Carfilzomib (PR-171)

What is Carfilzomib?

Carfilzomib is an intravenously administered proteasome inhibitor being developed by Onyx Pharmaceuticals, with several trials 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.

Carfilzomib was granted fast track designation by the US Food and Drug Administration (FDA) in January 2011. Onyx Pharmaceuticals completed its submission of a New Drug Application (NDA) for potential accelerated approval of carfilzomib in the United States.

What do we know about Carfilzomib's 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 four Phase II trials, three of which were facilitated by the MMRC, have demonstrated that carfilzomib has notable activity when given as a single agent.

Learn More: See how the MMRC has helped to advance clinical development of carfilzomib.

 

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.

A second trial (PX-171-004) evaluated carfilzomib in patients with relapsed or refractory myeloma after 1 to 3 prior therapies. In this study, carfilzomib exhibited one of the highest single-agent response rates and longest durations of responses seen in this patient population.

• In patients who had never received Velcade (n=53), an interim analysis showed that carfilzomib (20 mg/m²) led to an overall response rate of 45%.
• 2% of patients achieved a complete response (CR), 13% achieved a very good partial response (VGPR), and 30% achieved a partial response (PR).
• The overall response rate was increased to 55% when a higher dose of carfilzomib (27 mg/m²) was given following the initial 20 mg/m² dose.
• Updated data on 123 evaluable patients show similar results, with an overall response rate of 51% in patients receiving the higher dose.
• Responses were durable, lasting a median of 13.1 months in the group receiving the lower dose of carfilzomib. The group receiving the higher dose of carfilzomib has only been followed for 10.3 months, so the median duration of response has not yet been reached.
  
  
• In patients who had previously received Velcade and stopped responding to it (n=34), the overall response rate was 21%, including 9% VGPR, and 12% PR.
• The median time until the disease started to progress was 8.1 months.
• Responses lasted a median of 11.5 months.
  
  
• Carfilzomib was well tolerated for over 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 nearly half of patients already had peripheral neuropathy at the start of the study.

A third trial (PX-171-005) evaluated carfilzomib in patients with relapsed or refractory myeloma who also had reduced kidney function.

• Results from this study show that carfilzomib can be safely given to patients with renal impairment without any dose adjustments.

A fourth trial (PX-171-003-A1) is evaluating carfilzomib in patients with relapsed and refractory myeloma. This is an expansion of the first Phase II study described earlier, using the higher dose of carfilzomib (27 mg/m² following an initial 20 mg/m² dose). Patients had received a median of five prior lines of therapy (comprising 13 anti-myeloma agents) and had progressive disease upon entering this Phase IIb trial, which enrolled 266 patients.

• Results of this trial show that 24% of patients achieved a partial response or better.
• The median duration of response was 7.8 months.
• The median overall survival for all patients was 15.5 months. However, overall survival for patients who responded to treatment with a minimal response or better has not yet been reached.
• Carfilzomib was as effective in patients with high-risk disease as it was in patients with low-risk disease, and response and survival were not affected by the presence of high-risk cytogenetic features.
• In patients who already had peripheral neuropathy, it did not affect their response to carfilzomib or its tolerability.
• Carfilzomib was active in patients who had previously stopped responding to Velcade.
• Data from this trial will be used to support the registrational filing for accelerated approval of carfilzomib with the FDA, given the high response rates in patients who had largely run out of treatment options.

In all 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.
• Carfilzomib was well-tolerated, which has permitted prolonged administration of the drug.
• Low blood cell and platelet counts were the main serious side effects seen.
• Reports of peripheral neuropathy and other nerve disorders were generally mild and did not result in missed doses or discontinuations of carfilzomib.
  
  

Carfilzomib administered as maintenance therapy also appears to maintain disease control and is well-tolerated, according to results of an ongoing Phase II study.

• The study, which is monitoring the safety and efficacy of a maintenance therapy schedule for patients who previously received carfilzomib as part of a clinical trial and achieved at least stable disease, suggests that the agent can be administered for an extended period of time.
• Patients receive carfilzomib according to their original schedule or an alternate week schedule at an increased dose.
  
  

Combination Studies

Carfilzomib was also evaluated in combination with Revlimid and low-dose dexamethasone in relapsed myeloma in a Phase I trial (PX-171-006). 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 51 evaluable patients receiving full doses of the combination therapy was 78%, including 24% of patients achieving a complete or near complete response and 18% achieving a very good partial response.
• Responses improved with continued therapy and median duration of response has not yet been reached.
• The combination was well tolerated at the highest dose levels tested, with expected and manageable hematologic toxicities seen. Some patients have received therapy for up to 23 months.
• The highest doses of carfilzomib and Revlimid continue to be evaluated in an expansion of the study.

Carfilzomib has been shown to be active in advanced relapsed and refractory disease when combined with other anti-myeloma therapies, with improvement in disease seen in over half of the patients.

• As part of a Phase II study, 74 enrolled patients initially received carfilzomib along with dexamethasone, and other agents could be added if a partial response was not achieved.
• The overall response rate was 37%, including 18% of patients achieving a complete or near complete response.
• Overall survival was 42% at 12 months.
  
  

Combination Studies in Newly Diagnosed Myeloma

Carfilzomib is also being evaluated in combination with Revlimid and low-dose dexamethasone in patients with newly diagnosed myeloma in a Phase I/II MMRC trial. The trial includes both transplant and non-transplant candidates. Interim results from the Phase I portion of the trial show the combination to be well tolerated and highly active.

• After 4 cycles, 100% of the 22 patients in this portion of the study achieved a clinical benefit, including 36% achieving a stringent complete (sCR), complete (CR), or near-complete response (nCR).
• Of the 12 patients who had received 8 cycles, 67% had achieved a sCR, CR, or nCR.

How is Carfilzomib currently being studied in myeloma?

Carfilzomib is being studied in relapsed and/or refractory disease as well as upfront therapy for patients with newly diagnosed disease.

Relapsed/Refractory Myeloma

Two Phase III trials are underway to evaluate carfilzomib in the relapsed/refractory setting.

• The ASPIRE study (CArfilzomib, Lenalidomide, and DexamethaSone versus aLenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma, PX-171-009) trial is an international study that is evaluating carfilzomib in combination with Revlimid and low-dose dexamethasone in patients with relapsed myeloma. This study will enroll approximately 700 patients who have received one to three prior therapies and will compare the effect of this three-drug combination on time to disease progression with that seen with Revlimid-low-dose dexamethasone.
  
  
• The FOCUS (CarFilzOmib for AdvanCed Refractory MUltiple Myeloma European Study, PX-171-011) trial is comparing carfilzomib to best supportive care in patients with relapsed and refractory myeloma who have received at least three prior therapies. This randomized trial is expected to enroll 300 patients across Europe and is designed to support registrational filing with the European regulatory agency. It will determine the effect of carfilzomib on overall survival.

Several Phase I and II studies of carfilzomib in relapsed and/or refractory myeloma are underway, including in combination with:

• Doxil® (pegylated liposomal doxorubicin)
• Panobinostat (LBH589), which is set to begin
• Revlimid, Zolinza™ (vorinostat, Merck), and dexamethasone, which is set to begin
• ARRY-520 (Array BioPharma), which is set to begin

A Phase I study is also being conducted whereby patients who have progressed on or relapsed after receiving a Velcade-containing combination therapy will receive treatment with carfilzomib in place of Velcade.

Newly Diagnosed Myeloma

Carfilzomib is also being evaluated in several early-stage clinical trials in newly diagnosed, previously untreated myeloma:

• In combination with Revlimid and dexamethasone (two trials)
• In combination with cyclophosphamide, Thalomid, and dexamethasone

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