Phase II Study of Orelabrutinib Combined With PD-1 Inhibitor in Relapsed/Refractory Primary Central Nervous System Lymphoma

Study Overview
=================
Brief Summary
-----------------
This is a prospective multicenter single-arm phase II study, and the purpose of this study is to evaluate the efficiency of Orelabrutinib combined with PD-1 inhibitor regimen relapsed/refractory primary intraocular lymphoma. Overall response rate （ORR） after 4 cycles is the primary endpoint.

Detailed Description
-----------------
All the patients will be treated with Orelabrutinib combined with PD-1 inhibitor ：Orelabrutinib 150mg qd，Tislelizumab Injection 200mg d1 or Sintilimab injection 200mg d1， every 21-day for 1 cycle). Patients will be evaluated every 2 cycles by MRI scan during the first 6 cycles，and then the interval of investigation will be prolonged to 12 weeks. The patients who achieved complete remission (CR) or partial remission (PR) or stable disease (SD) will receive further treatment. The patients progressed disease (PD) will withdraw from the trial and receive salvage regimens. The treatment will be continued for 2 years or until progression of the disease (PD), unacceptable toxicity, or patient/investigator discretion. During following-up, surveillance ophthalmologic examination and brain magnetic resonance imaging (MRI) scans can be performed every 3 months up for 2 years.

Official Title
-----------------
Orelabrutinib Combined With PD-1 Inhibitor in Relapsed/Refractory Primary Central Nervous System Lymphoma: a Prospective Multi-center Phase II Study

Conditions
-----------------
Primary Central Nervous System Lymphoma

Intervention / Treatment
-----------------
* Drug: orelabrutinib
* Drug: Sintilimab
* Drug: Tislelizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥18 years old ≤75 Years old, male or female Primary Central nerves system lymphoma confirmed by cytology or histology according to WHO2016 criteria No evidence of systemic lymphoma Patients with a clear diagnosis of relapsed and/or refractory PCNSL: they received at least one regimen containing methotrexate. At least one measurable lesion according to Lugano 2014 criteria Adequate organ function and adequate bone marrow reserve Exclusion Criteria: Malignant tumors other than B-NHL within 5 years prior to screening, except cervical carcinoma in situ, basal cell or squamous cell skin cancer, local prostate cancer after radical surgery, and breast ductal carcinoma in situ after radical surgery Active HIV, HBV, HCV or treponema pallidum infection Any instability of systemic disease, including but not limited to active infection (except local infection), severe cardiac, liver, kidney, or metabolic disease need therapy Female subjects who have been pregnant or breastfeeding, or who plan to conceive during or within 1 year after treatment, or male subjects' partner plans to conceive within 1 year after their cell transfusion Active or uncontrolled infections requiring systemic treatment within 14 days before enrollment Any systemic antitumor therapy performed within 2 weeks before enrollment Previous use of other BTK inhibitors or PD-1 inhibitors.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 inhibitor<br>The experimental arm will be treated orelabrutinib plus PD-1(programmed death）inhibitor every 21 days as one cycle. The responses will be evaluated every 2 cycles during the first 6 cycles and every 3 months until progression. The investigators can choose Sintilimab Injection or Tislelizumab Injection at the beginning of treatment，but they can't exchange to another during the whole treatment. | Drug: orelabrutinib<br>* Orelabrutinib will be given as 150mg per day orally, until progression of the disease (PD), unacceptable toxicity, or patient/investigator discretion.<br>Drug: Sintilimab<br>* Sintilimab 200mg intravenous infusion d1, every 21 days for 1 cycle. The medicine will be given until progression of the disease (PD), unacceptable toxicity, or patient/investigator discretion.<br>Drug: Tislelizumab<br>* Tislelizumab 200mg intravenous infusion d1, every 21 days for 1 cycle. The medicine will be given until progression of the disease (PD), unacceptable toxicity, or patient/investigator discretion.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate | ORR was calculated by the proportion of patients who achieved complete remission and partial remission. | 3 weeks after the end of 4 cycles of induction (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1 years progression-free survival | 1 years progression-free survival was calculated from the date of therapy until death from lymphoma or 1-year follow up without relapsing | from the date of treatment to the subject finished his 1 years follow-up phase or the disease relapsed or the death due to lymphoma | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Primary Central Nervous System Lymphoma, orelabrutinib, PD-1 inhibitor, Overall response rate