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; Fathallah‐Shaykh, Hassan M.; Mohile, Nimish; Lager, Joanne; Laird, A. Douglas; Tang, Jiali; Jiang, Jason; Égile, Coumaran; Cloughesy, Timothy F.

doi:10.1093/neuonc/nov083

Cited by 68 publications

(38 citation statements)

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“…Cloughesy et al (28) administered voxtalisib (XL765), a pan PI3K/mTOR inhibitor or XL147, a pan PI3K inhibitor, to patients with recurrent glioblastoma and showed that voxtalisib had better tumor penetration than XL147, although both drugs produced significant reduction of pS6K1 compared to archived tumor and reduction of Ki-67, suggesting that some inhibition of the PI3K pathway was achieved. Wen et al (29) subsequently conducted a Phase I trial of voxtalisib with temozolomide, with or without radiation therapy in patients with high-grade gliomas. The MTD was 90 mg once daily or 40 mg twice daily.…”

Section: Discussionmentioning

confidence: 99%

First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma

Wen

Cloughesy

Olivero³

et al. 2020

Clinical Cancer Research

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word count (limit 250): 250 Body word count (limit 5000): 3495 Figures and tables (limit 6): 6 References (limit 50): 40 Disclosure of potential conflicts of interest: Research. on March 6, 2020. AbstractPurpose: GDC-0084 is an oral, brain-penetrant small molecule inhibitor of phosphoinositide 3kinase (PI3K) and mammalian target of rapamycin (mTOR). A first-in-human, Phase I study was conducted in patients with recurrent high-grade glioma.Experimental design: GDC-0084 was administered orally, once-daily to evaluate safety, pharmacokinetics (PK) and activity. Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed to measure metabolic responses.

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Section: Discussionmentioning

confidence: 99%

First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma

Wen

Cloughesy

Olivero³

et al. 2020

Clinical Cancer Research

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“…In a study that used temsirolimus as maintenance therapy in castration-resistant prostate cancer after docetaxel induction, the regimen proved safe, and delayed the time to treatment failure to 6 months [274]. Voxtalisib plus temozolomide, an alkylating agent, with or without radiotherapy also displayed a favorable safety profile and moderate amount of PI3K/mTOR pathway inhibition in patients with high-grade glioma [275]. Based on these clinical trial results, combining mTOR inhibition with conventional cytotoxic chemotherapy warrants further investigation.…”

Section: Combining Mtor Inhibition With Conventional Chemotherapies Amentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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“…The dosage used typically varies between 40 and 60 Gy divided into daily fractions of 1.8–10 Gy depending on tumor size, metastases, invasiveness and possible side effects [ 12 , 13 ]. In many clinical protocols, the radiation therapy accompanies treatment with the protein kinase inhibitor drugs, in different combinations [ 14 – 17 ]. Since the clinical trials of TKIs and rapalogs for the ovarian cancer and the neuroblastoma are still in progress, we aimed to investigate if this treatment may cooperate or interfere with the radiation therapy, thus altering its efficiency.…”

Section: Introductionmentioning

confidence: 99%

Acquired resistance to tyrosine kinase inhibitors may be linked with the decreased sensitivity to X-ray irradiation

et al. 2017

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Acquired resistance to chemotherapy and radiation therapy is one of the major obstacles decreasing efficiency of treatment of the oncologic diseases. In this study, on the two cell lines (ovarian carcinoma SKOV-3 and neuroblastoma NGP-127), we modeled acquired resistance to five target anticancer drugs. The cells were grown on gradually increasing concentrations of the clinically relevant tyrosine kinase inhibitors (TKIs) Sorafenib, Pazopanib and Sunitinib, and rapalogs Everolimus and Temsirolimus, for 20 weeks. After 20 weeks of culturing, the half-inhibitory concentrations (IC50) increased by 25 – 186% for the particular combinations of the drugs and cell types. We next subjected cells to 10 Gy irradiation, a dose frequently used in clinical radiation therapy. For the SKOV-3, but not NGP-127 cells, for the TKIs Sorafenib, Pazopanib and Sunitinib, we noticed statistically significant increase in capacity to repair radiation-induced DNA double strand breaks compared to naïve control cells not previously treated with TKIs. These peculiarities were linked with the increased activation of ATM DNA repair pathway in the TKI-treated SKOV-3, but not NGP-127 cells. Our results provide a new cell culture model for studying anti-cancer therapy efficiency and evidence that there may be a tissue-specific radioresistance emerging as a side effect of treatment with TKIs.

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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: 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.

Cited by 68 publications

References 29 publications

First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma

First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Acquired resistance to tyrosine kinase inhibitors may be linked with the decreased sensitivity to X-ray irradiation

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