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

Int J Radiat Oncol Biol Phys. 1999 May 1;44(2):349-53. doi: 10.1016/s0360-3016(99)00016-4.


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 > or = 60% and had adequate hematologic, hepatic, and renal function. Dose escalation began at 9 mg/m(2)/dose and was increased using a modified Fibonacci schema. The maximum tolerated dose was not reached and dose escalation was stopped at 260 mg/m(2) because of other data that became available suggesting 330 mg/m(2) was associated with dose-limiting toxicity (1, 2).

Conclusion: Tirapazamine in doses of up to 260 mg/m(2) times 12 doses can be given safely with fractionated 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 if tirapazamine is a radiation enhancer in the clinic.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Cell Hypoxia / drug effects*
  • Cell Hypoxia / radiation effects*
  • Dose Fractionation, Radiation
  • Drug Administration Schedule
  • Drug Eruptions / etiology
  • Female
  • Humans
  • Hypotension / chemically induced
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Muscle Cramp / chemically induced
  • Neoplasms / drug therapy
  • Neoplasms / physiopathology
  • Neoplasms / radiotherapy*
  • Radiation-Sensitizing Agents / administration & dosage*
  • Radiation-Sensitizing Agents / adverse effects
  • Tirapazamine
  • Triazines / administration & dosage*
  • Triazines / adverse effects


  • Antineoplastic Agents
  • Radiation-Sensitizing Agents
  • Triazines
  • Tirapazamine