Pharmacyclics is stepping back up to the plate for a second Phase III trial of its cancer therapy candidate. The company began its pivotal Phase III trial of Xcytrin injection to treat lung cancer patients with brain metastases - lung cancer that has spread to the brain from another part of the body.

The randomized, controlled study, named the SMART (Study of Neurologic Progression with Motexafin Gadolinium And Radiation Therapy) trial, is designed to enroll 550 patients at more than 100 U.S., Canadian, European and Australian medical centers. It follows an earlier large, randomized Phase III study, which missed its primary endpoints but demonstrated Xcytrin (motexafin gadolinium), when added to whole-brain radiation therapy, significantly prolonged time to neurologic progression and decreased deaths due to brain tumor progression in lung cancer patients. The pivotal trial, designed to confirm observations from the original Phase III study, was first discussed in the spring. (See BioWorld Today, April 17, 2002.)

"When we started the last trial, we didn't anticipate that we'd have to do another," Pharmacyclics President and CEO Richard Miller told BioWorld Today. "But with the results that we found, we have made some changes in the design and eligibility that give us a lot of confidence in this trial."

Almost a year ago, Sunnyvale, Calif.-based Pharmacyclics reported that though Xcytrin had missed its co-primary endpoints in the first Phase III trial, it showed promise in the 251 patients with lung cancer (the most common cause of brain metastasis), as compared to 75 with breast cancer and 75 with other cancers. (See BioWorld Today, Jan. 9, 2002.)

"Two-thirds of the patients had lung cancer, and we saw this substantial benefit consistently using several different criteria," Miller said, pointing to similar results from an unrelated study carried out by the Radiation Therapy Oncology Group, a consortium of radiation centers.

Based on such findings, the new trial will compare the effects of whole-brain radiation therapy alone to combination therapy with Xcytrin in lung cancer patients. The primary efficacy endpoint will measure time to neurologic progression. Pharmacyclics said the study should show that lung cancer patients with CNS metastases are more amenable to treatments aimed at delaying neurologic progression.

"By focusing on the lung cancer group of patients, we improve our chances of showing a quantitative benefit," Miller said. "Our drug probably is working in other cancers as well, it's just that you can show more significant differences in these lung cancer patients because they're not so severely impaired by having a lot of cancer outside of the brain."

The trial's secondary endpoints include survival and neurocognitive function after treatment with Xcytrin, the first of a new class of drugs called texaphyrins that selectively accumulate in cancer and other diseased cells to disrupt cellular metabolism. The small molecule is paramagnetic, and when localized in cancer cells, enhances an MRI signal, which can be used to image the tumor.

Pharmacyclics continues to study the drug in other indications. It finished Phase I and Phase II trials of Xcytrin for glioblastoma multiforme (primary brain tumors), with plans for more trials in that indication. A Phase I trial is ongoing to investigate the drug's potential for enhancing chemotherapy in advanced cancer.

The National Cancer Institute, a unit of the National Institutes of Health in Bethesda, Md., is sponsoring trials under a Cooperative Research and Development Agreement to study Xcytrin to treat non-small-cell lung cancer, glioblastoma multiforme, childhood gliomas and pancreatic cancer.

"We have several other trials looking at Xcytrin in other cancers," Miller said. "If you show clinical benefit in one trial, certainly it generates enthusiasm for doing other studies. So typically with oncology drugs you get an approval for one kind of cancer or indication, and then very rapidly physicians and investigators begin to test its utility in other diseases.

"There are very few drugs in oncology that have broad applications throughout many tumor types, but Xcytrin is one such possibility," Miller said.

Pharmacyclics' stock (NASDAQ:PCYC) fell 6 cents Thursday to close at $3.30.