Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates, CD38 (Clusters of Differentiation 38) inhibitors, ATC code: L01FC01.

Mechanism of action
Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed at a high level on the surface of multiple myeloma tumour cells, as well as other cell types and tissues at various levels. CD38 protein has multiple functions such as receptor mediated adhesion, signalling and enzymatic activity.

Daratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumour cells.
Based on in vitro studies, daratumumab may utilise multiple effector functions, resulting in immune mediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysis through complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis in malignancies expressing CD38. A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab mediated cell lysis. T cells (CD3+, CD4+, and CD8+) are also known to express CD38 depending on the stage of development and the level of activation. Significant increases in CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observed with daratumumab treatment in peripheral whole blood and bone marrow. In addition, T-cell receptor DNA sequencing verified that T-cell clonality was increased with daratumumab treatment, indicating immune modulatory effects that may contribute to clinical response.

Daratumumab induced apoptosis in vitro after Fc mediated cross-linking. In addition, daratumumab modulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating the hydrolase activity. The significance of these in vitro effects in a clinical setting, and the implications on tumour growth, are not well-understood.

Pharmacodynamic effects
Natural killer (NK) cell and T-cell count
NK cells are known to express high levels of 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 daratumumab treatment. However, baseline levels of NK cells did not show an association with clinical response.

Immunogenicity
In patients treated with intravenous daratumumab in clinical studies, less than 1% of patients developed treatment-emergent anti-daratumumab antibodies.

Clinical efficacy and safety

Newly diagnosed multiple myeloma
Combination treatment with lenalidomide and dexamethasone in patients ineligible for autologous stem cell transplant
Study MMY3008, an open-label, randomised, active-controlled phase III study, compared treatment with DARZALEX 20MG/ML I.V 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. 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 20MG/ML I.V infusion days, the dexamethasone dose was given as a pre- infusion medicinal product. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer’s prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.

A total of 737 patients were randomised: 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, 49.5% 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 and overall survival (OS).

With a median follow-up of 28 months, the primary analysis of PFS in study MMY3008 showed an improvement 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. Results of an updated PFS analysis after a median follow-up of 64 months continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was 61.9 months in the DRd arm and 34.4 months in the Rd arm (HR=0.55; 95% CI: 0.45, 0.67).


Figure 1:   Kaplan-Meier curve of PFS in study MMY3008



With a median follow-up of 56 months, DRd has shown an OS advantage over the Rd arm (HR=0.68; 95% CI: 0.53, 0.86; p=0.0013). Results of an updated OS analysis after a median of 64 months continued to show an improvement in OS for patients in the DRd arm compared to the Rd arm.
Median OS was not reached in the DRd arm and was 65.5 months in the Rd arm (HR=0.66; 95% CI: 0.53, 0.83).


Figure 2:      Kaplan-Meier curve of OS in study MMY3008



Additional efficacy results from study MMY3008 are presented in table 7 below.

Table 7:       Additional efficacy results from study MMY3008a
DRd (n=368)                    Rd (n=369)
Overall response (sCR+CR+VGPR+PR) n(%)a                             342 (92.9%)                    300 (81.3%) p-valueb                                                            <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-valueb                                                            <0.0001 VGPR or better (sCR + CR + VGPR)                                    292 (79.3%)                    196 (53.1%) p-valueb                                                            <0.0001 MRD negativity ratea,c n(%)                                         89 (24.2%)                     27 (7.3%) 95% CI (%)                                                          (19.9%, 28.9%)                 (4.9%, 10.5%) Odds ratio with 95% CId                                             4.04 (2.55, 6.39) p-valuee                                                            <0.0001 DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval a   Based on intent-to-treat population b   p-value from Cochran Mantel-Haenszel Chi-Squared test.
c   Based on threshold of 10-5 d   Mantel-Haenszel estimate of the odds ratio for un-stratified tables is used. An odds ratio >1 indicates an advantage for DRd.
e   p-value from Fisherʼs exact test.

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
Study MMY3007, an open-label, randomised, active-controlled phase III study, compared treatment with DARZALEX 20MG/ML I.V 16 mg/kg in combination with bortezomib, melphalan and prednisone (D-VMP), to treatment with VMP in patients with newly diagnosed multiple myeloma.
Bortezomib was administered by subcutaneous 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 20MG/ML I.V treatment was continued until disease progression or unacceptable toxicity.
A total of 706 patients were randomised: 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. Patients had IgG/IgA/Light chain myeloma in 64%/22%/10% of instances, 19% had ISS stage I, 42% had ISS stage II, 38% had ISS stage III disease and 84% had standard risk cytogenetics. Efficacy was evaluated by PFS based on IMWG criteria and overall survival (OS).

With a median follow-up of 16.5 months, the primary analysis of PFS in study MMY3007 showed an improvement in the D-VMP arm as compared to the VMP arm; the median PFS had not been reached in the D-VMP arm and was 18.1 months in the VMP arm (HR=0.5; 95% CI: 0.38, 0.65; p < 0.0001).
Results of an updated PFS analysis after a median follow-up of 40 months continued to show an improvement in PFS for patients in the D-VMP arm compared with the VMP arm. Median PFS was 36.4 months in the D-VMP arm and 19.3 months in the VMP arm (HR=0.42; 95% CI: 0.34, 0.51; p < 0.0001), representing a 58% reduction in the risk of disease progression or death in patients treated with D-VMP.


Figure 3:   Kaplan-Meier curve of PFS in study MMY3007



After a median follow-up of 40 months, D-VMP has shown an OS advantage over 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. After a median follow-up of 87 months, the median OS was 83 months (95% CI: 72.5, NE) in the D-VMP arm and 53.6 months (95% CI: 46.3, 60.9) in the VMP arm.
.

Figure 4:   Kaplan-Meier curve of OS in study MMY3007


Additional efficacy results from study MMY3007 are presented in table 8 below.

Table 8:     Additional efficacy results from study MMY3007a
D-VMP (n=350)                         VMP (n=356)
Overall response (sCR+CR+VGPR+PR) [n(%)]          318 (90.9)                            263 (73.9) p-valueb                                     <0.0001
Stringent complete response (sCR) [n(%)] 63 (18.0)                                 25 (7.0) Complete response (CR) [n(%)]                86 (24.6)                             62 (17.4) Very good partial response (VGPR) [n(%)] 100 (28.6)                                90 (25.3) Partial response (PR) [n(%)]                 69 (19.7)                             86 (24.2) MRD negativity rate (95% CI) c (%)                22.3 (18.0, 27.0)                     6.2 (3.9, 9.2) Odds ratio with 95% CI  d
4.36 (2.64, 7.21) p-valuee                                     <0.0001
D-VMP=daratumumab-bortezomib-melphalan-prednisone; VMP=bortezomib-melphalan-prednisone; MRD=minimal residual disease; CI=confidence interval a   Based on intent-to-treat population b   p-value from Cochran Mantel-Haenszel Chi-Squared test.
c   Based on threshold of 10-5 d   A Mantel-Haenszel estimate of the common odds ratio for stratified tables is used. An odds ratio >1 indicates an advantage for D-VMP.
e p-value from Fisherʼs exact test.

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: 18.4, not estimable) in the VMP group.

A subgroup analysis was performed on patients at least 70 years old, or those 65-69 years old with ECOG performance score of 2, or aged less than 65 years of age with significant comorbidity or ECOG performance score of 2 (D-VMP: n=273, VMP: n=270). The efficacy results in this subgroup were consistent with the overall population. In this subgroup, median PFS was not reached in the D- VMP group and was 17.9 months in the VMP group (HR=0.56; 95% CI: 0.42, 0.75; p < 0.0001). The overall response rate was 90% in the D-VMP group and 74% in theVMP group (VGPR rate:29% in D-VMP group and 26% in VMP group; CR: 22% in D-VMP group and 18% in VMP group; sCR rate: 20% in D-VMP group and 7% in VMP group). The safety results of this subgroup were consistent with the overall population. Furthermore, safety analysis of the subgroup of patients with an ECOG performance score of 2 (D-VMP: n=89, VMP: n=84), was also consistent with the overall population.

Combination treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients eligible for autologous stem cell transplant (ASCT)
Study MMY3006 is a 2 part, open-label, randomised, active-controlled phase III study. Part 1 compared induction and consolidation treatment with DARZALEX 20MG/ML I.V 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (D-VTd) 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. In part 2, subjects with at least a partial response (PR) by day 100 post-transplant were re-randomised in a 1:1 ratio to daratumumab maintenance or observation only. Only results from part 1 are described henceforth.

Bortezomib was administered by subcutaneous injection or intravenous 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 20MG/ML I.V infusion, the dexamethasone dose was administered intravenously as a pre-infusion medicinal product. Dose adjustments for bortezomib, thalidomide and dexamethasone were applied according to manufacturer’s prescribing information.

A total of 1085 patients were randomised: 543 to the D-VTd 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 (range: 22 to 65) years. All patients were ≤ 65 years: 43% were in the age group ≥ 60-65 years, 41% were in the age group ≥ 50-60 years and 16% below age of 50 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 International Staging System (ISS) stage I, 45% had ISS stage II and 15% had ISS stage III disease.

Efficacy was evaluated by the stringent complete response (sCR) rate at day 100 post-transplant and PFS.


Table 9:     Efficacy results from study MMY3006a
D-VTd (n=543)            VTd (n=542)          P valueb
Response assessment day 100 post- transplant
Stringent complete response (sCR)    157 (28.9%)              110 (20.3%)          0.0010 CR or better (sCR+CR)                211 (38.9%)              141 (26.0%)          <0.0001 Very good partial response or better
(sCR+CR+VGPR)                        453 (83.4%)              423 (78.0%) MRD negativityc, d n(%)                     346 (63.7%)              236 (43.5%)          <0.0001 95% CI (%)                           (59.5%, 67.8%)           (39.3%, 47.8%) Odds ratio with 95% CIe              2.27 (1.78, 2.90)
MRD negativity in combination with CR or 183 (33.7%)                 108 (19.9%)          <0.0001 betterc n(%)
95% CI (%)                           (29.7%, 37.9%)           (16.6%, 23.5%) Odds ratio with 95% CIe              2.06 (1.56, 2.72)
D-VTd=daratumumab-bortezomib-thalidomide-dexamethasone; VTd=bortezomib-thalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval a
Based on intent-to-treat population b p-value from Cochran Mantel-Haenszel Chi-Squared test.
c
Based on threshold of 10-5 d
Regardless of response per IMWG e
Mantel-Haenszel estimate of the common odds ratio for stratified tables is used.


With a median follow-up of 18.8 months, the primary analysis of PFS by censoring patients who were randomised to daratumumab maintenance in the second randomisation at the date of the second randomisation showed HR=0.50; 95% CI: 0.34, 0.75; p=0.0005. Results of an updated PFS analysis with a median follow-up of 44.5 months, censoring patients who were randomised to daratumumab maintenance in the second randomisation, showed HR=0.43; 95% CI: 0.33, 0.55; p < 0.0001. Median PFS was not reached in the D-VTd arm and was 37.8 months in the VTd arm.


Figure 5:    Kaplan-Meier curve of PFS in study MMY3006



Relapsed/refractory multiple myeloma
Monotherapy:
The clinical efficacy and safety of DARZALEX 20MG/ML I.V monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who had demonstrated disease progression on the last therapy, was demonstrated in two open-label studies.

In study MMY2002, 106 patients with relapsed and refractory multiple myeloma received 16 mg/kg DARZALEX 20MG/ML I.V until disease progression. The median patient age was 63.5 years (range, 31 to 84 years), 11% of patients were ≥75 years of age, 49% were male and 79% were Caucasian.
Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatory agent (IMiD), 77% were refractory to alkylating agents, 63% were refractory to pomalidomide and 48% of patients were refractory to carfilzomib.

Efficacy results of the pre-planned interim analysis based on Independent Review Committee (IRC) assessment are presented in table 10 below.


Table 10: IRC assessed efficacy results for study MMY2002
Efficacy endpoint                                         DARZALEX 20MG/ML I.V 16 mg/kg
N=106
Overall response rate1 (ORR: sCR+CR+VGPR+PR) [n (%)]             31 (29.2) 95% CI (%)                                                      (20.8, 38.9) Stringent complete response (sCR) [n (%)]                    3 (2.8)
Complete response (CR) [n]                                      0
Very good partial response (VGPR) [n (%)]                   10 (9.4)
Partial response (PR) [n (%)]                              18 (17.0)
Clinical benefit rate (ORR+MR) [n (%)]                           36 (34.0) Median duration of response [months (95% CI)]                  7.4 (5.5, NE) Median time to response [months (range)]                        1 (0.9; 5.6) 1
Primary efficacy endpoint (International Myeloma Working Group criteria) CI=confidence interval; NE=not estimable; MR=minimal response

Overall response rate (ORR) in MMY2002 was similar regardless of type of prior anti-myeloma therapy.
At a survival update with a median duration of follow-up of 14.7 months, median OS was 17.5 months (95% CI: 13.7, not estimable).

In study GEN501, 42 patients with relapsed and refractory multiple myeloma received 16 mg/kg DARZALEX 20MG/ML I.V until disease progression. The median patient age was 64 years (range, 44 to 76 years), 64% were male and 76% were Caucasian. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% were refractory to both a PI and IMiD, 60% were refractory to alkylating agents, 36% were refractory to pomalidomide and 17% were refractory to carfilzomib.

Pre-planned interim analysis showed that treatment with daratumumab at 16 mg/kg led to a 36% ORR with 5% CR and 5% VGPR. The median time to response was 1 (range: 0.5 to 3.2) month. The median duration of response was not reached (95% CI: 5.6 months, not estimable).

At a survival update with a median duration of follow-up of 15.2 months, median OS was not reached (95% CI: 19.9 months, not estimable), with 74% of subjects still alive.

Combination treatment with lenalidomide
Study MMY3003, an open-label, randomised, active-controlled phase III study, compared treatment with DARZALEX 20MG/ML I.V 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with relapsed or refractory multiple myeloma who had received at least one prior therapy.
Lenalidomide (25 mg once daily orally on days 1-21 of repeated 28-day [4-week] cycles) was given with low dose dexamethasone at 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or BMI < 18.5). On DARZALEX 20MG/ML I.V infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medicinal product and the remainder given the day after the infusion.
Treatment was continued in both arms until disease progression or unacceptable toxicity.

A total of 569 patients were randomised; 286 to the DRd arm and 283 to the Rd arm. The baseline demographic and disease characteristics were similar between the DARZALEX 20MG/ML I.V and the control arm. The median patient age was 65 years (range 34 to 89 years) and 11% were ≥75 years.
The majority of patients (86%) received a prior PI, 55% of patients had received a prior IMiD, including 18% of patients who had received prior lenalidomide; and 44% of patients had received both a prior PI and IMiD. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory to a PI only, and 21% were refractory to bortezomib.
Patients refractory to lenalidomide were excluded from the study.

With a median follow-up of 13.5 months, the primary analysis of PFS in study MMY3003 demonstrated an improvement in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 18.4 months in the Rd arm (HR=0.37; 95% CI: 0.27, 0.52; p < 0.0001). Results of an updated PFS analysis after a median follow-up of 55 months continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was 45.0 months in the DRd arm and 17.5 months in the Rd arm (HR=0.44; 95% CI: 0.35, 0.54; p <
0.0001), representing a 56% reduction in the risk of disease progression or death in patients treated with DRd (see figure 6).

Figure 6:   Kaplan-Meier curve of PFS in study MMY3003



After a median follow-up of 80 months, DRd has shown an OS advantage over the Rd arm (HR=0.73; 95% CI: 0.58, 0.91; p=0.0044), The median OS was 67.6 months in the DRd arm and 51.8 months in the Rd arm.


Figure 7:     Kaplan-Meier curve of OS in study MMY3003



Additional efficacy results from study MMY3003 are presented in table 11 below.

Table 11: Additional efficacy results from study MMY3003
Response evaluable patient number           DRd (n=281)                            Rd (n=276) Overall response (sCR+CR+VGPR+PR) n(%)                                        261 (92.9)                             211 (76.4) p-valuea                               <0.0001
Stringent complete response (sCR)      51 (18.1)                              20 (7.2) Complete response (CR)                 70 (24.9)                              33 (12.0) Very good partial response (VGPR)      92 (32.7)                              69 (25.0) Partial response (PR)                  48 (17.1)                              89 (32.2) Median time to response [months (95% CI)]   1.0 (1.0, 1.1)                         1.3 (1.1, 1.9) Median duration of response [months (95%    NE (NE, NE)                            17.4 (17.4, NE) CI)]
MRD negative rate (95% CI) b (%)            21.0 (16.4, 26.2)                      2.8 (1.2, 5.5) Odds ratio with 95% CIc                9.31 (4.31, 20.09)
P-valued                               <0.0001
DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval; NE=not estimable.
a p-value from Cochran Mantel-Haenszel Chi-Squared test.
b
Based on Intent-to-treat population and threshold of 10-5 c
Mantel-Haenszel estimate of the common odds ratio is used. An odds ratio >1 indicates an advantage for DRd.
d p-value is from a Fisher’s exact test.


Combination treatment with bortezomib
Study MMY3004, an open-label, randomised, active-controlled phase III study, compared treatment with DARZALEX 20MG/ML I.V 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma who had received at least one prior therapy. Bortezomib was administered by subcutaneous injection or intravenous 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 21 day (3-week) treatment cycles, for a total of 8 cycles. Dexamethasone was administered orally at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 8 bortezomib cycles (80 mg/week for two out of three weeks of the bortezomib cycle) or a reduced dose of 20 mg/week for patients >75 years, BMI <18.5, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of DARZALEX 20MG/ML I.V infusion, 20 mg of the dexamethasone dose was administered as a pre-infusion medicinal product. DARZALEX
20MG/ML I.V treatment was continued until disease progression or unacceptable toxicity.

A total of 498 patients were randomised; 251 to the DVd arm and 247 to the Vd arm. The baseline demographic and disease characteristics were similar between the DARZALEX 20MG/ML I.V and the control arm. The median patient age was 64 years (range 30 to 88 years) and 12% were ≥75 years.
Sixty-nine percent (69%) of patients had received a prior PI (66% received bortezomib) and 76% of patients received an IMiD (42% received lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment. Thirty-three percent (33%) of patients were refractory to an IMiD only, and 28% were refractory to lenalidomide. Patients refractory to bortezomib were excluded from the study.

With a median follow-up of 7.4 months, the primary analysis of PFS in study MMY3004 demonstrated an improvement in the DVd arm as compared to the Vd arm; the median PFS had not been reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% CI]: 0.39 [0.28, 0.53]; p- value < 0.0001). Results of an updated PFS analysis after a median follow-up of 50 months continued to show an improvement in PFS for patients in the DVd arm compared with the Vd arm. Median PFS was 16.7 months in the DVd arm and 7.1 months in the Vd arm (HR [95% CI]: 0.31 [0.24, 0.39]; p- value < 0.0001), representing a 69% reduction in the risk of disease progression or death in patients treated with DVd versus Vd (see figure 8).


Figure 8:   Kaplan-Meier curve of PFS in study MMY3004



After a median follow-up of 73 months, DVd has shown an OS advantage over the Vd arm (HR=0.74; 95% CI: 0.59, 0.92; p=0.0075). The median OS was 49.6 months in the DVd arm and 38.5 months in the Vd arm.


Figure 9:     Kaplan-Meier curve of OS in study MMY3004



Additional efficacy results from study MMY3004 are presented in table 12 below.

Table 12: Additional efficacy results from study MMY3004
Response evaluable patient number               DVd (n=240)                              Vd (n=234) Overall response (sCR+CR+VGPR+PR) n(%)          199 (82.9)                               148 (63.2) P-valuea                                   <0.0001
Stringent complete response (sCR)          11 (4.6)                                 5 (2.1) Complete response (CR)                     35 (14.6)                                16 (6.8) Very good partial response (VGPR)          96 (40.0)                                47 (20.1) Partial response (PR)                      57 (23.8)                                80 (34.2) Median time to response [months (range)]        0.9 (0.8, 1.4)                           1.6 (1.5, 2.1) Median duration of response [months (95% CI)]   NE (11.5, NE)                            7.9 (6.7, 11.3) MRD negative rate (95% CI)b                     8.8% (5.6%, 13.0%)                       1.2% (0.3%, 3.5%) Odds ratio with 95% CIc                    9.04 (2.53, 32.21)
P-valued                                   0.0001
DVd=daratumumab- bortezomib-dexamethasone; Vd=bortezomib-dexamethasone; MRD=minimal residual disease; CI=confidence interval; NE=not estimable.
a p-value from Cochran Mantel-Haenszel Chi-Squared test.
b
Based on Intent-to-treat population and threshold of 10-5 c
Mantel-Haenszel estimate of the common odds ratio is used. An odds ratio >1 indicates an advantage for DVd.
d p-value is from Fisher’s exact test.


Cardiac electrophysiology
Daratumumab as a large protein has a low likelihood of direct ion channel interactions. The effect of daratumumab on the QTc interval was evaluated in an open-label study for 83 patients (study GEN501) with relapsed and refractory multiple myeloma following daratumumab infusions (4 to 24 mg/kg). Linear mixed PK-PD analyses indicated no large increase in mean QTcF interval (i.e.
greater than 20 ms) at daratumumab Cmax.

Paediatric population
DARZALEX 20mg/ml I.V is indicated for use in adults above the age of 18 (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetics (PK) of daratumumab following intravenous administration of daratumumab monotherapy were evaluated in patients with relapsed and refractory multiple myeloma at dose levels from 0.1 mg/kg to 24 mg/kg.

In the 1 to 24 mg/kg cohorts, peak serum concentrations (Cmax) after the first dose increased in approximate proportion to dose and volume of distribution was consistent with initial distribution into the plasma compartment. Following the last weekly infusion, Cmax increased in a greater than dose-proportional manner, consistent with target mediated drug disposition. Increases in AUC were more than dose-proportional and clearance (CL) decreased with increasing dose. These observations suggest CD38 may become saturated at higher doses, after which the impact of target binding clearance is minimised and the clearance of daratumumab approximates the linear clearance of endogenous IgG1. Clearance also decreased with multiple doses, which may be related to tumour burden decreases.

Terminal half-life increases with increasing dose and with repeated dosing. The mean (standard deviation [SD]) estimated terminal half-life of daratumumab following the first 16 mg/kg dose was 9 (4.3) days. The estimated terminal half-life of daratumumab following the last 16 mg/kg dose increased, but there are insufficient data for a reliable estimation. Based on population PK analysis, the mean (SD) half-life associated with non-specific linear elimination was approximately 18 (9) days; this is the terminal half-life that can be expected upon complete saturation of target mediated clearance and repeat dosing of daratumumab.

At the end of weekly dosing for the recommended monotherapy schedule and dose of 16 mg/kg, the mean (SD) serum Cmax value was 915 (410.3) micrograms/mL, approximately 2.9-fold higher than following the first infusion. The mean (SD) predose (trough) serum concentration at the end of weekly dosing was 573 (331.5) micrograms/mL.

Four population PK analyses were performed to describe the PK characteristics of daratumumab and to evaluate the influence of covariates on the disposition of daratumumab in patients with multiple myeloma; analysis 1 (n=223) in patients receiving DARZALEX 20MG/ML I.V monotherapy while analysis 2 (n=694), analysis 3 (n=352) and analysis 4 (n=355) were conducted in patients with multiple myeloma that received daratumumab combination therapies. Analysis 2 included 694 patients (n=326 for lenalidomide-dexamethasone; n=246 for bortezomib-dexamethasone; n=99 for pomalidomide-dexamethasone; n=11 for bortezomib-melphalan-prednisone; and n=12 for bortezomib- thalidomide-dexamethasone), analysis 3 included 352 patients (bortezomib-melphalan-prednisone) and analysis 4 included 355 patients (lenalidomide-dexamethasone).

Based on the population PK analysis of daratumumab monotherapy (analysis 1), daratumumab steady state is achieved approximately 5 months into the every 4-week dosing period (by the 21st infusion), and the mean (SD) ratio of Cmax at steady-state to Cmax after the first dose was 1.6 (0.5). The mean (SD) central volume of distribution is 56.98 (18.07) mL/kg.

Three additional population PK analyses (analysis 2, analysis 3 and analysis 4) were conducted in patients with multiple myeloma that received daratumumab combination therapies. Daratumumab concentration-time profiles were similar following the monotherapy and combination therapies. The mean estimated terminal half-life associated with linear clearance in combination therapy was approximately 15-23 days.

Based on the four population PK analyses (analyses 1-4) body weight was identified as a statistically significant covariate for daratumumab clearance. Therefore, body weight based dosing is an appropriate dosing strategy for the multiple myeloma patients.
Simulation of daratumumab pharmacokinetics was conducted for all recommended dosing schedules in 1309 patients with multiple myeloma. The simulation results confirmed that the split and single dosing for the first dose provide similar PK, with the exception of the PK profile in the first day of the treatment.

Special populations
Age and gender
Based on four individual population PK analyses (1-4) in patients receiving daratumumab monotherapy or various combination therapies (analyses 1-4), age (range: 31-93 years) had no clinically important effect on the PK of daratumumab, and the exposure of daratumumab was similar between younger (aged <65 years, n=518) and older (aged ≥65 to <75 years n=761; aged ≥75 years, n=334) patients.

Gender did not affect exposure of daratumumab to a clinically relevant degree in the population PK analyses.

Renal impairment
No formal studies of daratumumab in patients with renal impairment have been conducted. Four individual population PK analyses were performed based on pre-existing renal function data in patients receiving daratumumab monotherapy, or various combination therapies (Analyses 1-4), and included a total of 441 patients with normal renal function (creatinine clearance [CRCL] ≥90 mL/min), 621 with mild renal impairment (CRCL < 90 and ≥60 mL/min), 523 with moderate renal impairment (CRCL < 60 and ≥30 mL/min), and 27 with severe renal impairment or end stage renal disease (CRCL <30 mL/min). No clinically important differences in exposure to daratumumab were observed between patients with renal impairment and those with normal renal function.

Hepatic impairment
No formal studies of daratumumab in patients with hepatic impairment have been conducted. Changes in hepatic function are unlikely to have any effect on the elimination of daratumumab since IgG1 molecules such as daratumumab are not metabolised through hepatic pathways.
Four individual population PK analyses were performed in patients receiving daratumumab monotherapy or various combination therapies (Analyses 1-4), and included a total of 1404 patients with normal hepatic function (total bilirubin [TB] and aspartate aminotransferase [AST] ≤ upper limit of normal [ULN]), 189 with mild hepatic impairment (TB 1.0 x to 1.5 x ULN or AST >ULN) and 8 patients with moderate (TB > 1.5 x to 3.0 x ULN; n=7), or severe (TB > 3.0 x ULN; n=1) hepatic impairment. No clinically important differences in the exposure to daratumumab were observed between patients with hepatic impairment and those with normal hepatic function.

Race
Based on four individual population PK analyses in patients receiving either daratumumab monotherapy or various combination therapies (analyses 1-4), the exposure to daratumumab was similar between white (n=1371) and non-white subjects (n=242).