title: Efficacy, safety, pharmacokinetics and pharmacodynamics of SAR245409 (voxtalisib, XL765), an orally administered phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor: a phase 1 expansion cohort in patients with relapsed or refractory lymphoma.
abstract: The maximum tolerated dose of SAR245409 (voxtalisib), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, was determined in a phase 1 dose-escalation study in advanced solid tumors. We report safety, pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of SAR245409 capsules 50 mg twice daily in an expansion cohort of 16 patients with relapsed/refractory lymphoma. The most common treatment-related adverse events (AEs) were nausea (31.3%) and diarrhea (25.0%). The most common grade 3/4 treatment-related AE was increased alanine aminotransferase (12.5%). PK results were consistent with solid tumors, confirming a relatively short steady-state half-life (mean 4.61 h). Among 12 evaluable patients, one complete response and two partial responses were achieved in patients with and without PI3K/mTOR pathway alterations. In a patient with mantle cell lymphoma achieving PR, SAR245409 was associated with significant inhibition of PI3K/mTOR and extracellular signal-related kinase (ERK) pathways. Preliminary efficacy warrants further evaluation of SAR245409 in lymphoma.
authors.affiliation: South Texas Accelerated Research Therapeutics , San Antonio, TX , USA.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.forename: Coumaran
authors.initials: C
authors.lastname: Egile
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Ruiz-Soto
authors.forename: Jason
authors.initials: J
authors.lastname: Jiang
authors.forename: Weiliang
authors.initials: W
authors.lastname: Shi
authors.forename: Frauke
authors.initials: F
authors.lastname: Bentzien
authors.forename: Drew
authors.initials: D
authors.lastname: Rasco
authors.forename: Pau
authors.initials: P
authors.lastname: Abrisqueta
authors.forename: Julie M
authors.initials: JM
authors.lastname: Vose
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D019540:Area Under Curve; D003967:Diarrhea / Q000139:chemically induced; D019008:Drug Resistance, Neoplasm; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009364:Neoplasm Recurrence, Local; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012074:Remission Induction; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; C576808:XL765; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: PI3K; lymphoma; mTOR; pharmacodynamics; pharmacokinetics; signaling therapies