Azacitidine for Injection Combined with Chidamide in Relapsed/Refractory Peripheral T-Cell Lymphoma: A Phase I Study

Abstract

Background: Peripheral T-cell lymphoma (PTCL) is a group of highly heterogeneous malignant tumors with poor prognosis, especially in patients with relapesd/refractory. The efficacy of traditional salvage chemotherapy in the treatment of Relapsed/Refractory (R/R) PTCL was poor, and the median OS and PFS after the first recurrence or progression were only 5.5 months and 3.1 months, respectively. There is an urgent need for more effective treatment regimens to improve the poor prognosis of these patients. Epigenetics, as a new discipline involved in gene expression regulation, provides a new approach for the occurrence, development mechanism research and clinical diagnosis and treatment of PTCL.This phase I study is a prospective, single center clinical study and designed to evaluate the safety, tolerability and efficacy of Azacitidine for injection combined with Chidamide in Relapsed/Refractory peripheral T-cell lymphoma. Methods: Eligible pts (18-75 years of age, ECOG PS 0-2) had histologically confirmed peripheral T-cell lymphoma that was either relapsed or refractory to at least 1 line of therapy. Considering that both Dose Group 2 (Azacitidine 75mg/m 2, Chidamide 20mg) and Group 3 (Azacitidine 50mg/m 2, Chidamide 30mg) adjust the dosage of a single drug based on Dose Group 1 (Azacitidine 50mg/m 2 ih d1-7, Chidamide 20mg po biw; 4 weeks/cycle), this study derived a “3+3” two-dimensional dose increasing design based on the classic “3+3” design, which allows two Dose Groups (Dose Group 2 and Group 3) to start ramp up trials simultaneously according to random principles. Enrollment in dose group 4(Azacitidine 75mg/m 2, Chidamide 30mg) can begin when either group 2 or 3 completes and no DLT occurs. The primary objectives of this study were to evaluate the safety and preliminary anti-tumor activity of Azacitidine for injection combined with Chidamide according to the Lugano 2014 criteria. Adverse events (AEs) were reported according to CTCAE v5.0. Results: Nineteen R/R PTCL pts (median age: 61 years, range: 52-71 years; male: 11 (57.9%) pts; ECOG PS=0: 10 (52.6%) pts) who was either relapsed or refractory to at least 1 line of therapy (median therapy lines:2) were enrolled. Among them, 11 pts were angioimmunoblastic T-cell lymphoma (AITL) and 8 pts were PTCL, NOS. 16 pts could evaluate the efficacy and safety. For 16 treated patients, treatment-related adverse events (TRAEs) of any grade occurred in 15 (93.7%) pts, ≥3 TRAEs occurred in 7 (43.8%) pts. The most frequent TRAEs (≥ 20%) were Pain at the injection site (n=12, 75.0%), Neutropenia (n=9, 56.3%), Erythema at the injection site (n=8, 50.0%), Nausea (n=7, 43.8%), Thrombocytopenia (n=6, 37.5%), Feeble (n=6, 37.5%), Anemia (n=5, 31.3%), Diarrhea (n=5, 31.3%), Neutropenia with fever (n=4, 25.0%). The most frequent grade ≥ 3 TRAEs (≥5%) was Neutropenia (n=3, 18.8%). 3 pts experienced TRAE leading to drug dosage adjustment. The recommended phase II dose (RP2D) was Azacitidine 75mg/m2, Chidamide 20mg (Dose Group 2). As of data cut-off date, 3 pts remained on Azacitidine for injection combined with Chidamide therapy. The objective response rate (ORR) and disease control rate (DCR) were 56.25% (9/16; 95% CI: 31.9-80.5) and 75% (12/16; 95% CI: 53.8-96.2), respectively. For AITL pts, the ORR was and DCR were 60% (6/10; 95% CI: 36.0-84.0) and 80% (8/10; 95% CI: 60.4-99.6), and 4 pts achieved CR. For all PTCL pts enrolled, Median PFS 6.45 months (95% CI: 3.97-12.7); Median OS 17.5 months (95% CI: 2.11-32.9). Conclusion: Azacitidine for injection combined with Chidamide showed a promising anti-tumor effectivity with a manageable safety profile in Relapsed/Refractory peripheral T-cell lymphoma patients, especially for AITL patients.