Three studies shed light on carfilzomib, a novel, highly selective proteasome inhibitor
Multi-centre clinical trial results demonstrate safety and efficacy of carfilzomib for newly diagnosed and relapsed multiple myeloma patients
- Date : 30 Jul 2012
- Topic : Haematologic malignancies
Carfilzomib is a novel, highly selective proteasome inhibitor, also known by its branded name Kyprolis™. On July 20 the USA Food and Drug Administration (FDA) approved carfilzomib as a new treatment for advanced multiple myeloma. The treatment was fast-tracked due to the unmet needs in multiple myeloma. Researchers reported recently in Blood, a peer-reviewed scientific journal of the American Society of Haematology, results from three separate multi-centre studies with carfilzomib.
The most recent Blood study, published online on 25 July, includes results from the open-label, single arm phase IIb 003-A1 study of single-agent carfilzomib for patients with relapsed and refractory multiple myeloma. Carfilzomib's New Drug Application (NDA) is based primarily on this study. This research, along with the two other Blood studies, may change the way multiple myeloma is managed for newly diagnosed and relapsed/refractory patients.
Phase IIb clinical trial data
Dr David Siegel of the John Theurer Cancer Centre at Hackensack University, USA was the lead investigator of this pivotal multi-centre, phase IIb study involving 30 cancer centres in the United States and Canada. The trial evaluated 266 heavily-pretreated patients with relapsed and refractory multiple myeloma who had received at least two prior therapies, including bortezomib and either thalidomide or lenalidomide.
The researchers found that carfilzomib produced clinically significant responses with an acceptable safety profile in heavily pretreated patients with relapsed and refractory multiple myeloma. Given the limited number of treatment options available to patients in that stage of multiple myeloma and the diminished prospects for retreatment once an agent has been utilized, there is significantly unmet need in this patient population, according to Dr Siegel.
Two hundred and sixty-six patients received single agent carfilzomib twice weekly for 3 out of 4 weeks. The study's primary endpoint was overall response rate (≥partial response) and secondary endpoints included clinical benefit response rate (≥minimal response), duration of response, time to progression, progression-free survival, overall survival, and safety.
Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events were manageable without cumulative toxicities. The researchers concluded that durable responses and an acceptable tolerability profile in this heavily-pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit.
Phase I/II results for front-line therapy for newly diagnosed multiple myeloma patients
The study was published on June 4 in Blood, and involved researchers from six leading cancer centres. This multi-centre, open-label phase I/II study looked at carfilzomib in combination with lenalidomide and low-dose dexamethasone as a front-line treatment for multiple myeloma.
Triple-agent regimens with bortezomib, lenalidomide, and/or thalidomide are currently the preferred front-line strategy for newly diagnosed multiple myeloma. However, maintaining dose levels over time can be limited by toxicities. According to Dr Vesole, the study co-author, this study demonstrated that the combination of carfilzomib, lenalidomide and dexamethasone is well tolerated and highly active for these patients.
The researchers enrolled 53 patients with newly-diagnosed multiple myeloma who had symptomatic disease. Patients received low-dose dexamethasone induction therapy in 28-day cycles for up to eight cycles or until disease progression or unacceptable toxicity. After eight cycles, patients received maintenance low-dose dexamethasone for up to 24 cycles and then moved to a single-agent lenalidomide.
During phase I, the primary endpoints were safety and determination of the maximum tolerated dose of carfilzomib within the context of low-dose dexamethasone combination therapy. Carfilzomib doses were escalated, while lenalidomide and dexamethasone were given at standard low-dose induction levels. Once the maximum tolerated dose of carfilzomib was reached, the researchers began phase II with a primary endpoint of near complete response. Secondary endpoints were overall response rate, time on study, duration of response, progression-free survival, time to progression, overall survival and overall treatment toxicity.
Study results indicated that patients experienced a rapid and good initial response to low-dose dexamethasone, and their responses improved as the trial continued. Of the 49 patients who completed four treatment cycles, 67% achieved at least near complete response, with 45% in stringent complete response, defined as no detectable tumour cells or myeloma protein in the blood or bone marrow. Of the 36 patients who completed eight or more treatment cycles, 78% achieved near complete response with 61% in stringent complete response. Overall, 62% of trial participants achieved at least near complete response, with 42% achieving stringent complete response. The investigators also found progression-free survival rates were 97% at 12 months and 92% at 24 months. All patients who achieved stringent complete response continued to respond to therapy for a median of nine months, demonstrating the durability of responses to this regimen. Importantly, these periods of extended treatment were well tolerated, including low rates of peripheral neuropathy, a treatment-limiting side effect of bortezomib, the first-generation proteasome inhibitor.
Bortezomib is currently FDA approved to treat advanced multiple myeloma, however, it has been shown to cause peripheral neuropathy in approximately 38% of treated patients with subcutaneous administration.
Phase II 004 clinical trial results for advanced myeloma
An 18-center, phase II open-label efficacy and safety clinical trial, also known as 004, of carfilzomib in combination with bortezomib, another proteasome inhibitor, was published in the June 14 issue of Blood.
The researchers saw significant responses in patients considered more difficult to treat, including those with more advanced disease and poor prognoses. According to Dr Siegel, the senior author of the study, the results support the potential use of carfilzomib in this patient population.
The researchers enrolled 129 patients with multiple myeloma who had relapsed following one to three previous courses of treatment. Patients treated with bortezomib were excluded, as it is in the same drug class as carfilzomib and its use might make the effect of carfilzomib more difficult to determine. The study's primary endpoint was overall response rate. Researchers also measured patients' responses at various intervals as well as time to disease progression, and recorded adverse events to treatment.
The most common adverse events in the study were fatigue (62%) and nausea (48.8%), while 17.1% of patients developed peripheral neuropathy, mostly grades 1 and 2. Peripheral neuropathy has been reported in 37-70% of myeloma patients receiving other commonly used drug therapies.
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