Journal Article

Duvelisib plus romidepsin in relapsed/refractory T cell lymphomas: a phase 1b/2a trial

Davey, Theresa, Ganesan, Nivetha, Khodadoust, Michael, Horwitz, Steven M., Fisher, David C., Degryse, Sandrine, Xu, Ran, Kim, Youn H., Drill, Esther, Kotlov, Nikita, Moskowitz, Alison, Boelens, Jaap J., Maccaro, Catherine, Perez, Leslie, Appelt, Jackson W., Nirmal, Ajit J., Nikitina, Anastasia, Amaka, Sam, Zubareva, Valeria, Rahman, Jahan, Kumar, Anita, Marzouk, Evan, Zornikova, Ksenia, Wu, Wenchao, Weinstock, David M., Galasso, Natasha, Sorokina, Maria, McAvoy, Devin, Jacobsen, Eric, Bagaev, Aleksander, Mehta-Shah, Neha, Noy, Ariela, Shin, Nara, Hosszu, Kinga, Bahgat, Alexandra, Hancock, Helen, Kudryashova, Olga, Trevisani, Christopher, Ciantra, Zoe, Postovalova, Ekaterina, Vardhana, Santosha A., Cathcart, Elizabeth

2024

Overview

PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin ( n  = 66) or bortezomib ( n  = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations. ClinicalTrials.gov identifier: NCT02783625 . In a phase 1b/2a trial, the combination of the oral PI3K inhibitor duvelisib and romidepsin had limited toxicity and exhibited encouraging clinical activity in patients with relapsed or refractory T cell lymphoma, suggesting an approach whereby PI3K inhibitors can be safely used in this patient population.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 1-Phosphatidylinositol 3-kinase / 692/699/67/1059 / 692/699/67/1990/291/1621/1916 / Adult / Adverse events / Aged / Aged, 80 and over / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Biomedical and Life Sciences / Biomedicine / Bortezomib / Bortezomib - administration & dosage / Bortezomib - adverse effects / Bortezomib - therapeutic use / Cancer Research / Depsipeptides - administration & dosage / Depsipeptides - adverse effects / Depsipeptides - therapeutic use / Diarrhea / Female / Gene expression / Hepatotoxicity / Histone deacetylase / Humans / Infectious Diseases / Inflammation / Inhibitor drugs / Inhibitors / Isoquinolines / Lymphocytes / Lymphocytes T / Lymphoma / Lymphoma, T-Cell - drug therapy / Lymphoma, T-Cell - pathology / Male / Malignancy / Maximum Tolerated Dose / Metabolic Diseases / Middle Aged / Molecular Medicine / Neurosciences / Neutropenia / Patients / Purines / Response rates / T-cell lymphoma / Toxicity