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 Journal Article


Authors: Wen, P. Y.; Omuro, A.; Ahluwalia, M. S.; Fathallah-Shaykh, H. M.; Mohile, N.; Lager, J. J.; Laird, A. D.; Tang, J.; Jiang, J.; Egile, C.; Cloughesy, T. F.
Article 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/m2 TMZ (n = 49), or voxtalisib 20 mg q.d. with 75 mg/m2 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. © 2015 The Author(s).
Keywords: adult; controlled study; aged; major clinical study; constipation; fatigue; neutropenia; area under the curve; diarrhea; drug efficacy; drug safety; drug withdrawal; cancer radiotherapy; temozolomide; glioma; cancer grading; enzyme inhibition; liver toxicity; multiple cycle treatment; pharmacodynamics; anemia; skin biopsy; heart disease; leukopenia; nausea; thrombocytopenia; vomiting; delirium; qt prolongation; phosphatidylinositol 3 kinase; alanine aminotransferase blood level; aspartate aminotransferase blood level; drug dose escalation; febrile neutropenia; fever; gamma glutamyl transferase blood level; lymphocytopenia; pneumonia; pruritus; rash; alanine aminotransferase; aspartate aminotransferase; bilirubin; maculopapular rash; drug mechanism; glioblastoma; pancreatitis; thrombocyte count; cataract; retinopathy; open study; oligodendroglioma; pancytopenia; headache; maximum plasma concentration; time to maximum plasma concentration; leukocyte count; maximum tolerated dose; phase 1 clinical trial; gamma glutamyltransferase; amylase blood level; triacylglycerol lipase blood level; bilirubin blood level; amylase; pharmacokinetics; triacylglycerol lipase; decreased appetite; retina disease; pi3k/mtor; cornea disease; optic nerve disease; convulsion; human; male; female; article; voxtalisib; anaplastic mixed glioma; lens disease
Journal Title: Neuro-Oncology
Volume: 17
Issue: 9
ISSN: 1522-8517
Publisher: Oxford University Press  
Date Published: 2015-09-01
Start Page: 1275
End Page: 1283
Language: English
DOI: 10.1093/neuonc/nov083
PROVIDER: scopus
PMCID: PMC4588757
PUBMED: 26019185
DOI/URL:
Notes: Export Date: 2 October 2015 -- Source: Scopus
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MSK Authors
  1. Antonio Marcilio Padula Omuro
    200 Omuro