Your browser doesn't support javascript.
loading
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.
Wen, Patrick Y; Omuro, Antonio; Ahluwalia, Manmeet S; Fathallah-Shaykh, Hassan M; Mohile, Nimish; Lager, Joanne J; Laird, A Douglas; Tang, Jiali; Jiang, Jason; Egile, Coumaran; Cloughesy, Timothy F.
Afiliação
  • Wen PY; 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
  • Omuro A; 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
  • Ahluwalia MS; 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
  • Fathallah-Shaykh HM; 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
  • Mohile N; 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
  • Lager JJ; 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
  • Laird AD; 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
  • Tang J; 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
  • Jiang J; 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
  • Egile C; 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
  • Cloughesy TF; 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
Neuro Oncol ; 17(9): 1275-83, 2015 Sep.
Article em En | MEDLINE | ID: mdl-26019185
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.
Assuntos
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinoxalinas / Sulfonamidas / Neoplasias Encefálicas / Glioma / Antineoplásicos Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Neuro Oncol Assunto da revista: NEOPLASIAS / NEUROLOGIA Ano de publicação: 2015 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinoxalinas / Sulfonamidas / Neoplasias Encefálicas / Glioma / Antineoplásicos Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Neuro Oncol Assunto da revista: NEOPLASIAS / NEUROLOGIA Ano de publicação: 2015 Tipo de documento: Article