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Phase I, open-label, multicentre study of buparlisib in combination with temozolomide or with concomitant radiation therapy and temozolomide in patients with newly diagnosed glioblastoma.

ABSTRACT: BACKGROUND:Most glioblastoma tumours exhibit intrinsic phosphatidylinositol 3-kinase (PI3K) pathway activation. Preclinical in vitro and in vivo models suggest that buparlisib (an oral pan-PI3K inhibitor) can have an effect on glioblastoma directly and by enhancing the activity of radiation and of temozolomide. METHODS:This was a phase I, two-stage, multicentre, open-label, dose-escalation study of buparlisib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. In stage I, patients who completed the concomitant phase of combination of temozolomide and radiation prior to study entry received buparlisib in combination with temozolomide. In stage II, patients received buparlisib in combination with temozolomide and radiotherapy in the concomitant phase and temozolomide in the adjuvant treatment phase. The primary objective was to estimate the maximum tolerated dose (MTD) of buparlisib when combined with the approved first-line treatment of temozolomide and radiotherapy. RESULTS:The MTD of buparlisib in combination with temozolomide at stage I (adjuvant phase only) was 80 mg/day, which was used as the starting dose in stage II. The MTD of buparlisib in combination with temozolomide and radiotherapy in stage II (concomitant + adjuvant phase) was not determined due to the observed dose-limiting toxicities and treatment discontinuations due to adverse events (AEs). In stage I, the most commonly reported AEs were nausea (72.7%) and fatigue (59.1%). In stage II, the most commonly reported AEs were fatigue and nausea (56.3% each). No on-treatment deaths were reported during the study. CONCLUSION:Considering that the primary objective of estimating the MTD was not achieved in addition to the observed challenging safety profile of buparlisib in combination with radiotherapy and temozolomide, Novartis decided not to pursue the development of buparlisib in newly diagnosed glioblastoma.Trial registration numberClinicalTrials.gov identifier: NCT01473901.

SUBMITTER: Wen PY

PROVIDER: S-EPMC7359189 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Phase I, open-label, multicentre study of buparlisib in combination with temozolomide or with concomitant radiation therapy and temozolomide in patients with newly diagnosed glioblastoma.

Wen Patrick Yung PY Rodon Jordi A JA Mason Warren W Beck Joseph T JT DeGroot John J Donnet Valerie V Mills David D El-Hashimy Mona M Rosenthal Mark M

ESMO open 20200701 4

<h4>Background</h4>Most glioblastoma tumours exhibit intrinsic phosphatidylinositol 3-kinase (PI3K) pathway activation. Preclinical in vitro and in vivo models suggest that buparlisib (an oral pan-PI3K inhibitor) can have an effect on glioblastoma directly and by enhancing the activity of radiation and of temozolomide.<h4>Methods</h4>This was a phase I, two-stage, multicentre, open-label, dose-escalation study of buparlisib in combination with temozolomide and radiotherapy in patients with newly ...[more]

PMID: 32661186

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Project description:BackgroundThe impact of prolonging temozolomide (TMZ) maintenance beyond six cycles in newly diagnosed glioblastoma (GBM) remains a topic of discussion. We investigated the effects of prolonged TMZ maintenance on progression-free survival (PFS) and overall survival (OS).Patients and methodsIn this retrospective single-center cohort study, we included patients with GBM who were treated with radiation therapy with concomitant and adjuvant TMZ. For analysis, patients were considered who either completed six TMZ maintenance cycles (group B), continued with TMZ therapy beyond six cycles (group C), or stopped TMZ maintenance therapy within the first six cycles (group A). Patients with progression during the first six TMZ maintenance cycles were excluded.ResultsClinical data from 107 patients were included for Kaplan-Meier analyses and 102 for Cox regressions. Median PFS times were 8.1 months (95% confidence interval [CI] 6.1-12.4) in group A, 13.7 months (95% CI 10.6-17.5) in group B, and 20.9 months (95% CI 15.2-43.5) in group C. At first progression, response rates of TMZ/lomustine rechallenge were 47% in group B and 13% in group C. Median OS times were 12.7 months (95% CI 10.3-16.8) in group A, 25.2 months (95% CI 17.7-55.5) in group B, and 28.6 months (95% CI 24.4-open) in group C. Nevertheless, multivariate Cox regression for patients in group C compared with group B that accounted for imbalances of other risk factors showed no different relative risk (RR) for OS (RR 0.77, p = .46).ConclusionOur data do not support a general extension of TMZ maintenance therapy beyond six cycles. The Oncologist 2017;22:570-575 IMPLICATIONS FOR PRACTICE: Radiation therapy with concomitant and adjuvant temozolomide (TMZ) maintenance therapy is still the standard of care in patients below the age of 65 years in newly diagnosed glioblastoma. However, in clinical practice, many centers continue TMZ maintenance therapy beyond six cycles. The impact of this continuation is controversial and has not yet been addressed in prospective randomized clinical trials. We compared the effect of more than six cycles of TMZ in comparison with exactly six cycles on overall survival (OS) and progression-free survival (PFS) by multivariate analysis and found a benefit in PFS but not OS. Thus, our data do not suggest prolonging TMZ maintenance therapy beyond six cycles, which should be considered in neurooncological practice.

Project description:IntroductionStandard-of-care treatment for patients with newly diagnosed glioblastoma (GBM) after surgery or biopsy includes concurrent chemoradiation followed by maintenance temozolomide (TMZ) with tumor treating fields (TTFields). Preclinical studies suggest TTFields and radiotherapy work synergistically. We report the results of our trial evaluating the safety of TTFields used concurrently with chemoradiation.MethodsThis is a single-arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma and a Karnofsky performance score (KPS) of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with TMZ (75 mg/m2 daily) and TTFields (200 kHz). Maintenance therapy included TMZ and continuation of TTFields. Scalp-sparing radiation treatment was used to reduce radiation dermatitis. Radiation treatment was delivered through the TTFields arrays. The primary endpoint was safety and toxicity of tri-modality treatment within 30 days of completion of chemoradiation treatment.ResultsThere were 30 patients enrolled, including 20 (66.7%) men and 10 (33.3%) women, with a median age of 58 years (range 19 to 77 years). Median KPS was 90 (range 70 to 100). A total of 12 (40%) patients received a gross total resection and 18 (60%) patients had a subtotal resection. A total of 12 (40%) patients had multifocal disease at presentation. There were 20 (66.7%) patients who had unmethylated O(6)-methylguanine-DNA-methyltransferase (MGMT) promotor status and 10 (33.3%) patients who had methylated MGMT promoter status. Median follow-up was 15.2 months (range 1.7 to 23.6 months). Skin adverse events were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. The primary end point was met; no TTFields discontinuation occurred during the evaluation period due to high grade scalp toxicity. A total of 27 (90%) patients had progression, with a median progression-free survival (PFS) of 9.3 months (95% confidence interval (CI): 8.5-11.6 months). The 1-year progression-free survival was 23% (95% CI: 12%-45%). The median overall survival (OS) was 15.8 months (95% CI: 12.5 months-infinity). The 1-year overall survival was 66% (95% CI: 51%-86%).ConclusionsConcurrent TTFields with scalp-sparing chemoradiation is a feasible and well-tolerated treatment option with limited toxicity. A phase 3, randomized clinical trial (EF-32, clinicaltrials.gov Identifier: NCT04471844) investigating the clinical benefit of concurrent TTFields with chemoradiation treatment is currently enrolling.Clinical trial registrationClinicaltrials.gov, identifier NCT03477110.

Project description:Abstract INTRODUCTION Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide (TMZ) with tumor treatment fields (TTFields). Preclinical studies suggest TTFields and radiotherapy work synergistically. We report our experience evaluating toxicity of scalp-sparing radiation with concurrent TTFields. METHODS This is a single-arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Patients (age≥ 18 years) with KPS≥ 60 with newly diagnosed glioblastoma were eligible. Patients received concurrent scalp-sparing radiation (60 Gy/30 fx), standard TMZ (75 mg/m2 daily), and TTFields. Maintenance therapy included standard TMZ and TTFields continuation. Radiotherapy was delivered through TTFields arrays. Primary endpoint was safety and toxicity of concurrent TTFields with chemoradiation. RESULTS We report the first eighteen patients on trial. Majority were male (66.7%) with median age 59 years (34 to 77). Median KPS was 90 (70–100). Median follow-up was 6.0 months (1.4 to 18.0). Twelve (66.6%) patients had unmethylated MGMT, five (27.8%) were methylated, and one patient’s status was not obtained. Scalp dose constraints were achieved, with mean dose having a median value of 7.4 Gy (4.3–13.2), D20cc median 23.2 Gy (17.7–36.8), and D30cc median 20.3 Gy (14.8–33.4). Only one possible Grade 3 toxicity was observed in a patient who experienced a seizure in month six of the maintenance phase. Skin toxicity (erythema or dermatitis) was limited to Grade 1 (83.3%) or 2 (5.6%) during the concurrent phase and resolved spontaneously or responded to topical medications. Other Grade 1 events included fatigue (47.3%), cognitive impairment (31.6%), pruritis (52.6%), headache (26.3%), dizziness (15.8%), and nausea (26.3%). Other Grade 2 events included fatigue (21.1%) and headache (10.5%). Nine patients (50%) had progression, with median PFS of 7.6 months (2.2–9.6 months). CONCLUSIONS Concurrent TTFields with scalp-sparing chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trials are warranted to define therapeutic advantages of concurrent TTFields with chemoradiation.

Project description:PurposeThis open-label, prospective, multicenter single-arm phase II study combined bevacizumab (BV) with radiation therapy (RT) and temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma (GBM). The objectives were to determine the efficacy of this treatment combination and the associated toxicity.Patients and methodsSeventy patients with newly diagnosed GBM were enrolled between August 2006 and November 2008. Patients received standard RT starting within 3 to 6 weeks after surgery with concurrent administration of daily TMZ and biweekly BV. After completion of RT, patients resumed TMZ for 5 days every 4 weeks and continued biweekly BV. MGMT promoter methylation was assessed on patient tumor tissue. A University of California, Los Angeles/Kaiser Permanente Los Angeles (KPLA) control cohort of newly diagnosed patients treated with first-line RT and TMZ who had mostly received BV at recurrence was derived for comparison.ResultsThe overall survival (OS) and progression-free survival (PFS) were 19.6 and 13.6 months, respectively, compared to 21.1 and 7.6 months in the University of California, Los Angeles/KPLA control cohort, and 14.6 and 6.9 months in the European Organisation for Research and Treatment of Cancer-National Cancer Institute of Canada cohort. Correlation of MGMT promoter methylation and improved OS and PFS was retained in the study group. Comparative subset analysis showed that poor prognosis patients (recursive partitioning analysis class V/VI) may derive an early benefit from the use of first-line BV. Toxicity attributable to RT/TMZ was similar, and additional toxicities were consistent with those reported in other BV trials.ConclusionPatients treated with BV and TMZ during and after RT showed improved PFS without improved OS compared to the University of California, Los Angeles/KPLA control group. Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence.

Dataset Information

Phase I, open-label, multicentre study of buparlisib in combination with temozolomide or with concomitant radiation therapy and temozolomide in patients with newly diagnosed glioblastoma.

Publications

Phase I, open-label, multicentre study of buparlisib in combination with temozolomide or with concomitant radiation therapy and temozolomide in patients with newly diagnosed glioblastoma.

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