Clinical Trials Register

Summary
EudraCT Number:	2017-000265-67
Sponsor's Protocol Code Number:	APR-486
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-03-21
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

UK - MHRA

A.2

EudraCT number

2017-000265-67

A.3

Full title of the trial

PiSARRO-R: p53 Suppressor Activation in Platinum-Resistant High Grade Serous Ovarian Cancer, a Phase II Study of Systemic Pegylated Liposomal Doxorubicin Chemotherapy With 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/PLD combination chemotherapy with or without APR-246 in patients with Platinum-resistant high grade serous ovarian
cancer

A.4.1

Sponsor's protocol code number

APR-486

A.5.4

Other Identifiers

Name:

IND

Number:

124841

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 Therapeutics 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 Therapeutics 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	regulatory@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	Yes
D.2.5.1	Orphan drug designation number	EU/3/14/1386
D.3 Description of the IMP
D.3.1	Product name	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.3.9.3	Other descriptive name	APR-246
D.3.9.4	EV Substance Code	SUB31235
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	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	Yes
D.2.1.1.1	Trade name	doxorubicin hydrochloride 2mg/ml solution for infusion
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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 and solvent 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

Platinum-resistant high grade serous ovarian carcinoma

E.1.1.1

Medical condition in easily understood language

Platinum-resistant 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	20.0
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

• To assess the preliminary efficacy of APR-246 with PLD chemotherapy in patients with platinum-resistant HGSOC with mutated TP53

E.2.2

Secondary objectives of the trial

• To evaluate the pharmacokinetics (PK) of APR-246 when administered with PLD chemotherapy
• To evaluate cardiac safety of APR-246 when administered with PLD chemotherapy
• To assess the safety and tolerability of APR-246 with PLD chemotherapy in patients with platinum-resistant HGSOC with mutated TP53
• To assess:
o Duration of response (complete or partial response)
o Progression-free survival (PFS) by assessment of cancer antigen 125 (CA-125)
o PFS by RECIST 1.1
• To evaluate potential biomarkers and tumor activity based on CA-125
• To assess the biological activity in tumor and surrogate tissues

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Archived sections from the original formalin fixed paraffin embedded sample reviewed by a gynecological pathologist confirming HGSOC, high grade serous peritoneal cancer or primary fallopian tube cancer and positive immunohistochemistry staining for p53 assessed according to the local methodology (as detailed in the laboratory manual). Cases that do not show p53 staining will not be included.
2. Disease progression between 4 weeks and 6 months after the last platinum-based treatment was administered.
3. At least a single (RECIST 1.1) measurable lesion.
4. Adequate organ function prior to registration:
a) Bone marrow reserve
• Absolute neutrophil count (ANC) ≥ 1.5 x109/L
• Platelets ≥ 100 x 109/L
• Hemoglobin ≥ 9 g/dL
b) Hepatic
• Total bilirubin level < 1.5 x ULN without hepatic metastasis, and < 4 x ULN with hepatic metastasis
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN without hepatic metastasis, and < 4 x ULN with hepatic metastasis
c) Renal
• Calculated creatinine clearance > 30 mL/min calculated per local practice
d) Electrolytes
• Potassium within institutional normal ranges.
5. Toxicities from previous cancer therapies (excluding alopecia) must have recovered to grade 1 (defined by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 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.
6. If of childbearing potential, negative pretreatment serum pregnancy test.
7. If of childbearing potential, willing to use an effective form of contraception (see below) during chemotherapy treatment and for at least 6 months thereafter. Such methods include the following (if using hormonal contraception, this method must be supplemented with a barrier method, preferably male condom):
• combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
o oral
o intravaginal
o transdermal
• progestogen-only hormonal contraception associated with inhibition of ovulation:
o oral
o injectable
o implantable
• intrauterine device (IUD)
• intrauterine hormone-releasing system (IUS)
• bilateral tubal occlusion
• vasectomized partner
• true sexual abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Appendix I).
9. ≥ 18 years of age.
10. 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:
a) A myocardial infarct within 6 months prior to registration,
b) New York Heart Association Class II or worse heart failure (Appendix II)
c) A history of familial long QT syndrome
d) Clinically significant pericardial disease
e) Electrocardiographic evidence of acute ischemia
f) Symptomatic atrial or ventricular arrhythmias not controlled by medications
g) QTc ≥ 480 msec calculated from a single electrocardiogram (ECG) reading or a mean of three ECG readings using Fridericia’s correction (QTcF = QT/RR0.33)
h) Bradycardia (< 40 bpm)
i) Left ventricular ejection fraction (LVEF) < the institution lower limit of normal as assessed by echocardiogram.
3. Major abdominal surgery or peritonitis within 6 weeks prior to study treatment.
4. Unresolved bowel obstruction, subocclusive disease or the presence of brain metastases.
5. Hypersensitivity to PLD or to any of the excipients.
6. Unable to undergo imaging by either computed tomography (CT) scan or magnetic resonance imaging (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 any concurrent (or within 4 weeks prior to registration) anti-cancer therapy, immunotherapy, radiotherapy, biological, or ancillary anti-cancer therapy, or any 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. Palliative limited radiation therapy for pain reduction is allowed.
12. Use of concomitant treatment with QT/QTc prolonging drugs.

E.5 End points

E.5.1

Primary end point(s)

• Overall response rate according to RECIST 1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

Please refer to protocol

E.5.2

Secondary end point(s)

• PFS rate, 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 tumor assessment without any such event (censored observation)
• PK profile of APR-246 and concentration in plasma
• Cardiac profile of APR-246 and concentration of PLD
• The safety profile (adverse events [AEs], laboratory assessments, physical findings and biomarkers) of APR 246 and PLD chemotherapy
• Duration of response (complete or partial response)
• Progression-free survival (PFS) by assessment of CA-125
• Evaluation of potential biomarkers
• Biological activity in tumor and surrogate tissues

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to 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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

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)

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

E.8.1.1

Randomised

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)

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

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

LVLS

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

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

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)

Survival after progression will be monitored every 6 months until death. This can be done remotely (e.g., via telephone, via general practitioner or via review of medical records).

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

2017-05-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-08-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-07-15

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