Oral histone deacetylase inhibitor tucidinostat (HBI‐8000) in patients with relapsed or refractory adult T‐cell leukemia/lymphoma: Phase IIb results

Abstract This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI‐8000) in patients with relapsed or refractory (R/R) adult T‐cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty‐three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end‐point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression‐free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.

Japan has one million HTLV-1 carriers. 5 Worldwide, at least 3000 new cases of ATLL are diagnosed each year. 6 A rising incidence of ATLL has been reported in nonendemic regions such as the United States, 7 especially in urban communities with Caribbean and Latin American populations. 8 The median age of ATLL patients in the United States is 54 years, 9 whereas in Japan it is around 68 years. 10 Adult T-cell leukemia/lymphoma generally has a poor prognosis, with shorter OS than other common subtypes of PTCL. 11 Aggressive types of ATLL are associated with a particularly poor prognosis (median OS approximately 8-10 months); the median OS of indolent types is approximately 5 years. 12 In Japan, approximately 1000 people die from ATLL each year. 13 In Japan, the Practical Guidelines for Hematological Malignancies 2018 recommended multidrug combination chemotherapy for aggressive ATLL (acute type, lymphoma type, and unfavorable chronic type) that progresses rapidly. 14 For aggressive ATLL, chemotherapy with the multiagent protocol modified VCAP-AMP-VECP regimen (mLSG15) has been recommended as first-line treatment in Japan based on the results of a phase III trial, however, the prognosis after treatment is still poor. 14 In the phase III study JCOG9801, the PFS rate at 1 year with mLSG15 was 28% and survival at 3 years was 24%, with median survival of 13 months. 15 Mogamulizumab, a defucosylated anti-CC chemokine receptor 4 Ab, is approved as first-line therapy in combination with chemotherapy for untreated aggressive ATLL. 16 For R/R ATLL, mogamulizumab monotherapy and lenalidomide monotherapy have been approved in Japan. 16,17 As the response to intensive chemotherapy is not generally durable, and cumulative toxicities discourage the use of long-term intensive chemotherapy, early allo-HSCT is recommended after response to first-line therapy. 18 Allogeneic HSCT has the potential to cure some patients with aggressive ATLL, but carries the risk of transplant-related mortality, 19 and the clinical outcome of allo-HSCT after PD is poor. 20 Patient age is a key factor in determining the eligibility of allo-HSCT and the type of conditioning regimen, 21 and allo-HSCT is less likely to be an option for elderly patients. As the age of ATLL patients in Japan at diagnosis has been increasing, 10 treatment options for elderly patients are needed.
Especially challenging is the management of patients with R/R aggressive ATLL. 1 The prognosis for these patients is dismal, although the use of lenalidomide or mogamulizumab has produced some encouraging results. 22 Options for treatment of R/R ATLL are very limited and might include a clinical trial, best supportive care, or an alternative therapy not previously used. 23,24 The low survival

Abstract
This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI-8000) in patients with relapsed or refractory (R/R) adult T-cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab.
Twenty-three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end-point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression-free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin).
Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.

K E Y W O R D S
ATLL, HBI-8000, HDAC inhibitor, ORR, tucidinostat rates in patients with ATLL and the lack of curative therapy present an unmet medical need for which we should explore new targeted therapies. 22 T-cell lymphomas have been responsive to HDACi, 25

and several
HDACi have achieved marketing approval, including tucidinostat (HBI-8000; chidamide in China). Tucidinostat is a benzamide HDACi of HDAC isoenzymes 1, 2, 3, and 10 selectively. There are three distinct mechanisms of action associated with tucidinostat: direct tumor suppression, immunomodulation, and epigenetic modification of cellular functions. 26,27 Histone deacetylase inhibitors cause apoptosis of ATLL cells, 28 precancerous lymphocytes infected with HTLV-1, or HTLV-1 transfected cell lines. Therefore, tucidinostat presents a novel mechanism of action that does not overlap with approved drugs to treat R/R ATLL.
The antitumor effect of tucidinostat in ATLL was investigated using cell lines derived from Japanese patients with ATLL and primary tumor cells obtained directly from patients with ATLL. In most cases tucidinostat induced apoptosis in both cell lines and primary ATLL cells. 29 Tucidinostat stimulates accumulation of acetylated histones H3 and H4 in tumor cells, which can increase the gene expression of various tumor suppressors, such as p53 and p21. Tucidinostat inhibits proliferation and cell viability in both ATLL-derived cell lines and primary ATLL cells freshly obtained from ATLL patients. 29 These preclinical observations support the hypothesis that tucidinostat will be efficacious in ATLL.
Clinical studies of tucidinostat have been undertaken mainly in patients with T-cell lymphomas. 30,31 A phase I study in Japanese patients with R/R NHL, including ATLL patients, showed a manageable safety profile, and 40 mg twice per week was selected for subsequent clinical development. An encouraging efficacy signal was observed in patients with ATLL (three of four patients with ATLL achieved PR), along with an acceptable tolerability/safety profile. 31 The aim of the current phase IIb study was to evaluate the efficacy and safety of tucidinostat in patients with R/R ATLL. This is the first study for patients with R/R aggressive ATLL with a treatment history of mogamulizumab. The recommended dose of tucidinostat was selected based on the previous Japanese phase I study in R/R NHL, which is slightly higher than the chidamide (HBI-8000) approved dose for PTCL in China. The data described herein led to the approval of tucidinostat in 2021 by Japan's Ministry of Health, Labour and Welfare for R/R aggressive ATLL. This paper reports the results of the final analysis when all patients had completed follow-up assessments.

| Patients
The study cohort included Japanese adult patients with R/R aggressive ATLL (acute, lymphoma or unfavorable chronic types, histologically or cytologically diagnosed) after receiving prior therapy with mogamulizumab, or at least one systemic therapy with cytotoxic chemotherapy if intolerance/contraindication for mogamulizumab was observed, and for whom no other standard treatment could be considered appropriate. Patients had to have at least one evaluable ATLL lesion, ECOG performance status 32 of 0-2, estimated life expectancy of more than 3 months, no previous organ transplantation, no previous allo-HSCT, no autologous HSCT within 12 weeks of starting the study drug, and no active infection or heart abnormalities/arrhythmias. The primary efficacy end-point of the study was ORR, which was analyzed in the per-protocol set. Secondary end-points included PFS, DOR, and ORR in each ATLL subtype.

| Assessments
Response to treatment and progression of ATLL was evaluated according to modified criteria of the International Consensus Meeting. 23 Best responses were determined from the efficacy assessments conducted at end of the 4th week, the 8th week after first study dose, and then every 8 weeks from the 8th week through the study period. An IOERC of hematologic oncologists reviewed all data related to disease status, including evaluation of imaging studies by Independent Radiology Review, a modification of the Severity-Weighted Assessment Tool score for skin lesions, 35

| Statistical analyses
The target sample size was 22 patients to have at least 18 evaluable patients for efficacy analysis. The target ORR for this study was 30%. To show a response rate of more than 5% in 18 subjects, the power was 80% at a 5% significance level and a two-sided alpha.
First and final analyses were planned. The first analysis was for the purpose of regulatory submission and planned to be carried out when all patients completed end of treatment assessment. The final analysis was planned to be carried out when all patients completed follow-up assessments.

| RE SULTS
The study was conducted from November 2016 to November 2019.

| Patients
A total of 23 eligible Japanese patients from 18 study sites were treated with at least one dose of tucidinostat and included in analyses.
All patients had advanced ATLL with rapidly progressing disease.
All but one patient had ECOG performance status 0-1. The median time from initial diagnosis was 1.5 years. The median time from the last treatment before the first dose of the study drug was 89 days (range, 30-496 days; mean, 131 days). All patients had previously received chemotherapy and mogamulizumab in combination or sequentially. In fact, 73.9% (17/23) already had at least two lines of treatment. Furthermore, 13.0% (3/23) had five or more regimens.
Overall, 21.7% (5/23) of patients had disease progression during their last treatment and were thus classified as refractory ( Table 1).

| Efficacy
The primary end-point of ORR was determined to be 30.4%  Table 2).
When analyzed by ATLL subtype, ORR in acute ATLL was 46.2%, in lymphoma ATLL ORR was 12.5%, and there was no response in the two patients with unfavorable chronic ATLL ( Table 2).  Table 3).
Subgroup analysis showed a tendency for higher ORR in patients with acute type disease, of female gender, younger than 75 years, who had undergone fewer than three prior regimens, and prior mogamulizumab combination therapy (Figure 1).

| DISCUSS ION
This is the first prospective study for the treatment of patients with R/R aggressive ATLL who had previously been treated with chemotherapy and mogamulizumab and patients with refractory ATLL.
Tucidinostat 40 mg twice per week, given orally, showed an ORR of 30.4% by the IOERC and 34.8% by investigator assessment. As a post hoc analysis, the ORR in patients with relapsed or recurrent ATLL was 38.9% (7/18). This result is comparable to phase II studies of the currently available treatments in Japan. Mogamulizumab was reported to produce an ORR of 50% in patients with relapsed ATLL, 37 and an ORR of mogamulizumab in a study of mogamulizumab versus investigator's choice of chemotherapy in patients who were refractory or relapsed after at least one prior systemic therapy was 34% by investigator assessment and 28% by independent review. 38 Lenalidomide was reported to produce an ORR of 42% in patients with relapsed or recurrent ATLL. 17 In our study, 78.3% of patients had two or more prior treatment regimens, and 17.4% had five or more; five (22%) of the enrolled patients were refractory to their previous chemotherapy. In addition, the median time since last ATLL treatment was 89.0 days in our study, but 234.5 days in the lenalidomide study, 17 suggesting that patients with more aggressive ATLL were enrolled in our study.
Tucidinostat showed an acceptable safety profile. The most common AEs were hematological, such as thrombocytopenia, neutropenia, leukopenia, and anemia, and these laboratory abnormalities also constituted the grade 3 or higher TEAEs.  TA B L E 4 Treatment-emergent adverse events (TEAEs) related to tucidinostat in more than 10% of study patients with adult T-cell leukemia/lymphoma, and any TEAEs grade 3 or higher (N = 23)