DARZALEX (Page 5 of 8)

11 DESCRIPTION

Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human monoclonal antibody that binds to CD38 antigen. It is produced in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology. The molecular weight of daratumumab is approximately 148 kDa.

DARZALEX® (daratumumab) injection is supplied as a colorless to pale yellow preservative-free solution for intravenous use in a single-dose vial. The pH is 5.5.

Each DARZALEX 20 mL single-dose vial contains 400 mg daratumumab, glacial acetic acid (3.7 mg), mannitol (510 mg), polysorbate 20 (8 mg), sodium acetate trihydrate (59.3 mg), sodium chloride (70.1 mg), and Water for Injection, USP.

Each DARZALEX 5 mL single-dose vial contains 100 mg daratumumab, glacial acetic acid (0.9 mg), mannitol (127.5 mg), polysorbate 20 (2 mg), sodium acetate trihydrate (14.8 mg), sodium chloride (17.5 mg), and Water for Injection, USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs ) and B cells (CD38+Bregs ) are decreased by daratumumab.

12.2 Pharmacodynamics

NK cells express CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with DARZALEX treatment.

Exposure-Response Relationship

The exposure-response relationship and time course of pharmacodynamics of DARZALEX have not been fully characterized.

Cardiac Electrophysiology

DARZALEX as a large protein has a low likelihood of direct ion channel interactions. There is no evidence from non-clinical or clinical data to suggest that DARZALEX has the potential to delay ventricular repolarization.

12.3 Pharmacokinetics

Daratumumab area under the concentration-time curve (AUC) increases more than proportionally over a dosage range from 1 to 24 mg/kg (0.06 to 1.5 times the approved recommended dosage) as monotherapy or 1 to 16 mg/kg (0.06 to 1 time the approved recommended dosage) as combination therapy.

Following administration of the approved recommended dosage of DARZALEX as monotherapy or in combination therapy, the mean serum maximal concentration (Cmax ) was approximately 2.7 to 3-fold higher at the end of weekly dosing compared to the first dose. The mean ± standard deviation (SD) trough serum concentration (Cmin ) at the end of weekly dosing was 573 ± 332 µg/mL when DARZALEX was administered as monotherapy and 502 ± 196 to 607 ± 231 µg/mL when DARZALEX was administered as combination therapy. Split dosing of the first dose resulted in a different PK profile in the first day compared to single dosing; however, similar Cmax and Cmin concentrations were both predicted and observed following the administration of the second split dose on Week 1 Day 2.

When DARZALEX was administered as monotherapy, daratumumab steady state was achieved approximately 5 months into the every 4-week dosing period (by the 21st infusion). At steady state, daratumumab mean ± SD accumulation ratio for Cmax was 1.6 ± 0.5.

Distribution

Daratumumab volume of distribution was 4.7 ± 1.3 L as monotherapy and 4.4 ± 1.5 L as combination therapy following administration of the approved dosage.

Elimination

Daratumumab clearance decreased with increasing dose and with multiple dosing. The mean ± SD linear clearance was estimated to be 171.4 ± 95.3 mL/day and the mean ± SD estimated terminal half-life associated with linear clearance was 18 ± 9 days following administration of the approved recommended dosage of DARZALEX as monotherapy. Terminal half-life was similar when DARZALEX was administered as combination therapy.

Specific Populations

No clinically significant differences in the pharmacokinetics of daratumumab as monotherapy or as combination therapy were observed based on sex, age (31 to 93 years), mild [total bilirubin 1 to 1.5 times upper limit of normal (ULN) or aspartate aminotransaminase (AST)>ULN] and moderate (total bilirubin 1.5 to 3 times ULN and any AST) hepatic impairment, or renal impairment [Creatinine clearance (CLcr) 15–89 mL/min]. The effect of severe (total bilirubin >3 times ULN and any AST) hepatic impairment on daratumumab pharmacokinetics is unknown.

Body Weight

The central volume of distribution and clearance of daratumumab increased with increasing body weight.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development, or to determine potential effects on fertility in males or females.

14 CLINICAL STUDIES

14.1 Newly Diagnosed Multiple Myeloma

Combination Treatment with Lenalidomide and Dexamethasone in Patients Ineligible for Autologous Stem Cell Transplant

MAIA (NCT02252172), an open-label, randomized, active-controlled trial, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant. Lenalidomide (25 mg once daily orally on Days 1–21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On DARZALEX infusion days, the dexamethasone dose was given as a pre-infusion medication. Treatment was continued in both arms until disease progression or unacceptable toxicity.

A total of 737 patients were randomized: 368 to the DRd arm and 369 to the Rd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 73 (range: 45–90) years, with 44% of the patients ≥75 years of age. The majority were white (92%), male (52%), 34% had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1 and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II and 29% had ISS Stage III disease. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.

MAIA demonstrated an improvement in Progression Free Survival (PFS) in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR]=0.56; 95% CI: 0.43, 0.73; p<0.0001), representing 44% reduction in the risk of disease progression or death in patients treated with DRd.

Figure 1: Kaplan-Meier Curve of PFS in MAIA

Figure 1
(click image for full-size original)

Additional efficacy results from MAIA are presented in Table 23.

Table 23: Additional Efficacy Results From MAIA *
DRd (N=368)Rd (N=369)
DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval
*
Based on intent-to-treat population
p-value from Cochran Mantel-Haenszel Chi-Squared test.
Based on threshold of 10-5 using a next-generation sequencing assay (clonoSEQ).
§
p-value from Fisherʼs exact test
Overall response (sCR+CR+VGPR+PR) n(%)*342 (92.9%)300 (81.3%)
p-value <0.0001
Stringent complete response (sCR)112 (30.4%)46 (12.5%)
Complete response (CR)63 (17.1%)46 (12.5%)
Very good partial response (VGPR)117 (31.8%)104 (28.2%)
Partial response (PR)50 (13.6%)104 (28.2%)
CR or better (sCR + CR)175 (47.6%)92 (24.9%)
p-value <0.0001
VGPR or better (sCR + CR + VGPR)292 (79.3%)196 (53.1%)
p-value <0.0001
MRD negativity rate *, n(%)89 (24.2%)27 (7.3%)
95% CI (%)(19.9%, 28.9%)(4.9%, 10.5%)
p-value §<0.0001
MRD negativity rate in patients with CR or better
Number of patients with CR or betterN=175 N=92
MRD negativity rate n(%)89 (50.9%)27 (29.3%)
95% CI (%)(43.2%, 58.5%)(20.3%, 39.8%)

In responders, the median time to response was 1.05 months (range: 0.2 to 12.1 months) in the DRd group and 1.05 months (range: 0.3 to 15.3 months) in the Rd group. The median duration of response had not been reached in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rd group.

Combination Treatment with Bortezomib, Melphalan and Prednisone (VMP) in Patients Ineligible for Autologous Stem Cell Transplant

ALCYONE (NCT02195479), an open-label, randomized, active-controlled trial, compared treatment with DARZALEX 16 mg/kg in combination with bortezomib, melphalan and prednisone (D-VMP), to treatment with VMP in patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant. Bortezomib was administered by subcutaneous (SC) injection at a dose of 1.3 mg/m2 body surface area twice weekly at Weeks 1, 2, 4 and 5 for the first 6-week cycle (Cycle 1; 8 doses), followed by once weekly administrations at Weeks 1, 2, 4 and 5 for eight more 6-week cycles (Cycles 2–9; 4 doses per cycle). Melphalan at 9 mg/m2 , and prednisone at 60 mg/m2 were orally administered on Days 1 to 4 of the nine 6-week cycles (Cycles 1–9). DARZALEX was continued until disease progression or unacceptable toxicity.

A total of 706 patients were randomized: 350 to the D-VMP arm and 356 to the VMP arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 71 (range: 40–93) years, with 30% of the patients ≥75 years of age. The majority were white (85%), female (54%), 25% had an ECOG performance score of 0, 50% had an ECOG performance score of 1 and 25% had an ECOG performance score of 2. Nineteen percent of patients had ISS Stage I, 42% had ISS Stage II and 38% had ISS Stage III disease. Efficacy was evaluated by PFS based on IMWG criteria and overall survival (OS).

ALCYONE demonstrated an improvement in PFS in the D-VMP arm as compared to the VMP arm (HR=0.50; 95% CI: 0.38, 0.65; p<0.0001), representing a 50% reduction in the risk of disease progression or death in patients treated with D-VMP. After a median follow-up of 40 months, the median PFS was 36.4 months (95% CI: 32.1, 45.9) in the D-VMP arm and 19.3 months (95% CI: 18.0, 20.4) in the VMP arm.

*
PFS median follow-up of 16.5 months
Figure 2: Kaplan-Meier Curve of PFS in ALCYONE *

Figure 2
(click image for full-size original)

After a median follow-up of 40 months, ALCYONE demonstrated an improvement in overall survival (OS) in the D-VMP arm as compared to the VMP arm (HR=0.60; 95% CI: 0.46, 0.80; p=0.0003), representing a 40% reduction in the risk of death in patients treated in the D-VMP arm. Median OS was not reached for either arm.

Figure 3: Kaplan-Meier Curve of OS in ALCYONE

Figure 3
(click image for full-size original)

Additional efficacy results from ALCYONE are presented in Table 24.

Table 24: Additional Efficacy Results From ALCYONE
D-VMP (N=350)VMP (N=356)
D-VMP = daratumumab-bortezomib-melphalan-prednisone; VMP = bortezomib-melphalan-prednisone; MRD = minimal residual disease; CI = confidence interval
*
Based on intent-to-treat population
p-value from Cochran Mantel-Haenszel Chi-Squared test.
Based on threshold of 10-5 using a next-generation sequencing assay (clonoSEQ).
§
p-value from Fisher’s exact test.
Overall response (sCR+CR+VGPR+PR) n(%)*318 (90.9%)263 (73.9%)
p-value <0.0001
Stringent complete response (sCR)63 (18.0%)25 (7.0%)
Complete response (CR)86 (24.6%)62 (17.4%)
Very good partial response (VGPR)100 (28.6%)90 (25.3%)
Partial response (PR)69 (19.7%)86 (24.2%)
MRD negativity rate *, n(%)78 (22.3%)22 (6.2%)
95% CI (%)(18.0, 27.0)(3.9, 9.2)
p-value §<0.0001
MRD negativity rate in patients with CR or better
Number of patients with CR or betterN=149 N=87
MRD negativity rate n(%)74 (49.7%)22 (25.3%)
95% CI (%)(41.4, 58.0)(16.6, 35.7)

In responders, the median time to response was 0.79 months (range: 0.4 to 15.5 months) in the D-VMP group and 0.82 months (range: 0.7 to 12.6 months) in the VMP group. The median duration of response had not been reached in the D-VMP group and was 21.3 months (range: 0.5+, 23.7+) in the VMP group.

Combination Treatment with Bortezomib, Thalidomide and Dexamethasone in Patients Eligible for Autologous Stem Cell Transplant (ASCT)

CASSIOPEIA (NCT02541383), an open-label, randomized, active-controlled trial compared induction and consolidation treatment with DARZALEX 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (DVTd) to treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT. The consolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete. The trial was limited to patients 65 years of age and younger. Bortezomib was administered by subcutaneous (SC) injection or intravenous (IV) injection at a dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 28-day (4-week) induction treatment cycles (Cycles 1–4) and two consolidation cycles (Cycles 5 and 6) following ASCT after Cycle 4. Thalidomide was administered orally at 100 mg daily during the six bortezomib cycles. Dexamethasone (oral or intravenous) was administered at 40 mg on Days 1, 2, 8, 9, 15, 16, 22 and 23 of Cycles 1 and 2, and at 40 mg on Days 1–2 and 20 mg on subsequent dosing days (Days 8, 9, 15, 16) of Cycles 3–4. Dexamethasone 20 mg was administered on Days 1, 2, 8, 9, 15, 16 in Cycles 5 and 6. On the days of DARZALEX infusion, the dexamethasone dose was administered intravenously as a pre-infusion medication.

A total of 1,085 patients were randomized: 543 to the DVTd arm and 542 to the VTd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 58 years (range: 22 to 65 years). The majority were male (59%), 48% had an ECOG performance score of 0, 42% had an ECOG performance score of 1 and 10% had an ECOG performance score of 2. Forty percent had ISS Stage I, 45% had ISS Stage II and 15% had ISS Stage III disease.

Efficacy was evaluated by stringent Complete Response (sCR) rate at Day 100 post-transplant, Complete Response Rate (CR) at Day 100 post-transplant, and Progression-Free Survival (PFS).

Table 25: Efficacy Results From CASSIOPEIA at Day 100 Post-Transplant
DVTd (N=543)VTd (N=542)
D-VTd = daratumumab-bortezomib-thalidomide-dexamethasone; VTd = bortezomib-thalidomide-dexamethasone
*
Based on intent-to-treat population
p-value from Cochran Mantel-Haenszel Chi-Squared test.
Overall response (sCR+CR+VGPR+PR) n(%)*503 (92.6%)487 (89.9%)
Stringent complete response (sCR)157 (28.9%)110 (20.3%)
p-value 0.0010
Complete response (CR)54 (9.9%)31 (5.7%)
Very good partial response (VGPR)242 (44.6%)282 (52.0%)
Partial response (PR)50 (9.2%)64 (11.8%)

CASSIOPEIA demonstrated an improvement in PFS in the DVTd arm as compared to the VTd arm; with a median follow up of 18.8 months, the median PFS had not been reached in either arm. Treatment with DVTd resulted in a reduction in the risk of progression or death by 53% compared to VTd alone (HR=0.47; 95% CI: 0.33, 0.67; p<0.0001).

*
based on interim analysis and the boundary for PFS was crossed.
Figure 4: Kaplan-Meier Curve of PFS in CASSIOPEIA *

Figure 4
(click image for full-size original)

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