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 B- and T-Cell Lymphomas
Authors: Mehta-Shah Neha , Moskowitz Alison J. , Lunning Matthew A. , Lynch Peggy , Scheuerman Mark , Minnal Veenna , Galasso Natasha , Kumar Anita , Gerecitano John , Zelenetz Andrew D. , Hamlin Paul A. , Noy Ariela , Matasar Matthew J. , Palomba Maria Lia , Younes Anas , Schaffer Wendy , Grewal Ravinder , Rademaker Jurgen , Sauter Craig S. , Dahi Parastoo B. , Myskowski Patricia , Kheterpal Meenal , Dogan Ahmet , Pulitzer Melissa , Lubin Lakeisha , Tang Laura , Ganesan Nivetha , Ni Ai , Horwitz Steven M. 
Published: April 2021

Abstract
Background: Epigenetic manipulation and immunomodulation are therapeutic strategies in hematologic malignancies. In our previous study, the combination of romidepsin and lenalidomide showed a 51% overall response rate (ORR), 23% complete response (CR) rate in patients with relapsed/ refractory B-cell (BCL) and T-cell (TCL) lymphoma. Given the potential synergy of proteasome inhibitors with histone deacetylase inhibitors and lenalidomide, we conducted a phase Ib/IIa study evaluating the safety and toxicity of romidepsin and lenalidomide with carfilzomib in patients with relapsed/refractory lymphoma. Here we report the completed phase II results.
Methods: 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 was followed: The starting dose was romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 36mg/m2. Tumor response was based on disease-specific criteria.Patients could be treated until progression, intolerance, or response adequate to allow allogeneic transplantation.
Results: 24 of the 27 patients treated as part of the study were evaluable for determination of the maximum tolerated dose. Additionally, one was evaluable for efficacy and 2 were evaluable for toxicity only. 16 patients were treated for TCL: PTCL-NOS-7, AITL-5, MF-2, transformed MF-1, extra-nodal NK/T-cell lymphoma-1. 11 patients were treated for BCL: DLBCL (7) mantle cell lymphoma (MCL) (2), follicular lymphoma (FL) (2). Of note, one of the aforementioned AITL patients had concurrent DLBCL and was evaluated for efficacy in both B-cell and T-cell cohorts.
Dose level 2 (romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 45mg/m2) exceeded the MTD with 2/6 DLTs: 1 grade 3 thrombocytopenia resulting in treatment delay and 1 grade 4 thrombocytopenia. There were no DLTs among 6 patients treated in dose level 1 (romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 36mg/m2) and dose level 1 was deemed the MTD.
Overall, grade 3-4 toxicities in &gt;10% patients included neutropenia and thrombocytopenia. 16 treatment related serious adverse events were seen in 9 patients and included: anemia-1, vomiting/diarrhea-1, dyspenea-1, edema-1, febrile neutropenia-1, fever-2, generalized weakness-1, heart failure-1, hypotension-1, infection-2, gastrointestinal bleed-1, and DVT-1.
Of the 11 TCL evaluable for response at the MTD, ORR was 45.5% (5/11, 95% CI: 23.4 to 83.3%). The complete response (CR) rate was 36.4% (4/11, 95% CI: 10.9 to 69.2%) and the partial response (PR) rate was 9% (1/11, 95% CI: 2.3 to 51.8%). The median event free survival (EFS) for patients with TCL was 13.6 w (95% CI: 5.7-74.6). Among all patients with TCL (N=16), the ORR was 50% (8/16). CRs were seen in 4/5 AITL and 1/7 PTCL-NOS; PRs were seen in PTCL-NOS-1, AITL-1, and transformed MF-1.
Of the 8 BCL evaluable for response at MTD, the ORR was 50% (4/8, 95% CI: 0-41%) with 3 PRs and 1 CR. The median EFS for patients with BCL was 19.8 w (95% CI: 5.4-NR). Among all patients with BCL evaluable for response (n=10), PRs were seen in 4 patients with DLBCL and 1 patient with MCL. One patient with concurrent DLBCL and AITL achieved a CR.
The median EFS for all patients treated at the MTD was 14.5 w (95% CI: 5.7 to NR). The median time to best response was 5.7 w. The median duration of response was 38.7 w (95% CI: 9.7 to NR). 3 patients with TCL and 1 with MCL underwent allogeneic transplantation following response to this therapy and were censored at time of transplant. Sustained complete responses were seen in 2 additional patients with TCL: one remained in CR for 11.7 months and another remains on treatment at 17 months. The median duration of follow up was 56.0 w (range 2.4 to 102.1 w).
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. At this dose, the overall response rate for BCL and TCL was 50%. Responses were seen across various BCL and TCL histologies. In particular, in AITL, the regimen has shown responses in all 5 patients. Given the promising overall and complete response rates, the regimen warrants further study.

Disclosures
Mehta-Shah: Celgene: Research Funding; Verastem: Research Funding; Bristol Myers-Squibb: Research Funding. Moskowitz: Bristol Myers-Squibb: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria; ADC Therapeutics: Research Funding; Incyte: Research Funding. Lunning: Onyx: Consultancy; Pharmacyclics: Consultancy; Spectrum: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy; Juno: Consultancy; Genentech: Consultancy; Gilead: Consultancy; BMS: Consultancy; AbbVie: Consultancy; Epizyme: Consultancy. Kumar: Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Gerecitano: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aratana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mass Medical International: Honoraria, Membership on an entity's Board of Directors or advisory committees; Orexo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Royal Bank of Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Arcus Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zelenetz: Amgen: Consultancy; Celgene: Consultancy. Hamlin: Gilead: Consultancy, Honoraria; Portola: Consultancy, Honoraria, Other: research support; Incyte: Other: research support; Celgene: Consultancy, Honoraria; Seattle Geneitcs: Other: research support; Novartis: Other: research support. Noy: Pharmacyclics LLC, an AbbVie Company: Honoraria, Other: Travel, Accommodation, Expenses, Research Funding, Speakers Bureau. Younes: Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Bayer: Honoraria; Johnson & Johnson: Research Funding; Novartis: Research Funding; Incyte: Honoraria; Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Curis: Research Funding; Takeda Millenium: Honoraria; Seattle Genetics: Honoraria; Sanofi: Honoraria; Merck: Honoraria; Janssen: Honoraria. Dogan: Roche Pharmaceuticals: Consultancy; Peer Review Institute: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz: Mundipharma: Consultancy; Aileron Therapeutics: Research Funding; BMS: Consultancy; HUYA: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Forty-Seven: Consultancy, Research Funding.