Clinical Trials Register

Summary
EudraCT Number:	2012-000589-38
Sponsor's Protocol Code Number:	M13-367
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:	2018-05-02
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2012-000589-38

A.3

Full title of the trial

A Phase 1/2 Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Subjects with Relapsed or Refractory Multiple Myeloma

A.3.1

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

A Phase 1/2 Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Subjects with Relapsed or Refractory Multiple Myeloma

A.4.1

Sponsor's protocol code number

M13-367

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	Genentech Inc
B.4.2	Country	United States
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	AbbVie House, Vanwall Business Park
B.5.3.2	Town/ city	Maidenhead, Berkshire
B.5.3.3	Post code	SL6 4UB
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441628561090
B.5.5	Fax number	+441628461153
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	Venetoclax 100 mg
D.3.2	Product code	ABT-199
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	Venetoclax
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: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Dexamethasone JENAPHARM®
D.2.1.1.2	Name of the Marketing Authorisation holder	mibe GmbH Arzneimittel
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Dexamethasone
D.3.4	Pharmaceutical form	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	DEXAMETHASONE
D.3.9.1	CAS number	50-02-2
D.3.9.4	EV Substance Code	SUB07017MIG
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	4
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

Relapsed/refractory multiple myeloma

E.1.1.1

Medical condition in easily understood language

Relapsed/refractory multiple myeloma

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	16.1
E.1.2	Level	HLT
E.1.2	Classification code	10028229
E.1.2	Term	Multiple myelomas
E.1.2	System Organ Class	100000004851

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The phase 1 primary objectives of this study are to assess the safety profile, characterize pharmacokinetics (PK) and determine the dosing schedule, maximum tolerated dose (MTD), and recommended phase 2 dose (RPTD) of ABT-199 (venetoclax) monotherapy when administered in subjects with relapsed or refractory multiple myeloma. This study will also assess the safety profile and PK of venetoclax in combination with dexamethasone in subjects with t(11;14)-positive multiple myeloma.

The phase 2 primary objective is to further evaluate the objective response rate (ORR) and very good partial response or better rate (VGPR+) in subjects with t(11;14)-positive multiple myeloma.

E.2.2

Secondary objectives of the trial

The Phase 1 secondary objectives are to evaluate preliminary efficacy data regarding the effect of venetoclax monotherapy or combined with dexamethasone on objective response rate (ORR), time to response (TTR), time to disease progression (TTP), and duration of response (DOR).

The phase 2 secondary objectives are to monitor safety, progression free survival (PFS), DOR , TTR, TTP, and overall survival (OS), and to evaluate patient report outcomes.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject must be ≥ 18 years of age.
2. Subject has an ECOG performance score of ≤ 1.
- For subjects in phase 2 portion: ECOG performance score of ≤ 2.
3. Diagnosis of multiple myeloma which requires treatment and has been previously treated with:
- For subjects in the Dose Escalation portion of the study:
o ≥ 1 prior line of therapy. Induction therapy followed by stem cell transplant and maintenance therapy will be considered as a single line of therapy.
- For subjects in the Safety Expansion portion of the study:
o Have received treatment with a proteasome inhibitor and an immunomodulatory (IMiD®) agent (e.g., thalidomide, lenalidomide, pomalidomide). Induction therapy followed by stem cell transplant and maintenance therapy will be considered as a single line of therapy.
- For subjects in the Venetoclax-Dexamethasone Combination Portion:
○ Have received treatment with a proteasome inhibitor and an immunomodulatory (IMiD®) agent (e.g., thalidomide, lenalidomide, pomalidomide), AND
○ Have MM positive for t(11;14) translocation as determined by an analytically validated fluorescence in-situ hybridization (FISH) assay per the central laboratory testing
- For subjects in the Phase 2 cohort:
○ Subject must have documented MM positive for the t(11;14) translocation. If testing has been performed by a laboratory other than the Sponsor-directed central laboratory, subjects may be enrolled but must be re-tested
by the central laboratory for confirmation of t(11;14) status. The investigator should ensure that the testing is consistent with local guidelines and clinical practice, and the test uses either 1) plasma cell enriched or 2) cytoplasmic immunoglobulin-enhanced interphase fluorescence in-situ hybridization (FISH) analysis of bone marrow aspirate
samples per International Myeloma Working Group (IMWG) guidelines AND
○ Subject must have evidence of disease progression on or within 60 days of the last dose of the most recent previous treatment regimen based on the IMWG criteria, AND
○ Subject must have previously received at least 3 lines of therapy, including an immunomodulatory drug (lenalidomide or pomalidomide), a proteasome inhibitor (bortezomib, carfilzomib or ixazomib), daratumumab, and glucocorticoids. Daratumumab combination regimen must be one of the prior lines of therapy (for this study, daratamumab plus corticosteroids will not be considered a combination regimen).
4. Subject must have measurable disease at Screening, defined as any of the following:
- Serum monoclonal protein ≥ 1.0 g/dL (≥ 10 g/L) by protein electrophoresis,
- ≥ 200 mg of monoclonal protein in the urine on 24-hour electrophoresis, or
- Serum immunoglobulin free light chain (FLC) ≥ 10 mg/dL provided serum FLC ratio is abnormal.
5. Subjects with a history of autologous or allogenic stem cell transplantation must have adequate peripheral blood counts independent of any growth factor support, and have recovered from any transplant-related toxicity(s) and be: > 100 days post-autologous transplant (prior to first dose of study drug), or; ≥ 6 months post-allogenic transplant (prior to first dose of study drug), and not have active graft-vs-host disease (GVHD) i.e requiring treatment.
6. Subjects must meet certain laboratory parameters (refer to protocol for parameters).

E.4

Principal exclusion criteria

1. Subject exhibits evidence of other clinically significant uncontrolled condition(s), including, but not limited to: uncontrolled systemic infection (viral, bacterial, or fungal), diagnosis of fever and neutropenia within 1 week prior to first dose of study drug.
2. Subject has a cardiovascular disability status of New York Heart Association Class ≥ 3.
3. Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular or hepatic disease within the last 6 months that, in the opinion of the investigator, would adversely affect his/her participation in the study.
4. Subject has a history of other active malignancies other than multiple myeloma within the past 3 years prior to study entry, with the following exceptions:
- Adequately treated in situ carcinoma of the cervix uteri;
- Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
- Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment
- Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
5. Known Human Immunodeficiency Viral (HIV) infection
6. Active hepatitis B or C infection based on screening blood testing.
7. Subject is receiving other ongoing anti-myeloma therapy.
8. Subject has received any of the following within 7 days prior to the first dose of study drug:
- Strong or moderate CYP3A inhibitors, or
- Strong or moderate CYP3A inducers
9. Subject has received any of the following within 14 days prior to the first dose of study drug or has not recovered to less than a Grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy: any anti-myeloma therapy including chemotherapy, radiotherapy, or investigational therapy, including targeted small molecule agents.
10. Subject has received prior treatment with a BCL-2 family inhibitor.
11. Subject is pregnant, parturient, or breastfeeding; deprived of freedom by judicial or administrative decision; hospitalized and unable to provide consent, or otherwise unable to provide consent.
12. Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit within 3 days prior to the first dose of study drug.
13. Subject has received immunization with live vaccine within 60 days of dosing.
14. Recent corticosteroid therapy at a cumulative dose equivalent to > 140 mg of prednisone or a single dose equivalent to ≥ 40 mg/day of dexamethasone within 2 weeks prior to the first dose of study drug.

E.5 End points

E.5.1

Primary end point(s)

Phase 1 -to assess the safety profile, characterize pharmacokinetics (PK) and determine the dosing schedule, maximum tolerated dose (MTD), and recommended phase 2 dose (RPTD) of ABT-199 (venetoclax) when administered in subjects with relapsed or refractory multiple myeloma. This study will also assess the safety profile and PK of venetoclax in combination with dexamethasone in subjects with t(11;14)-positive multiple myeloma.

Phase 2 - to further evaluate the objective response rate (ORR) and very good partial response or better rate (VGPR+) in subjects with t(11;14)-positive multiple myeloma.

E.5.1.1

Timepoint(s) of evaluation of this end point

Weekly for the Lead In Period, Cycle 1, Cycle 2 and Day 1 of every cycle thereafter.

E.5.2

Secondary end point(s)

Phase 1 - to evaluate the preliminary efficacy data regarding the effect of venetoclax monotherapy or combined with dexamethasone on objective response rate (ORR), time to response (TTR), time to disease progression (TTP), and duration of response (DOR).

Phase 2 - to monitor safety, progression free survival (PFS), DOR, TTR, TTP, and overall survival (OS) and to evaluate patient reported outcomes.

E.5.2.1

Timepoint(s) of evaluation of this end point

Phase 1 - Cycle 5 and every 4 cycles thereafter.
Phase 2 - Day 1 of every cycle

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

Yes

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

Safety and PK study in patients

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)

E.8.2.2

Placebo

E.8.2.3

Other

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

Belgium

France

Norway

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

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:

112

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

F.4.2.2

In the whole clinical trial

166

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)

Per subject/investigator decision. The subject will be treated in accordance with the investigator's best clinical judgement. Patient may stay on drug until progression.

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

2018-06-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-11-29

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