Clinical Trials Register

Summary
EudraCT Number:	2013-001472-38
Sponsor's Protocol Code Number:	APR-407
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-04-27
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

France - ANSM

A.2

EudraCT number

2013-001472-38

A.3

Full title of the trial

PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study of Systemic Carboplatin Combination Chemotherapy With or Without APR-246

A.3.1

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

A study of systemic carboplatin combination chemotherapy with or without APR-246 in patients with recurrent high grade serous ovarian cancer

A.3.2

Name or abbreviated title of the trial where available

PiSARRO

A.4.1

Sponsor's protocol code number

APR-407

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	Aprea 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	Aprea 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	Theradex (Europe) Ltd
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	2nd Floor, The Pinnacle, Station Way
B.5.3.2	Town/ city	Crawley
B.5.3.3	Post code	RH10 1JH
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441293510319
B.5.5	Fax number	+441293510322
B.5.6	E-mail	mmoores@theradex.co.uk

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.3.2	Product code	APR-246
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	APR-246
D.3.9.2	Current sponsor code	APR-246
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
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	Carboplatin
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Carboplatin
D.3.9.3	Other descriptive name	CARBOPLATIN
D.3.9.4	EV Substance Code	SUB06614MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
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	Doxorubicin hydrochloride (pegylated liposomal)
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Doxorubicin hydrochloride
D.3.9.3	Other descriptive name	DOXORUBICIN HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB01827MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Recurrent high grade serous ovarian carcinoma

E.1.1.1

Medical condition in easily understood language

Recurrent high grade serous ovarian carcinoma

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10033131
E.1.2	Term	Ovarian carcinoma
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

In Phase Ib:
- To assess the safety and tolerability of APR-246 in combination with a carboplatin/PLD chemotherapy regimen in patients with platinum sensitive recurrent HGSOC.
- To confirm the Phase II dose level of APR-246 when administered in combination with carboplatin/PLD chemotherapy.
- To evaluate the pharmacokinetics of APR-246 when administered in combination with carboplatin/PLD chemotherapy.
In Phase II:
- To make a preliminary assessment of the efficacy of a combined APR-246 and carboplatin/PLD chemotherapy regimen patients with platinum sensitive recurrent HGSOC with mutated p53.

E.2.2

Secondary objectives of the trial

In Phase Ib:
- To evaluate potential biomarkers.
- To assess the biological activity in tumourtumor and surrogate tissues.

In Phase II:
- To assess the safety profile of the combined APR-246 and carboplatin/PLD chemotherapy regimen compared with carboplatin/PLD chemotherapy regimen alone.
- To evaluate potential biomarkers.
- To assess the biological activity in tumourtumor and surrogate tissues.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Archived sections from the original FFPE sample reviewed by a gynecological pathologist confirming High Grade Serous Ovarian Cancer, and positive nuclear IHC staining for p53 assessed according to local laboratory standard. Cases that do not show nuclear p53 staining will not be included.
2. Disease Progression between six and twenty-four (6-24) months after a first or second platinum based regimen.
3. At least a single (RECIST v1.1) measurable lesion. Phase II patients only.
4. A tumour that is accessible to repeat biopsies. Phase I highly desirable. Phase II mandatory.
5. Adequate organ function prior to registration:
Bone Marrow Reserve:
- Absolute neutrophil count (ANC) > or = 1.5 x10^9/L,
- Platelets > or = 100 x10^9/L,
- Hemoglobin > or = 9 g/dL.
Hepatic:
- Total bilirubin level < 1.5 x ULN,
- ALT, AST, GGT, and alkaline phosphatase levels < 2.5 x ULN.
Renal:
- Calculated creatinine clearance > 60ml/min.
6. Toxicities from previous cancer therapies must have recovered to grade 1 (defined by CTCAE 4.0). Chronic stable grade 2 peripheral neuropathy secondary to neurotoxicity from prior therapies may be considered on a case by case basis by the Principal Investigator.
7. If of childbearing potential, negative pre-treatment serum pregnancy test.
8. If of childbearing potential, willing to use an effective form of contraception such as hormonal birth control, intrauterine device or double barrier method during chemotherapy treatment and for at least six months thereafter.
9. ECOG performance status of 0 to 1.
10. > or = 18 years of age.
11. Signed, informed consent.

E.4

Principal exclusion criteria

1. Prior exposure to cumulative doses of doxorubicin >400 mg/m2 or epirubicin >720 mg/m2.
2. Confirmed cardiac history of any of the following:
Myocardial infarct within six months prior to registration,
New York Heart Association Class II or worse heart failure,
A history of familial long QT syndrome,
Clinically significant pericardial disease,
Electrocardiographic evidence of acute ischemia,
Arrhythmias not controlled by medications,
Serious ventricular arrhythmia (VT>130 bpm and > 5 beats, QTc ? 480 msec calculated from a single ECG reading or a mean of 3 ECG readings using Friderica?s correction (QTcF = QT/RR0.33) or bradycardia (<45bpm)
Left ventricular ejection fraction (LVEF) < the institution lower limit of normal as assessed by ECHO or MUGA.
3. Major abdominal surgery or peritonitis within six weeks prior to study treatment.
4. Unresolved bowel obstruction, sub-occlusive disease or the presence of brain metastases.
5. History of allergic reactions to carboplatin, platinum containing compounds or mannitol and/or hypersensitivity to PLD or to any of the excipients.
6. Unable to undergo imaging by either CT scan or MRI.
7. Evidence of any other medical conditions (such as psychiatric illness, infectious diseases, neurological conditions, physical examination or laboratory findings) that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment related complications.
8. Breast feeding
9. Concurrent malignancy requiring therapy (excluding non-invasive carcinoma or carcinoma in situ).
10. Known HIV positive status, active hepatitis B or C status.
11. Is taking concurrent (or within 4 week prior to registration) chemotherapy, immunotherapy, radiotherapy, hormone replacement therapy, or any ancillary therapy that is considered to be investigational (i.e., used for non-approved indications(s) and in the context of a research investigation). Supportive care measures are allowed.

E.5 End points

E.5.1

Primary end point(s)

In Phase Ib:
? Dose-limiting toxicities (DLT) and the safety profile (AEs, laboratory assessments, physical findings and biomarkers) of the combined APR 246 and carboplatin/PLD chemotherapy regimen.
? Sparse PK profiles of APR-246 and concentrations of carboplatin and PLD in plasma.

In Phase II:
? Progression Free Survival (PFS), defined as the time from registration to the time of disease progression or relapse (according to RECIST 1.1 only) or death, or the date of last tumourtumor assessment without any such event (censored observation).

E.5.1.1

Timepoint(s) of evaluation of this end point

Please refer to the study protocol.

E.5.2

Secondary end point(s)

In Phase Ib:
? Evaluation of potential biomarkers.
? Biological activity in tumour and surrogate tissues.

In Phase II:
? PFS by assessment of CA-125 as a tumour marker.
? Overall Survival (OS), calculated as the time from registration to the date of death from any cause.
? Overall Response Rate (RR), calculated as the proportion of patients with a best overall response of confirmed Complete Response (CR) or Partial Response (PR).
? Safety profile (AEs, laboratory assessments and physical findings) of the combined APR-246 and carboplatin/PLD chemotherapy regimen or the carboplatin/PLD chemotherapy regimen alone.
? Evaluation of potential biomarkers.
? Biological activity in tumourtumor and surrogate tissues.

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to the study protocol.

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Dose escalation (Phase Ib) and randomized exploratory (Phase II)

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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)

Yes

E.8.2.2

Placebo

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

Belgium

France

Netherlands

Spain

Sweden

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 end of the study is defined as the date of the last visit of the last patient taking part in 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)

F.1.3.1

Number of subjects for this age range:

120

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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

180

F.4.2.2

In the whole clinical trial

180

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)

It is expected that patients will go on to receive treatment according to usual hospital practice.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	EUTROC
G.4.3.4	Network Country	United Kingdom

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-04-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-12-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-04-26

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