Phase I Study of Romidepsin in Combination with ICE (Ifosfamide, Carboplatin and Etoposide) in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma
Authors: Chihara Dai , Oki Yasuhiro , Fayad Luis , Wesson Emily , Ruben Charnelle , Horowitz Sandra B , Woolery Joseph , Feng Lei , Garg Naveen , Ahmed Sairah , Khouri Issa F. , Fanale Michelle A. 
Published: October 2019

Abstract
Background:
Despite recent approval of 4 new drugs for relapsed PTCL, an unmet need remains for new therapies. Survival of relapsed/refractory PTCL patients is improved by stem cell transplant particularly if patients are in CR prior to transplant (Smith 2013). ICE (ifosfamide, carboplatin and etoposide) is commonly used salvage regimen which produces CR rates ranging from 7% to 23% in patients with PTCL (Zelenetz 2003, Mikesch 2013). Romidepsin is a HDAC inhibitor which showed overall response rate of 25% with CR rate of 15% in a large phase II trial for relapsed/refractory PTCL (Coiffier 2012). To further improve outcomes particularly in CR rates pre-transplant, we conducted a phase I study of romidepsin in combination with standard ICE in patients with relapsed/refractory PTCL.
Methods:
The primary objective of this trial is to determine the toxicity profile and to identify the maximum tolerated dose of the romidepsin in combination with standard ICE. A statistical design of modified toxicity probability interval method was used (Ji 2010). Romidepsin was administered intravenously on days 1 and 4 of ICE, at 8mg/m2 (dose level 1), 10mg/m2 (level 2), or 12mg/m2 (level 3). All patients received G-CSF support. Patients could receive next cycle of treatment on day 14 if ANC was > 1 and platelets were ≥ 75,000 with ≥ 20,000 allowed if patients had bone marrow involvement with PTCL at time of enrollment.
Results:
As the time of the data cut off (August 2014), a total of 9 patients were registered (4 PTCL-NOS, 4 AITL, 1 NK/TCL) and 7 were assessable for toxicity and response (Cheson 2007). Two patients were consented but did not received treatment. Median age of patients was 60 (range 59-70) years, 5 patients had primary refractory disease and 5 patients had advanced stage disease at the time of enrollment. Median number of prior regimens was 1 (range 1-2) and 1 patient had received a prior front-line consolidative ASCT.
At the time of data cut off a total of 7 patients were treated with 2, 4 and 1 patients respectively at dose level 1, 2 and 3, respectively. Median number of treatment cycles were 2 (range 1-4). The common non-hematologic toxicity of grade 3/4 was fatigue (71%), nausea (43%), shortness of breath (29%), and vomiting (14%). With a total of 15 cycles overall given, grade 3/4 thrombocytopenia and neutropenia occurred in 87% and 40% of the cycles and febrile neutropenia occurred once in 1 patient. Dose limiting toxicities occurred in a 70 year-old female treated at dose level 2 with renal failure which was considered to be associated with ifosfamide and etoposide and in 67 year-old male with bone marrow involvement who previously had a front-line consolidative ASCT 6 months earlier and was treated at dose level 3 with persistent grade 3/4 thrombocytopenia. The overall response rate was 71% (5/7, 95%CI: 22-96%) with all in CR. Two patients who received dose level 1 underwent allogeneic transplant and one patient in dose level 2 underwent autologous stem cell transplant but all patients relapsed after transplant. Median duration of response was 7.2 months and six of the 7 patients experienced further disease progression.
Summary:
In conclusion, romidepsin plus ICE is an effective salvage regimen but with a higher rate of thrombocytopenia and neutropenia as anticipated than with romidepsin or ICE alone. Even though romidepsin plus ICE produces a high CR rate, early relapse despite this even when followed by transplant indicates the crucial need to develop methods to detect minimal residual disease and approaches to best address this. Enrollment continues to this trial.

Disclosures
Fanale: Seattle Genetics, Inc.: Consultancy, Honoraria, Other, Research Funding.