PMID- 26019185 OWN - NLM STAT- MEDLINE DCOM- 20160511 LR - 20211203 IS - 1523-5866 (Electronic) IS - 1522-8517 (Print) IS - 1522-8517 (Linking) VI - 17 IP - 9 DP - 2015 Sep TI - 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. PG - 1275-83 LID - 10.1093/neuonc/nov083 [doi] AB - 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. CI - (c) The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Wen, Patrick Y AU - Wen PY 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 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.). FAU - Omuro, Antonio AU - Omuro A 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 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.). FAU - Ahluwalia, Manmeet S AU - Ahluwalia MS 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 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.). FAU - Fathallah-Shaykh, Hassan M AU - Fathallah-Shaykh HM 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 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.). FAU - Mohile, Nimish AU - Mohile N 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 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.). FAU - Lager, Joanne J AU - Lager JJ 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 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.). FAU - Laird, A Douglas AU - Laird AD 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 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.). FAU - Tang, Jiali AU - Tang J 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 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.). FAU - Jiang, Jason AU - Jiang J 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 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.). FAU - Egile, Coumaran AU - Egile C 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 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.). FAU - Cloughesy, Timothy F AU - Cloughesy TF 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 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.). LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150526 PL - England TA - Neuro Oncol JT - Neuro-oncology JID - 100887420 RN - 0 (Antineoplastic Agents) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Quinoxalines) RN - 0 (Sulfonamides) RN - 0 (XL765) RN - 7GR28W0FJI (Dacarbazine) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - YF1K15M17Y (Temozolomide) SB - IM MH - Administration, Oral MH - Adult MH - Aged MH - Antineoplastic Agents/adverse effects/pharmacokinetics/*therapeutic use MH - Brain Neoplasms/blood/*drug therapy/pathology/radiotherapy MH - Dacarbazine/analogs & derivatives/therapeutic use MH - Dose-Response Relationship, Drug MH - Drug Therapy, Combination MH - Female MH - Glioma/blood/*drug therapy/pathology/radiotherapy MH - Humans MH - Male MH - Middle Aged MH - Phosphoinositide-3 Kinase Inhibitors MH - Quinoxalines/adverse effects/pharmacokinetics/*therapeutic use MH - Sulfonamides/adverse effects/pharmacokinetics/*therapeutic use MH - TOR Serine-Threonine Kinases/antagonists & inhibitors MH - Temozolomide MH - Treatment Outcome PMC - PMC4588757 OTO - NOTNLM OT - PI3K/mTOR OT - glioblastoma OT - pharmacodynamics OT - pharmacokinetics OT - temozolomide EDAT- 2015/05/29 06:00 MHDA- 2016/05/12 06:00 PMCR- 2016/09/01 CRDT- 2015/05/29 06:00 PHST- 2014/12/18 00:00 [received] PHST- 2015/04/11 00:00 [accepted] PHST- 2015/05/29 06:00 [entrez] PHST- 2015/05/29 06:00 [pubmed] PHST- 2016/05/12 06:00 [medline] PHST- 2016/09/01 00:00 [pmc-release] AID - nov083 [pii] AID - 10.1093/neuonc/nov083 [doi] PST - ppublish SO - Neuro Oncol. 2015 Sep;17(9):1275-83. doi: 10.1093/neuonc/nov083. Epub 2015 May 26.