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.