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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pomeranian Medical University

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Nervous System Diseases [C10]

Trial duration

18 Nov 2024 → 4 May 2026

Decision date (initial)

2024-11-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Medical Research Agency

External identifiers

EU CT number

2024-516773-69-00

EudraCT number

2021-006028-41

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Efficacy, Pharmacokinetic, Safety

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

Secondary objectives 6

1. To evaluate Progression Free Survival (PFS) 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 the effect of Berubicin on overall survival (OS) in patients with Primary Central Nervous System Lymphoma and secondary Non-Hodgkin’s Lymphoma with CNS involvement
3. 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)
4. 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
5. To assess overall response rate (ORR) in patients treated with Berubicin (at the End of Treatment). ORR is defined as the proportion of participants who achieved a complete response (CR) or partial response (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
6. To confirm the pharmacokinetic (PK) profile of Berubicin and its metabolite, berubicinol

Conditions and MedDRA coding

central nervous system (CNS) lymphomas

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

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 the upper limit of normal (ULN), unless due to organ involvement. d. Hepatic function: bilirubin ≤3 × ULN (excluding Gilbert's 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.

Exclusion criteria 10

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 cervical cancer 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 8

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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pomeranian Medical University

Sponsor organisation

Pomeranian Medical University

Address

Ul. Rybacka 1

City

Szczecin

Postcode

70-204

Country

Poland

Scientific contact point

Organisation

Pomeranian Medical University

Contact name

Sławomir Milczarek

Public contact point

Organisation

Pomeranian Medical University

Contact name

Sławomir Milczarek

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications