Ignite Creation Date:
2024-10-26 @ 3:43 PM
Last Modification Date:
2024-10-26 @ 3:43 PM
Study NCT ID:
NCT06646211
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-10-12
Brief Title:
High-dose Methotrexate Combined with Thiotepa and Zanubrutinib in the Treatment of Newly Diagnosed PCNSL MTZ
Sponsor:
None
Organization:
None
Study Overview
Official Title:
A Single-arm Multicenter Phase Ⅱclinical Study Evaluating High-dose Methotrexate Combined with Thiotepa and Zanubrutinib in the Treatment of Newly Diagnosed Central Nervous System Diffuse Large B-cell Lymphoma MTZ
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a phase Ⅱ clinical study of ZanubrutinibZ in combination with methotrexate M and thiotepaT 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
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 80gm² 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 35gm² 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 relapsedrefractory 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 relapsedrefractory 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 relapsedrefractory 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 remissionHowever 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
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 80gm² 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 35gm² 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 relapsedrefractory 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 relapsedrefractory 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 relapsedrefractory 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 remissionHowever 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None