High-dose Methotrexate Combined with Thiotepa and Zanubrutinib in the Treatment of Newly Diagnosed PCNSL (MTZ)

NCT06646211 | Not Yet Recruiting Phase 2

• 1 other identifier: B2024-503-01
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase Ⅱ clinical study of Zanubrutinib(Z) in combination with methotrexate (M) and thiotepa(T) in treating newly diagnosed primary CNS lymphoma (PCNSL). The purpose of the study is to test the efficacy and tolerability of a combination treatment of MTZ regimen in treating patients who have newly diagnosed PCNSL

Conditions

Primary Central Nervous System Lymphoma (PCNSL); Non Hodgkin Lymphoma (NHL)

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate (ORR) at the end of TZ / MTZ treatment, Investigator-Assessed

  The overall response rate (ORR) including complete response (CR), and partial response (PR) according to the 2005 Response Criteria of the International Primary CNS Lymphoma Collaborative Group (IPCG)

  12 month

Secondary Outcomes (5)

• Overall Response Rate (ORR) at the end of TZ treatment, Investigator-Assessed

  12 month

• Duration of response（DOR）

  12 month

• Progression-free survival (PFS)

  12 month

• Overall survival (OS)

  12 month

• Frequency and severity of adverse effects as defined by CTCAE version 5.0

  12 month

Study Arms (1)

Participant Group/Arm： Experimental: Methotrexate , Thiotepa and Zanubrutinib(MTZ)

EXPERIMENTAL

Drug: Zanubrutinib , Thiotepa; Drug: Methotrexate , Thiotepa and Zanubrutinib; Drug: ASCT±Zanubrutinib

Interventions

Zanubrutinib , Thiotepa DRUG

First 1-4 cycle Drug: Thiotepa * 40mg/m2，d1 each 21-day cycle from cycle 1 for up to 4 cycle Drug: Zanubrutinib * Zanubrutinib will be given at a dose of 160mg，bid，d1-d21

Participant Group/Arm： Experimental: Methotrexate , Thiotepa and Zanubrutinib(MTZ)

Methotrexate , Thiotepa and Zanubrutinib DRUG

Cycle 5 - 10 Drug: Methotrexate * Intravenous methotrexate at 3.5g/m2 for 6 hours will be given on day 1 each 21-day cycle 【Leucovorin Calcium (CF): 15mg/m², rescue begins 12 hours after the infusion of methotrexate (MTX) ends, administered every 6 hours until the MTX plasma concentration is ≤ 0.1 μmol·L-¹ at 48 hours; plasma concentration monitoring time points: 0, 6, 24, 48, 72 hours.】 Other Names: MTX Drug: Thiotepa * 40mg/m2，d1 each 21-day cycle from cycle 5 for up to 10 cycle Drug: Zanubrutinib Zanubrutinib will be given at a dose of 160mg，bid，d1-d21

Participant Group/Arm： Experimental: Methotrexate , Thiotepa and Zanubrutinib(MTZ)

ASCT±Zanubrutinib DRUG

Consolidation / maintenance treatment Patients who achieve a Complete Response (CR) or Partial Response (PR) after the ZT/ZMT treatment will enter consolidation/maintenance therapy. Patients age ≤65 years old will undergo Autologous Stem Cell Transplantation (ASCT, with a recommended conditioning regimen that includes Thiotepa), followed by 6 months of maintenance treatment with zanubrutinib. Patients age \> 65 will receive 6 months of maintenance treatment with zanubrutinib. \*The study permits the prophylactic use of Granulocyte Colony-Stimulating Factor (G-CSF). For detailed usage, please refer to the guidelines from the National Comprehensive Cancer Network (NCCN) or the Chinese Society of Clinical Oncology (CSCO)

Participant Group/Arm： Experimental: Methotrexate , Thiotepa and Zanubrutinib(MTZ)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and woman who are 18 to 70 years of age
• Histologically documented PCNSL
• ECOG performance status ≤ 2
• Life expectancy of \> 3 months
• Imaging show at least one measurable lesion in the central nervous system.
• Adequate bone marrow and organ function shown by:
• Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L
• Platelets ≥ 75 x 10\^9/L and no platelet transfusion within the past 14 days
• Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 14 days
• International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3×ULN
• Serum bilirubin ≤ 1.5×ULN
• Serum creatinine ≤ 2×ULN
• Lipase ≤ 1.5 x LUN
• Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of medication; women who are pregnant or breastfeeding are not eligible to participate in this study. Women of childbearing potential: from the time of signing the Informed Consent Form (ICF) until 30 days after the study ends, sexually active men: from the time of signing the ICF until 90 days after the study ends, must use contraceptive measures.

You may not qualify if:

• Diagnosed with a malignant tumor other than PCNSL or has received treatment, except for the following cases:
• Received curative treatment and has no known active disease at least 3 years or more before screening for enrollment.
• Fully treated non-melanoma skin cancer or malignant lentigo, with no evidence of disease.
• Fully treated carcinoma in situ, with no evidence of disease currently.
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure (New York Heart Association \> Class 2), unstable angina, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
• Uncontrolled hypertension despite optimal medical management (per investigators assessment)
• Patient has poorly controlled diabetes (per investigators assessment)
• Patient is known to have an uncontrolled active systemic infection (\>CTCAE grade 2) and recent infection requiring intravenous anti-infective treatment that was completed ≤14 days before the first dose of study drug
• Cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 3 months before the start of study treatment
• Non-healing wound, ulcer or bone fracture in a short time
• Known bleeding diathesis or hemophilia
• Known history of infection with human immunodeficiency virus (HIV) or active stage of infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) . Active HBV infection must be confirmed by a positive test for HBV surface antigen or a positive test for hepatitis B core antibody with a positive determination of HBV DNA by polymerase chain reaction (PCR). For Hepatitis C virus (HCV), confirmation must be made by a positive test for HCV antibodies, unless the subject has been treated and has shown a sustained virological response. Note: Subjects with positive HCV antibodies who have been treated and have shown a sustained virological response (negative virus detection for at least 6 months after completing treatment) will not be excluded.
• Patient underwent major systemic surgery ≤ 2 weeks prior to starting the trial treatment or who has not recovered from the side effects of such surgery
• Unable to swallow capsules or disease significantly affecting gastrointestinal function
• Life-threatening illness, medical conditions, or organ dysfunctions that may endanger the safety of the subject or put the study outcomes at risk.

Sponsors & Collaborators

• Sun Yat-sen University: lead

Study Sites (1)

Sun Yat-sen University Cancer Center

Guangzhou, Guangdong, 510060, China

Location

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

zanubrutinib; Thiotepa; Methotrexate

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramides; Organophosphorus Compounds; Organic Chemicals; Triethylenephosphoramide; Aziridines; Azirines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Central Study Contacts

Yan Gao, Doctor

CONTACT

+86 020 87343350; gaoyan@sysucc.org.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 12, 2024
• First Posted: October 17, 2024
• Study Start: January 1, 2025
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2028
• Last Updated: October 17, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)