Duvelisib plus romidepsin in relapsed/refractory T cell lymphomas: A phase 1b/2a trial Journal Article
| Authors: | Horwitz, S. M.; Nirmal, A. J.; Rahman, J.; Xu, R.; Drill, E.; Galasso, N.; Ganesan, N.; Davey, T.; Hancock, H.; Perez, L.; Maccaro, C.; Bahgat, A.; Marzouk, E.; Cathcart, E.; Moskowitz, A.; Noy, A.; Kumar, A.; Jacobsen, E.; Fisher, D. C.; Mehta-Shah, N.; Kim, Y. H.; Khodadoust, M.; Kotlov, N.; Nikitina, A.; Kudryashova, O.; Zubareva, V.; Zornikova, K.; Shin, N.; Sorokina, M.; Degryse, S.; Postovalova, E.; Bagaev, A.; Hosszu, K.; McAvoy, D.; Boelens, J. J.; Wu, W.; Ciantra, Z.; Appelt, J. W.; Trevisani, C.; Amaka, S.; Weinstock, D. M.; Vardhana, S. A. |
| Article Title: | Duvelisib plus romidepsin in relapsed/refractory T cell lymphomas: A phase 1b/2a trial |
| Abstract: | 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. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024. |
| Keywords: | adult; controlled study; human tissue; treatment response; aged; aged, 80 and over; middle aged; major clinical study; clinical trial; constipation; fatigue; neutropenia; cancer recurrence; cancer combination chemotherapy; diarrhea; drug efficacy; drug safety; hypertension; liver function; monotherapy; side effect; comparative study; antineoplastic agent; anorexia; bortezomib; controlled clinical trial; drug eruption; infection; liver toxicity; phase 2 clinical trial; gene expression; anemia; thrombocytopenia; antineoplastic combined chemotherapy protocols; pathology; abdominal pain; coughing; dyspnea; febrile neutropenia; lymphocytopenia; pneumonia; pruritus; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; bilirubin; maculopapular rash; t cell lymphoma; lymphoma, t-cell; blood sampling; multicenter study; colitis; purines; purine derivative; bone marrow cell; maximum tolerated dose; phase 1 clinical trial; drug therapy; lung infection; bilirubin blood level; romidepsin; depsipeptides; sensorimotor neuropathy; rank sum test; skin infection; upper respiratory tract infection; depsipeptide; enterocolitis; isoquinoline derivative; isoquinolines; skin pain; esophagus candidiasis; electrolyte; lymphocytosis; thrush; refractory cancer; electrolyte blood level; erythroderma; very elderly; humans; human; male; female; article; duvelisib; complete heart block; alanine aminotransferase level; aspartate aminotransferase level; qtc interval; tfh cell; alkaline phosphatase level |
| Journal Title: | Nature Medicine |
| Volume: | 30 |
| Issue: | 9 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-09-01 |
| Start Page: | 2517 |
| End Page: | 2527 |
| Language: | English |
| DOI: | 10.1038/s41591-024-03076-6 |
| PUBMED: | 38886623 |
| PROVIDER: | scopus |
| PMCID: | PMC11862811 |
| DOI/URL: | |
| Notes: | Article -- MSK corresponding authors are Steven Horwitz and Santosha Vardhana -- Erratum issued, see DOI: 10.1038/s41591-024-03404-w -- Source: Scopus |
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