Clinical Trials Register

Summary
EudraCT Number:	2017-004714-25
Sponsor's Protocol Code Number:	REALIB-LLA-2017
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-05-21
Trial 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

Spain - AEMPS

A.2

EudraCT number

2017-004714-25

A.3

Full title of the trial

Phase I-II trial, open and nonrandomized, to assess the role of Idelalisib in patients with acute lymphoblastic leukemia (ALL) relapsed or refractory to other treatments, and in elderly patients with ALL in which it is advised against the use of conventional therapies

Ensayo en fase I-II, sin enmascaramiento y no aleatorizado, para evaluar el papel de Idelalisib en pacientes con leucemia linfoblástica aguda (LLA) en recaída o refractarios a otros tratamientos, y en pacientes ancianos con LLA en los que se desaconseja el uso de terapias convencionales

A.3.1

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

Clinical trial to assess the role of Idelalisib in patients with acute lymphoblastic leukemia (ALL) relapsed or refractory to other treatments, and in elderly patients with ALL in which it is advised against the use of conventional therapies

Ensayo para evaluar el papel de Idelalisib en pacientes con leucemia linfoblástica aguda (LLA) en recaída o refractarios a otros tratamientos, y en pacientes ancianos con LLA en los que se desaconseja el uso de terapias convencionales

A.3.2

Name or abbreviated title of the trial where available

REALIB

A.4.1

Sponsor's protocol code number

REALIB-LLA-2017

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	Fundación PETHEMA
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Fundación PETHEMA
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fundación PETHEMA
B.5.2	Functional name of contact point	Dr. Juan José Lahuerta Palacios
B.5.3	Address:
B.5.3.1	Street Address	Hospital Clínico San Carlos 2ª Sur Hematología - C/ Profesor Martín Lagos s/n
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28040
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34 91 779 28 76
B.5.5	Fax number	+34 91 330 33 12
B.5.6	E-mail	pethema@pethema.es

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	Yes
D.2.1.1.1	Trade name	Zydelig
D.2.1.1.2	Name of the Marketing Authorisation holder	Zydelig
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	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	IDELALISIB
D.3.9.1	CAS number	870281-82-6
D.3.9.4	EV Substance Code	SUB126168
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	100 to 300
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 lymphoblastic leukemia

Leucemia linfoblástica aguda

E.1.1.1

Medical condition in easily understood language

Acute lymphoblastic leukemia

Leucemia linfoblástica aguda

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	LLT
E.1.2	Classification code	10000845
E.1.2	Term	Acute lymphoblastic 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

We intend to verify the hypothesis that Idelalisib could constitute a new therapeutic alternative for patients with ALL in a series of particularly complex cases: relapse, refractoriness to conventional treatments and old age. For this reason, the main objective is the determination of the overall response rate [GFR, defined as complete response (CR) or CR with partial hematological recovery (RCh)] and the duration of the response (RD) in adult patients with ALL. in relapse, refractory or in elderly people unfit to be treated with conventional therapies.

Se pretende verificar la hipótesis de que Idelalisib podría constituir una nueva alternativa terapéutica para pacientes con LLA en una serie de supuestos particularmente complejos: recaídas, refractariedad a tratamientos convencionales y ancianidad. Por tal motivo, el objetivo principal es la determinación de la tasa de respuesta global [TRG, definida como respuesta completa (RC) o RC con recuperación hematológica parcial (RCh)] y la duración de la respuesta (DR) en pacientes adultos con LLA en recaída, refractaria o en ancianos no aptos para ser tratados con terapias convencionales.

E.2.2

Secondary objectives of the trial

• Determine the GRT in different subgroups of ALL (Ph + and Ph-).
• Determine disease-free survival (SLE).
• Determine overall survival (SG).
• Value the safety of the treatment.

• Determinar la TRG en distintos subgrupos de LLA (Ph+ y Ph-).
• Determinar la supervivencia libre de enfermedad (SLE).
• Determinar la supervivencia global (SG).
• Valorar la seguridad del tratamiento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥18 years.
2. ALL of B cell precursors, in any of the following cases:
a) Second or subsequent relapses [including relapse after transplantation of hematopoietic progenitors (TPH)], in patients not candidates for a later TPH.
b) Resistance to at least two treatment lines. Treatment line is understood as initial treatment and rescue treatment after first relapse (which may include HSCT).
c) Elderly patients (age> 65 years) in whom standard therapies are clinically discouraged.
3. In patients with Ph + ALL, failure after receiving at least two treatments with different TKI (tyrosine kinase inhibitors): imatinib, dasatinib or ponatinib, in patients not candidates for a later TPH
4. ECOG between 0 and 2.
5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values <2 times the upper limit of normal (ULN) and total bilirubin <2 mg / dL.
6. Creatinine <2 mg / dL.
7. More than 10% of blasts in the bone marrow in the two weeks prior to the start of the trial.
8. Negative pregnancy test

1. Edad ≥18 años.
2. LLA de precursores de células B, en cualquiera de los siguientes supuestos:
a) Segunda o ulteriores recaídas [incluyendo recaída tras trasplante de progenitores hematopoyéticos (TPH)], en pacientes no candidatos a un ulterior TPH.
b) Resistencia a, al menos, dos líneas de tratamiento. Se entiende como línea de tratamiento el tratamiento inicial y el tratamiento de rescate tras primera recaída (que puede incluir el TPH).
c) Pacientes ancianos (edad >65 años) en los que se desaconsejen clínicamente las terapias estándar.
3. En pacientes con LLA Ph+, fracaso después de recibir al menos dos tratamientos con diferentes TKI (inhibidores de la tirosincinasa): imatinib, dasatinib o ponatinib, en pacientes no candidatos a un ulterior TPH
4. ECOG entre 0 y 2.
5. Valores de aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) < 2 veces el límite superior de la normalidad (LSN) y bilirrubina total < 2 mg/dL.
6. Creatinina < 2 mg/dL.
7. Más del 10% de blastos en médula ósea en las dos semanas previas al comienzo del ensayo.
8. Test de embarazo negativo

E.4

Principal exclusion criteria

1. Isolated relapse in the central nervous system.
2. Patients in whom a TPH is planned.
3. Active infection.
4. Active grade II-IV diarrhea.
5. Active grade II-IV hepatic toxicity.
6. Having previously received treatment with other PI3K / mTOR inhibitors.
7. Being, at the time of entry into the trial, receiving another experimental drug. The inclusion of patients who have completed the 4 week washout period will be allowed.
8. Be, at the time of entry into the trial, receiving other antineoplastic drugs (except for patients who are being treated with hydroxyurea or glucocorticoids, which will be allowed to use up to 24 hours before the start of therapy with Idelalisib).
9. Patients being treated with inhibitors or inducers of CYP3A4, whether they have a moderate or potent effect.
10. Patients with Stevens-Johnson syndrome and toxic epidermal necrolysis.
11. Patients with chronic active hepatitis including viral hepatitis.
12. Patients with HIV.

1. Recaída aislada en el sistema nervioso central.
2. Pacientes en los que esté previsto efectuar un TPH.
3. Infección activa.
4. Diarrea activa de grado II-IV.
5. Toxicidad hepática activa de grado II-IV.
6. Haber recibido previamente tratamiento con otros inhibidores de PI3K/mTOR.
7. Estar, en el momento de la entrada en el ensayo, recibiendo otro fármaco experimental. Se permitirá la inclusión de pacientes que hayan cumplido el periodo de lavado de 4 semanas.
8. Estar, en el momento de la entrada en el ensayo, recibiendo otros fármacos antineoplásicos (a excepción de los pacientes que estén siendo tratados con hidroxiurea o glucocorticoides, en los que se permitirá su uso hasta 24 horas antes del comienzo de la terapia con Idelalisib).
9. Pacientes que estén siendo tratados con inhibidores o inductores de CYP3A4, sean éstos de efecto moderado o potente.
10. Pacientes con Síndrome de Stevens-Johnson y necrólisis epidérmica tóxica.
11. Pacientes con hepatitis crónica activa incluyendo hepatitis vírica.
12. Pacientes con VIH.

E.5 End points

E.5.1

Primary end point(s)

• Percentage of patients that reach the TRG, defined as CR and RCh.
• DR in adult patients with R / R ALL or in elderly patients with ALL not suitable to be treated with conventional therapies.

• Porcentaje de pacientes que alcanzan la TRG, definida como RC y RCh.
• DR en pacientes adultos con LLA R/R o en pacientes ancianos con LLA no aptos para ser tratados con terapias convencionales.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 meses

E.5.2

Secondary end point(s)

• TRG in different subgroups of ALL (Ph + and Ph-).
• SLE.
• SG.
• Treatment safety degree

• TRG en distintos subgrupos de LLA (Ph+ y Ph-).
• SLE.
• SG.
• Grado de seguridad del tratamiento

E.5.2.1

Timepoint(s) of evaluation of this end point

6 months

6 meses

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

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

Dosage response for new indication

Dosis respuesta para nueva indicación

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.8.3

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LPLV

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

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:

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.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)

According to clinical practice

Acorde a práctica clínica

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

2018-07-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-20

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-06-02

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