title: Phase I Trial of the Pan-PI3K Inhibitor Pilaralisib (SAR245408/XL147) in Patients with Chronic Lymphocytic Leukemia (CLL) or Relapsed/Refractory Lymphoma.
abstract: OBJECTIVE
  This phase I expansion-cohort study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed or refractory lymphoma.
  
  
  METHODS
  Patients were treated with the maximum tolerated dose of pilaralisib previously determined in patients with solid tumors (600 mg capsules once daily). Adverse events (AE) and response were evaluated. Plasma pharmacokinetics and pharmacodynamic effects on cytokines and chemokines were also assessed.
  
  
  RESULTS
  Twenty-five patients were included in the study: 10 with CLL and 15 with lymphoma. The most frequent AEs of any grade were diarrhea (92.0%), pyrexia (52.0%), and fatigue (44.0%). The most frequent grade ≥3 AEs were neutropenia (32.0%), diarrhea (20.0%), and anemia (16.0%). Pilaralisib exposure on cycle 1 day 28 was similar to exposure in patients with solid tumors. In patients with CLL, pilaralisib significantly reduced plasma levels of several cytokines and chemokines involved in B-cell trafficking. Five patients (50.0%) with CLL and 3 patients (20.0%) with lymphoma had a partial response. Six patients (60.0%) with CLL had nodal shrinkage ≥50%. Overall, 14 patients (56.0%; 7 patients with CLL and 7 patients with lymphoma) had progression-free survival ≥6 months.
  
  
  CONCLUSIONS
  Pilaralisib demonstrated an acceptable safety profile in patients with CLL and lymphoma, generally consistent with findings in patients with solid tumors. Single-agent pilaralisib showed preliminary clinical activity in patients with CLL and lymphoma, supporting further development.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts. jennifer_brown@dfci.harvard.edu.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Davids
authors.affiliation: Val d'Hebron University Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.affiliation: Val d'Hebron University Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Abrisqueta
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Siddha N
authors.initials: SN
authors.lastname: Kasar
authors.affiliation: Sanofi Oncology, Cambridge, Massachusetts.
authors.forename: Joanne
authors.initials: J
authors.lastname: Lager
authors.affiliation: Sanofi, Bridgewater, New Jersey.
authors.forename: Jason
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Sanofi Oncology, Vitry sur Seine, France.
authors.forename: Coumaran
authors.initials: C
authors.lastname: Egile
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Farrukh T
authors.initials: FT
authors.lastname: Awan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; C581157:XL147