Trial Title:
Study of Purinostat Mesylate for Injection in the Treatment of Diffuse Large B-cell Lymphoma (DLBCL)
NCT ID:
NCT05563844
Condition:
Diffuse Large B Cell Lymphoma,DLBCL
Conditions: Official terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Other
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Intervention:
Intervention type:
Drug
Intervention name:
PM 8.4 mg/m2
Description:
1 case, Take the medicine once on D1,D 1-21.
Arm group label:
PM 8.4 mg/m2
Intervention type:
Drug
Intervention name:
PM 11.2 mg/m2
Description:
1 case, Take the medicine once on D1,D 1-21.
Arm group label:
PM 11.2 mg/m2
Summary:
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.
Criteria for eligibility:
Criteria:
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;
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Shandong University Qilu Hospital
Address:
City:
Jinan
Zip:
250000
Country:
China
Status:
Not yet recruiting
Contact:
Last name:
Guoning Zhan
Phone:
15232190720
Email:
zhanguoning@stemexcel.com
Facility:
Name:
West China Hospital Sichuan University
Address:
City:
Chengdu
Zip:
610000
Country:
China
Status:
Recruiting
Contact:
Last name:
Guoning Zhan, Bachelor's degree
Phone:
15232190720
Email:
zhanguoning@stemexcel.com
Start date:
November 8, 2022
Completion date:
May 1, 2025
Lead sponsor:
Agency:
Chengdu Zenitar Biomedical Technology Co., Ltd
Agency class:
Industry
Source:
Chengdu Zenitar Biomedical Technology Co., Ltd
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05563844