Treatment Options - Panobinostat
What is Panobinostat?
Panobinostat is an oral anticancer agent being developed by Novartis that inhibits multiple enzymes that cancer cells need to grow and survive. It is known as a deacetylase (DAC) inhibitor, and is also known by the name LBH589. Panobinostat also inhibits the growth of new blood vessels needed for tumors to grow. Panobinostat is being studied in myeloma as well as other blood cancers and solid tumors.
The Multiple Myeloma Research Consortium (MMRC) has played a role in this drug’s development and is currently facilitating trials evaluating panobinostat in combination with another myeloma agent.
What do we know about Panobinostat’s activity in myeloma?
In the laboratory, panobinostat has been shown to kill myeloma cells, including those that are resistant to other anti-myeloma drugs. In addition, panobinostat acts synergistically with other anti-myeloma drugs, such as Velcade.
Panobinostat has been evaluated in several trials in myeloma, including two that were facilitated by the MMRC.
Panobinostat has been evaluated as part of various combination therapies.
- The safety of panobinostat in combination with Velcade was evaluated in a Phase I trial in relapsed or relapsed/refractory myeloma, which was facilitated by the MMRC.
- Dexamethasone could be added in cases of worsening disease.
- Promising results were seen, with an overall response rate of 55% achieved among the 62 patients in the trial.
- Forty-two of patients who were refractory to previous Velcade therapy responded to the combination with a partial response or better.
- Low blood cell and platelet counts and weakness were the main serious side effects seen. Fatigue, gastrointestinal effects, fever, dizziness, and neuropathy (nerve problems) were the most common side effects seen.
- In a Phase II trial known as PANORAMA 2, The combination of panobinostat, Velcade® (bortezomib), and dexamethasone was effective in patients who had previously received several other myeloma drugs including an immunomodulatory drug (ie, Thalomid® [thalidomide],Revlimid® [lenalidomide], or Pomalyst™ [pomalidomide]) and no longer responded to Velcade. Fifty-five patients were enrolled in this study.
- An overall response rate of 35% was seen, and both time to disease progression and progression-free survival were 5.4 months.
- The most common side effects included diarrhea, tiredness, and low platelet counts. Low platelet count was also the most serious side effect, and was managed with dose reduction and/or interruption. Peripheral neuropathy, which was reported in 27% of patients, was typically mild.
- The safety of panobinostat in combination with Revlimid-dex was also evaluated in an MMRC-facilitated Phase I trial in relapsed or relapsed/refractory myeloma.
- Low blood cell and platelet counts, gastrointestinal effects, and fatigue were the most common side effects seen.
- Preliminary efficacy was encouraging, with an overall response rate of 56% seen, including 2 complete responses, 7 very good partial responses, and 8 partial responses.
- Panobinostat was evaluated in combination with melphalan, Thalomid, and prednisone (MPT) in a Phase I/II trial in relapsed/refractory myeloma that enrolled 24 patients.
- The four-drug regimen showed encouraging anti-myeloma activity since responses were seen in patients with advanced disease and in myeloma that was resistant to Velcade, Revlimid, or Thalomid.
- A total of 39% of patients achieved a partial response or better.
- However, the initial panobinostat dose tested in the Phase I part of the study, as well as a reduced dose, were associated with severely low blood counts, indicating that different dosing schedules need to be investigated.
- Panobinostat is also being evaluated in combination with oral melphalan in an ongoing Phase I/II study in relapsed or refractory myeloma.
- Preliminary results from the first 25 (of 40 planned) patients enrolled in the Phase I portion of the study show encouraging responses. These patients had previously received several other myeloma therapies.
- An intravenous form of panobinostat in combination with Velcade was shown to have a predictable and manageable safety profile, as well as anti-myeloma activity and beneficial bone effects in a small Phase I study.
How is Panobinostat currently being studied in myeloma?
Panobinostat is being evaluated in combination with Velcade-dex in patients with relapsed myeloma in an international Phase III trial.
- Known as the PANORAMA 1 study, this trial is evaluating the time it takes for the disease to progress in patients receiving this three-drug combination compared with Velcade-dex plus placebo.
- The study will also evaluate survival, overall response, time to response and duration of response, safety, and quality of life.
- Approximately 762 patients who have received 1 to 3 prior myeloma therapies and whose disease is not refractory to Velcade have been enrolled in the study.
- Preliminary safety data from the first 267 patients enrolled show no new or unexpected side effects.
Panobinostat is also being tested in several early-stage clinical trials in relapsed and/or refractory myeloma, including:
- Phase I and I/II studies in combination with the proteasome inhibitor Kyrpolis™ (carfilzomib), including a study being facilitated by the MMRC
- Preliminary data from one Phase I study of this combination are encouraging, with responses seen in patients who had previously received a stem cell transplant and/or no longer responded to Velcade or Revlimid. The combination also appears to have a manageable side effect profile.
- A Phase II study in combination with Revlimid and dexamethasone
- A Phase I study that is evaluating an intravenous form of panobinostat in combination with Velcade, which has completed enrollment
A Phase I/II trial is also set to begin evaluating panobinostat in combination with Revlimid, Velcade, and dexamethasone in patients with newly diagnosed myeloma who are eligible for stem cell transplant.