Interim results from a Phase 2 study show that panobinostat may be clinically beneficial for certain multiple myeloma patients with advanced disease.

In the study, patients who had relapsed and were no longer responsive to Velcade-based treatments received panobinostat in combination with Velcade and dexamethasone.

Although the results generally are being viewed as favorable, “It is hard to interpret them because you don’t really know how the patients would have done with just Velcade and dexamethasone alone,” explained Dr. Leif Bergsagel, a myeloma specialist from the Mayo Clinic in Arizona, in a discussion with The Beacon.  Dr. Bergsagel was not involved in the study.
 
“My interpretation right now is that the combination is helping a subset of patients, and we need to try and identify that subset in order to move the therapy forward,” added Dr. Bergsagel. 

Dr. Paul Richardson from the Dana-Farber Cancer Institute in Boston presented the study results at the American Society of Hematology (ASH) annual meeting in San Diego last month.

Panobinostat (Farydak) is an oral drug that is being developed by the pharma­ceutical company Novartis (NYSE: NVS) for a variety of different cancers. It belongs to a class of drugs called histone deacetylase (HDAC) inhibitors, which work by increasing the production of proteins that slow cell division and cause cell death.

Zolinza (vorinostat), another HDAC inhibitor being studied for the treatment of myeloma, was recently shown to have a small impact on progression-free survival when used in combination with Velcade in relapsed/refractory myeloma patients (see related Beacon news).

Previous laboratory studies have shown that panobinostat in combination with Velcade (bortezomib) may have significant anti-myeloma effects. Furthermore, a Phase 1 trial of this combination in relapsed and treatment-resistant (refractory) myeloma patients resulted in a high overall response rate (see related Beacon news).

The purpose of this Phase 2 trial was to determine the efficacy and safety of panobinostat with Velcade and dexamethasone (Decadron) in relapsed and Velcade-refractory myeloma patients.

All patients in the trial also were required to have been treated at some point with one of the immuno­modulatory anti-myeloma drugs, such as thalidomide (Thalomid), Revlimid (lenalidomide),  or poma­lidomide.

Fifty-five patients with a median age of 61 years participated in this study. The patients had received a median of four prior treatments, including 64 percent who had undergone stem cell transplantation.

The treatment regimen was composed of two phases. In the first phase, patients received eight 3-week treatment cycles, which included 20 mg of panobinostat on days 1, 3, 5, 8, 10, and 12 plus 1.3 mg/m² of Velcade on days 1, 4, 8, and 11 as well as 20 mg of dexamethasone on the day of and day after each Velcade dose.

Patients who responded or demonstrated stable disease proceeded to the second treatment phase, which consisted of four 6-week cycles including 20 mg of panobinostat three times per week on weeks 1, 2, 4, and 5 plus 1.3 mg/m² of Velcade on days 1, 8, 22, and 29 as well as 20 mg of dexamethasone on the day of and day after each Velcade dose.

Of the evaluated patients, 29 percent achieved at least a partial response, including 4 percent who achieved a near complete response.  No patients achieved a complete response.

Thus far, 16 patients have completed the first treatment phase and proceeded to the second phase. Ten patients are currently still in the second phase of treatment, including two patients who have completed 12 or more cycles.

Severe to life-threatening side effects included low platelet counts (53 percent of patients), fatigue (16 percent), anemia (16 percent) diarrhea (14 percent), pneumonia (14 percent), and low white blood cell counts (12 percent), most of which were manageable with a dose reduction. Peripheral neuropathy, a condition characterized by pain and tingling in the extremities due to nerve damage, occurred in 24 percent of patients, with 2 percent classified as having severe peripheral neuropathy.

The combination of panobinostat, Velcade, and dexamethasone is currently being tested in a Phase 3 clinical trial, which is comparing the combination to Velcade and dexamethasone without panobinostat. Dr. Bergsagel of the Mayo Clinic noted that these results will be critical for determining to what extent, and for which patients, the panobinostat combination is helpful.

Panobinostat is also being studied in combination with other common anti-myeloma drugs, including Revlimid, carfilzomib (Kyprolis), and pomalidomide.

For more information, please see abstract 814 on the ASH annual meeting website and Dr. Richardson’s slide deck, which he has made available as a courtesy to The Beacon’s readers.