Clinical Trials Register

Summary
EudraCT Number:	2009-010548-32
Sponsor's Protocol Code Number:	CLBH589H2101
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-02-14
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

UK - MHRA

A.2

EudraCT number

2009-010548-32

A.3

Full title of the trial

A phase Ib/IIb, open-label, multi-center study of oral Panobinostat (LBH589) administered with 5-Azacitidine (Vidaza®) in adult patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML)

A.3.2

Name or abbreviated title of the trial where available

N/A

A.4.1

Sponsor's protocol code number

CLBH589H2101

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00946647

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	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma AG
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Forum 1 Novartis Campus
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4056
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	41 613241111
B.5.5	Fax number	41613248001
B.5.6	E-mail	clinicaltrial.enquiries@novartis.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	panobinostat
D.3.2	Product code	LBH589
D.3.4	Pharmaceutical form	Capsule, hard
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	panobinostat
D.3.9.1	CAS number	404950-80-7
D.3.9.2	Current sponsor code	LBH589
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	5
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	Vidaza
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe Ltd
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/07/509 (AML) EU/3/01/084 (myelodysplastic)
D.3 Description of the IMP
D.3.1	Product name	5-azacitidine
D.3.4	Pharmaceutical form	Powder for suspension 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	5-azacitidine
D.3.9.1	CAS number	320-67-2
D.3.9.3	Other descriptive name	5-aza
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
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: 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	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	panobinostat
D.3.2	Product code	LBH589
D.3.4	Pharmaceutical form	Capsule, hard
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	panobinostat
D.3.9.1	CAS number	404950-80-7
D.3.9.2	Current sponsor code	LBH589
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	20
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: 4
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	panobinostat
D.3.2	Product code	LBH589
D.3.4	Pharmaceutical form	Capsule, hard
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	panobinostat
D.3.9.1	CAS number	404950-80-7
D.3.9.2	Current sponsor code	LBH589
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	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)	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

Myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML)

E.1.1.1

Medical condition in easily understood language

Myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML)

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	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10000886
E.1.2	Term	Acute myeloid leukemia
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	19.1
E.1.2	Level	PT
E.1.2	Classification code	10009018
E.1.2	Term	Chronic myelomonocytic leukaemia
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	19.1
E.1.2	Level	PT
E.1.2	Classification code	10028533
E.1.2	Term	Myelodysplastic syndrome
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination at RPIID relative to treatment with single agent 5-Aza through the assessment of composite CR (CR or CRi or bone marrow CR).

E.2.2

Secondary objectives of the trial

•To assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination at RPIID relative to treatment with single agent 5-Aza through the assessment of clinical response other than the composite CR specified in the primary objective, 1-year survival, and time to progression (TTP).
•To characterize the safety and tolerability of panobinostat at RPIID in combination with 5-AZA, as well as, 5-AZA alone in the target patient population.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Adult patients (age ≥ 18 years) who are candidates for treatment with 5-Aza and present with one of the following:
• intermediate-2 or high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS). OR
• AML with multilineage dysplasia and maximum of 30% blasts (former RAEB-T according to FAB) OR
• chronic myelomonocytic leukemia (CMML)
• ECOG performance status ≤ 2
• Patients must have the following laboratory values unless elevations are considered due to MDS or leukemia: AST/SGOT and/or ALT/SGPT ≤ 2.5 x ULN; serum creatinine ≤ 1.5 x ULN; serum bilirubin (total and direct) ≤ 2 x ULN; serum electrolytes (i.e., calcium, magnesium and potassium) within normal ranges for the institution.
• Negative pregnancy test
• Patients who are not clinically euthyroid.
• Written informed consent obtained prior to any screening procedures

E.4

Principal exclusion criteria

• Planned hematopoietic stem-cell transplantation (HSCT)
• Patients with therapy-related MDS
• Patients with therapy-related AML and/or relapsed/refractory AML
• Clinical symptoms suggesting CNS leukemia
• Concurrent therapy with any other investigational agent
• Prior treatment with deacetylase inhibitor(s)
• Prior treatment with 5-Azacytidine or 5-aza-2'-deoxycytidine
• Time windows for prior therapies: Last dose of therapy, including cytokines and/or retinoids, immunotherapy, low-dose ara-C, investigational agent less than 28 days with the exception of hydroxyurea (24 hours) prior to receipt of study medication or AEs that have not recovered at least to NCI CTCAE Grade 1.
• Patients with impaired cardiac function including any of the following:
• Complete left bundle branch block or use of a permanent cardiac pacemaker, congenital long QT syndrome, history or presence of ventricular tachyarrhythmia, clinically significant resting bradycardia (<50 beats per minute), QTcF > 460 ms on screening ECG, or right bundle branch block + left anterior hemiblock (bifascicular block)
• Presence of unstable atrial fibrillation (ventricular response rate >100 bpm). Patients with stable atrial fibrillation are eligible provided they do not meet the other cardiac exclusion criteria
• Previous history of angina pectoris or acute MI within 6 months
• Screening LVEF <45% by echocardiography or MUGA
• Other clinically significant heart disease (e.g. uncontrolled hypertension or history of poor compliance with an antihypertensive regimen).
• Drugs which may cause QT prolongation and the treatment cannot be discontinued or switched to a different medication prior to starting study drug.
• Any of concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study. For example:
• Uncontrolled diabetes
• Active or uncontrolled infection
• Uncontrolled hypothyroidism
• Acute or chronic liver or renal disease
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat (e.g., ulcerative diseases, diarrhea, malabsorption syndrome, or small bowel resection).
• HIV, Hepatitis B/C infection according to the medical history (testing will not be performed).
• Female patients who are pregnant or breast feeding or patients of childbearing potential (WOCBP) not willing to use a double barrier method of contraception during the study and for 3 months following the last dose of study drug.
• Male patients whose sexual partner(s) are WOCBP who are not willing to use a double barrier method of contraception, one of which includes a condom, during the study and for 3 months after the end of treatment.
• Suspected hypersensitivity to 5-Aza or Mannitol
• Inability to swallow capsules
• Unwilling or unable to comply with the protocol
• Patient has evidence of clinically significant mucosal or internal bleeding

E.5 End points

E.5.1

Primary end point(s)

Composite CR (CR or CRi or bone marrow CR)

E.5.1.1

Timepoint(s) of evaluation of this end point

Every 8 weeks and at end of trial

E.5.2

Secondary end point(s)

•Clinical response for AML: PR; for MDS/CMML: PR and Hematologic Improvement (HI)
•Overall response (CR or CRi or bone marrow CR or PR)
•1-year survival
•Time to progression (TTP) based on the Guidelines for Implementation of IWG response criteria in AML, MDS and CMML according to Cheson 2003 and 2006 Post-text supplement 1
•Type, duration, frequency and relatedness of Adverse Events (AE). AE severity will be assessed according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0)
•Laboratory (biochemistry, hematology)
•ECG monitoring (central review by eRT)

E.5.2.1

Timepoint(s) of evaluation of this end point

As per visit schedules

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

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

Yes

E.6.13.1

Other scope of the trial description

To assess gene mutation status of specific target genes known to be relevant to MDS/CMML/AML disease.

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Information not present in EudraCT

E.7.1.2

Bioequivalence study

Information not present in EudraCT

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

phase Ib

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

Yes

E.8.1.3

Single blind

Information not present in EudraCT

E.8.1.4

Double blind

Information not present in EudraCT

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

Information not present in EudraCT

E.8.1.7

Other

Information not present in EudraCT

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

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

Austria

Belgium

Canada

France

Germany

Hungary

Italy

Korea, Republic of

Spain

Sweden

Switzerland

Thailand

United Kingdom

United States

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

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

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	Information not present in EudraCT
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	Information not present in EudraCT
F.1.1.3	Newborns (0-27 days)	Information not present in EudraCT
F.1.1.4	Infants and toddlers (28 days-23 months)	Information not present in EudraCT
F.1.1.5	Children (2-11years)	Information not present in EudraCT
F.1.1.6	Adolescents (12-17 years)	Information not present in EudraCT
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	6
F.4.2	For a multinational trial
F.4.2.1	In the EEA	69
F.4.2.2	In the whole clinical trial	119

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

2012-02-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-08

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2019-04-29

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