Phase II, Open Label, Single Arm Study to Investigate Anti-tumor Effect of Ixabepilone in Patients With Locally Recurrent or Metastatic Breast Cancer (mBC) Selected by the Ixabepilone DRP After Failure of an Anthracycline and Taxanes.
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Sponsor: Allarity Therapeutics

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 1 of 62
 
CLINICAL STUDY PROTOCOL 
 
Protocol no.: AL-2001 
EudraCT no.: 2020-004610-35 
 
 
 
Title: 
Phase II, open label, single arm study to investigate anti-tumor effect of ixabepilone in patients with 
locally recurrent or metastatic breast cancer (mBC) selected by the ixabepilone Drug Response 
Prediction (DRP) after failure of an anthracycline and a taxane. 
 
 
Investigational medicinal product:  
Ixabepilone  
 
Indication:  
Locally Recurrent and Metastatic Breast Cancer 
 
 
Development phase:  
 
Phase 2  
 
 
 
Coordinating Investigator: 
Dr. Collignon Joelle,  
Department of Medical Oncology 
Breast Cancer CHU-Sart-Tilman,  
4000 Liège, Belgium  
Email: joelle.collignon@chuliege.be 
 
 
 
Sponsor: 
Allarity Therapeutics Europe Aps 
Venlighedsvej 1 
2970 Hørsholm, Denmark  
Web: www.allarity.com 
 
 
 
 
  
 
 
CONFIDENTIALITY STATEMENT 
This material is confidential and the property of Sponsor. Its contents must not be disclosed or used 
except as authorised in writing by Sponsor. 
 
 
 
 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 2 of 62
 
Contact Information 
 
Sponsor 
 
 
Primary contact: 
Marie Foegh, MD, Chief Medical Officer  
Allarity Therapeutics  Europe ApS 
Venlighedsvej 1 
2970 Hørsholm, Denmark  
Web: www.allarity.com 
 
 
 
 
 
 
 
 
 
 
CRO  
 
 
 
 
 
 
 
Contract Research Organization : 
SMERUD Medical Research International AS 
Karenslyst allé 6 
N-0278 Oslo 
Norway 
Tel.: +47 2327 2000 
Fax: +47 2327 2001 
Web: http://www.smerud.com 
 
 
 
 
 
 
 
 
 
 
 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 3 of 62
 
TABLE OF CONTENTS 
 
1 
PROTOCOL OUTLINE .............................................................................................................6 
2 
LIST OF ABBREVIATIONS .................................................................................................. 11 
3 
INTRODUCTION ................................................................................................................... 13 
3.1 
BREAST CANCER AND STANDARD TREATMENT ................................................................... 13 
3.2 
DRUG CLASS ................................................................................................................... 13 
3.3 
PREVIOUS CLINICAL STUDIES WITH IXABEPILONE IN METASTATIC BREAST CANCER ............. 14 
3.3.1 
Efficacy .................................................................................................................. 14 
3.3.2 
Safety ..................................................................................................................... 15 
3.3.3 
Specific safety concerns ........................................................................................ 16 
3.4 
RATIONALE FOR STUDY DESIGN ......................................................................................... 17 
3.5 
DRP®  GENERAL DESCRIPTION ..................................................................................... 18 
3.6 
IXABEPILONE DRP® ......................................................................................................... 19 
3.7 
BENEFIT/RISK ASSESSMENT ............................................................................................. 20 
4 
OBJECTIVES ........................................................................................................................ 20 
4.1 
PRIMARY OBJECTIVE: ....................................................................................................... 20 
4.2 
SECONDARY OBJECTIVE: .................................................................................................. 20 
5 
PATIENT SELECTION .......................................................................................................... 20 
5.1 
INCLUSION CRITERIA ........................................................................................................ 20 
5.2 
EXCLUSION CRITERIA ....................................................................................................... 21 
5.3 
RECRUITMENT ................................................................................................................. 22 
5.4 
METHODS FOR ASSIGNING PATIENTS TO TREATMENT ........................................................ 23 
5.5 
FORMALIN-FIXED PARAFFIN-EMBEDDED (FFPE) TUMOR TISSUE FOR DRP ANALYSIS .......... 23 
6 
TREATMENT PROCEDURES .............................................................................................. 23 
6.1 
OVERALL STUDY DESIGN.................................................................................................. 23 
6.2 
STUDY FLOW-CHART ........................................................................................................ 25 
6.3 
ASSESSMENTS AND PROCEDURES .................................................................................... 27 
6.3.1 
Clinic visits ............................................................................................................. 27 
6.3.2 
Demographics ........................................................................................................ 27 
6.3.3 
Urinary pregnancy test ........................................................................................... 27 
6.3.4 
Laboratory tests ..................................................................................................... 27 
6.3.5 
Medical history ....................................................................................................... 28 
6.3.6 
Vital signs............................................................................................................... 28 
6.3.7 
Physical examination ............................................................................................. 29 
6.3.8 
ECG ....................................................................................................................... 29 
6.3.9 
Concomitant diseases ........................................................................................... 29 
6.3.10 
Concomitant medication ........................................................................................ 29 
6.3.11 
Tumor assessment ................................................................................................ 29 
6.3.12 
Baseline documentation ........................................................................................ 30 
6.3.13 
Evaluation of target lesions.................................................................................... 31 
6.3.14 
Evaluation of non-target lesions ............................................................................ 31 
6.3.15 
Evaluation of best overall response ....................................................................... 31 
6.3.16 
Adverse events ...................................................................................................... 32 
6.4 
DESCRIPTION OF INDIVIDUAL VISITS .................................................................................. 32 
6.4.1 
Screening visit (within 6 weeks prior to treatment start): ....................................... 32 
6.4.2 
Baseline visit (within 2 weeks prior to treatment start): ......................................... 32 
6.4.3 
Day 1 of each cycle (within 24 hours before dosing): ............................................ 33 
6.4.4 
Day 8±3   and Day 15±3 of each cycle .................................................................. 33 
6.4.5 
Imaging .................................................................................................................. 33 
6.4.6 
End of treatment (EOT); approximately 28 days after end of last cycle ................ 33 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 4 of 62
 
6.4.7 
Consecutive follow-up: ........................................................................................... 34 
7 
INVESTIGATIONAL MEDICINAL PRODUCT ...................................................................... 34 
7.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) .................................................................. 34 
7.2 
SUPPLY, PACKAGING, LABELLING, HANDLING AND STORAGE .............................................. 34 
7.3 
DOSAGE AND ADMINISTRATION ......................................................................................... 34 
7.4 
TOXICITY GRADING .......................................................................................................... 34 
7.5 
DOSE MODIFICATIONS ...................................................................................................... 35 
7.5.1 
Dose Adjustments during Treatment ..................................................................... 35 
7.5.2 
Dose modification - according to toxicity ............................................................... 36 
7.5.3 
Retreatment Criteria .............................................................................................. 36 
7.6 
PROHIBITED AND RESTRICTED THERAPIES DURING THE STUDY .......................................... 37 
7.6.1 
Prohibited Therapies .............................................................................................. 37 
7.6.2 
Restricted Therapies .............................................................................................. 37 
7.6.3 
Other Restriction .................................................................................................... 37 
7.7 
CONCOMITANT MEDICATION ............................................................................................. 38 
7.8 
DURATION OF TREATMENT ................................................................................................ 38 
7.9 
DRUG ACCOUNTABILITY.................................................................................................... 38 
8 
PREMEDICATION AND HYPERSENSITIVITY REACTIONS .............................................. 38 
8.1 
PREMEDICATION BEFORE TREATMENT WITH IMP ................................................................ 38 
8.2 
HYPERSENSITIVITY REACTIONS......................................................................................... 39 
8.3 
ADDITIONAL RECOMMENDED PRE-MEDICATION TO PREVENT HYPERSENSITIVITY REACTIONS IF 
ORAL MEDICATION FAILS .............................................................................................................. 39 
9 
PATIENT WITHDRAWAL AND REPLACEMENT OF PATIENTS ....................................... 39 
9.1 
COMPLETE WITHDRAWAL .................................................................................................. 40 
9.2 
WITHDRAWAL FROM THE STUDY: ....................................................................................... 40 
9.3 
REPLACEMENT OF PATIENTS ............................................................................................ 40 
9.4 
IMP ACCOUNTABILITY ...................................................................................................... 40 
10 
RESPONSE VARIABLES AND ENDPOINTS .................................................................. 41 
10.1 
ASSESSMENT OF EFFICACY .............................................................................................. 41 
10.1.1 
Primary Efficacy Variable ....................................................................................... 41 
10.1.2 
Secondary Efficacy Variables ................................................................................ 41 
10.2 
ASSESSMENT OF SAFETY ................................................................................................. 41 
10.2.1 
Study-specific Safety Variables ............................................................................. 41 
10.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .......................................................... 42 
10.3.1 
Definitions of Adverse Events ................................................................................ 42 
10.3.2 
Adverse Event assessment definitions .................................................................. 43 
10.3.3 
Follow-up of unresolved AEs ................................................................................. 44 
10.3.4 
Reporting of adverse events .................................................................................. 44 
10.4 
SERIOUS ADVERSE REACTIONS AND UNEXPECTED ADVERSE REACTIONS ........................... 45 
10.4.1 
Definitions .............................................................................................................. 45 
10.4.2 
Reporting of suspected unexpected serious adverse reactions by SMERUD ...... 45 
11 
STATISTICAL METHODOLOGY AND DATA MANAGEMENT ...................................... 46 
11.1 
STUDY STATISTICAL DESIGN ............................................................................................. 46 
11.2 
ESTIMATION OF SAMPLE SIZE ........................................................................................... 46 
11.3 
STATISTICAL ANALYSIS PLAN ............................................................................................ 46 
11.4 
STUDY POPULATIONS ....................................................................................................... 46 
11.5 
DATA COLLECTION / CASE REPORT FORMS ....................................................................... 47 
11.6 
DATA MANAGEMENT ......................................................................................................... 48 
12 
REGULATORY AND ADMINISTRATIVE PROCEDURES .............................................. 48 
12.1 
INSTITUTIONAL REVIEW .................................................................................................... 48 
12.2 
PATIENT INFORMATION / INFORMED CONSENT ................................................................... 48 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 5 of 62
 
12.3 
PATIENT CONFIDENTIALITY ............................................................................................... 48 
12.4 
DATA PROTECTION .......................................................................................................... 49 
12.5 
PATIENT TREATMENT PLAN .............................................................................................. 49 
12.6 
GCP ............................................................................................................................... 49 
12.7 
ESSENTIAL DOCUMENTS ................................................................................................... 49 
12.8 
RECORD RETENTION ........................................................................................................ 50 
12.9 
MONITORING / QUALITY CONTROL .................................................................................... 50 
12.10 
QUALITY ASSURANCE ................................................................................................... 50 
12.11 
INSURANCE AND LIABILITY ............................................................................................ 50 
12.12 
END OF TRIAL .............................................................................................................. 50 
12.13 
STUDY REPORT ........................................................................................................... 51 
12.14 
PUBLICATION AND DATA RIGHTS ................................................................................... 51 
13 
REFERENCES .................................................................................................................. 53 
14 
SIGNATURES ................................................................................................................... 56 
15 
SIGNATURE PAGE FOR INVESTIGATOR...................................................................... 57 
16 
APPENDICES ................................................................................................................... 58 
APPENDIX 1. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS ........................ 59 
APPENDIX 2. NEUROPATHY ASSESSMENT PATIENT EVALUATION FORM ........................................... 60 
APPENDIX 3. VERSION TRACKER ................................................................................................... 61 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 6 of 62
 
1 PROTOCOL OUTLINE 
 
Working title 
Phase II, open label, single arm study to investigate anti-tumor effect 
of ixabepilone in patients with locally recurrent or metastatic breast 
cancer (mBC) selected by the ixabepilone Drug Response Prediction 
(DRP) after failure of an anthracycline and a taxane  
 
Objectives 
Primary:  
 
To evaluate the clinical benefit rate (CBR) of ixabepilone 
Secondary: 
 
To evaluated progression free survival (PFS) 
 
To evaluate overall survival (OS) 
 
To evaluate objective response rate (ORR) defined as 
Complete Response (CR) and Partial Response (PR) 
 
To evaluate the safety profile of ixabepilone in patient with
locally recurrent or metastatic breast cancer  
 
To further establish the clinical validation of the use of the 
DRP-Ixabepilone-Breast in selecting patients with locally 
recurrent or metastatic breast cancer  
 
Assess difference in prediction based on archival and fresh 
biopsy from same patient (percent agreement in binary 
prediction, and difference in primary and secondary 
endpoints with archival versus fresh biopsies) 
 
Efficacy 
variables 
Primary 
 
Clinical Benefit Rate (CBR) will be defined as the proportion of
patients having a Complete Response (CR), Partial Response 
(PR), or Stable Disease (SD) for at least 24 weeks 
  
Secondary 
 
PFS defined as time from randomisation until progressive 
disease(PD) according to RECIST v 1.1 or death, whichever
occurs first  
 
OS defined as the time from randomization until death from 
any cause 
 
ORR defined as the proportion of patients with complete 
response (CR) + partial response (PR) according to RECIST 
v 1.1  
 
Duration of response (DOR) defined as time  of first 
documented CR or PR response until documented tumor 
progression (RECIST v 1.1) 
 
Safety variables 
 
An elicited toxicity in target organs based on the Common 
Terminology Criteria for Adverse Events (NCI-CTCAE v.5.0)  
 
A description of the frequency and severity of adverse events 
based on CTCAE v.5.0  
 
Hematology and clinical biochemistry 
 
Vital signs 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 7 of 62
 
Selection 
criteria  
Inclusion 
1. Signed informed consent form 
2. Age 18 years or older 
3. Patients with histologically or cytological confirmed 
adenocarcinoma of the breast and with confirmed locally 
recurrent or metastatic disease 
4. Patients with hormone receptor positive and HER2 negative 
or triple negative primary tumor. 
5. Previous chemotherapies (neoadjuvant, adjuvant or in the 
metastatic setting) must have included a taxane and an 
anthracycline unless anthracycline therapy is not indicated. 
6. Maximum of three (3) prior chemotherapies in the metastatic 
setting in addition to any number of prior lines of endocrine 
therapy 
7. Measurable disease by RECIST v 1.1 criteria 
8. Performance status of ECO
 
9.  Ixabepilone DRP - score of >67%.  
10. Adequate conditions as evidenced by the following clinical 
laboratory values: 
a. 
9/L 
b. Hemoglobin > 10 g/dL (6.2 mmol/L) 
c. 
9 /L 
d. Alanine aminotransferase (ALT) and aspartate 
 
e. 
1.0 ULN  
f. 
 
g. 
 x ULN or 
documented liver/bone metastases. 
h. Blood urea within normal limits 
11. Because of possible interference of cytochrome P450 3A4 
activity by ixabepilone, patients will be excluded from 
receiving the following medications at enrollment and while 
enrolled onto the study: amiodarone, clarithromycin, 
erythromycin, fluconazole, itraconazole, ketoconazole, 
indinavir, nelfinavir, ritonavir, and saquinavir 
12. Negative pregnancy test at baseline 
13. Women of childbearing age and potential must be willing to 
use highly effective contraception during the study and at 
least until 30 days after last dose of study drug. Male patients 
or male patients who have female partners of childbearing 
age and potential must be willing to use effective 
contraception during the study and at least until 90 days after 
last dose of study drug. Highly effective methods of birth 
control are defined as those which result in a low failure rate 
(i.e. less than 1% per year) when used consistently and 
correctly.  
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 8 of 62
 
Exclusion 
1. HER2 positive tumor 
2. Concurrent chemotherapy, radiotherapy, hormonal therapy, 
or other investigational drug except non-disease related 
conditions (e.g. insulin for diabetes) during study period  
3. Patients with intracranial disease 
4. Other malignancies with exception of curative treated non-
melanoma skin cancer or cervical carcinoma in situ within 5 
years prior to entering the study 
5. Any active infection requiring parenteral or oral antibiotic 
treatment. 
6. Patients with grade 2, in case of diabetes grade 1 or greater 
neuropathy 
7. Clinically significant (i.e. active) cardiovascular disease:  
a. 
 
b. 
prior to day 1 
c. 
 
d. Unstable angina 
e. New York Hart Association (NYHA) Class II or 
greater congestive heart failure (CHF) 
f. 
Serious cardiac arrhythmia requiring medication 
8. Other medications or conditions, including surgery, that in the 
for safety reasons or interfere with the interpretation of study 
results 
9. Requiring immediate palliative treatment of any kind 
including surgery and/or radiotherapy 
10. Female patients who are pregnant or breast-feeding 
(pregnancy test with a positive result before study entry) 
11. Known prior severe hypersensitivity reactions to agents 
containing polyoxyethylated castor oil (Cremophor EL) 
12. Patients must not continue treatment with the following 
strong inhibitors of CYP3A4: 
ketoconazole, itraconazole, ritonavir, amprenavir, indinavir, 
nelfinavir, delavirdine and voriconazole. These therapies 
should be discontinued 72 hours prior to initiation of study 
drug therapy. Similarly, patients must not continue treatment 
with the following strong inducers of CYP3A4: phenytoin, 
carbamazepine, rifampin, rifabutin, dexamethasone, and 
phenobarbital. (20 mg dexamethasone can be used for pre-
treatment if required). These therapies should be 
discontinued 72 hours prior to initiation of study drug therapy 
13. Positive HIV and hepatitis B and C status, assessed from 
medical records only 
 
Methods & procedures 
This study is a multi-center, open-label, non-randomized, phase II 
study of ixabepilone as treatment in patients with locally recurrent or 
metastatic breast cancer. Previous chemotherapies (neoadjuvant, 
adjuvant or in the metastatic setting) must have included a taxane 
and an anthracycline unless anthracycline therapy is not indicated. 
The patients should have received a maximum of three (3) prior 
chemotherapies in the metastatic setting.  
Patients will be screened with the ixabepilone DRP. If the DRP score 
is above >67% the patient can be included in the clinical study, if all 
the other eligibility criteria are fulfilled.  The biopsy should be taken 
after the last anticancer treatment has been stopped. If such biopsy 
is not available it has to be done during the screening (first 2 weeks, 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 9 of 62
 
if possible). The biopsy can be taken from any lesion, and the sample 
will be used to obtain the DRP score. 
Patients will receive ixabepilone every 3 weeks until the occurrence 
of: 
 disease progression, or 
 unacceptable toxicity, or 
 patient refusal/withdrawing of consent, or 
 non-compliance to the protocol, or 
 physician decision to discontinue treatment, or 
  treatment delay > 2 weeks (except in the case of perceived 
patient benefit)  
 
Medication 
(dose, route,  
duration) 
Test 
Ixabepilone is classified as a microtubule inhibitor and is a 
semisynthetic analog of the natural product epothilone B. 
The dose of ixabepilone is 40 mg/m2 infused intravenously over 3 
hours every 3 weeks. Doses for patients with body surface area 
(BSA) greater than 2.2 m2 should be calculated based on 2.2 m2. 
To minimize the chance of occurrence of a hypersensitivity reaction, 
all patients must be premedicated approximately 1 hour before the 
infusion of ixabepilone with: 
 
An H1 antagonist (e.g., diphenhydramine 50 mg 
orally or equivalent)  
and 
 
An H2 antagonist (e.g., famotidine 20 -40 mg orally, 
cimetidine 200 - 400 mg orally or equivalent) 
 
Patients who experienced a hypersensitivity reaction to ixabepilone 
require premedication with corticosteroids (e.g., dexamethasone 20 
mg intravenously, 30 minutes before infusion or orally, 60 minutes 
before infusion) in addition to pretreatment with H1 and H2 
antagonists.  
Neuropathy will be closely monitored in order to adjust or delay 
dosing of ixabepilone (according to US IXEMPRA package insert; 
instruction for use). 
Comparator 
None 
 
Statistics 
Sample 
size 
Up to 200 patients with sufficient tumor tissue material will be 
screened to include 60 patients (53 patients evaluable for response), 
who consent to participate in the study. 
Patients for whom a biopsy after last anticancer treatment is not 
available or has a DRP below 67 % will not count towards the 200 
patients screened, and 60 patients treated, and will not be included in 
the primary analysis. 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 10 of 62
 
Methods 
 
Simon's two-stage design (Simon, 1989, Minimax) will be used. The 
null hypothesis that the true clinical benefit rate is 25% will be tested 
against a one-sided alternative. In the first stage, 30 patients will be 
accrued, and 28 patients are expected to be evaluable. If there are 7 
or fewer with clinical benefit in these 28 patients, the study will be 
stopped. Otherwise, 30 additional patients will be accrued for a total 
of 60, of which 53 are expected to be evaluable. The null hypothesis 
will be rejected if 19 or more with clinical benefit are observed in 53 
patients. This design yields a type I error rate of 0.05 and power of 
0.8 when the true response rate is 41%.  
 
The clinical benefit rates may differ in the actual population, but the 
difference between unselected historical control and selected 
population should remain constant. One-sided comparisons of CBR 
between treatment and historic control will be performed, and will be 
repeated for subgroups defined by ER status. 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 11 of 62
 
2 LIST OF ABBREVIATIONS  
 
ADC 
ADL 
AE 
Allarity 
ALT 
ANC 
APTT 
AST 
BMS 
BSA 
CBC 
CBR 
CHF 
CI 
CR 
Analog-to-Digital Converter 
Activities of Daily Living 
Adverse Event 
Allarity Therapeutics  
Alanine Aminotransferase 
Absolute Neutrophils Count 
Activated Partial Thromboplastin Time 
Aspartate Aminotransferase 
Bristol-Myers Squibb 
Body Surface Area 
Complete Blood Count 
Clinical Benefit Rate 
Congestive Heart Failure 
Confidence Interval 
Complete Response 
CRA 
Clinical Research Associate 
CRF 
CRO 
Case Report Form 
Contract Research Organization 
CSR 
CT 
CTC 
Clinical Study Report 
Computed Tomography 
Common Terminology Criteria 
DM 
DOR 
DPD 
DPO 
DRP 
ECG 
ECOG 
Data Manager 
Duration of Response 
Dihydropyrimidine Dehydrogenase Deficiency 
Data Protection Officer 
Drug Response Prediction 
Electrocardiogram 
Eastern Cooperative Group Performance 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
EOT 
ER 
EU 
FDA 
FFPE 
The European Medicines Agency 
End of Treatment  
Estrogen Receptor 
European Union 
Food and Drug Administration 
Formalin-Fixed Paraffin-Embedded 
GCP 
G-CSF 
GM-CSF 
HCG 
HER2 
HIV 
HSR 
IB 
Good Clinical Practice 
Granulocyte Colony-stimulating Factor 
Granulocyte-macrophage Colony-stimulating Factor 
Human Chorionic Gonadotropin 
Human Epidermal Growth Factor Receptor 2 
Human Immunodeficiency Viruses 
Hyper Sensitivity Reaction 
Investigators Brochure 
ICF 
Informed Consent Form 
ICH 
ICR 
IEC 
International Conference on Harmonisation 
Independent Committee Review 
Independent Ethics Committee 
IMP 
INR 
IRB 
Investigational Medicinal Product 
International Normalized Ratio 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
IV 
Intention-To-Treat 
Intravenous 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 12 of 62
 
L 
mBC 
mg 
mL 
MRI 
mRNA 
MRP1 
NCI 
NCI-CTCAE 
NYHA 
ORR 
OS 
OTC   
pCR 
pCRB 
pCRBL 
PD 
Litre 
Metastatic Breast Cancer 
Milligram 
Millilitre 
Magnetic Resonance Imaging 
Messenger Ribonucleic Acid 
Multidrug Resistance-related Protein 1 
National Cancer Institute 
National Cancer Institute Common Terminology Criteria for Adverse Events 
New York Hart Association 
Objective Response Rate 
Overall Survival 
Over the Counter 
Pathological Complete Remission 
Pathologic Complete Response in the Breast at surgery 
Pathologic Complete Response in the Breast and Lymph nodes at surgery 
Progressive Disease 
PI 
Principal Investigator 
PIS 
PR 
PSF 
Q3 
RECIST 
SADR 
Patient Information Sheet  
Partial Response 
Progression Free Survival 
Every 3 weeks 
Response evaluation criteria in solid tumors 
Serious Adverse Drug Reaction 
SAE 
SAP 
Serious Adverse Event 
Statistical Analysis Plan 
SD 
SD 
Standard Deviation 
Stable Disease 
SDV 
SmPC 
SOP 
Source Data Verification 
Summary of product characteristics 
Standard Operating System 
SUSAR 
TEAE 
TIA 
ULN 
 
Suspected Unexpected Serious Adverse Reaction 
Treatment-emerging Adverse Events 
Transient Ischemic Attach 
Upper Limit Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 13 of 62
 
 
3 INTRODUCTION 
3.1 Breast Cancer and standard treatment 
 
Breast cancer is the leading cancer disease and the leading cause of cancer related deaths in 
women. A large proportion of patients with primary breast cancer are categorized as having high 
risk disease based on tumor histology grade, estrogen receptor measurements, lymph node 
involvement, and age and tumor size. These high-risk breast cancer patients are offered adjuvant 
chemotherapy which often includes anthracyclines, cyclophosphamide and taxanes. Despite 
adjuvant treatment approximately 20% of all breast cancer patients will experience disease 
recurrence with local or distant recurrences, some of which will be metastasis to the brain. 
Treatment for metastatic breast cancer includes endocrine treatment and/or chemotherapy in 
combination with biological treatment in HER2 positive patients. 
The outcome after chemotherapy and endocrine therapy for metastatic breast cancer becomes 
poorer and poorer at each time a new treatment is introduced due to progression on the former 
treatment. With first line treatment, the expected objective response rate is approximately 50% 
declining to less than 25% at 3-4th line treatment (1). Worldwide about 500,000, in Europe about 
189.000 and in Denmark about 1100 breast cancer patients die annually (2,3).  
Anthracyclines and taxanes are generally considered the most active cytotoxic drug classes in 
breast cancer. As a result, both classes of agents are commonly used in the metastatic as well as 
the adjuvant setting. However, some patients demonstrate primary resistance to anthracyclines 
and taxanes and some patients fail to respond to taxanes in the first-line setting.  
Capecitabine is approved to treat patients with metastatic breast cancer who have received prior 
anthracycline- and taxane-based chemotherapy for early or late-stage breast cancer (4) and FDA 
have approved capecitabine in combination with ixabepilone for this indication. However, this 
treatment regime was not approved by EMA in EU as they concluded, that combination with 
ixabepilone did not substantially improve the effect of capecitabine alone (5). Patient selection 
with the ixabepilone DRP is expected to enrich the trial population with likely responders.  
 
3.2 Drug Class 
The IMP ixabepilone is FDA approved as IXEMPRA® for the treatment of Breast Cancer 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022065s002lbl.pdf) and is a semisynthetic 
analog of the natural product epothilone B. The epothilones and their analogs are a novel class of 
non-taxane microtubule-stabilizing agents obtained from the fermentation of Sorangium 
cellulosum. Ixabepilone was developed by Bristol-Myers Squibb (BMS) for its potential use in the 
treatment of cancer.  
Ixabepilone is a novel antineoplastic agent that stabilizes microtubule dynamics, resulting in 
blockade of cancer cells in mitosis during cell division, leading to cell death (6). Ixabepilone 
induces a distinct pathway of cellular apoptosis via activation of caspase-2, whereas other tubulin 
agents, such as the taxanes, act via caspase-9 (7). Ixabepilone is a poor substrate for efflux 
transporters such as the multidrug resistance-related protein (MRP1) and P-glycoprotein (P-gp) 
that are involved in drug-resistance mechanisms (8). Epothilones have a tubulin-binding mode 
distinct from that of other microtubulestabilizing agents 1(9). Ixabepilone
-binding mode 
affects the microtubule dynamics of multiple -tubulin isoforms, including the class III isoform of 
-tubulin ( -III tubulin) (8, 10, 11) the expression of which has been implicated in clinical taxanes 
resistance (12-15). 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 14 of 62
 
 
3.3 Previous Clinical Studies with ixabepilone in Metastatic Breast 
Cancer  
Ixabepilone has been evaluated in 13 BMS-sponsored clinical studies hereof 8 in Metastatic 
Breast Cancer. 
In Phase 1 studies of ixabepilone as monotherapy, objective responses were demonstrated in 9 
various tumor types (16, 17). Dose-limiting toxicities observed in ixabepilone as monotherapy 
included sensory neuropathy, neutropenia, myalgia, and fatigue. Adverse events (AEs) in patients 
where ixabepilone was used in combination with other chemotherapy agents were similar 
qualitatively, no toxicities unique to combination therapies were reported. 
Pharmacokinetics results indicate that exposure to ixabepilone is increased by 22%, 30%, and 
81% in patients with mild, moderate, or severe hepatic dysfunction, respectively (18). After 
coadministration of ixabepilone and capecitabine, PK differences are minor and are not expected 
to affect the safety profile or efficacy of either ixabepilone or capecitabine. 
 
Phase 2 studies demonstrated the activity of ixabepilone in advanced breast cancer (19-24), and 
other malignancies, the most notable toxicities reported of ixabepilone as monotherapy are 
peripheral neuropathy, neutropenia, myalgia, arthralgia, alopecia, and fatigue. The peripheral 
neuropathy has been predominantly sensory, cumulative in nature, and reversible upon 
discontinuation of ixabepilone. 
 
Five studies of ixabepilone monotherapy (40 mg/m2/3 hours) have shown effect in breast cancer 
as neoadjuvant treatment and 4 in advanced, locally recurrent or metastatic, breast cancer (see 
Table 1). 
 
Table 1. Survey of Phase 2 Studies, Monotherapy (40 mg/m2/3 h) in Breast Cancer (25) 
 
Study No. 
 
Setting/Population 
 
N 
 
Treatment 
 
Efficacy end-point 
CA163009 
Advanced breast cancer 
Taxane resistant 
49 
Ixabepilone 40 mg/m2 Q3 
week 
ORR1 
CA163010 
Advanced breast cancer 
Anthracycline pretreated 
65 
Ixabepilone 40 mg/m2 Q3 
week 
ORR1 
CA163081 
Advanced breast cancer - 
resistant to anthracycline, 
taxane, and capecitabine 
126 
Ixabepilone 40 mg/m2 Q3 
week 
ORR1 
CA163080 
Neoadjuvant therapy 
Invasive breast 
 
not amenable to breast 
conservation surgery 
164 
Ixabepilone 40 mg/m2 Q3 
week (max 4 cycles) 
1° Best ORR1 (CR2 or 
PR3) 
Co-2°: 
pCRB4 and 
pCRBL5 
CA163107 
Metastatic breast cancer 
Anthracycline pretreated, 
taxane resistant 
54 
Ixabepilone 40 mg/m2 Q3 
week (max 9 cycles) 
1° RR6 (by IRC7) 
2°:duration of response 
time to progression 
1ORR=Objective Response Rate, 2CR=Complete Response, 3PR=Partial Response, 4pCRB = pathologic 
complete response in the breast at surgery, 5pCRBL= pathologic complete response in the breast and lymph 
nodes at surgery, 6RR=Response Rate, 7IRC= Independent Review Committee; Q3=every 3 weeks 
3.3.1 Efficacy 
In advanced breast cancer  the ORR of ixabepilone monotherapy varies from 11.5 to 42 % 
depending on the lines of chemotherapy and resistancy (26). In the large phase 2 study 
(CA163081) in patients resistant to anthracycline, taxane and capecitabine, ORR was 11.5% (CI-

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 15 of 62
 
95% 6.3 to 18.9%) and with SD >24 weeks in 14.3%. Furthermore, the median PFS and duration 
of response was 3.1 months and 5.7 months respectively (24). 
3.3.2 Safety 
3.3.2.1 General safety concerns 
The most common Treatment-emerging Adverse Events (TEAE) of ixabepilone monotherapy in 
advanced breast cancer  (Studies CA163081, CA163009, CA163010 and CA163080)  were 
alopecia (59%), fatigue (53%), myalgia (50%), peripheral sensory neuropathy (49%), nausea 
(48%), arthralgia (31%), vomiting (30%), stomatitis (28%), and diarrhea (26%). Treatment-related 
cardiac events were rare in patients who received ixabepilone as monotherapy. 
The most frequently reported grade 3/4 TEAEs appear from Table 2.  
 
Table 2. Grade 3/4 treatment-emerging adverse events most frequently reported in patients 
with advanced breast cancer (monotherapy)(Studies CA163081, CA163009, CA163010 and 
CA163080). 
 
Table 3 presents both the nonhematologic and hematological most commonly reported treatment 
related adverse events occurring in patients with metastatic or locally advanced breast cancer 
treated with ixabepilone as monotherapy in the published study CA163081. 
 
 
 
 
 
 
 
 
 
 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 16 of 62
 
Table 3. Most common treatment-emerging adverse events in CA163081,(24) 
 
 
3.3.3 Specific safety concerns 
3.3.3.1 Peripheral neuropathy 
Peripheral neuropathy is the main non-hematologic toxicity of ixabepilone. Peripheral neuropathy 
was reported in 62% of patients in study CA163081 (64% across the 3 monotherapy studies). 
Painful neuropathies, as defined by the occurrence of neuropathic pain, dysesthesia or neuralgia, 
were reported in 6% of patients in the 3 monotherapy studies. Peripheral motor neuropathy was 
reported in 7% of patients in the 3 monotherapy studies and usually occurred in patients with 
sensory neuropathy. Autonomic neuropathy was rare, occurring in 1% of patients in the 3 
monotherapy studies. The ixabepilone studies focused on patients who were resistant to prior 
therapies, including taxanes. As such, a proportion of patients had baseline peripheral sensory 
neuropathy (27% in CA163081), though patients with Grade 2 or higher peripheral neuropathy 
(sensory or motor) at study entry were excluded from studies with ixabepilone.   
The neuropathy is cumulative with the time of treatment and partly reversible after dose-
reduction. In CA163081 the median number of cycles to onset of grade 3/4 neuropathy was 4 and 
the median time to improvement and resolution of grade 3/4 neuropathy was 4.6 and 5.4 weeks 
respectively 
(EMA) London, 23 April 2009) (5). 
3.3.3.2 Myelosuppression 
Myelosuppression was summarized across studies CA163081, CA163009, CA163010 and 
CA163080. In this population Grade 3 or 4 neutropenia was reported in 55% of all patients 
treated with monotherapy in advanced breast cancer. Furthermore, thrombocytopenia was mostly 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 17 of 62
 
Grade 1 (35%) and Grades 3 or 4 thrombocytopenia was reported in 6% of patients. The majority 
of cases of anemia were Grade 1 or 2 and Grades 3 or 4 anemia was reported in 8% of all 
patients. 
 
3.3.3.3 Hypersensitivity Reactions 
The diluent used with BMS-247550 is a BMS-purified polyoxyethylated castor oil (CremophorEL) 
and has the potential for inducing a hypersensitivity reaction. In clinical trials of BMS-247550, 
anaphylaxis and severe hypersensitivity reactions 
dyspnea requiring bronchodilators, 
hypotension requiring treatment, syncope, and bradycardia) that were reported as serious 
adverse events have occurred in less than 1% of patients. Routine premedication, including H1 
and H2 blockers (e.g., diphenhydramine and ranitidine) was instituted after 2 patients developed 
severe hypersensitivity adverse events (dyspnea and bronchospasm) in the weekly Phase I 
monotherapy trial. Since the institution of premedication the incidence of CTC term: 
hypersensitivity of any grade is < 1% in 439 patients treated in all BMS sponsored Phase II trials. 
Additionally, 17% of patients had CTC terms of allergy/immunology: Other, (of any grade) 
reported; the majority of incidents consisted of skin rash.  Steroids were not required as 
premedication, unless prior hypersensitivity reaction (HSR) had been reported. Patients with a 
prior history of HSR to polyoxyethylated castor oil were excluded from the studies. 
Hypersensitivity reactions were reported in 79 (6%) of the 1323 patients who received any 
ixabepilone in the Phase II and III studies. Most HSR occurred in Cycles 1 (32/79; 41%) and 2 
(36/79; 46%). Grade 3/4 hypersensitivity reactions, including anaphylaxis, were rare and were 
reported in 9 (1%) patients (all but 1 in the first 2 cycles), 3 of whom subsequently received 
additional cycles of ixabepilone. HSRs rarely led to discontinuation (< 1% of patients). There were 
no deaths due to hypersensitivity reactions. 
3.4 Rationale for study design 
Ixabepilone is approved by FDA for use in patients with with metastatic or locally advanced breast 
cancer. Ixabepilone has documented treatment effect both in combination with capecitabine and 
as monotherapy (see current SmPC for Ixempra). Since there are few treatment options for 
patients resistant to antracylines, taxanes and capecitabine, ixabepilone is an alternative 
treatment option for these late stage breast cancer patients. Ixabepilone given as monotherapy 
has a documented ORR that varies between 11.5 to 42% (26). With this relatively low response 
rate a relatively high amount of patients will be exposed to treatment without having an effect, and 
thereby also exposed to the side effects of the product. Therefore, a Drug Response Prediction 
methodology (see below) has been introduced in the current study. Patients expected to respond 
to treatment will be selected according to a tumor biopsy mRNA expression profiling, leading to a 
DRP score (see section 3.5) and only patients having a DRP score > 67% will be considered as 
possible positive responders and included in the study. About half of patients are expected to 
have a positive DRP score (above > 67%) and can be offered therapy with ixabepilone. 
 
This is a clinical study with an enrichment design to facilitate precision medicine. The DRP profile 
is used to allocate the patients with high likelihood of response to therapy with ixabepilone (Figure 
1).  
 
 
 
 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23
Page 18 of 62
Figure 1. Schematic diagram of trial design and procedures for patient selection 
3.5
DRP®
General Description
Allarity Therapeutics (Allarity) in Hoersholm, Denmark, is developing the Drug Response 
Prediction (DRP®) for individual systemic anti-cancer treatments. A DRP® is an assay that is 
based on samples from a tumor that can estimate the likelihood of whether the tumor will respond 
to a specific drug. The DRP® method builds on the comparison of sensitive and resistant cell 
lines including genomic information from the NCI (USA) NCI60 cell lines, clinical tumor biology 
and clinical correlates in a systems biology network. Allarity uses messenger RNA (mRNA) to 
make such a drug specific estimate. Analytical validation is established. Clinical validation has 
been investigated and established in several study settings and have been published (27-33). 
The further clinical validity of the ixabepilone DRP® in advanced breast cancer is one of the 
objectives of this phase 2 study.
Each drug for which Allarity Therapeutics develops a DRP® based on in vitro data and big data 
from patients, has a unique signature of 200 to 400 genes. This signature is matched to the 
corresponding genes in the universal microarray (which contains all genes) in order to make 
prediction for a specific drug for a specific patient. Even drugs, for which a signature is developed 
in the future, can be matched to the existing microarray data for a specific patient.

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 19 of 62
 
3.6 Ixabepilone DRP® 
The procedure for developing ixabepilone DRP® is based on mRNA expression data on data 
from growth inhibition studies in 60 cancer cell lines (NCI60). The prediction has been tested in a 
cross-validation on the cell line data. The correlation between measured and predicted sensitivity 
was 0.28 which points to an ability to predict in a clinical setting. The genes that differed in 
expression between sensitive and resistant cell lines were analyzed for clues to resistant 
mechanisms. In an analysis of 26 different cancer indications, it was predicted that in addition to 
hematological malignancies, breast cancer, renal cancer, melanoma, glioma and others were 
sensitive to ixabepilone.  
Evaluation of ixabepilone DRP in neoadjuvant breast cancer. 
The ixabepilone DRP, an mRNA-based predictor of responsiveness to ixabepilone was 
developed and applied to gene expression data prepared using clinical samples from breast 
cancer patients treated neoadjuvantly with ixabepilone (34). The samples were diagnostic 
biopsies analyzed with Affymetrix GeneChips.  Using the ixabepilone DRP, patients with 
pathological complete remission (pCR) were predicted to be more sensitive to ixabepilone than 
patients with no pCR (Figure 2). 
 
Figure 2. Sensitivity to ixabepilone predicted by the ixabepilone DRP. 
 
Table 4 shows the number of responders correctly predicted at a cutoff of 67, demonstrating an 
increased response rate for breast cancer patients having DRP scores above the cutoff. 
 
Table 4.  Number of predicted responders at a cutoff of 67 
 
Responders (pCR)
Non responders (no pCR)
DRP positive (>67) 
21 
29 
DRP negative (<=67)
14 
68 
Response rate above cutoff: 42% 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 20 of 62
 
Response rate below cutoff: 17% 
 
3.7 Benefit/Risk Assessment 
Locally advanced or metastatic breast cancer is a life-threatening disease. The outcome after 
chemotherapy and endocrine therapy for metastatic breast cancer becomes poorer and poorer 
each time a new treatment is introduced due to progression on the former treatment. The 
management of metastatic breast cancer continuous to evolve and improve towards a chronic 
disease model with sequential use of lines of therapy. Therefore there is a need for alternative 
treatment options, for patients who progress on various taxanes, anthracyclines, and 
capecitabine; that can be supported by a methodology (Drug Response Prediction) for selecting 
the most efficient drug for the patient. 
 
If DRP selection identifies those patients who have a high likelihood of responding to ixabepilone, 
we can select those patients who will benefit while excluding those patients that will not. The 
toxicity profile of ixabepilone is generally manageable and predictable. The potential benefit of 
treatment would then most likely outweigh the expected risks. 
 
4 OBJECTIVES 
4.1 Primary objective: 
 
To evaluate the clinical benefit rate (CBR) ixabepilone. 
4.2 Secondary objective: 
 
To evaluated progression free survival (PFS). 
 
To evaluate overall survival (OS). 
 
To evaluate objective response rate (ORR) defined as Complete Response (CR) 
and Partial Response (PR).  
 
To evaluate the safety profile of treatment with in locally recurrent or metastatic 
breast cancer.  
 
To further establish the clinical validation of the use of the DRP-Ixabepilone-
Breast in selecting patients locally recurrent or with metastatic breast cancer.  
 
Assess difference in prediction based on archival and fresh biopsy from same 
patient (percent agreement in binary prediction, and difference in primary and 
secondary endpoints with archival versus fresh biopsies) 
 
5 PATIENT SELECTION 
The target study population is patients with locally recurrent or metastatic breast 
adenocarcinoma, with hormone positive and HER2 negative or triple negative primary tumors, 
who have received a maximum of 3 prior chemotherapies in the advanced setting. 
5.1 Inclusion Criteria 
In order to participate in this study the patients must meet all of the following inclusion criteria: 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 21 of 62
 
1. Signed informed consent form 
2. Age 18 years or older 
3. Patients with histologically or cytological confirmed adenocarcinoma of the breast and 
with confirmed locally recurrent or metastatic disease 
4. Patients with hormone receptor positive and HER2 negative or triple negative primary 
tumor 
5. Previous chemotherapies (neoadjuvant, adjuvant or in the metastatic setting) must have 
included a taxane and an anthracycline unless anthracycline therapy is not indicated 
6. Maximum of three (3) prior chemotherapies in the metastatic setting in addition to any 
number of prior lines of endocrine therapy 
7. Measurable disease by RECIST v 1.1 criteria 
8. Performance 
 
9. DRP®-Ixabepilone score of >67%.  
10. Adequate conditions as evidenced by the following clinical laboratory values: 
a. 
9/L 
b. Hemoglobin  10 g/dL (6.2 mmol/L) 
c. 
9 /L 
d. Alanine aminotransf
ULN  
e. 
0 ULN 
f. 
 
g. 
 x ULN or 
metastases  
h. Blood urea within normal limits 
11. Because of possible interference of cytochrome P450 3A4 activity by ixabepilone, 
patients will be excluded from receiving the following medications at enrollment and while 
enrolled onto the study: amiodarone, clarithromycin, erythromycin, fluconazole, 
itraconazole, ketoconazole, indinavir, nelfinavir, ritonavir, and saquinavir 
12. Negative pregnancy test before study entry 
13. Women of childbearing age and potential must be willing to use highly effective 
contraception during the study and at least until 90 days after last dose of study drug. 
Male patients or male patients who have female partners of childbearing age and 
potential must be willing to use effective contraception during the study and at least until 
90 days after last dose of study drug. Highly effective methods of birth control are defined 
as those which result in a low failure rate (i.e. less than 1% per year) when used 
consistently and correctly. 
5.2 Exclusion Criteria 
 
In order to participate in the study the patients must not meet any of the following exclusion 
criteria: 
1. HER2 positive tumors 
2. Concurrent chemotherapy, radiotherapy, hormonal therapy, or other investigational drug 
except non-disease related conditions (e.g. insulin for diabetes) during study period and 
terminated within 4 weeks prior to entering the study 
3. Patients with intracranial disease 
4. Other malignancy with exception of curative treated non-melanoma skin cancer or 
cervical carcinoma in situ within 5 years prior to entering the study 
5. Any active infection requiring parenteral or oral antibiotic treatment. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 22 of 62
 
6. Patients with grade 2, in case of diabetes grade 1 or greater neuropathy 
7. Clinically significant (i.e. active) cardiovascular disease:  
a. 
 
b. 
 
c. 
 months prior to day 1 
d. Unstable angina 
e. New York Hart Association (NYHA) Class II or greater congestive heart failure 
(CHF) 
f. 
Serious cardiac arrhythmia requiring medication 
8. 
n 
would contraindicate study participation for safety reasons or interfere with the 
interpretation of study results 
9. Requiring immediate palliative treatment of any kind including surgery and/or 
radiotherapy 
10. Female patients who are pregnant or breast-feeding (pregnancy test with a positive result 
before study entry) 
11. Known prior severe hypersensitivity reactions to agents containing polyoxyethylated 
castor oil (Cremophor EL) 
12. Patients must not continue treatment with the following strong inhibitors of CYP3A4: 
ketoconazole, itraconazole, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine 
and voriconazole. These therapies should be discontinued 72 hours prior to initiation 
of study drug therapy 
Similarly, patients must not continue treatment with the following strong inducers of 
CYP3A4: phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, and 
phenobarbital (20 mg dexamethasone can be used for pre-treatment if required). These 
therapies should be discontinued 72 hours prior to initiation of study drug therapy 
13. Positive HIV and hepatitis B and C status, assessed from medical records only 
 
5.3 Recruitment  
 
Eligible patients will have the study explained to them and will receive the written patient 
information sheet (PIS). After having had the time to review the nature of the study, they will have 
the opportunity to ask questions to the investigational team. If, after this, the patients agree to 
participate, they will be asked to sign and date one original of the written informed consent form 
(ICF). The patients will then receive a copy of the signed and dated patient information/informed 
consent form. The original signed ICF will be filed in the Investigator Site File (ISF). The PIS will 
contain site contact information in case of any questions or medical emergency. 
 
Any written information given to potential patients will be submitted to, and approved by, the 
respective Ethics Committee(s) prior to implementation. 
 
The Investigator will maintain a Patient Screening Log to collect information on all patients who 
sign an ICF regardless of whether or not they meet the study eligibility criteria following 
completion of the screening evaluations. After completion of Screening, all patients deemed 
eligible to take part in this study will be entered onto a Patient Identification Log. 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 23 of 62
 
5.4 Methods for Assigning Patients to Treatment 
All patients signing the ICF and who enter the formal screening process will be assigned a unique 
screening number automatically via the eCRF system. This number will consist of two letters and 
5 digits. The letters identifying the country,  the first two digits being the site number (e.g., 01) and 
the last three digits consisting of the sequence number in which the patient was screened at the 
site (e.g., the third patient screened would be 003). 
Following successful compltion of the screening/baseline evaluations and confirmation that the 
patient is eligible for participation, the patient will be assigned to treatment. 
 
5.5 Formalin-Fixed Paraffin-Embedded (FFPE) tumor tissue for DRP 
analysis 
A biopsy should be taken after the last anticancer treatment has been stopped. If such biopsy is 
not available it may be done during the screening (first 2 weeks, if possible). This sample will be 
used for DRP assessment.  
The biopsy can be taken from any lesion, most likely the most accessible lesion, but this will be 
the 
. Formalin-Fixed Paraffin-Embedded (FFPE) tissue specimens should be 
prepared (see the Standard Guidelines for FFPE Tissue Collection for DRP analysis). 
Patients can be included based on an archival biopsy, but a new biopsy should be obtained 
wherever possible before treatment start. If included on archival biopsy and the new biopsy is 
negative or not possible, patients can continue treatment. 
 
Tumor tissue will be obtained from the local pathology department in accordance with  
 Standard Guidelines for FFPE Tissue Collection for DRP analysis and relevant tissue section 
(2-6 sections of 10-20µm for a total of 40-60µm) will be cut at the pathological department. Tissue 
collection kits are produced for participating sites. The collection kits are produced as single 
unique, serialized and pseudonymized kits ensuring confidentiality for the patient. All data is 
stored secured and all data transfers are encrypted. 
 
Allarity Therapeutics will receive the samples. RNA is isolated from the tumor biopsy, amplified, 
labelled and hybridized to microarray gene chips to obtain gene expression data of the tumor 
tissue. The gene expression data is patented to Allarity 
 DRP analysis algorithm for 
generation of a DRP score ranging from 0 to 100. Investigator sites will get binary DRP result 
reported, i.e. 1 for a DRP positive score and 0 for a DRP negative score. 
Analyses of the tumor tissue will be performed Allarity Therapeutics, Hoersholm, Denmark. They 
will calculate the DRP score and report back to the site within approximately 2 weeks. The 
samples will be destroyed at the end of study. 
 
6 TREATMENT PROCEDURES 
6.1 Overall Study Design 
This study is a multi-center, open-label, non-randomized, phase II study of ixabepilone as 
treatment in patients with locally recurrent or metastatic breast cancer. Previous chemotherapies 
(neoadjuvant, adjuvant or in the metastatic setting) must have included a taxane and an 
anthracycline unless anthracycline therapy is not indicated. The patients should have received a 
maximum of three (3) prior chemotherapies in the metastatic setting.  

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 24 of 62
 
 
A biopsy should be taken after the last anticancer treatment has been stopped. If such biopsy is 
not available it may be done during the screening (first 2 weeks, if possible). This sample will be 
used for DRP assessment. The patient mRNA expression profiling will lead to a DRP score 
selected by the Ixabepilone DRP methodology. 
  
Up to 200 patients with sufficient tumor tissue material will be screened to include 60 patients (53 
patients evaluable for response) with a DRP score of > 67%. The study will be performed in 
accordance with the Simon two-stage design. In the first stage, 30 patients will be accrued, and 
28 patients are expected to be evaluable. If there are 7 or fewer with clinical benefit in these 28 
patients, the study will be stopped. Otherwise, 30 additional patients will be accrued for a total of 
60, of which 53 are expected to be evaluable. Patients for whom a biopsy after last anticancer 
treatment is not available or has a DRP below 67% will not count towards the 200 patients 
screened, and 60 patients treated, and will not be included in the primary analysis. 
 
 
The patients will come to the screening visits within 6 weeks prior to the first possible 
administration of IMP. Patients will receive ixabepilone 40 mg/m2 as a 3-h intravenous infusion on 
day 1 in a 21 days cycle.  
Patients will continue the treatment until the occurrence of: 
 
disease progression, or 
 
unacceptable toxicity, or 
 
patient refusal/withdrawing of consent, or  
 
non-compliance to the protocol, or  
 
 
 
treatment delay > 2 weeks (except in the case of perceived patient benefit).  
 
An End of Treatment visit will be conducted 4 weeks after administration of ixabepilone is 
stopped. Patients with CR, PR or SD where treatment have been stopped will continue to be 
follow-up and tumour assessment will be performed until disease progression.  
All study related visits will be conducted within the period approved by the Regulatory Authorities 
and Ethics Committees. Any delay in the study that will affect the overall approved period will be 
amended to the authorities. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 25 of 62
 
6.2 Study Flow-chart 
Procedures 
Pre-treatment 
 
 All Treatment Cycles 
End of 
Treatment19
Post 
treatment 
follow-up 
(~every 3 
months) 
Day 1 
 
 
Day 8 ±3 days 
and 
Day 15±3 days
 
Screening 
< 6 weeks 
Baseline 
< 2 weeks 
Informed Consent1 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria2
Xa 
Xb 
 
 
 
 
Tumor biopsy - DRP/Tumor 
mRNA expression profiling3
X 
 
 
 
 
 
DRP results4 
 
X 
 
 
 
 
Medical  history5 
 
X 
 
 
 
 
Physical examination and 
vital signs6 
 
X 
X 
 
X 
 
Neurotoxicity questionnaire7
 
 
X 
 
X 
 
Complete Blood Count 
(CBC)8 
 
X 
X 
Xc 
X 
 
Blood chemistry9 
 
X 
X 
 
X 
 
Pregnancy test10 
X 
X 
 
Tumor 
assessments/Scans11 
X 
At Week 6 and thereafter every 9
Weeks for 24 weeks; thereafter 
every 3 months 
X (every 3 
months until 
progression) 
12-lead ECG12 
X 
 
 
X 
 
Pre- Medication13 
 
X 
 
 
 
IMP (ixabepilone)14 
 
X 
 
 
 
Follow up during infusion of
ixabepilone15 
 
 
X 
 
 
 
 
Adverse events / Baseline 
Conditions / Toxicity 
assessments16 
X 
X 
 
Xd 
X 
X 
Concomitant 
medication/therapies17 
X 
X 
 
Xe 
 
X 
 
Survival follow-up18 
 
 
 
 
X 
 
1. 
Acquire a signed Written Informed Consent prior to conducting any study related procedures.  
2. 
Verify and confirm eligibility a. Verify inclusion criteria 1-9 and all exclusion criteria. b. Verify and confirm all 
eligibility prior assigning a patient to the study treatment. 
3. 
Tumor biopsy DRP/Tumor mRNA expression profiling; A biopsy should be taken after the last anticancer 
treatment has been stopped. If such biopsy is not available an archival biopsy can be used as primary 
screening. If score is >67% patient will continue screening. If eligible an additional biopsy should be obtained 
prior to treatment initiation if possible. 
4. 
Only patient with an ixabepilone DRP - score of >67% will continue screening.  
5. 
Prior to Cycle 1 (Day 1) complete medical history/Baseline conditions, including breast cancer history, its 
previous therapy, and current medication will be recorded.  
6. 
Physical examination, in addition the patients should be monitored for symptoms of neuropathy, such as 
burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain),  vital signs 
(including heart rate, blood pressure, respiratory rate and temperature), measurements of height (only at 
baseline), weight and Performance status (ECOG). All assessments will be performed within 14 days prior to 
Day 1 and within 24 hours prior to treatment start, prior to each cycle (drug administration) thereafter and at 
end of treatment visit, when study discontinuation. 
7. 
Patients to fulfil the questionnaire before each ixabepilone infusion and at end of treatment visit 
8. 
Complete Blood Count (CBC) including absolute neutrophil, lymphocyte, monocyte, basophil, eosinophil 
count, and platelets. CBC will be performed prior to and weekly at day 8 and 15 in each cycle, at end of 
treatment  and, if applicable, post treatment every 4 weeks until all related toxicities resolved, stabilized or 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 26 of 62
 
returned to baseline or are able deemed irreversible. c Day 8 and day 15 Complete Blood Count can be 
carried out at a local hospital or in primary care after 1st cycle, if required .  
9. 
Blood Chemistry assessments (sodium, potassium, chloride, urea, creatinine, glucose (non-fasting), total 
protein, albumin, free calcium, total bilirubin, alkaline phosphatase, magnesium, phosphate, ALT, AST, INR, 
APTT and prothrombin time will be performed prior to each cycle and at end of treatment and, if applicable, 
post treatment every 4 weeks until all related toxicities resolved, stabilized or returned to baseline or are able 
deemed irreversible. 
10. Pregnancy test will be performed prior to day 1 cycle 1 and before each drug administration in the following 
cycles by all female patients with reproductive potential.  
11. Tumor measurements (e.g. CT or MRI etc.) will be performed within 4 weeks prior to day 1 cycle 1, at Week 
6, prior Day 1 cycle 3 and then approximately every 9 weeks for 24 weeks and then every 3 months until 
progression. To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed 4 weeks after the criteria for response are first met. In the 
case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a 
minimum interval of 12 weeks. Patients who discontinue protocol treatment for other reason than 
progression will have tumor assessments every 9 weeks until week 24 and then every 3 month until disease 
progression. 
12. A 12-lead ECG will be performed prior first cycle and at any other time if clinically indicated.  
13. All patients will receive premedication prior to each infusion of ixabepilone (see section 6.1) 
14. Infusion to start after all safety measurements have been done and pre-medication given. 
15. Follow-up subjects for symptoms during infusion, as applicable (e.g. observed by a study nurse for 
approximately 30 min for the 2 first cycles, if no reactions observed). 
16. Patients will be monitored for adverse events (AEs)/Baseline conditions prior to the study start and 
continuously throughout the study until end of treatment. After that only events related to IMP should be 
reported. Only related AEs and all SAEs will be followed unti
stability is reached.d May be performed by telephone call after 1st cycle. 
17. Concomitant medication/therapies will be recorded prior to the study start and continuously throughout the 
study until end of treatment. After that, only anticancer related medications/therapies will be collected during 
the post treatment follow up period. e May be performed by telephone call after 1st cycle. 
18. Survival will be followed until death or until last patient have been in the study for 2 years.  
19. Approximately 28 days after end of last cycle 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 27 of 62
 
6.3 Assessments and Procedures 
6.3.1 Clinic visits 
After signing the Informed Consent the patient will visit the clinic for the screening procedures that 
may start up to 6 weeks prior to treatment start. While on treatment the patient will visit clinic at 
Day 1 (±3 days window) and Day 8 (±3 days window) and Day 15 (±3 days window) for all cycles 
and at end of treatment and post treatment follow-up. Please see flowchart section 4.2. 
6.3.2 Demographics 
At screening/baseline the  date  of  birth,  sex,  and  ethnicity  will  be  recorded  in  the  eCRF  for   
all enrolled patients. 
6.3.3 Urinary pregnancy test 
A urine pregnancy test (or serum blood test, see section 6.3.4)  will be performed at all visits for 
participating female patients of child-bearing potential. 
 
Note: Female patients participating in the study: 
 
will be considered to be of child-bearing potential after the onset of their first menstrual 
period. 
 
who are documented as being of non-child-bearing potential (infertile, surgically sterile or 
post-menopausal) are to be exempt from pregnancy testing and the contraceptive 
requirements. 
 
will be considered post-menopausal if they have had 12 months of consecutive 
spontaneous amenorrhea, without an alternative medical cause. In case of doubt, a urine 
pregnancy test should be performed. 
 
will be considered surgically sterile if they are post-hysterectomy, 6 months post-surgical 
bilateral oophorectomy or 6 months post tubal ligation. 
 
who become pregnant during the study must immediately discontinue study medication 
and undergo an Early Termination visit according to the procedures described for end of 
treatment visit (Section 6.4.6). 
 
A positive urine pregnancy test (or serum blood test, see section 6.3.4) at Screening or 
Randomisation Visits would result in exclusion of the patient from study participation (see 
exclusion criteria in Section 5.2) 
A diagnosed pregnancy at later visits must be recorded on the Pregnancy Report Form. In 
addition, the patient must immediately stop IMP intake, be withdrawn from study participation and 
the pregnancy must be followed up until termination and/or birth. If the pregnancy does not reach 
full term, the reasons must be provided. Details concerning the health of the new-born must also 
be collected, if the pregnancy leads to a birth. 
6.3.4 Laboratory tests 
If an unexpected, clinically significant change from baseline occurs in a laboratory value or other 
measurement, the Investigator should repeat the test, if appropriate, to verify the result. The 
Investigator must comment on all clinically significant changes in laboratory values. All clinically 
significant adverse events must, if not resolved at end of study, be followed-up and this follow-up 
documented until the event returns to Grade 1 or becomes stabilized. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 28 of 62
 
Laboratory tests will be assessed according to the hospital clinical practice. The samples will be 
analyzed at the local laboratory. Upon review of the results the Investigator should assess the 
clinical significance of all results. All clinically significant findings should be recorded as medical 
history at baseline or as an Adverse Event (AE) at later visits.  
 
Hematology: Complete Blood Count (CBC) including absolute neutrophil, lymphocyte, monocyte, 
basophil, eosinophil count and platelets. CBC will be performed at predefined time points, see 
study flow chart, section 6.2. 
 
Biochemistry: Blood Chemistry assessments (sodium, potassium, chloride, urea, creatinine, 
glucose (non-fasting), total protein, albumin, free calcium, total bilirubin, alkaline phosphatase, 
magnesium, phosphate, ALT, AST, INR, APTT and prothrombin will be performed at predefined 
time points, see study flow chart, section 6.2.   
 
All women of reproductive potential must be screened for pregnancy by serum hCG test (if urine 
pregnancy test is not performed, see section above) at baseline (performed within 14 days prior 
to Cycle 1, Day 1 all cycles). If a female patient becomes pregnant during the study, she will need 
to discontinue the study treatment. 
 
HIV and hepatitis B and C: status will be assessed at screening from medical records only. 
Patients infected with HIV or hepatitis are not eligible for inclusion in this study unless the disease 
is deemed under control by the investigator. 
6.3.5 Medical history  
A complete review of the patient
istory will be undertaken by the Investigator to check 
that no exclusion criteria have been met. New MRI/CT scans will not be taken at screening if 
recent scanning information is available for tumor assessment (baseline). The baseline scans 
must have been done within 4 weeks prior Day 1 Cycle 1; first drug administration. 
 
6.3.5.1 Previous cancer history and anti-cancer treatment  
-cancer treatment will be 
conducted with no time limitation. 
6.3.6 Vital signs 
The following vital sign evaluations will be performed prior to each drug administration for all 
cycles during the study and at end of treatment and recorded as applicable in the Case Report 
Form.  
 
 
Blood pressure (systolic and diastolic): Will be performed as seated after at least 5 
minutes of rest) (in mmHg) 
 
Heart rate: Taken after at least 5 minutes of  rest (in beats per minute (bpm)) 
 
Respiratory rate: Taken after at least 5 minutes of  rest (in breaths per minute (bpm)) 
 
Temperature:Tympanic temperatures will be measured(in ºC) 
 
All new findings or changes to previous findings considered clinically significant are to be 
recorded in the eCRF, either as Medical history if the finding is made prior to administration of the 
IMP, or as an adverse event if the finding is made subsequent to the first IMP administration. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 29 of 62
 
6.3.7 Physical examination 
A complete physical evaluation will include a thorough review of all organ systems, by the 
Investigator. The complete physical examination will include examination of the following: general 
appearance, head, ears, eyes, nose, throat, neck (including thyroid), skin, cardiovascular system, 
respiratory system, gastrointestinal system, musculoskeletal system, lymph nodes and nervous 
system. Any findings made during the physical examination must be noted regardless of if they 
 
Symptom-directed evaluations on the other hand, will only be performed on the organ systems 
which are warranted, e.g., when the patient has indicated any problems with the affected system 
or for which the Investigator or study nurse has reason to believe there may be a problem with 
the affected organ system. 
 
In addition, the patients will be monitored for symptoms of neuropathy, such as burning 
sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. The 
patients will also be asked to fulfil a Neurotoxicity Questionnaire (see Appendix 2) before each 
ixabepilone infusion and at end of the treatment visit (Day 1).  
 
All new findings, or changes to previous findings, considered clinically significant are to be 
recorded on the eCRF either as medical history if the finding is made prior to IMP administration, 
or as an adverse event (Section 8.3), if the finding is made subsequent to first IMP administration. 
6.3.8 ECG 
A 12-lead ECG will be recorded within 14 days prior to treatment start and at any time it is 
clinically needed. 
6.3.9 Concomitant diseases  
Any concomitant disease, whether considered relevant for the study or not by the Investigator, 
must be reported in the eCRF. The duration of diagnosis should be noted. See also above 
(medical history). 
6.3.10 Concomitant medication 
All concomitant medication will be reported from 4 weeks prior to the first dosing visit (Day 1) 
and until approximately 4 weeks after last cycle (End of Treatment visit). 
6.3.11 Tumor assessment 
Clinical efficacy will be assessed by RECIST 1.1(35). Tumor response will be assessed by 
CT/MRI using RECIST 1.1 at Week 6 (before infusion) and then approximately every 9 weeks 
until 6 months and then approximately every 3 months until progression, withdrawal or death, 
which ever comes first. Every attempt should be made to use whichever imaging technique(s) 
used initially for repeat evaluations throughout the study.The hospitals imaging procedure for 
diagnostic CT or MRI of chest, abdomen and pelvis should be followed. The images should be 
evaluated by a dedicated radiologist at site.  
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST 1.1 criteria 
(35).  

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 30 of 62
 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-
ray, as >10 mm with CT scan, or >10 mm with callipers by clinical exam. All tumor 
measurements must be recorded in millimetres (or decimal fractions of centimetres).  
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator believes it is appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol. 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.  
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable.  
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, 
considered as measurable lesions, if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
6.3.12 Baseline documentation 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.  
Non-target lesions. All other lesions (or sites of disease) including any non-measureable as 
well as measurable lesions over and above the 5 target lesions should be identified as non-
target lesions and should also be recorded at baseline. Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of each should 
be noted throughout follow-up. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 31 of 62
 
6.3.13 Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.  
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters  
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference 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. (Note: the appearance of one or more new lesions is also 
considered progressions).  
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study  
6.3.14 Evaluation of non-target lesions 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (<10 mm short axis)  
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase.  
-
physician should prevail in such circumstances, and the progression status should be confirmed 
at a later time by the review panel (or Principal Investigator).  
6.3.15 Evaluation of best overall response  
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started (Table 5 (35)).   
 
Table 5. Evaluation of Best Overall Response for Patients with Measurable Disease  
Target 
Lesions
Non-Target Lesions 
New 
Lesions 
Overall 
Response
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes 
or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes 
or 
No. 
PD 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 32 of 62
 
Any 
Any 
Yes 
PD 
 
*See RECIST 1.1. (35) for further details on what is evidence of a new lesion. 
**Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progress
symptomatic 
  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
6.3.16 Adverse events 
Documentation of AEs will start as soon as the patient has signed the Informed Consent and will 
last until patient
 10.3. 
 
6.4 
Description of Individual Visits 
All patients will perform the screening and baseline visits before receiving the IMP. Day 1, Day 8 
and Day 15 will be repeated for each cycle (~3 weeks between each drug administration). 
When the subject discontinue from the study, an end of treatment visit will be performed 
approximately 4 weeks after last treatment cycle.  
6.4.1 Screening visit (within 6 weeks prior to treatment start): 
 
Signed and dated written informed consent (must be obtained before any study 
related procedures are initiated) 
 
Patient demographic information will be collected 
 
Verify and confirm inclusion criteria 1 to 9 are meet  
 
Verify and confirm all exclusion criteria  
 
Tumor biopsy for DRP/Tumor mRNA expression profiling. The biopsy should be 
taken after the last anticancer treatment stopped. 
 
6.4.2 Baseline visit (within 2 weeks prior to treatment start): 
 
Review ixabepilone Drug Response Predictor (DRP®) - must have a score >67% for 
the patient to continue the baseline screening. 
 
Review of all inclusion/exclusion criteria  
 
Medical/Surgical history/concomitant diseases, including breast cancer history 
 
Review concomitant medication and previous anti-cancer therapies 
 
Evaluation of performance status using the ECOG scale 
 
Physical examination, vital signs, height and weight 
 
12-lead ECG 
 
Laboratory measurements including: Hematology and Biochemistry (see section 
6.3.3) 
 
Urine or Serum Pregnancy test  
 
Adverse events 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 33 of 62
 
6.4.3 Day 1 of each cycle (within 24 hours before dosing): 
 
Physical examination, vital signs and weight 
 
Evaluation of performance status using the ECOG scale 
 
Laboratory measurements including: Hematology and Biochemistry (see section 
6.3.3). Hematology results to be evaluated before infusion. 
 
Urine or Serum Pregnancy test  
 
 before 
drug administration  
 
Review concomitant medication and therapies 
 
Administer pre-medication approximately 60 minutes before IMP infusion 
 
Dispensing of IMP and follow-up subject  for symptoms during infusion, as 
applicable (e.g. observed by a study nurse for approximately 30 min for the 2 first 
cycles, if no reactions observed). 
 
Adverse events 
 
discharged.  
 
6.4.4 Day 8±3   and Day 15±3 of each cycle 
 
Laboratory measurements including: Hematology (see section 4.3.3) (Complete Blood 
       Count can be carried out at a local hospital or in primary care after 1st cycle, if 
required) 
 
Adverse events (may be reviewed by telephone call at day 8 and day 15 after 1st 
cycle) 
 
Review concomitant medication and therapies (may be reviewed by telephone call at 
day 8 and day 15, after 1st cycle) 
 
 
6.4.5 Imaging  
 
Tumor assessment according to RECIST criteria version 1.1 (35) by MRI or CT scan 
of thoracic, abdominal and pelvic region, and other imaging studies which might be 
required to determine the extent of disease. Scans will be performed within 4 weeks 
of screening, at Week 6, and then approximately every 9 weeks up to 24 weeks and 
then every three months until progression or death. 
 
6.4.6 End of treatment (EOT); approximately 28 days after end of last cycle 
 
Physical examination (including tumor evaluation by clinical examination), vital signs 
and weight 
 
Laboratory measurements: Hematology and Biochemistry (see section 6.3.4) 
 
Adverse events 
 
12-lead ECG 
 
Review concomitant medication and therapies 
 
Evaluation of performance status using the ECOG scale 
 
Neurological examination and patients to complete neurotoxicity questionnaire 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 34 of 62
 
6.4.7 Consecutive follow-up: 
Patients who discontinue protocol treatment for other reason than progression will have tumor 
assessments every 9 weeks until week 24 and then every 3 month until disease progression and 
thereafter followed for survival every 3 months until death. 
For patients stopping treatment with ixabepilone due to progression, survival follow up to be 
performed approximately every 3 months until death. All patients are to be followed until death or 
until last patient has been in the study for 2 years, whichever comes first. Death certificates or 
other official proof of date of death to be obtained. Treatment related adverse events and 
anticancer medication will be reported.  
 
7 INVESTIGATIONAL MEDICINAL PRODUCT 
7.1 Investigational Medicinal Product (IMP) 
 
The following medication supplies will be used in the study: 
The IMP vial contains the active substance ixabepilone as a single-use, sterile lyophilised powder 
for concentrate for solution for infusion. Two strengths 15 and 45 mg/vial will be available. The 
medicinal product contains two vials; one for the powder and one for the constituting solvent for 
IV administration supplied by the Sponsor. 
7.2 Supply, Packaging, Labelling, Handling and Storage 
 
The IMP ixabepilone for Injection and its Vehicle for Constitution (diluent) will be supplied by the 
Sponsor via a Vendor (Klifo). The IMP will be labelled in accordance with text that is in full 
regulatory compliance with each participating country and is translated into the required 
language(s) for each of those countries. 
The IMP should be stored refrigerated at 2°C to 8°C (36 to 46°F) and should be protected from 
light.  
The IMP for injection must be constituted with supplied DILUENT. The IMP concentration in 
constituted solution is 2 mg/mL. Constituted solution must be diluted with one of the specified 
fluids (see current SmPC for Ixempra and the Study Specific Pharmacy Manual), to a final IMP 
concentration of 0.2 mg/mL to 0.6 mg/mL.  
The infusion must be administered through an appropriate in-line filter with a microporous 
membrane of 0.20 to 5.0 microns. Administration of the entire infusion volume must be completed 
within the 6 hour time period. For further information see the study specific Pharmacy Manual.  
7.3 Dosage and Administration 
 
Ixabepilone 40 mg/m2 will be administrated as a continuous 3-hour intravenous infusion Day 1 in 
a 3-week cycle. BSA should be calculated using DuBois formula (BSA = 0.007184 * Height 0.725 * 
Weight 0.425) for each cycle. Dose reduction is required in certain patients See section 7.5.1  
7.4 
Toxicity Grading 
All toxicities observed will be graded according to the NCI-CTCAE, Version 5.0 (34) and recorded 
as adverse events. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 35 of 62
 
For those toxicities not graded in the NCI-CTCAE, grade of the adverse experience shall be 
recorded as adverse events as mild, moderate, severe or life-threatening, based on the following 
definitions: 
 Mild: Sign or symptom noticeable but does not interfere with normal daily activities. 
 Moderate: Sign or symptom sufficient to interfere with normal daily activities. 
 Severe: Sign or symptom is incapacitating with inability to perform daily activities. 
 Life-Threatening: Sign or symptom significantly increases risk of death. 
If an unexpected, clinically significant change from baseline occurs in a laboratory value or other 
measurement, the Investigator should repeat the test if appropriate, to verify the result. The 
Investigator must comment on all clinically significant changes in laboratory values. All clinically 
significant adverse events must be followed-up and this follow-up documented until the events 
return to normal or become stabilized. 
7.5 
Dose Modifications 
7.5.1 Dose Adjustments during Treatment 
 
Patients should be evaluated during treatment by periodic clinical observation and laboratory 
tests including complete blood cell counts. If toxicities are present, treatment should be delayed 
to allow recovery. Dosing adjustment guidelines for monotherapy is shown in Section 7.5.2, Table 
7. If toxicities recur, an additional 20% dose reduction should be made.  
 
The dose of the IMP will be reduced as described in Table 6. 
 
Table 6. Dose Levels of IMP 
Dose Level 
IMP 
 Starting dose 
40 mg/m2 
Dose after 1st  dose reduction  
(20% dose reduction) 
 
32 mg/m2 
Dose after 2nd dose reduction  
(additional 20% dose reduction) 
25 mg/m2 
 
Patients requiring dose reductions after the second dose reduction must discontinue IMP.No 
dose re-escalation will be allowed after dose reduction. 
 
 
 
 
 
 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 36 of 62
 
7.5.2 Dose modification - according to toxicity  
 
Table 7 Dose Adjustment Guidelines
 
 
 
Patients with hepatic impairment should be dosed based on the guidelines in Table 8. 
 
Table 8 Dose Adjustments in Patients with Hepatic Impairment 
 
Transaminase Levels 
 
BilirubinLevelsa 
Ixabepiloneb(mg/m2) 
Mild             
        and 
 
40  
                   
         and 
 
32 
Moderate    
         and 
>1.5 x ULN - 
 
20  30 
 
a Excluding patients whose total bilirubin is elevated due 
 
b Dosage recommendations are for first course of therapy; further decreases in subsequent courses 
should be based on individual tolerance. 
 
7.5.3 Retreatment Criteria 
 
Patients may be retreated with a new cycle of study therapy if ANC is at least 1,500/mm3, platelet 
count is at least > 100,000/mm3 and treatment-related non-hematologic toxicity has resolved to 
baseline or Grade 1 (excluding Grade 2 alopecia and Grade 2 fatigue, for which resolution is not 
required) (according to the SmPC). Patients with Grade 2 neuropathy will not be retreated until 
resolution to Grade 1. Refer to Tables 6 and 7, for specific instructions on dose interruption and 
retreatment. 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 37 of 62
 
If a patient fails to meet criteria for retreatment on Day 21, then retreatment should be delayed 
and the patient should be re-evaluated at least weekly. 
 
Initiation of subsequent cycles may be delayed for a maximum of three weeks. Any patient who 
fails to recover from a treatment related toxicity to baseline or Grade 1 (except Grade 2 alopecia 
and Grade 2 fatigue) within three weeks of scheduled retreatment (i.e., beyond Day 42) will be 
removed from the study. Patients who are clinically benefiting may continue treatment on study 
after consultation with and approval by the Sponsor. 
 
 
7.6 
Prohibited and Restricted Therapies during the Study 
7.6.1 Prohibited Therapies 
No other chemotherapy, hormonal therapy, immunotherapy, radiation therapy or experimental 
anticancer medications will be permitted while the patient is on treatment. Patients may continue 
to receive hormonal replacement therapy. Substances that inhibit CYP3A4 activity may decrease 
metabolism and increase ixabepilone concentrations. There is a significant increase in exposure 
to ixabepilone when ixabepilone is co-administered with ketoconazole. It is recommended that 
ixabepilone not be co-administered with the following strong inhibitors of CYP3A4: ketoconazole, 
itraconazole, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine and voriconazole. Caution 
should be used when considering the use of other CYP3A4 inhibitors with ixabepilone. Patients 
who receive drugs that are known to inhibit 3A4 other than those described above should be 
monitored closely for safety.  
 
Conversely, inducers of CYP3A4 may decrease plasma concentrations of ixabepilone. The use of 
concomitant strong CYP3A4 inducers should be avoided (eg, phenytoin, carbamazepine, 
rifampin, rifabutin, dexamethasone, and phenobarbital). (20mg dexamethasone can be used as 
premedication if required). Selection of an alternative concomitant medication with no or minimal 
enzyme induction potential should be considered. 
7.6.2 Restricted Therapies 
Palliative and supportive care for disease-related symptoms will be offered to all patients on this 
trial. The use of bisphosphonates for palliation of bone metastases will be allowed if initiated prior 
to study entry. Although, colony-stimulating factors (i.e., G-CSF, GM-CSF, etc.) are allowed, their 
prophylactic use should not replace the dose reduction schema. Growth factor use must be 
consistent with product label. Growth factor may not be given for 24 hours before or after 
ixabepilone. Prophylactic or therapeutic use of erythropoietin will be permitted. 
7.6.3 Other Restriction 
The patients will be instructed to abstain from grapefruit or products containing grapefruit for 24 
hours prior to first dose administration and throughout the study until the end of treatment visit. 
The inhibitory interaction of grapefruit juice on CYP3A4 may decrease metabolism and increase 
ixabepilone concentrations in blood. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 38 of 62
 
7.7 
Concomitant Medication 
Any medication (prescription as well as over the counter (OTC) drugs) or therapeutic intervention 
deemed necessary for the patient, and which, in the opinion of the Investigator, do not interfere 
with the safety and efficacy evaluations, may be continued unless they are included in the list of 
. However, the 
Investigator should be cautious in evaluating the need for change in dosage and should carefully 
assess if any concomitant medication is necessary. If possible, all unnecessary concomitant 
medication should be stopped before entering the patient into this study. 
Any new medications or changes to the dose or regimen of pre-existing medications will be 
updated on a routine basis during the study.   
7.8 Duration of Treatment 
Patients will continue the treatment until one or more of the following: 
 Disease progression 
 Unacceptable toxicity 
 Patient refusal 
 Physician decision 
 Non-compliance to the protocol 
 Treatment delay of > 2 weeks (except in cases of potential or perceived benefit) 
7.9 
Drug Accountability 
All IMP supplies for this study must be retained in a safe place at all times of the study. Only 
personnel authorized by the PI at each site should dispense the IMP, and the accountability is the 
responsibility of the Investigator. The Investigator or pharmacist must complete and return the 
IMP supply form to the monitor, verifying the receipt of the IMP. 
 
8 PREMEDICATION AND HYPERSENSITIVITY REACTIONS 
8.1 Premedication before treatment with IMP 
All patients must be premedicated before each treatment with ixabepilone to prevent a 
hypersensitivity reaction, Regimen 1 described below is the premedication regimen 
recommended for routine use.  
 
Regimen 1) Premedicate approximately one hour prior to the infusion of ixabepilone with: 
 
 
An H1 antagonist (e.g., diphenhydramine 50 mg orally or equivalent)  
and 
 
An H2 antagonist (e.g., famotidine 20 -40 mg orally, cimetidine 200 - 400 mg 
orally or equivalent) 
 
Note that, in the event of patient intolerability to the antihistamines specified, alternatives 
 antihistamine is not 
available, alternate antihistamines may be substituted (including intravenous formulations at 
equivalent doses). 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 39 of 62
 
8.2 Hypersensitivity Reactions 
The IMP is formulated in polyoxyethylated castor oil (Cremophor EL), thus, 
hypersensitivity reactions may occur. Therefore, patients should be monitored closely for 
any signs or symptoms of hypersensitivity. Appropriate emergency equipment and 
medications (e.g., epinephrine, corticosteroids, antihistamines) should be made available 
in the event of an HSR. Refer to Section 8.3  for additional recommended 
premedication regimens (Regimen 2 and 3) to prevent hypersensitivity reactions in 
patients who developed hypersensitivity reactions despite premedication with Regimen 1. 
 
A hypersensitivity reaction will generally occur within seconds or minutes of drug 
administration. Reactions may include urticaria, dyspnea, bronchospasm, angiodema, 
hypotension, tachycardia or occasionally cardio-respiratory arrest. In case of 
hypersensitivity reactions, the Investigator should institute treatment measures deemed 
medically appropriate. 
8.3 Additional Recommended Pre-medication to Prevent 
Hypersensitivity Reactions if Oral Medication Fails 
 
If a patient experiences a hypersensitivity reaction with oral H1 and H2 blockers 
(Regimen 1) then the patient, if re-treated, should be premedicated according to the 
recommended regimen below: 
 
Regimen 2) Premedicate approximately 30 - 45 minutes prior to each infusion of 
ixabepilone with: 
a) Dexamethasone 20 mg IV (or equivalent), 
b) Diphenhydramine 50 mg IV (or equivalent), and 
c) Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent). 
 
If a patient continues to experience a hypersensitivity reaction with Regimen 2 then the 
patient, if retreated, should be premedicated according to the recommended regimen 
below: 
 
Regimen 3) Premedicate with: 
a) Dexamethasone 20 mg po administered, approximately 12 and 6 hours 
prior to the infusion of ixabepilone 
b) Diphenhydramine 50 mg IV, approximately 30 - 45 minutes prior to 
each infusion of ixabepilone, 
c) Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent), 
approximately 30 - 45 minutes prior to each infusion of ixabepilone.  
 
9 PATIENT WITHDRAWAL AND REPLACEMENT OF PATIENTS 
In accordance with the Declaration of Helsinki, the Investigator must explain to the patient that 
they have the right to withdraw from the study at any time, and that this will in no way prejudice 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 40 of 62
 
their future treatment. However, unless safety issues occur, we plan to follow the patients for the 
entire duration of the study in order to analyse efficacy and safety variables also for those 
patients withdrawing from the study. The reason for any kind of withdrawal must be recorded on 
the appropriate CRF. 
There will be two main categories for withdrawals from the study: 
9.1 Complete withdrawal 
Stopping ixabepilone and also continued efficacy and safety evaluations. 
Standard reasons for withdrawing from further participation in the study and from the follow-up 
visits may be: 
 
Patient
 
 
Patient lost to follow-up 
9.2 Withdrawal from the study: 
Stopping ixabepilone but continuing follow-up visits, including efficacy and safety evaluations. 
Standard reasons for withdrawing from taking further ixabepilone, but continuing follow-up visits 
and safety evaluations may be: 
 
Unacceptable adverse events 
 
Patient request 
 
Investigator's discretion 
 
Patient lost to follow-up/non-attendance 
 
Intercurrent illness 
 
However, whenever a patient is withdrawn from a study, or for whatever reason is not coming to 
any further visits, a final study evaluation must be completed for that patient (End of treatment 
visit) - stating the reason(s) why the patient was withdrawn from the study. All documentation 
concerning the patient must be as complete as possible.  
Withdrawals due to non-attendance must be followed up by the Investigator to obtain the reason 
for non-attendance. Withdrawals due to intercurrent illnesses or adverse events must be fully 
documented in the case record form, with the addition of supplementary information if available 
and/or appropriate. 
9.3 
Replacement of Patients 
Replacement of patients will be permitted under the following circumstances: 
If the patient was properly screened and enrolled into the study, and started taking the IP, but 
then subsequently had to withdraw from the study, and did not complete 2 full cycles of treatment, 
this patient can be replaced.  
9.4 IMP Accountability 
All IMPs supplies for this study must be retained in a safe place at all times of the study. Only 
personnel authorised by the PI at each site should dispense the IMP, and the accountability is the 
responsibility of Investigator. The Investigator or pharmacist must complete and return the IMP 
supply form to the CRO-monitor, verifying the receipt of IMP. 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 41 of 62
 
10 RESPONSE VARIABLES AND ENDPOINTS 
10.1 Assessment of Efficacy 
10.1.1 Primary Efficacy Variable 
 
Clinical Benefit Rate will be defined as the proportion of patients having a Complete 
Response (CR), Partial Response (PR), or Stable Disease (SD) for at least 24 weeks, 
according to RECIST v 1.1 
10.1.2 Secondary Efficacy Variables 
 
PFS defined as time from randomisation until progressive disease (PD) according to 
RECIST v 1.1 or death, whichever occur first. 
 
OS defined as the time from randomisation until death from any cause. 
 
ORR defined as the proportion of patients with complete response (CR) + partial 
response (PR) according to RECIST v 1.1 
 
Duration of response (DOR) defined as time of first documented CR or PR response until 
documented tumor progression (RECIST v 1.1)  
10.2 Assessment of Safety 
Safety evaluation will include assessments of adverse events, medical history, physical 
examinations, vital signs, concomitant medications, performance status and laboratory 
assessments at baseline and throughout the study period.  
 
 
A description of the extent, duration and reversibility of ixabepilone elicited toxicity in 
target organs based on the Common Terminology Criteria for Adverse Events (NCI-
CTCAE v.5.0).  
 
A description of the frequency and severity of adverse events based on CTCAE v.5.0.  
 
Changes of Hematology and clinical biochemistry over time from baseline. 
 
Changes in Vital signs over time from baseline. 
 
Changes in ECOG over time. 
10.2.1 Study-specific Safety Variables 
The safety profile will be analysed by assessing clinical and laboratory adverse events. 
If an unexpected, clinically significant change from baseline occurs in a laboratory value or other 
measurement, the Investigator should repeat the test if appropriate, to verify the result. The 
Investigator must comment on all clinically significant changes in laboratory values. All clinically 
significant adverse events must be followed-up and this follow-up documented until the events 
return to normal or become stabilised. 
Myelosuppression, primarily neutropenia, is common. To monitor for myelosuppression, frequent 
peripheral blood cell counts will be performed on all patients receiving ixabepilone. Patients who 
experience severe neutropenia or thrombocytopenia should have their dose reduced (see section 
7.5).  
 
Further safety variables will be based on vital signs (blood pressure, heart rate) and physical 
examinations,  
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 42 of 62
 
In addition special focus will be on peripheral neuropathy which is a common reported adverse 
event. Patients treated with ixabepilone should be monitored for symptoms of neuropathy, such 
as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. 
Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy 
occurred during the first 3 cycles. Patients experiencing new or worsening symptoms may require 
a reduction or delay in the dose of ixabepilone (see Section 7.5). Peripheral neuropathy will be 
managed through dose reductions, dose delays, and treatment discontinuation.  
 
10.3 Adverse Events and Serious Adverse Events 
10.3.1 Definitions of Adverse Events 
10.3.1.1 Adverse Events (AE):  
An AE is any untoward medical occurrence in a clinical study subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including clinically 
significant abnormal values from relevant tests, such as clinical safety laboratory tests, ECGs, 
vital signs), symptom, or disease temporally associated with the use of an IMP, regardless of 
whether it is considered related to the IMP. 
A baseline symptom is any medical event in a clinical study subject that occurs after the subject 
signed the ICF up until the first administration of IMP. 
A treatment emergent AE (TEAE) is any AE not present prior to the initiation of IMP administration 
or any event already present that worsens in either intensity or frequency following exposure to 
the IMP. 
Only TEAEs are collected in this study (i.e. events occurring between screening and the first IMP 
administration are regarded as baseline symptoms and should not be recorded in the AE log in 
the CRF). 
10.3.1.2  Serious Adverse Events (SAE): 
An SAE is any AE that: 
 
results in death 
 
is life-threatening (this refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death had it been more severe) 
 
requires inpatient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability/incapacity 
 
is a congenital anomaly/birth defect 
 
is medically important (this refers to an event that may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent any of the SAEs defined above) 
Examples of medically important events are intensive treatment in an emergency room for allergic 
bronchospasm or blood dyscrasias, convulsions that do not result in hospitalization, development 
of drug dependency, and drug abuse. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 43 of 62
 
Planned hospitalizations or surgical interventions for a condition that existed before the subject 
signed the ICF and that did not change in grade are not SAEs. 
Events not considered SAEs in this study: 
The following events will not be considered nor recorded as SAEs in this study: 
 Progressive disease 
 Elective hospital admission including planned treatment for progressive disease.  
 Admission to hospital for socio-economic reasons 
 Admission to hospital due to progressive disease 
 Death from progressive disease 
 
10.3.1.3 Unexpected Adverse Event:  
An experience not previously reported in the current SmPC for for ixabepilone (IXEMPRA). 
10.3.1.4 Serious Adverse Drug Reaction  
The term Serious Adverse Drug Reaction (SADR) is to be used whenever either the Investigator 
or Sponsor or designee assessed the SAE as possibly, probably or definitely related to the IMP. 
10.3.1.5 Suspected unexpected serious adverse reaction  
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is any SADR whose nature or 
grade is not consistent with the current version of the SmPC for ixabepilone (IXEMPRA). 
10.3.2 Adverse Event assessment definitions  
10.3.2.1 Severity 
The grading of the AEs will follow the CTCAE v5.0 (36). Grade refers to the severity of the AE. The 
CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE 
based on this general guideline. 
The Investigator must assess the severity/intensity of an AE using the following definitions, and 
record it on the Adverse Event Form in the CRF: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting
self- care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**Self- care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 44 of 62
 
10.3.2.2 Causality of AEs 
All available evidence for the cause of the AE should be considered, such as, the pharmacology 
of the IMP, the nature of the event, timing with respect to IMP administration, dechallenge, and 
other causes. Possible other causes could include: 
- 
 
- 
Lack of efficacy or worsening of the treated condition. 
- 
Other treatment, concomitant or previous. 
- 
Withdrawal of study treatment. 
- 
Treatment error. 
- 
Protocol-related procedure. 
- 
Other factors. 
 
10.3.2.3 Relationship to IMP 
The causal relationship between the IMP and the AE should be indicated, such as: 
Unrelated: No evidence of a relationship with IMP use. 
Unlikely: There is a temporal relationship only with IMP use; there is little or no 
pharmacological plausibility to suggest a relationship; there is at least one other 
more likely cause for the AE. 
Possible: There is a temporal relationship with IMP use; it is pharmacologically plausible that 
the IMP is the cause of the AE; there may be one or more other possible causes 
for the AE. 
Probable: There is a strong temporal relationship with IMP use; it is pharmacologically likely 
that the IMP is the cause of the AE; other causes of the AE are unlikely. 
Definite: All available evidence indicates that the IMP is the cause of the AE. 
 
10.3.3 Follow-up of unresolved AEs 
All ongoing (S)AEs will be followed-up at least until at least 30 days after last IMP administration, 
resolved or returned to baseline value. 
10.3.4 Reporting of adverse events 
All Adverse Events must be recorded in the case report form, defining relationship to study 
medication and severity. 
As soon as the Investigator is aware of a potential Serious Adverse Event (SAE), he/she should 
contact the local SMERUD monitor by phone, fax or e-mail, and in any case no later than 24 
hours after the knowledge of such a case.  
If identification of the event occurs outside of office hours, the emergency phone number 
described in the Investigator Site File may be used. At the time of the call, the Investigator must 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 45 of 62
 
provide as a minimum requirement, the subject number, birth date, nature of the SAE, and a 
preliminary assessment of causality. The Investigator should follow-up the initial notification of the 
potential SAE by faxing a copy of the SAE reporting form to SMERUD at the number provided in 
the Investigator Site File. The faxed SAE reporting form should be received at SMERUD within 
24 hours after knowledge of such a case. 
Smerud medical Research International AS 
E-mail: pharmacovigilance@smerud.com 
Fax: +47 23 27 20 01 
Tel: +47 23 27 20 00 
 
Follow-up information on an existing SAE that is fatal or life-threatening should be reported by the 
Investigator to SMERUD within 5 days after the initial report. Where appropriate, hospitalization 
or autopsy reports should be made available. All Serious Adverse Events will be followed up until 
resolution (i.e., asymptomatic, stabilization or death). 
 
10.4 Serious Adverse Reactions and Unexpected Adverse Reactions 
10.4.1 Definitions 
Adverse Reaction: 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions.  
The phrase "responses to a medicinal product" means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out.  
For marketed medicinal products, an adverse reaction is a response to a drug which is noxious 
and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of disease or for modification of physiological function.  
Unexpected Adverse Reaction: 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (the Summary of Products Characteristics (SmPC)). 
Suspected Unexpected Serious Adverse Reaction (SUSAR): 
Any serious adverse reaction that might be related to the study medication and are unexpected 
according to the definition above. 
10.4.2 Reporting of suspected unexpected serious adverse reactions by SMERUD 
Suspected unexpected serious adverse reactions (SUSARs) will be reported by SMERUD 
according to appropriate Competent Authority and Ethics Committee requirements. SMERUD will 
report SUSARs to Investigators twice yearly according to ICH Good Clinical Practice and to local 
regulations. SUSAR reporting to the Competent Authorities and Ethics Committees will be 
performed according to local regulations in an unblinded manner. The Competent Authorities will 
be notified of all SUSARs through the Eudravigilance database. 
Fatal and life-threatening SUSARs should be reported by SMERUD as soon as possible to the 
Competent Authorities and Ethics Committees according to local regulations, and in any case no 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 46 of 62
 
later than seven calendar days, after knowledge by SMERUD of such a case. Relevant follow-up 
information on the case will be subsequently communicated within an additional eight days. All 
other SUSARs shall be reported to the Competent Authorities concerned and to the Ethics 
Committee concerned according to local regulations as soon as possible but within a maximum of 
fifteen days of first knowledge by SMERUD. 
 
11 STATISTICAL METHODOLOGY AND DATA MANAGEMENT 
11.1 Study Statistical Design 
Simon's two-stage design will be used (37). The null hypothesis that the true overall objective 
response rate is 25% will be tested against a one-sided alternative. In the first stage, 30 patients 
will be accrued, and 28 patients are expected to be evaluable. If there are 7 or fewer with clinical 
benefit in these 28 patients, the study will be stopped. Otherwise, 30 additional patients will be 
accrued for a total of 60 of which 53 are expected to be evaluable. The null hypothesis will be 
rejected if 19 or more objective responses are observed in 53 patients. This design yields a type I 
error rate of 0.05 and power of 0.8 when the true clinical benefit rate is 41%. The null hypothesis 
that the true overall objective response rate is 25% will be tested against the alternative 
hypothesis of true response rate 41%  
The objective response rates may differ in the actual population, but the difference between 
unselected historical control and selected population should remain constant. One-sided 
comparisons of ORR between treatment and historic control will be performed, and will be 
repeated for subgroups defined by ER. 
11.2 Estimation of Sample Size 
Up to 53 evaluable patients can be included to give a power of 80% in the Simon two-stage 
design.  
11.3 Statistical Analysis Plan 
A separate document, Statistical Analysis Plan (SAP) will be developed and will detail all 
analysis to be performed in this study. 
11.4 Study Populations 
11.4.1 Intention-to-treat population (ITT): 
Patients will be included in the primary intention-to-treat population for analysis of efficacy if 
they receive treatment for at least 1 dose of ixabepilone and have measurable disease at 
baseline. The ITT population will be used as the primary analysis population. 
Patients for whom a biopsy after last anticancer treatment is not available or has a DRP score 
below 67% will not count towards the 200 patients screened, and 60 patients treated, and will 
not be included in the primary analysis. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 47 of 62
 
11.4.2 Safety population: 
Patients will be included in the safety population if they receive treatment for at least 1 dose of 
ixabepilone. 
11.4.3 Per protocol population: 
In order to qualify for the stringent per protocol population, the patients must have followed the 
study protocol without any major violations and they should have received at least 2 cycles of 
treatment. Any examinations missed will be substituted with the last observation carried 
forward, but examinations from not more than 1 visit may be lost. The per protocol population 
will be identified prior to database lock. 
11.4.4 Total population: 
Any patient who withdraws from the study will be included in the safety analysis (adverse 
events and laboratory parameters). Data for all patients will be listed, and a list of withdrawn 
patients, with all reasons for withdrawal, will be given. 
This also applies to data for those patients who - after having consented to participate - 
underwent screening examinations required for inclusion into the study but whom - because a 
criterion for exclusion was met or for other reasons - were not included in the study. 
11.5 Data Collection / Case Report Forms  
Data will be collected using an electronic data capture (EDC) solution. Electronic Case report 
forms (eCRFs) will be utilised for recording data from each patient meeting the eligibility criteria 
and being included in the study. The eCRF system, ViedocTM, will be available on an internet 
portal accessible through any standard computer with internet access. All study staff responsible 
for entering data into the eCRF system will be trained by the Clinical Research Associate (CRA) 
prior to the start-up of the study. A personal log-in will be provided for all responsible personnel to 
allow for an audit trail relating to the study data to be maintained. No clinical trial information will 
be transferred via the eCRF system until the site has been qualified through completion of a 
validation eCRF. 
 
All evaluations performed shall be entered in a timely manner into the eCRF by a member of the 
site staff delegated responsibility for this specific task by the Principal Investigator (PI) of the 
clinical site. It is the responsibility of the Investigator to ensure that the eCRFs are properly 
completed. The data in the eCRFs should be consistent with the relevant source documents.  The 
Investigator will sign the designated signature fields of the eCRF data entry screens to confirm 
that the information on each screen is accurate and complete. All data must be stored in an 
unidentifiable form treated with strict confidentiality in accordance with applicable data protection 
regulations. 
 
Captured data will be monitored electronically and Source Data Verification (SDV) will take place 
at the site, i.e. relevant information (as outlined in the monitoring plan) will be verified against the 
individual patient records unless the eCRF is considered source data.  
 
Any inconsistencies will be presented as queries; either as automatically generated queries if 
raised by the logical data checks of the eCRF system, or by manually generated queries if raised 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 48 of 62
 
by the data validation checks or the SDV performed by the Data Manager (DM) or the CRA, 
respectively. Queries shall be resolved in a timely member by a trained member of the site staff.  
 
11.6 Data Management 
Data will be transmitted electronically into the web based EDC system. Upon receipt, data will be 
coded according to pre-specified dictionaries and in accordance with CRO Standard Operating 
Procedures (SOP). The handling of data, including data quality control, will comply with all 
applicable regulatory guidelines. 
 
12 REGULATORY AND ADMINISTRATIVE PROCEDURES 
12.1 Institutional Review  
The study will be conducted in accordance with the Fortaleza, 2013 amendment to the 
Declaration of Helsinki 1964. 
 
The Protocol and the Patient Information Sheet / Informed Consent Form will be approved by the 
relevant Competent Authorities and Ethics Committees, and possibly other public bodies 
according to local requirements before commencement. If a protocol amendment is necessary, 
this will be prepared with the agreement of the Principal Investigator and signed by the relevant 
parties. If the amendment is considered to be substantial, it will be submitted to the Competent 
Authorities and Ethics Committees, and possibly other public bodies according to local 
requirements for review and approval. The protocol amendment will not be implemented before 
the required approvals are obtained. Minor amendments which do not affect the safety or physical 
or mental integrity of the clinical trial participants or the scientific value of the trial (i.e. non-
substantial amendments) will not be submitted to Competent Authorities or Ethics Committees.  
 
SUSAR reports and Periodic Safety Reports will be sent to Competent Authorities and Ethics 
Committees according to local regulations.   
12.2 Patient Information / Informed Consent  
The Investigator is responsible for giving the study patient full and adequate verbal and written 
information about the nature, purpose, possible risk and benefit of the study. Study patients must 
also be notified that they are free to withdraw from the study at any time. The patients should 
have reasonable time to read and understand the information before signing. The Investigator is 
responsible for obtaining signed informed consent from all patients before including the patient in 
any study related procedures. 
 
A signed copy of the patient information and of the Informed Consent Form in local language, will 
be given to the patients. 
12.3 Patient Confidentiality 
The Investigator must ensure that patient
documents submitted to the sponsor should only identify patients by their initials and study 
number. The Investigator should keep a separate log of patient codes and names. Documents 
not for submission to the Sponsor, e.g., patient
rms, should be retained 
by the Investigator in strict confidence. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 49 of 62
 
 
The Investigator is required to record primary efficacy and safety data, concomitant medication 
and patient progress in the patient
 
 
The patient
CRO monitor and possibly by other sponsor 
personnel or regulatory authorities, to verify adequate source documentation, accuracy and 
completeness of eCRFs. The review will be conducted with strict adherence to professional 
standards of confidentiality. No patient identifiable data will be taken out of the investigator site. 
 
All patients screened for the study will have their initials and birth date entered chronologically on 
the Patient Screening Log at the initial visit. An explanation for exclusion from admission to the 
protocol is to be provided on the Patient Screening Log. 
12.4 Data Protection 
The collection and processing of personal data from subjects enrolled in this study will be limited 
to those data that are necessary to investigate the potential effects of ixabepilone. Collection, 
handling and storage of personal data from the clinical trial will only take place as described in the 
PIS/ICF as well as in section 9.5 (Data Collection) and in accordance with the General Data 
Protection Regulation (EU 2016/679), current EU clinical trial regulations (currently Directive 
2001/20/EC and 2005/28/EC; to be replaced by regulation 536/2014) and any applicable local 
regulations. 
 
A dedicated Data Protection Officer (DPO) employed by SMERUD is registered at the Data 
Protection Authority. 
a protection is 
maintained by auditing and approving the electronic data capture (EDC) provider, ensuring data 
protection procedures are in place and ensuring that the annual audit programs include also 
checks of subject data protection. 
 
12.5 Patient Treatment Plan 
Patients will continue treatment until disease progression or unacceptable toxicity or patient 
refusal/withdrawing of consent, or non-compliance to the protocol, or physician decision to 
discontinue treatment, or treatment delay > 2 weeks (except in the case of perceived patient 
benefit). Further treatment will be given on the discretion of the investigator. 
12.6 GCP 
The study will be managed and conducted according to the latest International Conference on 
Harmonisation (ICH) guidelines for Good Clinical Practice (GCP). A copy of these guidelines can 
be found in the Investigator Site File (ISF). 
12.7 Essential Documents 
The ICH guideline for GCP lists a number of essential GCP documents required prior to, during 
and after the conduct of the study. It is the responsibility of the monitor to ensure that the 
Investigator is always provided with a copy of such documents prepared by the study 
management, and it is likewise the responsibility of the Investigator to provide the monitor with 
essential documents prepared by the Investigator or the local Ethics Committee. A complete list 
of essential GCP documents can be found in the Investigator Site File. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 50 of 62
 
12.8 Record Retention 
The investigator site file, eCRFs and all medical records upon which the eCRFs are based 
(source data) must be kept for at least 15 years or according to local legislation whichever is the 
longest after completion of the study. Image carriers or other data carriers may be used for this 
purpose. The documentation should be easily retrievable and readable during the entire archiving 
duration. 
12.9 Monitoring / Quality Control 
Prior to the start of the study, the CRO monitor will review the protocol and eCRFs with the 
Investigator and his/her staff. The Investigator will be visited on a regular basis by the CRO 
monitor, who will check study procedures, including safety assessments, IMP handling, data 
recording and perform source data verification (SDV). The CRO monitor must be allowed to 
review patient records to confirm that required protocol procedures are being followed and check 
consistency between patient record and eCRF data. Incorrect or missing entries in the CRFs will 
be queried and must be corrected immediately.  
 
Risk based monitoring of source data verification will be done. 
The monitor will record dates of the visits in a monitoring visit log that will be kept at the site. 
The first monitoring visit at each site will be scheduled after the first patient has been enrolled. 
12.10 Quality Assurance  
During or after the study is completed, sponsor representatives or regulatory authorities may wish 
to carry out an audit or an inspection. These representatives must have the same access to study 
data and patient source data as the CRO monitor. 
12.11 Insurance and Liability 
Subject insurances will be issued according to local requirements. Liability for IMP-induced injury 
will be according to local requirements. The sponsor will indemnify the Investigator in accordance 
to national regulations. 
12.12 End of Trial 
Regular Trial Termination 
The end of the trial is defined as the last visit of the last patient included in the trial. Within 90 
days of the end of the trial, the Sponsor/CRO will notify Competent Authorities and Ethics 
Committees the regular termination of the of the study as required according to national law 
and regulations. 
Premature Trial Termination  
For safety reasons, this trial may be terminated prematurely at any time by the sponsor, or 
competent authorities. If the sponsor decides to terminate the trial for any other reason, the 
investigator, ethics committee and competent authority will be informed about the reason(s) for 
stopping the study. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 51 of 62
 
12.13 Study Report 
A clinical study report (CSR) will be prepared covering clinical and statistical aspects and 
summarising all findings of the clinical study. The content has to be treated as strictly confidential. 
The study report will be sent to the Investigators, the Competent Authorities and Ethics 
Committees according to local requirements. 
12.14 Publication and Data Rights 
It is envisaged that the findings of the study will, in due course and by mutual agreement, be 
published in a scientific journal and/or presented at a scientific meeting. The final determination of 
authorship of this publication will be decided by the sponsor, Inc.; all participating Investigators 
will be mentioned and listed as members of the study group. 
 
The information developed during the conduct of this clinical study is confidential and may only be 
disclosed as authorized in writing by the sponsor. 
 
The published international guidelines for authorship (International Committee of Medical Journal 
authorship. Each author should have participated sufficiently in the work to take public 
responsibility for the content. 
 
Authorship credit will therefore be based only on substantial contributions to 1) conception and 
design, or analysis and interpretation of data; and to 2) drafting the article or revising it critically 
for important intellectual content; and on 3) final approval of the version to be published. 
Conditions 1), 2) and 3) must all be met. Participation solely in acquisition of funding or the 
collation of data does not justify authorship. General supervision of the research group is not 
sufficient for authorship. It is intended that information on what each author has contributed will 
be published. 
It is emphasized however, that only those who entirely meet the above-mentioned criteria will be 
listed as authors. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 52 of 62
 
 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 53 of 62
 
13 REFERENCES 
1. Roché H, Vahat LT. Treatment of metastatic breat cancer: second line and beyond. 
Annals of Oncology 22: 1000 1010, 2011 doi:10.1093/annonc/mdq429 Published online 
21 October 2010 
2. Global Burden of Disease Cancer C, Fitzmaurice C, Abate D, Abbasi N, Abbastabar H, 
Abd-Allah F, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of 
Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer 
Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study. 
JAMA Oncol. 2019. 
3. Ferlay J, Colombet M, Soerjomataram I, Dyba T, Randi G, Bettio M, et al. Cancer 
incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major 
cancers in 2018. Eur J Cancer. 2018;103:356-87. 
4. Fumoleau P, Largillier R, Clippe C, Dieras V, Orfeuvre H, Lesimple T, et al. Multicentre, 
phase II study evaluating capecitabine monotherapy in patients with anthracycline- and 
taxane-pretreated metastatic breast cancer. Eur J Cancer. 2004;40(4):536-42 
5. Agency EM. Withdrawal Assessment Report for Ixempra (Doc.Ref.: EMEA/594033/2008). 
London; 2009. 
6. Lee FYF. Preclinical pharmacology of BMS-247550, an epothilone analog. Document 
Control No. 910074590. Bristol-Myers Squibb Research and Development,; 1999 
7. Lee FYF. Further studies on the preclinical pharmacology of ixabepilone (BMS-247550), 
a novel microtubule stabilizer. Document Control No 930009639.: Bristol-Myers Squibb 
Research and Development,; 2005. 
8. Ixabepilone (BMS-247550) - Nonclinical pharmacology written summary.  Document 
Control No 930014941. Bristol-Myers Squibb Research and Development,; 2006. 
9. Nettles JH, Li H, Cornett B, Krahn JM, Snyder JP, Downing KH. The binding mode of 
epothilone 
A 
on 
alpha,beta-tubulin 
by 
electron 
crystallography. 
Science. 
2004;305(5685):866-9. 
10. Kamath K, Wilson L, Cabral F, Jordan MA. BetaIII-tubulin induces paclitaxel resistance in 
association with reduced effects on microtubule dynamic instability. J Biol Chem. 
2005;280(13):12902-7. 
11. Dumontet C, Jordan MA, Lee FF. Ixabepilone: targeting betaIII-tubulin expression in 
taxane-resistant malignancies. Mol Cancer Ther. 2009;8(1):17-25. 
12. Hasegawa S, Miyoshi Y, Egawa C, Ishitobi M, Taguchi T, Tamaki Y, et al. Prediction of 
response to docetaxel by quantitative analysis of class I and III beta-tubulin isotype 
mRNA expression in human breast cancers. Clin Cancer Res. 2003;9(8):2992-7. 
13. Paradiso A, Mangia A, Chiriatti A, Tommasi S, Zito A, Latorre A, et al. Biomarkers 
predictive for clinical efficacy of taxol-based chemotherapy in advanced breast cancer. 
Ann Oncol. 2005;16 Suppl 4:iv14-9. 
14. Seve P, Mackey J, Isaac S, Tredan O, Souquet PJ, Perol M, et al. Class III beta-tubulin 
expression in tumor cells predicts response and outcome in patients with non-small cell 
lung cancer receiving paclitaxel. Mol Cancer Ther. 2005;4(12):2001-7. 
15. Mozzetti S, Ferlini C, Concolino P, Filippetti F, Raspaglio G, Prislei S, et al. Class III beta-
tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian 
cancer patients. Clin Cancer Res. 2005;11(1):298-305. 
16. Aghajanian C, Burris HA, 3rd, Jones S, Spriggs DR, Cohen MB, Peck R, et al. Phase I 
study of the novel epothilone analog ixabepilone (BMS-247550) in patients with 
advanced solid tumors and lymphomas. J Clin Oncol. 2007;25(9):1082-8. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 54 of 62
 
17. Gadgeel SM, Wozniak A, Boinpally RR, Wiegand R, Heilbrun LK, Jain V, et al. Phase I 
clinical trial of BMS-247550, a derivative of epothilone B, using accelerated titration 2B 
design. Clin Cancer Res. 2005;11(17):6233-9. 
18. S0355 CSR. A phase 1 pharmacokinetic study of epothilone analogue BMS-247550 
(ixabepilone) (NSC-710428D) in patients with advanced malignancies and varying levels 
of liver dysfunction. BMS Document Control No. 930019540. Bristol-Myers Squibb 
Research and Development; 2007. 
19. Denduluri N, Low JA, Lee JJ, Berman AW, Walshe JM, Vatas U, et al. Phase II trial of 
ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previously 
untreated with taxanes. J Clin Oncol. 2007;25(23):3421-7. 
20. Low JA, Wedam SB, Lee JJ, Berman AW, Brufsky A, Yang SX, et al. Phase II clinical trial 
of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced 
breast cancer. J Clin Oncol. 2005;23(12):2726-34. 
21. Roche H, Yelle L, Cognetti F, Mauriac L, Bunnell C, Sparano J, et al. Phase II clinical trial 
of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy in patients 
with metastatic breast cancer previously treated with anthracycline chemotherapy. J Clin 
Oncol. 2007;25(23):3415-20. 
22. Thomas E, Tabernero J, Fornier M, Conte P, Fumoleau P, Lluch A, et al. Phase II clinical 
trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-
resistant metastatic breast cancer. J Clin Oncol. 2007;25(23):3399-406. 
23. Smith JW, 2nd, Vukelja S, Rabe A, Wentworth-Hartung N, Koutrelakos N, Shao SH, et al. 
Phase II randomized trial of weekly and every-3-week ixabepilone in metastatic breast 
cancer patients. Breast Cancer Res Treat. 2013;142(2):381-8. 
24. Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, et al. Efficacy and safety 
of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer 
resistant 
to 
an 
anthracycline, 
a 
taxane, 
and 
capecitabine. 
J 
Clin 
Oncol. 
2007;25(23):3407-14. 
25. INVESTIGATOR BROCHURE Ixabepilone BMS-247550  Version 10. BRISTOL-MYERS 
SQUIBB RESEARCH AND DEVELOPMENT 2009. 
26. Denduluri N, Swain S. Ixabepilone: clinical role in metastatic breast cancer. Clin Breast 
Cancer. 2011;11(3):139-45. 
27. Buhl ASK, Christensen TD, Christensen IJ, Nelausen KM, Balslev E, Knoop AS, et al. 
Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a 
Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective 
blinded study. Breast Cancer Res Treat. 2018;172(2):391-400. 
28. Buhl IK, Santoni-Rugiu E, Ravn J, Hansen A, Christensen IJ, Jensen T, et al. Molecular 
prediction of adjuvant cisplatin efficacy in Non-Small Cell Lung Cancer (NSCLC)-
validation in two independent cohorts. PLoS One. 2018;13(3):e0194609. 
29. Chen JJ, Knudsen S, Mazin W, Dahlgaard J, Zhang B. A 71-gene signature of TRAIL 
sensitivity in cancer cells. Mol Cancer Ther. 2012;11(1):34-44. 
30. Knudsen S, Hother C, Gronbaek K, Jensen T, Hansen A, Mazin W, et al. Development 
and blind clinical validation of a microRNA based predictor of response to treatment with 
R-CHO(E)P in DLBCL. PLoS One. 2015;10(2):e0115538. 
31. Knudsen S, Jensen T, Hansen A, Mazin W, Lindemann J, Kuter I, et al. Development and 
validation of a gene expression score that predicts response to fulvestrant in breast 
cancer patients. PLoS One. 2014;9(2):e87415. 
32. Wang W, Baggerly KA, Knudsen S, Askaa J, Mazin W, Coombes KR. Independent 
validation of a model using cell line chemosensitivity to predict response to therapy. J 
Natl Cancer Inst. 2013;105(17):1284-91. 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 55 of 62
 
33. Vangsted AJ, Helm-Petersen S, Cowland JB, Jensen PB, Gimsing P, Barlogie B, et al. 
Drug response prediction in high-risk multiple myeloma. Gene. 2018;644:80-6. 
34. Horak CE, Pusztai L, Xing G, Trifan OC, Saura C, Tseng LM et al. Biomarker Analysis of 
Neoadjuvant Doxorubicin/ Cyclophosphamide Followed by Ixabepilone or Paclitaxel in 
Early-Stage Breast Cancer. Clin Cancer Res. 2013; 19(6); 1587 95 
35. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur 
J Cancer. 2009;45(2):228-47. 
36. Institute NC. Common Terminology Criteria for Adverse Events (CTCAE) v5.0  U.S. 
DEPARTMENT OF HEALTH AND HUMAN SERVICES 2017. 
37. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 
1989;10(1):1-10. 
 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 56 of 62
 
14 SIGNATURES 
 
The protocol has been approved by:  
 
 
Name and function 
Signature 
Date 
 
Peter Gimsing 
Medial Monitor 
 
 
 
 
Marie Foegh  
 
 
 
 
 
Nils Meland Statistician 
CRO, Smerud Medical Research  
International 
 
 
 
  
 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 57 of 62
 
 
15 SIGNATURE PAGE FOR INVESTIGATOR 
 
I agree: 
 
To assume responsibility for the proper conduct of the study at this site. 
 
To conduct the study in compliance with this protocol, any future amendments, 
and with any other study conduct procedures provided by Allarity Therapeutics  
 
Not to implement any changes to the protocol without the agreement from the 
sponsor and prior review and written approval from the Institutional Review 
Board (IRB) or the Independent Ethics Committee (IEC), except where 
necessary to eliminate an immediate hazard to the patents, or for purely 
administrative aspects of the study where all applicable regulatory requirements 
are permissive. 
 
That I am thoroughly familiar with the appropriate use of the investigational 
product(s), as described in this protocol, and any other information provided by 
the sponsor in writing including, but not limited to, the following: 
o 
The current protocol and the current Summary of product characteristics       
for IXEMPRA 
 
That I am aware of and will fully comply with Good Clinical Practices (GCP) as 
outlined in 21 CFR Parts 50, 54, 56 and 312 and 45 CFR Part 46 and all other 
applicable regulatory requirements. 
 
To insure that all persons assisting me with this study are adequately informed 
about the Allarity Therapeutics  investigational product and of their study-related 
duties and functions as described in this protocol. 
 
That I have been informed that certain regulatory authorities require Allarity 
Therapeutics to obtain and supply, as neces
ownership interest in Allarity Therapeutics, its investigational product, and more 
Allarity Therapeutics. For this 
reason, 
 
I further agree: 
o 
To supply Allarity Therapeutics with any requested information 
regarding ownership interest and financial ties, including those of my 
spouse and dependent children; 
o 
To promptly update this information if any relevant changes occur 
during the course of the study and for one (1) year following completion 
of the study; and 
o 
That Allarity Therapeutics will maintain this information in a confidential 
matter, but that it may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities. 
 
  
      Investigator Name 
  
 
  Date: 
  
Investigator Signature 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 58 of 62
 
16 APPENDICES 
 
 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 59 of 62
 
Appendix 1. Eastern Cooperative Oncology Group Performance 
Status 
 
 
 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 60 of 62
 
Appendix 2. Neuropathy Assessment Patient evaluation form  
 
Neurotoxicity Questionnaire  
 
The patients are asked to fulfill the questionnaire before each ixabepilone infusion as a tool for 
identifying patients with neurologic AEs. 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days.  
  
Concerns 
Not at 
all 
A 
little 
bit 
Somewhat
Quite 
a bit 
Very 
much 
I have numbness or tingling in my hand 
0 
1 
2 
3 
4 
I have numbness or tingling in my feet 
0 
1 
2 
3 
4 
I feel discomfort in my hands 
0 
1 
2 
3 
4 
I feel discomfort in my feet 
0 
1 
2 
3 
4 
I have joint pain or muscle cramps 
0 
1 
2 
3 
4 
I feel weak all over 
0 
1 
2 
3 
4 
I have trouble hearing 
0 
1 
2 
3 
4 
I get a ringing or buzzing in my ears 
0 
1 
2 
3 
4 
I have trouble buttoning buttons 
0 
1 
2 
3 
4 
I have trouble feeling the shape of small 
objects when they are in my hand 
0 
1 
2 
3 
4 
I have trouble walking 
0 
1 
2 
3 
4 
 
 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 61 of 62
 
Appendix 3. Version tracker 
Protocol version  
 
Revisions 
Version 2.0 
 
The following text was added to 
exclusion criteria no. 14: 
. 
Similarly, 
patients 
must 
not 
continue 
treatment with the following strong inducers of 
CYP3A4: phenytoin, carbamazepine, rifampin, 
rifabutin, dexamethasone, and phenobarbital. 
(20 mg dexamethasone can be used for pre-
treatment if required). 
 
 
Screening period has been increased 
from 4 to 6 weeks. 
 
 
It has been added that: Complete
blood count at day 8 and 15 may be done at
local hospital or in primary care after 1st cycle 
is completed. 
 
 
It has been added that: Follow-up on 
AEs and concomitant medication at day 8 and 
15 may be done by phone after the 1st cycle.  
 
 
Dose Adjustments in Patients with 
Hepatic Impairment have been added in 
section 7.5.2 Table 8.  
 
 
The following text has been added to 
section 7.6.1:  
Conversely, 
inducers 
of 
CYP3A4 
may 
decrease 
plasma 
concentrations 
of 
ixabepilone. The use of concomitant strong 
CYP3A4 inducers should be avoided (eg, 
phenytoin, carbamazepine, rifampin, rifabutin, 
dexamethasone, and phenobarbital). (20mg 
dexamethasone can be used as premedication 
if 
required). 
Selection 
of 
an 
alternative 
concomitant medication with no or minimal 
enzyme 
induction 
potential 
should 
be 
considered. 
 
Version 3.0 
Sponsor has been changed from Allarity
Therapeutic AS to Allarity Therapeutics Europe 
ApS 
 
It has been added to the protocol that patients 
can be included based DRP conducted on 
archival tisse (section 5.5). DRP shoud be 
repeated on a biopsy taken after last cancer 
tratemnt if possible.  
 
Exclusion criteria 12 and 13 have been 

Confidential / Clinical Study Protocol No.AL-2001 / Final3.0 / date 2022-03-23 
 
Page 62 of 62
 
deleted.  
 
A secondary endpoint was added:  
 
Assess difference in prediction based 
on archival and fresh biopsy from 
same patient (percent agreement in 
binary prediction, and difference in 
primary and secondary endpoints with 
archival versus fresh biopsies) 
 
 
 
 

Certificate Of Completion
Envelope Id: FFBCF822173B45F4BCED32EE905C02C8
Status: Completed
Subject: Please DocuSign: Ixabepilone mBC_Final Protocol v 3.0_23.02.2022 _final new CI.pdf
Source Envelope: 
Document Pages: 62
Signatures: 3
Envelope Originator: 
Certificate Pages: 2
Initials: 0
Charlotte Kleiveland
AutoNav: Enabled
EnvelopeId Stamping: Enabled
Time Zone: (UTC-08:00) Pacific Time (US & Canada)
Smerud Medical Research AS
nil
Oslo, Oslo  0274
charlotte.kleiveland@smerud.com
IP Address: 109.74.178.98
Record Tracking
Status: Original
             3/28/2022 11:27:53 PM
Holder: Charlotte Kleiveland
             charlotte.kleiveland@smerud.com
Location: DocuSign
Signer Events
Signature
Timestamp
Marie Foegh
mfoegh@allarity.com
Chief Medical Officer
Security Level: Email, Account Authentication 
(None)
Signature Adoption: Pre-selected Style
Using IP Address: 98.7.68.224
Sent: 3/28/2022 11:30:50 PM
Viewed: 3/29/2022 4:14:07 AM 
Signed: 3/29/2022 4:15:00 AM
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
Peter Gimsing
pgimsing@allarity.com
Security Level: Email, Account Authentication 
(None)
Signature Adoption: Pre-selected Style
Using IP Address: 83.94.33.24
Sent: 3/29/2022 4:15:05 AM
Viewed: 3/29/2022 4:22:40 AM 
Signed: 3/29/2022 4:23:33 AM
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
Nils Meland
nils.meland@smerud.com
Security Level: Email, Account Authentication 
(None)
Signature Adoption: Pre-selected Style
Using IP Address: 109.74.178.98
Sent: 3/29/2022 4:23:38 AM
Resent: 3/29/2022 6:46:57 AM
Viewed: 3/29/2022 6:51:08 AM 
Signed: 3/29/2022 6:57:29 AM
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
In Person Signer Events
Signature
Timestamp
Editor Delivery Events
Status
Timestamp
Agent Delivery Events
Status
Timestamp
Intermediary Delivery Events
Status
Timestamp
Certified Delivery Events
Status
Timestamp
Carbon Copy Events
Status
Timestamp

Witness Events
Signature
Timestamp
Notary Events
Signature
Timestamp
Envelope Summary Events
Status
Timestamps
Envelope Sent
Hashed/Encrypted
3/28/2022 11:30:50 PM
Certified Delivered
Security Checked
3/29/2022 6:51:08 AM
Signing Complete
Security Checked
3/29/2022 6:57:29 AM
Completed
Security Checked
3/29/2022 6:57:29 AM
Payment Events
Status
Timestamps