Relapsed/Refactory Patients:

Panobinostat (LBH589)

What are the key facts about Panobinostat?

• Oral anticancer agent from a class of drugs known as deacetylase inhibitors.

• The combination of panobinostat and Velcade was active in heavily pretreated myeloma patients who had previously received an immunomodulatory drug (ie, Thalomid, Revlimid, or pomalidomide) and no longer responded to Velcade, with an overall response rate of 29% seen. This suggests the ability of panobinostat to overcome resistance to Velcade.

• The combination of panobinostat and Revlimid-dex also displayed encouraging preliminary efficacy.

• Being evaluated in combination with Velcade-dex in an international Phase III trial.

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.

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 Multiple Myeloma Research Consortium (MMRC).

Single-agent Panobinostat

A Phase II study of panobinostat in patients with advanced refractory myeloma showed the drug to be well-tolerated and safe. The dose used in this study was lower than that used in subsequent studies, but responses were noted.

Combination Studies

Panobinostat has been evaluated as part of various combination therapies.

• The safety of panobinostat in combination with Velcade was evaluated in a Phase Ib trial in relapsed or relapsed/refractory myeloma, which was facilitated by the MMRC.
  
  
• Dexamethasone could be added in cases of worsening disease.
  
  
• Promising activity was seen in the 62 evaluable patients, with an overall response rate of 55%.
  
  
• 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 were the most common side effects seen.
  
  
• The maximum tolerated doses of combination Velcade and panobinostat were determined
  
  
• In a Phase II trial known as PANORAMA 2, the combination of panobinostat and Velcade was shown to be active in heavily pretreated myeloma patients who had previously received an immunomodulatory drug (Thalomid, Revlimid, or pomalidomide) and no longer responded to Velcade (n=55).
  
  
• There were two parts to the study. In the first part, patients received eight 3-week cycles of therapy. Patients who experienced clinical benefit (stable disease or better) could continue receiving 6-week cycles of therapy in the second part.
  
  
• An overall response rate of 29% was seen, which included near complete responses in 4% of patients and partial responses in 25% of patients.
  
  
• The most common side effect was fatigue and the most common serious side effect was low platelet count, which was managed with dose reduction and/or interruption.
  
  
• The safety of panobinostat in combination with Revlimid-dex was also evaluated in an MMRC-facilitated Phase Ib 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 1 stringent complete response, 1 complete response, 7 very good partial responses, and 8 partial responses.
  
  
• Panobinostat was evaluated in combination with melphalan, thalidomide, 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) heavily-pretreated patients enrolled in the Phase I portion of the study show encouraging responses.

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 will evaluate 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 overall survival, overall response, time to response and duration of response, safety, and quality of life.
  
  
• Approximately 672 patients who have received 1 to 3 prior lines of therapy and whose disease is not refractory to Velcade will be 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 carfilzomib
  
  
• A Phase I study in combination with carfilzomib, which is being facilitated by the MMRC
  
  
• A Phase I study that is evaluating an intravenous form of panobinostat in combination with Velcade in patients
  

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.

To find a clinical trial, call 1-866-603-MMCT (-6628) or click here to go to the MMRF Patient Navigator Program.