Time Of Interim Analysis Research Articles

161. Prospective Study of Cytomegalovirus (CMV) Reactivation in Patients with Multiple Myeloma Receiving anti-CD38 and BCMA Therapies: An Interim Data Analysis

Abstract Background The landscape of multiple myeloma (MM) treatment has shifted over the past decade, leading to increased cumulative immunosuppression as patients live longer and receive treatment for multiple relapses. Newer MM therapies, including anti-CD38 and BCMA directed agents, impact cell-mediated immunity. We hypothesized that patients receiving such therapies are at risk of CMV infection and we launched a prospective pilot study to assess CMV incidence in this population.Table 1:Characteristics of CMV reactivation among patients with multiple myeloma Methods Eligible patients included seropositive adults with MM undergoing treatment with anti-CD38 or anti-BCMA therapies. Plasma CMV PCR was monitored every 14 days (+/- 7 days) for three months (Cobas 6800 System, limit of quantification 34.5 IU/mL). The primary endpoint was CMV viral load >500 IU/mL. Treating providers were blinded to results unless CMV PCR was sent outside of the study for clinical reasons.Figure 1:Proportion with CMV > 500 IU/mL during follow-up period Results Twenty-two patients had data available at the time of interim analysis. Eleven (50%) patients received anti-CD38 containing regimens (10 daratumumab, 1 isatuximab), 5 (23%) received anti-BCMA bispecific antibody, and 6 (27%) received BCMA-targeted CAR-T. Eight (36%) patients had newly diagnosed MM and 14 (64%) had relapsed disease. Among relapsed patients, median prior lines of chemotherapy was 4 (range 1-13). Nine (41%) patients had prior autologous stem cell transplant. Fourteen (64%) patients had detectable CMV DNA, but CMV viral load remained < 34.5 IU/mL in the majority (8/14, 57%). Only three (13.6%) patients had CMV viral load >500 IU/mL, including one asymptomatic CAR-T cell recipient who received valganciclovir. Median duration of DNA-emia was 2 weeks (range 1-15). There was a trend toward more DNA-emia in subjects with newly diagnosed compared to relapsed MM (88% vs 29%, HR 2.58 [95% CI 0.86-7.79], p=0.0758). Previous history of CMV infection was also associated with CMV reactivation during the study (HR 5.54 [95% CI 1.36 - 22.48], p=0.0063). There were no patients with end-organ CMV disease and no mortality during the study.Figure 2:Proportion with any CMV DNA detection during follow-up period Conclusion Low-level CMV reactivation occurs frequently in patients with MM receiving anti-CD38 and BCMA therapies, but clinically significant CMV infection remains uncommon. Future studies should also evaluate the impact of subclinical CMV DNA-emia on oncologic outcomes.Figure 3:Proportion with any CMV DNA detection, stratified by prior MM treatment Disclosures Emily Baneman, MD, Merck: Grant/Research Support Samantha E. Jacobs, MD, MS, Ansun Biopharma: Advisor/Consultant|Eurofins, Viracor, LLC.: Grant/Research Support

Implementation and preliminary efficacy of a risk stratification system +/- patient-reported outcomes monitoring for patients with hospital-diagnosed advanced lung cancer.

11095 Background: Risk stratification systems may improve quality of care for patients with advanced lung cancer (ALC) by identifying those at high risk of rehospitalization and directing them to supportive care. The purpose of this study was to evaluate the implementation and preliminary efficacy of a risk-based system, with/without electronic patient-reported outcome (ePRO) symptom monitoring, to trigger supportive care for patients with hospital-diagnosed ALC. Methods: In this single-site, non-randomized, pragmatic study, patients in an academic center with hospital-diagnosed ALC were stratified to low or high risk using an established tool. High-risk patients were referred to two-pronged supportive care: patient navigation and outpatient palliative care. Eligible patients were recruited for 3 months of ePRO symptom monitoring coupled with provider alerts. Healthcare utilization was assessed at 90 days post-discharge. Program feasibility and acceptability were assessed using percent of eligible supportive care referrals made and completed, enrollment rates in ePROs, ePRO completion, and notifications to providers of concerning symptoms. Preliminary efficacy was defined as percentage of concerning ePRO symptoms resulting in new clinical action and 90-day readmissions. Results: At the time of interim analysis, 49 patients had been assessed with 48/49 (98%) identified as high risk. Patients had a mean age of 66 years, and were non-Hispanic, 51% male, and 22% Black. Patient navigation referral (92%) and completion (88%) was high. Palliative care referral (89%) and completion (45%) was lower. 14/39 (36%) of eligible patients enrolled in ePRO symptom monitoring, with competing priorities or feeling overwhelmed as the primary reasons for non-participation. Patient-level ePRO completion ranged from 0-100% (mean 53%). Nearly all (97%) concerning symptoms were reported to the clinical team; 27% of these resulted in new clinical action. By 90 days, 16/37 (43%) had hospital readmissions. Conclusions: Patient navigation was feasible and acceptable in patients with hospital-diagnosed ALC. However, there are ongoing barriers to implementation of post-hospitalization ePRO symptom monitoring and palliative care. Additional evaluation is needed to understand the barriers and facilitators and to measure the impact of navigation on patient outcomes. Since nearly all patients met high-risk criteria, future programs will eliminate risk stratification and target all patients with hospital-diagnosed ALC. Clinical trial information: NCT05722847 . [Table: see text]

First results of the NOGGO PERCEPTION: Phase II investigational study of pembrolizumab in combination with chemotherapy in platinum-sensitive recurrent low-grade serous ovarian cancer.

e17550 Background: Low-grade serous ovarian cancer (LGSOC), a rare ovarian malignancy, exhibits a very limited responsiveness to chemotherapy. There is a pressing need for new therapeutic combinations with modern agents to enhance response rates and prognosis in this patient subgroup. Immune checkpoint inhibitors offer a promising pathway, having shown effectiveness in various malignant diseases, including selected cases of ovarian cancer. If our trial should show pembrolizumab effectivity in LGSOC, it would be a signal and impulse for future clinical studies in this rare disease. Methods: This clinical trial is a multi-center, single-arm phase 2 study to evaluate pembrolizumab therapy concomitant to platinum-based chemotherapy (carboplatin plus pegylated liposomal doxorubicin & carboplatin plus gemcitabine) and as maintenance in recurrent LGSOC cases. Eligible for the trial are LGSOC patients with progression or recurrence at least six months after most previous platinum-containing therapy and in good general performance (ECOG 0/1). The primary objective is the 12 months progression free survival (PFS) rate. Secondary end-points include overall survival, response rate (RR), PFS and RR according to Ki67 expression levels, time to first subsequent therapy and its response, safety and quality of life. The trial is planned according to Simon’s two-stage design with total sample size up to 33 patients. The null hypothesis is PFS-rate of at least 12 months of 20%. During the first stage 18 patients were enrolled and since 5 patients showed PFS of 12 months the study has been continued within stage 2 to enrol additional 15 patients. The trial can be claimed as successful, if at least 11 patients show PFS after 12 months. Assuming a true PFS-rate of 40%, this trial has 5% type I error rate and 80% power. Results: Data from 18 patients enrolled into this trial from FPI up to the time of interim analysis have been analyzed. 5 patients had reached the primary endpoint. 6 patients progressed or died before they reached the primary endpoint. At this time, 10 patients are still undergoing treatment and 7 patients may still reach the primary endpoint. Patients have a median age of 60 years (range: 43-81), ECOG score of 0 was recorded in 16 patients (88.9%) and most received one prior line of chemotherapy (61.1%, range: 1-5). 14 patients (77.8%) received carboplatin + PLD and 4 patients (22.2%) received carboplatin + gemcitabine as chemotherapy. 10 patients (55.6%) had at least one SAE. 3 patients (16.7%) had at least one SAE with relation to study treatment. 1 SAE resulted in a fatal outcome but was assessed not be related to study treatment. Conclusions: The interim analysis showed positive results, strengthening the hypothesis that pembrolizumab is an effective agent capable of extending progression-free survival in the studied patient population. Clinical trial information: NCT04575961 .

Randomized double-blind placebo-controlled trial of the effects of oral trehalose in spinocerebellar ataxia type 3: An interim analysis

IntroductionSpinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease characterized by increasingly worsening ataxia and non-ataxia features, negatively impacting patients’ quality of life. This study was designed to test formally evaluate whether oral trehalose was effective in SCA3 patients. MethodsIn this double-blind, randomized controlled trial, SCA3 patients received either 100 g oral trehalose or 30 g maltose to improve ataxia severity over six months. We also measured other clinical (non-ataxia), patient-reported (quality of life, motivations), and safety endpoints. An unscheduled interim analysis was conducted using two-way ANOVAs to analyze the interaction between time (baseline, 3-months, 6-months) and intervention (Trehalose vs. Placebo). ResultsFifteen participants (Trehalose = 7 vs. Placebo = 8) completed the study at the time of interim analysis. There was no interaction effect on the ataxia severity, and available data suggested an estimated sample size of 132 (66 per arm) SCA3 patients required to demonstrate changes in a 6-month trial. There were significant interaction effects for executive function (ƞ2 = 0.28–0.43). Safety data indicated that 100 g oral trehalose was well-tolerated. ConclusionWe performed an unplanned interim analysis due to a slow recruitment rate. The new estimated sample size was deemed unfeasible, leading to premature termination of the clinical trial. In this small, current sample of SCA3 patients, 100 g oral trehalose did not differentially impact on ataxia severity compared to placebo. Interestingly, our findings may suggest an improvement in executive function. Future efforts will require a large multi-country, multi-center study to investigate the potential effect of trehalose.

Abstract PO3-20-05: Phase II Study of Genomically Guided Radiation Dose Personalization in the Management of Triple Negative Breast Cancer

Abstract Background: Our group has previously developed the radiosensitivity index (RSI) using a multigene expression model that is directly proportional to tumor radioresistance (high RSI = increased radioresistance). RSI has been previously validated in two datasets of patients with triple negative breast cancer (TNBC). In this study, we will run a selective dose personalization study in TNBC patients undergoing breast conservation therapy (BCT). Based on patients RSI scores, they will either receive a radiation therapy (RT) boost of 10 Gy to the tumor cavity or not. Given our data in two independent datasets, the current study will reveal the feasibility and benefit of selective genomic dose personalization in TNBC following BCT. Trial Design: The study is designed as a prospective, nonrandomized, phase II trial of genomically guided RT in the management of TNBC undergoing BCT. Patients will be allocated to one of two groups based on their RSI determination from fresh frozen tissue collected by biopsy or at the time of BCT. These groups will be Group A, RSI optimized whole breast radiotherapy alone or with a 10 Gy boost or Group B, RSI not optimized whole breast radiotherapy with a boost of 10 Gy to tumor cavity. Patients will receive standard of care chemotherapy, neoadjuvant or adjuvant. Eligibility: TNBC patients undergoing BCT. Specific Aims: To determine the three-year local control following genomically guided dose personalization in the management of TNBC following BCT. Secondary objectives include determination of overall survival (OS), progression free survival (PFS), and quality of life (QOL) following genomically guided dose personalization. Statistical Methods: The primary hypothesis is the three-year local control rates differ for groups A and B, against the null hypothesis that the two rates are identical. Patients will allocate approximately 78% in group A and 22% in group B and local control rates are expected to be 96% and 75%, respectively. Assuming 80% power and 10% type I error for a log-rank test, 86 patients are needed. An interim analysis will be completed when 4 disease progression events are observed. There will be approximately 43 patients at the time of interim analysis. Patient Accrual: This study is open with 1 patient enrolled at the time of submission. A total of 86 patients will be enrolled. Contact Information: Kamran A. Ahmed MD, Moffitt Cancer Center, email: kamran.ahmed@moffitt.org, Clinical trial information: NCT05115474. Funding: Moffitt and Morton Plant Mease Foundations. Citation Format: Kamran Ahmed, Iman Washington, Matthew Mills, Michelle DeJesus, Youngchul Kim, Ronica Nanda, Javier Torres-Roca, Steven Eschrich, Janis De La Iglesia, John Puskas, Marilin Rosa, Jason Wilson, Paula Lundgren, Negar Golesorkhi, Nazanin Khakpour, Susan Hoover, Marie Lee, John Kiluk, Melissa Mallory, Christine Laronga, Laura Kruper, Brian Czerniecki, Roberto Diaz. Phase II Study of Genomically Guided Radiation Dose Personalization in the Management of Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-20-05.

Bayesian interim analysis for prospective randomized studies: reanalysis of the acute myeloid leukemia HOVON 132 clinical trial

Randomized controlled trials (RCTs) are the gold standard to establish the benefit-risk ratio of novel drugs. However, the evaluation of mature results often takes many years. We hypothesized that the addition of Bayesian inference methods at interim analysis time points might accelerate and enforce the knowledge that such trials may generate. In order to test that hypothesis, we retrospectively applied a Bayesian approach to the HOVON 132 trial, in which 800 newly diagnosed AML patients aged 18 to 65 years were randomly assigned to a “7 + 3” induction with or without lenalidomide. Five years after the first patient was recruited, the trial was negative for its primary endpoint with no difference in event-free survival (EFS) between experimental and control groups (hazard ratio [HR] 0.99, p = 0.96) in the final conventional analysis. We retrospectively simulated interim analyses after the inclusion of 150, 300, 450, and 600 patients using a Bayesian methodology to detect early lack of efficacy signals. The HR for EFS comparing the lenalidomide arm with the control treatment arm was 1.21 (95% CI 0.81–1.69), 1.05 (95% CI 0.86–1.30), 1.00 (95% CI 0.84–1.19), and 1.02 (95% CI 0.87–1.19) at interim analysis 1, 2, 3 and 4, respectively. Complete remission rates were lower in the lenalidomide arm, and early deaths more frequent. A Bayesian approach identified that the probability of a clinically relevant benefit for EFS (HR < 0.76, as assumed in the statistical analysis plan) was very low at the first interim analysis (1.2%, 0.6%, 0.4%, and 0.1%, respectively). Similar observations were made for low probabilities of any benefit regarding CR. Therefore, Bayesian analysis significantly adds to conventional methods applied for interim analysis and may thereby accelerate the performance and completion of phase III trials.

Effectiveness of IMPUTE ADT-1 mobile application in children with autism spectrum disorder: An interim analysis of an ongoing randomized controlled trial.

IMPUTE Inc., a software firm dedicated to healthcare technology, has developed a mobile medical application known as IMPUTE ADT-1 for children with autism spectrum disorder (ASD) based on the principle of applied behavior analysis. The primary objective of this trial was to compare the efficacy of add-on treatment with IMPUTE ADT-1 in children with ASD aged two to six years as compared to standard care alone for 12 weeks (in terms of change in Autism Diagnostic Observation Schedule [ADOS-2] scores). The secondary objective of the study was to assess the compliance with IMPUTE ADT-1 among participants and also to evaluate the feedback of parents regarding IMPUTE ADT-1 at the end of 12 weeks. The application provides personalized programs tailored to each user's needs, and the program evolves based on the user's progress. It also utilizes face tracking, eye tracking, and body tracking to gather behavior-related information for each child and apply it in reinforcement learning employing artificial intelligence-based algorithms. Till the time of interim analysis, 37 and 33 children had completed 12-week follow-up in IMPUTE ADT-1 and control arm. At 12 weeks, as compared to baseline, change in social affect domain, repetitive ritualistic behavior domain, total ADOS-2 score, and ADOS-2 comparison score was better in the intervention group as compared to the control group (P < 0.001 for all). A total of 30 (81%), 28 (75%), and 29 (78%) caregivers in the IMPUTE ADT-1 group believed that the ADT-1 app improved their child's verbal skills, social skills, and reduced repetitive behavior, respectively. IMPUTE ADT-1 mobile application has the efficacy to improve the severity of autism symptoms in children. Parents of these children also feel that the application is beneficial for improving the socialization and verbal communication of their children.

Changing interim monitoring in response to internal clinical trial data.

Designing clinical trials for emerging infectious diseases such as COVID-19 is challenging because information needed for proper planning may be lacking. Pre-specified adaptive designs can be attractive options, but what happens if a trial with no such design needs to be modified? For example, unexpectedly high efficacy (approximately 95%) in two COVID-19 vaccine trials might cause investigators in other COVID-19 vaccine trials to increase the number of interim analyses to allow earlier stopping for efficacy. If such a decision is based solely on external data, there are no issues, but what if internal trial data by arm are also examined? Fortunately, the conditional error principle of Müller and Schäfer (2004) can be used to ensure no inflation of the type 1 error rate, even if no interim analyses were planned. We study the properties, including limitations, of this method. We provide a shiny app to evaluate changes in timing of interim analyses in response to outcome data by arm in clinical trials.

Prevalence of Trauma History and Symptoms in Patients Who Have Received Vaginal Brachytherapy as Part of their Endometrial Cancer Treatment

Vaginal brachytherapy (VBT) is an essential component of curative intent treatment for many patients with endometrial cancer. The prevalence of trauma history in this population is unknown and is important to understand considering VBT requires patients to have an instrument vaginally inserted while in the vulnerable lithotomy position. We aim to retrospectively identify patients treated with VBT for early-stage endometrial cancer and collect survey data to assess the prevalence of trauma history, whether VBT re-induced trauma symptoms, and whether VBT was considered an independent traumatic event by patients. We retrospectively identified patients with endometrial cancer treated with VBT at our institution from January 2017 to August 2022. Patients were mailed a cover letter and unique-identifier coded survey that included the Brief Trauma Questionnaire (BTQ) and Primary Care Post Traumatic Stress Disorder Screen for DSM-V (PC-PTSD-5), both validated instruments. Patients were instructed to fill out the surveys as it relates to their trauma history prior to VBT and again considering any trauma symptomatology related to VBT. BTQ was interpreted as positive if the patient responded yes to any question. PC-PTSD-5 was interpreted positive if the patient responded yes to at least 3 questions. Electronic medical record review was performed to identify clinical and pathologic features. Descriptive statistics and qualitative analysis were used to assess survey responses. A total of 51 of 206 patients returned the survey at the time of interim analysis. 43 patients (84%) screened positive on the BTQ for having trauma history. Of those patients, 7 (16%) screened positive on the PC-PTSD-5 for a probable PTSD diagnosis. Additionally, 22 (51%)/18 (42%) patients answered yes to at least one/two symptoms on the PC-PTSD-5 respectively. Of the patients who answered yes to at least one question on the PC-PTSD-5, 18% (4 patients) responded that VBT triggered flashbacks of their past trauma. Regarding PC-PTSD-5 considering trauma symptomatology related to VBT, 20 patients (39%) answered yes to any question, though only 2 patients (4%) met the threshold to screen positive for probable PTSD. 20 patients (39%) indicated they would have accepted a referral to psychology before or during VBT. Suggested improvements made via free text responses included minimizing the time the cylinder was inserted and eliminating the need to transfer via hallway from the simulation room to the treatment room. This study provides a baseline for understanding the prevalence of trauma history and trauma related to VBT in patients with endometrial cancer. This data can be used to guide patient centered discussions of endometrial cancer care, importantly including to counsel patients that a possible toxicity of VBT is trauma symptomatology, particularly for those with a history of trauma.

386 Complete/near-complete itch response observed in adult and adolescent patients with moderate-to-severe atopic dermatitis initiating dupilumab treatment in real-world practice

Abstract Chronic itch (pruritus) is a defining characteristic of atopic dermatitis (AD) and is a significant contributor to poor quality of life in patients. A Pruritus/Peak Pruritus Numerical Rating Scale (NRS) score of 0/1 could be considered a complete or near-complete itch response. This study aims to report Pruritus NRS and Overall Disease Severity (ODS) score of 0/1 over time in patients older than 12 years with moderate-to-severe AD initiating dupilumab treatment in real-world practice. Patients aged ≥12 years with moderate-to-severe AD, initiating real-world dupilumab treatment for AD per approved prescribing information in the USA and Canada, were eligible for entry into PROSE (NCT03428646). Enrolled patients received their first dose of dupilumab at the baseline visit; there were no restrictions on post-baseline dupilumab dosing changes, or concomitant medication use; patients were encouraged to stay in the study if they discontinued dupilumab. Data presented are from an interim analysis (data cut taken as of November 2022); only ≥36 months of patient experience in PROSE at the time of interim analysis is reported. No formal hypothesis testing was performed; descriptive statistics are presented. Among 857 patients [mean (SD) age 40.1 (17.9) years and 42% male], mean (SD) duration of dupilumab treatment was 23.1 (13.7) months. At Month 36, 185 patients (21.6%) had discontinued from the study; the main reason was withdrawal of consent by the patient (76 patients, 8.9%). The proportion of patients with available observations reporting a Pruritus NRS score of 0/1 increased from baseline (2.7%) to Month 3 (28.1%) and continued to increase up to Month 36 (56.3%). Similarly, the proportion of patients with a clinician-reported ODS score of 0/1 also increased from baseline (2.2%) to Month 3 (39.8%) and up to Month 36 (65.1%). Safety was consistent with the known dupilumab safety profile. In this interim analysis of PROSE, a majority of patients reported a complete/near-complete pruritus response and overall disease severity response over a 36-month period.

Phase II trial evaluating nivolumab in patients with recurrent IDH-mutant gliomas with and without hypermutation phenotype.

e14043 Background: Tumor mutational burden (TMB) may predict immunotherapy response in solid tumors. Response to immune checkpoint inhibitor (ICI) treatment in the rare gliomas with biallelic mismatch repair deficiencies have been attributed to their hypermutation phenotype (HMP). This has not been tested in other gliomas. We developed a phase II clinical trial using nivolumab in recurrent IDH-mutant gliomas evaluating response in tumors with HMP (approximately 10% of cases) and in tumors with non-HMP (NHMP). Here we report the results of the interim analysis of the NHMP cohort. Methods: Adults with recurrent IDH-mutant glioma, KPS ≥ 60, normal organ function, with known somatic TMB (analyzed at NIH) were enrolled to a phase II trial. Nivolumab is given at 480mg IV every 28-day cycle with a maximum of 16 cycles. The primary endpoint is PFS rate at 6 months (PFS6) in both HMP and NHMP cohorts. Responses to treatment are evaluated by MRI every 2 cycles using iRANO criteria. A Simon’s two-stage design was used for conducting the HMP/NHMP cohort independently. For NHMP cohort, the null and alternative hypotheses for PFS6 are 0.3 and 0.5, respectively. Fifteen patients were planned to accrue in stage I. If ≥10 have disease progression at 6 months, the cohort will be terminated, otherwise continue to stage II and accrue additional 31 patients, resulting a total cohort size of 46. The design controls the type I error at 0.05 and yields a power of 0.8. Tumor samples and peripheral blood were collected for correlative studies. Patient-reported outcomes (PRO) were evaluated by longitudinal symptom burden analysis using Brain Tumor Module of the MD Anderson Symptom Inventory. Results: As of May 2022, 17 patients were enrolled to NHMP cohort and 15 were treated (TMB˂5 mut/Mb). Among 15 evaluable patients, 10 were male, median age 39.5 and KPS 90. Histological diagnosis included 12 astrocytoma (grade 3, n = 4; grade 4, n = 8) and oligodendroglioma (grade 2, n = 1; grade 3, n = 2). Median number of prior recurrences is 3. At the time of interim analysis, four patients were receiving ongoing treatment, but all have received more than 6 cycles, with 100% PRO completion. Eleven patients were off study treatment, 2 completed all 16 cycles, 9 had disease progression. Six out of 15 (40%) patients were progression free at 6 months. Per design, the NHMP cohort proceeded to stage II. One treatment related grade 3 immune-related colitis was reported. Conclusions: Nivolumab is well tolerated and has demonstrated efficacy in a cohort of patients with recurrent IDH-mutant gliomas with low TMB. Accrual to this NHMP cohort continues along with continued enrollment to the HMP cohort. Clinical benefit measured by objective response, PFS, OS and longitudinal PRO measure along with longitudinal immune monitoring will help address whether TMB correlates with tumor, immunologic and clinical response, and benefit of ICI therapy in IDH-mutant gliomas. Clinical trial information: NCT03718767 .

Development and Evaluation of a Simulation-Based Algorithm to Optimize the Planning of Interim Analyses for Clinical Trials in ALS.

Late-phase clinical trials for neurodegenerative diseases have a low probability of success. In this study, we introduce an algorithm that optimizes the planning of interim analyses for clinical trials in amyotrophic lateral sclerosis (ALS) to better use the time and resources available and minimize the exposure of patients to ineffective or harmful drugs. A simulation-based algorithm was developed to determine the optimal interim analysis scheme by integrating prior knowledge about the success rate of ALS clinical trials with drug-specific information obtained in early-phase studies. Interim analysis schemes were optimized by varying the number and timing of interim analyses, together with their decision rules about when to stop a trial. The algorithm was applied retrospectively to 3 clinical trials that investigated the efficacy of diaphragm pacing or ceftriaxone on survival in patients with ALS. Outcomes were additionally compared with conventional interim designs. We evaluated 183-1,351 unique interim analysis schemes for each trial. Application of the optimal designs correctly established lack of efficacy, would have concluded all studies 1.2-19.4 months earlier (reduction of 4.6%-57.7% in trial duration), and could have reduced the number of randomized patients by 1.7%-58.1%. By means of simulation, we illustrate the efficiency for other treatment scenarios. The optimized interim analysis schemes outperformed conventional interim designs in most scenarios. Our algorithm uses prior knowledge to determine the uncertainty of the expected treatment effect in ALS clinical trials and optimizes the planning of interim analyses. Improving futility monitoring in ALS could minimize the exposure of patients to ineffective or harmful treatments and result in significant ethical and efficiency gains.

Validation of Predictive Analyses for Interim Decisions in Clinical Trials.

Adaptive clinical trials use algorithms to predict, during the study, patient outcomes and final study results. These predictions trigger interim decisions, such as early discontinuation of the trial, and can change the course of the study. Poor selection of the Prediction Analyses and Interim Decisions (PAID) plan in an adaptive clinical trial can have negative consequences, including the risk of exposing patients to ineffective or toxic treatments. We present an approach that leverages data sets from completed trials to evaluate and compare candidate PAIDs using interpretable validation metrics. The goal is to determine whether and how to incorporate predictions into major interim decisions in a clinical trial. Candidate PAIDs can differ in several aspects, such as the prediction models used, timing of interim analyses, and potential use of external data sets. To illustrate our approach, we considered a randomized clinical trial in glioblastoma. The study design includes interim futility analyses on the basis of the predictive probability that the final analysis, at the completion of the study, will provide significant evidence of treatment effects. We examined various PAIDs with different levels of complexity to investigate if the use of biomarkers, external data, or novel algorithms improved interim decisions in the glioblastoma clinical trial. Validation analyses on the basis of completed trials and electronic health records support the selection of algorithms, predictive models, and other aspects of PAIDs for use in adaptive clinical trials. By contrast, PAID evaluations on the basis of arbitrarily defined ad hoc simulation scenarios, which are not tailored to previous clinical data and experience, tend to overvalue complex prediction procedures and produce poor estimates of trial operating characteristics such as power and the number of enrolled patients. Validation analyses on the basis of completed trials and real world data support the selection of predictive models, interim analysis rules, and other aspects of PAIDs in future clinical trials.

OR27-4 Placebo-Controlled and Open-Label Extension Study of a Novel Hepatic-Targeted Antisense Cimdelirsen (IONIS-GHR-LRx) Under Investigation in Acromegaly Patients

Abstract Cimdelirsen (IONIS-GHR-LRx; ISIS 766720) is a novel, ligand-conjugated, hepatic-targeted investigative antisense molecule designed to reduce growth hormone receptor (GHr) synthesis, thereby inhibiting deleterious effects of growth hormone (GH) hypersecretion and reducing circulating insulin-like growth factor-1 (IGF-1) levels in acromegaly patients. Methods Cimdelirsen was evaluated in a 4-month double-blind, placebo-controlled phase 2 study (DBL) in uncontrolled acromegaly patients (IGF-1&amp;gt;1.3-&amp;lt;5xULN) treated with stable long-acting somatostatin receptor ligand (SRL) injections (NCT03548415). Due to COVID-19 pandemic, the study closed early resulting in smaller cohorts than planned. While no longer powered to assess Day 141 primary endpoint (PE), the study permitted placebo-controlled evaluation of safety and efficacy. The final analysis included 41 patients in the cimdelirsen low dose (60 and 80 mg; n=22), high dose (120 and 160 mg; n=7) or placebo (n=12) cohorts. 39 of these patients subsequently entered an open label extension (OLE) safety study where all patients were treated with cimdelirsen and at the time of interim analysis, 23 patients were treated for ≥ 1 year (NCT03967249).Patient reported outcomes were assessed using the validated ACROQoL and an acromegaly symptoms questionnaire. Results Cimdelirsen treatment resulted in a significant, dose dependent reduction in GH-binding protein (GHBP), a biomarker of hepatic GHR reduction: -2% placebo, -43% low dose, -64% high dose; p&amp;lt;0.001. Importantly, GHBP reductions were not associated with fasting GH increases. The GH mean change from baseline to PE was 1 ng/mL placebo, 0 ng/mL low dose and 1 ng/mL high dose (p&amp;gt;0.5). GHBP reductions without GH increases were maintained for up to 1 year of treatment in all patients.Integrated AUC for IGF-1 calculated after GHBP had reached near-maximal reductions (Day 57 to PE) demonstrated dose-dependent reductions that were significant at the high dose (+692%*day placebo, -460 low dose, and -1378 high dose; p=0.21 and 0.05 for the low dose and high dose groups, respectively). A greater reduction in IGF-1 AUC was observed in patients who had higher IGF-1 levels at baseline.Patients with higher IGF-1 levels showed significant improvements in ACROQoL at the PE; all patients demonstrated improvements after 1 year. Importantly, high-dose cimdelirsen improved sweating and headaches at PE.In both studies, there were no drug-related SAEs. The most frequently reported TEAE were UTI (16.1%) and COVID-19 (12.8%) in DBL and OLE, respectively. No safety signals were observed including no ALT elevation &amp;gt;3×ULN and no thrombocytopenia (&amp;lt;100 10^3/uL). Glycemic control remained stable and showed no worsening of HbA1c. Conclusion Once monthly SC cimdelirsen injections demonstrated long-term safety, were well-tolerated, and resulted in significant reductions in GHBP and IGF-1 AUC without increased GH levels. Cimdelirsen also improved PRO, collectively supporting further development of this novel, liver-directed potential therapy for uncontrolled acromegaly. Presentation: Tuesday, June 14, 2022 10:30 a.m. - 10:45 a.m.

LBODP002 Phase II Open-label Pilot Trial Of Liraglutide In Adolescents With Obesity After Vertical Sleeve Gastrectomy: Interim Results From 8-weeks Of Treatment

Abstract Background Metabolic and bariatric surgery (MBS) is currently the most effective weight loss treatment in adults and children with severe obesity. However, up to 50% of adolescents continue to have obesity three years post-MBS. Vertical sleeve gastrectomy (VSG), the most common MBS performed in adolescents, causes an increase in post-prandial glucagon-like peptide 1 (GLP-1) post-operatively, but the duration of this incretin hormone response is unclear. Liraglutide, a GLP-1 analogue, may supplement the physiological increase in GLP-1 following VSG and promote weight loss via appetite suppression. We hypothesized that daily liraglutide treatment would significantly reduce body weight in adolescents who had previously undergone VSG but who continued to have insufficient weight loss. This abstract reports interim data from our prospective clinical trial of liraglutide in adolescents with obesity after VSG (ClinicalTrials.gov Identifier: NCT04883346). Methods This trial is an active, open-label, phase II pilot study to investigate the efficacy of daily subcutaneous liraglutide to promote reduction of BMI in adolescents with persistent obesity 1 year or more after VSG. The primary objective is to determine the effect size for the change in BMI of liraglutide 3. 0 mg daily at 16 weeks in study participants to calculate the sample size of a subsequent randomized controlled trial. Inclusion criteria are age 12 to 20.99 years, good general health, BMI≥30 kg/m2, and a personal history of VSG ≥1-year prior. Exclusion criteria include major medical illnesses, use of medications associated with weight gain, or use of weight-loss medications within the last 3 months of screening. Liraglutide is initiated at 0.6 mg daily and escalated by 0.6mg weekly to 3 mg/d for the last 12 weeks of treatment. Participants receive monthly nutrition counseling throughout the study. Results At time of interim analysis (3/24/22), 26 participants (baseline age 18±1.9y, mean±SD; 65% female; 55% black; baseline BMI 42. 0±7. 0 kg/m2) were screened and 20 started liraglutide. Among 17 participants who reached 8 weeks of treatment, mean absolute change in weight was -3.9±2.6 kg, percent change in weight was -3.6±2.6%, absolute change in BMI was -1.4±0.9 kg/m2, and percent change in BMI was -3.6±2.6%. There were no serious treatment-emergent adverse events (TEAEs) reported; 16/20 participants reported non-serious TEAEs including low energy (40%), nausea (40%), and vomiting (20%). In this interim analysis of an open-label phase II pilot study, the mean weight change from baseline was -3.6% after 8 weeks of liraglutide treatment in adolescents with persistent obesity after VSG. No new TEAEs were identified. Completion of this study will help determine if weight reduction with liraglutide suggests value to carry out a randomized placebo controlled study using liraglutide. Presentation: No date and time listed

A Brighton Collaboration standardized template with key considerations for a benefit/risk assessment for the Moderna COVID-19 Vaccine (mRNA-1273)

The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group has prepared standardized templates to describe the key considerations for the benefit-risk assessment of several vaccine platform technologies, including nucleic acid (RNA and DNA) vaccines. This paper uses the BRAVATO template to review the features of a vaccine employing a proprietary mRNA vaccine platform to develop Moderna COVID-19 Vaccine (mRNA-1273); a highly effective vaccine to prevent coronavirus disease 2019 (Covid-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In response to the pandemic the first in human studies began in March 2020 and the pivotal, placebo-controlled phase 3 efficacy study in over 30,000 adults began in July 2020. Based on demonstration of efficacy and safety at the time of interim analysis in November 2020 and at the time of trial unblinding in March 2021, the mRNA-1273 received Emergency Use Authorization in December 2020 and full FDA approval in January 2022.

Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study

AbstractIptacopan (LNP023) is a novel, oral selective inhibitor of complement factor B under clinical development for paroxysmal nocturnal hemoglobinuria (PNH). In this ongoing open-label phase 2 study, PNH patients with active hemolysis were randomized to receive single-agent iptacopan twice daily at a dose of either 25 mg for 4 weeks followed by 100 mg for up to 2 years (cohort 1) or 50 mg for 4 weeks followed by 200 mg for up to 2 years (cohort 2). At the time of interim analysis, of 13 PNH patients enrolled, all 12 evaluable for efficacy achieved the primary endpoint of reduction in serum lactate dehydrogenase (LDH) levels by ≥60% by week 12 compared with baseline; mean LDH levels dropped rapidly and durably, namely by 77% and 85% at week 2 and by 86% and 86% at week 12 in cohorts 1 and 2, respectively. Most patients achieved a clinically meaningful improvement in hemoglobin (Hb) levels, and all but 1 patient remained transfusion-free up to week 12. Other markers of hemolysis, including bilirubin, reticulocytes, and haptoglobin, showed consistent improvements. No thromboembolic events were reported, and iptacopan was well tolerated, with no severe or serious adverse events reported until the data cutoff. In addition to the previously reported beneficial effect of iptacopan add-on therapy to eculizumab, this study showed that iptacopan monotherapy in treatment-naïve PNH patients resulted in normalization of hemolytic markers and rapid transfusion-free improvement of Hb levels in most patients. This trial was registered at www.clinicaltrials.gov as #NCT03896152.

Bayesian Optimal Phase II Design for Randomized Clinical Trials

Randomized clinical trials are the gold standard to evaluate the efficacy of an experimental treatment. We propose a flexible Bayesian optimal phase II (BOP2) design for two-arm randomized trials. The proposed two-arm BOP2 design is flexible and can handle single, multiple primary and coprimary endpoints for superiority and noninferiority trials under a unified framework. It also allows users to specify the number and timing of interim analyses to meet clinical needs. While enjoying the flexibility of Bayesian adaptive designs, the two-arm BOP2 design explicitly controls the Type I error rate and is optimal for maximizing power, thereby ensuring desirable frequentist operating characteristics. Another feature of the two-arm BOP2 design is that its decision rule can be tabulated and included in the trial protocol prior to trial commence. To conduct the trial, no complicated Bayesian calculation is needed; clinicians can simply look up the table and make go/no-go decisions. Simulation studies show that the two-arm BOP2 design has desirable operating characteristics. Easy-to-use online application is freely available at www.trialdesign.org to facilitate the use of the two-arm BOP2 design in clinical trials.

Early Use of Donor Derived Cell-Free DNA (dd-cfDNA) in Heart Transplantation

Purpose Novel non-invasive cardiac allograft surveillance methods such as dd-cfDNA has emerged as a viable noninvasive tool for rejection surveillance, however, with limited data for early use. We sought to describe the incidence and outcomes of early dd-cfDNA use (< 14 days) for HT rejection surveillance. Methods Consecutive adult HT recipients were identified retrospectively from a single center (n=66). Patients were included if heart-only with at least one dd-cfDNA drawn within 14-days post HT between 8/2/2019 and 10/1/2021 (n=45). Baseline donor/recipient demographics, clinical characteristics, serial echocardiographic parameters, laboratory testing, medication regimens, and clinical course were collected over a 6-month period. The composite endpoint was defined as graft dysfunction (LVEF < 40% or >=25% decline in consecutive visit) triggering EMB, rejection >= 2R, development of de-novo donor specific antibodies (DSAs), or death. Results 45 HT recipients were identified. The cohort was predominantly male (71%), non-Caucasian (67%) with DM (40%) and HTN (38%), and had a mean follow up time of 273-days. Donors were male (33%) with mean ischemic time and donor age of 2.9h and 29.5y, respectively. Mean number of biopsies performed in the first 6 months was 1.6 and mean initial dd-cfDNA (obtained <14d) was 0.3 ± 0.2% (NL <0.12). Overall, there was no difference in baseline demographics by composite endpoint. Eleven patients (24%) met the composite endpoint (rejection >= 2R (n=4), de-novo DSAs (n=6), graft dysfunction (n=4)). Biopsy frequency was increased in those meeting the endpoint (2.4 vs 1.4, p<0.004). There were no deaths during the study period. No significant association was demonstrated between dd-cfDNA < 14 d and the composite endpoint p=0.547) at time of interim analysis. Conclusion Early use of dd-cfDNA (< 14 d) for rejection surveillance is effective in lieu of protocol endomyocardial biopsy. Interim analysis demonstrates significant reduction in protocol biopsy frequency with no deaths in this cohort to date. Completion of follow up is expected in March 2022. Novel non-invasive cardiac allograft surveillance methods such as dd-cfDNA has emerged as a viable noninvasive tool for rejection surveillance, however, with limited data for early use. We sought to describe the incidence and outcomes of early dd-cfDNA use (< 14 days) for HT rejection surveillance. Consecutive adult HT recipients were identified retrospectively from a single center (n=66). Patients were included if heart-only with at least one dd-cfDNA drawn within 14-days post HT between 8/2/2019 and 10/1/2021 (n=45). Baseline donor/recipient demographics, clinical characteristics, serial echocardiographic parameters, laboratory testing, medication regimens, and clinical course were collected over a 6-month period. The composite endpoint was defined as graft dysfunction (LVEF < 40% or >=25% decline in consecutive visit) triggering EMB, rejection >= 2R, development of de-novo donor specific antibodies (DSAs), or death. 45 HT recipients were identified. The cohort was predominantly male (71%), non-Caucasian (67%) with DM (40%) and HTN (38%), and had a mean follow up time of 273-days. Donors were male (33%) with mean ischemic time and donor age of 2.9h and 29.5y, respectively. Mean number of biopsies performed in the first 6 months was 1.6 and mean initial dd-cfDNA (obtained <14d) was 0.3 ± 0.2% (NL <0.12). Overall, there was no difference in baseline demographics by composite endpoint. Eleven patients (24%) met the composite endpoint (rejection >= 2R (n=4), de-novo DSAs (n=6), graft dysfunction (n=4)). Biopsy frequency was increased in those meeting the endpoint (2.4 vs 1.4, p<0.004). There were no deaths during the study period. No significant association was demonstrated between dd-cfDNA < 14 d and the composite endpoint p=0.547) at time of interim analysis. Early use of dd-cfDNA (< 14 d) for rejection surveillance is effective in lieu of protocol endomyocardial biopsy. Interim analysis demonstrates significant reduction in protocol biopsy frequency with no deaths in this cohort to date. Completion of follow up is expected in March 2022.

Robust group sequential designs for trials with survival endpoints and delayed response.

Randomized clinical trials in oncology typically utilize time-to-event endpoints such as progression-free survival or overall survival as their primary efficacy endpoints, and the most commonly used statistical test to analyze these endpoints is the log-rank test. The power of the log-rank test depends on the behavior of the hazard ratio of the treatment arm to the control arm. Under the assumption of proportional hazards, the log-rank test is asymptotically fully efficient. However, this proportionality assumption does not hold true if there is a delayed treatment effect. Cancer immunology has evolved over time and several cancer vaccines are available in the market for treating existing cancers. This includes sipuleucel-T for metastatic hormone-refractory prostate cancer, nivolumab for metastatic melanoma, and pembrolizumab for advanced nonsmall-cell lung cancer. As cancer vaccines require some time to elicit an immune response, a delayed treatment effect is observed, resulting in a violation of the proportional hazards assumption. Thus, the traditional log-rank test may not be optimal for testing immuno-oncology drugs in randomized clinical trials. Moreover, the new immuno-oncology compounds have been shown to be very effective in prolonging overall survival. Therefore, it is desirable to implement a group sequential design with the possibility of early stopping for overwhelming efficacy. In this paper, we investigate the max-combo test, which utilizes the maximum of two weighted log-rank statistics, as a robust alternative to the log-rank test. The new test is implemented for two-stage designs with possible early stopping at the interim analysis time point. Two classes of weights are investigated for the max-combo test: theFleming and Harrington (1981) weights and theMagirr and Burman (2019) modest weights.