Clinical Trials Register

Summary
EudraCT Number:	2009-010777-20
Sponsor's Protocol Code Number:	155-CL-031
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-10-16
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

France - ANSM

A.2

EudraCT number

2009-010777-20

A.3

Full title of the trial

A Phase II, Multicenter, Open-Label Study Of YM155 Plus Rituximab In Previously Treated Subjects With CD20-Positive B Cell Non-Hodgkin’s Lymphoma Who Are Ineligible For Or Have Previously Received An Autologous Stem Cell Transplant

A.4.1

Sponsor's protocol code number

155-CL-031

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Astellas Pharma Global Development, Inc. (APGD)
B.1.3.4	Country	United States
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	YM155
D.3.2	Product code	YM155
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	781661-94-7
D.3.9.2	Current sponsor code	YM155
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	10
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Mabthera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.2	Current sponsor code	N/A
D.3.9.3	Other descriptive name	N/A
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	10
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	Monoclonal antibody
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.2.1.1.1	Trade name	Mabthera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.2	Current sponsor code	N/A
D.3.9.3	Other descriptive name	N/A
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	10
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	Monoclonal antibody

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

CD20-positive primary or transformed diffuse large B cell lymphoma (DLBCL), grade 3 follicular lymphoma (FL) and mantle cell lymphoma (MCL).

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	12.0
E.1.2	Level	HLT
E.1.2	Classification code	10029592
E.1.2	Term	Non-Hodgkin's lymphomas NEC

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 determine objective response rate (ORR) (complete remission [CR] + partial remission [PR]) per [the International Working Group (IWG) Revised Response Criteria for Malignant Lymphomas (2007)].

E.2.2

Secondary objectives of the trial

To evaluate the following:
• Safety and tolerability of YM155 given in combination with rituximab.
• CR Rate.
• PR Rate.
• Time to response.
• Duration of response.
• Clinical benefit rate (CBR).
• Progression-free survival (PFS).
• Overall survival (OS).

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

The pharmacogenomic sub-study is included in the main protocol.

Study objectives are to comprehensively analyze:
• Suspected disease-related genes such as oncogenes, survivin and vascular
endothelial growth factor (VEGF)
• Genes potentially involved in drug excretion and/or metabolism such as the
organic anion/cation transporters (OAT, OCT)
• Genes of relevance to toxicity/safety issues, to be identified in a
precautionary / retrospective setting

E.3

Principal inclusion criteria

A subject is eligible for the study if all of the following apply:
1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved
written Informed Consent and privacy language as per national regulations (e.g.,
HIPAA Authorization for U.S. sites) must be obtained from the subject or legally
authorized representative prior to any study-related procedures (including
withdrawal of prohibited medication, if applicable).
2. Male or female subject aged 18 years or older at the Baseline Visit.
3. Any stage, histologically confirmed CD20-positive primary or transformed DLBCL,
grade 3 FL or MCL.
4. Ineligible for or have previously received an ASCT.
5. Relapsed following receipt of last dose of systemic chemotherapy or ASCT.
o Relapsed = Completed systemic chemotherapy or ASCT exhibiting at least
a PR that was maintained for at least 6 months following completion of the
treatment.
6. At least one, but no more than 3 prior chemotherapy regimens, including one
anthracycline-based combination regimen.
o Any planned maintenance therapy should be considered as part of the
previous treatment regimen.
o Any preparative treatment (salvage chemotherapy, high-dose
chemotherapy, radiation therapy, etc.) should be included with the ASCT
as one treatment regimen.
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 at the
Baseline Visit.
8. Life expectancy greater than 12 weeks at the Baseline Visit.
9. At least one measurable lesion ≥ or equal to 1.5 cm in the longest transverse
diameter as assessed via Screening Period computed tomography (CT) scan.
10. The subject with a previous history of non-CD20+ B cell NHL malignancy is
eligible for this study only if the subject meets the following criteria for a cancer
survivor:
o Subject having basal cell or squamous cell carcinoma of the skin or
carcinoma-in-situ of the cervix is eligible if he/she has had potentially
curative treatment anytime prior to enrollment.
o The subject has undergone potentially curative therapy for all prior
malignancies, and the subject has been considered disease free for at
least 5 years.
11. If the subject is female, she must be non-pregnant and non-lactating at the
Baseline Visit. All sexually active males and females of childbearing potential
must agree to use an adequate method of contraception (double barrier)
throughout the study period.

E.4

Principal exclusion criteria

A subject will be excluded from participation if any of the following apply:
1. Use of any standard/experimental anti-lymphoma drug therapy, within 21 days of the Baseline Visit.
2. Use of systemic steroids within 5 days of the Baseline Visit.
o A subject receiving steroids at the time of the Baseline Visit is eligible as
long as the subject is receiving a biologic dose or has been on a stable,
non-biologic dose for at least 4 weeks prior to the first dose of YM155 and
plans on continuing to receive the stable, non-biologic dose during study
participation.
3. Prior allogeneic stem cell transplant (SCT).
4. Inadequate marrow, hepatic and/or renal function at the Baseline Visit defined as:
o Serum creatinine ≥ 1.5 x upper limit of normal (ULN) or calculated serum
creatinine clearance < 60 mL/min.
o Absolute neutrophil count (ANC) ≤ 1000/mm3.
o Platelet ≤ 100,000/mm3.
o Alanine transaminase (ALT) and Aspartate transaminase (AST)
≥ 2.5 x ULN or ≥ 5 x ULN if secondary to liver metastases.
5. Central nervous system (CNS) or leptomeningeal involvement by lymphoma as
determined by the Investigator through physical examination and medical history
review at the Baseline Visit.
6. The subject has significant and/or uncontrolled cardiac, renal, hepatic, or other
systemic disorders or significant psychological conditions at the Baseline Visit that
in the Investigator’s judgment would jeopardize subject enrollment or compliance
with the study procedures.
7. The subject has known human immunodeficiency virus (HIV), hepatitis B surface
antigen, or hepatitis C antibody.
8. The subject has been previously treated with YM155.
9. The subject has received other investigational therapy or procedures within 28
days prior to the first study drug administration.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint for this study is the objective response rate (ORR). The ORR is defined as the proportion of subjects with CR or PR assessed by independent third party reviewer during the study per the International Working Group (IWG) Revised Response Criteria for Malignant Lymphomas (2007).

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

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Potential efficacy 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

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

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.8.5

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

Information not present in EudraCT

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

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

End of study reflects when the last subject receives the last survival contact. The End of Study date could include a study visit, successful telephone contact, etc. Definition provided in the protocol.

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
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	15
F.4.2.2	In the whole clinical trial	60

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

2009-12-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-12-15

P. End of Trial
P.	End of Trial Status	Completed

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