’21, with line for targeted cumulative enrollment; 
• Tabulate accrual per center (with center code & name, sorted largest to smallest 
enrollment), by year (2017-2020*) and total (*include Jan’21 with 2020) 
• Tabulate/list per center: N randomized, N started treatment, N discontinued treatment (TTF 
event) at db lock, N with alive at db lock, N alive with updated status at db lock 
There was no review for deviations from inclusion/exclusion criteria for this trial. 
The status of survival follow-up submission, according to center, will be summarized. Tables:  
• Tabulation providing for each center: N randomized, N died, N alive, month/year of last 
vital status for those alive  
2.6.3 
 Stratification 
For both the randomized population, and the efficacy analysis population. Tables and listing: 
• Distribution of stratification factors (individually and combined), overall and according to 
treatment assignment 
• Distribution of stratification factors (individually and combined) according to center and 
according to year randomized 
• Cross-tabulation of factors as reported at (and used for) randomization vs actual. The 
randomization form (RA form) collects the values entered into the IBCSG randomization 
system and used for stratification of the randomization assignment. If these values are 
incorrect then they are amended on the Registration form (54-A form). For primary and 
secondary overall analyses we will use the stratification factors entered on randomization 
form. For tabulating characteristics and subgroup analyses, the actual values entered in the 
A form will be reported (stratification factors also will be tabulated; and will be labeled as 
such). 
• Listing of incorrect stratification factors (patid, center code, treatment assignment, 
randomization date (mon/yr), both stratification factors: RA and A forms). 


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2.6.4 
Patient, Disease and Prior Treatment Characteristics 
Characteristics are taken from the Registration (54-A) form; IBCSG standard is to use A form 
when available and otherwise resort to the RA (randomization) internal form. RA is as reported at 
time of randomization & never changes; A form would correct a value, if necessary. In this trial, 
the A-form data are complete, thus no need to combine info from both forms.  
• Stratification factors: ECOG PS at randomization, prior treatment for ABC 
• Patient characteristics: age at randomization, ECOG PS at randomization (A form), BMI 
at randomization (derived) 
• Disease characteristics: weeks from MBC diagnosis to enrollment (derived); ER status 
determination (primary or metastatic tissue); measurable disease yes/no 
• Prior treatment characteristics: Prior treatment for ABC (A form: none, ET only, CT±ET),  
prior ET±CDK4/6 inhibitor use (derived: no prior ET, ET without CDK46i, ET+CDK46i 
just prior to enrollment, ET+CDK46i previously) 
• Baseline AEs  
Tables/figures/listings, for the efficacy analysis population: 
• Tabulation, N patients randomized, stratification factors, patient disease & treatment 
characteristics; overall and according to treatment assignment; age in groups needed for 
CT.gov & EudraCT should be included 
• Descriptive  summary for age and BMI, overall and according to treatment assignment (N 
pts randomized, N missing values, mean, SD, min, Q1, median Q3, max) 
 
2.6.5 
Primary Efficacy Analysis 
The primary efficacy analysis will proceed as summarized in Section 2.5 above. The data cut-off 
and database lock dates used for the analyses and the median follow-up duration (see §2.4) will be 
reported (MFU overall and also by treatment group). 
2.6.5.1 
Models 
Stratified Cox PH regression models will be used to: estimate HRs (95% CI) for treatment effect, 
unadjusted for covariates and stratified log-rank test statistic and p-value; and estimate HRs (95% 
CI) for treatment effect within subgroups by including treatment-by-covariate interaction in the 
model.  
2.6.5.2 
Sensitivity and Subgroup Analyses  
1) Primary efficacy analysis test and HR (CI) estimates will be re-estimated, with each of the two 
stratification factors as the only stratification factor for the model and with both (6 strata). 
2) Subgroup analysis planned per protocol was according to prior chemotherapy use (yes/no); HRs 
and CIs will be reported for subgroups defined by actual prior therapy (no prior CT/ET, prior 


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CT±ET, and prior ET only), and a new variable also incorporating whether prior ET included 
CDK4/6 inhibitor.  
2.6.5.3 
Tables and Figures 
• KM plot of distribution of TTF, x-axis in months by 3-monthly intervals until max of 24 
mos; x-axis labeled as ‘Months from randomization’ and y-axis labeled as ‘Percentage free 
from treatment failure’  
• Table of Kaplan-Meier estimates for distribution of TTF according to treatment 
assignment, including median (95% CI), and 6- and 12- month failure-free %  (SE, 95% 
CI) 
• Table of TTF hazard ratio comparing treatment: N pts, N events, median mos w/95% CI 
(by treatment assignment), stratified Logrank chisq and p-value 
• Table of test statistics and HR (95% CI) estimates from sensitivity analysis 
• KM plots and estimates, HR (95% CI) estimates in subgroups as described above 
 
2.6.6 
Secondary Efficacy Endpoints 
Same analysis population as the primary endpoint; also ITT approach.  
2.6.6.1 
Best overall response and disease control 
Disease control will be summarized overall and according to treatment assignment as N (%) with 
two-sided exact binomial 95% CI, and compared between the two treatment groups using stratified 
exact CMH test. 
Tables: 
• Best overall response (CR, PR, SD, PD, NE) as N(%); overall and by measurable/non-
measurable only disease status; overall and according to treatment assignment. 
• Disease control as N(%); overall and by measurable/non-measurable only disease status; 
overall and according to treatment assignment 
• Disease control will also be summarized according to subgroups  
2.6.6.2 
Progression free survival (PFS) 
PFS analysis will follow that for TTF.  The y-axis of KM plot will be “Percentage alive and 
treatment-free.” Estimates also according to subgroups will be provided. Sensitivity analyses will 
not be conducted, unless indicated from the primary analysis. 
2.6.6.3 
Overall survival (OS) 
OS analysis will follow that for TTF. The x-axis of KM plot will be to max 36 months; y-axis will 
be “Percentage alive.”  Estimates also according to subgroups will be provided. 


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2.6.7 
Adverse Events / Safety 
The maximum grade of each of 25 targeted AE while on treatment (until EOT visit) will be 
determined, and the frequencies summarized and tabulated according to grade and treatment 
assignment, with two-sided exact binomial 95% CIs. The maximum grade, both with and without 
other grade 3-5 AEs, will also be determined and summarized. The protocol proposed comparisons 
between treatment groups, but these were omitted as unnecessary except for maximum grade 
(using stratified exact CMH chi-square test). 
In implementation: Because we had some patients with permanent discontinuation (TTF) date 
wrong (i.e., continuing treatment beyond protocol specification), the primary summary excludes 
any AEs reported after the revised TTF date. The changes to AE reporting by including the 
additional cycles after revised TTF will be summarized, including any grade 3+ AEs after the 
revised permanent discontinuation date will be listed.  
The analysis is repeated for the subset of AEs indicated as causality=suspected [as related to 
protocol treatment(s)].  
Note all patients who initiated therapy did initiate the assigned therapy, and thus summaries by 
treatment assignment reflect actual treatment received.  
Tables and listings: 
• Targeted AEs max grade throughout treatment (N patients; % of patients) according to 
treatment assignment 
• Patients’ maximum AE grade for targeted AEs, according to treatment assignment 
• Patients’ maximum AE grade for targeted or other grade 3+ reported AE, according to 
treatment assignment 
• N (%) patients experiencing ≥1 targeted AE, by treatment assignment 
• N (%) patients experience ≥1 targeted grade 3+ AE (or experiencing ≥1 grade 3+ AE any 
report), by treatment assignment 
• All of the above, for the subset of AEs with causality=suspected 
• Listing of AEs after revised TTF date (patid, AE type, max prior to TTF and max all 
reported cycles) and any grade 3+ AEs after revised TTF date (variables as below) 
• Listing of other grade 3-5 AEs, including indicator of causality suspicion and if after 
revised TTF date (patid, AE type, grade, causality, cycle, indicator if after revised TTF) 
• Listing of patients with grade 4 and grade 5 AEs (deaths during treatment) (variables as 
above); and narratives for grade 5 AEs  
 
2.6.8 
Treatment  
As noted in §2.3.1, there are a few patients in each treatment group for whom there is an interval 
of  treatment interruption exceeding the protocol specifications. In these cases, the TTF endpoint 


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variables were redefined. As well, the calculated variables described below only considered the 
cycles before the revised TTF event date/status. 
Variables:  
The number of days between randomization and treatment initiation 
The last (or latest) cycle number, as well as the reason permanently discontinued treatment.  
For VEX: which agent(s) were stopped at TTF date (i.e., all or some) 
For paclitaxel: the cumulative number of doses administered (i.e., sum actual d1,d8,d15 doses 
administered) and cumulative dose administered (i.e., sum actual dose given on d1,d8,e15) prior 
to TTF were summed across cycles; these were also expressed as relative dose (i.e., denominator 
is expected number of doses, or total dose, across all cycles initiated).  
Dose Modifications indicators are determined for each regimen. 
Paclitaxel, indicators created for whether ever dose reduction, ever given off-schedule, and ever 
dose not given prior to TTF (n.b., for not given, it was meant to indicate skipped dose, so if cycle 
also indicated permanent discontinuation then it was not counted as skipped). More detailed 
variables not derived, as other variables will convey this information. 
VEX regimens, indicators created for whether ever V,E,X dose modification(s) across cycles prior 
to TTF were determined: 
• V could be <3x/week, 50% dose reduction, or not taken during cycle;  
• E could be interruptions >3 days, 50% reduction [every-other-day], or not taken;  
• X could be interruptions >3 days, 67% reduction (1 tab bid), or not taken. 
In all cases, “not taken” here would indicate an interruption <21 days as described by protocol.  
 
Tables/Figures/Listings: 
• Listing of those patients for whom TTF date was revised and differs from eCRF-reported 
permanent discontinuation date (patid, center code, treatment assignment, rando date 
(mon/yy), last cycle per eCRF, reported permanent discontinuation date, reported 
permanent discontinuation reason, revised last cycle corresponding to TTF date, revised 
TTF date, revised TTF reason) 
• Tabulate (N,%) number of cycles, reason permanent discontinuation, for VEX what 
stopped (all or 1 or 2); by treatment assignment 
• Descriptive stats (N, Nmiss, min, max, median, Q1,Q3) number of cycle, by treatment 
assignment 
• Tabulate treatment modifications (N,%), by treatment assignment 
• Descriptive stats (N, Nmiss, min, max, median, Q1,Q3) cumulative number of doses and 
of dose administered, for those assigned paclitaxel 


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