Genotype-guided Targeted Agents Plus EZH2i for Primary Refractory PTCL

Genotype-guided Targeted Agents in Combination With EZH2 Inhibitor, Zeprumetostat for Primary Refractory Peripheral T-cell Lymphoma (PTCL), a Prospective, Open-label, Multi-center Study

To evaluate the safety and efficacy of Zeprumetostat-based combination therapy, selected according to genotyping results, in patients with primary refractory peripheral T-cell lymphoma (PTCL).

Study Overview

• Status: Not yet recruiting
• Conditions: Refractory; PTCL
• Intervention / Treatment: Drug: Zeprumetostat+Azacitadine; Drug: Zeprumetostat+Chidamide; Drug: Zeprumetostat+Decitabine; Drug: Zeprumetostat+Golidocitinib

Detailed Description

Peripheral T-cell lymphoma (PTCL) is a distinct and heterogeneous histopathologic subtype of non-Hodgkin lymphoma (NHL), accounting for ~10%. Patients with PTCL still have poor treatment response and prognosis under conventional CHOP regimen. Clinical outcomes of refractory patients are even poorer. Targeted drugs are warranted in this group of patients to improve survival. This prospective, multi-center, open-label study will evaluate the efficacy and safety of targeted drug in combination with Zeprumetostat, an EZH2 inhibitor in treatment of primary refractory peripheral peripheral T-cell lymphoma.

• Study Type: Interventional
• Enrollment (Estimated): 86
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Weili Zhao; Phone Number: 086-022-64370045; Email: zwl_trial@163.com
• Study Contact Backup: Name: Pengpeng Xu; Email: pengpeng_xu@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years, male or female.
• Patients with a histopathologically confirmed diagnosis of peripheral T-cell lymphoma (PTCL) based on 2016 WHO classification
• Previously treated with 3 or 6 cycles of a CHOP-like regimen as first-line therapy and considered primary refractory. Patients with anaplastic large cell lymphoma (ALCL) must have adequately received brentuximab vedotin (BV) as part of their first-line treatment.
• Tumor tissue genotyping performed and results available prior to enrollment.
• ECOG 0, 1, or 2.
• Life expectancy greater than 3 months.
• Adequate organ function
• Contraception during study
• Informed consented

Exclusion Criteria:

• Has a prior malignancy other than the malignancies under study within 3 years without relieve
• Primary CNS lymphoma
• Known hypersensitivity to any study drug.
• Pregnant or lactation
• Active infection.

• Diseases and medical history:

  1. Requires continuous treatment with strong or moderate CYP3A inhibitors or CYP3A inducers
  2. Has multiple factors affecting oral medication administration (e.g., inability to swallow, chronic diarrhea, intestinal obstruction, etc.);
  3. Has a history of psychoactive substance abuse that cannot be discontinued
  4. Has any severe and/or uncontrolled disease.
• Uncontrollable autoimmune disease,
• Not able to comply to the protocol for mental or other unknown reasons
• Any other condition that, in the investigator's judgment, makes the patient unsuitable for study participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zeprumetostat+Azacitadine (if with TET2 plus RHOA gene mutation); Zeprumetostat: 350 mg bid, orally, till disease progression (PD) or unacceptable toxicity. Azacitadine :100mg D1-D7, subcutaneous injection, should ≥2 out of 6 pts experience a DLT, the dose will be adjusted to: Azacitidine 100 mg D1-D5, subcutaneous injection for total 3 cycles.	Drug: Zeprumetostat+Azacitadine; Zeprumetostat: 350 mg bid, orally, till disease progression (PD) or unacceptable toxicity. Azacitadine :100mg D1-D7, subcutaneous injection, should ≥2 out of 6 pts experience a DLT, the dose will be adjusted to: Azacitidine 100 mg D1-D5, subcutaneous injection for total 3 cycles.
Experimental: Zeprumetostat+Decitabine (if with TP53 gene mutation); Zeprumetostat: 350 mg bid, orally, till disease progression (PD) or unacceptable toxicity. Decitabine 10mg/m2 D1-D5, intravenous infusion, should ≥2 out of 6 pts experience a DLT, the dose will be adjusted to: Decitabine 10mg/m2 D1-D3 for total 3 cycles.	Drug: Zeprumetostat+Chidamide; Zeprumetostat: 350 mg bid, orally, till disease progression (PD) or unacceptable toxicity. Chidamide 30 mg biw orally, should ≥2 out of 6 pts experience a DLT, the dose will be adjusted to: Chidamide 20 mg biw for total 3 cycles.
Experimental: Zeprumetostat+Chidamide (if with CREBBP/EP300/KMT2C/KMT2D/NCOR2 gene mutation); Zeprumetostat: 350 mg bid, orally, till disease progression (PD) or unacceptable toxicity. Chidamide 30 mg biw orally, should ≥2 out of 6 pts experience a DLT, the dose will be adjusted to: Chidamide 20 mg biw for total 3 cycles.	Drug: Zeprumetostat+Decitabine; Zeprumetostat: 350 mg bid, orally, till disease progression (PD) or unacceptable toxicity. Decitabine 10mg/m2 D1-D5, intravenous infusion, should ≥2 out of 6 pts experience a DLT, the dose will be adjusted to: Decitabine 10mg/m2 D1-D3 for total 3 cycles.
Experimental: Zeprumetostat+Golidocitinib (if not above genotype); Zeprumetostat: 350 mg bid, orally, till disease progression (PD) or unacceptable toxicity. Golidocitinib 150 mg qd orally, should ≥2 out of 6 pts experience a DLT, the dose will be adjusted to: Golidocitinib 150 mg qod for total 3 cycles.	Drug: Zeprumetostat+Golidocitinib; Zeprumetostat: 350 mg bid, orally, till disease progression (PD) or unacceptable toxicity. Golidocitinib 150 mg qd orally, should ≥2 out of 6 pts experience a DLT, the dose will be adjusted to: Golidocitinib 150 mg qod for total 3 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Summary of DLT events (Phase Ib)	Measure Description: Enroll 6 pts per cohort and observe the number of pts experiencing dose-limiting toxicity.	At the end of Cycle 1 (each cycle is 28 days)
Overall response rate (Phase Ⅱ)	Percentage of participants with overall response was determined on the basis of investigator assessments according to 2014 Lugano criteria	At the end of Cycle 3 (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response rate	Percentage of participants with complete response was determined on the basis of investigator assessments according to 2014 Lugano criteria	At the end of Cycle 3
Disease Control Rate	Percentage of participants with complete response, partial response, or stable disease, as determined by investigator assessment according to the 2014 Lugano criteria, at the end of Cycle 3	each cycle is 28 days
Duration of response	Time from first occurrence of documented CR or PR to disease progression/relapse, or death from any cause for participants with a response of CR or PR. Tumor assessments were performed with PET-CT.	Baseline up to data cut-off
Duration of complete response	Time from first occurrence of documented CR to disease progression/relapse, or death from any cause for participants with a response of CR or PR. Tumor assessments were performed with PET-CT.	Baseline up to data cut-off
Progression free survival	Progression-free survival was defined as the time from the date of diagnosis until the date of the first documented day of disease progression or relapse, using 2014 Lugano criteria, or death from any cause, whichever occurred first.	Baseline up to data cut-off
Overall survival	Overall survival was defined as the time from the date of diagnosis to the date of death from any cause. Reported is the percentage of participants with event. of disease progression or relapse, using 2014 Lugano criteria,or death from any cause, whichever occurred first.	Baseline up to data cut-off
Treatment-Related Adverse Events	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.	Baseline up to data cut-off
Exploratory biomarker analysis	Exploratory biomarker to predict treatment response and survival	Baseline up to data cut-off

Collaborators and Investigators

• Sponsor: Ruijin Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): March 23, 2026
• Primary Completion (Estimated): December 12, 2029
• Study Completion (Estimated): December 12, 2030

Study Registration Dates

• First Submitted: March 19, 2026
• First Submitted That Met QC Criteria: March 19, 2026
• First Posted (Actual): March 25, 2026

Study Record Updates

• Last Update Posted (Actual): April 7, 2026
• Last Update Submitted That Met QC Criteria: April 1, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Refractory; PTCL; Genotype-guided; Zeprumetostat
• Other Study ID Numbers: Target

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No