Adebrelimab Combined With SHR2554 in Relapsed/Refractory PTCL and NK/T-Cell Lymphoma

A Single-Arm, Multicenter, Phase Ib/II Exploratory Study to Evaluate Adebrelimab in Combination With EZH2 Inhibitor SHR2554 for the Treatment of Relapsed or Refractory Peripheral T-Cell Lymphoma and NK/T-Cell Lymphoma

To evaluate the safety of adebrelimab combined with SHR2554 in the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) and NK/T-cell lymphoma (NKTCL), to determine the recommended Phase 2 dose (RP2D) of the combination regimen, and to assess preliminary efficacy.

This is a single-arm, multicenter, Phase Ib/II clinical study consisting of two parts: a Phase Ib safety lead-in phase and a Phase II expansion phase.

Phase Ib is the safety lead-in phase. The primary objective is to determine the Recommended Phase 2 Dose (RP2D) based on dose-limiting toxicities (DLTs). It plans to enroll 6 subjects to observe the safety of SHR2554 (350 mg, twice daily) combined with adebrelimab (600 mg or 1200 mg) after 1 treatment cycle. If < 2 DLTs occur, the RP2D for adebrelimab will be 1200 mg; if ≥ 2 DLTs occur, the RP2D will be 600 mg.

Phase II is the expansion phase, utilizing an induction treatment of 6 cycles of SHR2554 twice daily combined with adebrelimab at the RP2D administered via intravenous infusion once every 3 weeks. All patients achieving a Complete Response (CR) or Partial Response (PR) after induction treatment will receive SHR2554 maintenance therapy (28 days per cycle) until disease progression or treatment discontinuation due to other reasons. The duration of SHR2554 administration during the maintenance phase will not exceed 24 months. The primary objective is to evaluate the efficacy of the combination regimen, with a planned enrollment of 40 subjects. If the RP2D for adebrelimab is determined to be 1200 mg, the 6 subjects from the safety lead-in phase will also be included in the Phase II analysis.

Inclusion Criteria:

1. Age ≥18 years old,regardless of gender;

2. Centrally confirmed histopathological/cytologic diagnosis of PTCL with the following subtypes:

   1. Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS);
   2. Systemic anaplastic large cell lymphoma (ALK+ and ALK-);
   3. Follicular helper T (TFH) cell lymphoma of lymph nodes, including angioimmunoblastic, follicular, NOS;
   4. NKTCL
   5. and any other PTCL subtypes deemed by the investigator to be eligible for inclusion.

3. Met the criteria of relapsed/refractory lymphoma: Relapsed lymphoma was defined as relapsed lymphoma after achieving complete response (CR) or partial response(PR)after initial therapy. Refractory is defined as having an evaluation of progressive disease (PD) after 2 cycles, or stable disease (SD) after 4 cycles of a previous systemic therapy regimen.

4. There must be at least one measurable or evaluable lesion that meets the Lugano 2014 criteria for lymphoma: Measurable lesion: Nodal lesions with major diameter greater than 1.5cm and minor diameter greater than 1.0cm as assessed by PET/CT or Computed Tomography (CT) and/or Magnetic Resonance Imaging (MRI); Or the length of extranodal lesions >1.0cm; 2)Evaluable lesions: PET-CT showed increased uptake in lymph nodes or extranodal regions (higher than liver) and imaging features consistent with lymphoma;

5. ECOG performance status score: 0-2;

6. Expected survival time ≥3 months;

7. Have adequate organ and bone marrow function, defined as follows(The patients had not received granulocyte growth factor, platelet transfusion, or red blood cell transfusion within 14 days before the examination):

   1. Blood routine: absolute neutrophil count (ANC) ≥ 1.0×109/L;
   2. platelet count (PLT) ≥ 60×109/L;
   3. hemoglobin (HGB) ≥ 8.0 g/dL;
   4. white blood cell (WBC) ≥ 3.5×109/L;
   5. Renal function: serum creatinine (Cr) ≤1.5×ULN.or creatinine clearance (CrCl) ≥ 40 mL/min (calculated using the Cockcroft-Gault formula);
   6. serum total bilirubin (TBIL) ≤1.5× upper limit of normal value ;
   7. alanine aminotransferase (ALT) and aspartate transferase (AST) ≤2.5×ULN ;
   8. Coagulation function: International Normalized Ratio (INR) ≤1.5 × ULN; Prothrombin Time (PT), Activated PartialThromboplastin Time (APTT) ≤1.5×ULN (unless the subject is receiving anticoagulant therapy, And PT and APTT at screening were within the expected range for anticoagulant therapy).
   9. Thyroid stimulating hormone (TSH) or free thyroxine (FT4) or free triiodothyronine (FT3) within the normal range ±10% (Note: non-autoimmune causes of abnormal TSH, FT3 and FT4 can be maintained in the normal range after replacement treatment of hypothyroidism can be enrolled).

8. Capable of understanding the study procedures and voluntarily signing a written informed consent form (ICF).;

9. Women of childbearing potential must have a negative serum pregnancy test within 7 days before the first dose of medication; Effective contraception should be used from the time of informed consent until 6 months after the last dose of study drug.

Exclusion Criteria:

1. Pregnant or lactating women;
2. Patients with hemophagocytic lymphohistiocytosis;
3. Primary central nervous system (CNS) lymphoma or secondary CNS involvement.
4. History of allogeneic organ transplantation;
5. Received allogeneic hematopoietic stem cell transplantation (allo-HSCT) within 3 years prior to the first dose of study drug (patients who received allo-HSCT > 3 years prior to the first dose of study drug and currently have no active graft-versus-host disease [GVHD] are eligible to enroll);
6. Known allergy or hypersensitivity to the study drugs or their related metabolites;
7. Uncontrolled active infection;
8. Currently participating in another clinical study, or less than 4 weeks elapsed from the end of treatment in a previous clinical study to the planned start of study treatment;
9. Planned autologous hematopoietic stem cell transplantation (auto-HSCT);
10. Less than 3 months elapsed since the last dose of prior treatment with any immune checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, anti-CTLA-4).
11. Active autoimmune disease that required systemic treatment within the past 2 years (hormone replacement therapy is not considered systemic treatment, e.g., type 1 diabetes mellitus, hypothyroidism requiring only thyroxine replacement therapy, or adrenal/pituitary insufficiency requiring only physiologic doses of corticosteroids). Patients with an autoimmune disease that did not require systemic treatment within the past 2 years are eligible to enroll;
12. Required systemic treatment with corticosteroids or other immunosuppressive agents for any condition within 14 days prior to the start of study treatment (except for topical or short-term use of corticosteroids, or corticosteroids used for non-autoimmune conditions such as delayed-type hypersensitivity caused by contact allergens);
13. Diagnosis of another malignancy within the past 5 years, except for malignancies treated with curative intent, including basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the breast, or carcinoma in situ of the cervix.
14. Received systemic anti-tumor therapy within 28 days prior to the start of study treatment, including chemotherapy, immunotherapy, and biological therapy (tumor vaccines, cytokines, or growth factors to control cancer);
15. Underwent major surgery within 28 days, or received radiotherapy within 90 days prior to the start of study treatment;
16. Received live vaccines within 28 days prior to the start of study treatment (excluding attenuated influenza vaccines);
17. Patients with a known history of Human Immunodeficiency Virus (HIV) infection and/or acquired immunodeficiency syndrome;
18. Patients with active chronic hepatitis B or active hepatitis C. Hepatitis B SurfaceAntigen (HBsAg) or hepatitis B core Antibody (HBcAb) or Hepatitis C Virus (HCV) during the screening period HCV) antibody positive patients must be further tested for Hepatitis B Virus (HBV) DNA (no more than 2500 copies /mL or 500 IU/mL) and HCV RNA (no more than the lower limit of detection of the assay), Enrollment in the trial occurred after the exclusion of patients with active hepatitis B or hepatitis C infection requiring treatment. Hepatitis B virus (HBV) carriers, medically stable hepatitis B (DNA > 2500 copies /mL or 500IU/mL) and cured hepatitis C patients are eligible for enrollment.
19. Active tuberculosis (TB);
20. Uncontrolled fungal or bacterial infections;
21. Known history of alcohol or substance abuse;
22. Uncontrolled comorbidities, including but not limited to symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, active peptic ulcer, or bleeding disorders;
23. History of interstitial lung disease or non-infectious pneumonitis (subjects with a history of asymptomatic drug-induced or radiation-induced non-infectious pneumonitis are eligible for enrollment);
24. QTcF interval > 450 msec, unless secondary to bundle branch block;
25. History of psychiatric disorders;
26. Severe concomitant diseases that, in the judgment of the investigator, would compromise patient safety or interfere with the patient's ability to complete the study;
27. Any other condition that, in the opinion of the investigator, makes the patient unsuitable for inclusion in this study.