A Preoperative "Window-opportunity", Multicenter, Pharmacokinetic-pharmacodynamic Study to Evaluate the Inhibitory Effects of Single Agent AZD2281 (Olaparib), in Patients With Early-stage Endometrial Carcinoma
Conditions: Endometrial Carcinoma
Sponsor: MedSIR

 
Clinical Trial Protocol v4.0 03 Nov 2016 
MedOPP044_POLEN Trial 
NCT02506816 
 
 
Confidential 
 
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Clinical Trial Protocol 
 
 
A preoperative “window-opportunity”, multicenter, pharmacokinetic-pharmacodynamic study to 
evaluate the inhibitory effects of single agent AZD2281 (Olaparib), in patients with early-stage 
endometrial carcinoma. 
 
Preoperative OLaparib ENdometrial Carcinoma Study (POLEN) 
 
 
 
 
Study Drug(s):  
 
 
Olaparib (AZD2281) 
 
EudraCT#: 
 
 
 
2015-001156-30 
 
Clinical Trials.gov#: 
 
 
NCT02506816 
 
Protocol#:  
 
 
 
MedOPP044 
 
Protocol version: 
 
 
Final amendment no. 4 
 
Protocol date:  
 
 
November 3, 2016 
 
 
 
 
 
 
 
Confidentiality Statement 
This confidential document is the property of the Sponsor. No unpublished information contained 
herein may be disclosed without prior written approval from the Sponsor. Access to this document 
must be restricted to relevant parties. 
 

 
Clinical Trial Protocol v4.0 03 Nov 2016 
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NCT02506816 
 
 
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CLINICAL TRIAL PROTOCOL SYNOPSIS 
Product: 
Olaparib (AZD2281) 
Protocol Number: 
MedOPP044 
EudraCT Number: 
2015-001156-30 
Protocol Title: 
 
 
Short title: 
A preoperative “window-opportunity”, multicenter, pharmacokinetic-
pharmacodynamic study to evaluate the inhibitory effects of single 
agent AZD2281 (Olaparib), in patients with early-stage endometrial 
carcinoma. 
Preoperative OLaparib in ENdometrial carcinoma (POLEN) 
Target disease: 
Endometrial carcinoma (EC) 
Subjects: 
Patients diagnosed with endometrial carcinoma prior surgery 
Number of patients: 
36 patients  
Selection criteria: 
Patients are eligible for inclusion into the study only if they meet ALL 
of the following criteria: 
 
Inclusion criteria 
1. Patients must have histologically confirmed type I primary 
endometrial carcinoma (EC). Diagnosis biopsy must contain 3-12 
mg of tumor cellularity/stroma (Tumor: 5-20 mm) and this will be 
checked in the central laboratory for this trial. If tumour 
cellularity/stroma is inadequate, one re-biopsy with adequate 
tumour cellularity/stroma will be mandatory before study entry. 
2. Age ≥ 18 years. 
3. WHO performance status ≤ 2. 
4. Adequate bone marrow function as shown by ANC ≥ 1.5 x 109/L, 
Platelets ≥ 100 x 109/L, Hb >10g/dL. 
5. Adequate liver function as shown by: 
o 
serum bilirubin ≤ 1.5 x ULN 

 
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o 
INR < 1.3 (or < 3 on anticoagulants) 
o 
ALT and AST ≤ 2.5x ULN 
6. Adequate renal function: serum creatinine ≤ 1.5 x mg/dL. 
7. Fasting serum cholesterol ≤300 mg/dL or ≤7.75 mmol/L and 
fasting triglycerides ≤ 2.5 x ULN.  
NOTE: In case one or both of these thresholds are exceeded, 
the patient can only be included after normalization values 
with appropriate lipid lowering medication. 
8. Signed informed consent, including consent to tissue collection 
and blood samples as specified by the protocol. 
 
Exclusion criteria 
Patients will be excluded from the study if they meet ANY of the 
following criteria: 
1. Subjects who have received prior anticancer therapies for the 
current 
endometrial 
cancer 
(including 
chemotherapy, 
radiotherapy, antibody-based therapy, hormonotherapy or 
surgery). 
2. Patients, who have had a major surgery or significant traumatic 
injury within 4 weeks of start of study drug, patients who have not 
recovered from the side effects of any major surgery (defined as 
requiring general anesthesia) or patients that may require major 
surgery during the course of the study. 
3. Prior treatment with any investigational drug within the preceding 
4 weeks. 
4. Patients 
receiving 
chronic, 
systemic 
treatment 
with 
corticosteroids or another immunosuppressive agent, except 
corticosteroids with a daily dosage equivalent to prednisone ≤ 20 
mg. However, patients receiving corticosteroids must have been 
on a stable dosage regimen for a minimum of 4 weeks prior the 
study entry. Topical or inhaled corticosteroids are allowed. 
5. Patients who have received immunization with attenuated live 
vaccines within one week of study entry (note:  during study 
period these kinds of vaccines are also not allowed). 

 
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6. Patients who need treatment with inhibitors or potent inductors of 
CYP3A4  
7. Patients who have any severe and/or uncontrolled medical 
conditions or other conditions that could affect their participation 
in the study such as: 
o 
Symptomatic congestive heart failure of New York heart 
Association Class III or IV 
o 
unstable angina pectoris, myocardial infarction within 6 
months of start of study drug, serious uncontrolled cardiac 
arrhythmia or any other clinically significant cardiac disease 
o 
severely impaired lung function 
o 
uncontrolled diabetes as defined by fasting serum glucose 
>1.5 x ULN 
o 
active (acute or chronic) or uncontrolled severe infections 
o 
liver disease such as cirrhosis, chronic active hepatitis or 
chronic persistent hepatitis 
o 
a known history of HIV seropositivity. 
8. Patients with an active, bleeding diathesis. 
9. Female patients who are pregnant or breast feeding, or adults of 
reproductive potential who are not using effective birth control 
methods (e.g. total sexual abstinence*, doble barrier methods like 
condom + spermicide, or condom + diaphragm with spermicide ,  
intra-uterine device (IUD) and condom, diaphragm with 
spermicide, or vasectomize partner with azoospermia confirmed. 
Hormonal contraceptives are acceptable as a sole method of 
contraception. 
Women able to conceive and using hormonal contraceptives have 
to be into the administration of a stable doses of the contraceptive 
at least 4 weeks before the first dose of drug study, during the 
whole study period and until 30 days after the study treatment will 
be retired. The women in fertile period must have a negative urine 
or serum pregnancy test within 7 days prior to administration of 
AZD2281. 
The only women exempt of this requirement are the 
postmenopausal (define by not having a menstrual period for 12 

 
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consecutive months, from the corresponding group age, and 
without any other known or possible reason), the ones submitted 
to a chirurgic sterilization o can demonstrate sterility by other 
means (that is, chirurgic bilateral tubal ligation, and bilateral 
chirurgic hysterectomy or oophorectomy at least one month 
before the first dose of experimental drug administration. 
*Total sexual abstinence will be acceptable only in the case that 
is in consonance with the way of life of the patient. 
10. History of noncompliance to medical regimens. 
11. Patients unwilling to or unable to comply with the protocol. 
Study objectives: 
Primary Objective: 
The primary objective of this study is to identify, the antitumoral 
biological efficacy, by measuring, biomarker changes associated to 
short exposure to AZD2281 as potential predictors of activity in 
Endometrial Carcinoma (EC) in human tumor samples.  
This is an exploratory study with a biological primary endpoint.  
 
Secondary Objectives 
- 
To consider the tolerability to AZD2281 during the study and until 
28 days after the last dose of AZD2281. 
- 
To correlate changes induced by AZD2281 with the different type 
of endometrial carcinoma and other tumor biomarkers (NFkBp65 
and p50, PARP, PARP-1, pHistone 2AX, pHistoneH3, VEGF 
(Vascular Endothelial Growth Factor), HIF(Hypoxia inducible 
factor)-1alpha). 
- 
To estimate the potential predictive value of histological type: 
Endometrioid endometrial carcinoma (EEC) versus Non 
Endometrioid Endometrial Carcinoma (NEEC), and some 
biomarkers (immunostaining for PTEN (Phosphatase and tensin 
homolog), MLH-1 (mutL homolog 1), MSH-2 (mutS Homologue 
2), 
MSH-6 
(MutS 
homologue 
6), 
PMS-2 
(Postmeiotic 
Segregation Increased S. Cerevisiae. 2). 

 
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- 
To estimate the potential predictive role of microsatellite 
instability and PTEN loss in clinical tumor changes and PARP 
inhibition. 
- 
To correlate clinical tumor changes with several targets of PARP 
inhibition. 
- 
To further explore the use of Pharmacokinetic-dynamic 
modelling (PBMC modelling) as surrogate pharmacodynamic 
marker of AZD2281 activity in endometrial tumors. 
- 
To quantify AZD2281 levels in human tissues after the oral 
administration of the drug  
- 
To explore the correlation between intra-tumoral AZD2281 
concentrations with plasma PK parameters and molecular 
alterations in EC after AZD2281 treatment. 
- 
To compare intra-tumoral AZD2281 concentrations with those 
present in healthy tissues. 
- 
To establish a kinetic-dynamic modelling, based on the status of 
the variables of time (t), concentration (C) in blood and in tissue, 
and molecular effect (E). 
- 
To estimate the tolerability to AZD2281 throughout the study and 
up to 28 days after the last dose of AZD2281. 
Type of study: 
This is an open-label, non-randomized, non-controlled, multicenter 
phase 0 study that will enroll approximately 36 patients. 
Therapy: 
Eligible patients will receive 300mg of AZD2281 (two tablets of 150 
mg of AZD2281) twice daily throughout 28 (+/- 5) days. Total daily 
dose will be 600 mg of AZD2281. 
Evaluation Criteria: 
Primary Endpoint: The primary endpoint for this study is to assess 
the histological score of the cell cycle-related proteins cyclin D1, ki67 
and active caspase 3, directly on endometrial tumor tissue after 28 
(+/-5) days of therapy.  
The histological score will be obtained by applying the following 
formula:  
 

 
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Hscore= 1x(%light staining) + 2x(%moderate staining) + 3x(%strong 
staining). 
 
Secondary Endpoint-Safety 
- 
To measure the correlation between PARP inhibitor effect and 
other changes in tumor-tissue:  
o 
DNA repair: PARP, PARP-1, pHistone 2AX  
o 
Mitosis: pHistone 2AX 
o 
Angiogenesis (VEGF, HIF-1alpha) 
o 
Apoptosis (NFkB p65, p50)  
o 
Mutations and deletions 
o 
Microsatellite instability 
- 
AZD2281 blood levels on days 1, 7, 14, 21,28 of the therapy and 
day of surgery 
- 
Drug tumoral tissue levels on day 28 of the treatment. 
- 
Drug healthy tissue levels on day 28 of the treatment. 
- 
To test the tolerability for all AZD2281-treated patients measured 
by CTCAE v.4. 
Study follow-up: 
Inclusion period: 12 months. 
Follow-up period: 28 days 
 
 
 
 

 
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NCT02506816 
 
 
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Appendix 1: Schedule of assessments and study procedures 
Study Procedures 
SCREENING 
Day (-14) -Day 0 
BASELINE 
Day (-7) -Day 
0 
THERAPY PERIOD 
Day 1 – Day 28 
(+/-5 days) 
SURGERY or 
TC-biopsy 
Day 29 
FOLLOW UP 
28 days after 
last drug 
dose 
Informed consent signed 
 
X 
 
 
 
Anamnesis and Physical examination 
 
X 
 
 
 
Concomitant medication record 
 
X 
D7-D14-D21-D28 
 
 
Functional status (WHO) and Vital signs 
 
X 
D7-D14-D21-D28 
 
X 
Safety assessment (CTCAE v 4.1) 
 
X 
D7-D14-D21-D28 
 
X 
Imaging assessment 
 
X 
 
 
 
Standard laboratory procedures: 
 
 
 
 
Pregnancy test 
 
X 
 
 
 
Hematology / Biochemistry values 
 
X 
D7-D14-D21-D28 
X 
X 
     Experimental 
laboratory 
(Sampling 
collection): 
 
 
 
 
Blood sample 
 
 
 
 
 
 
 
 
 
D1 (before first dose), 
BS1 
D1 (after first dose), 
BS2 
D7, BS3, 
D14, BS4, 
D21, BS5 
D28, BS6 
 
 
 
 
 
 
D29 (before 
surgery), BS7 
 
 
 
 
 

 
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NCT02506816 
 
 
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Study Procedures 
SCREENING 
Day (-14) -Day 0 
BASELINE 
Day (-7) -Day 
0 
THERAPY PERIOD 
Day 1 – Day 28 
(+/-5 days) 
SURGERY or 
TC-biopsy 
Day 29 
FOLLOW UP 
28 days after 
last drug 
dose 
Formalin-fixed, paraffin-embedded (FFPE) tumor 
tissue 
X 
MT1 
 
 
X 
MT2 
 
Frozen tumor tissue 
X(1) 
 
 
X 
 
 
Tumor tissue samples will obtained as follow: 
• 
Biopsy: at least 1 paraffin-embedded biopsy will be obtained, prior to initiating therapy period. (1) It will be recommended to collect frozen tissue sample if 
possible.  
• 
Surgical tumor section or biopsy samples will be obtained in the 24 hours following the last dose of therapy study. In case that surgical tumor sections are 
taken, 50% will be frozen and 50% paraffin embedded. In the case that biopsy samples are taken, at least 2 tumors will be obtained, 50% will be frozen and 
50% paraffin embedded.