Results of two Phase 1b clinical trials suggest that panobinostat (Farydak) in combination with Velcade (bortezomib) or Revlimid (lenalidomide) and dexamethasone (Decadron) is effective and well-tolerated in patients who are resistant (refractory) to previous multiple myeloma treatment. The findings were presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago in early June.

“There are novel therapies that have improved the outcome, literally doubled the survival, of patients with myeloma. Despite these incredible advances, inevitably most patients relapse, and so we need [new] novel therapies,” said Dr. Kenneth Anderson of the Dana-Farber Cancer Institute.

For this reason, panobinostat is being developed by Novartis for the treatment of relapsed and refractory myeloma patients. Panobinostat works by preventing the breakdown of proteins in tumor cells. It is the resulting accumulation of these proteins that causes the cancerous cell to die.

Initial studies to determine the efficacy of panobinostat as a single drug therapy showed only two patients out of 38 responded. “This degree of activity did not warrant going forward as a single agent,” said Dr. Anderson.

The goal of each Phase 1b combination trial was to determine the maximum tolerated dose of panobinostat. Efficacies of the therapy regimens were also monitored.

Panobinostat In Combination With Velcade

The Phase 1b clinical trial investigating panobinostat in combination with Velcade was presented at ASCO by Dr. Anderson.

Forty-seven patients were enrolled in the panobinostat-Velcade combination trial. All patients had received prior treatment for multiple myeloma, including some patients who had been previously treated with Velcade.

To determine the maximum tolerated doses of panobinostat and Velcade in combination together, patients were divided into five groups. Each group of patients received a different combination of doses.

Researchers found that there were responses even at the lowest doses, and complete and very good partial responses were observed at the highest tolerated dose of panobinostat. The overall response rate was 70 percent, with 10 percent complete response.

“Importantly, and I think this is key, if you look at the patients who are Velcade refractory, we actually have 60 percent responses,” said Dr. Anderson.

Dr. Anderson commented, “I think this is among the most active, if not the most active, combination in Velcade-refractory disease.”

Dose-limiting side effects occurred in patients receiving more rigorous regimens. As a result of these side effects, Dr. Anderson concluded, “Panobinostat can safely be combined with Velcade with a recommended dose of 20 mg of panobinostat three times per week and Velcade at 1.3 mg/m² given twice a week for two weeks.”

Though significantly low platelet counts (81 percent of patients), white blood cell counts (57 percent), and red blood cell counts (21 percent) were side effects of treatment, these levels could be managed with dose modification and platelet transfusion. Other common side effects included diarrhea, nausea, fever, fatigue, and weakness.

An international Phase 3 trial of panobinostat-Velcade compared to Velcade alone in relapsed myeloma is ongoing. Additionally, a Phase 2 trial of panobinostat-Velcade treatment for refractory multiple myeloma is underway in the United States, “hopefully to achieve accelerated approval for this unmet medical need,” said Dr. Anderson.

Panobinostat In Combination With Revlimid And Dexamethasone

Results of the ongoing Phase 1b clinical trial of panobinostat-Revlimid-dexamethasone were presented at ASCO during a poster session. The trial enrolled 46 multiple myeloma patients, 25 of whom had refractory disease.

Patients received 5, 10, 20, or 25 mg panobinostat plus 25 mg Revlimid and 40 mg dexamethasone.

Among the participants who have been evaluated, 57 percent responded to the combination therapy. Additionally, 26 percent of all participants remain on the study.

Dose-limiting side effects occurred in 25 percent of evaluated patients, with nearly half of the patients in the 25 mg panobinostat group experiencing such side effects. The most common serious side effects were low platelet levels (44 percent of patients) and low white blood cell levels (37 percent). Two deaths occurred during the study and were suspected to be treatment related.

Researchers concluded that “no new safety concerns were identified and preliminary efficacy [of panobinostat-Revlimid-dexamethasone therapy] was very encouraging.”

However, during a discussion about the results, Dr. Robert Z. Orlowski of the MD Anderson Cancer Center expressed concern about the side effects, which he said were most likely due to high-dose dexamethasone.

Further studies are ongoing to determine the maximum tolerated dose of panobinostat as well as effects of lower dexamethasone and non-continuous panobinostat dosing.

Although panobinostat alone had minimal benefit as a therapy for myeloma, Phase 1b trials suggest that panobinostat may be highly effective against advanced multiple myeloma when given in combination with other currently used therapies.

For more information, please see abstract 8001 (combination with Velcade) and abstract 8030^ (combination with Revlimid and dexamethasone) on the ASCO Meeting website.