A phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan for children with neoplastic meningitis: A pediatric brain tumor consortium study

Susan M. Blaney, Michael Tagen, Arzu Onar-Thomas, Stacey L. Berg, Sri Gururangan, Kathleen Scorsone, Jack Su, Stewart Goldman, Mark W. Kieran, Larry Kun, Jim Boyett, Clinton Stewart

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Purpose: We performed a phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan (IT), administered daily 5×, to determine whether, the maximum tolerated dose of IT topotecan was also the pharmacokinetic optimal dose. Patients and Methods: Patients received topotecan administered through an intraventricular access device (0.1 or 0.2mg/dose), daily×5 every other week 2× (Induction); every 3 weeks×2 (Consolidation); then every 4 weeks for up to 11 courses (Maintenance). Ventricular CSF pharmacokinetic studies were performed on day 1, week 1 of induction, and in a subset of patients after a single intralumbar topotecan dose on day 1, week 3. Results: Nineteen patients were enrolled. All were evaluable for toxicity and 18 were assessable for pharmacokinetics. Arachnoiditis requiring corticosteroid therapy occurred in or one of three patients at the 0.1mg dose level and two of the initial three patients enrolled at the 0.2mg dose level. All subsequent patients were therefore treated with concomitant dexamethasone. Pharmacokinetic evaluation after accrual of the first seven patients revealed that a topotecan lactone concentration >1ng/ml for 8hours was attained in all patients and thus, further dose escalation was not pursued. Results of simulation studies showed that at the dose levels evaluated, >99.9% of patients are expected to achieve CSF topotecan lactone concentrations >1ng/ml for at least 8hours. Conclusion: Intraventricular topotecan, 0.2mg, administered daily for 5 days with concomitant dexamethasone is well tolerated and was defined to be the pharmacokinetic optimal dose in this trial.

Original languageEnglish (US)
Pages (from-to)627-632
Number of pages6
JournalPediatric Blood and Cancer
Volume60
Issue number4
DOIs
StatePublished - Apr 1 2013

Fingerprint

Topotecan
Meningitis
Brain Neoplasms
Pharmacokinetics
Pediatrics
Lactones
Dexamethasone
Arachnoiditis
Maximum Tolerated Dose
Adrenal Cortex Hormones
Maintenance

Keywords

  • Intraventricular
  • Leptomeningeal
  • Neoplastic meningitis
  • Pharmacokinetic
  • Topotecan

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

A phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan for children with neoplastic meningitis : A pediatric brain tumor consortium study. / Blaney, Susan M.; Tagen, Michael; Onar-Thomas, Arzu; Berg, Stacey L.; Gururangan, Sri; Scorsone, Kathleen; Su, Jack; Goldman, Stewart; Kieran, Mark W.; Kun, Larry; Boyett, Jim; Stewart, Clinton.

In: Pediatric Blood and Cancer, Vol. 60, No. 4, 01.04.2013, p. 627-632.

Research output: Contribution to journalArticle

Blaney, SM, Tagen, M, Onar-Thomas, A, Berg, SL, Gururangan, S, Scorsone, K, Su, J, Goldman, S, Kieran, MW, Kun, L, Boyett, J & Stewart, C 2013, 'A phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan for children with neoplastic meningitis: A pediatric brain tumor consortium study', Pediatric Blood and Cancer, vol. 60, no. 4, pp. 627-632. https://doi.org/10.1002/pbc.24309
Blaney, Susan M. ; Tagen, Michael ; Onar-Thomas, Arzu ; Berg, Stacey L. ; Gururangan, Sri ; Scorsone, Kathleen ; Su, Jack ; Goldman, Stewart ; Kieran, Mark W. ; Kun, Larry ; Boyett, Jim ; Stewart, Clinton. / A phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan for children with neoplastic meningitis : A pediatric brain tumor consortium study. In: Pediatric Blood and Cancer. 2013 ; Vol. 60, No. 4. pp. 627-632.
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abstract = "Purpose: We performed a phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan (IT), administered daily 5×, to determine whether, the maximum tolerated dose of IT topotecan was also the pharmacokinetic optimal dose. Patients and Methods: Patients received topotecan administered through an intraventricular access device (0.1 or 0.2mg/dose), daily×5 every other week 2× (Induction); every 3 weeks×2 (Consolidation); then every 4 weeks for up to 11 courses (Maintenance). Ventricular CSF pharmacokinetic studies were performed on day 1, week 1 of induction, and in a subset of patients after a single intralumbar topotecan dose on day 1, week 3. Results: Nineteen patients were enrolled. All were evaluable for toxicity and 18 were assessable for pharmacokinetics. Arachnoiditis requiring corticosteroid therapy occurred in or one of three patients at the 0.1mg dose level and two of the initial three patients enrolled at the 0.2mg dose level. All subsequent patients were therefore treated with concomitant dexamethasone. Pharmacokinetic evaluation after accrual of the first seven patients revealed that a topotecan lactone concentration >1ng/ml for 8hours was attained in all patients and thus, further dose escalation was not pursued. Results of simulation studies showed that at the dose levels evaluated, >99.9{\%} of patients are expected to achieve CSF topotecan lactone concentrations >1ng/ml for at least 8hours. Conclusion: Intraventricular topotecan, 0.2mg, administered daily for 5 days with concomitant dexamethasone is well tolerated and was defined to be the pharmacokinetic optimal dose in this trial.",
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T2 - A pediatric brain tumor consortium study

AU - Blaney, Susan M.

AU - Tagen, Michael

AU - Onar-Thomas, Arzu

AU - Berg, Stacey L.

AU - Gururangan, Sri

AU - Scorsone, Kathleen

AU - Su, Jack

AU - Goldman, Stewart

AU - Kieran, Mark W.

AU - Kun, Larry

AU - Boyett, Jim

AU - Stewart, Clinton

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N2 - Purpose: We performed a phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan (IT), administered daily 5×, to determine whether, the maximum tolerated dose of IT topotecan was also the pharmacokinetic optimal dose. Patients and Methods: Patients received topotecan administered through an intraventricular access device (0.1 or 0.2mg/dose), daily×5 every other week 2× (Induction); every 3 weeks×2 (Consolidation); then every 4 weeks for up to 11 courses (Maintenance). Ventricular CSF pharmacokinetic studies were performed on day 1, week 1 of induction, and in a subset of patients after a single intralumbar topotecan dose on day 1, week 3. Results: Nineteen patients were enrolled. All were evaluable for toxicity and 18 were assessable for pharmacokinetics. Arachnoiditis requiring corticosteroid therapy occurred in or one of three patients at the 0.1mg dose level and two of the initial three patients enrolled at the 0.2mg dose level. All subsequent patients were therefore treated with concomitant dexamethasone. Pharmacokinetic evaluation after accrual of the first seven patients revealed that a topotecan lactone concentration >1ng/ml for 8hours was attained in all patients and thus, further dose escalation was not pursued. Results of simulation studies showed that at the dose levels evaluated, >99.9% of patients are expected to achieve CSF topotecan lactone concentrations >1ng/ml for at least 8hours. Conclusion: Intraventricular topotecan, 0.2mg, administered daily for 5 days with concomitant dexamethasone is well tolerated and was defined to be the pharmacokinetic optimal dose in this trial.

AB - Purpose: We performed a phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan (IT), administered daily 5×, to determine whether, the maximum tolerated dose of IT topotecan was also the pharmacokinetic optimal dose. Patients and Methods: Patients received topotecan administered through an intraventricular access device (0.1 or 0.2mg/dose), daily×5 every other week 2× (Induction); every 3 weeks×2 (Consolidation); then every 4 weeks for up to 11 courses (Maintenance). Ventricular CSF pharmacokinetic studies were performed on day 1, week 1 of induction, and in a subset of patients after a single intralumbar topotecan dose on day 1, week 3. Results: Nineteen patients were enrolled. All were evaluable for toxicity and 18 were assessable for pharmacokinetics. Arachnoiditis requiring corticosteroid therapy occurred in or one of three patients at the 0.1mg dose level and two of the initial three patients enrolled at the 0.2mg dose level. All subsequent patients were therefore treated with concomitant dexamethasone. Pharmacokinetic evaluation after accrual of the first seven patients revealed that a topotecan lactone concentration >1ng/ml for 8hours was attained in all patients and thus, further dose escalation was not pursued. Results of simulation studies showed that at the dose levels evaluated, >99.9% of patients are expected to achieve CSF topotecan lactone concentrations >1ng/ml for at least 8hours. Conclusion: Intraventricular topotecan, 0.2mg, administered daily for 5 days with concomitant dexamethasone is well tolerated and was defined to be the pharmacokinetic optimal dose in this trial.

KW - Intraventricular

KW - Leptomeningeal

KW - Neoplastic meningitis

KW - Pharmacokinetic

KW - Topotecan

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