Clinical Trials Register

Summary
EudraCT Number:	2019-000111-84
Sponsor's Protocol Code Number:	ACE-LY-003
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-05-24
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2019-000111-84

A.3

Full title of the trial

An Open-label, Phase 1b/2 Study of Acalabrutinib Alone or in Combination Therapy in Subjects with B-cell Non-Hodgkin Lymphoma

Studio di fase 1b/2, in aperto di acalabrutinib in monoterapia o in associazione in soggetti con linfoma non Hodgkin a cellule B

A.3.1

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

A study of Acalabrutinib alone, or in combination with Rituximab and Lenalidomide for subjects with B-cell Non Hodgkin Lymphoma

Studio di acalabrutinib da solo o in associazione con Rituximab e Lenalidomidein soggetti con linfoma non Hodgkin a cellule B

A.3.2

Name or abbreviated title of the trial where available

ACE-LY-003

A.4.1

Sponsor's protocol code number

ACE-LY-003

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02180711

A.5.4

Other Identifiers

Name:

IND number

Number:

118717

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 BV
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	Acerta Pharma BV
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Acerta Pharma BV
B.5.2	Functional name of contact point	ACE-LY-003 Clinical Team
B.5.3	Address:
B.5.3.1	Street Address	Kloosterstraat 9
B.5.3.2	Town/ city	Oss
B.5.3.3	Post code	5349 AB
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	5912800
B.5.5	Fax number	5912816
B.5.6	E-mail	ace-ly-003@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	No
D.2.5.1	Orphan drug designation number
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	SUB-182073
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.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	MabThera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
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	Rituximab
D.3.2	Product code	[Rituximab]
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.3.9.2	Current sponsor code	Rituximab
D.3.9.4	EV Substance Code	SUB12570MIG
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	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	Yes
D.3.11.13.1	Other medicinal product type	Chimeric/murine/human monoclonal antibody
D.IMP: 3
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	Revlimid®
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe B.V. Netherlands
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/868 (DBCL) & EU/3/12/1097 (FL)
D.3 Description of the IMP
D.3.1	Product name	Revlimid®
D.3.2	Product code	[Revlimid®]
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	Lenalidomide
D.3.9.1	CAS number	191732-72-6
D.3.9.2	Current sponsor code	Lenalidomide
D.3.9.4	EV Substance Code	SUB25389
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	10
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.IMP: 4
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	Revlimid®
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe B.V. Netherlands
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/868 (DBCL) & EU/3/12/1097 (FL)
D.3 Description of the IMP
D.3.1	Product name	Revlimid
D.3.2	Product code	[Revlimid]
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	LENALIDOMIDE
D.3.9.1	CAS number	191732-72-6
D.3.9.2	Current sponsor code	Revlimid
D.3.9.4	EV Substance Code	SUB25389
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	15
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

B-cell Non-Hodgkin Lymphoma

Linfoma Non-Hodgkin a cellule B

E.1.1.1

Medical condition in easily understood language

B-cell Non-Hodgkin Lymphoma

Linfoma Non-Hodgkin a cellule B

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10067070
E.1.2	Term	Follicular B-cell non-Hodgkin's lymphoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10076596
E.1.2	Term	Marginal zone lymphoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10012818
E.1.2	Term	Diffuse large B-cell lymphoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part 1/Primary Objective:
To characterize the safety profile of acalabrutinib alone or in combination with rituximab in subjects with R/R FL

Part 2/Primary Objective
To characterize the activity of acalabrutinib alone or in combination with rituximab in subjects with R/R MZL, as measured by ORR

Part 3 and Part 4/Primary Objective
To characterize the safety of acalabrutinib in combination with rituximab and lenalidomide in subjects with R/R FL or R/R non-GCB DLBCL

Parte 1/Obiettivo primario:
Caratterizzare il profilo di sicurezza di acalabrutinib in monoterapia o in combinazione con rituximab in soggetti con LF R/R

Parte 2/Obiettivo primario:
Caratterizzare l’attività di acalabrutinib in monoterapia o in combinazione con rituximab in soggetti con MZL R/R, misurata mediante ORR

Parte 3 e Parte 4/Obiettivo primario:
Caratterizzare la sicurezza di acalabrutinib in combinazione con rituximab e lenalidomide in soggetti con LF R/R o DLBCL non-GCB R/R

E.2.2

Secondary objectives of the trial

Part 1:
To characterize the safety profile of acalabrutinib in combination with rituximab in subjects with previously untreated FL,
To characterize the PK profile of acalabrutinib alone or in combination with rituximab,
To evaluate the PD effects of acalabrutinib alone or in combination with rituximab,
To evaluate the activity of acalabrutinib alone or in combination with rituximab as measured by ORR, duration of response (DOR), time-to-next treatment, and PFS.

Part 2:
To characterize the safety of acalabrutinib alone or in combination with rituximab in subjects with R/R MZL,
To evaluate the activity of acalabrutinib alone or in combination with rituximab in subjects with R/R MZL, Product: Acalabrutinib as measured by DOR, PFS, and overall survival (OS).

Part 3 and Part 4 :
To characterize the activity of acalabrutinib in combination with rituximab and lenalidomide in subjects with R/R FL or R/R non-GCB DLBCL as measured by ORR, DOR, PFS, and OS.

Parte 1:
Caratterizzare il profilo di sicurezza di acalabrutinib in combinazione con rituximab in soggetti con LF precedentemente non trattato
Caratterizzare il profilo di PK per acalabrutinib in monoterapia o in combinazione con rituximab
Valutare gli effetti PD per acalabrutinib in monoterapia o in combinazione con rituximab
Valutare l’attività di acalabrutinib in monoterapia o in combinazione con rituximab misurata mediante ORR, durata della risposta (DOR), tempo al trattamento successivo e PFS

Parte 2:
Caratterizzare la sicurezza di acalabrutinib in monoterapia o in combinazione con rituximab in soggetti con MZL R/R
Valutare l’attività di acalabrutinib in monoterapia o in combinazione con rituximab in soggetti con MZL R/R, misurata mediante DOR, PFS e sopravvivenza complessiva (OS)

Parte 3 e Parte 4:
Caratterizzare l’attività di acalabrutinib in combinazione con rituximab e lenalidomide in soggetti con LF R/R o DLBCL non-GCB R/R, misurata mediante ORR, DOR, PFS e OS

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Part 1
1. Men and women = 18 years of age.
2. Relapsed/Refractory Cohort
3. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy
4. Eastern Cooperative Oncology Group (ECOG) performance status of = 2.
5. Agreement to use highly effective forms of contraception
6. Men must agree to refrain from sperm donation during the study and for 12 months after the last dose of rituximab.

Part 2
1. Men and women = 18 years of age.
2. Histologically confirmed MZL including splenic, nodal, and extranodal sub-types
3. Previous therapy
4. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy.
5. ECOG performance status of = 2.
6. Women must agree to use highly effective methods of contraception during the study and for 2 days after the last dose of acalabrutinib or 12 months after the last dose of rituximab, whichever is longer, if sexually active and able to bear or beget children. Highly effective methods of contraception are defined in Section 3.6.6.

Part 3 and Part 4
1. Men and women = 18 years of age
2. For subjects with FL: Pathologically confirmed diagnosis of FL Grade 1, 2, or 3a, which has relapsed after, or been refractory to = 1 prior therapy for FL and which requires treatment per National Cancer Institute or ESMO clinical practice guidelines.
3. For subjects with non-GCB DLBCL: Pathologically confirmed de novo non-GCB DLBCL based on local IHC using Hans algorithm (Hans 2004) or else subjects must have available archival tissue for central pathology review to be eligible
4. Subjects must have previously received at least 1 frontline standard chemoimmunotherapy regimen.
5. Subjects with suspected residual disease after the treatment regimen directly preceding study enrollment must have biopsy-demonstrated residual FL or DLBCL.

Please, refer to the protocol for the rest of the inclusion criteria

Parte 1
1. Uomini e donne di età =18 anni.
2. Coorte recidivante/refrattaria
3. Presenza di linfoadenopatia radiograficamente misurabile o linfoma maligno extralinfonodale
4. Stato di performance =2 nella scala del Gruppo orientale cooperativo di oncologia (ECOG).
5. Consenso a utilizzare metodi contraccettivi altamente efficaci
6. I soggetti di sesso maschile devono astenersi dalla donazione di sperma durante lo studio e nei 12 mesi successivi all’ultima dose di rituximab.

Parte 2
1. Uomini e donne di età =18 anni.
2. LZM confermato istologicamente, compresi i sottotipi splenico, nodale ed extranodale
3. Terapia precedente
4. Presenza di linfoadenopatia radiograficamente misurabile o linfoma maligno extralinfonodale
5. Stato di validità =2 secondo la scala ECOG.
6. Le donne devono acconsentire a utilizzare metodi contraccettivi altamente efficaci durante lo studio e nei 2 giorni successivi all’ultima dose di acalabrutinib o 12 mesi successivi all’ultima dose di rituximab, a seconda di quale periodo duri di più, se il soggetto è sessualmente attivo e in grado di procreare o avviare una gravidanza.

Parte 3 e Parte 4
1. Uomini e donne di età =18 anni
2. Per i soggetti con LF: una diagnosi con conferma patologica di LF di grado 1, 2 o 3a che ha mostrato recidiva dopo o è risultato refrattario a =1 precedente terapia per LF e che richiede un trattamento secondo le linee guida di pratica clinica del National Cancer Institute o dell’ESMO.
3. Per i soggetti con linfoma diffuso a grandi cellule B (DLBCL) non a cellule B del centro germinale (non- GCB): DLBCL non-GCB de novo confermato mediante esame patologico in base all’analisi immunoistochimica (IHC) locale usando l’algoritmo di Hans (Hans 2004)
4. I soggetti devono aver precedentemente ricevuto almeno 1 regime chemioimmunoterapico standard di prima linea.
5. I soggetti con malattia residua sospetta dopo il regime di trattamento direttamente precedente all’arruolamento nello studio devono presentare LF o DLBCL residuo dimostrato mediante biopsia.

Fare riferimento al protocollo per l’elenco completo dei criteri di inclusione

E.4

Principal exclusion criteria

Part 1:
1. Prior malignancy (other than indolent B-cell NHL),
2. Known central nervous system (CNS) lymphoma or leptomeningeal disease.
3. A life-threatening illness, medical condition, or organ system dysfunction,
4. Known history of a bleeding diathesis ,
5. Significant cardiovascular disease

Part 2
1. Prior malignancy,
2. Known medically apparent CNS lymphoma or leptomeningeal disease.
3. Known evidence of transformation to another aggressive lymphoma.
4. A life-threatening illness, medical condition, or organ system dysfunction
5. Known history of a bleeding diathesis (eg, hemophilia, von Willebrand disease).

Part 3 and Part 4:
1. Prior malignancy ,
2. Subjects for whom the goal of therapy is tumor debulking before stem cell transplant.
3. Known history or presence of CNS lymphoma or leptomeningeal disease.
4. Transformed DLBCL or DLBCL with coexistent histologies

Please, refer to the protocol for the rest of the exclusion criteria

Parte 1
1. Precedente malignità (diversa da LNH a cellule B indolente)
2. Linfoma o malattia leptomeningea noto/a a carico del sistema nervoso centrale (SNC):
3. Una malattia, condizione medica o disfunzione d’organo potenzialmente letale
4. Anamnesi nota di una diatesi emorragica
5. Malattia cardiovascolare significativa,

Parte 2
1. Precedente malignità
2. Linfoma o malattia leptomeningea noto/a a carico del SNC evidente dal punto di vista medico.
3. Evidenza nota di trasformazione in un altro linfoma aggressivo.
4. Una malattia, condizione medica o disfunzione d’organo potenzialmente letale
5. Anamnesi nota di una diatesi emorragica

Parte 3 e Parte 4
1. Precedente malignità
2. Soggetti per i quali l’obiettivo della terapia consiste nella citoriduzione tumorale prima del trapianto di cellule staminali.
3. Anamnesi o presenza nota di linfoma o malattia leptomeningea del SNC.
4. DLBCL trasformato o DLBCL con istologie coesistenti

Fare riferimento al protocollo per l’elenco completo dei criteri di esclusione

E.5 End points

E.5.1

Primary end point(s)

Efficacy endpoints will include:
Part 1
- ORR
- DOR
- PFS
- Time-to-next treatment

Part 2, Part 3,Part 4
- ORR
- DOR
- PFS
- OS

Part 1
Pharmacokinetics
1. AUC0-t: Area under the plasma concentration-time curve calculated using linear trapezoidal summation.
2. AUC0-12: Area under the plasma concentration-time curve
3. AUC0-8: Area under the plasma concentration-time curve
4. AUC0-24calc: Area under the plasma concentration-time curve
5. Cmax: Maximum observed plasma concentration
6. Tmax: Time of the maximum plasma concentration
7. t½: Terminal elimination half-life
8. ¿z: Terminal elimination rate constant
9. CL/F: Oral clearance
10. Vz/F: Oral volume of distribution

Gli endpoint di efficacia includeranno:
Parte 1
- ORR
- DOR
- PFS
- Time-to-next treatment

Parte 2, Parte 3,Parte 4
- ORR
- DOR
- PFS
- OS

Parte 1
Farmacocinetica
1. AUC0-t: area sotto la curva concentrazione plasmatica-tempo calcolata utilizzando la somma trapezoidale lineare
2. AUC0-12: area sotto la curva concentrazione plasmatica-tempo
3. AUC0-8: area sotto la curva concentrazione plasmaticatempo
4. AUC0-24calc: area sotto la curva concentrazione plasmatica-tempo
5. Cmax: concentrazione plasmatica massima osservata
6. Tmax: tempo al raggiungimento della concentrazione plasmatica massima
7. t½: emivita di eliminazione
8. ¿z: costante della velocità di eliminazione terminale
9. CL/F: clearance orale
10. Vz/F: volume di distribuzione orale

E.5.1.1

Timepoint(s) of evaluation of this end point

Efficacy: Response assessments are done throughout the study but at least within 30 days
Part 1/PK
1. from time 0 to time t, where t is the time of the last measurable concentration (Ct).
2. from 0 to 12 hours, calculated using linear trapezoidal summation.
3. from 0 to infinity, calculated using the formula: AUC0-8 = AUC0-t + Ct / ¿z, where ¿z is the apparent terminal elimination rate constant.
4. from 0 to 24 hours, calculated by doubling the value for AUC0-12.
5. Cmax: Maximum observed plasma concentration
6. Tmax: Time of the maximum plasma concentration (obtained without interpolation)
7. t½: Terminal elimination half-life (whenever possible)
8. ¿z: Terminal elimination rate constant (whenever possible)

Efficacia
Valutazioni di risposta vengono eseguite durante tutto lo studio ma almeno entro 30 giorni dalla Parte 1/PK
1. dal tempo 0 al tempo t, dove t è il tempo dell’ultima concentrazione misurabile (Ct).
2. da 0 a 12 ore, calcolata utilizzando la somma trapezoidale lineare.
3. da 0 a infinito, calcolato usando la seguente formula: AUC0-8 = AUC0-t + Ct / ¿z, dove ¿z è la costante di velocità di eliminazione terminale apparente.
4. da 0 a 24 ore, calcolato il valore per AUC0-12.
5. Cmax: Concentrazione plasmatica massima osservata
6. Tmax: Tempo della concentrazione plasmatica massima (ottenuta senza interpolazione)
7. t½: Termine dell’emivita di eliminazione (quando possibile)
8. ¿z: Termine della costante di velocità di eliminazione (quando possibile)

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

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

Phase I

Fase I

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

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

Yes

E.8.1.7.1

Other trial design description

Il disegno del protocollo dello studio consiste attualmente di 4 parti. L’Italia parteciperà solo al

The study will be conducted in 4 Parts, Italy will only participate in Part 2, 3 and 4

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

Canada

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

120

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)

None

Nessuno

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

2020-02-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-01-22

P. End of Trial
P.	End of Trial Status	Ongoing

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Orphan Designation Number:
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