Non-hodgkin Lymphoma, Peripheral T-cell Lymphoma
Conditions
Keywords
EZH2 inhibitor, XNW5004
Brief summary
In this study, the XNW5004 tablets combined with CHOP/CHOEP will be used for the treatment of newly diagnosed PTCL patients.
Interventions
DRUGXNW5004 combined with CHOP (incremental)
The XNW5004 protocol has preset four dosage groups: 400mg, 800mg, 1200mg and 1600mg, administered twice daily (BID). The CHOP regimen is administered at a fixed dose, for a total of 6 cycles. After completing the combined treatment and without disease progression, the subjects will continue to receive XNW5004 at 1200mg BID for maintenance therapy.
DRUGXNW5004 combined with CHOEP (incremental)
It is expected to conduct dose escalation studies for XNW5004 in combination with CHOEP using 1-3 dose groups. The CHOEP regimen will be administered at a fixed dose for a total of 6 cycles. After completing the combined treatment and without disease progression, the subjects will continue to receive XNW5004 at 1200mg BID for maintenance therapy.
DRUGXNW5004 combined with CHOP (extended)
Those who received the combination treatment of XNW5004 and CHOP, and who did not experience disease progression after the combined treatment, will continue to receive maintenance treatment with XNW5004 at a dose of 1200mg twice daily.
DRUGXNW5004 combined with CHOEP (extended)
Those who received the combination treatment of XNW5004 and CHOEP, and who did not experience disease progression after the combined treatment, will continue to receive maintenance treatment with XNW5004 at a dose of 1200mg twice daily.
Sponsors
Evopoint Biosciences Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age 18 to 75 years (inclusive); both genders are eligible. * Pathologically confirmed peripheral T-cell lymphoma (PTCL). * No prior systemic anti-PTCL therapy. * At least one measurable lesion as the basis for evaluation: nodal lesions with a long diameter \> 1.5 cm; extranodal lesions with a long diameter \> 1.0 cm. * Life expectancy of at least 12 weeks. * ECOG performance status score of 0-1. * Vital organ function reserves meet the following requirements: * Hematopoietic function: * White blood cell count \>= 3.5 x 10\^9/L (no G-CSF administration within 1 week before the screening blood test, and no long-acting leukocyte-elevating agent administration within 2 weeks) * Platelet count \>= 75 x 10\^9/L (no platelet transfusion or TPO receptor agonist administration within 1 week before the screening blood test) * Hemoglobin \>= 80 g/L (no red blood cell transfusion or EPO administration within 1 week before the screening blood test) * Hepatic function: serum total bilirubin \<= 1.5 x ULN (\<= 3 x ULN for Gilbert's syndrome), and ALT and AST \<= 2.5 x ULN; for subjects with liver infiltration, ALT/AST \<= 5 x ULN; for subjects with liver and/or bone infiltration, alkaline phosphatase \<= 5 x ULN * Renal function: serum creatinine \<= 1.5 x ULN or estimated creatinine clearance \>= 60 mL/min according to the Cockcroft-Gault formula * Left ventricular ejection fraction (LVEF) \>= 50% * International normalized ratio (INR) \<= 1.5 x ULN, or prothrombin time (PT) and activated partial thromboplastin time (APTT) \<= 1.5 x ULN * Women of childbearing potential must have a negative serum pregnancy test before entering this study and agree to use effective contraception from the start of the study until at least 6 months after the last dose of the investigational drug. Female subjects who are not capable of childbearing must have been naturally amenorrheic for at least 12 months and be confirmed by a specialist physician as having no reproductive function based on female hormone testing; or have undergone bilateral oophorectomy, hysterectomy, or tubal ligation at least 6 weeks prior to screening. Male subjects must agree to use adequate contraceptive measures from the start of the study until at least 6 months after the last dose of the investigational drug, and must not donate sperm. * Provide a signed and dated written informed consent form prior to undergoing study-specific procedures, and be able to comply with clinical visits and study-related procedures.
Exclusion criteria
* Prior treatment with any anti-tumor therapy, including but not limited to: chemotherapy, immunotherapy, radiotherapy, targeted therapy, anti-tumor traditional Chinese medicine, or anti-tumor investigational drugs. * Subjects with known hypersensitivity to the investigational drug or its active ingredients or excipients. * Subjects who have undergone major surgery within 4 weeks prior to the first dose of the investigational drug, or who plan to undergo major surgery during the study period (except for procedures such as puncture or lymph node biopsy). * Prior or planned allogeneic hematopoietic stem cell transplantation or solid organ transplantation. * Receipt of steroid hormones for anti-tumor purposes (daily dose \> 20 mg prednisone or equivalent dose of other glucocorticoids) within 7 days prior to the first dose of the investigational drug; or diseases requiring systemic treatment with steroid hormones (daily dose \> 10 mg prednisone or equivalent dose of other glucocorticoids) or other immunosuppressive drugs within 14 days prior to the first dose of the investigational drug. In the absence of active autoimmune disease, inhaled or topical steroids and adrenal replacement therapy with a daily dose \<= 10 mg prednisone or equivalent dose of other glucocorticoids are permitted. * Subjects who have taken known moderate or strong CYP3A4 inhibitors/inducers within 14 days prior to the first dose. * Receipt of live virus vaccine (including attenuated live vaccine) within 28 days prior to dosing. Inactivated vaccines are permitted. * History of psychotropic substance abuse or drug addiction. * History of other malignancies within 3 years prior to enrollment that do not meet clinical cure criteria. The following are exceptions: basal cell carcinoma or squamous cell carcinoma of the skin that can be treated locally and has been cured, superficial bladder cancer, cervical carcinoma in situ, ductal carcinoma in situ of the breast, and papillary thyroid carcinoma. * Mycosis fungoides, Sezary syndrome, and primary cutaneous T-cell lymphoma. * Presence of central nervous system involvement. * Presence of testicular or breast involvement. * Prior or current hemophagocytic syndrome. * Prior or current immune thrombocytopenia, autoimmune hemolytic anemia, aplastic anemia, or other primary or secondary hematological diseases that may affect bone marrow function other than the primary malignancy. * Prior or current acute myeloid leukemia (AML). * Prior or current T-cell lymphoblastic lymphoma (T-LBL) or T-cell lymphoblastic leukemia (T-ALL). * History of any myeloid malignancy, including myelodysplastic syndrome (MDS), or abnormal laboratory markers associated with MDS or myeloproliferative neoplasm (MPN). * Prior or concomitant central nervous system disorders, including but not limited to: epilepsy, paralysis, stroke, severe brain injury, Alzheimer's disease, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis, etc. * Impaired cardiac function or clinically significant cardiac disease, including any of the following: * Acute myocardial infarction within 12 months prior to the first dose * Unstable angina pectoris * Congestive heart failure (New York Heart Association functional class III or IV) * Uncorrected serious arrhythmia, hypertension \>= 150/100 mmHg * Prolonged QTc interval (defined as \> 450 ms for males and \> 470 ms for females, by Fredericia's formula) * Prior history of other major cardiovascular diseases (e.g., valve replacement, coronary artery bypass grafting, etc.) * Tumor invasion of surrounding vital organs and blood vessels (e.g., heart and pericardium, trachea, esophagus, aorta, superior vena cava, etc.) with risk of bleeding, or risk of tracheoesophageal fistula or esophagopleural fistula. * Subjects with clinically symptomatic pleural effusion, ascites, or pericardial effusion that is poorly controlled despite repeated treatment. * Active severe systemic infection: a washout period of at least 2 weeks is required after completion of antifungal therapy (whether administered intravenously or orally); a washout period of at least 1 week is required after completion of other intravenous anti-infective therapy; other oral anti-infective therapies must be discontinued before the first dose of the investigational drug. * Active tuberculosis under treatment. * HIV-positive or syphilis (Anti-TP) positive subjects (subjects with negative syphilis non-specific antibody test results and judged by the investigator to have been cured of syphilis are not excluded). * HBsAg positive with HBV-DNA copy number above the lower limit of normal detection, or HBcAb positive with HBV-DNA copy number above the lower limit of normal detection; HCV antibody positive with HCV-RNA copy number above the lower limit of normal detection. * Subjects who are unable to swallow, or have active gastrointestinal inflammation, chronic diarrhea, known diverticular disease, or a history of gastrectomy or gastric banding that may affect drug absorption. However, gastroesophageal reflux treated with proton pump inhibitors is permitted (if there is no potential for drug interaction). * Known hemorrhagic diathesis such as von Willebrand disease or hemophilia. * Females who are pregnant or breastfeeding. * Subjects who may not be able to complete the study for other reasons or whom the investigator considers should not be enrolled.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ib/II:Incidence and severity of treatment-emergent adverse events (AEs) [Safety and Tolerability]. | through study completion, an average of 1 year | Incidence and severity of adverse events that are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. |
| II：Objective response rate (ORR) | 36 months | ORR is defined as the proportion of subjects who have a confirmed CR or a PR per lugano2014 assessed by Investigator. |
| Ib:Maximum tolerated dose (MTD) and/or the recommended Part 2 dose | The first 21-day cycle of therapy | To determine the maximum tolerated dose (MTD) and the recommended Part 2 dose with XNW5004. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ib/II:The maximum (peak) blood drug concentration (Cmax) is XNW5004 | through study completion, an average of 1 year | Collect blood samples at the specified intervals to determine the Cmax. |
| Ib/II：XNW5004 Peak Time (Tmax) | through study completion, an average of 1 year | Collect blood samples at the specified intervals to determine the Tmax. |
| Ib/II：The area under the blood drug concentration-time curve of XNW5004 (AUC) | through study completion, an average of 1 year | Collect blood samples at specified intervals to determine AUC |
| Ib/II:The maximum (peak) blood drug concentration in the steady state (Css,max) | through study completion, an average of 1 year | Collect blood samples at specified intervals to determine Css,max |
| Ib/II:XNW5004 Steady-state Baseline Concentration (Css, min) | through study completion, an average of 1 year | Collect blood samples at specified intervals to determine Css, min |
| Ib/II:The area under the blood drug concentration-time curve (AUCss) under steady-state conditions of XNW5004 | through study completion, an average of 1 year | Collect blood samples at specified intervals to determine AUCss |
| Ib/II:XNW5004 Elimination Half-Life (T1/2) | through study completion, an average of 1 year | Collect blood samples at specified intervals to determine T1/2 |
| Ib/II:Pharmacodynamic indicators, the relative change of H3K27me3 (trimethylation of lysine at position 27 of histone H3) compared to the baseline of histone H3 | through study completion, an average of 1 year | Collect blood samples at the specified time to determine the relative changes of H3K27me3 (trimethylation of lysine at position 27 of histone H3) compared to the baseline. |
| Ib/II:Objective Response Rate (ORR) | 36 months | ORR is defined as the Lugano 2014 assessment, representing the proportion of subjects who were diagnosed with CR or PR. |
| Ib/II:Disease Control Rate (DCR) | 36 months | Rate of complete response \[CR\], partial response \[PR\], and stable disease per lugano2014 assessed by Investigator. |
| Ib/II:Duration of response (DOR) | 36 months | Duration of response (DOR) per lugano2014 assessed by Investigator. |
| Ib/II:Progression free survival (PFS) | 36 months | Progression free survival (PFS) per lugano2014 assessed by Investigator |
| Ib/II：Overall Survival (OS) | 36 months | The period from when the patient begins receiving treatment until the patient dies for any reason |
Countries
China
Contacts
CONTACTLinlin.li Li
Outcome results
None listed