Surrogate Markers Of Efficacy Research Articles

#425 Felzartamab (anti-CD38) in patients with IgA Nephropathy—interim results from the IGNAZ study

Abstract Background and Aims Most patients with IgA nephropathy (IgAN) will progress to kidney failure within 10-15 years of diagnosis. Sustained proteinuria is the best predictor of adverse long-term kidney outcomes and is a surrogate marker for efficacy. CD38+ plasma cells are likely the main source of pathogenic Gd-IgA1, and the related autoantibodies in IgAN. Felzartamab (felza; HIB202) is a recombinant purified human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to CD38 on plasma cells and is being studied across immune-mediated kidney diseases such as IgAN, Primary Membranous Nephropathy, Lupus Nephritis, and Antibody Mediated Rejection. The primary aims of the IGNAZ study were to assess: 1) efficacy of felza compared to placebo on urine protein:creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) change from baseline, and 2) the relationship between exposure, safety, and efficacy in each of 3 dose groups vs. placebo. Interim results with 15 months of follow-up from this 24-month trial are presented. Method In Part 1, 48 IgAN subjects were randomized in a 1:1:1:1 ratio across a placebo and 3 active arms in this multicenter, double-blind placebo-controlled, phase IIa trial. The M1, M2, and M3 active arms received 2 doses in 15 days, 5 doses in 2 months, and 9 doses in 5 months, respectively. In Part 2, 6 Japanese subjects received the M3 regimen, open-label, and have been followed for 9 months. Key inclusion criteria included ages 18-80 years, biopsy confirmed diagnosis of IgAN within the past 8 years, proteinuria at screening ≥1.0 g/d, eGFR ≥30 ml/min/1.73 m2 (by CKD-EPI), and background stable and maximally tolerated renin angiotensin system inhibitors. Results 48 randomized subjects were enrolled at 28 sites in the US and in 14 different countries in Europe and in Asia, of which 46 completed the treatment phase. Mean (SD) baseline characteristics (Parts 1 and 2 combined): age 41.6 (12.3) yrs, UPCR 1.67 (1.0) g/g, eGFR 74.6 (30.3) ml/min/1.73 m2. 67% of subjects were male. Intention-to-treat with felza demonstrated rapid, clinically meaningful reductions in UPCR with the maximal treatment effect being observed in the M3 9-dose regimen. In Part 1, percentage change from baseline in UPCR was −14% for placebo and −25% for M3 9-dose arm at month 3, and +9% for placebo and −35% for M3 at month 6 (Fig. A). Reductions in proteinuria observed at month 6 persisted until Month 15, 10 months after the last dose: +6% and −38% mean UPCR change from baseline for placebo and the M3 9-dose arm, respectively (Fig. B). Relatively stable eGFR values were observed for the felza arms compared to loss of eGFR in the placebo arm. Rapid, durable reductions in IgA and Gd-IgA1 levels were seen across the dosing arms, with reductions lasting 10 months after the last dose (Fig. C). IgG recovery occurred faster off-treatment than IgA. Results in the Part 2 subjects were similar to the Part 1 M3 cohort through 9 months. There were no apparent dose-dependent adverse events and no exposure-safety relationship. Treatment-emergent adverse events (TEAEs) were generally of mild or moderate intensity or toxicity grade. The most common TEAE assessed as related by study investigator was infusion related reactions (IRR), most of which occurred on the first infusion. There was one treatment-related serious AE due to an IRR. Five subjects discontinued treatment due to IRRs or drug hypersensitivity; for four of the five subjects, the infusion rate was higher than protocol-specified or had an error in pre-medication. TEAE infections were comparable between placebo and felza arms: Placebo (33.3%), M1 (33.3%), M2 (36.4%), M3 (38.5%), Part 2 (50.0%); all were Grades 1 or 2, and non-serious. Conclusion This proof-of-concept study highlights the potential for disease modification in IgAN with the anti-CD38 mAb felza and supports continued research as a potential treatment for high-risk IgAN patients. Felza treatment resulted in clinically meaningful, prolonged UPCR reductions and eGFR stabilization sustained ≥10 months after dosing was completed. Felza was generally well tolerated with rapid recovery of IgG with durable reductions in IgA and pathogenic Gd-IgA1 levels.

Safety and efficacy of whole-body chlorhexidine gluconate cleansing with or without emollient in hospitalised neonates (NeoCHG): a multicentre, randomised, open-label, factorial pilot trial

Healthcare-associated infections account for substantial neonatal in-hospital mortality. Chlorhexidine gluconate (CHG) whole body skin application could reduce sepsis by lowering bacterial colonisation density, although safety and optimal application regimen is unclear. Emollients, including sunflower oil, may independently improve skin condition, thereby reducing sepsis. We aimed to inform which concentration and frequency of CHG, with or without emollient, would best balance safety and the surrogate marker of efficacy of reduction in bacterial colonisation, to be taken forward in a future pragmatic trial evaluating clinical outcomes of sepsis and mortality. In this multicentre, randomised, open-label, factorial pilot trial, neonates in two hospital sites (South Africa, Bangladesh) aged 1-6 days with gestational age ≥ 28 weeks and birthweight 1000-1999 g were randomly assigned in a factorial design stratified by site to three different concentrations of CHG (0.5%, 1%, and 2%), with or without emollient (sunflower oil) applied on working days vs alternate working days. A control arm received neither product. Caregivers were unblinded although laboratory staff were blinded to randomisation Co-primary outcomes were safety (change in neonatal skin condition score incorporating dryness, erythema, and skin breakdown) and efficacy in reducing bacterial colonisation density (change in total skin bacterial log10CFU from randomisation to day-3 and day-8). The trial is registered at the ISRCTN registry, ISRCTN69836999. Between Apr 12 2021 and Jan 18 2022, 208 infants were randomised and 198 were included in the final analysis. Skin condition scores were low with mean 0.1 (sd=0.3; N=208) at baseline, 0.1 (sd=0.3; N=199) at day 3 and 0.1 (sd=0.3; N=189) at day 8, with no evidence of differences between concentration (1% CHG vs 0.5% estimate=-0.3, 95% CI= (-1.2, 0.6), p=0.55. 2% CHG vs 0.5% CHG estimate=0.5 (-0.4, 1.4), p=0.30), increasing frequency (estimate=-0.4; 95% CI= (-1.1, 0.4), p=0.33), emollient (estimate=-0.5, (-1.2, 0.3), p=0.23) or with control (estimate=-0.9, (-2.3, 0.4), p=0.18). Mean log10CFU was 4.9 (sd=3.0; N=208) at baseline, 6.3 (sd=3.1; N=198) at day 3 and 8.4 (sd=2.6; N=183) with no evidence of differences between concentration (1% CHG vs 0.5% estimate=-0.4; 95% CI= (-1.1, 0.23); p=0.23. 2% CHG vs 0.5% CHG estimate=0.0 (-0.6, 0.6), p=0.96), with increasing frequency (estimate=-0.4; 95% CI= (-0.9, 0.2); p=0.17), with emollient (estimate=0.4, 95% CI= (-0.2, 0.9); p=0.18) or with control (estimate=-0.2, 95% CI= (-1.3, 0.9); p=0.73). By day-8, overall 158/183 (86%) of neonates were colonised with Enterobacterales, and 72/183 (39%) and 69/183 (9%) with Klebsiella spp resistant to third-generation cephalosporin and carbapenems, respectively. There were no CHG-related SAEs, emollient-related SAEs, grade 3 or 4 skin scores or grade 3 or 4 hypothermias. In this pilot trial of CHG with or without sunflower oil, no safety issues were identified, and further trials examining clinical outcomes are warranted. The relatively late start application of emollient, at a mean of 3.8 days of life, may have reduced the impact of the intervention although no subgroup effects were detected. There was no clear evidence in favour of a specific concentration of chlorhexidine, and there was rapid colonisation with Enterobacterales with frequent antimicrobial resistance, regardless of skin application regimen. The MRC Joint Applied Global Health award, the Global Antibiotic Research and Development Partnership (GARDP), MRC Clinical Trials Unit core funding (UKRI) and St. George's, University of London.

Overall Survival Following First and Second Relapse of DLBCL Treated with Therapies Including Autologous Transplant and CAR-T Cells: Results from the Lion Prospective Observational Registry

Background: Diffuse large B cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma (NHL) and is curable with first-line conventional chemotherapy, but a significant fraction of patients relapse or do not respond to initial therapy. There are a variety of treatments available for relapsed/refractory (RR) disease, including platinum-based salvage chemotherapy often used historically both with or without autologous stem cell transplant, and chimeric antigen receptor T-cell (CAR-T) therapy emerging more recently as a second-line option. We report survival data following 2 nd and 3 rd line therapy for RR DLBCL in a large contemporary prospective cohort. Methods: We selected patients (pts) from the Lymphoma Innovations ORIEN Network (LION) with diffuse large B-cell lymphoma, not otherwise specified and high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (“double-hit” lymphoma) who had previously received R-CHOP chemotherapy. All patients had signed written consent. Clinical data were abstracted from medical records using standardized protocol. Overall survival was estimated using Kaplan-Meier and defined as time from start of 2 nd (OS2) or 3 rd (OS3) line treatment until death, censoring patients alive at last follow-up. Comparisons of OS were performed using the log-rank test. Results: A total of 328 patients with RR DLBCL who received 2 nd line treatment were included, 177 of whom went on to receive 3 rd line therapy. Baseline characteristics included male sex in 205 pts (65%), stage III/IV disease in 244 pts (81%), and extranodal involvement in 183 pts (63%). Second line treatments included platinum-based salvage chemotherapy both with (99 pts) and without (88 pts) autologous stem cell transplant, rituximab plus gemcitabine and oxaliplatin (30 pts, grouped distinctly from platinum-based salvage chemotherapy), CAR-T therapy (43 pts), polatuzumab vedotin (17 pts), and other classes of treatment (51 pts). Median OS2 for 2 nd line platinum-based salvage chemotherapy with autologous transplant was 110.4 months compared with 50.4 months for platinum-based salvage chemotherapy without transplant. OS2 for platinum-based salvage chemotherapy with autologous transplant was 96.5% (95% CI 90-99) at 12 months, 90.7% (95% CI 81-96) at 24 months, and 79.3% (95% CI 67-88) at 60 months compared with 77.1% (95% CI 66-85) at 12 months, 65.5% (95% CI 52-76) at 24 months, and 38.1% (95% CI 21-55) for platinum-based salvage without transplant. OS2 for rituximab plus gemcitabine and oxaliplatin was 81.7% (95% CI 58-93) at 12 months, still 81.7% (95% CI 58-93) at 24 months, and 70.1% (95% CI 37-88) at 60 months. OS2 for CAR-T cell therapy was 75% (95% CI 50-89) at 12 months and 62.5% (95% CI 36-80) at 24 months, it could not be calculated at 60 months. OS2 for polatuzumab vedotin was 73.5% (95% CI 36-91) at 12 months and could not be calculated at 24 or 60 months. OS3 for platinum-based salvage chemotherapy with autologous transplant was 100% at 12 months and 83.3% (95% CI 27-98) at 24 months compared with 70.7% (95% CI 34-90) at both 12 and 24 months for platinum-based salvage without transplant. OS3 for rituximab plus gemcitabine and oxaliplatin was 75% (95% CI 13-96) at 12 months and 50% (95% CI 6-85). OS3 for CAR-T therapy was 86.3% (95% CI 75-93) at 12 months, 65.8% (95% CI 50-78) and 46.3% (95% CI 22-68) at 60 months. OS3 for polatuzumab vedotin was 53.4% (95% CI 24-76) at 12 months and 40.1% (95% CI 12-67) at 24 months. Conclusions: We observed a statistically significant difference by log-rank in OS2 in patients receiving platinum-based salvage chemotherapy followed by autologous stem cell transplant compared to other therapies in a contemporary cohort of pts with RR DLBCL. This difference is likely driven in part by transplant being a surrogate marker for efficacy of salvage chemotherapy. OS3 was also highest at 12, 24, and 60 months in patients receiving platinum-based salvage chemotherapy followed by transplant. Other therapies including CAR-T cells, polatuzumab vedotin, and rituximab plus gemcitabine and oxaliplatin did not demonstrate significantly different rates of overall survival in the 2 nd or 3 rd line setting.

Immune checkpoint inhibitor treatment of brain metastasis associated with a less invasive growth pattern, higher T-cell infiltration and raised tumor ADC on diffusion weighted MRI

BackgroundBrain metastases are the most common intracranial tumors with an increasing incidence. They are an important cause of morbidity and mortality in patients with solid organ cancer and a focus of recent clinical research and experimental interest. Immune checkpoint inhibitors are being increasingly used to treat solid organ cancers.MethodsTo determine whether immune checkpoint inhibitors were biologically effective in the brain, we compared melanoma brain metastasis samples where treatment with ipilimumab had occurred preoperatively to those who had not received any immune modulating therapy and looked for histopathological (invasion, vascularity, metastasis inducing proteins, matrix metalloproteinases, immune cell infiltration, tissue architecture) and advanced MRI differences (diffusion weighted imaging).ResultsCo-localized tissue samples from the same regions as MRI regions of interest showed significantly lower vascularity (density of CD34 + vessels) in the core and higher T-cell infiltration (CD3 + cells) in the leading edge for ipilimumab-treated brain metastasis samples than for untreated cases and this correlated with a higher tumor ADC signal at post-treatment/preoperative MRI brain.ConclusionsTreatment of a melanoma brain metastasis with ipilimumab appears to cause measurable biological changes in the tumor that can be correlated with post-treatment diffusion weighted MRI imaging, suggesting both a mechanism of action and a possible surrogate marker of efficacy.

Efficacy of rFIXFc versus N9-GP Prophylaxis in Patients with Hemophilia B: Matching-Adjusted Indirect Comparison of B-LONG and PARADIGM 2 Trials.

For patients with hemophilia B, extended half-life factor IX (FIX) products are available for prophylaxis and for treating bleeds. Different methods are used to extend the half-lives of recombinant FIX Fc fusion protein (rFIXFc) and nonacog beta pegol (N9-GP). This affects their biodistribution and plasma FIX levels, although differences do not always correlate with clinical outcomes. A matching-adjusted indirect comparison (MAIC) of prophylaxis with rFIXFc and N9-GP was performed, based on licensed dosing in the European Union. Combined rFIXFc data from the weekly and individualized interval prophylaxis arms of the B-LONG clinical trial, and N9-GP data from the 40 IU/kg once-weekly prophylaxis arm of PARADIGM 2 were used in a MAIC. Individual patient data for rFIXFc (n=87) were matched to aggregated data for N9-GP (n=29). Estimated annualized bleeding rates (ABRs) for rFIXFc were recalculated using a Poisson regression model with adjustment for over-dispersion, and compared with ABRs reported for N9-GP, using incidence rate ratios (IRRs) with 95% confidence interval (CI). There was no evidence of significant differences in estimated ABRs between prophylaxis with rFIXFc and N9-GP. Analysis of pooled rFIXFc weekly and interval-adjusted dosing compared with N9-GP 40 IU/kg once weekly produced estimated ABRs of 2.59 versus 2.51 (IRR 1.03; 95% CI 0.56-1.89), as well as 1.34 versus 1.22 (IRR 1.10; 95% CI 0.42-2.91) and 1.13 versus 1.29 (IRR 0.88; 95% CI 0.47-1.63) for overall, spontaneous, and traumatic bleeding events, respectively. The study did not reveal any significant differences in the efficacy of rFIXFc and N9-GP prophylaxis. Given differences in trough levels (rFIXFc dosing was targeted to achieve a trough 1-3 IU/dL above baseline versus a reported estimated N9-GP mean trough of 27.3 IU/dL), interpreting plasma FIX levels as potential surrogate efficacy markers requires consideration of compound-specific pharmacokinetic profiles.

Health‐economic innovation headroom in mild cognitive impairment due to Alzheimer’s diseas

AbstractBackgroundEstimating health‐economic impact of new therapies for prodromal Alzheimer’s disease (AD) requires extrapolating short‐term effects on surrogate markers of efficacy to long‐term clinically relevant outcomes. This requires assumptions on the nature of the treatment (symptomatic versus disease‐modifying) and depends on the target population (which varies in disease progression associated to biological subtypes). We aim to estimate the innovation headroom (potential value) of AD treatment in mild cognitive impairment (MCI), describe the impact of assumptions on treatment nature (symptomatic/disease‐modifying) and disease progression (fast/slow progressors), and discuss challenges for health‐economic evaluation of future AD treatments; to ensure patients timely access treatment innovations.MethodThe IPECAD open‐source decision‐analytic model was used to estimating time spent with MCI, mild, moderate and severe dementia, discounted quality‐adjusted life years (QALYs) and costs, under different treatment strategies. Innovation headroom was estimated by simulating a usual care strategy, and compare it with a strategy reflecting a fictive disease‐modifying treatment with 100% efficacy, and a strategy reflecting a fictive 100% efficacious symptomatic therapy; in preventing all individuals to progress to dementia.ResultThe innovation headroom analysis resulted in 4.1 additional QALYs and k€13 lower costs of care with disease‐modifying, and 0.8 additional QALYs and k€71 lower costs of care with symptomatic therapy. The higher QALY gain for disease‐modification is mainly explained by an indirect effect on mortality, resulting in a 5.5 year increase in life expectancy. The innovation headroom was about twice as large in the persons with fast progression compared to persons with slow progression in MCI. The disease‐modifying therapy mainly generated improved health (QALY gains), while the symptomatic therapy mainly generated savings in costs of care; which is contingent on their mortality assumptions.ConclusionThe potential health and economic benefit of (non‐)pharmacological interventions in MCI is substantial. However, its dependency on assumptions related to treatment nature argues for research efforts to better understand the relation between surrogate and long‐term outcomes. Its dependency on target population indicates a potential for individualized treatment based on profiles of disease progression. Finally, we recommend incorporating age‐related comorbidities as a result of the relatively large life years gained.

Prevention of Skeletal-Related Events With Extended-Interval Denosumab: A Review of the Literature.

To review published clinical trial data related to efficacy and safety of administering denosumab at extended dosing intervals for prevention of skeletal-related events (SREs) in cancer patients. A literature search of PubMed was performed (January 2006 to February 2023) using the following search terms: denosumab, bone metastasis, bone lesions, and lytic lesions. Abstracts from conferences, article bibliographies, and product monographs were also reviewed. Relevant English-language studies were considered. Early phase II denosumab trials included treatment arms that utilized extended-interval denosumab, and various retrospective reviews, meta-analyses, and prospective trials have included extended-interval regimens. Most recently, the ongoing randomized REDUSE trial is comparing the efficacy and safety of extended-interval denosumab to standard dosing. At this time, the best available data are restricted to small, randomized trials not designed to compare efficacy and safety of extended-interval denosumab to conventional dosing and did not use consistent endpoints. Furthermore, primary endpoints of available trials largely consisted of surrogate markers of efficacy that may not be reflective of clinical outcomes. Historically, denosumab has been dosed at 4-week intervals for prevention of SREs. If efficacy is maintained, extending the dosing interval could potentially reduce toxicity, drug cost, and clinic visits compared to every 4-week dosing. At this time, data demonstrating efficacy and safety of extended-interval denosumab remain limited, and the results of the REDUSE trial are eagerly anticipated to help answer remaining questions.

Trends and Predictors of Peripheral CD19+ B-cell Repopulation in Patients Treated with Ocrelizumab during COVID-19 Pandemic (P7-3.014)

<h3>Objective:</h3> To assess the predictors of B-cell repopulation in patients treated with ocrelizumab during COVID-19 pandemic. <h3>Background:</h3> Ocrelizumab (OCR) is used for multiple sclerosis (MS) administered every 6 months (SID). Peripheral CD19+ lymphocyte (CD19L) count is a surrogate marker of efficacy of OCR. B-cell repopulation (≥1% CD19L of total lymphocytes) is a potential biomarker to guide OCR extended interval dosing (EID) beyond 6 months. During COVID-19 pandemic, adjusted OCR treatment-cycle based on CD19L repopulation has been a strategy to minimize the risk of prolonged B-cell depletion associated higher potential complications of COVID. We studied the predictors of B-cell repopulation in patients treated with OCR. <h3>Design/Methods:</h3> Retrospective study of patients receiving OCR between 2020–2022 in whom CD19L counts were available &lt;30 days prior to next infusion. Data collected included age, gender, race, body mass index (BMI), MS subtype, prior immunosuppressive therapy, time-to-repopulation. Multiple linear regression was used to look for predictors of B-cell repopulation. <h3>Results:</h3> Total 248 patients (mean age 48±12.8 years; 172 female, 76 male) studied. Forty-five percent (111 patients) had CD19L repopulation, fifty-five percent (137 patients) had persistently low (&lt;1%) counts. Mean number of infusion cycles prior to CD19L repopulation was significantly longer in extended interval group (4.36±2.16 days vs. 2.33±2.04; p&lt;0.05). BMI and inter-infusion interval were predictors of repopulation (p&lt;0.001); age, race, gender, disease type, prior immunosuppressive therapy did not predict repopulation. All patients remained clinically stable. <h3>Conclusions:</h3> In this observational study of MS patients treated with OCR with standard or extended interval dosing, BMI and inter-infusion dosing interval were the only predictors of B-cell repopulation. The number of infusions prior to repopulation was higher in the extended dosing group. In the future, these data can be used to provide guidance on extending OCR dosing interval. <b>Disclosure:</b> Dr. Padron has nothing to disclose. Ms. Jimsheleishvili has nothing to disclose. Dr. Tornes has nothing to disclose. Dr. Delgado has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. The institution of Dr. Delgado has received research support from Novartis. The institution of Dr. Delgado has received research support from EMD Serono. The institution of Dr. Delgado has received research support from NIH/NINDS. Dr. Garg has nothing to disclose.

Impact of Maximal Transurethral Resection on Pathological Outcomes at Cystectomy in a Large, Multi-institutional Cohort.

While the presence of residual disease at the time of radical cystectomy for bladder cancer is an established prognostic indicator, controversy remains regarding the importance of maximal transurethral resection prior to neoadjuvant chemotherapy. We characterized the influence of maximal transurethral resection on pathological and survival outcomes using a large, multi-institutional cohort. We identified 785 patients from a multi-institutional cohort undergoing radical cystectomy for muscle-invasive bladder cancer after neoadjuvant chemotherapy. We employed bivariate comparisons and stratified multivariable models to quantify the effect of maximal transurethral resection on pathological findings at cystectomy and survival. Of 785 patients, 579 (74%) underwent maximal transurethral resection. Incomplete transurethral resection was more frequent in patients with more advanced clinical tumor (cT) and nodal (cN) stage (P < .001 and P < .01, respectively), with more advanced ypT stage at cystectomy and higher rates of positive surgical margins (P < .01 and P < .05, respectively). In multivariable models, maximal transurethral resection was associated with downstaging at cystectomy (adjusted odds ratio 1.6, 95% CI 1.1-2.5). In Cox proportional hazards analysis, maximal transurethral resection was not associated with overall survival (adjusted HR 0.8, 95% CI 0.6-1.1). In patients undergoing transurethral resection for muscle-invasive bladder cancer prior to neoadjuvant chemotherapy, maximal resection may improve pathological response at cystectomy. However, the ultimate effects on long-term survival and oncologic outcomes warrant further investigation.

Biosimilars: Fundamentals and authorization as per U.S. perspective

Biosimilars are biological products that are the replicas of their innovator biopharmaceuticals. At the moment, biological products account for 10 -15% of the total pharmaceutical market. More than one-fifth of new medicines launched on the world market each year are now biotechnology derived. These are developed after patent expiration of innovator biopharmaceuticals and are submitted for separate marketing approval. In view of the structural and manufacturing complexities of biopharmaceuticals, biosimilars should not be considered as biological generics. Each class of biologic varies in its benefit and risk profile, the nature and frequency of adverse events, the breadth of clinical indications and whether surrogate markers for efficacy are available and validated. But most of the countries do not have specific guidelines for potential market of biological products. Following the legislation that allowed the FDA to approve biosimilars in the United States, biological products that are similar to the reference product in terms of safety, purity and potency are gradually entering into the market. To date, only five biosimilars have been approved in the U. S. although many agents are currently undergoing trials and may soon become available. This article will address the differences between biosimilars and generics, issues concern with the approval process, use of biosimilars and need.

Predictors of Survival after Vaccination in a Pneumonic Plague Model.

Background: The need for an updated plague vaccine is highlighted by outbreaks in endemic regions together with the pandemic potential of this disease. There is no easily available, approved vaccine. Methods: Here we have used a murine model of pneumonic plague to examine the factors that maximise immunogenicity and contribute to survival following vaccination. We varied vaccine type, as either a genetic fusion of the F1 and V protein antigens or a mixture of these two recombinant antigens, as well as antigen dose-level and formulation in order to correlate immune response to survival. Results: Whilst there was interaction between each of the variables of vaccine type, dose level and formulation and these all contributed to survival, vaccine formulation in protein-coated microcrystals (PCMCs) was the key contributor in inducing antibody titres. From these data, we propose a cut-off in total serum antibody titre to the F1 and V proteins of 100 µg/mL and 200 µg/mL, respectively. At these thresholds, survival is predicted in this murine pneumonic model to be >90%. Within the total titre of antibody to the V antigen, the neutralising antibody component correlated with dose level and was enhanced when the V antigen in free form was formulated in PCMCs. Antibody titre to F1 was limited by fusion to V, but this was compensated for by PCMC formulation. Conclusions: These data will enable clinical assessment of this and other candidate plague vaccines that utilise the same vaccine antigens by identifying a target antibody titre from murine models, which will guide the evaluation of clinical titres as serological surrogate markers of efficacy.

Lessons Learned from Phase II and Phase III Trials Investigating Therapeutic Agents for Cerebral Ischemia Associated with Aneurysmal Subarachnoid Hemorrhage.

One of the challenges in bringing new therapeutic agents (since nimodipine) in for the treatment of cerebral ischemia associated with aneurysmal subarachnoid hemorrhage (aSAH) is the incongruence in therapeutic benefit observed between phase II and subsequent phase III clinical trials. Therefore, identifying areas for improvement in the methodology and interpretation of results is necessary to increase the value of phase II trials. We performed a systematic review of phase II trials that continued into phase III trials, evaluating a therapeutic agent for the treatment of cerebral ischemia associated with aSAH. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for systematic reviews, and review was based on a peer-reviewed protocol (International Prospective Register of Systematic Reviews no. 222965). A total of nine phase III trials involving 7,088 patients were performed based on eight phase II trials involving 1558 patients. The following therapeutic agents were evaluated in the selected phase II and phase III trials: intravenous tirilazad, intravenous nicardipine, intravenous clazosentan, intravenous magnesium, oral statins, and intraventricular nimodipine. Shortcomings in several design elements of the phase II aSAH trials were identified that may explain the incongruence between phase II and phase III trial results. We suggest the consideration of the following strategies to improve phase II design: increased focus on the selection of surrogate markers of efficacy, selection of the optimal dose and timing of intervention, adjustment for exaggerated estimate of treatment effect in sample size calculations, use of prespecified go/no-go criteria using futility design, use of multicenter design, enrichment of the study population, use of concurrent control or placebo group, and use of innovative trial designs such as seamless phase II to III design. Modifying the design of phase II trials on the basis of lessons learned from previous phase II and phase III trial combinations is necessary to plan more effective phase III trials.

AML-310: Prognostic Value of CRh in Acute Myeloid Leukemia Treated with Venetoclax and Decitabine

Introduction: Recent FDA approvals of novel therapies and hypomethylating agents/venetoclax (HMA-ven) has transformed AML therapy. CR with partial hematological recovery (CRh), defined as bone marrow blasts 0.5×109/L, and platelet count >50×109/L, was used as a surrogate marker for efficacy due to limited data on HMA-ven. We evaluated the impact of CRh on pts treated with 10-day decitabine and venetoclax (DEC10-VEN, NCT03404193). Method: Patients with newly diagnosed AML aged >60 years or patients with secondary AML and antecedent hematological disorder were included. Decitabine 20 mg/m2 IV for 10 days with oral venetoclax 400 mg daily was administered for induction and decitabine (5 days) with daily venetoclax for consolidation. Responses initially recorded were complete response (CR), CR with incomplete hematologic recovery (CRi), and morphologically leukemia-free state (MLFS), according to ELN 2017 criteria. Pts who achieved CRi and MLFS were re-classified to CRh. Outcomes evaluated were overall survival (OS) and event-free survival (EFS). Full protocol and interim results have been published (DiNardo et al. Lancet Haematol. 2020;7:e724–36) Results: From January 2018 to February 2021, 125 patients (79 [63%] newly diagnosed, 46 [37%] secondary AML) with a median age of 71 yrs (range 48–89) were included. 69 (55%) pts achieved CR, 11 (8%) pts achieved CRh, 14 (11%) pts achieved CRi, 10 (8%) pts achieved MLFS, and 21 (17%) pts were refractory. Of the 11 CRh pts, 8 (73%) patients were previously classified as CRi and 3 (27%) as MLFS. Among pts achieving CR, the median OS was 24.5 mo, and median EFS was 18.0 mo. CRh was achieved with a median of 1 (range 1–3) cycles. Median OS of CRh vs CRi was 16.9 vs 5.8 mo (HR: 0.47, 95% CI: 0.19–1.13, p=.06), and CRh vs MLFS was 16.9 vs 6.2 mo (HR: 0.34, 95% CI: 0.13–0.93, p=.007). Median EFS of pts with CRh vs CRi was 14.1 vs 5.8 mo (HR: 0.49, 95%CI: 0.21–1.14, p=.08); CRh vs MLFS was 14.1 vs 6.2 mo (HR: 0.37, 95% CI: 0.14–1.01, p=.016). Pts achieving CRh had durable remission with a duration of response of 6.0 vs 2.5 mo with CRi and 1 mo with MLFS. Conclusion: In pts with newly diagnosed and secondary AML treated with DEC10-VEN, pts achieving CRh had a trend toward improved OS and EFS compared with CRi or MLFS.

PK/PD Analysis of Marbofloxacin by Monte Carlo Simulation against Mycoplasmaagalactiae in Plasma and Milk of Lactating Goats after IV, SC and SC-Long Acting Formulations Administration.

Simple SummaryIn some countries like Spain and France, contagious agalactia (CA) is a highly relevant issue. CA is a mycoplasmosis affecting small ruminants and it is associated with a relevant economic impact on dairy. The poor efficacy of vaccines and their inability to prevent disease transmission is conducive to the use of antibiotics to control CA. However, only a few groups of antimicrobial agents are effective against these species, and selecting an adequate antimicrobial agent following the categorization of antibiotics made by the different international organisms (European Medicine Agency, World Health Organization) in veterinary medicine becomes a difficult task. The PK/PD approach is a useful tool to guide veterinarians on the appropriate targets through a rational selection of the best dose regimen of antimicrobial agents. In this study, marbofloxacin pharmacokinetics was studied after three routes of administration with two long-acting formulations. The minimum inhibitory concentrations (MIC) values of Mycoplasma agalactia isolated from goats affected by CA in Spain were calculated. The results show that systemic exposure achieved in lactating goats following these formulations provides rate of drug release that could be adequate to maintain effective plasma concentrations against M. agalactiae. The PK/PD analysis by Monte Carlo simulation showed that a dosage regimen from 8.47 to 11.57 mg/kg every 24 h could effectively treat goats affected by CA.Contagious agalactia is a mycoplasmosis affecting small ruminants that have become an important issue in many countries. However, PK/PD studies of antibiotics to treat this problem in lactating goats affected by Mycoplasma (M.) agalactiae, the main CA-causing mycoplasma are almost non-existent. The aims of this study were to evaluate the plasma and milk disposition of marbofloxacin in lactating goats after intravenous (IV), subcutaneous (SC) and subcutaneous poloxamer P407 formulations with and without carboxy-methylcellulose (SC-P407-CMC and SC-P407) administration. Marbofloxacin concentrations were analysed by the High Performance Liquid Chromatography (HPLC) method. Minimum inhibitory concentrations (MIC) of M. agalactiae field isolates from mastitic goat’s milk were used to calculate surrogate markers of efficacy. Terminal half-lives of marbofloxacin after IV, SC, SC-P407 and SC-P407-CMC administration were 7.12, 6.57, 13.92 and 12.19 h in plasma, and the half-lives of elimination of marbofloxacin in milk were 7.22, 7.16, 9.30 and 7.74 h after IV, SC, SC-P407 and SC-P407-CMC administration, respectively. Marbofloxacin penetration from the blood into the milk was extensive, with Area Under the Curve (AUCmilk/AUCplasma) ratios ranged 1.04–1.23, and maximum concentrations (Cmax-milk/Cmax-plasma) ratios ranged 0.72–1.20. The PK/PD surrogate markers of efficacy fAUC24/MIC and the Monte Carlo simulation show that marbofloxacin ratio (fAUC24/MIC > 125) using a 90% of target attainment rate (TAR) need a dose regimen between 8.4 mg/kg (SC) and 11.57 mg/kg (P407CMC) and should be adequate to treat contagious agalactia in lactating goats.

Induction with ATG in DCD kidney transplantation; efficacy and relation of dose and cell markers on delayed graft function and renal function

AimWe aimed to analyse the efficacy of the Thymoglobulin dose used for induction in controlled DCD kidneys, and its initial impact on blood cell and CD3 count, as predictors of efficacy. Methods140 DCD patients who received ATG induction, were analysed. Intended dose was 1.25 mg/kg/day over 5 days, rounded to nearest 25 mg and not exceeding 125 mg/dose. Outcomes included the total dose in relation with rejection, DGF, graft survival, eGFR. The cell count response to ATG was assessed as predictors of outcome. ResultsGraft survival, was 96.2%, 92.4%, 85% at 1, 3 and 5 years. Rejection was 7% at 1 year and associated with eGFR at 3 (p = 0.003) and 5 years. ATG dose was not predictive of rejection but was associated with the day5 leucocyte and lymphocyte count (p < 0.001) and negatively with DGF (p = 0.05). In 31 patients day3 CD3 count was available and it was associated with rejection (p = 0.002), less DGF (p = 0.09), and 3 years eGFR (p = 0.01). ConclusionThymoglobulin provides excellent results in DCD kidneys that do not significantly differ with small dose variations. In higher doses it reduces DGF. Lymphocytes and CD3 count, may be useful surrogate markers of efficacy and outcome.

New ‘ase’ in the hole for treatment of acute ischemic stroke

New ‘ase’ in the hole for treatment of acute ischemic stroke

Efficacy and tolerability of metronomic chemotherapy in patients with metastatic breast cancer – an international experience in West Sweden and in the South of Ireland.

IntroductionMetronomic chemotherapy (MCT) is the continuous administration of low dose chemotherapy. It has significant clinical efficacy with minimal toxicity as compared to conventional chemotherapy regimens. Thus represents an attractive treatment modality in selected patients with advanced breast cancer. MethodsPatients who received MCT in the form of Capecitabine/Cyclophosphamide for the treatment of advanced breast cancer between May 2014 and October 2018 in Sahlgrenska University Hospital in Sweden and in Cork University Hospital, University Hospital Kerry and the South Infirmary-Victoria University Hospital in Ireland were identified. Medical records were retrospectively reviewed to collect data. All survival analyses were described by Kaplan-Meier curves and analysed with log-rank tests. The primary end-point was time on treatment, used as a surrogate marker for efficacy. Results148 patients were identified (84 – Sweden, 64 – Ireland), with a median age of64.2 (range 31–89). The overall mean time on treatment for all patients in both countries is 9.05 months (range 0.36 – 67.21). In patients with bone only disease the mean time on treatment was 10.1 months (range 0.7 – 67.2), compared to patients with visceral disease of 8.91 months (range 0.36 – 39.77). Treatment was ended in the majority of patients because of progression of disease, representing 108 patients (72.9%). ConclusionThis is an observational, retrospective study demonstrating the real world effectiveness of MCT in the treatment of advanced breast cancer. In this cohort of unselected pre-treated patients, the efficacy of MCT was comparable with the survival outcomes of landmark clinical trials.

237P - PARP inhibitor in platinum resistant ovarian cancer: Single center real world experience

BackgroundThere is paucity of data of role of PARP inhibitors (PARPi) in BRCA mutation (gBRCAm) positive platinum resistant ovarian cancer (OC) disease. We report here analysis of outcome of PARPi treatment in patients including those with platinum resistant disease. MethodsIn this study, we analyzed efficacy of PARPi in all consecutive patients of OC with gBRCAm who received the drug. The drug was procured through compassionate program. ResultsBetween July 1, 2015 and June 30, 2019, 28 patients received PARPi. At the time of data censoring (June 30, 2019), 6 (21.4%) patients are still on treatment. 5 patient received Talazoparib and 23 Olaparib. Median age is 54.5 years (range 39-75). BRCAm 1 positive patients were 20. Median number of previous lines of chemotherapy received were 3 (range 1-6). 7 platinum sensitive patients received the drug as maintenance (3 in complete response [CR] and 4 in partial response [PR]) while 21 had platinum resistant progressive disease. Overall response rate (ORR) was 82% with CR as the best response in 5 which also includes 3 patients who received the drug while in CR and maintained it. With the median treatment duration (mTD) of 14.14 months (95%CI 8.43-23.33), 71.4 % patients eventually progressed. The median follow up was 15.3 months (range 4- 42.6 months). The median overall survival (OS) was 32.9 months (95% CI 13.03 NR) The below table describes results of 21 platinum resistant patients. With the mTD of 10.4 months (95%CI 8.17 23.33), 86 % patients had progressed. Three (14%) platinum resistant patients are still on treatment with the treatment duration (TD) of 5.47, 32.9 and 37 months.Table237PUnlabelled ImageResponseN (%)ORR16 (76)CR1 (4.7)PR15 (71.4)PD5 (24)Median OS in months (95% CI)28.8 (9.6 NR)Progression free survival was not calculated as disease assessment was not done at defined time point. The TD was taken as the surrogate marker for efficacy. Grade ≥3 side effects were documented in 33% patients (anemia 23.5%, thrombocytopenia 17.6%, fatigue 25%). ConclusionsThis study suggests that PARPi is a viable treatment option in patients of platinum resistant OC with gBRCAm. This should be further evaluated in randomized clinical controlled trial. Legal entity responsible for the studyAmit Agarwal. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Abstract 1357: Serum levels of programmed cell death molecule-1 (PD-1) as a biomarker in metastatic melanoma patients randomized for treatment with autologous dendritic cell or tumor cell vaccines

Abstract The purpose of this study was to analyze PD-1 serum levels, in patients with metastatic melanoma who were enrolled in a randomized phase 2 trial, to determine: [1] if baseline PD-1 serum levels were prognostic for overall survival (OS), [2] if baseline PD-1 levels were predictive for survival benefit in the specific treatment arms, [3] if PD-1 levels changed between week-0 and week-4 by treatment, and [4] if changes in PD-1 levels were predictive of survival benefit overall and by treatment. Patients with metastatic melanoma were enrolled in a randomized phase 2 clinical trial comparing treatment with autologous dendritic cell vaccines (DCV) presenting autologous tumor antigens (ATA) derived from irradiated cancer cells from short-term autologous cell lines, compared to tumor cell vaccines (TCV) consisting of irradiated tumor cells [Dillman et al. J ImmunoTher Cancer 2018]. Vaccines were injected s.c. weekly for three weeks, then at weeks 8, 12, 16, 20, and 24. OS was longer for patients treated with DCV (median 43 vs 20 months; 70% reduction in risk of death). Cryopreserved serum samples from week-0 and week-4 for 39/42 patients were analyzed using a quantitative, multiplex enzyme-linked immunosorbent assay (Raybiotech, Inc., Norcross, GA). The patients for whom PD-1 levels were missing were two TCV-treated subjects who had rapidly progressive disease and had no week-4 samples, and one DCV-treated subject who survived more than 5-years, but rescinded permission to test his blood. Baseline serum PD-1 levels ranged from 0 to 511 ng/ml. After three weekly vaccinations, median serum levels of PD-1 did not change between week-0 and week-4 (1.51 and 1.58 ng/ml), nor did mean serum levels change (52.5 and 52.6 ng/ml). For all 39 patients, baseline PD1 levels were not prognostic for OS. DCV was associated with longer OS than TCV both in patients whose baseline PD1 was &amp;lt;1.2 ng/ml and &amp;gt; 1.2 ng/ml. Among DCV-treated subjects, baseline levels &amp;lt;50 ng/ml were associated with OS &amp;gt; 3.5 years in 9/13 compared to 0/4 for those with levels &amp;gt; 50 ng/ml (p=0.029), but there was no difference in the TCV arm (5/19 vs 1/3, p=1.00). Overall, PD1 levels decreased after 3 DCV injections, but increased after 3 TCV injections. DCV-treated subjects who had a decrease in PD-1 were more likely to survive 4 years (6/9 vs 1/8, p=0.05) but this difference was not seen in patients treated with TCV (0/6 vs 6/16, p=0.289). CONCLUSONS: In these metastatic melanoma patients, baseline serum PD1 levels were not prognostic for survival, but were predictive of survival benefit in patients treated with DCV, as was a decrease in PD1 level after 3 weekly DCV vaccinations. PD1 levels should be prospectively evaluated in larger studies to see if they may be useful as a companion diagnostic and/or surrogate marker for efficacy. Citation Format: Robert O. Dillman, Gabriel I. Nistor, Aleksandra J. Poole, Andrew N. Cornforth. Serum levels of programmed cell death molecule-1 (PD-1) as a biomarker in metastatic melanoma patients randomized for treatment with autologous dendritic cell or tumor cell vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1357.

Single-centre retrospective observational study comparing trough blood concentration and safety of teicoplanin formulations

Teicoplanin formulations are marketed as antibiotic mixtures with several compounds that share the same core structure. Recent studies conducted in vitro have reported differences in the composition ratio of different teicoplanin products. In this retrospective study, we examined the trough blood concentration of the originator brand and a generic teicoplanin product. Target patients were retrospectively assigned to the originator (Targocid) or generic group. The groups were matched 1:1 using propensity scores. The initial trough blood concentration analysis identified 44 matches. In both groups, the median dosing day for the first measurements was 4, respectively. The initial trough blood concentration of the originator group was significantly higher (mean ± SD, 16.3 ± 4.5 mg/L) than that of the generic group (12.8 ± 4.7 mg/L; 95% CI, −5.4 to −1.6). A significant difference was observed in the frequency of serum creatinine elevation in the study of the frequency of adverse events using Common Terminology Criteria for Adverse Events (originator group, 41.9% vs generic group, 20.9%). In cases where discontinuation was necessary due to side effects, there were three patients in the originator group and one patient in the generic group. This study found that trough blood concentration differed between formulations. Therefore, correction might be necessary while monitoring drug concentration in the blood. Trough blood concentrations are used as surrogate markers for efficacy and safety, so further studies on differences in efficacy and safety between formulations are required.