Dataset Information

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/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.

SUBMITTER: Wen PY

PROVIDER: S-EPMC4588757 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Publications

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 PY Omuro Antonio A Ahluwalia Manmeet S MS Fathallah-Shaykh Hassan M HM Mohile Nimish N Lager Joanne J JJ Laird A Douglas AD Tang Jiali J Jiang Jason J Egile Coumaran C Cloughesy Timothy F TF

Neuro-oncology 20150526 9

<h4>Background</h4>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.<h4>Methods</h4>Patients received voxtalisib 30-90 mg once daily (q.d.) or 20-50 mg twice daily (b.i.d. ...[more]

PMID: 26019185

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Project description:BackgroundGlutathione S-Transferase P 1 (GSTP-1) gene plays an important physiological role in the body. The present study was conducted to identify the clinical implication of GSTP-1 gene polymorphism on the prognosis of patients with high-grade glioma (HGG) who received temozolomide plus radiotherapy adjuvant treatment.MethodsThis study recruited a total of 186 patients with HGG who were treated with temozolomide plus radiotherapy adjuvant regimen (retrospectively). Baseline clinical characteristics were obtained and the prognostic data of the patients were collected. Peripheral blood specimen of patients was preserved for genotyping of GSTP-1 polymorphism during hospitalization. Correlation analysis was carried out accordingly. Additionally, fresh peripheral blood specimens that were available for mRNA expression analysis were collected for the mRNA expression analysis.ResultsThe median progression-free survival (PFS) and overall survival (OS) of the 186 patients with HGG who received temozolomide plus radiotherapy regimen was 8.5 months (95% CI: 5.95-11.05) and 15.5 months (95% CI: 11.49-19.51), respectively. The prevalence of 313A>G among 186 patients with glioma was AA genotype: 126 cases (67.7%), AG genotype: 54 cases (29.1%), GG genotype: 6 cases (3.2%), minor allele frequency of 313A>G was 0.18. Association analysis suggested that the median PFS of patients with AA and AG/GG genotypes was 11.2 and 5.0 months, respectively (χ2=11.17, P=0.001). Furthermore, the median OS of patients with AA and AG/GG genotypes was 18.9 and 10.5 months, respectively (χ2=12.684, P<0.001). Besides, when adjusted for PFS in multivariate Cox regression analysis, AG/GG genotype was an independent factor for PFS (HR=0.48, P=0.006). The mRNA expression results indicated that mRNA expression of GSTP-1 in patients with AG/GG genotypes of 313A>G was significantly higher than that of patients with AA genotype (P<0.001).ConclusionGSTP-1 polymorphism 313A>G might be used as a potential biomarker to predict the prognosis of patients with HGG who received temozolomide plus radiotherapy adjuvant treatment.

Project description:The standard therapy strategy for high-grade glioma (HGG) is based on the maximal surgery followed by radio-chemotherapy (RT-CT) with insufficient control of the disease. Recurrences are mainly localized in the radiation field, suggesting an interest in radiotherapy dose escalation to better control the disease locally. We aimed to identify a similarity between the areas of high uptake on O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography/computed tomography (PET) before RT-CT, the residual tumor on post-therapy NADIR magnetic resonance imaging (MRI) and the area of recurrence on MRI. This is an ancillary study from the IMAGG prospective trial assessing the interest of FET PET imaging in RT target volume definition of HGG. We included patients with diagnoses of HGG obtained by biopsy or tumor resection. These patients underwent FET PET and brain MRIs, both after diagnosis and before RT-CT. The follow-up consisted of sequential brain MRIs performed every 3 months until recurrence. Tumor delineation on the initial MRI 1 (GTV 1), post-RT-CT NADIR MRI 2 (GTV 2), and progression MRI 3 (GTV 3) were performed semi-automatically and manually adjusted by a neuroradiologist specialist in neuro-oncology. GTV 2 and GTV 3 were then co-registered on FET PET data. Tumor volumes on FET PET (MTV) were delineated using a tumor to background ratio (TBR) ≥ 1.6 and different % SUVmax PET thresholds. Spatial similarity between different volumes was performed using the dice (DICE), Jaccard (JSC), and overlap fraction (OV) indices and compared together in the biopsy or partial surgery group (G1) and the total or subtotal surgery group (G2). Another overlap index (OV') was calculated to determine the threshold with the highest probability of being included in the residual volume after RT-CT on MRI 2 and in MRI 3 (called "hotspot"). A total of 23 patients were included, of whom 22% (n = 5) did not have a NADIR MRI 2 due to a disease progression diagnosed on the first post-RT-CT MRI evaluation. Among the 18 patients who underwent a NADIR MRI 2, the average residual tumor was approximately 71.6% of the GTV 1. A total of 22% of patients (5/23) showed an increase in GTV 2 without diagnosis of true progression by the multidisciplinary team (MDT). Spatial similarity between MTV and GTV 2 and between MTV and GTV 3 were higher using a TBR ≥ 1.6 threshold. These indices were significantly better in the G1 group than the G2 group. In the FET hotspot analysis, the best similarity (good agreement) with GTV 2 was found in the G1 group using a 90% SUVmax delineation method and showed a trend of statistical difference with those (poor agreement) in the G2 group (OV' = 0.67 vs. 0.38, respectively, p = 0.068); whereas the best similarity (good agreement) with GTV 3 was found in the G1 group using a 80% SUVmax delineation method and was significantly higher than those (poor agreement) in the G2 group (OV'= 0.72 vs. 0.35, respectively, p = 0.014). These results showed modest spatial similarity indices between MTV, GTV 2, and GTV 3 of HGG. Nevertheless, the results were significantly improved in patients who underwent only biopsy or partial surgery. TBR ≥ 1.6 and 80-90% SUVmax FET delineation methods showing a good agreement in the hotspot concept for targeting standard dose and radiation boost. These findings need to be tested in a larger randomized prospective study.

Dataset Information

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.

Background

Methods

Results

Conclusions

Publications

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.

Similar Datasets

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