Dose Arm Research Articles

P483 Golimumab response in Ulcerative Colitis as early as week 2: What can we take from this?

Abstract Background Golimumab is a monoclonal anti-TNF drug used in the treatment of Ulcerative Colitis (UC). GOAL-ARC is a multi-centered investigator initiated randomized control trial seeking to evaluate the utility of personalized Golimumab dose adjustment in UC versus standard dosing as per summary of product characteristics (SMPC) post-induction. From early analysis data, we aimed to ascertain if Golimumab induces response at 2 weeks and if this early response impacts disease activity at 6 weeks and the need for dose escalation at this interval. Methods Patients recruited to the trial were randomized to an intervention or a standard dosing arm. Golimumab was administered at 200mg at week 0 and 100mg at week 2 with assessments at weeks 0, 2, and 6. Baseline data was obtained including patient demographics and burden of disease. Outcomes measured were clinical response (defined by a decrease in partial mayo score of 2 points or a decrease of ≥30% from baseline), change in Faecal Calprotectin (FCP) as well as improvement in Short Health Scale (SHS) score and serum golimumab levels at 6 weeks. We also looked at FCP≤250μg/g (STRIDE II – intermediate treatment target) as an outcome. Results A total of 94 patients were recruited with 90 (95.7%) patients completing 2-week follow up and 79 (84%) patients completing 6-week follow-up. The median age was 37 years (IQR 28-46), 58.5% were male, and 76.6% (n=72) had a Mayo endoscopic subscore of 2 and the median DUBLIN Score was 4 (IQR 4-6). At 2 weeks, a clinical response was observed in 68.9% of patients (n=62). There was a significantly lower median modified partial mayo score (2 vs 4, p<0.001), rectal bleeding score (0 vs 2, p<0.001), stool frequency score (1 vs 2, p<0.001) and total SHS score (21.0 vs 25.8, p<0.001) after 2 weeks of treatment. The median FCP was numerically lower (354.7μg/g vs 1111.5μ/g, p=0.207) with an overall reduction by 32.5%. Patients who achieved a clinical response at 2 weeks were noted to have a lower baseline total SHS score (23.9 vs 29.0, p=0.017). 2-week response did not correlate with 6-week outcomes. Median FCP was significantly lower at 6 weeks (254.2μg/g vs 1111.5μ/g, p=0.008) with an overall reduction by 74.0%. There was a significantly higher median Golimumab level in patients with FCP≤250μg/g at 6 weeks (5.59μg/ml vs 2.41μg/ml, p<0.001). Conclusion Golimumab shows efficacy in Ulcerative Colitis as early as 2 weeks with significant clinical response and a biochemical response. Early data suggests that response at 2 weeks, however, is not a reliable indicator of a sustained clinical response.

Investigation of the Utility of Multivariate Meta-Analysis Methods in Estimating the Summary Dose Response Curve.

Traditional meta-analyses often assess the effectiveness of different doses of the same intervention separately or examine the overall differences between intervention and placebo groups. The present study aimed to model the effect sizes obtained from different doses in multiple studies using a two-stage dose-response meta-analytic approach while taking dose variations into account. Different dose-response meta-analysis models using linear, quadratic, and restricted cubic spline (RCS) functions were fitted. A two-stage approach utilizing multivariate meta-analysis was performed and the obtained results were compared with those of the univariate meta-analysis. A random effect dose-response meta-analysis was performed using data from an existing systematic review on combination therapy with zonisamide and anti-Parkinson drugs for Parkinson's disease. The effective or optimum dose for producing maximum response was also investigated. Moreover, a sensitivity analysis was performed by changing the knots of the RCS model. Dose-response meta-analysis was performed using data from four double-blinded randomized controlled trials with 724 and 309 patients with Parkinson's disease in dose and placebo arms, respectively. The quadratic model yielded the smallest Akaike information criterion (AIC), compared to the linear and RCS models, indicating it to be the best fit for the data. Compared to the traditional approach, the two-stage approach could model the dose-dependent effect of zonisamide on the Unified Parkinson's Disease Rating Scale (UPRDS) part III score and predict the outcome for different doses through a single analysis.

1283. Safety, Tolerability, and Pharmacokinetics of BRII-778, A Modified-Release Oral Formulation of Rilpivirine in Healthy Adult Subjects

Abstract Background BRII-778 is a modified release (MR) formulation of rilpivirine for once-weekly (QW) oral administration. BRII-778 aims to prolong oral absorption, lower Cmax, relatively, and reduce peak to trough ratio achieved with a MR formulation of rilpivirine, within the known efficacy and safety bounds established by once daily oral administration of rilpivirine. QW BRII-778 dosing may have advantages over once daily rilpirvirine in terms of patient convenience, and treatment adherence. Multiple MR formulations of rilpivirine were evaluated in healthy adult subjects in this Phase 1 study. Methods This was a Phase 1, randomized, double-blinded, placebo-controlled, study of single ascending dose (SAD) and multiple ascending dose (MAD) cohorts, evaluating the safety, tolerability, and PK of BRII-778. Three MR formulations of rilpivirine, BRII-778-A1, -A2, and -A3, were evaluated in this study. Rilpivirine PK profiles after single or multiple doses of the three BRII-778 formulations were characterized under the fed state over the dose range of 150 mg to 750 mg. Food effect was assessed after a single oral dose of BRII-778-A3 750 mg. Exploratory concentration-QTc (C-QTc) analysis was conducted using combined SAD and MAD data. Results BRII-778 as single dose or multiple doses was generally safe and well-tolerated when administered to healthy adult subjects. There were no Grade ≥3 AEs, SAEs or AEs leading to withdrawal in BRII-778 dosing arms. PK profiles of BRII-778 were consistent with slower oral absorption with MR formulation. The increase in exposure was less than dose proportional. Mild accumulation in plasma was observed after 3 QW BRII-778-A3 doses. BRII-778-A3 750 mg under the fed state enhanced bioavailability by improving gastric dissolution and/or subsequent absorption. Exploratory C-QTc analysis confirmed a concentration-dependent effect on the QTc interval with escalating doses of BRII-778, but the interpretations are limited by small sample size. There were no clinically significant EKG changes and no individual subject met QTc stopping criteria. Conclusion SAD and MAD administration of BRII-778 formulations were generally safe and well tolerated. Rilpivirine PK profiles post BRII-778 dosing supports further evaluation of BRII-778 for potential QW regimen. Disclosures David A. Margolis, MD MPH, Brii Biosciences: Stocks/Bonds Ji Ma, PhD, Brii Biosciences: Stocks/Bonds Michael Watkins, PharmD, Brii Biosciences: Stocks/Bonds Yujin Wang, M.Sc., Brii Biosciences: Stocks/Bonds Chetana Trivedi, B.A., Brii Biosciences: Stocks/Bonds Xuelian Wei, PhD, Brii Biosciences: Stocks/Bonds Lijie Zhong, PhD, Brii Biosciences: Stocks/Bonds Kamlesh Patel, PhD, Brii Biosciences: Stocks/Bonds Li Yan, MD PhD, Brii Biosciences: Stocks/Bonds Zhi Hong, PhD, Brii Biosciences: Ownership Interest Jean-Luc Girardet, PhD, Brii Biosciences: Stocks/Bonds Lianhong Xu, PhD, Brii Biosciences: Stocks/Bonds.

Renal function-based versus standard dosing of pemetrexed: a randomized controlled trial.

Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing. A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration-time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164mg×h/L ± 25%) was calculated. A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155mg × h/L vs 160mg × h/L (p = 0.436). We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing. Clinicaltrials.gov identifier: NCT03655821.

Immunomodulators in Mechanically Ventilated Patients With COVID-19: Lessons Learned From Underpowered Trials.

Immunomodulators in Mechanically Ventilated Patients With COVID-19: Lessons Learned From Underpowered Trials.

Individualized, PK-Guided Dosing of Hydroxyurea Is Not Associated with Increased Hematologic Toxicity Compared to Weight-Based Initial Dosing: Interim Results from the Hops Trial

Introduction: Initiation of hydroxyurea (HU) in the first year of life is becoming an increasingly accepted standard of care for children with sickle cell anemia (SCA). Stepwise dose escalation to maximum tolerated dose (MTD) typically starts empirically at 20 mg/kg/day, based on early studies of adults and the subsequent BABY HUG study. However, recent results from the NOHARM trial in Uganda demonstrated the clinical superiority and similar safety profile of a higher initial dose (25 mg/kg with dose escalation) compared to fixed 20 mg/kg dosing. Despite these findings, many providers remain hesitant to start at doses higher than 20 mg/kg/day, mostly related to possible hematologic toxicity. Similarly, there is great variability in dose escalation strategies and variation in laboratory thresholds used to decide whether to hold or dose escalate HU therapy. Study Design and Rationale: Recognizing the significant interpatient variability in dosing and the importance in optimizing exposure, we have developed an individualized, pharmacokinetics (PK)-guided dosing strategy of HU for children with SCA. The single center TREAT trial demonstrated that an individualized dosing strategy, using higher starting doses (27.7 ± 4.9 mg/kg/day) was feasible and effective, achieving MTD almost immediately and HbF ≥30% for most patients. To further validate these results, the follow-up Hydroxyurea Optimization through Precision Study (HOPS, NCT03789591) is a randomized, multicenter trial comparing standard, weight-based initial dosing with conventional dose-escalation vs. PK-guided initial dosing for children with SCD as they initiate HU therapy. Participants (ages 6 months through 21 years), recruited from 15 pediatric sickle cell centers across the US, are randomized to receive HU either using a starting dose of 20 mg/kg/day or a PK-guided dose. Participants in both arms subsequently use the same dose adjustment strategy, more aggressive than historical dosing strategies to optimize clinical response (See Table). The primary endpoint is clinical response defined by %HbF measured 6 months after starting HU. As recruitment for the HOPS Trial is nearly complete but ongoing, we do not report primary or clinical results here. Here we demonstrate the feasibility of a PK-guided dosing across multiple centers and present data related to HU dosing and laboratory toxicity to demonstrate the safety of higher starting doses for young children with SCA. Results: As of August 1, 2022, there have been 95, of a planned 104, participants enrolled in the HOPS Trial. The median age of enrollment was 10 months with most (72%) participants ≤ 2 years of age. Despite the young starting age, most participants had at least one complication or hospitalization related to SCA prior to starting HU, and 84% demonstrated significant hemolytic anemia, evidenced by a hemoglobin < 10.5 g/dL with absolute reticulocyte count > 150 x109/L prior to initiation of HU. The mean starting absolute neutrophil count (ANC) across this entire, mostly young cohort was relatively low (3.5 ± 2.2 x 109/L) with 52% of participants having a baseline ANC < 3.0x109/L and 24% with an ANC < 1.5 x 109/L prior to hydroxyurea initiation. The starting doses were higher, as expected, for the PK-guided dosing arm (28.2 ± 5.2 mg/kg/day) compared to the weight-based dosing arm (20.2 ± 0.6 mg/kg/day). Despite high starting doses, there was no evidence of increased hematologic toxicity through the first 12 months of hydroxyurea therapy in the PK-guided dosing arm. To date, there have been a total of 24 dose holds in 18 participants due to hematologic toxicity, most commonly transient incidental neutropenia, with no differences between starting dose (i.e. higher or lower PK-guided dose) or study arm assignment (10 in PK-guided arm, 8 in weight-based arm). ANC was lower in the PK-guided dosing arm at month 6 compared to the weight-based dosing arm (2.2 ± 1.4 vs. 3.2 ± 1.9) but not in an unsafe range. Conclusions: These preliminary results from the HOPS Trial demonstrate that starting doses of hydroxyurea as high as 25-30 mg/kg/day are safe and not associated with an increased risk of clinically significant hematologic toxicity in young children with SCA, even among young children with relatively low ANCs. Complete results of the HOPS trial are forthcoming. Which will formally evaluate the clinical benefits of PK-guided initial dosing compared to the traditional 20 mg/kg starting dose strategy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pretreatment with Tocilizumab Prior to the CD3 Bispecific Cevostamab in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Showed a Marked Reduction in Cytokine Release Syndrome Incidence and Severity

Background: Blockade of the cytokine IL-6 receptor by monoclonal antibodies, such as tocilizumab (TCZ), is a key strategy for the management of both CAR-T and T-cell dependent bispecific monoclonal antibody (TDB) induced cytokine release syndrome (CRS). Preclinical data indicate that inhibition of IL-6, IL-1, or TNF-α signaling prior to TDB administration can prevent development of CRS without any impact on anti-tumor activity (Li et al. Sci Transl Med 2019). To test this hypothesis in the clinic, a dedicated TCZ pretreatment arm was added to the ongoing GO39775 Phase I study (NCT03275103) of cevostamab, an FcRH5xCD3 TDB, to determine whether a single dose of TCZ administered prior to the first dose of cevostamab can reduce the incidence of CRS. Methods: Patients (pts) who have RRMM for which no established therapy is available, appropriate or tolerable were enrolled in a dedicated TCZ pretreatment arm. Cevostamab was administered intravenously (IV) in a 21-day Cycle (C). A single 3.6mg priming dose was given on Day (D) 1 of C1 followed by a target dose of 90mg on C1D8 and then C2D1 and beyond. A single IV 8mg/kg dose of TCZ was administered as a pretreatment on C1D1 two hours prior to the administration of cevostamab. Patient data from the previously enrolled non-TCZ 3.6/90mg dosing arm served as a retrospective comparator. Pts in both arms received corticosteroid, antihistamine and acetaminophen premedication prior to cevostamab. CRS is reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: At data cut-off (March 8, 2022), 28 pts had enrolled in the TCZ pretreatment arm (median age: 64.5 years) and 44 pts in the non-TCZ comparator (median age: 63.0 years). Median prior lines of therapy were 4 (2.0-7.0) and 6 (2.0-11.0) in the TCZ pretreatment and non-TCZ arms, respectively. Twenty-two pts (78.6%) were triple-class refractory and 12 pts (42.9%) were penta-refractory in the TCZ pretreatment arm, vs. 38 (86.4%) triple-class refractory and 32 (72.7%) penta-refractory pts in the non-TCZ arm. Pts in the TCZ arm had a median time on study of 4.7 months (range: 0.3-11.3) vs. 13.1 months (range: 0.2-30.8) in the non-TCZ arm. All patients in the TCZ arm experienced at least one adverse event (AE). Overall, 35.7% of pts in the TCZ arm experienced CRS as compared to 90.9% in the non-TCZ 3.6/90mg group (see figure). One patient in each group experienced G3 CRS and no G4/G5 events were observed. Fewer pts required TCZ to treat CRS (5/28) in the TCZ arm than the non-TCZ arm (16/44). Only two pts on the TCZ arm had more than one CRS event (vs. 12/44 non-TCZ) and no CRS events were observed at C2 and beyond (vs. 5/44 non-TCZ). Rates of non-CRS AEs (notably thrombocytopenia, infections, and liver enzyme elevations) in the TCZ arm were similar to the non-TCZ arm with the exception of neutropenia (Trudel et al. ASH 2021). In the TCZ arm 64.3% of pts experienced G3/G4 neutropenia as compared to 38.6% in the comparator arm. In both arms, neutropenia events were reversible, manageable with growth factor as indicated, and none led to the discontinuation of cevostamab. Consistent with preclinical data, no apparent negative impact on anti-tumor activity was observed. The overall response rate in the TCZ arm with 90mg target dose was 50% (13/26) [95% CI: 28.9-71.2] compared to 37.2% (16/43) [95% CI: 21.6-52.8] in pts receiving 90mg without TCZ pretreatment. Very good partial response or better (VGPR+) rates were 26.9% vs. 25.6%, respectively. Available pharmacodynamic data did not demonstrate any apparent change in measures of T-cell activation and proliferation in pts receiving TCZ pretreatment. Consistent with the known mechanism of action of TCZ, levels of C-reactive protein, a downstream product of hepatic IL-6 activation, were heavily suppressed in the vast majority of pts in TCZ arm suggestive of near-complete inhibition of the IL-6 signaling pathway. Conclusions: Clinical data from the GO39775 study shows for the first time that TCZ pretreatment can significantly reduce the risk of developing TDB-induced CRS without an apparent impact on anti-myeloma activity. The data support additional investigation of the use of anti-cytokine pretreatment with the goal of substantially reducing the frequency and potentially the severity of CRS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hydroxyurea Dosing in Very Young Children with Sickle Cell Anemia: A Multicenter, Randomized, Controlled Trial (HUGKISS)

Introduction: In the BABY HUG trial, fixed-dose hydroxyurea (20 mg/kg/day) was safe and effective in decreasing sickle cell anemia (SCA)-related complications in very young children (9-18 months). Nevertheless, children in the treatment arm of BABY HUG continued to experience vaso-occlusive symptoms and incur organ damage. In older children/adults with SCA, intensification of hydroxyurea to a maximum tolerated dosage, defined by mild to moderate myelosuppression, has been associated with improved laboratory parameters and clinical benefits compared to fixed lower dosing. However, relatively little has been published regarding hydroxyurea dose escalation in infants with SCA. We designed the Hydroxyurea Management in Kids: Intensive versus Stable Dosage Strategies (HUGKISS) to determine the feasibility of enrolling, randomizing, and treating very young children with SCA with either a fixed or intensified dose of hydroxyurea. Methods: We performed a single-blind, randomized, multicenter pilot trial of hydroxyurea in infants and toddlers (9-36 months old) with SCA to compare a "standard" treatment (20 mg/kg/day) with an "intensive" treatment defined by a goal absolute neutrophil count (ANC) of 1500-3000 cells/µL. Participants were randomized in a 1:1 ratio to receive "standard" or "intensive" therapy based on a block randomization and were stratified by clinical center and age (9 to <24 months or 24 to <36 months). In both the standard and intensive treatment arms, participants began hydroxyurea at 20 (±2.5) mg/kg/day. There was no dose escalation in the HUGKISS standard arm. Participants treated in the intensive arm were dose-escalated by 5 mg/kg/day increments (if tolerated) to a maximum of 35 mg/kg/day, adjusted every 8 weeks to maintain the goal ANC. Participants underwent clinical, laboratory, and medication adherence assessments every 4 (±2) weeks. The medical coordinating center staff and study center principal investigators were blinded to treatment allocation, while hydroxyurea volume was not blinded to participants or caregivers. Results: Twenty-six subjects were randomized to standard treatment and 25 to intensive treatment, with no statistical difference in the subjects' mean age at enrollment (12.8 months) or laboratory values at randomization. One year after randomization, 19 and 23 subjects were evaluable in the standard and intensive arms respectively. The mean hydroxyurea doses at exit were 27.2 mg/kg/day (intensive arm) and 18.8 mg/kg/day (standard arm). Significantly greater increases in fetal hemoglobin (HbF) were noted in the intensive versus standard arm (p=0.002, final levels, 38.8% vs 26.1%), and the median hemoglobin (Hb) (p=0.033, +1.2g/dl vs +0.4 g/dl). Significantly greater increases in mean corpuscular volume and greater decreases in reticulocyte count and ANC also occurred in the intensive arm. Significant differences were not seen in SCA-related adverse event rates. The intensive arm had more frequent neutropenic toxicity (ANC<1000 cells/µL) than the standard arm (52% versus 23%), but no serious infections occurred. Data from the BABY HUG treatment arm were pooled with our standard dose arm since both groups received the same dose of hydroxyurea and were of similar age. When the data were summarized and compared in longitudinal curves (Figure), similar differences from our intensive arm were found, often within 6 months of dose initiation. Conclusions: Intensive hydroxyurea treatment induced greater increases in HbF and Hb than standard dosing without significant toxicity in very young children with SCA, and may blunt or delay the fall in HbF seen after 6 months of therapy with lower doses. HUGKISS demonstrated the feasibility of treating very young children with SCA with intensive dose hydroxyurea. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efzofitimod for the Treatment of Pulmonary Sarcoidosis

Pulmonary sarcoidosis is characterized by the accumulation of immune cells that form granulomas affecting the lungs. Efzofitimod (ATYR1923), a novel immunomodulator, selectively binds neuropilin 2, which is upregulated on immune cells in response to lung inflammation. What is the tolerability, safety, and effect on outcomes of efzofitimod in pulmonary sarcoidosis? In this randomized, double-blind, placebo-controlled study evaluating multiple ascending doses of efzofitimod administered intravenously every 4weeks for 24weeks, randomized patients (2:1) underwent a steroid taper to 5mg/d by week 8 or<5mg/d after week 16. The primary end point was the incidence of adverse events (AEs); secondary end points included steroid reduction, change in lung function, and patient-reported outcomes on health-related quality-of-life scales. Thirty-seven patients received at least one dose of study medication. Efzofitimod was well tolerated at all doses, with no new or unexpected AEs and no dose-dependent AE incidence. Average daily steroid doses through end of study were 6.8mg, 6.5mg, and 5.6mg for the 1 mg/kg, 3 mg/kg, and 5 mg/kg groups compared with 7.2mg for placebo, resulting in a baseline-adjusted relative steroid reduction of 5%, 9%, and 22%, respectively. Clinically meaningful improvements were achieved across several patient-reported outcomes, several of which reached statistical significance in the 5 mg/kg dose arm. A dose-dependent but nonsignificant trend toward improved lung function also was observed for 3 and 5mg/kg. Efzofitimod was safe and well tolerated and was associated with dose-dependent improvements of several clinically relevant end points compared with placebo. The results of this study support further evaluation of efzofitimod in pulmonary sarcoidosis. ClinicalTrials.gov; No.: NCT03824392; URL: www. gov.

Comparison of efficacy between two doses of dexamethasone as an intratympanic injection in Idiopathic Sudden Sensorineural Hearing Loss

Introduction: Most cases of sudden sensorineural hearing loss (SSHL) are idiopathic, so there is no specific treatment protocol for this set of patients, which is accepted worldwide. Some temporal bone studies regarding histopathological findings in SSHL cases found that most of the lesions were in the cochlea and its structures. The histological findings suggest that some inflammatory, vascular or immunological aetiology are present behind such lesions in cochlea. Inflammation being one of the major among all the aetiologies, so steroids are the mainstay of treatment for Idiopathic sudden sensorineural hearing loss (ISSHL) cases. Material and methods: A prospective comparative study was done on 56 patients aged 18 to 70 years. Patients received 4mg/ml dose (Arm A) or 8mg/ml dose (Arm B) ofintratympanic dexamethasone injection. The targeted recovery on 5th day after 1st intratympanic steroid injection was compared with baseline Pure tone Audiometry (PTA)of day 1 for both the groups. Statistical analysis: More than 20db improvement in PTA average (0.5K,1k and 2k) onassessment at 5th day after 1stinjection was considered as recovery criteria. A comparison was done on improvement between two arms.

Safety and Outcomes of a Plasmid DNA Vaccine Encoding the ERBB2 Intracellular Domain in Patients With Advanced-Stage ERBB2-Positive Breast Cancer

High levels of ERBB2 (formerly HER2)-specific type 1 T cells in the peripheral blood are associated with favorable clinical outcomes after trastuzumab therapy; however, only a minority of patients develop measurable ERBB2 immunity after treatment. Vaccines designed to increase ERBB2-specific T-helper cells could induce ERBB2 immunity in a majority of patients. To determine the safety and immunogenicity of 3 doses (10, 100, and 500 μg) of a plasmid-based vaccine encoding the ERBB2 intracellular domain (ICD). Single-arm phase 1 trial including 66 patients with advanced-stage ERBB2-positive breast cancer treated in an academic medical center between 2001 and 2010 with 10-year postvaccine toxicity assessments. Data analysis was performed over 2 periods: January 2012 to March 2013 and July 2021 to August 2022. Patients were sequentially enrolled to the 3 dose arms. The vaccine was administered intradermally once a month with soluble granulocyte-macrophage colony-stimulating factor as an adjuvant for 3 immunizations. Toxicity evaluations occurred at set intervals and yearly. Peripheral blood mononuclear cells were collected for evaluation of immunity. Biopsy of vaccine sites at weeks 16 and 36 measured DNA persistence. Safety was graded by Common Terminology Criteria for Adverse Events, version 3.0, and ERBB2 ICD immune responses were measured by interferon-γ enzyme-linked immunosorbent spot. Secondary objectives determined if vaccine dose was associated with immunity and evaluated persistence of plasmid DNA at the vaccine site. A total of 66 patients (median [range] age, 51 [34-77] years) were enrolled. The majority of vaccine-related toxic effects were grade 1 and 2 and not significantly different between dose arms. Patients in arm 2 (100 μg) and arm 3 (500 μg) had higher magnitude ERBB2 ICD type 1 immune responses at most time points than arm 1 (10 μg) (arm 2 compared with arm 1, coefficient, 181 [95% CI, 60-303]; P = .003; arm 3 compared with arm 1, coefficient, 233 [95% CI, 102-363]; P < .001) after adjusting for baseline factors. ERBB2 ICD immunity at time points after the end of immunizations was significantly lower on average in patients with DNA persistence at week 16 compared with those without persistence. The highest vaccine dose was associated with the greatest incidence of persistent DNA at the injection site. In this phase 1 nonrandomized clinical trial, immunization with the 100-μg dose of the ERBB2 ICD plasmid-based vaccine was associated with generation of ERBB2-specific type 1 T cells in most patients with ERBB2-expressing breast cancer, and it is currently being evaluated in randomized phase 2 trials. ClinicalTrials.gov Identifier: NCT00436254.

A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial)

PurposeThe purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients. Patients and methodsPatients with mCRC and progression during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm. ResultsThere were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: population for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 patients), and hand–foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0–13.7) months in arm A, 8.6 (IQR 3.8–13.4) in arm B, and 7.1 (IQR 4.4–12.4) in arm C. ConclusionsThe alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher numerical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles. Clinicaltrials.gov identifierNCT02835924.

Vancomycin Loading Doses and Nephrotoxicity on Medicine Teaching Services.

BackgroundInfectious Disease Society of America (IDSA) guidelines recommend the usage of a loading dose when using vancomycin for seriously ill patients. While the relationship between vancomycin and nephrotoxicity is the focus of many studies, few studies have examined the relationship between vancomycin loading doses and nephrotoxicity.MethodsWe performed a retrospective cohort study examining vancomycin dosing for internal medicine teaching services’ patients over the 2014–15 academic year at one academic medical center. We generated a list of all hospitalized patients aged 18–85 who received vancomycin and were admitted to a teaching service. Nephrotoxicity was determined by 7-day acute kidney injury (AKI) rate. Patients in the loading dose cohort were compared with those in the standard-dose cohort. Primary modeling used multivariable logistic regression with AKI as our outcome of interest.ResultsFour hundred and thirty-eight patients were included for analysis. The loading dose (n = 365, 83%) and standard dosing (n = 73, 17%) cohorts were not significantly different regarding demographics, GFR, nephrotoxic drug exposure, total vancomycin received, trough levels, or comorbidities and were only significantly different regarding body mass index (BMI). The 7-day AKI rate was not significantly different between the two arms (6.3% in the standard dosing arm and 8.2% in the loading dose arm, p = 0.6).ConclusionFew studies have examined the relationship between nephrotoxicity and vancomycin loading doses. The results of this study provide evidence that the use of loading doses is not significantly associated with increased 7-day AKI rate.

Erratum: Zhao et al., "Histochemical Characterization of the Dorsal Raphe-Periaqueductal Grey Dopamine Transporter Neurons Projecting to the Extended Amygdala".

<h3>Objective:</h3> Characterize the levodopa pharmacokinetic profile achieved with continuous subcutaneous administration of ND0612. <h3>Background:</h3> Continuous levodopa/carbidopa infusion is the optimal delivery route for patients with advanced Parkinson’s disease (PD), but current delivery systems require invasive surgical interventions. ND0612 is a proprietary liquid formulation of levodopa/carbidopa administrated subcutaneously through a mini-pump delivering a range of levodopa doses from 270mg/day to 720mg/day. <h3>Design/Methods:</h3> Two Phase II studies were performed. The first was a phase IIa study in which 16 PD patients were randomized to low-or high- dose ND0612 for 8-hours administration. The second was a double-blind, placebo-controlled study, in which 30 PD patients received low dose ND0612 or placebo, as adjunct to their current optimized oral treatment for 2-weeks, followed by a 1-week open label extension of ND0612 either with or without oral entacapone. <h3>Results:</h3> In the first study, fluctuations in levodopa plasma levels were markedly reduced (both doses) in comparison to baseline oral levodopa/carbidopa. Levodopa maximal plasma concentrations were dose proportionate; low and high ND0612 doses achieved 487ng/mL and 1454ng/ml respectively. Co-administration of entacapone BID increased levodopa plasma levels to 604ng/mL and 1844ng/mL in the low and high dose arms respectively. In the second study, adjunct treatment with low-dose ND0612 eliminated the levodopa troughs associated with oral levodopa/carbidopa. Furthermore, when oral levodopa was discontinued, peaks and troughs in levodopa plasma levels were abolished, and mean levodopa levels were maintained at 550ng/ml. Co-administered entacapone further increased levodopa levels to 800ng/ml. In addition, the trial met its futility analysis endpoint; adjunct ND0612 reduced mean OFF by 2.42h in clinic and 2.13h in pilot home diaries, (vs. 0.41h and 1.39h with optimized oral therapy and placebo). <h3>Conclusions:</h3> Subcutaneous administration of ND0612 provides steady, therapeutic levodopa plasma concentrations that were associated with clinical improvement, and may provide an effective, non-invasive alternative for continuous levodopa delivery. <b>Study Supported by:</b> NeuroDerm Ltd. <b>Disclosure:</b> Dr. Giladi has received personal compensation for activities with Teva-Lundbeck, Merz Inc., and UCB for activities with the Advisory Boards . f Teva-Lundbeck, Merz Inc. Dr. Giladi has received personal compensation for activities with Teva Israel, Intec Pharma and NeuroDerm Inc. as a consultant. Dr. Caraco has received personal compensation for activities with NeuroDerm Ltd. as a consultant. Dr. Caraco has received research support from NeuroDerm Ltd. Dr. Gurevich has nothing to disclose. Dr. Djaldetti has nothing to disclose. L. Adar has received personal compensation for activities with NeuroDerm Ltd. as an employee. Dr. Cohen has received personal compensation for activities with Neuroderm as an employee. Dr. Rahmilevich has received personal compensation for activities with NeuroDerm Ltd., a an employee. Dr. Oren has received personal compensation for activities with NeuroDerm Ltd.

Definitive chemoradiotherapy versus neoadjuvant chemoradiotherapy followed by surgery in patients with locally advanced esophageal squamous cell carcinoma who achieved clinical complete response when induction chemoradiation finished: A phase II random

Background and purposeMore than 40% of patients with esophageal squamous cell carcinoma (ESCC) exhibit pathological complete responses (pCR) after neoadjuvant chemoradiotherapy (nCRT), and theoretically, these patients may be cured by CRT and omit surgery. This prospectively randomized pilot study compared definitive chemoradiotherapy (dCRT) with nCRT in patients with locally advanced ESCC who achieved clinical complete responses (cCRs) to nCRT. Materials and methodsSingle center, randomized, open phase 2 study of 256 patients with locally advanced ESCC enrolled between April 2016 and November 2018. Immediately when nCRT finished, patients enrolled underwent response evaluations within 1 week. Patients with cCR were randomly allocated to undergo surgery (arm A) or complete CRT up to the definitive radiation dose (arm B). The primary end point was 3-year disease-free survival (DFS). ResultsFinally, 71 patients were randomly assigned to the nCRT (n = 36) and dCRT (n = 35) arms. The median observation time was 35.7 months. The 3-year DFS rate was 56.43 % in arm A versus 54.73 % in arm B (hazard ratio [HR] = 0.862, 95 % confidence interval [CI] = 0.452 to 1.645, P = 0.652). The 3-year overall survival (OS) rates in arms A and B were 69.5 % and 62.3 % (HR = 0.824, 95 % CI = 403–1.688, P = 0.597), respectively. ConclusionsAccording to our treatment response evaluation criteria, survival of the patients with cCR after nCRT was not significant different between nCRT group and dCRT group. An optimized response evaluation strategy soon after nCRT may guide next therapy decisions for patients with locally advanced ESCC.

Clinical and radiological predictors of organ preservation in patients with rectal cancer treated with total neoadjuvant therapy.

3619 Background: Baseline rectal MRI is routinely used for tumor staging, selecting the initial treatment and prognostication of patients with rectal adenocarcinoma. However, associations of baseline clinical and MRI variables with organ preservation (OP) in a prospective randomized trial have not been reported. Methods: Patients with MRI staged clinical stage II or III rectal adenocarcinoma treated in a prospective phase II clinical trial were randomized to either induction chemotherapy (FOLFOX or CAPEOX) followed by chemoradiation or chemoradiation followed by consolidation chemotherapy (FOLFOX or CAPEOX) and recommended total mesorectal excision (TME) or watch-and-wait (WW) based on clinical response. The primary outcome was OP, defined as the time from randomization to the clinical decision of TME or last follow-up, whichever occurred first. Clinical variables included: age, sex, race, tumor grade, radiation dose and treatment arm. Radiological variables (evaluated by baseline MRI prior to randomization) included: distance from the anal verge, tumor length, clinical T stage, clinical N stage, relationship to the mesorectal fascia, presence of extramural vascular invasion (EMVI) and mucinous radiographic findings (&gt;50%). Associations of OP with clinical and radiological variables were assessed utilizing the Cox regression model in univariate and multivariate settings. The final multivariate model was chosen using backward selection. Results were analyzed by intention to treat. Results: Case report forms (CRFs) from baseline MRI were available for 289 of 324 randomized patients (89%). Patients with CRFs differed from those without CRFs in race, distance of the tumor from the anal verge and clinical T stage. Median follow-up was 3.4 years. A total of 156 of 324 patients were recommended TME during the study period. The 3-year OP rate was 47%. Independent predictors of OP in the multivariate analysis can be seen in the table. Conclusions: Although the patients included in this analysis may not be fully representative of the entire cohort, our data shows that several radiological variables associated with unfavorable tumor biology – tumor involvement of the mesorectal fascia, presence of EMVI and involved mesorectal nodes – were negatively associated with organ preservation. This information will be useful in selecting rectal cancer patients for WW and should be used for patient stratification in future clinical trials. Clinical trial information: NCT02008656. [Table: see text]

Efficient Estimation of the Efficacy and Safety Endpoints for Clinical Trials with Preplanned Dose Titrations

Preplanned dose titrations are sometimes used in clinical trials to improve patient tolerability to treatment. Such titrations often start from a low dose and gradually increase to the targeted dose, and therefore, the low-dose and high-dose arms may share the same dose for a certain period of time. Traditionally, the analysis has been performed according to the treatment arm, ignoring the fact that there are overlapping initial doses between arms. This article describes an alternative method of analysis that exploits the design feature on titrations to produce a more efficient estimation for the mean response over time for each treatment regimen as well as the comparison between treatment regimens for continuous, time-to-event, binary, and count variables. For continuous and count data, we used the (generalized) linear mixed model framework to construct the new estimators; for time-to-event data, we developed a novel logrank test; and for the binary variable, we derived the point and variance estimators based on the events that occurred in each study period. Simulation studies and the application to a real clinical dataset demonstrate the newly proposed approach is advantageous over the traditional approach.

Abstract OT1-11-02: A pragmatic, randomised, multicentre trial evaluating the dose timing (morning vs evening) of endocrine therapy and its effects on tolerability and compliance (REaCT-CHRONO Study)

Abstract Background. Endocrine therapy (ET) is the mainstay treatment for hormonal receptor positive (HR+) breast cancer. ET non-compliance and non-persistence vary from 30 to 70% and are associated with reduced disease-free and overall survival. ET side effects are an important cause of non-adherence. In clinical practice, there are anecdotal reports that time of the day at which ET is taken may affect ET side effects and compliance. However, we are not aware of any high-quality studies supporting this practice. In other fields of medicine, there is evidence to suggest that the time of the day at which medication is taken can alter its effect and/or the adherence. This is known as chronotherapy. Methods. In this pragmatic, open-label, multicenter trial, eligible and consented patients with an early stage or locally advanced HR+ breast cancer will be randomized (1:1) to receive either: an ET morning dose (Arm A: within 1 hour of the patient wake up time) or an ET evening dose (Arm B: within 1 hour of patient bed time). The primary endpoint is endocrine toxicity and tolerability measured by the change in total Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES) score from baseline to 12 weeks following the beginning of ET. Secondary endpoints include: endocrine toxicity/tolerability and quality of life measured respectively by the change in total score and individual items of FACT-ES and FACT-B (a validated Functional Assessment of Cancer Therapy for patients with a Breast cancer) from baseline to 4, 8, 12 and 52 weeks following the beginning of ET, rates of non-persistence or non-compliance and cost-effectiveness. A timing preference questionnaire will be filled out at the beginning and the end of the study by patients to evaluate their preferred time. As per the Rethinking Clinical Trials (REaCT) program, the integrated consent model will be used and patients will complete questionnaires in the online patient portal. For randomization, a permuted block design developed by the Ottawa Methods Centre will be used and patients will be stratified by center, type of endocrine therapy (tamoxifen yes/no) and if prior chemotherapy was received. Using a two-sided, alpha=0.05 Fisher’s exact test, and assuming a 10% of loss to follow up, the planned sample size is 235 patients. Accrual. This study opened for enrollment at The Ottawa Hospital Cancer Centre on June 30, 2021 and will open soon at the Thunder Bay Regional Health Sciences Centre. The maximum accrual period is 2 years. Conclusion. This will be world’s first prospective randomized clinical trial to evaluate ET dose timing (morning versus evening) and its effects on tolerability and adherence. Changing the time of the day at which a medication is taken is a new, simple and easy intervention that does not generate additional costs and can improve the quality of life of breast cancer patients. Funding provided by: NOAMA (Northern Ontario Academic Medicine Association) Innovation Grant (2021) Clinical Trial Registration: NCT04864405 Citation Format: Marie-France Savard, Mohammed Ibrahim, Gregory Pond, Deanna Saunders, Lisa Vandermeer, Ana-Alicia Beltran-Bless, Lesley Fallowfield, Mark Clemons. A pragmatic, randomised, multicentre trial evaluating the dose timing (morning vs evening) of endocrine therapy and its effects on tolerability and compliance (REaCT-CHRONO Study) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-11-02.

Antipsychotic-Induced Weight Gain: Dose-Response Meta-Analysis of Randomized Controlled Trials.

Weight gain is among the most important side-effects of antipsychotics. It is, however, unclear whether it is associated with antipsychotic doses. We aimed to fill this gap with a dose-response meta-analysis. We searched multiple electronic databases (last update search June 2021) for all fixed-dose studies that investigated 16 second-generation antipsychotics and haloperidol in adults with acute exacerbation of schizophrenia or with negative symptoms. We estimated the dose-response curves by conducting random-effects dose-response meta-analyses. We used the restricted cubic spline to model the dose-response relationship. The primary outcome was mean weight gain in kg from baseline to endpoint, the secondary outcome was the number of patients with clinically important weight gain. Ninety-seven studies with 333 dose arms (36 326 participants) provided data for meta-analyses. Most studies were short-term with median duration of 6 weeks (range 4 to 26 weeks). In patients with acute exacerbation, amisulpride, aripiprazole, brexpiprazole, cariprazine, haloperidol, lumateperone, and lurasidone produced mild weight gain in comparison to placebo (mean difference at any dose≤1 kg), while more significant weight gain was observed by all other drugs. For most drugs, dose-response curves showed an initial dose-related increase in weight which plateaued at higher doses, while for others there was no plateau and some even had bell-shaped curves, meaning less weight gain to be associated with higher doses. Second-generation antipsychotics do not only differ in their propensity to produce weight gain, but also in the shapes of their dose-response curves. This information is important for dosing decisions in clinical practice.

Prospective study evaluating dynamic changes of cell-free HPV DNA in locoregional viral-associated oropharyngeal cancer treated with induction chemotherapy and response-adaptive treatment

BackgroundHuman papillomavirus (HPV)-associated oropharyngeal cancer (OPC) has a favorable prognosis which has led to efforts to de-intensify treatment. Response-adaptive de-escalated treatment is promising, however improved biomarkers are needed. Quantitative cell-free HPV-DNA (cfHPV-DNA) in plasma represents an attractive non-invasive biomarker for grading treatment response and post-treatment surveillance. This prospective study evaluates dynamic changes in cfHPV-DNA during induction therapy, definitive (chemo)radiotherapy, and post-treatment surveillance in the context of risk and response-adaptive treatment for HPV + OPC.MethodsPatients with locoregional HPV + OPC are stratified into two cohorts: High risk (HR) (T4, N3, ge 20 pack-year smoking history (PYH), or non-HPV16 subtype); Low risk (LR) (all other patients). All patients receive induction chemotherapy with three cycles of carboplatin and paclitaxel. LR with ≥ 50% response receive treatment on the single-modality arm (minimally-invasive surgery or radiation alone to 50 Gy). HR with ≥ 50% response or LR with ≥ 30% and < 50% response receive treatment on the intermediate de-escalation arm (chemoradiation to 50 Gy with cisplatin). All other patients receive treatment on the regular dose arm with chemoradiation to 70 Gy with concurrent cisplatin. Plasma cfHPV-DNA is assessed during induction, (chemo)radiation, and post-treatment surveillance. The primary endpoint is correlation of quantitative cfHPV-DNA with radiographic response.DiscussionA de-escalation treatment paradigm that reduces toxicity without compromising survival outcomes is urgently needed for HPV + OPC. Response to induction chemotherapy is predictive and prognostic and can select candidates for de-escalated definitive therapy. Assessment of quantitative cfHPV-DNA in the context of response-adaptive treatment of represents a promising reliable and convenient biomarker-driven strategy to guide personalized treatment in HPV + OPC.Trial registrationThis trial is registered with ClinicalTrials.gov on October 1st, 2020 with Identifier: NCT04572100.