Clinical Trials Register

Summary
EudraCT Number:	2017-001060-38
Sponsor's Protocol Code Number:	NLG-MCL7
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-10-31
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

Denmark - DHMA

A.2

EudraCT number

2017-001060-38

A.3

Full title of the trial

Venetoclax, lenalidomide and rituximab in patients with relapsed/refractory mantle cell lymphoma.

A.3.1

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

Venetoclax, lenalidomide and rituximab in patients with relapsed/refractory mantle cell lymphoma.

A.3.2

Name or abbreviated title of the trial where available

VALERIA

A.4.1

Sponsor's protocol code number

NLG-MCL7

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	Nordic Lymphoma Group
B.1.3.4	Country	Sweden
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	Skåne University Hospital, Department of Oncology
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Celgene Corporation
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	AbbVie
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Nordic Lymphoma Group, Department of Hematology, Aarhus University Hospital
B.5.2	Functional name of contact point	Academic Clinical Trial Office
B.5.3	Address:
B.5.3.1	Street Address	Palle Juul-Jensens Boulevard 99, C104
B.5.3.2	Town/ city	AARHUS N
B.5.3.3	Post code	8200
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4578465855
B.5.5	Fax number	+4578467597
B.5.6	E-mail	a-cto@aarhus.rm.dk

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.3.4	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.3.8	INN - Proposed INN	VENETOCLAX
D.3.9.3	Other descriptive name	Antineoplastic agent
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	range
D.3.10.3	Concentration number	10 to 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	Revlimid
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe BV
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/3/11/924
D.3 Description of the IMP
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.3.9.4	EV Substance Code	SUB25389
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	5 to 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	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: 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	Mabthera
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 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	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
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	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	Yes
D.3.11.13.1	Other medicinal product type	Monoclonal antibody.
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	Mabthera
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	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous 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 milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1400
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	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	Yes
D.3.11.13.1	Other medicinal product type	Monoclonal antibody.

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/refractory mantle cell lymphoma.

E.1.1.1

Medical condition in easily understood language

Relapsed/refractory mantle cell lymphoma.

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	HLT
E.1.2	Classification code	10026798
E.1.2	Term	Mantle cell lymphomas
E.1.2	System Organ Class	100000004851

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to assess the overall response rate (ORR) at 6 months with lenalidomide-venetoclax and rituximab, in patients with relapsed or refractory mantle cell lymphoma, by use of an MRD driven strategy.

E.2.2

Secondary objectives of the trial

To evaluate, at 24 months:
1. ORR in untreated patients, not candidates for chemotherapy
2. ORR in patients previously treated with ibrutinib
3. ORR in patients with TP53-mutation and/or 17p deletion
4. Progression-free survival (median)
5. Response duration (median)
6. Molecular remission rate by PCR according to EURO-MRD guidelines
7. MRD vs PET-CT for correlation with PFS/OS
8. Overall survival (median)
9. Safety (Grade 3-4 AE according to CTC v 4.03)
10. Health-related quality of Life assessment
11. Evaluation of biomarkers for efficacy, by mutational profile and immunohistochemistry

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age >18 years
2. Histologically confirmed (according to the WHO 2016 classification) mantle cell lymphoma stage I-IV
3.
a. Who have received at least 1 prior rituximab-containing chemotherapy regimen, with documented relapse or disease progression following
the last anti-MCL treatment
OR
b. Are not considered to be candidates for chemotherapy due to frailty or comorbidity
4. At least 1 measurable site of disease (>1.5 cm long axis)
5. WHO performance status 0 – 3
6. Written informed consent.
7. Female subjects of childbearing potential must (see page 52 for definition of not fertile):
a. Understand that the study medication is expected to be teratogenic
b. Agree to use, and be able to comply with, highly effective contraception without interruption, 4 weeks before starting study drug,
throughout study drug therapy (including dose interruptions) and for 4 weeks after the end of study drug therapy, even if she has
amenorrhoea.
c. All fertile women must agree to perform monthly pregnancy tests while on study medication and until 4 weeks after completion of study
drug. Tests must have a minimum sensitivity of 25 mIE/ml and be medically witnessed
d. Highly effective contraception include:
e. Implant*
f. Levonorgestrel-releasing intrauterine system (IUS)*
g. Medroxyprogesterone acetate depot
h. Tubal sterilisation
i. Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses
j. Ovulation inhibitory progesterone-only pills (i.e., desogestrel)
NB! Patients using a hormonal method, must also use a second barrier method.
k. Sexual abstinence (if refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The
reliability of sexual abstinence needs to be evaluated in relation to the preferred and usual lifestyle of the subject).
8. Male subjects must
a. Agree to use condoms throughout study drug therapy, during any dose interruption and for one week after cessation of study therapy if
their partner is of childbearing potential and has no contraception.
b. Agree not to donate semen during study drug therapy and for one week after end of study drug therapy.
9. All subjects must
a. Agree to abstain from donating blood while taking study drug therapy and for one week following discontinuation of study drug therapy.
b. Agree not to share study medication with another person and to return all unused study drug to the investigator

E.4

Principal exclusion criteria

1.
a. Chemotherapy or radiotherapy within 3 weeks
b. Therapeutic antibodies or BTK inhibitors within 4 weeks
c. Radioimmunotherapy within 10 weeks
d. Major surgery within 4 weeks of inclusion in this trial.
2. Previous treatment with venetoclax
3. Impaired liver function: AST and ALT >3.0 × the upper normal limit (ULN) of institution's normal range; Bilirubin > 1.5 × ULN. Subjects with
Gilbert's Syndrome may have a bilirubin > 1.5 × ULN, per discussion between the investigator and medical monitor. Elevated Bilirubin due
to haemolytic anemia or caused by lymphoma, is not an exclusion criterion.
4. Absolute neutrophil count (ANC) <1.0x 109, unless caused by bone marrow infiltration by lymphoma.
5. Platelet count <60 x 109, unless caused by bone marrow infiltration by lymphoma.
6. Creatinine clearance below 50 ml/min (Cockcroft-Gault)
7. Known CNS lymphoma.
8. Heart failure in NYHA stage IV or other serious CVD
9. Pulmonary failure (ex chronic disease with hypoxemia)
10. Active serious infections such as hepatitis B or C and HIV
11. Conditions with serious immunocompromised state
12. Breastfeeding women must be excluded or stop breastfeeding
13. Other active malignancy.
14. Psychiatric illness or condition which could interfere with the subjects’ ability to understand the requirements of the study.
15. Requirement of corticosteroid therapy at a dose >10 mg prednisolone/day.
16. Hypersensitivity to venetoclax, lenalidomide or rituximab, or HACA against rituximab.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variable is the evaluation of overall response rate (ORR) at 6 months with lenalidomide-venetoclax and rituximab, in patients with relapsed or refractory mantle cell lymphoma (MCL), using an MRD driven strategy.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 6 months of treatment.

E.5.2

Secondary end point(s)

1. ORR in untreated patients, not candidates for chemotherapy
2. ORR in patients previously treated with ibrutinib
3. ORR in patients with TP53-mutation and/or 17p deletion
4. Progression-free survival
5. Response duration
6. Molecular remission rate by PCR according to EURO-MRD guidelines
7. Overall survival
8. Safety
9. Evaluation of biomarkers for efficacy, by mutational profile and immunohistochemistry

E.5.2.1

Timepoint(s) of evaluation of this end point

Continously during treatment.

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

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

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

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

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.

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

2019-02-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-07-15

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

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