title: Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  SAR245408 is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I study determined the maximum tolerated dose (MTD) of two dosing schedules [first 21 days of a 28-day period (21/7) and continuous once-daily dosing (CDD)], pharmacokinetic and pharmacodynamic profiles, and preliminary efficacy.
  
  
  METHODS
  Patients with refractory advanced solid malignancies were treated with SAR245408 using a 3 + 3 design. Pharmacokinetic parameters were determined after single and repeated doses. Pharmacodynamic effects were evaluated in plasma, hair sheath cells, and skin and tumor biopsies.
  
  
  RESULTS
  Sixty-nine patients were enrolled. The MTD of both schedules was 600 mg; dose-limiting toxicities were maculopapular rash and hypersensitivity reaction. The most frequent drug-related adverse events included dermatologic toxicities, diarrhea, nausea, and decreased appetite. Plasma pharmacokinetics showed a median time to maximum concentration of 8 to 22 hours, mean terminal elimination half-life of 70 to 88 hours, and 5- to 13-fold accumulation after daily dosing (first cycle). Steady-state concentration was reached between days 15 and 21, and exposure was dose-proportional with doses up to 400 mg. SAR245408 inhibited the PI3K pathway (∼40%-80% reduction in phosphorylation of AKT, PRAS40, 4EBP1, and S6 in tumor and surrogate tissues) and, unexpectedly, also inhibited the MEK/ERK pathway. A partial response was seen in one patient with advanced non-small cell lung cancer. Eight patients were progression-free at 6 months. Pharmacodynamic and clinical activity were observed irrespective of tumor PI3K pathway molecular alterations.
  
  
  CONCLUSIONS
  SAR245408 was tolerable at doses associated with PI3K pathway inhibition. The recommended phase II dose of the capsule formulation is 600 mg administered orally with CDD.
authors.affiliation: Authors' Affiliations: Dana-Farber Cancer Institute; Massachusetts General Hospital; Beth Israel Deaconess Medical Center, Boston, Massachusetts; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Mary Crowley Cancer Research Centers, Dallas, Texas; Exelixis Inc., South San Francisco, California; and Sanofi, Cambridge, Massachusetts, and Vitry-sur-Seine, France.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bedell
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.forename: Irene
authors.initials: I
authors.lastname: Braña
authors.forename: Shuchi S
authors.initials: SS
authors.lastname: Pandya
authors.forename: Christian
authors.initials: C
authors.lastname: Scheffold
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Laird
authors.forename: Linh T
authors.initials: LT
authors.lastname: Nguyen
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.forename: Coumaran
authors.initials: C
authors.lastname: Egile
authors.forename: Gerald
authors.initials: G
authors.lastname: Edelman
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015398:Signal Transduction; D012871:Skin Diseases / Q000139:chemically induced; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; C581157:XL147; D058539:Phosphatidylinositol 3-Kinase