A Phase 1 Study of SHR2554 in Subjects With Relapsed or Refractory Mature Lymphoid Neoplasms

NCT03603951 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: SHR2554-I-101
• Study Type: interventional
• Target: 272
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 1 multicenter, single-arm, open-label, dose escalation and dose expansion study of enhancer of zeste homolog 2 (EZH2 ) inhibitor SHR2554. This study will assess the tolerability, safety, pharmacokinetics, and preliminary anti-tumor activity of SHR2554 in participants with relapsed or refractory mature lymphoid neoplasms in part I, and the the efficacy in PTCL patients will be studied in Part II.

Conditions

Relapsed or Refractory Mature Lymphoid Neoplasms

Keywords

SHR2554; EZH2 inhibitor; phase 1; mature lymphoid neoplasm

Outcome Measures

Primary Outcomes (3)

• Incidence and severity of treatment-emergent adverse events (AEs) [Safety and Tolerability])（Part I）

  The incidence and severity of treatment-emergent AEs will be collected and the safety and tolerability of SHR2554 will be assessed.

  through study completion, an average of about 6 months

• Recommended phase 2 dose (RP2D)（Part I）

  Recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD) will be established according to the incidence of dose-limiting toxicities (DLTs) of escalated doses of SHR2554.

  30 days since the date of first dose

• Objective response rate (ORR)（Part II）

  assessed by independent radiology review committee (IRC)

  60 days since the date of first dose

Secondary Outcomes (18)

• Time to peak (Tmax)

  Day 1 and Day 2 of the single dose

• Maximum plasma concentration (Cmax)

  Day 1 and Day 2 of the single dose

• Halflife (T1/2)

  Day 1 and Day 2 of the single dose

• Clearance/ bioavailability (CL/F)

  Day 1 and Day 2 of the single dose

• apparent volume of distribution/bioavailability (Vd/F)

  Day 1 and Day 2 of the single dose

Other Outcomes (3)

• Effect of escalated doses of SHR2554 on the histone H3 lysine 27 trimethylation (H3K27me3) level（Part I-exploratory endpoints）

  day 1 of the single dose to day 1 of continuous medication cycle 2

• EZH2 gene mutation（Part I-exploratory endpoints）

  within 2 weeks after the last dose

• EZH2 expression level（Part I-exploratory endpoints）

  within 2 weeks after the last dose

Study Arms (1)

SHR2554 treated group

EXPERIMENTAL

Part I：treated with escalated doses of EZH2 inhibitor SHR2554 respectively； Part II：treated with fixed dose (RP2D) SHR2554 respectively

Drug: SHR2554

Interventions

SHR2554 DRUG

SHR2554 is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2.

Also known as: EZH2 Inhibitor

SHR2554 treated group

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• to 70 years old (Adult, Senior)
• Part I: Histologically or cytologically confirmed Mature lymphoid neoplasms; Part II: peripheral T cell lymphomas
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1；
• Has a life expectancy of ≥12 weeks；
• Resistant to standard therapy or no standard therapy available，have indications for treatment；
• Have measurable disease （lymphoma participants，any nodes/nodal masses\>1.5 cm in longest diameter (LDi) or extralymphatic sites of disease \>1.0 cm in LDi；Multiple myeloma (MM) or Waldenström macroglobulinemia (WM) participants，serum M protein ≥0.5 g/dL or Bence Jones protein≥0.2 g/24 h）. （dose expansion study must satisfy）
• Has sufficient tumor tissue (slides or blocks) available for testing EZH2 mutation status and expression level. （dose expansion study must satisfy）
• Diffuse large B-cell lymphoma (DLBCL) participants have immunohistochemistry test results of cell origin (germinal center B-cell-like (GCB) or non-GCB), as well as myelocytomatosis oncogene (MYC), B cell lymphoma/leukemia 2 (BCL2) and B-cell lymphoma 6 (BCL6), or provide sufficient tumor tissue for testing. （dose expansion study must satisfy）
• With adequate bone marrow function;
• With adequate renal and liver function;
• Coagulation function index：PT ≤1.5×ULN，APTT ≤1.5×ULN；
• Women of childbearing potential (WOCBP) should be proven to be negative by human chorionic gonadotropin (hCG) test in 7 days before the first dose of SHR2554. They must be willing and able to employ a highly effective method of birth control/contraception to prevent pregnancy from the day they sign the informed consent form (ICF) to at least 30 days after receiving the last dose of study treatment. Male subjects with WOCBP partner should receive Surgical sterilization or consent to employ a highly effective method of birth control/contraception to prevent pregnancy；
• Any prior treatment-related clinically significant toxicities have resolved to ≤ Grade 1 per CTCAE version 4.03 or prior treatment-related toxicities evaluated by physicians are not clinically significant at time of enrollment.
• Participant who has provided written consent to participate in the study and ability to comply with all aspects of the protocol.

You may not qualify if:

• Prior exposure to other inhibitor(s) of EZH2.
• FL 3b or (potentially) transformed FL
• Participants with a presence of central nerves invasion
• Auto-transplantation within 60 days or allo-transplantation within 90 days before the first dose of study drug； \>1 grade graft-versus-host disease (GVHD) or using GVHD control medicines that are not allowed by this trial；
• Major surgery or serious trauma within 4 weeks before the first dose of study drug.；
• anti-tumor agents within 4 weeks before the first dose of study drug（such as chemotherapy, radiotherapy, immunotherapy, target therapy and other clinical research）；Use of Chinese Herbal within 2 weeks before the first dose of study drug；use of Glucocorticoids to anti tumor within 7 days before the first dose of study drug（equivalent to prednisone\>20 mg/d）；
• Has known active infection with hepatitis B virus or hepatitis C virus（HBV DNA≥2×10\^3 IU/mL，HCV RNA≥10\^3 IU/mL）and liver dysfunction，need the intervention of anti-virus therapy;
• Immunocompromised (i.e. has congenital immunodeficiency), including subjects known history of infection with human immunodeficiency virus (HIV) or has known active infection with tubercle bacillus；
• Has an active infection or has a temperature \> 38.5°C with unknown reasons（Investigators will decide the enrollment of participants with a fever that contributed to tumors）；
• Has cardiovascular impairment，including history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction, or stroke within 1 year prior to the planned first dose of study drug; or ventricular cardiac arrhythmia requiring medical treatment；
• abnormal of ECG with clinical significance：such as prolongation of corrected QT interval using Fridericia's formula (QTcF)(male \> 450 ms、female\> 470 ms）；
• History of cerebrovascular accident or transient ischemic attack within 6 months；
• Has a prior malignancy other than the malignancies under study within 2 years- EXCEPTION: A subject with a history of a completely resected skin basal cell carcinoma, skin squamous-celled carcinoma, in situ cervical cancer or other in situ carcinomas, and has been relapse-free for 5 years；
• Has serious acute/chronic disease or psychic disease，such as suicide intention or action in resent 1 year; or there are abnormal conditions that will increase the risk of using or managing study drug or affect the assessment of study results or investigator's judgment；
• Staffs of institute sites directly related to the study or their family members, subordinates. Staffs of the sponsor pharmaceuticals company that directly related to the study；

Sponsors & Collaborators

• Jiangsu HengRui Medicine Co., Ltd.: lead
• Peking University Cancer Hospital & Institute: collaborator

Study Sites (1)

Beijing Cancer Hospital, Peking University

Beijing, Beijing Municipality, China

Location

Related Publications (2)

• Song Y, Jin Z, Li ZM, Liu Y, Li L, He C, Su H, Zhou H, Li K, Hao S, Zuo X, Wu J, Li D, Wu M, Sun X, Qi J, Cai Z, Li Z, Li Y, Huang Y, Shen J, Xiao Z, Zhu J. Enhancer of Zeste Homolog 2 Inhibitor SHR2554 in Relapsed or Refractory Peripheral T-cell Lymphoma: Data from the First-in-Human Phase I Study. Clin Cancer Res. 2024 Apr 1;30(7):1248-1255. doi: 10.1158/1078-0432.CCR-23-2582.

  PMID: 38190117 DERIVED

• Song Y, Liu Y, Li ZM, Li L, Su H, Jin Z, Zuo X, Wu J, Zhou H, Li K, He C, Zhou J, Qi J, Hao S, Cai Z, Li Y, Wang W, Zhang X, Zou J, Zhu J. SHR2554, an EZH2 inhibitor, in relapsed or refractory mature lymphoid neoplasms: a first-in-human, dose-escalation, dose-expansion, and clinical expansion phase 1 trial. Lancet Haematol. 2022 Jul;9(7):e493-e503. doi: 10.1016/S2352-3026(22)00134-X.

  PMID: 35772429 DERIVED

MeSH Terms

Conditions

Recurrence

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 10, 2018
• First Posted: July 27, 2018
• Study Start: August 14, 2018
• Primary Completion: February 14, 2026
• Study Completion (Estimated): August 14, 2026
• Last Updated: October 1, 2024

Record last verified: 2024-09

Locations

CN (1)