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Background: Mortality remains high in patients with ST-segment–elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS), and early reperfusion has been shown to improve outcomes. We analyzed the association between first medical contact (FMC)-to-percutaneous coronary angiography time with mortality and major adverse cardiovascular events among patients with STEMI with and without CS. Methods: We performed a retrospective analysis of the Vancouver Coastal Health Authority STEMI registry, including all patients with STEMI who received primary percutaneous coronary angiography between January 1, 2010, and December 31, 2020, and stratified them by presence or absence of CS at hospital arrival. The primary outcome was in-hospital mortality, the secondary outcome was in-hospital major adverse cardiovascular events, defined as a composite of the first occurrence of mortality, cardiac arrest, heart failure, intracerebral hemorrhage, cerebrovascular accident, or reinfarction. Mixed effects logistic regression with restricted cubic splines was used to estimate the relationships between FMC-to-device time and the outcomes in the CS and non-CS groups. Results: 2929 patients were included, 9.4% (n=275) had CS. Median FMC-to-device time was 113.5 (interquartile range, 93.0–145.0) and 103.0 (interquartile range, 85.0–130.0) minutes for patients with CS and without CS, respectively. More patients with CS had FMC-to-device times above guideline recommendations (76.6% versus 54.1%, P <0.001). Between 60 and 90 minutes, for each 10-minute increase in FMC-to-device time, absolute mortality for patients with CS increased by 4% to 7%, whereas for patients without CS, it increased by <0.5%. Conclusions: Among patients with STEMI undergoing primary percutaneous coronary angiography, reperfusion delays among patients with CS are associated with significantly worse outcomes. Strategies to reduce FMC-to-device times for patients with STEMI presenting with CS are required.

Abstract Intrinsic brainstem tumors arising in pediatric, adolescent, and young adult patients comprise a spectrum of entities, predominantly diffuse midline gliomas (DMG) and IDH mutant astrocytomas. Accurate molecular diagnosis is essential for prognostication and optimal therapy. Therapeutic considerations include inclusion (in IDH mutant) or exclusion (in H3K27M) of adjuvant Temozolomide post radiotherapy and use of molecular targeted therapy (IDH inhibitors). Surgical biopsy, however, is associated with increased risk of permanent neurological deficits and may yield insufficient or non-diagnostic tissue. We hypothesized that minimally-invasive “liquid biopsy” of cerebrospinal fluid (CSF) could represent a superior diagnostic modality in this patient population, employing molecular analysis of cell free DNA (cfDNA). We analyzed 44 CSF samples from 38 unique patients for recurrent driver mutations in brainstem gliomas, including H3K27M, IDH1, and IDH2. MSK-IMPACT, a NY state-authorized hybridization capture-based next-generation panel DNA sequencing assay, was used for analysis. Samples without a detectable driver mutation by MSK-IMPACT testing were further subjected to gene targeted testing by droplet digital PCR. In all, 10/44 (22.7%) samples had mutations detected by MSK-IMPACT using standard calling criteria and 13 of the remaining 34 samples (38.2%) had supporting evidence of a mutation based on manual review. Further testing by ddPCR was performed on a subset of cases (based on DNA availability) which confirmed 7 of the previous low-level mutations and uncovered 4 additional mutations. Overall, 27/44 (61.4%) of cases had detectable evidence of a mutation, and of the 23 patients without a known tissue diagnosis, a driver in the CSF was identified for 47.8% of patients (11/23). Minimally-invasive analysis of CSF cfDNA in patients with intrinsic brainstem tumors has a high diagnostic yield and may obviate the need for tissue biopsy in a majority of patients. Testing with high sensitivity assays is valuable to maximize the rate of detection.

Background Hematologic toxicities, including coagulopathy, endothelial activation, and cytopenias, with CD19-targeted chimeric antigen receptor (CAR) T-cell therapies correlate with cytokine release syndrome (CRS) and neurotoxicity severity, but little is known about the extended toxicity profiles of CAR T-cells targeting alternative antigens. This report characterizes hematologic toxicities seen following CD22 CAR T-cells and their relationship to CRS and neurotoxicity. Methods We retrospectively characterized hematologic toxicities associated with CRS seen on a phase 1 study of anti-CD22 CAR T-cells for children and young adults with relapsed/refractory CD22+ hematologic malignancies. Additional analyses included correlation of hematologic toxicities with neurotoxicity and exploring effects of hemophagocytic lymphohistiocytosis-like toxicities (HLH) on bone marrow recovery and cytopenias. Coagulopathy was defined as evidence of bleeding or abnormal coagulation parameters. Hematologic toxicities were graded by Common Terminology Criteria for Adverse Events V.4.0. Results Across 53 patients receiving CD22 CAR T-cells who experienced CRS, 43 (81.1%) patients achieved complete remission. Eighteen (34.0%) patients experienced coagulopathy, of whom 16 had clinical manifestations of mild bleeding (typically mucosal bleeding) which generally subsided following CRS resolution. Three had manifestations of thrombotic microangiopathy. Patients with coagulopathy had higher peak ferritin, D-dimer, prothrombin time, international normalized ratio (INR), lactate dehydrogenase (LDH), tissue factor, prothrombin fragment F1+2 and soluble vascular cell adhesion molecule-1 (s-VCAM-1). Despite a relatively higher incidence of HLH-like toxicities and endothelial activation, overall neurotoxicity was generally less severe than reported with CD19 CAR T-cells, prompting additional analysis to explore CD22 expression in the central nervous system (CNS). Single-cell analysis revealed that in contrast to CD19 expression, CD22 is not on oligodendrocyte precursor cells or on neurovascular cells but is seen on mature oligodendrocytes. Lastly, among those attaining CR, grade 3–4 neutropenia and thrombocytopenia were seen in 65% of patients at D28. Conclusion With rising incidence of CD19 negative relapse, CD22 CAR T-cells are increasingly important for the treatment of B-cell malignancies. In characterizing hematologic toxicities on CD22 CAR T-cells, we demonstrate that despite endothelial activation, coagulopathy, and cytopenias, neurotoxicity was relatively mild and that CD22 and CD19 expression in the CNS differed, providing one potential hypothesis for divergent neurotoxicity profiles. Systematic characterization of on-target off-tumor toxicities of novel CAR T-cell constructs will be vital as new antigens are targeted. Trial registration number NCT02315612 .

3109 Background: WSD0922-Fu is an oral, central nervous system (CNS)-penetrant, small molecule, ATP non-competitive, reversible EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). We report initial results of a first-in-human phase 1 dose-escalation trial (NCT04197934) in patients with EGFR aberrant recurrent HGA and NSCLC. Methods: Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR mutant and/or EGFR amplified HGA were enrolled. WSD0922-Fu was orally administered, and dose escalated in cohorts based on a standard 3+3 design to determine the maximum tolerated dose (MTD). Toxicities were graded per CTCAE v5.0 and preliminary efficacy was based on modified RANO criteria or RECIST 1.1 as appropriate. Results: 25 patients (17 HGA, 8 NSCLC) were enrolled and treated in six cohorts (40 mg once daily to 320 mg twice daily, 28-day cycles). The median age was 57 years (range 39-75 years). 24% were female and 36% were ECOG 0. For patients with HGA, all patients were previously treated with radiation and temozolomide; the median number of prior lines of systemic therapy was 1 (range 1-4). For patients with NSCLC, all patients were previously treated with an EGFR inhibitor (prior osimertinib 88%); the median number of prior lines of systemic therapy was 1.5 (range 1-6). The median duration of exposure to WSD0922-Fu among all patients was 54 days (range 2-258 days). The most common (≥25%) treatment-related adverse events included fatigue (68%), acneiform rash (68%), diarrhea (52%), nausea (48%) and pruritis (28%). The frequency of severe AEs was dose dependent. The most common Grade 3+ AEs (≥10%) included lymphopenia (16%), acneiform rash (12%), headache (12%) and diarrhea (12%). The MTD was defined as 160 mg twice daily. At Cycle 1 Day 15 for patients treated at this dose level, the mean terminal elimination half-life (%CV) in the plasma was 31.6 h (102%) (median 14.5 h; range 6.2-78.7 h). The mean Cmax, Tmax, oral clearance at steady state, and AUC (0-12 h) (%CV) were 4513 ng/mL (50%), 2.0 hr (69%), 6.9 L/hr/m2 (42%), and 28084 h*ng/mL (52%), respectively. Oral clearance at steady state was inversely related with dose, suggesting either inhibition or saturation of clearance processes. Among patients treated at MTD or higher dose levels and with available response data, 100% (5/5) of patients with NSCLC demonstrated clinical benefit (SD + PR) while 60% of patients had partial responses (intracranial and extracranial). Furthermore, prolonged stable disease (9 cycles) was observed in a patient with EGFRvIII mutant GBM. Conclusions: The MTD for WSD0922-Fu monotherapy is 160 mg BID. Preliminary efficacy was observed in patients with osimertinib-resistant NSCLC and EGFRvIII mutant HGA. Enrollment to expansion cohorts is ongoing. Clinical trial information: NCT04197934 .

TPS2085 Background: Glioblastoma (GBM) is the most common and aggressive form of brain tumor in adults. Despite maximal surgical resection, irradiation, and chemotherapy, median overall survival (OS) remains at only 30 weeks for recurrent GBM (rGBM) patients, emphasizing the need for novel treatments. GBM tumors are immunologically ‘cold,’ in that they have an immune-suppressive microenvironment with a low number of tumor-infiltrating lymphocytes (TIL). Interleukin 7 (IL-7) plays a key role in T cell development and survival. The physiological level of IL-7 increases to stimulate T cell expansion in lymphopenic condition. Previous studies have shown that lymphopenic GBM patients have shorter survival. However, their IL-7 levels are unexpectedly low. Efineptakin alfa (NT-I7), a long-acting IL-7, has been shown to increase effector CD8 T cells and reduce suppressor T-regulatory cells in murine GBM models, with subsequently improved OS. Further, we recently completed a Phase I study which showed that NT-I7 is safe, well- tolerated, and increased absolute lymphocyte counts (ALC) in newly diagnosed GBM patients. Phase II dosing was determined through this Phase I study reaching maximum tolerated dose. Thus, we hypothesized that NT-I7 may reverse GBM-associated immune suppression and potentiate the effect of an immune checkpoint inhibitor, leading to an increase in TILs and improved survival. Our preliminary data suggests that combining NT-I7 with pembrolizumab, an anti-PD-1 antibody, improves survival in murine glioma models. The purpose of this study is to evaluate the safety and efficacy of combining NT-I7 and pembrolizumab in rGBM patients. Methods: This is an open-label single arm one-stage Phase II study of NT-I7 and pembrolizumab as neoadjuvant and adjuvant therapy with surgery for adult patients with rGBM. We plan to enroll 30 evaluable patients, including a 6-patient safety run-in. Key eligibility criteria include candidates willing to undergo clinically indicated resection or biopsy, age ≥ 18 years, Karnofsky performance status ≥ 70, and dexamethasone dose > 2 mg/day ≤ 2 days prior to registration. The primary endpoint is a 9-month OS rate. Secondary endpoints include progression-free survival, objective response rate, changes in ALC, and adverse events profile. The correlative endpoints include studies to assess the anti-glioma immune response, changes in T cell subsets, T cell effector function, cytokine analysis, and immunohistochemical analysis of GBM tissue. Longitudinal cerebrospinal fluid proteomics is optional. This study opened on 1/20/2023. Two of the planned 30 patients had been enrolled by submission on 2/14/2023. Clinical trial information: NCT05465954 .

TPS2084 Background: Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) levels in blood due to the blood-brain barrier (BBB). This results in challenges to the identification of blood-based biomarkers and the development of novel biomarker-driven systemic therapies. Real-time image-guided low intensity focused ultrasound (LIFU) combined with IV microbubble oscillators (DEFINITY), non-invasively causes BBB disruption (BBBD). This clinical trial aims to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM. Methods: LIBERATE is a prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged >18-80 years with suspected GBM planned for tumor biopsy or resection at eleven centers in North America are being included. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered IV oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using a 220 kHz LIFU device is performed with real-time acoustic feedback for effective cavitation. Before and after procedure, phlebotomies and MRI brain are performed to evaluate outcomes. The primary study endpoint is defined, per subject, as the ratio between their cfDNA level in blood 1-hour post-LIFU compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in cfDNA sample from 1-hour post-LIFU sample and biomarker pattern in tumor tissue obtained later. The trial has been powered to evaluate both primary and secondary hypotheses. Based on an assumed true agreement rate of 91% and a one-sided alpha of 0.025, an exact test for binomial proportions provides a sample of N=50 with 84% power for the secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels post-LIFU in samples collected at 30 minutes, 1 hour, 2 hour, and 3 hour to determine time of greatest yield, (3) correlation of MRI parameters related to grading of BBBD and biomarkers positive in cfDNA from post-LIFU blood samples. Patient enrollment commenced in 2022 and 7 patients have been recruited by 02/13/2023. Clinical trial information: NCT05383872 .

TPS2082 Background: No drug has improved survival for patients with high-grade gliomas (HGGs) since temozolomide in 2005. Relatively little is known about the live response of in situ gliomas to therapeutic intervention. Phase 0 studies that leverage access to the live human glioma in situ, including via microdialysis to sample the live glioma microenvironment, provide an attractive and feasible solution to this problem. We performed intraoperative microdialysis to evaluate the extracellular metabolome of divergent regions in 15 HGG resections. Our data revealed a conserved metabolic signature of HGGs and a novel glioma-associated metabolite, guanidinoacetate (GAA). Pathways enriched in this tumor signature included methionine and polyamine metabolism. Although GAA is typically converted to creatine, we hypothesize that the high flux of ornithine through ornithine decarboxylase (ODC) results in excess GAA accumulation. As such, in a Phase 0 trial, we will evaluate in situ glioma responses to polyamine depletion via ODC inhibition (Difluoromethylornithine, DFMO), with or without blockade of polyamine uptake (AMXT 1501), to identify candidate extracellular biomarkers of target engagement and cytotoxicity. Methods: Patients will be recruited who are undergoing a clinically indicated subtotal resection for a known or suspected high-grade glioma (NCT05717153). At the end of the surgery, two microdialysis catheters will be implanted for post-operative microdialysis, one in residual tumor and one in brain adjacent to tumor for an internal control. Beginning on post-operative day (POD) 1, patients will be randomized to one of the following three groups, including administration of vehicle, DFMO (500 mg, PO, BID) and AMXT 1501 (600 mg, PO, BID): 1) DFMO + AMXT 1501 (POD1-5); 2) Vehicle (POD1–POD2), followed by DFMO + AMXT 1501 (POD3-POD5); 3) DFMO alone (POD1–POD2), followed by DFMO + AMXT 1501 (POD3- POD5). Throughout this time, extracellular metabolite levels of polyamines, guanidinoacetate, and glutamate will be quantified from microdialysate collected every two hours from intraoperatively implanted 100 kDA microdialysis catheters. The primary outcome of this study is to determine how polyamine depletion impacts extracellular intratumoral guanidinoacetate abundance. The secondary outcomes of this study are to (1) determine the impact of polyamine depletion on polyamine abundance and the global extracellular metabolome within live human gliomas, in situ, and (2) assess the feasibility of longitudinal microdialysis for pharmacodynamic analysis within live human gliomas in situ in the post-operative setting. Clinical trial information: NCT05717153 .

TPS2081 Background: Murine double minute 2 (MDM2) directly regulates the stability of the tumor suppressor p53, and dysregulation of this pathway can critically disrupt cellular response to genomic stress and lead to cell death. BI 907828 is a highly potent inhibitor of the MDM2-p53 interface that triggers accumulation of p53 and subsequent apoptosis in multiple GBM patient-derived xenografts (PDXs) with wild-type p53. Moreover, the combination of BI 907828 and radiotherapy provides significant survival extension in multiple orthotopic GBM PDXs. Methods: An integrated Phase 0/1 trial design is being used to evaluate the potential for BI 907828 to achieve a therapeutic concentration in brain tumor tissue and to test the safety of the combination with radiation. The co-primary endpoints for the Phase 0 study are i) measured total concentration of BI 907828 and ii) calculated unbound concentration of BI 907828 in contrast and non-contrast enhancing regions of tumor. Key inclusion criteria for the Phase 0 study are patients at least 18 years of age, ECOG performance status of 0 or 1, histologic or radiologic new diagnosis of GBM, and planned surgical resection. The first approximately 6 patients enrolled in the Phase 0 will be treated at the starting dose of 30 mg, and the future patients enrolled will be dosed at higher levels (45 mg or 60 mg) provided there are no safety concerns. If dose-limiting toxicities (DLTs) are encountered, then a Bayesian Logistic Regression Model (BLRM) with overdose control will be used to guide the dose level decisions for the additional patients. Multiple, image-registered tumor samples and intra-operative plasma samples will be analyzed for BI 907828 by LC-MS/MS. Intra-tumoral variation in BI 907828 will be correlated with pharmacodynamic effects of MDM2 inhibition (elevation of p53, p21, MDM2, GDF15, PUMA). Those patients completing the Phase 0 study and who meet additional eligibility criteria can enroll on the Phase 1a portion of the study. The pathologic inclusion criteria are TP53 wild-type, IDH1/2 wild-type, MGMT unmethylated GBM. Co-primary endpoints for the Phase 1a trial are i) occurrence of DLTs during and within 21 days after completion of radiation therapy, and ii) occurrence of adverse events throughout the treatment period. Tolerability of inter-patient dose-escalation of BI 907828 (30, 45, 60 mg) combined with radiation therapy (60 Gy in 30 fractions) will be evaluated with dose-escalation guided by a two-parameter BLRM with overdose control. Patients will remain on BI 907828 monotherapy following completion of radiotherapy until progression. To date, two patients have enrolled on the Phase 0 study, and one patient went on to enroll on the Phase 1a portion of the study. Clinical trial information: NCT05376800 .

Abstract Background Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring. Methods Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring. Results Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months. Conclusions BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.

BACKGROUND AND OBJECTIVES: No new drug has improved survival for glioblastoma since temozolomide in 2005, due in part to the relative inaccessibility of each patientʼs individualized tumor biology and its response to therapy. We have identified a conserved extracellular metabolic signature of enhancing high-grade gliomas enriched for guanidinoacetate (GAA). GAA is coproduced with ornithine, the precursor to protumorigenic polyamines through ornithine decarboxylase (ODC). AMXT-1501 is a polyamine transporter inhibitor that can overcome tumoral resistance to the ODC inhibitor, difluoromethylornithine (DFMO). We will use DFMO with or without AMXT-1501 to identify candidate pharmacodynamic biomarkers of polyamine depletion in patients with high-grade gliomas in situ . We aim to determine (1) how blocking polyamine production affects intratumoral extracellular guanidinoacetate abundance and (2) the impact of polyamine depletion on the global extracellular metabolome within live human gliomas in situ. METHODS: DFMO, with or without AMXT-1501, will be administered postoperatively in 15 patients after clinically indicated subtotal resection for high-grade glioma. High–molecular weight microdialysis catheters implanted into residual tumor and adjacent brain will be used for postoperative monitoring of extracellular GAA and polyamines throughout therapeutic intervention from postoperative day (POD) 1 to POD5. Catheters will be removed on POD5 before discharge. EXPECTED OUTCOMES: We anticipate that GAA will be elevated in tumor relative to adjacent brain although it will decrease within 24 hours of ODC inhibition with DFMO. If AMXT-1501 effectively increases the cytotoxic impact of ODC inhibition, we expect an increase in biomarkers of cytotoxicity including glutamate with DFMO + AMXT-1501 treatment when compared with DFMO alone. DISCUSSION: Limited mechanistic feedback from individual patientsʼ gliomas hampers clinical translation of novel therapies. This pilot Phase 0 study will provide in situ feedback during DFMO + AMXT-1501 treatment to determine how high-grade gliomas respond to polyamine depletion.