Phase I trial of MK-0752 in children with refractory CNS malignancies

A pediatric brain tumor consortium study

Maryam Fouladi, Clinton F. Stewart, James Olson, Lars M. Wagner, Arzu Onar-Thomas, Mehmet Kocak, Roger J. Packer, Stewart Goldman, Sridharan Gururangan, Amar Gajjar, Tim Demuth, Larry E. Kun, James M. Boyett, Richard J. Gilbertson

Research output: Contribution to journalArticle

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Abstract

Purpose: To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies. Patients and Methods: MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m2. The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752. Results: Twenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m 2/dose. At 260 mg/m2/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non-dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m2; apparent volume of distribution, 7.36 (24%) L/m2; and ka, 0.358 (99%) hr-1. Conclusion: MK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m2/dose once daily.

Original languageEnglish (US)
Pages (from-to)3529-3534
Number of pages6
JournalJournal of Clinical Oncology
Volume29
Issue number26
DOIs
StatePublished - Sep 10 2011

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Brain Neoplasms
Pediatrics
Maximum Tolerated Dose
Pharmacokinetics
Neoplasms
Glioma
Primitive Neuroectodermal Tumors
Ependymoma
Amyloid Precursor Protein Secretases
Lymphopenia
Medulloblastoma
Hypokalemia
Glioblastoma
Brain Stem
Blood Cells
Appointments and Schedules
3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid
Population
Proteins
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Phase I trial of MK-0752 in children with refractory CNS malignancies : A pediatric brain tumor consortium study. / Fouladi, Maryam; Stewart, Clinton F.; Olson, James; Wagner, Lars M.; Onar-Thomas, Arzu; Kocak, Mehmet; Packer, Roger J.; Goldman, Stewart; Gururangan, Sridharan; Gajjar, Amar; Demuth, Tim; Kun, Larry E.; Boyett, James M.; Gilbertson, Richard J.

In: Journal of Clinical Oncology, Vol. 29, No. 26, 10.09.2011, p. 3529-3534.

Research output: Contribution to journalArticle

Fouladi, M, Stewart, CF, Olson, J, Wagner, LM, Onar-Thomas, A, Kocak, M, Packer, RJ, Goldman, S, Gururangan, S, Gajjar, A, Demuth, T, Kun, LE, Boyett, JM & Gilbertson, RJ 2011, 'Phase I trial of MK-0752 in children with refractory CNS malignancies: A pediatric brain tumor consortium study', Journal of Clinical Oncology, vol. 29, no. 26, pp. 3529-3534. https://doi.org/10.1200/JCO.2011.35.7806
Fouladi, Maryam ; Stewart, Clinton F. ; Olson, James ; Wagner, Lars M. ; Onar-Thomas, Arzu ; Kocak, Mehmet ; Packer, Roger J. ; Goldman, Stewart ; Gururangan, Sridharan ; Gajjar, Amar ; Demuth, Tim ; Kun, Larry E. ; Boyett, James M. ; Gilbertson, Richard J. / Phase I trial of MK-0752 in children with refractory CNS malignancies : A pediatric brain tumor consortium study. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 26. pp. 3529-3534.
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abstract = "Purpose: To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies. Patients and Methods: MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m2. The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752. Results: Twenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m 2/dose. At 260 mg/m2/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non-dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values ({\%} coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38{\%}) L/h/m2; apparent volume of distribution, 7.36 (24{\%}) L/m2; and ka, 0.358 (99{\%}) hr-1. Conclusion: MK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m2/dose once daily.",
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T2 - A pediatric brain tumor consortium study

AU - Fouladi, Maryam

AU - Stewart, Clinton F.

AU - Olson, James

AU - Wagner, Lars M.

AU - Onar-Thomas, Arzu

AU - Kocak, Mehmet

AU - Packer, Roger J.

AU - Goldman, Stewart

AU - Gururangan, Sridharan

AU - Gajjar, Amar

AU - Demuth, Tim

AU - Kun, Larry E.

AU - Boyett, James M.

AU - Gilbertson, Richard J.

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N2 - Purpose: To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies. Patients and Methods: MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m2. The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752. Results: Twenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m 2/dose. At 260 mg/m2/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non-dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m2; apparent volume of distribution, 7.36 (24%) L/m2; and ka, 0.358 (99%) hr-1. Conclusion: MK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m2/dose once daily.

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