title: Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma.
abstract: BACKGROUND
  This phase I study aimed to evaluate safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics, and preliminary efficacy of voxtalisib (SAR245409, XL765), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, in combination with temozolomide (TMZ), with or without radiation therapy (RT), in patients with high-grade glioma.
  
  
  METHODS
  Patients received voxtalisib 30-90 mg once daily (q.d.) or 20-50 mg twice daily (b.i.d.), in combination with 200 mg/m(2) TMZ (n = 49), or voxtalisib 20 mg q.d. with 75 mg/m(2) TMZ and RT (n = 5). A standard 3 + 3 dose-escalation design was used to determine the maximum tolerated dose. Patients were evaluated for adverse events (AEs), plasma pharmacokinetics, pharmacodynamic effects in skin biopsies, and tumor response.
  
  
  RESULTS
  The maximum tolerated doses were 90 mg q.d. and 40 mg b.i.d. for voxtalisib in combination with TMZ. The most frequently reported treatment-related AEs were nausea (48%), fatigue (43%), thrombocytopenia (26%), and diarrhea (24%). The most frequently reported treatment-related grade ≥3 AEs were lymphopenia (13%), thrombocytopenia, and decreased platelet count (9% each). Pharmacokinetic parameters were similar to previous studies with voxtalisib monotherapy. Moderate inhibition of PI3K signaling was observed in skin biopsies. Best response was partial response in 4% of evaluable patients, with stable disease observed in 68%.
  
  
  CONCLUSIONS
  Voxtalisib in combination with TMZ with or without RT in patients with high-grade gliomas demonstrated a favorable safety profile and a moderate level of PI3K/mTOR pathway inhibition.
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA (P.Y.W.); Memorial Sloan Kettering Cancer Center, New York, New York, USA (A.O.); Cleveland Clinic, Cleveland, Ohio, USA (M.S.A.); University of Alabama, Birmingham, Alabama, USA (H.M.F.-S.); University of Rochester Medical Center, Rochester, New York, USA (N.M.); Sanofi, Cambridge, Massachusetts, USA (J.J.L); Exelixis Inc., South San Francisco, California, USA (A.D.L.); Quintiles, Durham, North Carolina, USA (J.T.); Sanofi, Bridgewater, New Jersey, USA (J.J.); Sanofi, Vitry-sur-Seine, France (C.E.); University of California-Los Angeles, Los Angeles, California, USA (T.F.C.).
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA (P.Y.W.); Memorial Sloan Kettering Cancer Center, New York, New York, USA (A.O.); Cleveland Clinic, Cleveland, Ohio, USA (M.S.A.); University of Alabama, Birmingham, Alabama, USA (H.M.F.-S.); University of Rochester Medical Center, Rochester, New York, USA (N.M.); Sanofi, Cambridge, Massachusetts, USA (J.J.L); Exelixis Inc., South San Francisco, California, USA (A.D.L.); Quintiles, Durham, North Carolina, USA (J.T.); Sanofi, Bridgewater, New Jersey, USA (J.J.); Sanofi, Vitry-sur-Seine, France (C.E.); University of California-Los Angeles, Los Angeles, California, USA (T.F.C.).
authors.forename: Antonio
authors.initials: A
authors.lastname: Omuro
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA (P.Y.W.); Memorial Sloan Kettering Cancer Center, New York, New York, USA (A.O.); Cleveland Clinic, Cleveland, Ohio, USA (M.S.A.); University of Alabama, Birmingham, Alabama, USA (H.M.F.-S.); University of Rochester Medical Center, Rochester, New York, USA (N.M.); Sanofi, Cambridge, Massachusetts, USA (J.J.L); Exelixis Inc., South San Francisco, California, USA (A.D.L.); Quintiles, Durham, North Carolina, USA (J.T.); Sanofi, Bridgewater, New Jersey, USA (J.J.); Sanofi, Vitry-sur-Seine, France (C.E.); University of California-Los Angeles, Los Angeles, California, USA (T.F.C.).
authors.forename: Manmeet S
authors.initials: MS
authors.lastname: Ahluwalia
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA (P.Y.W.); Memorial Sloan Kettering Cancer Center, New York, New York, USA (A.O.); Cleveland Clinic, Cleveland, Ohio, USA (M.S.A.); University of Alabama, Birmingham, Alabama, USA (H.M.F.-S.); University of Rochester Medical Center, Rochester, New York, USA (N.M.); Sanofi, Cambridge, Massachusetts, USA (J.J.L); Exelixis Inc., South San Francisco, California, USA (A.D.L.); Quintiles, Durham, North Carolina, USA (J.T.); Sanofi, Bridgewater, New Jersey, USA (J.J.); Sanofi, Vitry-sur-Seine, France (C.E.); University of California-Los Angeles, Los Angeles, California, USA (T.F.C.).
authors.forename: Hassan M
authors.initials: HM
authors.lastname: Fathallah-Shaykh
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA (P.Y.W.); Memorial Sloan Kettering Cancer Center, New York, New York, USA (A.O.); Cleveland Clinic, Cleveland, Ohio, USA (M.S.A.); University of Alabama, Birmingham, Alabama, USA (H.M.F.-S.); University of Rochester Medical Center, Rochester, New York, USA (N.M.); Sanofi, Cambridge, Massachusetts, USA (J.J.L); Exelixis Inc., South San Francisco, California, USA (A.D.L.); Quintiles, Durham, North Carolina, USA (J.T.); Sanofi, Bridgewater, New Jersey, USA (J.J.); Sanofi, Vitry-sur-Seine, France (C.E.); University of California-Los Angeles, Los Angeles, California, USA (T.F.C.).
authors.forename: Nimish
authors.initials: N
authors.lastname: Mohile
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA (P.Y.W.); Memorial Sloan Kettering Cancer Center, New York, New York, USA (A.O.); Cleveland Clinic, Cleveland, Ohio, USA (M.S.A.); University of Alabama, Birmingham, Alabama, USA (H.M.F.-S.); University of Rochester Medical Center, Rochester, New York, USA (N.M.); Sanofi, Cambridge, Massachusetts, USA (J.J.L); Exelixis Inc., South San Francisco, California, USA (A.D.L.); Quintiles, Durham, North Carolina, USA (J.T.); Sanofi, Bridgewater, New Jersey, USA (J.J.); Sanofi, Vitry-sur-Seine, France (C.E.); University of California-Los Angeles, Los Angeles, California, USA (T.F.C.).
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Lager
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA (P.Y.W.); Memorial Sloan Kettering Cancer Center, New York, New York, USA (A.O.); Cleveland Clinic, Cleveland, Ohio, USA (M.S.A.); University of Alabama, Birmingham, Alabama, USA (H.M.F.-S.); University of Rochester Medical Center, Rochester, New York, USA (N.M.); Sanofi, Cambridge, Massachusetts, USA (J.J.L); Exelixis Inc., South San Francisco, California, USA (A.D.L.); Quintiles, Durham, North Carolina, USA (J.T.); Sanofi, Bridgewater, New Jersey, USA (J.J.); Sanofi, Vitry-sur-Seine, France (C.E.); University of California-Los Angeles, Los Angeles, California, USA (T.F.C.).
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Laird
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA (P.Y.W.); Memorial Sloan Kettering Cancer Center, New York, New York, USA (A.O.); Cleveland Clinic, Cleveland, Ohio, USA (M.S.A.); University of Alabama, Birmingham, Alabama, USA (H.M.F.-S.); University of Rochester Medical Center, Rochester, New York, USA (N.M.); Sanofi, Cambridge, Massachusetts, USA (J.J.L); Exelixis Inc., South San Francisco, California, USA (A.D.L.); Quintiles, Durham, North Carolina, USA (J.T.); Sanofi, Bridgewater, New Jersey, USA (J.J.); Sanofi, Vitry-sur-Seine, France (C.E.); University of California-Los Angeles, Los Angeles, California, USA (T.F.C.).
authors.forename: Jiali
authors.initials: J
authors.lastname: Tang
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA (P.Y.W.); Memorial Sloan Kettering Cancer Center, New York, New York, USA (A.O.); Cleveland Clinic, Cleveland, Ohio, USA (M.S.A.); University of Alabama, Birmingham, Alabama, USA (H.M.F.-S.); University of Rochester Medical Center, Rochester, New York, USA (N.M.); Sanofi, Cambridge, Massachusetts, USA (J.J.L); Exelixis Inc., South San Francisco, California, USA (A.D.L.); Quintiles, Durham, North Carolina, USA (J.T.); Sanofi, Bridgewater, New Jersey, USA (J.J.); Sanofi, Vitry-sur-Seine, France (C.E.); University of California-Los Angeles, Los Angeles, California, USA (T.F.C.).
authors.forename: Jason
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA (P.Y.W.); Memorial Sloan Kettering Cancer Center, New York, New York, USA (A.O.); Cleveland Clinic, Cleveland, Ohio, USA (M.S.A.); University of Alabama, Birmingham, Alabama, USA (H.M.F.-S.); University of Rochester Medical Center, Rochester, New York, USA (N.M.); Sanofi, Cambridge, Massachusetts, USA (J.J.L); Exelixis Inc., South San Francisco, California, USA (A.D.L.); Quintiles, Durham, North Carolina, USA (J.T.); Sanofi, Bridgewater, New Jersey, USA (J.J.); Sanofi, Vitry-sur-Seine, France (C.E.); University of California-Los Angeles, Los Angeles, California, USA (T.F.C.).
authors.forename: Coumaran
authors.initials: C
authors.lastname: Egile
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA (P.Y.W.); Memorial Sloan Kettering Cancer Center, New York, New York, USA (A.O.); Cleveland Clinic, Cleveland, Ohio, USA (M.S.A.); University of Alabama, Birmingham, Alabama, USA (H.M.F.-S.); University of Rochester Medical Center, Rochester, New York, USA (N.M.); Sanofi, Cambridge, Massachusetts, USA (J.J.L); Exelixis Inc., South San Francisco, California, USA (A.D.L.); Quintiles, Durham, North Carolina, USA (J.T.); Sanofi, Bridgewater, New Jersey, USA (J.J.); Sanofi, Vitry-sur-Seine, France (C.E.); University of California-Los Angeles, Los Angeles, California, USA (T.F.C.).
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005910:Glioma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; C576808:XL765; D003606:Dacarbazine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000077204:Temozolomide
keywords: PI3K/mTOR; glioblastoma; pharmacodynamics; pharmacokinetics; temozolomide