Clinical Trials Register

Summary
EudraCT Number:	2017-002577-18
Sponsor's Protocol Code Number:	APR-633
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-09-06
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2017-002577-18

A.3

Full title of the trial

A phase I/IIa study to investigate the safety and clinical activity of APR-246 in combination with dabrafenib in patients with BRAF V600 mutant unresectable metastatic melanoma resistant to dabrafenib /trametinib combination

A.3.1

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

study to investigate the safety and clinical activity of APR-246 in combination with dabrafenib in patients with unresectable metastatic melanoma resistant to dabrafenib /trametinib combination

A.3.2

Name or abbreviated title of the trial where available

EMERA

A.4.1

Sponsor's protocol code number

APR-633

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	APREA THERAPEUTICS AB
B.5.2	Functional name of contact point	Maria Klockare
B.5.3	Address:
B.5.3.1	Street Address	Nobel väg 3
B.5.3.2	Town/ city	Solna
B.5.3.3	Post code	SE-171 65
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+4670 6232505
B.5.6	E-mail	Maria.Klockare@aprea.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	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.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	Tafinlar
D.3.4	Pharmaceutical form	Capsule, hard
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	dabrafenib
D.3.9.1	CAS number	1195765-45-7
D.3.9.3	Other descriptive name	DABRAFENIB
D.3.9.4	EV Substance Code	SUB45696
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	75
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	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.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	Tafinlar
D.3.4	Pharmaceutical form	Capsule, hard
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	dabrafenib
D.3.9.1	CAS number	1195765-45-7
D.3.9.3	Other descriptive name	DABRAFENIB
D.3.9.4	EV Substance Code	SUB45696
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	50
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

BRAF V600 Mutant Metastatic Melanoma

E.1.1.1

Medical condition in easily understood language

BRAF V600 Mutant Metastatic Melanoma

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	10027481
E.1.2	Term	Metastatic melanoma
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase I: Dose Safety Cohort
To determine the safety and tolerability of APR-246 given weekly in combination with dabrafenib in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to the dabrafenib/trametinib combination.
To determine the recommended phase II dose (RP2D) of the combination of dabrafenib and APR-246.
Phase IIa: Expansion Cohort:
To evaluate antitumor activity of APR-246 in combination with dabrafenib in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to the dabrafenib/trametinib combination. .

E.2.2

Secondary objectives of the trial

Phase Ib and II
To further determine the safety of APR-246 and dabrafenib in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to a dabrafenib /trametinib combination.
To describe pharmacokinetics of APR-246 given weekly in combination with dabrafenib.
To further describe the anti-tumour activity of the combination of APR-246 and dabrafenib.
To determine the value of early FDG PET/CT-based metabolic response assessment in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to the dabrafenib /trametinib combination treated with APR-246 and dabrafenib.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must meet all of the following criteria in order to be eligible for this study:
1. Age ≥ 18 years
2. Patients with confirmed BRAF V600 mutation-positive unresectable and/or metastatic malignant cutaneous melanoma, as determined locally by a validated test and treated with dabrafenib/trametinib first line combination therapy or second line after first line immunotherapy
3. Patients that have progressed according to RECIST 1.1 after at least 4 weeks of treatment with dabrafenib/trametinib and remained on dabrafenib full dose (150mg bid) treatment for the study
4. Measurable disease according to RECIST 1.1 criteria. For phase II only, metabolic measurable disease (according to PERCIST)
5. Availability of tissue from a metastatic lesion. A new biopsy is required unless inaccessible. An archival sample is accepted in that case after discussion with the Sponsor.
6. ECOG Performance Status of 0 or 1
7. Patients able to swallow and retain oral medication
8. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
9. For female patients of childbearing potential, a pregnancy test (serum) will be performed within 7 days before inclusion. Woman of childbearing potential must be willing to use one highly effective form of contraception such as described in section 6.3 during anticancer treatment and for at least six months thereafter. Men must agree to use condom during the course of this study and at least six months after the last administration of the study treatment and contraception should be considered for partner of childbearing potential
10. Adequate organ system function
11. Signed informed consent before any study specific procedure and/or treatment happens

E.4

Principal exclusion criteria

Patients meeting one of the following criteria are not eligible for this study:
1. Presence of Uveal melanoma and/or other non-cutaneous melanomas

2. Current use of a prohibited medication (see section 6.4.2) or need for any of these medications during treatment with study drug and within 28 days before the first administration of APR-246
3. Unresolved toxicity greater than NCI-CTCAE(v4) Grade 1 from previous anti-cancer therapy except alopecia
4. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs.
5. Known HIV, active hepatitis B or hepatitis C infection
6. Primary malignancy of the central nervous system
7. History of familial long QT, serious ventricular arrhythmia (no VT > 130 bpm and > 5 extra beats per minute), no QTc ≥ 480 msec calculated from a single ECG reading or a mean of 3 ECG readings using Fridericia’s correction (QTcF = QT/RR0.33) or bradycardia (< 45 bpm)
8. Untreated or symptomatic brain metastasis, leptomeningeal disease or spinal cord compression. Patients who are on a stable dose of corticosteroids > 1 month or off corticosteroids for 2 weeks can be enrolled
9. History of acute coronary syndromes (including unstable angina), coronary angioplasty, stenting or thrombo-embolic event within the past 24 weeks from signature of ICF.
10. Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
11. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs, or excipients
12. Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity
13. Pregnant or lactating woman

E.5 End points

E.5.1

Primary end point(s)

Phase Ib:
Adverse Events (AEs) and Dose Limiting Toxicities (DLTs)
Phase II:
Objective response rate by RECIST1.1 as calculated as the proportion of patients with a best objective response of confirmed CR or PR.

E.5.1.1

Timepoint(s) of evaluation of this end point

Please refer to the protocol

E.5.2

Secondary end point(s)

Phase Ib and II:
- To determine clinical benefit rate (defined as the proportion of patients with a CR, PR or SD ≥ 4 months) of APR-246 and dabrafenib in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to the dabrafenib/trametinib combination
- To determine duration of response (defined as time from documentation of tumor response to disease progression) of APR-246 and dabrafenib in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to the dabrafenib/trametinib combination.
- To determine the progression free survival (PFS) (defined as the time from registration to the time of disease progression or relapse or death, or the date of last tumor assessment without any such event) of APR-246 and dabrafenib in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to the dabrafenib /trametinib combination.
- PK parameters including area under plasma concentration-time curve (AUC (0-τ)), plasma drug concentration at a specified time t (Ct), Maximum plasma drug concentration (Cmax), and time to reach maximum plasma concentration following drug administration (tmax).
- Assessment of metabolic response according to classical PERCIST criteria (30%) modified PERCIST criteria (15%) and the consistency classification

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to the 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

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)

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 safety cohort

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

Yes

E.8.1.7.1

Other trial design description

[3+3] scheme followed by an expansion phase

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.8.3

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

The end of study will be declared when all the following criteria will have been met:
- After last visit of the last patient remaining in the study.
- The trial is mature for the analysis of the endpoints as defined in the protocol, if the trial reaches its endpoints.
- The database has been fully cleaned and frozen for all analyses

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

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.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

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)

At the discretion of the physician according to local guidelines and standard of care

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-10-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-13

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-08-13

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