Clinical studies show Genta's Genasense may make chemotherapy more effective

By E. Janene Geiss

Philadelphia, Dec. 12 - Genta Inc. said preliminary clinical results of the use of its lead anticancer compound, Genasense (oblimersen sodium) injection, in combination with fludarabine plus Genentech/Idec's Rituxan (rituximab) in patients with chronic lymphocytic leukemia showed major responses.

Two clinical studies have explored the use of Genasense plus rituximab, with and without cytotoxic chemotherapy, in patients with non-Hodgkin's lymphoma.

The goal of the ongoing phase 1 /2 study was to evaluate safety and preliminary activity across a range of fludarabine and Genasense doses when used in combination with a "stepped dosing" schedule of rituximab, according to a company news release.

The first 24 patients were treated in cycle one with 1.5 mg a day of Genasense (50% of the usual dose) for seven days, plus three days of fludarabine and two rituximab doses.

In cycles two through six, the Genasense dose was escalated to 3 mg a day and the rituximab dose was given once on day five. Of these patients, 19 had relapsed from previous treatment and five were previously untreated.

All five previously untreated patients achieved a major response, including one "molecular" complete response, one nodular partial response and three partial responses. Sixty-eight percent of the previously treated patients had received therapy with rituximab, and 74% had previously received fludarabine. Nonetheless, 10 of the 19 previously treated patients achieved major responses, including one molecular complete response, one nodular partial response and 10 partial responses.

Seven patients developed grade three rituximab-associated infusion reactions, two of which were considered serious, officials said. But most of these reactions occurred during the first cycle of treatment and most patients were able to continue rituximab treatment, officials said.

No other serious reactions occurred in more than one patient each.

Having demonstrated adequate safety in the initial cohort, accrual is continuing to a second cohort wherein full doses of all three drugs including fludarabine at 25 mg twice a day for five days.

In another study, a randomized phase 3 trial of 241 patients who received fludarabine plus cyclophosphamide (Flu/Cy) with or without Genasense showed the addition of Genasense was associated with a significant increase in the proportion of patients who achieved a complete response or nodular partial response.

All of the responses in the Genasense group lasted for six months, significantly longer than responses that occurred in patients treated with Flu/Cy alone, officials said.

This level of response was associated with significant clinical benefit, including relief of prospectively defined symptoms of chronic lymphocytic leukemia, officials said.

Genta said it expects to complete its submission of a New Drug Application to the Food and Drug Administration for Genasense in combination with fludarabine and cyclophosphamide in patients with relapsed or refractory chronic lymphocytic leukemia later this month.

The data were presented this past weekend at the annual American Society of Hematology meeting in Atlanta.

Genasense is the first oncology drug to directly target the biochemical pathway known as apoptosis whereby cancer cells are ultimately killed by chemotherapy. A protein known as Bcl-2 is highly expressed in many forms of human cancer and is believed to be a fundamental cause of resistance to anticancer therapy. By inhibiting production of Bcl-2, Genasense may enhance the activity of many forms of anticancer treatment, officials said.

Genta is a Berkeley Heights, N.J., biopharmaceutical company focused on developing treatments for cancer.

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