Clinical Trials Register

Summary
EudraCT Number:	2017-004443-20
Sponsor's Protocol Code Number:	HP-LY-CL-2063
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-02-12
Trial 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

Finland - Fimea

A.2

EudraCT number

2017-004443-20

A.3

Full title of the trial

A Phase II, double-blind, placebo-controlled, randomized study to assess the efficacy, safety
and tolerability of Lymfactin® (AdAptVEGF-C Adenoviral Vector) in combination with a
surgical lymph node transfer for the treatment of patients with secondary lymphedema
associated with the treatment of breast cancer

A.3.1

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

A Phase II, placebo-controlled study of the efficacy, safety and tolerability of Lymfactin® in combination with a surgical lymph node transfer for the treatment of patients with secondary lymphedema associated with the treatment of breast cancer

Kaksoissokkoutettu, lumelääkekontrolloitu, vaiheen 2 teho-, turvallisuus- ja
siedettävyystutkimus imusolmukesiirtoleikkauksen yhteydessä annettavalla Lymfactintutkimusvalmisteella (adenovirusvälitteinen VEGF-C imusuonikasvutekijä) rintasyöpähoidon seurauksena kehittyneen lymfaturvotuksen hoitoon.

A.3.2

Name or abbreviated title of the trial where available

AdeLE

A.4.1

Sponsor's protocol code number

HP-LY-CL-2063

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	Herantis Pharma Plc
B.1.3.4	Country	Finland
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	Herantis Pharma Plc
B.4.2	Country	Finland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Herantis Pharma Plc
B.5.2	Functional name of contact point	Sponsor Study Contact
B.5.3	Address:
B.5.3.1	Street Address	Bertel Jungin Aukio 1
B.5.3.2	Town/ city	Espoo
B.5.3.3	Post code	02600
B.5.3.4	Country	Finland
B.5.6	E-mail	satu.leikas@herantis.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	Lymfactin
D.3.2	Product code	LX-1101
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Other use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not known
D.3.9.2	Current sponsor code	LX-1101
D.3.9.3	Other descriptive name	AdAptVEGF-C adenoviral vector
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2x10^11 vp/mL
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
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	Yes
D.3.11.3.5.1	CAT classification and reference number	Gene Therapy Medicinal Product (Ref EMA/CAT/758151/2009)
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	Yes
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	Solution for injection
D.8.4	Route of administration of the placebo	Other use (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Secondary lymphedema associated with the treatment of breast cancer

E.1.1.1

Medical condition in easily understood language

Swelling caused by a build-up of lymph fluid in the surface tissues of the
body associated with the treatment of breast cancer

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

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	10036389
E.1.2	Term	Postmastectomy lymphedema syndrome
E.1.2	System Organ Class	100000004863

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	10025233
E.1.2	Term	Lymphedema
E.1.2	System Organ Class	100000004866

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10006187
E.1.2	Term	Breast cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 efficacy of Lymfactin® in patients with secondary lymphedema associated with the treatment of breast cancer by comparing the effects of active study treatment Lymfactin® to placebo. Efficacy of Lymfactin® will be evaluated by the change in the volume of the affected arm, quantitative lymphoscintigraphy and patient quality of life assessment.

E.2.2

Secondary objectives of the trial

To assess the safety and tolerability of Lymfactin® by comparing the effects of active study treatment to placebo, to investigate the biodistribution of Lymfactin® in blood and in wound secretion, the development of anti-Lymfactin® antibodies, the VEGF-C concentration in wound secretion and the systemic VEGF-C concentration after Lymfactin® administration.

Exploratory Study Objectives: To evaluate two new methods in the assessment of lymphedema: MRI lymphangiography, and PWC measurement for water content and edema in tissue (MoistureMeterD Compact, Delfin Technologies).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Female or male patients with secondary lymphedema
associated with the treatment of breast cancer and
a. Has undergone sentinel lymph node biopsies
and/or lymph node resection in the axilla on the
affected side of their breast cancer with initial
N1-N2a staging and lymph node metastasis in
≤ 9 axillary lymph nodes.
b. Requires garment use as a compression
treatment for the lymphedema in the affected
arm.
c. Has the volume of the affected arm at least
10% greater than the unaffected arm following
7 days without compression garment.
d. Has the presence of pitting edema in the
affected arm without compression garment.
e. Has had lymphedema for less than 5 years.
2. No evidence of recurrent or active breast cancer for at
least 2 years after the breast cancer surgery and/or the
end of chemotherapy and/or radiotherapy (excluding
endocrine treatment).
3. The patient understands and voluntarily signs the
written informed consent prior to any screening
procedure.
4. 18-70 years of age at time of the informed consent.
5. ECOG Performance Status of 0 or 1.
6. BMI between 18 and 32 inclusive.
7. PET CT scan of the chest and the abdomen within 45
days before the study treatment without signs of active
breast cancer or any other malignancy.
8. Adequate hematologic and end-organ function:
a. Aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) ≤ 2.5 x the
institutional upper limit of normal (ULN)
b. Bilirubin ≤ 1.5 x ULN (except in patients with
previously documented Gilbert’s syndrome, in
which case total bilirubin ≤ 3 x ULN)
c. INR and aPTT ≤ 1.5 x ULN (for patients
requiring therapeutic anticoagulation therapy,
a stable INR ≤ 2,5)
d. Serum creatinine ≤ 1,5 x ULN or creatinine
clearance ≥ 50 ml/min
e. Absolute neutrophil count (ANC) ≥ 1,5 E9/l
f. Platelet count ≥ 100 E9/l
g. Hemoglobin ≥ 100 g/l
9. Willingness to comply with scheduled visits,
laboratory assessments, and other study-related
procedures due to the regulatory requirements related
to gene based therapies.
10. Non-smoker or willing to stop smoking or use of
nicotine-containing products for at least 4 weeks prior
to the study entry.
11. Negative urine pregnancy test (only patients with
childbearing potential) at screening and use of
adequate contraceptive measures from screening until
six months after the study treatment administration:
a) A patient with childbearing potential should be
using a reliable contraception method: combined
(estrogen and progestogen containing) hormonal
contraception associated with inhibition of
ovulation (oral, intravaginal or transdermal,
progestogen-only hormonal contraception
associated with inhibition of ovulation (oral,
injectable or implantable), intrauterine device
(IUD), intrauterine hormone releasing system
(IUS), bilateral tubal occlusion, vasectomised
partner or sexual abstinence defined as refraining
from heterosexual intercourse during the entire
period of risk associated with the study treatments.
b) A male patient is not allowed to donate sperm.��
c) A patient with no current heterosexual relationship
may be included according to the judgement of the
Investigator.
d) For a patient in postmenopausal state neither
contraception nor a pregnancy test is required. A
postmenopausal state is defined as no menses for
12 months without an alternative medical cause. A
high follicle stimulating hormone (FSH) level in
the postmenopausal range may be used to confirm
a postmenopausal state in women not using
hormonal contraception or hormonal replacement
therapy.
e) For a permanently sterile patient neither
contraception nor a pregnancy test is required. A
permanently sterile is defined by history of
hysterectomy, bilateral salpingectomy or bilateral
oophorectomy.

E.4

Principal exclusion criteria

1. Diagnosed for T4 and/or N2b/N3 stage breast cancer
at the time of the original diagnosis.
2. Evidence (clinical, laboratory or imaging) or history of
a neoplasm other than breast cancer (except basal cell
carcinoma or cervical in situ carcinoma).
3. Diagnosed for metastatic breast cancer.
4. Pregnancy, lactation or a positive or indeterminate
pregnancy test.
5. Current treatment with COX-2 inhibitors should be
interrupted from 2 weeks prior until 4 weeks posttreatment.
6. Previous treatment with, or participation in a trial of a
gene therapy product.
7. Participation in a clinical trial, which has included
interventions in the preceding 6 months or will involve
future interventions. Participation in a noninterventional
clinical trial, or in a non-interventional
follow-up of any clinical trial, does not make the
patient inappropriate for the entry into this study.
8. Current treatment with systemic immunosuppressive
drugs.
9. Current history of drug abuse, including nicotinecontaining
products, or alcohol abuse.
10. Known human immunodeficiency virus- or acquired
immunodeficiency syndrome-related illness.
11. History of hepatic dysfunction, cirrhosis, or hepatitis.
12. Allergy to any ingredients of the Lymfactin® solution
for injection (glycerol, N-2-hydroxyethylpiperazine-
N´-2-ethanesulfonic acid (HEPES), sodium
hydroxide).
13. Other concurrent severe acute and/or chronic medical
or psychiatric condition or laboratory abnormality that
may increase the risk associated with the study
participation or study drug administration, that would,
in the Investigator’s judgement, affect the patient's
ability to follow study-related procedures, or that may
interfere with the interpretation of study results and
would make the patient inappropriate for the entry into
this study.
14. Doubtful availability, in the opinion of the
Investigator, to complete the study.

E.5 End points

E.5.1

Primary end point(s)

Efficacy is the primary endpoint of this study. The effects
of the treatment on the signs and symptoms of lymphedema
will be assessed by comparing the effects of the active
study treatment Lymfactin® to placebo up to 36 months
post-treatment by:
• The measurement of the volume of the affected arm
and the unaffected arm.
• Quantitative lymphoscintigraphy (99Tc-nanocolloid
clearance rate) with calculation of transport index
(change from baseline)
• Patient quality of life assessment using the
Lymphedema Quality of Life Inventory (LQOLI)
filled out by the patients (change from baseline).

E.5.1.1

Timepoint(s) of evaluation of this end point

as spesified

E.5.2

Secondary end point(s)

Safety endpoints
To assess the safety of Lymfactin® treatment by:
• Incidence, type and severity of clinically
significant adverse events (based on NCI CTCAE
v4.0) up to 5 years post-treatment.
• Incidence, type and severity of serious adverse
events up to 5 years post-treatment.
• Physical examination, vital signs (blood pressure,
heart rate, weight), 12-lead electrocardiogram
(ECG) and laboratory tests including clinical
chemistry, hematology and urinalysis up to 24
months. Physical examination, weight and laboratory tests also at the 36 months visit.
• Annual CT scan (chest and abdomen) with radiocontrast up to 5 years post-treatment with a brief
medical history.
• To evaluate the potential development of edema at
the donor site/limb, volume measurements of both
legs will be performed (change from baseline and
comparison to the unaffected/contralateral limb)
up to 12 months.
Pharmacological Endpoints
• To assess the biodistribution (presence and titer) of
Lymfactin® in blood up to 30 days and in wound
secretion up to 5-7 days (until hospital discharge)
through qPCR post-treatment.
• To assess the presence and titer of anti-Lymfactin®
antibodies in serum up to 12 months posttreatment.
• To assess the concentration of VEGF-C in wound
secretion up to 5-7 days (until hospital discharge)
post-treatment.
• To assess the systemic concentration of VEGF-C
in serum up to 30 days post-treatment.
Exploratory Study Endpoints
• Newly developed MRI lymphangiography
assessment and comparison of the correlation of
the method to the already established
lymphoscintigraphy in the assessment of
lymphedema up to 24 months post-treatment.
• PWC measurement of water content and edema in
tissue by a sensitive, non-invasive device
(MoistureMeterD Compact, Delfin Technologies)
up to 24 months post-treatment.

E.5.2.1

Timepoint(s) of evaluation of this end point

as spesified

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

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

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

LSLV

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

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)

None

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

2018-05-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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