Intrathecal mafosfamide

A preclinical pharmacology and phase I trial

Susan M. Blaney, Frank M. Balis, Stacey Berg, Carola A.S. Arndt, Richard Heideman, J. Russell Geyer, Roger Packer, Peter C. Adamson, Kurt Jaeckle, Renee Klenke, Alberta Aikin, Robert Murphy, Cynthia McCully, David G. Poplack

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Purpose: Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. Patients and Methods: In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. Results: The cytotoxic target exposure for mafosfamide was 10 μmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 μmol/L Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. Conclusion: The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

Original languageEnglish (US)
Pages (from-to)1555-1563
Number of pages9
JournalJournal of Clinical Oncology
Volume23
Issue number7
DOIs
StatePublished - Dec 1 2005

Fingerprint

Pharmacology
Headache
Pharmacokinetics
Clinical Trials, Phase I
Rhabdomyosarcoma
Feasibility Studies
Granulocyte-Macrophage Colony-Stimulating Factor
Meningitis
Analgesia
Cyclophosphamide
Primates
mafosfamide
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Blaney, S. M., Balis, F. M., Berg, S., Arndt, C. A. S., Heideman, R., Geyer, J. R., ... Poplack, D. G. (2005). Intrathecal mafosfamide: A preclinical pharmacology and phase I trial. Journal of Clinical Oncology, 23(7), 1555-1563. https://doi.org/10.1200/JCO.2005.06.053
Blaney, Susan M. ; Balis, Frank M. ; Berg, Stacey ; Arndt, Carola A.S. ; Heideman, Richard ; Geyer, J. Russell ; Packer, Roger ; Adamson, Peter C. ; Jaeckle, Kurt ; Klenke, Renee ; Aikin, Alberta ; Murphy, Robert ; McCully, Cynthia ; Poplack, David G. / Intrathecal mafosfamide : A preclinical pharmacology and phase I trial. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 7. pp. 1555-1563.
@article{b40b1506052a47a5a29a256a68a9060f,
title = "Intrathecal mafosfamide: A preclinical pharmacology and phase I trial",
abstract = "Purpose: Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. Patients and Methods: In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. Results: The cytotoxic target exposure for mafosfamide was 10 μmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 μmol/L Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. Conclusion: The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.",
author = "Blaney, {Susan M.} and Balis, {Frank M.} and Stacey Berg and Arndt, {Carola A.S.} and Richard Heideman and Geyer, {J. Russell} and Roger Packer and Adamson, {Peter C.} and Kurt Jaeckle and Renee Klenke and Alberta Aikin and Robert Murphy and Cynthia McCully and Poplack, {David G.}",
year = "2005",
month = "12",
day = "1",
doi = "10.1200/JCO.2005.06.053",
language = "English (US)",
volume = "23",
pages = "1555--1563",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "7",

}

Blaney, SM, Balis, FM, Berg, S, Arndt, CAS, Heideman, R, Geyer, JR, Packer, R, Adamson, PC, Jaeckle, K, Klenke, R, Aikin, A, Murphy, R, McCully, C & Poplack, DG 2005, 'Intrathecal mafosfamide: A preclinical pharmacology and phase I trial', Journal of Clinical Oncology, vol. 23, no. 7, pp. 1555-1563. https://doi.org/10.1200/JCO.2005.06.053

Intrathecal mafosfamide : A preclinical pharmacology and phase I trial. / Blaney, Susan M.; Balis, Frank M.; Berg, Stacey; Arndt, Carola A.S.; Heideman, Richard; Geyer, J. Russell; Packer, Roger; Adamson, Peter C.; Jaeckle, Kurt; Klenke, Renee; Aikin, Alberta; Murphy, Robert; McCully, Cynthia; Poplack, David G.

In: Journal of Clinical Oncology, Vol. 23, No. 7, 01.12.2005, p. 1555-1563.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Intrathecal mafosfamide

T2 - A preclinical pharmacology and phase I trial

AU - Blaney, Susan M.

AU - Balis, Frank M.

AU - Berg, Stacey

AU - Arndt, Carola A.S.

AU - Heideman, Richard

AU - Geyer, J. Russell

AU - Packer, Roger

AU - Adamson, Peter C.

AU - Jaeckle, Kurt

AU - Klenke, Renee

AU - Aikin, Alberta

AU - Murphy, Robert

AU - McCully, Cynthia

AU - Poplack, David G.

PY - 2005/12/1

Y1 - 2005/12/1

N2 - Purpose: Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. Patients and Methods: In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. Results: The cytotoxic target exposure for mafosfamide was 10 μmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 μmol/L Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. Conclusion: The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

AB - Purpose: Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. Patients and Methods: In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. Results: The cytotoxic target exposure for mafosfamide was 10 μmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 μmol/L Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. Conclusion: The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

UR - http://www.scopus.com/inward/record.url?scp=20144373178&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20144373178&partnerID=8YFLogxK

U2 - 10.1200/JCO.2005.06.053

DO - 10.1200/JCO.2005.06.053

M3 - Article

VL - 23

SP - 1555

EP - 1563

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 7

ER -

Blaney SM, Balis FM, Berg S, Arndt CAS, Heideman R, Geyer JR et al. Intrathecal mafosfamide: A preclinical pharmacology and phase I trial. Journal of Clinical Oncology. 2005 Dec 1;23(7):1555-1563. https://doi.org/10.1200/JCO.2005.06.053