Clinical Trials Register

Summary
EudraCT Number:	2015-002760-16
Sponsor's Protocol Code Number:	IB2015-04
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-09-04
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

France - ANSM

A.2

EudraCT number

2015-002760-16

A.3

Full title of the trial

Targeting Microenvironment and Cellular Immunity in Sarcomas Weekly trabectedin combined with Metronomic Cyclophosphamide in Patients with Advanced Pretreated Soft-tissue Sarcomas. A Phase I/II study from the French Sarcoma Group.

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

Protocol TARMIC

A.4.1

Sponsor's protocol code number

IB2015-04

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 BERGONIE
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pharma Mar S.A.
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	Institut Bergonié
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 BERGONIE
B.5.2	Functional name of contact point	Pauline BEAUFRERE
B.5.3	Address:
B.5.3.1	Street Address	229 cours de l'Argonne
B.5.3.2	Town/ city	BORDEAUX Cedex
B.5.3.3	Post code	33076
B.5.3.4	Country	France
B.5.4	Telephone number	+33(0)556333270
B.5.5	Fax number	+33(0)556333330
B.5.6	E-mail	p.beaufrere@bordeaux.unicancer.fr

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	Yes
D.2.1.1.1	Trade name	ENDOXAN
D.2.1.1.2	Name of the Marketing Authorisation holder	BAXTER SAS
D.2.1.2	Country which granted the Marketing Authorisation	France
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.3.4	Pharmaceutical form	Coated tablet
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	CYCLOPHOSPHAMIDE
D.3.9.1	CAS number	50-18-0
D.3.9.4	EV Substance Code	SUB06859MIG
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.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	YONDELIS
D.2.1.1.2	Name of the Marketing Authorisation holder	PHARMA MAR S.A.
D.2.1.2	Country which granted the Marketing Authorisation	France
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.3.4	Pharmaceutical form	Powder for 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	TRABECTEDIN
D.3.9.1	CAS number	114899-77-3
D.3.9.4	EV Substance Code	SUB20756
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	1
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

Adult patients with unresectable locally advanced or metastatic soft-tissue
sarcoma.

E.1.1.1

Medical condition in easily understood language

Adult patients with unresectable locally advanced or metastatic soft-tissue
sarcoma.

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	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10039494
E.1.2	Term	Sarcoma NOS
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

Phase I:
To establish the recommended phase II dose (RP2D), the maximum tolerated dose (MTD) evaluated on the first cycle (D1 to D28), the safety profile, and the dose limiting toxicities (DLT) of trabectedin given in combination with cyclophosphamide (CP).

Phase II:
To evaluate the antitumor activity of trabectedin in association with CP in terms of non-progression at 6 months (complete or partial responses or stable disease more than 24 weeks, as per RECIST v1.1 criteria) after centralized radiological review, in patients with advanced STS who already failed anthracycline-containing chemotherapy (CT).

E.2.2

Secondary objectives of the trial

Phase I:
· To evaluate preliminary signs of antitumor activity of trabectedin given in combination with CP in terms of objective response under treatment (as per RECIST v1.1 criteria), 6-month non-progression, 1-year progression-free survival (PFS) and 1-year overall survival (OS).
· To describe the pharmacokinetics (PK) of trabectedin given in combination with CP.
· Biomarker study: To perform pharmacodynamic (PD)/mechanism of action (MOA) biomarkers analysis as well as predictive biomarkers analysis (levels of angiogenic and immunologic biomarkers in blood at baseline and different study time points).

Phase II:
· To evaluate the antitumor activity of trabectedin in association with CP in terms of objective response under treatment (as per RECIST v1.1 criteria), 1- year progression free survival (PFS) and 1-year overall survival (OS).
· To evaluate the toxicity of trabectedin in association with CP (NCI-CTC v4).

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Pharmacokinetic, pharmacodynamic and biomarkers studies

E.3

Principal inclusion criteria

1. Patients with soft-tissue sarcoma histologically confirmed by central review (Pr. Coindre team), except in case of diagnosis was already confirmed by the RRePS Network,
2. Metastatic or unresectable locally advanced disease,
3. Age ≥ 18 years,
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2,
5. Life expectancy > 3 months,
6. Measurable disease according to RECIST v1.1 outside any previously irradiated field,
7. For patients included in phase II study, progressive disease according to RECIST v1.1 criteria diagnosed on the basis of two CT scan or MRI obtained at an interval less than 6 months in the period of 12 months prior to inclusion and confirmed by central review,
8. Previous use of Anthracyclines,
9. Have provided tissue from an archival tissue sample,
10. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy,
11. Adequate hematological, renal, metabolic and hepatic function: a. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 x 109/l, and platelet count ≥ 100 x 109/l
b. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of extensive liver involvement) and alkaline phosphatase (AP) ≤ 2.5 x ULN
c. Total bilirubin ≤ ULN.
d. Albumin ≥ 25 g/l
e. Serum Creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockroft formula).
f. Creatine Phosphokinase (CPK) ≤ 2.5 x ULN
12. Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment. Acceptable methods of contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier,
13. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma,
14. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.0),
15. Patients with a French social security in compliance with the Law relating to biomedical research (Article 1121-11 of French Public Health Code),
16. Voluntarily signed and dated written informed consent prior to any study specific procedure.

E.4

Principal exclusion criteria

1. Previous treatment with Trabectedin,
2. Currently active bacterial or fungus infection (> grade 2 CTC [CTCAE] HIV1, HIV2, hepatitis B or hepatitis C infections,
3. History of chronic alcohol use and/or cirrhosis,
4. The following unstable cardiac conditions are not allowed:
- Congestive heart failure
- Angina pectoris
- Myocardial infarction within 1 year before registration
- Uncontrolled arterial hypertension defined as blood pressure ≥ 150/100 mmHg despite optimal medical therapy
- Arrhythmias clinically significant
5. Patients unable to receive corticotherapy,
6. Known central nervous system malignancy (CNS),
7. Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding,
8. Participation to a study involving a medical or therapeutic intervention in the last 30 days,
9. Previous enrolment in the present study,
10. Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons,
11. Known hypersensitivity to any involved study drug or any of its formulation components.
12. Recent vaccination (in the last 2 weeks before inclusion) for yellow fever.

E.5 End points

E.5.1

Primary end point(s)

Phase I trial:
· Toxicity graded using the common toxicity criteria from the NCI v4.0
· Incidence rate of DLT at each dose level on cycle 1

Phase II trial:
· 6-month non-progression as defined above for the phase I escalation study

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I trial:
- Toxicity is assessed as long as patient is under treatment
- Incidence rate of DLT is assessed during the first 28 days of treatment, for each patient

Phase II trial:
- 6-months non-progression is assessed 6 months after the beginning of treatment

E.5.2

Secondary end point(s)

Phase I trial:
· 6-month non-progression defined as CR, PR or stable disease more than 24 weeks according to RECIST v1.1 criteria.
· 1-year Overall Survival (OS) defined as the time from study treatment initiation to death (of any cause).
· 1-year Progression-Free Survival (PFS) defined as the time from study treatment initiation to disease progression (defined as per RECIST v1.1) or death (of any cause), whichever occurs first.
· PK measurements expressed as the AUC, the half-life of trabectedin, CP and concentration peak.
· Pharmacodynamic study:
Blood: Serum/plasma cytokines levels (INFγ, TNFα, IL2,4,6,10) by ELISA ; Serum/plasma VEGF and TPS-1 levels by ELISA, monocytes, Treg, CD4+, CD8+ and DR lymphocytes subpopulations monitoring, CD4+/CD8+ ratio (Flow Cytometry),
Tumor: Fresh pre-treatment and on-treatment tumor biopsies will be collected to assess pharmacodynamics changes of TAM infiltration and additional tumor markers. Frozen biopsy samples will be analyzed for:
- Hematoxylin and eosin staining (H&E).
- Immunohistochemistry (IHC) assessments include, but are not limited to the following markers: CSF-1R, CD68/CD163, CD68/MHC class II, CD31 (microvessel density), Ki67 and other exploratory markers. The analysis will be prioritized based on the amount of material available.

Phase II trial:
Toxicity, objective response under treatment, 1-year OS and 1-year PFS defined above for the phase I escalation study except for the PD study which is optional in this phase II trial.

E.5.2.1

Timepoint(s) of evaluation of this end point

Phase I trial:
-Objective response under treatment: from treatment initiation until the end of treatment
-6-months non-progression: 6 months after the beginning of treatment
-1-year OS and 1-year PFS: 1 year after treatment initiation
-AUC, half-life of trabectedine, CP and trabectedine concentration peak: from samples collected on Days 1 and 15 of cycle 1
-Blood samples markers levels (pharmacodynamics study): from samples collected at baseline, and on Days 1 of cycles 1 and 2
-Tumor markers: from tumor biopsies obtained at baseline and at Cycle 1 day 28

Phase II trial:
-Toxicity: as long as patient is under treatment
-Objective response under treatment: as patient is under treatment
-1-year OS and 1-year PFS: 1 year after treatment initiation

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

Yes

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

Biomarkers study

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 escalation

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

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

dose level

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

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

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

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.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

2015-10-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-09-30

P. End of Trial
P.	End of Trial Status	Ongoing

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