Cell Therapeutics Inc. lost almost half of its value Monday, following news that Xyotax missed the primary endpoint in its Stellar 3 pivotal trial in non-small-cell lung cancer patients.
The stock (NASDAQ:CTIC) dropped 47.5 percent, or $4.75, to close at $5.25.
While the Seattle-based company stayed positive - stressing that Xyotax has fewer side effects than paclitaxel - the fact remained that the product, in combination with carboplatin, showed only an equivalent survival efficacy to paclitaxel used with carboplatin.
"While on the surface this is obviously somewhat disappointing," said James Bianco, CTI's president and CEO, "given what we are learning from the unblinding of Stellar 3, we believe that Xyotax can be an approvable alternative to paclitaxel."
The company had planned on filing for approval in the third quarter with a launch expected in early 2006. Bianco told BioWorld Today that the news will delay a filing by only a month or two. The company intends to disclose complete results from Stellar 3 at the American Society of Clinical Oncology meeting in mid-May.
As for "the silver lining," Bianco said, "people are going to have to wait for ASCO to see that. Xyotax did for the most part what we thought it was going to do, except it fell short on the primary endpoint."
Stellar 3 was studying carboplatin in combination with either Xyotax or paclitaxel as a front-line treatment of poor performance status (PS2) patients with NSCLC. The trial sought a 30 percent improvement in average survival rates.
The multicenter, randomized, controlled Phase III study met statistical significance for non-inferiority of survival, compared to paclitaxel in combination with carboplatin.
Patients receiving the Xyotax combination also had significantly less hair loss and a reduction in other side effects, such as muscle and joint pain, cardiac symptoms, and an overall reduction in neurologic toxicities, compared with patients who received the standard paclitaxel and carboplatin regimen.
In addition, an intent-to-treat analysis, which was pre-specified in the protocol's statistical analysis plan, uncovered some positive findings.
By putting risk factors, such as LDH (a marker of tumor aggressiveness), weight loss and calcium levels, into the equation, "the single most important and highly statistically significant determinant of survival," Bianco said, "was whether or not a patient receives Xyotax treatment instead of paclitaxel."
The trial wasn't a homerun, he said, "but it clearly was a strong base hit. And we have two other times at bat."
Another trial, Stellar 2, is testing Xyotax vs. docetaxel as second-line treatment of NSCLC patients, while Stellar 4 is focused on Xyotax vs. either gemcitabine or vinorelbine for front-line treatment of PS2 patients with NSCLC. Results from Stellar 2 are expected in April and will be followed by results from Stellar 4.
"If the endpoint for Stellar 2 is successful, then Stellar 3 and 2 would be the first two studies to be submitted," Bianco said.
In Stellar 3, patients received the Xyotax regimen in a 10-minute infusion. When used with carboplatin, the infusion time was about 45 minutes, compared with four hours for patients receiving the standard paclitaxel and carboplatin regimen.
While steroids and other premedications were not used, hypersensitivity reactions were rare in the Xyotax combination arm. The study compared Xyotax (210 mg/m2) in combination with carboplatin to paclitaxel (225 mg/m2) with carboplatin every three weeks for up to six cycles of therapy in 400 patients.
Xyotax (paclitaxel poliglumex) links paclitaxel to a biodegradable polyglutamate polymer, enabling the delivery of higher and more effective levels of active chemotherapeutics to tumors. Blood vessels in tumor tissue are porous to molecules like polyglutamates.
Preclinical studies have indicated that Xyotax is preferentially trapped in the tumor blood vessels allowing more dose of chemotherapy to localize there, instead of in regions of normal tissue.
"The whole premise is that if you're able to give more of the drug with less toxicity, would that show up in a clinical study?" Bianco said. "And we saw that here" with Stellar 3.
CTI raised $42.8 million in July when it learned the Stellar 3 trial would take longer than expected. Although it completed enrollment in November 2003 and results were planned for as early as August, the company needed to reach 311 death events before analyzing the data. It reached the number of events in January. (See BioWorld Today, July 29, 2004.)
Likewise, CTI is waiting for Stellar 2 and Stellar 4 to reach their events before releasing any data. Those trials completed enrollment in July and May, respectively.
Xyotax is not partnered, but CTI has received interest in the product, whether it proves to have a benefit over paclitaxel, or whether it proves to be equivalent to paclitaxel, but with fewer side effects, Bianco said.
"We have always taken the position that we would wait to see the results of the trials," he said, "and then see what the commercial interest is."
Aside from studying Xyotax for NSCLC, CTI plans on beginning a Phase III study of the product this year in treating ovarian cancer.
CTI has one marketed product, Trisenox, approved in September 2000 to treat patients with relapsed or refractory acute promyelocytic leukemia. It gained European approval in March 2002. CTI recorded cumulative net product sales for Trisenox of about $66.8 million through Dec. 31.
The company started Phase III trials last year of Pixantrone to treat non-Hodgkin's lymphoma. Enrollment of 320 patients should be complete by the middle of the year. That product has fast-track designation.
As of Dec. 31, the company had about $116 million in cash and cash equivalents. CTI raised $18.5 million in a December private placement. (See BioWorld Today, Dec. 22, 2004.)