Clinical Trials Register

Summary
EudraCT Number:	2015-004411-20
Sponsor's Protocol Code Number:	M14-031
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:	2021-06-17
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

2015-004411-20

A.3

Full title of the trial

A Phase 3, Multicenter, Randomized, Double Blind Study of Bortezomib and Dexamethasone in Combination with Either Venetoclax or Placebo in
Subjects with Relapsed or Refractory Multiple Myeloma Who are Sensitive or Naïve to Proteasome Inhibitors.

Sperimentazione Multicentrica di Fase 3, Randomizzata ed in Doppio Cieco per Valutare Bortezomib e Desametasone in combinazione con Venetoclax oppure Placebo in Soggetti affetti da Mieloma Multiplo Recidivante o Refrattario e Sensibili o Naïve agli Inibitori del Proteasoma.

A.3.1

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

A study evaluating venetoclax in Multiple Myeloma subjects, who are receiving bortezomib and dexamethasone as standard therapy.

Sperimentazione per valutare venetoclax in Soggetti affetti da Mieloma Multiplo, in trattamento con bortezomib e desametasone come terapia standard.

A.3.2

Name or abbreviated title of the trial where available

M14-031

A.4.1

Sponsor's protocol code number

M14-031

A.5.4

Other Identifiers

Name:

N.A.

Number:

N.A.

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.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, Vanwall Road
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
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.3.9.4	EV Substance Code	SUB176260
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
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	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Relapsed or Refractory Multiple Myeloma

Mieloma multiplo recidivante o refrattario

E.1.1.1

Medical condition in easily understood language

Subjects with a type of blood cancer (multiple myeloma) that is either relapsed (comes back) or refractory (did not get better) after prior treatment.

Soggetti con una tipologia di tumore del sangue (mieloma multiplo) che è sia recidivante (ritorna) o refrattario (non migliora) dopo il precedente trattamento.

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	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10074470
E.1.2	Term	Plasma cell 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

Progression Free Survival

Sopravvivenza libera da progressione

E.2.2

Secondary objectives of the trial

- Overall Survival
- Very Good Partial Response
- Progression Free Survival in subjects with high BLC2 expression
- Duration of response
- Patient Reported Outcomes
- Time to Progression
- Overall Response Rate
- Minimal Residual Disease Status

- Sopravvivenza globale
- Risposta parziale molto buona o miglior tasso di risposta
- Sopravvivenza libera da prograssione nei soggetti con espressione elevata della proteina BCL-2;
- Durata della risposta
- Esiti segnalati dai pazienti
- Tempo alla progressione della malattia
- Tasso di risposta oggettiva
- Status relativo alla malattia residua minima
- Sicurezza

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Eastern Cooperative Oncology Group (ECOG) performance status = 2.
2. Subject has documented relapsed or progressive multiple myeloma on or after any regimen or is refractory to the most recent line of therapy.
¿ Relapsed myeloma is defined as previously treated myeloma that progresses and requires initiation of salvage therapy, but does not meet
the criteria for refractory myeloma.
¿ Refractory myeloma is defined as disease that is nonresponsive (failure to achieve minimal response or development of PD) while on primary or
salvage therapy, or progresses within 60 days of last therapy.
3. Subject must have received prior treatment with at least one, but no more than three, prior lines of therapy for multiple myeloma.
¿ A line of therapy consists of = 1 complete cycle of a single agent, a regimen consisting of combination of several drugs, or a planned sequential therapy of various regimens.
4. Prior treatment with bortezomib or other proteasome inhibitor is allowed, provided ALL of the following criteria are met:
¿ Disease is NOT refractory to any proteasome inhibitor, defined as no disease progression (i.e., PD, per IMWG or European Society for Blood
and Marrow Transplantation [EBMT] criteria) while receiving proteasome inhibitor therapy or within 60 days after the last dose, AND
¿ Best response achieved with any proteasome inhibitor therapy (alone or in combination) was at least a PR, AND
¿ Subject did not discontinue any proteasome inhibitor due to intolerance or = Grade 3 related toxicity.
5. Subject has measurable disease at Screening, defined as at least one of the following:
¿ Serum M-protein = 0.5 g/dL, OR
¿ Urine M-protein = 200 mg in 24-hours, OR
¿ Serum immunoglobulin free light chain (FLC) = 10 mg/dL provided serum FLC ratio is abnormal.

1. Soggetti con Punteggio ECOG (Eastern Collaborative Oncology Group) di valutazione dello stato funzionale = 2.
2. Soggetti con conferma di mieloma multiplo recidivante o progressivo in corso di o dopo la conclusione di qualsiasi regime di trattamento, oppure soggetti che sono refrattari alla linea più recente di terapia.
• Per mieloma recidivante si intende mieloma con trattamento pregresso che progredisce e richiede l’avvio di una terapia di salvataggio, senza tuttavia soddisfare i criteri di mieloma refrattario.
• Per mieloma refrattario si intende la malattia che non risponde (mancato raggiungimento di risposta minima oppure sviluppo di PD) in corso di terapia primaria o di salvataggio, o che progredisce nei 60 giorni successivi all’ultima terapia.
3. Soggetti che hanno ricevuto trattamento pregresso con un minimo di una a un massimo di tre linee pregresse di terapia per il mieloma multiplo.
• Una linea di terapia consiste di = 1 ciclo completo con singolo agente, un regime che consiste nella combinazione di farmaci diversi oppure una terapia sequenziale programmata che comprende diversi regimi.
4. E’ permesso il trattamento pregresso con bortezomib o altri inibitori del proteasoma, purché TUTTI i seguenti criteri siano soddisfatti:
• La malattia NON è refrattaria a qualsiasi inibitore del proteasoma, definita quale assenza di progressione di malattia (ovvero PD determinato in base ai criteri IMWG o EBMT [European Society for Blood and Marrow Transplantation]) durante il trattamento con l’inibitore del proteasoma oppure nei 60 giorni dopo l’ultima dose, E
• La miglior risposta ottenuta con qualsiasi inibitore del proteasoma (in monoterapia o in terapia combinata) è stata almeno la Risposta Parziale (Partial Response, PR), E
• Il soggetto non ha interrotto il trattamento con l’inibitore del proteasoma a causa di intolleranza o di tossicità correlata di grado = 3.
5. Soggetti con malattia misurabile allo Screening, definita in base ad almeno uno dei seguenti parametri:
• Proteina M sierica = 0.5 grammi (gr)/decilitro (dL), OPPURE
• Proteina M urinaria = 200 mg nell’arco delle 24 ore, OPPURE
• Immunoglobulina catena leggera libera sierica (free light chain, FLC) = 10 mg/dL purché il rapporto sierico FLC sia alterato.

E.4

Principal exclusion criteria

1. Subject is refractory to any proteasome inhibitor, defined as progression on or within 60 days of the last dose of a proteasome inhibitor-containing regimen.
2. Subject has had prior treatment with proteasome inhibitor within 60 days prior to first dose of study drug.
3. Subject has any of the following conditions:
¿ Non-secretory multiple myeloma
¿ Active plasma cell leukemia i.e., either 20% of peripheral white blood cells comprised of plasma cells or > 2.0 × 10^9/liter (L) circulating plasma cells by standard differential
¿ Waldenström's macroglobulinemia
¿ Amyloidosis
¿ POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
¿ Known Human Immunodeficiency Viral (HIV) infection
¿ Active hepatitis B or C infection based on screening blood testing
¿ Significant cardiovascular disease, including uncontrolled angina, severe or uncontrolled arrhythmia, recent myocardial infarction within 6
months of randomization, or congestive heart failure New York Heart Association (NYHA) Class = 3
¿ Major surgery within 4 weeks prior to randomization
¿ Acute infections requiring parenteral therapy (antibiotic, antifungal, or antiviral) within 14 days prior to randomization
¿ Peripheral neuropathy = Grade 3 or = Grade 2 with pain within 2 weeks prior to randomization
¿ Uncontrolled diabetes or uncontrolled hypertension within 14 days prior to randomization
¿ Any other medical condition that, in the opinion of the Investigator, would adversely affect the subject's participation in the study
4. Subject has a history of other active malignancies, including myelodysplastic syndrome (MDS), within the past 3 years prior to study entry, with the following exceptions:
¿ Adequately treated in situ carcinoma of the cervix uteri or the breast
¿ 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 with no evidence of disease, confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study
5. If subject had prior stem cell transplant (SCT), subject has evidence of ongoing graft-versus-host disease (GvHD).

1. Soggetti refrattari a qualsiasi inibitore del proteasoma, definito in base alla progressione in corso di trattamento o nei 60 giorni dopo l’ultima dose di un regime a base di inibitori del proteasoma.
2. Soggetti che hanno ricevuto un pregresso trattamento con inibitore del proteasoma nei 60 giorni precedenti la prima dose del medicinale sperimentale.
3. Soggetti che presentano una delle seguenti patologie:
• Mieloma multiplo non secernente.
• Leucemia plasmacellulare in fase attiva, ovvero 20% di globuli bianchi periferici oppure > 2,0 × 10^9/Litro (L) di plasmacellule circolanti in base a diagnosi differenziale standard
• Macroglobulinemia di Waldenström
• Amiloidosi
• Polineuropatia, organomegalia, endocrinopatia, proteina monoclonale, e alterazioni cutanee (sindrome POEMS)
• Nota Infezione da Virus dell’Immunodeficienza Umana (HIV)
• Infezione da epatite B o C in fase attiva, rilevata da analisi di laboratorio allo screening
• Malattia cardiovascolare significativa, fra cui angina non controllata, ipertensione, aritmia, infarto miocardico recente nei 6 mesi precedenti la randomizzazione, scompenso cardiaco congestizio di classe NYHA (New York Heart Association) = 3
• Intervento chirurgico maggiore nelle 4 settimane precedenti la randomizzazione
• Infezioni acute che richiedono terapia parenterale (con antibiotici, antimicotici o antivirali) nei 14 giorni precedenti la randomizzazione
• Neuropatia periferica di grado = 3 oppure di grado = 2 associato a dolore, nelle 2 settimane precedenti la randomizzazione
• Diabete non controllato oppure ipertensione non controllata nei 14 giorni precedenti la randomizzazione
• Qualsiasi altra condizione medica che a giudizio dello Sperimentatore avrebbe un effetto avverso sulla partecipazione del soggetto alla sperimentazione
4. Soggetti con storia di altre neoplasie attive, fra cui sindromi mielodisplasiche (myelodysplastic syndrome, MDS), negli ultimi 3 anni precedenti l’ingresso nella sperimentazione, con le seguenti eccezioni:
• Carcinoma in situ ed adeguatamente trattato della cervice uterina o della mammella
• Carcinoma cutaneo basocellulare oppure carcinoma cutaneo squamocellulare localizzato,
• Carcinoma prostatico di grado = 6 secondo Gleason E valori stabili di PSA (Prostate Specific Antigen) dopo aver concluso il trattamento,
• Neoplasia pregressa senza evidenza di malattia circoscritta e trattata chirurgicamente (o trattata mediante altre modalità) con intento curativo e con scarse probabilità di avere un impatto sulla sopravvivenza durante la sperimentazione
5. Nei soggetti che in precedenza sono stati sottoposti a trapianto di cellule staminali (stem cell transplant, SCT), evidenza di malattia del trapianto contro l’ospite (graft versus host disease, GvHD) in atto.

E.5 End points

E.5.1

Primary end point(s)

Progression Free Survival

Sopravvivenza Libera da Progressione

E.5.1.1

Timepoint(s) of evaluation of this end point

When 136 Progression Free Survival events occur

Quando si verificano 136 eventi di sopravvivenza libera da progressione

E.5.2

Secondary end point(s)

Overall Survival
Very Good Partial Response
Progression Free Survival in subjects with high BLC2 expression
Duration of response
Patient Reported Outcomes
Time to Progression
Overall Response Rate
Minimal Residual Disease Status

Sopravvivenza globale
Risposta parziale molto buona o miglior tasso di risposta
Sopravvivenza libera da progressione nei soggetti con espressione elevata della proteina BCL-2;
Durata della risposta
Esiti segnalati dai pazienti
Tempo alla progressione della malattia
Tasso di risposta oggettiva
Status relativo alla malattia residua minima

E.5.2.1

Timepoint(s) of evaluation of this end point

Overall Survival: when approximately 116 OS events are observed.
Other secondary endpoints will be evaluated in the final analyses,
following positive analysis for Progression Free Survival.

Sopravvivenza Globale: quando si verificano circa 116 eventi di OS.
Gli altri endpoints secondari saranno valutati nell'analisi finale, a seguito dell'analisi positiva della Sopravvivenza Libera da Progressione

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

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)

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

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

Australia

Canada

Japan

Korea, Democratic People's Republic of

Korea, Republic of

Russian Federation

United States

Belgium

Denmark

France

Germany

Ireland

Italy

Spain

Sweden

United Kingdom

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

LSLV

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:

140

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

140

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

107

F.4.2.2

In the whole clinical trial

280

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)

Treatment or care will be assessed by the Investigator on an individual patient basis.

Trattamento o cura sarà definita dallo Sperimentatore su basse individuale.

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

2016-05-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-08-15

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