A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma

Michael D. Prados, S. Clifford Schold, Howard A. Fine, Kurt Jaeckle, Fred Hochberg, Laszlo Mechtler, Michael R. Fetell, Surasak Phuphanich, Lynn Feun, Todd J. Janus, Kathleen Ford, William Graney

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml × time for patients who had received prior chemotherapy, or 7 mg/ml × time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of fife assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.

Original languageEnglish (US)
Pages (from-to)96-103
Number of pages8
JournalNeuro-Oncology
Volume5
Issue number2
DOIs
StatePublished - Apr 1 2003

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Carboplatin
Glioma
Placebos
Therapeutics
Neoplasms
Drug Therapy
RMP 7
Pharmacokinetics
Bradykinin
Glioblastoma
Blood-Brain Barrier
Intravenous Infusions
Brain Neoplasms
Area Under Curve
Permeability
Appointments and Schedules
Radiotherapy
Randomized Controlled Trials
Quality of Life
Outcome Assessment (Health Care)

All Science Journal Classification (ASJC) codes

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Prados, Michael D. ; Schold, S. Clifford ; Fine, Howard A. ; Jaeckle, Kurt ; Hochberg, Fred ; Mechtler, Laszlo ; Fetell, Michael R. ; Phuphanich, Surasak ; Feun, Lynn ; Janus, Todd J. ; Ford, Kathleen ; Graney, William. / A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. In: Neuro-Oncology. 2003 ; Vol. 5, No. 2. pp. 96-103.
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abstract = "RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml × time for patients who had received prior chemotherapy, or 7 mg/ml × time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95{\%} CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95{\%} CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95{\%} CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95{\%} CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of fife assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.",
author = "Prados, {Michael D.} and Schold, {S. Clifford} and Fine, {Howard A.} and Kurt Jaeckle and Fred Hochberg and Laszlo Mechtler and Fetell, {Michael R.} and Surasak Phuphanich and Lynn Feun and Janus, {Todd J.} and Kathleen Ford and William Graney",
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Prados, MD, Schold, SC, Fine, HA, Jaeckle, K, Hochberg, F, Mechtler, L, Fetell, MR, Phuphanich, S, Feun, L, Janus, TJ, Ford, K & Graney, W 2003, 'A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma', Neuro-Oncology, vol. 5, no. 2, pp. 96-103. https://doi.org/10.1215/S1522851702000340

A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. / Prados, Michael D.; Schold, S. Clifford; Fine, Howard A.; Jaeckle, Kurt; Hochberg, Fred; Mechtler, Laszlo; Fetell, Michael R.; Phuphanich, Surasak; Feun, Lynn; Janus, Todd J.; Ford, Kathleen; Graney, William.

In: Neuro-Oncology, Vol. 5, No. 2, 01.04.2003, p. 96-103.

Research output: Contribution to journalArticle

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T1 - A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma

AU - Prados, Michael D.

AU - Schold, S. Clifford

AU - Fine, Howard A.

AU - Jaeckle, Kurt

AU - Hochberg, Fred

AU - Mechtler, Laszlo

AU - Fetell, Michael R.

AU - Phuphanich, Surasak

AU - Feun, Lynn

AU - Janus, Todd J.

AU - Ford, Kathleen

AU - Graney, William

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N2 - RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml × time for patients who had received prior chemotherapy, or 7 mg/ml × time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of fife assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.

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