Background: Peripheral T-cell lymphomas (PTCLs) are a highly heterogeneous group of aggressive malignant lymphomas, usually exhibit a poor prognosis, with a 5-year survival <50%, the risk of relapse remains quite high and relapsed or refractory (R/R) patients have been shown to have a very dismal outcome. Immunotherapy with anti-PD-1 antibodies may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. So far the largest study (Gxplore-002) including 102 patients with R/R PTCL showed that anti-PD-1 antibody is safe and has promising activity with overall response rate (ORR) of 40.4%. However, the depth of remission and long term prognosis are not satisfied with complete response rate (CRR) of 14.6% and the median progression-free survival of 2.7 months. Combination therapy is a potential strategy to increase the efficacy. Epigenetic agents may promote effect of anti-PD-1 antibody by stimulating antigen presentation, enhancing the migration of T cells to the tumor microenvironment, restoring T cell activation. These rationales support the combination of anti-PD-1 antibody and epigenetic agents. Therefore, the combination of sintilimab (anti-PD-1 antibody) and chidamide (histone deacetylase inhibitors, HDACi), azacitidine (hypomethylating agents, HMA) may have potent synergy in treating patients with relapsed or refractory PTCLs. Methods: This is a single-arm-phase II clinical trial for patients with relapsed or refractory PTCLs. Patients with at least one line of standard therapy are required. Prior HDACi or PD-1/PD-L1 antibodies or HMA is allowed. Patients with CNS disease or cutaneous T-cell lymphoma are excluded. Eligible patients will be treated with sintilimab (200 mg IV Q3W on day 1) in combination with chidamide (30 mg PO BIW on d1 and d4) and azacitidine (100 mg SC Q3W days 1-7). Cycles repeat every 3 weeks for up to 24 months in the absence of disease progression, death, unacceptable toxicity, hematopoietic stem cell transplantation, withdrawal of informed consent, other reasons specified in the protocol or the decision of the researcher. After completion of study treatment, participants are followed up at 90 days for safety and then every 90 days for survival. The study intends to enroll approximately 30 patients. Considering the safety of patients, the first 6 patients will be recruited slowly, if a DLT is observed in 2 of 6 patients, the investigators will decide to reduce the dose of chidamide to 20 mg, otherwise, all patients use 30 mg chidamide. The primary objective is ORR; the secondary objectives are CRR, duration of response (DOR), progression-free survival (PFS), overall survival(OS) and adverse events; the exploratory objective is the correlation of clinical response with the expression of PD-L1, CD4, CD8, CD68 in tumor environment. Clinical trial information: NCT04052659 The research was funded by: Innovent Biologics Inc. Keywords: Combination Therapies, Immunotherapy, Aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.
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