Trial Title:
High-dose Methotrexate Combined with Thiotepa and Zanubrutinib in the Treatment of Newly Diagnosed PCNSL (MTZ)
NCT ID:
NCT06646211
Condition:
Primary Central Nervous System Lymphoma (PCNSL)
Non Hodgkin Lymphoma (NHL)
Conditions: Official terms:
Lymphoma
Lymphoma, Non-Hodgkin
Methotrexate
Thiotepa
Zanubrutinib
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Zanubrutinib , Thiotepa
Description:
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
Arm group label:
Participant Group/Arm： Experimental: Methotrexate , Thiotepa and Zanubrutinib(MTZ)
Intervention type:
Drug
Intervention name:
Methotrexate , Thiotepa and Zanubrutinib
Description:
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
Arm group label:
Participant Group/Arm： Experimental: Methotrexate , Thiotepa and Zanubrutinib(MTZ)
Intervention type:
Drug
Intervention name:
ASCT±Zanubrutinib
Description:
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)
Arm group label:
Participant Group/Arm： Experimental: Methotrexate , Thiotepa and Zanubrutinib(MTZ)
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
Detailed description:
PCNSL is a rare extranodal aggressive lymphoma accounting for 4%- 6% of all extranodal
lymphomas and 3%- 4% of brain tumors, with an overall low incidence rate. However, with
the extension of life expectancy, the incidence of PCNSL has increased by 2-3 times in
Western Europe and the United States over the past 20 years.
Conventional dose methotrexate (MTX) does not effectively cross the blood-brain barrier,
and the treatment for newly diagnosed PCNSL is still based on high-dose methotrexate
(HD-MTX) combined chemotherapy. In the early stages PCNSL, Batchelor et al. used an MTX
dose of 8.0g/m², which could reach effective therapeutic concentrations in the
cerebrospinal fluid (CSF). However, HD-MTX has significant nephrotoxicity, especially for
elderly patients and those with renal insufficiency. In 2005, Khan et al. found that
reducing the dose of MTX to 3.5g/m² could significantly reduce kidney toxicity. Although
single-agent HD-MTX has some efficacy in treating PCNSL, the remission rate is still
relatively low. High doses of cytarabine, dacarbazine, and thiotepa have a higher
blood-brain barrier penetration rate, and these drugs combined with HD-MTX for treating
PCNSL can further improve upon HD-MTX alone. The overall response rate (ORR) is
approximately 60%-70%, the complete response (CR) rate is about 40%-50%, and the 5-year
survival rate is around 30%. Neither the short-term efficacy nor the long-term survival
is satisfactory.
Basic research has found that excessive activation of the BCR signaling pathway in PCNSL
tumor tissue, and BTK inhibitors such as ibrutinib can effectively inhibit the BCR
pathway to achieve therapeutic goals. A study used single agent ibrutinib to treat
relapsed/refractory PCNSL, with an overall response rate (ORR) of 50%. Grommes et al.
reported that ibrutinib combined with high-dose methotrexate (HD-MTX) with or without
rituximab showed specific efficacy in treating relapsed/refractory PCNSL, with an ORR of
89% and a complete response (CR) rate of 67%. The efficacy was significantly higher than
that of single-agent ibrutinib in treating relapsed/refractory PCNSL.
Based on these studies, we hypothesize that first-line treatment with BTK inhibitors
combined with HD-MTX-based chemotherapy may further improve the efficacy of newly
diagnosed PCNSL and prolong the duration of remission.However, as a first-generation BTK
inhibitor, ibrutinib has a relatively high off-target effect, leading to increased drug
resistance and adverse reaction rates. Zanubrutinib, as a new generation of BTK
inhibitors, has shown more potent antitumor activity and lower adverse reactions than
ibrutinib in head-to-head clinical studies. Previously, we conducted a phase II clinical
study of ibrutinib combined with methotrexate and temozolomide in PCNSL, which showed
that ibrutinib significantly improved patients' overall response rate and complete
response rate. However, the duration of remission was relatively short. Therefore, this
study uses the new generation of zanubrutinib and thiotepa, which have intense
penetration into the central nervous system, aiming to improve patients' remission
duration further.
At the same time, based on previous studies and clinical experience, elderly and patients
with renal insufficiency have poor tolerance to methotrexate, often experiencing delayed
MTX clearance and renal damage. The first four courses of this study removed methotrexate
and only used the less toxic zanubrutiniba and thiotepa, providing a reference for future
methotrexate-free treatment options.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Men and woman who are 18 to 70 years of age
2. Histologically documented PCNSL
3. ECOG performance status ≤ 2
4. Life expectancy of > 3 months
5. Imaging show at least one measurable lesion in the central nervous system.
6. Adequate bone marrow and organ function shown by:
7. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
8. Platelets ≥ 75 x 10^9/L and no platelet transfusion within the past 14 days
9. Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 14
days
10. International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper
limit of normal
11. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3×ULN
12. Serum bilirubin ≤ 1.5×ULN
13. Serum creatinine ≤ 2×ULN
14. Lipase ≤ 1.5 x LUN
15. 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.
16. Must be able to tolerate MRI/CT scans
17. Must be able to tolerate lumbar puncture and/or Ommaya tap
Exclusion Criteria:
1. Diagnosed with a malignant tumor other than PCNSL or has received treatment, except
for the following cases:
1. Received curative treatment and has no known active disease at least 3 years or
more before screening for enrollment.
2. Fully treated non-melanoma skin cancer or malignant lentigo, with no evidence
of disease.
3. Fully treated carcinoma in situ, with no evidence of disease currently.
2. 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
3. Uncontrolled hypertension despite optimal medical management (per investigators
assessment)
4. Patient has poorly controlled diabetes (per investigators assessment)
5. 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
6. Cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 3 months
before the start of study treatment
7. Non-healing wound, ulcer or bone fracture in a short time
8. Known bleeding diathesis or hemophilia
9. 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.
10. 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
11. Unable to swallow capsules or disease significantly affecting gastrointestinal
function
12. Life-threatening illness, medical conditions, or organ dysfunctions that may
endanger the safety of the subject or put the study outcomes at risk.
13. Lactating or pregnant
14. Requires anticoagulation therapy with warfarin or equivalent vitamin K antagonists;
requires treatment with potent CYP3A4/5 inhibitors.
15. Requires long-term use of dexamethasone ≥4mg/day or equivalent doses of
corticosteroid formulations.
16. Requires treatment with immunosuppressive agents, including cyclosporine A,
tacrolimus, and sirolimus. Patients must discontinue the use of immunosuppressive
agents 28 days before receiving study medication.
Gender:
All
Minimum age:
18 Years
Maximum age:
70 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Sun Yat-sen University Cancer Center
Address:
City:
Guangzhou
Zip:
510060
Country:
China
Contact:
Last name:
HuiQiang Huang, Professor
Phone:
+86-020-87343350
Email:
huanghq@sysucc.org.cn
Contact backup:
Last name:
HuiQiang Huang, Professor
Start date:
January 1, 2025
Completion date:
January 1, 2028
Lead sponsor:
Agency:
Sun Yat-sen University
Agency class:
Other
Source:
Sun Yat-sen University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06646211
