First-in-human Phase I Trial of TPST-1120, an Inhibitor of PPARα, as Monotherapy or in Combination with Nivolumab, in Patients with Advanced Solid Tumors.

PURPOSE: TPST-1120 is a first-in-class oral inhibitor of peroxisome proliferator-activated receptor α (PPARα), a fatty acid ligand-activated transcription factor that regulates genes involved in fatty acid oxidation, angiogenesis, and inflammation, and is a novel target for cancer therapy. TPST-1120 displayed antitumor activity in xenograft models and synergistic tumor reduction in syngeneic tumor models when combined with anti-PD-1 agents. EXPERIMENTAL DESIGN: This phase I, open-label, dose-escalation study (NCT03829436) evaluated TPST-1120 as monotherapy in patients with advanced solid tumors and in combination with nivolumab in patients with renal cell carcinoma (RCC), cholangiocarcinoma (CCA), or hepatocellular carcinoma. Objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity (RECIST v1.1). RESULTS: A total of 39 patients enrolled with 38 treated (20 monotherapy, 18 combination; median 3 prior lines of therapy). The most common treatment-related adverse events (TRAE) were grade 1-2 nausea, fatigue, and diarrhea. No grade 4-5 TRAEs or dose-limiting toxicities were reported. In the monotherapy group, 53% (10/19) of evaluable patients had a best objective response of stable disease. In the combination group, 3 patients had partial responses, for an objective response rate of 20% (3/15) across all doses and 30% (3/10) at TPST-1120 ≥400 mg twice daily. Responses occurred in 2 patients with RCC, both of whom had previously progressed on anti-PD-1 therapy, and 1 patient with late-line CCA. CONCLUSIONS: TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers. SIGNIFICANCE: TPST-1120 is a first-in-class oral inhibitor of PPARα, whose roles in metabolic and immune regulation are implicated in tumor proliferation/survival and inhibition of anticancer immunity. This first-in-human study of TPST-1120 alone and in combination with nivolumab supports proof-of-concept of PPARα inhibition as a target of therapeutic intervention in solid tumors.

A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma.

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.

Food Sovereignty and Health: A Conceptual Framework to Advance Research and Practice.

Settler colonialism disrupted traditional Indigenous foodways and practices and created high rates of diet-related disease among Indigenous peoples. Food sovereignty, the rights of Indigenous peoples to determine their own food systems, is a culturally centered movement rooted in traditional Indigenous knowledge. This approach directly intervenes upon systems-level barriers to health, making it an important strategy for health equity. While food sovereignty initiatives can be found within many Indigenous communities, the conceptual linkages between food sovereignty and health have not been well documented within the public health literature. We present a practice-informed conceptual framework developed as part of the Center for Indigenous Innovation and Health Equity (CIIHE) initiative, a community-academic partnership with the goal of strengthening Indigenous food systems and practices to promote health and well-being. The framework emphasizes connectedness, including the transmission of knowledge across generations and the restoration of relational responsibilities, as central to Indigenous concepts of health and wellness.

Food Systems, Food Sovereignty, and Health: Conference Shares Linkages to Support Indigenous Community Health.

The Center for Indigenous Innovation and Health Equity (CIIHE) at Oklahoma State University Center for Health Sciences (OSU-CHS) is a community-academic partnership with Indigenous peoples from Alaska, Hawai'i, and Oklahoma. The CIIHE supports communities to strengthen traditional food practices and food sovereignty and evaluate the impact of those efforts on health. In February 2022, the CIIHE sponsored and hosted a virtual conference to better understand how food sovereignty initiatives can improve health. More than 600 participants gathered to hear the latest research and practice in the areas of public health and agriculture, nutrition, community-based and Indigenous knowledge, and health economics. Community-led food sovereignty initiatives being implemented as part of the CIIHE were featured along with other Indigenous initiatives in urban, rural, and reservation communities. A survey was administered to conference participants to assess food sovereignty topics and priorities for future research. In this Practice Note, we describe innovative community-led initiatives presented as part of the conference and recommendations for action emerging from qualitative and quantitative data collected from conference participants.

The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial.

Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3+ non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2+ tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268 .

Global Bifurcation for Corotating and Counter-Rotating Vortex Pairs.

The existence of a local curve of corotating and counter-rotating vortex pairs was proven by Hmidi and Mateu (in Commun Math Phys 350(2):699-747, 2017) via a desingularization of a pair of point vortices. In this paper, we construct a global continuation of these local curves. That is, we consider solutions which are more than a mere perturbation of a trivial solution. Indeed, while the local analysis relies on the study of the linear equation at the trivial solution, the global analysis requires on a deeper understanding of topological properties of the nonlinear problem. For our proof, we adapt the powerful analytic global bifurcation theorem due to Buffoni and Toland to allow for the singularity at the bifurcation point. For both the corotating and the counter-rotating pairs, along the global curve of solutions either the angular fluid velocity vanishes or the two patches self-intersect.

First-in-human Study of AZD5153, A Small-molecule Inhibitor of Bromodomain Protein 4, in Patients with Relapsed/Refractory Malignant Solid Tumors and Lymphoma.

AZD5153, a reversible, bivalent inhibitor of the bromodomain and extraterminal family protein BRD4, has preclinical activity in multiple tumors. This first-in-human, phase I study investigated AZD5153 alone or with olaparib in patients with relapsed/refractory solid tumors or lymphoma. Adults with relapsed tumors intolerant of, or refractory to, prior therapies received escalating doses of oral AZD5153 once daily or twice daily continuously (21-day cycles), or AZD5153 once daily/twice daily continuously or intermittently plus olaparib 300 mg twice daily, until disease progression or unacceptable toxicity. Between June 30, 2017 and April 19, 2021, 34 patients received monotherapy and 15 received combination therapy. Dose-limiting toxicities were thrombocytopenia/platelet count decreased (n = 4/n = 2) and diarrhea (n = 1). The recommended phase II doses (RP2D) were AZD5153 30 mg once daily or 15 mg twice daily (monotherapy) and 10 mg once daily (intermittent schedule) with olaparib. With AZD5153 monotherapy, common treatment-emergent adverse events (TEAE) included fatigue (38.2%), thrombocytopenia, and diarrhea (each 32.4%); common grade ≥ 3 TEAEs were thrombocytopenia (14.7%) and anemia (8.8%). With the combination, common TEAEs included nausea (66.7%) and fatigue (53.3%); the most common grade ≥ 3 TEAE was thrombocytopenia (26.7%). AZD5153 had dose-dependent pharmacokinetics, with minimal accumulation, and demonstrated dose-dependent modulation of peripheral biomarkers, including upregulation of HEXIM1. One patient with metastatic pancreatic cancer receiving combination treatment had a partial response lasting 4.2 months. These results show AZD5153 was tolerable as monotherapy and in combination at the RP2Ds; common toxicities were fatigue, hematologic AEs, and gastrointestinal AEs. Strong evidence of peripheral target engagement was observed.

Cannabis use among adults undergoing cancer treatment.

BACKGROUND: Little is known about the risks and benefits of cannabis use in the context of cancer care. This study characterized the prevalence, reasons for use, and perceived benefits of cannabis and compared symptoms and perceived risks between those who reported past 30-day cannabis use and those who did not. METHODS: Adults undergoing cancer treatment at a National Cancer Institute-designated cancer center completed measures of sociodemographic characteristics, cannabis use, use modalities, reasons for use, perceived harms/benefits of use, physical and psychological symptoms, and other substance/medication use. Analyses compared patients who used or did not use cannabis in the past 30 days. RESULTS: Participants (N = 267) were 58 years old on average, primarily female (70%), and predominantly White (88%). Over a quarter of respondents (26%) reported past 30-day cannabis use, and among those, 4.5% screened positive for cannabis use disorder. Participants who used cannabis most often used edibles (65%) or smoked cannabis (51%), and they were younger and more likely to be male, Black, and disabled, and to have lower income and Medicaid insurance than participants who did not use cannabis. Those who used cannabis reported more severe symptoms and perceived cannabis as less harmful than those who did not use cannabis. The most common medical reasons for cannabis use were pain, cancer, sleep problems, anxiety, nausea/vomiting, and poor appetite. Participants reported the greatest cannabis-related symptom relief from sleep problems, nausea/vomiting, headaches, pain, muscle spasms, and anxiety. CONCLUSIONS: Patients with cancer who used cannabis perceived benefits for many symptoms, although they showed worse overall symptomatology. PLAIN LANGUAGE SUMMARY: Among adults undergoing cancer treatment, 26% reported cannabis use in the past 30 days. Those who used cannabis were more likely to be male and disabled and to have lower income and Medicaid insurance than those who did not use cannabis. Participants most commonly reported using cannabis for pain, cancer, sleep, anxiety, and nausea/vomiting and reported the greatest perceived benefits for sleep, nausea/vomiting, headaches, pain, muscle spasms, and anxiety, yet participants who used cannabis also reported feeling worse physically and psychologically compared to those who did not use cannabis. Participants who used cannabis were more likely to report that cannabis was less risky to their health than alcohol, smoking, and opioids than those who did not use cannabis.

Flexible Ink-Jet Printed Polymer Light-Emitting Diodes using a Self-Hosted Non-Conjugated TADF Polymer.

Thermally activated delayed fluorescent (TADF) emitters have become the leading emissive materials for highly efficient organic light-emitting diodes (OLEDs). The deposition of these materials in scalable and cost-effective ways is paramount when looking toward the future of OLED applications. Herein, a simple OLED with fully solution-processed organic layers is introduced, where the TADF emissive layer is ink-jet printed. The TADF polymer has electron and hole conductive side chains, simplifying the fabrication process by removing the need for additional host materials. The OLED has a peak emission of 502 nm and a maximum luminance of close to 9600 cd m-2 . The self-hosted TADF polymer is also demonstrated in a flexible OLED, reaching a maximum luminance of over 2000 cd m-2 . These results demonstrate the potential applications of this self-hosted TADF polymer in flexible ink-jet printed OLEDs and, therefore, for a more scalable fabrication process.

Phase 1b study of pan-AKT inhibitor vevorisertib alone or with paclitaxel or fulvestrant in PIK3CA/AKT/PTEN-mutated advanced solid tumors.

BACKGROUND: In this first-in-human phase 1b study (ClinicalTrials.gov identifier NCT02761694) of advanced solid tumors with PIK3CA/AKT/PTEN mutations, the authors investigated the safety and efficacy of the pan-AKT inhibitor vevorisertib (MK-4440; ARQ 751) as monotherapy or with paclitaxel or fulvestrant. METHODS: Patients with histologically confirmed, advanced or recurrent, PIK3CA/AKT/PTEN-mutated solid tumors, measurable disease according to Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status ≤1 received vevorisertib (dose range, 5-100 mg) alone or with paclitaxel 80 mg/m2 or fulvestrant 500 mg. The primary end point was safety and tolerability. Secondary end points included pharmacokinetics and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Of 78 patients enrolled, 58 received vevorisertib monotherapy, 10 received vevorisertib plus paclitaxel, and nine received vevorisertib plus fulvestrant. Dose-limiting toxicity occurred in three patients (vevorisertib monotherapy, n = 2 [grade 3 pruritic and maculopapular rashes]; vevorisertib plus paclitaxel, n = 1 [grade 1 asthenia]). Across doses, treatment-related AEs occurred in 46 patients (79%) with vevorisertib monotherapy, in 10 patients (100%) with vevorisertib plus paclitaxel, and in nine patients (100%) with vevorisertib plus fulvestrant; and grade 3 treatment-related AEs occurred in 13 (22%), 7 (70%), and 3 (33%) patients, respectively. No grade 4/5 treatment-related AEs occurred. Maximum vevorisertib concentrations were reached 1-4 hours after dosing; the elimination half-life ranged from 8.8 to 19.3 hours. The objective response rate was 5% with vevorisertib monotherapy (three partial responses), 20% with vevorisertib plus paclitaxel (two partial responses), and 0% with vevorisertib plus fulvestrant. CONCLUSIONS: Vevorisertib alone or with paclitaxel or fulvestrant had a manageable safety profile, and vevorisertib alone or with paclitaxel had minimal to modest antitumor activity in this patient population with PIK3CA/AKT/PTEN-mutated advanced solid tumors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02761694.

Short-term mating orientation as a predictor of alcohol use and risky sexual behavior.

OBJECTIVES: Sexual Strategies Theory suggests people fall on a continuum between having short-term mating orientation (STMO) and long-term mating orientation. One way STMO individuals signal mating goals is via risky drinking. The current study therefore aims to investigate drinks per week (DPW) as a mediator between STMO and risky sexual behavior (RSB), with gender as a moderator between STMO and DPW. PARTICIPANTS: Undergraduate students (N = 300) from a Midwestern university during Fall 2019. METHOD: Participants completed questionnaires assessing STMO, DPW, and RSB frequency. RESULTS: A moderated-mediation model indicated DPW significantly mediated the relationship between STMO and RSB. Positive associations were found among all three variables. Gender was not a moderator between STMO and DPW. CONCLUSIONS: Mating orientation was a correlate of alcohol use and RSB for women and men, contributing to the literature identifying STMO as an indicator of those in need of substance use and RSB intervention.

Displacement imposition scale assesses reactions of cigarette and e-cigarette users impacted by a campus-wide smoking ban.

OBJECTIVE: The present study developed a measure assessing the emotional responses, "Displacement Imposition," of cigarette and e-cigarette users on a college campus with a smoking/vaping ban. It also examined the relationship between Displacement Imposition and readiness to quit smoking/vaping, and how this relationship differed between cigarette and e-cigarette users. PARTICIPANTS: Participants (N = 297) were from a large, Midwestern university. METHODS: Participants completed online questionnaires assessing demographics, cigarette and e-cigarette use, Displacement Imposition, and readiness to quit. RESULTS: All six Displacement Imposition items loaded onto a single factor. A significant interaction emerged between Displacement Imposition and product use in predicting readiness to quit. At high levels of Displacement Imposition, cigarette users were less ready to quit than e-cigarette users. CONCLUSIONS: Findings suggest restrictions imposed on cigarette and e-cigarette users were associated with reduced readiness to quit. Findings inform tobacco control policies as tobacco denormalization may increase the burden placed on tobacco users.

Avelumab Plus Talazoparib in Patients With BRCA1/2- or ATM-Altered Advanced Solid Tumors: Results From JAVELIN BRCA/ATM, an Open-Label, Multicenter, Phase 2b, Tumor-Agnostic Trial.

Importance: Nonclinical studies suggest that the combination of poly(ADP-ribose) polymerase and programmed cell death 1/programmed cell death-ligand 1 inhibitors has enhanced antitumor activity; however, the patient populations that may benefit from this combination have not been identified. Objective: To evaluate whether the combination of avelumab and talazoparib is effective in patients with pathogenic BRCA1/2 or ATM alterations, regardless of tumor type. Design, Setting, and Participants: In this pan-cancer tumor-agnostic phase 2b nonrandomized controlled trial, patients with advanced BRCA1/2-altered or ATM-altered solid tumors were enrolled into 2 respective parallel cohorts. The study was conducted from July 2, 2018, to April 12, 2020, at 42 institutions in 9 countries. Interventions: Patients received 800 mg of avelumab every 2 weeks and 1 mg of talazoparib once daily. Main Outcomes and Measures: The primary end point was confirmed objective response (OR) per RECIST 1.1 by blinded independent central review. Results: A total of 200 patients (median [range] age, 59.0 [26.0-89.0] years; 132 [66.0%] women; 15 [7.5%] Asian, 11 [5.5%] African American, and 154 [77.0%] White participants) were enrolled: 159 (79.5%) in the BRCA1/2 cohort and 41 (20.5%) in the ATM cohort. The confirmed OR rate was 26.4% (42 patients, including 9 complete responses [5.7%]) in the BRCA1/2 cohort and 4.9% (2 patients) in the ATM cohort. In the BRCA1/2 cohort, responses were more frequent (OR rate, 30.3%; 95% CI, 22.2%-39.3%, including 8 complete responses [6.7%]) and more durable (median duration of response: 10.9 months [95% CI, 6.2 months to not estimable]) in tumor types associated with increased heritable cancer risk (ie, BRCA1/2-associated cancer types, such as ovarian, breast, prostate, and pancreatic cancers) and in uterine leiomyosarcoma (objective response in 3 of 3 patients and with ongoing responses greater than 24 months) compared with non-BRCA-associated cancer types. Responses in the BRCA1/2 cohort were numerically higher for patients with tumor mutational burden of 10 or more mutations per megabase (mut/Mb) vs less than 10 mut/Mb. The combination was well tolerated, with no new safety signals identified. Conclusions and Relevance: In this phase 2b nonrandomized controlled trial, neither the BRCA1/2 nor ATM cohort met the prespecified OR rate of 40%. Antitumor activity for the combination of avelumab and talazoparib in patients with BRCA1/2 alterations was observed in some patients with BRCA1/2-associated tumor types and uterine leiomyosarcoma; benefit was minimal in non-BRCA-associated cancer types. Trial Registration: ClinicalTrials.gov Identifier: NCT03565991.

An Updated Narrative Review on the Role of Alcohol Among Indigenous Communities.

Purpose of Review: The role of alcohol varies considerably among Indigenous Peoples and is the backdrop of persistent stereotypes despite decades of research. This paper provides an updated narrative review on the alcohol literature among Indigenous communities, highlighting recent studies published since 2017. Recent Findings: We examined published literature involving alcohol use rates, including abstinence; risk and protective factors; treatment; and recovery, as well as future directions for alcohol prevention and intervention efforts with Indigenous communities. Summary: Evidence-based alcohol use prevention, intervention, and recovery strategies with Indigenous communities are outlined. Recommendations are provided for researchers, health providers, and public policy advocates to address and better understand alcohol use, treatment, prevention, and recovery among Indigenous Peoples. Specific recommendations include using community-based participatory research strategies and harm reduction approaches to prevent and treat alcohol use problems with Indigenous communities. Future research is needed to elucidate mechanisms of resilience and recovery from Alcohol Use Disorder and possible shifts in perceptions of alcohol use for Indigenous Peoples.

Intentions to Reduce Alcohol Use Following Brief Alcohol-Related Health Messages Among College Students.

OBJECTIVE: Health care providers using brief alcohol-related health messaging is an effective manner of reducing risky drinking; however, research is needed to guide the content of such messages. The present study compared current drinkers' and nondrinkers' perspectives on the value of four different alcohol-related messages and the hypothetical impact of the messages on intentions to reduce drinking. METHOD: Undergraduates (n = 286 current drinkers, n = 101 nondrinkers) from a large, public, Southern Plains university identified primarily as White (82.9%) and female (70%), with a mean age of 19.98 years. They viewed four video recordings containing different alcohol-related messages in random order and were asked to rate how likely they were to change their drinking behaviors after watching each video. RESULTS: All participants generally had a comparably positive appraisal of all four messages. Among current drinkers, one-way analyses of variance revealed significant differences across messages for intention to change drinking frequency, F(3, 260) = 5.69, p = .001, ηp2 = .06, and quantity, F(3, 263) = 4.95, p = .002, ηp2 = .05. Post hoc tests showed that the condition warning students of severe consequences resulted in higher intentions to reduce drinking compared with other conditions describing less severe consequences, drinking norms, or protective behavioral strategies. No significant differences emerged among nondrinkers. CONCLUSIONS: Despite mixed research regarding the effectiveness of fear-based warning messages in reducing high-risk drinking, the message containing severe alcohol-related consequences evoked the greatest hypothetical intentions to reduce quantity and frequency of drinking. Future studies should track actual drinking behaviors longitudinally following each message.

Social norms of alcohol use among American Indian/Alaska Native college students.

OBJECTIVE: Research on misperceived descriptive and injunctive drinking norms, or normative perceptions of frequency, quantity, and acceptability of drinking, has rarely been extended to American Indian/Alaska Native (AI/AN) college student populations. Ethnic identity, or strength of one's ties to their AI/AN culture, has been hypothesized as a protective factor against problematic alcohol use. As a step toward informing culturally appropriate and gender-specific norms-based interventions for AI/AN students, this study examined differences between perceived and actual descriptive and injunctive drinking norm reference groups (e.g., AI/AN males/females, "typical" males/females), and investigated ethnic identity as a moderator between perceived and actual drinking norms. METHOD: AI/AN college students (N = 356) completed an online survey assessing drinking patterns, descriptive norms, injunctive norms, and ethnic identity. RESULTS: Compared to actual drinking levels, participants overestimated all gender-specific descriptive norm groups and all gender-specific injunctive norm groups except for AI/AN males. Participants estimated lower drinking levels for AI/AN-specific groups than non-AI/AN groups. Descriptive AI/AN male and best male friend norms significantly predicted drinking for men while only best female friend norms predicted drinking for women. Injunctive typical male norms significantly predicted drinking for men, and no injunctive norms predicted drinking for women. Finally, ethnic identity was unrelated to drinking and did not significantly moderate the relation between perceived and actual drinking. CONCLUSIONS: Current findings may inform norms-based alcohol use interventions, as AI/AN-specific reference groups may have a significant impact on drinking among men, but not women. Future culturally relevant alcohol use intervention research for AI/AN young adults is warranted. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A Phase 1a/b Open-Label, Dose-Escalation Study of Etigilimab Alone or in Combination with Nivolumab in Patients with Locally Advanced or Metastatic Solid Tumors.

PURPOSE: TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) is a co-inhibitory receptor of T-cell and natural killer cell activity. Targeting TIGIT with or without PD-1/PD-L1 checkpoint inhibition may enhance antitumor immunity. PATIENTS AND METHODS: This Phase 1a/b trial was a first-in-human, open-label, multicenter, dose-escalation and -expansion study in patients with locally advanced or metastatic solid tumors. Using 3 + 3 design, patients underwent 14-day treatment cycles with anti-TIGIT antibody etigilimab alone (Phase 1a; 0.3, 1.0, 3.0, 10.0, 20.0 mg/kg intravenously) or in combination with anti-PD-1 antibody nivolumab (Phase 1b; 3.0, 10.0, 20.0 mg/kg etigilimab and 240 mg nivolumab). Primary objective was safety and tolerability. RESULTS: Thirty-three patients were enrolled (Phase 1a, n = 23; Phase 1b, n = 10). There were no dose-limiting toxicities (DLT). MTD for single and combination therapy was not determined; maximum administered dose was 20 mg/kg. The most commonly reported adverse events (AE) were rash (43.5%), nausea (34.8%), and fatigue (30.4%) in Phase 1a and decreased appetite (50.0%), nausea (50.0%), and rash (40%) in Phase 1b. Six patients experienced Grade ≥3 treatment-related AEs. In Phase 1a, 7 patients (30.0%) had stable disease. In Phase 1b, 1 patient had a partial response; 1 patient had prolonged stable disease of nearly 8 months. Median progression-free survival was 56.0 days (Phase 1a) and 57.5 days (Phase 1b). Biomarker correlative analyses demonstrated evidence of clear dose-dependent target engagement by etigilimab. CONCLUSIONS: Etigilimab had an acceptable safety profile with preliminary evidence of clinical benefit alone and in combination with nivolumab and warrants further investigation in clinical trials.

Reversible HER2 antibody-drug conjugate-induced ocular toxicity.

PURPOSE: To report 3 cases of reversible epitheliopathy induced by A166-a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate (ADC) therapy for resistant HER2 tumours. METHODS: Advanced HER2 tumour patients were enrolled in A166 phase I/II clinical trial using Bayesian logistic regression model dose escalation. Key exclusion criteria were ≥grade 2 (G2) corneal pathology, severe organ disease, and other cancer therapy within 4 weeks. Eye exams were performed at baseline, regularly scheduled intervals, and additionally upon A166-induced ocular symptoms. Topical therapy with autologous serum tears (ASTs) was implemented based on visual acuity, symptoms, and slit lamp exam. A166 was withheld if ≥G2 ocular toxicity developed; if status improved to ≤G1, A166 therapy was resumed. Visual acuity, corneal exam, and subjective comfort were recorded. RESULTS: After ≥2 cycles of A166, 6 eyes of 3/23 enrolled patients developed whorl pattern epitheliopathy suggestive of limbal stem cell (LSC) dysfunction requiring cessation of A166 despite positive tumour response. Patients 1 and 3 received 3.6 mg/kg A166 dose, and patient 2 received 3.0 mg/kg. Topical steroids (2/4 eyes) failed to improve epitheliopathy. Adding ASTs improved vision, ocular comfort, and whorl pattern epitheliopathy in 6/6 eyes within 3 weeks. Patient 1 continues to improve on ASTs; patient 2 withdrew from the study; and patient 3 resumed A166 therapy. CONCLUSION: A166 precipitates LSC dysfunction-like epitheliopathy. Combination therapy including aggressive lubrication, withholding drug, and ASTs help reverse toxicity. Recognizing that ADC-induced epitheliopathy can respond to ocular management may enable cancer patients to continue lifesaving therapy.

A Phase 1b Trial of Prexasertib in Combination with Standard-of-Care Agents in Advanced or Metastatic Cancer.

BACKGROUND: The checkpoint kinase 1 (CHK1) inhibitor prexasertib exhibited modest monotherapy antitumor activity in prior trials, suggesting that combination with chemotherapy or other targeted agents may be needed to maximize efficacy. OBJECTIVES: The aim of this study was to determine the recommended phase II dose and schedule of prexasertib in combination with either cisplatin, cetuximab, pemetrexed, or 5-fluorouracil in patients with advanced and/or metastatic cancer, and to summarize preliminary antitumor activity of these combinations. PATIENTS AND METHODS: This phase Ib, nonrandomized, open-label study comprised dose-escalation phase(s) with multiple sub-arms evaluating different prexasertib-drug combinations: Part A, prexasertib + cisplatin (n = 63); Part B, prexasertib + cetuximab (n = 41); Part C, prexasertib + pemetrexed (n = 3); Part D, prexasertib + 5-fluorouracil (n =8). Alternate dose schedules/regimens intended to mitigate toxicity and maximize dose exposure and efficacy were also explored in sub-parts. RESULTS: In Part A, the maximum tolerated dose (MTD) of prexasertib in combination with cisplatin (75 mg/m2) was declared at 80 mg/m2, with cisplatin administered on Day 1 and prexasertib on Day 2 of a 21-day cycle. The overall objective response rate (ORR) in Part A was 12.7%, and 28 of 55 evaluable patients (50.9%) had a decrease in target lesions from baseline. The most frequent treatment-related adverse events (AEs) in Part A were hematologic, with the most common being white blood cell count decreased/neutrophil count decreased, experienced by 73.0% (any grade) and 66.7% (grade 3 or higher) of patients. In Part B, an MTD of 70 mg/m2 was established for prexasertib administered in combination with cetuximab (500 mg /m2), both administered on Day 1 of a 14-day cycle. The overall ORR in Part B was 4.9%, and 7 of 31 evaluable patients (22.6%) had decreased target lesions compared with baseline. White blood cell count decreased/neutrophil count decreased was also the most common treatment-related AE (56.1% any grade; 53.7% grade 3 or higher). In Parts A and B, hematologic toxicities, even with the addition of prophylactic granulocyte colony-stimulating factor, resulted in frequent dose adjustments (> 60% of patients). In Part C, evaluation of prexasertib + pemetrexed was halted due to dose-limiting toxicities in two of the first three patients; MTD was not established. In Part D, the MTD of prexasertib in combination with 5-fluorouracil (label dose) was declared at 40 mg /m2, both administered on Day 1 of a 14-day cycle. In Part D, overall ORR was 12.5%. CONCLUSIONS: This study demonstrated the proof-of-concept that prexasertib can be combined with cisplatin, cetuximab, and 5-fluorouracil. Schedule was a key determinant of the tolerability and feasibility of combining prexasertib with these standard-of-care agents. Reversible hematologic toxicity was the most frequent AE and was dose-limiting. Insights gleaned from this study will inform future combination strategies for the development of prexasertib and next-generation CHK1 inhibitors. CLINICALTRIALS. GOV IDENTIFIER: NCT02124148 (date of registration 28 April 2014).

Understanding Perceptions of Nonsuicidal Self-Injury: Descriptive and Injunctive Norms.

Nonsuicidal self-injury (NSSI) is a major public health concern. Web-based personalized feedback interventions (PFIs) may be a cost-effective and efficient way to treat NSSI. In order to develop a PFI, it is imperative to assess descriptive and injunctive norms. The current study examines descriptive and injunctive norms of NSSI within college students and adults in the community, comparing how perceived norms may differ for those who do or do not engage in NSSI. Study 1 calculated percentages of NSSI behavior within the student sample. Study 2 then examined perceived descriptive and injunctive norms between those with and without history of NSSI in both samples. Study 1 indicated that 19% of undergraduate students had histories of NSSI. Additionally, there was a general tendency to overestimate the percentage of people who engage in NSSI and the number of times a typical person engages in NSSI. Finally, those who engaged in NSSI believed that most people do not understand why individuals engage in NSSI; comparatively, the majority of people without history of NSSI still indicated that they understand why others would engage in NSSI. These research findings may be utilized in a PFI to reduce shame and NSSI behavior.