Clinical Trials Register

Summary
EudraCT Number:	2014-002610-23
Sponsor's Protocol Code Number:	M14-387
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-10-02
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-002610-23

A.3

Full title of the trial

A Phase 1/2 Study of ABT-199 in Combination with Low-Dose Cytarabine in Treatment-Naïve Subjects with Acute Myelogenous Leukemia Who Are ≥ 65 Years of Age and Who Are Not Eligible for Standard Anthracycline-Based Induction Therapy

A.3.1

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

A.4.1

Sponsor's protocol code number

M14-387

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	AbbVie Deutschland GmbH & Co. KG
B.1.3.4	Country	Germany
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	AbbVie Inc.
B.4.2	Country	United States
B.4.1	Name of organisation providing support	F. Hoffmann-La Roche Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AbbVie Ltd.
B.5.2	Functional name of contact point	EU Clinical Trials Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	Abbott House, Vanwall Business Park
B.5.3.2	Town/ city	Maidenhead, Berkshire
B.5.3.3	Post code	SL6 4XE
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	441628773355
B.5.5	Fax number	441628672566
B.5.6	E-mail	eu-clinical-trials@abbvie.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	ABT-199 (GDC-0199) 10 mg
D.3.2	Product code	ABT-199 (GDC-0199)
D.3.4	Pharmaceutical form	Film-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	ABT-199 (GDC-0199) 10 mg
D.3.9.2	Current sponsor code	ABT-199
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.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	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	ABT-199 (GDC-0199) 100 mg
D.3.2	Product code	ABT-199 (GDC-0199)
D.3.4	Pharmaceutical form	Film-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	ABT-199 (GDC-0199) 100 mg
D.3.9.2	Current sponsor code	ABT-199
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	100
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	Yes
D.2.1.1.1	Trade name	Cytarabine
D.2.1.1.2	Name of the Marketing Authorisation holder	Hospira UK 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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Cytarabine
D.3.2	Product code	n/a
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	Cytarabine 20mg/ml
D.3.9.3	Other descriptive name	CYTARABINE
D.3.9.4	EV Substance Code	SUB06880MIG
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	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.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

Acute Myelogenous Leukemia

E.1.1.1

Medical condition in easily understood language

Cancer of the blood and bone marrow

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10001941
E.1.2	Term	AML
E.1.2	System Organ Class	100000004864

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

The primary objective of the Phase 1 portion of the study is to determine the Maximal Tolerated Dose (MTD) of ABT-199 in combination with low-dose cytarabine (LDC) in treatment-naïve subjects with Acute Myelogenous Leukemia (AML) who are ≥ 65 years of age and who are not eligible for standard Anthracycline-Based induction therapy due to co-morbidity or other factors.
The primary objective of the Phase 2 portion of the study is to evaluate the leukemia response rate and duration and characterize the toxicities of the combination at the Recommended Phase 2 Dose (RPTD).

E.2.2

Secondary objectives of the trial

To evaluate rate and duration of hematological response, including transfusion support needs and Progression-Free survival.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject must be ≥ 65 years of age.
2. Subject must have a projected life expectancy of at least 12 weeks.
3. Subject must have histological confirmation of AML and be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to co-morbidity or other factors.
4. Subject must have received no prior treatment for AML with the exception of hydroxyurea, allowed through first cycle of treatment. NOTE: Subject may have been treated for prior Myelodysplastic Syndrome.
5. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2.
6. Subject must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 50 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula.
7. Subject must have adequate liver function as demonstrated by: aspartate aminotransferase (AST) ≤ 2.5 × ULN*, alanine aminotransferase (ALT) ≤ 2.5 × ULN*, bilirubin ≤ 1.5 × ULN*, Unless considered due to leukemic organ involvement.
Note: Subjects with Gilbert's Syndrome may have a bilirubin > 1.5 × ULN per discussion between the investigator and AbbVie medical monitor.

E.4

Principal exclusion criteria

1. Subject has received treatment with cytarabine for a pre-existing myeloid disorder.
2. Subject has acute promyelocytic leukemia .
3. Subject has known active CNS involvement with AML.
4. Subject has tested positive for HIV (due to potential drug-drug interactions between antiretroviral medications and ABT-199, as well as anticipated ABT-199 mechanism-based lymphopenia that may potentially increase the risk of opportunistic infections). Note: HIV testing is not required.
5. Subject has received the following within 7 days prior to the initiation of study treatment:
• Potent CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's Wort;
• Warfarin or requires the use of warfarin (due to potential drug-drug interactions that may potentially increase the exposure of warfarin and complications of this effect).
6. Subject has received the following within 5 days prior to the initiation of study treatment:
• CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin.
7. Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
8. Subject has a cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which subjects are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
9. Subject has a white blood cell count > 25 × 109/L. Note: Hydroxyurea is permitted to meet this criterion.

E.5 End points

E.5.1

Primary end point(s)

Phase 1: Safety profile, characterize PK, maximum tolerated dose (MTD) and recommended phase 2 dose (RPTD)
Phase 2: Overall response rate (ORR), time to progression (TTP), and progression-free survival (PFS) and to characterize the toxicities of the combination at the RPTD.

E.5.1.1

Timepoint(s) of evaluation of this end point

First week of treatment (MTD); throughout the study (Safety); Cycle 1 Day 1, Cycle 1 Day 10 and Cycle 1 Day 18 (PK); Cycle 1 Day 1, Cycle 2 Day 1, Cycle 4 Day 1, every 12 Weeks thereafter and as clinically indicated and final visit (MRD and other phase 2 primary end points)

E.5.2

Secondary end point(s)

Phase 2: Response rates of CR, Cri, PR, HR and Duration of Response (DOR) and Progression-Free Survival (PFS).

E.5.2.1

Timepoint(s) of evaluation of this end point

Cycle 1 Day 1, Cycle 2 Day 1, Cycle 4 Day 1, every 12 Weeks thereafter and as clinically indicated and final visit (MRD and other phase 2 primary end points)

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

Yes

E.6.11

Pharmacogenomic

Yes

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

safety, pharmacodynamic and pharmacokinetic

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

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)

Information not present in EudraCT

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

Australia

Germany

Italy

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

The end of study is defined as the date of the last subject's last visit.

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)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

F.4.2.2

In the whole clinical trial

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)

For subjects that continue to derive benefit after 2 years of treatment following the date of the last subject enrolled, AbbVie will work with the investigator to evaluate options for continuation of ABT-199. Other subjects will be treated after end of trial according to the standard of medical care.

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

2014-12-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-02-10

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

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