Phase I trial of the hypoxic cell cytotoxin tirapazamine with concurrent radiation therapy in the treatment of refractory solid tumors

Lawrence N. Shulman, Lori Buswell, Nancy Riese, Nancy Doherty, Jay S. Loeffler, Reinhard W. Von Roemeling, C. Norman Coleman

Research output: Contribution to journalArticle

Abstract

Purpose: Patients with refractory solid tumors were treated with the combination of fractionated radiation therapy and multiple-dose intravenous tirapazamine to determine the toxicities and maximum tolerated dose of tirapazamine when given concurrently with radiation therapy. Methods: Patients received radiation therapy in accordance with standard treatment practice in relation to fraction size and number of fractions for their particular cancer. In all cases, the course of radiation therapy exceeded the time of tirapazamine administration. Initially, tirapazamine was administered 5 days per week for 2 weeks for a total of 10 doses. After the first 8 patients, the schedule was changed to 3 times per week (Monday, Wednesday, Friday) for 4 weeks for a total of 12 doses. Between 3 and 6 patients were treated at each dose level. Results: A total of 43 patients were treated in the study between 1991 and 1995. All patients were 18 years old or older, had a Karnofsky performance status of ≥ 60% and had adequate hematologic, hepatic, and renal function. Dose escalation began at 9 mg/m2/dose and was increased using a modified Fibonacci schema. The maximum tolerated dose was not reached and dose escalation was stopped at 260 mg/m2 because of other date that became available suggesting 330 mg/m2 was associated with dose- limiting toxicity (1, 2). Conclusion: Tirapazamine in doses of up to 260 mg/m2 times 12 doses can be given safely with fractionate radiation therapy. This dose appears to result in adequate plasma exposure (2) for radiation sensitization, and this schedule is being tested in a Phase II trial by the Radiation Therapy Oncology Group to determine tirapazamine is a radiation enhancer in the clinic.

Original languageEnglish (US)
Pages (from-to)349-353
Number of pages5
JournalInternational Journal of Radiation Oncology, Biology, Physics
Volume44
Issue number2
DOIs
StatePublished - May 1999
Externally publishedYes

Fingerprint

tirapazamine
Cytotoxins
refractories
radiation therapy
Radiotherapy
tumors
dosage
Neoplasms
Maximum Tolerated Dose
Appointments and Schedules
Therapeutics
Karnofsky Performance Status
Radiation Oncology
schedules
toxicity

Keywords

  • Bioreductive cytotoxins
  • Clinical trial
  • Hypoxic cytotoxic agents
  • Muscle cramping
  • Phase I
  • Radiation sensitizers
  • SR4233
  • Tirapazamine
  • WIN59075

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation

Cite this

Phase I trial of the hypoxic cell cytotoxin tirapazamine with concurrent radiation therapy in the treatment of refractory solid tumors. / Shulman, Lawrence N.; Buswell, Lori; Riese, Nancy; Doherty, Nancy; Loeffler, Jay S.; Von Roemeling, Reinhard W.; Coleman, C. Norman.

In: International Journal of Radiation Oncology, Biology, Physics, Vol. 44, No. 2, 05.1999, p. 349-353.

Research output: Contribution to journalArticle

Shulman, Lawrence N. ; Buswell, Lori ; Riese, Nancy ; Doherty, Nancy ; Loeffler, Jay S. ; Von Roemeling, Reinhard W. ; Coleman, C. Norman. / Phase I trial of the hypoxic cell cytotoxin tirapazamine with concurrent radiation therapy in the treatment of refractory solid tumors. In: International Journal of Radiation Oncology, Biology, Physics. 1999 ; Vol. 44, No. 2. pp. 349-353.
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abstract = "Purpose: Patients with refractory solid tumors were treated with the combination of fractionated radiation therapy and multiple-dose intravenous tirapazamine to determine the toxicities and maximum tolerated dose of tirapazamine when given concurrently with radiation therapy. Methods: Patients received radiation therapy in accordance with standard treatment practice in relation to fraction size and number of fractions for their particular cancer. In all cases, the course of radiation therapy exceeded the time of tirapazamine administration. Initially, tirapazamine was administered 5 days per week for 2 weeks for a total of 10 doses. After the first 8 patients, the schedule was changed to 3 times per week (Monday, Wednesday, Friday) for 4 weeks for a total of 12 doses. Between 3 and 6 patients were treated at each dose level. Results: A total of 43 patients were treated in the study between 1991 and 1995. All patients were 18 years old or older, had a Karnofsky performance status of ≥ 60{\%} and had adequate hematologic, hepatic, and renal function. Dose escalation began at 9 mg/m2/dose and was increased using a modified Fibonacci schema. The maximum tolerated dose was not reached and dose escalation was stopped at 260 mg/m2 because of other date that became available suggesting 330 mg/m2 was associated with dose- limiting toxicity (1, 2). Conclusion: Tirapazamine in doses of up to 260 mg/m2 times 12 doses can be given safely with fractionate radiation therapy. This dose appears to result in adequate plasma exposure (2) for radiation sensitization, and this schedule is being tested in a Phase II trial by the Radiation Therapy Oncology Group to determine tirapazamine is a radiation enhancer in the clinic.",
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AU - Loeffler, Jay S.

AU - Von Roemeling, Reinhard W.

AU - Coleman, C. Norman

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