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PRESCRIBER'S CORNER Carfilzomib J. MICHAEL VOZNIAK, PharmD, BCOP From Hospital of the University of ultiple myeloma event-free survival of 5 months and Pennsylvania, Philadelphia, Pennsylvania (MM), a B-cell ma- overall survival of 9 months (Kumar Author's disclosures of potential conflicts of lignancy in which et al., 2012). Treatment and manage- interest are found at the end of this article. Mthere is an expan- ment of patients with relapsed and Correspondence to: J. Michael Vozniak, PharmD, sion and accumulation of abnor- refractory (RR) MM is complicated BCOP, Hospital of the University of Pennsyl- mal plasma cells in the bone mar- by the symptoms of the disease as vania, Department of Pharmacy, Silverstein row (Dimopoulos & Terpos, 2010), well as side effects associated with Building, Philadelphia, PA 19104. E-mail: michael.vozniak@uphs.upenn.edu accounts for 10% of all hemato- the treatments (Laubach et al., 2011; © 2013 Harborside Press® logic cancers. In 2013, an estimat- van de Donk et al., 2011). ed 22,350 new cases of MM will Proteasome inhibition is an be diagnosed and 10,710 deaths effective treatment approach for are expected in the United States MM (McBride & Ryan, 2013). Two (American Cancer Society [ACS], proteasome inhibitors approved 2013; Siegel, Naishadham, & Jemal, by the US Food and Drug Adminis- 2012). Characteristic symptoms of tration (FDA) for the treatment of MM include calcium elevation, MM are bortezomib (Velcade) and renal insufficiency, anemia, and carfilzomib (Kyprolis). Bortezomib, lytic bone lesions, commonly re- a dipeptidyl boronic acid derivative ferred to by the mnemonic CRAB proteasome inhibitor, was approved (Dimopoulos & Terpos, 2010; for the treatment of MM nearly 10 Raab, Podar, Breitkreutz, Richard- years ago (Rajkumar, Richardson, son, & Anderson, 2009). Hideshima, & Anderson, 2005). The survival rate for patients Carfilzomib is a selective protea- diagnosed with MM has significant- some inhibitor that was granted ly improved over the past decade FDA approval in 2012 for the treat- with the development of newer ment of patients with MM who have treatments, but MM remains incur- received at least two prior therapies, able (Eshaghian & Berenson, 2012). including bortezomib and an immu- Patients with relapsed disease— nomodulatory agent, and who have especially those who have become demonstrated disease progression J Adv Pract Oncol refractory to available treatments— on or within 60 days of the last treat- 2013;4(Suppl 1):15–21 have a poor prognosis, with median ment (Onyx Pharmaceuticals, 2012). AdvancedPractitioner.com Vol 4 No 6 Suppl 1 Nov/Dec 2013 15 PRESCRIBER'S CORNER VOZNIAK PHARMACOLOGY proteasome inhibitors due to their inherent func- Mechanism of Action tion in antibody production (Kortuem & Stewart, Proteasomes, which are present in all 2013). Carfilzomib and bortezomib both inhibit eukaryotic cells, degrade ubiquitinated proteins constitutive proteasomes and immunoprotea- and thus influence cellular processes, includ- somes present in MM cells (Kuhn, Orlowski, & ing proliferation and DNA repair (Kortuem & Bjorklund, 2011). Stewart, 2013). Proteasome inhibition can also Carfilzomib, an epoxyketone tetrapeptide induce cell cycle arrest and apoptosis by induc- proteasome inhibitor (see Figure), is an analog ing an unfolded protein stress response. The of epoxomycin, a natural proteasome inhibitor constitutive 26S proteasome carries three cata- shown to specifically inhibit the chymotrypsin- lytic sites that can be inhibited by proteasome in- like (CT-L) activity of the 20S proteasome core hibitors: the chymotrypsin, trypsin, and caspase- (Kuhn et al., 2007; Meng et al., 1999). Carfilzo- like sites. Additionally, immunoproteasomes mib is structurally and mechanistically distinct exist in immune or hematopoietic cells. Multiple from bortezomib: The latter forms a reversible myeloma cells are particularly susceptible to bond with the proteasome (Arastu-Kapur et al., 2011; Kortuem & Stewart, 2013), while carfilzomib forms an irreversible, covalent bond with a cata- A Tetrapeptide Epoxyketone lytic site of the proteasome and an analogous site of the immunoproteasome (Demo et al., 2007). Additionally, in preclinical models, carfilzomib OO showed dose- and time-dependent inhibition of H H O proliferation, was more selective than bortezomib N N N N N at therapeutic concentrations, and showed little O O H O H O activity against the trypsin-like or caspase-like ac- tivities of the proteasome (Demo et al., 2007; Kuhn et al., 2007). Moreover, carfilzomib showed signif- icantly less preclinical neurotoxicity and neuro- degeneration than bortezomib (Arastu-Kapur et B + al., 2011). The specificity and irreversible binding of carfilzomib may give it a tolerability advantage Cellular as well as an efficacy advantage over bortezomib protein Ubiquin (Arastu-Kapur et al., 2011; Yang et al., 2011). Protein tagged for degradaon by proteasomes PHARMACOKINETICS/ PHARMACODYNAMICS 26S Proteasome Carfilzomib inhibits the Carfilzomib is extensively metabolized into inactive metabolites (Yang et al., 2011) and has a proteasome and results in: short half-life,with the majority of drug eliminat- • mpaired ell ed from plasma within 30 minutes (Alsina et al., 2012; Badros et al., 2013; O’Connor et al., 2009). proliferaon Carfilzomib is distributed to all tissues except the 20S brain (Demo et al., 2007) and is largely metabo- Core • aon of lized extrahepatically, with < 1% excreted intact apopto pathays (Yang et al., 2011). The rapid clearance of carfilzo- ligases • Upregulaon of mib may contribute to the tolerability of the drug. de novo proteasome A drug interaction study showed that cytochrome produon P450 pathways play only a minor role in carfilzo- mib metabolism (Wang et al., 2013). Clinical stud- ies to date have not demonstrated any need for Figure. (A) Carfilzomib structure and (B) the avoidance of any concomitant medications due to ubiquitin-proteasome pathway. drug-drug interactions (Onyx Pharmaceuticals, J Adv Pract Oncol AdvancedPractitioner.com 16 CARFILZOMIB PRESCRIBER'S CORNER 2012). Both the area under the curve and maxi- tion to 27 mg/m2 is recommended to help reduce mum concentration of carfilzomib increased with the risk of potential flu-like infusion-related increasing carfilzomib doses, but the increases symptoms, including dyspnea. Dexamethasone were not dose-dependent (Alsina et al., 2012; premedication can be reinstated in later cycles if O’Connor et al., 2009). Additionally, renal insuffi- symptoms develop or reappear. ciency does not appear to affect the pharmacoki- netics of carfilzomib (Badros et al., 2013). KEY CLINICAL STUDIES In pharmacodynamic studies of carfilzomib, In phase I trials and a pilot phase II trial, the CT-L activity of the proteasome and the carfilzomib showed efficacy in patients with immunoproteasome were 70% to 80% inhibited RR MM. The phase I trials showed efficacy 2 at lower doses and approximately 90% inhibited both with doses ranging from 1.2 to 20 mg/m 2 after a dose of 27 mg/m ; progressive recovery of on days 1 through 5 of a 14-day cycle (PX-171- proteasome activity occurred at 24 and 72 hours, 001 study) and in a dose-escalation study and complete recovery was observed on day 1, (PX-171-002) using the now approved dosing cycle 2, following a 12-day rest period (Alsina et schedule (O’Connor et al., 2009; Alsina et al., al., 2012; Arastu-Kapur et al., 2011; Demo et al., 2012). In the latter study, 4 of the 9 patients 2 2007; Kuhn et al., 2007; O’Connor et al., 2009). who started carfilzomib at ≥ 20 mg/m had a partial response (PR). In 42 response-evalu- DOSING AND ADMINISTRATION able patients in a pilot phase II study in which 2 Carfilzomib dose is calculated based on the carfilzomib was administered at 20 mg/m (PX- patient’s body surface area at baseline (treatment 171-003-A0), overall response rate (ORR, ≥ PR) initiation). Patients with a body surface area of was 16.7% and the median duration of response 2 > 2.2 m should receive a dose based on a body (DOR) was 7.2 months (Jagannath et al., 2012). 2 surface area of 2.2 m (Onyx Pharmaceuticals, Accelerated approval of carfilzomib was based 2012). Dose adjustments are only necessary for on the efficacy observed in the PX-171-003-A1 weight changes > 20%. Carfilzomib is adminis- phase II study (003-A1) of 266 patients with RR 2 tered at a dose of 20 mg/m in cycle 1 and, if toler- MM in which the current recommended dose and ated, should be increased to 27 mg/m2 beginning schedule were established (Siegel et al., 2012). in cycle 2 and continuing in subsequent cycles. The ORR was 23.7%, progression-free survival Carfilzomib is supplied in single-use vials con- (PFS) was 3.7 months, DOR was 7.8 months in the taining 60 mg sterile lyophilized powder, which 61 patients who achieved ≥ PR, and overall surviv- should be reconstituted with 29 mL sterile water al (OS) was 15.4 months. (Onyx Pharmaceuticals, 2012). Carfilzomib is ad- In the PX-171-004 phase II study, which had ministered intravenously (IV) over 2 to 10 min- a very similar patient population as 003-A1, pa- utes on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. tients were stratified according to their prior The IV catheter should be flushed with 0.9% sa- bortezomib treatment status. In patients who had line or 5% dextrose solution immediately before prior treatment with bortezomib, ORR was 17.1%, and after administration. Carfilzomib should not DOR was > 10.6 months, and the median time to be administered as a bolus. progression (TTP) was 4.6 months (Vij et al., It is recommended that patients receive prop- 2012a). Predictably, the responses were better in er prophylaxis prior to carfilzomib treatment. bortezomib-naive patients, who were separated Immediately prior to carfilzomib administration, into cohorts that received carfilzomib 20 mg/m2 patients should receive 250 to 500 mL of normal (cohort 1) and carfilzomib 20/27 mg/m2 (cohort saline or other appropriate IV fluid and should 2; Vij et al., 2012b). In bortezomib-naive patients, receive the same amount following administra- ORR was 47.6% (42.4% in cohort 1 and 52.2% in tion as needed to reduce the risk of fatigue and cohort 2) and PFS was 8.2 and > 11.5 months, re- other potential adverse events (AEs), including spectively. Duration of response was 13.1 months tumor lysis syndrome and renal toxicities (Onyx for cohort 1 (not reached for cohort 2), and TTP Pharmaceuticals, 2012). Additionally, prophylax- was 12.0 months in both cohorts combined. is with dexamethasone 4 mg prior to all doses in In a fourth phase II study, patients with varying cycle 1 and during the first cycle of dose escala- degrees of renal impairment (including those on di- AdvancedPractitioner.com Vol 4 No 6 Suppl 1 Nov/Dec 2013 17 PRESCRIBER'S CORNER VOZNIAK alysis) were evaluated for ORR. Thirty-six patients and 14.8% discontinued treatment due to an AE with renal impairment had an ORR of 27.7% com- (Siegel et al., 2013). A summary of the most com- pared with an ORR of 25.5% in the overall group (N mon AEs occurring in > 20% of patients receiving = 50; Badros et al., 2013). The subset of 11 patients carfilzomib is presented in Table 1. The greatest without renal insufficiency had an ORR of 18.2%. proportion of AEs were hematologic in nature, In this study, there were no appreciable differences and nonhematologic AEs were mainly grade 1 or 2 in carfilzomib clearance or exposure among the pa- (Onyx Pharmaceuticals, 2012). In the cross-study tients, regardless of renal function. analysis, specific groups of AEs were analyzed in detail, including hematologic, cardiac, and renal ADVERSE EFFECTS effects as well as peripheral neuropathy (PN). Safety data for single-agent carfilzomib have Upon study entry, any grade hematologic AEs been analyzed and summarized in a cross-study were reported in patients as follows: 37.4% throm- analysis of 526 patients with advanced MM who bocytopenia, 65.4% lymphopenia, 64.4% neutro- took part in four phase II trials: 003-A0, 003- penia, and 89.3% anemia. Hematologic AEs were A1, 004, and 005. In this analysis, 14.6% of pa- common in these studies, including anemia in tients required a dose modification or reduction, 46.8% of patients and thrombocytopenia in 37.8% of patients, but were generally transient and not dose-limiting. Among thrombocytopenia, lym- Table 1. Treatment-Emergent Adverse Events in phopenia, neutropenia, and anemia AEs, ≤ 1.1% of > 20% of Patients Across Four Phase II patients required a dose reduction and ≤ 1.0% dis- a Studies and Treatment-Related continued treatment for each (Nooka et al., 2012). b Adverse Events in the 003-A1 Study Overall, 73.6% of patients had a history of Phase II studies 003-A1 cardiovascular events; patients fit this category if (N = 526) (N = 266) they were taking ≥ 1 cardiac medication at study Adverse event, n All grades Grade 3/4 All grades entry. The most common grouped cardiac AEs Hematologic were cardiac arrhythmia (13.3%), cardiac failure Anemia 246 (46.8%) 118 (22.4%) 59 (22.2%) (7.2%), and ischemic heart disease (3.4%). Dose Thrombocytopenia 191 (36.3%) 123 (23.4%) 77 (28.9%) reductions and discontinuations due to a car- Lymphopenia 126 (24.0%) 95 (18.1%) 44 (16.5%) diac AE were low at 1.1% and 4.4%, respectively. Neutropenia 109 (20.7%) 54 (10.3%) 40 (15.0%) There were 8 (1.5%) cardiac-related deaths (all Nonhematologic related to carfilzomib): 5 patients (1.0%) died Fatigue 292 (55.5%) 40 (7.6%) 98 (36.8%) due to a cardiac AE and an additional 3 patients had a cardiac component to their death (Lonial, Nausea 236 (44.9%) 7 (1.3%) 90 (33.8%) Niesvisky, McCulloch, Rajangam, & Vij, 2012). Dyspnea 182 (34.6%) 26 (4.9%)c 45 (16.9%) At baseline, 23.8% of patients had moderate Diarrhea 172 (32.7%) 5 (1.0%) 64 (24.1%) to severe renal dysfunction (creatinine clear- Pyrexia 160 (30.4%) 9 (1.7%) 40 (15.0%) ance [CrCl] < 50 mL/min), and 39.4% had mild Upper RTI 149 (28.3%) 17 (3.2%) 15 (5.6%) renal dysfunction (CrCl ≥ 50 to < 80 mL/min). Headache 145 (27.6%) 7 (1.3%) 46 (17.3%) Overall, 33.1% of patients had ≥ 1 renal AE (78.2% of which were grade 1 or 2), including Cough 137 (26.0%) 1 (0.2%) NR increased blood creatinine (24.1%), acute renal Increased blood 127 (24.1%) 14 (2.7%) 44 (16.5%) failure (ARF, 5.3%), renal failure (3.8%), and creatinine increased blood urea (2.7%). The two deaths Peripheral edema 126 (24.0%) 3 (0.6%) NR attributed to renal AEs were ARF due to septic Vomiting 117 (22.2%) 5 (1.0%) 44 (16.5%) shock and a grade 5 event of “progressive renal Constipation 110 (20.9%) 1 (0.2%) NR failure,” both unrelated to carfilzomib. Overall, Back pain 106 (20.2%) 15 (2.9%) NR 21 patients (4.0%) discontinued treatment due Note. RTI = respiratory tract infection; NR = not reported. to a renal AE, and 19 (10.9%) required a dose a Information from Onyx Pharmaceuticals (2012). reduction. Fifty percent of patients with an ARF b c Information from Siegel et al. (2012). One event was of AE did not require a change in carfilzomib ther- grade 5 severity. apy (Harvey et al., 2012). J Adv Pract Oncol AdvancedPractitioner.com 18
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