A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors

A pediatric brain tumor consortium study

Lindsay B. Kilburn, Mehmet Kocak, Rodney L. Decker, Cynthia Wetmore, Murali Chintagumpala, Jack Su, Stewart Goldman, Anuradha Banerjee, Richard Gilbertson, Maryam Fouladi, Larry Kun, James M. Boyett, Susan M. Blaney

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background We sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cβ 2, in children with recurrent central nervous system malignancies. Methods Enzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m 2) and twice daily at 440 mg/m 2/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples. Results Thirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m 2 given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m 2 dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease >3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma. Conclusion Enzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m 2/day administered once daily.

Original languageEnglish (US)
Pages (from-to)303-311
Number of pages9
JournalNeuro-Oncology
Volume17
Issue number2
DOIs
StatePublished - Jan 1 2015

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Central Nervous System Neoplasms
Brain Neoplasms
Pharmacokinetics
Pediatrics
Glioma
Protein Kinase C
Ependymoma
Neoplasms
Alanine Transaminase
Thrombocytopenia
Nausea
Brain Stem
Fatigue
Anemia
Blood Cells
Central Nervous System
enzastaurin

Keywords

  • brain tumor
  • enzastaurin
  • pediatric
  • pharmacokinetic
  • phase 1

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors : A pediatric brain tumor consortium study. / Kilburn, Lindsay B.; Kocak, Mehmet; Decker, Rodney L.; Wetmore, Cynthia; Chintagumpala, Murali; Su, Jack; Goldman, Stewart; Banerjee, Anuradha; Gilbertson, Richard; Fouladi, Maryam; Kun, Larry; Boyett, James M.; Blaney, Susan M.

In: Neuro-Oncology, Vol. 17, No. 2, 01.01.2015, p. 303-311.

Research output: Contribution to journalArticle

Kilburn, LB, Kocak, M, Decker, RL, Wetmore, C, Chintagumpala, M, Su, J, Goldman, S, Banerjee, A, Gilbertson, R, Fouladi, M, Kun, L, Boyett, JM & Blaney, SM 2015, 'A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: A pediatric brain tumor consortium study', Neuro-Oncology, vol. 17, no. 2, pp. 303-311. https://doi.org/10.1093/neuonc/nou114
Kilburn, Lindsay B. ; Kocak, Mehmet ; Decker, Rodney L. ; Wetmore, Cynthia ; Chintagumpala, Murali ; Su, Jack ; Goldman, Stewart ; Banerjee, Anuradha ; Gilbertson, Richard ; Fouladi, Maryam ; Kun, Larry ; Boyett, James M. ; Blaney, Susan M. / A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors : A pediatric brain tumor consortium study. In: Neuro-Oncology. 2015 ; Vol. 17, No. 2. pp. 303-311.
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abstract = "Background We sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cβ 2, in children with recurrent central nervous system malignancies. Methods Enzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m 2) and twice daily at 440 mg/m 2/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples. Results Thirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m 2 given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m 2 dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease >3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma. Conclusion Enzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m 2/day administered once daily.",
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T1 - A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors

T2 - A pediatric brain tumor consortium study

AU - Kilburn, Lindsay B.

AU - Kocak, Mehmet

AU - Decker, Rodney L.

AU - Wetmore, Cynthia

AU - Chintagumpala, Murali

AU - Su, Jack

AU - Goldman, Stewart

AU - Banerjee, Anuradha

AU - Gilbertson, Richard

AU - Fouladi, Maryam

AU - Kun, Larry

AU - Boyett, James M.

AU - Blaney, Susan M.

PY - 2015/1/1

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N2 - Background We sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cβ 2, in children with recurrent central nervous system malignancies. Methods Enzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m 2) and twice daily at 440 mg/m 2/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples. Results Thirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m 2 given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m 2 dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease >3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma. Conclusion Enzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m 2/day administered once daily.

AB - Background We sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cβ 2, in children with recurrent central nervous system malignancies. Methods Enzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m 2) and twice daily at 440 mg/m 2/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples. Results Thirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m 2 given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m 2 dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease >3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma. Conclusion Enzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m 2/day administered once daily.

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