Final Analysis of the RO-CHOP Phase Ib/II Study: Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphoma (PTCL)

Background: Romidepsin is a histone deacetylase inhibitor approved by the FDA for patients with cutaneous T-cell lymphoma and PTCL who have received at least 1 prior therapy. In recurrent/refractory PTCL, it has been evaluated as a single agent in 2 phase II studies with overall response rates of 25-38%(Piekarz, Blood 2011 & Coiffier, J Clin Oncol 2012). Toxicity is mainly hematologic and digestive. We here present the final analysis of a phase Ib/II trial aiming to evaluate the safety, tolerability and efficacy of romidepsin in association with CHOP in patients with previously untreated PTCL.

Patients & methods: Patients with PTCL were planned to receive 8 cycles of CHOP

(cyclophosphamide 750 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, vincristine 1,4 mg/m2 day 1, prednisone 40 mg/m2 days 1 – 5) in association with varying doses of romidepsin. Based on pharmacokinetic data and results of previous phase II studies, the starting dose of 10 mg/m2 days 1 & 8 was chosen. The dose-variation scheme followed a traditional “3+3” design. Dose-limiting toxicities (DLT) were considered during the first 2 cycles. DLT was initially defined as: Non hematological toxicity grade 3-4 or hematological toxicity grade 3 lasting more than 7 days or grade 4 lasting more than 3 days. The protocol was subsequently amended to tolerate if lasting less than 10 (grade 3) or 7 days (grade 4).

Results: Eighteen patients have been treated in phase Ib of the study (Dupuis, Hematol Oncol 2013). Significant, albeit tolerable hematological toxicity having been observed in the first two cohorts, the definition of DLT was modified during the course of the study. The dose of 12 mg/m2 was chosen as the recommended dose for phase II. Nineteen patients were treated in the phase II part of the study. Two patients had an early cardiac event (myocardial infarction) and were excluded from the efficacy analysis. A third patient had a cardiac event (acute cardiac failure) after cycle 1 day one and continued on CHOP alone. There were no deaths attributable to toxicity. Late hematological toxicity was observed, thus some cycles after cycle 2 were delivered with only one administration of romidepsin at day 1: Among 509 planned romidepsin administrations, 93 (18%) were cancelled on decision of the investigator, mainly during the last 2 cycles and mainly because of hematological toxicity. Sixty-seven percent of patients had at least on serious adverse event (SAE). The most frequent SAEs were: Febrile neutropenia (13.5%), general physical health deterioration (13.5%), lung infection (10.8%), vomiting (8%). Thirty-eight percent of patients had Grade 3-4 neutropenia at any time of the study, 19% grade 3-4 thrombocytopenia, 8% grade 3-4 anemia. Observed response rates (IHP 2007 criteria) were (n=35): Complete response 51%, partial response 17%, and progressive disease 25%. With a median follow-up of 17.5 months, the estimated progression-free survival is 57% at 18 months with 5 progressions among the 24 responding patients. The overall survival rate at 18 months is 76,5%. Longer follow-up will be presented during the meeting.

Conclusion: Romidepsin can be combined with CHOP at the price of foreseeable hematological toxicity. Some cardiovascular events have been observed but the relationship with romidepsin is questionable. The progression-free survival rates seem promising, and the combination of romidepsin and CHOP is actually compared with CHOP alone in the setting of a phase III randomized trial (phase III RO-CHOP study).

References :

1. Piekarz R, Blood. 2011;117(22):5827-34.

2. Coiffier B, J Clin Oncol. 2012;30(6):631-6

3. Dupuis J, Hematological Oncology 2013;31(Suppl.1):96-150