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The Combination of Chidamide with the CHOEP Regimen in Previously Cancer Biol Med 2021. doi: 10.20892/j.issn.2095-3941.2020.0413 ORIGINAL ARTICLE The combination of chidamide with the CHOEP regimen in previously untreated patients with peripheral T-cell lymphoma: a prospective, multicenter, single arm, phase 1b/2 study Wei Zhang1, Liping Su2, Lihong Liu3, Yuhuan Gao3, Quanshun Wang4, Hang Su5, Yuhuan Song6, Huilai Zhang7, Jing Shen8, Hongmei Jing9, Shuye Wang10, Xinan Cen11, Hui Liu12, Aichun Liu13, Zengjun Li14, Jianmin Luo15, Jianxia He16, Jingwen Wang17, O. A. O’Connor18, Daobin Zhou1 1Department of Hematology, Peking Union Medical College Hospital, Beijing 100730, China; 2Department of Hematology, Shanxi Provincial Cancer Hospital, Taiyuan 030013, China; 3Department of Hematology, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China; 4Department of Hematology, Chinese PLA General Hospital, Beijing 100039, China; 5Department of Lymphoma, the 307 Hospital of PLA, Beijing 100071, China; 6Department of Lymphoma, Peking University Cancer Hospital and Institute, Beijing 100142, China; 7Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China; 8Department of Hematology, Beijing Friendship Hospital, Beijing 100050, China; 9Department of Hematology, Peking University Third Hospital, Beijing 100191, China; 10Department of Hematology, the First Affiliated Hospital of Harbin Medical University, Harbin 150081, China; 11Department of Hematology, Peking University First Hospital, Beijing 100034, China; 12Department of Hematology, Beijing Hospital, Beijing 100730, China; 13Department of Lymphoma, Harbin Medical University Cancer Hospital, Harbin 150081, China; 14Lymphoma Diagnosis and Treatment Center, Institute of Hematology and Blood Diseases Hospital, Tianjin 300052, China; 15Department of Hematology, Second Hospital of Hebei Medical University, Shijiazhuang 050000, China; 16Department of Hematology, Shanxi Provincial People’s Hospital, Taiyuan 030012, China; 17Department of Hematology, Beijing Tongren Hospital, Beijing 100730, China; 18Columbia University Medical Center, New York 10032-3784, NY, USA ABSTRACT Objective: To assess the efficacy and safety of the novel histone deacetylase inhibitor, chidamide, in combination with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (Chi-CHOEP) for untreated peripheral T-cell lymphoma (PTCL). Methods: A prospective, multicenter, single arm, phase 1b/2 study was conducted. A total of 128 patients with untreated PTCL (18–70 years of age) were enrolled between March 2016 and November 2019, and treated with up to 6 cycles with the Chi-CHOEP regimen. In the phase 1b study, 3 dose levels of chidamide were evaluated and the primary endpoint was determination of the maximum- tolerated dose and recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 study was 2-year progression-free survival (PFS). Results: Fifteen patients were enrolled in the phase 1b study and the RP2D for chidamide was determined to be 20 mg, twice a week. A total of 113 patients were treated at the RP2D in the phase 2 study, and the overall response rate was 60.2%, with a complete response rate of 40.7%. At a median follow-up of 36 months, the median PFS was 10.7 months, with 1-, 2-, and 3-year PFS rates of 49.9%, 38.0%, and 32.8%, respectively. The Chi-CHOEP regimen was well-tolerated, with grade 3/4 neutropenia occurring in approximately two-thirds of the patients. No unexpected adverse events (AEs) were reported and the observed AEs were manageable. Conclusions: This large cohort phase 1b/2 study showed that Chi-CHOEP was well-tolerated with modest efficacy in previously untreated PTCL patients. KEYWORDS Peripheral T-cell lymphoma; chidamide; histone deacetylase inhibitor; epigenetic Introduction Correspondence to: Daobin Zhou E-mail: [email protected] ORCID ID: https://orcid.org/0000-0002-1592-1932 Peripheral T-cell lymphomas (PTCLs) constitute a group Received August 07, 2020; accepted October 26, 2020 of heterogeneous lymphomas, mainly including PTCL-not Available at www.cancerbiomed.org ©2021 Cancer Biology & Medicine. Creative Commons otherwise specified (PTCL-NOS), angioimmunoblastic T-cell Attribution-NonCommercial 4.0 International License lymphoma (AITL), anaplastic large cell lymphoma (ALCL), 842 Zhang et al. Chi-CHOEP for previously untreated PTCL and other rare entities. PTCLs account for 10%–15% of according to the 2016 WHO classification10, and ALCL all non-Hodgkin lymphomas (NHLs) worldwide, being (ALK+), NK/T-cell lymphoma, and primary cutaneous lym- significantly higher in China (23.3%–30.2%)1,2. No stand- phoma were excluded. ard treatments have been established and commonly used (cyclophosphamide, doxorubicin, vincristine, and prednisone Treatment protocol (CHOP) or etoposide with CHOP (CHOEP) regimens result in poor outcomes, except for anaplastic lymphoma kinase The treatment protocol involved induction therapy with up (ALK)-positive ALCL3. Upfront autologous stem cell trans- to 6 cycles of the Chi-CHOEP regimen as follows: CHOEP plantation (ASCT) has been recommended to improve the [intravenous cyclophosphamide (750 mg/m²), doxorubicin prognosis of PTCL4. Frequent epigenetic dysregulation has (50 mg/m²), or epirubicin (70 mg/m²), and vincristine been documented in patients with PTCL, which makes his- (1.4 mg/m²) or vindesine (4 mg on day 1), etoposide (100 mg tone deacetylase (HDAC) a potential target5. Several HDAC on days 1–3), and oral prednisone (60 mg/m² on days 1–5), inhibitors have been approved for PTCL in a relapsed/refrac- repeated every 21 days] in combination with oral escalating tory setting, such as belinostat6, romidepsin7, and chidamide8. doses of chidamide twice a week. Patients were restaged by Chidamide, a novel benzamide class of HDAC inhibitor, has computed tomography (CT) or positron emission tomogra- demonstrated broad spectrum activity against various neo- phy-CT after the first 3 cycles according to the revised response plasms9. In a pivotal phase 2 trial with refractory or relapsed criteria for NHL. Patients with stable disease (SD) or progres- PTCL, chidamide produced an overall response rate (ORR) sive disease (PD) discontinued study treatment and went on and complete response (CR) rate of 28% and 14%, respec- to receive salvage therapy at the discretion of the treating phy- tively, leading to approval by the National Medical Products sician. Patients with a complete response or partial response Administration (China) in 2014 for treatment of refractory or received 3 additional cycles to complete the planned 6 cycles. relapsed PTCL8. Whether first-line use of HADC inhibitors in The selection of subsequent therapy was left to the discretion combination with the CHOEP regimen will further improve the of the treating physician (either ASCT consolidation or chid- prognosis in PTCL is unknown. Thus, we conducted a prospec- amide maintenance). tive, multicenter, phase 1b/2 study to evaluate the efficacy and safety of combination chidamide and CHOEP (Chi-CHOEP) Study endpoints in previously untreated patients with PTCL, hoping to establish a more effective regimen for this aggressive lymphoma. This study consisted of dose-escalation (phase 1b) and expan- sion (phase 2) phases. In phase 1b, 3 dose levels of chidamide Materials and methods (15, 20, and 25 mg twice a week) were evaluated at a tradi- tional 3 + 3 dose-escalation design. Dose-limited toxicity Study design and participants (DLT) was defined in the first 2 cycles and predefined DLTs included non-hematological toxicity of any grade ≥ 3, grade A prospective, multicenter, single arm, phase 1b/2 study was 4 agranulocytosis with granulocyte colony-stimulating factor conducted at 17 sites across China to evaluate the safety and support, or grade 4 thrombocytopenia lasting > 7 days. The efficacy of Chi-CHOEP in previously untreated patients with primary endpoint of the phase 2 study was 2-year progres- PTCL (ClinicalTrials.gov Identifier: NCT02987244). This sion-free survival (PFS), and secondary endpoints included study was carried out in accordance with the principles of overall response rate (ORR), CR, 2-year overall survival (OS), good clinical practice and the Declaration of Helsinki. The and adverse events (AEs). PFS was defined as the time from protocol, informed consent forms, and other relevant study treatment initiation until disease progression, death from any documentation were approved by the Ethics Committee of cause, or last follow-up, whichever came first. each center. All patients provided written informed consent before study entry. Statistical analysis A total of 142 patients (18–70 years of age) were screened and 128 were enrolled between March 1, 2016 and November All statistical analyses were performed with SPSS statistical 30, 2019 (Figure 1). The diagnosis of PTCL was confirmed software for Windows, version 24.0 (SPSS, Chicago, IL, USA). Cancer Biol Med Vol 18, No 3 Month 2021 843 Screened (n = 142) Exclusion (n = 14): -Histological diagnosis not met (n = 7) - Patients withdrew (n = 4) - Investigator decision (n = 3) Enrolled (n = 128) Phase 1b chidamide dose: 15 mg (n = 6), 20 mg (n = 6), 25 mg (n = 3) Phase 2 chidamide dose: 20 mg (n = 113) In phase 2 study Completed 6 cycles Completed 3–5 cycles Completed 1–2 cycles (n = 49) (n = 37) (n = 27) Reason for early discontinuation Investigator decision Disease progression Adverse
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