Kavanagh B D, Khandelwal S R, Schmidt-Ullrich R K, Roberts J D, Shaw E G, Pearlman A D, Venitz J, Dusenbery K E, Abraham D J, Gerber M J
Department of Radiation Oncology, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA 23298-0058, USA.
Int J Radiat Oncol Biol Phys. 2001 Mar 15;49(4):1133-9. doi: 10.1016/s0360-3016(00)01532-7.
Preclinical studies indicate that RSR13 oxygenates and radiosensitizes hypoxic solid tumors by decreasing the oxygen (O(2))-binding affinity of hemoglobin (Hb). A Phase I open-label, multicenter dose and frequency escalation study was conducted to assess the safety, tolerance, pharmacokinetics, and pharmacodynamic effect of daily RSR13 administration to cancer patients receiving concurrent palliative radiotherapy (RT).
Eligibility criteria included the following: ECOG performance status < or =2; resting and exercise arterial oxygen saturation (SaO(2)) > or =90%; an indication for palliative RT, 20-40 Gy in 10-15 fractions. RSR13 was administered i.v. via central 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 pharmacodynamic effect of RSR13 on Hb-O(2) binding affinity was quantified by multipoint 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 cohort was 75 mg/kg once a week for two doses; successive cohorts received higher, more frequent doses up to 100 mg/kg/day for 10 days during RT.
Twenty patients were enrolled in the study. Repeated daily doses of RSR13 were generally well tolerated. Two adverse events of note occurred: (1) A patient with pre-existing restrictive lung disease had transient persistent hypoxemia after the sixth RSR13 dose; (2) a patient with a recurrent glioma receiving high-dose corticosteroids had edema after the seventh RSR13 dose, likely due to the daily high-volume fluid infusions. Both patients recovered to baseline status with conservative management. Maximum pharmacodynamic 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 physiologic effect, and then diminished with a half-life of approximately 5 h.
RSR13 was well tolerated in daily doses up to 100 mg/kg administered for 10 days during RT. The combined administration of RSR13 with 4 L/min supplemental O(2) yielded pharmacodynamic conditions in which hypoxic tumor radiosensitization can occur. Ongoing Phase II and Phase III studies are evaluating the combination of RT and RSR13 for selected indications, including primary brain tumors, brain metastases, and non-small-cell lung cancer.
临床前研究表明，RSR13可通过降低血红蛋白（Hb）与氧（O₂）的结合亲和力，使缺氧实体瘤发生氧合作用并产生放射增敏效果。开展了一项I期开放标签、多中心剂量及给药频率递增研究，以评估每日给予接受姑息性同步放疗（RT）的癌症患者RSR13的安全性、耐受性、药代动力学及药效学效应。
入选标准包括：东部肿瘤协作组（ECOG）体能状态≤2；静息及运动时动脉血氧饱和度（SaO₂）≥90%；有姑息性RT指征，10 - 15次分割照射，剂量为20 - 40 Gy。在RT前60分钟经中心静脉静脉注射RSR13。在输注RSR13及RT期间，患者通过鼻导管以4 L/分钟的速度接受补充氧气。检测血浆、红细胞（RBC）及尿液中RSR13的浓度。通过多点张力测定法定量RSR13对Hb - O₂结合亲和力的药效学效应，并以p50的增加来表示，p50定义为导致50% SaO₂的氧分压。第一组的RSR13剂量为75 mg/kg，每周一次，共两剂；后续组接受更高、更频繁的剂量，在RT期间高达100 mg/kg/天，共10天。
20名患者入组该研究。每日重复给予RSR13总体耐受性良好。发生了两起值得注意的不良事件：（1）一名患有既往限制性肺病的患者在第6剂RSR13后出现短暂持续性低氧血症；（2）一名接受高剂量皮质类固醇治疗的复发性神经胶质瘤患者在第7剂RSR13后出现水肿，可能是由于每日大量液体输注所致。两名患者经保守治疗后恢复至基线状态。最大药效学效应出现在RSR13输注结束时，且与RBC中RSR13浓度成正比。给予100 mg/kg的RSR13剂量后，p50的峰值平均增加8.1 mmHg，与目标生理效应一致，随后以约5小时的半衰期下降。
在RT期间每日给予高达100 mg/kg剂量的RSR13耐受性良好。RSR13与4 L/分钟补充氧气联合给药产生了可使缺氧肿瘤发生放射增敏的药效学条件。正在进行的II期和III期研究正在评估RT与RSR13联合用于特定适应症，包括原发性脑肿瘤、脑转移瘤和非小细胞肺癌。
