Clinical Trials Register

Summary
EudraCT Number:	2015-002892-30
Sponsor's Protocol Code Number:	1315.2
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-11-05
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

2015-002892-30

A.3

Full title of the trial

An open-label, Phase I/II trial to determine the maximum tolerated dose
and investigate safety, pharmacokinetics and efficacy of BI 836858 in
combination with decitabine in patients with acute myeloid leukemia

Studio di fase I/II in aperto, volto a determinare la dose massima tollerata e a valutare la sicurezza, la farmacocinetica e l¿efficacia di BI 836858 in combinazione a decitabina in pazienti affetti da leucemia mieloide acuta.

A.3.1

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

A study to find and investigate a safe dose of BI 836858 in combination with decitabine for patients with acute myeloid leukemia (AML)

Studio per determinare e valutare una dose sicura di di BI 836858 in combinazione a decitabina in pazienti affetti da leucemia mieloide acuta.

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

1315.2

A.5.4

Other Identifiers

Name:

Trial Number

Number:

1315-0002

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	BOEHRINGER-INGELHEIM ITALIA S.P.A.
B.1.3.4	Country	Italy
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	Boehringer Ingelheim Italia S.p.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Boehringer Ingelheim Pharma GmbH & Co. KG
B.5.2	Functional name of contact point	QRPE PSC CT Information Disclosure
B.5.3	Address:
B.5.3.1	Street Address	Binger Strasse 173
B.5.3.2	Town/ city	Ingelheim am Rhein
B.5.3.3	Post code	55216
B.5.3.4	Country	Germany
B.5.4	Telephone number	0018002430127
B.5.5	Fax number	0018008217119
B.5.6	E-mail	clintriage.rdg@boehringer-ingelheim.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	BI 836858
D.3.2	Product code	-
D.3.4	Pharmaceutical form	Concentrate for solution for injection
D.3.4.1	Specific paediatric formulation	No
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	-
D.3.9.2	Current sponsor code	BI 836858
D.3.9.3	Other descriptive name	CD33 MONOCLONAL ANTIBODIES
D.3.9.4	EV Substance Code	SUB129677
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)	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

patients with acute myeloid leukemia

pazienti affetti da leucemia mieloide acuta

E.1.1.1

Medical condition in easily understood language

patients with acute myeloid leukemia (AML), a type of cancer of the
blood and bone marrow

pazienti affetti da leucemia mieloide acuta

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10000886
E.1.2	Term	Acute myeloid leukemia
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase I Dose Escalation: To determine the maximum tolerated dose (MTD) and the recommended dose for Phase I Extension and to investigate the safety, pharmacokinetics (PK) and efficacy of BI 836858 in combination with
decitabine in patients >/= 65 years of age with previously untreated acute myeloid leukemia (AML) and considered ineligible for standard
intensive therapy, or patients >/= 18 years of age with refractory or relapsed AML.
Phase I Extension: To collect additional data on safety, PK and efficacy and to define the
Recommended Phase II Dose (RP2D) of BI 836858 in combination with decitabine in patients >/= 65 years of age with previously untreated AML and considered ineligible for standard intensive therapy.
Phase II:
To investigate efficacy, safety and PK of BI 836858 in combination with decitabine compared to decitabine monotherapy in patients >/= 65
years of age with previously untreated AML and considered ineligible for standard intensive therapy.

Fase I, dose escalation: determinare la dose massima tollerata (MTD) e la dose raccomandata per la fase I di estensione (RExP1D) e indagare la sicurezza, la farmacocinetica e l¿efficacia di BI 836858 in combinazione con decitabina in pazienti = 65 anni di et¿ con leucemia mieloide acuta (LMA) non trattata in precedenza e considerati non eleggibili alla terapia intensiva standard, o pazienti = 18 anni di et¿ con LMA refrattaria o recidivante.
Fase I, estensione: raccogliere dati aggiuntivi sulla sicurezza, la farmacocinetica e l¿efficacia e definire la dose raccomandata per la fase II (RP2D) di BI 836858 in combinazione con decitabina in pazienti = 65 anni di et¿ con LMA non trattata in precedenza e considerati non eleggibili alla terapia intensiva standard.
Fase II: valutare BI 836858 in combinazione con decitabina vs decitabina in monoterapia in pazienti = 65 anni di et¿ con LMA non trattata in precedenza e considerati non eleggibili per la terapia intensiva standard.

E.2.2

Secondary objectives of the trial

The secondary endpoint of the Phase I part of this trial is objective response (Complete Remission/ Complete Remission with incomplete
blood count recovery).
Secondary endpoints of the Phase II part of this trial are Event-free survival (EFS), Relapse-free survival (RFS), Remission duration and Time
to remission.

Endpoint secondario (Fase I):
¿Numero di pazienti con risposta obiettiva (CR+Cri)
Endpoint secondari (Fase II):
¿Sopravvivenza libera da eventi (EFS)
¿Sopravvivenza libera da recidiva (RFS)
¿Durata della remissione
¿Tempo alla remissione

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1)Phase I Dose Escalation:
a.Male or female patients >/= 18 years of age with relapsed or
refractory AML
b.Male or female patients >/= 65 years of age with previously untreated
AML ineligible for receiving standard intensive therapy
Phase I Extension and Phase II:
Male or female patients >/= 65 years of age with previously untreated
AML ineligible for receiving standard intensive therapy
2)Histologically or cytologically confirmed AML according to the WHO
classification
3)Patients must be eligible for treatment with decitabine
4)Eastern co-operative oncology group (ECOG) performance score </=2
at screening
5)Signed and dated written informed consent (including consent for biomarker and
genetic testing; refer to Section 8.1) by the start date of the Screening Visit in
accordance with GCP and local legislation.

1) Fase I - Dose Escalation:
a. Pazienti di sesso maschile o femminile = 18 anni di età con LMA recidivante o refrattaria (definite come LMA persistente dopo almeno due cicli di induzione) e non trattati con terapia anti-leucemica nelle 2 settimane precedenti il primo trattamento con decitabina.
b. Pazienti di sesso maschile o femminile = 65 anni di età con LMA non trattata in precedenza e non eleggibili a ricevere la terapia intensiva standard, sulla base di criteri medici documentati, come definiti nella sezione 5.6.1 del protocollo.
Fase I Estensione e Fase II:
Pazienti di sesso maschile o femminile = 65 anni di età con LMA non trattata in precedenza e non eleggibili a ricevere la terapia intensiva standard, sulla base di criteri medici documentati, come definiti nella sezione 5.6.1 del protocollo.
2) LMA confermata istologicamente o citologicamente secondo la classificazione WHO (R09-2581).
3) I pazienti devono essere eleggibili al trattamento con decitabina.
4) Punteggio ECOG (Eastern Co-operative Oncology Group) di performance < 2 allo screening.
5) Consenso informato scritto e datato (incluso il consenso per i test dei biomarcatori e genetici; riferirsi alla sezione 8.1 del protocollo) entro la data di inizio dello screening, in accordo alle GCP e alla legislazione locale.

E.4

Principal exclusion criteria

1) Acute promyelocytic leukemia (APL, French-American-British (FAB)
subtype M3), according to WHO classification
2) Patients who are candidates for allogeneic stem cell transplantation.
3) Active chronic graft versus host disease requiring immunosuppressive
treatment
4) Prior treatment with a hypomethylating agent (this also includes prior
MDS treatment with decitabine or azazitidine)
5) Prior treatment with Cluster of differentiation 33 (CD33) antibody

1)Leucemia promielocitica acuta (FAB sottotipo M3), in accordo alla classificazione WHO (R09-2581).
2)Pazienti che siano candidati al trapianto allogenico di cellule staminali.
3)Malattia cronica del trapianto contro l’ospite che richieda trattamento immunosoppressivo.
4)Precedente trattamento con un agente ipometilante (incluso il trattamento precedente per MDS con decitabina e azazitidina).
5)Precedente trattamento con anticorpi CD33.
6)Tumore maligno secondario che attualmente richieda terapia attiva (con l’eccezione del trattamento ormonale/anti-ormonale, per esempio nel cancro della prostata o della mammella).
7)Presenza di sintomi clinici del sistema nervoso centrale (SNC) che, secondo il giudizio dello sperimentatore, siano correlati al coinvolgimento leucemico del SNC (non è richiesta la puntura lombare, è sufficiente la valutazione clinica dello sperimentatore).
8)Aspartato amino transferasi (AST) o alanina amino transferasi (ALT) maggiore di 2.5 volte il limite superiore di normalità (ULN) o AST o ALT maggiore di 5 volte ULN per i pazienti con sindrome di Gilbert.
9)Tempo di protrombina > 1.5 volte ULN per i pazienti che non siano in terapia con antagonisti della vitamina K (phenprocoumon, varfarin).
10)Bilirubina totale = 1.5 mg/dL (>26 µmol/L) a meno che l’aumento non sia dovuto a infiltrazione epatica della LMA, a sindrome Gilbert, o a emolisi.
11)Creatinina sierica = 2.0 mg/dL.
12)Presenza di malattia concomitante intercorrente, o qualsiasi altra condizione che nell’opinione dello sperimentatore, possa compromettere la sicurezza durante la partecipazione allo studio, per esempio infezione grave attiva, angina pectoris instabile, nuova insorgenza di esacerbazione di aritmia cardiaca.
13)Malattia psichiatrica o stato sociale che, nell’opinione dello sperimentatore, possa limitare la compliance con i requisiti richiesti dallo studio.
14)Nota infezione da HIV o infezione virale attiva di epatitie B o epatite C. Pazienti con qualunque evidenza sierologica di presente o pregressa esposizione all’epatite B devono essere esclusi a meno che i finding sierologici non siano chiaramente riconducibili alla vaccinazione.
15)Pazienti in gravidanza o che allattino.
16)Pazienti di sesso femminile potenzialmente fertili che siano sessualmente attive e non acconsentano ad utilizzare un metodo di contraccezione clinicamente accettabile durante lo studio e per almeno 6 mesi dopo la conclusione del trattamento sperimentale [associazione di due metodi di contraccezione efficaci (contraccezione ormonale, dispositivo intrauterino, cerotto contraccettivo transdermico, contraccettivi impiantabili o inettabili, occlusione bilaterale delle tube, etc.)].
Le pazienti potenzialmente fertili sono definite come donne che:
a)abbiano avuto il menarca e
b)non siano in postmenopausa (12 mesi senza mestruazioni in assenza di un’altra causa clinica) e
c)non siano sterilizzate in modo permanente (isterectomia, ovariectomia bilaterale o salpingectomia bilaterale)
17)Pazienti di sesso maschile con partner potenzialmente fertili che non acconsentano ad utilizzare preservativi in associazione a un secondo metodo di contraccezione clinicamente accettabile durante lo studio e per almeno 6 mesi dopo il completamento del trattamento sperimentale.
18)Trattamento con un altro agente sperimentale sotto le seguenti condizioni:
a)Entro 2 settimane (per agenti biologici 4 settimane o 5 emivite, la più lunga delle due) dalla prima somministrazione di BI 836858; o
b)Paziente che abbia tossicità persistenti dalle precedenti terapie anti-leucemiche, che siano giudicate rilevanti dallo sperimentatore.
c)Trattamento concomitante con un’altra molecola sperimentale durante la partecipazione a questo studio.
19)Nota ipersensibilità ai farmaci sperimentali.
20)Pazienti incapaci o che non accettino di essere complianti con il protocollo.

E.5 End points

E.5.1

Primary end point(s)

1: Phase I: MTD of BI 836858 in combination with decitabine
2: Phase I: Number of patients with dose limiting toxicity (DLT(s))
during first treatment cycle
3: Phase II:Number of patients with objective response combining
- Complete remission (CR)
- CR with incomplete blood count recovery (CRi)

Endpoint primari (Fase I):
1) Dose massima tollerata (MTD) di BI836858 in combinazione con decitabina.
2) Numero di pazienti con tossicità dose-limitante (DLT) per BI 836858 in combinazione con decitabina durante il Ciclo 1.
Endpoint primario (Fase II):
3) Numero di pazienti con risposta oggettiva, combinando:
- Remissione Completa (CR)
- CR con incomplete blood count recovery (Cri)

E.5.1.1

Timepoint(s) of evaluation of this end point

1: 12 months
2: 12 months
3: 30 months

1) 12 mesi
2) 12 mesi
3) 30 mesi

E.5.2

Secondary end point(s)

1: Phase I: Number of patients with objective response combining
- Complete remission (CR)
- CR with incomplete blood count recovery (CRi)
2: Phase II:
- Event free survival (EFS)
3: Phase II:
- Relapse free survival (RFS)
4: Phase II:
- Remission duration
5: Phase II:
- Time to remission

Endpoint secondario (Fase I):
1) numero di pazienti con risposta obiettiva (CR+Cri)
Endpoint secondari (Fase II):
2) Sopravvivenza libera da eventi (EFS)
3) Sopravvivenza libera da recidiva (RFS)
4) Durata della remissione
5) Tempo alla remissione

E.5.2.1

Timepoint(s) of evaluation of this end point

1: 30 months
2: 30 months
3: 30 months
4: 30 months
5: 30 months

1) 30 mesi
2) 30 mesi
3) 30 mesi
4) 30 mesi
5) 30 mesi

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

Dose finding trial

determinazione della dose

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

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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

Yes

E.8.2.3.1

Comparator description

Tutti i pazienti riceveranno decitabina come "standard care" (backbone chemotherapy)

All patients will receive treatment with decitabine as standard of care (backbone chemotherapy)

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

Belgium

France

Germany

Italy

Spain

United States

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

The end of the trial will be defined as when the following have
occurred:
1. All randomized patients have discontinued trial drug
2. The last patient has completed the EoR visit

La fine della sperimentazione sar¿ quando:
1. Tutti i pazienti randomizzati hanno interrotto il farmaco sperimentale
2. L'ultimo paziente ha completato la visita EoR

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

145

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

150

F.4.2.2

In the whole clinical trial

200

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)

The patients will be treated according to local standard care by their investigators after they terminated the trial.

Trattamento in accordo alle cure standard locali

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

2017-11-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-09-12

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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