Abstract PO-007: A phase 1 study of romidepsin, azacitidine, dexamethasone, and lenalidomide (RAdR) for relapsed/refractory T-cell malignancies
Authors: Gordon Max , Miljkovic Milos , Ng Samuel , Lakhotia Rahul , Melani Christopher , Conlon Kevin , Phelan James , Bryant Bonita , Pittaluga Stefania , Jaffe Elaine , Staudt Louis , Wilson Wyndham , Roschewski Mark 
Published: June 2024

Abstract
Romidepsin, azacitidine and lenalidomide are all active in T-cell malignancies (TCM) demonstrating single agent objective response rates (ORR) of 20 to 30% (Coiffier 2012; Morschhauser 2013; Dupuis 2022). Combinations of these targeted agents improves the rates of complete response (CR) but have significant toxicity due to indefinite schedules. We hypothesized that use of a multi-targeted therapy regimen such as RAdR given in fixed duration cycles would be safe and effective. We tested escalating doses of lenalidomide (5-20mg) with fixed doses of romidepsin, azacitidine and dexamethasone in a phase 1 study. Patients (pts) first received a 7-day window of lenalidomide for cytokine correlative research followed by six cycles of romidepsin (12mg/m2; days 1 and 10), azacitidine (300mg; days 1-10), dexamethasone (40mg; days 1 and 10), and lenalidomide (5-20mg; days 1-10) in 21-day cycles for up to 6 cycles. The primary endpoint was the maximum tolerated dose (MTD) of lenalidomide and the primary objective was the overall safety of the regimen. A 3+3 design was used with an additional 9 pts treated at the MTD. 26 pts were enrolled with a median age of 61 years (range, 28-80) including 31% over 65. Eight (31%) pts had PTCL, NOS, 6 (23%) had mycosis fungoides (MF), 5 (19%) had angioimmunoblastic T-cell lymphoma, and 4 (15%) ATLL. Median prior lines of therapy were 2 (range, 1-8), 31% had received &gt;3 prior lines and 2 patients had received prior allogeneic transplantation. The median number of cycles was 4 (range, &lt;1-6). The most frequent reasons for stopping therapy were progressive disease (38%), completion of planned therapy (27%) and adverse events (23%). The most frequent grade 1-2 non-hematologic adverse events were vomiting (52%), diarrhea (48%) and dysgeusia (48%), and AE grade 3+ included infection (16%) and hypokalemia (16%). Grade 3+ neutropenia occurred in 24% of cycles and both grade 3+ anemia and thrombocytopenia in 12% of cycles. Two DLTs were observed, grade 4 thrombocytopenia at dose level 1 and grade 3 abdominal pain at dose level 2. The MTD of lenalidomide was determined to be 20mg. In evaluable pts (N=21) the ORR was 66% and CR rate was 14%. After a median follow-up of 23 months. Median progression free survival (PFS) and overall survival (OS) were 4 months and not reached, respectively. 2-year OS was 53%. Two pts (PTCL, NOS and MF) completed the planned 6 cycles of therapy and remain in remission without consolidation at 30 months. Five pts were successfully bridged to SCT, all of whom remain alive and without progression. In pts treated at the MTD, the ORR was 89% and the CR rate was 22%. The multi-targeted therapy regimen RAdR is safe and can achieve CR after fixed duration in patients with relapsed refractory TCM. Toxicity is predominantly gastrointestinal and hematologic. Most patients do not achieve durable CR with RAdR alone, but it may be effective bridging therapy to consolidation.
This study was supported by the Intramural Research Program of the NIH and was registered at Clinicaltrials.gov [NCT04447027].
Citation Format: Max Gordon, Milos Miljkovic, Samuel Ng, Rahul Lakhotia, Christopher Melani, Kevin Conlon, James Phelan, Bonita Bryant, Stefania Pittaluga, Elaine Jaffe, Louis Staudt, Wyndham Wilson, Mark Roschewski. A phase 1 study of romidepsin, azacitidine, dexamethasone, and lenalidomide (RAdR) for relapsed/refractory T-cell malignancies [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-007.