Washington Editor

Cell Therapeutics Inc. continues to move forward with a new direction for Xyotax (paclitaxel poliglumex) by beginning a confirmatory, female-only pivotal study of the experimental cancer drug for non-small-cell lung cancer.

"We knew there was a difference in how women handled the drug vs. men," President and CEO James Bianco told BioWorld Today. "And we now understand much more accurately what that basis is and how that can actually be translated into a survival advantage."

In recent months, the Seattle company has disclosed plans to push what Bianco called its "biologically enhanced cytotoxic therapy" into the FDA review phase for a certain subset of female patients, and the study underscores that strategy. (See BioWorld Today, Aug. 25, 2005.)

The trial, called PIONEER 1, will compare Xyotax to paclitaxel in 600 poor performance status patients who haven't had chemotherapy but do have an advanced stage of the disease. Its enrollment period will continue over the next 12 to 14 months, with recruitment in the U.S., Eastern Europe and Latin America. Superior overall survival is the primary endpoint, with several secondary endpoints measuring disease control, response rate in patients with measurable disease, time to disease progression and disease-related symptoms.

The study's design speaks to the role of estrogen in the development and progression of lung cancer, especially given the growing number of diagnoses among women, including nonsmokers. Many of them are diagnosed at younger ages than men and end up with different outcomes.

"It's very exciting that we're exploiting a risk factor," Bianco said, referring to the presence of estrogen's receptor on tumors and the hormone itself. "So if you can exploit something that is a poor risk factor and turn it around and essentially make it an advantage because of the way you're using the biology of a new drug - it's amazing how quickly the clinical community has rallied behind this."

Recently reported studies seem to support the idea that Xyotax-treated women have an enhanced survival benefit compared to standard chemotherapy.

Data reported at Chemotherapy Foundation Symposium XXIII in New York showed that exposure of lung cancer cells to estrogen increased the gene expression of cathepsin B, an estrogen-dependent enzyme that metabolizes Xyotax to release active paclitaxel within the tumor cell. That finding suggested that patients with normal estrogen levels might benefit best because of estrogen's favorable effect on the drug's metabolism.

Other data stemmed from a pooled analysis of previous pivotal trials of Xyotax, STELLAR 3 and 4, and found superior survival in the 198 women treated with the drug in those trials (p=0.03). Pre-stratified on gender lines, STELLAR 3 compared the combination of Xyotax and paclitaxel to paclitaxel and carboplatin, and STELLAR 4 compared Xyotax vs. gemcitabine and vinorelbine. Both were front-line studies.

The most notable impact was among those younger than 55 and presumably pre-menopausal, who, when treated with Xyotax, had a median survival of 10 months, nearly double those on standard chemotherapy (p=0.038). While a survival trend was observed in post-menopausal women 55 and older (p=0.134), the greater benefit observed among younger women is supportive of a positive impact of estrogen in Xyotax patients.

Further support for that was observed in STELLAR 3, where blood estrogen levels were retrospectively analyzed. Women with higher estrogen levels, regardless of age, who were treated with Xyotax in combination with carboplatin had a 10.2-month median overall survival, compared to 5.5 months for women treated with paclitaxel and carboplatin (p=0.039).

"We think that the data in the STELLAR 3 and STELLAR 4 trials, for women, are important enough that they warrant a review from the FDA," Bianco said, adding that the company expects to begin submitting a new drug application early in the second half of next year. Looking a bit further, interim PIONEER 1 findings could be available about a year later as a supplement.

That could prove helpful in clearing hurdles along the regulatory route due to the potentially less enticing full data set from STELLAR 3 and 4, two of the three Phase III studies in which Xyotax missed its primary endpoint of improved performance over chemotherapy, although the efficacy was equivalent. But Xyotax exhibited a more favorable side-effect profile compared to its controls, with better ease of use, fewer hematopoetic issues and no hair loss. (See BioWorld Today, March 8, 2005, and May 3, 2005.)

"Essentially, you can look at this being very robust Phase II data," Bianco conceded. "Clearly it wasn't the intent of the trials to be Phase IIs, but they taught us a lot about the biology differences to exploit for future studies."

With a narrow label, Xyotax could enter a market with 70,000 American women with poor performance status and late-stage disease. Looking more broadly, Cell Therapeutics has its sights set on estrogen receptor-positive tumors such as prostate cancer, colon and breast cancers. Therefore, Bianco said PIONEER 1 represents the proverbial "tip of the iceberg" as it sets out to establish survival in a difficult-to-treat patient population and "underscore the importance of the science behind the product and its applicability to a much larger set of indications."

Studies in some of those additional areas already are under way, including trials of Xyotax in ovarian, prostate and breast cancers.

On Tuesday, Cell Therapeutics' shares (NASDAQ:CTIC) gained 6 cents to close at $2.35.