Interim Futility Analysis Research Articles

Phase 2 randomized trial of neoadjuvant or palliative chemotherapy with or without immunotherapy for peritoneal mesothelioma (Alliance A092001).

TPS8598 Background: Peritoneal mesothelioma is a rare and poorly studied disease with few treatment options. For patients who are not surgical candidates, treatment recommendations for systemic therapy have been extrapolated from clinical trials for pleural mesothelioma that commonly exclude patients with peritoneal mesothelioma. Recently, the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab received FDA-approval for the frontline treatment of non-resectable pleural mesothelioma. Additionally, a prospective, non-randomized phase 2 trial demonstrated activity with combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade in peritoneal mesothelioma. In parallel, encouraging activity with combined chemo-immunotherapy has been reported in pleural mesothelioma. Given the benefits observed with immunotherapy, and the potential to improve upon those with chemotherapy and VEGF inhibition, we seek to determine whether the addition of the PD-L1 inhibitor atezolizumab improves outcomes with chemotherapy and bevacizumab in patients with newly diagnosed peritoneal mesothelioma. Methods: A092001 is a prospective, randomized phase 2 clinical trial. All patients with newly diagnosed peritoneal mesothelioma will be randomized 1:1 using a dynamic allocation Pocock-Simon procedure to receive carboplatin, pemetrexed, and bevacizumab, with or without atezolizumab, every 21 days for four cycles. Patients who are eligible to proceed with surgery after four cycles of therapy will then do so. Patients who are not eligible to proceed with surgery may receive maintenance bevacizumab and atezolizumab, or second-line atezolizumab with bevacizumab until progression of disease or toxicity. The primary objective is to determine whether frontline treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab results in a superior best response rate (RR) to carboplatin, pemetrexed and bevacizumab as determined by RECIST. With 31 eligible patients per arm (62 eligible total), this randomized design has 80% power to detect an improvement in the RR from 20% to 45%, with a 1-sided significance level of 0.10 where an interim futility analysis will be conducted after 32 patients are enrolled. As stratification factors we have included eligibility for cytoreductive surgery at diagnosis, and histologic subtype. Secondary endpoints include assessment of progression-free survival, overall survival, and adverse events. As integrated biomarkers, we will determine if soluble mesothelin-related peptides and megakaryocyte potentiating factor correlate with responses. This trial was recently approved by the National Cancer Institute Central IRB and is activating at sites across the country. Support: U10CA180821, U10CA180882. Clinical trial information: NCT05001880.

Phase 2 study to evaluate palbociclib in combination with irinotecan and temozolomide in pediatric patients with recurrent or refractory Ewing sarcoma.

TPS11583 Background: Palbociclib (PD-0332991) is a highly selective, reversible, small molecule inhibitor of cyclin-dependent kinases (CDK) 4 and 6, administered orally. Functional dependence of Ewing Sarcoma (EWS) cell lines and tumor xenografts on Cyclin D1/CDK4 via genetic knockdown has shown both Cyclin D1 and CDK4 as critical dependencies for EWS cell line proliferation. The phase 1 portion of the study established the recommended Phase 2 dose (RP2D) with two chemotherapy backbones in children with solid tumors. The Phase 2 portion of the study now enrolls patients with EWS. The primary objective of this portion of the study is to determine whether the addition of palbociclib to irinotecan (IRN) and temozolomide (TMZ) will prolong event-free survival (EFS) of pediatric and young adult patients with recurrent or refractory EWS. Methods: Patients with recurrent or refractory EWS are randomized 2:1 to receive either palbociclib in combination with IRN and TMZ or IRN and TMZ alone. Randomization is stratified by type and time of disease recurrence (primary refractory or 1st recurrence <2 years vs. 1st recurrence ≥2 years or 2nd or greater recurrence). The primary efficacy endpoint is EFS per investigator assessment. Secondary efficacy endpoints include objective response, progression-free survival and overall survival. An interim futility analysis will be conducted to allow for early stopping of the study due to futility/no signal of activity based on the primary endpoint of EFS. Safety and planned interim efficacy data will be assessed by an Independent Data Monitoring Committee (DMC). Key eligibility criteria include: recurrent or refractory EWS with evaluable disease, no known bone marrow metastases, histopathological confirmation of EWSR1-ETS or FUS-ETS rearrangement or availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample for central testing, age ≥2 and <21 years at the time of study entry. Treatment intervention: Patients randomized to palbociclib with IRN and TMZ treatment arm will receive palbociclib at the RP2D of 75 mg/m2 orally (either as a capsule or oral solution) once daily on Days 1-14 of each 21-day treatment cycle. TMZ will be administered orally once daily at 100 mg/m2 on Days 1-5 (intravenously (IV) if patient cannot swallow the TMZ capsule). IRN will be administered IV at 50 mg/m2 on Days 1-5. Patients randomized to the chemotherapy only treatment arm will receive IRN and TMZ at the same doses on Days 1-5 of the 21-day treatment cycle. Treatment will continue until disease progression, patient and/or legal guardian refusal, unacceptable toxicity , or up to 24 months of treatment, whichever occurs first. The Phase 2 enrolment has been initiated and 1/75 patients has been enrolled as of Jan 2022. Clinical trial information: NCT03709680.

FLORA-5/GOG3035: Frontline chemo-immunotherapy (paclitaxel-carboplatin-oregovomab [PCO] versus chemotherapy (paclitaxel-carboplatin-placebo [PCP]) in patients with advanced epithelial ovarian cancer (EOC)—Phase III, double-blind, placebo-controlled, global, multinational study.

TPS5619 Background: Oregovomab, a murine IgGκ1 monoclonal antibody, has high affinity binding to tumor associated antigen CA125, thus, rendering the target antigen CA125 more immunogenic or “neoantigen-like” through altered and enhanced antigen processing and presentation to specific T cells. This phenomenon is hypothesized to bypass tumor-associated immune suppression when oregovomab is combined with chemotherapy. In a randomized phase II study, oregovomab in combination with paclitaxel and carboplatin (PC) induced tumor immunity and demonstrated significant improvement in median PFS (41.8 months(m) PCO vs 12.2 m PC, HR 0.46, p=0.0027) and median OS (N.E. PCO vs 43.2 m PC, HR O.35, p=0.043) in patients with previously untreated EOC. Oregovomab combined with PC had a favorable toxicity profile. FLORA-5/GOG3035, the definitive confirmatory global registration trial, is currently recruiting patients in the front-line setting. Methods: The study is a phase 3, multicenter, double-blind, placebo-controlled trial. Optimally debulked patients with FIGO III/IV EOC and serum CA125 ≥ 50 U/ml receiving adjuvant (Cohort 1) or patients receiving neoadjuvant chemotherapy post-interval cytoreductive surgery (Cohort 2) will be randomized to PC + oregovomab or placebo (PCO vs. PCP). Patients with germline BRCA1/2 mutations are excluded. Chemotherapy will be administered every 3 weeks in both cohorts. Oregovomab/placebo is administered simultaneously at cycles 1, 3, and 5 of chemotherapy with an additional dose at 12 weeks following cycle 5 in Cohort 1. Neoadjuvant patients will be administered oregovomab/placebo after debulking surgery at cycles 4 and 6 with two additional doses at 6- and 18-weeks following cycle 6 in Cohort 2. No other front-line maintenance therapy is permitted. The primary objective is PFS determined by RECIST 1.1. Cohort 1 will recruit 372 patients with a 90% power to detect a difference with an alpha of 0.025 and a hazard ratio of 0.65 when 252 PFS events have been observed. Cohort 2 will be analyzed separately recruiting 232 patients with a 90% power to detect a difference with an alpha of 0.025 and a hazard ratio of 0.60 when 165 PFS events have been observed. An interim futility analysis will be performed. Secondary objectives include OS, frequency and severity of AEs, and QoL. Exploratory objectives include iRECIST, TFST, TSST, PFS2, and evaluation of correlative biomarkers. The study is actively enrolling in the US, Canada, Belgium, Italy, Spain, Czech Republic, Hungary, Poland, Korea, Taiwan, Mexico, Argentina, and Chile. 179 patients were enrolled at time of submission. Clinical trial information: NCT04498117.

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.

TPS1110 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, the combination known as GLSI-100. 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 was treated with GLSI-100, survived and was followed from more than 6 months ( 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. Methods: 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 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: HER2/neu positive and HLA-A*02; Residual disease or High risk pCR (Stage III at presentation) post neo-adjuvant therapy; Exclude Stage IV; Completed at least 90% of planned trastuzumab-based therapy. Trial Objectives: To determine if GP2 therapy increases IBCFS; To assess the safety profile of GP2; 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. Clinical trial information: 05232916.

ROCC/GOG-3043: A randomized non-inferiority trial of robotic versus open radical hysterectomy for early-stage cervical cancer.

TPS5605 Background: Minimally invasive surgery (MIS) is associated with improved perioperative safety outcomes, but, in 2018, the Laparoscopic Approach to Cervical Cancer (LACC) trial, a non-inferiority study comparing laparoscopic versus open radical hysterectomy for early stage cervical cancer, reported significantly worse disease-specific (DSS) and overall survival (OS) in the MIS group. Criticisms of the LACC trial include lack of proper preoperative imaging and assessment, use of transcervical uterine manipulators, and lack of proper tumor containment leading to peritoneal contamination. Subsequent retrospective studies have reported conflicting results. Given the potential benefit of MIS, the ROCC trial seeks to address the limitations of the LACC trial. Methods: ROCC is a multi-center, prospective, randomized, non-inferiority trial. The primary objective is to determine whether robotic-assisted (RBT) radical hysterectomy is not inferior to abdominal (OPEN) approach with respect to 3-year disease-free survival (DFS). Secondary objectives include DSS, OS, patterns of recurrence, peri- and postoperative complications, long-term morbidity, impact on patient-reported outcome (PRO) measures and development of lower extremity lymphedema (LEL). Key inclusion criteria include patients with histologically confirmed adenocarcinoma, squamous cell, and adenosquamous cell carcinoma of FIGO 2018 stage IA2-IB2. All patients must have a preoperative pelvic MRI confirming that the cervical tumor is < 4 cm in size, no obvious evidence of extracervical extension and no nodal or other regional metastasis. Intraoperatively, the use of transcervical uterine manipulators is not allowed and specific detailed surgical techniques for proper tumor containment is required. Photographic evidence of specimen with tumor contained is mandated. We estimate the 3-year DFS to be 92% in the control (OPEN) arm. If the DFS does not differ by more than 7% and the one-sided 95% CI does not cross the non-inferiority boundary, then the RBT arm will be deemed non-inferior. 840 patients will be enrolled (420 per arm, 89 events total), which provides 90% power to exclude an absolute decrease in DFS by 7% (HR < = 1.375) with a log-rank test for non-inferiority with a one-sided alpha of 0.05. The primary analysis will be conducted in all randomized patients (ITT). Given the LACC findings of worse oncologic outcomes with MIS, a formal DSMC will conduct periodic reviews of safety including two planned formal interim analyses for futility (harm) after accrual of 370 and 640 patients using an aggressive Lan-DeMets beta-spending function similar to a Pocock boundary. Results of this trial may be practice changing and will either support or refute the findings of the LACC trial. The study is currently activating sites for enrollment. Clinical trial information: NCT04831580.

Interim results of a phase II multicenter study with the oral histone deacetylase inhibitor abexinostat in patients with relapsed/refractory follicular lymphoma.

7513 Background: Follicular lymphoma (FL) is generally considered incurable with patients (pts) often experiencing multiple relapses requiring varying lines of subsequent treatments. Abexinostat (Abx) is a novel potent oral pan- Histone Deacetylase Inhibitor (HDACi) with a pharmacokinetic profile that allows maintenance of sufficient drug concentrations for anti-tumor activity with twice daily (BID) dosing. In prior phase 1/2 studies, Abx was shown to be well-tolerated with significant clinical activity and durable responses in patients with Relapsed/Refractory (R/R) FL. Methods: This open label, single arm study is being conducted to assess the efficacy and safety of Abx in pts with R/R FL. Adults with histologically confirmed grade 1, 2 or 3a FL who have previously received at least 2 lines of therapies, and ECOG PS of 0-2 are being recruited. Abx is administered orally at 80 mg BID 4 hours apart in “one week on, one week off” schedule (Days 1 to 7 & 15 to 21 of a 28-day cycle). Pts undergo efficacy assessment by enhanced CT/MRI every 8 weeks for the first 24 weeks, and every 12 weeks thereafter, and PET-CT at weeks 12 and 24 and to confirm a complete response, in accordance with the Lugano 2014 criteria. The primary endpoint is overall response rate (ORR) assessed by independent review committe (IRC), defined as the % of pts who achieve complete response (CR) or partial response (PR). Secondary endpoints include duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. In a planned interim futility analysis conducted with the first 37 pts, if <12/37 (32%) responded (CR or PR), the study was to be terminated. Results: Between June 17, 2020 and Jan 28, 2022, 41 pts received Abx. 37 pts underwent at least one post baseline tumor assessment. Median age was 55 (range 34 – 79), 46% of pts were male, 70% had stage IV disease and 24% had >3 FLIPI-2. Pts had a median of 3 prior lines of therapy (range 2-6), and 22% were refractory to the last prior treatment. As of the data cutoff date on Jan 31, 2022, of 37 pts evaluable for efficacy, the ORR was 70% (26/37 pts), 16% CR (6/37) and the disease control rate was 92% (34/37). The median time to response was 10.8 weeks. The study has met the pre-defined stage I criteria and has entered stage II, aiming to enroll up to 81 evaluable pts. Of 41 pts evaluable for safety, the most common treatment emergent adverse events (TEAEs) (≥ 30%) were thrombocytopenia (85%), diarrhea (61%), neutropenia (54%), leukopenia (49%), asthenia (39%), nausea (37%), and anemia (34%). Grade ≥ 3 TEAEs (≥ 5%) included thrombocytopenia (41%), neutropenia (27%), leukopenia (7%), lymphopenia (7%), prolonged QT (7%), and anemia (5%). One pt discontinued treatment due to AEs. Conclusions: Oral Abx demonstrated promising efficacy and was well tolerated in patients with R/R FL. Clinical trial information: NCT03934567.

Feasibility and Research Insights From a Randomized Controlled Trial for Recurrent Urinary Tract Infection Prevention in Postmenopausal Women Using Vaginal Estrogen Therapy.

The aim of the study was to inform feasibility parameters (eligibility, enrollment, and retention) for a recurrent urinary tract infection (rUTI) prevention randomized controlled trial (RCT). We assessed feasibility parameters of an RCT of postmenopausal women with uncomplicated rUTIs using vaginal estrogen. Participants were randomized to either d-mannose or a control arm. All participants were required to be using vaginal estrogen and to have a negative urine culture before 90-day trial participation. An RCT exit survey and separate survey for UTI patients (N = 196) were added to inform feasibility parameters and patient preferences for rUTI prevention and study participation after slower enrollment than anticipated. At the time of interim and subsequent futility analyses, 545 patients had been evaluated for frequent/recurrent UTIs from March 1, 2018, to January 18, 2020. Of these, 213 (39.1%) had culture-proven rUTIs and 71 (33.3% of those with culture-proven rUTIs) were eligible for the RCT. Reasons for ineligibility included complicated UTIs, premenopausal/perimenopausal status, or existing UTI prevention regimen. Of the 71 eligible participants, 57 (80.3%) enrolled, and 44 began their planned 90-day study period (77.2%; 80.0% after excluding 2 participants awaiting negative urine cultures at the time of analysis). The study was halted before conclusion. Study retention (76.0%-83.7%) was slightly lower than expected. Urinary tract infection survey patients demonstrated significant interest in rUTI research participation. We learned several important lessons that can benefit future research. Many patients with frequent/recurrent UTIs are interested in research, but rigorous eligibility criteria and referral urine culture documentation made recruitment challenging.

An optimal two-stage exploratory basket trial design with aggregated futility analysis

A basket trial investigates the effects of one drug on multiple tumor indications. To discontinue potentially inactive indications early, an interim futility analysis is usually conducted for each indication individually once it reaches the pre-specified sample size. As enrollment rates vary among indications, the futility decisions for slow-enrolling indications could be made much later than other fast-enrolling indications, which could delay the overall decision for the trial significantly. To accelerate the futility decision in early-stage exploratory basket trials and potentially reallocate resources to other compounds earlier while still controlling the global type-I and type-II errors, we propose an optimal two-stage basket trial design with one aggregated futility analysis by aggregating (e.g., pooling) all indications together. The total sample size across all indications is pre-specified for the futility analysis, while the sample size per indication can be adapted to the enrollment rate. The final analysis is performed using the pruning and pooling approach (Chen et al. 2016). The design parameters are optimized by minimizing the expected total sample size under the null hypothesis, while explicitly controlling the global type-I and the type-II error rates. Simulation studies demonstrate that the proposed design has better operating characteristics than the designs with individual futility analysis (Zhou et al. 2019; Wu et al. 2021), while allowing for earlier futility decision.

Phase 2 LEAP-009: Lenvatinib (Lenva) With or Without Pembrolizumab (Pembro) vs. Chemotherapy (Chemo) for Recurrent or Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC) That has Progressed on Platinum and Immunotherapy

<h3>Purpose/Objective(s)</h3> Pembro monotherapy and pembro plus platinum-based chemo are now standard-of-care options for the first-line treatment of R/M HNSCC. However, the optimal second-line regimen for R/M HNSCC that has progressed on or after immunotherapy or platinum-based chemo remains unclear. Pembro given in combination with the multikinase inhibitor lenva showed promising antitumor activity and acceptable safety in patients with metastatic HNSCC in the phase 1b/2 Study 111/KEYNOTE-146 trial. The open-label, randomized, phase 2 LEAP-009 (NCT04428151) study is designed to investigate the efficacy and safety of lenva ± pembro versus SOC chemo in patients with R/M HNSCC that has progressed after platinum-based chemo and a PD-1/PD-L1 inhibitor. <h3>Materials/Methods</h3> Key eligibility criteria include age ≥18 years; histologically confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; disease incurable by local therapy; measurable disease per RECIST v1.1 by BICR; ECOG performance status of 0 or 1; and no major blood vessel invasion/infiltration. Patients must have had disease progression on or after platinum-containing chemo ± cetuximab and have had disease progression on a PD-1/PD-L1 inhibitor (progression within 12 weeks of the last dose; must have received ≥2 doses). Patients will be randomly allocated 3:3:2 to lenva 20 mg PO QD + pembro 200 mg IV Q3W (≤35 pembro cycles), investigator's choice of SOC chemotherapy (docetaxel, paclitaxel, cetuximab, or capecitabine), or lenva monotherapy 24 mg PO QD. Treatment will continue until centrally verified disease progression, unacceptable toxicity, or withdrawal from study. Randomization will be stratified by PD-L1 tumor proportion score (<50% vs ≥50%) and ECOG performance status (0 vs 1). Patients with disease progression in the chemo or lenva monotherapy arms may be eligible to cross over to pembro + lenva. The primary end point is ORR per modified RECIST v1.1 by BICR. Secondary end points are PFS and DOR per RECIST v1.1 by BICR, OS, and safety. Imaging by CT or MRI will be performed every 6 weeks through year 1 and every 9 weeks thereafter. Safety will be monitored throughout the study and for 30 days after treatment end (90 days for serious AEs unless new anticancer treatment is initiated). An interim futility analysis will be conducted for the lenva monotherapy arm. Estimated enrollment is 400 patients. Recruitment is currently underway. <h3>Results</h3> TBD <h3>Conclusion</h3> TBD

Effect of cilobradine in cats with a first episode of congestive heart failure due to primary cardiomyopathy

IntroductionHeart rate (HR) is often elevated in cats with cardiomyopathies (CMPs). Pharmacologic modulation of HR may reduce cardiac morbidity and mortality. ObjectivesTo investigate the effects of cilobradine vs. placebo, regarding time to cardiac mortality or morbidity in cats with first episode of congestive heart failure (CHF) due to primary CMP. AnimalsThree hundred and sixty-seven client-owned cats with primary CMP that had presented with a first episode of CHF at 50 centers in Europe. Per-protocol population comprised 193 cats (n = 89 cilobradine, n = 104 placebo). An interim analysis for futility was planned. MethodsProspective, randomized, placebo-controlled, double-blinded, multicenter clinical trial. Primary outcome variable was the time to a composite of cardiac mortality or cardiac morbidity. ResultsMedian time to primary outcome was 84 days (95% confidence interval [CI]: 63–219 days) in the cilobradine group (CG) and 203 days in the placebo group (95% CI: 145–377 days) with observed hazard ratio of 1.44, indicating a higher hazard for the CG (P = 0.057). Mean HR was 28 beats per minute (bpm) lower at Day 7 (P < 0.0001) and remained 29 bpm lower at Day 360 (P = 0.026) in the CG than that in the placebo group. Although the number of adverse events did not differ, there were more serious adverse events in the CG. ConclusionsHeart rate reduction by cilobradine in cats with a first episode of CHF due to primary CMP did not reduce cardiac mortality and morbidity.

Efficacy and Safety of Enteral Recombinant Human Insulin in Preterm Infants

Feeding intolerance is a common condition among preterm infants owing to immaturity of the gastrointestinal tract. Enteral insulin appears to promote intestinal maturation. The insulin concentration in human milk declines rapidly post partum and insulin is absent in formula; therefore, recombinant human (rh) insulin for enteral administration as a supplement to human milk and formula may reduce feeding intolerance in preterm infants. To assess the efficacy and safety of 2 different dosages of rh insulin as a supplement to both human milk and preterm formula. The FIT-04 multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 46 neonatal intensive care units throughout Europe, Israel, and the US. Preterm infants with a gestational age (GA) of 26 to 32 weeks and a birth weight of 500 g or more were enrolled between October 9, 2016, and April 25, 2018. Data were analyzed in January 2020. Preterm infants were randomly assigned to receive low-dose rh insulin (400-μIU/mL milk), high-dose rh insulin (2000-μIU/mL milk), or placebo for 28 days. The primary outcome was time to achieve full enteral feeding (FEF) defined as an enteral intake of 150 mL/kg per day or more for 3 consecutive days. The final intention-to-treat analysis included 303 preterm infants (low-dose group: median [IQR] GA, 29.1 [28.1-30.4] weeks; 65 boys [59%]; median [IQR] birth weight, 1200 [976-1425] g; high-dose group: median [IQR] GA, 29.0 [27.7-30.5] weeks; 52 boys [55%]; median [IQR] birth weight, 1250 [1020-1445] g; placebo group: median [IQR] GA, 28.8 [27.6-30.4] weeks; 54 boys [55%]; median [IQR] birth weight, 1208 [1021-1430] g). The data safety monitoring board advised to discontinue the study early based on interim futility analysis (including the first 225 randomized infants), as the conditional power did not reach the prespecified threshold of 35% for both rh-insulin dosages. The study continued while the data safety monitoring board analyzed and discussed the data. In the final intention-to-treat analysis, the median (IQR) time to achieve FEF was significantly reduced in 94 infants receiving low-dose rh insulin (10.0 [7.0-21.8] days; P = .03) and in 82 infants receiving high-dose rh insulin (10.0 [6.0-15.0] days; P = .001) compared with 85 infants receiving placebo (14.0 [8.0-28.0] days). Compared with placebo, the difference in median (95% CI) time to FEF was 4.0 (1.0-8.0) days for the low-dose group and 4.0 (1.0-7.0) days for the high-dose group. Weight gain rates did not differ significantly between groups. Necrotizing enterocolitis (Bell stage 2 or 3) occurred in 7 of 108 infants (6%) in the low-dose group, 4 of 88 infants (5%) in the high-dose group, and 10 of 97 infants (10%) in the placebo group. None of the infants developed serum insulin antibodies. Results of this randomized clinical trial revealed that enteral administration of 2 different rh-insulin dosages was safe and compared with placebo, significantly reduced time to FEF in preterm infants with a GA of 26 to 32 weeks. These findings support the use of rh insulin as a supplement to human milk and preterm formula. ClinicalTrials.gov Identifier: NCT02510560.

Disease Modeling and Model-Based Meta-Analyses to Define a New Direction for a Phase III Program of Gantenerumab in Alzheimer's Disease.

Selecting the right dose is a significant challenge in designing clinical development programs, especially for slowly progressing diseases lacking predictive biomarkers of efficacy that may require long‐term treatment to assess clinical benefit. Gantenerumab, a fully human monoclonal antibody (mAb) that binds to aggregated amyloid‐beta, was tested in two 24‐month phase III studies (NCT01224106, NCT02051608) in participants with prodromal and mild Alzheimer’s disease (AD), respectively. Dosing in the first phase III study was suspended after a preplanned interim futility analysis in 2014. Subsequently, a dose–response relationship was observed in a subgroup of fast AD progressors that, together with contemporary aducanumab (another anti–amyloid‐beta mAb) data, indicated higher doses may be needed for clinical efficacy. The gantenerumab phase III studies were therefore transformed into dose‐finding, open‐label extension (OLE) trials. Two exposure–response models were developed to support dose selection via simulations for the OLEs: a pharmacokinetics (PK)/PET (positron emission tomography) model describing amyloid removal using PET data from low‐dose gantenerumab and high‐dose aducanumab, and a PK/ARIA‐E (amyloid‐related imaging abnormalities‐edema) model describing the occurrence of ARIA‐E events leveraging an existing bapineuzumab model. Multiple regimens were designed to gradually up‐titrate participants to the target dose of 1,200 mg gantenerumab every 4 weeks to mitigate the increased risk of ARIA‐E events that may be associated with higher doses of anti–amyloid‐beta antibodies. Favorable OLE data that matched well with model predictions supported the decision to continue the gantenerumab clinical development program and further apply model‐based analytical techniques to optimize the design of new phase III studies.

Abstract P5-16-12: Neoadjuvant letrozole plus palbociclib in patients (pts) with hormone receptor (HR)-positive/HER2-negative early breast cancer (EBC) with baseline Ki67 ≥20% and an Oncotype DX Breast Recurrence Score® result (RS) ≥18: DxCARTES

Abstract Background: Cyclin-dependent kinases 4 and 6 inhibitors in combination with endocrine therapy frequently lead to a complete cell-cycle arrest (CCCA) in luminal EBC. However, the rates of pathological complete response (pCR) or Residual Cancer Burden (RCB) 0-I are modest. The effect of this treatment in terms of molecular downstaging as assessed by a genomic signature more refined than Ki67 remains undetermined. We aimed to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment in HR-positive/HER2-negative EBC pts with an Oncotype DX RS ≥18. Methods: DxCARTES was a multicenter, open-label, non-comparative, phase 2 trial across 16 hospitals in Spain. Participants were pre- and post-menopausal women aged ≥18 years with centrally confirmed HR-positive/HER2-negative, Ki67≥20%, stage II-IIIB EBC with a RS ≥18. Eligible pts with baseline RS 18-25 (cohort A) and RS 26-100 (cohort B) received six 28-days cycles of letrozole (2.5 mg QD), ± goserelin if premenopausal, plus palbociclib (125 mg QD, 3/1 schedule) before surgery. Tumor samples were prospectively collected at baseline and surgery for Ki67 and RS assessments. The coprimary endpoint was the proportion of pts in either cohort who achieved RS ≤25 or a pCR (ypT0/is ypN0) at surgery. Secondary endpoints included analysis of RCB, preoperative endocrine prognostic index (PEPI), CCCA (Ki67&amp;lt;2.7%), overall response rate (ORR) as per RECIST v.1.1, and safety as per CTCAE v.5.0. A Simon’s 2-stage design was planned to recruit 33 pts in each cohort. Interim futility analyses were planned with 12 and 18 pts included in cohort A and B, respectively. The analyses were designed to attain an 80% power, with a 10% drop out rate assumption, at a nominal 1-sided α level of 2.5%. The response probabilities for null (H0) and alternative hypotheses (H1) in cohort A were H0: ≤ 72% and H1: ≥ 93%, and in cohort B were H0: ≤ 13% and H1: ≥ 35%, respectively. Results: Between May 5, 2019 to Dec 30, 2019, 67 pts were enrolled and received the study treatment (33 pts allocated to cohort A and 34 pts to cohort B). Pts’ characteristics at diagnosis were well balanced between the two cohorts and of the 67 pts included, 32.8% were premenopausal, 49.3% had axillary node involvement, and median Ki67 was 27% (24-37.5%). A total of 32 pts from cohort A and 33 pts from cohort B were evaluable for the coprimary endpoint. Median duration of treatment was 5.6 months (IQR 5.5-5.8) and median time from the last dose of palbociclib and surgery was 10.5 days (IQR 5.5-14). At surgery, 22 of 32 (68.8%) pts in cohort A and 19 of 33 (57.6%) pts in cohort B had RS ≤25. No pts in cohort A and 2 of 33 (6.1%) pts in cohort B achieved a pCR, meeting the coprimary endpoint in cohort B, but not in cohort A. In cohort A, the proportion of pts with RCB 0-1 was 5.3%, PEPI 0 was 11.1%, and CCCA was 58.1%. In cohort B, the proportion of pts with RCB 0-1 was 23.1%, PEPI 0 was 33.3%, and CCCA was 59.4%. The ORR by breast MRI was 78.1% (25 of 32 pts) in cohort A and 63.6% (21 of 33 pts) in cohort B. The most common grade 3-4 adverse event in both cohorts was neutropenia (23 of 33 [69.7%] pts in cohort A vs 20 of 34 [58.8%] pts in cohort B). No deaths were observed during the study in either cohort. Conclusions: Our results suggest that the neoadjuvant palbociclib plus letrozole activity is independent of the molecular aggressiveness of the disease. Although the prognostic value of molecular downstaging is unknown, a significant proportion of HR-positive/HER2-negative EBC pts with high RS at baseline achieve a pathological or molecular downstaging with this regimen. Further investigation is needed to determine if this strategy could avoid the use of chemotherapy in this population. Citation Format: Antonio Llombart-Cussac, Ángel Guerrero-Zotano, Manuel Ruiz, Begoña Bermejo, Miguel Gil-Gil, Juan de la Haba, Emilio Alba, Vanesa Quiroga, Vicente Carañana, Ander Urruticoechea, Serafín Morales, Meritxell Bellet, Antonio Antón, José Manuel Pérez-García, María Fernández-Abad, Sonia Servitja, Pedro Sánchez-Rovira, Sofia Braga, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes. Neoadjuvant letrozole plus palbociclib in patients (pts) with hormone receptor (HR)-positive/HER2-negative early breast cancer (EBC) with baseline Ki67 ≥20% and an Oncotype DX Breast Recurrence Score® result (RS) ≥18: DxCARTES [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-12.

Abstract PD4-06: Trastuzumab deruxtecan in patients with HER2[+] or HER2-low-expressing advanced breast cancer and central nervous system involvement: Preliminary results from the DEBBRAH phase 2 study

Abstract Background: Approximately 30% to 40% of patients (pts) with HER2[+] advanced breast cancer (ABC) will develop brain metastases (BM) during the course of their disease. Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate containing an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In the phase 2 DESTINY-Breast01 trial, T-DXd showed efficacy in the subgroup of HER2[+] ABC pts with stable BM at baseline. DEBBRAH is assessing the efficacy and safety of T-DXd in HER2[+] and HER2-low-expressing ABC pts with a history of BM and/or leptomeningeal carcinomatosis (LMC). Here, we report primary results from cohorts A and C. Methods: This is an ongoing, multicenter, open-label, 5-cohort, non-comparative, phase 2 study across 18 hospitals in 2 countries. A total of 39 pts aged ≥18 years with pretreated HER2[+] or HER2-low-expressing ABC with stable, progressing, or untreated BM and/or LMC are being enrolled in 5 cohorts: (A) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (B) HER2[+] or HER2-low-expressing ABC with asymptomatic untreated BM; (C) HER2[+] ABC with progressing BM after local treatment; (D) HER2-low-expressing ABC with progressing BM after local treatment; (E) HER2[+] or HER2-low-expressing ABC with LMC. In cohorts A and C, pts must have received prior taxane and ≥1 HER2-targeted therapy for ABC. Pts received 5.4 mg/kg T-DXd intravenously on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint for cohort A is 16-week progression-free survival (PFS) per local assessment using RANO-BM for central nervous system (CNS) lesions and RECIST v.1.1 for extracranial lesions (H0: 5%); for cohort C, CNS overall response rate (ORR; H0: 10%). A single-arm binomial design is used for cohorts A and C. A futility interim analysis has been planned in cohort A after accrual of 4 pts. Sample size was planned to attain an 80% power at nominal level of one-sided α of 0.05 in each cohort. Results: Between Jun 29, 2020, and Feb 18, 2021, 26 pts were allocated in the study. Enrollment is complete in cohorts A (n=8 pts) and C (n=9 pts), and ongoing in the remaining cohorts. At data cutoff (May 21, 2021), median follow-up for the cohort A was 5.5 months (IQR 4.4-6.9) and 6.2 months (IQR 5.1-6.4) for the cohort C. In the cohort A, 6 (75.0%) of 8 pts were alive without disease progression at 16 weeks, reaching the primary endpoint (p&amp;lt;0.01). In the cohort C, the CNS ORR was 55.6% (5 pts with partial response), also meeting the primary endpoint (p&amp;lt;0.01). At the time of this analysis, 75.0% of pts of the cohort A and 55.6% of the cohort C remained on therapy. The most frequent adverse events of any grade in 26 pts who received at least 1 dose of T-DXd were fatigue (11 [42.3%]; 3.8% of grade 3), nausea (10 [38.5%]), a decreased neutrophil count (9 [34.6%]; 11.5% of grade 3), and anemia (6 [23.1%]). Treatment-related serious adverse events occurred in 1 (3.8%) of 26 pts due to grade 1 pneumonitis. No treatment-related deaths were reported. Conclusions: T-DXd demonstrated preliminary efficacy with manageable toxicity in pretreated pts with HER2[+] ABC with stable and progressing BM after local treatment. Further investigation is required in larger cohorts to validate these findings. The assessment of the T-DXd antitumor activity in cohorts B, D, and E is currently ongoing. Citation Format: Marta Vaz Batista, Patricia Cortez, Manuel Ruiz, Juan Miguel Cejalvo, Juan de la Haba, Laia Garrigós, Fabricio Racca, Sonia Servitja, Salvador Blanch, Iris Teruel, José Manuel Pérez-García, María Gion, Monica Nave, Antonio Llombart-Cussac, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes, Sofia Braga. Trastuzumab deruxtecan in patients with HER2[+] or HER2-low-expressing advanced breast cancer and central nervous system involvement: Preliminary results from the DEBBRAH phase 2 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-06.

Abstract OT1-18-07: 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

Abstract Background: GP2 is a biologic nine amino acid peptide of the HER2/neu protein delivered in combination with an FDA-approved immunoadjuvant Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF, Sargramostim, Leukine) that stimulates an immune response targeting HER2/neu expressing cancers. In a prospective, randomized, single-blinded, placebo-controlled, multicenter Phase IIb clinical trial, no recurrences were observed in the HER2/neu positive adjuvant setting after median 5 years of follow-up, if the HLA-A*02 patient received the 6 primary intradermal GLSI-100 injections over the first 6 months (p = 0.0338) in a pre-specified subgroup analysis. Furthermore, the immunotherapy elicited a potent immune response measured by local skin tests and immunological assays. Of the 138 patients that have been treated with GLSI-100 to date over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events were observed related to the immunotherapy. This Phase III trial aims to reproduce the Phase IIb trial and will explore the use of GLSI-100 as adjuvant therapy to increase invasive disease-free survival in HER2/neu positive and HLA-A*02 patients, post-surgery and following the first year of treatment with any trastuzumab-based therapy. Method: This Phase 3 trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy or an approved biosimilar, 6 intradermal injections of GLSI-100 or placebo (Bacteriostatic Saline/WFI) will be administered for the primary immunization series 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 of treatment. 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. An interim analysis is planned, and patients will be stratified based on prior and current treatments. Study Size - Interim Analysis: Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in IDFS, 28 events will be required. An interim analysis for superiority and futility will be conducted when at least half of those events, 14, have occurred. This sample size provides 80% power if the annual rate of events in placebo-treated patients is 2.4% or greater. Eligibility Criteria: The patient population is defined by these key eligibility criteria: Trial Objectives: Contact information: Website: greenwichlifesciences.com. Funding: This trial is supported by Greenwich LifeSciences. Citation Format: Snehal S Patel, David B McWilliams, Christine T Fischette, Jaye Thompson, 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 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-07.

Efficacy and safety of balovaptan for socialisation and communication difficulties in autistic adults in North America and Europe: a phase 3, randomised, placebo-controlled trial

There are no approved pharmacological therapies to support treatment of the core communication and socialisation difficulties associated with autism spectrum disorder in adults. We aimed to assess the efficacy, safety, and pharmacokinetics of balovaptan, a vasopressin 1a receptor antagonist, versus placebo in autistic adults. V1aduct was a phase 3, randomised, placebo-controlled, double-blind trial, conducted at 46 sites across six countries (the USA, the UK, France, Italy, Spain, and Canada). Eligible participants were aged 18 years or older with an intelligence quotient (IQ) of 70 or higher, and met the criteria for moderate-to-severe autism spectrum disorder (DSM-5 and Autism Diagnostic Observation Schedule). Participants were randomly allocated (1:1), with an independent interactive voice or web-based response system, to receive balovaptan (10 mg) or placebo daily for 24 weeks. Randomisation was stratified by an individual's baseline Vineland-II two-domain composite (2DC) score (<60 or ≥60), sex, region (North America or rest of world), and age (<25 years or ≥25 years). Participants, study site personnel, and the sponsor were masked to treatment assignment. The primary endpoint was change from baseline in Vineland-II 2DC score (the mean composite score across the Vineland-II socialisation and communication domains) at week 24. The primary analysis was done with ANCOVA in the intention-to-treat population. The V1aduct study was terminated for futility after around 50% of participants completed the week 24 visit. This trial is registered with ClinicalTrials.gov (NCT03504917). Between Aug 8, 2018, and July 1, 2020, 540 people were screened for eligibility, of whom 322 were allocated to receive balovaptan (164 [51%]) or placebo (158 [49%]). One participant from the balovaptan group was not treated before trial termination and was excluded from the analysis. 60 participants in the balovaptan group and 55 in the placebo group discontinued treatment before week 24. The sample consisted of 64 (20%) women and 257 (80%) men, with 260 (81%) participants from North America and 61 (19%) from Europe. At baseline, mean age was 27·6 years (SD 9·7) and mean IQ score was 104·8 (18·1). Two (1%) participants were American Indian or Alaska Native, eight (2%) were Asian, 15 (5%) were Black or African American, 283 (88%) were White, four (1%) were of multiple races, and nine (3%) were of unknown race. Mean baseline Vineland-II 2DC scores were 67·2 (SD 15·3) in the balovaptan group and 66·2 (17·7) in the placebo group. The interim futility analysis showed no improvement for balovaptan versus placebo in terms of Vineland-II 2DC score at week 24 compared with baseline, with a least-squares mean change of 2·91 (SE 1·52) in the balovaptan group (n=79) and 4·75 (1·60) in the placebo group (n=71; estimated treatment difference -1·84 [95% CI -5·15 to 1·48]). In the final analysis, mean change from baseline in Vineland-II 2DC score at week 24 was 4·56 (SD 10·85) in the balovaptan group (n=111) and 6·83 (12·18) in the placebo group (n=99). Balovaptan was well tolerated, with similar proportions of participants with at least one adverse event in the balovaptan group (98 [60%] of 163) and placebo group (104 [66%] of 158). The most common adverse events were nasopharyngitis (14 [9%] in the balovaptan group and 19 [12%] in the placebo group), diarrhoea (11 [7%] and 14 [9%]), upper respiratory tract infection (ten [6%] and nine [6%]), insomnia (five [3%] and eight [5%]), oropharyngeal pain (five [3%] and eight [5%]), and dizziness (two [1%] and ten [6%]). Serious adverse events were reported for two (1%) participants in the balovaptan group (one each of suicidal ideation and schizoaffective disorder), and five (3%) participants in the placebo group (one each of suicidal ideation, panic disorder, limb abscess, urosepsis, colitis [in the same participant with urosepsis], and death by suicide). No treatment-related deaths occurred. Balovaptan did not improve social communication in autistic adults. This study provides insights into challenges facing autism spectrum disorder trials, including the considerable placebo response and the selection of appropriate outcome measures. F Hoffmann-La Roche.

Phase II trial of organ preservation program using short-course radiation and folfoxiri for rectal cancer (SHORT-FOX).

TPS218 Background: Locally advanced rectal cancer is treated with preoperative chemoradiotherapy followed by total mesorectal excision (TME). While this trimodal approach achieves low rates of local recurrences, distant metastasis rates can exceed 25%. Total neoadjuvant therapy (TNT) has been shown in OPRA, RAPIDO, and PRODIGE23 to reduce risk of distant metastasis and improve rates of pathological complete response compared to standard preoperative chemoradiotherapy. Thus, TNT not only addresses distant disease, but gives opportunity to reduce locoregional morbidity through organ preservation. We propose a treatment approach that incorporates TNT with FOLFOXIRI and up-front short-course radiation with the goal of increasing clinical complete response (cCR) rates and thereby eligibility for organ preservation. Currently, clinical response following neoadjuvant therapy is best assessed by a multidisciplinary team and includes flexible endoscopy and MRI. Circulating tumor DNA (ctDNA) analysis can be used as a noninvasive method for tumor monitoring. Biomarker development is essential to better select patients for treatment de-escalation and monitor for recurrence in order not to jeopardize the excellent cure rates following standard of care therapy. Methods: This is a single-arm, open-label, non-randomized study of an organ preservation approach using short-course radiation followed by FOLFOXIRI for patients with &gt; T2N0 or low T2N0, M0 rectal adenocarcinoma (NCT04380337). Patients undergo radiation (25 Gy/5 fractions + 5 Gy/1 fraction boost) followed by 8 cycles of FOLFOXIRI. Patients are assessed for response at 8 weeks following chemotherapy completion using pelvic MRI (MRI Tumor Regression Grading), flexible sigmoidoscopy, and digital rectal exam. Those who achieve a cCR can defer TME and be surveilled. The primary objective is to assess cCR, with the hypothesis that this approach will achieve higher cCR rates than historical controls (40 versus 20%). Secondary objectives include assessing toxicity, local regrowth rate, disease-free survival, colostomy-free survival, overall survival, and longitudinal health-related quality of life. ctDNA will be collected throughout treatment and surveillance, and correlative studies will assess the association between ctDNA levels and cCR, local regrowth, and disease-free survival. A Simon 2-stage design addressed our primary objective. Assuming a one-sided type 1 error of 0.1, power of 0.9, a null cCR of 0.2 versus an alternate cCR of 0.4, we plan to enroll 37 patients. The null hypothesis will be rejected if &gt; = 11 patients have cCR. Seventeen patients have been enrolled and the trial is currently on hold for planned interim analysis for futility and safety. If &lt; = 3 patients have cCR or if &gt; = 7 patients have non-hematologic grade 4+ toxicity, the study will be stopped. Otherwise, we will continue to enroll 20 more patients. Clinical trial information: NCT04380337.

A randomized phase II trial of MEK and CDK4/6 inhibitors vesus tipiracil/trifluridine (TAS-102) in metastatic KRAS/NRAS mutant (mut) colorectal cancer (CRC).

116 Background: Constitutively activating KRAS or NRAS muts occur in ̃50% of CRC, increasing RAF-MEK-ERK signaling and causing overexpression of cyclin D1, which binds to cyclin dependent kinase 4/6 (CDK4/6) to drive cell cycle progression. Combination MEK and CDK4/6 inhibitors caused tumor regression in patient-derived xenografts of KRAS mut CRC. We hypothesized that binimetinib and palbociclib (B+P) would improve progression-free survival (PFS) compared to TAS-102 in refractory KRAS/NRAS mut mCRC. Methods: ACCRU-GI-1618 was a multicenter, randomized phase II clinical trial (NCT03981614). Key inclusion criteria were KRAS/NRAS mut mCRC, with prior fluoropyrimidine/ oxaliplatin/ irinotecan/ anti-VEGF therapy. There was a 6-patient safety run-in with binimetinib 30 mg po BID D1-28 and palbociclib 100 mg po daily D1-21. After, patients were randomized 1:1 to B+P vs TAS-102 (stratified by KRAS mut type and prior regorafenib use), with optional crossover at progression. The primary endpoint was PFS; 73 PFS events (from a sample size of 112) provided 90% power to detect improvement of PFS (hazard ratio = 0.5, i.e. median PFS of 2 vs. 4 months) with 1-sided α = 0.05. A prespecified interim analysis for futility was planned after 37 PFS events were observed, with completion of accrual if 1-sided stratified log-rank p-value &lt; 0.551. Hazard ratios (HR) and 95% confidence intervals (CI) are estimated by stratified Cox proportional hazards models. Results: After the safety run-in, 93 patients at 6 sites were randomized; 82 (41 B+P, 41 TAS-102) comprise the primary analysis population (eligible, consented, and started treatment). In this population, median age was 52 years, 50% female, 68% left-sided, 79% with KRAS codon 12/13 mut, 12% with prior regorafenib. Enrollment was halted at interim analysis as the futility boundary was crossed (1-sided p = 0.67). At final analysis, 68 subjects had a PFS event (34 in each arm). Median PFS was 2.1 mo (95% CI 2.0-3.0) with B+P vs 2.1 mo (2.0-2.4) with TAS-102; HR 0.86 (0.52-1.44). 4-mo PFS rate was 22.2% (11.9-41.6) with B+P vs 10.6% (3.8-30.0) with TAS-102. With 37 OS events (14 in B+P arm), median OS was 7.7 mo (5.1-NE) with B+P vs 6.6 mo (4.8-8.9) with TAS-102; HR 0.77 (95% CI 0.39-1.51). TAS-102 had greater grade 3-4 hematologic AEs (46% vs 22%), and B+P had more grade 3-4 non-hematologic AEs (47% vs 32%). Grade 3-4 AEs more common with B+P were fatigue (8% vs 0%), oral mucositis (6% vs 0%), and nausea (4% vs 2%). Though 63% of patients on B+P had acneiform rash, only 2% was grade 3-4. Grade 1-2 diarrhea occurred in 35% of B+P and 24% of TAS-102 patients. No new safety signal was observed. Conclusions: B+P did not significantly improve median PFS or OS compared to TAS-102 in KRAS/NRAS mut mCRC. Subgroup analyses and translational studies are ongoing to determine which subgroups may be more likely to attain 4-mo PFS or identify mechanisms of resistance. Clinical trial information: NCT03981614.

Periop-01: A randomized controlled trial of extended perioperative tinzaparin to improve disease-free survival in patients with resectable colorectal cancer.

124 Background: Cancer patients undergoing surgical resection of their tumor are hypercoagulable beyond the period of hospitalization. Preclinical studies demonstrate that the postoperative hypercoagulable state promotes metastases, an effect that is abrogated by administration of perioperative low molecular-weight heparin (LMWH). Methods: We conducted a randomized, open label clinical trial to determine if extended duration thromboprophylaxis using subcutaneous LMWH (tinzaparin 4,500 IU daily), beginning at decision to operate and continuing for 56 days postoperatively, compared to inpatient postoperative thromboprophylaxis only, increased the 3-year disease-free survival (DSF) in patients undergoing resection for colorectal cancer. Secondary outcomes included 5-year overall survival (OS), postoperative bleeding and venous thromboembolism (VTE). Results: Trial recruitment was stopped prematurely after 614 of the planned 1075 patients were registered, following a pre-defined interim analysis for futility. The intention-to-treat analysis included 602 patients with demographics in the table. The 3-year DFS was 78.9% (63/299 recurrences) in the tinzaparin group and 80.5% (59/303 recurrences) in the control group (hazard ratio (HR) 1.09; [95% CI 0.91,1.31; p=0.3]). The 5-year OS was 91.3% in the tinzaparin group and 92.4% in the control group (HR 1.08; [95% CI 0.66,1.79; p=0.1]). The incidence of postoperative VTE was 1.7% and 1.3% in the tinzaparin and control groups, respectively (HR 1.3; [95% CI 0.30,5.69; p=0.7]. The incidence of major bleeding in the first postoperative week was 0.3% and 2% in the tinzaparin and control groups, respectively (HR 0.16; [95% CI 0.02,1.15; p=0.07]. Conclusions: Extended duration perioperative anticoagulation with tinzaparin did not improve DFS or OS in colorectal cancer patients undergoing surgical resection. The incidences of postoperative bleeding and VTE were low. Funded by Canadian Institute of Health Research and Leo Pharma Clinical trial information: NCT01455831. [Table: see text]

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

BackgroundWe aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.MethodsIn this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FindingsBetween Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50–72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74–1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67–1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74–1·58]; BRII-196 plus BRII-198 1·00 [0·68–1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91–1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88–1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.InterpretationNeither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FundingUS National Institutes of Health and Operation Warp Speed