This clinical trial is a Phase II study investigating the effectiveness and safety of a three-drug combination-Zeprumetostat, Azacitidine, and Mitoxantrone Hydrochloride Liposome-in adults with relapsed or refractory peripheral T-cell lymphoma (PTCL). PTCL is an aggressive type of non-Hodgkin lymphoma that has limited treatment options after the first line of therapy.

The study aims to enroll approximately 26 patients at a single center in China. Eligible participants will receive up to 6 cycles of induction therapy with all three drugs, followed by up to 2 years of maintenance therapy with Zeprumetostat alone if they respond to treatment.

The main goal is to evaluate the overall response rate (how many patients experience tumor shrinkage). Secondary goals include assessing how long patients live without their disease getting worse, how long they survive overall, and the safety profile of this treatment combination. The study will also explore whether specific genetic markers or viral infections are linked to how well patients respond.

This study is important because it tests a novel, potentially less toxic, and more effective combination for a patient population with high unmet medical need. All participants will be closely monitored for treatment response and side effects throughout the trial.

Inclusion Criteria:

1. Relapsed or refractory peripheral T-cell lymphoma after first-line or higher treatment.

2. Age ≥ 18 years.

3. Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2.

4. Presence of measurable target lesions [Note: Target lesions are defined as lesions with at least one longest diameter (LD) measurement > 1.5 cm and longest perpendicular diameter (LPD) measurement ≥ 1.0 cm, as assessed by computed tomography (CT) or magnetic resonance imaging (MRI). A maximum of six target lesions can be selected].

5. Adequate function of major organs must meet the following criteria:

   • Hematological parameters: HB ≥ 70 g/L, PLT ≥ 50 × 10^9/L, NE ≥ 1.0 × 10^9/L (Note: Patients who have not received transfusions or drugs to support NE, PLT, or HB increase within 1 week before screening are eligible. Patients with bone marrow involvement by lymphoma resulting in cytopenia are not restricted by this criterion).
   • Echocardiographic left ventricular ejection fraction ≥ 50%.
   • Creatinine ≤ 132 umol/L or creatinine clearance ≥ 60 ml/min.
   • ALT and AST ≤ 3 times the upper limit of normal.

6. Women of childbearing potential must have a negative pregnancy test. Both male and female patients must agree to use effective contraception during treatment and for 1 year thereafter.

7. Life expectancy of more than 3 months.

8. Voluntary signed informed consent form.

Exclusion Criteria:

1. Underwent major surgery or severe trauma within 2 weeks before enrollment, or significant adverse effects have not yet recovered.
2. Currently suffering from or having had other malignancies within 3 years before enrollment, except for cured basal or squamous cell carcinoma of the skin, superficial bladder cancer, prostatic intraepithelial neoplasia, and cervical carcinoma in situ.
3. History of stroke or intracranial hemorrhage within the past 3 months.
4. Presence of complications or medical conditions that may interfere with the conduct of the study or pose a significant risk to the patient, including but not limited to severe cardiovascular diseases (e.g., cardiac disease classified as New York Heart Association class III or IV, myocardial infarction within the past 6 months, unstable arrhythmias, or unstable angina) and/or severe pulmonary diseases (e.g., severe obstructive pulmonary disease and history of symptomatic bronchospasm).
5. Human immunodeficiency virus infection, or presence of uncontrollable active hepatitis C virus or hepatitis B virus infection.
6. Uncontrollable active infection.
7. Pregnant or breastfeeding women.
8. Any life-threatening disease, medical condition, or organ system dysfunction that may endanger the safety of the patient, as determined by the investigator.
9. Any condition that may interfere with the absorption or metabolism of zemtovistat, azacitidine, or doneda, or place the study results at unnecessary risk.
10. Lymphoma involvement of the central nervous system.
11. Presence of conditions judged by the investigator to interfere with full participation in the study; conditions posing significant risk to the subject; or conditions that may interfere with the interpretation of study data.