DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma.

Abstract

PURPOSE:

Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy.

PATIENTS AND METHODS:

Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma.

RESULTS:

This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%).

CONCLUSION:

In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.

• Authors: Ian W Flinn, Carole B Miller, Kirit M Ardeshna, Scott Tetreault, Sarit E Assouline, Jiri Mayer, Michele Merli, Scott D Lunin, Andrew R Pettitt, Zoltan Nagy, Olivier Tournilhac, Karem-Etienne Abou-Nassar, Michael Crump, Eric D Jacobsen, Sven de Vos, Virginia M Kelly, Weiliang Shi, Lori Steelman, NgocDiep Le, David T Weaver, Stephanie Lustgarten, Nina D Wagner-Johnston, Pier Luigi Zinzani
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 37 Issue 11 Pg. 912-922 (04 10 2019) ISSN: 1527-7755 [Electronic] United States
• PMID: 30742566 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Enzyme Inhibitors
• Isoquinolines
• Purines
• Rituximab
• duvelisib

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Anti-Inflammatory Agents, Non-Steroidal (adverse effects, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Diarrhea (chemically induced)
• Drug Administration Schedule
• Drug Resistance, Neoplasm (drug effects)
• Enzyme Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Female
• Humans
• Isoquinolines (administration & dosage, adverse effects, therapeutic use)
• Kaplan-Meier Estimate
• Lymphoma, Non-Hodgkin (drug therapy, pathology)
• Male
• Middle Aged
• Neoplasm Recurrence, Local
• Phosphatidylinositol 3-Kinases (metabolism)
• Purines (administration & dosage, adverse effects, therapeutic use)
• Rituximab (administration & dosage)