Sequential Treatment With RO-MTX After Pomalidomide, Orelabrutinib, Rituximab (POR) in Newly-diagnosed PCNSL

Study Overview
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Brief Summary
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This is a multicenter prospective single arm phase II study, and the purpose of this study is to evaluate the safety and efficacy of sequential treatment regimens with RO-MTX after pomalidomide, orelabrutinib, rituximab (POR) in newly-diagnosed primary central nervous system lymphoma, and explore the feasibility of chemo-free treatment in PCNSL. The primary objective was the overall response rate (ORR; defined as partial response [PR] or better) after 4 cycles of POR.

Detailed Description
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There are 2 sections of this trial. Step1: the patients will be treated with 4 cycles of POR regimen （Pomalidomide 4mg d1-d14, Orelabrutinib 150mg d1-d21, Rituximab 375mg/m2 d1, 21 days per cycle). The response will be evaluated every 2 cycles. The patients with PD will drop out of the study. Step2: Patients with CR/PR/SD after 4 cycles of POR treatment will be treated with 2 cycles of RO-MTX regimen（methotrexate 3.5g/m2 civ d1, Orelabrutinib 150mg d1-d21, Rituximab 375mg/m2 d1, 21 days per cycle). After 6 cycles of induction therapy, all patients were followed for survival data every 12 week until disease progression, disease recurrence, death, or study termination. Patients with progression were also followed up for survival data as above. Overall survival will be followed up to 3 years after the last subject entered the study. Establishing the feasibility of chemo-free treatment in primary central nervous system lymphoma will provide the foundation for a larger study of efficacy and long-term outcomes of chemo-free therapy for patients with PCNSL.

Official Title
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Sequential Treatment Regimens With RO-MTX After Pomalidomide, Orelabrutinib, Rituximab (POR) as Frontline Therapy for Primary Central Nervous System Lymphoma: a Multicenter Prospective Single Arm Trial

Conditions
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Primary Central Nervous System Lymphoma

Intervention / Treatment
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* Drug: Orelabrutinib
* Drug: Pomalidomide
* Drug: Rituximab
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Newly diagnosed primary central nervous system lymphoma Pathological type is B cell lymphoma Age 18-70 years Demonstrate adequate marrow hemopoietic function as defined below:WBC>3.0×109/L,ANC>1.5×109/L,HGB>90g/L,PLT>80×109/L Demonstrate adequate organ function as defined below: cardiac function grade 0-2（NYHA）；SpO2>88%( natural state)；ALT<3UNL，TBil<2ULN; SCr>60ml/min/m2 Having at least one measurable lesions Sign the Informed consent Exclusion Criteria: • The pathological diagnosis was T-cell lymphoma. systemic lymphoma involved CNS Pre-existing uncontrolled active infection Acute myocardial infarction or unstable angina within 6 months; Uncontrolled hypertension and arrhythmia Active bleeding Allergic to any component of the investigational product. Subjects who are suspected to be unable to comply with the study protocol Pregnancy or active lactation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: POR-ROMTX<br>The experimental arm will be treated with 4 cycles of POR regimen （Pomalidomide 4mg d1-d14, Orelabrutinib 150mg d1-d21, Rituximab 375mg/m2 d1, 21 days per cycle). The response will be evaluated every 2 cycles. The patients with PD will drop out of the study.Patients with CR/PR/SD after 4 cycles of POR treatment will be treated with 2 cycles of RO-MTX regimen（methotrexate 3.5g/m2 civ d1, Orelabrutinib 150mg d1-d21, Rituximab 375mg/m2 d1, 21 days per cycle). | Drug: Orelabrutinib<br>* Orelabrutinib will be given as 150mg orally d1-d21 for 6 cycles,every 21 days for 1 cycle.<br>Drug: Pomalidomide<br>* Pomalidomide will be given as 4mg d1-d14 for 4 cycles,every 21 days for 1 cycle.<br>Drug: Rituximab<br>* Rituximab 375mg/m2 intravenous infusion d1, every 21 days for 1 cycle. 6 cycles will be prescribed as protocol<br>Drug: Methotrexate<br>* methotrexate 3.5g/m2 civ d1/cycle5-6<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate | ORR is defined as the proportion of patients with a best response of CR, CRu or PR | The ORR will be evaluated at 82 days from the POR treatment, which means after 4 cycles and each cycle is 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate | ORR is defined as the proportion of patients with a best response of CR, CRu or PR | The ORR will be evaluated at 126 days from date of signing the informed consent , which means after 6 cycles and each cycle is 21 days | 
| complete response rate | CR is defined as the proportion of patients with a best response of CR or CRu | The ORR will be evaluated at 82 days from the POR treatment, which means after 4 cycles and each cycle is 21 days | 
| 2 years progression-free survival | 2 years progression-free survival was calculated from the date of therapy until death from lymphoma or 2-year follow-up without relapsing | From date of signing the informed consent until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| 2 years overall survival | 2 years progression-free survival was calculated from the date of therapy until death from lymphoma or 2-year follow-up alive | From date of signing the informed consent until the date of death from any cause, whichever came first, assessed up to 2 years | 
| The occurrence of adverse events and serious adverse events | Adverse events will be graded by the investigator according to the NCI-CTCAE Version 5.0. | during follow-up, up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Orelabrutinib, Pomalidomide, Rituximab, primary central nervous system lymphoma, methotrexate