Early Results of a Phase Ib/II Dose-Escalation Trial of Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphomas (PTCL)

Romidepsin is a potent histone deacetylase inhibitor approved by the FDA for patients with cutaneous T-cell lymphoma and PTCL who have received at least 1 prior systemic therapy. In recurrent/refractory PTCL, it has been evaluated as a single agent in 2 previous phase II studies with overall response rates of 30–38% (Piekarz et al., Blood 2011;117:5827; Coiffier et al., Blood 2010;116(21S):114). The observed toxicity was mainly hematological and digestive. Prolongation of the QT interval has been reported. The aim of the present study was to evaluate the safety, tolerability and efficacy of escalating doses of romidepsin in association with CHOP in patients with previously untreated PTCL.

Patients with biopsy-proven PTCL are 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 escalating doses of romidepsin. Based on pharmacokinetic data and results of previous phase II studies, the starting dose of 10 mg/m² on days 1 & 8 has been chosen as the starting dose. At least 3 patients are to be treated at each dose level, and 3 more at the same dose level if 1 of the first three exhibited dose-limiting toxicity (DLT) during the first 2 cycles.

Six patients (3 male, 3 female, aged 47 to 67) have been included so far and are analyzable for toxicity on the first two cycles. Diagnoses were: PTCL, not otherwise specified (n=3), angioimmunoblastic TCL (n=1), primary cutaneous CD4+ small-medium TCL (n=1), enteropathy-associated TCL (n=1). ECOG performance status was good (0–1) in all patients; 5/6 had stage IV disease; IPI score was 1 (n=1), 2 (n=3), 3 (n=1), 4 (n=1). Among the first 3 patients treated at the starting dose of 10 mg/m², one exhibited a DLT (grade 3 malaise after cycle 2), thus 3 more patients were treated at this dose level. Among those 3, we observed 2 other DLTs: one grade 3 general status deterioration and grade 3 haematological toxicity lasting more than 7 days in the same patient, and one grade 4 hematological toxicity lasting more than 3 days. A total of 269 adverse events (AEs) were observed during 34 analyzable cycles. The most frequent AEs were: neutropenia n=22 (grade 3–4 =12), thrombocytopenia n=28 (grade 3–4 n=5), digestive complaints n=18 (no grade >2), and asymptomatic increase of liver enzymes n=7 (1 grade 3). The mean increase in the corrected QT interval between pre- and post-romidepsin EKGs was 19 ms (range −43 to +79). No clinically relevant cardiac event was reported. One patient progressed after 5 cycles, 2 have finished the 8 planned cycles and are both in CR, and 3 are still under treatment without evidence of progression.

Romidepsin can be combined with CHOP without unexpected toxicity. The dose of 10 mg/m² on days 1& 8 is associated with excessive hematological toxicity. The study is ongoing with a lower dose of 8 mg/m² on day 1 & 8 of each cycle. Updated results will be presented at the meeting.

Coiffier:CELGENE: Consultancy, Research Funding, Speakers Bureau; ALLOS THERAPEUTICS: Consultancy, Research Funding, Speakers Bureau; ESAI: Consultancy, Research Funding, Speakers Bureau.