Conditions: Metastatic Breast Cancer
Keywords: Triple negative metastatic breast cancer Cancer Stem Cells
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 194
Healthy volunteers: no

Brief summary:
The Objectives of this study:

The primary objective of the study was to evaluate progression-free survival (PFS) (defined as the number of days between the date of randomization and the date of clinical disease progression (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1, as assessed by Independent Radiology Review, or death for any cause, whichever occured first) in patients with metastatic triple-negative breast cancer (TNBC) treated with the combination of paclitaxel and orally administered reparixin compared to paclitaxel alone.

The secondary objectives were:

* To determine overall survival (OS).
* To evaluate objective response rates (ORR).
* To determine median PFS (mPFS).
* To assess the safety of the combination of paclitaxel and orally administered reparixin (referred to as combination treatment).

Detailed description:
The study is a two arm, phase 2 study to evaluate the efficacy of the combination of paclitaxel and reparixin compared to paclitaxel and placebo in metastatic TNBC patients.

In the study two groups There were two groups:

Group 1: paclitaxel 80 mg/m2 intravenous (i.v.) (Days 1, 8, and 15 of 28-day cycle) + reparixin oral tablets 1200 mg three times a day (t.i.d.) continuing from Day 1 to Day 21.

Group 2: paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15 of 28-day cycle) + placebo oral tablets 1200 mg t.i.d. continuing from Day 1 to Day 21.

Study drug (reparixin/placebo) was administered with water prior to the start of the i.v. paclitaxel infusion on Cycle 1, Day 1 and then administered approximately every eight hours (six to ten hours) for 21 consecutive days during each cycle with seven days off-treatment between each cycle. It was preferable that reparixin was taken with food. However, if the patient was unable to eat, study drug was allowed to be administered. When in combination with paclitaxel (Day 1, 8 and 15 of each cycle), reparixin or placebo was administered every approximately eight hours with about 250 mL water and a light meal or snack. Paclitaxel was administered in combination with study drug (reparixin/placebo) as an i.v. infusion on Days 1, 8 and 15 of each 28-day cycle.

On Cycle 1, Day 1, paclitaxel was administered at the clinic after the administration of study drug (reparixin/placebo). From that point forward, study drug (reparixin/placebo) was self-administered t.i.d. for 21 days. Combination treatment (three weeks on and one week off) continued until PD according to RECIST criteria version 1.1, withdrawal of consent or unacceptable toxicity, whichever occurred first.

The next clinic visits were on Days 8 and 15 when a paclitaxel infusion was administered to the patient. The patients returned to the clinic again on Day 29/Day 1 of the next cycle.

Tumor response and/or progression assessments were performed and documented every eight weeks according to RECIST criteria version 1.1. Metastatic tissue samples were analyzed for evaluation of CD24-CD44+ and aldehyde dehydrogenase positive (ALDH+) CSCs.

Arms:
arm 1: paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15) + reparixin oral tablets 1200 mg t.i.d.

continuing from D 1 to Day 21 of 28-day cycle arm 2: paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15) + placebo oral tablets 1200 mg t.i.d. continuing from D 1 to Day 21 of 28-day cycle

Interventions: intervention 1: paclitaxel intervention 2: Reparixin intervention 3: placebo
Intervention descriptions: intervention 1: paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15) intervention 2: reparixin oral tablets 1200 mg t.i.d. continuing from D 1 to Day 21 of 28-day cycle intervention 3: placebo oral tablets 1200 mg t.i.d. continuing from D 1 to Day 21 of 28-day cycle

Protocol document:
Prot_000.pdf: 
 
REP0114 
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REP0114 
 
PROTOCOL No. REP0114 (Final Version 9.0 – 25 November 2019 ) 
This protocol version results from revision of protocol version No. 8 (Final 09 April 2019) 
according to Amendment No 5 (Final version 25 November 2019)  
 
A randomized, double-blind, placebo-controlled phase 2 study of paclitaxel in combination 
with reparixin compared to paclitaxel alone as front-line therapy for Metastatic Triple-
Negative Breast Cancer (FRIDA) 
 
Study Phase:   II 
Investigational Medicinal Product: Reparixin oral tablets 
IND number: 112502 
EudraCT number: 2014-004796-23 
 
Sponsor: 
Dompé Farmaceutici s.p.a.  
Via Santa Lucia, 6 
20122 MILANO 
Italy 
Tel: +39 02 58383.1 
Clinical Research Organization (CRO): 
Pharm Research Associates (UK) Ltd. 
500 South Oak Way 
Green Park 
Reading, Berkshire RG2 6AD, UK 
Tel: +44 (0)1189-181-000 
Medical Monitor: 
PRA Health Sciences 
Medical and Oncology Support Center USA 
Tel: 1 866 326 5053 
Fax: 1 800 280 7035 
 
PRA Health Sciences 
Medical and Oncology Support Center Europe 
Tel: +44 179 252 5608 
Fax: +49 621 878 2828 
Safety Contact (SAE reporting): 
PRA Health Sciences Drug Safety Center 
Americas 
995 Research Park Blvd. Suite 300 
Charlottesville, VA 22911 
USA 
Tel: 1 800 772 2215 
Fax: 1 888 772 6919 
Email: CHOSafety@prahs.com 
 
PRA Health Sciences Drug Safety Center 
EAPA 
Gottlieb-Daimler-Str. 10 
68165 Mannheim 
Germany 
Tel: +49 621 8782 154 
Fax: +44 1792 525 720 
Email: MHGSafety@prahs.com 
CONFIDENTIAL 
Information in this protocol and accompanying documents contains privileged or confidential information that is the property of Dompé 
farmaceutici s.p.a. It is understood that the information will not be used, divulged, or published without the prior written consent of  
Dompé farmaceutici s.p.a., except to the extent longer available disclosure is required by applicable laws and regulations. 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) as set forth in the International Conference on 
Harmonization (ICH) guidelines on GCP (ICH E6), and applicable local regulatory requirements. 


 
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APPROVAL OF THE PROTOCOL 
 
 
 
 
Approved and Signed by 
Date 
 
 
 
 
Pier Adelchi Ruffini, MD 
 ____________________________  
___/___/____ 
Dompé Farmaceutici s.p.a. –  
 
Global Medical Development Director 
 
 
 
Susan McCanna, BSc 
 ____________________________  
___/___/____ 
Dompé Farmaceutici s.p.a. –  
Clinical Development Manager 
 
 
 
 
I have read and agree to the protocol REP0114, entitled ‘A randomized, double-blind, 
placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to 
paclitaxel alone as front-line therapy for Metastatic Triple-Negative Breast Cancer’. I am 
aware of my responsibilities under the guidelines of GCP, local regulations (as applicable), the 
declaration of Helsinki, and the study protocol. I agree to conduct the study according to these 
responsibilities and to appropriately direct and assist the staff under my control, who will be 
involved in the study. 
 
 
 
 
Clinical Site Name: 
 
 
Site Number: 
 
 
Site Principal Investigator: 
 
 
Signature/Date: 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
 
1 
GENERAL INFORMATION 
 
 
 
 
 
 
6 
1.1 
PROTOCOL SUMMARY ...................................................................................................................8 
1.2 
STUDY FLOW CHART ................................................................................................................... 14 
1.3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................. 16 
2 
INTRODUCTION  
 
 
 
 
 
 
 
19 
2.1 
CANCER STEM CELLS .................................................................................................................. 19 
2.2 
REPARIXIN BACKGROUND ........................................................................................................... 19 
2.2.1 
Drug Description and Mechanism of Action ......................................................................... 19 
2.2.2 
Pharmacological Profile ........................................................................................................ 19 
2.2.3 
Pharmacokinetics and Product Metabolism .......................................................................... 20 
2.2.4 
Preclinical Toxicology Profile ............................................................................................... 21 
2.2.5 
Clinical Results ...................................................................................................................... 22 
2.2.6 
Safety Results ......................................................................................................................... 24 
3 
TRIAL RATIONALE AND OBJECTIVES 
 
 
 
 
26 
3.1 
RATIONALE ................................................................................................................................. 26 
3.1.1 
Dose and Schedule Rationale ................................................................................................ 28 
3.2 
OBJECTIVES ................................................................................................................................. 29 
4 
STUDY PLAN 
 
 
 
 
 
 
 
 
29 
4.1 
STUDY DESIGN ............................................................................................................................ 29 
4.1.1 
Patient Participation.............................................................................................................. 30 
4.2 
STUDY ENDPOINTS ...................................................................................................................... 31 
4.3 
SAMPLE SIZE ............................................................................................................................... 32 
5 
STUDY POPULATION 
 
 
 
 
 
 
 
32 
5.1 
PATIENT SELECTION CRITERIA .................................................................................................... 33 
5.1.1 
Inclusion Criteria ................................................................................................................... 33 
5.1.2 
Exclusion Criteria .................................................................................................................. 34 
5.2 
REMOVING PATIENTS FROM THE STUDY ..................................................................................... 34 
5.3  
DISCONTINUATION CRITERIA ...................................................................................................... 35 
6 
RANDOMIZATION 
 
 
 
 
 
 
 
35 
7 
STUDY TREATMENT 
 
 
 
 
 
 
 
36 
7.1 
STUDY DRUG (REPARIXIN OR PLACEBO) AND PACLITAXEL ................................................ 36 
7.1.1 
Formulation ........................................................................................................................... 36 
7.1.2 
Container and Closure System............................................................................................... 36 
7.2 
DOSE AND ROUTE OF ADMINISTRATION ...................................................................................... 37 
7.3 
DRUG COMPLIANCE .................................................................................................................... 37 
7.4 
DRUG STORAGE AND ACCOUNTABILITY ..................................................................................... 37 
7.5 
CONCOMITANT THERAPIES AND BIRTH CONTROL ....................................................................... 38 
7.6 
CRITERIA FOR PACLITAXEL DOSE MODIFICATIONS AND DELAYS ................................................. 38 
8 
TREATMENT ASSESSMENTS  
 
 
 
 
 
39 
8.1 
PRE-TREATMENT EVALUATIONS ................................................................................................. 39 
8.2 
ON STUDY EVALUATIONS ........................................................................................................... 40 
8.3 
EVALUATION AT OFF TREATMENT VISIT (TERMINATION OR WITHDRAWAL) .............................. 41 


 
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8.4 
FOLLOW-UP EVALUATIONS ......................................................................................................... 42 
8.5 
OTHER ASSESSMENTS ................................................................................................................. 42 
8.5.1 
Correlative Studies ................................................................................................................ 42 
9 
EFFICACY ASSESSMENT 
 
 
 
 
 
 
43 
9.1 
EFFICACY PARAMETERS .............................................................................................................. 43 
9.1.1 
Evaluation by RECIST Version 1.1 ........................................................................................ 43 
9.1.2 
Confirmation Criteria ............................................................................................................ 45 
9.1.3 
Central Independent Radiology Review ................................................................................. 45 
10 
SAFETY ASSESSMENT  
 
 
 
 
 
 
45 
10.1 
SAFETY PARAMETERS ................................................................................................................. 45 
10.1.1 
Vital Signs and Physical Examination ................................................................................... 46 
10.1.2 
Concomitant treatments ......................................................................................................... 46 
10.1.3 
Chest X-ray ............................................................................................................................ 46 
10.1.4 
Laboratory Examinations ...................................................................................................... 46 
10.2 
ADVERSE EVENTS ....................................................................................................................... 46 
10.3 
SERIOUS ADVERSE EVENTS ......................................................................................................... 47 
10.4 
ADVERSE EVENT COLLECTION .................................................................................................... 48 
10.5 
RELATIONSHIP OF AES TO THE INVESTIGATIONAL PRODUCT ...................................................... 48 
10.6 
REPORTING PROCEDURES FOR SERIOUS ADVERSE EVENTS ......................................................... 49 
10.7 
NON SERIOUS ADVERSE EVENTS................................................................................................. 50 
10.8 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION ..................................................... 50 
10.9 
UNBLINDING ............................................................................................................................... 50 
10.10 
OVERDOSE .................................................................................................................................. 51 
10.11 
PREGNANCY ................................................................................................................................ 51 
10.12 REPORTING PROCEDURE TO IRB/IEC AND TO REGULATORY AUTHORITIES .................................... 52 
10.13 REPORTING OF PACLITAXEL ADVERSE REACTIONS AND OVERDOSE ................................................. 52 
11 
DIRECT ACCESS TO ORIGINAL DOCUMENTS 
 
 
 
53 
12 
CONTROL AND QUALITY ASSURANCE PROCEDURES  
 
53 
12.1 
CLINICAL MONITORING AND IDENTIFICATION OF SOURCE DATA ................................................ 53 
12.2 
AUDIT ......................................................................................................................................... 54 
12.3 
INSPECTIONS ............................................................................................................................... 54 
12.4  
DATA MONITORING COMMITTEE ................................................................................................ 54 
12.5  
 INDEPENDENT RADIOLOGY REVIEW ........................................................................................... 55 
13 
DATA MANAGEMENT 
 
 
 
 
 
 
 
56 
13.1 
CASE REPORT FORM (CRF) ......................................................................................................... 56 
14 
STATISTICAL CONSIDERATIONS 
 
 
 
 
 
56 
14.1 
EFFICACY ANALYSIS ................................................................................................................... 57 
14.2 
SAFETY ANALYSIS ...................................................................................................................... 57 
14.3 
EXPLORATORY ANALYSES .......................................................................................................... 58 
14.4 
ASSIGNMENT OF PATIENT NUMBER ............................................................................................. 58 
15 
ETHICAL ASPECTS 
 
 
 
 
 
 
 
58 
15.1 
INDEPENDENT REVIEW BOARDS/INDEPENDENT ETHICS COMMITTEES ........................................ 59 
15.2 
INFORMATION FOR THE PATIENT AND INFORMED CONSENT ........................................................ 59 
16 
ADMINISTRATIVE PROCEDURES 
 
 
 
 
 
59 
16.1 
CHANGES TO THE STUDY PROTOCOL ........................................................................................... 59 
16.2 
SUSPENSION/INTERRUPTION OF THE STUDY ................................................................................ 60 
16.3 
END OF STUDY ............................................................................................................................ 60 


 
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16.4 
ARCHIVING.................................................................................................................................. 60 
16.5 
USE OF THE INFORMATION AND PUBLICATION OF THE RESULTS ................................................. 60 
16.6 
INSURANCE COVERING PUBLIC LIABILITY .................................................................................. 61 
16.7 
FINANCING OF THE STUDY .......................................................................................................... 61 
17 
RESPONSIBILITIES OF THE INVESTIGATOR 
 
 
 
61 
18 
FINAL STUDY REPORT  
 
 
 
 
 
 
61 
19 
REFERENCES 
 
 
 
 
 
 
 
 
62 
20 
APPENDICES 
 
 
 
 
 
 
 
 
64 
APPENDIX 1 - DECLARATION OF HELSINKI ................................................................................................ 66 
APPENDIX 2 - PERFORMANCE STATUS SCALE: ZUBROD/ECOG ................................................................ 67 
APPENDIX 3 - COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) VERSION 4.03 ......... 68 
APPENDIX 4 - RESPONSE CRITERIA (RECIST) VERSION 1.1 ...................................................................... 69 
APPENDIX 5 - REPARIXIN AND PLACEBO DESCRIPTION AND COMPOSITION ............................................... 70 
APPENDIX 6 - REPARIXIN AND PLACEBO PACKAGING AND LABELING DETAILS .......................................... 72 
APPENDIX 7 - PACLITAXEL PACKAGE INSERT ............................................................................................ 73 
APPENDIX 8 - SAFETY DETAILS ................................................................................................................. 74 
APPENDIX 9 – CYP2C9 INDUCERS AND INHIBITORS .................................................................................. 77 
APPENDIX 10 – ACCEPTABLE METHODS OF BIRTH CONTROL ..................................................................... 78 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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1 
GENERAL INFORMATION 
TITLE 
A randomized, double-blind, placebo-controlled phase 2 
study of paclitaxel in combination with reparixin 
compared to paclitaxel alone as front-line therapy for 
Metastatic Triple-Negative Breast Cancer (FRIDA) 
DOMPE PROTOCOL N° 
REP0114  
SPONSOR 
Address 
Dompé Farmaceutici s.p.a.,  
Via Santa Lucia, 6, 20122 Milano, Italy. 
DOMPE 
DEVELOPMENT 
DIRECTOR 
Tel/Fax 
Mobile 
E-mail 
Pier Adelchi Ruffini, MD 
 
+39 02/583.83.500/02 583.83.324 
+39 346 8745908 
pieradelchi.ruffini@dompe.com 
MEDICAL MONITORING 
 
PRA Health Sciences 
Medical and Oncology Support Center USA 
Tel: 1 866 326 5053 
Fax: 1 800 280 7035 
 
PRA Health Sciences 
Medical and Oncology Support Center Europe 
Tel: +44 179 252 5608 
Fax: +49 621 878 2828 
SAE REPORTING 
PRA Health Sciences 
Drug Safety Center Americas 
995 Research Park Blvd. Suite 300 
Charlottesville, VA 22911, USA 
Tel: 1 800 772 2215 
Fax: 1 888 772 6919 
Email: CHOSafety@prahs.com 
 
PRA Health Sciences Drug Safety Center EAPA 
Gottlieb-Daimler-Str. 10 
68165 Mannheim 
Germany 
Tel: +49 621 8782 154 
Fax: +44 1792 525 720 
Email: MHGSafety@prahs.com 
ORGANIZATION 
RESPONSIBLE FOR 
MONITORING 
Pharm Research Associates (UK) Ltd. 
500 South Oak Way 
Green Park 
Reading, Berkshire RG2 6AD, UK 
+44 (0)1189-181-000 


 
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DATA MANAGEMENT 
PRA Health Sciences  
World Headquarters, USA 
CLINICAL LABORATORIES 
Local labs at participating center 
CENTRAL LABORATORIES 
Istituto Europeo di Oncologia (IEO) 
Via Ripamonti 435, 20141 Milano, Italy  
 
CENTRAL 
RADIOLOGY 
REVIEW 
BioClinica Inc. 
826 Newtown Yardley Road, Newtown, PA 18940, USA 
COORDINATING 
INVESTIGATOR 
Lori J. Goldstein – USA 
 
 


 
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1.1 
Protocol Summary 
 
TRIAL SYNOPSIS 
Study Number: REP0114 
Title of Study: A randomized, double-blind, placebo-controlled Phase 2 Study of paclitaxel in 
combination with reparixin compared to paclitaxel alone as front-line therapy for Metastatic 
Triple-Negative Breast Cancer (FRIDA) 
Investigational Medicinal Product: Reparixin oral tablets 
Study Sites: Approximately 60 sites located in the USA and EU 
Phase of Development: II 
Background information  
Cancer Stem Cells (CSCs) have the ability to self-renew and generate the full range of cells 
that make up a bulk tumor. CSC have been identified in several human haematological and 
non-haematological tumors. In breast cancer, CSC were originally identified as cells expressing 
the CD24-CD44+ phenotype (Al-Hajj, et al., 2003). Later, CSC in breast and other human 
cancers were found to express the enzyme aldehyde dehydrogenase (ALDH+). Gene expression 
profiling of the ALDH+ populations in breast cancer (BC) revealed selective expression of 
CXCR1, a receptor for the cytokine CXCL8 (formerly, IL-8). CXCR1 expression was limited 
to a subpopulation of ALDH+ cells. In vitro, the addition of recombinant CXCL8 increased the 
CSC population as well as its propensity for invasion (Charafe-Jauffret, et al., 2009). Using 
CXCR1-blocking antibodies or reparixin (a small molecular weight allosteric inhibitor of 
CXCR1), it was demonstrated that CXCR1 blockade selectively decreased the breast CSC 
population in vitro and in NOD/SCID xenograft models. Furthermore, administration of 
reparixin in combination with chemotherapy to tumor bearing NOD/SCID mice reduced tumor 
burden and the proportion of both ALDH+ and CD24-CD44+ BC CSCs. Finally, administration 
of reparixin single agent reduced development of systemic breast cancer metastasis in 
NOD/SCID mice. These studies provide experimental support to strategies aimed at interfering 
with the CXCL8/CXCR1 axis, which is activated by conventional chemotherapy. CXCR1 
inhibition may be able to target BC CSCs and increase the efficacy of current therapies which 
address the proliferating, non-CSC component of the tumor. 
Clinical investigation of reparixin as a BC CSC targeting agent was started in metastatic BC. 
In keeping with the animal model, three dose levels of reparixin (400 mg, 800 mg and 1200 mg 
three times daily) were administered in combination with weekly paclitaxel 80 mg/m2, in a 
phase Ib clinical trial, open to patients with non-HER2 amplified metastatic BC. The study 
provided evidence that the combination is safe and well tolerated across the three dose levels 
explored, with a MTD not having been formally reached, and produces a sizeable response rate 
with some long term responders. Reparixin 1200 mg t.i.d. was chosen as recommended phase 
II dose. 
Among non-HER2 amplified BC, Triple Negative BC (TNBC) is a subtype where <1% of the 
cells express estrogen or progesterone receptors (Hammond, et al., 2010).  As a consequence, 
TNBC is amenable neither to hormonal nor to HER2-targeted therapies, with the only 
treatments available consisting of surgery, radiotherapy and chemotherapy. Metastatic TNBC 
carries a dismal prognosis, with median overall survival not exceeding 13 months (Kassam, et 
al., 2009). Similar to other BC types, treatment of metastatic TNBC is based upon sequential 
monotherapies in all patients, except those with a rapidly progressing or highly symptomatic 


 
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TRIAL SYNOPSIS 
disease. Most patients with metastatic TNBC relapsed following a (neo)adjuvant chemotherapy 
regimen which most often contains a taxane (i.e., paclitaxel or docetaxel). Patients who relapsed 
following a taxane-containing (neo)adjuvant regimen can be re-challenged with a taxane as 
long as a sizeable Disease-free/Progression-free survival has been recorded. 
Among BC subtypes, TNBC is the one where CSCs are most represented. Considering its 
dismal prognosis, its sensitivity to single agent paclitaxel even in the re-challenge setting, and 
the safety and activity data of the combination reparixin + weekly paclitaxel as assessed in the 
phase Ib study, this randomized phase 2 clinical trial aims at formally evaluating activity and 
safety of the combination in comparison with single agent weekly paclitaxel in patients with 
metastatic TNBC. 
Study Objectives:  
Primary Objective 
 The primary objective of the study is to evaluate Progression Free Survival (PFS) 
(defined as the number of days between the date of randomization and the date of 
clinical disease progression (PD) according to RECIST criteria version 1.1, as assessed 
by Independent Radiology Review, or death for any cause, whichever occurs first) in 
patients with metastatic TNBC treated with the combination of paclitaxel and orally 
administered reparixin compared to paclitaxel alone.  
 
Secondary Objectives 
• 
To determine Overall Survival (OS) 
• 
To evaluate Objective Response Rates (ORR) 
• 
To determine median PFS (mPFS) 
• 
To assess the safety of the combination treatment 
 
Exploratory Objectives 
• 
To determine Median Time To new Metastasis (TTM) (new lesions at existing or new 
sites) 
• 
To determine Proportion of patients progressing with new metastatic lesions 
• 
To compare the incidence and severity of peripheral neuropathy between the two 
treatment groups 
• 
Evaluation of CSCs in metastatic tissue 
Study Design and Methodology:  
Randomized (1:1), double-blind, placebo-controlled, multicentre phase II clinical trial.  
 
Treatment Groups: 
Group 1: paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15) + reparixin oral tablets 1200 mg t.i.d. 
continuing from D 1 to Day 21 of 28-day cycle 
Group 2: paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15) + placebo oral tablets 1200 mg t.i.d. 
continuing from D 1 to Day 21 of 28-day cycle 
Number of Patients: 
The trial is designed to provide 80% statistical power to detect an improvement in PFS from 5 
months with paclitaxel monotherapy in patients with metastatic TNBC (Awada, et al., 2014; 


 
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TRIAL SYNOPSIS 
Finn, et al., 2009, Harris, et al., 2006; Miller et al, 2007) to 8 months with the addition of 
Reparixin, corresponding to a hazard ratio 0.625, when using a logrank statistic having (one-
sided) 0.025 false positive error rate.  This requires 142 PFS events and the approximate sample 
size will be 156 randomized patients (78 patients per group).  
Due to extreme enrollment difficulties during the first 6 months of 2018, enrollment to the study 
was terminated early (30 July 2018) and the final sample size is equal to 123 randomized 
patients. No formal recalculation of sample size/required PFS events could be made under these 
circumstances and although the above assumptions remain, the true statistical power and hazard 
ratio will be known after database lock and will be presented in the CSR. 
 
Duration of Study Drug Treatment:  
28-day cycles of combination therapy reparixin oral tablets + paclitaxel i.v. weekly (group 1) 
or placebo oral tablets + paclitaxel i.v. weekly (group 2) three weeks on and one week off until 
disease progression by RECIST version 1.1, withdrawal of consent, or unacceptable toxicity, 
whichever occurs first. 
Test Product; Dose and Mode of Administration:   
Reparixin or placebo 600 mg oral tablets 
Reparixin or placebo will be administered at the dose of 1200 mg three times daily (2 x 600 mg 
tablets every six to ten hours) for 21 consecutive days (days 1-21) during each 28 day cycle. 
Paclitaxel will be administered i.v. 80 mg/m2 on Days 1, 8 and 15 of a 28-day cycle. 


 
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Inclusion Criteria:   
To be checked at the pre-study visit within 14 days before study treatment: 
 Female aged > 18 years. 
 Patients with pathologically documented metastatic triple negative breast cancer 
(TNBC), eligible for treatment with paclitaxel. Paraffin-embedded tissue must be 
available from metastatic sites, if reasonably accessible, or from the primary 
tumor, to confirm the diagnosis of TNBC and for correlative studies (only on 
metastatic tissue). Fifteen slides can be obtained if the full block is not available to be 
sent or released.  
TNBC will be defined as breast cancer with <1% ER+ and <1% PgR+ cells, and 
HER2 immunohistochemistry score of 0 or 1+ and/or in situ hybridization (ISH) with 
HER2 gene copy number <4 or a ratio of less than 2 between HER2 gene copy 
number and centromere of chromosome 17. Patients whose metastatic disease is 
TNBC are eligible even when their primary tumor expressed hormone receptors 
and/or HER2. 
 Patients must be newly diagnosed metastatic or must have relapsed following a prior 
(neo)adjuvant chemotherapy regimen. If a taxane (i.e., paclitaxel or docetaxel) was 
administered as part of the (neo)adjuvant regimen, PD must have occurred > 12 
months from the end of previous (neo)adjuvant treatment. For non-taxane 
(neo)adjuvant regimen, PD must have occurred > 6 months from the end of previous 
(neo)adjuvant treatment. . 
 Patients with at least one baseline measurable lesion according to RECIST criteria 
version 1.1. 
 Zubrod (Eastern Co-operative Oncology Group [ECOG]) Performance Status (PS) of 
0-1. 
 Life expectancy of at least three months. 
 Patients must be able to swallow and retain oral medication (intact tablet). 
 Able to undergo all screening assessments outlined in protocol. 
 Adequate organ function (defined by the following parameters):  
a) Serum creatinine < 140 µmol/L (< 1.6 mg/dL) or creatinine clearance > 60 mL/min.  
b) Serum hemoglobin ≥ 9 g/dL; absolute neutrophil count ≥ 1.5 x 109/L; platelets ≥ 100 
x 109/L. 
c) Serum bilirubin ≤ 1.5 x upper normal limit (UNL), except patients with Gilbert’s 
syndrome. 
d) Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x 
UNL but ≤ 5.0 x UNL in case of liver metastases; alkaline phosphatase (ALP) ≤ UNL 
but i) ≤ 2.5 x UNL in case of liver metastases and ii) ≤5 x UNL in case of bone 
metastases; albumin > 2.5 g/dl . 
 No history or evidence by CT scan or MRI, of brain metastases or leptomeningeal 
disease. 
 No known hepatitis B virus (not due to immunization), hepatitis C virus, human 
immunodeficiency virus- and - positive status. 
 No history or evidence of any other clinically significant disorder, condition or disease 
(with the exception of those outlined above) that, in the opinion of the investigator or 


 
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TRIAL SYNOPSIS 
Medical Monitor, if consulted, would pose a risk to subject safety or interfere with the 
study evaluation, procedures or completion  
 Dated and signed IEC/IRB-approved informed consent 
Exclusion Criteria: 
 Prior therapy for metastatic TNBC (chemotherapy, hormone therapy or biological 
therapy).  Patients may receive bisphosphonates and other therapies to treat bone 
metastases, however if used, bone lesions will not be considered as measurable 
disease. 
 Less than four weeks since last radiotherapy (excluding palliative radiotherapy). 
 Pregnancy or lactation or unwillingness to use adequate method of birth control 
 Neurological or psychiatric disorders which may influence understanding of study 
and informed consent procedures.  
 Active or uncontrolled infection. 
 Malabsorption syndrome, disease significantly affecting gastrointestinal function. 
 G>1 pre-existing peripheral neuropathy. 
 Any other invasive malignancy from which the patient has been disease-free for less 
than 5 years with the exception of curatively treated basal or squamous cell skin 
cancer 
 Hypersensitivity to: 
a) 
paclitaxel 
b) 
ibuprofen or to more than one non-steroidal anti-inflammatory drug. 
c) 
more than one medication belonging to the class of sulfonamides, such
as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or
celecoxib; hypersensitivity to sulphanilamide antibiotics alone (e.g.
sulfamethoxazole) does not qualify for exclusion. 
 
Criteria for Evaluation: 
Efficacy: Disease status (up to progression of disease [PD]) will be measured by Response 
Evaluation Criteria In Solid Tumors (RECIST) version 1.1 at screening and every eight weeks 
until study end. Evaluation of disease status will be performed at the participating clinical site. 
An independent radiological review of images for disease response and PFS measurement will 
also be performed.  
 
Safety: Recording of adverse events (AEs), clinical examinations, hematology parameters, 
clinical chemistry parameters, urinalysis, vital signs, chest X-ray, physical examination, 
Zubrod PS will be performed according to the study flow chart included in the protocol.  
An independent Data Monitoring Committee will assess safety periodically. 
 
Correlative studies: 
 
1) Paraffin-embedded metastatic tumor tissue  
The following analyses will be performed on sections of paraffin embedded tissue: 
 Evaluation of CD24-CD44+ CSC 
 Evaluation of ALDH+ CSC 
 


 
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TRIAL SYNOPSIS 
Statistical Methods: 
For the primary endpoint, PFS as measured from time of randomization to time to disease 
progression or death, whichever occurs first, will be compared between treatment arms using 
stratified log-rank test.. 
Kaplan-Meier curves will be generated to estimate themedian PFS in the intent-to-treat 
population (all randomly assigned patients). Kaplan-Meier curves will also be produced for OS 
outcomes. In a supportive analysis, a Cox regression analysis will be performed. Patients will 
be randomized to the two treatment groups with a 1:1 ratio. Randomization will be stratified 
between two subpopulations, newly diagnosed metastatic patients and patients that have 
relapsed following a prior (neo)adjuvant chemotherapy regimen. 
The disease response (disease status up to PD) at pre-study (baseline) and every eight weeks 
until the end of the study based on the RECIST version 1.1 criteria will be summarized by 
counts and percents.  
Safety and tolerability analysis will be applied on the safety population (all patients having 
taken at least one dose of the study treatment). AEs, physical examination, vital signs, 
concomitant medications and laboratory data will be considered for the safety analyses. 
Descriptive statistics will be provided for these variables. 
Study Procedures: 
Patients will be assessed for eligibility and will have the following procedures done during the 
14 days prior to start of treatment (with the exception of x-rays, scans and tumor tissue which 
will be done during the 28 days prior to start of treatment): medical history, physical exam, 
labs, x-rays and/or CT scans, including a CT scan or MRI of the brain. A sample of tumor tissue 
will be collected for analysis. 
Laboratory tests performed within 14 days prior to screening period even if before ICF signed 
are acceptable. 
During study participation and while the patient is receiving study treatment, the patient will 
continue to be followed with physical exams, a pregnancy test prior to each treatment cycle, 
review of concomitant medications and adverse events, labs, and scans (CT, MRI etc, ). The 
patient will also complete a diary to record intake of study medication. 
After completion of study treatment, the patient will be followed for 30 days to assess safety, 
and then followed until death,  to assess disease status, new treatments, and survival status or 
until  30 September 2019 (1 year after last enrolled subject off treatment), whichever occurs 
first. 
Please refer to section 1.2, Study Flow Chart for full details. 


 
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1.2 
Study Flow Chart 
Procedure 
Pre-Study1 
Treatment Cycles14 
OTV15 
Long term 
Follow up16 
D1 
D8 
D15 
D21 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
Demographic data/tumor characteristics 
X 
 
 
 
 
 
 
Tumor history surgery, radiotherapy, 
systemic therapies 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Disease status 
X2,3 
Every 8 weeks4 
X3 
 
Physical examination 
X 
X5 
 
 
 
X 
 
Vital signs (BP, pulse)6 
 
X 
 
 
 
X 
 
ECG 
X 
 
 
 
 
 
 
Chest X-ray (if not already performed to 
follow tumor. Thoracic CT scan may 
substitute chest X-ray ) 
X 
 
 
 
 
X 
 
Zubrod PS  
X 
 
 
 
 
X 
 
Urinalysis 
X7 
As clinically indicated 
X7 
 
Hematology 
X8 
X8 
X8 
X8 
 
X8 
 
Clinical chemistry 
X9 
X9 
As clinically indicated 
X9 
 
D1 = Day 1 etc, OTV = off-treatment visit 
1  All pre-study examinations should be performed within 14 days (+ 1 day window) of beginning study treatment unless otherwise specified. Informed consent should be signed before any study specific 
procedures are performed (with the exception of routine lab tests). 
2 Pre-study disease evaluation should be obtained within 28 days of study treatment initiation. 
3 Disease evaluations and a brain CT or MRI will be performed at pre-study. The scans (with exception of brain scans) will be repeated  every eight weeks until documented PD. A brain scan will be 
repeated if patient presents with symptoms of brain metastases or PD of baseline lesions. At study end, a Best Overall Response Assessment (BOR) will be made: the disease assessments do not need to be 
repeated if done within four weeks prior to the off treatment visit. Copies of all scans (CT, MRI of chest abdomen, pelvis etc ) will be submitted to the central radiology vendor for review at each time 
point. 
4  For tumor assessment (i.e. scans) beginning at Week 8, a ± 3-day window will be allowed. 
5 Physical exam, including weight will be performed at pre-study and Day 1 of each cycle beginning with cycle 2. Pretreatment signs and symptoms, height, and BSA will also be collected at the pre-study 
visit only. 
6  Vital signs must be performed within 24 hours prior to the first study drug (reparixin/placebo) administration , and then on Day 1 of subsequent cycles. 
7  PH, specific gravity,  protein, glucose, ketones, bilirubin, blood, nitrite, leukocytes and urobilinogen (by dipstick or in lab) at pre-study, as clinically indicated, and at off-treatment visit. Laboratory tests 
performed within 14 days screening period even if before ICF signed are acceptable. 
8 Hematology tests: hemoglobin, WBC and differential WBC, platelets at pre-study and on Days 1, 8 and 15 of each cycle and at the off-treatment visit. Routine laboratory tests performed within 14 days 
screening period even if before ICF signed are acceptable 
9 Clinical chemistry tests: sodium, potassium, calcium, serum creatinine, total protein, albumin, AST, ALT, ALP, urea, total bilirubin at pre-study,  on Day 1 of treatment cycles and as clinically indicated 
and at the off treatment visit. Laboratory tests performed within 14 days screening period even if before ICF signed are acceptable. 


 
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Procedure 
Pre-Study1 
Treatment Cycles14 
OTV15 
Long term 
Follow up16 
D1 
D8 
D15 
D21 
 
 
Urine or serum pregnancy test 
X10 
X10 
 
 
 
X10 
 
Record concomitant treatments 
X 
Throughout study 
X 
 
AE monitoring 
 
Throughout study 
X 
 
Peripheral neuropathy monitoring 
X 
Throughout study 
X 
 
Reparixin/Placebo administration11 
 
Continuously days 1 to 21 
 
 
Paclitaxel administration 
 
X 
X 
X 
 
 
 
Dispense diary card12 
 
X 
 
 
 
Xreview only 
 
Tumor tissue (archival or new biopsy)13 
X 
 
 
 
 
 
 
Date of progression and documentation of 
additional cancer therapy (if not off study 
due to PD) and Survival Status 
 
 
 
 
 
 
X 
 
 
10 Urine or serum pregnancy test required for women of childbearing potential only 
11 Study drug (Reparixin/Placebo) administered orally every 6 to 10  hours t.i.d. for 21 consecutive days during each cycle with seven days off treatment between each cycle 
12 Patients will be given a diary card to record information about date, time and dose taken. At each scheduled visit before the start of a new cycle of dose administration and at OTV, the diary should be 
reviewed with the patient for completeness. 
13 Tumor tissue will be sampled within 28 days of study treatment initiation, to confirm recurrence of metastatic breast cancer, confirm TNBC, and to conduct the following correlative studies: evaluation 
of CD24-CD44+CSC, ALDH+CSC. 
14  During Cycle 1, a ± 1-day window will be allowed for study visits. After Cycle 1, a ± 2-day window will be allowed for study visits. 
15 Off treatment Visit to be performed 14 to 28 days following the last dose of study drug. Patients with ongoing treatment-related AEs still present in the 30 days after treatment discontinuation should 
     continue to be followed until recovery or assessment of chronicity or as instructed by the medical monitor. Patients off treatment without documented PD should continue to have disease assessments 
     every 8 weeks until PD or another anti-cancer therapy is initiated, whichever comes first. 
16 Following PD, survival status will be collected every 3 months until death or until  30 September 2019 (1 year after last enrolled subject off treatment), whichever occurs first. 


 
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1.3 
List of Abbreviations and Definition of Terms  
ABC 
 
ATP-binding cassette 
ADR 
 
Adverse drug reaction 
AE 
 
Adverse event 
AKT 
 
Serine-threonine protein kinase (also known as protein kinase B, PKB) 
ALDH1+ 
 
Aldehyde dehydrogenase 1 positive 
ALP 
 
Alkaline phosphatase 
ALT (SGPT) 
 
Alanine aminotransferase (serum glutamate pyruvate transaminase) 
AST (SGOT) 
 
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
AUC0-8 
Area under the plasma concentration-time curve from time zero to 8 hours post-dosing 
AUC0-24 
Area under the plasma concentration-time curve from time zero to 24 hours post-dosing 
AUCinf 
Area under the plasma concentration-time curve from time zero to infinity 
AUCtau 
Area under the plasma concentration-time curve for a dosing interval 
AUCtot 
Overall exposure 
b.i.d. 
bis in die (twice daily) 
BOR 
Best overall response 
BP 
Blood pressure 
BSA 
Body surface area 
CBR 
Clinical benefit rate 
CFR 
Code of Federal Regulations 
CL/F 
 
Oral clearance 
Cmax 
Maximal concentration 
CMH  
Cochran-Mantel-Haeszel 
C0 
Concentration at pre-dose 
CPB 
Cardiopulmonary bypass 
CR 
 
Complete remission/response 
CRF 
 
Case Report Form 
CRO 
 
Contract Research Organization 
CSC 
 
Cancer stem cell 
Css 
 
Concentration at steady-state 
CT 
 
Computed tomography  
CTC 
 
Circulating tumor cells 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CXCL8; IL-8 
 
Interleukin-8 
CXCR 
 
chemokine receptor 
CXCR-1 
 
Chemokine receptor 1 
CXCR-2 
 
Chemokine receptor 2 
CYP2C19 
 
Cytochrome P450 2C19 
CYP2C9 
 
Cytochrome P450 2C9 
CYP3A4 
 
Cytochrome P450 3A4 
DLT 
 
Dose limiting toxicity 
DMC 
 
Data Monitoring Committee 
ECOG 
 
Eastern Co-operative Oncology Group 
EGFR  
 
Epidermal growth factor receptor 
EMT 
 
 
Epithelial-mesenchymal transition 
EOC 
 
 
End of cycle 
ER 
 
 
Estrogen receptor 
FAK 
 
 
Focal adhesion kinase 
FAS/FASL 
 
Fas/Fas ligand 
FDA 
 
 
Food and Drug Administration 
FISH 
 
 
Fluorescence in Situ Hybridization 
GCP 
 
 
Good Clinical Practice 
GI 
 
 
Gastrointestinal 
GM-CSF 
 
Granulocyte macrophage colony stimulating factor 
HED 
 
Human equivalent dose 


 
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HER-2 
 
Human epidermal growth factor receptor-2 
ICH 
 
International Conference on Harmonization 
IEC 
 
Independent Ethics Committee 
IHC 
 
Immunohistochemistry 
IL 
 
Interleukin 
IL-1 
 
Interleukin-1beta 
IL-6 
 
Interleukin-6 
IMP 
 
Investigational Medicinal Product 
IRB 
 
Independent Review Board 
IRR 
 
Independent Radiology Review 
IRT 
 
Interactive Response Technology  
i.v. 
 
Intravenous 
Kel 
 
Terminal elimination rate constant 
kg 
 
Kilogram 
L 
 
Litre 
LD 
 
Longest diameter 
LFT 
 
Liver function test 
LPS 
 
Lipopolysaccharide 
max 
 
Maximum 
MBC 
 
Metastatic breast cancer 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
mg 
 
Milligram 
min 
 
Minimum 
mL 
 
Milliliter 
mm 
 
Millimeter 
m2 
 
Square meter 
MTD 
 
Maximum tolerated dose 
n 
 
Number of patients 
NIMP 
 
Non-investigational Medicinal Product 
NOAEL  
 
No Observed Adverse Effect Level  
NOD/SCID 
 
Non-obese diabetic/severe combined immunodeficiency disease 
NOEL  
 
No Observed Effect Level 
PD 
 
Progression of disease/disease progression 
PDG/DGF 
 
Primary Graft Dysfunction/Delayed Graft Function 
PgR 
 
Progesterone receptor 
PK 
 
Pharmacokinetic 
PMN 
 
Polymorphonuclear leukocytes 
p.o. 
 
Orally 
PR 
 
Partial remission/response 
PS 
 
Performance status 
PTEN 
 
Phosphatase and tensin homolog 
Rac  
 
Accumulation ratio 
RECIST 
 
Response Evaluation Criteria In Solid Tumors 
RT-PCR 
 
Reverse transcriptase polymerase chain reaction 
SAE 
 
Serious adverse event 
SAP 
 
Statistical Analysis Plan 
SD 
 
Stable disease 
SOPs 
 
Standard Operating Procedures 
T1D 
 
Type 1 diabetes 
TEAE 
Treatment-emergent adverse event 
t.i.d. 
ter in die (3 times daily) 
TNBC 
Triple Negative Breast Cancer 
TNF- 
Tumor necrosis factor-alpha 
tmax 
Time to maximum plasma concentration 
t½ 
Terminal half-life, calculated as (ln 2)/z 
TTP 
Median time to tumor progression in days 
UNL 
 
Upper normal limit  
USA 
 
United States of America 


 
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Vz 
Apparent volume of distribution during the terminal phase 
Vz/F 
Apparent volume of distribution following oral administration 
WBC 
 
White blood cell 
 
 


 
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2 INTRODUCTION 
2.1 
Cancer Stem Cells  
 
According to the cancer stem cell (CSC) model, tumors are initiated and maintained by a cellular 
subcomponent that displays stem cell properties. These properties include self-renewal, which 
drives tumorigenesis, and differentiation (albeit aberrant), which contributes to tumor cellular 
heterogeneity. The existence of CSCs has been described in a variety of haematologic and solid 
tumors including those of the breast, brain, colon, pancreas, lung, liver, and head and neck 
(Visvader, et al., 2008). 
In addition to driving tumorigenesis, CSCs may contribute to tumor metastasis as well as to 
tumor recurrence after treatment (Reya, et al., 2001). Although currently available drugs can 
shrink metastatic tumors, these effects are usually transient and often do not appreciably extend 
the life of patients. One reason for the failure of these treatments is the acquisition of drug 
resistance by the cancer cells as they evolve; another non-mutually exclusive possibility is that 
existing therapies fail to kill CSCs. (Cojoc, et al., 2014) The ability to shrink a tumor mass mainly 
reflects an ability to kill bulk, non CSC tumor cells. This is because CSCs represent only a tiny 
percentage of the total tumor cells in a neoplastic lesion and the majority of the bulk tumor cells 
have limited proliferative potential. It seems that normal stem cells from various tissues tend to 
be more resistant to chemotherapeutics than mature cell types from the same tissues. The reasons 
for this are not clear, but may relate to high levels of expression of anti-apoptotic proteins or 
ATP-binding cassette (ABC) transporters such as the multidrug resistance gene. If the same were 
true of CSCs, then one would predict that these cells would be more resistant to 
chemotherapeutics than bulk tumor cells with limited proliferative potential. Even therapies that 
cause complete regression of tumors might spare enough CSCs to allow regrowth of the tumors. 
Thus, therapies that are more specifically directed against CSCs might result in much more 
durable responses and even cures of metastatic tumors (Reya, et al., 2001). 
2.2 
Reparixin Background 
2.2.1 DRUG DESCRIPTION AND MECHANISM OF ACTION 
Reparixin (DF1681Y, formerly repertaxin) is a specific inhibitor of CXC ligand 8 [CXCL8; 
formerly IL-8] biological activity, stemming from a program of drug design of molecules 
intended to modulate chemokine action (Reparixin Investigator’s Brochure, 2014).  
Reparixin is the first low molecular weight blocker of CXCL8 biological activity in clinical 
development. Relevant pre-clinical, toxicological and Phase I and II clinical data are summarized 
below. Please also refer to the Investigator’s Brochure for more detailed information.  
2.2.2 PHARMACOLOGICAL PROFILE  
Reparixin (formerly repertaxin) is a novel, potent and specific inhibitor of the biological activity 
of the chemokine CXCL8 (Reparixin Investigator’s Brochure, 2014). 
Mechanism of action studies have shown that reparixin is a non-competitive allosteric inhibitor 
of the CXCL8 receptors CXCR1 and CXCR2. Interaction of repertaxin with CXCL8 receptors 


 
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inhibits the intracellular signal transduction events activated by binding of CXCL8 to CXCR1 
and CXCR2. Chemical computational studies and alanine scanning mutagenesis have identified 
the interaction site between reparixin and CXCR1/2 in the transmembrane region of CXCR1 and 
CXCR2 (Bertini, et al., 2004 & Allegretti, et al., 2005).  
A number of in vitro and in vivo assays on recognized breast cancer models have been conducted 
in support of the planned clinical development in Oncology. In vitro assays to assess the effect 
of reparixin on breast cancer cell growth showed that reparixin reduces metabolic capability and 
also reduces cell number. In vitro chemotaxis of rat polymorphonuclear leukocytes (PMN) 
induced by the rat counterparts of human CXCL8 was also inhibited by reparixin. In vivo 
modelling studies of advanced breast cancer with CXCR1 inhibition in the presence of 
conventional chemotherapeutics (docetaxel and paclitaxel) demonstrate that reparixin 
specifically targets and reduces the CSC population. Both docetaxel and paclitaxel target the 
differential tumor cells, the association of docetaxel or paclitaxel with reparixin is capable of 
dramatically reducing both the bulk of the tumor mass as well as resident CSC population 
(Reparixin Investigator’s Brochure, 2014). 
2.2.3 PHARMACOKINETICS AND PRODUCT METABOLISM 
Pharmacokinetic (PK) studies by intravenous (i.v.) injection revealed that reparixin is very 
rapidly eliminated in rats and humans (t1/2 0.5-3 hours and 1.0-1.5 hours, respectively) whereas 
elimination is slower in dogs (12-28 hours). The PK of reparixin was linear in rats and in dogs 
but linearity was less evident in humans (Reparixin Investigator’s Brochure, 2014).  
Reparixin undergoes complete metabolism (oxidation + conjugation) in all the species tested. 
The in vitro human hepatic phase I metabolism of reparixin is catalyzed by CYP2C9 and to a 
lesser extent by CYP2C19. DF2243Y, DF2188Y, methanesulfonamide and ibuprofen are the 
metabolites detected in human plasma and urine, with DF2243Y being the major metabolite. 
Exposure to ibuprofen after administration of reparixin 2.77 mg/kg/hour for 48 hours (the highest 
dose tested in humans) was similar or lower than that obtained after a standard therapeutic single 
dose of ibuprofen (300 mg) (Reparixin Investigator’s Brochure, 2014). 
Due to extensive metabolism, unchanged reparixin was poorly or not excreted into the urine of 
rat, dogs and humans so that the PK profile of reparixin is not influenced by renal impairment 
(Reparixin Investigator’s Brochure, 2014).  
In vitro protein binding of [14C]-reparixin showed that reparixin is highly bound (approximately 
99%) to plasma proteins in rats, dogs, rabbits, cynomolgus monkeys and humans. Albumin is 
likely to be the major plasma binding protein in all species, accounting for 99.2% in humans 
(Reparixin Investigator’s Brochure, 2014).  
Reparixin has some potential in vitro for a non-competitive inhibition of the human hepatic 
enzyme CYP3A4 that is involved in the metabolism of cyclosporine A, tacrolimus and 
rapamycin. However, since inhibition is evident at concentration far higher than the free plasma 
concentration of reparixin at steady state (Css) in humans, it is predicted that the clinical relevance 
of such inhibition is remote. Indeed, reparixin does not affect to a clinically relevant extent the 
activity of CYP3A4 and CYP2C9 (enzyme involved in reparixin metabolism), as revealed by an 
interaction study where the PK of midazolam and tolbutamide (probe substrates for these 
enzymes) was evaluated in healthy subjects receiving single oral doses of the probes alone or in 
combination with reparixin (Reparixin Investigator’s Brochure, 2014). 
A 14-day oral toxicity and PK study has been performed in rats. It could be concluded from a 
comparison of the PK data, that the overall exposure to DF1681Y, in terms of overall exposure 


 
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(AUCtot), attained in the i.v. continuous infusion studies, both in dogs and rats, was well above 
the AUCtot attained in the 14 days oral study in the rats. At the same time, the maximum plasma 
concentration (Cmax) attained was higher in the 14-day oral study in rats.  
 
The PK profile of the oral formulation of reparixin has been studied in humans in a phase 1b 
clinical trial in metastatic breast cancer patients. In this study, reparixin was administered at 3 
dose levels (400 mg, 800 mg and 1200 mg tid) as single agent for a 3 day run in period and then 
in combination with weekly paclitaxel for 21 days of each 28 day cycle. This trial has completed 
enrollment with 33 patients enrolled and data analysis is currently underway. Preliminary PK 
data from this study indicate that there is no pharmacokinetic interaction of Reparixin with 
Paclitaxel. Reparixin, in the oral tablet formulation, displayed a short half-life (mean  t1/2 <3 hrs) 
similar to the intravenous form. The increase in exposure with dose, following single dose 
administration and multiple dose administration was not linear in the dose range explored.  
2.2.4 PRECLINICAL TOXICOLOGY PROFILE 
Reparixin L-lysine salt was tested for toxicity in rodent and non-rodent animal species after 
single or repeated dose administrations. The repeated dose administration studies were 
conducted by infusional route and by oral route according to the human foreseen administration 
routes (Reparixin Investigator’s Brochure, 2014). 
The general toxicological profile of reparixin L-lysine salt, as for the studies conducted to date, 
is characterised by a low toxicity after single administration by i.v. or oral route to mice (LD50 =  
i.v. 609 mg/kg; LD50 = orally (p.o.) >3 g/kg) and to rats (LD50 = i.v. 348 mg/kg; LD50 =  p.o. 
1303 mg/kg) (Reparixin Investigator’s Brochure, 2014). 
Single ascending doses of reparixin L-lysine salt (DF1681B) and reparixin acid (DF1681Y) were 
administered orally (by gavage) to rats up to the dose of 1000 mg/kg twice daily (b.i.d.). The 
daily doses up to 2000 mg/kg were very well tolerated and no mortality, clinical signs or body 
weight changes were observed (Reparixin Investigator’s Brochure, 2014). 
The repeated dose administration to rats by continuous infusion for 28 days resulted in a 
determination of a safe dose of 1000 mg/kg/day (no observed adverse effect level [NOAEL]), 
while the continuous infusion administration to dogs for two weeks resulted in a safe dose of 
60 mg/kg/day (in a preliminary study conducted in dogs at the dosage of 50 mg/kg/day/24 hours 
one male animal showed a mucosal ulceration in the fundic area of the stomach) (Reparixin 
Investigator’s Brochure, 2014). 
The repeated oral administration by gavage in rats for a period of 14 days up to the doses of 400 
mg/kg b.i.d. resulted to be well tolerated and only minor adaptive liver changes of metabolic 
nature were observed in females at the dose of 400 mg/kg/b.i.d. They consisted of an increase in 
liver weight and hepatocellular hypertrophy. The no observed effect level (NOEL) could be 
determined at 400 mg/kg/b.i.d. in males. In females 400 mg/kg/b.i.d. represents the NOAEL 
(Reparixin Investigator’s Brochure, 2014).  
DF1681Y was administered twice daily (8 hrs apart) via gavage to SPF-bred Wistar rats at dose 
levels of 100, 200 or 400 mg/kg bw/bid for a period of 13 weeks. The treatment did not result in 
mortality, relevant clinical signs, body weight, food consumption, hematology, ophthalmoscopic 
examination or urinalyses. Minor changes in blood chemistry, organ weights and in the 
morphology of liver and of male kidneys at 400 mg/kg/bid were of no toxicological relevance 
and reversed after 4-week of recovery period. The NOAEL was settled at 400 mg/kg/bid 
(Reparixin Investigator’s Brochure, 2014). 


 
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Continuous i.v. infusion of reparixin L-lysine salt to the male and female rat at dose levels of up 
to 1000 mg/kg/day did not have any significant adverse effects on mating performance and 
fertility (Reparixin Investigator’s Brochure, 2014).  
Reparixin poses no genotoxic hazard for humans (Reparixin Investigator’s Brochure, 2014). 
In order to provide evidence of the safety of DF2243Y, the main metabolite of reparixin excreted 
in urine in humans, safety pharmacology and toxicity studies have been performed at doses 2 to 
3 times higher than those reached in man. Also, at this high level of exposure, no significant 
toxicity was observed (Reparixin Investigator’s Brochure, 2014). 
2.2.5 CLINICAL RESULTS 
A total of 372 subjects have been involved in phase I and phase II completed clinical studies 
with reparixin. Among these, 236 subjects have been exposed to reparixin (Reparixin 
Investigator’s Brochure, 2014). 
2.2.5.1  
Phase I Studies 
Six Phase I PK/safety/pharmacodynamic studies have been conducted (Reparixin Investigator’s 
Brochure, 2014). 
In the first of these studies, reparixin L-lysine salt 1 to 16 mg/kg was administered by short 
infusion (30min). The compound was well tolerated at all doses, with minor and unspecific AEs 
which were not dose-related.  
 
In the second study, the compound was administered as 48h i.v. infusion targeting to reparixin 
Css of 10, 20 and 30 μg/mL. Reparixin resulted well tolerated; again AEs were minor and not 
dose related. The local reactions were observed to subside by administering a more diluted 
solution at a higher infusion rate.  
 
In the third study (interaction study), co-administration of midazolam/tolbutamide (probe 
substrates for CYP3A4 and CYP2C9) with reparixin did not raise safety concerns.  
 
The fourth study was performed in subjects with different degree of renal impairment. The i.v. 
infusion of 2 mg/kg/h of reparixin L-lysine salt was safe and well tolerated both in patients with 
different degree of renal impairment and in subjects with normal renal function. Very few AEs 
were reported, the majority of which were mild in intensity and unlikely due to reparixin.  
 
Two studies were performed in the cantharidin blister model to assess if reparixin can reduce 
the influx of PMNs inflammatory mediators, during acute inflammation. The safety of reparixin 
was confirmed in both of these studies.  
 
 
 


 
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2.2.5.2 Phase II Studies 
 
Three Phase II studies have been completed to date (Reparixin Investigator’s Brochure, 2014). 
Two studies investigating the efficacy of reparixin in the prevention of PGD/DGF in lung/kidney 
transplantation were conducted with reparixin administered by continuous intravenous infusion, 
up to a maximum of 48h. Neither of the two studies was able to show a statistically significant 
effect of reparixin on short- and long- term functional and clinical outcomes after transplantation. 
The AE profile was similar for both reparixin and placebo groups. SAEs were reported in 21 
patients. SAEs possibly related to study drug were reported for only 2 patients, both in the 
reparixin continuous infusion group. An assessment performed by DMC on a possible study-
related higher incidence of thrombosis, excluded the potential relationship of reparixin with 
these events.  
 
A phase II study evaluating the efficacy of reparixin in improving transplant outcome in T1D 
patients undergoing pancreatic islet transplantation was conducted with reparixin administered 
by intravenous infusion over 7 days. Data obtained from this pilot trial further support the safety 
of reparixin in this clinical setting. The safety profile was in line with previous clinical 
experience and there were no safety issues that would preclude further development of reparixin 
in islet transplantation.  
 
Due to encouraging data obtained in the pilot trial, a phase 3 study has been implemented and is 
ongoing in EU/ US to further evaluate the efficacy of reparixin in pancreatic islet transplantation. 
To date, 27 patients have been randomized, and 24 have gone on to treatment and transplant. 11 
patients have received a second islet infusion.  
 
In addition, a phase 2/3 is being conducted at 5 centers in the US to assess the efficacy and safety 
of reparixin in pancreatic islet auto-transplantation. To date, two sites are active and 5 patients 
have been randomized.  
 
Two studies are ongoing in breast cancer patients. One is a phase 1b pilot study where reparixin 
oral tablets are given as single agent for a 3-day run in period and subsequently in combination 
with weekly paclitaxel in metastatic breast cancer patients to evaluate the safety, the PK profile 
and the effects of reparixin on Cancer Stem Cell (CSC) markers. This study began enrolment in 
February 2012 and has completed enrolment to all 3 dosing cohorts (400 mg t.i.d., 800 mg t.i.d., 
and 1200mg t.i.d.). An expansion cohort at the 1200mg t.i.d. dosing level was also initiated and 
completed enrolment in April 2014. The first data analysis is currently underway. 
 
The second is a pilot “window of opportunity” clinical study in operable breast cancer patients 
where reparixin is administered as single agent in the time period between clinical diagnosis and 
surgery. This study aims to evaluate the effects of orally administered reparixin on CSCs in the 
primary tumor and the tumoral microenvironment in an early breast cancer population. 
Enrolment to this study began in April 2013 and continues in the enrolment phase. 
 
 
 
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Two academic independent clinical trials have been conducted by the Medical University of 
Vienna (Reparixin Investigator’s Brochure, 2014). In the first study the effects of reparixin on 
humoral and cellular parameters in lipopolysaccharide (LPS)-induced acute systemic 
inflammation was tested and in the second reparixin was studied in patients undergoing elective 
coronary artery bypass grafting with cardiopulmonary bypass (CPB). 
2.2.6 SAFETY RESULTS 
A total of 372 subjects have been involved in phase I and phase II completed (CSR issued) 
clinical studies. Among these, 236 have been exposed to reparixin (Reparixin Investigator’s 
Brochure, 2014). 
Phase 1 studies  
A total of 136 subjects, of whom 103 adult healthy volunteers (including 3 females) and 17 
patients with different grades of renal impairment (including 5 females) and 16 patients 
undergoing cardiopulmonary bypass (including 6 females), have been treated with reparixin. 
 
Phase 2 studies  
A total of 100 patients, 46 undergoing lung transplantation (23 male and 23 female), 48 patients 
undergoing kidney transplant (including 17 females) and 6 patients undergoing intrahepatic islet 
transplantation (3 male and 3 female) have been treated with reparixin. 
 
Appendix 8 summarizes Cumulative Adverse Drug Reactions (ADRs) from completed studies with a 
CSR issued. It includes data from the studies mentioned above and from 14 healthy volunteers 
concomitantly treated with reparixin and the two probe drugs (midazolam/tolbutamide), 
therefore the ADRs evidenced in this group were included in this evaluation even though they 
were reasonably related to the pharmacological properties of the two probe drugs. 
 
Exposure included short or prolonged i.v. infusion being 10.6 mg/kg over 30 min, 133.9 mg/kg 
over 48 h and 465.7 mg/kg over 7 days respectively the maximum administered doses of 
reparixin. 
Reparixin was generally well tolerated at all doses studied. Overall, 115 ADRs were reported in 
a total of 70 subjects out of 236 exposed to reparixin (phase 1 studies: 71 ADRs in 45 subjects 
out of 136 treated; in Phase 2 studies: 44 ADRs in 25 subjects out of 100 treated). 
The most frequent (>10%) ADRs observed in the phase 1 and phase 2 studies were: 
Nervous system disorders (about 22%), including headache, dizziness, hypoaesthesia, 
somnolence.  
Gastrointestinal disorders (about 22%), including nausea, vomiting, abdominal pain, dyspepsia, 
flatulence, gastroesophageal reflux disease.  
 
General disorders and administration site conditions (about 19%), including cannula site 
reaction, injection site thrombosis, infusion site oedema and peripheral oedema, fatigue, 
lethargy.  
 
The relatively high frequency of the administration site reaction is due to a cluster of events 
occurring in cohort 1 of the 48 h-infusion study. The use of a less concentrated solution with 
increased administration volume, i.e. increased infusion rate, in cohort 2 and 3 reduced the 
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The safety of reparixin seems to be confirmed also in patients with different grades of renal 
impairment. Out of 17 such patients only 3 experienced mild ADRs.  There were no increases of 
the ADRs in the lung and kidney transplant studies. A similar incidence of ADRs was also seen 
after intermittent or continuous infusion during the kidney transplant study.  
 
Data obtained in the pilot trial in islet transplantation, using the i.v. formulation, further support 
the safety profile of the proposed dose, even after a 7 days i.v. administration, repeated twice in 
a few patients. Most frequent ADRs were erythema, hypotension, nausea, vomiting; the great 
majority of these were mild to moderate in nature and none required discontinuation of the 
Investigational Product.  
Both studies in breast cancer using reparixin oral tablets are ongoing. An update of safety 
information is outlined below: 
In the phase Ib trial of combination paclitaxel and reparixin in metastatic breast cancer patients, 
all reported SAEs were considered unrelated or unlikely to be related by the treating investigator. 
No DLTs have been observed and the Safety Monitoring Committee approved escalation of the 
reparixin dose at each of the dose levels to reach the maximum studied dose of 1200 mg t.i.d. 
From preliminary data, the most frequent ADRs reported to date are dyspepsia, feeling of 
fullness, nausea, fatigue. All were mild to moderate in intensity and only in one patient 
discontinuation of IP was required. The ADR quickly resolved after study drug discontinuation. 
There may be a temporal relationship of gastrointestinal AEs to paclitaxel or the combination as 
the onset of gastrointestinal  events often occurs in the days immediately following paclitaxel 
dosing. No gastrointestinal AEs were reported during the reparixin single agent run-in period, 
although this was a short run in consisting of 3 days treatment to perform PK evaluations. Grade 
3-4 toxicities (according to CTCAE version 4.03) have been recorded in a minority of patients 
and about half consisted of haematological toxicities in patients receiving myelotoxic 
chemotherapy. G>2 Peripheral neuropathy was not reported in any of the 33 patients, which is 
lower than expected in patients undergoing weekly treatment with paclitaxel and particularly for 
long periods of time. Peripheral neuropathy is the most common non-hematological toixicity of 
taxanes. With weekly paclitaxel, G3-4 peripheral neuropathy has been reported in about 15-20% 
of patients (Miller K et al., 2007), (Seidman A et al., 2008). In a preclinical study reparixin 
showed potential to reduce CXCL8-induced motor neuron degeneration in a rat model (De Paola 
et al., 2007). No neuroprotective agents are currently approved and the present trial represents 
an ideal setting to explore the potential of reparixin in prevention of taxane-induced peripheral 
neuropathy. 
In the pilot window of opportunity trial for early stage breast cancer patients, only one unrelated 
SAE has been reported to date out of 18 patients enrolled. All AEs recorded thus far have been 
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3 TRIAL RATIONALE AND OBJECTIVES 
3.1 
Rationale 
The CSC concept has important implications for understanding carcinogenesis as well as for the 
development of novel cancer therapeutics.  
In BC, CSC were originally identified as cells expressing the CD24-CD44+ phenotype (Al-Hajj, 
et al., 2003). Later, CSC in breast and also other human cancers were found to express the 
enzyme aldehyde dehydrogenase (ALDH+). ALDH+ as well as CD24-CD44+ cells can be 
identified either by assaying live cells with flow cytometry or by IHC in paraffin-embedded 
clinical specimens (Ginestier, et al., 2007). In breast carcinomas, the ALDH+ phenotype shows 
only partial overlap with the CD44+CD24–CSC phenotype (Ginestier, et al., 2007 & Liu, et al., 
2013). 
Numerous clinical studies have addressed the role of CSC in breast cancer. In patients 
undergoing neoadjuvant chemotherapy, it has been shown that the percentage of CSC increase 
following administration of chemotherapy even when the tumor shrinks, highlighting the 
chemoresistance of such cells (Li, et al., 2008 & Creighton, et al., 2009 & Tanei, et al., 2009).  
A recent meta-analysis investigated the prognostic role of CSC in BC and found that presence 
of CSC is associated with a negative outcome. One prospective study in BC patients undergoing 
neoadjuvant chemotherapy came to the same conclusion (Alamgeer, et al., 2014). Overall, 
clinical data are in keeping with experimental findings and identify BC CSC as a novel 
therapeutic target. 
One of the therapeutic strategies being pursued to target CSCs involves inhibition of self-renewal 
or survival pathways in these cells. These pathways include NOTCH, Hedgehog, and WNT 
(Korkaya,  2007). Such strategies may be limited by the role of these pathways in normal stem 
cell function, which could result in systemic toxicities from pathway inhibition.  
In addition to intrinsic pathways regulating stem cell functions, normal and malignant stem cells 
are regulated by extrinsic signals generated in the microenvironment or CSC niche. In the breast, 
this niche is composed of immune cells, mesenchymal elements that include fibroblasts, 
endothelial cells, adipocytes, and extracellular matrix components (Brisken, et al., 2007). These 
components play an important role in normal breast development and carcinogenesis. If the 
cellular microenvironment plays an important role in the regulation of CSC growth and survival, 
then strategies aimed at interfering with these interactions represent a rational approach to target 
BC CSCs. 
Gene expression profiling of the ALDEFLUOR+ populations of BC CSC revealed selective 
expression of CXCR1, a receptor for the cytokine CXCL8 (formerly IL-8). CXCR1 expression 
was limited to a proportion of ALDEFLUOR+ cells. In vitro, addition of recombinant CXCL8 
increased the CSC population as well as  its propensity for invasion (Charafe-Jauffret, et al., 
2009). Furthermore, tissue damage induced by chemotherapeutic agents may induce CXCL8 
secretion as part of the injury response (Ginestier, et al., 2010 & Bhola, et al., 2013). Using 
CXCR1-blocking antibodies or reparixin (a small molecular weight allosteric inhibitor of 
CXCR1), it was demonstrated that CXCR1 blockade selectively decreased the breast CSC 
population in vitro and in NOD/SCID xenograft models. Also the CD24-CD44+ BC CSC 
population was reduced following treatment with reparixin in the same NOD/SCID xenograft 
models (Ginestier, et al., 2010). It was shown that CXCR1 blockade induced massive apoptosis 
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CSC viability as well as FASL production were mediated by the focal adhesion 
kinase/AKT/forkhead 
transcription 
factor 
FKHRL1 
(FAK/AKT/FOXO3A) 
pathway. 
Furthermore, administration of reparixin retarded tumor growth and reduced the development of 
systemic breast cancer metastasis in NOD/SCID mice (Ginestier, et al., 2010). 
An independent report (Singh, et al., 2013) confirmed the role of CXCL8 in survival and 
proliferation of BC CSC. Overall, these data suggest that strategies aimed at interfering with the 
CXCL8/CXCR1 axis may be able to target CSCs, increasing the efficacy of current therapies 
which address the proliferating, non CSC component of the tumor. 
However, reparixin or any CXCR1 inhibitor could hardly be applied as single agent to patients 
with metastatic BC, as eliminating the small population of BC CSC would do little in the short 
term to reduce tumor burden and preserve organ function, as observed also in tumor bearing 
animals (Ginestier, et al., 2010 & Bhola, et al., 2013). 
Breast cancer can be divided in distinct subtypes based upon estrogen and progesterone receptor 
expression assessed by IHC and HER2 amplification evaluated by IHC and/or FISH. Triple 
negative breast cancer (TNBC) is characterized by both lack of expression of ER and PgR and 
lack of amplification of HER2 according to current guidelines (Hammond, et al., 2010 & Wolff, 
et al., 2013). TNBC represents roughly 15% of BC and currently is treated at diagnosis by 
surgery and (neo)adjuvant chemotherapy. However, a substantial proportion of patients relapse 
within 3 years from diagnosis and eventually succumb to the disease. 
In metastatic TNBC, the general consensus on treatment with chemotherapy is a sequence of 
monotherapies in all cases, except those with a rapidly progressing or highly symptomatic 
disease (Cardoso, et al., 2012). TNBC biology on its own is not a sufficient reason to give 
combination chemotherapy (Cardoso, et al., 2012). 
In TNBC, no prospective studies have established that the disease has particular sensitivity or 
resistance to any specific chemotherapy agent.  
The taxanes, docetaxel and paclitaxel have been a mainstay in the treatment of MBC for many 
years. Currently, FDA approved dosing schedules in MBC of 175 mg/m2 as a 3-hour intravenous 
infusion every three weeks for paclitaxel. However, paclitaxel administered as a weekly schedule 
(80-100 mg/m2) has been studied extensively as a single agent in MBC as a means to increase 
dose density and improve tolerability. In a randomized Phase 3 trial weekly paclitaxel 80 mg/m2 
outperformed every three weeks paclitaxel 175 mg/m2 in metastatic BC (Seidman, et.al., 2008). 
Several Phase 2 studies reported on the activity of single agent weekly paclitaxel in MBC (Eniu, 
et al., 2005). Response rates have been observed in the range of 22-53% in pretreated patients, 
with a median time to progression of 5-6 months. The toxicity associated with this regimen was 
mild and consisted mainly of neutropenia and peripheral neuropathy. Taxane-based regimens are 
the only standard of care in first-line therapy both in patients with TNBC diagnosed in stage IV 
and in patients with TNBC progressing after adjuvant anthracycline-based, non-taxane-
containing chemotherapy regimens (Cardoso, et al., 2012). However, patients with TNBC who 
are newly diagnosed with metastatic disease or patients who do not receive (neo)adjuvant 
chemotherapy are rare given the aggressive behavior of this BC subtype (Awada, et al., 2014; 
(Isakoff, et al.,  2011; Carey, et al., 2012; Baselga, et al., 2013; Smith, et al., 2011; Hamilton, et 
al., 2013; O'Shaughnessy, et al., 2011). TNBC patients commonly receive neoadjuvant treatment 
which often involves administration of a taxane. Taxanes have been proposed as a re-challenge 
regimen in patients with 6-12 months of disease-free survival following completion of 
neoadjuvant chemotherapy (Palmieri, et al., 2010). Re-challenge with a taxane as frontline 
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challenge cohort study identified participants from 6 prospective neoadjuvant taxane-based 
studies with recurrent disease and collected data on their subsequent treatment. The response 
rate to taxane (either single agent paclitaxel or docetaxel) was dependent on the disease-free 
interval prior to re-challenge (<1 year 34.8%, 1-2 years 42.9%). 21 out of 35 patients re-
challenged with paclitaxel responded (60%). The observed response rate for TNBC was 50% 
(Guo, et al., 2011).  
TNBC is characterized by a CSC signature (Idowu, et al., 2012) which, coupled with sensitivity 
to chemotherapy, current lack of targeted therapies and dismal prognosis, makes this BC subtype 
an attractive candidate for a novel CSC targeting agent to be tested in combination with single 
agent chemotherapy. Moreover, the majority of the BC cell lines and patient-derived xenografts 
used in preclinical work with reparixin were TNBC (Ginestier, et al., 2010). 
Reparixin oral tablets are being tested as a CSC targeting agent in patients with metastatic non-
human epidermal growth factor receptor (HER2)-amplified BC. An open label Phase 1b clinical 
study (REP0111) is ongoing (enrolment completed) in five US sites, under  IND # 112502, to 
test safety, tolerability, pharmacokinetics and detect early signs of antitumor activity of 
increasing doses of reparixin oral tablets in combination with a fixed dose of weekly paclitaxel. 
The study has demonstrated safety and tolerability of the combination across the three dose levels 
explored and recorded objective responses in the published range for single agent weekly 
paclitaxel in the target population (Eniu, et al., 2005). The highest dose level explored (i.e., 1200 
mg t.i.d.) was identified as the recommended phase 2 dose. Durable responses have been 
recorded in patients with TNBC.  
The current phase 2 study thus aims to evaluate the Progression Free Survival of patients with 
metastatic TNBC receiving reparixin in combination with paclitaxel versus paclitaxel alone. 
3.1.1 DOSE AND SCHEDULE RATIONALE  
Reparixin administration in oncology is by the oral route and the toxicity studied by this route 
have been conducted to support clinical development in this indication, which complement the 
i.v. toxicity studies conducted in support of the transplantation studied. 
Toxicology studies performed include a 28-day i.v study in the rat, one 14-day i.v study in the 
dog, and one each of a 14-day and 13 week oral study in the rat. 
The repeated dose administration to rats by continuous infusion for 28 days resulted in a 
determination of a safe dose of 100 mg/kg/day (NOAEL); while the continuous infusion 
administration to dogs for two weeks resulted in a safe dose of 60 mg/kg/day. 
The NOAEL, in the repeated (14 days) oral dose study in the rat is 400 mg/kg b.i.d. in females. 
The NOEAL from this study, converted to human equivalent dose (HED) is equal to 65 mg/kg 
b.i.d. and was used as a reference for the starting dose calculation in the phase Ib clinical trial. 
The NOAEL was settled at 400 mg/kg/bid in the repeated (13 weeks) oral dose study in the rat.  
The first clinical trial with oral reparixin was in metastatic breast cancer patients with the aim of 
establishing a safe and effective dose of reparixin in combination with weekly paclitaxel. No 
maximum tolerated dose (MTD) was established and the highest cohort dose of 1200 mg t.i.d. 
was well tolerated. A total of 20 patients have been treated at the 1200 mg t.i.d. dose in 
combination with paclitaxel at 80 mg/m2 weekly 3 out of 4 weeks. No DLT’s were observed and 
all SAE’s were unrelated or unlikely related to reparixin. Several confirmed RECIST responses 
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the same dose and schedule of reparixin and paclitaxel for this current phase 2 study in metastatic 
triple negative breast cancer patients. 
3.2 
Objectives 
The primary objective of the study is to evaluate Progression Free Survival (PFS), defined as the 
number of days between the date of randomization and the date of clinical disease progression 
(PD) according to RECIST criteria version 1.1, as assessed by Independent Radiology Review, 
or death for any cause, whichever occurs first, in patients with Triple-Negative metastatic breast 
cancer treated with the combination of paclitaxel and orally administered reparixin compared to 
paclitaxel alone. 
 
The secondary objectives are: 
 To determine Overall Survival (OS). 
 To evaluate Objective Response Rates (ORR) 
 To determine the median PFS (mPFS)  
 To assess the safety of the combination of paclitaxel and orally administered reparixin. 
The exploratory objectives are: 
 To determine Median Time to new Metastasis (TTM)  
 To determine the proportion of patients progressing with new metastatic lesions 
 To compare the incidence and severity of peripheral neuropathy between the two 
treatment groups 
 Evaluation of CSCs in metastatic tissue 
 
4 STUDY PLAN 
4.1 
Study Design 
This is a two arm, phase 2 study to evaluate the efficacy of the combination of paclitaxel and 
reparixin compared to paclitaxel and placebo in metastatic Triple-Negative breast cancer 
patients. 
Centralized patient registration and randomization will be coordinated by the Contract Research 
Organization (CRO) (PRA Health Sciences) using IRT.  
There will be 2 groups:  
Group 1: 
paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15 of 28-day cycle) + reparixin oral 
tablets 1200 mg t.i.d. continuing from D 1 to Day 21 
Group 2: 
paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15 of 28-day cycle) + placebo oral tablets 
1200 mg t.i.d. continuing from D 1 to Day 21 
Study drug (reparixin/placebo) will be administered orally every six to ten hours t.i.d. for 21 
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will be administered in combination with study drug (reparixin/placebo) as an i.v. infusion on 
Days 1, 8 and 15 of each 28-day cycle. 
Combination treatment will continue until disease progression according to RECIST criteria 
version 1.1, withdrawal of consent or unacceptable toxicity, whichever occurs first. 
Tumor response and/or progression assessments will be performed and documented every eight 
weeks according to RECIST criteria version 1.1. 
Metastatic tissue samples will be analysed for evaluation of CD24-CD44+ and ALDH+ CSCs.  
It is planned that approximately 60 centers located in the USA and Europe will participate in the 
study. 
4.1.1 PATIENT PARTICIPATION  
On Cycle 1, Day 1, paclitaxel will be administered at the clinic after the administration of study 
drug (reparixin/placebo). From that point forward, study drug (reparixin/placebo) will be self-
administered t.i.d. (every 6-10 hours) for 21 days. Treatment (three weeks on and one week off) 
will continue until disease progression according to RECIST criteria version 1.1, withdrawal of 
consent or unacceptable toxicity, whichever occurs first. The next clinic visits are on Days 8 and 
15 when a paclitaxel infusion is administered to the patient. The patients will return to the clinic 
again on Day 29/Day 1 of the next cycle. A diary card will be kept by the patient to record the 
self-administration of study drug (reparixin/placebo). 
Blood samples will be taken from the patient throughout the study for hematology and clinical 
chemistry analysis.  
Archival tissue samples or newly collected metastatic biopsy samples will be analyzed at the 
site’s pathology lab to confirm diagnosis of TNBC. Metastatic tissue samples will also be 
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4.2 
Study Endpoints 
The primary endpoint of the study is: 
 
1) Progression Free Survival (PFS) defined as the number of days between the date of 
randomization and the date of clinical disease progression (PD) according to RECIST 
criteria version 1.1, as assessed by Independent Radiology Review, or death for any 
cause, whichever occurs first.,  
 
 
The secondary endpoints of the study are: 
1) Overall survival defined as the interval (days) between randomization and death 
from any cause 
2) Objective response rates (ORR) defined as the percentage of the patients reaching 
complete remission (CR), partial remission (PR) or stable disease (SD) according to 
RECIST criteria version 1.1. 
Disease response (disease status up to progression of disease [PD]) at pre-study 
(baseline) and every eight weeks until the end of the study: 
 
 CR rate 
 PR rate 
 SD rate 
 PD rate 
3) Median PFS (mPFS) where PFS is defined as the number of days between the date of 
randomization and the date of clinical disease progression (PD) according to RECIST 
criteria version 1.1, or death for any cause, whichever occurs first 
4) safety of the combination treatment 
 Monitoring of AEs throughout the study and at the off-treatment visit 
 Vital signs will be assessed at Day 1 of each cycle and off-treatment visit 
 Physical examination will be assessed at pre-study, on Day 1 of each cycle 
starting from cycle 2 and at the off-treatment visit. 
 Concomitant medications will be reported at pre-study and at each visit 
throughout the study and at the off-treatment visit 
 Safety labs: 
o Hematology parameters (hemoglobin, white blood cell (WBC) and 
differential count, platelets) will be measured at pre-study and on 
Days 1, 8 and 15 of each cycle and at the off-treatment visit.  
o Clinical chemistry parameters (sodium, potassium, calcium, serum 
creatinine, total protein, albumin, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), alkaline phosphatase (ALP), urea, 
total bilirubin) will be measured at pre-study on Day 1 of each cycle 
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o Urinalysis: pH, specific gravity,  protein, glucose, ketones, bilirubin, 
blood, nitrite, leukocytes and urobilinogen parameters (by dipstick or 
in lab)  will be measured at pre-study, throughout each cycle if 
clinically indicated and at the off-treatment visit. 
 
 
Exploratory endpoints of this study are:  
 
1) Median Time to new Metastasis (TTM), where TTM is defined as the interval (days) 
between randomization and the date of the first observation that the new lesion was 
detected at existing or new sites (Oxnard, et al., 2012) 
New lesions at existing or new sites will be assessed at each disease assessment 
timepoint 
 
2) proportion of patients progressing with new metastatic lesions defined as the 
percentage of the patients who at progression display new lesions at existing or new 
sites 
 
3) Peripheral neuropathy will be closely monitored throughout the study and at the off-
treatment visit by the investigators to evaluate the extent of peripheral neuropathy. 
 
4) Evaluation of CSCs in metastatic tissue 
 
Correlative studies: evaluate on paraffin-embedded metastatic tumor tissue: 
• 
CD24-CD44+ CSC (by IHC) 
• 
ALDH+ CSC (by IHC) 
 
Full details of the study assessments are provided in Section 8 (Treatment Assessments). 
4.3 
Sample Size 
The trial is designed to provide 80% statistical power to detect an improvement in PFS from 5 
months with paclitaxel monotherapy in patients with metastatic TNBC (Awada, et al., 2014; 
Finn, et al., 2009, Harris, et al., 2006;Miller, et al., 2007 ) to 8 months with the addition of 
Reparixin, corresponding to a hazard ratio 0.625, when using a logrank statistic having (one-
sided) 0.025 false positive error rate.  This requires 142 PFS events and the approximate sample 
size will be 156 randomized patients (78 patients per group). 
Due to extreme enrollment difficulties during the first 6 months of 2018, enrollment to the study 
was terminated early (30 July 2018) and the final sample size will be 123 randomized patients. 
No formal recalculation of sample size/required PFS events could be made under these 
circumstances and although the above assumptions remain, the true statistical power and hazard 
ratio will be known after database lock and will be presented in the CSR. 
 
 
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Patients with Metastatic Triple-Negative breast cancer, attending the breast cancer clinics at the 
sites, will be enrolled. Enrolment will be competitive. Sites will be allowed to enrol patients until 
the complete sample size is met. 
5.1 
Patient Selection Criteria  
The patient selection criteria will be checked at the pre-study visit within 14 days before 
treatment with study drug (reparixin/placebo). 
5.1.1 INCLUSION CRITERIA 
1. Female aged > 18 years.   
2. Patients with pathologically documented metastatic triple negative breast cancer 
(TNBC), eligible for treatment with paclitaxel. Paraffin-embedded tissue must be 
available from metastatic sites, if reasonably accessible, or from the primary tumor, 
to confirm the diagnosis of TNBC and for correlative studies (only on metastatic 
tissue). Fifteen slides can be obtained if the full block is not available to be sent or 
released.  
TNBC will be defined as breast cancer with <1% ER+ and <1% PgR+ cells, and HER2 
immunohistochemistry score of 0 or 1+ and/or in situ hybridization (ISH) with HER2 
gene copy number <4 or a ratio of less than 2 between HER2 gene copy number and 
centromere of chromosome 17. Patients whose metastatic disease is TNBC are eligible 
even when their primary tumor expressed hormone receptors and/or HER2. 
3. Patients must be newly diagnosed metastatic or must have relapsed following a prior 
(neo)adjuvant chemotherapy regimen. If a taxane (i.e., paclitaxel or docetaxel) was 
administered as part of the (neo)adjuvant regimen, PD must have occurred > 12 months 
from the end of previous (neo)adjuvant treatment. For non-taxane (neo)adjuvant 
regimen, PD must have occurred > 6 months from the end of previous (neo)adjuvant 
treatment 
4. Patients with at least one baseline measurable lesion according to RECIST criteria 
version 1.1. 
5. Zubrod (Eastern Co-operative Oncology Group [ECOG]) Performance Status (PS) of 
0-1. 
6. Life expectancy of at least three months. 
7. Patients must be able to swallow and retain oral medication (intact tablet). 
8. Able to undergo all screening assessments outlined in the protocol. 
9. Adequate organ function (defined by the following parameters): 
a) Serum creatinine < 140 µmol/L (< 1.6 mg/dL) or creatinine clearance > 60 
mL/min.  
b) Serum hemoglobin ≥ 9 g/dL; absolute neutrophil count ≥ 1.5 x 109/L; platelets 
≥ 100 x 109/L. 
c) Serum bilirubin ≤ 1.5 x upper normal limit (UNL) except patients with Gilbert’s 
syndrome 
d) Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x 
UNL but ≤ 5.0 x UNL in case of liver metastases; alkaline phosphatase (ALP) ≤ 
UNL but i) ≤ 2.5 x ULN in case of liver metastases and ii) ≤5 x ULN in case of 
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10. No history or evidence by CT scan or MRI, of brain metastases or leptomeningeal 
disease. 
11. No known hepatitis B virus (not due to immunization), hepatitis C virus, human 
immunodeficiency virus- and - positive status. 
12. No history or evidence of any other clinically significant disorder, condition or disease 
(with the exception of those outlined above) that, in the opinion of the investigator or 
Medical Monitor, if consulted, would pose a risk to subject safety or interfere with the 
study evaluation, procedures or completion  
13. Dated and signed IEC/IRB-approved informed consent. 
5.1.2 EXCLUSION CRITERIA 
1. Prior therapy for metastatic TNBC (chemotherapy, hormone therapy or biological 
therapy), Patients may receive bisphosphonates and other therapies to treat bone 
metastases, however if used, bone lesions will not be considered as measurable disease. 
2. Less than four weeks since last radiotherapy (excluding palliative radiotherapy).  
3. Pregnancy or lactation or unwillingness to use adequate method of birth control. 
4. Neurological or psychiatric disorders which may influence understanding of study and 
informed consent procedures. 
5. Active or uncontrolled infection. 
6. Malabsorption syndrome, disease significantly affecting gastrointestinal function. 
7. G>1 pre-existing peripheral neuropathy 
8. Any other invasive malignancy from which the patient has been disease-free for less than 
5 years with the exception of curatively treated basal or squamous cell skin cancer 
9. Hypersensitivity to: 
 
a) paclitaxel 
 
b) ibuprofen or to more than one non-steroidal anti-inflammatory drug. 
 
c) more than one medication belonging to the class of sulfonamides, such as 
sulfamethazine, 
sulfamethoxazole, 
sulfasalazine, 
nimesulide 
or 
celecoxib; 
hypersensitivity to sulphanilamide antibiotics alone (e.g. sulfamethoxazole) does not 
qualify for exclusion. 
5.2 
Removing Patients from the Study 
A patient should be withdrawn from the trial if, in the opinion of the Investigator, it is medically 
necessary or if it is the wish of the patient. 
The study treatment will be discontinued at any time if any of the following events occur: 
 Development of AE or unacceptable toxicity, precluding further therapy with the study 
drug. 
 Documented disease progression. 
 Severe protocol violations, such as an incorrect treatment administration, or a 
concomitant use of not permitted medications. Before removal, these cases should first 
be discussed with Dompé farmaceutici s.p.a. 
 Patient request. 
 Patient has been enrolled, but has not started study treatment (e.g. due to onset of AE, 
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 Patient becomes pregnant. 
 Treating physician decision in the patient’s best interest. 
 Request of Dompé farmaceutici s.p.a.  
 Study end while a patient is still on treatment. The sponsor will allow any ongoing 
patients to continue treatment outside of the trial via post-trial access, following approval 
by local Ethics Committee and Competent Authorities according to local requirements 
Any treatment discontinuation must be recorded on the case report form (CRF) by the 
Investigator, who will indicate date and reason(s) for treatment withdrawal. Unless the patient 
has withdrawn consent, the off-treatment visit assessments should be performed as detailed in 
Section 8.3. 
Patients who come off study will not be replaced. 
5.3  
Discontinuation Criteria 
The Investigator or Dompé farmaceutici s.p.a. may decide to terminate the study if in the opinion 
that continuing in the study poses unacceptable risks to the patients. If such a decision is reached, 
no further patients will receive study drug and the study will stop. The decision will be based on 
an overall assessment of safety and tolerability. The Data Monitoring Committee (Section 12.4) 
will review the data and decide if the study should be terminated. 
In particular, the following should be closely monitored:  
Liver function tests: 
 Any considerable increase in AST or ALT or bilirubin values which, in the Investigator’s 
opinion, are not compatible with underlying disease. 
Renal function tests: 
 Any considerable increase in serum creatinine values. 
 
6 RANDOMIZATION 
Before randomization, and any study related procedures, at study entry all patients must have 
given a written informed consent for the study. All patients who enter trial screening are 
documented in the Subject Screening and Enrollment Log (each new patient entered onto that 
center’s log will have a progressive patient number which is used until the patient leaves  the 
study). In order to request randomization to the study, all the pre-treatment evaluations must be 
completed (see Section 8.1) and a Subject Registration Form should be completed and submitted 
along with supporting documentation to PRA Health Sciences for review and approval. 
Following approval to randomize by the PRA Medical Monitor, investigators will randomize the 
patient through IRT by responding to the prompts within the system. Screen failed subjects may 
be re-screened up to twice at the Investigator’s discretion (ie, total of 3 screens including initial 
screening). The subject will maintain the same subject ID number provided at the initial 
screening. Subjects must be re-consented if more than 30 days have elapsed between date of 
initial informed consent and date of re-screen/randomization. 
 
 


 
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Patients will be randomized in a 1:1 fashion between paclitaxel and reparixin vs paclitaxel and 
placebo using IRT. Randomization will be stratified between the two sub-populations, newly 
diagnosed metastatic patients and patients that have relapsed following a prior (neo)adjuvant 
chemotherapy regimen. 
The randomization groups will be generated with a computer procedure by the method of random 
permuted blocks.   
The randomization system will be prepared and implemented by the IRT vendor 
Individual treatment codes will be provided via the IRT system to PRA Health Sciences and the 
Dompé Pharmacovigilance department for safety procedures. 
The treatment codes will also be accessible to an Independent Statistician (liaison between the 
CRO database and DMC Biostatistician) who will generate the reports for the Data Monitoring 
Committee (DMC) evaluation (see Section 12.4). 
 
7 STUDY TREATMENT  
7.1 
Investigational Medicinal Product (IMP): REPARIXIN or Placebo and non 
Investigational Medicinal Product (NIMP): PACLITAXEL  
7.1.1 FORMULATION 
The IMP (Reparixin and matching placebo) will be supplied to the study investigators by Dompé 
farmaceutici s.p.a. free of charge. The drug product is in the form of oral immediate release 600 
mg tablets containing the active ingredient reparixin or placebo. Reparixin 600 mg immediate 
release or placebo tablets are white oblong tablets. Refer to Appendix 5 for Reparixin and 
Placebo Description and Composition. 
The NIMP (Paclitaxel) is commercially available. The drug is presented as a clear, colourless to 
yellow, slightly viscous solution for infusion. Stocks of paclitaxel will be purchased directly 
from the supplier by the site pharmacy according to standard practice and will not be labeled for 
the study. Refer to Appendix 7 for paclitaxel package insert. 
7.1.2 CONTAINER AND CLOSURE SYSTEM 
Reparixin tablets and placebo tablets will be packaged in white PVDC/PE/PVC/Aluminum 
blister packages and should be stored at temperatures not higher than 30°C.  
The drug is manufactured according to current Good Manufacturing Practice requirements. 
Medication labels will comply with the Competent Authority requirements of each country 
involved and will be printed in a Multilanguage format. Refer to Appendix 6 for reparixin and 
placebo packaging and labeling details. 
Dompé farmaceutici s.p.a. will supply all details and documentation regarding the study drug in 
the pharmacy manual. The investigator will also be provided with written procedures regarding 
the dispensing of the study drug to the patient.  
Paclitaxel will be obtained directly by the site from the manufacturer as a commercially available 
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7.2 
Dose and Route of Administration 
Study drug will be administered with water prior to the start of the paclitaxel infusion on Cycle 
1, Day 1 and then administered approximately every eight hours. It is preferable that reparixin 
is taken with food. However, if the patient is unable to eat, study drug may still be administered. 
When in combination with paclitaxel (Day 1, 8 and 15 of each cycle), reparixin or placebo will 
be administered every eight hours with about 250 mL water and a light meal or snack. 
Group 1: 
paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15 of 28-day cycle) + reparixin oral 
tablets 1200 mg t.i.d. continuing from D1 to Day 21 
Group 2: 
paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15 of 28-day cycle) + placebo oral tablets 
1200 mg t.i.d. continuing from D1 to Day 21 
Combination treatment will continue until disease progression, withdrawal of consent or 
unacceptable toxicity, whichever occurs first. 
Study drug (Reparixin or Placebo) will be administered orally at the dose of 1200 mg three times 
daily (2 x 600 mg tablets every six to ten hours) for 21 consecutive days during each cycle with 
seven days off treatment between each cycle. If the patient forgets to take the study drug, it 
should be taken as soon as the patient remembers and the time of dosing should be registered in 
the patient diary.  
Paclitaxel will be administered as an i.v. infusion on Days 1, 8 and 15 of each 28-day cycle. 
Premedication must be administered prior to each infusion. The choice of premedication drugs 
will be made according to each institution’s standard procedure. During Cycle 1, a ± 1-day 
window will be allowed for study visits. After Cycle 1, a ± 2-day window will be allowed for 
study visits. For tumor assessment (i.e. scans) beginning at Week 8, a ± 3-day window will be 
allowed. 
Prior to infusion, paclitaxel must be diluted using aseptic techniques in 0.9% sodium chloride 
injection, or 5% glucose injection, or 0.9 sodium chloride and 5% glucose injection or 5% 
glucose in Ringer’s injection, to a final concentration of 0.3 mg/mL to 1.2 mg/mL. The diluted 
product should ideally be used immediately, or if not used immediately, storage times should not 
be longer than 24 hours at 2 to 8 ˚C, unless reconstitution and dilution have taken place in 
controlled and validated aseptic conditions. Diluted paclitaxel solutions should be administered 
through polyethylene-lined administration sets.  
7.3 
Drug Compliance 
The Investigator should accurately complete all the Drug Accountability Forms. A patient diary 
will be provided in which patients will keep note of treatment administrations and any missed 
doses. Both will be checked by the monitor during site visits and be available for audit or 
inspection at any time.  
7.4 
Drug Storage and Accountability 
Reparixin tablets and placebo tablets are packaged in white PVDC/PE//PVC/Aluminum blisters 
in the form of patient kits, numbered to maintain blinding and should be stored at temperature 
not higher than 30°C. The vials of paclitaxel must be stored per prescribing information  (see 
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The Investigator (or pharmacist in those countries where it is required that shipment is made 
directly to the hospital pharmacy) is responsible for receipt, proper storage and usage of study 
drug. Partially used or unused study drug boxes should be destroyed on site (and documentation 
of destruction provided to Dompé farmaceutici s.p.a.) or returned to Dompé farmaceutici s.p.a., 
at the end of the study. The Investigator, who will keep a cumulative inventory and dispensing 
records, will maintain all supplies under adequate security. Adequate record of receipt, use or 
loss of drug will be retained. 
Patients will be given a diary card to record information about date, time and dose taken of study 
drug. At each scheduled visit before the start of a new cycle of treatment and at the off treatment 
visit, the diary should be reviewed with the patient for completeness.  
7.5 
Concomitant Therapies and Birth Control 
In general, concomitant medications and therapies deemed necessary for the supportive care and 
safety of the patient are allowed, including palliative radiation and bisphosphonates or other 
drugs for the palliative treatment of bone metastases, provided their use is documented in the 
patient records and on the appropriate CRF. The use of growth factors is allowed, according to 
local institution guidelines. The administration of any other anticancer agent is NOT permitted. 
Ibuprofen must not be administered in the pre-study period and concomitant to study drug 
treatment (including the 7 days off at each cycle) as it is a metabolite of reparixin. Inhibitors or 
inducers of CYP2C9 should not be administered in the pre-study period (starting from 28 days 
pre-therapy) and concomitant to study drug treatment (including the 7 days off at each cycle) as 
reparixin is metabolized by CYP2C9. See Appendix 9 for list of medications. 
Similarly, the use of other investigational drugs is not allowed in the pre-treatment period (28 
days prior to treatment) and treatment period of the study.  
All concomitant therapies taken during the study from the first day to the end of treatment must 
be recorded in the specific section of the CRF. 
Adequate methods of birth control must be adopted by subjects and their partners during the 
study treatment period and during the 6 months following the completion of study therapy. See 
Appendix 10 for list of acceptable methods of birth control. 
7.6 
Criteria for dose modifications and delays 
For re-dosing with weekly paclitaxel, courses of paclitaxel should not be repeated until the 
neutrophil count is at least 1500 cells/mm3 on Day 1 and 1000 cells/mm3 on Days 8 and 15 and 
the platelet count is at least 100,000 cells/mm3 (Days 1, 8 and 15) 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 subsequent course. If a patient experiences G3 peripheral neuropathy 
lasting >7 days, paclitaxel dosing should be withheld until the adverse event returns to G<2  and, 
when reinstated, paclitaxel dose should be reduced by 20% for subsequent courses. The 
incidence of neurotoxicity increases with dose. 
 
In the event that elevated LFT’s (greater than three times the baseline values of AST/ ALT and 
in addition, value >ULN, or greater than twice the baseline values ALP) are determined on a day 
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paclitaxel therapy will be held and the values repeated weekly. If LFT elevation is persistent > 
14 days and not due to progressive disease, the patient should discontinue from study. 
If values decrease within 14 days, the patient may be retreated at the same paclitaxel dose. If 
within 1 week the patient again has an increase in LFT’s (greater than three times the baseline 
values of AST/ ALT and in addition, value >ULN, or greater than twice the baseline values 
ALP), the patient’s study drug (reparixin/placebo) and paclitaxel therapy will be held and the 
values repeated weekly. The patient may subsequently continue on therapy at a paclitaxel dose 
reduced by 20% at the investigator’s discretion. If dose delays of paclitaxel become necessary 
due to toxicity, study drug (reparixin/placebo) treatment will also be delayed until normal 
paclitaxel treatment resumes. Paclitaxel dosing can be delayed by a maximum of 2 weeks. This 
will be documented on the diary card and the CRF. Once treatment resumes after a dose delay, 
the patient will continue to take study drug (reparixin/placebo) tablets for a total of 21 days. 
No dose reductions or dose delays of reparixin (independent of paclitaxel toxicity as described 
above) are foreseen. In the case of toxicity which may, in the investigator’s judgement, be related 
to reparixin, guidance will be provided by medical monitor and sponsor on a case-by-case basis.  
In case of IP discontinuation in the absence of disease progression, patients may continue 
receiving paclitaxel outside of the protocol, as this will be considered a new therapy, and will be 
followed up as patients without PD. 
 
8 TREATMENT ASSESSMENTS 
 
After obtaining written informed consent and checking whether all inclusion and exclusion 
criteria are met, patients will be included in the study. The visits comprise the implementation 
and documentation in the CRF of the following procedures: 
8.1 
Pre-treatment Evaluations 
All pre-treatment evaluations are to be performed within 14 days (+ 1 day window) prior to the 
start of study treatment (see Study Flow Chart, Section 1.2), unless otherwise specified, and 
should be repeated within one week if abnormal. 
Pre-treatment evaluations include: 
 Assessment of demographic data and tumor characteristics 
 Assessment of tumor history, surgery, radiotherapy and systemic therapies 
 A complete medical history including a detailed history of primary diagnosis, prior 
treatment and baseline clinical conditions 
 Confirmation of no current tumor therapy and check of current concomitant 
pharmacological or non-drug tumor treatments 
 Complete physical examination including weight, height, BSA, pre-treatment signs and 
symptoms, and Zubrod PS (Appendix 2) 
 An ECG 
 Chest X-ray (if not already performed to follow tumor). A thoracic computed tomography 
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 Laboratory tests:  
 Hematology: hemoglobin, WBC and differential count, platelets. 
 Clinical chemistry: sodium, potassium, calcium, serum creatinine, urea, total protein, 
albumin, AST, ALT, ALP, total bilirubin.  
 Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, 
leukocytes and urobilinogen (by dipstick or in lab) 
 Urine or serum pregnancy test (women of childbearing potential only) 
Routine laboratory tests performed within 14 days screening period even if before ICF signed 
are acceptable 
Baseline disease status will be assessed and lesions will be defined as “target” (measurable 
lesions) or “non-target” (non-measurable lesions) according to RECIST criteria version 1.1. A 
minimum of one and a maximum of five (two per organ) lesions will be defined as target 
lesions. Pre-study disease evaluation should be obtained within 28 days of study treatment 
initiation. Copies of scans (CT, MRI of chest, abdomen, pelvis etc.) will be submitted to the 
central radiology vendor for review. 
 A CT scan or MRI of the brain 
 Specific monitoring of peripheral neuropathy 
 Collection of tumor tissue, within 28 days of study treatment initiation, for confirmation of 
recurrent breast cancer 
 confirmation of TNBC and correlative studies, including evaluation of CD24-CD44+CSC, 
ALDH+CSC. 
8.2 
On Study Evaluations 
Patients will be randomized to the study through the IRT system. 
The procedures to be performed and the time schedule (+ 1 day window at cycle 1 and + 2 day 
window after cycle 1) are as follows (see Study Flow Chart, Section 1.2):  
 Pulse rate, systolic and diastolic BP (after 3 mins in the sitting position) will be performed 
pre-study within 24 hours prior to the first study drug (reparixin/placebo) administration 
and then on Day 1 of subsequent cycles. From cycle 2 onwards, physical examination 
will be performed on Day 1 of each treatment cycle. 
 At each visit any AE (including specific monitoring of peripheral neuropathy) 
experienced since the previous visit will be collected and graded according to CTCAE 
version 4.03 grading scale (Appendix 3). 
 Concomitant pharmacological and non-pharmacological treatments will also be recorded 
throughout the study. 
 Laboratory tests: 
 Hematology: hemoglobin, WBC and differential count, platelets, will be repeated weekly 
(Days 1, 8, and 15) during all cycles and more often in case of Grade > 2 toxicity.  
 Clinical chemistry: sodium, potassium, calcium, serum creatinine, urea, total protein, 
albumin, AST, ALT, ALP, total bilirubin will be performed on Day 1 of each cycle and 
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 Urinalysis will be repeated during treatment only if clinically indicated. 
 Urine or serum pregnancy test (women of childbearing potential only) prior to each 
treatment cycle. 
 Assignment of new reparixin/placebo patient treatment kit through the IRT system on 
Day 1 of each cycle (if hematology and clinical chemistry results allow paclitaxel 
infusion). 
 Reparixin/placebo and paclitaxel administration 
 
 Disease response (disease status up to PD) assessed by the same method of assessment and 
the same technique as at pre-study for each lesion will be performed every eight weeks from 
the start of therapy until study end. A CT scan or MRI of the brain will be performed if 
patient presents with symptoms of brain metastases or PD of baseline lesions (it is not 
necessary for PD with new lesions). According to RECIST criteria version 1.1, CR or PR 
should be confirmed by further evaluations that should be performed no less than four weeks 
after the criteria for response are first met. Copies of scans will be submitted to the central 
radiology vendor for independent review. 
 Review patient diary from previous cycle and dispense a new one at each scheduled visit 
prior to the start of a new cycle of treatment.  
8.3 
Evaluation at Off Treatment Visit (Termination or Withdrawal) 
The off-treatment visit should be performed 14 to 28 days following the last dose of study drug.  
At study termination or in the event of premature discontinuation, it must be ensured that the 
following evaluations have been performed:  
 Complete physical examination, weight, Zubrod PS, pulse rate, systolic and diastolic BP 
(after 3 mins in the sitting position)  and chest X-ray (or CT scan if performed at baseline) 
 AEs (including specific monitoring of peripheral neuropathy) and concomitant 
pharmacological and non-pharmacological treatments 
 Laboratory tests: 
 Hematology: hemoglobin, WBC count and differential count, platelets 
 Clinical chemistry: sodium, potassium, calcium, serum creatinine, urea, total protein, 
albumin, AST, ALT, ALP,  total bilirubin 
 Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, 
leukocytes and urobilinogen (by dipstick or in lab). 
 Urine or serum pregnancy test (women of childbearing potential only)  
 Disease response assessed by the same method of assessment and the same technique as at 
pre-study for each lesion. The assessment should include a CT scan or MRI of the brain if 
patient presents with symptoms of brain metastases or PD of baseline lesions (it is not 
necessary for PD with new lesions). The disease assessments do not need to be repeated if 
done within four weeks prior to the off treatment visit or for patients off treatment without 
documented PD – such patients should continue with their established schedule of disease 
assessments (every 8 weeks from start of therapy). Copies of scans will be submitted to the 
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 Best overall tumor response (BOR) assessment: this assessment evaluation should be 
recorded in the CRF in the appropriate section of the last cycle of treatment received.  
 Any treatment suspension or discontinuation during the study must be recorded on the CRF 
by the Investigator on the treatment administration page of the cycle of occurrence (in case 
of suspension) or on the Off Treatment page (in case of discontinuation). The Investigator 
will indicate date and reasons of treatment interruption and also duration in case of 
treatment suspension.  
 Review patient diary 
8.4 
Follow-up Evaluations 
After treatment discontinuation, any medical conditions (e.g., AEs, laboratory abnormalities) 
still present in the 30 days after treatment discontinuation or any new condition occurring in the 
30 days after treatment discontinuation must be reported and followed until recovery or 
assessment of chronicity. The Investigator has to follow all events until they resolve or as 
instructed by the medical monitor. In particular, SAEs still present at the end of the study 
treatment period and for the subsequent 30 days must be followed until the final outcome is 
determined, even if this implies that follow up continues after the patient leaves the trial and, 
when appropriate, until the end of any planned follow up period foreseen by the study protocol.  
Safety assessments can include performance status, physical examination, assessment of AEs 
and any other procedures (e.g., laboratory tests, chest X-ray) as clinically indicated. 
Patients off treatment without documented PD should continue to have disease 
assessments  every eight weeks until PD or another anti-cancer therapy is initiated, 
whichever comes first. Following PD, survival status will also be collected every 3 months 
until death or until 30 September 2019 (1 year after last enrolled subject off treatment) , 
whichever occurs first. This will allow further data to be collected for descriptive 
purposes, in addition to the data from unblinded ongoing subjects, as described in section 
10.9 
 
Any subjects still on therapy after 30 September 2019 will be allowed to continue their treatment, 
for as long as they receive clinical benefit, via post-trial access, only after approval by local 
Ethics Committee and Competent Authorities according to local requirements. Any such subjects 
will be followed for safety for as long as they are on treatment and their data will be reported to 
the local Ethics Committee as per local requirements. At the end of post-trial treatment, the 
investigator will be asked to provide to the Sponsor the reason for treatment termination and in 
the case of PD or death, the date on which this occurred.  
8.5 
Other Assessments 
8.5.1 CORRELATIVE STUDIES 
8.5.1.1 CSC Markers (CD24-CD44+, ALDH+ by Immunohistochemistry)  
At pre-study an archival paraffin-embedded metastatic tumor sample or a newly collected biopsy 
from a metastatic site will be analyzed for the presence of CD24-CD44+ CSCs and ALDH+ 
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Newly collected biopsies will be obtained at study sites, within 28 days of study treatment 
initiation, by a specialist and under radiologist supervision (where necessary). The tissue will be 
immediately placed into formalin after retrieval and the specimen will be embedded using 
paraffin at the study site prior to transportation to central laboratory for further processing. Cells 
will be stained with ALDH1 and CD24/CD44 specific antibodies and analyzed using 
immunohistochemistry.  
 
9 
EFFICACY ASSESSMENT 
9.1 
Efficacy Parameters 
Tumor response is to be assessed according to the Response Evaluation Criteria in Solid Tumors 
(RECIST) criteria version 1.1, evaluating tumor response in target and non-target lesions, for 
patients with measurable disease (see details in Appendix 4 and Section 9.1.1). 
Patients must have completed at least one course of treatment and performed at least one 
disease assessment to be considered evaluable for response.  
 
9.1.1 EVALUATION BY RECIST VERSION 1.1 
The response status of each patient with measurable disease at baseline will be assessed by the 
Investigator. 
All treatment decisions related to tumor assessment will be based on the Investigator and local 
radiologist evaluation of scans 
Measurable lesions (target):   
Lesions that at baseline can be accurately measured in at least one dimension (longest diameter 
[LD] to be recorded) as  10 mm by CT scan,  10 mm by caliper measurement by clinical 
examination, or  20 mm by chest X-ray. A minimum of one and a maximum of five (two per 
organ) lesions will be defined as target lesions. 
Non measurable lesions (non-target): 
All other lesions, including small lesions (LD < 10 mm or pathological lymph nodes with 
 10 mm to  15 mm short axis) as well as truly non-measurable lesions. 
All measurements should be recorded in metric notation, using a ruler or calipers. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 
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Lesions that are considered as truly non-measurable include the following: 
 Leptomeningeal disease. 
 Ascites. 
 Pleural/pericardial effusion. 
 Inflammatory breast disease. 
 Lymphangitic involvement of skin or lung. 
 Abdominal masses/abdominal organomegaly identified by physical examination that is 
not measurable by reproducing imaging techniques. 
 
Note: Tumor lesions that are situated in a previously irradiated area should not be considered 
measurable disease, unless these lesions are new lesions (i.e. lesions appeared after irradiation 
and before study treatment). 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature NEED NOT be 
confirmed by cytology/histology.  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
 
Overall evaluation of target lesions 
Complete Response/Remission (CR) 
disappearance of all target lesions. 
Partial Response/Remission (PR) 
at least a 30% decrease in the sum of LD of target lesions 
taking as reference the baseline sum LD. 
Progression of Disease (PD) 
at least a 20% increase in the sum of LD of target lesions 
taking as references the smallest sum LD recorded since 
the treatment started or the appearance of one or more 
new lesions. 
Stable Disease (SD) 
neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest 
sum LD since the treatment started. 
 
Overall evaluation of non-target lesions  
Complete Response/Remission (CR) 
disappearance of all non-target lesions and 
normalization of tumor marker level. 
Non-CR/Non-PD 
persistence of one or more non-target lesion and/or 
the maintenance of tumor marker level above the 
normal limits. 
Progression of Disease (PD) 
appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
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The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence. The patient's best response assignment will depend on the 
achievement of both measurements and confirmation criteria (see also Section 9.1.2). 
The overall responses for all possible combinations of tumor responses in target and non-target 
lesions, with or without the appearance of new lesions, are detailed below. 
 
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 
 
9.1.2 CONFIRMATION CRITERIA 
The main goal of confirmation of tumor responses is to minimize the risk of overestimation of 
the response rate observed.  
RECIST version 1.1 criteria:  
1. PR or CR: changes in tumor measurements must be confirmed by further evaluations that 
should be performed no less than four weeks after the criteria for response are first met.  
2. SD: measurements must have met the SD criteria at least once after study entry at a 
minimum interval between two measurements (eight weeks). 
9.1.3 CENTRAL INDEPENDENT RADIOLOGY REVIEW 
Copies of all scans will be submitted to the Central Radiology Vendor (Bioclinica Inc.) for 
independent review (see section 12.5). Each scan will be reviewed by two separate radiologists. 
In the case of disagreement of disease response, a third radiologist will act as adjudicator.  
Further details are provided in the Independent Radiology Review charter. 
10 
SAFETY ASSESSMENT 
The qualitative and quantitative toxicities will be evaluated. 
10.1 
Safety Parameters 
All the following examinations will be included in the evaluation and analysis of safety. 


 
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10.1.1 VITAL SIGNS AND PHYSICAL EXAMINATION 
Diastolic and systolic BP (after 3 mins in the sitting position) and pulse rate will be performed 
at pre-study within 24 hours of the first study drug (reparixin) treatment, on Day 1 of subsequent 
cycles and at off treatment visit. A complete physical examination will be performed at pre-
study, on Day 1 of each cycle from cycle 2 onwards and at the off treatment visit. Any observed 
abnormalities relevant to each system and apparatus will be recorded. 
10.1.2 CONCOMITANT TREATMENTS 
Concomitant treatments (both pharmacological and non-pharmacological, including 
transfusions) will be reported at pre-study, throughout the study and at the off-treatment visit.  
10.1.3 CHEST X-RAY 
A chest X-ray (if not already performed to follow the tumor) will be performed at pre-study and 
at the off treatment visit. A thoracic CT scan may substitute the chest X-ray.  
10.1.4 LABORATORY EXAMINATIONS 
The following laboratory tests will be performed locally at the study sites as scheduled in 
Section 8: 
 Hematology: hemoglobin, WBC and differential count, platelet count 
 Clinical chemistry: sodium, potassium, calcium, serum creatinine, total protein, albumin, 
AST, ALT, ALP, urea, total bilirubin.  
 Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, 
leukocytes and urobilinogen parameters (by dipstick or in lab). 
 
 
10.2 
Adverse Events 
The Adverse Event (AE) definitions and reporting procedures provided in this protocol comply 
with the current Code of Federal Regulations (CFR) 21 Part 312 and EU regulations. 
Information about all AEs, whether volunteered by the patient, discovered by questioning or 
detected through physical examination, laboratory test or other means, will be collected and 
recorded on the AE page of the CRF, and followed as appropriate. An AE is any undesirable 
sign, symptom or medical condition occurring in a patient or clinical trial subject administered 
a medicinal product, even if the event is not considered to be treatment-related. AE monitoring 
should continue for at least 30 days following the last dose of study drug.  
Any medical conditions/diseases, or cancer related signs/symptoms present in the 30 days before 
starting study treatment must be recorded on the Medical History/Baseline Conditions CRF, even 
if the patient already signed the Informed consent. 
Medical conditions/diseases, or cancer related signs/symptoms present after starting study 
treatment are considered AEs only if they increase either in frequency or severity once treatment 
starts. Diagnosis of Disease Progression per se (without any specific sign or symptom) 
occurring after starting study treatment  will not be considered an AE/SAE. If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported as 
an AE/SAE. Death due to disease progression must be reported as an SAE, preferable specifying 
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Abnormal laboratory values or test results occurring after the start of study treatment constitute 
AEs, only if they induce clinical signs and/or symptoms and require intervention/therapy, i.e. are 
clinically significant. In these cases, they will be recorded on the AE page of the CRF along with 
the signs, symptoms or diagnosis associated with them. In addition, each AE will also be 
described by:  
 Its duration (start and stop dates).  
 Severity grade using the CTCAE version 4.03 (Appendix 3). 
 Its relationship to the study drug; (suspected/unsuspected). 
 Action(s) taken. 
 Outcome. 
The severity of AEs and SAEs will be graded using the CTCAE version 4.03. Any AE not listed 
in the CTCAE will be graded as follows: 
Grade Definition: 
1. Mild 
2. Moderate 
3. Severe 
4. Life-threatening or disabling 
5. Death 
10.3 
Serious Adverse Events 
Information about all SAEs will be collected and recorded on the SAE Form. To ensure patient 
safety each SAE must be reported to PRA Health Sciences Drug Safety within 24 hours of 
learning of its occurrence. A SAE is an undesirable sign, symptom or medical condition which:  
1. is fatal;  
2. is life threatening; 
3. requires hospitalization or prolonged pre-existing hospitalization;  
4. results in persistent or significant disability/incapacity;  
5. constitutes a congenital anomaly or a birth defect; 
6. is medically significant, may jeopardize the patient's prognosis, and may require medical 
or surgical intervention to prevent one of the outcomes listed above.  
The events that required hospitalization for one of the reasons reported below are not considered 
to be SAEs:  
 Hospitalizations planned before entry into the clinical study which is part of the normal 
treatment or monitoring of the studied indication and not associated with any 
deterioration in condition.  
 Hospitalization for routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition. 
 Hospitalization for treatments, which was elective or pre-planned, for a pre-existing 
condition that is unrelated to the indication under study and did not worsen. 


 
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 Hospitalization for general care not associated with any deterioration in condition.  
 Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of SAEs  given above and not resulting in hospital admission.  
 These events must be recorded in the AE page of the CRF where a variable will be ticked 
to indicate that they are not SAEs.  
Any SAE occurring after the patient has started study treatment  and during 30 days  after the 
patient has taken the last dose of study treatment must be reported.  
Serious adverse events occurring to a subject after the treatment of that subject has ended should 
be reported to the sponsor if the investigator becomes aware of them. 
10.4 
Adverse Event Collection 
Information on all AEs (serious and non-serious, expected and unexpected, suspected and 
unsuspected) observed by the Investigator or reported by the patient, will be collected in the 
appropriate section of the CRF. 
Information on all AEs will be collected as soon as study treatment starts and throughout the 
study until resolution of the event.  
10.5 
Relationship of AEs to the Investigational Product 
The Investigator will assess the causality relationship between the AE and the investigational 
medication, according to the criteria in the Table below: 
Relationship of the Adverse Event to the Investigational Product 
None (Intercurrent Event) 
An event that is not and cannot be related to 
the Investigational Product, e.g. patient is a 
passenger in a road traffic accident. 
Unlikely (remote) 
 
Relationship is not likely e.g. a clinical event 
including laboratory test abnormality with 
temporal relationship to drug administration 
which makes a causal relationship improbable 
and in which other drugs, chemicals or 
underlying 
disease 
provide 
plausible 
explanations. 
Possible 
Relationship may exist, but could have been 
produced by the patient’s condition or 
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Probable 
Relationship is likely, the AE abates upon 
discontinuation of Investigational Product 
and cannot be due to the patient’s condition. 
Highly Probable 
Strong relationship, the event abates upon 
discontinuation of Investigational Product 
and, if applicable, re-appears upon repeat 
exposure. 
 
Adverse events are to be considered unsuspected if the relationship to the study drug as described 
in the table above is none or unlikely, whereas a possible, probable or highly probable 
relationship would mean that the adverse event would be considered suspected. 
An Adverse Drug Reaction (ADR) is defined as an adverse experience which is a reasonably 
likely to have been caused by the drug. Any AE reported in the study having a possible, probable 
or highly probable relationship to study drug will be considered as an ADR. 
10.6 
Reporting Procedures for Serious Adverse Events  
Any AE meeting the definition of serious, occurring after the patient has started study treatment, 
during the study or during 30 days after the last dose administration must be recorded on the 
SAE Report form provided by PRA Health Sciences. Any SAE occurring to a subject after the 
treatment of that subject has ended should be reported to the sponsor if the investigator becomes 
aware of them  
The SAE must be reported within 24 hours from the Investigator’s knowledge of its occurrence 
to: 
 
PRA Health Sciences Safety Faxline North America: 1-888-772-6919  
PRA Health Sciences Safety Faxline Europe: +44 1792 525 720 
PRA Health Sciences Safety Hotline North America: 1-800-772-2215 
PRA Health Sciences Safety Hotline Europe: +49 621 8782 154 
 
Email North America: CHOSafety@prahs.com 
Email Europe: MHGSafety@prahs.com 
 
 
The initial report should be completed with the information available at the time of reporting. 
PRA Health Sciences will check the data reported on the SAE form and forward relevant 
documentation by email to the Safety Manager, Dompé farmaceutici s.p.a. (Tel. +39 02 
58383462; Fax: +39 02 36026913 e-mail: farmacovigilanza@dompe.com) within one calendar 
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business Monday will be transmitted within one business day; in case of long weekends, source 
documents only will be forwarded within one calendar day). 
Further information on the event and its outcome, if missing on the initial report as well as 
follow-up information, should be provided by the Investigator as soon as available and forwarded 
to PRA Health Sciences, following the same procedure and timelines as for the initial report. In 
case of death, a copy of the autopsy report, if performed, should also be provided.  
Whenever more than one SAE is observed, the Investigator should identify which is the primary 
adverse event, i.e. the most relevant one. If other events are listed in the same report, the 
Investigator, along with their relatedness to the Investigational Product, should identify which 
adverse events are serious and which are non-serious. In any case, the Investigator is requested 
to record his/her opinion about the relatedness of the observed event(s) with the investigational 
medication. 
10.7 
Non Serious Adverse Events 
No immediate reporting is required. The Investigator will document the event in source and fill 
in the AE Form contained in the CRF and will describe the complete AE evolution till its 
outcome.  
Should a non-serious AE become serious, the Investigator will then follow the same reporting 
procedures as for SAEs. 
10.8 
Adverse Events Causing Treatment Discontinuation 
If a patient is withdrawn from the study as a consequence of an AE, this must be recorded and 
reasoned in the CRF, and the patient must be followed up until the resolution of the AE or as 
instructed by the medical monitor. 
10.9 
Unblinding 
In the case of an emergency, where knowledge of the individual patient’s blinded treatment could 
influence further patient care, Investigators will be allowed to unblind study medication, directly 
through the IRT system and must notify the CRO’s medical monitor so that the reason for any 
premature unblinding can be documented. Training is provided to investigators prior to 
authorization to use the IRT system and the unblinding function is outlined in the study specific 
user guide. 
The randomization code will be broken when the last enrolled patient has completed her therapy, 
and once the database has been locked. Following database lock, the randomization code for 
each of the subjects enrolled will be communicated by letter to the PI at each site, who will then 
transmit the information to their subjects still on treatment or in active follow up. Any previously 
enrolled subjects, still on therapy after database lock may continue treatment unblinded until 
disease progression by RECIST version 1.1, withdrawal of consent, or unacceptable toxicity, 
whichever occurs first. The data from the unblinded ongoing subjects will be collected, for 
descriptive purposes. Ongoing subjects randomized to the placebo group will be able to discuss 
with their treating physician whether to discontinue placebo treatment and continue on paclitaxel 
alone.  All procedures/tests and visit frequency will remain as described in protocol section 8. 


 
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10.10 Overdose 
Cases of overdose (accidental or intentional) which result in serious adverse reactions are to be 
handled following emergency procedures, and reported within 24 hours from the Investigator’s 
knowledge of its occurrence This includes reports related to drug intake with suicidal intentions 
and consequent drug overdose. 
The administration of 3 or more additional tablets on any given treatment day will be reported 
as an overdose even if not associated with adverse reactions and shall be reported to PRA Health 
Sciences by e-mail or fax within 24 hours, in order to have information about symptoms, 
corrective treatment and outcome of overdose. 
PRA Health Sciences Safety Faxline North America: 1-888-772-6919  
PRA Health Sciences Safety Faxline Europe: +44 1792 525 720  
PRA Health Sciences Safety Hotline North America: 1-800-772-2215  
PRA Health Sciences Safety Hotline Europe: +49 621 8782 154  
 
Email North America: CHOSafety@prahs.com 
Email Europe: MHGSafety@prahs.com 
The relevant documentation will be forwarded by PRA HS by email to the Safety Manager, 
Dompé farmaceutici s.p.a 
10.11 Pregnancy 
Female patients must inform the Investigator immediately if they become pregnant. The 
Investigator must inform PRA Health Sciences within 24 hours about the pregnancy, using the 
‘‘Pregnancy Reporting Form in Clinical Trials’’. The relevant documentation will be forwarded 
by PRA Health Sciences by email to the Safety Manager, Dompé farmaceutici s.p.a 
Any pregnancy leads to the immediate exclusion from the trial.  
The procedure for the follow-up of any reported pregnancy is as follows: 
From Onset of Pregnancy to Delivery or Termination: 
 If onset of pregnancy is reported prior to the first administration of the trial medication 
or if the woman decides for planned abortion, the pregnancy will be followed until 
termination or delivery. 
 Any reported pregnancy after the first administration of the trial medication has to be 
followed and documented by the Investigator until termination or delivery: 
 
o Initial report after information from the patient (the information in terms of a possible 
“high risk” pregnancy should be obtained from the trial patient and her gynecologist, 
respectively) 
o Follow-up report at the end of pregnancy (or at termination). 
 
After Birth: 
The birth of the infant has to be documented by the Investigator:  


 
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 Final report (the information in terms of “healthy child” should be obtained from the trial 
patient and her pediatrician, respectively).  
Miscarriage, stillbirth and any malformation/disease must be reported as a SAE. 
For documentation of any pregnancy outcome other than abortion, stillbirth or any 
malformation/disease the “Pregnancy Report Form” has to be used. The completed 
documents have to be provided by the Investigator within 24 hours after obtaining the 
information from the trial patient.  
10.12 Reporting Procedure to IRB/IEC and to Regulatory Authorities 
In addition to reporting the SAE to PRA Health Sciences, the Investigator must also comply with 
the requirements related to the reporting of SAEs to the IRB/IEC which approved the study. For 
reported deaths of a subject, the Investigator shall supply the sponsor and the Ethics Committee 
with any additional information requested. 
The requirements of IEC/IRB differ from one state and indeed one country to another, however 
as a minimum requirement all serious unexpected ADRs, life-threatening problems or deaths 
must be reported to the IEC/IRB which approved the protocol as soon as possible and in no event 
later than: 
(a) seven calendar days after becoming aware of the information if the event is fatal or life 
threatening; and 
(b) fifteen calendar days after becoming aware of the information if the event is neither fatal 
nor life threatening. 
In parallel, during the course of the clinical trial, Dompé (or designee) shall inform the 
Competent Authorities/FDA of any serious unexpected ADR. Reporting timeframe will be the 
same as described above. 
Furthermore, Dompé shall follow up safety information and shall report final findings in a 
written safety report as soon as the relevant information is available. 
If the results of an investigation show that an adverse drug reaction not initially determined to 
be reportable is reclassified as reportable, Dompé shall report such reaction in a written safety 
report as soon as possible, but in no event later than 7/15 calendar days after the determination 
is made. 
Copies of all correspondence relating to reporting of any SAEs to the IEC/IRB should be 
maintained in the Investigator’s Files. 
Each IEC/IRB and Competent Authority/FDA and Investigator will be informed of all serious 
unexpected ADRs which are reported from other Investigators, as applicable according to law 
requirements. 
10.13 Reporting of Paclitaxel adverse reactions and overdose 
Paclitaxel is used both as combination therapy with Reparixin or placebo in the comparator arm 
and is defined as a non-investigational medicinal product (NIMP). 
ADRs (serious or non serious) related to paclitaxel only (e.g. injection site reaction), will be 
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law requirements, in line with CT3 Art 7.11.3. and applicable national law, notwithstanding the 
seriousness.  
Unexpected Serious Adverse Events related to this NIMP will per definition not be SUSARs and 
need not be reported as SUSARs, but the investigator will report suspected Adverse Reactions 
to the NIMP to the MOHs or to the Marketing Authorization Holder (MAH) as per local 
requirements, as stated above..  
SAEs related to both IMP and NIMP and SAEs originating from a possible interaction between 
the IMP and the NIMP will be processed as SUSAR, if unexpected. 
Expectedness of events associated with paclitaxel will be determined according to the events 
listed for those drugs in the reference safety information for paclitaxel (Appendix 7). 
Overdoses of paclitaxel leading to signs and symptoms shall be reported by the investigator as 
AE or SAE to the sponsor.  
 
11 
DIRECT ACCESS TO ORIGINAL DOCUMENTS 
The Investigator/Institution must allow national and foreign Regulatory Authorities, individuals 
delegated by the Independent Ethics Committee (IEC)/Independent Review Board (IRB) or 
Dompé farmaceutici s.p.a. and their agents such as PRA Health Sciences to have free access to 
and to conduct the relevant verification of all the original documentation of the study, including 
the informed consent forms signed by the patients enrolled into the study, the relevant patient 
files and/or out-patient files. Those individuals who are given free access to the documentation 
must take every reasonable precaution to keep the identity of the patients and the proprietary 
information of Dompé farmaceutici s.p.a., as reserved information, in accordance with relevant 
applicable legislation. 
12 
CONTROL AND QUALITY ASSURANCE PROCEDURES 
Monitoring of the present clinical trial is the responsibility of PRA Health Sciences. 
Audit activities will be performed by PRA Health Sciences Quality Assurance (QA), under the 
supervision of Dompé QA except for audit to protocol/amendments, informed consent form and 
CRF that will be audited by Dompé QA. 
According to GCP, a number of measures and procedures aimed to guarantee data quality and 
reliability are to be applied and followed in carrying out this clinical trial. 
12.1 
Clinical Monitoring and Identification of Source Data 
The study will be monitored by regular monitoring visits in compliance with GCP and PRA 
Health Sciences Standard Operating Procedures (SOPs) to verify data entered and collected on 
the CRF(s). Monitoring will be performed by PRA Health Sciences. 
The Investigator should agree to receive periodic monitoring visits, based on patients’ enrolment 
rate or for other reasons, such as to verify SAEs. 
At each visit, the Investigator or a designated member of the study personnel should be available 
to provide direct access to all study-related documentation, including the original patient notes, 
and to make any necessary corrections to the CRF and/or other study documents. Source 
documents should be available to support the data recorded in the CRF, apart from those data for 
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on the source data identification list prior to study commencement . The confidentiality of the 
patients’ identities shall be well protected consistent with local and national regulations when 
the source documents are subject to direct access. 
The monitor will provide the Investigator with all the study materials before the study starts and, 
during the course of the study, will check at least the following: 
 Full compliance with ICH, GCP, the study protocol and applicable regulatory 
requirements. 
 Patient recruitment. 
 Patient compliance. 
 Drug accountability.  
 Signed Patient Informed Consent forms 
 Completeness and accuracy of the CRF data and their consistency with the source 
documents (appropriate source data verification will be conducted on all CRFs). 
 Verification of the facilities. 
 Investigator's Trial Master File. 
The monitor will ensure completeness of CRFs on an ongoing basis.  
12.2 
Audit 
The Investigator/Institution must allow Dompé farmaceutici s.p.a. and its agents to conduct the 
audits as an integral part of the quality assurance system as well as inspections from the IEC/IRB 
and relevant regulatory authorities. The audit is an independent verification, separate from the 
monitoring activity, of the activities and of the documents to ensure that the activities pertinent 
to the study were duly carried out and that they were recorded, analyzed and transferred in 
compliance with the protocol, with GCP, with the relevant SOPs and with applicable legislation. 
12.3 
Inspections 
The Investigator/Institution must allow national and foreign Regulatory Authorities to conduct 
inspections.  
The Inspection on the part of one or more Regulatory Authorities consists of an official review 
of the documents, facilities, records and any other resource considered by the authorities to be 
connected with the study. 
12.4  Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be established and will be responsible 
for safeguarding the interests of trial participants, and for enhancing the integrity and credibility 
of the trial. The DMC will assess the safety of the treatments during the trial, and will monitor 
the overall conduct of the clinical trial.  The DMC will provide recommendations to Dompé 
about stopping or continuing the trial.  To contribute to enhancing the integrity of the trial, the 
DMC 
may 
also 
formulate 
recommendations 
to 
Dompé 
relating 
to 
the 
selection/recruitment/retention of participants, their management, improving adherence to 


 
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protocol-specified regimens and retention of participants, and the procedures for data 
management and quality control. 
The DMC will operate independently of Dompé, and its members will not have connections to 
Dompé with the exception of the compensation to DMC members related to their activities.  
The DMC will comprise three members. They will be a multidisciplinary group that will include: 
 Two oncologists with extensive experience in clinical trial conduct 
 A Biostatistician with substantial experience in the DMC process. 
The DMC: 
 Will review unblinded data. To this purpose, an Independent Statistician will liaise with the 
CRO statistician and will have access to those components of the database necessary to 
generate the reports to the DMC. 
 Will be responsible for the ongoing (at least every 6 months) review of safety data 
throughout the trial.  Primary among the safety data that will be reviewed are Serious AEs. 
In particular, the DMC will monitor liver (AST, ALT and bilirubin) and renal (creatinine) 
function tests. 
 Will be advisory to Dompé and make recommendations to Dompé regarding the 
continuation of the trial and potential modifications to the design and conduct of the trial.  
These recommendations will be made in a manner to maintain confidentiality of emerging 
information about safety, unless access to certain data is needed to enable Dompé to make 
decisions about the DMC recommendations.  Dompé will be responsible for promptly 
reviewing the DMC recommendations, to decide whether to continue or terminate the trial, 
and to determine whether amendments to the protocol or changes in the study conduct are 
required. 
All details of the conduct and responsibilities of the DMC will comply with Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees and 
will be described in the ‘DMC Charter’ to be finalized during the set-up phase of the study and 
prior to the initiation of enrollment. 
12.5   
Independent Radiology Review 
An independent radiology review (IRR) committee will be appointed to provide a blinded review 
of all images of participating patients. Copies of all scans will be submitted to the Central 
Radiology Vendor (Bioclinica Inc.) for independent review. Each scan will be reviewed by two 
separate radiologists. In the case of disagreement of disease response a third radiologist will act 
as adjudicator.  
Progression and response will be evaluated according to RECIST 1.1 criteria. The primary 
endpoint will be PFS as measured from the time of randomization to the time of disease 
progression or death, whichever occurs first. The response obtained by the IRR will be 
considered the final response for study reporting purposes. 
Further details are provided in the Independent radiology review charter. 
 


 
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13 
DATA MANAGEMENT 
The data management of this study will be performed by PRA Health Sciences. PRA Health 
Sciences will perform data processing according to approved procedures including database 
specifications, CRF tracking, central laboratory data reconciliation, SAE reconciliation, 
dictionary coding and data validation. A quality control of site responses to data queries will also 
be performed on this study. PRA Health Sciences will create a conversion program to produce 
CDISC SDTM datasets. 
When the database has been declared to be complete and accurate, the database will be locked. 
Any changes to the database after that time can only be made by written agreement between 
Dompé s.p.a’s and PRA Health Sciences’ project team. 
Data will be transferred to Dompé farmaceutici s.p.a. by PRA Health Sciences. 
Medical terms will be coded according to the following dictionaries: 
 Medical Dictionary for Regulatory Activities (MedDRA) (latest available version) for 
AEs and Medical History;  
 WHO-drug dictionary with the Anatomical the Therapeutic Classification code, for 
previous and concomitant drugs.  
13.1 
Case Report Form (CRF) 
PRA Health Sciences will provide the electronic CRF customized for the study in compliance 
with the FDA 21 CFR part 11 and EU regulations. 
For each patient enrolled in the study, a CRF will be completed as soon as the data concerning 
that patient are available. The data are the sole property of Dompé farmaceutici s.p.a. and should 
not be made available in any form to third parties, except for authorized representatives of 
appropriate Health/regulatory Authorities, without written permission from Dompé farmaceutici 
s.p.a. 
14 
STATISTICAL CONSIDERATIONS 
The statistical analysis will be carried out with SAS version 9.4 (or later versions) from the SAS 
Institute. All patient data collected on the CRF and on the Diary will be listed by patient, 
treatment group and center.   
Appropriate descriptive statistics will be produced, according to the variable. For continuous 
variables, the data will be presented according to a clinically relevant discretization. For 
categorical data, frequencies and percentages will be presented. If appropriate, confidence 
intervals around the mean or the proportions will be presented. 
The data will be presented in the Clinical Study Report. A Statistical Analysis Plan (SAP) will 
be issued describing details of all the statistical methods and analyses to be applied to trial results, 
including censoring methods for PFS and TTM and sensitivity analyses for PFS based on 
different censoring mechanisms. Censoring dates will be defined as the last date on which 
progression status was adequately assessed using either the date of the last assessment performed 
or the date of the clinic visit corresponding to these radiological assessments (FDA Guidance for 
industry. Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics). Any 
deviations from the original statistical plan will be described in the Clinical Study Report. 


 
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All reasonable efforts will be made to prevent missing data. Methods for imputation of missing 
data will be presented in the SAP for the clinical trial. Censoring at the last adequate disease 
assessment will be applied to patients lost to follow-up. When intermediate visit(s) is/are missed, 
data from subsequent PFS/OS assessment will be included (FDA Guidance for industry. Clinical 
Trial Endpoints for the Approval of Cancer Drugs and Biologics).  
14.1 
Efficacy Analysis 
The Intent to Treat (ITT) population will consist of all patients who are randomized and will be 
based upon the treatment randomized, regardless of the treatment actually received. Patients will 
be in the ITT analysis whether or not they receive study drugs, because exclusions cannot be 
made for events occurring after randomization that could be influenced by the randomized 
assignment. The primary and secondary efficacy analyses will be presented primarily for the ITT 
Population. 
For the primary endpoint, the PFS (as measured from the time of randomization to the time of 
disease progression or death, whichever occurs first) will be compared between treatment arms 
using stratified log-rank test. For secondary endpoints, OS will be compared between treatment 
groups using stratified log-rank test and Kaplan-Meier curves will be produced to estimate 
median PFS and median OS outcomes. Patients will be randomized to the two treatment groups 
with a 1:1 ratio. 
In supportive analyses, Cox regression analyses may be performed if clinical factors potentially 
affecting PFS and/or OS will be identified.  
 
The disease response by IRR (disease status up to PD) at pre-study (baseline) and every eight 
weeks until the end of the study based on RECIST version 1.1 criteria will be summarized by 
counts, percents and 95% confidence intervals and by treatment and stratification group. 
 
14.2 
Safety Analysis 
Safety and tolerability analysis will be applied on the safety population (all patients randomized 
having taken at least one dose of the study treatment) and will be based on the treatment actually 
received. 
AEs, physical examination, vital signs, concomitant medications and laboratory data will be 
considered for the safety analyses. Descriptive statistics will be provided for these variables. 
AEs will be coded using the MedDRA dictionary at the Lowest Level Term. For each patient, 
AEs and all related information will be listed. Only treatment-emergent AEs (TEAEs) will be 
summarized. TEAEs are those which first occur or increase in severity or relationship to study 
drug after the first dose of study drug. 
A summary of TEAE, including the number of events reported, the number and percentage of 
patients reporting at least one TEAE, the number and percentage of patients discontinuing due 
to a TEAE, the number and percentage of patients with at least one serious TEAE, and the 
number and percentage of deaths will be presented by treatment group and overall.   
A breakdown of the number and percentage of patients reporting each TEAE, categorized by 
body system and preferred term coded according to the MedDRA dictionary, will be presented 


 
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by treatment group and overall. Counting will be by patient not event, and patients are only 
counted once within each body system or preferred term. A similar tabulation will be produced 
for those TEAEs related to study drug. In addition, a summary of events reported, categorized 
by severity will be provided by treatment group and overall. Patients with multiple events within 
a particular body system or preferred term will be counted under the category of their most severe 
event within that body system or preferred term.   
A summary of TEAEs leading to discontinuation will be provided, grouped by body system and 
preferred term by treatment group and overall. A summary of SAEs will be provided by 
treatment group and overall, grouped by body system and preferred term. A listing of any patient 
with an AE and outcome of death will be provided. 
Vital signs data will be summarized by descriptive statistics at schedule visit. Laboratory data 
will be summarized through descriptive statistics at scheduled visit and shift tables taking into 
account the change in the CTCAE version 4.03 grade from start to end of treatment. 
Hematological toxicity evaluations of thrombocytopenia, neutropenia and leukopenia and 
incidence of peripheral neuropathy will also be summarized by treatment group. 
 
14.3 
Exploratory Analyses 
 
Median TTM will be evaluated by means of Kaplan Meier survival curves. 
Proportion of patients progressing with new metastatic lesions will be evaluated using the 
Cochran-Mantel-Haenszel (CMH) test, stratified by the patient population (newly diagnosed vs 
relapsed). 
 
The CSC markers (CD24-CD44+CSC and ALDH+CSC assessed by IHC) will be summarized 
by descriptive statistics (n, mean, standard deviation, median, minimum and maximum). 
 
14.4 
Assignment of Patient Number 
Study sites will be identified on the basis of a specific site number. Each subject is uniquely 
identified in the study by a 6 digit patient number.  After written informed consent has been 
obtained, patients will be assigned the patient number starting with a 3 digit site number followed 
by  a 3 digit subject number  in numerical ascending order by site (e.g. 001-001). This number 
will identify the patient during the whole screening and treatment period until the end of the 
study. Once assigned to a patient, the patient number will not be re-used. The patient number 
will be recorded in both the IRT (See section 6) and EDC. 
15 
ETHICAL ASPECTS 
All the parties involved in the study agree and will verify that this study will be conducted in 
compliance with IRB/IEC, FDA and ICH GCP Guidelines – including Title 21 Part 56 of the 
USA CFR relating to IRBs and GCP as described in the United States FDA CFR (21 CFR § 50, 
56, 312) and ICH E6 - in accordance with applicable ICH regulations regarding clinical safety 
data management (E2A, E2B(R3)), and with ICH regulations regarding scientific integrity (E4, 
E8, E9 and E10). In addition this study will adhere to all local regulatory requirements,  
requirements for data protection, and the declaration of Helsinki. 


 
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15.1 
Independent Review Boards/Independent Ethics Committees 
A clinical trial may be initiated only after receiving written approval by the IRB/IEC to which 
the Investigator Site makes reference to. Dompé farmaceutici s.p.a. must therefore receive the 
favorable opinion of the IRB/IEC of the facility where the clinical trial will be conducted before 
the Investigator may begin to screen or enroll any patients into the study. Dompé farmaceutici 
s.p.a. and the Investigator must submit all the necessary documents required for attainment of 
the approval to the IRB/IEC. A copy of the approval by the IRB/IEC must be available at Dompé 
farmaceutici s.p.a. facility before the initiation of the study at each site.  
15.2 
Information for the Patient and Informed Consent  
Before the start of the study, the written information to be provided to the patients and the 
Informed Consent Form must be submitted for review and approval by the local IRB/IEC, 
together with the protocol.  
The Informed Consent must be requested, obtained and documented by the Investigator in 
accordance with applicable legislation, with GCP and with the ethical principles which derive 
from the Declaration of Helsinki.  
(For the details relevant to the procedure for requesting and obtaining the informed consent to 
be described in the protocol, see the ICH GCP E6, paragraphs: 4.3.3, 4.3.4, 4.8.2, 4.8.3, 4.8.4, 
4.8.5, 4.8.6, 4.8.7, 4.8.8, 4.8.11, 8.3.2 and 8.3.11.  
 
16 
ADMINISTRATIVE PROCEDURES 
16.1 
Changes to the Study Protocol 
Once the final clinical protocol has been issued and signed by the Investigator and the authorized 
signatures, it must not be informally altered. Clinical protocol amendments are alterations to a 
legal document (the clinical protocol) and have the same legal status and must pass through the 
appropriate steps before being implemented. In general, any important change which 
theoretically increases risk to the patients or a patient’s study participation must be approved by 
the IRB/IEC prior to be effective. Minor changes and administrative changes need only 
notification to the IRB/IEC without approval. 
Any subsequent amendments must be made on a separate sheet and must pass through the 
approval process. Dompé farmaceutici s.p.a. is responsible for ascertaining whether FDA/EU 
Competent Authorities must be notified of the clinical protocol change. 
The Investigator and the Regulatory Department of Dompé farmaceutici s.p.a. will be 
responsible to notify, respectively, the IRB/IEC and FDA/EU Competent Authority, if major 
changes to the study protocol are agreed with a specific amendment, as foreseen by laws and/or 
regulations in force. 
It should be noted that where an amendment to the protocol substantially alters the study design 
or the potential risks to the patients, a revised Informed Consent Form (ICF) will be reviewed 
and approved by the IRB/IEC and each participating patient will sign the revised ICF at their 
next study visit. 


 
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16.2 
Suspension/Interruption of the Study 
Should the trial be prematurely terminated or suspended for any reason, the FDA/EU Competent 
Authority and the IRB/IEC will be promptly informed in writing by the Investigator or by Dompé 
farmaceutici s.p.a., according to the Regulatory requirements and the procedures detailed in the 
GCP (ICH E6). 
The Investigator will promptly inform the trial patients, assuring appropriate therapy and follow-
up for all of them. 
16.3 
End of Study 
One subject (510-001) is still on study treatment, following the final cut off for follow up on 30th 
September 2019. The subject will be allowed to continue her combination therapy, off protocol, 
via post-trial access, for as long as she continues to receive clinical benefit. The study will 
terminate as soon as post-trial access for this subject is approved by the concerned Ethics 
Committee and Competent Authorities, as per local requirements.  
16.4 
Archiving 
The Investigator/Institution must ensure the archiving of the essential documents of the study as 
specified by GCP and in compliance with  US FDA regulations (21 CFR 312.62[c]) and EU 
regulations. The Investigator/Institution must adopt all the necessary measures to avoid 
accidental or premature destruction.  
The Investigator/Institution must store the specific essential documents for at least two years 
after the latest approval of an application for a marketing authorization and until there are no 
ongoing or foreseen applications for marketing authorizations, or until at least two years have 
passed from the formal interruption of the clinical development of the investigational medicinal 
product, and in any case, until Dompé farmaceutici s.p.a. has made a written notification that it 
is no longer necessary to maintain these documents. Nonetheless, these documents must be 
maintained for longer periods of time if so requested by relevant applicable legislation or by a 
specific agreement with Dompé farmaceutici s.p.a.  
16.5 
Use of the Information and Publication of the Results 
The Investigator will have access to study data and recognizes that all the information provided 
by Dompé farmaceutici s.p.a., which has not been made available to the public, in regard to the 
investigational medicinal product (indication, patents, chemical formula, synthesis and 
formulation processes, study data or other information) is the property of Dompé farmaceutici 
s.p.a. and are strictly confidential. The Investigator may utilize this information exclusively for 
the conduct of the research, within the limits of the signed letter of agreement. 
In regard to the data derived from this clinical research, the Investigator is obliged to provide all 
the results obtained to Dompé farmaceutici s.p.a. Dompé farmaceutici s.p.a. will support the 
publication of the data in due time in an appropriate peer-reviewed scientific journal. 
Should the Investigator intend to divulge any of the results of the study, except for the 
notification of the AEs foreseen by current legislation in regard to Pharmacovigilance, he/she 
must communicate this intention beforehand to Dompé farmaceutici s.p.a. by means of a 
Registered Letter. Dompé farmaceutici s.p.a. must answer the request of the Investigator within 
2 months of the date of receipt of the request.  


 
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Dompé farmaceutici s.p.a. will use the data derived from the clinical study in connection with 
the development of the drug and therefore may transmit this information, if necessary, to other 
Investigators and/or Regulatory Authorities.  
16.6 
Insurance Covering Public Liability 
This study is covered by an insurance policy for the civil liability towards third parties, stipulated 
by Dompé farmaceutici s.p.a. with PRA Health Sciences, which is obliged to provide the 
amounts with the Client is required to pay, as being responsible by law, for reimbursement of 
capital, interest or expenses for any kind of damage caused by the pharmaceutical products, 
whether registered or not, which were administered during the course of clinical trials, in 
hospitals, private clinics and health professionals for clinical trials and experimentation, as well 
as for the damage caused following administration for pharmacological research and 
experiments with drugs and pharmacological formulations already registered in Italy and/or 
abroad, but with a different dosage from the one indicated by the Pharmaceutical Manufacturer, 
or with new drugs under evaluation, as well as for all the activities pertaining to or connected 
with the experimentation itself, such as, the technical administration of the drugs and the 
withdrawal of blood from patients participating in the study.  
This insurance is valid also for:  
 Responsibilities which may derive from the Investigators/Monitors, on the basis of 
experimentation conducted upon request of the Insured entity;  
 Any responsibility for which the Insured entity is called upon to answer by law, 
regulation, internal requirements, standard procedures or methods.  
16.7 
Financing of the Study 
The financial aspects of this study are described in detail in the contract between, or on behalf 
of  Dompé farmaceutici s.p.a. and the Institution/s involved in this study. Financial Disclosure 
Statements will need to be completed, as requested by FDA CFR 21 part 54. 
 
17 
RESPONSIBILITIES OF THE INVESTIGATOR 
The Investigator is aware of his/her responsibility towards Dompé farmaceutici s.p.a. for all the 
actions delegated by him/her to other members of his/her staff assigned to the conduct of the 
study. Except where specifically required, the wording "Investigator" used in this protocol and 
in the CRF, refers to the Investigator or the qualified person designated by him/her, who may 
carry out activities relevant to the clinical trial and sign the study documents on his/her behalf. 
The Investigator is obliged to conduct the study in compliance with the study protocol and in 
adherence to GCP (ICH E6) and with the principles of the Declaration of Helsinki (1964) and 
subsequent revisions (Appendix 1) as well as in respect of applicable legislation. 
18 
FINAL STUDY REPORT 
The Final Clinical Report will be written by PRA Health Sciences and then approved by Dompé 
farmaceutici s.p.a., and the Principal Investigator. It will be structured as an Integrated Clinical 
Report containing clinical comments based on the data generated by the Statistical Analyses. It 
will be written in compliance with the ICH E3 guideline for both content and format. 


 
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19 
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Palmieri, C., Krell, J., & James, C. (2010, October). Rechallenging with Anthracyclines and 
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Monitoring Committees. March 2006 
20 
APPENDICES 
 
Appendix 1 
 
Declaration of Helsinki 
Appendix 2 
 
Performance Status Scale: Zubrod/ECOG 
Appendix 3 
 
Common Terminology Criteria for Adverse Events (CTCAE version 4.03)  


 
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Appendix 4 
 
Response Criteria (RECIST) version 1.1 
Appendix 5 
 
Reparixin and placebo Description and Composition 
Appendix 6 
 
Reparixin and placebo packaging and labeling details 
Appendix 7 
 
Paclitaxel Package Insert 
Appendix 8 
 
Safety Details  
Appendix 9 
 
CYP2C9 Inducers and Inhibitors 
Appendix 10  
Acceptable methods of birth control 
 
 


 
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Appendix 1 - Declaration of Helsinki 
The World Medical Association Declaration of Helsinki—Ethical Principles for Medical Research 
Involving Human Subjects--can be accessed via the following link:  
http://www.wma.net/en/30publications/10policies/b3/ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 2 - Performance Status Scale: Zubrod/ECOG 
 
0 = Fully active; no performance restrictions 
1 = Strenuous physical activity restricted; fully ambulatory and able to carry out light work 
2 = Capable of all self-care but unable to carry out any work activities. Up and about >50 percent of 
waking hours 
3 = Capable of only limited self-care; confined to bed or chair >50 percent of waking hours 
4 = Completely disabled; cannot carry out any self-care; totally confined to bed or chair 
 
Oken, MM, et al. Am J Clin Oncol 1982; 5:649. 


 
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Appendix 3 - Common Terminology Criteria for Adverse Events (CTCAE) version 4.03  
 
The CTCAE version 4.03 can be accessed via the following link:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 
 
 
 


 
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Appendix 4 - Response Criteria (RECIST) Version 1.1 
 
Response evaluation criteria using RECIST version 1.1. The full article can be accessed from the 
following link:  
http://www.eortc.be/recist/ 
 
 


 
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Appendix 5 - Reparixin and Placebo Description and Composition 
 
Description and Composition of the Drug Product and placebo 
 
The drug product consists of immediate release tablets for oral administration containing 600 mg of DF 
1681Y (Reparixin).  
The composition of the tablets  is reported in the two tables below along with information on the function 
and quality standard of each ingredient.  
Tablets are packaged in white PVDC/PE/PVC/Aluminum blisters and should be stored at temperature 
not higher than 30°C. 
 
Composition of DF1681Y tablet 
Names 
of 
ingredients 
Formula 
% 
Function 
of 
ingredient 
Reference  to quality  
standards 
 
Reparixin 
(DF 1681Y) 
66.67% 
Drug substance 
Internal monograph 
Cellulose 
Microcrystalline 
15.72 
Diluent/ 
Disintegrant 
Eur. Ph/USP. 
Lactose monohydrate 10.53 
Diluent 
Eur. Ph./USP 
Croscarmellose 
Sodium 
4.0 
Disintegrant 
Eur. Ph./USP 
Hydroxypropyl 
cellulose  
2.23 
Binder 
Eur. Ph. 
Colloidal 
silicon 
dioxide 
0.35 
Glidant  
Eur. Ph./USP 
Magnesium stearate 
0.50 
Lubricant 
Eur. Ph. 
Total 
100% 
- 
- 
 
 
Composition of placebo tablet 
Names 
of 
ingredients 
Formula 
% 
Function 
of 
ingredient 
Reference  to quality  
standards 
 
Reparixin 
(DF 1681Y) 
--- 
Drug substance 
Internal monograph 
Cellulose 
Microcrystalline 
47.42 
Diluent/ 
Disintegrant 
Eur. Ph./USP 
Lactose monohydrate 43.27 
Diluent 
Eur. Ph./USP 


 
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Page 71 of 79 
Croscarmellose 
Sodium 
4.0 
Disintegrant 
Eur. Ph./USP 
Hydroxypropyl 
cellulose  
4.46 
Binder 
Eur. Ph. 
Colloidal 
silicon 
dioxide 
0.35 
Glidant  
Eur. Ph./USP 
Magnesium stearate 
0.50 
Lubricant 
Eur. Ph. 
Total 
100% 
- 
- 
 
 
 


 
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REP0114 
 
 
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Dompé Farmaceutici s.p.a.  
Page 72 of 79 
Appendix 6 - Reparixin and placebo packaging and labeling details 
 
Patient Kits will be identified with a PATIENT Kit No. which is allocated by the IRT system at study 
enrolment and every  treatment cycle thereafter. Each kit consists of 1 box  containing 9 blisters of 15 
tablets each, for a total of 135 tablets  (126 tablets for each treatment cycle, with 9 tablets overage). 
sufficient for one treatment cycle.    
The labels  will have  a Multilanguage  format.  The template of the English label is provided 
below.  Label content will be adjusted to meet local regulatory requirements.     
NOTE: Patient Kit No. XXXXXX is allocated by the IRT system 
 
 
A: PRIMARY PACKAGING 
 
Specimen Label for each blister 
Sponsor Dompé farmaceutici s.p.a.        STUDY REP0114 CRO: 
PRA Health Sciences              coded BATCH No. 
 
 
PATIENT Kit No. XXXXXX 
 
 
For clinical trial use only. Keep out of reach of children. 
USA only Caution:  New Drug-Limited by Federal law to 
investigational use. 
 
 
 
B: SECONDARY PACKAGING 
 
Specimen Label for each Patient Treatment Cycle Box [multilanguage booklet label] 
STUDY REP0114             Sponsor Dompé farmaceutici s.p.a.; Via S. Lucia 6, Milano – Italy  
                                                       Tel +39 02 58383.1 
                                       CRO PRA Health Sciences 
 
PATIENT Kit No. XXXXXX  
 
(contains one treatment cycle) 
 
 
  
INVESTIGATIONAL PRODUCT: reparixin (600 mg) or placebo oral tablets 
 
CONTAINS: 9 BLISTERS OF 15 TABLETS EACH; TOTAL 135 TABLETS 
 
coded BATCH No. 
coded EXPIRY DATE mm/yyyy 
DO NOT STORE AT >30°C 
 
 
DO NOT FREEZE 
 
 
 
 
 
 
 
 
 
 
 
DIRECTIONS: Take the drug three times a day (2 tablets every 6-10 hours) for 21 consecutive days. 
See additional instructions in the Diary Card.  
 
Contact the Investigator should you have any questions. 
 
For clinical trial use only. Keep out of reach of children. 
USA only Caution:  New Drug-Limited by Federal law to investigational use.  
 
 


 
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                                                                                                                   Final Version 9.0 – 25 November 2019  
Dompé Farmaceutici s.p.a.  
Page 73 of 79 
Appendix 7 - Paclitaxel Package Insert 
 
Paclitaxel package insert can be accessed via the link below:  
 
Taxol - FDA prescribing information, side effects and uses 
 
 
 
 


 
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Dompé Farmaceutici s.p.a.  
Page 74 of 79 
Appendix 8 - Safety Details  
Summary of Adverse Drug Reactions (ADRs) – I.V. Formulation 
Number of Reports by Terms 
Frequency 
MedDRA Body System / LLT ADR term 
Non Serious 
Serious 
Blood and lymphatic system disorders 
3 
2 
4.30% 
 
 
Anaemia  
2 
1 
 
 
 
Coagulopathy 
  
1 
 
 
 
Lymphadenopathy 
1 
  
 
Cardiac Disorders 
1 
0 
0.9% 
 
 
Tachycardia 
1 
  
 
Gastrointestinal Disorders 
22 
3 
21.7.% 
 
 
Abdominal pain NOS 
 
 
Dyarrhea 
1 
1 
  
 
 
 
Dyspepsia 
1 
  
 
 
 
Flatulence 
2 
  
 
 
 
Gastroesophageal reflux disease 
 
 
Gastrointestinal haemorrhage 
1 
 
 
1 
 
 
 
Nausea 
11 
1 
 
 
 
Vomiting 
5 
1 
 
General disorders and administration site conditions 
22 
0 
19.1% 
 
 
Cannula site reaction 
13 
  
 
 
 
Fatigue 
1 
  
 
 
 
Injection site thrombosis 
3 
  
 
 
 
Infusion site oedema 
2 
  
 
 
 
Lethargy 
 
 
Oedema 
1 
1 
  
 
 
 
Oedema peripheral 
1 
  
 
Immune system disorders 
0 
1 
0.9% 
 
 
Lung transplant rejection  
  
1 
 
Injury, poisoning and procedural complications 
1 
1 
1.7% 
 
 
Complications of transplanted kidney 
 
 
Drug Administration Error 
1 
 
1  
 
Investigations 
2 
0 
1.7% 
 
 
Blood amylase increased 
1 
  
 
 
 
Liver function test abnormal 
1 
  
 
Metabolic and nutrition disorders 
1 
0 
0.9% 
 
 
Hyperkalaemia 
1 
  
 
Musculoskeletal and connective tissue disorders 
1 
0 
0.9% 
 
 
Arthralgia 
1 
  
 
Nervous system disorders 
25 
0 
21.7% 
 
 
Dizziness 
3 
  
 
 
 
Headache 
8 
  
 
 
 
Hypoaesthesia 
3 
  
 
 
 
Somnolence 
11 
  
 
Psychiatric disorders 
4 
0 
3.5% 
 
 
Abnormal dream 
1 
  
 
 
 
Restlessness 
1 
  
 
 
 
Euphoric mood 
2 
  
 
Renal and urinary disorders 
4 
0 
3.50% 
 
 
Renal failure 
1 
  
 
 
 
Renal tubular necrosis 
2 
  
 
 
 
Urinary retention 
1 
  
 
Respiratory, thoracic and mediastinal disorders 
6 
1 
6.1% 
 
 
Bradypnoea 
1 
  
 
 
 
Cough 
2 
  
 
 
 
Nasopharyngitis 
2 
  
 
 
 
Respiratory failure 
  
1 
 
 
 
Sore throat 
1 
  
 
Skin and subcutaneous system disorders 
9 
0 
7.8% 
 
 
Erythema 
6 
  
 
 
 
Infusion site erythema 
2 
  
 
 
 
Pruritis 
1 
  
 
Vascular disorders 
3 
3 
5.2% 
 
 
Haemorrhage 
  
1 
 
 
 
Hypotension 
3 
  
 
 
 
Retroperitoneal heamorrhage 
  
2 
 
TOTAL 
104 
11 
 
Table does not include ADRs reported from on-going studies 
 


 
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Page 75 of 79 
Summary of Adverse Drug Reactions (ADRs) – Oral Formulation 
Number of Reports by Terms 
N=207 events* 
Non-serious ADRs 
Serious ADRs 
Total 
 
MedDRA Body System/ADR 
Preferred   Term 
CTCAE 
Grade 1 
n (%) 
CTCAE 
Grade 2 
n (%) 
CTCAE 
Grade 3 
n (%) 
CTCAE 
Grade 4 
n (%) 
All CTCAE 
grades  
N (%) 
 
Blood and Lymphatic System 
Disorders 
2 (0.09%) 
3 (1.4%) 
3 (1.4%) 
0 (0%) 
0 (0%) 
8 (3.8%) 
  Anaemia 
1 
2 
1 
0 
0 
4 
  Neutrophil count 
decreased 
0 
1 
2 
0 
0 
3 
  Thrombocytopenia 
1 
0 
0 
0 
0 
1 
Cardiac Disorders 
1 (0.5%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
1 (0.5%) 
  Palpitations 
1 
0 
0 
0 
0 
1 
Eye Disorders 
0 (0%) 
0 (0%) 
1 (0.5%) 
0 (0%) 
0 (0%) 
1 (0.5%) 
  Ulcerative keratitis 
0 
0 
1 
0 
0 
1 
General Disorders and 
Administration Site Conditions 
39 (18.8%) 
13 (6.3%) 
0 (0%) 
0 (0%) 
0 (0%) 
52 (25.1%) 
  Chest discomfort 
2 
0 
0 
0 
0 
2 
  Fatigue 
20 
11 
0 
0 
0 
31 
  Asthenia 
0 
1 
0 
0 
0 
1 
  Feeling abnormal 
1 
0 
0 
0 
0 
1 
  Pain 
1 
0 
0 
0 
0 
1 
  Peripheral Oedema 
11 
1 
0 
0 
0 
12 
  Face oedema 
3 
0 
0 
0 
0 
3 
  Pyrexia 
1 
0 
0 
0 
0 
1 
Gastrointestinal Disorders 
73 (35.3%) 
9 (4.3%) 
0 (0%) 
0 (0%) 
0 (0%) 
82 (39.6%) 
  Abdominal distension 
5 
1 
0 
0 
0 
6 
  Abdominal discomfort 
4 
0 
0 
0 
0 
4 
  Abdominal pain 
3 
0 
0 
0 
0 
3 
  Constipation  
5 
3 
0 
0 
0 
8 
  Diarrhoea 
2 
0 
0 
0 
0 
2 
  Dry mouth 
1 
0 
0 
0 
0 
1 
  Dyspepsia 
7 
1 
0 
0 
0 
8 
  Dysphagia 
1 
0 
0 
0 
0 
1 
  Epigastric discomfort 
1 
0 
0 
0 
0 
1 
  Eructation 
3 
0 
0 
0 
0 
3 
  Flatulence 
7 
0 
0 
0 
0 
7 
  Gastroesopageal reflux 
disease 
2 
0 
0 
0 
0 
2 
  Gastrointestinal disorder 
0 
1 
0 
0 
0 
1 
  Headache 
2 
0 
0 
0 
0 
2 
  Lip pain 
1 
0 
0 
0 
0 
1 
  Nausea 
16 
2 
0 
0 
0 
18 
  Proctalgia 
1 
0 
0 
0 
0 
1 
  Stomatitis 
1 
1 
0 
0 
0 
2 
  Upper abdominal pain 
1 
0 
0 
0 
0 
1 
  Vomiting 
10 
0 
0 
0 
0 
10 
Infections and Infestations 
0 (0%) 
4 (1.9%) 
0 (0%) 
0 (0%) 
0 (0%) 
4 (1.9%) 
  Cellulitis 
0 
1 
0 
0 
0 
1 
  Herpes dermatitis 
0 
1 
0 
0 
0 
1 
  Upper Respiratory tract 
infection 
0 
1 
0 
0 
0 
1 
  Urinary tract infection 
0 
1 
0 
0 
0 
1 
Injury, Poisoning, and Procedural 
Complications 
0 (0%) 
1 (0.5%) 
0 (0%) 
0 (0%) 
0 (0%) 
1 (0.5%) 
  Infusion related reaction 
0 
1 
0 
0 
0 
1 
Investigations 
10 (4.8%) 
1 (0.5%) 
0 (0%) 
0 (0%) 
0 (0%) 
11 (5.3%) 
  Alanine aminotransferase 
increased 
2 
1 
0 
0 
0 
3 
  Aspartate 
aminotransferase increased 
2 
0 
0 
0 
0 
2 
  Blood calcium decreased 
1 
0 
0 
0 
0 
1 
  Weight decreased  
3 
0 
0 
0 
0 
3 
  White blood cell count 
decreased 
2 
0 
0 
0 
0 
2 
Metabolism  
7 (3.4%) 
3 (1.4%) 
0 (0%) 
0 (0%) 
0 (0%) 
10 (4.8%) 
  Hypercalcaemia 
1 
0 
0 
0 
0 
1 
  Decreased appetite 
6 
3 
0 
0 
0 
9 


 
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Page 76 of 79 
Safety details are updated annually in section 6.2 of Investigator’s Brochure.  
 
 
 
 
Musculoskeletal 
3 (1.4%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
3 (1.4%) 
  Arthralgia 
1 
0 
0 
0 
0 
1 
  Joint swelling 
1 
0 
0 
0 
0 
1 
  Pain 
1 
0 
0 
0 
0 
1 
Nervous System Disorders 
12 (5.8%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
12 (5.8%) 
  Dizziness 
2 
0 
0 
0 
0 
2 
  Dysgeusia 
2 
0 
0 
0 
0 
2 
  Headache 
4 
0 
0 
0 
0 
4 
  Peripheral motor 
neuropathy 
1 
0 
0 
0 
0 
1 
  Peripheral neuropathy 
2 
0 
0 
0 
0 
2 
  Sinus headache 
1 
0 
0 
0 
0 
1 
Reproductive System and Breast 
Disorders 
1 (0.5%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
1 (0.5%) 
  Pelvic pain 
1 
0 
0 
0 
0 
1 
Respiratory, Thoracic and 
Mediastinal disorders 
13 (6.3%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
13 (6.3%) 
  Cough 
4 
0 
0 
0 
0 
4 
  Dysphonia 
1 
0 
0 
0 
0 
1 
  Dyspnoea 
3 
0 
0 
0 
0 
3 
  Epistaxis 
2 
0 
0 
0 
0 
2 
  Nasal congestion 
1 
0 
0 
0 
0 
1 
  Nasal dryness 
1 
0 
0 
0 
0 
1 
  Pneumonitis 
1 
0 
0 
0 
0 
1 
Skin and Subcutaneous Tissue 
Disorders 
7 (3.4%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
7 (3.4%) 
  Alopecia 
2 
0 
0 
0 
0 
2 
  Erythema 
1 
0 
0 
0 
0 
1 
  Palmar erythema 
1 
0 
0 
0 
0 
1 
  Rash 
2 
0 
0 
 
0 
2 
  Skin hyperpigmentation 
1 
0 
0 
0 
0 
1 
Surgical and medical 
1 (0.5%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
1 (0.5%) 
  Sinus operation 
1 
0 
0 
0 
0 
1 
Total 
169 (82%) 
34 
(16%) 
4 
(2%) 
0  
(0%) 
0 
(0%) 
207 
*ADRs continuing across more than one treatment cycle without complete resolution and reported more than once in CRF to reflect changes in 
CTCAE grade, will be reported in this table as single ADRs with worst CTCAE grade. ADRs occurring more than once per patient but not 
continuing (i.e. with clear break between one occurrence and the next) will be reported in this table as separate ADRs.  


 
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                                                                                                                   Final Version 9.0 – 25 November 2019  
Dompé Farmaceutici s.p.a.  
Page 77 of 79 
Appendix 9 – CYP2C9 Inducers and Inhibitors 
 
The following medications should NOT be administered to study subjects during trial 
participation as reparixin is metabolized by CYP2C9. 
 
CYP2C9 Inducers: rifampin, carbamezapine, aprepitant, bosentan, phenobarbital, St. John’s 
Wort;  
 
CYP2C9 Inhibitors: amiodarone, fluconazole, miconazole, oxandrolone, capecitabine, 
cotrimoxazole, etravirine, fluvastatin, fluvoxamine, metronidazole, sulfinpyrazone, tigecycline, 
voriconazole, zafirlukast 
 
 


 
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                                                                                                                   Final Version 9.0 – 25 November 2019  
Dompé Farmaceutici s.p.a.  
Page 78 of 79 
Appendix 10 – Acceptable methods of birth control 
 
Birth control methods which may be considered as highly effective 
Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly 
are considered as highly effective birth control 
methods.  
Such methods include: 
 
combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
- oral 
- intravaginal 
- transdermal 
 
progestogen-only hormonal contraception associated with inhibition of ovulation: 
- oral 
- injectable 
- implantable1 
 
intrauterine device (IUD)1 
 
intrauterine hormone-releasing system ( IUS)1 
 
bilateral tubal occlusion1 
 
vasectomised partner 1,2 
 
sexual abstinence 3 
___________________________________________________________________________ 
1 Contraception methods that are considered to have low user dependency. 
2 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner 
of the Women of childbearing potential (WOCBP) trial participant and that the vasectomised partner has received medical assessment of the 
surgical success. 
3 sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse  
during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
 
 


 
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Page 79 of 79 
 
Acceptable  birth  control  methods  which  may  not  be  considered  as  highly effective 
 
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
 progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
 male or female condom with or without spermicide 4 
 cap, diaphragm or sponge with spermicide 4 
___________________________________________________________________________________ 
4 A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) 
are also considered acceptable, but not highly effective, birth control methods 
 
 

SAP_001.pdf: 
Final Clinical Study Report 
REP0114 
Confidential
Reparixin 
 
 
 
 
Documentation of Statistical Methods 
The following document is provided in this appendix: 
Statistical Analysis Plan 
Date 
Statistical Analysis Plan 
30 May 2019 
1


2
*PRAHEALTHSCIENCES 
Sponsor: Dompe Farmaceutici s;p,a 
Statistical AnalysisPlan 
Effective Date: .30 l\llil.y 20 l 9Nersion 2 
ProtocolNo. REP0114 
Statistic3I Analy$is _Plan 
S onsor: 
Protocol No: 
Protocol Version/ 
Date: 
Title 
CRF Version No./ . 
Date 
PRA Project ID: 
SAP Version No. / 
Date: 
APPROVALS 
Sponsor Representative 
Name / Title: 
Signature / Date: 
Sponsor Representative 
Name I Title: 
Signature / Date: 
PRA 
Project Manager: 
Signature / Date: 
Biostatistician / Title: 
Signature / Date: 
.a. 
REP0114 
Final Version7.0/01-Dec-2017 
A randomized, double-blind, placebo-controlled phase 2 study of 
paclitaxel in combination with reparixin compared to paclitaxel alone 
as front-line ther~py for Metastatic Triple-Negative Breast Cancer 
(FRIDA) 
6.1 /Q7-May-20-18 
DGEREP14-REP114 
2 I 30 May 2019 
Susan Mccanna /Ciinical _Dev~lopment Manager 
Pier Adelchi Ruffini/ Oncology Development Director 
Tatjana Stoever / Project Manager 
Kelly Guivet/ Principal Biostatistician 


Statistical Analysis Plan 
Effective Date: 30 May 2019/Version 2  
 
Sponsor: Dompé Farmaceutici s.p.a 
Protocol No. REP0114 
2 
 
TABLE OF CONTENTS 
Approvals ....................................................................................................................................... 1 
Table of Contents .......................................................................................................................... 2 
1. 
Introduction ........................................................................................................................... 4 
2. 
Study Objectives .................................................................................................................... 4 
3. 
Study Design........................................................................................................................... 5 
3.1 
Design Overview .............................................................................................................. 5 
3.2 
Randomization ................................................................................................................. 8 
3.3 
Sample Size Considerations ............................................................................................. 8 
4. 
Study Variables ...................................................................................................................... 9 
4.1 
Primary Variable .............................................................................................................. 9 
4.2 
Secondary and Exploratory Variables .............................................................................. 9 
4.2.1 
Efficacy Variables ....................................................................................................... 9 
4.2.2 
Safety Variables .......................................................................................................... 9 
4.2.3 
Exploratory Variables ................................................................................................. 9 
5. 
Definitions ............................................................................................................................ 10 
6. 
Analysis Populations ........................................................................................................... 18 
6.1 
Intent-to-Treat Population .............................................................................................. 18 
6.2 
Response Evaluable Population ..................................................................................... 18 
6.3 
Safety Population ........................................................................................................... 18 
7. 
Interim Analysis and reporting milestones ....................................................................... 18 
7.1 
INTERIM ANALYSIS .................................................................................................. 18 
7.2 
REPORTING MILESTONES ....................................................................................... 18 
7.2.1 
Primary Analysis Reporting ...................................................................................... 18 
7.2.2 
Follow-up Analysis Reporting .................................................................................. 19 
8. 
Data Management ............................................................................................................... 19 
8.1 
Data Handling and Transfer ........................................................................................... 19 
8.2 
Data Screening ............................................................................................................... 19 
9. 
Statistical Methods .............................................................................................................. 20 
9.1 
Patient Disposition ......................................................................................................... 20 
9.2 
Protocol Deviations ........................................................................................................ 20 
9.3 
Treatments ...................................................................................................................... 21 
9.3.1 
Extent of Study Drug Exposure ................................................................................ 21 
9.3.2 
Concomitant Medications and Concomitant Therapies ............................................ 21 
9.4 
Demographic and Baseline Characteristics .................................................................... 21 
9.5 
Pooling of Sites .............................................................................................................. 21 
3


Statistical Analysis Plan 
Effective Date: 30 May 2019/Version 2  
 
Sponsor: Dompé Farmaceutici s.p.a 
Protocol No. REP0114 
3 
 
9.6 
Efficacy Analysis ........................................................................................................... 21 
9.6.1 
Primary Efficacy Analysis ........................................................................................ 21 
9.6.2 
Secondary Efficacy Analysis .................................................................................... 24 
9.6.3 
Exploratory Analysis ................................................................................................ 26 
9.6.4 
Sub–group Analyses ................................................................................................. 26 
9.7 
Safety Analyses .............................................................................................................. 27 
9.7.1 
Adverse Events ......................................................................................................... 27 
9.7.2 
Serious Adverse Events ............................................................................................ 28 
9.7.3 
Laboratory Data ........................................................................................................ 28 
9.7.4 
Vital Signs ................................................................................................................. 29 
9.7.5 
Physical Examinations and Electrocardiograms ....................................................... 29 
10. Handling of Missing Data ................................................................................................... 30 
10.1 
Tumor data ..................................................................................................................... 30 
10.2 
survival data ................................................................................................................... 30 
10.3 
AE Date Imputation ....................................................................................................... 30 
10.4 
Incomplete Date for concomitant medication ................................................................ 32 
11. Validation ............................................................................................................................. 33 
12. References ............................................................................................................................ 33 
13. Appendix 1: Glossary of Abbreviations ............................................................................ 34 
14. Appendix 2: List of In-Text Tables, Figures, and Listings .............................................. 36 
15. Appendix 3: Shells for In-Text Tables, Figures, and Listings ......................................... 36 
16. Appendix 4: List of Post-Text Tables, Figures, and Listings .......................................... 36 
17. Appendix 5: Shells for Post-Text Tables, Figures, and Listings ..................................... 36 
 
 
4


Statistical Analysis Plan 
Effective Date: 30 May 2019/Version 2  
 
Sponsor: Dompé Farmaceutici s.p.a 
Protocol No. REP0114 
4 
 
1. INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under Dompé Farmaceutici s.p.a. Protocol No. 
REP0114.  
This SAP should be read in conjunction with the study protocol and case report forms (CRF). 
This version of the plan has been developed using the protocol final version 7.0 dated 01 Dec 
2017 and CRF version 6.1 dated 07 May 2018. Any further changes to the protocol or CRF may 
necessitate updates to the SAP. In the case of discrepancies between the SAP and the study 
protocol, the SAP will take precedence over the study protocol. 
The SAP is to be developed in two stages. The purpose is to “finalize” a SAP so that 
programming can begin earlier in the process. Versions of the SAP up to initial sponsor approval 
will be known as SAP1. Changes following approval of SAP1 will be tracked in the SAP Change 
Log and a final version of the SAP, known as SAP2, will be issued for sponsor approval prior to 
database lock. 
2. STUDY OBJECTIVES 
Primary Objective 
 
The primary objective of the study is to evaluate Progression-Free Survival (PFS) (defined as the 
the number of days between the date of randomization and the date of clinical disease 
progression (PD) according to RECIST criteria version 1.1,  as assessed by Independent 
Radiology Review, or death for any cause, whichever occurs first) in patients with metastatic 
triple negative breast cancer (TNBC) treated with the combination of paclitaxel and orally 
administered reparixin compared to paclitaxel alone.  
 
Secondary Objectives 
 
• 
To determine Overall Survival (OS) 
• 
To evaluate Objective Response Rates (ORR) 
• 
To determine median PFS (mPFS To assess the safety of the combination of paclitaxel 
and orally administered reparixin (referred to as combination treatment)). 
 
Exploratory Objectives 
 
• 
To determine median Time To New Metastasis (TTM) (new lesions at existing or new 
sites) 
• 
To determine proportion of patients progressing with new metastatic lesions 
• 
To compare the incidence and severity of peripheral neuropathy between the two 
treatment groups 
• 
Evaluation of Cancer Stem Cells (CSCs) in metastatic tissue. 
5


Statistical Analysis Plan 
Effective Date: 30 May 2019/Version 2  
 
Sponsor: Dompé Farmaceutici s.p.a 
Protocol No. REP0114 
5 
 
3. STUDY DESIGN 
3.1 DESIGN OVERVIEW 
This is a two arm, phase 2 study to evaluate the efficacy of the combination of paclitaxel and 
reparixin compared to paclitaxel and placebo in metastatic TNBC patients.  
Patients will be assessed for eligibility and will have the following procedures done: medical 
history, physical examination, laboratory assessments, chest x-rays and/or computed tomography 
(CT) scans, including a CT scan or magnetic resonance imaging (MRI) of the brain. A sample of 
tumor tissue will be collected for analysis. 
There will be two groups:  
Group 1: 
paclitaxel 80 mg/m2 intravenous (i.v.) (Days 1, 8, and 15 of 28-day cycle) + 
reparixin oral tablets 1200 mg t.i.d. continuing from Day 1 to Day 21 
Group 2: 
paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15 of 28-day cycle) + placebo oral tablets 
1200 mg t.i.d. continuing from Day 1 to Day 21 
Study drug (reparixin/placebo) will be administered orally every six to ten hours t.i.d. for 21 
consecutive days during each cycle with seven days off treatment between each cycle. 
 
 
Paclitaxel will be administered in combination with study drug (reparixin/placebo) as an i.v. 
infusion on Days 1, 8, and 15 of each 28-day cycle. 
Combination treatment will continue until disease progression according to Response Evaluation 
Criteria in Solid Tumors (RECIST) criteria version 1.1, withdrawal of consent, or unacceptable 
toxicity, whichever occurs first. 
Tumor response and/or progression assessments will be performed and documented every 8 
weeks according to RECIST criteria version 1.1. 
Metastatic tissue samples will be analyzed for evaluation of CD24-CD44+ and ALDH+ CSCs. 
It is planned that approximately 60 centers located in the USA and Europe will participate in the 
study. 
During study participation and while the patient is receiving study treatment, the patient will 
continue to be followed with physical examinations, review of concomitant medications and 
adverse events (AEs), laboratory assessments, and scans (CT, MRI, etc.). The patient will also 
complete a diary to record intake of study medication. 
After completion of study treatment, the patient will be followed for 30 days to assess safety and 
then followed every 3 months for 1 year thereafter to assess disease status, new treatments, and 
survival status. 
Please refer to Table 1 Study Flow Chart for full details on the schedule of assessments. 
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Statistical Analysis Plan 
Effective Date: 30 May 2019/Version 2  
 
Sponsor: Dompé Farmaceutici s.p.a 
Protocol No. REP0114 
6 
 
Table 1.  Study Flow Chart 
 
Procedure 
Pre-Study1 
Treatment Cycles14 
OTV15 
Long 
term 
Follow 
up16 
D1 
D8 
D15 
D21 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
Demographic data/tumor 
characteristics 
X 
 
 
 
 
 
 
Tumor history surgery, 
radiotherapy, systemic 
therapies 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Disease status 
X2,3 
Every 8 weeks4 
X3 
 
Physical examination 
X 
X5 
 
 
 
X 
 
Vital signs (BP, pulse)6 
 
X 
 
 
 
X 
 
Chest X-ray (if not already 
performed to follow tumor. 
Thoracic CT scan may 
substitute chest X-ray ) 
X 
 
 
 
 
X 
 
ECG 
X 
 
 
 
 
 
 
Zubrod Performance Status  
X 
 
 
 
 
X 
 
Urinalysis 
X7 
As clinically indicated 
X7 
 
Hematology 
X8 
X8 
X8 
X8 
 
X8 
 
Clinical chemistry 
X9 
X9 
 
 
 
X9 
 
D1 = Day 1 etc, OTV = off-treatment visit 
 
1  
All pre-study examinations should be performed within 14 days (± 1day window) of beginning study treatment unless 
otherwise specified. Informed consent should be signed before any study specific procedures are performed (with the exception of 
routine laboratory tests). 
2  
Pre-study disease evaluation should be obtained within 28 days of study treatment initiation. 
3 
Disease evaluations and a brain CT or MRI will be performed at pre-study. The scans (with exception of brain scans) will be 
repeated every eight weeks until documented PD. A brain scan will be repeated if patient presents with symptoms of brain 
metastases or progressive disease of baseline lesions. At study end, a Best Overall Response (BOR) assessment will be made: 
the disease assessments do not need to be repeated if done within four weeks prior to the off-treatment visit. Copies of all scans 
(CT, MRI of chest, abdomen, pelvis etc.) will be submitted to the central radiology vendor for review at each time point. 
4   
For tumor assessment (i.e. scans) beginning at Week 8, a ± 3-day window will be allowed. 
5 
Physical examination, including weight will be performed at pre-study and Day 1 of each cycle beginning with cycle 2. 
Pretreatment signs and symptoms, height, and BSA will also be collected at the pre-study visit only. 
6 
Vital signs must be performed within 24 hours prior to the first study drug (reparixin/placebo) administration, and then on 
Day 1 of subsequent cycles. 
7  
pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, leukocytes and urobilinogen (by dipstick or in 
laboratory) at pre-study, as clinically indicated, and at off-treatment visit. Laboratory tests performed within 14 days screening period 
even if before ICF signed are acceptable. 
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Statistical Analysis Plan 
Effective Date: 30 May 2019/Version 2  
 
Sponsor: Dompé Farmaceutici s.p.a 
Protocol No. REP0114 
7 
 
8 
Hematology tests: hemoglobin, white blood cell (WBC) and differential WBC, platelets at pre-study and on Days 1, 8 and 15 of 
each cycle and at the off-treatment visit. Routine laboratory tests performed within 14 days screening period even if before 
ICF signed are acceptable. 
9 
Clinical chemistry tests: sodium, potassium, calcium, serum creatinine, total protein, albumin, asparate aminotransferase 
(AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), urea, total bilirubin at pre-study, on Day 1 of treatment 
cycles and as clinically indicated and at the off-treatment visit (OTV). Laboratory tests performed within 14 days screening 
period even if before ICF signed are acceptable. 
 
 
Procedure 
Pre-Study1 
Treatment Cycles14 
OTV15 
Long 
term 
Follow 
up16 
D1 
D8 
D15 
D21 
 
 
Urine or serum pregnancy 
test 
X10 
X10 
 
 
 
X10 
 
Record concomitant 
treatments 
X 
Throughout study 
X 
 
AE monitoring 
 
Throughout study 
X 
 
Peripheral neuropathy 
monitoring 
X 
Throughout study 
X 
 
Reparixin/Placeboadministr
ation11 
 
Continuously days 1 to 21 
 
 
Paclitaxel administration 
 
X 
X 
X 
 
 
 
Dispense diary card12 
 
X 
 
 
 
Xreview only 
 
Tumor tissue (archival or 
new biopsy)13 
X 
 
 
 
 
 
 
Date of progression and 
documentation of additional 
cancer therapy (if not off 
study due to progressive 
disease) and Survival Status 
 
 
 
 
 
 
X 
 
 
10   
Urine or serum pregnancy test required for women of childbearing potential only 
11 
Study drug (reparixin/placebo) administered orally every 6 to 10 hours t.i.d. for 21 consecutive days during each cycle with 
seven days off treatment between each cycle 
12 
Patients will be given a diary card to record information about date, time, and dose taken. At each scheduled visit before the 
start of a new cycle of dose administration and at OTV, the diary should be reviewed with the patient for completeness. 
13 
Tumor tissue will be sampled within 28 days of study treatment initiation, to confirm recurrence of metastatic breast cancer, 
confirm TNBC, and to conduct the following correlative studies: evaluation of CD24-CD44+CSC, ALDH+CSC. 
14  
 During Cycle 1, a ± 1-day window will be allowed for study visits. After Cycle 1, a ± 2-day window will be allowed for study 
                   visits. 
 
15  
Off-treatment Visit to be performed 14 to 28 days following the last dose of study drug. Patients with ongoing treatment -   
 
 related AEs still present in the 30 days after treatment discontinuation should continue to be followed until recovery or   
                   assessment of chronicity or as instructed by the medical monitor. Patients off treatment without documented progressive  
                   disease should continue to have disease assessments every 8 weeks until progressive disease or another anticancer therapy is  
                   initiated, whichever comes first. 
 
16  
Following PD, survival status will be collected every 3 months until death or until last patient off treatment, whichever occurs 
first. 
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Statistical Analysis Plan 
Effective Date: 30 May 2019/Version 2  
 
Sponsor: Dompé Farmaceutici s.p.a 
Protocol No. REP0114 
8 
 
An independent Data Monitoring Committee (DMC)  is established and is responsible for 
safeguarding the interests of trial participants and for enhancing the integrity and credibility of 
the trial.  The DMC is assessing the safety of the treatments during the trial and is monitoring the 
overall conduct of the clinical trial.  The DMC will provide recommendations to Dompé about 
stopping or continuing the trial.   
 
3.2 RANDOMIZATION 
This is a randomized, double-blind, placebo-controlled phase 2 study. Patients are randomized in 
a 1:1 fashion between paclitaxel and reparixin versus paclitaxel and placebo using an Interactive 
Response Technology (IRT). Randomization is stratified between the two sub-populations, 
newly diagnosed metastatic patients and patients that have relapsed following a prior 
(neo)adjuvant chemotherapy regimen. Patients enrolled under the original Protocol or under 
Protocol Amendment 1 were not subject to stratification and per these versions of the protocol 
are all expected to be relapsed following a prior (neo)adjuvant chemotherapy regimen. 
 
The randomization groups are generated with a computer procedure by the method of randomly 
permuted blocks.  The treatment codes are also accessible to an Independent Statistician (liaison 
between the Contract Research Organization [CRO] database and DMC Biostatistician) who 
generates the reports for the DMC’s evaluation. 
 
3.3 SAMPLE SIZE CONSIDERATIONS 
The trial is designed to provide 80% statistical power to detect an improvement in PFS from 5 
months with paclitaxel monotherapy in patients with metastatic TNBC to 8 months with the 
addition of reparixin, corresponding to a hazard ratio 0.625, when using a logrank statistic 
having (one-sided) 0.025 false positive error rate.  This requires 142 PFS events and the 
approximate sample size will be 156 randomized patients (78 patients per group). 
 
Due to extreme enrollment difficulties during the first 6 months of 2018, enrollment to the study 
was terminated early (30 July 2018) and the final sample size is equal to 123 randomized 
patients. Based on current data, at least 113 out of 123 enrolled patients have had observed PFS 
events. 
 
If an analysis of PFS were to be conducted with 114 PFS events, statistical significance (at the 
level of a one-sided 2.5% false positive error rate) would be achieved with an estimated PFS HR 
< 0.6927. This would correspond approximately to an estimated 2-month improvement in PFS of 
4.5 vs 6.5 months. 
 
The targeted number of PFS events is therefore 114. 
 
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Statistical Analysis Plan 
Effective Date: 30 May 2019/Version 2  
 
Sponsor: Dompé Farmaceutici s.p.a 
Protocol No. REP0114 
9 
 
4. STUDY VARIABLES  
4.1 PRIMARY VARIABLE 
The primary variable of the study is PFS, defined as the time from randomization to first 
documentation of disease progression according to RECIST 1.1, or to death due to any cause, 
whichever occurs first, as assessed by Independent Radiology Review. 
4.2 SECONDARY AND EXPLORATORY VARIABLES 
4.2.1 Efficacy Variables 
Secondary efficacy variables are: 
 
• OS 
• ORR 
• mPFS  
 
4.2.2 Safety Variables 
• Number and percentage of TEAEs, overall and by grade 
• Serious adverse events (SAEs) 
• Fatal AEs 
• Concomitant medications 
• Vital sign parameters (pulse rate, systolic and diastolic blood pressure [BP]) 
• Hematology parameters (hemoglobin, WBC and differential count, and platelets) 
• Clinical chemistry parameters (sodium, potassium, calcium, serum creatinine, total 
protein, albumin, AST, ALT, ALP, urea, and total bilirubin) 
• Urinalysis parameters (pH, specific gravity, protein, glucose, ketones, bilirubin, blood, 
nitrite, leukocytes and urobilinogen (by dipstick  or in laboratory) 
4.2.3 Exploratory Variables 
Exploratory endpoints of this study are:  
 
• Median TTM 
• Proportion of patients progressing with new metastatic lesions 
 
• Extent of peripheral neuropathy 
 
• CSCs in metastatic tissue 
 
Correlative studies performed on paraffin-embedded metastatic tumor tissue: 
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Statistical Analysis Plan 
Effective Date: 30 May 2019/Version 2  
 
Sponsor: Dompé Farmaceutici s.p.a 
Protocol No. REP0114 
10 
 
• CD24-CD44+CSC (by Immunohistochemistry (IHC)) 
• ALDH+CSC (by IHC) 
 
 
5. DEFINITIONS 
Adverse Drug Reaction 
An adverse drug reaction (ADR) is defined as an adverse experience which is reasonably likely 
to have been caused by the drug. Any AE reported in the study having a possible, probable, or 
highly probable relationship to study drug will be considered as an ADR. 
Age 
The following SAS® code will be used to calculate patient age (years): 
Age = floor ((intck(‘month’, birth date, IC date) - (day(IC date) < day(birth date))) / 12), 
where intck is a SAS® function counting integer days, birth date is the database variable 
BRTHDT, and informed consent (IC) date is the database variable INFCDT. In cases where a 
subject rescreened and has more than one date of IC, the later IC date will be used to derive age. 
Baseline, Change from Baseline 
Baseline is defined as the last non-missing value before the initial administration of the study 
drug. 
Change from baseline will be defined as (value at post-baseline visit – value at baseline).  
Post-baseline values for tabulations generally will exclude unscheduled visit values. For tumor 
response evaluations only (investigator and independently assessed), post-baseline values at 
unscheduled visits will be analyzed. For unscheduled visits, the following visit windowing will 
be used. 
Timepoint 
Window 
Target Day 
Cycle 2 Day 1 
Day 2-56 
29 
Cycle 3 Day 1 
Day 57-84 
57 
Cycle 4 Day 1 
Day 85-112 
95 
Cycle 5 Day 1 
Day 113-140 
113 
Cycle 6 Day 1 
Day 141-168 
141 
Cycle 7 Day 1 
Day 169-196 
169 
Cycle 8 Day 1 
Day 197-224 
197 
Cycle 9 Day 1 
Day 225-252 
225 
Cycle 10 Day 1 
Day 253-280 
253 
Cycle 11 Day 1 
Day 281-308 
281 
Cycle 12 Day 1 
Day 309-336 
309 
Cycle 13 Day 1 
Day 337-364 
337 
Cycle 14 Day 1 
Day 365-392 
365 
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Statistical Analysis Plan 
Effective Date: 30 May 2019/Version 2 
Sponsor: Dompé Farmaceutici s.p.a 
Protocol No. REP0114 
11 
Cycle 15 Day 1 
Day 393-420 
393 
Cycle 16 Day 1 
Day 421-448 
421 
Cycle 17 Day 1 
Day 449-476 
449 
Cycle 18 Day 1 
Day 477-504 
477 
Cycle 19 Day 1 
Day 505-532 
505 
Cycle 20 Day 1 
Day 533-560 
533 
Cycle 21 Day 1 
Day 561-588 
561 
Cycle 22 Day 1 
Day 589-616 
589 
Cycle 23 Day 1 
Day 617-644 
617 
Cycle 24 Day 1 
Day 645-672 
645 
Cycle 25 Day 1 
Day 673-700 
673 
If two assessments fall into one window, then the assessment closest to the target day will be 
used for analysis. If two assessments were done on the same day, then the worst response of the 
two will be used for analysis. If one result is NE, NA or Unknown and the other is non-missing, 
then the non-missing value will be used for analysis. If both results are NE, NA or Unknown, 
then NE will be used for analysis. 
Concomitant Medications 
Concomitant medications will be defined as any medications ongoing at the date of first dose of 
the study drug, reparixin/placebo, or with a start date on or after the date of first dose of the study 
drug (but not after the last study drug dose date), or with a stop date on or after the date of the 
first study drug dose.  In the case of missing or partial medication start and end dates, 
medications will be assumed to be concomitant if they could have started or ended between first 
and last study drug dose date. Please follow section 10.2 to impute the missing or partial dates. A 
single medication may be both concomitant and prior. (See prior medications in this section.) 
Concomitant medications will be collected on the concomitant medications page of the CRF and 
are coded using WHO Drug Dictionary version 2014MAR01 DDE (Enhanced).  
Compliance of study drug (Reparixin or Placebo) 
Treatment compliance (%) is defined as (the number of tablets taken divided by the expected 
number of tablets)*100, where number of tablets taken = number of tablets dispensed minus the 
number of tablets returned collected via the Study Drug Accountability CRF page. If number of 
returned tablets is missing, doses will be assumed to follow dose regimen in protocol for that 
visit. Number of tablets expected = 6 tablets / day * 21 days/cycle * number of cycles.  
CTCAE Grading for Laboratory Data 
Laboratory abnormalities will be given a Common Terminology Criteria for Adverse Events 
(CTCAE; Version 4.03) grade for severity (1 = mild, 2 = moderate, 3 = severe, 4 = life-
threatening or disabling) for parameters which only have numeric CTCAE guidelines (i.e., not 
requiring clinical assessments) by programing. Those tests and their grading algorithms are listed 
in the table below:  
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Statistical Analysis Plan 
Effective Date: 30 May 2019/Version 2  
 
Sponsor: Dompé Farmaceutici s.p.a 
Protocol No. REP0114 
12 
 
 
Table 2.  CTCAE Grading for Laboratory Data 
 
Test name 
displayed in 
table  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin  
High 
Increase in > 0 - 2 
gm/dL 
above ULN or 
above baseline if 
baseline is above 
ULN 
Increase in >2 - 4 gm/dL 
above ULN or above 
baseline 
if baseline is above ULN 
Increase in > 4 gm/dL above ULN or 
above baseline if baseline is above ULN 
- 
Hemoglobin  
Low 
(Anemia) 
Hemoglobin (Hgb) 
<LLN - 10.0 g/dL; 
<LLN - 6.2 
mmol/L; <LLN - 
100 g/L 
Hgb <10.0 - 8.0 g/dL; 
<6.2 - 4.9 mmol/L;  
<100 - 80g/L 
Hgb <8.0 g/dL; <4.9 mmol/L; 
<80 g/L; transfusion indicated 
 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Platelet Low 
<LLN - 
75,000/mm3;             
<LLN -75.0 x 
10e9/L 
<75,000 - 50,000/mm3;     
<75.0 - 50.0 x 10e9/L 
<50,000 - 25,000/mm3;                    
<50.0 - 25.0 x 10e9/L 
<25,000/mm3;   
<25.0 x 
10e9/L 
Neutrophil 
Low 
<LLN - 
1500/mm3;                
<LLN - 1.5 x 
10e9/L 
<1500 - 1000/mm3;           
<1.5 - 1.0 x 10e9/L 
<1000 - 500/mm3;                                     
<1.0 - 0.5 x 10e9/L 
<500/mm3;        
<0.5 x 10e9/L 
Lymphocyte 
Low 
<LLN - 800/mm3; 
<LLN - 0.8 x 
10e9/L 
<800 - 500/mm3;               
<0.8 - 0.5 x 10e9/L 
<500 - 200/mm3;                                     
<0.5 - 0.2 x 10e9/L 
<200/mm3;        
<0.2 x 10e9/L 
Lymphocyte 
High 
- 
>4000/mm3 - 
20,000/mm3 
>20,000/mm3 
- 
White blood 
cell Low 
<LLN - 
3000/mm3; <LLN 
- 3.0 × 109/L 
<3000 - 2000/mm3; <3.0 
- 2.0 × 109/L 
<2000 - 1000/mm3; <2.0 - 1.0 × 109 /L 
<1000/mm3;  
<1.0 × 109/L 
Albumin Low 
<LLN - 3 g/dL; 
<LLN - 30 g/L 
<3 - 2 g/dL;  
<30 - 20 g/L 
<2 g/dL; <20 g/L 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
ALP 
High 
>ULN - 2.5 x 
ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
ALT High 
>ULN - 3.0 x 
ULN  
>3.0 - 5.0 x ULN  
>5.0 - 20.0 x ULN  
>20.0 x ULN 
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Statistical Analysis Plan 
Effective Date: 30 May 2019/Version 2  
 
Sponsor: Dompé Farmaceutici s.p.a 
Protocol No. REP0114 
13 
 
AST High 
>ULN - 3.0 x 
ULN  
>3.0 - 5.0 x ULN 
 >5.0 - 20.0 x ULN  
>20.0 x ULN 
Creatinine 
High 
 >1 - 1.5 × 
baseline; >ULN - 
1.5 × ULN 
 >1.5 - 3.0 × baseline; 
>1.5 - 3.0 × ULN 
 >3.0 baseline;  
>3.0 - 6.0 × ULN 
>6.0 x ULN 
Total 
bilirubin 
High                 
>ULN - 1.5 x 
ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
Calcium High 
Corrected serum 
calcium of 
>ULN - 11.5 
mg/dL; >ULN - 
2.9 
mmol/L; Ionized 
calcium >ULN 
- 1.5 mmol/L 
 
Corrected serum 
calcium of 
>11.5 - 12.5 mg/dL; 
>2.9 - 3.1 
mmol/L; Ionized 
calcium >1.5 - 
1.6 mmol/L; 
symptomatic 
 
Corrected serum calcium of 
>12.5 - 13.5 mg/dL; >3.1 - 3.4 
mmol/L; Ionized calcium >1.6 - 
1.8 mmol/L; hospitalization 
indicated 
Corrected 
serum 
calcium of 
>13.5 mg/dL; 
>3.4 mmol/L; 
Ionized 
calcium >1.8 
mmol/L; 
life-
threatening 
consequences 
 
Calcium Low 
Corrected serum 
calcium of 
<LLN - 8.0 
mg/dL; <LLN - 
2.0 
mmol/L; Ionized 
calcium <LLN - 
1.0 mmol/L 
 
Corrected serum 
calcium of 
<8.0 - 7.0 mg/dL; <2.0 - 
1.75 
mmol/L; Ionized 
calcium <1.0 - 
0.9 mmol/L; 
symptomatic 
 
Corrected serum calcium of 
<7.0 - 6.0 mg/dL; <1.75 - 1.5 
mmol/L; Ionized calcium <0.9 - 
0.8 mmol/L; hospitalization 
indicated 
Corrected 
serum 
calcium of 
<6.0 mg/dL; 
<1.5 mmol/L; 
Ionized 
calcium <0.8 
mmol/L; 
life-
threatening 
consequences 
 
Potassium 
Low 
<LLN - 3.0 
mmol/L 
<LLN - 3.0 mmol/L; 
symptomatic; 
intervention indicated 
<3.0 - 2.5 mmol/L; hospitalization 
indicated 
<2.5 mmol/L; 
life-threatenin
g 
consequences 
Potassium 
High 
>ULN - 5.5 
mmol/L 
>5.5 - 6.0 mmol/L 
>6.0 - 7.0 mmol/L; hospitalization 
indicated 
>7.0 mmol/L; 
life-threatenin
g 
consequences 
Sodium Low 
<LLN - 130 
mmol/L 
- 
<130 - 120 mmol/L 
<120 
mmol/L; 
life-threatenin
g 
consequences 
Sodium High 
>ULN - 150 
mmol/L 
>150 - 155 mmol/L 
>155 - 160 mmol/L; hospitalization 
indicated 
>160 
mmol/L; life-
threatening 
consequences 
 
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Statistical Analysis Plan 
Effective Date: 30 May 2019/Version 2  
 
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Protocol No. REP0114 
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*Note: CTCAE grade will be only based on value range in programming. No clinical assessment criteria will be 
used. 
 
Off-Treatment 
A patient who is off treatment will be captured in the Reason Off-Treatment CRF page with a 
Date of Last Dose of Study Medication as well as Reason Off-Treatment.  
Enrolled Patient 
An enrolled patient will be one who signs IC through the registration form.   
Duration of Exposure (days) 
Duration of exposure to study medication (reparixin/placebo) in days will be defined as the (last 
study medication dose date – first study medication dose date + 1). 
Duration of exposure to paclitaxel will be defined as the (last paclitaxel dose date – first 
paclitaxel dose date + 1). 
Total Exposure 
Total exposure to study medication or paclitaxel will be defined as the total mg of study 
medication or paclitaxel taken during the study. 
Total exposure to study medication will be calculated by cycle and overall according to study 
medication administration and study medication diary data. Total exposure to study medication 
will be calculated as [ (total # of tablets dispensed - total # of tablets returned) * 600 mg/tablet]. 
Any subject that does not return the dispensed randomized study medication kit for the pill count 
will be assumed for exposure and compliance (see definition of compliance in this section) 
calculation purposes to have taken the required number of pills corresponding to the number of 
days the subject was on study after the last dispensation. 
Total exposure to paclitaxel will be calculated as sum of total dose administered in mg for each 
cycle (by cycle) or across all cycles (overall). 
Geometric Coefficient of Variation 
The geometric coefficient of variation (CV), a percentage, is calculated as follows: 
1
)
exp(x
100
2 −
×
, where x is the standard deviation (std) of the ln-transformed (i.e., natural 
log) parameter values. 
Prior Medications 
Prior medications will be defined as any medications taken prior to initiation of study medication 
(reparixin/placebo) dosing. In the case of missing or partial medication start and end dates, 
medications will be assumed to be concomitant and not prior if they could have started or ended 
between first and last study drug dose date. Please follow section 10.2 to impute the missing or 
partial dates.  A single medication may be both concomitant and prior. (See also concomitant 
medications in this section.) 
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Statistical Analysis Plan 
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Protocol No. REP0114 
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Protocol Deviation, Important Protocol Deviation 
Potential protocol deviations noted during clinical monitoring will be documented by category: 
inclusion criteria, exclusion criteria, study drug, assessment of safety, assessment of efficacy, 
laboratory assessment, visit window, IC, or other. All protocol deviationss will be reviewed, 
categorized, designated important or not important, and finalized prior to database lock. 
Important protocol deviationss will be defined as potentially impacting safety or efficacy 
assessment following regulatory guidance criteria (ICH E3). Protocol deviationss for the safety 
population will be imported into SAS® for inclusion in a table and a data listing. 
Study Day 
Study day is defined relative to the date of the first administration of study drug, 
reparixin/placebo, per Clinical Data Interchange Standards Consortium (CDISC) Standard Data 
Tabulation Model (SDTM) conventions. For assessments that occur after this visit date, study 
day is calculated as (assessment date – study drug first dose date + 1). For assessments that occur 
prior to study drug first dose date, study day will be calculated as (assessment date – study drug 
first dose date); there is no Study Day 0. 
Study Drug/Medication 
In this study, study drug/medication will refer to reparixin or placebo, the only investigational 
product.  Paclitaxel will not be referenced as a study drug/medication. 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are those which first occur or increase in severity 
or relationship to study drug after the first dose of study drug and before 30 days after the last 
dose of study treatment, reparixin/placebo. In the case of missing or partial dates, any AE that 
could have started on or after first dose date will be assumed to be treatment-emergent.  In the 
case of missing or partial dates, imputed dates (see section 10.1 AE date imputation) will be 
used.  
 
Efficacy Definition  
Best Overall Response 
BOR is defined as the best response among all overall responses (in the order complete 
response [CR], partial response [PR], stable disease [SD], and progressive disease [PD]) 
recorded from the start of reparixin or placebo until disease progression/recurrence or end of 
treatment, or death, whichever comes first. The status of BOR of PR or CR needs to be 
confirmed by repeat tumor assessment within no less than 4 weeks according to RECIST 
version 1.1. If the status of CR or PR cannot be confirmed by repeat tumor assessment, the 
best overall response of unconfirmed CR and PR will be PR and SD, respectively. No 
confirmation measurement is needed for a BOR of SD. Best overall response of SD can only 
be made when the measurements that have met the SD criteria at least after 8 weeks of study 
entry (1st dose date of study drug). 
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BOR by investigator assessment is recorded on the “Best Overall Disease Response” CRF 
page. 
Complete Response 
CR is defined as the disappearance of all target lesions and disappearance of all non-target 
lesions. All lymph nodes must be non-pathological in size (< 10 mm short axis). No new 
lesions may be present. 
Duration of (Overall) Response 
Duration of overall response (DOR) in days for the investigator assessments is measured 
from the time response criteria are first met for CR or PR (whichever is first recorded on the 
“Disease Response” page on the CRF) until either death or the first date that recurrent or PD 
is objectively documented (on the “Disease Response” page on the CRF or the Follow-Up 
Disease Evaluation page indicates disease progression and there is supporting information in 
the Disease Status pages) per RECIST version 1.1. 
If a patient is lost to follow-up with no documentation of PD, DOR will be censored at the 
last evaluable tumor assessment. DOR will be calculated only for responding patients (PR or 
CR) as recorded on the CRF page “Disease Response” based upon the RECIST version 1.1. 
Duration of overall response will be calculated only for patients with confirmed CR or PR. 
Independent assessment responses will follow the same approach but based on independently 
adjudicated data rather than CRF data. 
Duration of Stable Disease 
Duration of stable disease in days for the investigator assessments is measured from the date 
of randomization until the time of death or the first documentation of PD (as assessed by 
“Disease Response” page on the CRF or the Follow-Up Disease Evaluation page indicates 
disease progression and there is supporting information in the Disease Status pages) per 
RECIST version 1.1. 
If a patient is lost to follow-up with no documentation of PD, duration of stable disease will 
be censored at the date of the last evaluable tumor assessment. Duration of stable disease will 
be calculated only for patients with best overall response of SD or better. 
Independent assessment responses will follow the same approach but based on independently 
adjudicated data rather than CRF data. 
 
Measurable (Target) Lesions, Non-Measurable (Non-Target) Lesions 
Measurable lesions are those that, at baseline, can be accurately measured in at least one 
dimension (longest diameter [LD] to be recorded) as ≥ 10 mm by CT scan, ≥ 10 mm by 
caliper measurement by clinical examination, or ≥ 20 mm by chest X-ray. A minimum of one 
and a maximum of five measurable lesions (2 per organ) will be defined as target lesions for 
the purpose of the study. All other measurable lesions, including small lesions (LD < 10 mm 
or pathological lymph nodes with ≥ 10 mm to < 15 mm for the short axis) as well as truly 
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non-measurable lesions will be considered non-target lesions (see Section 9.1.1 in the 
protocol for further details). 
Partial Response 
PR is defined as at least a 30% decrease in the sum of longest diameters of target lesions, 
relative to the sum of longest diameters at baseline, per the investigator’s assessment. 
Persistence of one or more non-target lesion may be present. No new lesions may be present.  
Progression-Free Survival 
PFS in days will be measured from the date of randomization until the date of PD according 
to RECIST 1.1 or death, whichever occurs first. If a patient is lost to follow-up with no 
documentation of PD, PFS will be censored at the date of the last evaluable tumor 
assessment. In the event that the date of tumor assessment is unavailable (i.e., there is no 
tumor assessment after randomization) or the patient did not receive study treatment, Day 1 
(based on randomization) will serve as the censoring date instead. Please see Table 3.1 for 
further details on censoring.  
Progressive Disease 
PD is defined as at least a 20% increase in the sum of longest diameters of target lesions 
relative to the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm to qualify as PD. Unequivocal progression of existing non-target 
lesions or appearance of one or more new lesions is also considered progression. 
Stable Disease 
SD is defined as, for the sum of longest diameters of target lesions, neither sufficient 
shrinkage to qualify for PR nor sufficient increase to qualify for PD, relative to the smallest 
sum of longest diameters while on study. Persistence of one or more non-target lesion may be 
present. No new lesions may be present. 
Sum of Target Lesion Diameters 
Sum of target lesion diameters is the sum of the longest diameter of non-nodal measurable 
lesions and the shortest axis of pathological lymph nodes. 
Time to New Metastasis 
Time to new metastasis is defined as the interval (days) between randomization and the date 
of the first observation that the new lesion was detected at existing or new sites. 
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6. ANALYSIS POPULATIONS 
6.1 INTENT-TO-TREAT POPULATION 
The intent-to-treat (ITT) population will consist of all patients who are randomized and will be 
based upon the randomized treatment, regardless of the treatment actually received.  Patients will 
be in the ITT analysis whether or not they receive study drug.  The primary and secondary 
efficacy analyses will be presented primarily for the ITT Population. 
 
6.2 RESPONSE EVALUABLE POPULATION 
The response evaluable population will consist of all patients who have completed at least one 
cycle of treatment and have baseline assessment and have undergone at least one post-baseline 
disease assessment.  
 
6.3 SAFETY POPULATION 
The safety population will consist of all patients who have taken at least one dose of the study 
treatment and will be based upon the treatment they actually receive. Patients who were 
randomized to Group 2 (paclitaxel + placebo) but who received at least one dose of reparixin will 
be counted in Group 1 (paclitaxel + reparixin). 
 
7. INTERIM ANALYSIS AND REPORTING MILESTONES 
7.1 INTERIM ANALYSIS  
There will be no interim analysis for this study. 
7.2 REPORTING MILESTONES  
There are two reporting milestones for this trial: Primary Analysis and Follow-up Analysis. 
7.2.1 Primary Analysis Reporting  
All primary analyses set out in this analysis plan will be generated from a data base cut that 
occured on 20 Feb, 2019. This analysis will take place while less than 5 subjects are still on 
treatment. Once the database is locked, the study will be unblinded, so that the primary results 
can be obtained based on the analyses of these unblinded data. 
Since some subjects will still be on treatment when unblinding takes place, they will be 
unblinded prematurely.  
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7.2.2 Follow-up Analysis Reporting  
Overall survival and selected safety, demographics and disposition will be reported at this 
milestone. This analysis will take place when all subjects have completed the study. The 
accompanying document of TFL shells specifies which outputs will form part of this analysis. 
This analysis will be for descriptive purposes only. 
 
8. DATA MANAGEMENT 
8.1 DATA HANDLING AND TRANSFER 
The data management of this study will be performed by PRA Health Sciences. PRA Health 
Sciences will perform data processing according to approved procedures including database 
specifications, CRF tracking, central laboratory data reconciliation, SAE reconciliation, and 
dictionary coding and data validation. A quality control of site responses to data queries will also 
be performed on this study.  
Data will be entered by investigational sites into a clinical database built with DataLabs 
version 4 and exported as SAS® version 9.4 or higher datasets (SAS Institute, Inc., Cary, NC). 
Converted datasets will be created using SAS® and following CDISC SDTM (version 1.2, 
implementation guide version 3.1.2) conventions. Derived analysis datasets will be generated 
using SAS® and following standard CDISC Analysis Dataset Model (ADaM) conventions. Data 
analyses including summary tables, figures, and listings (TFLs) will be produced using SAS®. 
Medical history and AEs will be coded using the latest version of Medical Dictionary for 
Regulatory Activities (MedDRA) to assign a system organ class (SOC) and preferred term (PT) 
to each AE. Prior and concomitant medications will be coded to preferred drug names using the 
World Health Organization Drug Dictionary Enhanced (WHODRUG DDE, 2014Mar01). 
Anatomic therapeutic classification coding will not be included. PRA's data handling and 
transfer procedures will be documented separately in the study specific Data Management Plan. 
 
8.2 DATA SCREENING 
Beyond the data screening built into the PRA Data Management Plan, the PRA programming of 
analysis datasets and TFLs provides additional data screening. Presumed data issues will be 
output into SAS® logs identified by the word “Problem” and sent to Data Management for 
review. 
Review of a pre-freeze TFL run and a post-freeze TFL run on the frozen database allow for 
further data screening prior to lock. The post-freeze TFLs will be discussed with the sponsor in a 
data review meeting to identify any final data issues and seek corrections prior to database lock. 
The PRA statistician and the sponsor must approve database lock. 
 
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9. STATISTICAL METHODS 
All analyses will use SAS® version 9.4 or higher. Summary tables will be organized by treatment 
group. All available scheduled data for the safety population will be used in the analyses, and 
important CRF data will be included in data listings, sorted by treatment group, patient, and, 
when appropriate, by study day or time point within patient.  
Unless otherwise noted, categorical data will be presented using counts and percentages, with the 
number of patients in the analysis population by treatment group as the denominator for 
percentages. Percentages will be rounded to one decimal place, except 0% and 100% will be 
displayed without any decimal places.  Continuous data, unless otherwise noted, will be 
summarized using the number of observations (n), mean, standard deviation, median, minimum, 
and maximum. Minima and maxima will be presented to the precision of the original value, and 
means, medians, and 95% confidence intervals (CIs) will be rounded to one more decimal place 
than the original value. Standard deviation will be rounded to two more decimal places than the 
original value, up to a maximum of three decimal places. 
Any hypothesis testing will be performed with a 2-sided level of α = 0.05.  
Partial dates for adverse event, death, and dosing records will be imputed. Imputation rules for 
partial and missing dates are described in Section 10. 
Patients who have missing randomized sub-population stratification due to enrollment under 
earlier versions of the protocol will be assigned to the “Relapsed” sub-population. Patients who 
otherwise have missing randomized sub-population stratification will be assigned to the 
sub-population derived from their medical history data. 
9.1 PATIENT DISPOSITION 
Patient disposition data will be summarized for all enrolled patients. A table will be presented 
that includes the number of patients enrolled and number of patients in each analysis population. 
The number and percentage of patients who are off-treatment, and a breakdown of the 
corresponding reasons for off-treatment, will also be presented. Denominators for percentages 
will be based on the number of patients in the safety population. In addition, the number of 
patients who are discontinued from the study follow-up will be summarized by reason for 
termination; the only valid reasons that patients should be discontinued from study follow-up 
would be death or formal withdrawal of consent. 
Another table will summarize the number and percentage of patients by region/country and study 
site. This summary will be presented for the safety population. 
 
9.2 PROTOCOL DEVIATIONS  
Per PRA processes, protocol deviation data will be entered into PRA’s Clinical Trials 
Management System (CTMS). The study team and Dompé will conduct ongoing reviews of the 
protocol deviation data from CTMS throughout the study, adjusting the protocol deviation 
criteria as appropriate. Protocol deviations for enrolled patients will be imported into SAS® and 
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important deviations will be summarized and all protocol deviations will be presented in a 
listing.  
 
9.3 TREATMENTS 
9.3.1 Extent of Study Drug Exposure 
Reparixin and paclitaxel exposure, including duration of exposure, total exposure, and total 
exposure by cycle, number of cycles and overall compliance will be tabulated for the safety 
population. Information regarding patients’ dosing regimen will be presented in a listing. 
 
9.3.2 Concomitant Medications and Concomitant Therapies 
Prior medications, concomitant medications, and concomitant therapies will be tabulated 
separately for the safety population by treatment group and preferred drug name using counts 
and percentages. The number and percentage of patients using at least one medication or therapy 
within each treatment group will also be displayed. See Section 5 for definitions of concomitant 
medications. Prior and concomitant medications will be included in a patient data listing. 
 
9.4 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic data, including age, ethnicity, race, weight, height, body surface area, and number 
of target lesion, will be summarized for all patients in the safety population.  Patient population 
will be summarized (newly diagnosed and relapsed), for both as stratified value and actual value. 
Medical history, tumor history, surgery, physical exam, x-rays and/or CT scans, including a CT 
scan or MRI of the brain data, will be listed but not tabulated. 
9.5 POOLING OF SITES 
All analyses will pool sites, since the numbers of patients enrolled at individual sites will be too 
small for separate analyses. 
 
9.6 EFFICACY ANALYSIS 
The primary and secondary efficacy analyses will be presented primarily for the ITT population. 
The randomization for this trial is stratified based on two patient sub-groups, newly diagnosed 
metastatic patients and patients that have relapsed following a prior (neo)adjuvant chemotherapy 
regimen. In few cases, subjects may be randomized into a category incorrectly. All efficacy 
analyses will be conducted using the randomized stratification factors. Sensitivity analysis will 
be conducted on actual sub-population. 
9.6.1 Primary Efficacy Analysis 
 
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PFS is defined as the number of days between the date of randomization and the date of clinical 
PD according to RECIST criteria version 1.1, or death for any cause, whichever occurs first.  
Disease progression will be based on the Independent Radiology Review assessments. The date 
of documented disease progression will be defined as either the date of radiological or 
symptomatic disease progression as assessed by Independent Radiology Review. If a patient has 
neither progressed nor died, then progression-free survival will be censored as follows:  
Table 3.1 details the primary PFS analysis. 
 
Table 3.1 PFS 
Situation 
Date of Progression or 
Censoring 
Outcome 
No tumor assessment after 
randomization 
Randomization date 
Censored 
No treatment received 
Randomization date 
Censored 
Progression documented  
Date of progression 
Progressed 
Treatment ongoing with no 
progression 
Date of last adequate radiological 
assessment of measured lesions 
Censored 
Treatment discontinuation with no 
progression either pre or post 
treatment discontinuation. 
Earliest of:  
• 
Date of last adequate 
radiological assessment of 
measured lesions 
• 
Start date of new 
anticancer treatment from 
the Long Term Follow up 
disease evaluation CRF 
page 
Censored 
Death without previous progression 
or any previous situation in this table 
Date of death 
Progressed 
 
For each treatment group, the Kaplan-Meier estimates for PFS using the ITT population, along 
with median and the first and third quartiles will be presented.  Greenwood’s formula will be 
used to calculate the standard error of the estimates from the Kaplan-Meier curve.  
As primary analysis: PFS will be compared between treatment arms using a stratified log-rank 
test, with randomized sub-group as stratifying factor. 
As supportive analysis: in the ITT population, an estimate of the treatment hazard ratio will be 
obtained based on a Cox proportional model stratified by randomized sub-group, and also will be 
obtained within sub-groups of newly diagnosed vs relapsed patients.  The corresponding CIs will 
be provided.  
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Sensitivity analyses can be helpful in determining whether the PFS analysis is robust [2]. The 
following two tables describe examples of two different sensitivity analyses. Table 3.2 represents 
a sensitivity analysis that includes well documented and verifiable progression events. 
 
Table 3.2 PFS 1 (includes documented progression only) 
Situation 
Date of Progression or 
Censoring 
Outcome 
No tumor assessment after 
randomization 
Randomization date 
Censored 
No treatment received 
Randomization date 
Censored 
Progression documented at a 
scheduled visit 
Date of progression 
Progressed 
Progression documented between 
scheduled visits 
Earliest of: 
• 
Date of radiological 
assessment showing new 
lesion (if progression is 
based on new lesion); 
or 
• 
Date of progression by 
radiological assessment of 
measured lesions (if 
progression is based on 
increase in sum of 
measured lesions) 
Progressed 
Treatment ongoing with no 
progression 
Date of last radiological 
assessment of measured lesions 
Censored 
Treatment discontinuation with no 
progression either pre or post 
treatment discontinuation. 
Earliest of 
• 
Date of last radiological 
assessment of measured 
lesions 
• 
Start date of new 
anticancer treatment from 
the Long Term Follow up 
disease evaluation CRF 
page 
Censored 
Death before first PD assessment  
Date of death 
Progressed 
Death between assessment visits 
Date of death 
Progressed 
Death or progression after more than 
one missed visit 
Date of last radiological 
assessment of measured lesions 
Censored 
 
The sensitivity analysis in Table 3.3 corrects for potential bias in follow-up schedules for tumor 
assessment by assigning the dates for censoring and events only at scheduled visit dates. 
 
Table 3.3 PFS 2 (uniform progression and assessment dates) 
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Situation 
Date of Progression or 
Censoring 
Outcome 
No tumor assessment after 
randomization 
Randomization date 
Censored 
No treatment received 
Randomization date 
Censored 
Progression documented at a 
scheduled visit 
Date of progression 
Progressed 
Progression documented between 
scheduled visits 
Date of next scheduled visit 
Progressed 
Treatment ongoing with no 
progression 
Date of last scheduled visit with 
radiological assessment of 
measured lesions  
Censored 
Treatment discontinuation  
Date of last scheduled visit with 
radiological assessment of 
measured lesions  
Censored 
New anticancer treatment started 
with no progression 
Date of last scheduled visit with 
radiological assessment of 
measured lesions 
Censored 
Death before first PD assessment  
Date of death 
Progressed 
Death between assessment visits 
Date of death 
Progressed 
Death or progression after more than 
one missed visit 
Date of last scheduled visit with 
radiological assessment of 
measured lesions 
Censored 
 
 
9.6.2 Secondary Efficacy Analysis  
The primary and secondary endpoints will be assessed hierarchically.  Using two-sided 0.05 
level tests to define statistical significance, the hierarchical ordering will be the primary 
endpoint, PFS, followed (in order) by OS and ORR. 
 
 
Overall Survival 
 
Overall survival is defined as the time from randomization until death due to any cause. For 
patients who do not die, time of death will be censored at the date of last contact. 
 
Overall survival will be summarized in the ITT population using Kaplan-Meier curves and 
compared between treatment arms using a stratified log-rank test.   
 
For each treatment group, the Kaplan-Meier estimates will be used to estimate the median 
overall survival time, and the first and third quartiles will be presented.  Greenwood’s formula 
will be used to calculate the standard error of the estimates from the Kaplan-Meier curve.   
 
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Objective Response Rate 
 
The ORR is defined as the percentage of patients achieving CR or PR in the evaluable 
population. The response rate will be calculated from the independently reviewed assessment 
best response. In case of PR or CR, only confirmed cases are responses.    
 
Patients with unknown or missing response, including response of “not all evaluated” or “unable 
to determine”, will be treated as non-responders; i.e., they will be included in the denominator 
when calculating the percentages. 
 
Exact 95% CI for objective response rate in each arm will be calculated. 
 
Objective response rates will be compared between treatment arms using Cochran-Mantel-
Haenszel (CMH) test. Estimated common odds ratio and corresponding exact 95% CI will be 
calculated. Zelen’s test for homogeneity of the odds ratios across all strata will be performed as a 
measure of validation. 
 
Overall tumor response rate based on the investigator assessments will also be summarized in the 
same way as that described for the independently reviewed response.  
 
 
All data relating to response from the investigator and independent reviews will be listed 
(including lesion measurements, response assessment, and best response) and the independent 
review best response assessments will be cross-tabulated with the investigator best response 
assessments. 
 
A listing of patients with a discrepancy between the investigator and independent review best 
response will be provided. 
 
The disease response by IRR (disease status up to PD) at pre-study (baseline) and every eight 
weeks until the end of the study based on RECIST version 1.1 criteria will be summarized by 
counts, percentages and 95% CIs and by treatment and stratification group. 95% CIs are 
calculated using either normal approximation method or exact binomial method, depending on if 
there are sufficient numbers of response or not. 
 
Median Progression Free Survival  
For each treatment group, the Kaplan-Meier estimates for the median PFS time, the first and 
third quartiles will be presented, along with approximate 95% CIs if there are a sufficient number 
of progressions or deaths.   
 
Duration of Response 
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Duration of response (Duration of response) will be summarized similarly to PFS.  For each 
treatment group, duration of response will be summarized descriptively using the K-M estimates,  
for the response-evaluable population. 
9.6.3 Exploratory Analysis  
For each treatment group, the Kaplan-Meier estimates for the TTM, and the median and the first and 
third quartiles will be presented, along with approximate 95% CIs if there are a sufficient number of 
progressions with new metastatic lesions among ITT population.  
 
The proportion of patients progressing with new metastatic lesions is defined as the percentage of 
patients who at progression display new lesions at existing or new sites. The proportion of patients 
progressing with new metastatic lesions will be summarized and evaluated using a CMH test for 
response evaluable population.  
 
The incidence of peripheral neuropathy will be summarized by treatment group.  The incidence and 
severity of peripheral neuropathy will be also presented in a listing. 
 
The CSC markers (CD24-CD44+CSC and ALDH+CSC assessed by IHC) will be summarized by 
descriptive statistics. 
 
 
9.6.4 Sub–group Analyses 
Descriptive analyses of multiple subgroups will be performed based on at least the following 
covariates: 
1. a) Newly diagnosed metastatic triple negative breast cancer  
b) Breast cancer relapsing to metastatic triple negative breast cancer after neoadjuvant or 
adjuvant treatment 
2. a) No previous treatment with a taxane  
b) Previous treatment with taxane 
3. a) Age < 40 years  
b) Age > 40 years 
4. a) Visceral disease 
b) No visceral disease 
5. Presence of markers of CSC (CD44/CD24 or ALDH+) in metastatic tumor tissue 
correlated with PFS 
 
Previous treatment with a taxane and visceral disease will be determined based on a manual 
medical review of the verbatim terms for prior therapies and lesions sites as appropriate. 
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9.7 SAFETY ANALYSES 
9.7.1 Adverse Events 
Information on all AEs will be collected from IC signature throughout the study until resolution 
of the event. Only TEAEs for the safety population will be summarized for this study. 
An overall summary of TEAEs, including the number of events reported, the number and 
percentage of patients reporting at least 1 TEAE, the number and percentage of patients 
discontinuing due to a TEAE, the number and percentage of patients with at least one serious 
TEAE, and the number and percentage of deaths will be presented by treatment group and 
overall. See Section 5 for TEAE definition. 
 
A breakdown of the number and percentage of patients reporting each TEAE, categorized by 
SOC and PT, will be presented by treatment group and overall. Note that counting will be by 
patient not event, and patients are only counted once within each SOC or PT. A similar 
tabulation will be produced for those TEAEs related to study drug (i.e., “suspected” per CRF). 
Missing relationship to study drug will be counted as related. 
A summary of reported TEAEs, categorized by severity (i.e., Grade 1 = Mild, Grade 2 = 
Moderate, Grade 3 = Severe, Grade 4 = Life-threatening or disabling, Grade 5 = death per CRF), 
will be provided by treatment group and overall. Patients with multiple events within a particular 
SOC or PT will be counted under the category of their most severe event within that body system 
or preferred term.  For a given patient, if the severity grade is missing for all TEAEs with the 
same preferred term, the TEAEs will be counted only once for that term under the “Missing” 
severity category. For a patient who has both missing and non-missing severity grades for 
adverse events with the same preferred term, the TEAE will be counted under the highest 
non-missing severity category. This summary will also be presented for treatment-related 
TEAEs. 
A summary of TEAEs leading to discontinuation will be provided, grouped by body system and 
preferred term by treatment group and overall. A similar tabulation will be produced for 
treatment related TEAEs. A number of additional summaries by SOC and PT will be provided 
for the safety population by treatment group and overall: 
• TEAE with outcome of death 
• Treatment related TEAE with outcome of death 
• Serious TEAE 
• Treatment related serious TEAE 
• Non-fatal serious TEAE 
All AEs will be listed for patients in the safety population. 
A summary of ADRs will be presented in tables. ADRs continuing across more than one 
treatment cycle without complete resolution and reported more than once in CRF to reflect 
changes in CTCAE grade, will be reported in this table as single ADRs with worst CTCAE 
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grade. ADRs occurring more than once per patient but not continuing (i.e. with clear break 
between one occurrence and the next) will be reported in this table as separate ADRs. 
ADRs related to reparixin and ADRs related to paclitaxel will be summarized in separate tables. 
9.7.2 Serious Adverse Events 
A summary of SAEs and treatment-related SAEs for the safety population will be provided by 
treatment group and overall, grouped by SOC and PT. 
9.7.3 Laboratory Data 
Hematology laboratory tests will be performed locally at the study sites at pre-study, on        
Days 1, 8 and 15 of each cycle, and at the OTV. Chemistry laboratory tests will be measured pre-
study, on Day 1 of each treatment cycle, as clinically indicated, and at the OTV. Urinalysis 
parameters will be at pre-study, throughout each cycle if clinically indicated, and at the OTV. 
Laboratory data will include parameter values, normal ranges, and out-of-range flags. In 
addition, laboratory abnormalities will be assigned a CTCAE (Version 4.03) grade for severity 
(1= mild, 2 = moderate, 3 = severe, 4 = life-threatening or disabling) for analyses that have 
numeric CTCAE guidelines only (i.e., not requiring clinical assessments) (see section 5 for 
detail). Laboratory parameters are listed in Table 4 below, and will be sorted by their order in the 
table. Laboratory test results will be converted and reported in International System of Units (SI) 
units. 
Clinical laboratory data summaries for safety analyses will include the following tables by 
treatment group for the safety population: 
•
Hematology and chemistry results and changes from baseline by cycle and study day
•
CTCAE shifts from baseline to worst post-baseline result for hematology and chemistry
•
Urinalysis results and changes from baseline for continuous variables
•
Hematological toxicity evaluations of thrombocytopenia, neutropenia, and leukopenia based
on CTCAE grading.
For change from baseline tables, descriptive statistics will be shown for baseline, specific 
scheduled post-baseline time points, and the change from baseline to each of these post-baseline 
time points. 
Table 4. List of Laboratory Tests 
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Hematology: 
• Hemoglobin (Hgb) 
• Platelets  
• WBC count with differential including: 
o Neutrophils 
o Lymphocytes 
o Monocytes 
o Eosinophils 
o Basophils 
 
Urinalysis:  
• Glucose 
• Ketones 
• pH 
• Protein 
• Bilirubin  
• Blood 
• Nitrite 
• Leukocyte 
• Specific gravity 
Serum Chemistry: 
• Albumin  
• ALP 
• ALT 
• AST 
• Blood urea nitrogen (BUN) 
• Calcium (Ca) 
• Serum Creatinine 
• Potassium (K) 
• Sodium (Na) 
• Total bilirubin 
• Total protein 
• Urea 
 
 
9.7.4  Vital Signs 
Vital signs will be assessed at Day 1 of each cycle (within 24 hours prior to the first study drug 
(reparixin/placebo) administration for the first cycle) and at the OTV. Vital sign parameters will 
include pulse rate and systolic and diastolic BP.  
A change from baseline summary by cycle will be displayed for vital signs parameters for the 
safety population. Descriptive statistics will be shown for baseline, scheduled visits, and the 
change from baseline to these visits. Vital sign parameters will be sorted by their order on the 
CRF. Vital signs data will also be listed by patient. 
 
9.7.5  Physical Examinations and Electrocardiograms 
Physical examination will be assessed at pre-study, on Day 1 of each cycle starting from Cycle 2, 
and at the OTV. Body systems assessed for physical examination include skin, 
head/eyes/ears/nose/throat, cardiovascular, respiratory, abdominal (including liver and kidneys), 
musculoskeletal, neurological, gastrointestinal, genitourinary, endocrine, lymph nodes, and 
other. Each body system will be assessed as normal, abnormal, or not performed, with 
abnormalities documented. The number and percentage of patients assessed as normal, abnormal, 
or not performed for each body system will be summarized at each scheduled visit for the safety 
population. 
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Zubrod Performance Status will be summarized at pre-study and at the OTV for safety 
population. Data will also be listed by patient. 
 
Electrocardiograms (ECGs) will be performed locally at the study sites at screening. Overall 
ECG impression will be assessed by the investigator as normal, abnormal, and clinically 
significant or not clinically significant if abnormal. The number and percentage of patients 
assessed as normal and abnormal (clinically significant or not clinically significant) will be 
summarized by visit for the safety population.  ECGs data will also be listed by patient 
 
10. HANDLING OF MISSING DATA 
10.1 TUMOR DATA 
In order to evaluate the potential effect of missing tumor data, two sensitivity analyses will be 
performed. See Section 9.6.1 for more details. 
10.2 SURVIVAL DATA 
For patients not known to have died prior to the end-of-study date: 
• All events with a start date before or on the end-of-study date, and with a missing end date 
will be reported as “continuing at the end-of-study date”. This approach applies in particular 
to AEs and concomitant medications. For these events, the end date will not be imputed and 
therefore will not appear in the listings.  
For patients known to have died: 
• All events with a start date before or on the end-of-study date, and with a missing end date 
will have the end date imputed to the death date. This approach applies in particular to AEs 
and concomitants. For these events, the imputed end date will not appear in the listings.  
 
10.3 AE DATE IMPUTATION 
Date imputation is the creation of a new, complete date from a partial one according to an agreed 
and acceptable algorithm. Missing dates for AEs will be handled according to rules specified 
below. A partial date is simply an incomplete date (e.g., DDOCT2001); the days are missing 
from this DDMMMYYYY date. 
 
There will be no attempt to impute the following: 
• Missing AE start dates 
• AE start dates missing the year 
• Partial/missing AE end dates 
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The following Table 5 explains the abbreviations used. 
 
Table 5. AE / Treatment Date Abbreviations 
  
 
Day 
Month 
Year 
Partial Adverse Event 
Start Date 
<not used> 
AEM 
AEY 
Treatment Start Date 
(TRTSTD) 
<not used> 
TRTM 
TRTY 
The following Table 6  describes the possible combinations and their associated imputations. The 
upper text indicates the imputation and the lower text the relationship of the AE start date to the 
treatment start date (TRTSTD). 
 
Table 6. AE Partial Date Imputation Algorithm 
 
 
 
AEM MISSING 
 
AEM < TRTM 
AEM = TRTM 
AEM > TRTM 
AEY MISSING 
NC 
Uncertain 
NC 
Uncertain 
NC 
Uncertain 
NC 
Uncertain 
AEY < TRTY 
( D ) 
Before TRTSTD 
( C ) 
Before TRTSTD 
( C ) 
Before TRTSTD 
( C ) 
Before TRTSTD 
AEY = TRTY 
( B ) 
Uncertain 
( C ) 
Before TRTSTD 
( B ) 
Uncertain 
( A ) 
After TRTSTD 
AEY > TRTY 
( E ) 
After TRTSTD 
( A ) 
After TRTSTD 
( A ) 
After TRTSTD 
( A ) 
After TRTSTD 
The following is the legend to the above table. 
 
Relationship 
 
Before TRTSTD 
Indicates AE start date prior to Treatment Start Date 
After TRTSTD 
Indicates AE start date after Treatment Start Date 
Uncertain 
Insufficient to determine the relationship of AE start 
date to Treatment Start Date 
Imputation Calculation 
NC / Blank 
No convention/imputation 
( A ) 
01MONYYYY 
( B ) 
TRTSTD+1 
( C ) 
15MONYYYY 
( D ) 
01JULYYYY 
( E ) 
01JANYYYY 
The following Table 7 gives a few examples. 
 
Table 7 
AE Imputation Example Scenarios 
 
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Protocol No. REP0114 
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Partial 
AE start date 
Treatment 
start date 
Relationship 
Imputation 
Calculation 
Imputed Date 
ddmmm2000 
20OCT2001 
Before 
( D ) 
01JUL2000 
ddmmm2001 
20OCT2001 
Uncertain 
( B ) 
21OCT2001 
ddmmm2002 
20OCT2001 
After 
( E ) 
01JAN2002 
ddSEP2001 
20OCT2001 
Before 
( C ) 
15SEP2001 
ddOCT2001 
20OCT2001 
Uncertain 
( B ) 
21OCT2001 
ddNOV2001 
20OCT2001 
After 
( A ) 
01NOV2001 
 
10.4 
INCOMPLETE DATE FOR CONCOMITANT MEDICATION 
If dates are missing or incomplete for concomitant medication, the following algorithm will be 
used for imputation: 
Table 7 
Imputation Rules for Partial or Missing Start Dates 
 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
<1st 
dose 
≥1st 
dose 
<1st 
dose 
yyyymm 
≥1st dose 
yyyymm 
<1st 
dose 
yyyy 
≥1st 
dose 
yyyy 
Partial: 
yyyymm 
= 1st 
dose 
yyyymm 
2 
1 
n/a 
1 
n/a 
1 
1 
≠ 1st 
dose 
yyyymm 
2 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st 
dose yyyy 
3 
1 
3 
1 
n/a 
1 
1 
≠ 1st 
dose yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
 
1 = Impute as the date of first dose 
2 = Impute as the first of the month 
3 = Impute as January 1 of the year 
4 = Impute as January 1 of the stop year 
 
Note: If the start date imputation leads to a start date that is after the stop date, then there is a 
data error and do not impute the start date. 
Imputation rules for partial or missing stop dates: 
1. Initial imputation 
a. For partial stop date “mmyyyy”, impute the last of the month. 
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b. For partial stop date “yyyy”, impute December 31 of the year.
c.
For completely missing stop date, do not impute.
2. If the stop date imputation leads to a stop date that is after the death date or date of off
treatment visit, then impute the stop date as the earlier date between the death date and
date of off treatment visit.
11. VALIDATION
PRA's quality control procedures will be documented separately in the study-specific quality 
control plan.  
12. REFERENCES
[1] National Cancer Institute, US National Institutes of Health. Response Evaluation Criteria In 
Solid Tumors (RECIST). http://www.eortc.be/recist/
[2] Food and Drug Administration, US Department of Health and Human Services. Guidance for 
Industry – Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics.
http://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf 
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13. APPENDIX 1: GLOSSARY OF ABBREVIATIONS 
ADaM 
 
Analysis Dataset Model 
ADR 
 
Adverse Drug Reaction 
AE 
 
Adverse Event 
ALP 
 
Alkaline Phosphatase 
ALT 
 
Alanine Aminotransferase 
AST 
 
Aspartate Aminotransferase 
BOR 
Best Overall Response 
BP                    
Blood Pressure 
CDISC             
Clinical Data Interchange Standards Consortium 
CI 
 
Confidence Interval 
CMH                           Cochran-Mantel-Haenszel  
CR 
 
Complete Response 
CRF 
 
Case Report Form 
CRO 
 
Contract Research Organization 
CSC 
 
Cancer Stem Cell 
CT 
 
Computed Tomography 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CTMS 
 
Clinical Trial Management System 
CV 
 
Coefficient of Variation 
DMC 
 
Data Monitoring Committee 
ECG 
 
Electrocardiogram 
IC 
 
Informed Consent 
IHC 
 
Immunohistochemistry 
IRT 
 
Interactive Response Technology 
ITT 
 
Intent-to-Treat 
i.v. 
 
Intravenous 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
mPFS 
 
Median Progression Free Survival 
MRI 
 
Magnetic Resonance Imaging 
ORR  
 
Objective Response Rates  
OS 
 
 
Overall Survival 
OTV  
 
Off-Treatment Visit 
PD 
 
 
Progressive Disease 
PFS 
 
 
Progression Free Survival 
PR 
 
 
Partial Response 
PT 
 
 
Preferred Term 
RECIST 
 
Response Evaluation Criteria In Solid Tumors 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SD 
 
Stable Disease 
SDTM 
 
Standard Data Tabulation Model 
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SI 
 
International System (of Units) 
SOC 
 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TFLs 
 
Tables, Figures, and Listings 
TNBC 
Triple Negative Breast Cancer 
TTM  
 
Time to New Metastasis 
TTP 
 
Time to Tumor Progression 
WBC 
 
White Blood Cell 
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14. APPENDIX 2: 
LIST OF IN-TEXT TABLES, FIGURES, AND 
LISTINGS 
A list of in-text TFLs will be finalized after SAP1 is approved. 
 
15. APPENDIX 3: 
SHELLS FOR IN-TEXT TABLES, FIGURES, AND 
LISTINGS 
Shells for in-text TFLs will be finalized after SAP1 is approved. 
 
16. APPENDIX 4: 
LIST OF POST-TEXT TABLES, FIGURES, AND 
LISTINGS  
See accompanying document of TFL shells. 
 
17. APPENDIX 5: 
SHELLS FOR POST-TEXT TABLES, FIGURES, 
AND LISTINGS 
See accompanying document of TFL shells. 
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