Four clinical trials presented at the American Society of Hematology (ASH) 2011 annual meeting in San Diego last month suggest that Zolinza, in combination with a number of approved myeloma drugs, may be a treatment option for relapsed and treatment-resistant multiple myeloma patients.

However, results of a key Phase 3 trial involving the drug were disappointing, and they call into question whether the drug will receive formal FDA approval as a treatment for myeloma.

Zolinza (vorinostat), which is marketed by the U.S. pharmaceutical company Merck (NYSE: MRK), is an oral drug already approved in the United States for a certain type of lymphoma. It also is approved for a similar use in Canada and Australia, but not in Europe.

Zolinza 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. Two other drugs that have been investigated as potential myeloma treatments – panobinostat and Istodax (romidep­sin) – belong to the same class of drugs.

Details of the key ASH oral presentations about Zolinza – as well as two related poster presentations – are summarized below.

Zolinza Plus Velcade - Phase 3 Trial Results

Two clinical trials, including a Phase 2b study called Vantage 095 and a Phase 3 study called Vantage 088, are investigating the combination of Zolinza and Velcade (bortezomib) in relapsed/refractory multiple myeloma patients. Preliminary data for these studies were presented at the ASH 2010 annual meeting (see related Beacon news).

Updated results of the key, large-scale Phase 3 trial were presented at the 2011 ASH meeting by Dr. Meletios Dimopoulos from the University of Athens in Greece.

The Phase 3 study included 637 patients from 174 treatment centers across 33 countries. The median patient age was 62 years. Patients in the study had received a median of two prior therapies; 24 percent of patients had previously received Velcade, 56 percent thalidomide (Thalomid), 13 percent Revlimid (lenalido­mide), 56 percent melphalan (Alkeran), and 35 percent a stem cell transplant.

Half of the participants in this study received received 400 mg Zolinza on days 1 to 14 and 1.3 mg/m² Velcade on days 1, 4, 8, and 11 of a 21-day treatment cycle.  The other half Velcade plus a placebo.

Among the patients who received Velcade in combination with Zolinza, 56 percent achieved at least a partial response, compared to 41 percent of patients who received Velcade plus placebo.

In addition, progression-free survival was longer (7.6 months) in patients who received Velcade plus Zolinza than in patients treated with Velcade plus placebo (6.8 months).

Although the 25-day difference in these time spans is statistically significant, it was not clear to many of the physicians attending the presentation that it is clinically significant.

Dr. Adam Cohen from the Fox Chase Cancer Center in Philadelphia told The Beacon that the results are unlikely to change day-to-day treatment decisions.

Dr. Craig Hofmeister from the Ohio State University went one step further and indicated in a published report that he was not convinced the 25-day progression-free survival advantage would be sufficient for the FDA to grant Zolinza approval for use in multiple myeloma.

Additionally, the difference in overall survival between the two groups of patients in the study was not statistically significant.  Dr. Dimopoulos noted, however, that there is a trend toward a survival advantage for the Velcade-Zolinza combination.

Side effects were more frequently observed in the patients who received the Velcade-Zolinza combination.  About half of the patients who received the combination had to reduce their dose or discontinue treatment as a result of side effects.  Only a quarter of the patients who received Velcade plus placebo had to reduce their dose or discontinue treatment.

Full details of the Phase 3 trial results presented by Dr. Dimopoulos are not available because the abstract for the presentation includes neither efficacy nor safety results, and Merck, the company that markets Zolinza, is not making copies of the presentation available to the press or the public.

Zolinza Plus Velcade - Phase 2 Trial Results

Final results of the Phase 2 study investigating combination treatment with Zolinza and Velcade were presented at the 2011 ASH meeting by Dr. David Siegel from the John Theurer Cancer Center in Hackensack, New Jersey.

The study included 143 patients with a median age of 63 years and a median of four prior therapies. All patients had previously received Velcade, 85 percent thalidomide, 71 percent Revlimid, 4 percent pomalidomide, and 74 percent a stem cell transplant.

As in the Phase 3 trial of the Zolinza-Velcade combination, participants in the Phase 2 trial received 400 mg Zolinza on days 1 to 14 and 1.3 mg/m² Velcade on days 1, 4, 8, and 11 of a 21-day treatment cycle for a median of six cycles. Patients who did not respond to the treatment could add 20 mg dexamethasone (Decadron) on the day of and day after each dose of Velcade.

No patients in the Phase 2 trial received treatment with a placebo.

Of 142 evaluated patients who participated in the Phase 2 trial, 17 percent achieved a partial response or better. The median duration of response was 6.3 months.

The median overall survival was 11.2 months, with a two-year overall survival rate of 32 percent.

The most common severe side effects included low platelet counts (68 percent of patients), low red blood cell counts (38 percent), low white blood cell counts (32 percent), and diarrhea (17 percent). Peripheral neuropathy, a condition characterized by pain and tingling in the extremities due to nerve damage was infrequent, with severe peripheral neuropathy occurring in 2 percent of patients.

Zolinza In Combination With Velcade And Doxil

In a poster presentation, Dr. Peter Voorhees from the University of North Carolina at Chapel Hill summarized results from a Phase 1 study of Zolinza plus Velcade and Doxil (pegylated liposomal doxorubicin) in patients with relapsed and refractory multiple myeloma. Interim results from this study were presented at ASH 2010 (see related Beacon news).

The purpose of this trial was to determine the maximum tolerated dose and efficacy of Zolinza in this combination regimen. The study included 32 patients, who had received a median of two prior therapies.  Three-quarters (78 percent) had previously received Velcade, 56 percent Doxil, 91 percent thalidomide and/or Revlimid, and 66 percent a stem cell transplant. Of the patients with prior exposure to Velcade, 44 percent were treatment-resistant.

Participants received 1.3 mg/m² Velcade on days 1, 4, 8, and 11, 30 mg/m² Doxil on day 4, and 200 mg to 400 mg Zolinza on days 4 to 11 or days 1 to 14 of a 21-day treatment cycle. They received a median of six cycles.

Among the 31 patients evaluated, 65 percent achieved at least a partial response.

Notably, of the 11 patients with Velcade-resistant disease, 45 percent achieved a partial response or better. Furthermore, 71 percent of Velcade-sensitive patients and 83 percent of patients without prior exposure to Velcade also reached a partial response or better.

The maximum tolerated dose of Zolinza in this treatment regimen was 400 mg on days 4 to 11. The most common side effects included fatigue as well as blood and gastrointestinal problems. Peripheral neuropathy was observed in 38 percent of patients (6 percent severe).

Zolinza Plus Revlimid And Dexamethasone

In another poster presentation, results of a recent Phase 1 study of Zolinza in combination with Revlimid and dexamethasone were summarized.  The results suggest that the combination is well tolerated and effective in patients who are refractory to Revlimid and dexamethasone alone.

The study included 29 patients with a median of four prior therapies, all of whom were refractory to Revlimid and dexamethasone. Additionally, 76 percent were refractory to at least one Velcade regimen, and 48 percent were resistant to the combination of Velcade, Revlimid, and dexamethasone. Ninety percent had undergone stem cell transplantation.

The participants received 300 mg or 400 mg Zolinza on days 1 to 7 and 15 to 21, 10 mg to 25 mg Revlimid on days 1 to 21, and 20 mg to 40 mg dexamethasone on days 1, 8, 15, and 22 of a 28-day treatment cycle.

Of the 29 participants, 24 percent achieved at least a partial response. The median overall survival time was 11 months.

Common side effects included diarrhea and fatigue. Severe to life-threatening side effects included low white blood cell counts (45 percent) and low platelet counts (34 percent).

Researchers are planning Phase 2 studies of the Zolinza-Revlimid-dexamethasone combination.

For more information, please see abstract 811, abstract 480, abstract 3985, and abstract 3986 on the ASH 2011 annual meeting website.