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Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma.

ABSTRACT: PURPOSE:Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well-tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti-tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose. METHODS:Adults with recurrent MG, Karnofsky Performance Status ? 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg. RESULTS:We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose-limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1). CONCLUSION:Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.

SUBMITTER: Kaley TJ

PROVIDER: S-EPMC7187704 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma.

Kaley Thomas J TJ Panageas Katherine S KS Pentsova Elena I EI Mellinghoff Ingo K IK Nolan Craig C Gavrilovic Igor I DeAngelis Lisa M LM Abrey Lauren E LE Holland Eric C EC Omuro Antonio A Lacouture Mario E ME Ludwig Emmy E Lassman Andrew B AB

Annals of clinical and translational neurology 20200415 4

<h4>Purpose</h4>Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well-tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti-tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safe ...[more]

PMID: 32293798

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Project description:BACKGROUND:Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS:Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ?2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi. RESULTS:The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ?3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. CONCLUSIONS:The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ?3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

Project description:Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting.Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles.In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome.mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs.

Project description:ImportanceClinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported.ObjectiveTo determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab.Design, setting, and participantsIn this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites.InterventionsPatients were randomized 1:1 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progression, unacceptable toxic effects, or death.Main outcomes and measuresThe primary end point was overall survival (OS).ResultsA total of 369 patients were randomized to nivolumab (n = 184) or bevacizumab (n = 185). The MGMT promoter was methylated in 23.4% (43/184; nivolumab) and 22.7% (42/185; bevacizumab), unmethylated in 32.1% (59/184; nivolumab) and 36.2% (67/185; bevacizumab), and not reported in remaining patients. At median follow-up of 9.5 months, median OS (mOS) was comparable between groups: nivolumab, 9.8 months (95% CI, 8.2-11.8); bevacizumab, 10.0 months (95% CI, 9.0-11.8); HR, 1.04 (95% CI, 0.83-1.30); P = .76. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab (23.1%; 95% CI, 16.7%-30.5%) vs nivolumab (7.8%; 95% CI, 4.1%-13.3%). Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups (nivolumab, 33/182 [18.1%]; bevacizumab, 25/165 [15.2%]), with no unexpected neurological TRAEs or deaths due to TRAEs.Conclusions and relevanceAlthough the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types.Trial registrationClinicalTrials.gov Identifier: NCT02017717.

Project description:Background There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population. Methods and Findings Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test). Conclusions Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development. Keywords: Comparative Genomic Hybridization

Project description:Abstract Background: vascular endothelial growth factor receptor (VEGFR) signal transduction mediates glioblastoma (GB) associated neo-angiogenesis. The AXIG trial (NCT01562197) is a randomized clinical trial that initially investigated the activity of axitinib as a monotherapy (AXI-arm) versus physicians best alternative choice of therapy (Duerinck et al. JNO Mar 2016) and following amendment versus axitinib plus lomustine (Duerinck et al. ASCO AM 2016). Methods: an updated pooled analysis was made of the clinical outcome of all patients who initiated treatment with axitinib mono-therapy or axitinib in combination with lomustine in the AXIG trial. Results: between August 2011 and July 2015, a total of 78 pts were enrolled in the trial and initiated treatment with axitinib monotherapy (N: 50; AXI) or axitinib plus lomustine (N: 28; AXILOM). Median age was 55y [range 18–80], 50M/28F, 19, 29, 19, 7 and 4 pts had a WHO-PS of 0, 1, 2, 3 and 4 respectively. Baseline characteristics were well balanced between study arms (AXI vs AXILOM). All pts had failed prior surgery, RT and TMZ. Thirteen pts in the AXI-arm crossed-over at the time of progression (AXIseqLOM). Treatment was generally well tolerated. AXILOM pts were at higher risk for grade 3/4 adverse events (most frequent gr3/4 AE on AXILOM vs AXI were: thrombocytopenia 3- vs 0 pts, hypertension 2 vs 2 pts, anorexia 3 vs 3 pts). The best overall tumor response (by RANO criteria) was 2 CR/ 11 PR/ 11 SD/ 26 PD in the AXI arm (BORR 26%) vs. 1 CR/ 9 PR/ 3 SD/ 13 PD in the AXILOM-arm (BORR 38%). Adding CCNU to axitinib after progression (AXIseqLOM) resulted in 1 pt experiencing PR and 8pts experiencing SD. Six-mths PFS and OS rates were respectively 26% (95% CI 14–38) vs 17% (95% CI 2–32), and 54% (95% CI 40–68) vs. 53% (95% CI 34–73) for pts treated in the AXI vs. AXILOM-arms; median PFS and OS were respectively 12 vs. 16 wks and 25 vs. 27 wks. When the time-to-second progression was taken into account for the 9 AXIseqLOM patients who experienced PR or SD following the addition of lomustine at first PD on axitinib, 6-mths PFS was 39% (95% CI 21–57). No significant correlation was found between clinical outcome measures and the MGMT promoter methylation status or IDH1/2 mutation status. Conclusion: Axitinib has single-agent activity in patients with recurrent GB; upfront combination of axitinib and LOM did not significantly increase progression-free or overall survival in patients with recurrent glioblastoma. Adding CCNU to axitinib after progression seems to result in improved PFS compared to upfront combination therapy.

Dataset Information

Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma.

Publications

Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma.

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