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Missed endpoints in two Phase III trials? No problem - Pharmacyclics Inc. submitted its new drug application for the cancer drug Xcytrin based on pooled data from the pair of studies testing the compound in patients with non-small-cell lung cancer metastasized to the brain.

Scientists in June cheered the full Phase III data set at the American Society of Clinical Oncology meeting, where Pharmacyclics' abstract was named among the "Best of ASCO." Wall Street added 4 cents Friday to the company's stock (NASDAQ:PCYC), which closed at $4.89. That's still a dollar below the level shares had reached a year ago, after Xcytrin underwent its second Phase III failure, a near miss. (See BioWorld Today, Dec. 20, 2005.)

Xcytrin (motexafin gadolinium) inhibits the enzyme thioredoxin reductase, which Pharmacyclics' president and CEO Richard Miller called "the symphony conductor in your cell with regard to managing oxidative stress."

The randomized, controlled Phase III trial, called SMART (Study of Neurologic Progression with Motexafin Gadolinium and Radiation Therapy), compared the safety and efficacy of whole-brain radiation therapy alone to WBRT plus Xcytrin, and enrolled 554 patients from 94 centers in North America, Australia and Europe. A blinded-events review committee determined the primary endpoint of time to neurologic progression (TNP).

Pharmacyclics had to design a novel endpoint that had never been used in cancer trials. "We've set the standard in neural oncology by what we did," Miller said. "We've opened up that field." Factors such as mental status, balance, speech, visual problems, paralysis and memory were measured.

Top-line results from the SMART trial showed a median TNP of 15.4 months for patients in the Xcytrin group compared to 10 months for those treated with WBRT alone (p=0.122, hazard ratio=0.78). Xcytrin also failed to show a significant difference in survival, a secondary endpoint.

But the data were compelling enough to look closer.

"We noticed right away that there were good and consistent results all over, except for a couple of centers in France," Miller said. "Rather than use radiation to the head promptly, we had centers in France where patients [went] months before they got randomized on our protocol. That's not standard practice, and in fact would be considered malpractice here."

Those centers gave patients more chemotherapy instead of radiation, "sometimes even a third or fourth line," even though it's known not to work very well against brain metastases.

The Phase III trial four years earlier in varied types of cancer that spread to the brain had used co-primary efficacy endpoints of survival and time to neurologic progression. The data showed median survival to be 5.2 months for all patients treated with Xcytrin plus radiation therapy, compared to 4.9 months for control patients receiving just radiation. Median time to neurologic progression for all patients treated with Xcytrin plus radiation therapy was 9.5 months, compared to 8.3 months for those patients receiving radiation alone. (See BioWorld Today, Dec. 17, 2001.)

The protocol for the trial analysis included examining patient subgroups based on cancer types and the extent of the disease. In lung cancer patients - the largest subgroup, 251 - neurologic progression was significantly improved in patients receiving Xcytrin, which is why the second Phase III trial focused on them.

In total, 805 patients with brain metastases from NSCLC have been treated in randomized clinical trials comparing Xcytrin plus whole-brain radiation therapy to WBRT alone. The median time to neurologic progression for the Xcytrin-treated patients was 15.4 months vs. 9.0 months for patients receiving only WBRT (p=0.016). Data were presented in November at the Society for Neuro-Oncology meeting in Orlando, Fla.

"We have a disease that nobody's ever done any kind of trial on, yet 90,000 people per year are affected," Miller said, and the number is increasing as lung-cancer patients live longer.

Regular contact with the FDA helped Sunnyvale, Calif.-based Pharmacyclics put together the NDA. "They met with us fairly often in the last several months," he said. "They spent the time and gave us a lot of good advice. They told us not to do certain things, like no subsets, so we're not [including] subsets."

The big question, of course, is whether the FDA will want another trial. "I don't anticipate doing that," Miller told BioWorld Today. While the NDA is undergoing review, Pharmacyclics is testing Xcytrin in other cancer types.

"It was intuitively obvious we would move it into systemic therapy of lung cancer," which the firm has done, with Phase II studies as a combination therapy and alone. Other indications include non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

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