Clinical Trials Register

Summary
EudraCT Number:	2017-002459-27
Sponsor's Protocol Code Number:	CL1-81694-003
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-09-27
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2017-002459-27

A.3

Full title of the trial

Phase I/II trial of S 81694 administered intravenously in
combination with paclitaxel to evaluate the safety,
pharmacokinetic and efficacy in metastatic breast cancer

A.3.1

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

Phase I/II trial of S 81694 plus paclitaxel in metastatic Breast
Cancer

A.4.1

Sponsor's protocol code number

CL1-81694-003

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	Institut de Recherches Internationales Servier
B.1.3.4	Country
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	ADIR
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	Institut de Recherches Internationales Servier
B.5.2	Functional name of contact point	Clinical Studies Department
B.5.3	Address:
B.5.3.1	Street Address	50 rue Carnot
B.5.3.2	Town/ city	Suresnes cedex
B.5.3.3	Post code	92284
B.5.3.4	Country	France
B.5.4	Telephone number	+33155724366
B.5.5	Fax number	+33155725412
B.5.6	E-mail	clinicaltrials@servier.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	S81694
D.3.2	Product code	S81694
D.3.4	Pharmaceutical form	Powder 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.3.9.2	Current sponsor code	S 81694
D.3.9.3	Other descriptive name	S 81694
D.3.9.4	EV Substance Code	SUB172545
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	30
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	Paclitaxel Amneal
D.2.1.1.2	Name of the Marketing Authorisation holder	Amneal Pharma Europe Limited
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	Paclitaxel Amneal
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	PACLITAXEL
D.3.9.1	CAS number	33069-62-4
D.3.9.4	EV Substance Code	SUB09583MIG
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	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.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

Metastatic Breast Cancer (mBC) and metastatic Triple Negative Breast Cancer (mTNBC)

E.1.1.1

Medical condition in easily understood language

Malignant tumors

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	10027475
E.1.2	Term	Metastatic breast cancer
E.1.2	System Organ Class	100000020826

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

For Phase I:
-To determine the safety profile and tolerability of S 81694 given in combination with paclitaxel by assessment of the DLT and the MTD based on safety data described using Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 in patients with mBC.
- To establish the recommended phase II dose (RP2D) of S 81694 in combination with paclitaxel.

For phase II:
- To evaluate Progression Free Survival (PFS).

E.2.2

Secondary objectives of the trial

For phase I:
-To characterize the plasma pharmacokinetic (PK) profiles of S 81694 and its metabolites (if applicable) and of paclitaxel in combination.
- To investigate any preliminary antitumour activity of this combination.

For phase II:
- To assess the anti-tumour activity using Response Evaluation Criteria In Solid Tumours version 1.1 in terms of:
o Objective Response Rate (ORR),
o Response duration (RD),
o Overall survival (OS).
- To characterize the safety and tolerability of S 81694 in combination with paclitaxel at RP2D according to NCI-CTCAE v4.03.
- To characterize the plasma PK profiles of S 81694 and of paclitaxel and its metabolites (if applicable) in combination.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

For Phase I :
- Histologically or cytologically confirmed metastatic breast cancer, refractory to any standard therapy or for which the standard therapy is considered unsuitable;
- Patient must have at least one evaluable or measurable metastatic lesion (lesions as defined by revised Response Evaluation Criteria in Solid Tumors

For Phase II :
- Histologically or cytologically confirmed advanced inoperable triple negative breast cancer with no prior anticancer therapy regimen in metastatic setting;
- Patient with a minimum washout period of 12 months following previous taxane based adjuvant therapy;
- Patient must have at least one measurable metastatic lesion. Ascites, pleural effusion, and bone metastases are not considered measurable;
- Acceptance of pre-treatment metastatic biopsies for all patients and on-treatment metastatic biopsies in selected centres.

For the whole study:
- Male or female subjects aged ≥ 18 years old, or legal age of the majority in the country;
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
- Estimated life expectancy of at least 3 months;
- Adequate haematological function based on the last assessment performed within 7 days prior to the first IMP administration;
-Adequate renal function based on the last assessment performed within 7 days prior to the first IMP administration;
- Adequate hepatic function based on the last assessment performed within 7 days prior to the first IMP administration;
- Female participant of childbearing potential must have a negative pregnancy test (serum) within 7 days prior to the first day of test drug administration. Effective contraception both for female patients of childbearing potential and male patients with parteners of childbearing potential.

E.4

Principal exclusion criteria

- Other active malignancy within the last 3 years (except for basal cell carcinoma or a non-invasive/in situ cervical cancer or intra-mucosal gastro-intestinal cancers that were treated curatively);
- Presence of grade ≥ 2 toxic effects (excluding alopecia) due to prior cancer therapy;
- Known hypersensitivity to the IMP (S 81694 and paclitaxel) or their excipients;
- Evidence of peripheral neuropathy of grade 2 or higher;
- Participant previously received paclitaxel and discontinued due to toxicity related to paclitaxel;
- Participant known as refractory to taxanes;
- Any prior cancer therapy within 4 weeks before the first IMP administration;
- Participant with current, serious, uncontrolled infections;
- Participant with brain metastasis or leptomeningeal metastasis (except patients with brain metastasis that have been stable post-radiation therapy and who are off steroids for > 2 months);
- History of cardiac disease;
- Uncontrolled arterial hypertension;
- Presence of risk factors for torsades de pointes (e.g. heart failure, hypokalaemia, family history of long QT syndrome);
- Any clinically significant medical condition (e.g. organ dysfunction) or laboratory abnormality likely to jeopardize the patient’s safety or to interfere with the conduct of the study, in the investigator’s opinion.

E.5 End points

E.5.1

Primary end point(s)

For phase I :
- incidence of DLTs occuring during the first cycle.
- Safety and tolerability of S 81694 in combination with paclitaxel assessed
by:
o Incidence and severity of AEs and SAEs,
o Laboratory tests (haematology, haemolysis, biochemistry, urinary analysis and pregnancy test),
o Vital signs and weight,
o Physical examination and performance status,
o ECG parameters,
o Dose interruptions, dose reductions and dose intensity.

For phase II :
- Progression-Free Survival is defined as the time from the date of randomisation until the date of the investigator-assessed radiological disease progression according to RECIST v1.1 or death due to any cause.

E.5.1.1

Timepoint(s) of evaluation of this end point

For Phase I : All over the study
For Phase II : At inclusion and during the study at the end of cycle 2, then every 2 cycles between D22 and D28

E.5.2

Secondary end point(s)

For phase I:
- PK parameters of S 81694 and
paclitaxel plasma concentration Tumour
response assessed by RECIST v1.1.

For phase II :
- Objective Response Rate (ORR);
- Response duration (RD);
- Overall survival;
- Safety and tolerability of S 81694 in combination with paclitaxel or with paclitaxel alone assessed by:
o Incidence and severity of AEs and SAEs,
o Laboratory tests (haematology, haemolysis biochemistry, urinary analysis and pregnancy test),
o Vital signs and weight,
o Physical examination and performance status,
o ECG parameters,
o Dose interruptions, dose reductions and dose intensity.
- PK parameters of S 81694 and paclitaxel concentrations.

E.5.2.1

Timepoint(s) of evaluation of this end point

All over the study

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

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

Phase I/II in combination with paclitaxel

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

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

Yes

E.8.2.3.1

Comparator description

Paclitaxel

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

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

Japan

Netherlands

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

Last Visit Last Patient

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

110

F.4.2.2

In the whole clinical trial

120

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)

After the discontinuation of the IMPs, the patient will receive a treatment and/or have access to other appropriate care by his/her doctor, which will be at the investigator’s discretion.

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

2017-11-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-06-08

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