R-MINE+X in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma

Study Overview
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Brief Summary
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Based on the modified R-MINE of mitoxantrone hydrochloride liposome, the corresponding targeted drug (X) was added according to the genotyping detected by second-generation gene sequencing (NGS) to explore the effectiveness and safety of R-MINE+X in the treatment of recurrent/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

Detailed Description
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Compared with traditional mitoxantrone, mitoxantrone liposomes can significantly prolong the survival time of patients and reduce the cardiotoxicity and non-hematological toxicity of anthracycline drugs. At present, there are no studies on the efficacy and safety of R-MINE+X regimen based on molecular typing in the treatment of R/R DLBCL. Therefore, based on NGS, R/R DLBCL was divided into different molecular types (MCD subtype, BN2 subtype, EZB subtype, A53 subtype and other subtype), and on this basis, different molecular types of targeted drugs (X: MCD/BN2 subtype - BTK inhibitor, EZB subtype - Chidamide, A53 subtype - PD-1 monoclonal antibody and other type - lenalidomide) were used to treat R/R DLBCL. The main purpose was to observe the effectiveness and safety of the program in R/R DLBCL.

Official Title
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An Open, Single-arm, Multi-center Clinical Trial of Molecular Subtype-guided R-MINE+X Regimen in the Treatment of Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL)

Conditions
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Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Rituximab
* Drug: Mitoxantrone hydrochloride liposome
* Drug: Isophosphamide
* Drug: Etoposide
* Drug: X: Orelabrutinib
* Drug: X: Chidamide
* Drug: X: Penpulimab
* Drug: X: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Join the study voluntarily and sign the informed consent; Age ≤ 18 years old ≤75 years old; Expected survival time ≥3 months; Recurrent or refractory diffuse large B-cell lymphoma confirmed by histopathology; Consistent with relapsed or refractory lymphoma: Relapsed lymphoma refers to lymphoma that relapsed after CR obtained from initial chemotherapy. Refractory lymphoma is diagnosed by meeting any of the following criteria: 1) tumor shrinkage < 50% or progression after 4 courses of chemotherapy prescribed by the standard regimen; 2) CR was achieved by standard chemotherapy, but recurrent within half a year; 3) Relapse for two or more times after CR; 4) Recurrence after hematopoietic stem cell transplantation; There must be at least one evaluable or measurable lesion in line with Lugano2014 criteria: lymph node lesion, the length and diameter of detectable lymph node must be greater than 1.5cm; For non-lymph node lesions, the diameter of extrinsic lesions should be > 1.0cm; ECOG score 0-2; Bone marrow function: neutrophil count ≥1.5×10^9/L, platelet count ≥75×10^9/L, hemoglobin ≥80g/L (neutrophil count ≥1.0×10^9/L, platelet count ≥50×10^9/L, hemoglobin ≥75g/L in patients with bone marrow involvement); Liver and kidney function: serum creatinine ≤1.5 times the upper limit of normal value; AST and ALT ≤2.5 times the upper limit of normal value (≤5 times the upper limit of normal value for patients with liver invasion); Total bilirubin ≤1.5 times the upper limit of normal value (≤3 times the upper limit of normal value for patients with liver invasion); Exclusion Criteria: The subject's previous history of antitumor therapy meets one of the following conditions: Previous recipients of mitoxantrone or mitoxantrone liposomes; Prior treatment with doxorubicin or anthracycline with a cumulative dose of doxorubicin > 360 mg/m2 (1 mg of doxorubicin for other anthracyclines); Patients who had received autologous hematopoietic stem cell transplantation or had received allogeneic hematopoietic stem cell transplantation within 100 days of the first medication; Received anti-tumor therapy (including chemotherapy, targeted therapy, hormone therapy, taking anti-tumor active Chinese medicine, etc.) or participated in other clinical trials and received clinical trial drugs within 4 weeks before the first use of the drug in this study; Hypersensitivity to any investigational drug or its components; Uncontrolled systemic diseases (such as advanced infections, uncontrolled hypertension, diabetes, etc.); Cardiac function and disease conform to one of the following conditions: Long QTc syndrome or QTc interval >480 ms; Complete left bundle branch block, complete right bundle branch block with left anterior branch block, second degree type II, or third degree atrioventricular block; severe, uncontrolled arrhythmias requiring medical treatment; New York College of Cardiology Grade ≥ III; A history of acute myocardial infarction, unstable angina pectoris, severely unstable ventricular arrhythmias or any other arrhythmia requiring treatment, a history of clinically severe pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction abnormalities within the 6 months prior to recruitment. Hepatitis B and hepatitis C active infection (hepatitis B virus surface antigen positive and hepatitis B virus DNA more than 1x10^3 copies /mL; HCV RNA over 1x10^3 copies /mL); Human immunodeficiency virus (HIV) infection (HIV antibody positive); Past or present co-existing malignancies (in addition to non-melanoma basal cell carcinoma of the skin, carcinoma in situ of the breast/cervix, and other malignancies that have been effectively controlled without treatment in the past five years); Primary or secondary central nervous system (CNS) lymphoma or history of CNS lymphoma at the time of recruitment; There is significant gastrointestinal disease at the time of screening that may affect drug intake, transport or absorption (e.g. inability to swallow, chronic diarrhea, intestinal obstruction, etc.); Pregnant and lactating women and patients of childbearing age who do not wish to take contraceptive measures; Situations in which other researchers have determined that participation in this study is not appropriate.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: R-MINE+X<br>R-MINE: Rituximab, Isophosphamide, Mitoxantrone hydrochloride liposome, Etoposide X: Orelabrutinib, Chidamide, Penpulimab, Lenalidomide | Drug: Rituximab<br>* 375 mg/m2, d0, Cycle 1 4<br>Drug: Mitoxantrone hydrochloride liposome<br>* 20 mg/m2, d1, Cycle 1 4<br>Drug: Isophosphamide<br>* 1.33 g/m2, d1-3(Rescue with equal dose of mesperidine), Cycle 1 4<br>Drug: Etoposide<br>* 65 mg/m2, d1-3, Cycle 1 4<br>Drug: X: Orelabrutinib<br>* MCD/BN2 subtype: BTK inhibitor-Orelabrutinib: 150 mg/d, d1-21, Cycle 2 4<br>Drug: X: Chidamide<br>* EZB subtype: Chidamide: 20 mg/d, d1, d4, d8, d11, Cycle 2 4<br>Drug: X: Penpulimab<br>* TP53 mutation - X: PD-1 monoclonal antibody - Penpulimab: 200mg/d, d0, Cycle 2 4<br>Drug: X: Lenalidomide<br>* Other-X: Lenalidomide: 25mg/d, d1-10, Cycle 2 4<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate(ORR) | Objective response rate (ORR) after 4 cycles of R-MINE+X chemotherapy | up to 4 cycles of chemotherapy(each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission rate(CRR) | Complete remission rate(CRR) after 4 cycles of R-MINE+X chemotherapy | up to 4 cycles of chemotherapy(each cycle is 21 days) | 
| Duration of remission(DOR) | Time from reaching CR or PR for the first time to disease progression | up to 4 cycles of chemotherapy(each cycle is 21 days) | 
| Progression-Free-Survival rate | from date of inclusion to date of progression, relapse, or death from any cause | 1 year | 
| Overall survival rate | from the date of inclusion to date of death, irrespective of cause | 1 year | 
| Adverse events (AE) | The safety of the drug was evaluated by NCI-CTC AE 5.0 standard | From the first day of medication to 28 days after the last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLBCL, R-MINE+X, Mitoxantrone liposome