Background: Colorectal cancer (CRC) is now the leading cause of cancer-related deaths among young Americans. Our study aims to predict early-onset CRC (EOCRC) using machine learning (ML) and structured electronic health record (EHR) data for individuals under the screening age of 45. Methods: We identified a cohort of patients under 45 from the OneFlorida+ Clinical Research Consortium. Given the distinct pathology of colon cancer (CC) and rectal cancer (RC), we created separate prediction models for each cancer type with various ML algorithms. We assessed multiple prediction time windows (0, 1, 3, and 5 years) and ensured robustness through propensity score matching (PSM) to account for confounding variables. Model performance was assessed using established metrics. Additionally, we employed the Shapley Additive exPlanations (SHAP) to identify risk factors for EOCRC. Results: Our study yielded results, with Area Under the Curve (AUC) scores of 0.811, 0.748, 0.689, and 0.686 for CC prediction, and 0.829, 0.771, 0.727, and 0.721 for RC prediction at 0, 1, 3, and 5 years, respectively. Notably, predictors included immune and digestive system disorders, along with secondary cancers and underweight, prevalent in both CC and RC groups. Blood diseases emerged as prominent indicators of CC. Conclusion: This study highlights the potential of ML techniques in leveraging EHR data to predict EOCRC, offering valuable insights for potential early diagnosis in patients who are below the recommended screening age. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the UF CTSI Precision Health Initiative. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study has been approved and the requirement to obtain any informed consent has been waived by the University of Florida Institutional Review Board (protocol no. IRB202201561). The research does not involve greater than minimal risk for participation. Analyses only involve the secondary analysis of data that are either limited data sets or de-identified. Our research team has no direct contact with human subjects. All methods were carried out in accordance with relevant guidelines and regulations. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

BACKGROUND:Standard adjuvant treatment of stage III colon cancer (CC) is fluoropyrimidine with oxaliplatin. Recently, stage III was subdivided into low-risk (T1-3, N1) and high-risk (T4 and/or N2), with the benefit of adding oxaliplatin varying across these substages. In this study, we aimed to assess the impact of oxaliplatin on survival outcomes in subdividing stage III CC patients based on T and N staging. PATIENTS AND METHODS:A total of 4942 stage III CC patients were pooled from the three randomized pivotal trials of oxaliplatin. Kaplan-Meier curves, Cox models stratified by study, and interaction tests were used to assess the oxaliplatin effect across subgroups based on T and N stages. The primary endpoint was overall survival (OS). RESULTS:The prevalence of tumor stages was T1-2 12.4%, T3 74.4%, and T4 13.1%; nodal stages were N1 64.7% and N2 35.3%. A significant OS benefit from oxaliplatin was seen only in T3 (5-year OS = 77.2% versus 73.0%, P < 0.001): T3N1 (hazard ratio 0.72, 95% confidence interval 0.62-0.85, P < 0.001) and T3N2 (hazard ratio 0.81, 95% confidence interval 0.69-0.95, P = 0.010). No benefit was observed for T1-2 (5-year OS = 87.8% versus 88.7%, P = 0.644) or T4 patients (5-year OS = 62.6% versus 60.2%, P = 0.648). Subgroup analysis revealed a significant interaction between T stage and the effect of oxaliplatin treatment on OS, whereas no such interaction was observed for N stage. CONCLUSIONS:Our analysis revealed that oxaliplatin-based chemotherapy offers a significant survival benefit in stage III CC patients with T3 tumors. In contrast, no survival benefit was observed for T1-2 or T4 patients. These results suggested that T stage plays a more crucial role than N stage in predicting treatment benefit, highlighting the need for tailored treatment strategies based on tumor characteristics.

Purpose/Objective(s) PROSPECT (Clinical Trials.gov NCT01515787) is a prospective randomized trial of neoadjuvant chemoradiation vs. neoadjuvant FOLFOX with selective use of chemoradiation for patients with locally advanced rectal cancer (cT2N+, cT3N-, cT3N+). The primary results demonstrated the non-inferiority of neoadjuvant FOLFOX. Here we report the quality assurance of radiation delivered in the trial. Materials/Methods All radiation plans were submitted to the Quality Assurance Review Center (QARC) and reviewed by QARC staff and the first author of this abstract (HM). Patients could be treated with either intensity-modulated radiation therapy (IMRT) or 3D conformal radiation, at the discretion of the treating radiation oncologist. Radiation plans were scored by HM as per-protocol, minor deviation, or major deviation, as defined in the protocol. Patient-reported toxicity and quality of life outcomes were collected. Results 1194 patients were randomized from June 2012 through December 2018. This analysis is limited to the 597 patients who were randomized to the control (chemoradiation) group. 543/597 (91%) started chemoradiation, 515/543 (95%) received the planned dose of 5040 cGy. 278/543 (51%) were treated with 3D-conformal radiation and 234/543 (43%) with IMRT. The treatment technique was not available for 31 patients. Although there was no randomization, the IMRT and 3D groups were well-matched by age, gender, and stage of the tumor. 427/512 (83.4%) were treated per protocol, with three major deviations (two treating above the recommended dose, one under-treating the pelvic sidewall) and 82 minor deviations (mostly minor dose deviations and not covering the pre-sacral space in the cone down fields). As only 2% of the patients had a local failure within 5 years, no differences in local recurrence or other survival endpoints were seen for patients based on whether their treatment plans were administered per protocol vs. with minor deviation, or with IMRT vs 3D. The most common Grade 3 and higher patient-reported adverse events (PRO-CTCAE) reported during chemoradiation therapy were diarrhea (20%), fatigue (20%) pain (18%) and constipation (11%). There were no significant differences in toxicity based on treatment with IMRT vs 3D or the presence of minor deviations. Conclusion 95% of patients starting chemoradiation on the PROSPECT trial completed the planned dose of radiation with very low rates of recurrence and low rates of patient-reported toxicities. There were only 3 major deviations and 83% of patients were treated per protocol. No differences in efficacy or toxicity were seen between IMRT and 3D conformal radiation.

PURPOSE A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). MATERIALS AND METHODS We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment. RESULTS A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years. CONCLUSION In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

105 Background: Decentralized clinical trials (DCT) involve conducting some or all trial-related activities at a location separate from the investigator's site. DCT can help reduce the burden on patients, sites, and sponsors while improving patient accrual and retention rates and increasing the diversity of trial participants. While DCT methods provide patient-centric trial flexibilities, they can impact trial operations. This survey aimed to gain insights into the perspectives and experiences of cancer centers regarding DCT in the field of oncology. Methods: A 13-question survey that addressed prior experience, perceived benefits, and challenges in implementing DCT was developed by members of the Association of American Cancer Institutes (AACI) Clinical Research Innovation (CRI) Steering Committee. The survey was sent via email to the AACI CRI listserv, which consists of members of 90 cancer research centers in North America. Respondents were asked to consider their activity related to treatment and non-treatment interventional trials. Results: There were 75 total responses from members affiliated with 55 individual cancer centers. Of these centers, 73% were NCI-designated cancer centers. Of the individual respondents, 57% were clinical trial office administrators. The issues of highest concern by respondents were 1) meeting study timelines, 2) patient recruitment and 3) cost (83%, 65%, 44% respectively). All respondents had prior experience with DCT tools with the most common components being the use of local facilities for labs/imaging, telemedicine and e-consent (89%, 69%, 68% respectively). The areas of most perceived benefit from DCT include reduced participant burden, increased diversity and participant retention (81%, 80%, 68% respectively) while areas of perceived challenges include quality control, regulatory compliance and cost (61%, 59%, 49% respectively). While 92% respondents agreed/strongly agreed that DCT can improve clinical trial access, 92% agreed/strongly agreed that additional site staff training is required for successful DCT implementation. Conclusions: DCT tools have been widely implemented in oncology trials with all surveyed sites reporting prior experience. This survey emphasizes the perceived benefits of DCT in oncology, while underscoring the importance of addressing challenges and meeting the specific requirements of cancer centers. Future work should identify specific areas that require additional staff training to enable DCT readiness.

Genetic testing can help determine the risk of many cancers and guide cancer prevention and treatment plans. Despite increasing concern about disparities in precision cancer medicine, public knowledge and cancer genetic testing by race and ethnicity have not been well investigated. We analyzed data from the 2020 Health Information National Trends Survey in 2022. Self-reported cancer genetic testing (e.g., Lynch syndrome, BRCA1/2) knowledge and utilization were compared by race and ethnicity. Perceived importance of genetic information for cancer care (prevention, detection, and treatment) was also examined in relation to the uptake of cancer genetic testing. Multivariable logistic regression models were employed to examine factors associated with knowledge and genetic testing to calculate predicted probability of undergoing genetic testing by race and ethnicity. Of 3551 study participants, 37.8% reported having heard of genetic testing for cancer risk and 3.9% stated that they underwent cancer genetic testing. Being non-Hispanic Black (OR=0.47, 95% CI=0.30–0.75) or Hispanic (OR=0.56, CI=0.35–0.90) was associated with lower odds of genetic testing knowledge. Although Hispanic or non-Hispanic Black respondents were more likely to perceive higher importance of genetic information versus non-Hispanic Whites, they had a lower predicted probability of cancer genetic testing. Non-Hispanic Black and Hispanic adults had lower knowledge and were less likely to undergo cancer genetic testing than non-Hispanic Whites. Further research is needed on sources of genetic testing information for racial and ethnic minorities and the barriers to accessing genetic testing to inform the development of effective cancer risk genetic testing promotion.

TPS3629 Background: For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free survival and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Further, despite the long history of treating oligometastatic CRC with local therapy, which is provider biased and not evidence based, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. Methods: A022101 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) with ≤4 sites of metastatic disease on baseline imaging. Liver-only metastatic disease is not permitted, and lesions must be amenable to any combination of surgical resection, MWA, and/or SBRT with SBRT required for at least one lesion. Patients receive first-line systemic therapy for 4-6 months and are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver and lungs in at least one site. Patients in Arm 1 will receive TAT which consists of treatment of all metastatic sites with SBRT ± MWA ± surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023 and recruitment is ongoing. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG); Clinicaltrials.gov identifier: NCT05673148 Clinical trial information: NCT05673148 .

BACKGROUND:The prognostic value of KRAS and BRAFV600E mutations in stage III colon cancer (CC) remains controversial and has never been clearly analyzed in patients with microsatellite instability-high (MSI-H) tumors due to sample size limitations. Data are also lacking for KRAS submutations and prognosis. PATIENTS AND METHODS:We examined clinicopathological variables and prognosis in patients with surgically resected stage III CC who participated in seven clinical trials from the ACCENT/IDEA databases. Associations between KRAS exon 2 and BRAFV600E mutations and time to recurrence (TTR), overall survival (OS), and survival after recurrence (SAR) were assessed using a Cox model. We also analyzed the prognostic value of KRAS exon 2 submutations. RESULTS:Among 8460 patients, 11.4% had MSI-H status. In the MSI-H group, BRAFV600E, KRAS exon 2 mutants, and double-wild-type statuses were detected in 40.6%, 18.1%, and 41.3%, respectively, whereas and in the microsatellite stable (MSS) group, these were detected in 7.7%, 38.6%, and 53.8%, respectively. In the MSS group, 5-year TTR rates of 61.8%, 66.3%, and 72.9% were observed among patients with BRAFV600E, KRAS exon 2 mutants, and those who were DWT, respectively [adjusted hazard ratio (HR) = 1.58 and 1.31, both P < 0.001]. In the MSI-H group, 5-year TTR rates did not differ significantly among the mutated subgroups. Similar results were found for OS. However, survival after relapse was significantly shorter in the KRAS exon 2- and BRAFV600E-mutated patients in both MSS (adjusted HR = 2.06 and 1.15; both P < 0.05) and MSI-H (adjusted HR = 1.99 and 1.81; both P < 0.05) groups. In the MSS group, KRAS exon 2 mutations were associated with TTR, but only p.G12C, p.G12D, and p.G13D were associated with poor outcomes after disease recurrence. CONCLUSIONS:Testing for both KRAS and BRAFV600E mutations in stage III patients should be considered as they can better define individual patient prognosis, and may also enable patient selection for (neo)adjuvant trials dedicated to specific molecular subtypes with poor prognosis.

We show that significant momentum exists in China equity returns outside the month of February for both the past return and the 52-week high momentum ranking criteria. For 6-month holding periods, the magnitudes range from 73 bp to 110 bp per month in both raw and factor-adjusted returns using the China factors of Liu et al. (2019). A strong seasonal February reversal masks momentum when all months are considered together. The reversal is associated with a spike in turnover for recent loser stocks, which we attribute to an appetite for lottery-like stocks by retail investors in the season of the Chinese New Year. We show that the turnover difference between winner and loser stocks is a significant determinant of momentum in all three culturally Chinese equity markets—China, Taiwan, and Hong Kong. However, consistent with the dominance of retail investors in China, the February seasonal is weaker in Taiwan and non-existent in Hong Kong, and strong enough to mask momentum in other months only in China.

Supplemental Figure S1. Tumor-associated stromal response to pattern recognition receptor ligands. Supplementary Figure S2. Pancreatic cancer cell conditioned media and TLR4 ligation induces expression of antigen presentation machinery and negative co-stimulatory ligands on TAS. Supplemental Figure S3. TAS-mediated T cell suppression is enhanced by neutralization of either IL6 or IL8 and unaffected by TLR4 knockdown in TAS.

Background Despite extensive effort, no immunotherapy has been approved for ovarian cancer patients. Ovarian cancer patients who fail more than two lines of systemic therapies have very poor prognosis. ONC-392 is an acid pH-sensitive anti-CTLA-4 antibody that preserves CTLA-4 recycling and avoids lysosomal degradation. ONC-392 is more effective for immunotherapy but largely devoid of immunotherapy-related adverse events (irAE) in preclinical studies. Our previous dose escalation study has established an RP2D for monotherapy at 10.0 mg/kg.1 Here we report safety and clinical response of ovarian cancer patients to monotherapy of ONC-392 at 10.0 mg/kg in dose finding and dose expansion studies (NCT04140526, Part A and Part C Arm L). Methods Thirty four patients with advanced/metastatic ovarian cancer, including primary peritoneal cancer and fallopian tube cancer, who have progressive disease after prior systemic treatments, including chemotherapy, targeted therapy or checkpoint inhibitors have been enrolled. Four patients were enrolled in Part A monotherapy dose finding with defined doses. Thirty patients in expansion cohort had ONC-392 administrated via IV infusion with starting two doses of 10.0 mg/kg, Q3W, followed by 6.0 mg/kg Q3W. The primary endpoints are safety and objective response rate (ORR) using RECIST 1.1 criteria. Results Thirty-four patients have received 1-11 cycles of ONC-392 treatment. The safety data set consists of 32 patients. The median age is 67.5 (range 40-82), White/Asian/Black: 27/3/2, and 5 Hispanic. The median follow up is 17 weeks. Treatment related AEs (TRAEs) were observed in 26 (81%) patients. Grade 3 TRAEs were observed in 10 pts (31%): myocarditis (1), diarrhea (2), immune-mediated colitis or colitis (4), immune hepatitis (1). Grade 4 TRAE in 1 patient with hypotensive shock (3%). No grade 5 AE was observed. Among 26 evaluable patients, the CR/PR/SD/PD numbers are 1/3/15/7 (ORR=15%, DCR=73%) (figure 1). Conclusions The safety profile of 10.0 mg/kg x 2, followed by 6.0 mg/kg Q3W is comparable to patients who received substantially lower doses other CTLA-4-targeting drug in the ovarian cancer patients. While the number of evaluable patients is small, the preliminary assessment suggests ONC-392 monotherapy has clinical activity among patients who has failed multiple lines of systemic therapy. The available data support continuous clinical testing of ONC-392 in ovarian cancer. A new Phase 2 study with combination of ONC-392 and pembrolizumab will initiated in Q32022 (ONC-392-004, MK3475-E24, GOG-3081). Acknowledgements The study is sponsored by OncoC4, Inc. Trial Registration NCT04140526. Reference LI T, Tang M, Kelly K, et al. First-in-human study of the fi rst acid pH-sensiti ve and recycling CTLA-4anti body that preserves the immune tolerance checkpoint to avoid immunotherapy-related adverse eventsin cancer pati ents. J Immunother Cancer. 2021; 9(5 Suppl 2): A998. Ethics Approval This study obtained ethic approval from WCG IRB with study #20193108 or the local institutional IRBs. All participants gave informed consent before taking part of the study.

Background Survival is a key metric of the effectiveness of a health system in managing cancer. We set out to provide a comprehensive examination of worldwide variation and trends in survival from brain tumors in adults, by histology. Methods We analyzed individual data for adults (15-99 years) diagnosed with a brain tumor (ICD-O-3 topography code C71) during 2000-2014, regardless of tumor behavior. Data underwent a 3-phase quality control as part of CONCORD-3. We estimated net survival for 11 histology groups, using the unbiased nonparametric Pohar Perme estimator. Results The study included 556,237 adults. In 2010-2014, the global range in age-standardized 5-year net survival for the most common sub-types was broad: in the range 20%-38% for diffuse and anaplastic astrocytoma, from 4% to 17% for glioblastoma, and between 32% and 69% for oligodendroglioma. For patients with glioblastoma, the largest gains in survival occurred between 2000-2004 and 2005-2009. These improvements were more noticeable among adults diagnosed aged 40-70 years than among younger adults. Conclusions To the best of our knowledge, this study provides the largest account to date of global trends in population-based survival for brain tumors by histology in adults. We have highlighted remarkable gains in 5-year survival from glioblastoma since 2005, providing large-scale empirical evidence on the uptake of chemoradiation at population level. Worldwide, survival improvements have been extensive, but some countries still lag behind. Our findings may help clinicians involved in national and international tumor pathway boards to promote initiatives aimed at more extensive implementation of clinical guidelines.

Purpose/Objective(s) Tisotumab vedotin (TV) is an antibody-drug conjugate directed against tissue factor, which is highly prevalent in some solid tumors. In Sep 2021, the US FDA approved TV monotherapy for recurrent or metastatic cervical cancer (r/mCC) patients with disease progression on or after chemotherapy. Encouraging early data from investigational TV combinations with carboplatin and pembrolizumab in relapsed cervical cancer suggest that these combinations may have activity in other cancers (Vergote 2021). innovaTV 207 evaluated TV in solid tumors, including a cohort of squamous cell carcinoma of the head and neck (SCCHN). We report the clinical activity and safety of TV 2 mg/kg Q3W in this cohort. Materials/Methods In this global, open label, phase 2, multicenter study, SCCHN cohort patients received 2 mg/kg TV (max dose: 200 mg per infusion) IV on Day 1 of each 21-day cycle. Eligible patients had: 1) relapsed, locally advanced, or metastatic SCCHN, and experienced disease progression on or after their most recent systemic therapy, 2) received prior therapy with a platinum-based regimen and a checkpoint inhibitor (if eligible), 3) received anti-epithelial growth factor receptor therapy prior to study entry (if eligible), and 4) received no more than 3 systemic regimens in the recurrent/metastatic setting. The primary endpoint was investigator confirmed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and tolerability. Results Of 31 SCCHN patients enrolled, median age was 65.0 (range 47-78) years. As of 15 Oct 2020, median duration of ongoing TV therapy was 12.0 weeks (range 3-36). Confirmed ORR was 16% (95% CI: 5.5-33.7); 5 patients had a partial response. Confirmed DCR was 58.1% (95% CI: 39.1-75.5). Median PFS was 4.2 months (95% CI: 2.7–4.8), and median OS was 9.4 months (95% CI: 8.1-11.8). Twenty-two (71.0%) patients developed Grade ≥3 treatment-emergent adverse events (TEAEs); most commonly (≥10% of patients) anemia (16.1%), pneumonia (12.9%), and dyspnea (12.9%). Reported incidence for all grade TEAEs of special interest for ocular, bleeding, and peripheral neuropathy events was 54.8%, 51.6%, and 29.0%, respectively. Incidence of treatment-emergent serious adverse events (SAEs) was 51.6%, and treatment related SAEs was 6.5% (grade 3 hemoptysis [n=1] and grade 3 post procedural hemorrhage [n=1]). There were 2 adverse events leading to death (aspiration and pulmonary embolism); none were considered treatment related. Conclusion TV has a manageable safety profile and favorable preliminary antitumor activity in patients with SCCHN that have progressed after a platinum containing regimen and a checkpoint inhibitor. Continued evaluation of TV is warranted. This trial is ongoing and is registered with ClinicalTrials.gov (NCT03485209). Tisotumab vedotin (TV) is an antibody-drug conjugate directed against tissue factor, which is highly prevalent in some solid tumors. In Sep 2021, the US FDA approved TV monotherapy for recurrent or metastatic cervical cancer (r/mCC) patients with disease progression on or after chemotherapy. Encouraging early data from investigational TV combinations with carboplatin and pembrolizumab in relapsed cervical cancer suggest that these combinations may have activity in other cancers (Vergote 2021). innovaTV 207 evaluated TV in solid tumors, including a cohort of squamous cell carcinoma of the head and neck (SCCHN). We report the clinical activity and safety of TV 2 mg/kg Q3W in this cohort. In this global, open label, phase 2, multicenter study, SCCHN cohort patients received 2 mg/kg TV (max dose: 200 mg per infusion) IV on Day 1 of each 21-day cycle. Eligible patients had: 1) relapsed, locally advanced, or metastatic SCCHN, and experienced disease progression on or after their most recent systemic therapy, 2) received prior therapy with a platinum-based regimen and a checkpoint inhibitor (if eligible), 3) received anti-epithelial growth factor receptor therapy prior to study entry (if eligible), and 4) received no more than 3 systemic regimens in the recurrent/metastatic setting. The primary endpoint was investigator confirmed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and tolerability. Of 31 SCCHN patients enrolled, median age was 65.0 (range 47-78) years. As of 15 Oct 2020, median duration of ongoing TV therapy was 12.0 weeks (range 3-36). Confirmed ORR was 16% (95% CI: 5.5-33.7); 5 patients had a partial response. Confirmed DCR was 58.1% (95% CI: 39.1-75.5). Median PFS was 4.2 months (95% CI: 2.7–4.8), and median OS was 9.4 months (95% CI: 8.1-11.8). Twenty-two (71.0%) patients developed Grade ≥3 treatment-emergent adverse events (TEAEs); most commonly (≥10% of patients) anemia (16.1%), pneumonia (12.9%), and dyspnea (12.9%). Reported incidence for all grade TEAEs of special interest for ocular, bleeding, and peripheral neuropathy events was 54.8%, 51.6%, and 29.0%, respectively. Incidence of treatment-emergent serious adverse events (SAEs) was 51.6%, and treatment related SAEs was 6.5% (grade 3 hemoptysis [n=1] and grade 3 post procedural hemorrhage [n=1]). There were 2 adverse events leading to death (aspiration and pulmonary embolism); none were considered treatment related. TV has a manageable safety profile and favorable preliminary antitumor activity in patients with SCCHN that have progressed after a platinum containing regimen and a checkpoint inhibitor. Continued evaluation of TV is warranted. This trial is ongoing and is registered with ClinicalTrials.gov (NCT03485209).

Tisotumab vedotin (TV) is an investigational antibody-drug conjugate directed to Tissue Factor (TF). In the phase I/II innovaTV 201 and phase II innovaTV 204 studies, TV demonstrated encouraging antitumor activity with a manageable safety profile in patients (pts) with multiple TF-expressing tumor types. The innovaTV 207 trial is a global, open label, multicenter phase II trial assessing the safety, tolerability, and activity of TV in solid tumors known to express TF. This abstract presents the addition of Part C, testing TV in squamous non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN). Based on pharmacokinetic (PK) and exposure-response analyses data, we will be evaluating an every other week dosing schedule (2Q4W), which is new across the TV program, in addition to administering TV on Days 1, 8, and 15 of a 28-day cycle in Part C. Up to 92 pts will be enrolled in Part C of innovaTV 207. TV will be administered by IV at 1.2 mg/kg on Days 1, 8, and 15 of a 28-day cycle (3Q4W), or at 1.7 mg/kg on Days 1 and 15 of a 28-day cycle (2Q4W) in pts with SCCHN or NSCLC. This part will start with a safety run-in with 6 pts per dosing schedule. Afterwards, a dose expansion phase will enroll 20 SCCHN (10 3Q4W + 10 2Q4W) and 20 NSCLC (10 3Q4W + 10 2Q4W) pts with the possibility of adding 20 more patients per indication at 1 given dosing schedule to evaluate preliminary antitumor activity. Pts must have measurable disease progression per RECIST v1.1 despite standard of care in locally advanced or metastatic settings (up to 3 prior lines for SCCHN, 2 for squamous NSCLC [3 for pts eligible for a tyrosine kinase inhibitor who should have received such therapy]), and an ECOG score of 0 or 1. The primary endpoint is Investigator-determined (Inv) confirmed objective response rate (ORR) per RECIST v1.1. Secondary endpoints include Inv, duration of response, progression-free survival, overall survival, disease control rate, and time to response, as well as safety and PK parameters. The trial opened in June 2018 and was amended to add Part C in February 2021. The study is enrolling for Part C across 28 sites in 7 countries: US, Canada, Italy, France, UK, Germany, and Spain. Enrollment updates will be provided at the meeting. NCT03485209; EudraCT 2017-005076-26. MMS Holdings. Genmab A/S and Seagen Inc. Genmab A/S and Seagen Inc.

In this study, we explored the feasibility of using real-world data (RWD) from a large clinical research network to simulate real-world clinical trials of Alzheimer’s disease (AD). The target trial (i.e., NCT00478205) is a Phase III double-blind, parallel-group trial that compared the 23 mg donepezil sustained release with the 10 mg donepezil immediate release formulation in patients with moderate to severe AD. We followed the target trial’s study protocol to identify the study population, treatment regimen assignments and outcome assessments, and to set up a number of different simulation scenarios and parameters. We considered two main scenarios: (1) a one-arm simulation: simulating a standard-of-care (SOC) arm that can serve as an external control arm; and (2) a two-arm simulation: simulating both intervention and control arms with proper patient matching algorithms for comparative effectiveness analysis. In the two-arm simulation scenario, we used propensity score matching controlling for baseline characteristics to simulate the randomization process. In the two-arm simulation, higher serious adverse event (SAE) rates were observed in the simulated trials than the rates reported in original trial, and a higher SAE rate was observed in the 23 mg arm than in the 10 mg SOC arm. In the one-arm simulation scenario, similar estimates of SAE rates were observed when proportional sampling was used to control demographic variables. In conclusion, trial simulation using RWD is feasible in this example of AD trial in terms of safety evaluation. Trial simulation using RWD could be a valuable tool for post-market comparative effectiveness studies and for informing future trials’ design. Nevertheless, such an approach may be limited, for example, by the availability of RWD that matches the target trials of interest, and further investigations are warranted.

Low trial generalizability is a concern. The Food and Drug Administration had guidance on broadening trial eligibility criteria to enroll underrepresented populations. However, investigators are hesitant to do so because of concerns over patient safety. There is a lack of methods to rationalize criteria design. In this study, we used data from a large research network to assess how adjustments of eligibility criteria can jointly affect generalizability and patient safety (i.e the number of serious adverse events [SAEs]). We first built a model to predict the number of SAEs. Then, leveraging an a priori generalizability assessment algorithm, we assessed the changes in the number of predicted SAEs and the generalizability score, simulating the process of dropping exclusion criteria and increasing the upper limit of continuous eligibility criteria. We argued that broadening of eligibility criteria should balance between potential increases of SAEs and generalizability using donepezil trials as a case study.

We examine the survey responses of 278 individuals who transitioned from the workplace to working from home (WFH) as a result of the Covid 19 pandemic to understand how individuals' attainment of productivity in work and meaning in life are affected by WFH. We also assess their perceived stress and health challenges experienced since WFH. On average, workers perceive that productivity and meaning changed in opposite directions with the shift to WFH-productivity increased while the meaning derived from daily activities decreased. Stress was reduced while health problems increased. By investigating these changes, we identify important common sources of support and friction associated with remote work that affect multiple dimensions of work and life. For example, personal fortitude is an important source of support, and the intrusion of work into life is an important friction. Our findings lead to concrete recommendations for both organizational leaders and workers in setting key priorities for supporting remote work.

Purpose/Objective(s)Total neoadjuvant therapy (TNT) including chemotherapy (chemo) and concurrent chemo and radiotherapy (RT) is a promising strategy for rectal cancer. Characterizing tumor regression during TNT represents an important area of research. We report a prospective validation study of the Magnetic Resonance Tumor Regression Grade (MR-TRG) using MRIs from NRG-GI002, a phase II trial of TNT for rectal cancer.Materials/MethodsThis was the a priori designed imaging biomarker study of NRG-GI002 seeking to correlate the MR-TRG with the pathologic Neoadjuvant Rectal score (NAR) and pathologic complete response (pCR). 110 patients (pts) were needed with 2 MRI's, 1 pre-TNT and 1 post. Three diagnostic radiologists independently reviewed each MRI and completed a consensus read. Radiologists’ assessment of complete response (mriCR) was tested for its positive predictive value (PPV), negative predictive value (NPV), sensitivity (sen), and specificity (spec) with pCR. Chi-squared test was used for association of mriCR and pCR, and Wilcoxon-Mann-Whitney test was used for association of MR-TRG and pCR. Spearman Rho was used for association of MR-TRG/mriCR and NAR. P-values < .05 (2-sided) were considered significant. Each reader's T-stage, N-stage, extra-mural vascular invasion (EMVI), MR-TRG score and diffusion weighted imaging (DWI) assessment was evaluated for inter-reader variability by Kappa statistics. Kappa values of agreement were interpreted as: poor, < 0.0; slight, 0.0–0.2; fair, 0.2–0.4; moderate, 0.4–0.6; substantial, 0.6–0.8; and almost perfect, 0.8–1.0. All analyses were performed using a data management and decision management software. Radiologists were blinded to pathologic data.ResultsA total of 126 patients, from 76 institutions, had 2 MRI's (pre-TNT and post), 3 radiologists completed 756 MRI interpretations. Of 126 patients, 29% were female (N = 37), 85% white (N = 107) and median age was 55 (24-76). Individual and consensus MR-TRG scores were highly associated with pCR (P < 0.01) and NAR (Rho = .39, P < 0.001). The addition of DWI to MR-TRG improved both sen and spec over MR-TRG alone (P = 0.035). On the consensus read for mriCR, sen = 53.3%, spec = 70.7%, PPV = 42.1%, and NPV = 79.1% compared to pCR, and was highly associated (P = 0.02). The Kappa agreement score for T-stage, N-stage, and EMVI was 0.34, 0.67, and 0.39 reflecting fair, substantial, and fair agreement respectively. The Kappa agreements score across readers were 0.26 for MR-TRG and 0.32 for DWI, reflecting fair agreement. The mriCR, had a Kappa statistic of 0.85, reflecting near perfect agreement.ConclusionMR-TRG is significantly correlated with pathologic NAR score. Binary assessment of CR, using MR-TRG and DWI, had near perfect agreement across readers. The addition of DWI to MR-TRG improved both the sen and spec, reflecting utility of DWI in this setting. Correlation of mriCR with pCR was statistically significant. Notably, PPVs here were limited, implicating the need for stronger biomarkers when planning a national rectal organ preservation study. NCT02921256.