Romidepsin in Combination with Gemcitabine, Oxaliplatin, and Dexamethasone Shows Durable Responses in Aggressive Lymphomas Including AITL and DLBCL: Phase I Results

Background: Histone deacetylase inhibitors (HDACi) and combination chemotherapy are independently used to treat relapsed/refractory (R/R) lymphoma. In vitro studies suggest that the addition of HDACi to platinum-based chemotherapy is synergistic. We conducted a phase I study of the combination of romidepsin, gemcitabine, oxaliplatin and dexamethasone in R/R lymphomas with an expansion cohort in T-cell lymphomas. Here we report the safety, maximum tolerated dose (MTD) and preliminary response data from the completed phase I portion of the study as part of a preplanned interim analysis.

Methods: The safety and tolerability of the combination of romidepsin, gemcitabine, oxaliplatin, and dexamethasone was assessed in this phase I study to determine the MTD. The treatment schedule included: gemcitabine 1000 mg/m² (day 1), oxaliplatin 100 mg/m² (day 1); romidepsin (day 2), dexamethasone 20 mg (days 1-4) and pegfilgrastim 6 mg (day 3) of a 21-day cycle. A standard 3+3 dose escalation schema was followed with 3 dose levels of romidepsin: 1) 8 mg/m², 2) 10 mg/m², 3) 12 mg/m². The study originally included romidepsin administration on days 2 and 8 but due to prolonged cytopenias, the day 8 dose was eliminated after the first 6 patients. Dose-limiting toxicity (DLT) was defined in cycle 1 as ≥ grade 3 non-hematologic toxicity, any grade 4 hematologic toxicity, grade ≥ 3 related laboratory changes not responsive to supportive measures, and grade ≥2 toxicity resulting in a >14 day treatment delay. Patients could be treated until progression, intolerance, or response adequate to allow autologous or allogeneic transplantation, to a maximum of 8 cycles. At the discretion of the treating physician, those in complete remission at their interim imaging were permitted to limit treatment to 2 cycles beyond complete response.

Results: 15 patients with R/R lymphoma (6 PTCL-NOS, 3 AITL, 6 DLBCL) were enrolled with all patients evaluable for toxicity and response in the phase I portion. The median age was 66 years (range 55-83) with 53% male (n=8). The median number of prior therapies was 2 (range: 1-4).

Dose level 2 (romidepsin 10 mg/m² on day 1) was found to be the MTD. There was 1 DLT among the 6 pts treated in dose level 1 (pneumonia, treated with romidepsin on days 1 and 8); 1 DLT among the 6 pts treated in dose level 2 (bleeding); and 2 DLTs in the 3 pts treated in dose level 3 (neutropenic fever, grade 4 thrombocytopenia). Treatment related toxicities (all grades in ≥10% of patients, and grades 3-4) are included in Table 1. SAEs included hospitalizations for pneumonia (1), nausea and vomiting (1), tumor lysis (1), and for complications related to disease progression (4).

The overall response rate was 47% (7/15) with complete response rate 40% (6/15) and the partial response rate 7% (1/15). Complete responses were seen in AITL (3/3), PTCL-NOS (1/6) and DLBCL (2/6). Partial response was seen in PTCL-NOS (1/6).

The median progression free survival for all pts was 2.8 months (95% CI: 0.0-9.9) .The median time to response was 5.6 weeks. The median duration of response for the 7 responding patients was 8.5 months (range: 1.2-36.6 months). Of patients who achieved a complete response, 4 remain in CR at 4.4 (AITL), 6.8 (PTCL), 27.3 (AITL) and 36.6 (DLBCL) months. 2 additional patients remained in CR for 29.1 months (AITL) and 8.5 months (DLBCL). 1 patient with PTCL-NOS achieved a PR for 1.2 months. 1 patient with DLBCL had stable disease and proceeded to allogeneic transplant after study treatment.

Conclusions: The MTD was identified as romidepsin 10 mg/m² (day 1) in combination with gemcitabine 1000 mg/m², oxaliplatin 100 mg/m², and dexamethasone 20 mg. No unexpected toxicities have emerged. The preliminary overall and complete response rates of this regimen are promising in T-cell lymphoma, particularly in AITL, and warrants further study. Durable responses were seen in AITL, PTCL-NOS and DLBCL. 3 patients have had complete responses for >24 months and multiple remissions are ongoing. An expansion cohort in T-cell lymphoma is ongoing.

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