National Editor

Having completed its $236 million stock-swap merger with Novuspharma SpA in January, Cell Therapeutics Inc. now said the FDA has cleared the way for the company to start a randomized, pivotal trial of Pixantrone, the anthracycline for non-Hodgkin's lymphoma gained in the deal.

Protocol and supporting data for the planned, 320-patient trial are in the final stages of review, and CTI said it expects to start the year-long study later this month.

"The primary endpoint is going to be basically durable responses, with basically [complete response, or CR] as the key," said Jack Singer, chief medical officer and founder of Seattle-based CTI.

To be evaluated along with CR are time to tumor progression and overall survival of patients with aggressive NHL who have failed front-line and at least one second-line multiagent chemotherapy regimen. Patients will be randomized to get either Pixantrone or another currently used single-agent drug of the physician's choice.

"Actually, none of them work," Singer said. "There's no approved drug in this space. What we did, as the agency suggested, is go through the literature and find everything we could at least justify from published, peer-review studies. Nothing is out there with a durable response rate of more than about 5 [percent] to 10 percent."

Pixantrone would qualify for accelerated approval based upon the successful conclusion of the trial and supporting data from ongoing as well as completed clinical studies, the FDA told CTI.

The trouble with current single-agent therapies for refractory NHL is that they work for a short time - only about three months - and only in about 10 percent to 15 percent of patients. Complete responses, considered the gold standard, rarely are reported.

What's more, the potent anthracyclines tend to cause heart damage when used as front-line, single-agent therapy, which leaves the patients unable to continue the drugs and without further options.

In a CTI Phase I/II study with Pixantrone in 36 relapsed or refractory NHL patients, though, 33 percent (12 patients) had significant tumor shrinkage and 20 percent (seven patients) had a complete disappearance of their cancers. Responses lasted a median of more than 11 months, and the regimen was generally well tolerated, though myelosuppression caused some dosing to be delayed or omitted.

Pixantrone is "significantly less toxic" than other anthracyclines at doses that are at least equivalent for efficacy, Singer said, estimating the drug is about 10 percent as toxic as others in the class.

Thus another boon, he said. Pixantrone can be administered in the ordinary intravenous way, rather than through a central line, which is a specialized form of IV that goes into a larger vein.

"I don't think you can overemphasize this," he said, noting that the central route often causes tissue necrosis, leading to a miserable patient and "an immediate lawsuit for the doc."

The design for the Pixantrone pivotal trial was supported by Phase I/II results from about 170 Pixantrone-treated patients in all, from "four or five different studies," Singer said.

When the subject of NHL arises, many think first of Rituxan (rituximab), from South San Francisco-based Genentech Inc. and Idec Pharmaceuticals Inc., of San Diego, (now Biogen Idec).

"Rituxan as a single agent really doesn't have a great role in late-stage aggressive [NHL]," Singer said. "Where people have been putting it, and - it's still a little controversial - is with CHOP up front." The CHOP chemotherapy regimen includes cyclophosphamide, adriamycin, vincristine and prednisone.

He noted that, by the time patients are qualified for the Pixantrone trial, they have failed at least two multiagent standard therapies.

"They'll probably have Rituxan in one of those, at least in the U.S.," he said. "It can't be the single agent in the comparator arm," though hardly any physicians would be likely to choose it in that setting anyway, he added.

Last summer, CTI said it was merging with Milan, Italy-based Novuspharma, gaining not only another drug, but also $120 million cash in the transaction, which closed in January. (See BioWorld Today, June 18, 2003.)

Also in late-stage development is the drug CTI brought to the deal - Xyotax, which is the subject of several Phase III non-small-cell lung cancer trials, and aimed for a Phase III trial in front-line ovarian cancer. Xyotax is the chemotherapeutic agent paclitaxel (sold as Taxol), linked to a polyglutamate chain for improved delivery of the active ingredient to the tumor site.

"We've completed accrual on the first [NSCLC] trial," with an analysis due by late fall, Singer said. The second trial is on track to complete enrollment by the end of the quarter, and the third study is "more than half accrued," and probably will finish "within the first half of the year," he said.

Often overlooked in CTI's toolbox, Singer said, is Trisenox (arsenic trioxide) for leukemia, launched in the U.S. in 2000 and in Europe in 2002.

The company recently won a notice of allowance from the U.S. Patent Office that protects the compound through 2018.

"This really changes our perspective on this drug quite a bit," Singer told BioWorld Today. "We thought we were going to lose it in 2007 and really didn't want to invest too much in it. We're starting to rethink this, because we think it's going to be a very impressive drug."

A paper is due to be published in the Proceedings of the National Academy of Sciences shortly, he said.

"We're starting to get some very nice data in myeloma and myelodysplasia" with Trisenox, he said, citing "bunches of Phase IIs."

The star in multiple myeloma lately is Velcade (bortezomib), the proteasome inhibitor from Cambridge, Mass.-based Millennium Pharmaceuticals Inc.

"If you look at [Trisenox] and compare it to Velcade, our response rates are pretty similar," thanks to the use of ascorbic acid, Singer said. "The toxicity [with Trisenox] is probably less. I think this is going to be a player going forward."