A Phase Ib/IIa Trial of the Combination of Romidepsin, Lenalidomide and Carfilzomib in Patients with Relapsed/Refractory Lymphoma Shows Complete Responses in Relapsed and Refractory T-Cell Lymphomas

Background:Epigenetic manipulation and immunomodulation are therapeutic strategies in hematologic malignancies. In our previous study, the combination of romidepsin and lenalidomide demonstrated a 58% overall response rate, complete response rate of 11% and median event free survival was 16 weeks in patients (pts) with relapsed or refractory T-cell lymphoma. Given the potential synergy of proteasome inhibitors with histone deacetylase inhibitors and lenalidomide, we conducted a phase Ib/IIa study to evaluate the safety and toxicity of romidepsin and lenalidomide in combination with carfilzomib in pts with relapsed or refractory lymphoma. Here we report the safety, toxicity, and maximum tolerated dose (MTD) from the completed phase I portion of the study as well as the efficacy data from the completed T-cell lymphoma phase IIa cohort.

Methods: The phase I portion evaluated toxicity and defined MTD. The clinicalactivity of the combination of romidepsin, lenalidomide, and carfilzomib was assessed in the phase I and lineage specific phase IIa cohorts. Romidepsin and carfilzomib were given IV on days 1, 8 and lenalidomide was given orally on days 1-14 of a 21-day cycle. A standard 3+3 dose escalation schema was followed: The starting dose was romidepsin 8 mg/m²,lenalidomide 15 mg, carfilzomib 36mg/m². Dose-limiting toxicity (DLT) was defined in cycle 1 as ≥ grade 3 non-hematologic toxicity, grade 4 hematologic toxicity, grade ≥ 3 thrombocytopenia with bleeding, grade 3 hematologic toxicity resulting in a significant delay of treatment or inability to receive day 1 of cycle 2 due to continued drug related toxicity. Tumor response was based on disease-specific criteria.Pts could be treated until progression, intolerance, or response adequate to allow allogeneic transplantation.

Results:20 pts were enrolled with 19 evaluable for toxicity (1 patient with T-cell lymphoma progressed prior to receipt of any study drug). 17 pts were treated for T-cell lymphoma (11 in the phase 1 portion and 6 in the phase IIa cohort): peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS)-9, angioimmunoblastic T-cell lymphoma (AITL)-4 (one with concurrent diffuse large B-cell lymphoma-DLBCL), mycosis fungoides (MF)-2, transformed MF-1, extra-nodal NK/T-cell lymphoma (ENKTCL)-1. 3 pts in the phase 1 portion were treated for B-cell lymphoma: DLBCL-3. The T-cell lymphoma cohort is complete and efficacy data is reported here.

Dose level 2 (romidepsin 8 mg/m²,lenalidomide 15 mg, carfilzomib 45mg/m²) exceeded the MTD with 2/6 DLTs: 1 pt with grade 3 thrombocytopenia resulting in treatment delay and 1 pt with grade 4 thrombocytopenia. There were no DLTs among 6 pts treated in dose level 1 (romidepsin 8 mg/m²,lenalidomide 15 mg, carfilzomib 36mg/m²) and dose level 1 was deemed the MTD. Grade 3-4 toxicities in >10% pts included neutropenia and thrombocytopenia. SAEs included: infection-3, progression of disease resulting in hospitalization-3, fever-2, febrile neutropenia-1, DVT-1, edema-1, dyspnea-1, atrial flutter-1, generalized weakness-1, and vomiting with diarrhea-1.

Of the 16 pts with T-cell lymphoma evaluable for response, the overall response rate was 50% (8/16, 95% CI: 25 to 75%). The complete responses rate was 31% (5/16, 95% CI: 11 to 59%) and the partial response rate was 19% (3/16, 95% CI: 4 to 46%). Complete responses were seen in AITL (4/5) and PTCL-NOS (1/8) with 3 pts in CR proceeding to allogeneic stem cell transplantation. Partial responses were seen in PTCL-NOS-1, AITL-1, and transformed MF-1.

In T-cell lymphoma, the median event free survival for all pts was 9.7 weeks (95% CI: 6.0 to NR) and for responders was not reached (95% CI: 15.0 to NR). The median time to response was 5.8 weeks. The median duration of response was 9.6 weeks (95% CI: 8.0 to NR). 3 pts underwent allogeneic transplantation following this therapy and another 2 pts with CR remain in continuous remission. Median duration of follow up was 20.4 weeks (range 3.4-40.9 weeks).

Conclusions: The MTD dose for phase 2 study was identified as romidepsin 8mg/m², lenalidomide 15mg and carfilzomib 36mg/m². 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. An expansion cohort in B-cell lymphoma cohort is ongoing.