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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 ...

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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 pathays         (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 
                                                    
                                                produon             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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...Prescriber s corner carfilzomib j michael vozniak pharmd bcop from hospital of the university ultiple myeloma event free survival months and pennsylvania philadelphia mm a b cell ma overall kumar author disclosures potential conflicts lignancy in which et al treatment manage interest are found at end this article mthere is an expan ment patients with relapsed correspondence to sion accumulation abnor refractory rr complicated pennsyl mal plasma cells bone mar by symptoms disease as vania department pharmacy silverstein row dimopoulos terpos well side effects associated building pa e mail uphs upenn edu accounts for all hemato treatments laubach harborside press logic cancers estimat van de donk ed new cases will proteasome inhibition be diagnosed deaths effective approach expected united states mcbride ryan two american cancer society inhibitors approved siegel naishadham jemal us food drug adminis characteristic tration fda include calcium elevation bortezomib velcade renal insufficie...

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