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Panobinostat And Vidaza Combination May Be Effective In Higher-Risk MDS Patients (ASH 2011)

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Published: Feb 6, 2012 1:48 pm
Panobinostat And Vidaza Combination May Be Effective In Higher-Risk MDS Patients (ASH 2011)

Preliminary results from two independent clinical trials indicate that panobinostat in combination with Vidaza may be effective and safe for higher-risk myelodysplastic syndromes patients.

The studies were presented at the American Society of Hematology (ASH) annual meeting in San Diego this past December.

Panobinostat (LBH589), which is being developed by the pharmaceutical company Novartis (NYSE: NVS), belongs to a class of drugs known as histone deacetylase (HDAC) inhibitors.  HDAC inhibitors work by increasing the production of proteins that slow cell division and cause cell death.

When used alone, panobinostat has shown little activity in myelodysplastic syndromes (MDS) patients (see related Beacon news).

However, the researchers speculated that panobinostat may act synergistically with other treatments.

The two studies presented at the meeting sought to determine whether panobinostat and Vidaza (azacitidine) are effective together against MDS and at what dose panobinostat should be administered.

Panobinostat Plus Five-Day Vidaza

Through a Phase 1b/2 study, researchers sought to determine the safety, tolerability, and efficacy of oral panobinostat in combination with a 5-day Vidaza treatment schedule.

The researchers determined that five days of Vidaza followed by 30 mg panobinostat three times weekly was tolerable and that the combination treatment may be effective in MDS.

Twenty-six patients with higher-risk MDS or acute myeloid leukemia who had not received previous treatment were included in this study conducted in Heidelberg, Germany, and throughout Australia.

All patients received 75 mg/m2 of Vidaza injected under the skin for the first five days of each 28-day treatment cycle.

On the fifth day of each cycle, the patients began taking 10 mg to 40 mg of panobinostat orally three times a week until they reached seven total doses during that cycle.

The patients were treated for a median of four cycles.

Of the eight MDS patients included in the study, 25 percent achieved a complete response, 38 percent experienced a partial response, and 25 percent maintained stable disease.  One patient withdrew from the trial.

The median overall survival for all participants was 239 days (about 7.9 months).

Because fatigue was common among patients who received 40 mg of panobinostat (67 percent), the researchers determined  that 30 mg panobinostat was the maximum tolerable dose when used with a five-day Vidaza schedule.

The most common side effects included redness or pain at the site of Vidaza injection, fatigue, nausea, loss of appetite, diarrhea, difficulty breathing, fever, high blood sugar levels, and lightheadedness.

At the time that this study was presented, 38 percent of patients were still participating in the trial.

Trial participants discontinued treatment due to disease progression (35 percent), infection (8 percent), interactions with other drugs the patients were taking (8 percent), patient choice (8 percent), and fatigue (4 percent).

Panobinostat Plus Seven-Day Vidaza

Dr. Oliver Ottmann of the Goethe University in Frankfurt, Germany presented the second study on the combined use of panobinostat and Vidaza.

This clinical trial, conducted in Germany, France, and multiple centers in the United States, evaluated the tolerability, safety, and efficacy of panobinostat in combination with a seven-day Vidaza treatment schedule.

Dr. Ottmann and his colleagues found that 30 mg panobinostat used with a seven-day Vidaza schedule may be effective and safe in MDS.

Thirty-one patients with higher-risk MDS, acute myeloid leukemia, or chronic myelomonocytic leukemia who were not eligible for stem cell transplantation participated in this study.

The patients received 75 mg/m2 of Vidaza injected under the skin during the first seven days of a 28-day treatment cycle.

In addition, the patients received 20 mg to 40 mg of panobinostat on days 3, 5, 8, 10, 12, and 15 of each treatment cycle.

Preliminary efficacy data were available for eight acute myeloid leukemia patients and eight patients with MDS or chronic myelomonocytic leukemia.

Of those 16 patients, 25 percent achieved a complete response and 38 percent maintained stable disease.

Four patients (25 percent) showed improved blood cell counts, but the blood counts of two of these patients fell again.

After evaluating the side effects and overall safety at the end of the first treatment cycle, the researchers decided to treat subsequent participants with 30 mg panobinostat.

The most common severe side effects included low platelet counts (28 percent),  low white blood cell counts accompanied by fever (21 percent), and low white blood cell counts alone (17 percent).

For more information on these studies, please see abstract 1529 and abstract 459 at the ASH 2011 meeting website.

Photo by ardelfin on morgueFile – some rights reserved.
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