A Prospective Clinical Study of BTK Inhibitor, PD-1 and Formustine in the First-line Treatment of Primary Central Nervous System Lymphoma

Study Overview
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Brief Summary
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To observe the efficacy and safety of a new generation of BTK inhibitor Orelabrutinib combined with PD-1 and fotemustine in the treatment of patients with primary central nervous system lymphoma (PCNSL).

Detailed Description
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This study includes a dose escalation phase and an extended treatment phase . The dose-escalation phase： Primary study endpoint: Safety endpoint: including dose-limiting toxicity (DLT), adverse events, ECOG performance score, laboratory tests, vital signs, physical examination . Secondary research endpoints: effectiveness endpoints: including complete response rate (CRR), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The study adopts the 3+3 design, that is, 3-6 subjects in each group complete the administration, and the dose group determined as the maximum tolerated dose (MTD) is included in the group of 6 subjects, totaling 9-18 example. The dose planned to be explored is the daily oral dose of the BTK inhibitor abutinib, which is 100 mg, 150 mg and 200 mg, respectively. The doses of other drugs in the plan will not be escalated. After the last subject in each dose group completes the 28-day restricted toxicity (DLT) assessment window after the administration, the investigator can start the entry into the next dose group after evaluating and agreeing to enter the next dose group based on clinical safety data.DLT was defined as any grade 3 or higher nonhematologic toxicity, any grade 4 hematologic toxicity, grade 3 febrile neutropenia, and grade 3 thrombocytopenia with significant bleeding. When 1 case of DLT occurs among 3 subjects in a certain dose group, 3 subjects need to be added to the same dose group (6 subjects in this dose group complete the DLT assessment): If the additional 3 subjects are tested If there is no DLT, continue the dose escalation; if 1 of the 3 increased subjects has DLT, stop the dose escalation; if the increased 3 subjects have >1 of the subjects DLT, the dose escalation is stopped, and the dose needs to be lowered to continue to enroll 3 subjects for DLT evaluation. If DLT occurs in 2 of the 3 or 6 subjects in the dose group, then the previous low dose is defined as the maximum tolerated dose (MTD). The extended treatment phase : Primary study endpoints: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) . Secondary endpoints: time to disease progression (TTP), median survival (MST), adverse reactions (ADR), quality of life (QOL) . The study adopts an open, one-arm, prospective clinical collaborative study . The initial treatment is BTK inhibitor (Obutinib), PD-1 monoclonal antibody combined with formustine ：Orelabrutinib continues to be taken orally until the tumor is relieved for 3 months; PD-1 monoclonal antibody is used by intravenous drip, 21 days as a treatment cycle, and a total of 1 year of observation; formustine is used by intravenous drip for 21 days It is a treatment cycle, a total of 6 cycles of observation; after 2 cycles, the efficacy is evaluated, and adverse reactions are recorded. At the same time, MTX 12mg+Ara-C 50mg+Dex 5mg was injected into the CSF cytology-positive sheath, and intrathecal injection once per treatment cycle, a total of 6 times. Second stage treatment ：The efficacy was evaluated after 6 cycles of treatment in the initial stage. The CR patients continued to take orally abutinib (150mg, qd) for three months, and the PD-1 monoclonal antibody was used for maintenance treatment for up to 1 year; the PR patients received whole brain radiotherapy (WBRT), and at the same time Continue oral obritinib (150mg, qd) for three months and PD-1 monoclonal antibody maintenance treatment for up to one year; SD and PD patients choose methotrexate + pemetrexed combined chemotherapy for 4 cycles followed by whole brain radiotherapy (WBRT). WBRT: Regardless of age, supplementary WBRT 30-36Gy + partial reduction field irradiation up to 45Gy.

Official Title
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A Prospective Clinical Study of a New Generation of BTK Inhibitors Combined With PD-1 and Formustine in the First-line Treatment of Primary Central Nervous System Lymphoma

Conditions
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Primary Central Nervous System Lymphoma

Intervention / Treatment
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* Drug: the dose-escalation phase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-69 years; KPS score ≥ 60 points or ECOG score ≤ 2 points; expected survival time of more than 3 months; PCNSL confirmed pathologically by tissue biopsy (limited to the brain, not accompanied by lymphoma in other parts of the body) , And histopathological type is diffuse large B-cell lymphoma; no chemotherapy contraindications (blood picture and physiological examination result time <7 days); at least one measurable lesion according to RECIST standards; no other serious diseases that conflict with this plan ; Follow-up is possible; other anti-tumor drugs are not used during this treatment period, and bisphosphonate anti-bone metastasis therapy and other symptomatic treatments can be applied; understand the situation of this study and sign the informed consent. Exclusion Criteria: Those who are currently receiving other chemical, radiotherapy and targeted therapies (received chemotherapy within 3 weeks, received radiotherapy within 2 weeks, or have not recovered from the acute toxicity of any previous treatment); pregnant or lactating women; yes Any uncontrollable medical disease (including active infection, uncontrolled diabetes, severe heart, liver, kidney dysfunction, and interstitial pneumonia, etc.); those who are contraindicated with chemotherapy such as cachexia; have had other malignant tumors in the past Those who have uncontrolled infections; those who have a history of uncontrollable mental illness; those who are considered unsuitable to participate in this trial by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Orelabrutinib combined with PD-1 and fotemustine<br>To observe the efficacy and safety of a new generation of BTK inhibitor abutinib combined with PD-1 and formustine in the treatment of newly-treated patients with primary central nervous system lymphoma (PCNSL) | Drug: the dose-escalation phase<br>* The study adopts the 3+3 design,The dose planned to be explored is the daily oral dose of the BTK inhibitor abutinib, which is 100 mg, 150 mg and 200 mg, respectively.Orelabrutinib continues to be taken orally until the tumor is relieved for 3 months; PD-1 monoclonal antibody is used by intravenous drip, 21 days as a treatment cycle, and a total of 1 year of observation; formustine is used by intravenous drip for 21 days It is a treatment cycle, a total of 6 cycles of observation; after 2 cycles, the efficacy is evaluated, and adverse reactions are recorded. At the same time, MTX 12mg+Ara-C 50mg+Dex 5mg was injected into the CSF cytology-positive sheath, and intrathecal injection once per treatment cycle, a total of 6 times.<br>* Other names: The extended treatment phase;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT | Dose-limiting toxicity | up to 24 months | 
| AE | adverse events | up to 24 months | 
| ECOG performance score | ECOG performance score | up to 24 months | 
| laboratory tests | laboratory tests | up to 24 months | 
| vital signs | vital signs | up to 24 months | 
| physical examination | physical examination | up to 24 months | 
| ORR | Objective Responder Rate | up to 24 months | 
| DCR | Disease Control Rate | up to 24 months | 
| PFS | Progression Free Survival | up to 24 months | 
| OS | Overall Survival | up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | Objective Responder Rate | up to 24 months | 
| DCR | Disease Control Rate | up to 24 months | 
| PFS | Progression Free Survival | up to 24 months | 
| OS | Overall Survival | up to 24 months | 
| ADR | Adverse Reaction Rate | up to 24 months | 
| CRR | complete response rate | up to 24 months | 
| TTP | Time to disease progression | up to 24 months | 
| MST | median survival | up to 24 months | 
| ADR | adverse reactions | up to 24 months | 
| QOL | quality of life | up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BTK inhibitor, PD-1, fotemustine, CRR, ORR, DCR, PFS, OS, ADR, Adverse events, ECOG score, laboratory examination, vital signs, physical examination, Time to disease progression (TTP), median survival (MST), quality of life (QOL), adverse reactions (ADR)