A Phase 1/2 Study of Oral 5-Azacitidine and Romidepsin in Patients with Lymphoid Malignancies Reveals Promising Activity in Heavily Pretreated Peripheral T-Cell Lymphoma (PTCL)

Introduction: Patients with PTCL are characterized by frequent alterations of epigenetic operations, including recurrent mutations in important genes governing genome wide methylation (i.e., TET2, IDH1/2, and DNMT3). This feature creates the rationale for the use of hypomethylating agents (HMA) in these diseases. Indeed, a recent study showed impressive preliminary activity of 5-azacitidine (AZA) in patients with angioimmunoblastic T-cell lymphoma (AITL). Histone deacetylases (HDACs), transcriptional modulators that operate through modification of histone proteins, are also overexpressed in select types of PTCL. HDAC inhibitors (HDACi), such as romidepsin (ROMI), have shown consistent class activity in patients with R/R PTCL, and received regulatory approval for this indication. Our group has previously shown that the combination of the HDACi and the HMA can 'reverse' the malignant signature of T-cell lymphoma lines in vitro. In addition, the combination induced the expression of a unique set of genes not induced by either single agent, including a unique methylation pattern. We therefore launched a phase 1/2 trial of combined AZA and ROMI in patients with lymphoid neoplasms, including PTCL. Herein we present updated analysis of the results of the phase 1 and 2 portions of the trial combined.

Methods: Patients with any from of lymphoma were eligible for the phase 1, while the phase 2 exclusively enrolled patients with PTCL. Patients with any number of prior therapies, including transplantation, were eligible for enrollment. In the phase 2 patients with newly diagnosed PTCL were also allowed to participate. Other inclusion criteria were ECOG PS <2 and adequate organ and marrow function. The phase 1 study followed a 3 + 3 dose-escalation design. The starting doses were AZA 100 mg/day and ROMI 10 mg/m2 with progressively increasing dose intensity in subsequent cohorts (7 cohorts). The primary objectives of the study were the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combination. Secondary objectives included ORR (CR + PR), progression free survival (PFS), and duration of response (DOR).

Results: 30 patients were enrolled in total, 27 in phase 1 (26 accrued, 1 screening failure) and 3 in phase 2, of whom one has been restaged. In the intention-to-treat population the median age was 49 years (23-79), male-to-female ratio 17:13, and median number of prior therapies 5 (0-18). Sixteen patients had had autologous stem cell transplant, and 1 prior allogeneic transplant. Lymphoma histology's included Hodgkin/other (12, 40%), B-cell (8, 27%), and T-cell (10, 33%). Twenty-seven patients are evaluable for toxicity. We recorded 5 DLTs across all cohorts, 3 of which occurred at the highest dose level (i.e., AZA 300 mg days 1-21 and ROMI 14 mg/m2 days 8, 15, and 22) and included neutropenia (N = 2) and thrombocytopenia (N = 1). Two additional DLTs were 1 pleural effusion and 1 missed dose. The MTD for the combination was AZA 300 mg days 1-14 and ROMI 14 mg/m2 days 8, 15, and 22. Other grade 3-4 toxicities included febrile neutropenia (N = 3), and thrombocytopenia (N = 5), only 2 being grade 4. Among 25 patients evaluable for efficacy (all NHL subtypes), the ORR was 28% (7/25) including a 16% (4/25) CR. Substantially higher response rates were seen in patients with PTCL, where the ORR and CR were 83% (5/6) and 50% (3/6). First dose PK revealed the AUC for R 10 and 14 mg/m2 were 2021.5 ± 1461.3 h*ng/mL, and 1765.9 ± 1002.0 h*ng/mL, respectively. The median t1/2 was 4.8 and 2.4 h, respectively. These data are comparable to historical single agent values.

Conclusions: Albeit in a small population, these promising clinical results suggest that a doublet of epigenetic modifiers is well tolerated and may represent a viable backbone to build the next generation of active regimens in PTCL. The complete response seen in the AITL patient enrolled in the phase 2 portion of the study is encouraging and is being specifically expanded. The study is now multicenter, and results on additional patients enrolled in the phase 2 portion will be presented at the meeting. This study is registered on www.clinicaltrials.gov (NCT01998035).