Daratumumab Plus Atezolizumab in Previously Treated Advanced or Metastatic NSCLC: Brief Report on a Randomized, Open-Label, Phase 1b/2 Study (LUC2001 JNJ-54767414).

INTRODUCTION: The programmed death-ligand 1 inhibitor atezolizumab improves progression-free survival (PFS) and overall survival (OS) for patients with previously treated advanced NSCLC. Preclinical studies indicate that targeting CD38-positive cells with daratumumab may synergistically enhance atezolizumab's antitumor activity by increasing the effector T-cell activity. METHODS: This phase 1b-2 study included a safety run-in (one cycle of daratumumab plus atezolizumab) and randomized phases (daratumumab plus atezolizumab versus atezolizumab alone). The primary objective of the randomized phase was to compare overall response rates. The secondary objectives included evaluations of safety, clinical benefit rate (stable disease or better), PFS, OS, and pharmacokinetics. RESULTS: In total, 99 patients were enrolled (safety run-in, n = 7; randomized, n = 46 per arm). In the randomized phase, the overall response rate was 4.3% for daratumumab plus atezolizumab and 13.0% for atezolizumab alone (OR: 0.30; 95% confidence interval: 0.03-1.92). The respective clinical benefit rates were 52.2% and 43.5%. No improvements were observed in the median PFS or median OS for combination therapy. The study was terminated because of the limited efficacy of daratumumab plus atezolizumab. CONCLUSIONS: Daratumumab plus atezolizumab therapy did not improve efficacy versus atezolizumab monotherapy for patients with previously treated advanced NSCLC.

Daratumumab With Cetrelimab, an Anti-PD-1 Monoclonal Antibody, in Relapsed/Refractory Multiple Myeloma.

BACKGROUND: Daratumumab is approved for relapsed or refractory multiple myeloma (RRMM) as monotherapy or in combination regimens. We evaluated daratumumab plus cetrelimab, a programmed death receptor-1 inhibitor, in RRMM. PATIENTS AND METHODS: This open-label, multiphase study enrolled adults with RRMM with ≥ 3 prior lines of therapy. Part 1 was a safety run-in phase examining dose-limiting toxicities of daratumumab (16 mg/kg intravenously weekly for cycles 1-2, biweekly for cycles 3-6, and monthly thereafter) plus cetrelimab (240 mg intravenously biweekly, all cycles). In Parts 2 and 3, patients were to be randomized to daratumumab with or without cetrelimab (same schedule as Part 1). Endpoints included safety, overall response rate, pharmacokinetics, and biomarker analyses. RESULTS: Nine patients received daratumumab plus cetrelimab in the safety run-in, and 1 received daratumumab in Part 2 before administrative study termination following a data monitoring committee's global recommendation to stop any trial including daratumumab combined with inhibitors of programmed death receptor-1 or its ligand (programmed death-ligand 1). The median follow-up times were 6.7 months (safety run-in) and 0.3 months (Part 2). No dose-limiting toxicities occurred. All 10 patients had ≥ 1 treatment-emergent adverse event; 7 patients had grade 3 to 4 treatment-emergent adverse events, and none led to treatment discontinuation or death. In the safety run-in, 7 (77.7%) patients had ≥ 1 infusion-related reaction (most grade 1-2), and 1 had a grade 2 immune-mediated reaction. Among safety run-in patients, the overall response rate was 44.4%. CONCLUSIONS: No new safety concerns were identified for daratumumab plus cetrelimab in RRMM. The short study duration and small population limit complete analysis of this combination.

Daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma: final results from the phase 2 GEN501 and SIRIUS trials.

BACKGROUND: Daratumumab showed encouraging efficacy as monotherapy in patients with heavily pretreated multiple myeloma in the GEN501 and SIRIUS studies. Here we report a pooled, post-hoc final analysis of these two studies. METHODS: GEN501 was an open-label, multicentre, phase 1-2, dose escalation and expansion study done in the Netherlands, the USA, Sweden, and Denmark. Eligible patients had multiple myeloma and had relapsed or were refractory to 2 or more previous lines of treatment that included a proteasome inhibitor or an immunomodulatory drug. SIRIUS was an open-label, multicentre, phase 2 study done in Canada, Spain, and the USA, in which eligible patients with multiple myeloma had received 3 or more previous lines of therapy, including a proteasome inhibitor or an immunomodulatory drug, or were double refractory. In both studies, eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status of 2 or less. In part 2 of GEN501, patients were given intravenous daratumumab 16 mg/kg once per week for 8 weeks, twice per month for 8 doses, and then once per month until disease progression. In part 2 of SIRIUS, patients received intravenous daratumumab 16 mg/kg once per week for 8 weeks, twice per month for 16 weeks, and once per month until disease progression. The primary endpoints (safety in GEN501 and overall response rate in SIRIUS) have previously been reported. These trials are registered on ClinicalTrials.gov, NCT00574288 (GEN501) and NCT01985126 (SIRIUS). FINDINGS: Patients were enrolled in GEN501 from March 27, 2008, until May 30, 2014, and in SIRIUS from Sept 30, 2013, until May 5, 2014. The combined analysis included 148 patients who received daratumumab 16 mg/kg (42 patients in GEN501 part 2; 106 patients in SIRIUS), with a median follow-up of 36·6 months (IQR 34·5-38·2). Patients had received a median of 5 previous lines of therapy (IQR 4-7), and 128 (87%) of 148 patients were double refractory. The overall response rate was 30·4% (95% CI 23·1-38·5), including 20 (14%) of 148 patients with very good partial response or better (8·5-20·1) and seven (5%) patients reporting complete response or better (1·9-9·5). Among 45 responders, the median duration of response was 8·0 months (95% CI 6·5-14·7). Median overall survival was 20·5 months (95% CI 16·6-28·1), with a 3-year overall survival rate of 36·5% (28·4-44·6). The most common grade 3-4 treatment-emergent adverse events (TEAEs) were anaemia (grade 3, 26 [18%] of 148 patients; no grade 4 events) and thrombocytopenia (grade 3, 13 [9%] of 148 patients; grade 4, 8 [5%] of 148 patients). Serious drug-related TEAEs occurred in 13 (9%) of 148 patients. There were no treatment-related deaths. INTERPRETATION: In this analysis, daratumumab 16 mg/kg monotherapy showed durable responses and there were no new safety concerns with longer follow-up. FUNDING: Janssen Research & Development.

Phase 2 Study of Daratumumab in Relapsed/Refractory Mantle-Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma.

BACKGROUND: Daratumumab is a CD38 monoclonal antibody approved for treating relapsed/refractory and newly diagnosed multiple myeloma. Preclinical daratumumab studies demonstrated cytotoxic activity and reduced tumor growth in B-cell non-Hodgkin lymphoma (NHL) subtypes, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle-cell lymphoma (MCL). PATIENTS AND METHODS: This was a phase 2, open-label, multicenter, 2-stage trial. Patients with relapsed/refractory DLBCL, FL, or MCL with ≥ 50% CD38 expression were eligible for stage 1. Daratumumab (16 mg/kg; 28-day cycles) was administered intravenously weekly for 2 cycles, every 2 weeks for 4 cycles, and every 4 weeks thereafter. Overall response rate was the primary end point. Pharmacokinetic and safety were also evaluated. Stage 2 was planned to further assess daratumumab in larger populations of NHL subtypes if futility criteria were not met. The study was registered with ClinicalTrials.gov (NCT02413489). RESULTS: The trial screened 138 patients resulting in accrual of 15 patients with DLBCL, 16 with FL, and 5 with MCL. Median CD38 expression across treated patients was 70%. Overall response rate was 6.7%, 12.5%, and not evaluable in DLBCL, FL, and MCL cohorts, respectively. The most common grade 3/4 treatment-emergent adverse event was thrombocytopenia (11.1%), and 4 (11.1%) patients discontinued treatment because of treatment-emergent adverse events. Infusion-related reactions occurred in 72.2% of patients (3 patients with grade 3; no grade 4). CONCLUSION: In NHL, the safety and pharmacokinetics of daratumumab were consistent with myeloma studies. Screen-fail rates were high, prespecified futility thresholds were met in 2 cohorts, and the study was terminated. Studies in other hematologic malignancies and amyloidosis are ongoing.

Blood Transfusion Management and Transfusion-Related Outcomes in Daratumumab-Treated Patients With Relapsed or Refractory Multiple Myeloma.

INTRODUCTION: Daratumumab, a human CD38 monoclonal antibody approved for multiple myeloma (MM) treatment, binds red blood cells (RBCs), resulting in panagglutination in compatibility tests. Published mitigation methods avoid additional testing, ensuring timely release of blood products. Blood transfusion management and transfusion-related outcomes of daratumumab-treated patients in the SIRIUS study are reported, with emphasis on 2 clinical sites. PATIENTS AND METHODS: Patients had MM treated with ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were refractory to a proteasome inhibitor and an immunomodulatory drug. RBC typing and alloantibody screening were performed in gel cards. Antibody identification using RBC panels was performed on patients with positive antibody screens. Hematology panels and serum chemistry were analyzed ≤ 2 days before each daratumumab infusion and the first daratumumab dose within each treatment cycle, respectively. Pre- and posttransfusion hemoglobin values were analyzed retrospectively. RESULTS: At clinical cutoff, patients received 236 transfusions; 47 (37.9%) of 124 patients received 147 packed RBC transfusions, and 17 (13.7%) received 89 platelet transfusions. No hemolysis was reported, and 1 platelet transfusion reaction was observed. At Mount Sinai, no transfusion adverse events were observed, no new unexpected RBC alloantibodies were identified, and transfusions increased hemoglobin values (median, 1.2 g/dL). At Levine Cancer Institute, 6 of 7 patients responded to transfusions, with a median hemoglobin change of 1.7 g/dL. CONCLUSION: In SIRIUS, no RBC transfusion reactions, including hemolysis, were observed. Observations from Mount Sinai and Levine Cancer Institute confirm that transfusions may be administered safely to daratumumab-treated patients.

A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.

This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3-4·0% in studies in relapsed/refractory MM and 1·2-4·7% in previously untreated MM (2·0-7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3-5·9% grade ≥2; 0·6-4·1% grade ≥3), IHD (1·2-2·9% all grades; 0·4-2·7% grade ≥3) and cardiac death (0-1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.

Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma.

The efficacy and favorable safety profile of daratumumab monotherapy in multiple myeloma (MM) was previously reported. Here, we present an updated pooled analysis of 148 patients treated with daratumumab 16 mg/kg. Data were combined from part 2 of a first-in-human phase 1/2 study of patients who relapsed after or were refractory to ≥2 prior therapies and a phase 2 study of patients previously treated with ≥3 prior lines of therapy (including a proteasome inhibitor [PI] and an immunomodulatory drug [IMiD]) or were double refractory. Among the pooled population, patients received a median of 5 prior lines of therapy (range, 2 to 14 prior lines of therapy), and 86.5% were double refractory to a PI and an IMiD. Overall response rate was 31.1%, including 13 very good partial responses, 4 complete responses, and 3 stringent complete responses. The median duration of response was 7.6 months (95% confidence interval [CI], 5.6 to not evaluable [NE]). The median progression-free survival (PFS) and overall survival (OS) were 4.0 months (95% CI, 2.8-5.6 months) and 20.1 months (95% CI, 16.6 months to NE), respectively. When stratified by responders vs stable disease/minimal response vs progressive disease/NE, median PFS was 15.0 months (95% CI, 7.4 months to NE) vs 3.0 months (95% CI, 2.8-3.7 months) vs 0.9 months (95% CI, 0.9-1.0 months), respectively, and median OS was NE (95% CI, NE to NE) vs 18.5 months (95% CI, 15.1-22.4 months) vs 3.7 months (95% CI, 1.7-7.6 months), respectively. No new safety signals were identified. In this pooled data set, daratumumab 16 mg/kg monotherapy demonstrated rapid, deep, and durable responses, with a clinical benefit that extended to patients with stable disease or better.

Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial.

BACKGROUND: New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. METHODS: In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. FINDINGS: The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. INTERPRETATION: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. FUNDING: Janssen Research & Development.

Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up.

This follow-up extension of a randomised phase II study assessed differences in long-term outcomes between bortezomib-thalidomide-dexamethasone (VTD) and VTD-cyclophosphamide (VTDC) induction therapy in multiple myeloma. Newly diagnosed patients (n = 98) were randomised 1:1 to intravenous bortezomib (1·3 mg/m(2); days 1, 4, 8, 11), thalidomide (100 mg; days 1-21), and dexamethasone (40 mg; days 1-4, 9-12), with/without cyclophosphamide (400 mg/m(2); days 1, 8), for four 21-day cycles before stem-cell mobilisation/transplantation. After a median follow-up of 64·8 months, median time-to-next therapy was 51·8 and 47·9 months with VTD and VTDC, respectively. Type of subsequent therapy was similar in both arms. After adjusting for asymmetric censoring, median time to progression was not significantly different between VTD and VTDC [35·7 vs. 34·5 months; Hazard ratio (HR) 1·26, 95% confidence interval: 0·76-2·09; P = 0·370]. Five-year survival was 69·1% and 65·3% with VTD and VTDC, respectively. When analysed by minimal residual disease (MRD) status, overall survival was longer in MRD-negative versus MRD-positive patients with bone marrow-confirmed complete response (HR 3·66, P = 0·0318). VTD induction followed by transplantation provides long-term disease control and, consistent with the primary analysis, there is no additional benefit from adding cyclophosphamide. This study was registered at ClinicalTrials.gov (NCT00531453).

The addition of dexamethasone to bortezomib for patients with relapsed multiple myeloma improves outcome but ongoing maintenance therapy has minimal benefit.

Despite the common practice of combining dexamethasone (Dex) with bortezomib (Bz) in patients with multiple myeloma (MM), until now there has been few prospective trials undertaken. We undertook a trial that recapitulated the original APEX study except that dexamethasone was incorporated from cycle 1. We also incorporated an exploratory maintenance component to the study. Twenty sites enrolled 100 relapsed/or refractory MM patients utilizing eight 21 day cycles of IV Bz [1.3 mg/m(2) ; Day (D) 1, 4, 8, 11] and three 35 day cycles; Bz (1.3 mg/m(2) ; Day (D) 1, 8, 15, 22). Our study was registered at www.clinicaltrials.gov (NCT00335348). Patients with stable disease or better received maintenance Bz (1.3 mg/m(2) ) every 14 days until progression. Dexamethasone (20 mg) was given for 2 days with each Bz dose. A prospectively defined matched-analysis of primary (overall response rate; ORR) and secondary endpoints [Complete Response (CR) and time to progression (TTP)] compared our cohort to those on the Bz arm of the APEX trial. The addition of Dex improved ORR by 20% (56% vs. 36%) [odds ratio 0.44 (0.24-0.80)]. The median TTP was also significantly longer (10.1 vs. 5.1 months) (hazard ratio 0.50, 95% CI: 0.35-0.72, P = 0.0002) and our landmark analysis demonstrated that this was largely due to the early use of dexamethasone, as we were unable to demonstrate any benefit of bortezomib/dexamethasone maintenance therapy.

Retrospective matched-pairs analysis of bortezomib plus dexamethasone versus bortezomib monotherapy in relapsed multiple myeloma.

Bortezomib-dexamethasone is widely used for relapsed myeloma in routine clinical practice, but comparative data versus single-agent bortezomib are lacking. This retrospective analysis compared second-line treatment with bortezomib-dexamethasone and bortezomib using 109 propensity score-matched pairs of patients treated in three clinical trials: MMY-2045, APEX, and DOXIL-MMY-3001. Propensity scores were estimated using logistic regression analyses incorporating 13 clinical variables related to drug exposure or clinical outcome. Patients received intravenous bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, in 21-day cycles, alone or with oral dexamethasone 20 mg on the days of/after bortezomib dosing. Median bortezomib cumulative dose (27.02 and 28.60 mg/m(2)) and treatment duration (19.6 and 17.6 weeks) were similar with bortezomib-dexamethasone and bortezomib, respectively. The overall response rate was higher (75% vs. 41%; odds ratio=3.467; P<0.001), and median time-to-progression (13.6 vs. 7.0 months; hazard ratio [HR]=0.394; P=0.003) and progression-free survival (11.9 vs. 6.4 months; HR=0.595; P=0.051) were longer with bortezomib-dexamethasone versus bortezomib, respectively. Rates of any-grade adverse events, most common grade 3 or higher adverse events, and discontinuations due to adverse events appeared similar between the groups. Two patients per group died of treatment-related adverse events. These data indicate the potential benefit of bortezomib-dexamethasone compared with single-agent bortezomib at first relapse in myeloma. The MMY-2045, APEX, and DOXIL-MMY-3001 clinical trials were registered at, respectively, clinicaltrials.gov identifier: 00908232, 00048230, and 00103506.

Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma.

PURPOSE: Bortezomib-thalidomide-dexamethasone (VTD) is an effective induction therapy in multiple myeloma (MM). This phase II, noncomparative study sought to determine whether addition of cyclophosphamide to this regimen (VTDC) could further increase efficacy without compromising safety. PATIENTS AND METHODS: Patients age 18 to 70 years with previously untreated, measurable MM, who were eligible for high-dose chemotherapy-autologous stem-cell transplantation (HDCT-ASCT), were randomly assigned to bortezomib 1.3 mg/m(2), thalidomide 100 mg, and dexamethasone 40 mg, with (n = 49) or without (n = 49) cyclophosphamide 400 mg/m(2) for four 21-day cycles, followed by HDCT-ASCT. The primary end point was postinduction combined rate of near-complete response (nCR) or better (including complete response [CR] with normalized serum κ:λ free light chain ratio, CR, and nCR). RESULTS: Postinduction, 51% (VTD) and 44% (VTDC) of patients achieved combined CR/nCR, with bone marrow-confirmed CR in 29% and 31%, overall response rates of 100% and 96%, respectively, and very good partial response or better rates of 69% per arm. Post-HDCT-ASCT, combined CR/nCR rates were 85% (VTD) and 77% (VTDC). In all, 35% (VTD) and 27% (VTDC) of patients were negative for minimal residual disease (MRD) during induction and postinduction. Three-year overall survival was 80% (both arms). Grade 3 to 4 adverse events (AEs) and serious AEs were observed in 47% and 22% (VTD) and 57% and 41% (VTDC) of patients, respectively. The primary health-related quality of life end point (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 [EORTC QLQ-C30] Global Health score) steadily increased with VTD during induction and reached a clinically relevant difference post-transplantation versus baseline. CONCLUSION: Both VTD and VTDC are highly active induction regimens producing high combined CR/nCR and MRD-negative rates; however, VTDC was associated with increased toxicity and suggestion of transient decreases in Global Health score, without an increase in activity.

Pharmacokinetic, pharmacodynamic and covariate analysis of subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma.

BACKGROUND AND OBJECTIVES: The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma (MM) and, in the US, for the treatment of mantle cell lymphoma following at least one prior therapy; the recommended dose and schedule is 1.3 mg/m(2) on days 1, 4, 8 and 11 of 21-day cycles, and the approved routes of administration in the US prescribing information are by intravenous and, following a recent update, subcutaneous injection. Findings from a phase III study demonstrated that subcutaneous administration of bortezomib, using the same dose and schedule, resulted in similar efficacy with an improved systemic safety profile (including significantly lower rates of peripheral neuropathy) versus intravenous bortezomib in patients with relapsed MM. The objectives of this report were to present a comprehensive analysis of the pharmacokinetics and pharmacodynamics of subcutaneous versus intravenous bortezomib, and to evaluate the impact of the subcutaneous administration site, subcutaneous injection concentration and demographic characteristics on bortezomib pharmacokinetics and pharmacodynamics. PATIENTS AND METHODS: Data were analysed from the pharmacokinetic substudy of the randomized phase III MMY-3021 study and the phase I CAN-1004 study of subcutaneous versus intravenous bortezomib in patients aged ≥18 (MMY-3021) or ≤75 (CAN-1004) years with symptomatic relapsed or refractory MM after 1-3 (MMY-3021) or ≥1 (CAN-1004) prior therapies. Patients received up to eight 21-day cycles of subcutaneous or intravenous bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11. Pharmacokinetic and pharmacodynamic (20S proteasome inhibition) parameters of bortezomib following subcutaneous or intravenous administration were evaluated on day 11, cycle 1. RESULTS: Bortezomib systemic exposure was equivalent with subcutaneous versus intravenous administration in MMY-3021 [mean area under the plasma concentration-time curve from time zero to the last quantifiable timepoint (AUC(last)): 155 vs. 151 ng·h/mL; geometric mean ratio 0.992 (90 % CI 80.18, 122.80)] and comparable in CAN-1004 (mean AUC(last): 195 vs. 241 ng·h/mL); maximum (peak) plasma drug concentration (C(max)) was lower with subcutaneous administration in both MMY-3021 (mean 20.4 vs. 223 ng/mL) and CAN-1004 (mean 22.5 vs. 162 ng/mL), and time to C(max) (t(max)) was longer with subcutaneous administration in both studies (median 30 vs. 2 min). Blood 20S proteasome inhibition pharmacodynamic parameters were also similar with subcutaneous versus intravenous bortezomib: mean maximum effect (E(max)) was 63.7 versus 69.3 % in MMY-3021 and 57.0 versus 68.8 % in CAN-1004, and mean area under the effect-time curve from time zero to 72 h was 1,714 versus 1,383 %·h in MMY-3021 and 1,619 versus 1,283 %·h in CAN-1004. Time to E(max) was longer with subcutaneous administration in MMY-3021 (median 120 vs. 5 min) and CAN-1004 (median 120 vs. 3 min). Concentration of the subcutaneous injected solution had no appreciable effect on pharmacokinetic or pharmacodynamic parameters. There were no apparent differences in bortezomib pharmacokinetic and pharmacodynamic parameters between subcutaneous administration in the thigh or abdomen. There were also no apparent differences in bortezomib exposure related to body mass index, body surface area or age. CONCLUSION: Subcutaneous administration results in equivalent bortezomib plasma exposure to intravenous administration, together with comparable blood 20S proteasome inhibition pharmacodynamic effects. These findings, together with the non-inferior efficacy of subcutaneous versus intravenous bortezomib demonstrated in MMY-3021, support the use of bortezomib via the subcutaneous route across the settings of clinical use in which the safety and efficacy of intravenous bortezomib has been established.

Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma.

The phase III MMY-3021 study compared safety and efficacy of subcutaneous versus intravenous administration of the proteasome inhibitor bortezomib in patients with relapsed myeloma. The initial report demonstrated non-inferior efficacy with subcutaneous versus intravenous bortezomib for the primary end point: overall response rate after four cycles of single-agent bortezomib. We report updated outcome analyses after prolonged follow up. Best response rate (after up to ten cycles of bortezomib ± dexamethasone) remained 52% in each arm, including 23% and 22% complete or near-complete responses with subcutaneous and intravenous bortezomib, respectively. Time to progression (median 9.7 vs. 9.6 months; hazard ratio 0.872, P=0.462), progression-free survival (median 9.3 vs. 8.4 months; hazard ratio 0.846, P=0.319), and overall survival (1-year: 76.4% vs. 78.0%, P=0.788) were comparable with subcutaneous versus intravenous bortezomib. Peripheral neuropathy rates remained significantly lower with subcutaneous versus intravenous bortezomib, with increased rates of improvement/resolution at the time of this analysis.

Adaptive group sequential test with changing patient population.

Standard group sequential test assumes that the treatment effects are homogeneous over time. In practice, however, this assumption may be violated. Often, this occurs when treatment effects are heterogeneous in patients with different prognostic groups, which are not evenly distributed over the time course of the group sequential trial. In this article, we consider a setting where the inclusion/exclusion criteria for patient entry are relaxed at interim analyses. This triggers heterogeneous treatment effects over the enlarged patient population. In particular, we assume that the population change relates to some baseline covariates. Simulation results show that the type I error can be severely inflated if adjustment is not made to the statistical analysis. We consider a set of linear regression models. With these models, we make inference on the target population based on all data from the changed populations. The proposed method leads to unbiased inference.

Effect of cytochrome P450 3A4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with multiple myeloma or non-Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVE: Bortezomib, an antineoplastic agent with proteasome inhibitory activity, is extensively metabolized by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C19. Drugs that affect these enzymes may therefore have an impact on the pharmacological profile of bortezomib. This study evaluated the effects of co-administration of a potent CYP3A4 inducer (rifampicin [rifampin]) and a weak CYP3A4 inducer (dexamethasone) on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib. PATIENTS AND METHODS: Patients aged ≥18 years with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma received intravenous bortezomib 1.3 mg/m2, administered on days 1, 4, 8 and 11 of a 21-day cycle, for 3 cycles. In stage 1, patients were randomized (1 : 1) to receive bortezomib alone or in combination with oral rifampicin 600 mg once daily on days 4-10 during cycle 3 only. If the mean area under the plasma concentration-time curve (AUC) of bortezomib was reduced by ≥30% during rifampicin co-administration, then stage 2 was initiated, in which patients received bortezomib with dexamethasone 40 mg once daily on days 1-4 and days 9-12 during cycle 3 only. Blood samples were collected on days 11 through 14 of cycles 2 and 3 before and after bortezomib administration, at prespecified time points, for pharmacokinetic and pharmacodynamic (proteasome inhibition) assessments. RESULTS: Twelve patients in the bortezomib-alone arm, six patients in the bortezomib plus rifampicin arm and seven patients in the bortezomib plus dexamethasone arm were included in the pharmacokinetics-evaluable set. Rifampicin reduced the mean AUC from 0 to 72 hours (AUC(72h)) of bortezomib by approximately 45% (223 ng · h/mL in cycle 2 vs 123 ng · h/mL in cycle 3), while dexamethasone had no effect (mean AUC(72h): 179 ng · h/mL in cycle 2 vs 170 ng · h/mL in cycle 3). Proteasome inhibition parameters in peripheral blood were unaffected by rifampicin or dexamethasone. Safety profiles were similar across the treatment arms and consistent with previous experience of bortezomib. CONCLUSIONS: In patients with multiple myeloma or non-Hodgkin's lymphoma, co-administration of rifampicin decreased the exposure to bortezomib but did not affect the proteasome inhibition or safety profiles; co-administration of dexamethasone did not affect the exposure to bortezomib, proteasome inhibition or safety profiles. Concomitant administration of bortezomib with strong CYP3A4 inducers such as rifampicin is not recommended, as it may result in a reduction of the clinical effect, whereas concomitant administration of weak CYP3A4 inducers such as dexamethasone does not affect the pharmacological profile of bortezomib.

Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study.

BACKGROUND: Intravenous injection is the standard administration route of bortezomib; however, subcutaneous administration is an important alternative. We compared the efficacy and safety of subcutaneous versus intravenous bortezomib at the approved 1·3 mg/m(2) dose and twice per week schedule in patients with relapsed multiple myeloma. METHODS: This randomised, phase 3 study was undertaken at 53 centres in ten countries in Europe, Asia, and South America. Patients aged 18 years and older with relapsed multiple myeloma after one to three previous lines of therapy were randomly assigned to receive up to eight 21-day cycles of bortezomib 1·3 mg/m(2), on days 1, 4, 8, and 11, by subcutaneous injection or intravenous infusion. Randomisation was by an interactive voice response system based on a computer-generated randomisation schedule, stratified by number of previous lines and disease stage. Patients and treating physicians were not masked to treatment allocation. The primary objective was to show non-inferiority of subcutaneous versus intravenous bortezomib in terms of overall response rate (ORR) after four cycles in all patients with a diagnosis of measurable, secretory multiple myeloma who received one or more dose of drug (response-evaluable population). Non-inferiority was defined as retaining 60% of the intravenous treatment effect. This study is registered with ClinicalTrials.gov, number NCT00722566, and is ongoing for long-term follow-up. FINDINGS: 222 patients were randomly assigned to receive subcutaneous (n=148) or intravenous (n=74) bortezomib. The response-evaluable population consisted of 145 patients in the subcutaneous group and 73 in the intravenous group. Patients received a median of eight cycles (range one to ten) in both groups. ORR after four cycles was 42% in both groups (61 patients in subcutaneous group and 31 in intravenous group; ORR difference -0·4%, 95% CI -14·3 to 13·5), showing non-inferiority (p=0·002). After a median follow-up of 11·8 months (IQR 7·9-16·8) in the subcutaneous group and 12·0 months (8·1-15·6) in the intravenous group, there were no significant differences in time to progression (median 10·4 months, 95% CI 8·5-11·7, vs 9·4 months, 7·6-10·6; p=0·387) and 1-year overall survival (72·6%, 95% CI 63·1-80·0, vs 76·7%, 64·1-85·4; p=0·504) with subcutaneous versus intravenous bortezomib. Grade 3 or worse adverse events were reported in 84 (57%) patients in the subcutaneous group versus 52 (70%) in the intravenous group; the most common were thrombocytopenia (19 [13%] vs 14 [19%]), neutropenia (26 [18%] vs 13 [18%]), and anaemia (18 [12%] vs six [8%]). Peripheral neuropathy of any grade (56 [38%] vs 39 [53%]; p=0·044), grade 2 or worse (35 [24%] vs 30 [41%]; p=0·012), and grade 3 or worse (nine [6%] vs 12 [16%]; p=0·026) was significantly less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated. INTERPRETATION: Subcutaneous bortezomib offers non-inferior efficacy to standard intravenous administration, with an improved safety profile. FUNDING: Johnson & Johnson Pharmaceutical Research and Development, and Millennium Pharmaceuticals.

Adaptive group sequential test for clinical trials with changing patient population.

In clinical trials, a standard group sequential test with a fixed number of planned interim analyses is usually considered to assess the effect of a test treatment under study. The standard group sequential test is statistically valid under the assumption that the patient population remains unchanged from one interim analysis to another. In practice, however, this assumption is often not met because the trial may be modified after the review of the clinical data at interim. As a result, the original patient population may have changed to a similar but different patient population. In this paper, we consider changes in patient population related to some covariates of an on-going trial through a linear regression model. Under this model, we can make inference on the original target population based on additional data from the changed populations. A new group sequential test procedure that accounts for the effect of population changes is proposed. A simulation was performed to evaluate the performance of the proposed method. The results indicate that the type I error rate of the proposed test procedure is well preserved, while the type I error rate of the standard group sequential test is inflated as the population changes. Statistical powers of the proposed group sequential test are also presented.

Group sequential t-test for clinical trials with small sample sizes across stages.

Interim analyses are often applied in clinical trials for various reasons. To assess the effect of a clinical treatment, the group sequential t-test with a fixed number of interim analyses is frequently used in clinical trials. The existing critical values used in group sequential t-tests are obtained from normal approximations of t-statistics. In practice, however, normal approximation is not accurate when some sample sizes of treatment arms in some stages are small. In this paper, instead of using normal approximation, we directly obtain the critical values via a Monte Carlo method. We list some critical values for certain sample sizes and number of interim analyses, and provide some SAS code for general situations. We also consider the sample size calculation and run some simulations to check the accuracy of our critical values. The simulation results show that our critical values yield type I error probabilities that are very close to the nominal significance level, whereas the existing critical values based on normal approximation are not accurate when some sample sizes are small across stages.