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A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study.

ABSTRACT: Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG.Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization.Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-?) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%.Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.

SUBMITTER: Banerjee A

PROVIDER: S-EPMC5570236 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study.

Banerjee Anuradha A Jakacki Regina I RI Onar-Thomas Arzu A Wu Shengjie S Nicolaides Theodore T Young Poussaint Tina T Fangusaro Jason J Phillips Joanna J Perry Arie A Turner David D Prados Michael M Packer Roger J RJ Qaddoumi Ibrahim I Gururangan Sridharan S Pollack Ian F IF Goldman Stewart S Doyle Lawrence A LA Stewart Clinton F CF Boyett James M JM Kun Larry E LE Fouladi Maryam M

Neuro-oncology 20170801 8

<h4>Background</h4>Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG.<h4>Methods</h4>Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed du ...[more]

PMID: 28339824

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Project description:Abstract BACKGROUND Children with recurrent or progressive pediatric CNS tumors have poor prognoses. Optune delivers TTFields, an anti-mitotic FDA-approved cancer therapy, for adult patients with newly diagnosed and recurrent supratentorial GBM. Methods This multicenter trial [NCT03033992] examines the feasibility and device-related toxicity of TTFields in 20 children aged 5–21 years with recurrent supratentorial HGG and ependymoma. Secondary objectives include: response rate, event-free survival, compliance and QoL. Feasibility in this trial is defined as the ability of pediatric subjects to wear Optune ≥18 hours/day for at least 23/28 days of cycle one following a 7-day learning period. Treatment may continue up to 26 cycles based on observed benefit and safety. QOL instruments include PROMIS and Neuro-QOL. Following enrollment of the 11th evaluable subject, the study will be temporarily suspended to share interim feasibility and safety data with the FDA. RESULTS This planned interim analysis included 11 patients (7 males/4 females) with supratentorial tumors: ten HGG and one ependymoma. Median age was 14.2 (6.4–21.3) years. Ten patients were evaluable (1 Progressive Disease) during the feasibility period) and 4 remained on study through 4 cycles and one patient is currently on Cycle 14. One grade 5 intracranial hemorrhage not associated with the device and no grade IV toxicities occurred, 3 patients had seizures (grade 1–3), fatigue, scalp pain, localized rash, and headache (none greater than grade 3). Of the 10 evaluable patients, 7 satisfied the feasibility criteria for the Optune therapy, which is above the prespecified threshold of at least 6/11. CONCLUSION This is the first prospective safety and feasibility trial for Optune in children with recurrent supratentorial HGG and ependymoma. Preliminary results indicate feasibility with minimal toxicity. Accrual to the study is ongoing. An amendment is in progress adding a stratum for newly diagnosed diffuse intrinsic pontine glioma (DIPG) patients.

Project description:BackgroundPaediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.MethodsThe Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.FindingsBetween July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported.InterpretationSelumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.FundingNational Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.

Dataset Information

A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study.

Publications

A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study.

Similar Datasets

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