tbuckley/cabot-search huggingface dataset:
Phase 1 and phase 2a, first-in-human (FIH) study, of DRP-104, a broad glutamine antagonist, in adult patients with advanced solid tumors.
Authors: Melissa Lynne Johnson, Deborah Blythe Doroshow, Tanguy Y. Seiwert, Michael K. Gibson, Vamsidhar Velcheti, Aaron Elliott Lisberg, Shetal Arvind Patel, Matthias Scheffler, Francois Lafleur, Margaret Han Dugan, Sunil Sharma
Journal: Journal of Clinical Oncology (2021)

TPS3149 Background: Dependence of cancer cells on glutamine has made glutaminolysis an attractive therapeutic target in cancer. Prior clinical trials evaluating glutamine analogues for the treatment of cancer were abandoned due to lack of efficacy and/or tolerability. DON (6-Diazo-5-oxo-L-norleucine) is an irreversible inhibitor of several enzymes that utilize glutamine as a metabolic substrate. In addition to direct anti-tumor efficacy, inhibition of glutamine metabolism in the tumor microenvironment has been shown to improve T-cell activation and tumor infiltration, increasing anti-tumor immune responses. As such, combining DON with an immune checkpoint inhibitor (ICI), has strong preclinical rationale. The investigational product DRP-104 (sirpiglenastat) is an inactive prodrug of DON designed to limit systemic DON exposure while targeting glutamine dependence in tumor cells. Methods: A phase 1/2a, FIH, multi-center, non-randomized, multi-cohort, open-label study of DRP-104 is currently open to accrual for patients with advanced solid tumors. This study will be conducted in 4 parts: A) Dose Escalation of IV and subQ DRP-104 (Run-In phase followed by modified Continual Reassessment Method) to define MTD/RP2D. Primary objective of dose escalation is to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of DRP-104 as a single agent; B) Dose Expansion of IV and subQ DRP-104 for safety assessment while primary objective is to select and recommend phase 2 DRP-104 route of administration; C) Phase 2a at recommended MTD/RP2D of selected route of DRP-104 in 2 patient cohorts: patients with locally advanced/metastatic NSCLC with KEAP1, NFE2L2 and/or STK11 mutation and patients with unresectable or metastatic SCCHN, in order to assess the safety, tolerability and preliminary antitumor activity of DRP-104 as a single agent; D) Phase 2a at recommended MTD/RP2D of selected route of DRP-104 in combination with atezolizumab in adult patients with advanced solid tumors previously treated with an ICI, in order to assess the safety, tolerability and preliminary antitumor activity of DRP-104 in combination with atezolizumab; DRP-104 IV is infused TIW over 1 hour infusion for 2 consecutive weeks followed by 1 week off. DRP-104 subQ is administered BIW weekly. Study is currently open with 6 IV patients (Run-In Phase completed and at Dose Level 4) and 3 subQ patients at Dose Level 1 at time of submission. Clinical trial information: NCT04471415.
Development and prognostic relevance of a histologic grading and staging system for alcohol-related liver disease
Authors: Carolin Lackner, Rudolf E. Stauber, Susan Davies, Helmut Denk, Hans Peter Dienes, Viviane Gnemmi, Maria Guido, Rosa Miquel, Valerie Paradis, Peter Schirmacher, Luigi Terracciano, Andrea Berghold, Gudrun Pregartner, Lukas Binder, Philipp Douschan, Florian Rainer, Stephan Sygulla, Marion Jager, Pierre-Emmanuel Rautou, Andreea Bumbu, Adelina Horhat, Ioana Rusu, Horia Stefanescu, Sönke Detlefsen, Aleksander Krag, Maja Thiele, Helena Cortez-Pinto, Christophe Moreno, Annette S.H. Gouw, Dina G. Tiniakos
Journal: Journal of Hepatology (2021)

The SALVE Histopathology Group (SHG) developed and validated a grading and staging system for the clinical and full histological spectrum of alcohol-related liver disease (ALD) and evaluated its prognostic utility in a multinational cohort of 445 patients.SALVE grade was described by semiquantitative scores for steatosis, activity (hepatocellular injury and lobular neutrophils) and cholestasis. The histological diagnosis of steatohepatitis due to ALD (histological ASH, hASH) was based on the presence of hepatocellular ballooning and lobular neutrophils. Fibrosis staging was adapted from the Clinical Research Network staging system for non-alcoholic fatty liver disease and the Laennec staging system and reflects the pattern and extent of ALD fibrosis. There are 7 SALVE fibrosis stages (SFS) ranging from no fibrosis to severe cirrhosis.Interobserver κ-value for each grading and staging parameter was >0.6. In the whole study cohort, long-term outcome was associated with activity grade and cholestasis, as well as cirrhosis with very broad septa (severe cirrhosis) (p <0.001 for all parameters). In decompensated ALD, adverse short-term outcome was associated with activity grade, hASH and cholestasis (p = 0.038, 0.012 and 0.001, respectively), whereas in compensated ALD, hASH and severe fibrosis/cirrhosis were associated with decompensation-free survival (p = 0.011 and 0.001, respectively). On multivariable analysis, severe cirrhosis emerged as an independent histological predictor of long-term survival in the whole study cohort. Severe cirrhosis and hASH were identified as independent predictors of short-term survival in decompensated ALD, and also as independent predictors of decompensation-free survival in compensated ALD.The SALVE grading and staging system is a reproducible and prognostically relevant method for the histological assessment of disease activity and fibrosis in ALD.Patients with alcohol-related liver disease (ALD) may undergo liver biopsy to assess disease severity. We developed a system to classify ALD under the microscope by grading ALD activity and staging the extent of liver scarring. We validated the prognostic performance of this system in 445 patients from 4 European centers.
Cardiac Sympathetic Activity by 123I-Meta-Iodobenzylguanidine Imaging in Women With Coronary Microvascular Dysfunction
Authors: Puja K. Mehta, Louise E.J. Thomson, Piotr J. Slomka, Sean W. Hayes, John D. Friedman, Amanda Swift, Odayme Quesada, Janet Wei, Leslee J. Shaw, Michael D. Nelson, Lian Li, David Hermel, Melody H. Hermel, Michael R. Irwin, David S. Krantz, Mark I. Travin, Carl J. Pepine, Daniel S. Berman, C. Noel Bairey Merz
Journal: JACC. Cardiovascular imaging (2021)
Safety and activity of single-agent giredestrant (GDC-9545) from a phase Ia/b study in patients (pts) with estrogen receptor-positive (ER+), HER2-negative locally advanced/metastatic breast cancer (LA/mBC).
Authors: Komal L. Jhaveri, Valentina Boni, Joohyuk Sohn, Rafael Villanueva-Vásquez, Aditya Bardia, Peter Schmid, Elgene Lim, Jaymin M. Patel, Jose Alejandro Perez-Fidalgo, Sherene Loi, Seock-Ah Im, Smita Kshirsagar, Mary R. Gates, John Bond, Jennifer Eng-Wong, Ching-Wei Chang, Nicholas C. Turner, Elena Lopez Miranda, Laura García-Estévez, Meritxell Bellet
Journal: Journal of Clinical Oncology (2021)

1017 Background: Targeting ER activity and/or E synthesis is a mainstay of ER+ BC treatment, but many pts relapse during/after adjuvant endocrine therapy (ET) or develop resistance via ESR1 mutations that drive E-independent transcription and proliferation. Most tumors remain ER signaling-dependent and pts may respond to second-/third-line ET after disease progression (PD) on prior therapies (Di Leo 2010; Baselga 2012). Giredestrant, a highly potent, nonsteroidal oral selective ER degrader, achieves robust ER occupancy, is active despite ESR1 mutations, and was well tolerated ± palbociclib with encouraging antitumor activity in the nonrandomized, open-label, dose-escalation and -expansion, phase Ia/b GO39932 study (NCT03332797; Jhaveri 2019; Lim 2020). We present updated interim data from the dose-escalation and -expansion single-agent giredestrant cohorts. Methods: Pts had ≤2 prior therapies in the LA/mBC setting with disease recurrence/PD while being treated with adjuvant ET for ≥24 mo and/or ET in the LA/mBC setting, and derived a clinical benefit (CB) from therapy (tumor response/stable disease [SD] ≥6 mo). Pts received 10, 30, 90/100, or 250 mg PO giredestrant QD on D1–28 of each 28-day cycle. Pts were postmenopausal (medical menopause on LHRH agonists was allowed with ≥100 mg giredestrant). Results: Clinical cutoff: Jul 31, 2020; median prior therapy lines in the LA/mBC setting: 1; mean dose intensity: 98%. Safety/activity: see the table below. No adverse events (AEs) led to study drug withdrawal. No dose-limiting toxicities (DLTs) occurred; maximum tolerated dose was not reached. Most common AEs in 107 pts: fatigue (22; 21%), arthralgia (18; 17%), and nausea (17; 16%); largely grade 1/2. Related grade 3 AEs were infrequent (5; 5%); none were grade 4/5 per investigator assessment (grade 5 duodenal perforation occurred with 90/100 mg after stopping giredestrant due to PD). 8 (7%) had bradycardia (none with 10 mg or the 30 mg phase 3 dose; all grade 1 except one grade 2 at 250 mg; no treatment interruptions/dose reductions were required). Objective responses and CB were observed at all doses. Conclusions: Single-agent giredestrant was well tolerated at all doses, with no DLTs. AEs were generally low grade and in keeping with expected AEs for ETs. Clinical activity was observed at all doses. Updated data, including biomarker and correlative data, will be presented. Clinical trial information: NCT03332797 .[Table: see text]
Racial and ethnic enrollment disparities in acute myeloid leukemia clinical trials.
Authors: Andrew Hantel, Daniel J. DeAngelo, Marlise Rachael Luskin, Jacqueline Suen Garcia, Gregory A. Abel
Journal: Journal of Clinical Oncology (2021)

6523 Background: Racial and ethnic disparities in clinical trial enrollment compound inequities in drug development and the delivery of patient-centered care. Despite significant survival disparities in acute myeloid leukemia (AML), enrollment disparities data are limited. Methods: We performed a structured search and abstraction of demographic data for all United States (US) AML clinical trials from 2002-2017 listed on clinicaltrials.gov and compared the results to the incidence and demographic distribution of AML using the Surveillance, Epidemiology, and End Results program and 2010 US Census. We calculated enrollment fractions (the number of enrollees divided by the number of incident cases) for the five mutually exclusive race/ethnicity groups of non-Hispanic White (NH-White), Black (NH-Black), Asian/Pacific Islander (NH-Asian/PI), American Indian/Native Alaskan (NH-AI/AN), and Hispanic patients. We compared these using X 2 testing, with NH-White as the comparator, and reported odds ratios with 95% confidence intervals (CI). To assess trends over time, we adjusted enrollment from 2005-2008 for changes in AML incidence and NH-White enrollment for a later period (2011-2014), comparing this expected enrollment fraction to the actual enrollment fraction during that later period. Results: Of 223 eligible studies (patient N=17372) on clinicaltrials.gov, 99 (44.4%) reported racial demographics (N=8417; 48.5%) and 68 (30.5%) reported race and ethnicity (N=6554; 37.7%). Enrollment and incidence proportions by race are shown in the table. Among trials reporting race and ethnicity, all groups had lower odds of enrollment compared to NH-White patients (Table). For the 99 trials reporting race data, Black and AI/AN patient enrollment odds were lower (OR 0.60 [95% CI: 0.55, 0.65]; 0.50 [95% CI: 0.33, 0.76]), but Asian/PI enrollment was not (OR 0.91 [95% CI: 0.82, 1.01]). The relative enrollment of NH-Black, NH-Asian/PI, and Hispanic patients declined later in the study period (Table). Conclusions: In AML clinical trials performed in the US from 2002-2017, NH-White patients were enrolled at higher rates compared to other racial and ethnic groups; enrollment diversity declined over time. An important first step to reducing enrollment disparities will be to improve the reporting of demographic enrollment data.[Table: see text]
A longitudinal study of the adherence to PORTEC-2 based adjuvant radiotherapy in high-intermediate-risk endometrial adenocarcinoma and associated oncologic outcomes.
Authors: Hadi Erfani, Atefeh Rezaei, Anthony Costales
Journal: Journal of Clinical Oncology (2021)

e17570 Background: In 2010, Nout et al. reported on PORTEC-2, which randomized patients with high intermediate risk (HIR) endometrial cancer to adjuvant vaginal brachytherapy or pelvic radiotherapy or observation, and showed that vaginal brachytherapy was non-inferior in terms of locoregional control and was deemed the adjuvant treatment of choice for these patients. We sought to evaluate the adherence to and the oncologic outcomes of the PORTEC-2 regimen. Methods: We utilized the SEER database to identify patients who met PORTEC-2 inclusion criteria. All patients underwent surgery followed by either vaginal brachytherapy (VBT) or whole pelvic radiotherapy (WPRT). Inclusion criteria were patients with the following characteristics: grade 1 with ≥ 50% myometrial invasion (MI), grade 2 with any invasion, and grade 3 with &lt; 50% MI. Patients were excluded if any lymph nodes were examined or involved, if they received any chemotherapy, or had any missing values for any of the variables. HIR endometrial adenocarcinoma was defined as the presence of 2 of the following: age &gt; 60, grade 3, and ≥50% myometrial invasion. Radiation status was extracted from the SEER Radiation/Chemotherapy database. Outcomes were overall death, cancer specific death and total survival months per SEER’s standard definitions. Variables are reported as median and interquartile range (IQR) or number (%). Mean survival was calculated using Kaplan Meier analysis and Mantel-Cox rank test was done to test for statistical significance between the study groups. Cox regression analysis was performed, and hazard ratios (HR) were calculated. Statistical analysis was performed using SPSS v. 22.0. Results: Between 2005- 2015, 571 patients met PORTEC-2 inclusion criteria of whom 349 (61.1%) and 222 (38.9%) received WPRT and VBT, respectively. We showed that the rate of VBT was significantly increased from 85 (27.4%) between 2005-2010 to 137 (52.5%) between 2011-2015 (p &lt; 0.001). There was no difference in grade and myometrial invasion between the study groups. Kaplan Meier analysis showed a 22.5 and 16.3 month improvement in overall and cancer specific survival in subjects who underwent VBT as compared to WPRT, respectively (p &lt; 0.001 for both). Cox regression analysis revealed a 36% and 66% decrease in the hazard of overall and cancer specific death, respectively, in the VBT group as compared to WPRT group (Overall death: HR = 0.64, 95% CI: 0.45-0.91, p = 0.012; Cancer specific death: HR = 0.34, 95% CI: 0.16-0.73, p = 0.006). Conclusions: Administration of vaginal brachytherapy following surgery has become significantly more popular after publication of the PORTEC-2 results in 2010. Our study shows a significant decrease in both overall and cancer related death and an increase in survival with VBT over WPRT in patients with HIR endometrial cancer.
First-in-human phase I study of the bifunctional EGFR/TGF<b>β</b> fusion protein BCA101 in patients with EGFR-driven advanced solid cancers.
Authors: Filip Janku, Glenn J. Hanna, Richard D. Carvajal, Paul K. Paik, Alberto Hernando-Calvo, Maura L. Gillison, Siqing Fu, Jennifer J. Wheler, David Bohr, Ralf Reiners, Seng-Lai Tan, Sanela Bilic, Philippe L. Bedard
Journal: Journal of Clinical Oncology (2021)

3074 Background: Therapeutic targeting of EGFR has demonstrated efficacy in common advanced malignancies such as colorectal cancer (CRC), squamous cell of the head and neck (SCCHN), and non-small cell lung cancer (NSCLC). TGFβ has pro-tumorigenic effects on migration, invasion and tumor-specific immunosuppression, which may enhance the oncogenic effects of activated EGFR. Inhibition of EGFR signaling can lead to TGFβ upregulation as a resistance mechanism. BCA101 is a bifunctional recombinant fusion protein consisting of a chimeric anti-EGFR antibody and an extracellular domain (ECD) of human TGFβRII which demonstrated anti-tumor activity in several preclinical models. Methods: Patients with EGFR-driven advanced solid cancers refractory to standard therapies received BCA101 at escalating doses from 64 mg to 1000 mg intravenously (IV) weekly across 6 dose levels using a 3+3 design to determine dose limiting toxicities (DLT, established within 21 days of initial dosing), maximum tolerated dose (MTD) and/or recommended dose (RD). Secondary endpoints include detailed pharmacokinetic (PK), pharmacodynamic (PD) studies in serial tumor and/or blood samples and assessment of anti-tumor activity. Results: As of 2/11/2021, 21 patients received single agent BCA101 at 64 (n = 3), 240 (n = 7), 500 (n = 2), 750 (n = 3), 800 (n = 3) or 1000 (n = 3) mg IV weekly, including patients with CRC (n = 6), SCCHN (n = 5) uveal melanoma (n = 2), ovarian cancer (n = 2), glioblastoma multiforme (n = 2), conjunctival melanoma, chordoma, pancreatic cancer and anal squamous cell carcinoma (all n = 1). These patients had 1-7 prior lines of antineoplastic therapy (median 4), including 3 patients with prior EGFR inhibitor exposure. Adverse events (AE) related to BCA101 observed in &gt; 1 patient included grade (G) 1-2 rash (n = 9), G 1-2 lipase elevation (n = 2). G3 vitreous hemorrhage at the 240 mg dose level has been the only DLT. The MTD has not been reached and the RD will be based on safety, exposure and pending PD data. Saturation of the clearance was observed at doses above 500mg. Dose proportional increase in Cmax and AUC were observed with doses of 750-1000mg. Best RECISTv1.1 response was stable disease (SD) in 3/10 evaluable patients, with 1 patient on drug ≥4 months. Conclusions: BCA101 is well tolerated at biologically active doses. BCA101 is now being tested in combination with the PD-1 antibody pembrolizumab in patients with SCCHN and anal carcinoma. Clinical trial information: NCT04429542.
Low incidence of hepatic veno-occlusive disease (VOD) in patients with B-cell acute lymphoblastic leukemia (B-ALL) treated with inotuzumab ozogamicin (INO) followed by allogeneic stem cell transplantation (allo-SCT).
Authors: Kirk Cahill, Juan Alban, Mylove Mortel, Emily Dworkin, Satyajit Kosuri, Adam Duvall, Hongtao Liu, Michael Russell Bishop, Richard A. Larson, Wendy Stock
Journal: Journal of Clinical Oncology (2021)

e19024 Background: Hepatic VOD is an uncommon, but often fatal complication of allo-SCT. The risk is increased after INO, an anti-CD22 antibody conjugated to calicheamicin with high remission rates in relapsed CD22-positive B-ALL. Previous reports have described VOD rates as high as 19% in INO-treated patients who then received allo-SCT. We report our safety experience using INO followed by allo-SCT. Methods: We identified patients &gt;18 yrs with B-ALL treated with allo-SCT and INO in the University of Chicago IRB-approved SCT database. We reviewed the EMR for patient details, toxicities (CTCAE v5.0), and outcomes. Hepatic VOD was defined according to EBMT criteria. Overall survival (OS) was from time of allo-SCT to death or last follow-up. Results: Between 2010-2021, 72 adult patients with B-ALL received allo-SCT, and 17 also received INO as salvage therapy (Table). Median follow-up was 19 months (1-110). All received ursodiol prophylaxis and 15/17 received an azole for antifungal prophylaxis. They had median 2 cycles (1-3) of INO with median of 1.9 months (1-14) from the last dose of INO to allo-SCT. For cycle 1, 13/17 (77%) received 0.8 mg/m 2 on D1 and 0.5 mg/m 2 on D8 and D15. Of these, 11 had a subsequent cycle (5 with same dosing and 7 had 0.5 mg/m 2 on D1, D8, and D15). 1 patient had 0.5 mg/m 2 on D1, D8, and D15 for 2 cycles. 3 patients received 0.8 mg/m 2 on D1 and 0.4 mg/m 2 on D8 and D15 for 2 cycles. After INO, 10 patients achieved CR and 3 had CRi for ORR of 13/17 (76%). The 4 patients with persistent disease despite INO went into remission with a different salvage therapy prior to allo-SCT. Conditioning regimens are listed in Table 1. No patients developed VOD after allo-SCT. Within 2 yrs of allo-SCT, 3/17 (18%) relapsed and 7/17 (41%) died. The median OS was 21.2 months [18 - NR]. Conclusions: Limiting the number of INO cycles (median 2) prior to allo-SCT, delaying allo-SCT for 2 months after INO exposure, and avoiding dual alkylating agent conditioning may have contributed to the absence of VOD in our patients. Larger data sets will be useful to validate these important safety observations.[Table: see text]
Emergency Department Visits for Suspected Suicide Attempts Among Persons Aged 12–25 Years Before and During the COVID-19 Pandemic — United States, January 2019–May 2021
Authors: Ellen Yard, Lakshmi Radhakrishnan, Michael F. Ballesteros, Michael Sheppard, Abigail Gates, Zachary Stein, Kathleen Hartnett, Aaron Kite-Powell, Loren Rodgers, Jennifer Adjemian, Daniel C. Ehlman, Kristin Holland, Nimi Idaikkadar, Asha Ivey-Stephenson, Pedro Martinez, Royal Law, Deborah M. Stone
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

During the COVID-19 pandemic, emergency department (ED) visits for suspected suicide attempts increased among adolescents aged 12–17 years, especially girls. During February–March 2021, suspected suicide attempt ED visits were 51% higher among girls aged 12–17 years than during 2019; among boys aged 12–17 years, suspected suicide attempt ED visits increased 4%.