Phase I study explores clinical activity of duvelisib in hematological malignancies

Duvelisib is an oral dual phosphoinositide-3-kinase-δ,γ inhibitor (PI3K- δ and PI3K-γ) that has shown promising results from 2017 congress oral abstracts as a treatment option in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). In 2018, a new drug application was submitted to the US Food and Drug Administration (FDA) for relapsed, refractory (R/R) CLL and FL.

Recent phase I study results exploring the safety and efficacy of duvelisib in hematological malignancies was published in Blood in February 2018 by Ian Flinn, director of the blood cancer research program at the Sarah Cannon institute, Nashville, TN, and colleagues. The open-label dose-escalation study involved 210 patients with a median age of 67 (range, 25–86). Patient diagnoses included a variety of hematological malignancies including; indolent non-Hodgkin lymphomas (iNHL) (14.8%), CLL/SLL (26.2%), T-Cell NHL (TCL) (16.7%) and other (33.8%). The maximum tolerated dose (MTD) was established as 75mg twice daily assessing 31 patients in a dose escalation phase. Pharmacokinetics and pharmacodynamics were also evaluated during this study as well as duvelisib’s safety and efficacy.

Key Findings

• Pharmacokinetic results found max plasma concentration range 471–3294 ng/ml, clearance range 3.6–11.2 L/h, volume of distribution range 26–102 L and half-life of duvelisib after a single dose range 5.2–10.9 hours
• Rapid inhibition of p-AKT (S473) was found in a duvelisib single dose of 25/75 mg
• Serum cytokine and chemokine levels significantly decreased in 9 of 72 serum analytes in CLL P < 0.0007 and a ≥30% median change in iNHL P < 0.05

Efficacy Results

• Overall response rate (ORR) for R/R CLL patients was 56% (1 complete response (CR)) and treatment-naive CLL was 83%
• ORR for iNHL = 58% (6 CRs)
• Partial responses (PR) seen in cutaneous TCL = 32% and peripheral TCL = 50% (3 CRs)
• In other NHL responses included:
  • Myelodysplastic syndrome ORR = 17% (n = 1) and 1 CR
  • Mantle cell lymphoma ORR = 50% (n = 5) and 1 CR
  • Aggressive lymphoma ORR = 19% (n = 5) and 2 CRs

Safety Results

• The most common grade ≥3 adverse events (AEs) included:
  • Neutropenia (n = 42)
  • Anemia (n = 30)
  • Increased levels of ALT (n = 41)
  • Increased levels of AST (n = 32)
  • Diarrhea (n = 24)
  • Pneumonia (n = 20)
• Protocol amendments occurred during the study to include prophylaxis treatment of pneumocystis and herpes simplex virus.

The authors reported that their study showed that duvelisib was pharmacologically active in a variety of hematological malignancies. Good response rates were seen in iNHL and CLL and the results of this study have warranted further research of duvelisib in phase II and III trials.