Study of Purinostat Mesylate for Injection in the Treatment of Diffuse Large B-cell Lymphoma (DLBCL)

Study Overview
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Brief Summary
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Purinostat mesylate for injection (PM) was the novel and highly potent Class I a and IIb HDAC-selective inhibitors. The results of regular blood sampling analysis of the mouse B-cell lymphoma model induced by ighmyc transgenic mice showed that the treatment of PM in each group reduced the proportion of peripheral blood tumor cells in mice. Therefore, PM has the potential to treat diffuse large B cell lymphoma. The results of in vitro enzymatic activity screening showed that PM has high inhibitory activity on HDAC tumors (including HDAC1, 2, 3, 8 subtypes) and type II HDACs (including HDAC6, 10 isoforms), which are closely related to tumors in the HDAC family. Therefore, the results of in vitro enzyme activity screening showed that the IC50 values of PM for inhibiting HDAC1, HDAC2, HDAC3, HDAC8, HDAC6, and HDAC10 subtypes of HDAC class I and HDAC class IIb were 0.81, 1.4, 1.7, 3.8, 11.5, and 11 nM, respectively. However, the inhibitory activity of HDAC IIa and HDAC IV enzymes was low, and its IC50 values for HDAC4, HDAC5, HDAC7, HDAC9, and HDAC11 subtypes of HDAC IIa and HDAC IV were 1072, 426, 590, 622, and 3349 nM, respectively. These data means PM exist high selectivity for tumor-associated HDAC class I and HDAC IIb. Compared with the blank control group, the body weight of the tumor-bearing animals in each dose of PM group did not decrease seriously during the treatment process, and the animals were in good condition during the whole experiment, indicating that the PM is efficacy and safe. Main purpose: To further explore the safe and effective dose of priinostat mesylate for injection in the treatment of relapsed or refractory diffuse large B-cell lymphoma. To evaluate the objective response rate (ORR) of priinostat mesylate for injection in the treatment of relapsed or refractory diffuse large B-cell lymphoma. Secondary purpose: To explore the biomarkers related to the efficacy of priinostat mesylate for injection. To evaluate the time to tumor response (TTR), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) in the treatment of relapsed or refractory diffuse large B-cell lymphoma with prilinostat mesylate for injection ), overall survival (OS). Assessing the safety and tolerability of priinostat mesylate for injection in the treatment of relapsed or refractory diffuse large B-cell lymphoma.

Official Title
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An Open-label, Multi-center Phase II Clinical Study on the Efficacy and Safety of Purinostat Mesylate for Injection in the Treatment of Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)

Conditions
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Diffuse Large B Cell Lymphoma，DLBCL

Intervention / Treatment
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* Drug: PM 8.4 mg/m2
* Drug: PM 11.2 mg/m2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females, of any race,18 Years and older 2. The pathology of tissue biopsy was diagnosed as relapsed refractory diffuse large B cell lymphoma (DLBCL)(including the DLBCL transformed from primary and indolent lymphoma, patients with recurrence more than one year should undergo a second biopsy to confirm the pathological diagnosis), the specific definitions: Previously received ≤ 5 line of adequate systemic anti DLBCL therapy; Relapsed including: 1) disease that has recurred ≥ 6 months after completion of the 2 line；2) recurrence within 3 months after second-line therapy followed by hematopoietic stem cell transplantation. Refractory including: 1) First line therapy to the refractory and idiopathic (ineffective treatment or recurrence within 6 months after completion of treatment); 2) recurrence within 6 months after completion of second-line treatment, couldn't achieved disease remission (PR) after 2 or more cycles of second-line treatment，or PD within the completion of the 2 line treatment regimen, can be accepted as refractory patients. Previously treated with anti CD20 sheet resistance (unless contraindicated) and chemotherapy containing anthracyclines (unless contraindicated due to the anthracycline); Anti-cd20 mab monotherapy for consolidation or induction does not count as a separate line of treatment; Prior stem cell transplantation is permitted；Autologous stem cell transplantation alone does not count as first-line therapy; Induction, consolidation, stem cell collection, pretreatment protocols, and transplant ± maintenance treatment are belong to one treatment line； Participants must have measurable lesions. The measurable lesions criteria：measure the lymph node of lymph node lesion > 15mm and the lymph node of outside the junction lesions > 10mm by enhancement CT, MRI, and PET-CT; Be able to accept the possibility of bone marrow aspiration cytology and (or) biopsy at efficacy evaluation. Whole body radiation therapy must be completed more than 4 weeks before this study；Latest local radiotherapy or radiotherapy for bone metastases must be completed more than 2 weeks before this study; No radiation was administered in prior 8 weeks of the first dose in this study; Latest prior chemotherapy or approved targeted therapy must be completed more than 3 weeks before this study; Biotherapy, immunotherapy, and other treatments must be completed more than 4 weeks before the first dose of the study; ECOG≤2; Life expectancy of more than 12 weeks; The results of routine blood met the following criteria: a) Absolute value of neutrophil count ≥1.0×109/L; b) hemoglobin (HGB) ≥80 g/L；c) Platelet count (PLT) ≥75×109/L，and without infusion of platelets and red blood cell suspension within 2 weeks prior before screening; PS: If investigator believed that the patient's examination value below the lower limit of the protocol was due to the lymphoma invading bone marrow, this patient can be acceptable or not after discussion with the sponsor and the medical director of CRO. The results of liver and kidney function tests met the following criteria：a) Total bilirubin (TBiL) ≤ 1.5 × upper normal value (ULN); b) Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Alkaline phosphatase (ALP) ≤ 2.5 × ULN；c) Serum creatinine ≤ 1.5 × ULN; PS: TBiL ≤ 5 × ULN is acceptable for the patients with gilbert syndrome; AST, ALT, and ALP ≤ 5 × ULN is acceptable for the patients with Liver lymphoma. Left ventricular ejection fraction (LVEF) ≥ 50%; Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for the time period between signing of the informed consent form and 12 months after last purinostat mesylate for injection dose. Pregnancy test within 7 days must be negative for WOCBP (including pre-menopausal women and women within 1 year after menopause). Ability to understand and willingness to sign written informed consent. Ability to communicate with researchers, adherence to plan visits in the study, treatment plan, laboratory tests, and other Exclusion Criteria: Known severe allergy to the test drug or any of its excipients; Primary central nervous system lymphoma or lymphoma invasion of the central nervous system; Large mass (tumor is the longest Diameter > 75 mm); Previous chronic lymphoma transformation (such as Richter syndrome, prelymphocytic leukemia, etc.); The presence of other active malignant tumors requiring treatment that may interfere with this study; Solid organ or allogeneic hematopoietic stem cell transplantation history; Coagulopathy, international normalized ratio (INR) >1.5×ULN or prothrombin time(PT) >1.5×ULN or activated partial thromboplastin time (APTT) >1.5×ULN or thrombin time (TT) >1.5×ULN or fibrinogen (FIB) < 1 g/L; Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in patients who are not Exceptions: a) HBV infection: Hepatitis B surface antigen (HbsAg) or hepatitis B Core Antibody (HbcAb)Patients with HBV DNA≤1×103 copies /ml were admittedGroup, antiviral therapy was required after enrollment, and hepatitis B DNA titer was tested every cycle. B). Patients with HCV seropositivity but negative HCV RNA test were enrolled. Human immunodeficiency virus Antibody (HIV-AB) or anti-treponema pallidum antibody (TP-AB) positive; Meeting any of the following cardiac function criteria: a) various clinically significant arrhythmia or conduction abnormalities. Often, clinical intervention is required; B) The mean corrected QT interval (QTcf) obtained from three electrocardiogram (ECG) examinations was >450 Msec (male) or >470 msec (female) (QTcf>450 msec (male) only on first ECG or >470 msec (female), the test should be retested and the average correction value should be taken three times; C) History or evidence of long QT syndrome. Family history of long QT syndrome; A history of clinically significant ventricular arrhythmias, or current use of antihypertensive agents. An arrhythmia drug or a defibrillation device implanted in the body to treat ventricular arrhythmias; D) All kinds have clinical implications. Cardiovascular disease, including acute myocardial infarction, unstable angina pectoris, and coronary motion within 6 months before enrollment. Pulse bypass surgery, cardiomyopathy, New York College of Cardiology (NYHA) grade 3 or above congestive heart failure, left ventricular ejection fraction (LVEF) <50%; Combined with other systemic diseases: a) diabetes mellitus with poor blood glucose control; B) Severe lung disease (CTCAE V5.0 Grade III-IV); C) A history of mental illness or psychosis as judged by the researcher or psychologist family history of illness or mood disorders, including medical records of depressive episodes, bipolar disorder (I or II), obsessive-compulsive disorder Illness, schizophrenia, history of suicide attempts or suicidal ideation, or thoughts of homicide (immediate harm to others), anxiety level 3 or above; Treatment before the trial: a). Chimeric antigen receptor T-cell immunotherapy was performed within 3 months before enrollment(CAR-T therapy); B) Received PI3K inhibitor, mTOR inhibitor, and other HDAC before enrollment inhibitors (except cedarbenamine) and other small molecule targeted drugs; C) Autologous surgery was performed within 3 months before enrollment hematopoietic stem cell transplantation; D) Received radiotherapy within 3 months before enrollment that affected the efficacy evaluation of this study, or local radiotherapy affecting the bone marrow function of subjects; E) Received myelosuppressive chemotherapy within 3 weeks before enrollment or biologic or targeted therapy; F) Underwent major surgery other than tumor biopsy or surgery within 4 weeks before enrollment side effects have not stabilized; G) Received any hematopoietic colony-stimulating factor therapy within 2 weeks prior to enrollment (e.g Granulocyte colony-stimulating factor G-CSF, granulocyte macrophage colony-stimulating factor GM-CSF), recombinant IL-11 or thrombopoietin or TPO-R agonists. Note: Subjects who started EPO or daypotin within 2 weeks before enrollment were eligible for enrollment; H) Received prednisone >10 mg daily within 7 days before enrollment (or other comparable doses of glucocorticoids, see Appendix 2). note: if used in the treatment of patients other than lymphoma other medical conditions, such as rheumatoid arthritis, polymyalgia rheumatica, adrenal insufficiency, or asthma, were tested. Patients may receive a stable dose of prednisone (or another comparable dose of glucocorticoid) at a maximum dose of 10 mg daily Hormone); Persistent grade 2 or higher (CTCAE) after previous treatment (chemotherapy, biotherapy, or targeted therapy)v5.0 criteria) toxic reaction, did not recover to ≤ grade 1 level at the time of enrollment (except hair loss); There is an active clinical infection of grade 2 or higher (CTCAE V5.0 criteria) that requires systemic (oral or oral) infection intravenous) to give anti-infective treatment; In the 7 days prior to study entry, patients had received the following treatments: known to be potent inhibitors of CYP3A4 inducer drugs, drugs known to significantly prolong the QT interval (allowing combination therapy with weak CYP3A4 inhibitors) Therapy; See Appendix 3 for a list of common CYP3A4 inhibitors or inducers); Participated in other interventional clinical trials within 4 weeks before enrollment; Pregnant or lactating women; Persons with alcohol dependence or drug abuse; Conditions that the investigator determines may compromise the subject's safety or compliance; Subjects deemed by the Investigator to be unsuitable for the study;

Ages Eligible for Study
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Minimum Age: 18 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: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PM 8.4 mg/m2<br>15 case，Take the medicine once on D1 ，D 1 through 21. | Drug: PM 8.4 mg/m2<br>* 1 case, Take the medicine once on D1,D 1-21.<br>|
| Experimental: PM 11.2 mg/m2<br>15 case，Take the medicine once on D1 ，D 1 through 21. | Drug: PM 11.2 mg/m2<br>* 1 case, Take the medicine once on D1,D 1-21.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) of PM | Proportion of patients whose tumor volume was reduced to a pre-specified value and maintained at the minimum time limit | 63day | 
| Tumor response time (TTR) of PM |  | 63day | 
| Duration of relief (DOR) of PM | The time from the first diagnosis of complete remission (CR) or partial remission (PR) to the discovery of disease progression (PD) | 63day | 
| Disease control rate (DCR) of PM | In all tumor patients receiving a certain treatment, the tumor shrinks or remains stable, and this state can be maintained for a certain period of time | 63day | 
| Progression-free survival (PFS) of PM | Time from randomization to first occurrence of disease progression or death from any cause | 63day | 
| Overall survival (OS) of PM | Time from randomization to death from any cause, | 63day |