Combination trial of duvelisib (IPI-145) with rituximab or bendamustine/rituximab in patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia

Am J Hematol. 2019 Dec;94(12):1325-1334. doi: 10.1002/ajh.25634. Epub 2019 Oct 4.

Abstract

Duvelisib, a potent δ- and γ-PI3K inhibitor, is a potential therapeutic for hematologic malignancies. Rituximab and bendamustine have demonstrated activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Combining duvelisib with either rituximab alone or rituximab and bendamustine may improve response rates and remission durability. We conducted this Phase one study in relapsed/refractory NHL and CLL patients. During expansion, each arm enrolled to disease-specific cohorts to assess efficacy. Arm one received rituximab 375 mg/m2 IV weekly for two 4-week cycles plus duvelisib until progression/intolerance. Arm two received rituximab 375 mg/m2 IV Day one, bendamustine 90 mg/m2 IV (NHL patients) or 70 mg/m2 IV (CLL patients) Days one-two for six cycles, plus duvelisib until progression/intolerance. Duvelisib doses of 50 mg and 75 mg BID were tested during dose escalation. Forty-six patients (27 NHL, 19 CLL) were treated. The adverse events of the drug combinations were consistent with single agent toxicities. The most common AEs were neutropenia (47.7%), fatigue (41.3%), and rash (41.3%). A duvelisib expansion dose of 25 mg BID was chosen based on the monotherapy phase one study, IPI-145-02, which confirmed that dose for further clinical development. Overall response rate was 71.8%. Median progression-free survival was 13.7 months. Median overall survival has not been reached, but 30-month overall survival probability was 62%. Duvelisib combined with rituximab, or bendamustine and rituximab did not appear to increase toxicities beyond the known safety profile of the individual agents. Further study is needed to determine if these combinations improve efficacy.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bendamustine Hydrochloride / administration & dosage
  • Bendamustine Hydrochloride / adverse effects
  • Chemical and Drug Induced Liver Injury / etiology
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
  • Drug Administration Schedule
  • Drug Eruptions / etiology
  • Drug Resistance, Neoplasm
  • Febrile Neutropenia / chemically induced
  • Female
  • Humans
  • Isoquinolines / administration & dosage
  • Isoquinolines / adverse effects
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / enzymology
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Lymphoma, Non-Hodgkin / enzymology
  • Male
  • Middle Aged
  • Molecular Targeted Therapy*
  • Neoplasm Proteins / antagonists & inhibitors
  • Phosphoinositide-3 Kinase Inhibitors / administration & dosage
  • Phosphoinositide-3 Kinase Inhibitors / adverse effects
  • Progression-Free Survival
  • Purines / administration & dosage
  • Purines / adverse effects
  • Rituximab / administration & dosage
  • Rituximab / adverse effects
  • Salvage Therapy
  • Thrombocytopenia / chemically induced

Substances

  • Isoquinolines
  • Neoplasm Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Purines
  • Rituximab
  • duvelisib
  • Bendamustine Hydrochloride
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CD protein, human

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