Clinical Trials Register

Summary
EudraCT Number:	2014-001589-85
Sponsor's Protocol Code Number:	D081FC00001
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-11-25
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-001589-85

A.3

Full title of the trial

A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre Study of Maintenance Olaparib Monotherapy in Patients with gBRCA Mutated Metastatic Pancreatic Cancer whose Disease Has Not Progressed on First Line Platinum Based Chemotherapy

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Olaparib in gBRCA Mutated Pancreatic Cancer whose Disease Has Not Progressed on First Line Platinum-Based Chemotherapy

A.3.2

Name or abbreviated title of the trial where available

POLO

A.4.1

Sponsor's protocol code number

D081FC00001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Astrazeneca AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Astrazeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca
B.5.2	Functional name of contact point	Information center
B.5.3	Address:
B.5.3.1	Street Address	Not applicable
B.5.3.2	Town/ city	Not applicable
B.5.3.3	Post code	Not applicable
B.5.3.4	Country	United States
B.5.6	E-mail	information.centre@astrazeneca.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	olaparib
D.3.2	Product code	AZD2281
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	olaparib
D.3.9.1	CAS number	763113-22-0
D.3.9.3	Other descriptive name	OLAPARIB
D.3.9.4	EV Substance Code	SUB32234
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	olaparib
D.3.2	Product code	AZD2281
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	olaparib
D.3.9.1	CAS number	763113-22-0
D.3.9.3	Other descriptive name	OLAPARIB
D.3.9.4	EV Substance Code	SUB32234
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with gBRCA mutated metastatic pancreatic cancer whose disease has not progressed on
first line platinum based chemotherapy

E.1.1.1

Medical condition in easily understood language

gBRCA mutated metastatic pancreatic cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the efficacy of Olaparib maintenance monotherapy compared to placebo by progression free survival (PFS)

E.2.2

Secondary objectives of the trial

• To determine the efficacy of Olaparib maintenance monotherapy compared to placebo
• To assess the effect of Olaparib on the Health-related Quality of Life (HRQoL) as measured by EORTC
QLQ-C30 global QoL scale.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

For inclusion in the study patients should fulfil the following criteria:
1. *Provision of informed consent prior to any study specific procedures
2. *Patients must be male or female ≥18 years of age
3. *Histologically or cytologically confirmed pancreas adenocarcinoma receiving initial chemotherapy for metastatic disease and without evidence of disease progression on treatment
4. Patients with measurable disease and/or non-measurable or no evidence of disease assessed at baseline by CT (or MRI where CT is contraindicated) will be entered in this study.
5. Documented mutation in gBRCA1 or gBRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function)
6. Patients are on treatment with a first line platinum-based regimen for metastatic pancreas cancer, have received a minimum of 16 weeks of continuous platinum treatment and have no evidence of progression based on investigator’s opinion.
7. Patients who have received platinum as potentially curative treatment for a prior cancer (eg ovarian cancer) or as adjuvant/neoadjuvant treatment for pancreas cancer are eligible provided at least 12 months have elapsed between the last dose of platinum-based treatment and initiation of the platinum-based chemotherapy for metastatic pancreas cancer.
8. Patients must have normal organ and bone marrow function measured within 4 weeks prior to administration of study treatment as defined below:
− Haemoglobin ≥ 9.0 g/dL with no blood transfusions (packed red blood cells and platelet transfusions) in the past 28 days
− Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
− White blood cells (WBC) >3 x 109/L
− No features suggestive of MDS/AML on peripheral blood smear
− Platelet count ≥ 100 x 109/L
− Total bilirubin ≤ 1.5 x institutional upper limit of normal
− AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal value unless liver metastases are present in which case they must be ≤ 5x ULN
− Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN)
9. *ECOG performance status 0-1 at date signing of informed consent
10. *Postmenopausal or evidence of non-childbearing status for women of childbearing
potential: negative urine or serum pregnancy test. Postmenopausal is defined as:
− Amenorrheic for 1 year or more following cessation of exogenous hormonal
treatments
− Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in
the post menopausal range for women under 50
− Radiation-induced oophorectomy with last menses >1 year ago
− Chemotherapy-induced menopause with >1 year interval since last menses
− Surgical sterilisation (bilateral oophorectomy or hysterectomy)
11. *Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
12. Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary tumour or a metastatic site if available or 3 unstained cytology slides if available.

E.4

Principal exclusion criteria

Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1. *Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or staff at the study site).
2. gBRCA1 and/or gBRCA2 mutations that are considered to be non detrimental (eg, “Variants of uncertain clinical significance” or “Variant of unknown significance” or “Variant, favour polymorphism” or “benign polymorphism” etc.).
3. Progression of tumour between start of first line platinum based chemotherapy for metastatic pancreas cancer and randomisation.
4. Cytotoxic chemotherapy or non-hormonal targeted therapy within 28 days of Cycle 1 Day 1 is not permitted. Palliative radiotherapy must have been completed 14 or more days before Cycle 1 Day 1. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 2 weeks prior to study treatment.
5. *Previous randomisation in the present study.
6. Exposure to an investigational product within 30 days or 5 half lives (whichever is
longer) prior to randomisation
7. *Any previous treatment with a PARP inhibitor, including Olaparib.
8. *Patients with second primary cancer, EXCEPTIONS: adequately treated nonmelanoma skin cancer, curatively treated in-situ cancer of the cervix, Ductal Carcinoma in Situ (DCIS), stage 1 grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥ 5 years prior to study entry.
9. Resting ECG with QTc > 470 msec detected on 2 or more time points within a 24 hour period or family history of long QT syndrome. If ECG demonstrates QTc >470 msec, patient will be eligible only if repeat ECG demonstrates QTc ≤470 msec.
10. Concomitant use of known potent CYP3A4/5 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
11. Persistent toxicities (≥CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 3 peripheral neuropathy.
12. *Patients with myelodysplastic syndrome/acute myeloid leukaemia.
13. Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery.
14. *Immunocompromised patients, eg, patients who are known to be serologically positive for human immunodeficiency virus (HIV).
15. *Clinically significant uncontrolled medical conditions are not permitted (eg active infection requiring IV antibiotics, symptomatic congestive heart failure, unstable angina pectoris, recent (3 months) myocardial infarction, extensive bilateral interstitial lung disease, psychiatric illness that would limit ability to comply with study procedures, and any other medical condition that, in the opinion of the investigator, places the patient at unacceptable risk of toxicity. NB: Diabetes which
is controlled by medication does not exclude participation in the study
16. *Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria: Disease outside the CNS is present. No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study. No history of intracranial haemorrhage or spinal cord haemorrhage. Minimum of 2 weeks between completion of radiotherapy and cycle 1 Day 1 and recovery from significant (Grade ≥3) acute toxicity with no ongoing
17. *Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study medication.
18. *Pregnant or breast feeding women.
19. *Previous allogeneic bone marrow transplant.
20. *Patients with a known hypersensitivity to Olaparib or any of the excipients of the
product.
21. *Whole blood transfusions in the last 120 days prior to enrolment to the study
which may interfere with gBRCA testing (packed red blood cells and platelet

E.5 End points

E.5.1

Primary end point(s)

Determine the efficacy of Olaparib maintenance monotherapy compared to placebo by progression free survival (PFS)-Progression Free Survival (PFS) by BICR using modified RECIST 1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

- Interim PFS analyses (~ 45 PFS events): PFS
- Final PFS (~ 89 PFS events): PFS, PFS2, TDT, TFST, TSST, OS, time to deterioration of Global QoL and PAN-26 pain scale Efficacy Data
- Final OS analyses (~ 106 OS events): PFS2, TFST, TSST, OS, time to deterioration of Global QoL and PAN-26 pain scale

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

- Overall Survival (observed and predicted using observed PFS and OS data), Time from randomisation to second progression (PFS2), Time from randomisation to first subsequent therapy or death (TFST), Time from randomisation to second subsequent therapy or death (TSST), Time from randomisation to study treatment discontinuation or death (TDT), Objective Response Rate by BICR using modified RECIST 1.1 criteria for evaluable patients, Disease Control Rate at 16 weeks by BICR using modified RECIST 1.1 criteria
- Adjusted mean change from baseline in global QoL score from the EORTC-QLQC30 questionnaire

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Belgium

Canada

France

Germany

Israel

Korea, Republic of

Netherlands

Spain

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

the last visit of the last patient undergoing the study

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

145

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Once a patient has discontinued study treatment, clinic visits will be reduced to every 8 weeks. Following discontinuation of study treatment, further treatment will be at the discretion of the investigator however it is anticipated (but not required) that patients will be retreated with their platinum based regimen.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-01-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-12-11

P. End of Trial
P.	End of Trial Status	Completed

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