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. Issue 9 (26th May 2015)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Neuro-oncology. Volume 17:Issue 9(2015:Sep.)
• Page Start: 1275
• Page End: 1283
• Publication Date: 2015-05-26
• Subjects: glioblastoma -- pharmacodynamics -- pharmacokinetics -- PI3K/mTOR -- temozolomide; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/nov083
• Languages: English
• ISSNs: 1522-8517

Abstract

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.