BioNumerik Pharmaceuticals Inc. started a pivotal Phase III trial comparing Karenitecin (BNP1350) with GlaxoSmithKline plc's Hycamtin (topotecan) in relapsed ovarian cancer.

Frederick Hausheer, chairman and CEO of San Antonio-based BioNumerik, said enrollment in the trial should be completed in the first or second quarter of 2009, with survival data available in the first half of 2010. The trial protocol was agreed to by the FDA under a special protocol assessment, so if it is successful, BioNumerik plans to file a new drug application.

The randomized, open-label trial will enroll about 500 advanced ovarian cancer patients who have failed first-line treatment with taxane and platinum-based chemotherapy drugs, such as paclitaxel and cisplatin. The emergence of resistance to those drugs is "one of the most important problems" in the treatment of ovarian cancer, Hausheer said. He estimated that about 80 percent of patients will initially respond to the drugs but later will relapse.

Relapsed patients have a variety of chemotherapy options, but Hausheer said there is "definitely room for improvement" in terms of both efficacy and side effects. The chemotherapies most often used to treat taxane/platinum-resistant ovarian cancer patients include Gemzar (gemcitabine, Eli Lilly & Co.), Doxil (doxorubicin, Johnson & Johnson or Hycamtin. Hycamtin generated $238 million in sales last year, and Hausheer said it is "probably less widely used" than the other two.

Yet BioNumerik chose Hycamtin for the comparator in its Phase III trial because it is "apples to apples," Hausheer explained. Both Karenitecin and Hycamtin belong to a class of chemotherapy drugs known as camptothecins, as does the colorectal cancer drug Camptosar (irinotecan, Pfizer Inc.). But while most camptothecins are formulated to be water soluble, Karenitecin is a fourth-generation, silicon-containing molecule specifically designed to be lipophilic, which BioNumerik believes could improve its efficacy, decrease side effects and lessen resistance.

In the Phase III trial, patients will receive either Karenitecin or Hycamtin daily for five days, in a cycle repeated every three weeks. The primary endpoint is progression-free survival, with secondary endpoints including overall survival and a reduction in anemia, neutropenia and thrombocytopenia.

BioNumerik designed its trial to show the superiority of Karenitecin to Hycamtin, rather than just noninferiority. The company's confidence comes from Phase II trials conducted in advanced ovarian cancer, metastatic malignant melanoma, advanced non-small-cell lung cancer and primary brain tumors.

In the combined Phase II trials, Hausheer said Karenitecin was associated with a 9 percent rate of anemia, a 25 percent rate of Grade 3/4 neutropenia, a 15 percent rate of Grade 3/4 thrombocytopenia and a 5 percent rate of diarrhea. According to its label, Hycamtin is associated with a 37 percent rate of severe anemia, a 78 percent rate of severe neutropenia, a 27 percent rate of severe thrombocytopenia and a 32 percent rate of diarrhea.

Time to progression in the Phase II Karenitecin trials was 4.6 months, while overall survival was 15 months. Hausheer noted that the trials involved heavily resistant patients, more than half of whom were refractory to treatment with Gemzar or Doxil in addition to taxane and platinum-based chemotherapy.

Hycamtin's approval in ovarian cancer was based on two trials in patients whose tumors had recurred or not responded to at least one platinum-based chemotherapy. Time to progression was 18.9 weeks (approx. 4.7 months) in one trial and 11.3 weeks (approx. 2.8 months) in the other, while overall survival was 63 weeks (approx. 15.75 months) in one trial and 67.9 weeks (approx. 17 months) in the other.

Hausheer also said that preclinical studies have shown Karenitecin to be "relatively insensitive" to BCR-mediated resistance, which he characterized as an important issue to camptothecins as a class.

After completing its Phase III trial comparing Karenitecin to Hycamtin, Hausheer said the company may consider a trial comparing Karenitecin to other drugs, like the $1.6 billion blockbuster Gemzar. The company also is in Phase I with an oral formulation of Karenitecin.

Elsewhere in its pipeline, BioNumerik is conducting a U.S. Phase II trial and a Japanese Phase III trial in non-small-cell lung cancer with the chemoprotective agent Tavocept. That drug failed to reduce the incidence of severe neuropathy or shrink tumors in two Phase III trials in breast cancer and NSCLC, causing partner Takeda Pharmaceutical Co. Ltd. to back out of its deal for North American rights. (See BioWorld Today, Aug. 2, 2006.)

BioNumerik thought subset analyses from the trials justified further development, especially since the trials were among the first ever to assess the potential reduction of chemotherapy-induced neuropathy. Tavocept is partnered with Baxter Healthcare SA everywhere outside of North America and Japan, and with Grelan Pharmaceutical Co. Ltd., of Tokyo, in Japan. Grelan also holds Japanese rights to Karenitecin.

BioNumerik also is in Phase I trials with MDAM, a non-polyglutamylatable antifolate for solid tumors, rheumatoid arthritis, psoriasis and asthma.