Clinical Trials Register

Summary
EudraCT Number:	2016-004707-32
Sponsor's Protocol Code Number:	IMPROVE(PS-CLL-002)
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-06-01
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

2016-004707-32

A.3

Full title of the trial

A Multi-Center, Open Label, Uncontrolled, Phase 2a Clinical Trial Evaluating the Safety and Efficacy of the Addition of Ibrutinib to Venetoclax through a MRD-guided Approach in Relapsed/Refractory Patients with Chronic Lymphocytic Leukemia (CLL)

Studio clinico multicentrico, in aperto, non controllato, di Fase 2a per valutare la sicurezza e l'efficacia dell'aggiunta di Ibrutinib a Venetoclax in base ad un approccio guidato dalla malattia minima residua (MRD) in pazienti con leucemia linfatica cronica (CLL) recidivata/refrattaria

A.3.1

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

Clinical trial with Ibrutinib and Venetoclax for patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Studio Clinico con Ibrutinib e Venetoclax per pazienti con Leucemia Linfatica Cronica Recidivante o Refrattaria

A.3.2

Name or abbreviated title of the trial where available

IMPROVE (PS-CLL-002)

A.4.1

Sponsor's protocol code number

IMPROVE(PS-CLL-002)

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	OSPEDALE SAN RAFFAELE
B.1.3.4	Country	Italy
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	Abbvie
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	ospedale san raffaele
B.5.2	Functional name of contact point	ufficio data management
B.5.3	Address:
B.5.3.1	Street Address	via Olgettina 60
B.5.3.2	Town/ city	MILANO
B.5.3.3	Post code	20132
B.5.3.4	Country	Italy
B.5.4	Telephone number	0226433919
B.5.5	Fax number	0226432611
B.5.6	E-mail	scarano.eloise@hsr.it

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	EU/3/12/1080
D.3 Description of the IMP
D.3.1	Product name	VENETOCLAX
D.3.2	Product code	[ABT-199]
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	ABT-199
D.3.9.4	EV Substance Code	SUB176260
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	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: 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	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	EU/3/12/1080
D.3 Description of the IMP
D.3.1	Product name	VENETOCLAX
D.3.2	Product code	[ABT-199]
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	ABT-199
D.3.9.4	EV Substance Code	SUB176260
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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: 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	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	EU/3/12/1080
D.3 Description of the IMP
D.3.1	Product name	VENETOCLAX
D.3.2	Product code	[ABT-199]
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	ABT-199
D.3.9.4	EV Substance Code	SUB176260
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Relapsed or Refractory Chronic Lymphocytic Leukemia

Leucemia Linfatica Cronica Recidivante o Refrattaria

E.1.1.1

Medical condition in easily understood language

Chronic Lymphocytic Leukemia relapsed or refractory to previous treatments

Leucemia Linfatica Cronica ricaduta o non responsiva ai trattamenti precedenti

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

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	10008957
E.1.2	Term	Chronic lymphatic leukemia
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of the addition of ibrutinib to venetoclax in terms of minimal residual disease (MRD) negativity in patients with relapsed/refractory CLL

Valutare l’efficacia dell’aggiunta di ibrutinib a venetoclax in termini di negatività per la malattia minima residua (MRD) in pazienti con leucemia linfatica cronica (CLL) recidivata/refrattaria

E.2.2

Secondary objectives of the trial

1) To evaluate the safety of the addition of ibrutinib to venetoclax in patients with relapsed/refractory CLL
2) To evaluate the efficacy of the addition of ibrutinib to venetoclax in terms of overall response rate, partial and complete response rate, progression-free survival, duration of response and overall survival in patients with relapsed/refractory CLL

1) Valutare la sicurezza dell’aggiunta di ibrutinib a venetoclax in pazienti con CLL recidivate/refrattaria
2) Valutare l’efficacia dell’aggiunta di ibrutinib a venetoclax in termini di risposta complessiva (overall response rate, ORR), risposte complete e parziali, sopravvivenza libera da progressione, durata della risposta e sopravvivenza complessiva in pazienti con CLL recidivata/refrattaria

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Documented CLL requiring treatment according to the IWCLL criteria (Hallek et al. 2008)
2. Relapsed/refractory CLL patients who received at least 1 prior therapy
3. Adequate bone marrow function without transfusion < 2 weeks of screening as follows:
a. Absolute neutrophil count (ANC) =1.0 x 109/L (growth factors administration is allowed)
b. Platelets =30 x 109/L. If thrombocytopenia due to BM involvement, platelets should be = 20 x 109/L
c. Hemoglobin value =8.0 g/dl

1. CLL documentata che richiede trattamento secondo i criteri IWCLL (Hallek et al. 2008)
2. Pazienti con CLL recidivate/refrattaria che hanno ricevuto almeno una linea di trattamento
3. Adeguata funzione midollare senza support trasfusionale a < 2 settimane di screening come riportato di seguito:
a. Conta assoluta dei neutrofili (ANC) =1.0 x 109/L (consentita la somministrazione di G-CSF)
b. Piastrine =30 x 109/L. Se la piastrinopenia è secondaria al coinvolgimento midollare da parte della malattia, le piastrine dovrebbero essere = 20 x 109/L
c. Valore di emoglobina =8.0 g/dl

E.4

Principal exclusion criteria

1. Transformation of CLL to aggressive NHL (Richter’s transformation or pro-lymphocytic leukemia)
2. Known central nervous system (CNS) involvement
3. Inadequate renal function: CrCl <30 mL/min
4. Previous treatment with BTK and/or BCL2 inhibitors (patients previously treated with PI3K inhibitors are eligible)
5. Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
6. Requires the use of warfarin, marcumar, or phenprocoumon (potential drug-drug interaction increasing exposure of warfarin or phenprocoumon): low molecular weight drugs e.g. heparin are acceptable
7. Treatment, administration or consumption of any of the following within 3 days prior to the first dose of venetoclax (see also Appendix G).

a. Strong Cytochrome P450 3A (CYP3A) inhibitors
b. Moderate CYP3A inhibitors
c. Moderate or strong CYP3A inducers
d. PI3K inhibitors (e.g. Idelalisib);
e. Grapefruit or grapefruit products
f. Seville oranges (including marmalade containing Seville oranges)
g. Star fruit
8. Known history of human immunodeficiency virus (HIV) or active with hepatitis B virus (HBV) or hepatitis C virus (HCV). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
9. History of other malignancies, except:
a. Malignancy treated with curative intent and with no known active disease present for =3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
c. Adequately treated carcinoma in situ without current evidence of disease.

1. Trasformazione della CLL a linfoma non Hodgkin (NHL) aggressivo (trasformazione di Richter o leucemia prolinfocitica)
2. Noto coinvolgimento del sistema nervosa centrale (CNS)
3. Inadeguata funzione renale: CrCl <30 mL/min
4. Precedente trattamento con inibitori di BTK e/o BCL2 (sono eleggibili i pazienti trattati in precedenza con inibitori di PI3K)
5. Anemaia emaolitica autoimmune o piastrinopenia autoimmune non controllata
6. Necessità di terapia con warfarin, marcumar, o fenprocumone (potenziali interazioni farmacologiche con aumentata esposizione al warfarin o fenprocumone): eparine a basso peso molecolare sono accettabili
7. Trattamento, somministrazione o consumo nei 3 giorni precedenti la prima dose di venetoclax di uno o più dei seguenti farmaci (vedi anche Appendice G).

a. Forti inibitori del citocromo P450 3A (CYP3A)
b. Moderati inibitori del CYP3A
c. Moderati o forti induttori del CYP3A
d. Inibitori della PI3K (e.g. Idelalisib);
e. Pompelmo o prodotti contenenti pompelmo
f. Arance di Siviglia (comprese marmellate contenenti arance di Siviglia)
g. Star fruit
8. Nota anamnesi positiva per infezione da virus dell’immunodeficienza umana (HIV) o infezione attiva da virus dell’epatite B (HBV) o dell’epatite (HCV). Soggetti che sono positivi per l’anticorpo per l’antigene core dell’epatite B, l’antigene Australia o gli anticorpi per l’epatite C devono avere un risultato della polymerase chain reaction (PCR) negativo prima dell’arruolamento. I pazienti con PCR positive verranno esclusi.
9. Anamnesi positiva per altri tumori, fatta eccezione per:
a. Neoplasia trattata con intento curativo ed assenza di segni di malattia attiva per =3 anni prima della prima dose del farmaco e ritenuti a basso rischio di recidiva da parte del medico curante.
b. Tumore cutaneo non melanomatoso o lentigo maligna senza evidenza di malattia.
c. Carcinoma in situ adeguatamente trattato senza attuale evidenza di malattia.

E.5 End points

E.5.1

Primary end point(s)

¿ Minimal residual disease (MRD) negativity rate evaluated by multi-colour flow cytometry analysis (limit of detection 10-4) within the treatment period

Percentuale di negatività per la MRD valutata con citofluorimetria multicolor (limite di rilevamento 10-4) all’interno del periodo di trattamento

E.5.1.1

Timepoint(s) of evaluation of this end point

during treatment period

durante il periodo di trattamento

E.5.2

Secondary end point(s)

1) Complete response (CR) rate
2) Progression-free survival (PFS) rate at 12 months
3) PFS
4) Overall response rate (ORR)
5) Duration of response (DOR)
6) Overall Survival (OS);
7) Safety [type, frequency, and severity of adverse events (AEs) and relationship of AEs], premature withdrawals.

1)Percentuale di risposte complete (CR) rate
2)Percentuale di sopravvivenza libera da progressione (PFS) a 12 mesi
3) PFS
4) Percentuale di risposte globali (ORR)
5) Durata della risposta (DOR)
6) Sopravvivenza globale (OS);
7) Sicurezza [tipo, frequenza, e gravità degli eventi avversi (AEs) e correlazione degli AEs], interruzioni precoci.

E.5.2.1

Timepoint(s) of evaluation of this end point

during treatment period and follow up

durante il periodo di trattamemtno e di follow up

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

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

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)

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

84 months (7 years)

84 mesi (7 anni)

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

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

not applicable

non applicabile

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

2017-05-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-09

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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IMP with orphan designation in the indication
Orphan Designation Number:
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