Clinical Trials Register

Summary
EudraCT Number:	2018-002492-17
Sponsor's Protocol Code Number:	CLL-RT1
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2019-07-31
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

Austria - BASG

A.2

EudraCT number

2018-002492-17

A.3

Full title of the trial

A prospective, open-label, multicentre Phase-II-Trial to evaluate the efficacy and safety of zanubrutinib (BGB-3111), a BTK Inhibitor, plus tislelizumab (BGB-A317), a PD-1 Inhibitor, for treatment of patients with Richter Transformation.

Eine prospektive, unverblindete, multizentrische Phase-II-Studie zur Evaluation der Effektivität und Sicherheit von Zanubrutinib (BGB-3111), einem BTK-Inhibitor in Verbindung mit Tislelizumab, einem PD-1 Inhibitor, zur Behandlung von Patienten mit einer Richter-Transformation.

A.3.1

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

Evaluation of a Treatment with tislelizumab and zanubrutinib in patients with a Richter Transformation.

Bewertung einer Behandlung mit Tislelizumab und Zanubrutinib bei Patienten mit einer Richter-Transformation.

A.3.2

Name or abbreviated title of the trial where available

CLL-RT1

A.4.1

Sponsor's protocol code number

CLL-RT1

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	Universität zu Köln
B.1.3.4	Country	Germany
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	BeiGene Ltd.
B.4.2	Country	Cayman Islands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	German CLL Study Group
B.5.2	Functional name of contact point	Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Gleueler Str. 176-178
B.5.3.2	Town/ city	Köln
B.5.3.3	Post code	50935
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049022147888220
B.5.5	Fax number	0049022147886886
B.5.6	E-mail	cllstudie@uk-koeln.de

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.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Tislelizumab
D.3.2	Product code	BGB-A317
D.3.4	Pharmaceutical form	Concentrate and solvent for 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	tislelizumab
D.3.9.1	CAS number	1858168-59-8
D.3.9.3	Other descriptive name	BGB-A317
D.3.9.4	EV Substance Code	SUB189550
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	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	Tislelizumab is a humanized immunoglobulin G4 (IgG4) variant monoclonal antibody
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Zanubrutinib
D.3.2	Product code	BGB-3111
D.3.4	Pharmaceutical form	Capsule
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	Zanubrutinib
D.3.9.1	CAS number	1691249-45-2
D.3.9.3	Other descriptive name	BGB-3111
D.3.9.4	EV Substance Code	SUB184615
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	80
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	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

Patients excluded are:
-Primary progressive patients, i.e. patients who did not respond to their first-line treatment (=> Exclusion criteria 1)
-Patients with 2 or more prior lines of therapy (=> Exclusion criteria 2)

Two groups of patients with RT are eligible (=> Inclusion criteria 3):
- Patients without previous treatment
- Patients with 1 prior line of therapy only if they responded to therapy

E.1.1.1

Medical condition in easily understood language

Patients with previously untreated Richter Transformation or patients who responded to up to one prior line of RT therapy

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	10008975
E.1.2	Term	Chronic lymphocytic leukaemia variants
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

The primary objective of the study is to evaluate the efficacy of a combinational therapy with tislelizumab and zanubrutinib in CLL pa-tients with Richter transformation to DLBCL.

E.2.2

Secondary objectives of the trial

The secondary objective is to evaluate the safety of combinational therapy with tislelizumab and zanubrutinib in CLL patients with Richter transformation to DLBCL.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Confirmed diagnosis of CLL according to iwCLL criteria (Hallek et al, 2018) [13]
2. Confirmed histopathological diagnosis of RT (diffuse large B-cell lymphoma or Hodgkin’s lymphoma [Hodgkin’s lymphoma only when not eligible for more in-tensive treatment])
3. Previously untreated RT or patients with objective response or non-tolerance to first-line RT treatment
4. Creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection or an equivalent method
5. Adequate liver function as indicated by a total bilirubin≤ 2 x, AST/ALT ≤ 2.5 x the institutional ULN value, unless di-rectly attributable to the patient’s CLL/RT or to Gilbert’s Syndrome, in which case a max. total bilirubin ≤ 4 x and AST/ALT ≤ 5 x the institutional ULN value are required.
6. Negative serological testing for hepatitis B (HBsAg nega-tive and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every two months until 2 months after last dose of zanubrutinib), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
7. Age at least 18 years
8. ECOG performance status 0-2, ECOG 3 is only permitted if related to CLL or RT (e.g. due to anaemia or severe constitutional symptoms)
9. Life expectancy ≥ 6 months
10. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

E.4

Principal exclusion criteria

1. Patients who did not respond to previous line of RT therapy (i.e. primary progressive patients)
2. Patients with more than one prior line of RT therapy
3. Allogenic stem cell transplantation within the last 100 days or signs of active GVHD after prior allogeneic stem cell transplantation within any time
4. Patients with confirmed PML
5. Uncontrolled autoimmune condition
6. Malignancies other than CLL currently requiring systemic therapies (unless the malignant disease is in a stable remission at the discretion of the treating physician)
7. Active infection currently requiring systemic treatment
8. Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) score of 4, exclud-ing the eyes/ears/nose/throat/larynx organ system, or any other life-threatening illness, medical condition or organ system dysfunction that – in the investigator´s opinion could comprise the patients safety or interfere with the absorption or metabolism of the study drugs
9. Requirement of therapy with strong CYP3A4 inhibitors/ inducers
10. Requirement of therapy with phenprocoumon or other vit-amin K antagonists.
11. Use of investigational agents, e.g. monoclonal antibodies or other experimental drugs within clinical trials, which might interfere with the study drug within 28 days (or 5 times half-life [t1/2] of the compound, whichever is longer) prior to registration
12. Known hypersensitivity to tislelizumab, zanubrutinib or any of the excipients
13. Pregnant women and nursing mothers (a negative preg-nancy test is required for all women of childbearing potential within 7 days before start of treatment)
14. Fertile men or women of childbearing potential unless:
- surgically sterile or ≥ 2 years after the onset of meno-pause, or
- willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 12 months af-ter the end of study treatment.
15. Vaccination with a live vaccine <28 days prior to randomi-zation
16. Legal incapacity
17. Prisoners or subjects who are institutionalized by regula-tory or court order

E.5 End points

E.5.1

Primary end point(s)

Overall response rate (ORR) after induction therapy (i.e. 6 cycles) according to the refined Lugano Classification (Cheson et al, 2016).
- Complete response (CR)
- Partial response (PR)

E.5.1.1

Timepoint(s) of evaluation of this end point

After induction therapy (i.e. 6 cycles)

E.5.2

Secondary end point(s)

• ORR after induction therapy (i.e. 6 cycles) according to IWCLL criteria (Hallek et al, 2018)
• ORR after consolidation therapy (i.e. 12 cycles)
• Duration of response
• Progression-free survival (PFS)
• Overall survival (OS)
• Time to next treatment (TTNT)
• Proportion of patients receiving SCT for consolidation
• Exploratory endpoints: Evaluation of relationship between various baseline markers, including PD-1/PD-L1 expression and mutational load, and clinical outcome parameters
• Safety parameters: type, frequency, severity of adverse events (AEs), and their relationship to study treatment

E.5.2.1

Timepoint(s) of evaluation of this end point

ORR after induction therapie (i.e. 6 cycles)
ORR after consolidation therapy (i.e. 12 cycles)

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

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.8.3

The trial involves single site in the Member State concerned

Yes

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

In contrast to the definition of end of study, the end of the clinical trial is defined as the time point once
the last patient completed the last follow up visit.

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

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

2019-08-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-12-05

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

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