Ongoing Phase Research Articles

Abstract PO2-19-08: INAVO121: Phase III study of inavolisib + fulvestrant vs alpelisib + fulvestrant in patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer

Abstract BACKGROUND Standard-of-care (SoC) endocrine therapy (ET) for patients (pts) with hormone receptor-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer (HR+, HER2–, PIK3CA-mut LA/mBC) was transformed by combinations with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is); a CDK4/6i-based combination is approved in high-risk early BC. However, in most pts, mechanisms of resistance that emerge during or after treatment with a CDK4/6i and ET combination lead to relapse/disease progression. Dysregulating mutations in PIK3CA, occurring in ~40% of HR+, HER2– BCs, represent a common mechanism of resistance to CDK4/6is and ET combinations. Alpelisib (ALP; a selective PI3Kα inhibitor; PI3Kαi) + fulvestrant (FUL) is approved for pts with HR+, HER2–, PIK3CA-mut LA/mBC, but its widespread implementation in clinical practice has been challenging. As such, there is a significant need to develop PI3Kαis with a better therapeutic index. Inavolisib (INAVO) is a highly potent and selective PI3Kαi that also facilitates the degradation of mutated PI3Kα isoform. INAVO has demonstrated manageable safety/tolerability, alone and in combination with SoC treatments in HR+, HER2–, PIK3CA-mut LA/mBC. Moreover, an ongoing Phase I trial showed that INAVO + FUL elicited encouraging preliminary antitumor activity in heavily pretreated pts, including a CDK4/6i-based regimen. TRIAL DESIGN INAVO121 is a Phase III, randomized, open-label study. Pts are randomized 1:1 to receive INAVO (9 mg oral daily; PO QD) + FUL (500 mg intramuscularly on Days [D] 1 and 15 of Cycle 1, then D1 of subsequent cycles), or ALP (300 mg PO QD) + FUL. Randomization is stratified by visceral disease (yes vs no) and prior CDK4/6i therapy (adjuvant vs metastatic setting). Pts will receive treatment until disease progression or unacceptable toxicity. ELIGIBILITY CRITERIA Pts have HR+, HER2–, PIK3CA-mut LA/mBC (confirmed by circulating-tumor DNA or tumor tissue), adequate hematologic and organ function, and disease progression after or during treatment with a CDK4/6i-based regimen. Up to two prior lines of systemic therapy in LA/mBC, including one line of chemotherapy, are allowed. AIMS The primary endpoint is progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints include overall survival, BICR-objective response rate, BICR-best overall response, BICR-duration of response, BICR-clinical benefit rate, safety, tolerability, pt-reported outcomes, and pharmacokinetics. STATISTICAL METHODS A stratified log-rank test at an overall 0.05 significance level (two-sided) will be used for the primary endpoint analysis. Median PFS will be estimated using Kaplan–Meier methodology. An independent data monitoring committee will be in place for safety and efficacy. ACCRUAL The study is open for enrollment and has randomized four pts; the study is targeting 400 pts at ~200 sites globally. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT05646862. This abstract was originally presented at ASCO 2023 (TPS1123). Citation Format: Dejan Juric, Kevin Kalinsky, Seock-Ah Im, Eva Ciruelos, Giampaolo Bianchini, Carlos Barrios, William Jacot, Peter Schmid, Sherene Loi, Hope Rugo, Veronica Craine, Katherine Hutchinson, Aulde Flechais, Eirini Thanopoulou, Nadia Harbeck. INAVO121: Phase III study of inavolisib + fulvestrant vs alpelisib + fulvestrant in patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-08.

Abstract PO2-06-12: Patients with metastatic triple-negative breast cancer who receive trilaciclib prior to cytotoxic chemotherapy exhibit improved survival after receiving subsequent anticancer therapy

Abstract Background In an open-label, randomized, phase 2 trial in patients (pts) with metastatic triple-negative breast cancer (mTNBC; NCT02978716), administering trilaciclib prior to gemcitabine plus carboplatin (GCb) significantly prolonged overall survival (OS; a key secondary endpoint) versus administering GCb alone (median 19.8 vs 12.6 months; hazard ratio 0.37; P < 0.0001), with a nonsignificant trend toward improved progression-free survival (median 9.0 vs 5.7 months; hazard ratio 0.62; P = 0.13; Tan et al. Clin Cancer Res. 2022). Given murine data suggesting trilaciclib may preserve the long-term function of hematopoietic stem and progenitor cells (He et al. Sci Transl Med. 2017) and improve T-cell memory (Goel et al. Nature. 2017; Lelliott et al. Cancer Discov. 2021; Heckler et al. Cancer Discov. 2021), we examined survival of pts with mTNBC who received subsequent lines of therapy after receiving GCb with or without trilaciclib. Methods In the phase 2 trial, pts with ≤ 2 prior chemotherapy regimens for locally recurrent or metastatic TNBC were randomized 1:1:1 to receive GCb on days 1 and 8, trilaciclib prior to GCb on days 1 and 8, or trilaciclib alone on days 1 and 8 and prior to GCb on days 2 and 9. The 2 trilaciclib arms were combined for this analysis. To determine if trilaciclib improved outcomes in pts who received additional therapy after GCb, a post hoc survival analysis was performed using data from pts who received any subsequent anticancer therapy (SACT). Results In the subanalysis of data from pts with mTNBC who received any SACT after the phase 2 trial, clinical characteristics such as demographics, disease variables, duration from study treatment to first SACT, and type of SACT were balanced between the trilaciclib (n = 43) and placebo (n = 20) arms. The most common SACTs were gemcitabine, capecitabine, eribulin, taxanes, checkpoint inhibitors, carboplatin, and anthracyclines. Median OS in pts who had previously received trilaciclib was 32.7 months versus 12.8 months in those who had received placebo, with increasing separation of survival curves over time. Median OS from start of first SACT was 17.4 months in the trilaciclib arms vs 5.8 months in the placebo arm. Improved survival and sustained separation of curves was also observed in pts unable to receive SACT (trilaciclib, n = 25; placebo, n = 14), although the magnitude of benefit was smaller (median 9.4 vs 5.4 months). Mechanistic in vivo murine and in vitro human studies are underway to examine the effect of trilaciclib on the generation of memory T cells. These studies will assess the preferential differentiation of specific memory T-cell subsets along with in vivo assessment of memory T-cell responses following a rechallenge. Further data will be presented to evaluate whether the enhanced generation and preservation of a memory T-cell pool is supportive of improved outcomes in pts receiving SACT. Conclusions Data from the phase 2 study suggest that pts with mTNBC who received trilaciclib prior to cytotoxic chemotherapy have prolonged survival, which is notably improved for pts who are able to receive SACT following discontinuation of trilaciclib. The survival benefit from trilaciclib extends to pts who subsequently received immune checkpoint inhibitors and/or chemotherapy, and also to those who did not receive any SACT. Improved OS in pts receiving trilaciclib may be associated with protection of hematopoietic stem and progenitor cells and formation of a memory T-cell pool, which is critical for long-term immune surveillance and in eliciting rapid recall responses. OS will be evaluated in pts with mTNBC in the ongoing phase 3 trial of trilaciclib prior to GCb (PRESERVE 2; NCT04799249) and phase 2 trial of trilaciclib prior to sacituzumab govitecan (NCT05113966). Citation Format: Shom Goel, Joyce O'Shaughnessy, Kun-Hui Lu, Andrew Beelen, Symantha Melemed, John Yi, Michael Danso, Antoinette Tan. Patients with metastatic triple-negative breast cancer who receive trilaciclib prior to cytotoxic chemotherapy exhibit improved survival after receiving subsequent anticancer therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-12.

Abstract PO4-27-07: A Phase 3, randomized, open-label study of upfront camizestrant vs standard endocrine therapy as adjuvant treatment for ER-positive/HER2-negative early breast cancer with intermediate-high or high risk of recurrence (CAMBRIA-2)

Abstract Background: Camizestrant is a next-generation oral selective estrogen receptor (ER) degrader and pure ER antagonist being investigated in early and advanced breast cancer (BC). In postmenopausal women with advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative BC and disease recurrence or progression on or after ≤1 endocrine therapy (ET) in the advanced setting, camizestrant significantly prolonged progression-free survival compared with fulvestrant in the Phase 2 SERENA-2 trial. Camizestrant may also provide benefit in the early BC setting. Following locoregional therapy (surgery ± radiotherapy), standard adjuvant treatment of ET with or without chemotherapy and/or a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has shown significant benefit in decreasing the risk of recurrence of stage I–III ER-positive/HER2-negative BC. However, BC recurrence as incurable metastatic disease is still common. Thus, adjuvant therapeutic options with improved clinical outcomes are needed. The CAMBRIA-2 study (NCT05952557) aims to assess whether upfront camizestrant can improve outcomes compared with standard ET as adjuvant treatment in patients with ER-positive/HER2-negative early BC with an intermediate-high or high risk of recurrence after definitive locoregional therapy. Trial design: This ongoing Phase 3, randomized, open-label study is enrolling women (pre-, peri-, or postmenopausal) and men with ER-positive/HER2-negative (HER2-negative status defined as immunohistochemistry 0, or 1+, or in situ hybridization-negative) early BC who are at intermediate-high or high risk of recurrence (as defined in the protocol) after having completed definitive locoregional therapy (surgery ± radiotherapy) ± (neo)adjuvant systemic chemotherapy, and who have no evidence of disease. Patients may have received up to 12 weeks of (neo)adjuvant ET prior to randomization. Patients are randomized (1:1) to receive camizestrant 75 mg ± abemaciclib ± luteinizing hormone-releasing hormone (LHRH) agonist or standard ET of the investigator’s choice (any aromatase inhibitor or tamoxifen) ± abemaciclib ± LHRH agonist for up to 7 years. The primary endpoint is invasive BC-free survival (IBCFS) (Standardized Definitions for Efficacy End Points [STEEP] 2.0 criteria). Secondary endpoints include invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) (STEEP 2.0 criteria), overall survival, safety, and health-related quality of life. Primary endpoint analysis will use a stratified log-rank test adjusting for stratification factors, assuming a two-sided significance level of 5%. Approximately 5500 patients will be randomized. Clinical trial identification: NCT05952557 Editorial acknowledgment: Writing assistance was provided by Clare Davis of BOLDSCIENCE Inc., funded by AstraZeneca. Legal entity responsible for the study: AstraZeneca Funding: This study was supported by AstraZeneca. Citation Format: Sibylle Loibl, Yeon Park, Sara Tolaney, Ioanna Gioni, Simon Johnston, Teresa Klinowska, Ingrid A. Mayer, Raquel Nunes, Barbara Pistilli, Mary Stuart, Angela Quintana, Andrew Walding, Michael Gnant. A Phase 3, randomized, open-label study of upfront camizestrant vs standard endocrine therapy as adjuvant treatment for ER-positive/HER2-negative early breast cancer with intermediate-high or high risk of recurrence (CAMBRIA-2) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-27-07.

Abstract PO3-18-06: First-in-human phase 1A study of RGT-419B, a next generation CDK4 inhibitor, in patients (pts) with hormone receptor positive (HR+) HER2- advanced/metastatic breast cancer (ABC) who progressed on prior CDK4/6 inhibitors (CDK4/6i)

Abstract Introduction: RGT-419B is a novel next generation CDK inhibitor. It has high potency against CDK4 with additional activity against CDK2 and selectivity against CDK6 to overcome resistance and reduce hematologic toxicity. In addition to anti-cancer activity in preclinical breast cancer models that are resistant to approved CDK4/6 inhibitors, we report the interim data from the first-in-human, multicenter trial of RGT-419B as a single agent in post-menopausal pts with HR+ HER2- ABC. Methods: Eligible pts received ≥2 lines of treatment and progressed on endocrine therapy (ET) and at least 1 line of an FDA approved CDK4/6i. Prior treatments of fulvestrant, other targeted agents and/or chemotherapy were allowed. Dose escalation of RGT-419B as oral (PO) monotherapy was administered in continuous 28-day cycles in 4 cohorts (25, 75,150 mg QD and 150 mg BID). A standard 3+3 design was employed to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). The primary objective was to assess safety and tolerability. The secondary objectives included pharmacokinetic (PK) assessment and exploratory efficacy. Results: At time of abstract submission, 12 eligible post-menopausal pts with HR+/HER2- ABC received RGT-419B. The median age was 64.8y (range 50-80y). All had prior palbociclib + ET (2 pts had abemaciclib or ribociclib after palbociclib); a majority received fulvestrant (67%) and prior chemotherapy (50%). Across the 4 cohorts (12 pts), the most observed treatment-emergent adverse events (TEAEs; all causality) with RGT-419B were nausea, reduced white blood cell counts (neutrophils and/or lymphocytes) and diarrhea. At data cutoff on June 30th 2023, there have been no CTCAE Grade 3 or higher treatment related AE (TRAEs). No ocular toxicity has been observed. No pts have discontinued treatment due to RGT-419B toxicity. Preliminary PK analyses for RGT-419B showed a dose-dependent increase of exposure at steady state with long half-life. Tumor assessments (RECIST v1.1) of pts in the first 3 cohorts treated with RGT-419B monotherapy (25-150 mg QD) showed partial responses in 2 pts (7 pts with measurable disease), 28.6% partial response (PR) (RECIST v. 1.1) and clinical benefit rate (CBR) 44%. Updated safety, PK and efficacy data will be presented. Conclusions: RGT-419B, with potent selective CDK4 activity, CDK2 activity and CDK6 selectivity, demonstrated a favorable safety and PK profile in an ongoing phase I study, with no grade 3 or higher TRAEs observed thus far. RGT-419B administered as once daily monotherapy also demonstrated preliminary evidence of efficacy as well. Dose expansions of RGT-419B as a single agent and in combination with ET in pts with HR+/HER2- ABC following prior CDK4/6i progression are planned. Citation Format: Seth Wander, Dave Valacer, Richard Zuniga, Heather Yeckes-Rodin, Christopher Perkins, Lisa Ge, Lili Yao, Jing Lin, Dawn Begley, Feifei Sun, Andie Zheng, Jing Han, Zhi (Julie) Xie, Aditya Bardia, Kevin Kalinsky. First-in-human phase 1A study of RGT-419B, a next generation CDK4 inhibitor, in patients (pts) with hormone receptor positive (HR+) HER2- advanced/metastatic breast cancer (ABC) who progressed on prior CDK4/6 inhibitors (CDK4/6i) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-06.

Abstract PS05-03: MagSense® HER2, a Molecularly Targeted Magnetic Resonance Imaging Agent for the Detection of Axillary Nodal Metastasis in Subjects with Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Breast Cancer

Abstract Background Precise nodal staging is critical in guiding systemic and regional treatments including surgery in the management of breast cancer. Regional nodal assessment includes axillary imaging (mostly by ultrasound) and lymph node sampling. Since imaging findings suggestive of nodal metastasis are based on size and morphologic changes and not specific to tumor type, pathologic confirmation through either biopsy or removal of sentinel lymph node (SLN) remains the gold standard. Imagion is developing the MagSense® HER2 Imaging Agent (MSH2IA), an anti-human epidermal growth factor receptor 2 (HER2) conjugated with iron oxide nanoparticles, for the detection of nodal metastasis in HER2+ breast cancer patients. MSH2IA is currently being investigated in a first-in-human phase 1 study (ACTRN12621000126819) in HER2+ breast cancer patients who are diagnosed to have suspicious nodes by conventional imaging. Methods The key objectives of the phase 1 study are safety and tolerability of MSH2IA and confirmation that MSH2IA drains to the axillary lymph nodes. The study also explores MSH2IA’s ability to detect metastatic nodes when used with magnetic resonance imaging (MRI), with tumor status assessed by standard tissue histopathology. All eligible subjects receive a 22.5 mg (iron equivalent) subareolar or peritumoral injection of MSH2IA. MRI of the axilla are obtained before and 24 to 72 hours after MSH2IA injection. Core biopsy or dissection of a node suspicious by ultrasound is obtained for histopathology assessments. After completing the first cohort of 6 subjects, the protocol was amended to include the insertion of an MRI compatible clip in a node suspicious by ultrasound to localize the suspicious node for core biopsy and postdose MRI scan. Review of MRI scans and histopathology are performed in respective central laboratories. Results Thirteen participants with HER2+ breast cancer have completed the study. MSH2IA appears safe and well tolerated. The imaging agent, as administered, is detectable by MRI and pathology, confirming that MSH2IA drains to the lymph nodes via the chosen route of administration. In postdose MRI scans, study central radiologists reported distinct and differentiable MRI appearance in morphologically normal and suspicious nodes. The presence of a distinct postdose MR image appearance was confirmed by a group of independent radiologists in a separate blinded review. While normal nodes appeared with homogeneous hypointensity, morphologically suspicious nodes showed partial irregular darkening and/or speckled heterogeneous hypointensity. In evaluable subjects, histopathology of the core biopsies obtained from the clipped nodes confirmed the presence of HER2+ nodal metastasis, providing preliminary evidence for node-level concordance between MRI vs pathology observations. Safety, imaging, and pathology results from all available subjects will be presented. This phase 1 study in Australia will be closing enrollment by July 31, 2023. A phase 2 study in the United States and elsewhere is being planned with the objectives of optimizing dose, schedule, and imaging parameters for best diagnostic performance for clinical utility. Conclusion Available data from the ongoing phase 1 study show that MSH2IA appears safe and drains to the axillary lymph nodes. MSH2IA displays a distinct and differentiable MRI appearance in nodes morphologically highly suspicious for tumor, which is confirmed to be HER2+ metastasis by histopathology by node level concordance. This data provides preliminary proof of principle for the mechanism of molecularly targeted MR imaging and suggests that MSH2IA has the potential to provide tumor-specific MR imaging not currently available in conventional axillary imaging. Citation Format: Jane Fox, Shanta Velaiutham, Natalie Yang, Eddie lau, Kowsi Murugappan, Beena Kumar, Alex Laslowski, Koushik Govindarajan, Steven Reich, Stephen Thomas, Nitika Neha, Marie Zhang, Isaac Bright. MagSense® HER2, a Molecularly Targeted Magnetic Resonance Imaging Agent for the Detection of Axillary Nodal Metastasis in Subjects with Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS05-03.

Abstract PO4-27-05: A phase I open-label dose escalation trial of FWD1802 as monotherapy and in combination with palbociclib in patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutations

Abstract Background: Estrogen receptor (ER) signaling sits at center of the tumor biology in ER+/HER2- breast cancers. Current standard of care involves hormone therapy with agents including selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs). Unfortunately, most patients eventually develop resistance to these therapies. Mutations in estrogen receptor 1 (ESR1) are partially responsible for the acquired resistance. Mutated estrogen receptors are still sensitive to fulvestrant but with a much less sensitivity. In January 2023, elacestrant received its first approval for the treatment of postmenopausal women or adult men with breast cancer harboring ESR1 mutations in US. However, there is still great unmet medical need for this population. FWD1802 is a third-generation oral SERD for ER-positive breast cancer patients. It binds competitively to ER, with a much higher affinity than that of fulvestrant. Preclinically, FWD1802 alone and in combination with palbociclib exhibits significant anti-tumor activity in the ER+/HER2- models and in ESR1-mutated models in vitro and in vivo. This ongoing phase I study is to assess the safety, tolerability, pharmacokinetics (PK) and clinical activity of FWD1802 as monotherapy and in combination with palbociclib in ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutations. Methods: This clinical study (CTR20232130) consists of three parts: monotherapy dose escalation (Part A), dose escalation in combination with palbociclib (Part B) and monotherapy dose expansion in ESR1-mutated patients (Part C). A conventional “3+3” design is used for this study. Approximately a total of 129 patients will be enrolled. FWD1802 is administered orally daily. In monotherapy dose escalation study (Part A), at each dose level, a single ascending dose (SAD) is followed by a 28-day continuous multiple ascending dose (MAD) period (defined as 1 cycle). In Part B dose, palbociclib (125 mg daily) is administered on a 28-day treatment cycle with 21-day on treatment and 7-day off treatment, along with the 28-day treatment cycle of FWD1802. The primary objectives include dose limiting toxicity (DLT), maximum tolerated dose (MTD), safety, tolerability, and the recommended phase 2 dose (RP2D) of FWD1802. Secondary objectives include pharmacokinetics characteristics of FWD1802 and its major metabolite as monotherapy and in combination with palbociclib. Preliminary anti-tumor activity including objective response rate (ORR), duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS) will also be evaluated. DLT evaluation will be conducted after the first cycle of multi-dose period, and tumor assessment will be conducted every 8 weeks by investigators according to RECIST version 1.1. Patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutation are eligible for the enrollment. Enrolled patients should have progressed disease, or failed from previous therapy, or intolerable or inaccessible to standard therapy. In addition, patients with ECOG score ≤1 and with adequate renal, cardiac, hepatic, and hematologic function are eligible for enrollment. The monotherapy dose escalation (Part A) is currently ongoing. The dose selection for Part B and Part C will be based on the data from the ongoing Part A. Clinical trial information: CTR20232130. Research Sponsor: Shenzhen Forward Pharmaceuticals Co., Ltd. (FORWARD PHARMA). Citation Format: Ling Zeng, Jin Liu, Dan Wu, Huiwen Ge, Zirui Bian, Chenggang Zhu. A phase I open-label dose escalation trial of FWD1802 as monotherapy and in combination with palbociclib in patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-27-05.

Abstract PS12-09: Capivasertib plus cyclin-dependent kinase 4/6 inhibitor and fulvestrant in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: updated Phase 1b analysis from CAPItello-292

Abstract Background AKT pathway activation is implicated in endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) resistance in patients (pts) with HR+/HER2– advanced breast cancer (ABC). In CAPItello-291, capivasertib (C, a potent inhibitor of all 3 AKT isoforms) + fulvestrant (F) significantly improved PFS versus placebo F in pts with aromatase inhibitor-resistant HR+/HER2– ABC. Simultaneous inhibition of AKT and CDK4/6 pathways may delay CDK4/6i resistance or re-sensitize tumors to ET plus CDK4/6i, leading to improved clinical outcomes. CAPItello-292 (NCT04862663) is an ongoing Phase 1b/3 study examining the efficacy and safety of C + CDK4/6i (palbociclib [P], ribociclib [R]) + F in HR+/HER2– ABC. The recommended Phase 3 dose (RP3D) of C+P+F has been determined (C 400 mg BID, 4 days on/3 days off, P 125 mg, F 500 mg). Here we report ongoing Phase 1b data on C+P+F and C+R+F. Methods: Phase 1b of CAPItello-292 uses a keyboard design (mTPI-2) with the following planned doses: C 200 mg, 320 mg, 400 mg; P 75 mg, 100 mg, 125 mg; R 200 mg, 400 mg, 600 mg; F is fixed at 500 mg every 28 days + loading dose on cycle 1 day 15. Starting doses for C+P+F were C 320 mg BID, 4 days on/3 days off, P 125 mg QD) for 21 days of each 28-day cycle. Starting doses for C+R+F (ongoing) are C 400 mg BID, 4 days on/3 days off, R 400 mg QD for 21 days of each 28-day cycle. Eligible pts have HR+/HER2− ABC and ≥1 prior ET in the advanced setting or disease recurrence within 12 months of completing (neo)adjuvant ET (HER2− defined as immunohistochemistry [IHC] 0, or 1-positive or IHC2-positive/in situ hybridization-negative). Prior use of CDK4/6i, selective estrogen receptor degraders, and chemotherapy is permitted in Phase 1b. Phase 1b primary objectives: assess safety/tolerability; confirm RP3D. Objective response and clinical benefit rates (24 weeks; RECIST v1.1) were also assessed. Results: At data cut-off (Apr 21, 2023), 40 pts (median age: 58.5 years [range 38–82]) who were heavily pre-treated (as follows: 82.5% [33/40] prior CDK4/6i; 47.5% [19/40] prior F; 70.0% [28/40] prior chemotherapy [median 1.5 lines]) were treated with C+P+F. No new dose-limiting toxicities (DLTs) were observed since determination of RP3D. The most frequent adverse events (AEs) occurring in >40% of pts were diarrhea (70.0% [28/40]; 1/28 grade [G] ≥3), neutropenia (55.0% [22/40]; 20/22 G≥3), fatigue, and nausea (both 42.5% [17/40]; all G1/2). Hyperglycemia occurred in 17.5% (7/40) pts (1/7 G3). No treatment-related deaths or new safety risks were identified. At the RP3D, the median (range) duration of exposure to C was 8.6 months (1.7–14.1); 5/8 pts with measurable disease at baseline had confirmed partial response (objective response rate: 62.5%, 95% confidence interval [CI] 24.5–91.5). Two additional pts had stable disease ≥7 weeks as a best objective response. At 24 weeks, the clinical benefit rate was 53.8% (7/13; 95% CI 25.1–80.8).Enrollment into C+R+F is ongoing: as of May 05, 2023, 8 pts had been dosed (6/8 pts had completed cycle 1). Based on clinical and safety review, the safety review committee has endorsed dose escalation to the highest dose level of R; no DLTs have been reported so far, although data are preliminary.Preliminary ctDNA analyses of pts treated with C+P/R+F will be presented. Conclusions: C+P+F was tolerable in heavily pre-treated pts with HR+/HER2– ABC at all dose levels; AEs were as expected, given the known safety profile of the individual treatments. Evidence of clinical activity has been observed in pts treated with the RP3D; data collection is ongoing. Preliminary safety analysis of C+R+F suggests no critical tolerability concerns; more pts and longer follow-up is required to characterize the safety of the combination. Updated data will be presented. Funding: AstraZeneca Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited) Citation Format: Erika Hamilton, Patrick Neven, Barbara Pistilli, Muralidhar Beeram, Virginia Borges, Mario Campone, José Luiz Miranda Guimarães, Theodoros Foukakis, Annette Raskov Kodahl, Peter Lau, Elgene Lim, Iwona Ługowska, Greg Rychlik, Christopher Gresty, Claire Miller, Roberto Sommavilla, Dhivya Sudhan, Hope Rugo. Capivasertib plus cyclin-dependent kinase 4/6 inhibitor and fulvestrant in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: updated Phase 1b analysis from CAPItello-292 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS12-09.

Abstract PO1-18-01: Patient Preferences for HR+/HER2- Metastatic Breast Cancer Treatments in Italy: A Qualitative Assessment

Abstract Objectives: Factors that influence treatment preferences of patients with hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) are being investigated using discrete choice experiment (DCE) methodology. Appropriate attributes for the ongoing quantitative online survey phase were identified by this initial qualitative pilot study. Methods: To generate hypotheses and inform variables of the quantitative survey, the pilot phase consisted in online telephone interviews with patients with a diagnosis of Stage IV HR+/HER2- breast cancer at various stages of treatment. Interviews focused on exploring patients' perspectives on their interaction with physicians, preferences, and treatment experiences. Transcripts were coded using NVivo software to identify key themes. The ongoing DCE online survey aims to recruit patients meeting the same selection criteria as in the qualitative phase, also at various stages of treatment. Results: Fifteen mBC patients (median age, 43 years [range, 29-64]), including nine chemotherapy-treated and six without chemotherapy exposure, were enrolled in the pilot qualitative study. Eight and four patients reported receiving little information about their treatment plan and their risk status beyond the risk of relapse, respectively. Most participants did not know what to expect from their therapy but expressed trust in their physician’s decision in terms of treatment goals. Few patients (n=3) looked for a second opinion before starting treatment. Four out of fifteen patients declared that they were actively involved in their treatment plan decision, although all relied on their physician’s knowledge and decision. Reduced symptoms and improved quality of life (QoL) were patients’ main treatment goals, and side-effects and efficacy of treatment were their main concerns. When asked about the degree of acceptability of certain side effects, some participants considered hair loss and vomiting as unacceptable side effects, regardless of severity, while others considered them to be the most acceptable. This discrepancy is to be interpreted in the light of participants’ own treatment journey. Severity and duration of side-effects were mentioned by three patients as acceptability factors. In a choice task, patients were asked to express preferences between two hypothetical treatments. Efficacy (n=9) and administration mode (n=6) were spontaneously deemed important for treatment selection. While assessing the difference in risk between the two hypothetical treatments, ten patients explained that the main choice feature was extended progression-free survival (PFS) rate. Risk of infection and neutropenia (n=12) were concerns expressed by most patients in the post-COVID-19 period. Considering their substantial impact on QoL, alopecia (n=9) and vomiting (n=9) were presented by patients as particularly important, regardless of their degree of severity; whereas almost all patients reported that only severe fatigue (n=12), diarrhea (n=13) or nausea (n=13) would be an issue. These results allowed selection of the following attributes for further quantification of their preference weights in a DCE: PFS, risk of neutropenia, risk of alopecia, risk of vomiting, risk of diarrhea, risk of grade 3/4 side effects and mode of administration. Conclusions: This qualitative pilot study allowed for identification of what matters most to patients when selecting a treatment for mBC, which will be further assessed in the DCE. It also highlighted the need of patients with HR+/HER2- mBC for information about their treatment, potential side-effects, and health management. This research suggests that there is a need for patients to be more involved in treatment plans, and that taking patient preferences into account may help improve the treatment selection experiences. Citation Format: Grazia Arpino, Carmine De Angelis, Lorenzo Gerratana, Matteo Lambertini, Sarah Igidbashian, Martina Bellini, Serena Giuntoli, Xavier Guillaume, Julie Behillil, Claire Graziani-Taugeron. Patient Preferences for HR+/HER2- Metastatic Breast Cancer Treatments in Italy: A Qualitative Assessment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-01.

Abstract PO4-12-11: Patient (pt) time burden with IV vs subcutaneous (SC) administration of trastuzumab/pertuzumab (HP): A time and motion (T+M) substudy of a single arm phase II trial of adjuvant endocrine therapy plus HP for stage I HER2+ breast cancer

Abstract Background: The time required for in-clinic drug administration may have a substantial detrimental impact on breast cancer patients’ quality of life. SC drug administration, as opposed to IV, may reduce this time commitment. The purpose of this study was to estimate the relative difference in time and logistical burden between IV and SC administration of HP. Methods: We prospectively enrolled a pre-specified sub-cohort of pts participating on the ADEPT trial (NCT04569747) to this T+M substudy. The ADEPT trial is an ongoing single arm prospective phase II trial of adjuvant SC HP (for 1 yr) plus endocrine therapy for pts with hormone receptor-positive (HR+) and HER2+ stage I (pT1N0 or pT1N1mi) breast cancer. Pts eligible for ADEPT have completed primary breast surgery and are systemic therapy-naïve. Pts who received cycle 1 of loading SC HP at Dana-Farber Cancer Institute and tolerated SC drug administration were eligible and enrolled consecutively to the T+M substudy until the T+M accrual goal; accrual to the T+M substudy was mandatory for eligible pts. The T+M substudy was a single arm crossover design in which pts received 2 cycles of IV HP, followed by 2 cycles of maintenance dose SC HP. During those 4 treatment (tx) cycles, timepoints in the drug preparation and administration process were captured from the electronic medical record or flowsheets filled out by infusion nurses. The primary endpoint of the T+M substudy was total pt chair time in the infusion area (measured from start of first drug administration to end of final post-drug observation period). Exploratory endpoints included total drug preparation time and total pt tx experience time. A sample size of 22 pts was estimated to provide 86% power with 2-sided alpha 0.05 to detect a difference of 70 mins in the primary endpoint by tx arm (IV vs SC). For all endpoints, the average time across both tx cycles was calculated for each pt, and the overall mean across pts for each of IV and SC administration was computed (with standard deviation). Average times for IV vs SC administration were compared via paired Wilcoxon signed rank tests. Adjustments for multiple comparisons were not included. Results: 22 pts participated on the T+M substudy, and each had timepoints captured during 4 tx cycles (2 IV and 2 SC cycles), for a total of 88 patient-cycles analyzed overall. Pts had median age 58 yrs (range 42-83), and were 96% female, 82% White, 9% Black, 9% Asian; and 100% non-Hispanic. Comparison of time intervals for IV vs SC drug administration is shown in the Table. Mean total pt infusion chair time was 84.3 mins with IV HP, vs 22.5 mins with SC HP, for a difference of 61.8 mins shorter pt time commitment in favor of SC administration (p< 0.0001). The mean total drug preparation time was significantly decreased in favor of SC administration (by 78.2 mins; p< 0.0001); and the total pt tx experience time was significantly decreased in favor of SC administration (by 81.8 mins; p< 0.0001). Conclusions: This prospective T+M study demonstrated that pt infusion chair time is significantly decreased with SC as compared to IV administration of HP, shortening this pt time burden by approximately one hour. SC drug administration is an approach that may help to improve and shorten the pt breast cancer therapy experience and decrease pharmacy burden. Table. SD, standard deviation Citation Format: Adrienne Waks, Noah Graham, Emily Chen, Anna Mae Frey, Victoria Attaya, Ibrahim Abbass, Anita Fung, Jesse Sussell, Patricia Cortazar, Caroline Harvey, Kenneth Almeida, Denise Leth, Wendy Chen, Jose Leone, Susan Schumer, Nabihah Tayob, Sara Tolaney. Patient (pt) time burden with IV vs subcutaneous (SC) administration of trastuzumab/pertuzumab (HP): A time and motion (T+M) substudy of a single arm phase II trial of adjuvant endocrine therapy plus HP for stage I HER2+ breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-11.

Abstract PO5-18-06: On-going phase 1A clinical trial of A01, a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) in patients with advanced malignancy

Abstract Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats which is the largest member of the granulin-epithelin protein family. PGRN/GP88 has been demonstrated as a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC), lung prostate, ovarian and digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence in breast, lung cancers while elevated serum PGRN/GP88 level in metastatic breast, lung, ovarian and prostate cancer patients. Elevated PGRN/GP88 levels are associated with poor outcomes such as progression and shortened survival. An anti-human PGRN/GP88 monoclonal antibody able to inhibit the the in vitro and in vivo action of human PGRN/GP88 has been developed, chimerized and expressed in CHO cells. All IND enabling activities including pharmacology, GMP manufacturing, formulation and GLP toxicology studies have been conducted. The IND application has been filed and cleared by the Food and Drug Administration. A first-in-human, first-in-class phase 1 safety and efficacy clinical study of AG01 in patients with solid tumors and advanced disease with special focus on patients with breast, lung and ovarian cancers has been initiated and is on-going at the University of Maryland Greenebaum Cancer Center. The trial is registered as NCT05627960 to clinicaltrials.gov site. The presentation will provide an update on the number of patients enrolled in this on-going phase 1A trial. Supported by grants R44CA162629 and R44CA224718 from the National Cancer Institute to GS. Citation Format: Katherine Tkaczuk, Paula Rosenblatt, Ranee Mehra, Katherine Scilla, Nancy Tait, Binbin Yue, Ginette Serrero. On-going phase 1A clinical trial of A01, a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) in patients with advanced malignancy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-06.

Sparsentan for Focal Segmental Glomerulosclerosis in the DUET Open-Label Extension: Long-term Efficacy and Safety

Rationale and ObjectiveSparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist (DEARA) examined in the ongoing phase 2 DUET trial for focal segmental glomerulosclerosis (FSGS). In the DUET 8-week double-blind period, sparsentan resulted in greater proteinuria reduction versus irbesartan. We report the long-term efficacy and safety of sparsentan during the open-label extension over more than 4 years. Study DesignPatients were examined from their first sparsentan dose (double-blind period or open-label extension) through 4.6 years. Setting and ParticipantsPatients with FSGS, excluding secondary FSGS. InterventionSparsentan (200, 400, and 800mg/day). OutcomesUrine protein/creatinine ratio (UP/C), FSGS partial remission endpoint (UP/C≤1.5g/g and >40% reduction from baseline), eGFR, and blood pressure approximately every 12 weeks. Treatment-emergent adverse events by year and cases/100 patient-years. Results109 patients were enrolled; 108 received ≥1 sparsentan dose; 103 entered the open-label extension (68 sparsentan, 35 irbesartan during double-blind period). Sparsentan was ongoing in 45/108 patients (41.7%); median time to treatment discontinuation was 3.9 years (95%CI, 2.6-5.2). Mean percent proteinuria reduction from baseline was sustained through follow-up. Achieving partial remission within 9 months of first sparsentan dose (52.8% of patients) versus not achieving (47.2%) was associated with significantly slower rate of eGFR decline over the entire treatment period (-2.70 vs -6.56, P=0.03) and in the first 2 years (-1.69 vs -6.46, P=0.03). The most common treatment-emergent adverse events (>9 cases/100 patient-years) were headache, peripheral edema, upper respiratory infection, hyperkalemia, and hypotension. Peripheral edema and hypotension declined from year 1 (13.9% and 15.7% of patients, respectively) to ≤4% in years ≥2. There were no cases of heart failure and no patient deaths. LimitationsThe open-label extension does not include a comparison group. ConclusionsLong-term sparsentan treatment showed sustained proteinuria reduction and a consistent safety profile.

Clinical and magnetic resonance imaging outcomes in pediatric-onset MS patients on fingolimod and ocrelizumab

BackgroundObservational studies looking at clinical a++nd MRI outcomes of treatments in pediatric MS, could assess current treatment algorithms, and provide insights for designing future clinical trials. ObjectiveTo describe baseline characteristics and clinical and MRI outcomes in MS patients initiating ocrelizumab and fingolimod under 18 years of age. MethodsMS patients seen at 12 centers of US Network of Pediatric MS were included in this study if they had clinical and MRI follow-up and started treatment with either ocrelizumab or fingolimod prior to the age of 18. ResultsEighty-seven patients initiating fingolimod and 52 initiating ocrelizumab met the inclusion criteria. Before starting fingolimod, mean annualized relapse rate was 0.43 (95 % CI: 0.29 – 0.65) and 78 % developed new T2 lesions while during treatment it was 0.12 (95 % CI: 0.08 – 1.9) and 47 % developed new T2 lesions. In the ocrelizumab group, the mean annualized relapse rate prior to initiation of treatment was 0.64 (95 % CI: 0.38–1.09) and a total of 83 % of patients developed new T2 lesions while during treatment it was 0.09 (95 % CI: 0.04–0.21) and none developed new T2 lesions. ConclusionThis study highlights the importance of evaluating current treatment methods and provides insights about the agents in the ongoing phase III trial comparing fingolimod and ocrelizumab.

Homologous Recombination Repair Deficiency in Metastatic Prostate Cancer: New Therapeutic Opportunities.

More than 20% of metastatic prostate cancer carries genomic defects involving DNA damage repair pathways, mainly in homologous recombination repair-related genes. The recent approval of olaparib has paved the way to precision medicine for the treatment of metastatic prostate cancer with PARP inhibitors in this subset of patients, especially in the case of BRCA1 or BRCA2 pathogenic/likely pathogenic variants. In face of this new therapeutic opportunity, many issues remain unsolved. This narrative review aims to describe the relationship between homologous recombination repair deficiency and prostate cancer, the techniques used to determine homologous recombination repair status in prostate cancer, the crosstalk between homologous recombination repair and the androgen receptor pathway, the current evidence on PARP inhibitors activity in metastatic prostate cancer also in homologous recombination repair-proficient tumors, as well as emerging mechanisms of resistance to PARP inhibitors. The possibility of combination therapies including a PARP inhibitor is an attractive option, and more robust data are awaited from ongoing phase II and phase III trials outlined in this manuscript.

Barriers and enablers to people-centred viral hepatitis care in Vietnam and the Philippines: Results of a patient journey mapping study.

In Vietnam and the Philippines, viral hepatitis is the leading cause of cirrhosis and liver cancer. This study aims to understand the barriers and enablers of people receiving care for hepatitis B and C to support both countries' efforts to eliminate viral hepatitis as a public health threat by 2030. Retrospective, semi-structured interviews were conducted with a purposive, quota-based sample of 63 people living with hepatitis B or C in one province of Vietnam and one region of the Philippines. A rapid deductive approach to thematic analysis produced key findings among the three phases of care: (1) pre-awareness and testing, (2) linkage and treatment initiation and (3) ongoing treatment and recovery. The research found that participants followed five typical journeys, from a variety of entry points. Barriers during the pre-awareness and testing phase included limited awareness about hepatitis and its management, stigma and psychological impacts. Enablers included being familiar with the health system and/or patients benefiting from social connections within the health systems. During the linkage and treatment initiation phase, barriers included difficult physical access, complex navigation and inadequate counselling. In this phase, family support emerged as a critical enabler. During the ongoing treatment and recovery phase, the cost of care and socially and culturally informed perceptions of the disease and medication use were both barriers and enablers. Exploring peoples' journeys with hepatitis B and C in Vietnam and the Philippines revealed many similarities despite the different cultural and health system contexts. Insights from this study may help generate a contextualized, people-centred evidence base to inform the design and improvement of primary care services for hepatitis in both research sites.

Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): an international, double-blind, randomised, phase 2 trial

Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo. STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete. Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98]). Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings. Australian Government Medical Research Future Fund.

Myeloid Cell-Derived IL-1 Signaling Damps Neuregulin-1 from Fibroblasts to Suppress Colitis-Induced Early Repair of the Intestinal Epithelium.

Neuregulin-1 (Nrg1, gene symbol: Nrg1), a ligand of the ErbB receptor family, promotes intestinal epithelial cell proliferation and repair. However, the dynamics and accurate derivation of Nrg1 expression during colitis remain unclear. By analyzing the public single-cell RNA-sequencing datasets and employing a dextran sulfate sodium (DSS)-induced colitis model, we investigated the cell source of Nrg1 expression and its potential regulator in the process of epithelial healing. Nrg1 was majorly expressed in stem-like fibroblasts arising early in mouse colon after DSS administration, and Nrg1-Erbb3 signaling was identified as a potential mediator of interaction between stem-like fibroblasts and colonic epithelial cells. During the ongoing colitis phase, a significant infiltration of macrophages and neutrophils secreting IL-1β emerged, accompanied by the rise in stem-like fibroblasts that co-expressed Nrg1 and IL-1 receptor 1. By stimulating intestinal or lung fibroblasts with IL-1β in the context of inflammation, we observed a downregulation of Nrg1 expression. Patients with inflammatory bowel disease also exhibited an increase in NRG1+IL1R1+ fibroblasts and an interaction of NRG1-ERBB between IL1R1+ fibroblasts and colonic epithelial cells. This study reveals a novel potential mechanism for mucosal healing after inflammation-induced epithelial injury, in which inflammatory myeloid cell-derived IL-1β suppresses the early regeneration of intestinal tissue by interfering with the secretion of reparative neuregulin-1 by stem-like fibroblasts.

Five-year Treatment with Tenofovir Alafenamide Achieves High Rates of Viral Suppression, Alanine Aminotransferase Normalization, and Favorable Bone and Renal Safety in Chinese Chronic Hepatitis B Patients.

After 3-years (144 week) of double-blind treatment in Chinese chronic hepatitis B patients in two ongoing phase 3 studies, tenofovir alafenamide (TAF) showed similar efficacy to tenofovir disoproxil fumarate (TDF), with improved renal and bone safety. In this study, we aimed to report the 5-year results from 2 years into the open-label TAF treatment phase. All participants completing the 144-week double-blind treatment were eligible to receive open-label TAF 25 mg once daily up to week 384. Serial analysis of viral suppression (hepatitis B virus DNA <29 IU/mL), alanine aminotransferase normalization, serological responses, and safety outcomes at year 5 (week 240) was performed. The open-label phase included 93% (311/334) of the enrolled participants, which included 212 who switched from double-blind TAF to open-label TAF (TAF-TAF) and 99 who switched from double-blind TDF to open-label TAF (TDF-TAF). Baseline characteristics were comparable. Week 240 viral suppression rates were similar between groups [93.4% vs. 93.9%; difference: -1.5%, (95% CI: -6.4 to -3.5), p=0.857]. Alanine aminotransferase normalization and serological response rates were higher in the TAF-TAF group than in the TDF-TAF group. The frequencies of adverse events and laboratory abnormalities were low and similar between groups. Both groups had similar small numerical declines from baseline in estimated glomerular filtration rate at year 5 (week 240, -2.85 mL/min vs. -3.29 mL/min, p=0.910). The greater declines in renal and bone parameters in the TDF-TAF group through week 144 improved after switching to TAF. The 5-year TAF treatment efficacy was high and similar to that of 3-year TDF followed by 2-year TAF in Chinese chronic hepatitis B patients. Favorable effects on bone and renal parameters were sustained with TAF treatment alone and were observed following the switch from TDF to TAF.

Efficacy and Safety of Ravulizumab in Adults With Anti-Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder (AQP4+ NMOSD): Interim Analysis From the Ongoing Phase 3 CHAMPION-NMOSD Trial (S32.003)

Efficacy and Safety of Ravulizumab in Adults With Anti-Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder (AQP4+ NMOSD): Interim Analysis From the Ongoing Phase 3 CHAMPION-NMOSD Trial (S32.003)

Phase I DAVIO Trial: EYP-1901 Bioerodible, Sustained-Delivery Vorolanib Insert in Patients With Wet Age-Related Macular Degeneration

PurposeTo evaluate safety and tolerability of EYP-1901, an intravitreal insert containing vorolanib, a pan–vascular endothelial growth factor (VEGF) receptor inhibitor packaged in a bioerodible delivery technology (Durasert E™) for sustained delivery, in patients with wet age-related macular degeneration (wAMD) previously treated with anti-VEGF therapy. DesignPhase 1, multicenter, prospective, open-label, dose-escalation trial. ParticipantsPatients with wAMD and evidence of prior anti-VEGF therapy response. MethodsPatients received a single intravitreal injection of EYP-1901. Main Outcome MeasuresThe primary objective was to evaluate safety and tolerability of EYP-1901. Secondary objectives assessed biologic activity of EYP-1901 including best-corrected visual acuity (BCVA) and central subfield thickness (CST). Exploratory analyses included reduction in anti-VEGF treatment burden and supplemental injection-free rates. ResultsSeventeen patients enrolled in the 440 μg (3 patients), 1030 μg (1 patient), 2060 μg (8 patients), and 3090 μg (5 patients) dose cohorts. No dose-limiting toxicity, ocular serious adverse events (AEs), or systemic AEs related to EYP-1901 were observed. There was no evidence of ocular or systemic toxicity related to vorolanib or the delivery technology. Moderate ocular treatment-emergent AEs (TEAEs) included reduced visual acuity (2/17) and retinal exudates (3/17). One patient with reduced BCVA had 3 separate reductions of 17, 18, and 16 letters, and another had a single drop of 25 letters. One severe TEAE, neovascular AMD (i.e., worsening/progressive disease activity), was reported in 1 of 17 study eyes but deemed unrelated to treatment. Mean change from baseline (CFB) in BCVA was –3.7 letters and –5.4 letters at 6 and 12 months. Mean CFB in CST was +1.7 μm and +2.3 μm at 6 and 12 months. Reduction in treatment burden was 76% and 72% at 6 and 12 months. Of 16 study eyes, 13, 9, and 6 were injection-free up to 3, 6, and 12 months. ConclusionIn the DAVIO trial (ClinicalTrials.gov identifier, NCT04747197), EYP-1901 had a favorable safety profile and was well tolerated in previously treated eyes with wAMD. Measures of biologic activity remained relatively stable following a single EYP-1901 injection. These preliminary data support ongoing Phase 2 and planned Phase 3 trials to assess efficacy and safety.

Abstract CT093: Vaccine immunotherapy by homologous antigenic loading as adjuvant therapy for glioblastoma: Ongoing phase I analysis

Abstract Glioblastoma (GBM) is a devastating tumor of the central nervous system (CNS) for which median survival remains 14-18 months despite aggressive standard of care. Early clinical studies of dendritic cell (DC) vaccination for the adjuvant treatment of GBM previously suggested mild to moderate clinical benefit, but results were both inconsistent and inconclusive. Homologous antigenic loading is an ex vivo technique that leverages p38MAPK and mTORC1 signaling cascades to initiate powerful cDC1-like skewing in monocyte-derived DC, leading to downstream induction of CD161int CD8+ cytolytic memory effectors. Here we report ongoing results of a completed phase I clinical trial with minimal exclusion criteria in which dendritic cell vaccines were prepared through homologous antigenic loading and administered to newly-diagnosed patients bilaterally in the vicinity of the deep cervical lymph nodes, assisted by ultrasound sonography. Patients were additionally adjuvanted with six weeks of concurrent type I interferon. Four dose levels from 3.5 x 106 to 3.6 x 107 total vaccine cells were tested, none of which resulted in AEs &amp;gt; grade 2 attributable to the investigational regimen. Immunohistochemistry of tumors derived from early post-vaccination second resections displayed enhanced CD8+ T-cell infiltration and pathologic findings consistent with residual rather than relapsed GBM in 2/3 patients. Radiologic pseudoprogression was also routinely observed among patients of all cohorts. Analysis of post-vaccination circulating PBMC indicated expansion of both CD4+ and CD8+ central memory T-cell compartments (p&amp;lt;0.05 for each by student’s two-tailed t-test) as well as expansion of CD8+CD127+ T-cells (p&amp;lt;0.05 by student’s two tailed t-test) in 4/4 patients analyzed. With an average of 10.9 months follow-up, median survival of this largely MGMT promoter unmethylated cohort was not yet reached and was statistically greater (p&amp;lt;0.05 by log-rank[Mantle-Cox]) than that of matched historical controls. At the time of submission, 13/15 trial patients remained alive with ECOG &amp;lt;/= 2. The results suggest that modern dendritic cell vaccines are safe, potentially efficacious, and can be effectively integrated within existing standards of care. Citation Format: Joseph F. Georges, Mazen Zaher, Corey M. Mossop, Christopher J. Bilbao, Christina M. Clay, Sabina Amin, Hamza A. Shaikh, Akshar Trivedi, Wei Liu, Madhuri Namekar, Colby J. Hofferek, Keenan Ernste, Eva H. Schumann, Mia Vu, Damilola Oyewole-Said, Nalini Bisht, Jonathan Vazquez-Perez, Ashley M. Goralczyk, Lindsey Colman, Lynne S. Kohler, Thuy V. Cao, Ngozi Okereke, Benjamin L. Musher, Vinod Ravi, Jan O. Kemnade, Rodrick C. Zvavanjanja, Jay-Jiguang Zhu, Sigmund H. Hsu, Yoshua Esquenazi-Levy, Nitin Tandon, Alan Turtz, Vanaja Konduri, William Karl Decker. Vaccine immunotherapy by homologous antigenic loading as adjuvant therapy for glioblastoma: Ongoing phase I analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT093.