Carfilzomib: New Drug with Accelerated Approval for Multiple Myeloma


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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication

In July 2012, carfilzomib (Kyprolis) was granted accelerated approval for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib (Velcade) and an immunomodulatory agent and exhibited disease progression during or within 60 days of completing their last therapy.1

Approval was based on results of a single-arm, multicenter trial of carfilzomib in 266 patients with relapsed multiple myeloma who had received at least two prior therapies, including bortezomib and either thalidomide (Thalomid) or lenalidomide (Revlimid).2,3 Carfilzomib was given by IV infusion over 2 to 10 minutes on 2 consecutive days weekly for 3 weeks followed by a 12-day rest period in each 28-day treatment cycle.

Patients received 20 mg/m2 at each dose in the first cycle and 27 mg/mat each dose in subsequent cycles for a maximum total of 12 cycles. To reduce carfilzomib-associated infusion reactions, patients were premedicated with dexamethasone (4 mg orally or IV) before carfilzomib doses during the first cycle, during the first dose-escalation cycle, and thereafter when symptoms of infusion reaction occurred. The primary outcome measure was overall response rate determined by an independent review committee.

Exclusion criteria included bilirubin levels at least two times the upper limit of normal, creatinine clearance < 30 mL/min, New York Heart Association class III/IV congestive heart failure, symptomatic cardiac ischemia, myocardial infarction within the past 6 months, peripheral neuropathy of grade 2 with pain or grade 3 or 4, and pleural effusion. Patients had a median age of 63 years, with 45% being 65 years of age or older; 58% were male, and 71% were Caucasian. Patients had undergone a median of five prior treatments; 74% had undergone transplantation, and 74% had shown disease progression during their last therapy.

The overall response rate was 22.9%, including 1 complete response, 13 very good partial responses, and 47 partial responses. The median duration of response was 7.8 months.

As a condition of the accelerated approval, Onyx must submit the complete analysis of an ongoing randomized phase III trial comparing carfilzomib, lenalidomide, and low-dose dexamethasone vs lenalidomide/low-dose dexamethasone in patients with relapsed/refractory multiple myeloma after one to three prior therapies. The primary endpoint of this trial is progression-free survival.

How It Works

Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, which is the proteolytic core particle within the 26S proteasome.3 It is a second-generation proteasome inhibitor that exhibits greater selectivity for chymotrypsin-like proteasomal activity than first-generation inhibitors (eg, bortezomib).4 The proteasome is a multicatalytic protein complex that acts to degrade cytosolic and nuclear proteins that are turned over as result of such processes as oxidation, proteolysis, and deamination.

The new drug also plays a regulatory role in cell proliferation by destroying proteins that trigger endoplasmic reticulum stress, cell-cycle progression, cell-signaling, apoptosis, and cell survival pathways. Carfilzomib produces antiproliferative and proapoptotic effects in solid and hematologic tumor cells and delays tumor growth in models of multiple myeloma and other hematologic tumors and solid tumors.

How It Is Given

Carfilzomib is given intravenously over 2 to 10 minutes on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) followed by a 12-day rest period in 28-day treatment cycles. The dose is 20 mg/m2 in the first cycle; if tolerated, the dose is increased to 27 mg/m2 in the second and subsequent cycles.

Patients must be hydrated to reduce the risk of renal toxicity and tumor lysis syndrome; adequate fluid volume status must be maintained throughout treatment, and blood chemistries must be closely monitored. Prior to each dose in cycle 1, patients should receive 250 to 500 mL of IV normal saline or other appropriate IV fluid. An additional 250 to 500 mL of IV fluids should be given as needed following administration, and IV hydration should be continued as needed in subsequent cycles. Patients need to be monitored for fluid overload.

Patients must be premedicated with dexamethasone 4 mg orally or IV prior to all doses during cycle 1, prior to all doses during the first cycle of dose escalation to 27 mg/m2, and thereafter if infusion reaction symptoms occur during subsequent cycles.

The full prescribing information for carfilzomib includes dose-modification guidelines for grade 3 or 4 neutropenia; grade 4 thrombocytopenia; grade 3 or 4 or new onset or worsening of congestive heart failure, left-ventricular dysfunction, and myocardial ischemia; pulmonary hypertension; grade 3 or 4 pulmonary complications; grade 3 or 4 elevation of transaminases or bilirubin or other liver abnormalities; serum creatinine at least two times the baseline value; grade 3 or 4 peripheral neuropathy; and other grade 3 or 4 nonhematologic toxicities.

Safety Profile

The safety of carfilzomib has been evaluated in 526 patients with relapsed multiple myeloma receiving carfilzomib monotherapy in clinical trials.3 The most common adverse events (≥ 30% of patients) were fatigue (55%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%). Serious adverse events occurred in 45% of patients, with the most common being pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%).

Adverse events leading to discontinuation of carfilzomib occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). Death occurred in 37 patients (7%) on-study. The most common causes of death other than underlying disease were cardiac effects (5 patients), end-organ failure (4 patients), and infection (4 patients).

Carfilzomib carries warnings/precautions for cardiac adverse effects including heart failure and ischemia, pulmonary hypertension and pulmonary complications, infusion reactions, tumor lysis syndrome, thrombocytopenia, hepatic toxicity and hepatic failure, and embryo-fetal toxicity.

Cost

The estimated cost of carfilzomib is approximately $10,000 for a 28-day cycle. ■

References

1. U.S. Food and Drug Administration: Approved drugs: Carfilzomib. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm312945.htm.

2. Siegel DS, Martin T, Wang M, et al: A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. July 25, 2012 (early release online).

3. KYPROLISTM (carfilzomib) for injection prescribing information. Onyx Pharmaceuticals, Inc, July 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf.

4. Parlati F, Lee SJ, Aujay M, et al: Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood 114:3439-3447, 2009.



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