Carfilzomib (PR-171)

What are the key facts about Carfilzomib?

• Proteasome inhibitor that is administered as an intravenous infusion.

• When given alone, demonstrated notable activity in four studies in relapsed and/or refractory myeloma, and has one of the highest single-agent response rates (up to 52% in patients who had never received Velcade) and longest durations of responses seen in this patient population.

• When combined with other anti-myeloma therapies, is active in advanced relapsed and refractory disease.

• High interim overall response rate of 94% seen in patients with newly diagnosed myeloma who received carfilzomib with Revlimid-dex. The depth of response increased with longer treatment duration.

• Generally as effective in patients with cytogenetic abnormalities that often indicate a poor prognosis as it was in patients without them.

• Peripheral neuropathy was infrequently seen in clinical studies. Severe neuropathy was rarely seen, even in patients who had pre-existing neuropathy.

• Being evaluated in two Phase III trials in relapsed/refractory myeloma. An international trial is evaluating carfilzomib, Revlimid, and dex (enrollment is complete), and a European trial is evaluating single-agent carfilzomib.

• Patients not eligible to receive carfilzomib as part of a clinical trial may be able to receive it through the Carfilzomib Myeloma Access Program (C-MAP), an expanded access program established by Onyx Pharmaceuticals and the MMRF.

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. In September 2011, Onyx Pharmaceuticals completed its submission of a New Drug Application (NDA) for potential accelerated approval of carfilzomib in the United States. The FDA granted a standard review designation for the NDA in December 2011, which means the FDA will complete its review of the NDA by July 27, 2012.

Learn More: See how Onxy Pharmaceuticals is helping advance personalized treatments for myeloma through its collaboration in support of the MMRF’s Personalized Medicine Initiative.

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 in Relapsed and/or Refractory Myeloma

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 165 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.

• Among the 129 patients in the study who had never received Velcade, the overall response rate was 42% in those patients who received carfilzomib at a dose of 20 mg/m² (n=59).
  
• 3% of patients achieved a complete response (CR), 14% achieved a very good partial response (VGPR), and 25% achieved a partial response (PR).
  
  
• The overall response rate was increased to 52% when a higher dose of carfilzomib (27 mg/m²) was given following the initial 20 mg/m² dose (n=67), including 2% CR, 27% VGPR, and 24% PR.
  
  
• 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 13.8 months, so the median duration of response has not yet been reached.
  
  
• The median overall survival has not yet been reached in either group.
  
• 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,nausea, anemia, shortness of breath, cough, and fever 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 was generally 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 was 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 in relapsed and/or refractory myeloma:

• Carfilzomib was generally as effective in patients with various cytogenetic abnormalities that often indicate a poor prognosis as those who did not have them.
  
  
• The higher dose of carfilzomib appeared to be more effective, as demonstrated by a statistical analysis of data from 430 patients.
  
  
• 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.
  

Maintenence Therapy in Relapsed and/or Refractory Myeloma

Carfilzomib administered as maintenance therapy also appears to maintain disease control and is well-tolerated, according to results of an ongoing Phase II study (PX-171-010).

• 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.
  
  
• No evidence of cumulative toxicity has been demonstrated.

Combination Studies in Relapsed and/or Refractory Myeloma

Carfilzomib was 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 in combination with Revlimid and low-dose dexamethasone (CRd) has demonstrated high response rates in patients with newly diagnosed myeloma in a Phase I/II MMRC trial. The trial includes both transplant and non-transplant candidates. Three doses of carfilzomib (20, 27, and 36 mg/m2) are being evaluated. After 4 cycles, patients eligible for transplant who have a partial response or better undergo stem cell collection for potential future stem cell transplant. After 8 cycles of treatment, all patients continue to receive CRd as maintenance therapy until disease progression or unacceptable toxicity.

Interim results from 49 patients who completed at least 1 month of treatment in the Phase II portion of the study and have been followed for a median of 9.5 months show the combination to be well tolerated and highly active.

• Overall, 94% of patients responded to treatment, with 53% of patients achieving a stringent complete (sCR), complete (CR), or near-complete response (nCR).
  
  
• Similar responses were seen in patients with unfavorable cytogenetic abnormalities and those with normal or favorable cytogenetic abnormalities.
  
  
• The depth of response increased with longer treatment duration. After 12 or more treatment cycles, all patients had achieved a VGPR or better and the percentage of patients achieving an sCR, CR, or nCR increased to 79%.
  
  
• CRd was well tolerated and the majority of patients remained on study treatment. Only mild-to-moderate peripheral neuropathy was seen, despite the long duration of treatment.
  

Carfilzomib is also being evaluated in combination with Thalomid (thalidomide, Celgene) and dexamethasone as induction therapy prior to stem cell transplantation in a Phase II study in Europe. After transplant, patients also receive 4 additional cycles of therapy as consolidation.

A total of 34 patients have received the therapy, which is also referred to as CARTHADEX. After induction, 84% of patients achieved a partial response or better, including 16% who achieved an sCR or CR. As with CRd, only mild-to moderate neuropathy was seen.

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 recently reached its target enrollment of 780 patients who had received one to three prior therapies and is comparing the effect of this three-drug combination on time to disease progression with that seen with Revlimid-low-dose dexamethasone. This study is designed to support regulatory approval of carfilzomib for use in relapsed myeloma.
  
  
• 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) (three studies, including one that is being facilitated by the MMRC)
  
  
• Revlimid, Zolinza™ (vorinostat, Merck), and dexamethasone
  
  
• ARRY-520 (Array BioPharma)
  
  
• Pomalidomide and dexamethasone
  

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.

A study is planned to compare the efficacy and safety of carfilzomib with Velcade in patients with relapsed and refractory myeloma.

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, one of which is being facilitated by the MMRC)
  
  
• 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.