Post-baseline Changes Research Articles

Soluble B-Cell Maturation Antigen As a Disease Biomarker in Relapsed or Refractory Multiple Myeloma (RRMM): Evaluation from Elranatamab (ELRA) Magnetismm Studies

BACKGROUND B-cell maturation antigen (BCMA) is primarily expressed on the cell membranes of terminally differentiated B cells and malignant or normal plasma cells. BCMA is a validated target for the treatment of multiple myeloma (MM). The γ-secretase enzyme cleaves the extracellular domain and releases soluble BCMA (sBCMA) in the circulation. sBCMA is elevated in patients with (pts) MM vs healthy subjects. Response to treatment in MM is routinely measured by serum and urine M-protein and free light chain (FLC). sBCMA could serve as a useful biomarker for disease response enabling a more rapid disease assessment given its faster turnover compared to serum FLC and/or M-protein (half-life of sBCMA, FLC, and M-protein is ~1, 2.75, and 11.9 days, respectively). This work a) evaluated the correlation of baseline sBCMA in plasma with key disease biomarkers and subgroups, and b) investigated the correlation of changes from baseline sBCMA with responses over time. METHODS Data from 4 studies in RRMM were pooled for the evaluation of baseline correlation with key disease biomarkers. These studies were the first-in-human MagnetisMM-1 (NCT03269136) study, the Japan Phase 1 MagnetisMM-2 (NCT04798586) study, MagnetisMM-3 (NCT04649359) study, and a Phase 1/2 MagnetisMM-9 (NCT05014412) study. Data from MagnetisMM-3 Cohort A only was used to investigate the correlation of changes from baseline sBCMA with responses over time. Two assays were used to measure sBCMA levels in plasma: 1) an electrochemiluminescent (ECL) ligand binding assay for measuring free (ie, drug unbound) sBCMA, and 2) an immunoaffinity LC-MS/MS assay for measuring total sBCMA (ie, free sBCMA in addition to drug bound and sBCMA bound to APRIL or BAFF). Plasma samples were collected at baseline and at various timepoints on treatment. Key disease biomarkers included disease stage [a: derived International Staging System (ISS), b) Revised-ISS (R-ISS) based on investigator assessment, and c) Derived R-ISS], tumor burden (high vs intermediate/low) which is derived as High: plasma cell in bone marrow (PCBM) ≥80%, or serum M-spike ≥ 5 g/dL, or FLC ≥5000 mg/L; Low: PCBM <50%, or serum M-spike < 3 g/dL, or FLC < 3000 mg/L; Intermediate: neither High nor Low. Other factors included β-2 microglobulin, cytogenetics, and presence of extramedullary disease (EMD). Statistical comparisons were conducted using t-test and one-way ANOVA. Statistical significance was defined as P <0.01. Correlations between post baseline changes in sBCMA levels and responses were explored graphically. RESULTS Baseline sBCMA was higher in participants with ISS or R-ISS 3 > 2 > 1 [ P <0.001]. Similarly, pts with high tumor burden had higher baseline sBCMA vs those with intermediate or low tumor burden. A moderate correlation was observed between baseline sBCMA and β-2 microglobulin. Participants with BMPC ≥50% had higher baseline sBCMA than those with <50%. A trend for association was observed in pts with EMD ( P=0.047). There was no statistically significant difference in baseline sBCMA levels between participants with high vs standard risk cytogenetics ( P=0.29). Results from the two assays for the baseline correlation were generally comparable. In MagnetisMM-3, free sBCMA declined in the majority of responding participants within 2 to 3 cycles. Concentrations of sBCMA in non-responding participants remained largely unchanged or increased in some patients. 92.5% (86/93) of responding participants (who also had free sBCMA measured) experienced at least 50% reduction from their baseline free sBCMA level vs 17.9% (12/67) in non-responding participants by Cycle 2 Day 1 (C2D1). An increase (or lack of decline) from baseline levels was observed in >90% of non-responders. Participants with deeper responses had higher magnitude of free sBCMA reduction by C2D1. Total sBCMA concentrations increased in non-responders and declined in responders, however, the decline was observed at later timepoints (eg, C6) as total sBCMA levels are affected by ELRA half-life. CONCLUSIONS Results from MagnetisMM studies showed that sBCMA is a potential disease biomarker of myeloma disease stage and disease burden. ELRA induced deep and rapid declines in free sBCMA levels. These declines correlated with clinical activity in patients with RRMM, which is demonstrated by ≥50% reduction in free sBCMA levels in >90% of responders, and an increase from baseline (or lack of decline) in >90% of non-responders.

Testing a tailored weight management program for veterans with PTSD: The MOVE! + UP randomized controlled trial

Post-traumatic stress disorder (PTSD), prevalent among Veterans, increases risk for having a high Body Mass Index. Although the Veterans Health Administration (VHA) offers an evidence-based behavioral weight management program called MOVE!, participants with PTSD lose less weight than those without mental health conditions, despite comparable participation. PTSD symptoms can interfere with one's ability to be physically active and maintain a healthy diet, the key targets in weight management programs. We developed and piloted a behavioral weight management program called MOVE! + UP that targets PTSD-related weight loss barriers. MOVE! + UP includes 16 group sessions with training in evidence-based weight management strategies, coupled with Cognitive Behavior Therapy (CBT) skills to address PTSD-specific barriers. The 16 sessions also include 30-min community walks to address PTSD-related barriers that may impede exercise. Two individual dietician sessions are provided. This hybrid type 1 randomized controlled trial (RCT) will compare MOVE! + UP to standard care—MOVE!—among 164 Veterans with BMI ≥ 25 who are receiving care for PTSD. We will randomize participants to MOVE! + UP or standard care and will compare absolute post-baseline change in weight at 6 (primary outcome) and 12 (secondary outcome) months, and PTSD symptom severity at 6 and 12 months (secondary outcome). Exploratory analyses will compare the treatment conditions on treatment targets measured at 6 months (e.g., physical activity, eating behavior, social support). Finally, we will estimate intervention costs, and identify MOVE! + UP implementation barriers and facilitators. If effective, MOVE! + UP could be an efficient way to simultaneously address physical and mental health for Veterans with PTSD.

The Impact of Aberrant Data Variability on Drug-Placebo Separation and Drug/Placebo Response in an Acute Schizophrenia Clinical Trial.

ObjectiveIn the current posthoc analyses, we evaluated the impact of markers of aberrant data variability on drug placebo separation and placebo and drug response in an acute schizophrenia clinical trial.MethodsPositive and negative syndrome scale data were obtained from a phase 2, randomized, double-blind, placebo controlled trial in hospitalized adults with schizophrenia experiencing an acute exacerbation. We assessed the impact of a total of six markers of aberrant data variability: erratic ratings, unusually large postbaseline improvement, high and low mean square successive difference (MSSD), identical and nearly identical ratings and compared the drug placebo difference, drug and treatment response at last visit in affected subjects vs those not affected. All analyses were conducted using generalized linear models.ResultsIn this posthoc analysis, drug placebo separation decreased with the presence of most markers of aberrant data variability. The only exception was high MSSD was associated with significant increase in the signal. In the affected subjects, the presence of indicators of increased data variability augmented the response to placebo, in the case of large postbaseline change and high MSSD, significantly. The presence of indicators of decreased variability numerically but not statistically decreased the response to placebo. Similar findings were observed in the drug treatment group with the exception of erratic ratings that numerically but not statistically decreased the response to the drug.DiscussionThe presence of most indicators of aberrant data variability had a detrimental effect on drug-placebo separation and showed different effects on placebo and treatment response.

COMT Genotype and Efficacy of Propranolol for TMD Pain: A Randomized Trial

Propranolol is a nonselective β-adrenergic receptor antagonist that is efficacious in reducing facial pain. There is evidence that its analgesic efficacy might be modified by variants of the catechol-O-methyltransferase (COMT) gene. We tested the hypothesis in a subset of 143 non-Hispanic Whites from a randomized controlled trial of patients with painful temporomandibular disorder (TMD). Patients were genotyped for rs4680, a single nucleotide polymorphism of COMT, and randomly allocated to either propranolol 60 mg twice daily or placebo. During the 9-wk follow-up period, patients recorded daily ratings of facial pain intensity and duration; the product was computed as an index of facial pain. Postbaseline change in the index at week 9 (the primary endpoint) was analyzed as a continuous variable and dichotomized at thresholds of ≥30% and ≥50% reduction. Mixed models for repeated measures tested for the genotype × treatment group interaction and estimated means, odds ratios (ORs), and 95% confidence limits (95% CLs) of efficacy within COMT genotypes assuming an additive genetic model. In secondary analysis, the cumulative response curves were plotted for dichotomized reductions ranging from ≥20% to ≥70%, and genotype differences in area under the curve percentages (%AUC) were calculated to signify efficacy. Mean index reduction did not differ significantly (P = 0.277) according to genotype, whereas the dichotomized ≥30% reduction revealed greater efficacy among G:G homozygotes (OR = 10.9, 95%CL = 2.4, 50.7) than among A:A homozygotes (OR = 0.8, 95%CL = 0.2, 3.2) with statistically significant interaction (P = 0.035). Cumulative response curves confirmed greater (P = 0.003) efficacy for G:G homozygotes (%AUC difference = 43.7, 95%CL = 15.4, 72.1) than for A:A homozygotes (%AUC difference = 6.5, 95%CL = -30.2, 43.2). The observed antagonistic effect of the A allele on propranolol’s efficacy was opposite the synergistic effect hypothesized a priori. This unexpected result highlights the need for better knowledge of COMT’s role in pain pathogenesis if the gene is to be used for precision-medicine treatment of TMD (ClinicalTrials.gov NCT02437383).

Health-Related Quality of Life in MONARCH 3: Abemaciclib plus an Aromatase Inhibitor as Initial Therapy in HR+, HER2- Advanced Breast Cancer.

BackgroundMONARCH 3, a phase III trial (NCT02246621) of postmenopausal women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC), previously demonstrated significantly improved progression‐free survival in patients receiving abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI). This study evaluated patient‐reported outcomes, including global health‐related quality of life (HRQoL), functioning, and symptoms.MethodsPatients were randomly assigned 2:1 to receive abemaciclib (150 mg twice daily; n = 328) or placebo (n = 165), plus 1 mg anastrozole or 2.5 mg letrozole daily. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Breast Cancer–Specific Quality of Life Questionnaire HRQoL instruments were administered at baseline, every two cycles during cycles 2 through 19 (each cycle being 28 days), every three cycles thereafter, and once at a short‐term posttherapy follow‐up visit (approximately 30 days after discontinuation). Longitudinal mixed regression and Cox proportional hazards models evaluated postbaseline change and time to sustained deterioration (TTSD), respectively.ResultsBaseline scores were similar between treatment arms. Although select scores statistically favored the placebo arm, global HRQoL, most symptoms, and functioning scales did not meet the threshold for clinically meaningful differences between treatment arms. Only diarrhea favored the placebo arm with statistically and clinically meaningful differences. There were no TTSD differences between treatment arms for global HRQoL, most symptoms (except diarrhea), or functioning.ConclusionOver a 2‐year period, there were no clinically meaningful differences in global HRQoL, functioning, and most symptoms for patients receiving abemaciclib plus NSAI compared with NSAI alone. Only diarrhea favored the placebo arm, consistent with prior safety data, which has been shown to be manageable and reversible. Combined with clinical efficacy, results support treatment with abemaciclib plus NSAI for postmenopausal women with HR+, HER2− ABC.Implications for PracticeThe addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) was not associated with a clinically meaningful detriment in patient‐reported global health‐related quality of life, functioning, and most symptoms in postmenopausal women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC). Prior studies have also demonstrated clinical efficacy of abemaciclib plus NSAI compared with NSAI alone, including improved progression‐free survival and objective response rate. These results also complement previously reported toxicity data, as measured by investigator‐assessed adverse events. Taken together, these results support treatment with abemaciclib plus NSAI for postmenopausal women with HR+, HER2− ABC.

Therapeutically-induced stable disease in oncology early clinical trials.

RationaleThe RECIST guideline defines four categories of response to treatment for cancer patients according to post-baseline changes in tumor burden, hence ignoring disease history. However, if left untreated, tumors grow exponentially, implying that pretreatment changes in tumor size are key to thoroughly assess efficacy. We present a model-based approach to estimate the rates of changes in tumor mass, before and after treatment onset.MethodsSixty-eight patients were eligible for the analysis of tumor size data from a Phase 1 study evaluating the effect of emactuzumab. In addition to tumor size measured at baseline and every six weeks during treatment, a pre-baseline measurement was gathered for each patient. A longitudinal regression model was used to estimate the rates of tumor size change before and after treatment onset.ResultsThe median pre-treatment tumor growth exponential rate was equal to 0.022 month-1, corresponding to a tumor size doubling time of 4 months, and the on-treatment median tumor shrinkage exponential rate was equal to 0.001 month-1. Among sixteen patients categorized as stable disease per RECIST, only five had similar slopes before and after treatment while nine actually improved. One patient in particular had a therapeutically induced stabilization of the disease.ConclusionOur analysis emphasizes the importance of collecting pre-baseline scans to distinguish therapeutically induced stable disease from cases where the tumor growth is not perturbed by treatment.

Afatinib versus methotrexate as second-line treatment for patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) progressing on or after platinum-based therapy: LUX-Head & Neck 3 phase III trial.

6024 Background: In a previous global phase III trial (LUX-Head & Neck 1), second-line (2L) afatinib significantly improved PFS vs methotrexate (MTX) in pts with R/M HNSCC. Here, we compared efficacy/safety of 2L afatinib vs MTX in Asian pts with R/M HNSCC. Methods: Pts progressing on/after platinum therapy were randomized (2:1) to 40 mg/day afatinib (feeding tube or oral) or 40 mg/m2/week iv MTX. Primary endpoint was PFS by independent review. Secondary endpoints were OS, ORR, and patient-reported outcomes. Results: 340 pts were randomized (afatinib 228, MTX 112). Median (range) duration of treatment (Tx) was 3.0 ( < 0.1–35.9) and 1.4 ( < 0.1–8.8) mos, respectively. Afatinib significantly decreased the risk of progression or death by 37% compared with MTX (HR 0.63; 95% CI: 0.48, 0.82 p = 0.0005, median PFS, 2.9 vs 2.6 mos; landmark analysis at 12 and 24 wks, 58 vs 41%, 21 vs 9%). There was no significant difference in OS (HR 0.88; 95% CI: 0.68, 1.13; median 6.9 vs 6.4 mos). ORR was 28% with afatinib and 13% with MTX (OR 2.8; 95% CI: 1.5, 5.2, p = 0.016). More pts had clinically relevant improvements in global health status/quality of life (GHS/QoL; 40 vs 23%, p < 0.01), swallowing (34 vs 18%, p = 0.01) and pain (34 vs 25%, p = 0.22) with afatinib vs MTX. Post-baseline change in GHS/QoL score was more favorable with afatinib (p < 0.001). Treatment-related adverse events (TRAEs; all/grade ≥3) were reported in 89/16% and 67/23% pts with afatinib and MTX. The most common grade ≥3 TRAEs were rash/acne (4%), diarrhea (4%), and stomatitis (3%) with afatinib, and anemia, leukopenia, and fatigue (all 5%) with MTX. Fatal AEs were reported in 23 and 11% pts with afatinib and MTX. Two ( hypoglycemia, pneumonitis/lung infiltration) and 4 pts had fatal AEs considered related to Tx with afatinib and MTX. 11% and 17% pts discontinued Tx due to TRAEs. Conclusions: LUX-Head & Neck 3 achieved its primary endpoint. Two randomized phase III trials have now demonstrated clinical benefit with 2L afatinib vs MTX. Safety data were consistent with the known tolerability profiles of afatinib and MTX. Clinical trial information: NCT01856478.

Idiopathic Pulmonary Fibrosis: The Association between the Adaptive Multiple Features Method and Fibrosis Outcomes.

Adaptive multiple features method (AMFM) lung texture analysis software recognizes high-resolution computed tomography (HRCT) patterns. To evaluate AMFM and visual quantification of HRCT patterns and their relationship with disease progression in idiopathic pulmonary fibrosis. Patients with idiopathic pulmonary fibrosis in a clinical trial of prednisone, azathioprine, and N-acetylcysteine underwent HRCT at study start and finish. Proportion of lung occupied by ground glass, ground glass-reticular (GGR), honeycombing, emphysema, and normal lung densities were measured by AMFM and three radiologists, documenting baseline disease extent and postbaseline change. Disease progression includes composite mortality, hospitalization, and 10% FVC decline. Agreement between visual and AMFM measurements was moderate for GGR (Pearson's correlation r = 0.60, P < 0.0001; mean difference = -0.03 with 95% limits of agreement of -0.19 to 0.14). Baseline extent of GGR was independently associated with disease progression when adjusting for baseline Gender-Age-Physiology stage and smoking status (hazard ratio per 10% visual GGR increase = 1.98, 95% confidence interval [CI] = 1.20-3.28, P = 0.008; and hazard ratio per 10% AMFM GGR increase = 1.36, 95% CI = 1.01-1.84, P = 0.04). Postbaseline visual and AMFM GGR trajectories were correlated with postbaseline FVC trajectory (r = -0.30, 95% CI = -0.46 to -0.11, P = 0.002; and r = -0.25, 95% CI = -0.42 to -0.06, P = 0.01, respectively). More extensive baseline visual and AMFM fibrosis (as measured by GGR densities) is independently associated with elevated hazard for disease progression. Postbaseline change in AMFM-measured and visually measured GGR densities are modestly correlated with change in FVC. AMFM-measured fibrosis is an automated adjunct to existing prognostic markers and may allow for study enrichment with subjects at increased disease progression risk.

Switching from zidovudine/lamivudine to tenofovir/emtricitabine improves fat distribution as measured by fat mass ratio.

Fat mass ratio (FMR) has been suggested as an objective indicator of abnormal body fat distribution in HIV infection. Although it could provide more comprehensive information on body fat changes than limb fat mass, FMR has scarcely been used in clinical trials examining body fat distribution in HIV-infected patients. A subanalysis of a controlled, randomized clinical trial in virologically suppressed HIV-1-infected men switching from zidovudine (ZDV)/lamivudine (3TC) to emtricitabine (FTC)/tenofovir (TDF) versus continuing on ZDV/3TC was carried out. FMR was assessed by dual X-ray absorptiometry (DEXA) for a period of 72 weeks. Lipoatrophy was defined as FMR ≥ 1.5. Multivariate linear regression models for the change in FMR from baseline were fitted. Sixty-five men were randomized and treated (28 in the FTC/TDF arm and 37 in the ZDV/3TC arm), and 57 completed the study (25 and 32 in each arm, respectively). In the FTC/TDF arm, adjusted mean FMR decreased by 0.52 at week 72 (P = 0.014), and in the ZDV/3TC arm it increased by 0.13 (P = 0.491; P between arms = 0.023). Among subjects with lipoatrophy (baseline FMR ≥ 1.5), adjusted FMR decreased by 0.76 (P = 0.003) in the FTC/TDF arm and increased by 0.21 (P = 0.411; P between arms = 0.009) in the ZDV/3TC arm. Baseline FMR and treatment group were significant predictors (P < 0.05) of post-baseline changes in FMR. Switching from ZDV/3TC to FTC/TDF led to an improvement in FMR, compared with progressive worsening of FMR in subjects receiving ZDV/3TC, showing that fat mass not only increased but was also distributed in a healthier way after the switch.

Persistence of a hyperthermic sign-reversal during nitrous oxide inhalation despite cue-exposure treatment with and without a drug-onset cue

We asked whether chronic tolerance and the hyperthermic sign-reversal induced by repeated 60% N2O exposures could be extinguished using a cue-exposure paradigm. Rats received 18 N2O administrations in a total calorimetry system that simultaneously measures core temperature (Tc), metabolic heat production (HP), and body heat loss (HL). Each exposure entailed a 2-h baseline period followed by a 1.5-h N2O exposure. The 18 drug exposures induced a robust intra-administration hyperthermia in which the initial hypothermic effect of N2O inverted to a significant hyperthermic sign-reversal during N2O inhalation due primarily to an acquired robust increase in HP. The rats were then randomized to one of 3 extinction procedures (n = 8/procedure) over a 20-d interval: 1) a N2O-abstinent home-cage group (HC) that received only the usual animal care; 2) a cue-exposure group (CEXP) in which the animals were placed in the calorimeter 8 times but received no N2O; and 3) a drug-onset-cue group (DOC) in which animals received a brief N2O exposure in the calorimeter that mimicked the first 3 min of an actual 60% N2O trial. Following the extinction sessions, all rats received a 60% N2O test trial and Tc, HP and HL were assessed. The hyperthermic sign-reversal remained fully intact during the test trial, with no significant differences observed among groups in any post-baseline change in any thermal outcome. These data suggest that cue exposure may not be an efficacious strategy to reduce sign-reversals that develop with chronic drug use.

Reducing depression in 9–10 year old children in low SES schools: A longitudinal universal randomized controlled trial

The Aussie Optimism: Positive Thinking Skills Program (AOP-PTS) is an innovative curriculum-based mental health promotion program based on cognitive and behavioural strategies. The program is aimed at preventing depressive and anxiety symptoms and disorders in middle primary school children aged 9–10 years. Students from 22 low SES primary schools (N = 910) were randomly assigned to an intervention or a control group and assessed at baseline, post-test, 6 months and 18 months. The intervention group received the program implemented by teachers and the control group received their regular Health Education curriculum. Students completed questionnaires on depression, anxiety, and attribution style. At risk students were further assessed with the computerised Diagnostic Interview for Children and Adolescents. Parents reported on their children's externalising and internalising problems at home. Children in the intervention condition reported a significant pre-post reduction in depressive symptoms, and there was a significant pre-post reduction in parent-reported emotional difficulties which was maintained at 6 month follow-up; no changes were evident in the control group. Both groups showed significant improvements in child-reported anxiety and attribution style, and significant improvements in parent-reported pro-social behaviours. For both groups, there were no significant post-baseline changes in incidence and recovery rates for depression, anxiety, or internalising symptoms. These findings suggest that AOP-PTS has the potential to treat depressive symptomatology in the immediate term but the effects were not sustained. There is also evidence of improved emotional resilience up to 6 months following the program. Further follow-up to investigate longer term effects is needed.

FRI0233 Tocilizumab administered in daily clinical practice - final results of the german non-interventional study “routine”

BackgroundTocilizumab (TCZ) is an interleukin-6-receptor inhibitor for treatment of patients (pts) with rheumatoid arthritis (RA), which was approved in the EU in JAN 2009.ObjectivesTo evaluate the effectiveness, safety, and utilization...

Hemodynamic Interaction Between a Daily Dosed Phosphodiesterase 5 Inhibitor, Tadalafil, and the α‐Adrenergic Blockers, Doxazosin and Tamsulosin, in Middle‐Aged Healthy Male Subjects

The hemodynamic interaction between tadalafil (5 mg/d) and doxazosin or tamsulosin was investigated in 2 randomized, double-blind, crossover phase 1 studies. Healthy men (n = 45) received tadalafil or placebo for 28 days and increasing doses of doxazosin (1, 2, and 4 mg/d) for the last 21 days of treatment. In the second study, participants (n = 39) received tadalafil or placebo for 14 days and tamsulosin (0.4 mg/d) for the last 7 days of treatment. Similar mean maximum postbaseline changes in standing systolic blood pressure were observed in subjects given tadalafil or placebo with 4 mg of doxazosin (-0.5 mm Hg; 95% confidence interval, -4 to 3.1 mm Hg) or with tamsulosin (0.9 mm Hg; 95% confidence interval, -1.4 to 3.2 mm Hg). Standing systolic blood pressure less than 85 mm Hg (blood pressure outlier) occurred in 1 subject treated with 4 mg of doxazosin plus tadalafil but was not reported in subjects treated with tamsulosin and tadalafil. Three subjects experienced moderate hypotensive events lasting less than 2 hours, 2 with syncope (after tadalafil alone or with 4 mg of doxazosin) and 1 without (after 4 mg of doxazosin with placebo). The incidence of hypotension was low in healthy men given increasing doses of doxazosin with chronically dosed tadalafil or placebo. Administration of tadalafil with tamsulosin was well tolerated in healthy men.