A Phase I study of RSR13, a radiation-enhancing hemoglobin modifier: Tolerance of repeated intravenous doses and correlation of pharmacokinetics withpharmacodynamics

Purpose: Preclinical studies indicate that RSR13 oxygenates and radiosensit izes hypoxic solid tumors by decreasing the oxygen (O-2)-binding affinity o f hemoglobin (Hb), A Phase I open-label, multicenter dose and frequency esc alation study was conducted to assess the safety, tolerance, pharmacokineti cs, and pharmacodynamic effect of daily RSR13 administration to cancer pati ents receiving concurrent palliative radiotherapy (RT), Methods and Materials: Eligibility criteria included the following: ECOG pe rformance status less than or equal to2; resting and exercise arterial oxyg en saturation (SaO(2)) greater than or equal to 90%; an indication for pall iative RT, 20-40 Gy in 10-15 fractions, RSR13 was administered i.v. via cen tral vein over 60 min immediately before RT. Patients received supplemental O-2 via nasal cannula at 4 L/min during RSR13 infusion and RT, Plasma, red blood cell (RBC), and urine RSR13 concentrations were assayed, The pharmac odynamic effect of RSR13 on Hb-O-2 binding affinity was quantified by multi point tonometry and expressed as an increase in p50, defined as the partial pressure of O-2 that results in 50% SaO(2), The RSR13 dose in the first co hort was 75 mg/kg once a week for two doses; successive cohorts received hi gher, more frequent doses up to 100 mg/kg/day for 10 days during RT, Results: Twenty patients were enrolled in the study. Repeated daily doses o f RSR13 were generally well tolerated. Two adverse events of note occurred: (I) A patient with pre-existing restrictive lung disease had transient per sistent hypoxemia after the sixth RSR13 dose; (2) a patient with a recurren t glioma receiving high-dose corticosteroids had edema after the seventh RS R13 dose, likely due to the daily high-volume fluid infusions. Both patient s recovered to baseline status with conservative management. Maximum pharma codynamic effect occurred at the end of RSR13 infusion and was proportional to the RBC RSR13 concentration. After an RSR13 dose of 100 mg/kg, the peak increase in p50 averaged 8.1 mm Hg, consistent with the targeted physiolog ic effect, and then diminished with a half-life of approximately 5 h, Conclusions: RSR13 was well tolerated in daily doses up to 100 mg/kg admini stered for 10 days during RT, The combined administration of RSR13 with 4 L /min supplemental O-2 yielded pharmacodynamic conditions in which hypoxic t umor radiosensitization can occur. Ongoing Phase II and Phase III studies a re evaluating the combination of RT and RSR13 for selected indications, inc luding primary brain tumors, brain metastases, and non-small-cell lung canc er. (C) 2001 Elsevier Science Inc.