The results of a number of clinical trials for the treatment of multiple myeloma with Zolinza were presented at the American Society of Hematology (ASH) 2010 annual meeting. The trials, ranging from Phase 1 to Phase 3, studied Zolinza in combination with a variety of approved myeloma drugs for the treatment of both early and advanced stages of the disease.

Zolinza (vorinostat) is manufactured by Merck Pharmaceuticals.  It is currently approved for a certain type of lymphoma and is being investigated as a treatment for multiple myeloma (see related Beacon news).  Zolinza is a histone deacetylase inhibitor and works by altering the production of proteins in cancer cells, thereby slowing growth of cancer cells and inducing cell death.

Zolinza With Revlimid And Dexamethasone For Relapsed/Refractory Myeloma

The results of a Phase 1 clinical trial of Zolinza with Revlimid (lenalidomide) and dexamethasone (Decadron) in relapsed or treatment-resistant (refractory) myeloma patients indicate that it is a well-tolerated and promising therapeutic option for this subset of patients.

A total of 31 patients have been treated in the trial as of July 2010.  Patients were placed into one of five treatment groups and received Zolinza (300 or 400 mg on days 15 to 21), Revlimid (10, 15, 20, or 25 mg on days 1 to 21), and dexamethasone (40 mg on days 1, 8, 15, and 22 of a 28-day cycle).

A complete response was achieved by 7 percent of patients, while very good partial and partial responses were achieved by 10 percent and 37 percent of patients, respectively.   Additionally, 17 percent achieved a minimal response and 17 percent achieved stable disease.

Of note, stable disease or better was achieved in 60 percent of patients who were previously relapsed, refractory, or intolerant to Revlimid treatment.

The median time to progression was 5 months.

Most observed side effects were mild to moderate, though 61 percent of patients experienced at least one severe side effect.  These included low white and red blood cell counts, low platelet levels, and diarrhea.  All doses tested were tolerated.

Researchers plan to continue studying this regimen in future trials.

Zolinza And Velcade For Relapsed/Refractory Myeloma

Two ongoing clinical trials, a Phase 2b trial called Vantage 095 and a Phase 3 trial called Vantage 088, are currently investigating the use of Zolinza with Velcade (bortezomib) for relapsed/refractory myeloma patients.

The Phase 2 trial will include 142 relapsed and refractory myeloma patients.  Data presented at the meeting showed that the first 108 participants were heavily pre-treated with a median of 5 prior treatments. Patients in this study received 21-day cycles of Velcade (1.3 mg/m² on days 1, 4, 8, and 11) and Zolinza (400 mg on days 1 to 14).  Patients who did not respond to Velcade and Zolinza alone could have dexamethasone added to their regimen (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12).

Interim results suggest that the regimen is effective in Velcade-refractory patients.  Final results are expected to be available in 2011.

In the Phase 3 trial, the same Velcade-Zolinza regimen is being compared to Velcade alone.  A total of 349 patients, who received one to three prior treatment regimens, have been enrolled.  Planned enrollment is 742 participants.

For more information, or to enroll in the Phase 3 trial, please see the clinical trial webpages for Vantage 095 and Vantage 088.

Zolinza With Doxil And Velcade For Relapsed/Refractory Myeloma

A Phase 1 study of Zolinza in combination with Doxil (doxorubicin liposomal) and Velcade for relapsed/refractory myeloma patients was designed to determine the maximum-tolerated dose of Zolinza when used in this combination regimen.

A total of 20 patients have been enrolled in the study thus far.  Patients were placed in one of four treatment groups receiving 21-day cycles of doxorubicin (30 mg/m² on day 4), Velcade (1.3 mg/m² on days 1, 4, 8 and 11), and Zolinza (200, 300, or 400 mg on days 4 to 11 or 1 to 14).

Thirty-eight percent of patients achieved a very good partial response or better, and an additional 23 percent achieved a partial response. Of note, 70 percent of patients with relapsed disease, 50 percent of patients with relapsed and refractory disease, and 33 percent of Velcade-refractory patients achieved a partial response or better.

Common side effects included low white blood cell and platelet levels, diarrhea, nausea, peripheral neuropathy (nerve damage in the limbs), fatigue, constipation, vomiting, and loss of appetite.

Two dose-limiting toxicities were observed at the highest dose level and one was observed at the next highest level, thus establishing the maximum-tolerated dose of Zolinza in this regimen at 400 mg administered on days 4 to 11.

Researchers believe the results of this study support further clinical testing of Zolinza with Doxil and Velcade.

Zolinza With Revlimid, Velcade, and Dexamethasone In Newly Diagnosed Myeloma

The initial results of a Phase 1 clinical trial for Zolinza with Revlimid, Velcade, and dexamethasone as frontline therapy for multiple myeloma suggest that the regimen is effective and tolerable.

To date, 11 patients have been enrolled in the study and placed into one of three patient groups.  All patients received the current standard Revlimid-Velcade-dexamethasone regimen in addition to 100, 200, 300, or 400 mg of Zolinza on days 1 to 14 of a 21-day cycle.  Participants could receive a stem cell transplant after 4 cycles.

All evaluable patients responded to the regimen, with 38 percent achieving complete response, 12 percent achieving very good partial response, and 50 percent achieving partial response.

Fifty-five percent of patients experienced the onset of peripheral neuropathy during the trial, and one patient discontinued therapy after experiencing severe peripheral neuropathy.  One dose-limiting toxicity occurred at 100 mg and another at 200 mg, but the maximum-tolerated dose of Zolinza has not yet been reached.

The study will continue to accrue patients to determine the maximum-tolerated dose of Zolinza in this regimen.  For more information or to enroll, see the clinical trial webpage for the study.

Zolinza Combinations In Relapsed/Refractory Myeloma

In this retrospective study, researchers sought to determine whether the addition of Zolinza to myeloma treatment combinations could overcome resistance to those combinations in relapsed/refractory myeloma patients.

The researchers analyzed the efficacy of Zolinza-Revlimid-dexamethasone in patients refractory to Revlimid-dexamethasone as well as the efficacy of Zolinza-Revlimid-Velcade-dexamethasone in patients refractory to Revlimid-Velcade-dexamethasone.

The study included 18 patients who had received Zolinza (300 or 400 mg) on days 1 to 7 and 15 to 21 of a 28-day cycle in combination with Revlimid and dexamethasone.  An additional 10 patients also received Velcade.

Partial responses or better were noted in 43 percent of patients, which included 14 percent very good partial responses and 29 percent partial responses. The duration of response ranged from 2 to more than 23 months.

The most common side effects were diarrhea and abdominal cramping.  Some patients experienced low red blood cell and platelet levels, but the rate was similar to that seen in patients treated with Revlimid-based therapy without Zolinza.

The results demonstrate Zolinza’s ability to overcome resistance to Revlimid, Velcade, and dexamethasone regimens.

For more information, please see abstracts 1951 (Zolinza, Revlimid, dexamethasone), 1952 (Zolinza and Velcade), 1955 (Zolinza, Doxil, Velcade), 3034 (Zolinza, Revlimid, Velcade, and dexamethasone), and 3065 (Zolinza analysis in refractory patients) on the American Society of Hematology Meeting annual meeting website.