Clinical Trials Register

Summary
EudraCT Number:	2015-002541-63
Sponsor's Protocol Code Number:	IMP321-P011
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-10-12
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

Netherlands - Competent Authority

A.2

EudraCT number

2015-002541-63

A.3

Full title of the trial

AIPAC (Active Immunotherapy PAClitaxel): A multicentre, Phase IIb, randomised, double blind, placebo-controlled study in hormone receptor-positive metastatic breast carcinoma patients receiving IMP321 (LAG-3Ig fusion protein) or placebo as adjunctive to a standard chemotherapy treatment regimen of paclitaxel.

A.3.1

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

A study in hormone receptor-positive metastatic breast carcinoma patients receiving IMP321 or placebo as adjunctive to a standard chemotherapy treatment regimen of paclitaxel.

A.3.2

Name or abbreviated title of the trial where available

AIPAC

A.4.1

Sponsor's protocol code number

IMP321-P011

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	Immutep S.A.S.
B.1.3.4	Country	France
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	Immutep S.A.S.
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CATO SMS
B.5.2	Functional name of contact point	Annika Tintel
B.5.3	Address:
B.5.3.1	Street Address	Stationsplein NO 438
B.5.3.2	Town/ city	Schiphol
B.5.3.3	Post code	1117 CL
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31204350580
B.5.5	Fax number	+31204350589
B.5.6	E-mail	SSUReg@cato-sms.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	IMP321
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	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	eftilagimod alfa
D.3.9.1	CAS number	1800476-36-1
D.3.9.3	Other descriptive name	IMP321
D.3.9.4	EV Substance Code	SUB178475
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	25 +/- 3mg/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)	Yes
	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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Female metastasized oestrogen receptor positive and/or progesterone receptor positive breast adenocarcinoma

E.1.1.1

Medical condition in easily understood language

Female hormone receptor-positive metastatic breast cancer

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	PT
E.1.2	Classification code	10006202
E.1.2	Term	Breast cancer stage IV
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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	10027475
E.1.2	Term	Metastatic 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

Primary objectives:
 Safety run-in stage: To determine the recommended phase two dose for the randomised stage
 Randomised stage: to determine efficacy of IMP321 combined with weekly paclitaxel compared to weekly paclitaxel plus placebo in hormone receptor-positive metastatic breast cancer patients

E.2.2

Secondary objectives of the trial

Secondary objectives:
 to further characterise the anti-tumour activity of IMP321 in combination with weekly paclitaxel in
terms of clinical responses and clinical outcomes and compare it to placebo
 to examine the safety and tolerability of IMP321 in combination with weekly paclitaxel and compare it to placebo
 to characterise the pharmacokinetic (safety run-in stage only) and immunogenic properties of IMP321
 to assess the quality of life related to IMP321 compared to placebo

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Able to give written informed consent and to comply with the protocol
2.1 Metastasized oestrogen receptor positive and/or progesterone receptor positive breast adenocarcinoma, histologically proven by biopsy of the primary tumour and/or a metastasis
3. Female of age 18 years or above
4. Patients who are indicated to received first line chemotherapy with weekly paclitaxel
5.1 All patients of childbearing potential must have a negative highly sensitive pregnancy test at screening and agree to use highly effective method for contraception according to the EU Clinical Trial Facilitation Group guidance from time of study entry until at least 6 months after the last administration of study drug. The partners of patients with childbearing potential must also apply
contraceptive methods. Patients who are either ,
o postmenopausal (≥ 60 years of age, or < 60 years of age and amenorrhoeic for 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression with folliclestimulating hormone (FSH) above 40 U/L and oestradiol below 30 ng/L; or if taking tamoxifen or toremifene, and age < 60 years, then FSH and oestradiol in the postmenopausal range), permanently sterilized (e.g., bilateral tubal occlusion, hysterectomy),
o or otherwise be incapable of pregnancy are not considered to be of childbearing potential
6. ECOG performance status 0-1
7. Expected survival longer than three months
8. Resolution of toxicity of prior therapy to grade < 2 (except for alopecia and transaminases in case of liver metastases)
9. Evidence of measurable disease as defined by RECIST version 1.1
10.1 Laboratory criteria:
 Total white cell count ≥ 3 x 10^9/L
 Platelet count ≥ 100 x 10^9/L
 Haemoglobin ≥ 9 g/dL or 5.58 mmol/L
 Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L
 Serum creatinine ≤ 1.5 × ULN
 Total bilirubin ≤ 20 μmol/L, except for familial cholaemia (Gilbert’s disease)
 Serum ASAT and ALAT ≤ 3 times ULN or ≤ 5 times ULN if liver metastases are present

E.4

Principal exclusion criteria

1. Prior chemotherapy for metastatic breast adenocarcinoma
2. Disease-free interval of less than twelve months from the last dose of
adjuvant chemotherapy
3. Prior high-dose chemotherapy requiring hematopoietic stem cell
rescue
4.1 Inflammatory carcinoma at time of screening
5.1 Candidate for treatment with trastuzumab (or other Her2/neu
targeted agents) or endocrine based therapy according to the applicable
treatment guidelines
6.2 Systemic chemotherapy, radiation therapy or any other
investigational agent within 4 weeks, endocrine therapy within 1 week
or CDK4/6 inhibitors within 5 times half-life (acc. to SPC) prior to first
dose of study treatment
7.1 Symptomatic known cerebral and/or leptomeningeal metastases
8. Women who are pregnant or lactating
9. Serious intercurrent infection within 4 weeks prior to first dose of
study treatment
10. QTcF >480 ms, family or personal history of long or short QT
syndrome, Brugada syndrome or known history of QTc prolongation, or
Torsade de Pointes (TdP)
11. Uncontrolled electrolyte disorders that can worsen the effects of a
QTc-prolonging drug (e.g., hypocalcaemia, hypokalaemia,
hypomagnesemia)
12.1 Evidence of severe or uncontrolled cardiac disease (NYHA III-IV)
within 6 months prior to first dose of study treatment including:
myocardial infarction, severe/unstable angina, ongoing cardiac
dysrhythmias of NCI CTCAE version 4.03 Grade ≥2, atrial fibrillation ,
coronary/peripheral artery bypass graft, symptomatic congestive heart
failure, cerebrovascular accident including transient ischemic attack,
ventricular arrhythmias requiring medication or symptomatic pulmonary
embolism
13. Active acute or chronic infection
14. Active autoimmune disease requiring immunosuppressive therapy
15.1 Positive test for HIV
16.1 Positive test for Hepatitis B (anti–HBc) or C (Patients who are anti-
HBc+ and HBsAg negative are eligible and are not excluded from
participation in this study)
17. Life threatening illness unrelated to cancer
18. Previous malignancies within the last three years other than breast
carcinoma, except successfully treated squamous cell carcinoma of the
skin, superficial bladder cancer, and in situ carcinoma of the cervix
19. Any current disorder that would impede the patient's ability to
provide informed consent or to comply with the protocol
20. Any condition requiring continuous systemic treatment with either
corticosteroids (>10 mg daily prednisone equivalents) or other
immunosuppressive medications within 4 weeks prior to first dose of
study treatment. Inhaled or topical steroids and physiological
replacement doses of up to 10 mg daily prednisone equivalent are
permitted in the absence of active autoimmune disease
21. Past history of severe allergic episodes and/ or Quincke's oedema
22. Alcohol or substance abuse disorder
23. Known hypersensitivity to any of the components of the study agents
24.1 Participation in an interventional clinical study within 4 weeks prior
to first dose of study treatment, with intervention not covered by
exclusion criterion 6.2
25. Unwilling or unable to follow protocol requirements
26. In the clinical judgment of the Investigator, the patient is unsuitable
for participation in this study
27. Persons with any kind of dependency on the Investigator or
employed by the sponsor or Investigator
28. Persons held in an institution by legal or official order
29. Patients with prior organ or stem cell transplantation
30. Patients having received a live, attenuated vaccine within 4 weeks
prior to the first administration of study treatment
31. Patients treated with systemic immune stimulatory agents within 6
weeks or five half lives
of the drug prior to first administration of study treatment

E.5 End points

E.5.1

Primary end point(s)

Stage 1: to determine DLTs and the recommended phase II dose
Stage 2: To determine progression free survival (PFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

Radiology assessments in the treatment phase will be every 8 weeks until week 73. It may bue performed ±3 days prior to that specific radiological assessment during the chemo-immunotherapy phase and ± 7 days during the maintenance and follow-up phase. PFS at Follow-Up Visits every 12 weeks (± 1 week) until PD, start of next line of therapy, withdrawal of consent, loss to follow-up, death from any cause, or the end of the study (whichever occurs first).
For patients who prematurely discontinue treatment for any reason except PD, PFS Follow-Up Visits will occur every 8 weeks until weeks 73 and every 12 weeks thereafter dependent on the most recent radiological assessment prior to discontinuation.

E.5.2

Secondary end point(s)

Secondary endpoints
• To assess overall survival (OS)
• To assess adverse events according to the current National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) and other safety parameters
• To assess the time to next treatment (TTNT), objective response rate
(ORR) according to RECIST 1.1, time to and duration of response and duration of stable disease
• To assess the plasma concentration time profile of IMP321 and derived
PK parameters
• To assess the quality of life (QOL)
• To assess development of anti-drug (IMP321) antibodies (ADA)

E.5.2.1

Timepoint(s) of evaluation of this end point

OS: After documented PD, every 12 weeks after enrolment into the trial for the first 2 years and every 24 weeks thereafter (± 4 weeks).
Other efficacy parameters (TTNT, ORR, time to and duration of response, duration of stable disease) at same timepoints as PFS and OS.

(S)AEs will be collected from the time of ICF signature until 30 days after last study drug administration, and after this period only when considered (in the opinion of the Investigator) related to study treatment.

PK parameters: run-in stage only at cycle 1 day 2, 3 and 4 and cycle 6 day 16, 17 and 18.

QoL: Chemo-immunotherapy phase visit 1 and visit 16; Maintenance phase visit 31 and visit 37; At end of treatment, visit 43.

ADA: at screening, visit 6, 11, 21, 31, 34, 37, 40 and at end of
treatment.

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Quality of life
Immuno-monitoring (On blood cells and soluble Th1 biomarkers)

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Run-in stage: open-label. Randomization stage: placebo-controlled double-blind.

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

Yes

E.8.2.3.1

Comparator description

Run-in stage: not placebo-controlled. Randomization stage: placebo-controlled double-blind.

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

36 months after last patient first visit (stage 2). Approximately 65 months after first patient first visit in the randomised stage 2. During this follow up period data on progression-free survival and overall survival will be collected. Additionally, any next line of anti-cancer therapy will be recorded.

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

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:

120

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

121

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

241

F.4.2.2

In the whole clinical trial

241

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)

Patients who progress while on study treatment may receive endocrine or any other therapy as clinically indicated and as part of the next line of therapy, after performing the EOT visit.
Patient who do not progress and complete the study treatment period (i.e. reach the end of maintenance phase without progression) may receive endocrine or any other therapy as clinically indicated and as part of the next line of therapy, after performing the EOT visit.

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

2015-10-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-12-21

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-05-14

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