Clinical evaluation of the hypoxic cytotoxin tirapazamine (SR-4233): phase I experience with repeated dose administration during fractionated irradiation

Purpose: Regions of chronic or transient hypoxia are common in many human tumors and are thought to limit tumor cell killing and tumor control with conventional irradiation and some chemotherapeutic agents. Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide) forms a cytotoxic free radical during reductive metabolism in regions of hypoxia. In well oxygenated regions, the tirapazamine radical reacts with molecular oxygen to form the inactive parent drug. This results in markedly greater toxicity for hypoxic cells than for the well oxygenated cells that comprise most normal tissues. Tirapazamine increased the anti-tumor effects of single dose or fractionated irradiation or cis-platin chemotherapy in murine tumors,in vivo . This study evaluated the ability to repeat the administration of Tirapazamine during courses of fractionated irradiation in humans after an earlier phase I trial established a maximum tolerated dose of 390 mg per square meter of body surface area (mg/m2) when given as a single dose with radiotherapy. Materials and Methods: Between December 1993 and August 1995 22 patients with locally advanced or metastatic tumors of varying histology, normal renal, hepatic, and hematologic functions, and Karnofsky performance status ≥ 60 received repeated doses of Tirapazamine during a planned, 6 weeks course of standardly fractionated radiotherapy. After anti-emetic treatment with ondansetron (32 mg) and dexamethasone (16 mg), Tirapazamine was administered during a 2 hour intravenous infusion that ended from 30 to 90 minutes before a radiation treatment. Patients were monitored for acute toxicity during the course of treatment and for a minimum of one month after radiotherapy. Results: The study was initiated with three, biweekly doses of Tirapazamine at 330 mg/m2. Four of 7 patients who initiated treatment at this dose refused the second (1 patient) or third dose of Tirapazamine (3 patients). Two of the three patients who received three doses developed Grade III esophagitis during radiation courses that included the mediastinum. Subsequently, doses were reduced to 220 mg/m2 and Tirapazamine treatments were given 6 (weekly), 12 (twice weekly) or 18 times (three times weekly) during the course of radiotherapy. Among 8 patients who initiated treatment at maximum number of treatments treatments at 220 mg/m2, 3 completed all therapy and 5 discontinued treatment after 1, 2, 13, 15, or 15 doses due to patient refusal, progressive debility or progression of disease. Despite anti-emetic precautions, most patients experienced Grade I-II nausea and vomiting. As with single dose administration, recurrent, migratory muscle cramps were common after Tirapazamine administration but seemed to decrease in frequency and severity with repeated drug exposure. Other, infrequent complaints that potentially related to the drug included transient diarrhea, generalized weakness, headache, sensing an unpleasant odor during drug infusion, mild, transient changes in auditory acuity, and phlebitis above the injection site. As is typical in phase I toxicity trials, responses have been difficult to assess. Favorable outcomes were observed in 2 patients who had no measurable disease prior to therapy remain disease-free 7 months and 17 months after post-operative treatment of a sarcoma in a previously irradiated field (220 mg/m2 x 18) and prostatic cancer with para-aortic node involvement (220 mg/m2 x 6), 1 patient with Stage IV squamous head and neck cancer of unknown primary and a 10 x 10 cm nodal mass who remains free of disease (220 mg/m2 x 6), and 1 patient with a durable partial response of a cardiac sarcoma after 45 Gy (220mg/m2 x 12). Conclusions: Tirapazamine remains a promising agent for approaching tumors with resistance to treatment due to cellular hypoxia with irradiation and/or cis-platin. Although objective signs of toxicity were few, the development of generalized malaise, fatigue, and recurrent nausea limited patient acceptance of more than 12 doses of Tirapazamine over 6 weeks. Tirapazamine did not appear to enhance normal tissue reactions to irradiation except in the esophagus, where Grade III reactions were observed during mediastinal irradiation with two, biweekly doses at 330 mg/m2 or 11 doses at 220 mg/m2 given twice weekly. Phase II studies have been initiated in malignant gliomas and advanced head and neck cancer, and the feasibility of oral administration is now under evaluation