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SRF388 is a first-in-class, anti-IL-27 antibody developed to enhance immune responses within the tumor microenvironment. Preclinical studies have demonstrated that IL-27 pathway blockade can inhibit tumor growth in mouse models of liver cancer and lung cancer metastases. There is also evidence that IL-27 pathway inhibition is accompanied by activation of the innate and adaptive arms of the immune system. An ongoing Phase I trial has shown good tolerability at all dose levels tested and preliminary monotherapy antitumor activity with SRF388 (NCT04374877). Here, we describe the preclinical and clinical data used to select a RP2D and characterize cytokine and chemokine changes observed in patients after treatment with SRF388. To guide selection of the RP2D, the relationship between maximal effective dose (MaxED), pharmacokinetics (PK), and whole blood inhibition of IL-27-mediated phosphorylation of STAT1 by SRF388 was evaluated in a mouse model of liver cancer. The concentration of SRF388 associated with optimal antitumor activity was ~20-fold above the concentration needed for complete inhibition (> 90%) of whole blood phosphorylated STAT1 (pSTAT1). These PK and activity relationships were also defined in patients during the dose-escalation phase of the trial and integrated with safety and efficacy data to select a monotherapy RP2D. In patients, PK were linear, no dose-limiting toxicities were reported, complete pSTAT1 inhibition was achieved throughout the first cycle at 0.3 mg/kg, and 1 patient experienced a confirmed partial response per RECIST version 1.1 at a dose of 10 mg/kg. In the MaxED mouse model, the area under the concentration versus time curve (AUC) associated with significant antitumor activity was 1720 day*μg/mL. In patients, the corresponding target AUC was achieved clinically at 10 mg/kg after a single dose of SRF388. Changes in the concentration of several serum cytokines and chemokines were observed after SRF388 treatment including an increase in IL-27, a phenomenon described for other anti-cytokine antibodies due to altered clearance of the cytokine-antibody complex. Changes in a subset of other serum cytokines/chemokines correlated with a reduction in target lesion size. Taken together, these data support the selection of a monotherapy RP2D of 10 mg/kg intravenously every 4 weeks for SRF388. These data highlight how complementary strategies utilizing preclinical and clinical biomarker evaluations can be employed to establish a monotherapy RP2D and assess biological activity of a first-in-class anti-cytokine antibody, SRF388, for patients with cancer. Citation Format: Jonathan A. Hill, Kerry F. White, Matthew Rausch, Jou-Ku Chung, Amita Patnaik, Aung Naing, Daniel Morgensztern, Charlene M. Mantia, Nizar M. Tannir, Lon S. Smith, Beth Bowers, Alex Alika, Lauren C. Harshman, Benjamin H. Lee. Determination of a recommended Phase 2 dose (RP2D) for SRF388, a first-in-class IL-27-blocking antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1137.

2551 Background: IL-27 is an immunosuppressive cytokine, consisting of two subunits p28 and EBI3, that upregulates immune checkpoint receptors (eg, PD-L1, TIGIT) and downregulates proinflammatory cytokines such as IFNγ, TNFα, and IL-17. SRF388 is a first-in-class, fully human IgG1 antibody to IL-27 that blocks the interaction between IL-27 and its receptor, thereby promoting immune activation in the tumor microenvironment. The IL-27 pathway is activated in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), and high circulating levels of EBI3 are associated with inferior outcomes in both. Circulating EBI3 levels may serve as a predictive biomarker of SRF388 activity. Methods: Patients with advanced solid tumors refractory to standard therapy were enrolled in a phase 1 dose-escalation study (accelerated single patient followed by standard 3+3) to establish the preliminary safety of SRF388 as a monotherapy and to identify a dose suitable for expansion (NCT04374877). SRF388 was administered intravenously every 4 weeks. Tumor response was assessed by RECIST v1.1. SRF388 pharmacokinetic (PK) and pharmacodynamic (PD) [phospho-STAT (pSTAT) inhibition] analyses were performed. Results: As of January 26, 2021, 12 patients have received SRF388 at doses ranging from 0.003 to 10 mg/kg with 2 patients undergoing intra-patient dose escalation. Median age was 68 years, 67% were female, and ECOG PS was 0/1 (42%/58%). Median number of prior therapies was 2 (range 1–9), and 75% were anti-PD-(L)1 experienced (n = 9). The only treatment-related adverse events observed across dose levels were low-grade fatigue (n = 1, 8%), nausea (n = 1, 8%) and excess salivation (n = 1, 8%). No dose-limiting toxicities (DLTs) or ≥ Grade 3 related toxicity have occurred. Mean time on study is 12.5 weeks (range 4–40). One patient with RCC who received prior anti-PD-1 has prolonged stable disease for > 9 months. SRF388 PK are linear with estimated T1/2 ranging from 6–19 days. There is evidence of accumulation and no anti-drug antibody development to date. Maximal inhibition of the IL-27 signaling pathway as measured by > 90% pSTAT inhibition in whole blood was achieved starting at 0.3 mg/kg. Given combined evidence of near-complete pathway inhibition and preclinical human equivalent dose modeling projecting biologically active doses, additional slots were opened for RCC and HCC starting at 1 mg/kg. Conclusions: Preliminary results of IL-27 pathway blockade with a first-in-class therapeutic demonstrates that SRF388 is well tolerated at doses that achieve maximal inhibition of downstream pSTAT signaling through the dosing period. Expansions are planned in HCC and RCC. Updated data including the recommended phase 2 dose, clinical outcomes, PK/PD and correlative analyses will be presented. Clinical trial information: NCT04374877.

3064 Background: CD47 is a transmembrane protein that acts as a “Don’t Eat Me” signal to evade immune recognition. It is overexpressed in multiple cancer subtypes and is associated with poor prognosis. SRF231 is an investigational, fully human, high-affinity CD47-targeting antibody that delivers an activating signal to myeloid cells and displays favorable preclinical characteristics regarding its receptor occupancy/tumor exposure/efficacy relationship. Methods: In a Phase 1 study, SRF231-101 (NCT03512340), patients with advanced solid and hematologic malignancies who had failed standard therapy were enrolled in dose escalation cohorts (accelerated single-patient followed by standard 3+3) to establish the preliminary safety of SRF231 as a monotherapy and identify a dose and schedule suitable for expansion. In addition to collection of safety data, clinical outcomes were evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and SRF231 pharmacokinetic (PK) and pharmacodynamic (receptor occupancy) analyses were performed. Results: As of January 11, 2020, a total of 46 patients were enrolled, 25 in every-3-week intravenous (IV) dosing schedules and 21 in weekly IV dosing schedules. Weekly dosing schedules also explored the use of a 1.0 mg/kg initiation dose. Other than one patient with recurrent follicular lymphoma, all patients had recurrent/refractory solid tumors. The most common treatment emergent adverse events across dosing schedules were low-grade fatigue (43%), headache (35%), and pyrexia (30%). On every-3-week dosing schedules, 2 dose-limiting toxicities (DLTs) were observed: Grade 3 febrile neutropenia and Grade 3 hemolysis, both at a 12.0 mg/kg dose level. On weekly dosing schedules, 3 DLTs were observed: Grade 4 thrombocytopenia (6.0 mg/kg), Grade 4 amylase and lipase increased (4.0 mg/kg with initiation dose), and Grade 3 fatigue (4.0 mg/kg). The maximum tolerated dose was 9.0 mg/kg on an every-3-week and 4.0 mg/kg on a weekly schedule. Receptor occupancy was maintained at > 90% throughout the dosing period with a 4.0 mg/kg weekly dose schedule. Out of 37 patients who were response evaluable by RECIST, there were no complete or partial responders, although prolonged stable disease has been observed. Conclusions: Preliminary data from a Phase 1 study of SRF231, an anti-CD47 antibody, demonstrate that SRF231 may be administered safely and doses of 4.0 mg/kg weekly maintain > 90% receptor occupancy throughout the dosing period. Updated safety data, clinical outcomes, and PK/pharmacodynamic data will be presented. Clinical trial information: NCT03512340 .

The trauma of child abuse resides not only in the event itself but also arises from dynamics of victimization which causes secondary trauma. Acting-out among adolescents is symbolic of these dynamics. This article has explored an ecological perspective to present a relational model of pastoral care, uplifting the impact of victimization on both the individual and the community, as well as the individual's interaction within the community.

This article examines female delinquency as a symptom of the primary traumas of physical and sexual abuse and secondary traumas, when the environment responds with blame or disbelief. While social workers are increasingly aware that such a relationship often exists, we have yet to operationalize the relevant implications for assessment, practice, and policy in the juvenile justice system. It will be sugested that delinquency may be an act of disclosure and thus effective intervention entails alleviating primary and secondary trauma at the individual-community interface.

The Alzheimer's Association and National Institutes of Health have emphasized the need for participation of racial/ethnic populations in Alzheimer disease (AD) clinical research. Many articles have described strategies to enhance participation including establishing enduring ties to the community and tailoring the site to be more culturally welcoming or user-friendly to the community. Yet, most of these reports are not data driven. To get a better indication of the knowledge base, this review summarizes research across a broad range of domains (e.g., cancer, kidney disease, AD) that used systematic approaches to identify methods and factors that reduce barriers to recruitment, participation, and retention of a more racially and ethnically diverse population. Overall, 121 reports were found with 8 of these in AD. As a relatively new area of investigation, the literature was primarily descriptive; outcome data were seldom provided. While these studies help to identify areas of potential importance in racial/ethnic participation, hypothesis-driven research remains necessary to tease apart the key techniques that engender racial/ethnic participation in AD studies. This article suggests several recommendations, including the need for prospective research of specific recruitment methods. Fundamentally, researchers should consider that these strategies apply to all potential research participants, and not simply to traditionally underserved racial/ethnic populations.