Interim Futility Analysis Research Articles

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.

OP33 Results of a randomised controlled trial to evaluate Interleukin 1 blockade with anakinra in patients with acute severe ulcerative colitis (IASO)

Abstract Background Acute severe ulcerative colitis (ASUC) is a severe manifestation of ulcerative colitis (UC) that requires hospitalisation. Despite significant advances in therapeutic options for UC and in the medical management of steroid-refractory ASUC, the initial treatment paradigm for ASUC has not changed since the 1950s and is based on the use of intravenous (IV) corticosteroids. Approximately 50% of patients do not respond and require further medical or surgical therapy. Interleukin 1 (IL-1) has been identified as a key mediator of colonic inflammation and plays a pivotal role in local activation of neutrophils and a number of downstream inflammatory mediators. The IL-1 axis has been repeatedly identified as a therapeutic target in UC. The Interleukin 1 (IL-1) blockade in Acute Severe Colitis (IASO) trial investigated whether antagonism of IL-1 signalling could improve outcomes in patients with ASUC. Methods We performed a phase II, multicentre randomised (1:1), placebo-controlled, double-blinded trial of IL-1 blockade with short-duration anakinra, given alongside IV corticosteroids to adult patients hospitalised with suspected or confirmed ASUC. The primary outcome was the incidence of medical (ie infliximab/ciclosporin) or surgical rescue therapy (colectomy) within 10 days following the commencement of IV corticosteroid therapy. Secondary outcomes included disease activity, time to clinical response, time to rescue therapy, colectomy incidence by day 98 post IV corticosteroids and safety. The trial aimed to recruit 214 patients across 20 sites in the UK. Prespecified analyses were performed for feasibility and for futility. Results At the time of the prespecified interim futility analysis, 113 patients had been randomised, 55 to placebo, and 58 to anakinra (figure 1). The incidence of medical or surgical rescue therapy by day 10 was higher in the anakinra group than in the placebo group (43% vs 26%). The incidence of colectomy by day 98 was higher in the anakinra group (11% vs 4%). These differences were not statistically significant. Logistic models containing a mixture of baseline stratification factors did not suggest that the need for rescue therapy would be reduced with anakinra treatment and on the advice of the independent data monitoring committee, the trial was terminated for futility. There was a higher incidence of adverse event in the placebo group, the most common was worsening of ulcerative colitis. Conclusion This trial shows that adding anakinra to current standard care with IV corticosteroids in patients with ASUC did not reduce the need for rescue therapy or colectomy. This suggests that IL-1 blockade is not a therapeutic target in ASUC. There were no safety concerns with anakinra treatment.

Magnetic Resonance Imaging–Guided vs Computed Tomography–Guided Stereotactic Body Radiotherapy for Prostate Cancer

Magnetic resonance imaging (MRI) guidance offers multiple theoretical advantages in the context of stereotactic body radiotherapy (SBRT) for prostate cancer. However, to our knowledge, these advantages have yet to be demonstrated in a randomized clinical trial. To determine whether aggressive margin reduction with MRI guidance significantly reduces acute grade 2 or greater genitourinary (GU) toxic effects after prostate SBRT compared with computed tomography (CT) guidance. This phase 3 randomized clinical trial (MRI-Guided Stereotactic Body Radiotherapy for Prostate Cancer [MIRAGE]) enrolled men aged 18 years or older who were receiving SBRT for clinically localized prostate adenocarcinoma at a single center between May 5, 2020, and October 1, 2021. Data were analyzed from January 15, 2021, through May 15, 2022. All patients had 3 months or more of follow-up. Patients were randomized 1:1 to SBRT with CT guidance (control arm) or MRI guidance. Planning margins of 4 mm (CT arm) and 2 mm (MRI arm) were used to deliver 40 Gy in 5 fractions. The primary end point was the incidence of acute (≤90 days after SBRT) grade 2 or greater GU toxic effects (using Common Terminology Criteria for Adverse Events, version 4.03 [CTCAE v4.03]). Secondary outcomes included CTCAE v4.03-based gastrointestinal toxic effects and International Prostate Symptom Score (IPSS)-based and Expanded Prostate Cancer Index Composite-26 (EPIC-26)-based outcomes. Between May 2020 and October 2021, 156 patients were randomized: 77 to CT (median age, 71 years [IQR, 67-77 years]) and 79 to MRI (median age, 71 years [IQR, 68-75 years]). A prespecified interim futility analysis conducted after 100 patients reached 90 or more days after SBRT was performed October 1, 2021, with the sample size reestimated to 154 patients. Thus, the trial was closed to accrual early. The incidence of acute grade 2 or greater GU toxic effects was significantly lower with MRI vs CT guidance (24.4% [95% CI, 15.4%-35.4%] vs 43.4% [95% CI, 32.1%-55.3%]; P = .01), as was the incidence of acute grade 2 or greater gastrointestinal toxic effects (0.0% [95% CI, 0.0%-4.6%] vs 10.5% [95% CI, 4.7%-19.7%]; P = .003). Magnetic resonance imaging guidance was associated with a significantly smaller percentage of patients with a 15-point or greater increase in IPSS at 1 month (6.8% [5 of 72] vs 19.4% [14 of 74]; P = .01) and a significantly reduced percentage of patients with a clinically significant (≥12-point) decrease in EPIC-26 bowel scores (25.0% [17 of 68] vs 50.0% [34 of 68]; P = .001) at 1 month. In this randomized clinical trial, compared with CT-guidance, MRI-guided SBRT significantly reduced both moderate acute physician-scored toxic effects and decrements in patient-reported quality of life. Longer-term follow-up will confirm whether these notable benefits persist. ClinicalTrials.gov Identifier: NCT04384770.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Venglustat, a Novel Glucosylceramide Synthase Inhibitor, in Patients at Risk of Rapidly Progressing ADPKD: Primary Results of a Double-Blind, Placebo-Controlled, Phase 2/3 Randomized Clinical Trial

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD. STAGED-PKD was a 2-stage, multicenter, double-blind, randomized, placebo-controlled phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease, who were selected based on Mayo Clinic imaging classification of ADPKD class 1C, 1D, or 1E and an estimated glomerular filtration rate (eGFR) of 30-89.9mL/min/1.73m2. Enrollment included 236 and 242 patients in stages 1 and 2, respectively. In trial stage 1, the patients were randomized 1:1:1 to venglustat, 8mg; venglustat, 15mg; or placebo. In stage 2, the patients were randomized 1:1 to venglustat, 15mg (highest dose identified as safe and well tolerated in stage 1), or placebo. Primary end points were rate of change in TKV over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary end points were eGFR slope over 18 months (stage 1), rate of change in TKV (stage 2), and safety/tolerability, pain, and fatigue (stages 1 and 2). A prespecified interim futility analysis showed that venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (stage 1) and had a faster rate of decline in eGFR slope over 24 months (stage 2). Due to this lack of efficacy, the study was terminated early. The short follow-up period after the end of treatment and limited generalizability of the findings. In patients with rapidly progressing ADPKD, treatment with venglustat at either 8mg or 15mg showed no change in the rate of change in TKV and a faster rate of eGFR decline in STAGED-PKD despite a dose-dependent decrease in plasma glucosylceramide levels. This study was funded by Sanofi. Registered at ClinicalTrials.gov with study number NCT03523728.

Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial

BackgroundGiven the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A.MethodsA randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between −6.0 and −2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events.DiscussionLithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup.Trial registrationEudraCT number 2020-000579-19. Registered on 29 March 2021.

A novel, efficient and seamless Phase 2A‐2B design to test varoglutamstat in early AD: the VIVA‐MIND study

AbstractBackgroundImproved Phase 2 study designs may increase success rates in late stage AD trials. Varoglutamstat (PQ912) is an oral small molecule glutaminyl cyclase inhibitor designed to address several key disease mechanisms. A Phase 2A study (NCT02389413) of 120 early AD patients treated for 12 weeks provided preliminary evidence of safety and tolerability, and effects on working memory, CSF biomarkers, and synaptic function (EEG theta‐power).ObjectiveTo design a well‐powered, safe, and efficient study of varoglutamstat in early AD incorporating adaptive dose selection in Phase 2A, a futility analysis testing pharmacological, biological and cognitive criteria, and a seamless transition to a larger Phase 2B study investigating longer‐term efficacy and safety.MethodsAn efficient and safe selection rule across 3 descending doses (600mg, 300mg, 150 mg BID) was established using a continuously monitored Pocock safety boundary targeting a set of treatment emergent AE’s of interest. Well‐powered stage‐gate criteria at a planned interim futility analysis included thresholds for target occupancy in plasma, and would detect negative effects on a cognitive composite or absence of benefit on EEG theta‐power. The Phase 2B study was powered to detect an effect size of 0.7 points on the Clinical Dementia Rating – Sum of Boxes score at 18 months, an established approvable endpoint.ResultsThe on‐going Phase 2A adaptive dose‐finding trial (NCT03919162) is randomizing 180 subjects with MCI or mild probable AD, initially to 24+ weeks of 600mg varoglutamstat dose or placebo, BID. If the safety boundary is hit, the dose will be discontinued and all subjects titrated down, with similar sequential testing of lower doses as needed. The interim futility analysis will occur when the first 180 randomized subjects have been on study for at least 24 weeks. If this stage‐gate is passed, Phase 2B will enroll 234 additional patients to achieve 414 total patients treated for 72 weeks at full dose of varoglutamstat or placebo.ConclusionThis novel study design enables adaptive dose selection, an early interim futility analysis, and longer‐term determination of cognitive and functional efficacy, and should support robust proof‐of‐concept for varoglutamstat using a total sample of 414 subjects treated for 72 weeks.

Pembrolizumab and Chemotherapy in Newly-Diagnosed, Early Unfavorable or Advanced Stage Classic Hodgkin Lymphoma: The Phase 2 Keynote-C11 Study

Introduction: In a recent study, pembrolizumab followed by doxorubicin, vinblastine, and dacarbazine (AVD) had promising efficacy in patients (pts) with newly-diagnosed, early unfavorable, or advanced-stage classic Hodgkin lymphoma (cHL) (Allen et al. 2021; Blood 137:1318-26). The current phase 2 KEYNOTE-C11 study (NCT05008224) evaluates the safety and efficacy of pembrolizumab followed by AVD chemotherapy and pembrolizumab consolidation in pts with untreated, early unfavorable or advanced-stage cHL without radiotherapy. Here, we present results of a protocol-specified interim efficacy analysis. Methods: Eligible pts aged ≥18 years with newly-diagnosed, early unfavorable or advanced stage cHL received induction with pembrolizumab 200 mg IV on d1 every 3 weeks (Q3W) for 3 cycles. Pembrolizumab monotherapy was followed by PET2 to assess response. All pts then received 2 cycles of standard dose AVD on d1 and 15 for 2 cycles (chemotherapy phase 1), followed by PET3. PET3-negative pts (Deauville score 1-3) received 2-4 additional cycles AVD based on stage/bulk. Pts aged ≤60 yrs who were PET3-positive (Deauville score 4-5) received 2-4 cycles of escalated bleomycin plus etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (esc BEACOPP, chemotherapy phase 2). At the end of chemotherapy, all pts received consolidation with 4 cycles pembrolizumab 400 mg Q6W. A post-hoc interim analysis was performed for pts who had either reached or had discontinued treatment prior to PET3 response assessment. The primary analysis endpoints for this interim analysis were PET3 response (negativity rate) by investigator. The data cutoff date for the interim analysis reported here is July 15, 2022. Results: A total of 146 pts with untreated cHL were enrolled. The median (range) age was 34.5 yrs (18-78); 29 (20%) pts had bulky disease, 81 (55%) and 61 (42%), respectively, had advanced and early unfavorable disease, and 4 (3%) had missing data regarding disease group. At data cut-off, the median (range) follow-up was 3.2 mo (1.0-8.9). Of 146 pts, 46 (32%) were on pembrolizumab monotherapy, 42 (29%) were on chemotherapy phase 1, 34 (23%) were on chemotherapy phase 2, and 7 pts were on pembrolizumab consolidation. A total of 101 pts reached PET2 assessment or discontinued pembrolizumab monotherapy for any reason before PET2. Of these 26 (26%) were PET2-negative by investigator, 53 (52%) were PET2-positive, 9 (9%) discontinued treatment, and 13 (13%) had missing data. A total of 56 pts reached PET3 assessment or discontinued during chemotherapy phase 1. Of these, 38 (68%) were PET3-negative, 4 (7%) were PET3-positive, 11 (20%) had discontinued treatment, and 3 (5%) pts had missing data. Adverse events (AEs) of any grade occurred in 108 of 146 (74%) pts who received pembrolizumab monotherapy or consolidation, 63 of 89 (71%) who received AVD, and 1 of 2 (50%) who received BEACOPP. Grade ≥3 drug related adverse events were reported in 20 of 146 (14%) pts who received pembrolizumab monotherapy or consolidation, 48 of 89 (54%) pts who received AVD, and in 1 of 2 pts who received escBEACOPP. There were no deaths due to drug-related events. Immune mediated events were reported in 28 (19%) pts who received pembrolizumab monotherapy or consolidation. Most were low-grade 1-2 events reported in 20 (14%) pts, most commonly hyperthyroidism (5%) and hypothyroidism (3%). There were no deaths due to immune-mediated events. Conclusion: Pembrolizumab induction followed by chemotherapy was well tolerated in pts with newly-diagnosed, early unfavorable, or advanced-stage cHL, with 26% of pts achieving a PET2-negative response following the initial course of pembrolizumab alone and 68% having a PET3-negative response as assessed by investigator following the initial chemotherapy phase. Data from this PET-adapted regimen show promising antitumor activity and no safety concerns mid-treatment, indicating that this regimen may be an effective treatment option in this patient population. Data from the full preplanned protocol-specified interim futility analysis will be presented at the meeting.

Radiotherapy with Durvalumab vs. Cetuximab in Patients with Locoregionally Advanced Head and Neck Cancer and a Contraindication to Cisplatin: Phase II Results of NRG-HN004

<h3>Purpose/Objective(s)</h3> The optimal treatment for patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) and contraindication to cisplatin is uncertain. This trial (NCT03258554) tested the primary hypothesis that radiation therapy (RT) with concurrent and adjuvant durvalumab, a PD-L1 inhibitor, improves progression-free survival (PFS) compared to standard RT with cetuximab. <h3>Materials/Methods</h3> This phase II/III randomized trial enrolled patients ≥ 18 years of age who had previously untreated AJCC 8^th stage III-IVB SCC of the larynx, hypopharynx, oral cavity, p16- oropharynx/unknown primary (OPC/UP) or stage III and selected stage I-II p16+ OPC/UP, with a contraindication to cisplatin: ECOG performance status (PS) 2; renal or hearing impairment; peripheral neuropathy; age ≥ 70 with moderate/severe comorbidity; age < 70 with severe comorbidity. Favorable-risk p16+ HNSCC, PS >2, inadequate end-organ function, or active autoimmune disease were exclusion criteria. Patients were randomized 2:1 to RT (70 Gy, 35 fractions, 7 weeks) plus either: (arm A) durvalumab 1500 mg IV q4 weeks starting 2 weeks before RT (7 cycles) or (arm B) cetuximab 400 mg/m² IV 1 week prior to RT then 250 mg/m² weekly (8 cycles). The primary phase II endpoint was PFS with planned sample size of 234 randomized patients (69 PFS events, hazard ratio 0.65, 80% power, 1-sided alpha 0.20). The difference in PFS between arms was tested using a log-rank test. <h3>Results</h3> This study enrolled 190 patients (186 randomized; 123 arm A; 63 arm B) from Mar 2019-Jul 2021. Following planned interim futility analysis, the trial was temporarily closed to accrual, pending analysis based on total required phase II PFS events (met in Jun 2022). Median age was 72 years (59% ≥ 70). 95% had ≥ 3 comorbidities (median 5); 58% had T3-4; 49% had N2-3; 47% had p16+ OPC/UP. 87% in arm A and 89% in arm B completed RT. 89%/63% completed concurrent/adjuvant durvalumab and 81% completed ≥ 7 cycles of cetuximab. At median follow-up of 1.2 years, PFS was not improved and locoregional failure (LRF) was higher with durvalumab (Table). Grade ≥ 3 adverse events were 69%/79% for arm A/B. Grade ≥ 3 dysphagia, mucositis, and dermatitis rates were 22%/30%, 11%/20%, and 5%/13% for arm A/B, respectively. <h3>Conclusion</h3> Novel eligibility criteria and feasibility of accrual were established. However, RT with durvalumab did not show a signal toward improved PFS and led to significantly worse LRF, compared to RT with cetuximab in HNSCC pts with a contraindication to cisplatin. The trial will not move to phase III.

CTNI-52. A RANDOMIZED CONTROLLED TRIAL OF BERUBICIN, A DOXORUBICIN ANALOG THAT EFFECTIVELY CROSSES THE BLOOD-BRAIN BARRIER (BBB), AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM): PRELIMINARY RESULTS

Abstract Berubicin is a doxorubicin (Dox) analog that crosses the BBB with significant central nervous system (CNS) uptake. Berubicin prolongs survival in orthotopic mouse intracranial models with greater infiltration of the tumor compared to normal tissue. A Phase 1 dose-escalation study showed myelosuppression as the dose-limiting toxicity, with 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease for a clinical benefit rate of 44%.A trial of Berubicin vs Lomustine in patients with recurrent GBM after first-line therapy in the US and EU is enrolling patients in a 2:1 randomization design of Berubicin:Lomustine. Patients will be stratified by MGMT methylation status. The primary endpoint is overall survival (OS) and secondary endpoints include progression-free survival and overall response rates. Advanced imaging technology is being utilized for consistency in the evaluation of MRI scans. An interim futility analysis to explore the relative efficacy of these drugs will be conducted after up to half of the patients enrolled have reached 6 months of therapy. Currently, 31 patients are enrolled with 21 in the Berubicin arm and 10 in the Lomustine arm. At present these patients show comparable demographics, with an unmethylated MGMT population of ~60% in both arms. Patients with all grades of adverse events were 57% and 60% on the Berubicin and Lomustine arms, respectively. Grade 3-4 events were 43% (Berubicin arm) and 30% (Lomustine arm). Less than 10% of patients discontinued the study due to adverse events.The available data to date shows that Berubicin and Lomustine arms are presently balanced with relatively comparable safety profiles. This study is continuing to evaluate the efficacy of this novel drug with the goal of providing therapeutic options for patients after first-line therapy. An updated patient population profile, safety, and initial efficacy will be presented.

A Prospective, Randomized Trial Examining the Use of G-CSF Versus No G-CSF in Patients Post-Autologous Transplantation

Contemporary, prospective data regarding the impact of granulocyte-colony stimulating factor (G-CSF) on outcomes after autologous hematopoietic stem cell transplantation (Auto-HSCT) in an era when stem cell grafts are more qualitatively robust are limited. Recent retrospective analyses have not supported a beneficial effect of post-transplantation G-CSF use on major outcomes after Auto-HSCT leading to strategies to delay or eliminate the use of G-CSF altogether in this context. To test the hypothesis that the infusion of consistently higher doses of stem cells (defined as ≥4 × 106/kg) in Auto-HSCT will obviate the need for post-transplantation G-CSF. If so, the impact of withholding G-CSF will be noninferior to the use of G-CSF in terms of length of stay (LOS). The specific objectives were to conduct a prospective, randomized clinical trial primarily examining the impact of post-transplantation G-CSF on LOS, and secondarily on engraftment, infectious complications, antibiotic usage, and incidence of engraftment syndrome after Auto-HSCT in patients receiving versus not receiving G-CSF after Auto-HSCT. Patients with multiple myeloma or non-Hodgkin lymphoma (NHL) who underwent Pegfilgrastim plus Plerixafor-primed stem cell collection followed by Auto-HSCT were randomized to the G-CSF group (receive G-CSF starting at day 3 after Auto-HSCT) or the no G-CSF group (G-CSF withheld after Auto-HSCT). Seventy patients per arm were planned to demonstrate the primary endpoint of noninferiority in LOS between the G-CSF and the no G-CSF groups. Patient outcomes in the two groups were followed up and compared after Auto-HSCT, and an interim analysis for futility was planned when accrual reached 50%.The primary finding of this study was that despite only a 2-day longer median absolute neutrophil count (ANC) recovery in the no G-CSF arm (median 11 versus 13 days; P = .001), LOS was 4 days longer in patients not treated with G-CSF (median 11 days versus 15 days; P = .001). G-CSF use was associated with more robust incremental daily increases in ANC once recovered (P = .001), fewer days of febrile neutropenia (P = .001), and fewer days on antibiotics (P = .001), potentially contributing to this disproportionate finding. Inferiority in LOS in the no G-CSF group was demonstrated on the interim analysis, and the study was closed at the half-way point. There were no significant group differences in platelet recovery, documented infections, hospital readmissions, or overall survival at 1 year. Engraftment syndrome occurred in 54.3% of patients and was not related to G-CSF use. These results suggest that the increased LOS associated with the omission of G-CSF is largely due to concerns regarding the potential for infection in patients without a stable, recovered ANC in a hospital setting. Engraftment syndrome represented a significant source of febrile neutropenia further contributing to patient safety concerns and requires strategies to decrease its incidence. Infectious complications and death were not affected by the omission of G-CSF supporting a carefully monitored outpatient approach to Auto-HSCT in which white blood cell growth factor is eliminated or given as needed for documented infection.© 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial

ObjectiveTo determine the efficacy and safety of extended duration perioperative thromboprophylaxis by low molecular weight heparin when assessing disease-free survival in patients undergoing resection for colorectal cancer.DesignMulticentre, open label, randomised...

Impact of Androgen Deprivation Therapy on Cardiovascular Outcomes in Prostate Cancer

Purpose: Substantial evidence indicates that men with prostate cancer are at an increased risk for cardiovascular disease, and medical and surgical androgen deprivation therapy is associated with further increased cardiovascular risk. There are conflicting reports of differences in cardiovascular safety between gonadotropin-releasing hormone (GnRH) agonists and antagonists. The purpose of this narrative review is to compare data on the cardiovascular risks and safety outcomes associated with different hormonal treatment options in prostate cancer patients and to provide guidance on how to manage the increased risk associated with the condition. Methods: A PubMed search was conducted for papers published in the last 15 years using the following MeSH terms: “prostate neoplasms,” “gonadotropin-releasing hormone,” “androgen agonist,” “androgen antagonists,” “cardiovascular disease,” “epidemiology.” Results: Evidence regarding the risk of cardiovascular events during treatment with GnRH agonists and antagonists is conflicting. Some retrospective studies have shown that agonists are associated with a greater risk of cardiovascular disease and cardiovascular mortality and morbidity, and a similar risk with agonists and combined androgen blockade. Some studies have reported that antagonists are associated with a decreased risk of cardiovascular mortality and morbidity compared with agonists. With respect to coronary heart disease, ischemic heart disease, myocardial infarction, stroke, or sudden cardiac death, current evidence has failed to demonstrate a significant difference between antagonists and agonists. Cardiovascular risks in patients should be mitigated by regular monitoring of blood pressure, blood glucose, and lipids, as well as counseling patients to abstain from alcohol and improve their diet and exercise. Statins, metformin, and aspirin should also be considered. Conclusions: The evidence for the increased cardiovascular risk of GnRH agonists over antagonists for androgen deprivation therapy is unclear. Differences in methodology, population sizes, risk stratification, and outcomes between studies make direct comparisons problematic. The single prospective, randomized prostate cancer trial with a primary cardiovascular end point in men with pre-existing cardiovascular disease comparing GnRH agonist to antagonist was stopped early due to an interim futility analysis. The results are inconclusive.

A randomized control trial of high-dose micronutrient-antioxidant supplementation in healthy persons with untreated HIV infection

Although micronutrient and antioxidant supplementation are widely used by persons with human immunodeficiency virus (HIV), a therapeutic role beyond recommended daily allowances (RDA) remains unproven. An oral high-dose micronutrient and antioxidant supplement (Treatment) was compared to an RDA supplement (Control) for time to progressive immunodeficiency or initiation of antiretroviral therapy (ART) in people living with HIV (PLWH). This study was a randomized, double-blind, placebo-controlled multicenter clinical trial. PLWH were recruited from Canadian HIV Trials Network sites, and followed quarterly for two years. Eligible participants were asymptomatic, antiretroviral treatment (ART)-naïve, HIV-seropositive adults with a CD4 T lymphocyte count (CD4 count) between 375-750 cells/μL. Participants were randomly allocated 1:1 to receive Treatment or Control supplements. The primary outcome was a composite of time-to-first of confirmed CD4 count below 350 cells/μL, initiation of ART, AIDS-defining illness or death. Primary analysis was by intention-to-treat. Secondary outcomes included CD4 count trajectory from baseline to ART initiation or two years. A Data and Safety Monitoring Board reviewed the study for safety, recruitment and protocol adherence every six months. Of 171 enrolled participants: 66 (38.6%) experienced a primary outcome: 27 reached a CD4 count below 350 cells/μL, and 57 started ART. There was no significant difference in time-to-first outcome between groups (Hazard Ratio = 1.05; 95%CI: 0.65, 1.70), or in time to any component outcome. Using intent-to-treat censoring, mean annualized rates of CD4 count decline were -42.703 cells/μL and -79.763 cells/μL for Treatment and Control groups, with no statistical difference in the mean change between groups (-37.06 cells/μL/52 weeks, 95%CI: (-93.59, 19.47); p = 0.1993). Accrual was stopped at 171 of the 212 intended participants after an interim analysis for futility, although participant follow-up was completed. In ART-naïve PLWH, high-dose antioxidant, micronutrient supplementation compared to RDA supplementation had no significant effect on disease progression or ART initiation. ClinicalTrials.gov Identifier: NCT00798772.

PMED: Optimal Bayesian Platform Trial Design with Multiple Endpoints

ABSTRACT In oncology drug development, indication selection and optimal dose identification are the primary objectives for the early phase of clinical trials and could significantly impact the probability of success. Master protocols, e.g., basket trial, umbrella trial, and platform trial, have become popular in practice considering the connection of trial designs with multiple indications and treatment candidates. They also enable the optimization of operational resources and maximize the capability of data-driven decision-making. However, most of the available designs are developed with the efficacy endpoint only for treatment effect estimation and testing, without consideration of the safety end point. Thus, it often lacks a comprehensive quantitative framework to allow optimal treatment selection, which could put future development at risk. We propose an optimal Bayesian platform trial design with multiple end points (PMED) to characterize the overall benefit-risk profile. The design is further extended to allow treatment and indication selection within and across arms, with continuous monitoring on multiple interim analyses for futility. In addition, we propose dynamic borrowing across arms to increase the efficiency and accuracy of estimation given the level of similarity across arms. A hierarchical hypothesis structure is utilized to achieve optimal indication and treatment combination selection by controlling family-wise error. Through simulation studies, we show that PMED is a robust design under the studied scenarios with superb power and controlled family-wise error rate.

Abstract CT530: Multiorgan metabolic imaging response assessment of abemaciclib (MiMe-A): Oncodistinct 002

Abstract Background: Abemaciclib (A) activity against breast cancer as monotherapy or combined with endocrine therapy warrants further investigations in other cancer types. However, its significant toxicity profile illustrates the challenge of defining more precisely the patients unlikely to benefit from it, sparing them from useless toxicities. FDG-PET/CT can identify treatment-refractory disease with high negative predictive value, soon after the treatment onset and before morphological changes are observed. MiMe-A was built on the assumption that a therapy that does not induce tumoral metabolic changes 14 days after its onset is unlikely to achieve a significant clinical benefit. Methods: A multicenter phase II basket trial assessed the efficacy of A in 5 cancers types (cholangiocarcinoma, endometrial, urothelial carcinomas, oesophagal adeno- and squamous cell carcinomas). The primary endpoint is the ‘treatment success’, defined as metabolic response according to PERCIST at FDG-PET/CT performed during the first cycle (D14) and absence of disease progression per RECIST 1.1 after two cycles of A. A Simon’s 2-stage design was used in each cohort based on the null hypothesis that the treatment success rate will be ≤20%. An interim analysis for futility was performed on each cohort after accrual of 17 patients during the first stage. Results: The baseline characteristics and the metabolic and morphologic evaluation of eligible patients are shown below. *: stop treatment before the two months (due to progression or toxicities) IQR: interquartile range, PR: partial response, SD: stable disease, PD: progressive disease The treatment success rate was 0% for each cancer type except for urothelial carcinoma (5,9% (1/17 treatment success). Toxicities were mainly graded 1 or 2, including diarrhea, nausea, fatigue and haematological. Conclusion: A did not show significant anti-tumour activity in any of the five cohorts. But early metabolic response was noted in 29% of the oesophageal squamous cell carcinoma population, this finding did not translate in disease control at two months. This could be explained by an initial response rapidly followed by tumoral escape. A combination of A with other drugs should be explored in this cancer type. Esophageal adenocarcinomaN=17 Esophageal Squamous cell carcinomaN=17 CholangiocarcinomaN=17 Endometrial carcinomaN=17 Urothelial CarcinomaN=17 Baselinecharacteristics Age range 36-83 56-77 50-85 57-84 46-80 Median age (IQR) 65 (55-68) 67 (63-71) 70 (67-74) 68(64-73) 67 (63-71) Median number of lines of prior treatments (IQR) 3 (2-4) 3 (2-4) 2 (1-2) 3 (2-3) 3 (2-3) Metabolic response (PERCIST) assessment Complete metabolic response 0/17 0/17 0/17 0/17 0/17 Partial metabolic response 2/17 5/17 1/17 0/17 2/17 Stable metabolic disease 8/17 4/17 5/17 8/17 7/17 Progressive metabolic disease 4/17 7/17 9/17 6/17 4/17 Not evaluable 3/17 1/17 2/17 3/17 4/17 % Complete or partial metabolic response (95% CI) 12% (2%-36%) 29% (10%-56%) 6% (0%-29%) 0% (0%-20%) 12% (1%-36%) Response by RECIST (after 2 cycles) PR 1/17 1/17 0/17 0/17 0/17 SD 3/17 2/17 5/17 5/17 8/17 PD 6/17 10/17 7/17 9/17 8/17 Not available* 7/17 4/17 5/17 3/17 1/17 Citation Format: Laura Polastro, Nuria Kotecki, Diogo Martins-Branco, Diane Delaroche, Philippe Barthelemy, Stephane Holbrechts, Philippe Vergauwe, JC Goemine, Gauthier Demolin, Hans Prenen, Florian Clatot, Carlos Gomez Roca, Paulus Kristanto, Marianne Peasmans, Ahmad Awada, Alain hendlisz, Aurélien Carnot, Fransceco Sclafani, Philippe Aftimos. Multiorgan metabolic imaging response assessment of abemaciclib (MiMe-A): Oncodistinct 002 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT530.

Abstract CT232: A randomized, multicenter, placebo-controlled, phase III study to evaluate the efficacy and safety of HER2/neu peptide GLSI-100 (GP2 + GM-CSF) in patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01

Abstract Background: GP2 is a biologic nine amino acid peptide of the HER2/neu protein delivered in combination with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) that stimulates an immune response targeting HER2/neu expressing cancers. In a prospective, randomized, single-blinded, placebo-controlled, multicenter Phase IIb study, no recurrences were observed in the HER2+ population after 5 years of follow-up, if the patient received the 6 primary intradermal GLSI-100 injections (p = 0.0338). Immunotherapy elicited a potent response measured by skin tests and immunological assays. Of the 146 patients that have been treated with GLSI-100 over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events were observed considered related to the immunotherapy. Trial Design: This Phase 3 trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years for a total of 11 injections over 3 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up for a total of 4 years following the first year of treatment with trastuzumab-based therapy. Patients will be stratified based on residual disease status at surgery, hormone receptor status, prior pertuzumab therapy and region. Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. Eligibility Criteria: The patient population is defined by these key eligibility criteria: 1. HER2/neu positive and HLA-A*02 2. Residual disease or High risk pCR (Stage III at presentation) post neo-adjuvant therapy 3. Exclude Stage IV 4. Completed at least 90% of planned trastuzumab-based therapy Trial Objectives: 1. To determine if GP2 therapy increases IBCFS 2. To assess the safety profile of GP2 3. To monitor immunologic responses to treatment and assess relationship to efficacy and safety Accrual: Site selection and study start-up is in progress at multiple sites. Target enrollment is 598 subjects. Contact information: Snehal Patel Greenwich LifeSciences, Inc. Stafford, TX Email: snehal.patel@greenwichlifesciences.com Website: greenwichlifesciences.com Funding: This trial is supported by Greenwich LifeSciences. Citation Format: Snehal S. Patel, Jaye Thompson, Mira S. Patel, F. Joseph Daugherty, C. Kent Osborne, Mothaffar F. Rimawi. A randomized, multicenter, placebo-controlled, phase III study to evaluate the efficacy and safety of HER2/neu peptide GLSI-100 (GP2 + GM-CSF) in patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT232.

A phase II/III, randomized, open-label, multicenter study of BI 907828 compared to doxorubicin in the first-line treatment of patients with advanced dedifferentiated liposarcoma (DDLPS): Brightline-1.

TPS11586 Background: The standard of care in the first-line treatment of patients (pts) with unresectable/metastatic DDLPS is doxorubicin, despite only moderate efficacy and many associated adverse events (AEs). BI 907828 is a mouse double minute 2 (MDM2)–p53 antagonist that binds to MDM2 and blocks its interaction with p53, leading to p53 stabilization, TP53 target gene induction, cell-cycle arrest and apoptosis in TP53 wild-type tumor cells. In a Phase I study, BI 907828 monotherapy demonstrated a manageable safety profile and preliminary signs of efficacy, particularly in pts with DDLPS (Gounder et al, ESMO 2021). Methods: NCT05218499 is a Phase II/III, randomized, open-label, international, multicenter study (̃125 sites) that aims to evaluate whether BI 907828 is superior to doxorubicin in the first-line treatment of advanced/metastatic DDLPS. In the Phase II part, ≤180 pts will be randomized 1:1:1 to receive BI 907828 30 mg or 45 mg orally every 3 weeks (q3w), or doxorubicin 75 mg/m2 intravenously q3w to a maximum cumulative dose of 450 mg/m2. Main inclusion criteria include: ≥18 years of age; histologically proven advanced/metastatic, unresectable DDLPS; positive MDM2 immunohistochemistry or amplification; ≥1 measurable target lesion (RECIST v1.1); and ECOG PS 0/1. Exclusion criteria include a known TP53 gene mutation and prior systemic therapy for liposarcoma. In the experimental arm, treatment will continue until disease progression, unacceptable AEs, or consent withdrawal. Pts who receive doxorubicin may cross-over to receive BI 907828 after confirmed progressive disease. The primary endpoint is progression-free survival (PFS; based on blinded independent central review), defined as the time from randomization to tumor progression (RECIST v1.1) or death from any cause, whichever occurs first. Secondary endpoints are objective response (OR), duration of OR, overall survival, disease control, and pt-reported health-related quality of life. In Phase II, an interim analysis (based on the totality of safety and PK/PD data) will be used to select the optimal BI 907828 dose. Subsequently, an interim futility analysis will be performed after ̃56 PFS events using a log-rank test stratified by the extent of disease (locally advanced vs metastatic). If the selected BI 907828 dose passes the futility boundary, the trial will proceed to Phase III. In the Phase III part, ≥120 additional pts will be randomized 1:1 to receive the selected BI 907828 dose or doxorubicin. The primary PFS analysis will be performed after ̃92 and ̃65 PFS events in pts enrolled before and after the interim futility analysis, respectively, using a weighted inverse normal method combining one-sided p-values from a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05218499.

A phase II trial evaluating combination pemetrexed and avelumab in patients with MTAP-deficient advanced urothelial cancer.

TPS4612 Background: MTAP-deficiency occurs primarily due to homozygous loss in chromosome 9p21 and is seen in approximately 25% of urothelial cancers. MTAP-deficiency portends aggressive biology with poorer outcomes than in MTAP-proficient tumors; for example, in the IMvigor210 data, MTAP-deficient patients had median overall survival of 8.0 months, compared to 11.3 months in MTAP-proficient patients (p = 0.042). MTAP-deficient tumors lack salvage nucleotide synthesis pathways and thus are uniquely sensitive to anti-folate agents; however, in prior clinical work with pemetrexed in these tumors, responses are relatively short-lived. In-vivo data has suggested that pemetrexed can increase tumor infiltrating T-cells, macrophages, dendritic cells, and PD-L1 expression in MTAP-deficient tumors and decrease myeloid-derived suppressor cells (MDSCs). As such, it was postulated that sequential treatment with anti-folate chemotherapy (pemetrexed) and immune checkpoint inhibition (avelumab) would improve responses in MTAP-deficient urothelial cancer. Methods: A prospective phase II trial of patients with advanced MTAP-deficient urothelial cancer is being conducted under IRB-approved protocol NCT03744793. This study will enroll 25 patients at a single site (The University of TX, MD Anderson Cancer Center). Key eligibility criteria include patients with advanced MTAP-deficient urothelial cancer with measurable disease in second-line or beyond. MTAP-deficiency is confirmed with CLIA-approved IHC or NGS. Patients are stratified as being IO-pretreated versus IO-naïve. All patients receive a lead-in cycle of pemetrexed (500 mg/m2) followed by combination pemetrexed (500 mg/m2) and avelumab (10 mg/kg) IV every three weeks until disease progression, patient withdrawal, or unacceptable toxicity. Three biopsies per patient with tissue collection at trial baseline, on single agent pemetrexed, and on combination pemetrexed-avelumab are performed. The primary objective of this trial is to evaluate response rate with sequential pemetrexed and avelumab in MTAP-deficient urothelial cancer. Imaging response assessment is done via RECIST v1.1. Secondary objectives are to evaluate progression-free survival (PFS) and overall survival (OS), as well as to perform correlative studies evaluating the effect of this therapy on immune cells and tumor microenvironment. This correlative work includes but is not limited to evaluation of peripheral T-cells, tumor-infiltrating T-cells, macrophages, and MDSCs. Interim analyses for futility and safety occur in cohorts of 5 patients and are performed based on Bayesian sequential methods. Fifteen patients have been enrolled thus far. Clinical trial information: NCT03744793.

Radiosurgery dose reduction for brain metastases on immunotherapy (RADREMI): Results of an a priori interim analysis of a multicenter phase I trial.

2013 Background: Symptomatic radiation necrosis rates in patients treated with immune checkpoint inhibitor (ICI) therapy and concomitant single-fraction stereotactic radiosurgery (SRS) are as high as 20% (PMID: 29327059). We present updated results from the Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI) trial following completion of an a priori interim analysis, aimed to identify reduced-dose SRS that is safe and efficacious for this patient population. Methods: RADREMI (clinicaltrials.gov, NCT04047602) is a prospective multicenter single arm Phase I trial involving patients age &gt; 18 receiving ICI with SRS for 1-10 brain metastases on MRI. Patients had biopsy-confirmed primary malignancy with disease-specific graded prognostic assessment estimated median survival of at least 6 months and no previous whole brain radiation therapy. Six-month symptomatic radiation necrosis (radiographic radiation necrosis + clinical symptoms requiring steroid administration and/or operative intervention) was the primary endpoint, based on an expected rate of 5% and a historical rate of 16%. Secondary endpoints included 6-month local control and radiographic radiation necrosis. Response Assessment in Neuro-Oncology criteria defined local control; findings were compared to historical 6-month local control of 87-91% with RTOG 90-05 SRS dosing. A pre-determined interim futility analysis (based on the null hypothesis of no fewer than 15 of the first 20 patients reaching the primary endpoint achieving 6-month local control for RADREMI dosing) was performed using the Fisher’s exact test. Results: Between December 18, 2019 and September 10, 2021, 43 lesions were treated in 16 patients receiving ICI delivered within 30 days before SRS who were enrolled on trial and met the primary endpoint (median follow-up = 9.1 months). All patients received RADREMI SRS dosing (18 Gy for lesions 0-2 cm, 14 Gy for lesions 2.1-3 cm, and 12 Gy for lesions 3.1-4 cm). The most common ICI used was single-agent pembrolizumab (51% of lesions, 56% of patients), followed by single-agent nivolumab (28% of lesions, 13% of patients). The six-month rates of symptomatic and radiographic radiation necrosis were zero; the six-month local control rate was 98% per treated lesion (42/43), and 94% per treated patient (15/16), comparable to historical controls (p &gt; 0.05) and sufficient to not reject the interim futility analysis null hypothesis. Conclusions: Interim analysis reveals that the safety and efficacy of RADREMI dosing for reducing SRS dose in brain metastasis patients receiving concomitant ICI persists with excellent local control and no morbidity in a multi-institutional collaborative trial. Further results following completion of trial enrollment will provide additional evidence regarding the safety and efficacy of RADREMI SRS dosing. Clinical trial information: NCT04047602.