Ignite Creation Date:
2024-06-16 @ 11:50 AM
Last Modification Date:
2024-10-26 @ 3:31 PM
Study NCT ID:
NCT06445257
Status:
RECRUITING
Last Update Posted:
2024-06-06
First Post:
2024-05-31
Brief Title:
A Clinical Study Evaluating the Safety and Efficacy of ZRMT Regimen in the Treatment of PCNSL
Sponsor:
Huaian First Peoples Hospital
Organization:
Huaian First Peoples Hospital
Study Overview
Official Title:
A Prospective Multicenter Open-label Single-arm Clinical Study Evaluating the Safety and Efficacy of ZRMT Regimen in the Treatment of Primary Central Nervous System Lymphoma PCNSL
Status:
RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This study is a prospective multicenter open-label single-arm clinical trial evaluating the safety and efficacy of the ZRMT Zanubrutinib-Rituximab-Methotrexate-Temozolomide regimen in the treatment of primary central nervous system lymphoma PCNSL with diffuse large B-cell lymphoma
This study includes an induction phase for PCNSL ASCT and a sequential maintenance phase
This study includes an induction phase for PCNSL ASCT and a sequential maintenance phase
Detailed Description:
This study is a single-arm open-label multicenter phase II clinical trial aimed at evaluating the safety tolerability and preliminary efficacy of ZRMT regimen ASCT followed by sequential zebutinib monotherapy as maintenance treatment for newly diagnosed PCNSL A total of 30 subjects are planned to be enrolled
Primary central nervous system lymphoma PCNSL accounts for only 1-2 of non-Hodgkin lymphoma NHL patients with over 90 of PCNSL cases being diffuse large B-cell lymphoma PCNSL is characterized by an aggressive clinical course and poor prognosis with a 5-year overall survival OS rate of only 301 even with intensive chemotherapy and autologous stem cell transplantation as first-line consolidation Additionally the median age of onset for PCNSL is close to 70 years Therefore a low-toxicity and highly effective treatment regimen is crucial in the management of PCNSL Currently the standard treatment for PCNSL is combination chemotherapy based on high-dose methotrexate HD-MTX which has improved the survival of PCNSL patients compared to previous surgical resection or whole-brain radiation therapy However the efficacy of HD-MTX is not durable with only 20 of patients achieving sustained remission after 2 years of HD-MTX monotherapy
Young and healthy patients with PCNSL are recommended to undergo ASCT consolidation therapy in CR1 phase after intensified induction However approximately 25-35 of PCNSL patients are aged 70 or above and these patients may not be suitable candidates for ASCT Therefore the treatment options for elderly and frail PCNSL patients still require further research
Studies have shown that PCNSL is primarily of the ABC subtype of DLBCL Whole exome sequencing has revealed that PCNSL patients typically have mutations in the MYD88 and CD79B genes leading to the classification of PCNSL as the MCD subtype Both of these genes are key molecules in the BCR signaling pathway Mutations in MYD88 and CD79B ultimately lead to activation of NF-кB promoting tumor cell proliferation and inhibiting apoptosis The high frequency and functional activation of this pathway also provide new targets for treatmentThe non-receptor tyrosine kinase Bruton tyrosine kinase BTK is a key molecule in the B-cell receptor BCR signaling pathway and is involved in the activation and survival of ABC subtype DLBCL cells The BTK inhibitor Ibrutinib has shown promising anti-tumor activity in relapsedrefractory DLBCL with higher response rates observed in ABC subtype patients compared to germinal center subtype patients 5 vs 37 p00106
Zanbrutinib is a novel and potent covalent selective inhibitor of Bruton tyrosine kinase BTK Currently the FDA has approved zanbrutinib for the treatment of relapsedrefractory chronic lymphocytic leukemia mantle cell lymphoma marginal zone lymphoma and Waldenström macroglobulinemia which are B-cell lymphomas It is actively being studied and explored in other B-cell tumors including diffuse large B-cell lymphoma and promising efficacy and safety data are being reported graduallyIn a multicenter single-arm phase 2 study 41 patients with relapsedrefractory DLBCL were treated with oral zanbrutinib at a dose of 160 mg twice daily until disease progression or intolerable toxicity With a median follow-up of 68 months the overall response rate ORR was 293 with a complete response CR rate of 171 The median duration of response DOR progression-free survival PFS and overall survival OS were 45 28 and 84 months respectively This study preliminarily demonstrates the efficacy of zanbrutinib in central nervous system-involved DLBCL Recent studies presented at ASH suggest that regimens containing BTK inhibitors show promising efficacy in first-line treatment of PCNSL and the exploration of novel drug combinations with chemotherapy holds the potential to bring deeper and more durable remissions for PCNSL patients However further investigation is needed to determine the optimal drug combinations
The main objective of this study is to evaluate the safety tolerability and preliminary efficacy of the ZRMT regimen in the treatment of newly diagnosed PCNSL The secondary objective is to assess the preliminary efficacy of the ZRMT regimen ASCT followed by sequential maintenance therapy with zanubrutinibAfter screening eligible patients will receive zanubrutinib 160 mg BID orally rituximab 375 mgm2 intravenously on day 7 methotrexate 3-35 gm2 intravenously on day 1 and temozolomide 100 mg on days 1-5 Treatment will be given for 6-8 cycles and patients who achieve a partial response PR or better can choose to undergo ASCT if they meet the transplantation criteria After transplantation or for patients who do not undergo transplantation zanubrutinib monotherapy maintenance treatment will be administered at a dose of 160 mg BID orally for 2 years or until disease progression death or intolerable adverse reactions
Primary central nervous system lymphoma PCNSL accounts for only 1-2 of non-Hodgkin lymphoma NHL patients with over 90 of PCNSL cases being diffuse large B-cell lymphoma PCNSL is characterized by an aggressive clinical course and poor prognosis with a 5-year overall survival OS rate of only 301 even with intensive chemotherapy and autologous stem cell transplantation as first-line consolidation Additionally the median age of onset for PCNSL is close to 70 years Therefore a low-toxicity and highly effective treatment regimen is crucial in the management of PCNSL Currently the standard treatment for PCNSL is combination chemotherapy based on high-dose methotrexate HD-MTX which has improved the survival of PCNSL patients compared to previous surgical resection or whole-brain radiation therapy However the efficacy of HD-MTX is not durable with only 20 of patients achieving sustained remission after 2 years of HD-MTX monotherapy
Young and healthy patients with PCNSL are recommended to undergo ASCT consolidation therapy in CR1 phase after intensified induction However approximately 25-35 of PCNSL patients are aged 70 or above and these patients may not be suitable candidates for ASCT Therefore the treatment options for elderly and frail PCNSL patients still require further research
Studies have shown that PCNSL is primarily of the ABC subtype of DLBCL Whole exome sequencing has revealed that PCNSL patients typically have mutations in the MYD88 and CD79B genes leading to the classification of PCNSL as the MCD subtype Both of these genes are key molecules in the BCR signaling pathway Mutations in MYD88 and CD79B ultimately lead to activation of NF-кB promoting tumor cell proliferation and inhibiting apoptosis The high frequency and functional activation of this pathway also provide new targets for treatmentThe non-receptor tyrosine kinase Bruton tyrosine kinase BTK is a key molecule in the B-cell receptor BCR signaling pathway and is involved in the activation and survival of ABC subtype DLBCL cells The BTK inhibitor Ibrutinib has shown promising anti-tumor activity in relapsedrefractory DLBCL with higher response rates observed in ABC subtype patients compared to germinal center subtype patients 5 vs 37 p00106
Zanbrutinib is a novel and potent covalent selective inhibitor of Bruton tyrosine kinase BTK Currently the FDA has approved zanbrutinib for the treatment of relapsedrefractory chronic lymphocytic leukemia mantle cell lymphoma marginal zone lymphoma and Waldenström macroglobulinemia which are B-cell lymphomas It is actively being studied and explored in other B-cell tumors including diffuse large B-cell lymphoma and promising efficacy and safety data are being reported graduallyIn a multicenter single-arm phase 2 study 41 patients with relapsedrefractory DLBCL were treated with oral zanbrutinib at a dose of 160 mg twice daily until disease progression or intolerable toxicity With a median follow-up of 68 months the overall response rate ORR was 293 with a complete response CR rate of 171 The median duration of response DOR progression-free survival PFS and overall survival OS were 45 28 and 84 months respectively This study preliminarily demonstrates the efficacy of zanbrutinib in central nervous system-involved DLBCL Recent studies presented at ASH suggest that regimens containing BTK inhibitors show promising efficacy in first-line treatment of PCNSL and the exploration of novel drug combinations with chemotherapy holds the potential to bring deeper and more durable remissions for PCNSL patients However further investigation is needed to determine the optimal drug combinations
The main objective of this study is to evaluate the safety tolerability and preliminary efficacy of the ZRMT regimen in the treatment of newly diagnosed PCNSL The secondary objective is to assess the preliminary efficacy of the ZRMT regimen ASCT followed by sequential maintenance therapy with zanubrutinibAfter screening eligible patients will receive zanubrutinib 160 mg BID orally rituximab 375 mgm2 intravenously on day 7 methotrexate 3-35 gm2 intravenously on day 1 and temozolomide 100 mg on days 1-5 Treatment will be given for 6-8 cycles and patients who achieve a partial response PR or better can choose to undergo ASCT if they meet the transplantation criteria After transplantation or for patients who do not undergo transplantation zanubrutinib monotherapy maintenance treatment will be administered at a dose of 160 mg BID orally for 2 years or until disease progression death or intolerable adverse reactions
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None