High Response Rate of Romidepsin in Combination with ICE (Ifosfamide, Carboplatin and Etoposide) in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma: Updates of Phase I Trial
Authors: Chihara Dai , Oki Yasuhiro , Westin Jason R , Nastoupil Loretta , Fayad Luis E. , Samaniego Felipe , Wesson Emily , Ruben Charnelle , Horowitz Sandra B. , Feng Lei , Garg Naveen , Ahmed Sairah , Khouri Issa F. , Hosing Chitra M. , Romaguera Jorge E. , Fowler Nathan , Fanale Michelle A. 
Published: October 2019

Abstract
Background:
Survival for patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) remains very poor. Outcomes for these patients may be improved by stem cell transplant particularly if in complete remission (CR) prior to transplant (Smith 2013). ICE (ifosfamide, carboplatin and etoposide) and romidepsin single agent are options for the treatment of relapsed/refractory PTCL; however, the CR rate of both treatments is less than 30% (Zelenetz 2003, Mikesch 2013, Coiffier 2012). With the goal of increasing CR rates pre-transplant, we conducted a phase I study of romidepsin in combination with 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 (MTD) of the romidepsin in combination with standard ICE. 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 pegfilgrastrim or filgrastrim for growth factor 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. Dose escalation was conducted using a modified toxicity probability interval method (Ji 2010). Dose limiting toxicity (DLT) was defined as any grade 3 or 4 non-hematologic toxicity attributed to therapy that could not be controlled or prevented by supportive care or grade 4 thrombocytopenia or neutropenia that lasts for more than 14 days.
Results:
At the time of the data cut off (August 2015), a total of 17 patients were registered (6 PTCL-NOS, 7 AITL, 1 ALK+ALCL, 1 ALK-ALCL, 1 HSTL, 1 NK/TCL); 15 were evaluable for toxicity and 14 were assessable for response (Cheson 2007). Two, 12 and 1 patients were treated at dose level 1, 2 and 3, respectively. Since DLT with thrombocytopenia was seen in patient who received dose level 3, we continued enrollment in dose level 2. Median age of patients was 60 (range 24-70) years and 10 patients (67%) had primary refractory disease. Median number of prior regimens was 1 (range 1-2) and 1 patient had received a prior front-line consolidative ASCT.
Overall, 37 cycles were given to the patients with a median number of treatment cycles of 2 (range 1-4). The median days to the next cycle was 21 days (range: 14-33). Common grade 1/2 non-hematologic toxicities included nausea (51%), vomiting (43%), fatigue (41%) and dyspnea (19%). Grade 3/4 thrombocytopenia, grade 3/4 neutropenia and grade 3 anemia occurred in 95%, 84% and 73% of the cycles; however, febrile neutropenia occurred only in 1 cycle. Dose limiting toxicities included renal failure in dose level 2 and persistent grade 4 thrombocytopenia in dose level 3, and these DLTs led to expansion of dose level 2. The overall response rate was 78% (11/14, 95%CI: 49-95%) with CR rate of 64% (9/14, 95%CI: 35-87%). Three patients each underwent allogeneic and autologous transplant, respectively. Among them, three patients (two after allogeneic and one after autologous transplant), experienced relapse. With censoring the patients at the date of transplant for the survival analysis, median progression-free survival is 10.0 months.
Summary:
In conclusion, romidepsin plus ICE is an effective salvage regimen but with a higher rate of hematologic toxicities. Despite a relatively high CR rate relapses do continue to occur indicating the need of improving consolidation or maintenance approaches. Treatment of a larger number of patients is underway to optimize the dose of romidepsin when combined with ICE.

Disclosures
Westin: Spectrum: Research Funding. Nastoupil:AbbVie: Research Funding; Genentech: Honoraria; Janssen: Research Funding; Celgene: Honoraria; TG Therapeutics: Research Funding. Fanale:Celgene: Honoraria.