Mitoxantrone Hydrochloride Liposome Combined With Rituximab and Lenalidomide (M+R2) in Patients With Relapsed and Refractory Diffuse Large B-Cell Lymphoma

Study Overview
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Brief Summary
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To evaluate the safety and efficacy of mitoxantrone hydrochloride liposome in combination with rituximab and lenalidomide in the treatment of relapsed and refractory diffuse large B-cell lymphoma (DLBCL).

Detailed Description
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This is a prospective, single-arm, multicenter phase Ⅱ clinical study to evaluate the safety and efficacy of mitoxantrone hydrochloride liposome in combination with rituximab and lenalidomide in patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL). Mitoxantrone hydrochloride liposome will be given on day 1 at the dose of 20 mg/m2 and be combined with rituximab and lenalidomide. A maximum of 6 cycles of therapy are planned.

Official Title
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A Prospective, Single-arm, Multicenter Clinical Study of Mitoxantrone Hydrochloride Liposome Combined With Rituximab and Lenalidomide in the Treatment of Relapsed and Refractory Diffuse Large B-cell Lymphoma

Conditions
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Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Mitoxantrone Hydrochloride Liposome
* Drug: Rituximab
* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1.Subjects fully understand and voluntarily participate in this study and sign the informed consent form (ICF); 2.60-75 years old; 3.Expected survival ≥ 3 months; 4.Subjects with histologically confirmed diagnosis of relapsed and refractory diffuse large B-cell lymphoma who have received at least 4 cycles of first-line chemotherapy including rituximab and anthracyclines; Relapsed lymphoma is defined as the lymphoma that relapse after obtaining complete response (CR) after initial chemotherapy; Refractory lymphoma subjects meet one of the following conditions: 1) The tumor shrinks <50% or disease progression after 4 cycles of standard chemotherapy,; 2) CR after standard chemotherapy, but relapse within half a year; 3) 2 or more relapses after CR; 4) relapse after hematopoietic stem cell transplantation; 5.Subjects who are not eligible for transplantation or do not plan to undergo transplantation at the beginning of the study; 6.ECOG Performance Status: 0-2; 7.Subjects must have at least one evaluable or measurable lesion per lugano2014 criteria: for lymph node lesions, the length should be > 1.5cm; For non-lymph node lesions, the length should be > 1.0cm; 8.Bone marrow function: Absolute neutrophil count ≥1.5×109/L, Platelet count ≥75×109/L, Hemoglobin ≥ 80g/L (Absolute neutrophil can be relaxed to ≥ 1.0×109/L, Platelet count can be relaxed to ≥50×109/L, Hemoglobin can be relaxed to ≥75 g/L in subjects with poor bone-marrow reserve); 9.Liver and kidney function: serum creatinine ≤ 1.5×ULN (upper limit of normal); AST and ALT ≤ 2.5×ULN (≤ 5×ULN for subjects with liver metastases); total bilirubin ≤ 1.5×ULN (≤ 3×ULN for subjects with liver metastases). Exclusion Criteria: 1. The subject had previously received any of the following anti-tumor treatments: Subjects who have been treated with mitoxantrone or mitoxantrone liposomes; Previously received doxorubicin or other anthracycline treatment, and the total cumulative dose of doxorubicin was more than 360 mg/m2 (1 mg doxorubicin equivalent to 2 mg epirubicin); Subjects who received anti-tumor treatment (including chemotherapy, targeted therapy, glucocorticoid, traditional Chinese medicine with anti-tumor activity, etc.) or participated in other clinical trials and received trial drugs within 4 weeks or 5 T1/2s before the first administration of the study drugs; Subjects who received lenalidomide. 2.Subjects with refractory lymphoma meet one of the following criteria: 1) Tumors assessed as SD/PD after ≥2 lines of chemotherapy; 2) Subjects relapse within 6 months after transplantation. 3.Hypersensitivity to any study drug or its components; 4.Uncontrolled systemic diseases (such as active infection, uncontrolled hypertension, diabetes, etc.) 5.Heart function and disease meet one of the following conditions: Long QTc syndrome or QTc interval > 480 ms; Complete left bundle branch block, grade II or III atrioventricular block; Serious and uncontrolled arrhythmias requiring drug treatment; New York Heart Association grade ≥ III; Cardiac ejection fraction (LVEF)< 50%; A history of myocardial infarction, unstable angina pectoris, severe unstable ventricular arrhythmia or any other arrhythmia requiring treatment, a history of clinically serious pericardial disease, or ECG evidence of acute ischemia or active conduction system abnormalities within 6 months before recruitment. 6.Hepatitis B and hepatitis C active infection (plus HBV DNA if one positive for hepatitis B surface antigen or core antibody and HBV DNA more than 1×103 copy/mL excluded; plus HCV RNA if hepatitis C antibody positive and HCV RNA more than 1×103 copy/mL exclude) 7.Baseline B-type pro-brain natriuretic peptide (NT-proBNP) > 1800pg/ml, troponin I (cTnI) > ULN of our center, and the retest data is still higher than the above range after three days; 8.Human immunodeficiency virus (HIV) infection (HIV antibody positive); 9.Subjects with other malignant tumors past or present (except for non-melanoma skin basal cell carcinoma, breast/cervical carcinoma in control, and other malignant tumors that have been effectively controlled without treatment within the past five years); 10.Subjects suffering from primary or secondary central nervous system (CNS) lymphoma or a history of CNS lymphoma at the time of recruitment; 11.Unsuitable subjects for this study determined by the investigator.

Ages Eligible for Study
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Minimum Age: 60 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: mitoxantrone hydrochloride liposome<br>Patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) will receive sequentially mitoxantrone hydrochloride liposome in combination with rituximab and lenalidomide for up to 6 cycles (28 days per cycle). | Drug: Mitoxantrone Hydrochloride Liposome<br>* Drug: Mitoxantrone hydrochloride liposome (20 mg/m2) will be administered by an intravenous infusion on day 1 of each 28-day cycle.<br>Drug: Rituximab<br>* Drug: Rituximab (375 mg/m2) will be administered by an intravenous infusion on day 1 of each 28-day cycle.<br>Drug: Lenalidomide<br>* Drug: Lenalidomide (25 mg) will be taken orally from day 1 to day 8 of each 28-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | To investigate the preliminary antitumor efficacy | through study completion, an average of 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | To investigate the preliminary antitumor efficacy | through study completion, an average of 2 year | 
| Duration of relief (DOR) | To investigate the preliminary antitumor efficacy | through study completion, an average of 2 year | 
| Disease Control Rate (DCR) | To investigate the preliminary antitumor efficacy | through study completion, an average of 2 year | 
| Best of response (BOR) | To investigate the preliminary antitumor efficacy | 6-8 weeks | 
| Safety endpoint: The incidence and severity of AE and SAE Safety endpoint: The incidence and severity of AE and SAE Safety endpoint:The incidence and severity of AE and SAE | To identify the incidence and severity of AE and SAE (NCI CTCAE v5.0) | through study completion, an average of 2 year |