Drugs R D. 2004;5(1):52-7. doi: 10.2165/00126839-200405010-00012.
Motexafin gadolinium [gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120] is a radiosensitising agent developed for use in cancer therapy. It is cytotoxic in haematological malignancies by selectively localising in cancer cells that have high rates of metabolism. Motexafin gadolinium inhibits cellular respiration resulting in the production of reactive oxygen species and inducing apoptosis. It is being developed by Pharmacyclics in the US. Bulk motexafin gadolinium is supplied to Pharmacyclics by the US company, Celanese, through a manufacturing and supply agreement between the two companies. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), the importance of having an agent for the treatment of brain metastases from lung cancer was highlighted. Results of a phase III study were presented that showed that motexafin gadolinium treatment was associated with a delay in time to neurological and neurocognitive progression in lung cancer patients. This was an important finding, as 46.6% of lung cancer patients already have brain metastases at the time of initial diagnosis, compared with only 2.7% of breast cancer patients. Brain metastases are also often the only site of metastatic disease in patients with lung cancer. In December 2002, Pharmacyclics began a phase III trial of motexafin gadolinium in patients with brain metastases (brain cancer in phase table) from lung cancer in the US, Europe, Canada and Australia. The trial is known as the Study of neurologic progression with Motexafin gadolinium And Radiation Therapy (SMART) and will compare whole-brain irradiation with whole-brain irradiation plus motexafin gadolinium in 550 patients. The primary efficacy endpoint is time to neurological progression and the secondary endpoints are survival and neurocognitive function. In January 2003, the US FDA completed its Special Protocol Assessment (SPA) of the SMART trial with a positive result and by June 2003, enrollment had begun. In addition, phase I trials are underway in children with intrinsic pontine glioma and adults with head and neck, lung and pancreatic cancers. A phase II trial is also being conducted in the US in patients with glioblastoma multiforme. Enrollment in this trial has been completed and preliminary results have been reported. Pharmacyclics has completed enrollment and follow-up of adults in its pivotal phase III trial of motexafin gadolinium as a radiation sensitiser for the treatment of brain metastases. The trial was conducted at 35 centres in Europe, Canada and the US. Full results from this initial phase III trial were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Florida, USA, held in May 2002. Pharmacyclics also announced in October 2002, at the 44th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), that motexafin gadolinium significantly prolonged time to neurological progression when added to whole brain radiation therapy and reduced the number of deaths in patients with brain tumour. Pharmacyclics announced in September 2000 that it has initiated two NCI-sponsored phase I trials conducted under a Cooperative Research and Development Agreement (CRADA) between Pharmacyclics and the NCI. The first trial, conducted in patients with stage IIIA non-small cell lung cancer, was designed to determine the safety of two different dosing regimens of motexafin gadolinium during preoperative radiotherapy after induction chemotherapy. The second study was designed to examine the use of motexafin gadolinium in combination with stereotactic Gamma Knife radiosurgery in patients with primary glioblastoma mutiforme. Two phase I clinical trials have also been conducted for the treatment of newly diagnosed glioblastoma multiforme at the UCLA Jonsson Comprehensive Cancer Center, USA. These phase I studies were sponsored by the NCI and were conducted under a CRADA with the NCI. Pharmacyclics has also completed multicentre US phase II clinical trials of motexafin gadolinium fin gadolinium in patients with metastatic tumours of the brain who require whole brain radiotherapy. Motexafin gadolinium is in a phase II trial in patients with lymphomas and multiple myeloma in the US.
莫特沙芬钆[钆（III）替克卟啉、钆替克卟啉、Gd-Tex、GdT2B2、PCI 0120]是一种开发用于癌症治疗的放射增敏剂。它通过选择性地定位于代谢率高的癌细胞中，对血液系统恶性肿瘤具有细胞毒性。莫特沙芬钆抑制细胞呼吸，导致活性氧的产生并诱导细胞凋亡。它由美国的Pharmacyclics公司研发。美国塞拉尼斯公司通过与Pharmacyclics公司的生产和供应协议，向其供应莫特沙芬钆原料药。2003年6月，在美国临床肿瘤学会第39届年会上（ASCO-2003），强调了拥有一种治疗肺癌脑转移药物的重要性。一项III期研究的结果表明，莫特沙芬钆治疗与肺癌患者神经和神经认知进展时间的延迟有关。这是一项重要发现，因为46.6%的肺癌患者在初诊时已有脑转移，而乳腺癌患者仅为2.7%。脑转移也常常是肺癌患者转移性疾病的唯一部位。2002年12月，Pharmacyclics公司在美国、欧洲、加拿大和澳大利亚开始了一项针对肺癌脑转移患者（阶段表中的脑癌）的莫特沙芬钆III期试验。该试验称为莫特沙芬钆与放射治疗的神经进展研究（SMART），将在550名患者中比较全脑照射与全脑照射加莫特沙芬钆。主要疗效终点是神经进展时间，次要终点是生存期和神经认知功能。2003年1月，美国食品药品监督管理局完成了对SMART试验的特殊方案评估（SPA），结果为阳性，到2003年6月，已开始入组。此外，针对脑干神经胶质瘤患儿以及头颈部、肺癌和胰腺癌成年患者的I期试验正在进行。美国也正在对多形性胶质母细胞瘤患者进行II期试验。该试验的入组已经完成并报告了初步结果。Pharmacyclics公司已完成莫特沙芬钆作为放射增敏剂治疗脑转移的关键III期试验中成年患者的入组和随访。该试验在欧洲、加拿大和美国的3５个中心进行。2002年5月在美国佛罗里达州奥兰多举行的美国临床肿瘤学会年会上公布了该初始III期试验的完整结果。Pharmacyclics公司还在2002年10月于美国放射肿瘤学会第44届年会上宣布，莫特沙芬钆添加到全脑放射治疗中可显著延长神经进展时间，并减少脑肿瘤患者的死亡人数。Pharmacyclics公司在2000年9月宣布，它已启动两项由美国国立癌症研究所（NCI）赞助的I期试验，这些试验是根据Pharmacyclics公司与NCI之间的合作研究与开发协议（CRADA）进行的。第一项试验针对IIIA期非小细胞肺癌患者，旨在确定诱导化疗后术前放疗期间两种不同剂量方案的莫特沙芬钆的安全性。第二项研究旨在研究莫特沙芬钆与立体定向伽玛刀放射外科联合用于原发性多形性胶质母细胞瘤患者的情况。美国加州大学洛杉矶分校琼森综合癌症中心也针对新诊断的多形性胶质母细胞瘤进行了两项I期临床试验。这些I期研究由NCI赞助，并根据与NCI的CRADA进行。Pharmacyclics公司还完成了针对需要全脑放疗的脑转移瘤患者的莫特沙芬钆美国多中心II期临床试验。莫特沙芬钆在美国正处于针对淋巴瘤和多发性骨髓瘤患者的II期试验中。
