Carfilzomib (PR-171)

What is Carfilzomib?

Carfilzomib is an oral proteasome inhibitor being developed by Onyx Pharmaceuticals, with several trials being facilitated by the Multiple Myeloma Research Consortium (MMRC). Carfilzomib is in the same class of agents as Velcade® (bortezomib). Proteasomes are enzymes found in cells and play an important role in regulating cell function and growth by controlling the breakdown of important proteins. Carfilzomib blocks the activity of proteasomes and by blocking the proteasome, it disrupts processes related to the growth and survival of cancer cells. Carfilzomib is also known as PR-171.

What do we know about Carfilzomib activity in myeloma?

Carfilzomib has been shown to have potent anti-myeloma activity in the laboratory and acts synergistically with dexamethasone. It can also overcome the resistance of myeloma cells to other drugs, including Velcade. Carfilzomib displayed anti-tumor effects against various hematologic malignancies, including myeloma, in two Phase I studies.

Single-agent Carfilzomib

Results of two ongoing Phase II trials that were facilitated by the MMRC have been reported.

The first trial (PX-171-003-A0) evaluated carfilzomib (20 mg/m2) in patients with relapsed and refractory myeloma who were heavily pretreated and were no longer responding to Velcade and either Revlimid or Thalomid.

• Of the 39 evaluable patients, 18% achieved a partial response.
• The responses were durable, lasting a median of 7.4 months.
• The median time until the disease started to progress was 5.1 months.
• Carfilzomib was well tolerated for up to a year, with fatigue, anemia, and low platelet counts the most common side effects reported.
• There was a low rate of peripheral neuropathy, a common side effect of the proteasome inhibitor Velcade, with only 2% of patients experiencing severe neuropathy.

A second trial (PX-171-004) evaluated carfilzomib in patients with relapsed or refractory myeloma after 1 to 3 prior therapies.

• In patients who had never received Velcade (n=54), an interim analysis showed that carfilzomib (20 mg/m2) led to an overall response rate of 46%.
• 2% of patients achieved a complete response (CR), 9% achieved a very good partial response (VGPR), and 35% achieved a partial response (PR).
• Responses were durable, lasting a median of 8.4 months.
• The median time until the disease started to progress was 7.6 months.
• The overall response rate was increased to 53% when a higher dose of carfilzomib (27 mg/m2) was given following the initial 20 mg/m2 dose.
  
  
• In patients who had previously received Velcade and stopped responding to it (n=33), the overall response rate was 18%, including 3% CR, 3% VGPR, and 12% PR.
• The median time until the disease started to progress was 5.3 months.
• Responses lasted a median of 10.6 months.
  
  
• Carfilzomib was well tolerated for up to a year, with fatigue, gastrointestinal effects, and shortness of breath being the most commonly reported side effects.
• Peripheral neuropathy was infrequently seen, and severe neuropathy was rare, despite the fact that more than half of patients already had peripheral neuropathy at the start of the study.

In both of these Phase II studies:

• Carfilzomib was as effective in patients with various cytogenetic abnormalities that often indicate a poor prognosis as those who did not have them.
• Reports of peripheral neuropathy and other nerve disorders were generally mild and did not result in missed doses or discontinuations of carfilzomib.

Combination Studies Carfilzomib was also evaluated in combination with Revlimid and low-dose dexamethasone in relapsed myeloma in a Phase I trial. Patients had received 1 to 3 previous treatments, including Velcade, Revlimid, and/or Thalomid. The study was designed to evaluate the safety, early efficacy, and maximum tolerated dose of various carfilzomib (15 – 27 mg/m2) and Revlimid dose (10 – 25 mg) combinations.

• The overall response rate in the 29 evaluable patients was 59%, including 21% of patients achieving a complete or near-complete response.
• Responses improved with continued therapy.
• The combination was well tolerated at the highest dose levels tested, with expected and manageable hematologic toxicities seen.
• The highest doses of carfilzomib and Revlimid continue to be evaluated in an expansion of the study.

How is Carfilzomib currently being studied in myeloma?

Carfilzomib is being evaluated in several Phase II clinical trials:

• As single-agent therapy in relapsed or relapsed and refractory myeloma (PX-171-003-A1). This is an expansion of the first Phase II study described earlier, using a higher dose of carfilzomib (27 mg/m2 following an initial 20 mg/m2 dose).
• As maintenance therapy in patients who achieved stable disease or better in a prior carfilzomib study.
• In patients with relapsed and refractory myeloma who also have impaired kidney function

Carfilzomib is also being evaluated in two Phase I trials in newly diagnosed, previously untreated myeloma:

• In combination with Revlimid-dex
• In combination with cyclophosphamide, Thalomid, and dexamethasone

A phase III trial is underway to evaluate carfilzomib in combination with Revlimid and low-dose dexamethasone in patients with relapsed myeloma.

Click here to go to the MMRF Clinical Trial Matching Service.