A phase Ib study to evaluate repeated daily intravenous doses of RSR13 administered to cancer patients receiving concurrent radiation therapy

Purpose: In animal models RSR13, a synthetic allosteric modifier of hemoglobin (Hb), oxygenates and thus radiosensitizes hypoxic solid tumors by decreasing the oxygen (O2) affinity of Hb. A phase Ib open label, multi-center dose-frequency escalation study was conducted to evaluate the safety, tolerance, pharmacokinetics, and pharmacodynamics of repeated daily intravenous (IV) infusions of RSR13 administered to cancer patients receiving palliative radiation therapy (RT). Methods and Materials: The RSR13 dose in the first patient cohort was 75 mg/kg once per week during the first two weeks of RT; successive cohorts received higher and more frequent doses up to 100 mg/kg/day for 10 days during the first two weeks of RT. RSR13 was administered IV via central vein over 60 minutes immediately prior to RT. Patients were given supplemental O2 via nasal cannula at a rate of 4L/min during drug infusion and radiation treatment. Plasma, RBC, and urine drug concentrations were assayed following treatment. The rightward shift of the whole blood Hb-O2 equilibrium curve was quantified ex-vivo by multi-point tonometry, from which the partial O2 pressure required for 50% Hb saturation, the p50, was calculated. Non-invasive cutaneous pulse oximetry was used to monitor arterial O2 saturation during and after RSR13 administration. The targeted pharmacodynamic endpoint was an increase in p50 of 10 mmHg. Results: Seventeen patients have been enrolled in the study. In general, repeated daily doses of RSR13 were well tolerated in this patient population. Two adverse events of note occurred: (1) a patient with pre-existing restrictive lung disease had persistent hypoxemia after the sixth RSR13 dose and required two days of hospitalization and O2 administration; (2) a patient with a recurrent glioma receiving high dose corticosteroids had fluid retention and presumed cerebral edema after the seventh RSR13 dose, suspected to result from the repeated daily high volume fluid infusions. Both individuals recovered to baseline status with conservative management. One patient had a transient NCI grade 2 elevation of serum creatinine after the fifth dose of RSR13. The drug is primarily renally cleared, with a half-life in RBCs ranging from 3.2-8.3 hours. For individual patients the increase in p50 varied proportionally with RBC concentration. After 100 mg/kg the peak increase in p50 (mean +/- s.d.) was 8.43 +/-0.64 mmHg, achieved while maintaining arterial O2 saturation greater than 90% by means of the supplemental O2 administration. Conclusions: RSR13 was well tolerated at multiple doses up to 100 mg/kg/day administered for 10 days during two weeks of RT. The combination of RSR13 with low flow supplemental O2 yielded pharmacodynamic conditions in which the radiosensitization of hypoxic solid tumors would be predicted. Subsequent clinical studies will evaluate whether RSR13 improves tumor control in selected patient populations receiving RT