tirapazamine and Muscle-Cramp

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.. 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.. 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).. 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.

Topics: Adult; Aged; Antineoplastic Agents; Cell Hypoxia; Dose Fractionation, Radiation; Drug Administration Schedule; Drug Eruptions; Female; Humans; Hypotension; Infusions, Intravenous; Male; Middle Aged; Muscle Cramp; Neoplasms; Radiation-Sensitizing Agents; Tirapazamine; Triazines

Tirapazamine (SR 4233; 3-amino-1,2,4-benzotriazine-1,4-di-N-oxide) is a bioreductive agent exhibiting up to 200 x greater toxicity for hypoxic cells as compared to oxygenated cells. In murine studies, a selective increase in tumor kill was observed when tirapazamine was coadministered with other agents, notably cisplatin. A Phase I study of single-agent tirapazamine administered i.v. every 3 weeks was conducted to determine the toxicity of a schedule for use with systemic chemotherapy. A total of 28 patients were given 50 courses of tirapazamine at doses ranging from 36-450 mg/m2. No tumor responses were observed. Reversible deafness and tinnitus were dose-limiting, with ototoxicity observed in 1 of 6 patients treated at 330 mg/m2, 1 of 4 patients treated at 390 mg/m2, and 3 of 3 patients treated at 450 mg/m2. Muscle cramps, nausea, and vomiting were also observed. Pharmacokinetic studies revealed a greater than dose-proportional increase in the area under the plasma concentration x time curve (AUCs) of the two major metabolites. Patients who developed ototoxicity generally showed higher plasma AUC values for the parent drug and metabolites. The mean plasma tirapazamine AUC at 330 mg/m2 was 1026.5 microgram/ml x min (range 863. 8-1252.3), but no pharmacokinetic data are available for the solitary patient who developed otoxicity at this dose level. These AUC values were in the (estimated) range required for therapeutic effect in murine studies. Ototoxicity was not observed when the AUC of tirapazamine was equal to or less than 1252 microgram/ml x min. The dose of 330 mg/m2 was therefore chosen as an appropriate level for combination chemotherapy studies.

Topics: Adult; Aged; Antineoplastic Agents; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Muscle Cramp; Nausea; Neoplasms; Thrombocytopenia; Tirapazamine; Triazines; Vomiting

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.. Tirapazamine 9 mg/m2 to 21 mg/m2 was given i.v. 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 i.v. 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.. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Muscle Cramp; Neoplasms; Radiation-Sensitizing Agents; Tirapazamine; Triazines