Washington Editor

Spectrum Pharmaceuticals Inc. and the FDA have agreed on the design of a pair of Phase III trials of EOquin (apaziquone), an investigational drug for superficial or non-invasive bladder cancer.

The pivotal program is intended to position the chemotherapy product as part of a front-line regimen with surgery known as transurethral resection, the current standard treatment for the disease, a cancer that has invaded the inner most lining of the bladder. Superficial bladder cancer isn't quickly lethal, but it is marked by frequent recurrences, so the need for regular surgical procedures in which physicians scrape away the bladder's mucus membrane lining is an expensive proposition.

"Because these patients do not die of bladder cancer, they in fact have to keep coming back to the doctor," said Spectrum Chairman, President and CEO Rajesh Shrotriya. He noted that transurethral resection itself is part of the reason for superficial bladder cancer's regular recurrence because the procedure isn't fully effective at eradicating every last tumor cell.

"Each successive time, the time to relapse is shorter and shorter and shorter, No. 1, and No. 2, the bladder wall gets thinner and thinner, and therefore the chances of perforation become quite common."

Hence, there's a need for a more extensive treatment to extend outcomes, but there is no FDA-approved therapy.

"There is a body of data that's published that shows if you clear the cancer completely, chances are it will not come back that quickly," Shrotriya told BioWorld Today.

The special protocol assessment agreement calls for two double-blinded studies that each include 562 patients with Ta G1 G2 non-invasive bladder cancer, the most prevalent type of the disease. Most will be newly diagnosed, or have had only one or two recurrences, and they will be randomized to receive either 4 mg of EOquin or placebo, which will be delivered intravesically into their bladder after surgery and left there for an hour. Patients will be evaluated thereafter every three months, and to achieve the primary endpoint, EOquin must demonstrate a statistically significant difference in the rate of tumor recurrence by year two compared to placebo.

Such data are intended to serve as the basis for an efficacy claim in support of an eventual new drug application. The company, of Irvine, Calif., expects to begin enrollment next quarter, so findings could be available in 2009 or 2010. Spectrum will conduct the study at sites across the U.S., and might also include facilities in Canada and Europe to increase enrollment.

Previous efficacy data from a Phase II trial in Europe showed that EOquin produced complete responses in 67 percent of patients, many of whom had been treated multiple times, and the drug was well tolerated in the study. This compares favorably with published data on prophylactic use of mitomycin, a cytotoxic cancer therapeutic that produces complete response rates between 30 percent and 40 percent, Shrotriya said, though the average duration of EOquin-generated complete responses is not yet known. Other Phase II data further demonstrated its safety profile, showing that it was not absorbed in any detectable amount from the bladder wall into the bloodstream.

"The drug is extremely well tolerated," Shrotriya said, "it doesn't get absorbed from the bladder into the general systemic circulation, and thirdly, the response rates are pretty high."

Bladder tumor cells have high levels of the enzyme DT-diaphorase, an enzyme that activates EOquin, essentially flipping a switch to turn on the alkylating agent. A bioreductive prodrug, it's an analog of mitomycin.

Shrotriya said bladder cancer strikes about 62,000 new patients in the U.S. each year, and at any given time more than 400,000 Americans have the diagnosis. Those figures are about three times higher in Europe. Superficial forms of bladder cancer represent about 80 percent of new cases.

When the disease advances and invades the bladder's muscle wall, it can quickly spread throughout a patient's body. Those with this later stage of bladder cancer are often treated with bacillus Calmette-Guerin (BCG), which causes a host of dangerous side effects, and mitomycin.

The company, which has a worldwide license to EOquin from the University of Amsterdam, plans to hold onto its U.S. rights but seek out-licensing partners for territories abroad. The Phase III studies are also expected to support overseas filings.

The rapid progression of EOquin into this pivotal program is representative of a quick evolution at Spectrum, which as recently as several years ago had negative working capital and was on the verge of losing its stock listing. That's when Shrotriya arrived and restructured the business, and "fast-forward three or four years later and we have some 10 drugs in development, and several of them in late stages," he said. "They could be on the market very soon."

Atop that list is the prostate cancer drug satraplatin, which could get FDA approval later this year. Its new drug application was completed last month, with a request for a priority review, and a European application is planned for June. Satraplatin is partnered with GPC Biotech AG, of Martinsried, Germany.

In addition, Phase IIb data are due this summer on ozarelix, a fourth-generation luteinizing hormone-releasing hormone antagonist for benign prostate hypertrophy. Further development of EOquin will focus on using it as a radiation sensitizer in cancers that overexpress DT-diaphorase, such as lung cancer.

On Tuesday, Spectrum's stock (NASDAQ:SPPI) dipped 15 cents to close at $5.74.

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