Clinical Trials Register

Summary
EudraCT Number:	2021-006028-41
Sponsor's Protocol Code Number:	BER-PUM-01
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-01-28
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2021-006028-41

A.3

Full title of the trial

Evaluation of the safety and efficacy of Berubicin in the treatment of central nervous system lymphomas- BERUBICIN

Ocena bezpieczeństwa i skuteczności berubicyny w leczeniu chłoniaków ośrodkowego układu nerwowego- BERUBICYNA

A.3.1

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

Evaluation of the safety and efficacy of Berubicin in the treatment of central nervous system lymphomas- BERUBICIN

Ocena bezpieczeństwa i skuteczności berubicyny w leczeniu chłoniaków ośrodkowego układu nerwowego- BERUBICYNA

A.3.2

Name or abbreviated title of the trial where available

BERUBICIN

BERUBICYNA

A.4.1

Sponsor's protocol code number

BER-PUM-01

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	Pomorski Uniwersytet Medyczny w Szczecinie
B.1.3.4	Country	Poland
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	Medical Research Agency
B.4.2	Country	Poland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pomorski Uniwersytet Medyczny w Szczecinie
B.5.2	Functional name of contact point	Dział Funduszy Zewnętrznych
B.5.3	Address:
B.5.3.1	Street Address	Rybacka 1
B.5.3.2	Town/ city	Szczecin
B.5.3.3	Post code	70-204
B.5.3.4	Country	Poland
B.5.4	Telephone number	+4891480 07 28
B.5.5	Fax number	+4891480 07 05
B.5.6	E-mail	ewa.piekarczyk@pum.edu.pl

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	Berubicin
D.3.2	Product code	WP 744
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
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	Berubicin
D.3.9.1	CAS number	293736-67-1
D.3.9.2	Current sponsor code	WP 744
D.3.9.3	Other descriptive name	Berubicin hydrochloride
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	18.9
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.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

Primary central nervous system lymphoma (PCNSL) and secondary non-Hodgkin's lymphoma with central nervous system involvement (NHL-CNSI)

Pierwotny chłoniak ośrodkowego układu nerwowego (PCNSL) i wtórny chłoniak nieziarniczy z zajęciem ośrodkowego układu nerwowego (NHL-CNSI)

E.1.1.1

Medical condition in easily understood language

Primary central nervous system lymphoma and secondary non-Hodgkin's lymphoma with central nervous system involvement

Pierwotny chłoniak ośrodkowego układu nerwowego i wtórny chłoniak nieziarniczy z zajęciem ośrodkowego układu nerwowego

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 safety and tolerability of Berubicin in combination with other cytostatic agents and to determine the recommended Phase 2 dose (RP2D) of Berubicin

E.2.2

Secondary objectives of the trial

●To evaluate PFS in patients with Primary CNSL and secondary NHL-CNSI treated with Berubicin containing chemotherapeutic regimens
●To assess the effect of Berubicin on OS in patients with Primary CNSL a and secondary NHL-CNSI
● To assess the effect of Berubicin on EFS defined as the length of time from the initiation of study drug administration to progression, death, or discontinuation of treatment
●To evaluate the concentration of complement factors (C3, C4, C5), CRP protein, and circulating miRNA particles in subjects’ plasma and CSF fluid using genomic microarray assessment
●To assess ORR in patients treated with Berubicin (at the EoT). ORR defined as the proportion of participants who achieved a CR or PR at the end of therapy as assessed by the Investigator according to the most recent Lugano Response Criteria for NHL or the Response Criteria of the International Primary CNSL Collaborative Group criteria
●To confirm the PK profile of Berubicin and its metabolite, berubicinol

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

For the first approximately 10 patients enrolled in each treatment arm only, serial, 3-mL blood samples will be collected for determination of plasma Berubicin and berubicinol concentrations during Cycle 1 - Cycle 6 at the following times:
● C1-6D2: pre-dose and 0.5, 2, 4, 6 hours post-start of infusion;
● C1-6D3: 24 hours (±3 hours) after start of infusion;
● C1-6D4: 48 hours (±3 hours) after start of infusion;

E.3

Principal inclusion criteria

1. Written informed consent prior to any study-related procedure, and willing and able to comply with the protocol and aware of the investigational nature of this study.
2. At least 18 years of age.
3. Confirmation of a diagnosis:
a. For patients with primary central nervous system lymphoma
i. A diagnosis of central nervous system lymphoma confirmed by a pathologist on brain tissue or on the meningeal or cranial nerve lesion
b. For patients with non-Hodgkin’s lymphoma
i. A diagnosis of non-Hodgkin’s lymphoma confirmed by a pathologist on the lymph node biopsy.
ii. Confirmed involvement of the CNS (brain, meninges, cranial nerves, eyes and/or spinal cord) at diagnosis (concomitant to extra-CNS disease) or relapse after conventional chemo(-immuno)therapy
iii. Diagnosis of CNS involvement either by biopsy or CSF cytopathologic or cytometric examination. Neuroimaging alone is acceptable when a stereotactic biopsy is formally contraindicated or when the disease has been previously histologically documented in other areas and the CNS localization is concomitant with a diffuse progression of systemic disease.
4. No previous treatment with high-dose methotrexate-based chemotherapy. For patients with non-Hodgkin’s lymphoma up to two courses of R-CHOP are allowed as upfront therapy in patients with advanced disease. The decision is made by the Investigator.
5. No prior investigational therapy within 4 weeks before the first dose of study drug
6. The Eastern Cooperative Oncology Group (ECOG) Performance Status 0-3.
7. Eligible for chemotherapy based on adequate bone marrow function cardiac, kidney and liver function as defined by the following laboratory guidelines, subject to the Investigator’s discretion:
a. Hematopoietic function: platelet count ≥75 x 109/L, hemoglobin ≥8 g/dL, absolute neutrophil count (ANC) ≥1 x 109/L, unless due to organ involvement
b. Cardiac function: ejection fraction LVEF ≥45%.
c. Renal function: creatinine ≤2 x ULN, unless due to organ involvement.
d. Hepatic function: bilirubin ≤3 × the upper limit of normal (ULN) (excluding Gilberts Syndrome, for which bilirubin must be ≤4 × ULN), and/or aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase <3 × ULN, unless due to organ involvement or Gilbert’s Syndrome
8. Women of childbearing potential must agree to practice a highly effective method of contraception beginning at least 28 days before the start of treatment until at least 3,5 months after the last dose of study drug. Male study patients and their female sexual partners of childbearing potential must agree to practice a highly effective method of contraception starting from the time of informed consent until at least 3,5 months after the last dose of study drug.
a. A woman of childbearing potential is defined as a woman who is not permanently sterilized or postmenopausal. Postmenopausal is defined as 12 months with no menses without an alternative medical cause.
b. Women of childbearing potential must have a negative serum or urine pregnancy test.
c. A highly effective method of birth control is defined as one which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence, or vasectomized partner. For patients using a hormonal contraceptive method, information regarding all medications being administered to the patient and their potential effect on the contraceptive should be addressed.

E.4

Principal exclusion criteria

1. Unable or not willing to comply with the protocol regulations.
2. Contraindications to the use of anthracyclines.
3. Presence of uncontrolled, active viral, bacterial, or fungal infection.
4. Severe heart failure (NYHA III / IV) with EF <45%, severe renal disease (CKD ≥4) and / or severe liver disease or cirrhosis (bilirubin> 3 mg/dL or ALT / AST> 3x ULN) not due to organ involvement.
5. History of unstable coronary artery disease CCS>2 or myocardial infarction within the last 6 months.
6. Previous treatment with autologous or allogeneic stem cells/bone marrow transplantation.
7. Presence of human immunodeficiency virus (HIV) infection and of detectable hepatitis C virus RNA (HCV-RNA) and/or hepatitis B virus surface antigen (HBsAg) and/or hepatitis B virus DNA (HBV-DNA).
8. Concurrent malignancies (with exceptions of BCC and carcinoma in situ). Previous malignancies are accepted if surgically cured or if there was no evidence of disease in the last 2 years at a regular follow-up.
9. Any other serious medical condition which, in the opinion of the Investigator, could impair the ability of the patient to participate in the trial or comply with the study protocol and follow-up schedule.
10. Patients that are pregnant, lactating, or not using adequate contraception.

E.5 End points

E.5.1

Primary end point(s)

o To evaluate the safety and tolerability of Berubicin in combination with other cytostatic agents and to determine the recommended Phase 2 dose (RP2D) of Berubicin

E.5.1.1

Timepoint(s) of evaluation of this end point

From D2C1 after every cycle, EoT, Follow-Up visits

E.5.2

Secondary end point(s)

1) To evaluate Progression Free Survival (PFS), defined as the time interval from the date of the first study drug administration to the date of first documentation of progressive disease (PD) or death (whichever occurs first) at 2 years in patients with Primary Central Nervous System Lymphoma and secondary Non-Hodgkin’s Lymphoma with CNS involvement treated with Berubicin-containing chemotherapeutic regimens
2) To assess overall response rate (ORR), defined as the proportion of participants who achieved a CR or PR at the end of therapy as assessed by the Investigator according to the most recent "Lugano Response Criteria for NHL" [1] or the "Response Criteria of the International Primary CNS Lymphoma Collaborative Group - IPCG" [2] criteria
3) To assess the effect of Berubicin on overall survival (OS) defined as the time interval from the date of the first study drug administration to the date of death at 2 years
4) Proportion of patients achieving CR at 12 months
5) Proportion of patients achieving PR at 12 months
6) To assess the effect of Berubicin on event-free survival (EFS), defined as the length of time from the initiation of study drug administration to disease progression, death, or discontinuation of treatment for any reason (e.g., toxicity, intolerance, disease-related conditions, or failure to respond)
7) To evaluate the concentration of complement factors (C3, C4, C5), CRP protein, and circulating miRNA particles in subjects’ plasma and CSF fluid using genomic microarray assessment
8) To confirm the pharmacokinetic (PK) profile of Berubicin and its metabolite, berubicinol

E.5.2.1

Timepoint(s) of evaluation of this end point

1) 2 years after D2C1
2) EoT
3) 2 years after D2C1
4) 12 months
5) 12 months
6) from C2D1 until disease progression, death, or discontinuation of treatment for any reason
7) Screening and/or Baseline, D0C3, D0Cx, D1-D7Cx, D14Dx, EoT
8)● C1-6D2: pre-dose and 0.5, 2, 4, 6 hours post-start of infusion;
● C1-6D3: 24 hours after start of infusion;
● C1-6D4: 48 hours after start of infusion;

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

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

Dose escalation

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

Escalated doses of Berubicin in an accelerated model

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

Yes

E.8.1.7.1

Other trial design description

Two regimens (two treatment arms) in the study given to patients depending on the disease

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

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

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

LSLV - Last Subject Last 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

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.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

2022-02-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-12-20

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

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