Ignite Creation Date:
2024-10-26 @ 3:37 PM
Last Modification Date:
2024-10-26 @ 3:37 PM
Study NCT ID:
NCT06552559
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-08-03
Brief Title:
Selinexor With ICE Chemotherapy in Secondary Central Nervous System Involving B-cell Non-Hodgkin Lymphoma
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Phase 12 Study of Selinexor With Dexamethasone Ifosfamide Carboplatin and Etoposide in Patients Who Have Secondary Central Nervous System Involvement With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma
Status:
RECRUITING
Status Verified Date:
2024-08
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:
SIENA
Brief Summary:
Secondary involvement of the central nervous system CNS such as CNS relapse after treatment or progression during treatment is a rare but deadly occurrence in patients with B-cell non-Hodgkin lymphoma NHL particularly in cases of diffuse large B-cell lymphoma DLBCL and transformed follicular lymphoma FL Despite the grim prognosis associated with secondary CNS involvement no definitive treatment strategy exists Selinexor an oral first-in-class potent selective inhibitor of nuclear export that binds to XPO1 leads to the nuclear retention of tumor suppressor and growth regulator proteins as well as topoisomerase II enzymes thereby restoring their functions Preclinical studies have also shown that selinexor can sensitize cancer cells to topoisomerase inhibitors alkylating agents and steroids Selinexor has been approved by the Food and Drug Administration for relapsed or refractory DLBCL We hypothesize that selinexor could work synergistically with ifosfamide an alkylating agent and etoposide a topoisomerase II inhibitor in the ifosfamide carboplatin and etoposide ICE regimen High-dose dexamethasone was added to this regimen to enhance the efficacy of ICE as a salvage regimen for secondary CNS involvement due to its ability to cross the blood-brain barrier
This phase III study aims to evaluate the efficacy and safety of selinexor in combination with ifosfamide carboplatin etoposide ICE and dexamethasone in patients with relapsed or refractory B-cell non-Hodgkin lymphoma with secondary CNS involvement
This phase III study aims to evaluate the efficacy and safety of selinexor in combination with ifosfamide carboplatin etoposide ICE and dexamethasone in patients with relapsed or refractory B-cell non-Hodgkin lymphoma with secondary CNS involvement
Detailed Description:
1 Background Secondary central nervous system CNS involvement such as CNS relapse after treatment or progression involving the CNS during treatment is a rare but deadly occurrence in patients with B-cell non-Hodgkin lymphoma NHL particularly in cases of diffuse large B-cell lymphoma DLBCL and transformed follicular lymphoma FL Despite the grim prognosis associated with secondary CNS involvement no definitive treatment strategy has been established Various salvage treatment regimens followed by autologous stem cell transplantation ASCT have been attempted but their effectiveness remains uncertain due to most data coming from retrospective analyses of small case series with a lack of prospective studies Since secondary CNS involvement often coincides with systemic disease progression high-dose methotrexate MTX-based regimens may be inadequate for treating systemic disease progression although they could be effective against CNS tumor cells Consequently ICED ifosfamide 1500 mgm2day on days 1-5 carboplatin AUC 55 on day 1 etoposide 100 mgm2 on days 1-5 and dexamethasone 40 mgday on days 1-4 every 3 weeks has emerged as another salvage treatment option due to its proven efficacy for both CNS and systemic disease However the outcomes of these regimens including high-dose MTX andor ICED are still unsatisfactory with response rates generally below 30-40 Moreover most patients who respond to these treatments eventually experience relapse even after undergoing consolidative ASCT highlighting the need for improved complete response rates in salvage regimens
Exportin 1 XPO1CRM1 serves as a nuclear export protein facilitating the movement of tumor suppressor and growth regulator proteins such as TP53 p21 p27 FOXO3 and nucleophosmin 1 NPM1 from the nucleus to the cytoplasm leading to their deactivation XPO1 overexpression is common in various malignancies and correlates with poor prognosis Additionally XPO1 is responsible for the cytoplasmic transport of topoisomerase II enzymes and their cytoplasmic presence is linked to drug resistance as the separation from DNA prevents topoisomerase II inhibitors from triggering cell death
Selinexor is an orally administered pioneering selective inhibitor of nuclear export targeting XPO1 to retain tumor suppressor and growth regulator proteins along with topoisomerase II enzymes in the nucleus thus reinstating their activity Preclinical studies have shown that selinexor can enhance the sensitivity of cancer cells to topoisomerase inhibitors alkylating agents and steroids Selinexor has been approved by the Food and Drug Administration for the treatment of relapsed or refractory DLBCL We propose that selinexor could enhance the effectiveness of the ifosfamide carboplatin and etoposide ICE regimen when combined with ifosfamide an alkylating agent and etoposide a topoisomerase II inhibitor and have included high-dose dexamethasone to potentially increase ICEs efficacy as a salvage therapy for secondary CNS involvement due to its ability to cross the blood-brain barrier
2 Study design Phase III Therapeutic Area Salvage treatment and maintenance for secondary CNS involvement of B-cell NHL Primary Compound Selinexor Additional compounds if applicable Ifosfamide carboplatin etoposide dexamethasone
3 Phase I In the phase 1 study patients must complete one therapy cycle 3 weeks at a given dose level before considering escalation to the next level Escalation is allowed if the initial three patients at a dose level show no dose-limiting toxicities DLTs during the first cycle If one patient experiences DLTs at a dose level of selinexor three more patients will be added to that level Escalation to the next selinexor dose level occurs if only one out of six patients experiences DLTs However if two out of six patients experience DLTs the previous dose level is established as the maximum tolerated dose MTD If two of the first three patients experience DLTs the previous dose is deemed the MTD after treating up to six patients at that dose with no more than two experiencing DLTs If none or only one of the initial three patients or one out of six patients at a dose level of selinexor experience DLTs the dose will be escalated If the dose level at 60mgdose of selinexor is to be increased further 60mgdose DL 2 will be considered the MTD and this dose will be used in the subsequent phase 2 study
Phase 1 part of the study
Treatment will be repeated every three weeks - Selinexor DL1 40mgDL2 60mgDL3 80mg PO day 3 5 7 - Ifosfamide 1500 mgm2 infused over 2 h on days 1-3 - Carboplatin 5 AUC on day 1
- Etoposide 100 mgm2 on days 1-3
- Dexamethasome 40 mg PO or IV on days 1-4
4 Phase 2 Patients with relapsed or refractory DLBCL or FL involving the CNS may be considered for enrollment Those eligible for transplantation may undergo ASCT following a minimum of two cycles of the study treatment Patients ineligible for ASCT may be administered up to six cycles of the study treatment Additionally maintenance selinexor may be provided irrespective of ASCT eligibility provided there is no disease progression after completing selinexor-ICED
Phase 2 part of the study
Treatment will be repeated every three weeks - Selinexor MTD determined by phase 1 part of the study PO day 3 5 7
- Ifosfamide 1500 mgm2 infused over 2 h on days 1-3
Carboplatin 5 AUC on day 1
Etoposide 100 mgm2 on days 1-3
Dexamethasome 40 mg PO or IV on days 1-4
6 Study endpoints
Primary Endpoint
Phase 1 part of the study To determine the maximum tolerated dose MTD and recommended phase 2 dose level RDL of Selinexor combined with ifosfamide carboplatin etoposide and dexamethasone Phase 2 part of the study Objective response rate - complete and partial response
Secondary Endpoints
Phase 1 part of the study Number of participants with dose limiting toxicities Phase 2 part of the study Duration of response Progression-free survival Overall survival and safety
7 Statistical analysis Phase 1 part of the study For phase 1 up to 12 patients for 3 levels of Selinexor 3 patients at each level one cycle will be recruited on the basis of 33 dose escalation design The aim of this phase 1 study is to evaluate the safety and adverse events and to reveal minimal efficacy for the next phase 2 clinical trial thus the sample size was not determined based on the statistical power
Phase 2 part of the study As the primary endpoint of the phase 2 study is objective response rate ORR consisting of complete and partial response at the end-of treatment Although there is limited data about the ORR for relapsed or refractory secondary CNS involving B-cell NHL the estimated ORR rates were around 20 for those patients Thus the sample size calculation for this study is as follows P1 as 40 40 being the response proportion that would imply the treatments warrants further investigation and P0 as 20 20 being the usual probability of response while using conventional therapy According to the Simons Minimax design we obtained a sample size of 33 a 005 b 080 If the ORR is 418 the trial would be stopped If the ORR is 418 the recruitment of subjects would be continued until the number of 33 Considering 10 drop-out rate a total of 37 patients will be recruited
Exportin 1 XPO1CRM1 serves as a nuclear export protein facilitating the movement of tumor suppressor and growth regulator proteins such as TP53 p21 p27 FOXO3 and nucleophosmin 1 NPM1 from the nucleus to the cytoplasm leading to their deactivation XPO1 overexpression is common in various malignancies and correlates with poor prognosis Additionally XPO1 is responsible for the cytoplasmic transport of topoisomerase II enzymes and their cytoplasmic presence is linked to drug resistance as the separation from DNA prevents topoisomerase II inhibitors from triggering cell death
Selinexor is an orally administered pioneering selective inhibitor of nuclear export targeting XPO1 to retain tumor suppressor and growth regulator proteins along with topoisomerase II enzymes in the nucleus thus reinstating their activity Preclinical studies have shown that selinexor can enhance the sensitivity of cancer cells to topoisomerase inhibitors alkylating agents and steroids Selinexor has been approved by the Food and Drug Administration for the treatment of relapsed or refractory DLBCL We propose that selinexor could enhance the effectiveness of the ifosfamide carboplatin and etoposide ICE regimen when combined with ifosfamide an alkylating agent and etoposide a topoisomerase II inhibitor and have included high-dose dexamethasone to potentially increase ICEs efficacy as a salvage therapy for secondary CNS involvement due to its ability to cross the blood-brain barrier
2 Study design Phase III Therapeutic Area Salvage treatment and maintenance for secondary CNS involvement of B-cell NHL Primary Compound Selinexor Additional compounds if applicable Ifosfamide carboplatin etoposide dexamethasone
3 Phase I In the phase 1 study patients must complete one therapy cycle 3 weeks at a given dose level before considering escalation to the next level Escalation is allowed if the initial three patients at a dose level show no dose-limiting toxicities DLTs during the first cycle If one patient experiences DLTs at a dose level of selinexor three more patients will be added to that level Escalation to the next selinexor dose level occurs if only one out of six patients experiences DLTs However if two out of six patients experience DLTs the previous dose level is established as the maximum tolerated dose MTD If two of the first three patients experience DLTs the previous dose is deemed the MTD after treating up to six patients at that dose with no more than two experiencing DLTs If none or only one of the initial three patients or one out of six patients at a dose level of selinexor experience DLTs the dose will be escalated If the dose level at 60mgdose of selinexor is to be increased further 60mgdose DL 2 will be considered the MTD and this dose will be used in the subsequent phase 2 study
Phase 1 part of the study
Treatment will be repeated every three weeks - Selinexor DL1 40mgDL2 60mgDL3 80mg PO day 3 5 7 - Ifosfamide 1500 mgm2 infused over 2 h on days 1-3 - Carboplatin 5 AUC on day 1
- Etoposide 100 mgm2 on days 1-3
- Dexamethasome 40 mg PO or IV on days 1-4
4 Phase 2 Patients with relapsed or refractory DLBCL or FL involving the CNS may be considered for enrollment Those eligible for transplantation may undergo ASCT following a minimum of two cycles of the study treatment Patients ineligible for ASCT may be administered up to six cycles of the study treatment Additionally maintenance selinexor may be provided irrespective of ASCT eligibility provided there is no disease progression after completing selinexor-ICED
Phase 2 part of the study
Treatment will be repeated every three weeks - Selinexor MTD determined by phase 1 part of the study PO day 3 5 7
- Ifosfamide 1500 mgm2 infused over 2 h on days 1-3
Carboplatin 5 AUC on day 1
Etoposide 100 mgm2 on days 1-3
Dexamethasome 40 mg PO or IV on days 1-4
6 Study endpoints
Primary Endpoint
Phase 1 part of the study To determine the maximum tolerated dose MTD and recommended phase 2 dose level RDL of Selinexor combined with ifosfamide carboplatin etoposide and dexamethasone Phase 2 part of the study Objective response rate - complete and partial response
Secondary Endpoints
Phase 1 part of the study Number of participants with dose limiting toxicities Phase 2 part of the study Duration of response Progression-free survival Overall survival and safety
7 Statistical analysis Phase 1 part of the study For phase 1 up to 12 patients for 3 levels of Selinexor 3 patients at each level one cycle will be recruited on the basis of 33 dose escalation design The aim of this phase 1 study is to evaluate the safety and adverse events and to reveal minimal efficacy for the next phase 2 clinical trial thus the sample size was not determined based on the statistical power
Phase 2 part of the study As the primary endpoint of the phase 2 study is objective response rate ORR consisting of complete and partial response at the end-of treatment Although there is limited data about the ORR for relapsed or refractory secondary CNS involving B-cell NHL the estimated ORR rates were around 20 for those patients Thus the sample size calculation for this study is as follows P1 as 40 40 being the response proportion that would imply the treatments warrants further investigation and P0 as 20 20 being the usual probability of response while using conventional therapy According to the Simons Minimax design we obtained a sample size of 33 a 005 b 080 If the ORR is 418 the trial would be stopped If the ORR is 418 the recruitment of subjects would be continued until the number of 33 Considering 10 drop-out rate a total of 37 patients will be recruited
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