Adv Ther (2020) 37:1464–1478 https://doi.org/10.1007/s12325-020-01247-8 ORIGINAL RESEARCH Split First Dose Administration of Intravenous Daratumumab for the Treatment of Multiple Myeloma (MM): Clinical and Population Pharmacokinetic Analyses Xu Steven Xu . Philippe Moreau . Saad Z. Usmani . Sagar Lonial . Andrzej Jakubowiak . Albert Oriol . Amrita Krishnan . Joan Bladé . Man Luo . Yu-Nien Sun . Honghui Zhou . Ivo Nnane . William Deraedt . Ming Qi . Jon Ukropec . Pamela L. Clemens Received: November 6, 2019 / Published online: February 20, 2020 Ó The Author(s) 2020 ABSTRACT subsequent intravenous infusions of daratu- mumab were 7.0, 4.3, and 3.4 h, respectively. Introduction: Daratumumab, a human immuno- Splitting the first intravenous infusion of dara- globulin Gj monoclonal antibody targeting tumumab over 2 days is an approved alternative CD38, is approved as monotherapy and in dosing regimen to reduce the duration of the combination with standard-of-care regimens for first infusion and provide flexibility for patients multiple myeloma. In clinical studies, the and healthcare providers. median durations of the first, second, and Methods: The feasibility of splitting the first 16-mg/kg infusion into two separate infusions of 8 mg/kg on Days 1 and 2 of the first treat- ment cycle was investigated in two cohorts Enhanced Digital Features To view enhanced digital [daratumumab, carfilzomib, and dexametha- features for this article go to https://doi.org/10.6084/ m9.figshare.11673591. sone (D-Kd) and daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd)] of Electronic Supplementary Material The online the phase 1b MMY1001 study. Additionally, a version of this article (https://doi.org/10.1007/s12325- population pharmacokinetic (PK) analysis and 020-01247-8) contains supplementary material, which is available to authorized users. simulations were used to compare the PK X. S. Xu (&) A. Oriol Janssen Research & Development, LLC, Raritan, NJ, Institut Català d’Oncologia and Institut Josep USA Carreras, Hospital Germans Trias i Pujol, Barcelona, e-mail: sxu26@its.jnj.com Spain P. Moreau A. Krishnan University Hospital of Nantes, Nantes, France City of Hope, Duarte, CA, USA S. Z. Usmani J. Bladé Levine Cancer Institute/Atrium Health, Charlotte, Servei d’Hematologia, Hospital Clı́nic de Barcelona, NC, USA Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, S. Lonial Barcelona, Spain Winship Cancer Institute, Emory University, Atlanta, GA, USA M. Luo  Y.-N. Sun  H. Zhou  I. Nnane  M. Qi  P. L. Clemens A. Jakubowiak Janssen Research & Development, LLC, University of Chicago Medical Center, Chicago, IL, Spring House, PA, USA USA Adv Ther (2020) 37:1464–1478 1465 profiles of the split first dose regimen with the recommended single first dose regimens of Key Summary Points daratumumab in previously approved indications. Splitting the first infusion of intravenous Results: In MMY1001, following administra- daratumumab over 2 days is an approved tion of the second half of a split first dose on alternative dosing regimen to reduce the Cycle 1 Day 2, postinfusion median (range) duration of the first infusion and provide daratumumab concentrations were similar flexibility for patients and healthcare between split first dose [D-Kd, 254.9 (125.8– providers, without increasing the rate of 435.5) lg/ml; D-KRd, 277.2 (164.0–341.8) infusion-related reactions. lg/ml; combined, 256.8 (125.8–435.5) lg/ml] and single first dose [D-Kd, 319.2 (237.5–394.7) Pharmacokinetics (PK) data from the lg/ml]. At the end of weekly dosing, median MMY1001 study and the population PK (range) Cycle 3 Day 1 preinfusion daratumumab simulation demonstrate that concentrations were similar between split first daratumumab concentration profiles were dose [D-Kd, 663.9 (57.7–1110.7) lg/ml; D-KRd, comparable following completion of 575.1 (237.9–825.5) lg/ml; combined, 639.2 administration of the first 16-mg/kg dose (57.7–1110.7) lg/ml] and single first dose [D-Kd, of daratumumab regardless of whether it 463.2 (355.9–792.9) lg/ml]. The population PK was administered as a split first dose or a simulations demonstrated virtually identical PK single first dose. profiles after the first day of treatment for all These findings support the use of an approved indications and recommended dosing alternative split first dose regimen of schedules of daratumumab. intravenous daratumumab for the Conclusion: These data support the use of an treatment of multiple myeloma. alternative split first dose regimen of intra- venous daratumumab for the treatment of MM. Trial Registration: ClinicalTrials.gov number, NCT01998971. Keywords: Clinical pharmacology; Daratumu- INTRODUCTION mab; Intravenous infusion; Multiple myeloma; Daratumumab is a human immunoglobulin Gj Pharmacokinetics; Single first dose; Split first (IgGj) monoclonal antibody targeting CD38 dose with a direct on-tumor [1–4] and immunomodulatory [5–7] mechanism of action. Daratumumab 16 mg/kg administered intravenously (IV) demonstrates activity as monotherapy and provides clinical benefit when combined with standard-of-care regimens for the treatment of multiple myeloma (MM) across lines of therapy [10–14]. Based on the findings of several phase 3 clinical studies, daratumumab (16 mg/kg) in combination with lenalidomide and dexamethasone (D-Rd), bortezomib and dexamethasone (D-Vd), and bortezomib, melphalan, and prednisone W. Deraedt (D-VMP) has received approval for the treatment of Janssen Research & Development, Beerse, Belgium patients with relapsed/refractory MM (D-Rd and J. Ukropec D-Vd) or transplant-ineligible newly diagnosed Janssen Scientific Affairs, LLC, Horsham, PA, USA MM (D-Rd and D-VMP) in many countries 1466 Adv Ther (2020) 37:1464–1478 worldwide. Daratumumab is also approved as concentration [Ctrough]) and efficacy in patients monotherapy in many countries and in com- with relapsed/refractory MM [18, 19]. A maxi- bination with pomalidomide and dexametha- mum Ctrough of 274 lg/ml was associated with sone (D-Pd) in the USA. 90% maximal effect on overall response rate, and Infusion-related reactions have been repor- a concentration of 236 lg/ml was required to ted in patients treated with IV daratumumab achieve 99% model-predicted target (CD38) sat- (16 mg/kg), which are predominately grade 1 or uration [18]. These data highlight the importance 2 in severity and occur primarily during the first of attaining daratumumab serum concentrations daratumumab infusion [9]. As early clinical data with a split first dose regimen that are similar to demonstrated an association between a higher the approved single first dose regimen. rate of infusion-related reactions and a faster The objective of this study was to present PK infusion rate of daratumumab, a prolonged analysis results of splitting the first daratu- infusion time for the first dose of daratumumab mumab 16-mg/kg IV dose into two separate is necessary to reduce the incidence of infusion- infusions of 8 mg/kg on Days 1 and 2 of the first related reactions. In clinical studies, the median treatment cycle. This dosing regimen was given durations of the first, second, and subsequent to patients in the daratumumab, carfilzomib, daratumumab infusions were 7.0, 4.3, and and dexamethasone (D-Kd) and daratumumab, 3.4 h, respectively [9]. The first daratumumab carfilzomib, lenalidomide, and dexamethasone infusion is administered in a larger infusion (D-KRd) arms of the phase 1b MMY1001 study volume (1000 ml) and at a slower initial infu- [15, 16]. In addition, population PK analyses and sion rate (50 ml/h) compared with the second simulations were used to compare the PK profiles (500 ml; 50 ml/h) and subsequent infusions of the split first dose regimen with the recom- (500 ml; 100 ml/h), thus prolonging the infu- mended single first dose regimens of daratu- sion time [9]. mumab in previously approved indications. Splitting the first infusion of daratumumab over 2 days has been proposed as an alternative dosing regimen to reduce the duration of the first METHODS infusion and reduce treatment burden for patients and healthcare providers. A split first MMY1001 Study Design and Treatment dose of daratumumab was evaluated in two cohorts of a phase 1b MMY1001 study of dara- MMY1001 is a phase 1b, open-label, nonran- tumumab in combination with standard-of-care domized, multicenter study evaluating the regimens in MM (NCT01998971). These analyses safety, tolerability, and dosing regimen of demonstrated that the split first dose of daratu- daratumumab in combination with established mumab is feasible and may improve patient treatment regimens for patients with newly convenience for initial dosing [15, 16]. However, diagnosed MM or relapsed/refractory MM. Eli- it is unknown whether patients can achieve gible patients were C 18 years of age with mea- effective daratumumab serum concentrations surable documented MM and an Eastern with a split first dose regimen. Data from Cooperative Oncology Group (ECOG) perfor- monotherapy studies show that daratumumab mance status B 2. The split first dose adminis- exhibits nonlinear pharmacokinetics (PK) con- tration for daratumumab was investigated in sistent with target-mediated drug disposition the D-KRd and D-Kd cohorts of MMY1001. [17]. The recommended dose regimen of 16 mg/kg Patients with newly diagnosed MM were enrol- weekly for 8 weeks rapidly saturates target- led in the D-KRd cohort irrespective of trans- mediated clearance, and subsequent dosing plant eligibility. Patients in the D-Kd cohort had every 2 weeks for 16 weeks and every 4 weeks relapsed/refractory MM with one to three prior thereafter maintains target saturation. Popula- lines of therapy including bortezomib and an tion PK and exposure-response analyses have immunomodulatory agent. Daratumumab demonstrated a strong association between 16 mg/kg IV was administered to D-KRd and daratumumab concentration (maximum trough D-Kd cohorts weekly for Cycles 1 and 2, Adv Ther (2020) 37:1464–1478 1467 every 2 weeks for Cycles 3–6, and every 4 weeks Population PK Analysis for the remaining cycles. In the D-Kd arm of MMY1001, ten patients received the first dara- The population PK analysis used nonlinear tumumab dose as a single infusion [16 mg/kg mixed-effects modeling and simulation to (1000 ml) on Day 1 Cycle 1] and 75 patients compare the PK profile of the daratumumab received a split first dose [8 mg/kg (500 ml) on split first dose regimen (8 mg/kg on Cycle 1 Days 1–2 Cycle 1]. In the D-KRd arm, all Day 1 and Cycle 1 Day 2) with approved or rec- patients received a split first dose of ommended single first dose regimens (16 mg/kg daratumumab. on Cycle 1 Day 1) using individual PK parameters Pharmacokinetic data from the D-Kd and of patients with MM from seven clinical studies D-KRd cohorts (n = 107) were used for PK analy- of daratumumab, including daratumumab sis. Serum samples were collected pre- and monotherapy studies [GEN501 (NCT00574288) postinfusion of daratumumab on Day 1 of Cycle 1 and SIRIUS (NCT01985126); n = 223]; D-Rd through Cycle 4 and then 3 and 9 weeks post- treatment studies [GEN503 (NCT01615029) and treatment for all patients in the D-Kd and D-KRd POLLUX (NCT02076009); n = 326]; D-Vd treat- cohorts. Serum samples were also collected pre- ment studies [CASTOR (NCT02136134) and and postinfusion on Cycle 1 Day 2 for patients MMY1001 (NCT01998971); n = 246]; D-VMP receiving the split first dose in the D-Kd and treatment studies [MMY1001 and ALCYONE D-KRd cohorts. An enzyme-linked immunosor- (NCT02195479); n = 352]; MMY1001 D-Pd bent assay (ELISA) validated in 2009 by Bio Ana- treatment arm (n = 99), and MMY1001 D-Kd and lytical Research Corporation (BARC) Global D-KRd treatment arms (n = 107), all of which Central Laboratory (Ghent, Belgium) was used to have been described in detail previously and are determine serum daratumumab concentrations briefly summarized in Online Resource 1 in previous studies. In 2014, the BARC ELISA PK [10–16, 22–24]. method was transferred to Janssen Research & The individual PK parameters for D-Kd and Development, LLC (Spring House, PA, USA), and D-KRd were generated using a newly developed, successfully cross-validated for reproducibility at nonlinear, mixed-effects population PK model two separate laboratories. The transferred ELISA in the current report. Serum concentration-time PK method was used by Janssen Research & data were used for nonlinear mixed-effects Development, LLC, to determine daratumumab modeling using NONMEM (ICON plc, version 7 concentrations in human serum in subsequent or higher). The population PK model included a analyses of daratumumab studies. In general, the two-compartment structure with parallel linear ELISA method was validated according to the and Michaelis-Menten nonlinear eliminations European Medicines Agency, the US Food and [25], where linear clearance represents the Drug Administration, bioanalytical method val- nonspecific clearance for IgG, and the Michae- idation guidance, and industry white papers lis-Menten elimination represents the saturable (EMEA/CHMP/EWP 2011, Guidance for Indus- target-mediated clearance. The interpatient try 2018) [20, 21]. The lowest quantifiable con- variability in structural parameters was modeled centration of daratumumab in a sample was with an exponential term to ensure positive 0.2 lg/ml, and the upper limit of quantification values of individual parameters, and an additive was 145.8 lg/l at a 1:40 dilution. The inter-assay model was used to model residual variability. variability across the standard curve range The final covariate model included body was \ 10%. weight, albumin, type of myeloma, and sex as Serum daratumumab concentrations were significant yet non–clinically relevant covari- summarized using descriptive statistics and ates. PK parameter estimates for individual presented as arithmetic mean, standard devia- patients treated with other regimens were tion, and coefficient of variation. PK values are obtained from previously developed population summarized by nominal time and presented as PK models [18, 19, 25]. Simulations were per- arithmetic mean, standard deviation (SD), and formed to predict the PK profiles for all patients coefficient of variation. who had participated in previous daratumumab 1468 Adv Ther (2020) 37:1464–1478 studies and to compare the difference in PK patients received a split first dose of daratu- between the split- and single-first dose of dara- mumab 8 mg/kg on Cycle 1 Day 1 and Cycle 1 tumumab among those patients. Therefore, we Day 2 (D-Kd, n = 75; D-KRd, n = 22). An addi- mimicked a cross-over design, so each patient tional ten patients in the D-Kd cohort received was assumed to receive both split- and single- the standard single first dose regimen of dara- first dose approaches in a sequential manner. tumumab 16 mg/kg on Cycle 1 Day 1. Patient The cross-over design removes the influence of demographics and baseline disease characteris- between-patient variability and enables a better tics are summarized in Table 1. Briefly, the comparison of PK for both dosing approaches. majority of patients in both treatment cohorts The empirical Bayesian estimates of PK param- had an ECOG score \ 2 (D-Kd, 91.8%; D-KRd, eters for each patient were used for simulations. 95.5%). Patients with relapsed/refractory MM in Simulations were conducted for individual the D-Kd cohort were numerically older (me- treatments or indications with dosing schedules dian: 66 years of age) than patients with newly for daratumumab monotherapy, D-Rd, D-Pd, diagnosed MM in the D-KRd cohort (median: D-Kd, and D-KRd that consisted of daratu- 60 years of age). However, the impact of the mumab 16 mg/kg given once weekly for difference in age between the populations was 8 weeks, every 2 weeks for 16 weeks, and every minimal since the relative difference in PK from 4 weeks thereafter. For D-Vd, the dosing sched- the split- and single-first dose regimens were ule consisted of daratumumab 16 mg/kg given compared and the PK parameters from each every week for 9 weeks, every 3 weeks for patient were used for simulations of both the 15 weeks, and every 4 weeks thereafter. The single-first and split-dose regimens. D-VMP dosing schedule consisted of daratu- mumab 16 mg/kg given every week for 6 weeks, PK Analysis of MMY1001 Split and Single every 3 weeks for 48 weeks, and every 4 weeks First Dose Cohorts thereafter. In MMY1001, measured daratumumab Cycle 1 Compliance with Ethics Guidelines Day 1 postinfusion median (range) concentra- tions after the first half (8 mg/kg) of a split first The individual protocols and amendments for dose [D-Kd, 151.5 (82.5–345.0) lg/ml; D-KRd, each study included in this report were 177.8 (121.9–215.7) lg/ml; combined, 156.7 reviewed and approved by affiliated local inde- (82.5–345.0) lg/ml] were lower than the con- pendent ethics committees or internal review centrations after a 16-mg/kg single first dose boards (see Online Resource 2 for a list of [D-Kd, 319 (237.5–394.7) lg/ml; Table 2]. committees for MMY1001). Studies were con- Following administration of the second half ducted in accordance with ethical principles (8 mg/kg) of a split first dose on Cycle 1 Day 2, that have their origin in the Declaration of postinfusion median (range) daratumumab Helsinki and are consistent with Good Clinical concentrations were similar between patients Practices and applicable regulatory require- who received a split first dose [D-Kd, 254.9 ments. All patients provided written consent (125.8–435.5) lg/ml; D-KRd, 277.2 (164.0– prior to any study-specific procedures. 341.8) lg/ml; combined, 256.8 (125.8–435.5) lg/ml] and those who received a single first dose (Table 2; Fig. 1). At the end of weekly dosing, RESULTS median (range) Cycle 3 Day 1 preinfusion daratumumab concentrations (Ctroughs) were Patient and Disease Characteristics similar between patients who received a split first dose [D-Kd, 663.9 (57.7–1110.7) lg/ml; The PK-evaluable population was composed of D-KRd, 575.1 (237.9–825.5) lg/ml; combined, 107 patients in the D-Kd (n = 85) and D-KRd 639.2 (57.7–1110.7) lg/ml] and those who (n = 22) cohorts of MMY1001. A total of 97 Adv Ther (2020) 37:1464–1478 1469 Table 1 Demographics and Baseline Disease Characteristics Characteristic D-Kd (N = 85) D-KRd (N = 22) Age, years Median (range) 66 (38–85) 60 (34–74) Category, n (%) \ 65 36 (42.4) 15 (68.2) 65 to \ 75 41 (48.2) 7 (31.8) C 75 8 (9.4) 0 (0.0) Gender Male 46 (54.1) 12 (54.5) Female 39 (45.9) 10 (45.5) Race White 68 (80.0) 19 (86.4) Black or African American 3 (3.5) 1 (4.5) Asian 3 (3.5) 0 (0.0) American Indian or Alaska Native 0 (0.0) 1 (4.5) Not reported 11 (12.9) 1 (4.5) Height, cm Median (range) 165.0 (141.5–185.4) 172.9 (153.7–193.0) Weight, kg Median (range) 70.0 (45.0–160.8) 79.9 (55.1–144.2) ECOG performance status, n (%) 0 32 (37.6) 12 (54.5) 1 46 (54.1) 9 (40.9) 2 7 (8.2) 1 (4.5) D-Kd daratumumab/carfilzomib/dexamethasone, D-KRd daratumumab/carfilzomib/lenalidomide/dexamethasone, ECOG Eastern Cooperative Oncology Group received a single first dose [D-Kd, 463.2 Similar concentrations were observed after (355.9–792.9) lg/ml; Table 2]. administration of the first total dose of Serum concentrations at the end of infusion 16 mg/kg per patient across monotherapy and on Days 1 and 2 of Cycle 1 and maximum combination therapies, indicating that the reg- serum Ctrough (at the end of weekly dosing) were imen has no meaningful impact on the con- compared between the split first dose regimens centration of daratumumab after Cycle 1 Day 1. and the single first dose regimens from the The maximum Ctrough at the end of weekly MMY1001 D-Kd and D-KRd cohorts with other dosing was also similar (\ 10% difference in single first dose daratumumab combination maximum Ctrough) across studies, regardless of studies, MMY1001, GEN503, POLLUX, CAS- the split or single first dose and dosing regimen. TOR, and ALCYONE (Online Resource 3). 1470 Adv Ther (2020) 37:1464–1478 Table 2 Summary of Daratumumab Serum Concentrations Over Time in MMY1001 D-Kd and D-KRd Dose Cohorts Sampling time point D-Kd D-KRd Combined Single dose Split dose Split dose Split dose PK-evaluable patients, n 10 75 22 97 a C1D1 postinfusion n 8 71 15 86 Median (range), lg/ml 319.2 (237.5–394.7) 151.5 (82.5–345.0) 177.8 (121.9–215.7) 156.7 (82.5–345.0) CV (%) 15.3 31.5 16.8 29.3 b C1D2 preinfusion n NA 65 16 81 Median (range), lg/ml – 110.5 (0.0–284.9) 118.0 (61.2–169.2) 111.6 (0.0–284.9) CV (%) – 37.9 24.5 35.4 a C1D2 postinfusion N NA 69 18 87 Median (range), lg/ml – 254.9 (125.8–435.5) 277.2 (164.0–341.8) 256.8 (125.8–435.5) CV (%) – 28.2 20.8 26.7 b C2D1 preinfusion N 10 63 21 84 Median (range), lg/ml 335.8 (186.6–556.4) 380.7 (0.0–721.6) 329.8 (112.1–473.4) 354.7 (0.0–721.6) CV (%) 34.5 49.4 32.9 47.0 a C2D1 postinfusion N 9 64 15 79 Median (range), lg/ml 726.6 (523.1–911.6) 688.6 (0.0–1202.4) 692.4 (458.8–961.0) 688.9 (0.0–1202.4) CV (%) 22.1 36.4 23.1 34.3 C3D1 preinfusionb N 9 52 19 71 Median (range), lg/ml 463.2 (355.9–792.9) 663.9 (57.7–1110.7) 575.1 (237.9–825.5) 639.2 (57.7–1110.7) CV (%) 26.5 41.4 30.7 39.1 C3D1 postinfusiona N 9 52 14 66 Median (range), lg/ml 844.1 (725.4–1176.0) 916.0 (36.9–1711.3) 939.3 (638.4–1301.0) 926.0 (36.9–1711.3) CV (%) 18.9 36.8 17.9 33.5 b C4D1 preinfusion N 7 24 21 45 Median (range), lg/ml 509.1 (291.2–743.5) 613.0 (92.3–1019.3) 457.3 (146.1–768.1) 523.0 (92.3–1019.3) CV (%) 30.9 41.8 33.2 39.2 Adv Ther (2020) 37:1464–1478 1471 Table 2 continued Sampling time point D-Kd D-KRd Combined Single dose Split dose Split dose Split dose C4D1 postinfusiona N 8 24 11 35 Median (range), lg/ml 918.6 (646.5–1142.6) 962.0 (347.0–1630.2) 939.4 (776.6–1205.0) 939.4 (347.0–1630.2) CV (%) 19.2 31.3 15.3 27.0 D-Kd daratumumab/carfilzomib/dexamethasone, D-KRd daratumumab/carfilzomib/lenalidomide/dexamethasone, PK pharmacokinetics, C cycle, D day, SD standard deviation, CV coefficient of variation, NA not applicable a Postinfusion PK sampling time window was up to 5 min after the end of infusion b Preinfusion PK sampling time window was up to 2 h prior to the start of the infusion or administration of the backbone medications Fig. 1 Mean daratumumab serum concentrations (lg/ml) daratumumab/carfilzomib/dexamethasone, D-KRd daratu- among PK-evaluable patients in MMY1001 D-Kd and mumab/carfilzomib/lenalidomide/dexamethasone, DARA D-KRd single/split first daratumumab dose cohorts. daratumumab, C Cycle, D Day, SD standard deviation Values are mean ± SD. PK pharmacokinetic, D-Kd 1472 Adv Ther (2020) 37:1464–1478 Population PK Analysis of daratumumab. Regimens included daratu- mumab monotherapy, D-Rd, D-Vd, D-Pd, A prediction-corrected visual predictive check D-VMP, D-Kd, and D-KRd. The split first dose of the final population PK model was performed and single first dose regimens were virtually to compare the simulation and observed dara- identical with respect to their overall PK profiles tumumab concentrations over time (Online (Fig. 2a, Online Resource 5). Simulated PK pro- Resource 4). The visual predictive check plot files of the split first dose and single first dose showed good agreement between the simulated regimens varied only during the first day of concentrations and the individual observed treatment (Cycle 1 Day 1) when the dosing concentrations (Online Resource 4). The esti- regimens were different (8 mg/kg versus 16 mg/kg; mated inter-patient variability adequately cap- Fig. 2b). Differences in simulated PK profiles tured the observed variability. were minimal following the second split dose Simulation of daratumumab PK following on Cycle 1 Day 2. The difference in concentra- the split first dose and single first dose regimens tions between the split-dose and single-infusion was conducted using individual PK parameters regimens was reduced to \ 1% for the majority of patients with MM from seven clinical studies of patients by Week 4 (Fig. 3). A B Fig. 2 Simulated daratumumab concentration-time by the 2.5th and 97.5th percentiles of the simulation. profiles (a) and simulated daratumumab concentration- D daratumumab, D-Rd daratumumab/lenalidomide/ time profiles for the first 2 weeks (b) for the split- and dexamethasone, D-Kd daratumumab/carfilzomib/ single-first dose of daratumumab 16 mg/kg in patients who dexamethasone, D-KRd daratumumab/carfilzomib/ received daratumumab monotherapy, D-Rd, D-Kd, lenalidomide/dexamethasone, D-Pd daratumumab/ D-KRd, and D-Pd (left); D-Vd (middle); and D-VMP pomalidomide/dexamethasone, D-Vd daratumumab/ (right) regimens. The red solid and blue dashed lines bortezomib/dexamethasone, D-VMP daratumumab/ represent the median, and the shaded regions are bounded bortezomib/melphalan/prednisone Adv Ther (2020) 37:1464–1478 1473 Fig. 3 Boxplot comparison of percent difference in sim- that the daratumumab concentration of the single first ulated daratumumab Ctrough in patients who received dose is less than the concentration of the split first daratumumab 16-mg/kg monotherapy, D-Rd, D-Kd, dose. Ctrough, trough concentration; D daratumumab, D-KRd, and D-Pd (left); D-Vd (middle); and D-VMP D-Rd daratumumab/lenalidomide/dexamethasone, (right) regimens. Percent difference in concentration is D-Kd daratumumab/carfilzomib/dexamethasone, calculated by the following formula: (SINGLE–SPLIT D-KRd daratumumab/carfilzomib/lenalidomide/dexametha- DOSE)/SINGLE 9 100%, where SINGLE is the daratu- sone, D-Pd, daratumumab/pomalidomide/dexamethasone, mumab concentration for single first dose and SPLIT D-Vd daratumumab/bortezomib/dexamethasone, DOSE is the daratumumab concentration for split first D-VMP daratumumab/bortezomib/melphalan/prednisone dose. A negative % difference in concentration indicates The final model of the monotherapy studies of treatment, a split or single first dose of IV was used to fit data for daratumumab serum daratumumab provides virtually identical PK for concentration versus time. The model-based all approved indications and recommended covariate analysis identified body weight, base- dosing regimens. Because the transient differ- line albumin level, and type of myeloma (IgG ence in daratumumab serum concentration on versus non-IgG) as statistically significant Cycle 1 Day 1 is not expected to have any covariates on linear clearance, whereas body impact on overall clinical outcomes, these weight and sex were identified as statistically findings suggest that the split first dose regimen significant covariates on the volume of distri- of IV daratumumab is feasible and provides an bution in the central compartment. Parameter alternative flexible dosing strategy for patients estimates of the final covariate model are shown and healthcare providers. in Online Resource 6. The estimated linear The primary objective of this modeling and clearance and volume of distribution parame- simulation study was to use simulation to ters were very close to the estimates from pre- compare single first dose versus split first dose. vious studies. The condition number of the final An appropriate design of the simulation study is model was 27.80, indicating the final covariate a cross-over design, so each patient was assumed model was appropriately parameterized. to receive both split and single first dose approaches in a sequential manner. The cross- over design allows removing the influence by DISCUSSION between-patient variability and better compar- ison of PK for both dosing approaches. This can Pharmacokinetic data from MMY1001 and the be achieved without pooling all the studies as population PK analysis suggest that, with the individual parameter estimates were available exception of the PK profile during the first day from previous models. Also, different patient 1474 Adv Ther (2020) 37:1464–1478 populations exhibited some difference in PK dose D-Kd group for the clinical PK analysis and behaviors, so pooling all studies may mask these the limited PK sampling over time in this differences. phase 1 study. In addition, the cross-over design Among patients in the PK-evaluable popula- in the simulation removed the between-patient tion, 97 received a split first dose of daratu- variability from the comparison of the two dosing mumab versus only ten patients who received approaches and therefore circumvented the the standard single first dose regimen of dara- limitations caused by cross-study heterogeneity tumumab. Based on the differences in the in previous clinical studies, such as sample sizes, number of patients in each dosing group, phases of drug testing, and eligibility criteria. shrinkage was evaluated and determined to Using data from seven clinical studies, the be \ 20%. In addition, since the relative differ- simulation results suggest that the PK profiles of ence in PK from the split- and single-first dose the split first dose regimen and single first dose regimens were compared and the PK parameters regimen should provide virtually identical PK, from each patient were used for simulations of with the exception of the PK profile during the both the split first dose and standard single first day of treatment, for all approved indica- dose, the impact of shrinkage on the relative tions and recommended dosing regimens. difference may have been cancelled out. Previous exposure-response analysis for The PK profile for the split first dose regimen daratumumab monotherapy and combination of daratumumab was similar to the PK profiles therapy studies has demonstrated a strong cor- of daratumumab demonstrated in previous relation between efficacy endpoints, including monotherapy and combination therapy studies, overall response rate and progression-free sur- regardless of the population treated. After the vival as well as daratumumab serum exposure first total dose of 16 mg/kg, mean daratumumab [18, 19]. In contrast, no apparent relationship serum concentrations (Table 2) for the split first between serum drug exposure and adverse dose (Cycle 1 Day 2) and single first dose events was observed [18, 19]. Given that the PK (Cycle 1 Day 1) regimens were similar to those profile, including the Ctrough at the end of observed after the first dose of daratumumab weekly dosing, was similar between the split monotherapy in SIRIUS (313 lg/ml) and dara- first dose and single first dose regimens, it is tumumab combination therapy in CASTOR anticipated that the efficacy and safety follow- (D-Vd; 318 lg/ml) and POLLUX (D-Rd; 329 lg/ml) ing the split first dose regimen would be similar [17]. The consistency of daratumumab exposure to that of the single first dose regimen. across split- and single-first dose regimens con- Clinical data from MMY1001 D-KRd and tinued through the end of weekly dosing D-Kd cohorts have demonstrated that split first (Cycle 3 Day 1) and was comparable to daratu- dosing of daratumumab is well tolerated, with mumab monotherapy in SIRIUS (574 lg/ml) and safety profiles consistent with previous reports D-Rd combination therapy in POLLUX (608 lg/ml) of daratumumab, KRd, and Kd [15, 16]. No [17]. At the end of weekly dosing, Ctrough for the increase in the rate of infusion-related reactions split dose regimen was also above the effective was observed with split compared with single Ctrough of daratumumab monotherapy (274 lg/ml) first dosing of daratumumab in MMY1001 [18]. Overall, these data support that daratu- D-KRd and D-Kd cohorts [15, 16]. On Cycle 1 mumab may be administered as a split dose on Day 1, infusion-related reactions were observed Day 1 and Day 2 of Cycle 1. in 37% and 23% of patients treated with split Results from the population PK analysis were first dose D-Kd and D-KRd, respectively, com- consistent with the clinical PK data from pared with 1% and 5% of patients who received MMY1001. The population PK simulation D-Kd and D-KRd, respectively, on Cycle 1 Day 2 implemented a cross-over design and allowed [15, 16]. Among patients treated with a single for comparison of daratumumab split first dose first dose of D-Kd, 50% experienced infusion- PK with single first dose PK within the same related reactions on Cycle 1 Day 1 [15, 16]. individual patient. The simulations overcame Findings from the MMY1001 study and the PK the relatively small sample size in the single first simulations led to the approval of the split first Adv Ther (2020) 37:1464–1478 1475 dose as an alternative daratumumab dosing Global Services, LLC, funded the Rapid Service protocol in many countries [26, 27]. Further- and Open Access Fees. more, a real-world observational study of patients with MM who received daratumumab Medical Writing and Editorial Assis- in US community oncology clinics found that tance. Editorial and medical writing support utilization of the split first dose of daratu- was provided by J. Matthew Kuczmarski, PhD, mumab increased over time and was used more of MedErgy and funded by Janssen Global Ser- frequently than the single first dose regimen by vices, LLC. the end of the study period [28]. The split first dose was associated with a shorter infusion Authorship. All named authors meet the duration on Day 1 and did not increase the rate International Committee of Medical Journal of infusion reactions compared with the single Editors (ICMJE) criteria for authorship for this first dose regimen [28], supporting the use of article, take responsibility for the integrity of split first dosing in patients with MM. Several the work as a whole, and have given their clinical studies using the split first dosing of approval for this version to be published. daratumumab are also ongoing, including the phase 2 LYRA (NCT02951819) study of daratu- Prior Presentation. These data were previ- mumab in combination with cyclophos- ously presented, in part, at the 60th Annual phamide, bortezomib, and dexamethasone in Meeting of the American Society of Hematol- newly diagnosed MM and relapsed MM [29] and ogy; 1–4 December 2018; San Diego, CA. the phase 3 CANDOR (NCT03158688) study of Disclosures. Man Luo, Yu-Nien Sun, Hon- D-Kd versus Kd in patients with relapsed/ ghui Zhou, Ivo Nnane, William Deraedt, Ming refractory MM. Qi, Jon Ukropec, and Pamela L. Clemens are employees of Janssen and hold equity in John- CONCLUSIONS son & Johnson. Xu Steven Xu was an employee of Janssen at the time of the study and manu- These data suggest that daratumumab concen- script preparation and may hold equity in tration profiles were comparable following Johnson & Johnson; his current affiliation is completion of administration of the first 16-mg/kg Genmab US Inc, Princeton, NJ, USA. Philippe dose of daratumumab, regardless of whether it Moreau served as a consultant for and received was administered as a split first dose or a single honoraria from Amgen, Celgene, Janssen, first dose, and support the use of a split first dose Takeda, Bristol-Myers Squibb, Novartis, Millen- regimen as an alternative to the single first dose nium, and Onyx Pharmaceuticals. Saad Z. regimen of daratumumab for the treatment of Usmani served as a consultant for AbbVie, patients with MM. Amgen, Celgene, Genmab, Merck, Mundi- Pharma, and Seattle Genetics; received research funding from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, and ACKNOWLEDGMENTS Takeda; and served as a member of the board of directors or advisory committees for and The authors thank the patients who partici- received research funding from Sanofi. Sagar pated in the MMY1001, GEN501, SIRIUS, Lonial received research funding from Amgen. GEN503, POLLUX, CASTOR, and ALCYONE Andrzej Jakubowiak served as a consultant for studies and their families as well as study co- AbbVie, Amgen, Bristol-Myers Squibb, Celgene, investigators, research nurses, and coordinators Janssen, Juno, Karyopharm, SkylineDx, and at each of the clinical sites. Takeda. Albert Oriol served as a consultant, as a member of the board of directors or advisory Funding. 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