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

Anuradha Banerjee, Regina I. Jakacki, Arzu Onar-Thomas, Shengjie Wu, Theodore Nicolaides, Tina Young Poussaint, Jason Fangusaro, Joanna Phillips, Arie Perry, David Turner, Michael Prados, Roger J. Packer, Ibrahim Qaddoumi, Sridharan Gururangan, Ian F. Pollack, Stewart Goldman, Lawrence A. Doyle, Clinton F. Stewart, James M. Boyett, Larry E. Kun & 1 others Maryam Fouladi

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Background. Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric lowgrade 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. Methods. 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. Results. 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%. Conclusion. Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.

Original languageEnglish (US)
Pages (from-to)1135-1144
Number of pages10
JournalNeuro-Oncology
Volume19
Issue number8
DOIs
StatePublished - Aug 1 2017

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Mitogen-Activated Protein Kinase Kinases
Brain Neoplasms
Glioma
Mucositis
Exanthema
Pediatrics
Amylases
Lipase
Poisons
Clinical Protocols
Mitogen-Activated Protein Kinases
Fluorescence In Situ Hybridization
Disease-Free Survival
Area Under Curve
Headache
Real-Time Polymerase Chain Reaction
Neoplasms
Pharmacokinetics
AZD 6244
Growth

Keywords

  • low-grade glioma
  • phase I trial
  • selumetinib

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

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; Jakacki, Regina I.; Onar-Thomas, Arzu; Wu, Shengjie; Nicolaides, Theodore; Young Poussaint, Tina; Fangusaro, Jason; Phillips, Joanna; Perry, Arie; Turner, David; Prados, Michael; Packer, Roger J.; Qaddoumi, Ibrahim; Gururangan, Sridharan; Pollack, Ian F.; Goldman, Stewart; Doyle, Lawrence A.; Stewart, Clinton F.; Boyett, James M.; Kun, Larry E.; Fouladi, Maryam.

In: Neuro-Oncology, Vol. 19, No. 8, 01.08.2017, p. 1135-1144.

Research output: Contribution to journalArticle

Banerjee, A, Jakacki, RI, Onar-Thomas, A, Wu, S, Nicolaides, T, Young Poussaint, T, Fangusaro, J, Phillips, J, Perry, A, Turner, D, Prados, M, Packer, RJ, Qaddoumi, I, Gururangan, S, Pollack, IF, Goldman, S, Doyle, LA, Stewart, CF, Boyett, JM, Kun, LE & Fouladi, M 2017, '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', Neuro-Oncology, vol. 19, no. 8, pp. 1135-1144. https://doi.org/10.1093/neuonc/now282
Banerjee, Anuradha ; Jakacki, Regina I. ; Onar-Thomas, Arzu ; Wu, Shengjie ; Nicolaides, Theodore ; Young Poussaint, Tina ; Fangusaro, Jason ; Phillips, Joanna ; Perry, Arie ; Turner, David ; Prados, Michael ; Packer, Roger J. ; Qaddoumi, Ibrahim ; Gururangan, Sridharan ; Pollack, Ian F. ; Goldman, Stewart ; Doyle, Lawrence A. ; Stewart, Clinton F. ; Boyett, James M. ; Kun, Larry E. ; Fouladi, Maryam. / 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. In: Neuro-Oncology. 2017 ; Vol. 19, No. 8. pp. 1135-1144.
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abstract = "Background. Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric lowgrade 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. Methods. 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. Results. 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{\%}. Conclusion. Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.",
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TY - JOUR

T1 - A phase i trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma

T2 - A Pediatric Brain Tumor Consortium (PBTC) study

AU - Banerjee, Anuradha

AU - Jakacki, Regina I.

AU - Onar-Thomas, Arzu

AU - Wu, Shengjie

AU - Nicolaides, Theodore

AU - Young Poussaint, Tina

AU - Fangusaro, Jason

AU - Phillips, Joanna

AU - Perry, Arie

AU - Turner, David

AU - Prados, Michael

AU - Packer, Roger J.

AU - Qaddoumi, Ibrahim

AU - Gururangan, Sridharan

AU - Pollack, Ian F.

AU - Goldman, Stewart

AU - Doyle, Lawrence A.

AU - Stewart, Clinton F.

AU - Boyett, James M.

AU - Kun, Larry E.

AU - Fouladi, Maryam

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Background. Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric lowgrade 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. Methods. 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. Results. 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%. Conclusion. Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.

AB - Background. Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric lowgrade 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. Methods. 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. Results. 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%. Conclusion. Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.

KW - low-grade glioma

KW - phase I trial

KW - selumetinib

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U2 - 10.1093/neuonc/now282

DO - 10.1093/neuonc/now282

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VL - 19

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