"Today the U.S. Food and Drug Administration granted approval for Ninlaro (ixazomib) in combination with two other therapies to treat people with multiple myeloma who have received at least one prior therapy.
Multiple myeloma is a form of bl"...
Mechanism Of Action
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitinproteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.
Following twice weekly administration of 1 mg/m² and 1.3 mg/m² bortezomib doses (n=12 per each dose level), the maximum inhibition of 20S proteasome activity (relative to baseline) in whole blood was observed 5 minutes after drug administration. Comparable maximum inhibition of 20S proteasome activity was observed between 1 and 1.3 mg/m² doses. Maximal inhibition ranged from 70% to 84% and from 73% to 83% for the 1 mg/m²and 1.3 mg/m² dose regimens, respectively.
Following intravenous administration of 1 mg/m² and 1.3 mg/m² doses to 24 patients with multiple myeloma (n=12, per each dose level), the mean maximum plasma concentrations of bortezomib (Cmax) after the first dose (Day 1) were 57 and 112 ng/mL, respectively. In subsequent doses, when administered twice weekly, the mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1 mg/m² dose and 89 to 120 ng/mL for the 1.3 mg/m² dose. The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1 mg/m² dose and 76 to 108 hours after the 1.3mg/m² dose. The mean total body clearances was 102 and 112 L/h following the first dose for doses of 1 mg/m² and 1.3 mg/m², respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1 and 1.3 mg/m², respectively.
Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m² dose to patients (n = 14 for intravenous, n = 17 for subcutaneous) with multiple myeloma, the total systemic exposure after repeat dose administration (AUClast) was equivalent for subcutaneous and intravenous administration. The Cmax after subcutaneous administration (20.4 ng/mL) was lower than intravenous (223 ng/mL). The AUClast geometric mean ratio was 0.99 and 90% confidence intervals were 80.18% -122.80%.
The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m² following single-or repeat-dose administration of 1 mg/m² or 1.3mg/m² to patients with multiple myeloma. This suggests bortezomib distributes widely to peripheral tissues. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 1000 ng/mL.
In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from 8 patients at 10 min and 30 min after dosing indicate that the plasma levels of metabolites are low compared to the parent drug.
The pathways of elimination of bortezomib have not been characterized in humans.
Analyses of data after the first dose of Cycle 1 (Day 1) in 39 multiple myeloma patients who had received intravenous doses of 1 mg/m²and 1.3 mg/m² showed that both dose-normalized AUC and Cmax tend to be less in younger patients. Patients < 65 years of age (n=26) had about 25% lower mean dose-normalized AUC and Cmax than those ≥ 65 years of age (n=13).
Mean dose-normalized AUC and Cmax values were comparable between male (n=22) and female (n=17) patients after the first dose of Cycle 1 for the 1 and 1.3 mg/m² doses.
The effect of race on exposure to bortezomib could not be assessed as most of the patients were Caucasian.
The effect of hepatic impairment (see Table 6 for definition of hepatic impairment) on the pharmacokinetics of bortezomib was assessed in 60 patients with cancer at bortezomib doses ranging from 0.5 to 1.3 mg/m² . When compared to patients with normal hepatic function, mild hepatic impairment did not alter dose-normalized bortezomib AUC. However, the dose-normalized mean AUC values were increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment, and those patients should be monitored closely [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].
A pharmacokinetic study was conducted in patients with various degrees of renal impairment who were classified according to their creatinine clearance values (CrCl) into the following groups: Normal (CrCl ≥ 60 mL/min/1.73 m², N=12), Mild (CrCl=40-59 mL/min/1.73 m², N=10), Moderate (CrCl=20-39 mL/min/1.73 m², N=9), and Severe (CrCl < 20 mL/min/1.73 m², N=3). A group of dialysis patients who were dosed after dialysis was also included in the study (N=8). Patients were administered intravenous doses of 0.7 to 1.3 mg/m² of bortezomib twice weekly. Exposure of bortezomib (dose-normalized AUC and Cmax) was comparable among all the groups [see Use in Specific Populations].
Bortezomib is a poor inhibitor of human liver microsome cytochrome P450 1A2, 2C9, 2D6, and 3A4, with IC50 values of > 30μM ( > 11.5μg/mL). Bortezomib may inhibit 2C19 activity (IC50 = 18 μM, 6.9 μg/mL) and increase exposure to drugs that are substrates for this enzyme. Bortezomib did not induce the activities of cytochrome P450 3A4 and 1A2 in primary cultured human hepatocytes.
Animal Toxicology And/Or Pharmacology
Studies in monkeys showed that administration of dosages approximately twice the recommended clinical dose resulted in heart rate elevations, followed by profound progressive hypotension, bradycardia, and death 12 to 14 hours post dose. Doses ≥ 1.2 mg/m² induced dose-proportional changes in cardiac parameters. Bortezomib has been shown to distribute to most tissues in the body, including the myocardium. In a repeated dosing toxicity study in the monkey, myocardial hemorrhage, inflammation, and necrosis were also observed.
In animal studies at a dose and schedule similar to that recommended for patients (twice weekly dosing for 2 weeks followed by 1-week rest), toxicities observed included severe anemia and thrombocytopenia, and gastrointestinal, neurological and lymphoid system toxicities. Neurotoxic effects of bortezomib in animal studies included axonal swelling and degeneration in peripheral nerves, dorsal spinal roots, and tracts of the spinal cord. Additionally, multifocal hemorrhage and necrosis in the brain, eye, and heart were observed.
Randomized, Open-Label Clinical Study in Patients with Previously Untreated Multiple Myeloma
A prospective, international, randomized (1:1), open-label clinical study of 682 patients was conducted to determine whether VELCADE administered intravenously (1.3 mg/m²) in combination with melphalan (9 mg/m²) and prednisone (60 mg/m²) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/m²) and prednisone (60 mg/m²) in patients with previously untreated multiple myeloma. Treatment was administered for a maximum of 9 cycles (approximately 54 weeks) and was discontinued early for disease progression or unacceptable toxicity. Antiviral prophylaxis was recommended for patients on the VELCADE study arm.
The median age of the patients in the study was 71 years (48;91), 50% were male, 88% were Caucasian and the median Karnofsky performance status score for the patients was 80 (60;100). Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median hemoglobin of 105 g/L (64;165), and a median platelet count of 221,500 /microliter (33,000;587,000).
Efficacy results for the trial are presented in Table 14. At a pre-specified interim analysis (with median follow-up of 16.3 months), the combination of VELCADE, melphalan and prednisone therapy resulted in significantly superior results for time to progression, progression-free survival, overall survival and response rate. Further enrollment was halted, and patients receiving melphalan and prednisone were offered VELCADE in addition. A later, pre-specified analysis of overall survival (with median follow-up of 36.7 months with a hazard ratio of 0.65, 95% CI: 0.51, 0.84) resulted in a statistically significant survival benefit for the VELCADE, melphalan and prednisone treatment arm despite subsequent therapies including VELCADE based regimens. In an updated analysis of overall survival based on 387 deaths (median follow-up 60.1 months), the median overall survival for the VELCADE, melphalan and prednisone treatment arm was 56.4 months and for the melphalan and prednisone treatment arm was 43.1 months, with a hazard ratio of 0.695 (95% CI: 0.57, 0.85).
Table 14: Summary of Efficacy Analyses in the
Previously Untreated Multiple Myeloma Study
|Efficacy Endpoint||VELCADE, Melphalan and Prednisone
|Melphalan and Prednisone
|Time to Progression|
|Events n (%)||101 (29)||152 (45)|
|Mediana (months)(95% CI)||20.7 (17.6, 24.7)||15.0 (14.1, 17.9)|
|Hazard ratiob||0.54 (0.42, 0.70)|
|Events n (%)||135 (39)||190 (56)|
|Mediana (months)(95% CI)||18.3 (16.6, 21.7)||14.0 (11.1, 15.0)|
|Hazard ratiob(95% CI)||0.61 (0.49, 0.76)|
|CRd n (%)||102 (30)||12 (4)|
|PRd n (%)||136 (40)||103 (30)|
|nCR n (%)||5 (1)||0|
|CR + PRd n (%)||238 (69)||115 (34)|
|Overall Survival at median follow up of 36.7 months|
|Events (deaths) n (%)||109 (32)||148 (44)|
|Mediana (months)(95% CI)||Not Reached (46.2, NR)||43.1(34.8, NR)|
|Hazard ratiob(95% CI)||0.65 (0.51, 0.84)|
|Note: All results are based on
the analysis performed at a median follow-up duration of 16.3 months except for
the overall survival analysis.
bHazard ratio estimate is based on a Cox proportional-hazard model adjusted for stratification factors: beta2-microglobulin, albumin, and region. A hazard ratio less than 1 indicates an advantage for VELCADE, melphalan and prednisone
cp-value based on the stratified log-rank test adjusted for stratification factors: beta2-microglobulin, albumin, and region
ep-value for Response Rate (CR + PR) from the Cochran-Mantel-Haenszel chi-square test adjusted for the stratification factors
TTP was statistically significantly longer on the VELCADE, melphalan and prednisone arm (see Figure 1). (median follow-up 16.3 months)
Figure 1: Time to Progression
VELCADE, Melphalan and Prednisone versus Melphalan and Prednisone
Overall survival was statistically significantly longer on the VELCADE, melphalan and prednisone arm (see Figure 2). (median follow-up 60.1 months)
Figure 2: Overall Survival
VELCADE, Melphalan and Prednisone versus Melphalan and Prednisone
Randomized, Clinical Study in Relapsed Multiple Myeloma of VELCADE versus Dexamethasone
A prospective phase 3, international, randomized (1:1), stratified, open-label clinical study enrolling 669 patients was designed to determine whether VELCADE resulted in improvement in time to progression (TTP) compared to high-dose dexamethasone in patients with progressive multiple myeloma following 1 to 3 prior therapies. Patients considered to be refractory to prior high-dose dexamethasone were excluded as were those with baseline Grade ≥ 2 peripheral neuropathy or platelet counts < 50,000/μL. A total of 627 patients were evaluable for response.
Stratification factors were based on the number of lines of prior therapy the patient had previously received (1 previous line versus more than 1 line of therapy), time of progression relative to prior treatment (progression during or within 6 months of stopping their most recent therapy versus relapse > 6 months after receiving their most recent therapy), and screening β2-microglobulin levels ( ≤ 2.5 mg/L versus > 2.5 mg/L).
Baseline patient and disease characteristics are summarized in Table 15.
Table 15: Summary of
Baseline Patient and Disease Characteristicsin the Relapsed Multiple Myeloma
|Median age in years (range)||62.0 (33, 84)||61.0 (27, 86)|
|Gender: Male/female||56% / 44%||60% / 40%|
|Race: Caucasian/black/other||90% / 6% / 4%||88% / 7% / 5%|
|Karnofsky performance status score ≤ 70||13%||17%|
|Hemoglobin < 100 g/L||32%||28%|
|Platelet count < 75 x 109/L||6%||4%|
|Type of myeloma (%): IgG/IgA/Light chain||60% / 23% / 12%||59% / 24% / 13%|
|Median p2-microglobulin (mg/L)||3.7||3.6|
|Median albumin (g/L)||39.0||39.0|
|Creatinine clearance ≤ 30 mL/min [n (%)]||17 (5%)||11 (3%)|
|Median Duration of Multiple Myeloma Since|
|Number of Prior Therapeutic Lines of Treatment|
|1 prior line||40%||35%|
|> 1 prior line||60%||65%|
|Any prior steroids, e.g., dexamethasone, VAD||98%||99%|
|Any prior anthracyclines, e.g., VAD, mitoxantrone||77%||76%|
|Any prior alkylating agents, e.g., MP, VBMCP||91%||92%|
|Any prior thalidomide therapy||48%||50%|
|Prior stem cell transplant/other high-dose therapy||67%||68%|
|Prior experimental or other types of therapy||3%||2%|
Patients in the VELCADE treatment group were to receive eight 3-week treatment cycles followed by three 5week treatment cycles of VELCADE. Patients achieving a CR were treated for 4 cycles beyond first evidence of CR. Within each 3-week treatment cycle, VELCADE 1.3 mg/m²/dose alone was administered by intravenous bolus twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21). Within each 5-week treatment cycle, VELCADE 1.3 mg/m²/dose alone was administered by intravenous bolus once weekly for 4 weeks on Days 1, 8, 15, and 22 followed by a 13-day rest period (Days 23 to 35) [see DOSAGE AND ADMINISTRATION].
Patients in the dexamethasone treatment group were to receive four 5-week treatment cycles followed by five 4week treatment cycles. Within each 5-week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4, 9 to 12, and 17 to 20 followed by a 15-day rest period (Days 21-35). Within each 4week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4 followed by a 24-day rest period (Days 5 to 28). Patients with documented progressive disease on dexamethasone were offered VELCADE at a standard dose and schedule on a companion study. Following a preplanned interim analysis of time to progression, the dexamethasone arm was halted and all patients randomized to dexamethasone were offered VELCADE, regardless of disease status.
In the VELCADE arm, 34% of patients received at least one VELCADE dose in all 8 of the 3-week cycles of therapy, and 13% received at least one dose in all 11 cycles. The average number of VELCADE doses during the study was 22, with a range of 1 to 44. In the dexamethasone arm, 40% of patients received at least one dose in all 4 of the 5-week treatment cycles of therapy, and 6% received at least one dose in all 9 cycles.
The time to event analyses and response rates from the relapsed multiple myeloma study are presented in Table 16. Response and progression were assessed using the European Group for Blood and Marrow Transplantation (EBMT) criteria. Complete response (CR) required < 5% plasma cells in the marrow, 100% reduction in M-protein, and a negative immunofixation test (IF-). Partial response (PR) requires ≥ 50% reduction in serum myeloma protein and ≥ 90% reduction of urine myeloma protein on at least 2 occasions for a minimum of at least 6 weeks along with stable bone disease and normal calcium. Near complete response (nCR) was defined as meeting all the criteria for complete response including 100% reduction in M-protein by protein electrophoresis; however, M-protein was still detectable by immunofixation (IF+).
Table 16: Summary of Efficacy Analyses in the Relapsed
Multiple Myeloma Study
|Efficacy Endpoint||All Patients||1 Prior Line of Therapy||> 1 Prior Line of Therapy|
|Time to Progression Events
|147 (44)||196 (58)||55 (42)||64 (54)||92 (46)||132 (61)|
|Median a (95% CI)||6.2 mo (4.9, 6.9)||3.5 mo (2.9, 4.2)||7.0 mo (6.2, 8.8)||5.6 mo (3.4, 6.3)||4.9 mo (4.2, 6.3)||2.9 mo (2.8, 3.5)|
|Hazard ratio b (95% CI)||0.55 (0.44, 0.69)||0.55 (0.38, 0.81)||0.54 (0.41, 0||.72)|
|p-value c||< 0.0001||0.0019||< 0.0001|
|Overall Survival Events (deaths) n (%)||51 (15)||84 (25)||12 (9)||24 (20)||39 (20)||60 (28)|
|Hazard ratio b (95% CI)||0.57 (0.40, 0.81)||0.39 (0.19, 0.81)||0.65 (0.43, 0.97)|
|p-value c,d||< 0.05||< 0.05||< 0.05|
|Response Rate Population e n = 627||n=315||n=312||n=128||n=110||n=187||n=202|
|CR f n (%)||20 (6)||2 ( < 1)||8 (6)||2 (2)||12 (6)||0 (0)|
|PR f n(%)||101 (32)||54 (17)||49 (38)||27 (25)||52 (28)||27 (13)|
|nCR f,g n (%)||21 (7)||3 ( < 1)||8 (6)||2 (2)||13 (7)||1 ( < 1)|
|CR + PR f n (%)||121 (38)||56 (18)||57 (45)||29 (26)||64 (34)||27 (13)|
|p-value h||< 0.0001||0.0035||< 0.0001|
bHazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for VELCADE
cp-value based on the stratified log-rank test including randomization stratification factors
dPrecise p-value cannot be rendered
eResponse population includes patients who had measurable disease at baseline and received at least 1 dose of study drug
fEBMT criteria; nCR meets all EBMT criteria for CR but has positive IF. Under EBMT criteria nCR is in the PR category
gIn 2 patients, the IF was unknown
hp-value for Response Rate (CR + PR) from the Cochran-Mantel-Haenszel chi-square test adjusted for the stratification factors
TTP was statistically significantly longer on the VELCADE arm (see Figure 3).
Figure 3: Time to Progression
Bortezomib versus Dexamethasone (relapsed multiple myeloma study)
As shown in Figure 4 VELCADE had a significant survival advantage relative to dexamethasone (p < 0.05). The median follow-up was 8.3 months.
Figure 4: Overall Survival
Bortezomib versus Dexamethasone (relapsed multiple myeloma study)
For the 121 patients achieving a response (CR or PR) on the VELCADE arm, the median duration was 8.0 months (95% CI: 6.9, 11.5 months) compared to 5.6 months (95% CI: 4.8, 9.2 months) for the 56 responders on the dexamethasone arm. The response rate was significantly higher on the VELCADE arm regardless of β2microglobulin levels at baseline.
Randomized, Open-Label Clinical Study of VELCADE Subcutaneous versus Intravenous in Relapsed Multiple Myeloma
An open-label, randomized, phase 3 non-inferiority study compared the efficacy and safety of the subcutaneous administration of VELCADE versus the intravenous administration. This study included 222 bortezomib na´ve patients with relapsed multiple myeloma, who were randomized in a 2:1 ratio to receive 1.3 mg/m² of VELCADE by either the subcutaneous (n=148) or intravenous (n=74) route for 8 cycles. Patients who did not obtain an optimal response (less than Complete Response (CR)) to therapy with VELCADE alone after 4 cycles were allowed to receive oral dexamethasone 20 mg daily on the day of and after VELCADE administration (82 patients in subcutaneous treatment group and 39 patients in the intravenous treatment group). Patients with baseline Grade ≥ 2 peripheral neuropathy or neuropathic pain, or platelet counts < 50,000/μL were excluded. A total of 218 patients were evaluable for response.
Stratification factors were based on the number of lines of prior therapy the patient had received (1 previous line versus more than 1 line of therapy), and international staging system (ISS) stage (incorporating beta2-microglobulin and albumin levels; Stages I, II, or III).
The baseline demographic and others characteristics of the two treatment groups are summarized as follows: the median age of the patient population was approximately 64 years of age (range 38-88 years), primarily male (subcutaneous: 50%, intravenous: 64%); the primary type of myeloma is IgG (subcutaneous: 65% IgG, 26% IgA, 8% light chain; intravenous: 72% IgG, 19% IgA, 8% light chain), ISS staging I/II/III (%) was 27, 41, 32 for both subcutaneous and intravenous, Karnofsky performance status score was ≤ 70% in 22% of subcutaneous and 16% of intravenous, creatinine clearance was 67.5 mL/min in subcutaneous and 73 mL/min in intravenous, the median years from diagnosis was 2.68 and 2.93 in subcutaneous and intravenous respectively and the proportion of patients with more than one prior line of therapy was 38% in subcutaneous and 35% in intravenous.
This study met its primary (non-inferiority) objective that single agent subcutaneous VELCADE retains at least 60% of the overall response rate after 4 cycles relative to single agent intravenous VELCADE. The results are provided in Table 17.
Table 17: Summary of Efficacy Analyses in the Relapsed
Multiple Myeloma Study of VELCADE Subcutaneous versus Intravenous
|Intent to Treat Population||Subcutaneous VELCADE
|Response Rate at 4 cycles|
|ORR (CR+PR) n(%)||63 (43)||31 (42)|
|Ratio of Response Rates (95% CI)||1.01 (0.73, 1.40)|
|CR n (%)||11 (7)||6 (8)|
|PR n (%)||52 (35)||25 (34)|
|nCR n (%)||9 (6)||4 (5)|
|Response Rate at 8 cycles|
|ORR (CR+PR)||78 (53)||38 (51)|
|CR n (%)||17 (11)||9 (12)|
|PR n (%)||61 (41)||29 (39)|
|nCR n (%)||14 (9)||7 (9)|
|Median Time to Progression, months||10.4||9.4|
|Median Progression Free Survival, months||10.2||8.0|
|1-year Overall Survival (%)a||72.6||76.7|
|aMedian duration of follow up is 11.8 months|
A Randomized Phase 2 Dose-Response Study in Relapsed Multiple Myeloma
An open-label, multicenter study randomized 54 patients with multiple myeloma who had progressed or relapsed on or after front-line therapy to receive VELCADE 1 mg/m² or 1.3 mg/m² intravenous bolus twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21). The median duration of time between diagnosis of multiple myeloma and first dose of VELCADE on this trial was 2.0 years, and patients had received a median of 1 prior line of treatment (median of 3 prior therapies). A single complete response was seen at each dose. The overall response rates (CR + PR) were 30% (8/27) at 1 mg/m²and 38% (10/26) at 1.3 mg/m² .
A Phase 2 Open-Label Extension Study in Relapsed Multiple Myeloma
Patients from the two phase 2 studies, who in the investigators' opinion would experience additional clinical benefit, continued to receive VELCADE beyond 8 cycles on an extension study. Sixty-three (63) patients from the phase 2 multiple myeloma studies were enrolled and received a median of 7 additional cycles of VELCADE therapy for a total median of 14 cycles (range 7 to 32). The overall median dosing intensity was the same in both the parent protocol and extension study. Sixty-seven percent (67%) of patients initiated the extension study at the same or higher dose intensity at which they completed the parent protocol, and 89% of patients maintained the standard 3-week dosing schedule during the extension study. No new cumulative or new long-term toxicities were observed with prolonged VELCADE treatment [see ADVERSE REACTIONS].
A Single-Arm Trial of Retreatment in Relapsed Multiple Myeloma
A single arm, open-label trial was conducted to determine the efficacy and safety of retreatment with VELCADE. One hundred and thirty patients ( ≥ 18 years of age) with multiple myeloma who previously had at least partial response on a VELCADE-containing regimen (median of 2 prior lines of therapy [range 1-7]) were retreated upon progression with VELCADE administered intravenously. Patients were excluded from trial participation if they had peripheral neuropathy or neuropathic pain of Grade ≥ 2. At least 6 months after prior VELCADE therapy, VELCADE was restarted at the last tolerated dose of 1.3 mg/m² (n=93) or ≤ 1.0 mg/m²(n=37) and given on days 1, 4, 8 and 11 every 3 weeks for maximum of 8 cycles either as single agent or in combination with dexamethasone in accordance with the standard of care. Dexamethasone was administered in combination with VELCADE to 83 patients in Cycle 1 with an additional 11 patients receiving dexamethasone during the course of VELCADE retreatment cycles.
The primary endpoint was best confirmed response to retreatment as assessed by European Group for Blood and Marrow Transplantation (EBMT) criteria. Fifty of the 130 patients achieved a best confirmed response of Partial Response or better for an overall response rate of 38.5% (95% CI: 30.1, 47.4). One patient achieved a Complete Response and 49 achieved Partial Response. In the 50 responding patients, the median duration of response was 6.5 months and the range was 0.6 to 19.3 months.
Mantle Cell Lymphoma
A Randomized, Open-Label Clinical Study in Patients with Previously Untreated Mantle Cell Lymphoma
A randomized, open-label, Phase 3 study was conducted in 487 adult patients with previously untreated mantle cell lymphoma (Stage II, III or IV) who were ineligible or not considered for bone marrow transplantation to determine whether VELCADE administered in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP) resulted in improvement in progression free survival (PFS) when compared to the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). This clinical study utilized independent pathology confirmation and independent radiologic response assessment.
Patients in the VcR-CAP treatment arm received VELCADE (1.3 mg/m²) administered intravenously on days 1, 4, 8, and 11 (rest period days 12-21); rituximab (375 mg/m²) on Day 1; cyclophosphamide (750 mg/m²) on Day 1; doxorubicin (50 mg/m²) on Day 1; and prednisone (100 mg/m²) on Day 1 through Day 5 of the the 21-day treatment cycle. For patients with a response first documented at cycle 6, two additional treatment cycles were allowed.
Median patient age was 66 years, 74% were male, 66% were Caucasian and 32% were Asian. 69% of patients had a positive bone marrow aspirate and/or a positive bone marrow biopsy for MCL, 54% of patients had an International Prognostic Index (IPI) score of 3 (high-intermediate) or higher and 76% had Stage IV disease.
The majority of the patients in both groups received 6 or more cycles of treatment, 84% in the VcR-CAP group and 83% in the R-CHOP group. Median number of cycles received by patients in both treatment arms was 6 with 17% of patients in the R-CHOP group and 14% of subjects in the VcR-CAP group receiving up to 2 additional cycles.
The efficacy results of the study with a median follow-up of 40 months are presented in Table 18. The response criteria used to assess efficacy were based on the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma (IWRC). The combination of VcR-CAP resulted in statistically significant prolongation of PFS compared with R-CHOP (see Table 18 and Figure 5).
Table 18: Summary of Efficacy Analyses in the
Previously Untreated Mantle Cell Lymphoma Study
|Efficacy endpoint n: Intent to Treat patients||VcR-CAP
|Progression-free Survival (by independent radiographic assessment)|
|Events n (%)||133(55)||165 (68)|
|Mediana (months)(95% CI)||25 (20, 32)||14 (12, 17)|
|Hazard ratiob(95% CI)||0.63 (0.50, 0.79)|
|p-value c||< 0.001|
|Complete Response Rate (CR)d|
|n (%)(95% CI)||108 (44)(38, 51)||82 (34)(28, 40)|
|Overall Response Rate (CR+CRu+PR)e|
|n (%) (95% CI)||214 (88) (83, 92)||208 (85) (80, 89)|
|aBased on Kaplan-Meier product limit estimates.
bHazard ratio estimate is based on a Cox's model stratified by IPI risk and stage of disease. A hazard ratio < 1 indicates an advantage for VcR-CAP.
cBased on Log rank test stratified with IPI risk and stage of disease.
dIncludes CR by independent radiographic assessment, bone marrow, and LDH using ITT population.
eIncludes CR+ CRu+PR by independent radiographic assessment, regardless of the verification by bone marrow and LDH, using ITT population.
CI=Confidence Interval; IPI= International Prognostic Index; LDH=Lactate dehydrogenase
Figure 5: Progression Free
VcR-CAP versus R-CHOP (previously untreated mantle cell lymphoma study)
Key: R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VcR-CAP=VELCADE, rituximab, cyclophosphamide, doxorubicin, and prednisone.
A Phase 2 Single-arm Clinical Study in Relapsed Mantle Cell Lymphoma After Prior Therapy
The safety and efficacy of VELCADE in relapsed or refractory mantle cell lymphoma were evaluated in an open-label, single-arm, multicenter study of 155 patients with progressive disease who had received at least 1 prior therapy. The median age of the patients was 65 years (42, 89), 81% were male, and 92% were Caucasian. Of the total, 75% had one or more extra-nodal sites of disease, and 77% were stage 4. In 91% of the patients, prior therapy included all of the following: an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. A total of thirty seven percent (37%) of patients were refractory to their last prior therapy. An intravenous bolus injection of VELCADE 1.3 mg/m²/dose was administered twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21) for a maximum of 17 treatment cycles. Patients achieving a CR or CRu were treated for 4 cycles beyond first evidence of CR or CRu. The study employed dose modifications for toxicity [see DOSAGE AND ADMINISTRATION].
Responses to VELCADE are shown in Table 19. Response rates to VELCADE were determined according to the International Workshop Response Criteria (IWRC) based on independent radiologic review of CT scans. The median number of cycles administered across all patients was 4; in responding patients the median number of cycles was 8. The median time to response was 40 days (range 31 to 204 days). The median duration of follow-up was more than 13 months.
Table 19: Response Outcomes
in a Phase 2 Relapsed Mantle Cell Lymphoma Study
|Response Analyses (N = 155)||N (%)||95% CI|
|Overall Response Rate (IWRC) (CR + CRu + PR)||48 (31)||(24, 39)|
|Complete Response (CR + CRu)||12 (8)||(4, 13)|
|CR||10 (6)||(3, 12)|
|CRu||2 (1)||(0, 5)|
|Partial Response (PR)||36 (23)||(17, 31)|
|Duration of Response||Median||95% CI|
|CR + CRu + PR (N = 48)||9.3 months||(5.4, 13.8)|
|CR + CRu (N = 12)||15.4 months||(13.4, 15.4)|
|PR (N=36)||6.1 months||(4.2, 9.3)|
Last reviewed on RxList: 10/9/2015
This monograph has been modified to include the generic and brand name in many instances.
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