Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or ...refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study.
DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries. Patients (aged ≥18 years) with relapsed or refractory multiple myeloma with disease progression after three or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody with an Eastern Cooperative Oncology Group performance status of 0–2 were recruited, centrally randomly assigned (1:1) with permuted blocks (block size 4), and stratified by previous lines of therapy (≤4 vs >4) and cytogenetic features to receive 2·5 mg/kg or 3·4 mg/kg belantamab mafodotin via intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. The intention-to-treat population comprised all randomised patients, regardless of treatment administration. The safety population comprised all patients who received at least one dose of belantamab mafodotin. The primary outcome was the proportion of randomly assigned patients in the intention-to-treat population who achieved an overall response, as assessed by an independent review committee. This study is registered with ClinicalTrials.gov, NCT03525678, and is ongoing.
Between June 18, 2018, and Jan 2, 2019, 293 patients were screened and 196 were included in the intention-to-treat population (97 in the 2·5 mg/kg cohort and 99 in the 3·4 mg/kg cohort). As of June 21, 2019 (the primary analysis data cutoff date), 30 (31%; 97·5% CI 20·8–42·6) of 97 patients in the 2·5 mg/kg cohort and 34 (34%; 23·9–46·0) of 99 patients in the 3·4 mg/kg cohort achieved an overall response. The most common grade 3–4 adverse events in the safety population were keratopathy (in 26 27% of 95 patients in the 2·5 mg/kg cohort and 21 21% of 99 patients in the 3·4 mg/kg cohort), thrombocytopenia (19 20% and 33 33%), and anaemia (19 20% and 25 25%); 38 (40%) of 95 patients in the 2·5 mg/kg cohort and 47 (47%) of 99 in the 3·4 mg/kg cohort reported serious adverse events. Two deaths were potentially treatment related (one case of sepsis in the 2·5 mg/kg cohort and one case of haemophagocytic lymphohistiocytosis in the 3·4 mg/kg cohort).
Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma.
GlaxoSmithKline.
Belantamab mafodotin (belamaf) has shown promising antimyeloma activity in relapsed or refractory multiple myeloma (RRMM) as a single agent. It was hypothesized that its multimodal activity may be ...enhanced by programmed cell death protein 1 pathway inhibition and activation of T cell-mediated antitumor responses. This study investigated the efficacy and safety of belamaf with pembrolizumab in patients with RRMM.
DREAMM-4 (NCT03848845) was an open-label, single-arm, phase 1/2 study divided into dose-escalation (part 1) and dose-expansion (part 2) phases. Patients were ≥18 years old with ≥3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 agent. Patients received belamaf (2.5 or 3.4 mg/kg, part 1; 2.5 mg/kg, part 2) and 200 mg pembrolizumab for ≤35 cycles.
Of 41 enrolled patients, 34 (n = 6 part 1, n = 28 part 2) who received 2.5 mg/kg belamaf plus pembrolizumab were included in this final analysis. Sixteen patients (47%) achieved an overall response. Minimal residual disease negativity was achieved in three of 10 patients who had very good partial response or better. Five of eight patients who had prior anti-B-cell maturation antigen therapy achieved partial response or better, including two who had B-cell maturation antigen-refractory disease. Common grade ≥3 adverse events were keratopathy (38%) and thrombocytopenia (29%). Despite belamaf-related ocular events, quality-of-life measures remained stable over time. No new safety signals were observed.
The results of DREAMM-4 demonstrated clinical activity and a favorable safety profile of belamaf plus pembrolizumab in patients with RRMM. This trial is registered at www.
gov as NCT03848845.
Ofatumumab is the first human anti‐CD20 monoclonal antibody to be approved for patients in the United States and the European Union. Ofatumumab received accelerated approval from the U.S. Food and ...Drug Administration in October 2009 and was granted a conditional marketing authorization by the European Medicines Agency in April 2010 for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab, based on interim results of a pivotal phase 2 trial. Preliminary positive results for ofatumumab in combination with chemotherapy in patients with CLL are currently being confirmed in larger randomized trials in both the frontline setting and the relapsed/refractory setting. Ofatumumab has also shown potential in treating B cell non‐Hodgkin's lymphoma, such as follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), and Waldenström's macroglobulinemia. Additional trials are ongoing to confirm activity of ofatumumab as monotherapy and in combination with chemotherapy in patients with FL or DLBCL.
Abstract Aims To evaluate relationships between plasma concentrations of belantamab mafodotin, total monoclonal antibody, and its payload and changes in electrocardiogram (ECG) parameters in patients ...with relapsed or refractory multiple myeloma from the DREAMM‐1 and DREAMM‐2 studies. Methods Hysteresis plots and linear regression analyses of pharmacokinetic (PK) analyte (belantamab mafodotin, total monoclonal antibody, and cytotoxic cysteine‐maleimidocaproyl monomethyl auristatin F payload) concentrations vs . time‐matched ECG parameters (absolute/change from baseline in QT interval corrected for RR interval QTc/ΔQTc and QT interval corrected for heart rate by Fridericia's formula QTcF/ΔQTcF) were performed. Concentrations of PK analyte required for a 10‐ms increase in QTc in DREAMM‐2 were calculated via simulation, as was the probability of ΔQTc/ΔQTcF exceeding 10 ms for the expected C max of PK analyte concentrations associated with the doses (2.5 and 3.4 mg/kg) administered in DREAMM‐2. Results Time‐matched PK and ECG data from 290 patients (DREAMM‐1, n = 73; DREAMM‐2, n = 217) were analysed. Hysteresis plots did not clearly indicate any concentration‐related prolongation in QTc or QTcF; regression analyses indicated a very small rate of increase in ΔQTc and ΔQTcF with increasing concentrations of PK analytes. Calculated concentrations of PK analyte required for a 10‐ms prolongation in QTc were higher than the maximum analyte concentrations observed following treatment with belantamab mafodotin in DREAMM‐2; the probability that each dose would prolong ΔQTc and ΔQTcF by >10 ms was 0 and <0.25%, respectively. Conclusion This study of belantamab mafodotin and its payload did not provide evidence of QT prolongation in patients with relapsed or refractory multiple myeloma at clinically relevant doses.
Belantamab mafodotin is an antibody–drug conjugate comprising a humanized anti‐B‐cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F (MMAF) via a ...protease‐resistant maleimidocaproyl linker. Single‐agent belantamab mafodotin showed clinically meaningful activity and manageable safety in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM) in the phase I DREAMM‐1 and phase II DREAMM‐2 studies and is approved by the US Food and Drug Administration and European Medicines Agency for RRMM treatment. To support monotherapy dose selection, the relationship between Cycle 1 exposure (derived using a population pharmacokinetic model) and clinical response (for multiple efficacy and safety end points) was explored. In DREAMM‐2, efficacy end points (probability of response (PoR) and progression‐free survival (PFS)) were associated with exposure in univariate evaluation; however, once disease burden factors were included in the model (e.g., baseline soluble BCMA, ß2‐microglobulin), exposure was no longer significant. Patients with higher disease burden had lower exposure. In DREAMM‐1, belantamab mafodotin exposure was the only variable to correlate with PoR and PFS. Probability of corneal events (keratopathy), but not dry eye or blurred vision, was strongly associated with belantamab mafodotin exposure (DREAMM‐2). Higher cys‐mcMMAF maximum plasma drug concentration (Cmax) and lower baseline platelet count were associated with increased probability of thrombocytopenia (DREAMM‐1 and DREAMM ‐2). In general, safety end points were more strongly associated with belantamab mafodotin exposure than efficacy end points, particularly after disease factors and patient characteristics were taken into account. Overall, these findings supported the monotherapy dose recommendation of belantamab mafodotin as 2.5 mg/kg every 3 weeks in patients with RRMM who have received four or more prior therapies.
Belantamab mafodotin (belamaf) is an antibody–drug conjugate (ADC) targeting B‐cell maturation antigen (BCMA). Nonlinear mixed‐effects models were developed to characterize the population ...pharmacokinetics (PopPK) of ADC, total monoclonal antibody (mAb), and cysteine‐maleimidocaproyl‐MMAF (cys‐mcMMAF) after 0.03–4.6 mg/kg dosing every 3 weeks in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM; DREAMM‐1, n = 73; DREAMM‐2, n = 218). Sequential modeling methodology was used. Individual post hoc parameter estimates from the final ADC model were used to develop total mAb and cys‐mcMMAF models. Formal covariate selection used a modified stepwise forward inclusion method with backward elimination. A linear, two‐compartment PopPK model with a time‐varying clearance (CL) described ADC PK. Initial ADC typical value for CL for a DREAMM‐2 patient was 0.936 L/day with a half‐life of 11.5 days, over time CL was reduced by 28% resulting in a half‐life of 14.3 days. Time to 50% maximal CL change was ~ 50 days. Baseline soluble BCMA (sBCMA), immunoglobulin (IgG), albumin, and bodyweight impacted ADC CL. Cys‐mcMMAF concentrations were described with a linear two‐compartment model linked to ADC; input rate was governed by deconjugation/intracellular proteolytic degradation of ADC represented by an exponentially decreasing MMAF:mAb (drug antibody ratio DAR) after each dose. Time to 50% DAR reduction was 10.3 days. Baseline sBCMA and IgG impacted cys‐mcMMAF central volume of distribution. In conclusion, ADC, total mAb, and cys‐mcMMAF concentration–time profiles in RRMM were well‐described by PopPK models, and exposure was most strongly impacted by disease‐related characteristics.
Abstract
Background
GSK2838232 is a second-generation, potent, small-molecule, oral human immunodeficiency virus type 1 (HIV-1) maturation inhibitor for once-daily administration boosted with a ...pharmacoenhancer.
Methods
The phase 2a, proof-of-concept study was an open-label, adaptive dose-ranging design. Safety, pharmacokinetics, and efficacy of GSK2838232 boosted by cobicistat were evaluated in individuals with HIV-1 infection. The study participants (N = 33) received GSK2838232 once daily across a range of doses (20–200 mg) with cobicistat 150 mg for 10 days.
Results
GSK2838232 was safe and well tolerated with no clinically meaningful changes in safety parameters or adverse events. Exposure (maximum concentration and area under the concentration-time curve from time zero to the concentration at 24 hours postdose) increased 2- to 3-fold with repeated dosing in an approximately dose-proportional manner, reaching steady-state by day 8 with a half-life (t½) from 16.3 to 19.2 hours. Clearance and t½ values were not dependent on dose. Viral load declined from baseline with all GSK2838232 doses. Mean maximum declines from baseline to day 11 in HIV-1 RNA log10 copies/mL with the 20-mg, 50-mg, 100-mg, and 200-mg cohorts were −0.67, −1.56, −1.32, and −1.70, respectively. CD4+ cell counts increased at doses ≥50 mg.
Conclusions
GSK2838232 with cobicistat was well tolerated and exhibited efficacy as a short-term monotherapy in participants with HIV-1. This positive proof-of-concept study supports the continued development of GSK2838232 for the treatment of HIV as part of combination antiretroviral therapy.
Clinical Trials Registration
NCT03045861.
A new oral HIV-1 maturation inhibitor, GSK2838232, when administered as capsules with cobicistat for 10 days, was well tolerated and exhibited antiviral efficacy in participants with HIV-1.
Belantamab mafodotin, a monomethyl auristatin F (MMAF)-containing monoclonal antibody-drug conjugate (ADC), demonstrated deep and durable responses in the DRiving Excellence in Approaches to Multiple ...Myeloma (DREAMM)-1 and pivotal DREAMM-2 studies in patients with relapsed/refractory multiple myeloma. As with other MMAF-containing ADCs, ocular adverse events were observed. To predict the effects of belantamab mafodotin dosing regimens and dose-modification strategies on efficacy and ocular safety end points, DREAMM-1 and DREAMM-2 data across a range of doses were used to develop an integrated simulation framework incorporating two separate longitudinal models and the published population pharmacokinetic model. A concentration-driven tumor growth inhibition model described the time course of serum M-protein concentration, a measure of treatment response, whereas a discrete time Markov model described the time course of ocular events graded with the GSK Keratopathy and Visual Acuity scale. Significant covariates included baseline β
-microglobulin on growth rate, baseline M-protein on kill rate, extramedullary disease on the effect compartment rate constant, and baseline soluble B cell maturation antigen on maximal effect. Efficacy and safety end points were simulated for various doses with dosing intervals of 1, 3, 6, and 9 weeks and various event-driven dose-modification strategies. Simulations predicted that lower doses and longer dosing intervals were associated with lower probability and lower overall time with Grade 3+ and Grade 2+ ocular events compared with the reference regimen (2.5 mg/kg every 3 weeks), with a less-than-proportional reduction in efficacy. The predicted improved benefit-risk profiles of certain dosing schedules and dose modifications from this integrated framework has informed trial designs for belantamab mafodotin, supporting dose-optimization strategies.
New treatments are required for rituximab-refractory follicular lymphoma (FL). In the present study, patients with rituximab-refractory FL received 8 weekly infusions of ofatumumab (CD20 mAb; dose 1, ...300 mg and doses 2-8, 500 or 1000 mg; N = 116). The median age of these patients was 61 years, 47% had high-risk Follicular Lymphoma International Prognostic Index scores, 65% were chemotherapy-refractory, and the median number of prior therapies was 4. The overall response rate was 13% and 10% for the 500-mg and 1000-mg arms, respectively. Among 27 patients refractory to rituximab monotherapy, the overall response rate was 22%. The median progression-free survival was 5.8 months. Forty-six percent of patients demonstrated tumor reduction 3 months after therapy initiation, and the median progression-free survival for these patients was 9.1 months. The most common adverse events included infections, rash, urticaria, fatigue, and pruritus. Three patients experienced grade 3 infusion-related reactions, none of which were considered serious events. Grade 3-4 neutropenia, leukopenia, anemia, and thrombocytopenia occurred in a subset of patients. Ofatumumab was well tolerated and modestly active in this heavily pretreated, rituximab-refractory population and is therefore now being studied in less refractory FL and in combination with other agents in various B-cell neoplasms. The present study was registered at www.clinicaltrials.gov as NCT00394836.
Purpose: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical animal models. A phase I study
of recombinant human IL-18 (rhIL-18) was done to determine the ...toxicity, pharmacokinetics, and biological activities of rhIL-18
in patients with advanced cancer.
Experimental Design: Cohorts of patients were given escalating doses of rhIL-18, each administered as a 2-hour i.v. infusion on 5 consecutive
days. Toxicities were graded using standard criteria. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic
measurements.
Results: Twenty-eight patients (21 with renal cell cancer, 6 with melanoma, and 1 with Hodgkin's lymphoma) were given rhIL-18 in doses
ranging from 3 to 1,000 μg/kg. Common side effects included chills, fever, nausea, headache, and hypotension. Common laboratory
abnormalities included transient, asymptomatic grade 1 to 2 neutropenia, thrombocytopenia, anemia, hypoalbuminemia, hyponatremia,
and elevations in liver transaminases. One patient in the 100 μg/kg cohort experienced transient grade 3 hypotension and grade
2 bradycardia during the first infusion of rhIL-18. No other dose-limiting toxicities were observed. Plasma concentrations
of rhIL-18 increased with increasing dose, and 2.5-fold accumulation was observed with repeated dosing. Biological effects
of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes and monocytes. Increases
in serum concentrations of IFN-γ, granulocyte macrophage colony-stimulating factor, IL-18 binding protein, and soluble Fas
ligand were observed. Two patients experienced unconfirmed partial responses after rhIL-18 treatment.
Conclusions: rhIL-18 can be safely given in biologically active doses to patients with advanced cancer. A maximum tolerated dose of rhIL-18
was not determined. Further clinical studies of rhIL-18 are warranted.
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