Muscle cramping in phase i clinical trials of tirapazamine (SR 4233) with and without radiation

Nancy Doherty, Steven L. Hancock, Stanley Kaye, C. Norman Coleman, Lawrence Shulman, Carol Marquez, Carol Mariscal, Roy Rampling, Suresh Senan, Reinhard V. Roemeling

Research output: Contribution to journalArticle

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Abstract

Purpose: Tirapazamine (SR 4233) is a benzotriazine di-N-oxide which acts as a hypoxic cytotoxic agent and as a radiation enhancer when given shortly before or after radiation. Three Phase I clinical trials were designed to determine the maximum tolerated dose, toxicities, pharmacokinetics, and effects on irradiated tumors and normal tissues. Methods and Materials: Tirapazamine 9 mg/m2 to 21 mg/m2 was given IV sol|1/2 to 1 h prior to irradiation on a multiple dose schedule of 10 consecutive doses. This was later revised to a three times-per-week schedule for 12 doses. In a second clinical trial, tirapazamine was given in a single dose of 18 mg/m2 to 293 mg/m2 IV after irradiation. In a third trial, tirapazamine was administered without irradiation in single doses of 36 mg/m2 to 250 mg/m2, with an option for retreatment. Results: Subjects reported muscle cramping of varying degrees of severity on all three dose schedules. One patient experienced Grade 3 cramping and treatment was discontinued. The most frequent site of cramping were the lower extremities. Creatine phosphokinase (CPK) values were elevated in three patients with associated muscle soreness in one patient. MB (cardiac) isoenzymes were elevated in one patient with no evidence of cardiac muscle damage, and returned to baseline at drug completion. No consistent abnormalities in clinical laboratory values were found. Stretching of the muscle was most effective in relieving the cramping. Conclusion: Muscle cramping has been the most frequently reported toxicity in Phase I studies of tirapazamine, though it does not appear to be dose limiting. Dose escalation on the three clinical trials continues. In vitro studies to investigate the cramping are ongoing.

Original languageEnglish (US)
Pages (from-to)379-382
Number of pages4
JournalInternational journal of radiation oncology, biology, physics
Volume29
Issue number2
DOIs
StatePublished - May 15 1994
Externally publishedYes

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tirapazamine
muscles
Clinical Trials
Radiation
Muscles
dosage
radiation
Appointments and Schedules
schedules
toxicity
Triazines
Clinical Trials, Phase I
irradiation
Retreatment
Maximum Tolerated Dose
Myalgia
Cytotoxins
Polymethyl Methacrylate
Creatine Kinase
creatine

Keywords

  • Hypoxic cytotoxic agents
  • Muscle cramping
  • Radiation sensitizers
  • SR 4233
  • Tirapazamine

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation

Cite this

Doherty, N., Hancock, S. L., Kaye, S., Norman Coleman, C., Shulman, L., Marquez, C., ... Roemeling, R. V. (1994). Muscle cramping in phase i clinical trials of tirapazamine (SR 4233) with and without radiation. International journal of radiation oncology, biology, physics, 29(2), 379-382. https://doi.org/10.1016/0360-3016(94)90293-3

Muscle cramping in phase i clinical trials of tirapazamine (SR 4233) with and without radiation. / Doherty, Nancy; Hancock, Steven L.; Kaye, Stanley; Norman Coleman, C.; Shulman, Lawrence; Marquez, Carol; Mariscal, Carol; Rampling, Roy; Senan, Suresh; Roemeling, Reinhard V.

In: International journal of radiation oncology, biology, physics, Vol. 29, No. 2, 15.05.1994, p. 379-382.

Research output: Contribution to journalArticle

Doherty, N, Hancock, SL, Kaye, S, Norman Coleman, C, Shulman, L, Marquez, C, Mariscal, C, Rampling, R, Senan, S & Roemeling, RV 1994, 'Muscle cramping in phase i clinical trials of tirapazamine (SR 4233) with and without radiation', International journal of radiation oncology, biology, physics, vol. 29, no. 2, pp. 379-382. https://doi.org/10.1016/0360-3016(94)90293-3
Doherty, Nancy ; Hancock, Steven L. ; Kaye, Stanley ; Norman Coleman, C. ; Shulman, Lawrence ; Marquez, Carol ; Mariscal, Carol ; Rampling, Roy ; Senan, Suresh ; Roemeling, Reinhard V. / Muscle cramping in phase i clinical trials of tirapazamine (SR 4233) with and without radiation. In: International journal of radiation oncology, biology, physics. 1994 ; Vol. 29, No. 2. pp. 379-382.
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abstract = "Purpose: Tirapazamine (SR 4233) is a benzotriazine di-N-oxide which acts as a hypoxic cytotoxic agent and as a radiation enhancer when given shortly before or after radiation. Three Phase I clinical trials were designed to determine the maximum tolerated dose, toxicities, pharmacokinetics, and effects on irradiated tumors and normal tissues. Methods and Materials: Tirapazamine 9 mg/m2 to 21 mg/m2 was given IV sol|1/2 to 1 h prior to irradiation on a multiple dose schedule of 10 consecutive doses. This was later revised to a three times-per-week schedule for 12 doses. In a second clinical trial, tirapazamine was given in a single dose of 18 mg/m2 to 293 mg/m2 IV after irradiation. In a third trial, tirapazamine was administered without irradiation in single doses of 36 mg/m2 to 250 mg/m2, with an option for retreatment. Results: Subjects reported muscle cramping of varying degrees of severity on all three dose schedules. One patient experienced Grade 3 cramping and treatment was discontinued. The most frequent site of cramping were the lower extremities. Creatine phosphokinase (CPK) values were elevated in three patients with associated muscle soreness in one patient. MB (cardiac) isoenzymes were elevated in one patient with no evidence of cardiac muscle damage, and returned to baseline at drug completion. No consistent abnormalities in clinical laboratory values were found. Stretching of the muscle was most effective in relieving the cramping. Conclusion: Muscle cramping has been the most frequently reported toxicity in Phase I studies of tirapazamine, though it does not appear to be dose limiting. Dose escalation on the three clinical trials continues. In vitro studies to investigate the cramping are ongoing.",
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