Clinical Trials Register

Summary
EudraCT Number:	2020-004409-30
Sponsor's Protocol Code Number:	PS-CLL-009
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:	2021-08-02
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

2020-004409-30

A.3

Full title of the trial

Venetoclax and delayed rituximab with ibrutinib consolidation aiming at undetectable minimal residual disease (uMRD) in treatment-naïve patients with chronic lymphocytic leukemia (CLL)

Venetoclax associato a rituximab ritardato e consolidamento con ibrutinib finalizzati alla malattia minima residua non rilevabile (uMRD) in pazienti con leucemia linfatica cronica (CLL) naïve al trattamento

A.3.1

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

Treatment with venetoclax consolidated with ibrutinib and rituximab to increase the possibility of minimal residual disease in patient with chronic lymphotic leukemia

Trattamento con venetoclax consolidato con ibrutinib e rituximab per aumentare possibilità di malattia minima residua in paziente con leucemia linfatica cronica

A.3.2

Name or abbreviated title of the trial where available

VALUABLE

A.4.1

Sponsor's protocol code number

PS-CLL-009

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	Programma di Ricerca Strategica sul
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	0226434797
B.5.5	Fax number	0226432611
B.5.6	E-mail	ghia.paolo@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	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.3.1	Product name	venclyxto
D.3.2	Product code	[venclyxto]
D.3.4	Pharmaceutical form	Modified-release 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.3.9.2	Current sponsor code	venetoclax
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	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

Previously Untreated Chronic Lymphophatic Leukaemia

Leucemia Linfatica Cronica non precedentemente trattata

E.1.1.1

Medical condition in easily understood language

Previously untreated low-risk blood cancer

Tumore del sangue a basso rischio, non precedentemente trattato

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	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

Evaluate the effectiveness of the sequential combination of venetoclax, delayed rituximab and ibrutinib in terms of minimal remaining undetectable disease (uMRD, <10-4) detected with 6-color cytofluorimetry in BM as the best response at any time during treatment up to 3 months after the completion of combined therapy

Valutare l'efficacia della combinazione sequenziale di venetoclax, rituximab ritardato e ibrutinib in termini di malattia minima residua non rilevabile (uMRD, <10-4) rilevata con citofluorimetria a 6 colori nel BM come migliore risposta in qualsiasi momento durante il trattamento fino a 3 mesi dopo il completamento della terapia combinata

E.2.2

Secondary objectives of the trial

Evaluate the effectiveness of the sequential combination of venetoclax, delayed rituximab and ibrutinib in terms of:
- uMRD detected with 6-color cytofluorytry in PB as the best response at any time during treatment up to 3 months after the completion of combined therapy
- Overall response (best response)
- Full answer, CR (best answer)
- Partial response, PR (best answer)
- Progression-free survival
- Global Survival

Valutare l'efficacia della combinazione sequenziale di venetoclax, rituximab ritardato e ibrutinib in termini di:
- uMRD rilevata con citofluorimetria a 6 colori nel PB come migliore risposta in qualsiasi momento durante il trattamento fino a 3 mesi dopo il completamento della terapia combinata
- Risposta complessiva (miglior risposta)
- Risposta completa, CR (miglior risposta)
- Risposta parziale, PR (miglior risposta)
- Sopravvivenza libera da progressione
- Sopravvivenza globale

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age =18 but <65 years
2. Active CLL/SLL requiring treatment according to iwCLL 2018 criteria
3. No previous CLL/SLL therapy
4. Appropriate medullary function:
a. ANC =1.0 x 109/L;
B. Plt =25 x 109/L;
c. Hb =8.0 g/dl

1. Età =18 anni ma <65 years
2. CLL/SLL attiva che richiede trattamento secondo i criteri iwCLL 2018
3. Nessuna precedente terapia per CLL/SLL
4. Funzione midollare adeguata:
a. ANC =1.0 x 109/L;
b. Plt =25 x 109/L;
c. Hb =8.0 g/dl

E.4

Principal exclusion criteria

1. Previous treatment for CLL/SLL
2. History of other malignant malignancies, except in situ carcinoma or malignant cancers treated with curative intent
3. Known story or suspected transformation of Richter
4. Hypersensitivity known to one or more drugs in the study
5. Inadequate kidney function: CrCl <30 ml/min
6. Autoimmune hemolytic anemia or uncontrolled autoimmune platelets
7. Need for warfarin or derivatives therapy
8. Treatment within 7 days before the first dose of the drug in the study with one of the following:
a. Steroid therapy with antineoplastic intent
B. Moderate or powerful cytochrome inhibitors P450 3A (CYP3A) (see Appendix G for examples)
C. Moderate or strong CYP3A inducers (see Appendix G for examples)
9. Administration or consumption of any of the following within 3 days before the first dose of the drug in the study:
a. Pompelmo or grapefruit products
B. Seville oranges (including jam containing Seville oranges)
c. Carambola
10. Known history of human immunodeficiency virus (HIV) or active infection with hepatitis B virus (HBV) or hepatitis C (HCV). Subjects who are positive for HBcAb, HBsAb or the hepatitis C antibody should have a negative result of the polymerase chain reaction (PCR) prior to enlistment. Those who test positive for PCR will be excluded.
11. Note hypersensitivity to one or more drugs in the study
12. Known hemorrhagic disorders (e.g. von Willebrand's disease) or haemophilia
13. History of stroke or intracranial bleeding in the 6 months prior to enlistment
14. Major surgery within 4 weeks of first dose of the drug in the study
15. Cardiovascular disease currently active and clinically significant such as uncontrolled arrhythmia or congestive heart failure of class 3 or 4 as defined by the functional classification of the New York Heart Association or a history of myocardial infarction, unstable angina

1. Precedente trattamento per CLL/SLL
2. Storia di altre neoplasie maligne, eccetto carcinoma in situ o neoplasie maligne trattate con intento curativo
3. Storia nota o sospetta trasformazione di Richter
4. Ipersensibilità nota a uno o più farmaci in studio
5. Funzione renale inadeguata: CrCl <30 ml/min
6. Anemia emolitica autoimmune o piastrinopenia autoimmune incontrollata
7. Necessità di terapia con warfarin o derivati
8. Trattamento entro 7 giorni prima della prima dose del farmaco in studio con uno dei seguenti:
a. Terapia steroidea con intento antineoplastico
b. Inibitori moderati o potenti del citocromo P450 3A (CYP3A) (vedere l'Appendice G per esempi)
c. Induttori moderati o forti del CYP3A (vedere l'Appendice G per esempi)
9. Somministrazione o consumo di uno qualsiasi dei seguenti entro 3 giorni prima della prima dose del farmaco in studio:
a. Pompelmo o prodotti a base di pompelmo
b. Arance di Siviglia (compresa la marmellata contenente arance di Siviglia)
c. Carambola
10. Storia nota di virus dell'immunodeficienza umana (HIV) o infezione attiva da virus dell'epatite B (HBV) o dell'epatite C (HCV). I soggetti che sono positivi per HBcAb, HBsAb o l'anticorpo dell'epatite C devono avere un risultato negativo della reazione a catena della polimerasi (PCR) prima dell'arruolamento. Saranno esclusi coloro che risultano positivi alla PCR.
11. Nota ipersensibilità a uno o più farmaci in studio
12. Disturbi emorragici noti (ad es. Malattia di von Willebrand) o emofilia
13. Storia di ictus o emorragia intracranica nei 6 mesi precedenti l'arruolamento
14. Intervento chirurgico maggiore entro 4 settimane dalla prima dose del farmaco in studio
15. Malattia cardiovascolare attualmente attiva e clinicamente significativa come aritmia incontrollata o insufficienza cardiaca congestizia di classe 3 o 4 come definita dalla classificazione funzionale della New York Heart Association o una storia di infarto miocardico, angina instabile

E.5 End points

E.5.1

Primary end point(s)

uMRD (<10-4) evaluated by 6-color cytofluorymetry in BM as the best response at any time during treatment up to 3 months after supplementation of combination therapy (VR or VR followed by VI)

uMRD (<10-4) valutata mediante citofluorimetria a 6 colori nel BM come migliore risposta in qualsiasi momento durante il trattamento fino a 3 mesi dopo il completamento della terapia combinata (VR o VR seguito da VI)

E.5.1.1

Timepoint(s) of evaluation of this end point

72 months

72 mesi

E.5.2

Secondary end point(s)

uMRD (<10-4) evaluated by 6-color cytofluorymetry in PB as the best response at any time during treatment up to 3 months after supplementation of combination therapy (VR or VR followed by VI)

uMRD (<10-4) valutata mediante citofluorimetria a 6 colori nel PB come migliore risposta in qualsiasi momento durante il trattamento fino a 3 mesi dopo il completamento della terapia combinata (VR o VR seguito da VI)

E.5.2.1

Timepoint(s) of evaluation of this end point

72 months

72 mesi

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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

stato di salute

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

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)

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)

The treatment in the study involves VENETOCLAX from cycle 1 to cycle 12 and Rituximab from cycle 7 to cycle 12. At the end of cycle 12 the disease status (MRD), kidney function and risk of bleeding will be assessed and based on the outcome of the reassessment the patient enters follow up or begins venetoclax 400 mg/die until (max 24 months) in combination with ibrutinib 420 mg/die up to uMRD or PD or unacceptable toxicity.

Il trattamento in studio prevede VENETOCLAX dal ciclo 1 al ciclo 12 e Rituximab dal ciclo 7 al ciclo 12. Alla fine del ciclo 12 verranno valutati lo stato della malattia (MRD), la funzionalità renale e il rischio di sanguinamento e in base al'esito della rivalutazione il paziente entra in follow up oppure inizia venetoclax 400 mg/die fino (max 24 mesi) in combinazione con ibrutinib 420 mg/die fino a uMRD o PD o tossicità inaccettabile.

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

2021-05-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-03-10

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

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