Final results from a recent Phase 2 clinical trial continue to indicate that panobinostat in combination with Velcade and dexamethasone is effective for heavily pretreated multiple myeloma.

In the study, known as “PANORAMA 2,” patients who had previously relapsed and were no longer responsive to Velcade (bortezomib)-based treatment received panobinostat in combination with Velcade and dexamethasone (Decadron).

The results show that one-third (35 percent) of the patients responded to the treatment, and the median progression-free survival was 5.4 months.

In comparison, myeloma experts found during a prior review of the myeloma literature that 20 percent of Velcade-refractory (resistant) myeloma patients typically respond to Velcade-based therapy.

The study investigators conclude, “Panobinostat, when combined with bortezomib [Velcade] and dexameth­asone, can recapture responses in heavily pretreated, bortezomib-refractory multiple myeloma patients.”

Novartis (NYSE: NVS), the pharmaceutical company developing panobinostat, plans to apply in the United States and Europe later this year for approval of panobinostat for the treatment of multiple myeloma.  The application will be based on the Phase 3 study, known as “PANORAMA 1,” which is comparing treatment with panobinostat plus Velcade and dexamethasone to treatment with Velcade and dexamethasone alone for relapsed myeloma.

Background

Panobinostat is an oral drug that 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.  Novartis is developing panobinostat for the treatment of a variety of different cancers.

Preclinical studies have shown that panobinostat in combination with Velcade more effectively kills myeloma cells than either drug alone.

Furthermore, a Phase 1 clinical trial of the panobinostat-Velcade-dexamethasone combination resulted in a high overall response rate of 73 percent, with 26 percent of Velcade-refractory patients achieving a re­sponse.

However, 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).

Preliminary results from the PANORAMA 2 trial were presented at the 2011 American Society of Hematology (ASH) meeting (see related Beacon news) and the 2013 American Society of Clinical Oncology meeting (see related Beacon news).

Study Design

Investigators from centers throughout the U.S. enrolled 55 relapsed and refractory multiple myeloma pa­tients in their study from June 2010 to July 2011. The median patient age was 61 years.

The patients had received a median of four prior lines of therapy, including a median of two Velcade-based regimens.  All of the patients were refractory to their last Velcade regimen, and 82 percent were refractory to the combination of Velcade plus dexamethasone.

In addition, 98 percent had previously been treated with Revlimid, 69 percent with thalidomide, and 56 per­cent had previously undergone stem cell transplantation.

The panobinostat-based regimen consisted of two phases of treatment.

In the first phase, patients underwent eight 3-week treatment cycles that 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 6-week cycles of treatment that included 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.

Patients were treated until their disease progressed or they could no longer tolerate the therapy.

The median follow-up time was 8.3 months.

Study Results

Overall, 35 percent of the patients responded to treatment with panobinostat, Velcade, and dexamethasone.  Specifically, 2 percent of the patients achieved a near-complete response and 33 percent achieved a partial response. An additional 36 percent of the patients had stable disease.

Median time-to-response was 1.4 months.

High-risk chromosomal abnormalities – del(17p), t(4;14), or t(14;16) – did not appear to affect response. The overall response rate for patients with chromosomal abnormalities was 43 percent.

However, the overall response rate was lower for patients who received Velcade in their last line of therapy, compared to those who received Velcade during an earlier line of therapy (26 percent versus 43 percent, respectively).

The median progression-free survival was 5.4 months.

Patients who progressed while on their last line of Velcade therapy had shorter progression-free survival than those who progressed within 60 days of completing their Velcade therapy (4.2 months versus 7.6 months, respectively).

The investigators point out, though, that all subgroup analyses rely on data from a small number of patients.

The median overall survival was not yet reached.

The most common severe and life-threatening side effects were low platelet counts (64 percent), fatigue (20 percent), and diarrhea (20 percent).

Moreover, 27 percent of the patients developed new or worse peripheral neuropathy (pain, tingling, or loss of sensation in the extremities). However, only one patient experienced severe peripheral neuropathy.

The study investigators conclude, “These data suggest that panobinostat can be safely combined with bortezomib [Velcade] without significant concern for increasing the severity of peripheral neuropathy.”

For more information, please refer to the study in the journal Blood (abstract).