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Mechanism Of Action
Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors.
Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like (CT-L) activity when measured in blood 1 hour after the first dose. Doses of carfilzomib ≥ 15 mg/m² with or without lenalidomide and dexamethasone induced a ≥ 80% inhibition of the CT-L activity of the proteasome. In addition, carfilzomib 20 mg/m² intravenously as a single agent, resulted in a mean inhibition of the low molecular mass polypeptide 2 (LMP2) and multicatalytic endopeptidase complex-like 1 (MECL1) subunits of the proteasome ranging from 26% to 32% and 41% to 49%, respectively. Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing.
The Cmax and AUC following a single intravenous dose of 27 mg/m² was 4232 ng/mL and 379 ng•hr/mL, respectively. Following repeated doses of carfilzomib at 15 and 20 mg/m², systemic exposure (AUC) and half-life were similar on Days 1 and 15 or 16 of Cycle 1, suggesting there was no systemic carfilzomib accumulation. At doses between 20 and 36 mg/m², there was a dose-dependent increase in exposure.
The mean steady-state volume of distribution of a 20 mg/m² dose of carfilzomib was 28 L. When tested in vitro, the binding of carfilzomib to human plasma proteins averaged 97% over the concentration range of 0.4 to 4 micromolar.
Carfilzomib was rapidly and extensively metabolized. The predominant metabolites measured in human plasma and urine, and generated in vitro by human hepatocytes, were peptide fragments and the diol of carfilzomib, suggesting that peptidase cleavage and epoxide hydrolysis were the principal pathways of metabolism. Cytochrome P450-mediated mechanisms played a minor role in overall carfilzomib metabolism. The metabolites have no known biologic activity.
Following intravenous administration of doses ≥ 15 mg/m², carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on Day 1 of Cycle 1. The systemic clearance ranged from 151 to 263 L/hour, and exceeded hepatic blood flow, suggesting that carfilzomib was largely cleared extrahepatically. In 24 hours, approximately 25% of the administered dose of carfilzomib was excreted in urine as metabolites. Urinary and fecal excretion of the parent compound was negligible (0.3% of total dose).
Population pharmacokinetic analyses that included patients ranging from 35 to 87.6 years of age indicate that the pharmacokinetics of carfilzomib are not influenced by age.
Population pharmacokinetic analyses indicate that the pharmacokinetics of carfilzomib are not influenced by gender.
No dedicated studies have been completed in patients with hepatic impairment.
A pharmacokinetic study was conducted in which 50 multiple myeloma patients who had various degrees of renal impairment and who were classified according to their creatinine clearances (CLcr) into the following groups: normal function (CLcr > 80 mL/min, n = 12), mild impairment (CLcr 50–80 mL/min, n = 12), moderate impairment (CLcr 30–49 mL/min, n =10), severe impairment (CLcr < 30 mL/min, n = 8), and chronic dialysis (n = 8). Kyprolis, as a single agent, was administered intravenously over 2 to 10 minutes, on two consecutive days, weekly for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period every 28 days. Patients received an initial dose of 15 mg/m², which could be escalated to 20 mg/m² starting in Cycle 2 if 15 mg/m² was well tolerated in Cycle 1. In this study, renal function status had no effect on the clearance or exposure of carfilzomib following a single or repeat-dose administration [see Use in Specific Populations].
Cytochrome P450: In an in vitro study using human liver microsomes, carfilzomib showed modest direct (Ki = 1.7 micromolar) and time-dependent inhibition (Ki = 11 micromolar) of human cytochrome CYP3A4/5. In vitro studies indicated that carfilzomib did not induce human CYP1A2 and CYP3A4 in cultured fresh human hepatocytes. Cytochrome P450-mediated mechanisms play a minor role in the overall metabolism of carfilzomib. A clinical trial of 17 patients using oral midazolam as a CYP3A probe demonstrated that the pharmacokinetics of midazolam were unaffected by concomitant carfilzomib administration. Kyprolis is not expected to inhibit CYP3A4/5 activities and/or affect the exposure to CYP3A4/5 substrates.
P-gp: Carfilzomib is a P-glycoprotein (P-gp) substrate. In vitro, carfilzomib inhibited the efflux transport of P-gp substrate digoxin by 25% in a Caco-2 monolayer system. However, given that Kyprolis is administered intravenously and is extensively metabolized, the pharmacokinetics of Kyprolis is unlikely to be affected by P-gp inhibitors or inducers.
Animal Toxicology And/Or Pharmacology
Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m² based on body surface area) experienced hypotension, increased heart rate, and increased serum levels of troponin-T. The repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m² based on body surface area. The dose of 2 mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on body surface area.
In Combination With Lenalidomide And Dexamethasone For The Treatment Of Patients With Relapsed Multiple Myeloma
Study 1 was a randomized, open-label, multicenter study which evaluated the combination of Kyprolis with lenalidomide and low-dose dexamethasone (KRd) versus lenalidomide and low-dose dexamethasone alone (Rd) in patients with relapsed multiple myeloma who had received 1 to 3 prior lines of therapy. (A line of therapy is a planned course of treatment (including sequential induction, transplantation, consolidation and/or maintenance) without an interruption for lack of efficacy, such as for relapse or progressive disease.) Patients who had the following were excluded from the trial: refractory to bortezomib in the most recent regimen, refractory to lenalidomide and dexamethasone in the most recent regimen, creatinine clearance rates < 50 mL/min, New York Heart Association Class III to IV congestive heart failure, or myocardial infarction within the last 4 months. Kyprolis treatment was administered for a maximum of 18 cycles unless discontinued early for disease progression or unacceptable toxicity. Lenalidomide and dexamethasone administration could continue until progression or unacceptable toxicity.
The 792 patients in Study 1 were randomized 1:1 to the KRd or Rd arm. The demographics and baseline characteristics were well-balanced between the two arms (see Table 9). Only 53% of the patients had testing for genetic mutations; a high-risk genetic mutation was identified for 12% of patients in the KRd arm and in 13% in the Rd arm.
Table 9: Demographics and Baseline Disease
Characteristics in Study 1 (Combination Therapy for Relapsed Multiple Myeloma)
|Characteristic||KRd Combination Therapy|
(N = 396)
(N = 396)
|Age, Median Years (min, max)||64.0 (38, 87)||65.0 (31, 91)|
|Age Group, ≥ 75 Years, n (%)||43 (11)||53 (13)|
|Males, n (%)||215 (54)||232 (59)|
|Race, n (%)|
|White||377 (95)||377 (95)|
|Black||12 (3)||11 (3)|
|Othera||7 (2)||8 (2)|
|Number of Prior Regimens|
|1||184 (46%)||157 (40%)|
|2||120 (30%)||139 (35%)|
|3b||92 (23%)||100 (25%)|
|Prior Transplantation||217 (55%)||229 (58%)|
|0||165 (42)||175 (44)|
|1||191 (48)||186 (47)|
|2||40 (10)||35 (9)|
|ISS Stage at study baseline, n (%)|
|I||167 (42%)||154 (39%)|
|II||148 (37%)||152 (38%)|
|III||73 (18%)||82 (21%)|
|CrCL, mL/min Median (min, max)||78.6 (38.7, 211.9)||79.2 (30.0, 207.8)|
|30 to < 50, n (%)||19 (5)||32 (8)|
|50 to < 80, n (%)||185 (47)||170 (43)|
|Refractory to Last Therapy, n (%)||(28%)||(30%)|
|Refractory at any time to (%):|
|Bortezomib + IMiD||(6%)||(7%)|
|ECOG PS = Eastern Cooperative Oncology Group Performance
Status; CrCL= creatinine clearance; IgG = immunoglobulin G; IMiD =
immunomodulators; ISS = International Staging System; KRd = Kyprolis,
lenalidomide, and low-dose dexamethasone; Rd = lenalidomide and low-dose dexamethasone
a Includes Other, Asian/Native Hawaiian/Other Pacific Islander, or American Indian or Alaska Native.
b Including 2 patients with 4 prior regimens.
Patients in the Kyprolis, Revlimid (lenalidomide), and low-dose dexamethasone (KRd) arm demonstrated improved progression-free survival (PFS) compared with those in the lenalidomide and low-dose dexamethasone (Rd) arm (HR = 0.69, with 2-sided p-value = 0.0001) as determined using standard objective International Myeloma Working Group (IMWG)/European Blood and Marrow Transplantation (EBMT) response criteria by an Independent Review Committee (IRC).
The median PFS was 26.3 months (95% CI: 23.3 to 30.5 months) in the KRd arm versus 17.6 months (95% CI: 15.0 to 20.6 months) in the lenalidomide and low-dose dexamethasone (Rd) arm (see Table 10).
The results of overall survival (OS) were not significantly different at the interim analysis (Figure 2).
Table 10: Efficacy Outcomes in Study 1 (Combination
Therapy for Relapsed Multiple Myeloma)
|KRd Combination Therapy|
(N = 396)
(N = 396)
|PFS Months Median (95% CI)||26.3 (23.3, 30.5)||17.6 (15.0, 20.6)|
|HR (95% CI); 2-sided p-valueb||0.69 (0.57, 0.83); 0.0001|
|ORR n (%)||345 (87)||264 (67)|
|sCR||56 (14)||17 (4)|
|CR||70 (18)||20 (5)|
|VGPR||151 (38)||123 (31)|
|PR||68 (17)||104 (26)|
|CI = confidence interval; CR = complete response; EBMT =
European Blood and Marrow Transplantation; IMWG = International Myeloma Working
Group; KRd = Kyprolis, lenalidomide, and low-dose dexamethasone; ORR = overall
response rate; PFS = progression-free survival; Rd = lenalidomide and low-dose
dexamethasone; sCR = stringent complete response; VGPR = very good partial
a As determined by an Independent Review Committee using standard objective IMWG/EBMT response criteria.
b Statistically significant.
The median duration of response was 28.6 months (95% CI: 24.9 to 31.3 months) for the 345 patients achieving a response in the KRd arm and 21.2 months (95% CI: 16.7 to 25.8 months) for the 264 patients achieving a response in the Rd arm. The median time to response was 1 month (range 1 to 14 months) in the KRd arm and 1 month (range 1 to 16 months) in the Rd arm.
Figure 1: Kaplan-Meier Curve of Progression-Free
Survival in Relapsed Multiple Myeloma in Study 1
CI = confidence interval; EBMT = European Blood and Marrow Transplantation; HR = hazard ratio; IMWG = International Myeloma Working Group; KRd = Kyprolis, lenalidomide, and low-dose dexamethasone; mo = months; PFS = progression-free survival; Rd = lenalidomide and low-dose dexamethasone arm
Note: The response and PD outcomes were determined using standard objective IMWG/EBMT response criteria.
Figure 2: Kaplan-Meier Curve of Interim Overall
Survival in Relapsed Multiple Myeloma in Study 1
KRd = Kyprolis, lenalidomide, and low-dose dexamethasone; NE = not estimable; OS = overall survival; PFS = progression-free survival; Rd = lenalidomide and low-dose dexamethasone arm Note: The interim OS analysis did not meet the protocol-specified early stopping boundary for OS.
Monotherapy For Treatment Of Patients With Relapsed And Refractory Multiple Myeloma
Study 2 was a single-arm, multicenter clinical trial of Kyprolis monotherapy. Eligible patients were those with relapsed multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) and had less than or equal to 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. Patients were excluded from the trial if they were refractory to all prior therapies, or with total bilirubin levels ≥ 2 × upper limit of normal (ULN); creatinine clearance rates < 30 mL/min; New York Heart Association Class III to IV congestive heart failure; symptomatic cardiac ischemia; myocardial infarction within the last 6 months; peripheral neuropathy Grade 3 or 4, or peripheral neuropathy Grade 2 with pain; active infections requiring treatment; or pleural effusion.
Kyprolis was administered intravenously over 2 to 10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. Patients received 20 mg/m² at each dose in Cycle 1, and 27 mg/m² in subsequent cycles. Dexamethasone 4 mg orally or intravenously was administered prior to Kyprolis doses in the first and second cycles.
A total of 266 patients were enrolled. Baseline patient and disease characteristics are summarized in Table 11.
Table 11: Demographics and Baseline Disease
Characteristics in Study 2 (Monotherapy for Relapsed and Refractory Multiple
|Characteristic||Number of Patients (%)|
|Enrolled patients||266 (100)|
|Median age, years (range)||63.0 (37, 87)|
|Age group, < 65 / ≥ 65 (years)||146 (55) / 120 (45)|
|Gender (male / female)||155 (58) / 111 (42)|
|Race (White / Black / Asian / Other)||190 (71) / 53 (20) / 6 (2) / 17 (6)|
|Number of Prior Regimens (median)||5a|
|Prior Transplantation||198 (74)|
|Refractory Status to Most Recent Therapyb|
|Refractory: Progression during most recent therapy||198 (74)|
|Refractory: Progression within 60 days after completion of most recent therapy||38 (14)|
|Refractory: ≤ 25% response to treatment||16 (6)|
|Relapsed: Progression after 60 days post treatment||14 (5)|
|Years since diagnosis, median (range)||5.35 (0.5, 22.3)|
|Plasma cell involvement ( < 50% / ≥ 50% / unknown or missing)||143 (54) / 106 (40) / 17 (6)|
|ISS, n (%)|
|Cytogenetics or FISH analyses|
|Poor Prognosis||75 (28)|
|Unknown/Not tested||32 (12)|
|Creatinine clearance < 30 (mL/min)||6 (2)|
|a Range: 1, 20.
b Categories for refractory status are derived by programmatic assessment using available laboratory data.
The median number of cycles started was four.
The primary endpoint was the overall response rate (ORR) as determined by Independent Review Committee assessment using International Myeloma Working Group criteria. The ORR (stringent complete response [sCR] + complete response [CR] + very good partial response [VGPR] + partial response [PR]) was 22.9% (95% CI: 18.0, 28.5) (N = 266) (see Table 12). The median duration of response (DOR) was 7.8 months (95% CI: 5.6, 9.2).
Table 12: Response Categories
|Characteristic||Study Patients n (%)|
|Number of Patients (%)||266 (100)|
|Complete Response||1 (0)|
|Very Good Partial Response||13 (5)|
|Partial Response||47 (18)|
|Overall Response||61 (23)|
|95% CIb||(18.0, 28.5)|
|a As assessed by the Independent Review
b Exact confidence interval.
Last reviewed on RxList: 9/14/2015
This monograph has been modified to include the generic and brand name in many instances.
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