title: Phase I safety and pharmacokinetic dose-escalation study of pilaralisib polymorph E, a phosphoinositide 3-kinase inhibitor in tablet formulation, in patients with solid tumors or lymphoma.
abstract: OBJECTIVE
  Pilaralisib (SAR245408), a pan-class I PI3K inhibitor, has been investigated in Phase I/II trials in several solid tumors and lymphomas in capsule and tablet formulations of polymorph A (capsule-A and tablet-A). This Phase I study was conducted to determine the recommended Phase II dose (RP2D) of a more thermodynamically stable form of pilaralisib (polymorph E), in tablet formulation (tablet-E), in patients with advanced solid tumors or relapsed/refractory lymphoma.
  
  
  METHODS
  A modified '3 + 3' dose-escalation design was employed. Patients received pilaralisib once daily (QD; starting dose 400 mg) for two 28-day cycles. Primary endpoints were safety and pharmacokinetics (PK). Exploratory endpoints were pharmacodynamics and efficacy.
  
  
  RESULTS
  Eighteen patients were enrolled: Six patients received pilaralisib 400 mg QD and 12 patients received pilaralisib 600 mg QD. Two patients in the 600 mg QD cohort had dose-limiting toxicities (DLTs) (one patient with Grade 3 maculopapular rash and one patient with Grade 3 generalized rash and Grade 4 lipase increased). The most frequently occurring treatment-related, treatment-emergent adverse events were decreased appetite (22 %), dry skin (22 %), nausea (22 %) and vomiting (22 %). In PK analyses, individual exposures observed with 600 mg tablet-E were within the range of data at steady state from previous studies of 400 mg tablet-A and 600 mg capsule-A. Five patients (28 %) had stable disease as best response.
  
  
  CONCLUSIONS
  With pilaralisib tablet-E, the RP2D was 600 mg QD, drug exposure was similar to the 400 mg tablet-A and 600 mg capsule-A formulations, and safety was consistent with the known safety profile of pilaralisib.
authors.affiliation: Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven - University of Leuven, 3000, Leuven, Belgium. oliver.bechter@uzleuven.be.
authors.forename: Oliver E
authors.initials: OE
authors.lastname: Bechter
authors.affiliation: Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven - University of Leuven, 3000, Leuven, Belgium.
authors.forename: Herlinde
authors.initials: H
authors.lastname: Dumez
authors.affiliation: Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven - University of Leuven, 3000, Leuven, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Costermans
authors.affiliation: Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven - University of Leuven, 3000, Leuven, Belgium.
authors.forename: Kevin
authors.initials: K
authors.lastname: Punie
authors.affiliation: Sanofi, Cambridge, MA, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Hsu
authors.affiliation: Sanofi, Chilly-Mazarin, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dedieu
authors.affiliation: Sanofi, Chilly-Mazarin, France.
authors.forename: Anne-Frédérique
authors.initials: AF
authors.lastname: Ghuysen
authors.affiliation: Sanofi, Vitry-sur-Seine, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Francesconi
authors.affiliation: Sanofi, Bridgewater, NJ, USA.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Sharma
authors.affiliation: Sanofi, Bridgewater, NJ, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven - University of Leuven, 3000, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002214:Capsules; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013607:Tablets
chemical_list: D000970:Antineoplastic Agents; D002214:Capsules; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; D013607:Tablets; C581157:XL147
keywords: Lymphoma; PI3K; Pharmacokinetics; Pilaralisib; Solid tumors; Tablets