Clinical Trials Register

Summary
EudraCT Number:	2018-002443-28
Sponsor's Protocol Code Number:	ACE-CL-311/D8221C00001
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2019-01-24
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

2018-002443-28

A.3

Full title of the trial

A Randomized, Multicenter, Open-Label, Phase 3 Study to Compare the Efficacy and Safety of Acalabrutinib (ACP-196) in Combination with Venetoclax with and without Obinutuzumab Compared to Investigator’s Choice of Chemoimmunotherapy in Subjects with Previously Untreated Chronic Lymphocytic Leukemia Without del(17p) or TP53 Mutation

Ensayo fase 3, aleatorizado, multicéntrico y abierto para comparar la eficacia y seguridad de acalabrutinib (ACP-196) en combinación con venetoclax con y sin obinutuzumab, con la eficacia y seguridad de la quimioinmunoterapia elegida por el investigador en pacientes con leucemia linfocítica crónica sin mutación del(17p) o TP53, no tratada previamente

A.3.1

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

This study is being done to test the effectiveness and safety of an investigational drug called acalabrutinib (ACP-196) when taken with already marketed drugs called Venetoclax and Obinutzumab in comparison to chemotherapy that is already in wide use for treatment of patients who have chronic lymphocytic leukemia and who have never been treated before.

Este estudio se está realizando para comprobar la efectividad y seguridad de un medicamento en investigación llamado acalabrutinib (ACP-196) cuando se toma con medicamentos ya comercializados llamados Venetoclax y Obinutzumab en comparación con la quimioterapia que ya se usa ampliamente para el tratamiento de pacientes con Leucemia linfocítica crónica y que nunca antes han sido tratados.

A.3.2

Name or abbreviated title of the trial where available

Not available at this time

No disponible aún

A.4.1

Sponsor's protocol code number

ACE-CL-311/D8221C00001

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	Acerta Pharma B.V.
B.1.3.4	Country	Netherlands
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	AstraZeneca
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Acerta Pharma B.V.
B.5.2	Functional name of contact point	Cheng Quah, Medical Director
B.5.3	Address:
B.5.3.1	Street Address	121 Oyster Point Blvd
B.5.3.2	Town/ city	South San Francisco
B.5.3.3	Post code	94080
B.5.3.4	Country	United States
B.5.4	Telephone number	16505912800
B.5.6	E-mail	cheng.quah@acerta-pharma.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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/196/15
D.3 Description of the IMP
D.3.1	Product name	acalabrutinib
D.3.2	Product code	ACP-196
D.3.4	Pharmaceutical form	Capsule, hard
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	ACALABRUTINIB
D.3.9.1	CAS number	1420477-60-6
D.3.9.2	Current sponsor code	ACP-196
D.3.9.4	EV Substance Code	SUB182073
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
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	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	Gazyvaro
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
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.3.4	Pharmaceutical form	Concentrate for solution for infusion
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	obinutuzumab
D.3.9.1	CAS number	949142-50-1
D.3.9.3	Other descriptive name	OBINUTUZUMAB
D.3.9.4	EV Substance Code	SUB32751
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	1000
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	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	Yes
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	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	MABTHERA
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.3.4	Pharmaceutical form	Concentrate for solution for infusion
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	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.4	EV Substance Code	SUB12570MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	375, 500
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	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	Yes
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: 4
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.2.5	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	Powder for solution for injection/infusion
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	cyclophosphamide monohydrate
D.3.9.1	CAS number	50-18-0
D.3.9.3	Other descriptive name	CYCLOPHOSPHAMIDE MONOHYDRATE
D.3.9.4	EV Substance Code	SUB16414MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
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: 5
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.2.5	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
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	FLUDARABINE
D.3.9.1	CAS number	21679-14-1
D.3.9.4	EV Substance Code	SUB07678MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
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: 6
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	Venclyxto
D.2.1.1.2	Name of the Marketing Authorisation holder	AbbVie Deutschland GmbH & Co.KG
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.3.4	Pharmaceutical form	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.3.9.1	CAS number	1257044-40-8
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	up to
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: 7
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.2.5	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
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	BENDAMUSTINE HYDROCHLORIDE
D.3.9.1	CAS number	16506-27-7
D.3.9.4	EV Substance Code	SUB00696MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	90
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

Previously untreated Chronic Lymphocytic Leukemia Without del(17p) or TP53 Mutation

Leucemia linfocítica crónica sin mutación del (17p) o TP53 sin tratamiento previo

E.1.1.1

Medical condition in easily understood language

Previously untreated low-risk blood cancer

Cáncer de sangre de bajo riesgo no tratado previamente

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	10009310
E.1.2	Term	CLL
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

To evaluate the efficacy of acalabrutinib/venetoclax (AV; Arm A) compared with chemoimmunotherapy
(fludarabine/cyclophosphamide/rituximab [FCR]/ bendamustine/rituximab [BR]; Arm C)

Evaluar la eficacia de acalabrutinib/venetoclax (AV; grupo A) en comparación con quimioinmunoterapia (fludarabina/ ciclofosfamida/ rituximab [FCR] / bendamustina/ rituximab [BR]; grupo C)

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of acalabrutinib/venetoclax/obinutuzumab (AVG; Arm B) versus FCR/BR (Arm C)

To evaluate the efficacy of AV (Arm A) versus FCR/BR (Arm C) and AVG (Arm B) versus FCR/BR (Arm C)

Evaluar la eficacia de acalabrutinib/ venetoclax/ obinutuzumab (AVG; grupo B) en comparación con FCR/BR (grupo C)
Evaluar la eficacia de AV (grupo A) en comparación con FCR/BR (grupo C) y de AVG (grupo B) en comparación con FCR/BR (grupo C)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Men and women ≥18 years of age.
2.Eastern Cooperative Oncology Group (ECOG) performance status of 0–2.
3.Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018):
Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing B-cell marker (CD19, CD20, and CD23) and CD5.
Prolymphocytes may comprise <55% of blood lymphocytes.
Presence of ≥5x109 B lymphocytes/L (5000/µL) in the peripheral blood (at any point since the initial diagnosis).
4.Active disease per IWCLL 2018 criteria that requires treatment (see Section 4.5.6).
5.Meet the following laboratory parameters:
a) Adequate bone marrow function independent of growth factor or transfusion support within 1 week of Screening, as follows:
i.ANC ≥750 cells/μL (0.75x109/L); ANC ≥500 cells/μL (0.50x109/L) in subjects with documented bone marrow involvement of CLL
ii.Platelet count ≥50,000 cells/μL (50x109/L); platelet count ≥30,000 cells/μL (30x109/L) in subjects with documented bone marrow involvement of CLL
b)Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5xULN.
c)Total bilirubin ≤2xULN, unless directly attributable to Gilbert’s syndrome
d)Estimated creatinine clearance of ≥50 mL/min, calculated using the formula of Cockcroft and Gault (if male, [140Age] x Mass (kg) / [72 x creatinine mg/dL]; multiply by 0.85 if female); estimated creatinine clearance of ≥70 mL/min for subjects selected by investigator to receive FCR in Arm C

1.Varones y mujeres de 18 años o más de edad.
2.Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0-2.
3.Diagnóstico de LLC que cumpla los criterios diagnósticos publicados (Hallek et al. 2018):
Linfocitos B monoclonales (con restricción de cadenas ligeras kappa o lambda) con coexpresión clonal de marcadores de linfocitos B (CD19, CD20 y CD23) y CD5.
Los prolinfocitos podrán suponer < 55 % de los linfocitos sanguíneos.
Presencia de ≥ 5 x 109 linfocitos B/l (5000/µl) en sangre periférica (en cualquier momento desde el diagnóstico inicial).
4.Enfermedad activa según los criterios IWCLL 2018 que requiere tratamiento (véase la Sección 4.5.6).
5.Cumplimiento de los siguientes parámetros analíticos:
a.Función medular adecuada con independencia del apoyo con factores de crecimiento o transfusiones en la semana previa a la selección, tal como sigue:
i.RAN ≥ 750 células/µl (0,75 x 109/l); RAN ≥ 500 células/µl (0,50 x 109/l) en pacientes con afectación documentada de la médula ósea por la LLC.
ii.Recuento de plaquetas ≥ 50.000 células/µl (50 x 109/l); recuento de plaquetas ≥ 30.000 células/µl (30 x 109/l) en pacientes con afectación documentada de la médula ósea por la LLC.
b.Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) en suero ≤ 2,5 veces el LSN.
c.Bilirrubina total ≤ 2 veces el LSN, a menos que sea atribuible directamente a un síndrome de Gilbert.
d.Aclaramiento de creatinina estimado ≥ 50 ml/min, calculado con la fórmula de Cockcroft y Gault (en caso de ser varón, [140 x edad] x masa (kg) / [72 x creatinina mg/dl]; multiplicado por 0,85 en caso de ser mujer); aclaramiento de creatinina estimado ≥ 70 ml/min en los pacientes seleccionados por el investigador para recibir FCR en el grupo C.

E.4

Principal exclusion criteria

•Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisone daily are permitted).
•Detected del(17p) or TP53 mutation.
•Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL) (e.g., Richter’s transformation, PLL, or diffuse large B cell lymphoma [DLBCL]), or central nervous system (CNS) involvement by leukemia.
•Any comorbidity or organ system impairment rated with a single CIRS score of 4 (excluding the eyes/ears/nose/throat/larynx organ system), or a total CIRS score of >6.
•Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.
•History of confirmed progressive multifocal leukoencephalopathy (PML).
•Received any investigational drug within 30 days before first dose of study drug.
•Major surgical procedure within 30 days before the first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
•History of prior malignancy that could affect compliance with the protocol, or interpretation of results, except for the following:
•Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ of the prostate at any time prior to study.
•Other cancers not specified above which have been curatively treated by surgery and/or radiation therapy from which subject is disease-free for ≥3 years without further treatment.

•Cualquier tratamiento previo específico para la LLC (excepto el tratamiento con corticosteroides administrado por una intervención inmediata necesaria; en los 10 días previos al comienzo del tratamiento del ensayo solo se permitirá la administración de equivalentes de dosis de hasta 20 mg de prednisona al día).
•Mutación del(17p) o TP53 detectada.
•Transformación de la LLC en un linfoma no hodgkiniano (LNH) agresivo (por ejemplo, transformación de Richter, leucemia prolinfocítica [LPL] o linfoma difuso de linfocitos B grandes [LDLBG]) o afectación del sistema nervioso central (SNC) por la leucemia.
•Cualquier comorbilidad o deterioro de un sistema orgánico valorado con una puntuación CIRS (Escala de valoración acumulada de enfermedades) única de 4 (excluido el sistema orgánico de ojos, oídos, nariz, garganta y laringe) o una puntuación CIRS total > 6.
•Anemia hemolítica autoinmunitaria o púrpura trombocitopénica idiopática no controlada.
•Antecedentes de leucoencefalopatía multifocal progresiva (LMP) confirmada.
•Recepción de cualquier fármaco en investigación en los 30 días previos a la primera dosis del fármaco del ensayo.
•Intervención de cirugía mayor en los 30 días previos a la primera dosis del fármaco del ensayo. Nota: Si un paciente se ha sometido a una intervención de cirugía mayor, deberá haberse recuperado debidamente de cualquier toxicidad o complicación de la intervención antes de la primera dosis del fármaco del ensayo.
•Antecedentes de una neoplasia maligna previa que pueda afectar al cumplimiento del protocolo o a la interpretación de los resultados, excepto lo siguiente:
•Carcinoma basocelular o espinocelular de piel tratado con intención curativa o carcinoma in situ de cuello uterino o carcinoma de próstata in situ en cualquier momento antes del ensayo.
•Otros cánceres no especificados anteriormente que hayan sido tratados con intención curativa mediante cirugía, radioterapia o ambas, de los que el paciente haya permanecido sin enfermedad durante ≥ 3 años sin más tratamiento.

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival (PFS), defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the Independent Review Committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria.

Supervivencia sin progresión (SSP), definida como el tiempo transcurrido entre la aleatorización y el primer episodio de progresión de la enfermedad o la muerte por cualquier causa (lo que ocurra antes), según lo determinado por el comité de revisión independiente (CRI) conforme a los criterios IWCLL (International Workshop on ChronicLymphocytic Leukemia) 2018.

E.5.1.1

Timepoint(s) of evaluation of this end point

64 months

64 meses

E.5.2

Secondary end point(s)

1.PFS, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the IRC assessment according to the IWCLL 2018 criteria.
2.Overall response rate (ORR), defined as the proportion of subjects with a complete response (CR), complete response with incomplete marrow recovery (CRi), or partial response (PR) per the investigator and IRC assessment as per IWCLL 2018 criteria
3.Duration of objective response (DOR), defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause per the investigator and IRC assessment as per IWCLL 2018 criteria
4.Time to next Therapy (TTNT), defined as the time from randomization to institution of non-protocol specified treatment for chronic lymphocytic leukemia (CLL)
5.Minimal residual disease (MRD) negativity rate (determined as the proportion of subjects with MRD-negativity) measured in the peripheral blood by flow cytometry (10-4) at the start of Cycle 9 (in Arm A), the start of Cycle 10 (in Arm B), and 12 weeks after the start of Cycle 6 (in Arm C)
6.Overall survival (OS), defined as the time from randomization to death from any cause

1.SSP, definida como el tiempo transcurrido entre la aleatorización y el primer episodio de progresión de la enfermedad o la muerte por cualquier causa (lo que ocurra antes), según lo determinado por el CRI conforme a los criterios IWCLL 2018
2.Tasa de respuesta global (TRG), definida como la proporción de pacientes con una respuesta completa (RC), respuesta completa con recuperación incompleta de la médula ósea (RCi) o respuesta parcial (RP) según la evaluación del investigador y del CRI conforme a los criterios IWCLL 2018.
3.Duración de la respuesta objetiva (DRO), definida como el tiempo transcurrido entre el primer episodio de una respuesta objetiva documentada y la progresión de la enfermedad o la muerte por cualquier causa, según la evaluación del investigador y del CRI conforme a los criterios IWCLL 2018.
4.Tiempo hasta el siguiente tratamiento (THST), definido como el tiempo transcurrido entre la aleatorización y la instauración de un tratamiento no especificado en el protocolo para la leucemia linfocítica crónica (LLC).
5.Tasa de negatividad de enfermedad residual mínima (ERM) (determinada como la proporción de pacientes con negatividad de ERM) medida en sangre periférica mediante citometría de flujo (10-4) al comienzo del ciclo 9 (en el grupo A), al comienzo del ciclo 10 (en el grupo B) y 12 semanas después del comienzo del ciclo 6 (en el grupo C).
6.Supervivencia global (SG), definida como el tiempo transcurrido entre la aleatorización y la muerte por cualquier causa.

E.5.2.1

Timepoint(s) of evaluation of this end point

64 months

64 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

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

health status, biomarkers

Estado de salud, biomarcadores

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

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

Yes

E.8.2.3.1

Comparator description

FCR/BR

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

105

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

Argentina

Australia

Austria

Belgium

Brazil

Bulgaria

Canada

China

Czech Republic

Denmark

France

Germany

Hungary

Israel

Italy

Korea, Democratic People's Republic of

Netherlands

New Zealand

Poland

Saudi Arabia

South Africa

Spain

Sweden

Taiwan

Turkey

Ukraine

United Kingdom

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 study is defined as approximately 5 years after the last subject is randomized in the study (unless all subjects have died). The approximate length of the study will be 7 years calculated from an estimated 24-month recruitment period.

El final del estudio se define como aproximadamente 5 años después de que el último sujeto sea randomizado en el estudio (a menos que todos los sujetos hayan fallecido). La duración aproximada del estudio será de 7 años calculada a partir de un período de reclutamiento estimado de 24 meses

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:

280

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

500

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

350

F.4.2.2

In the whole clinical trial

780

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 sponsor will offer post-study access to acalabrutinib free of charge in accordance with the AstraZeneca Global Policy on Early Access to IMP. Subject must meet all of the following eligibility criteria:
•The subject is suffering from a serious or life-threatening disease and has exhausted all available therapeutic options.
•medical status is deemed appropriate to receive the study drug.
•must be able to routinely travel to the clinic site for monitoring and follow up as required.

Sponsor ofrecerá acceso al post-estudio de acalabrutinib gratuitamente de acuerdo con la Política global de AZ sobre acceso temprano a IMP. El sujeto debe cumplir todos los siguientes criterios de elegibilidad:
• padecer enfermedad grave o potencialmente mortal y haber agotado todas opciones terapéuticas disponibles.
• estado médico considerado apropiado para recibir el medicamento del estudio.
• capaz de viajar rutinariamente a sitio clínico para monitorización y seguimiento según necesidad.

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

2019-05-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-04-11

P. End of Trial
P.	End of Trial Status	Restarted

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