Clinical Activity Research Articles

Ziftomenib in relapsed/refractory (R/R) NPM1 -mutant acute myeloid leukemia (AML): Phase 1b/2 clinical activity and safety results from the pivotal KOMET-001 study.

6506 Background: NPM1 -m drives leukemogenesis in ~30% of AML. Despite current risk stratification, nearly half will have R/R disease within a year, after which outcomes are poor with <10% complete response following chemotherapy. Ziftomenib – a potent, highly selective, oral, investigational menin inhibitor – has shown clinical activity as monotherapy and in combination for adults with R/R NPM1 -m and KMT2A -r AML, with 600 mg once-daily (QD) as the recommended phase 2 monotherapy dose for NPM1 -m. Here we present the primary analysis for NPM1 -m patients (pts) treated with ziftomenib 600 mg QD in the pivotal KOMET-001 study. Methods: KOMET-001 (NCT04067336) is a multicenter, open-label phase 1/2 study of ziftomenib in adults with R/R AML. In phase 2, pts with NPM1 -m R/R AML received ziftomenib 600 mg QD. Phase 2 primary endpoint: complete remission with full/partial hematologic recovery (CR/CRh); key secondary endpoints: composite complete remission (CRc), durations of CR/CRh and CRc, and safety. The analyses below include NPM1 -m pts pooled from phase 1b/2. Results: The phase 2 primary endpoint was met ( p =0.0058). As of 20 Dec 2024, 112 pts were enrolled (51% US/Canada, 49% Europe/UK) in phase 1b/2 and treated with ziftomenib 600 mg QD, with a median follow-up of 4.2 months. Median age was 69 yrs (range 22–86), 56% female, 83% ECOG PS 0–1, median of 2 prior therapies (range 1–7), including 60% prior venetoclax (VEN) and 23% prior transplant. CR/CRh rate in all phase 1b/2 pts was 25% (28/112; 95% CI 17–34) and overall response rate was 35% (39/112; 95% CI 26–44). In phase 2 pts, 23% (21/92; 95% CI 15–33) achieved CR/CRh (Table), with 67% (10/15) MRD negativity among CR/CRh responders tested (local). Comparable CR/CRh rates were observed in both VEN-naïve and exposed pts (21% vs. 24%). Ziftomenib was well tolerated with 3% (3/112) discontinuing due to treatment-related adverse events (TRAEs). 40% (45/112) of pts had Grade (Gr) ≥3 TRAEs, including 13% differentiation syndrome (all Gr3), ≤5% each anemia, febrile neutropenia and thrombocytopenia, and 2% QTc prolongation (Gr3). Updated clinical activity and safety data will be presented. Conclusions: In the pivotal KOMET-001, the phase 2 primary endpoint was met: Ziftomenib achieved deep and durable responses in R/R NPM1 -m AML, regardless of prior VEN. Ziftomenib was well tolerated with limited myelosuppression and only 3% ziftomenib-related discontinuations. Taken together, these data support the potential use of ziftomenib monotherapy as a new treatment option for R/R NPM1 -m AML. Clinical trial information: NCT04067336 . Response, n (%) Phase 2600 mg QDN=92 Phase 1b/2600 mg QDN=112 CR 13 (14) 20 (18) CR/CRh 21 (23) 28 (25) CRc 24 (26) 32 (29) Median duration, months (95% CI) CR/CRh 3.7 (1.9–NE) 3.7 (1.9–7.7) CRc 4.6 (2.8–11.4) 5.1 (2.8–8.1) Restricted mean duration, months (95% CI) CR/CRh 4.3 (3.1–5.6) 5.2 (3.6–6.7) CRc 5.9 (4.0–7.7) 6.4 (4.6–8.1)

Effects of androgen modifying therapies on disease activity in older men with multiple sclerosis.

Effects of androgen modifying therapies on disease activity in older men with multiple sclerosis.

An oral prostate cancer RIPTACtherapeutic in phase 1 for metastatic castrate resistant prostate cancer (mCRPC).

TPS5115 Background: New therapies are urgently needed to treat prostate cancer, especially for patients progressing on existing drugs that inhibit the activity of the Androgen Receptor (AR) (e.g. Androgen Receptor Pathway Inhibitors (ARPIs)). Metastatic Castration-Resistant Prostate Cancer (mCRPC) is a more aggressive stage of the disease, characterized by increased AR expression and signaling. To address this unmet medical need, we have developed a Regulated Induced Proximity Targeting Chimera (RIPTAC™) Therapeutic HLD-0915. HLD-0915 is a heterobifunctional small molecule that leverages full length AR (FL-AR) expression in tumor cells to form a trimeric complex with an Essential Protein (EP) needed for cell survival. This results in EP loss of function in prostate cancer cells and a selective antitumor effect. HLD-0915 activity requires only the presence of FL-AR and retains activity regardless of whether there are AR or non-AR aberrations that may otherwise serve as drivers of disease. Preclinically, HLD-0915 treatment results in tumor shrinkage and PSA declines following oral dosing in murine models of castration-resistant and ARPI-resistant forms of the disease, while delivering a favorable therapeutic index. The Phase 1 trial in mCRPC will investigate safety and early signs of efficacy in the intended patient population. Methods: This first-in-human, multicenter, open label Phase 1/2 study evaluates the safety, tolerability, and clinical activity of HLD-0915 in patients with mCRPC. Phase 1 consists of monotherapy dose levels employing a Bayesian Optimal Interval (BOIN) design with each dose level starting with a minimum of 3 patients per cohort with the primary objectives of defining the maximal tolerated dose and/or recommended dose for expansion and characterizing safety and tolerability of HLD-0915. This study also aims to characterize the PK profile and assess clinical activity by PSA declines and objective response rate per RECIST and will explore ctDNA, tumor cell genetics, and PD biomarkers. Patients with progressive mCRPC who may or may not have received prior novel antiandrogen therapy, a taxane, or PSMA targeted radioligand will be enrolled. Cohort 1 enrollment begins in January 2025. The Phase 2 portion of the study will confirm the RP2D and clinical activity in up to 3 cohorts which will be decided in the future based on emerging data. Clinical trial information: NCT06800313 .

International phase II randomized placebo-controlled study investigating the combination of YIV-906 plus sorafenib (SORA) in HBV (+) patients (Pts) with advanced hepatocellular carcinoma.

e16244 Background: YIV-906 (formerly PHY906/KD018), inspired by an 1800-year traditional botanical medicine formulation, is being developed under the FDA’s botanical drug guidance (IND’s 138525 and 62627) for treating gastrointestinal ailments associated with chemotherapeutics or chemoradiation. Multi-targeted tyrosine kinase inhibitors, SORA and Lenvatinib, are first-line systemictreatment options for advanced HCC pts, are limited by high rates of grade ≥ 3 treatment-related adverse events. Preclinical data suggests YIV-906 increases tumor microenvironment inflammation by M1 macrophage activation/proliferation resulting in HCC tumor rejection in vivo and reduces SORA-associated toxicity, suggesting improved safety and potential clinical benefit for pts. Methods: An international, multicenter, double-blind, placebo-controlled, randomized phase 2 study was conducted examining YIV-906's impact on SORA in advanced HCC pts (NCT04000737), stratified by metastatic status and ECOG Performance Status. The primary endpoint was progression-free survival (PFS). Secondary endpoints were TTP, ORR, and DCR by RECIST1.1; OS, QoL, and safety by CTCAE version 5.0. Per Protocol Set (PPS) analysis exclude patients with misrandomizations and major protocol violations impacting data integrity and quality. Translational correlatives include pharmacokinetics and exploratory soluble biomarkers analysis. Results: From 18 Feb 2020 to 03 Jun 2023, 107 pts were screened across 20 study sites in 4 regions (US and Asia). 62 chronic HBV(+) HCC systemic treatment naïve pts with Child-Pugh A liver function were randomized to a 2:1 ratio, (41 pts YIV-906 arm, 20 pts placebo arm). The Investigator-assessed mPFS per RECIST 1.1 was slightly longer in the YIV-906 arm than the placebo arm in ITT group (N = 62). PPS Subgroup analyses indicated: significant improvement in PFS in pts completing at least 2 treatment cycles (N = 49); YIV-906 arm mPFS is 5.6 months (95% CI: 3.6, 7.2) vs. placebo arm 2.3 months (95% CI: 1.9, 3.9) respectively; a 69% reduction in risk of disease progression or death (HR = 0.31 [95% CI: 0.13, 0.72]; p = 0.004). The YIV-906 arm mOS was 14.3 months (95% CI: 8.2, 18.8) vs placebo arm 8.0 months (95% CI: 4.6, 32.1), HR of 0.97 (95% CI: 0.51, 1.84; p = 0.92). In the secondary endpoint ORR, improvement was also observed by the investigator. YIV-906 arm pts tolerated SORA longer, with manageable toxicity profile. No new safety signals in YIV-906 + SORA treated pts were identified compared with sorafenib monotherapy. Conclusions: In this limited cohort of patients with confirmed HBV (+) HCC diagnosis, our findings suggest that YIV-906 is effective for increasing SORA’s therapeutic index and clinical activity, and supports further studies of YIV-906. Clinical trial information: NCT04000737 .

A phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of emactuzumab in patients with tenosynovial giant cell tumor (TANGENT).

TPS11584 Background: Tenosynovial giant cell tumor (TGCT) is a rare, non-malignant, locally aggressive tumor of the synovium, primarily affecting knee, hip, and ankle joints. TGCT is caused by excessive production of colony stimulating factor 1 (CSF-1), a cytokine involved in the proliferation, differentiation, and survival of monocytes and macrophages. It is a chronically debilitating disease, causing pain, stiffness, loss of function in the affected joints and a decline in quality of life. The worldwide incidence in digits, localized, and diffuse TGCT is about 29, 10, and 4 per million person-years, respectively. Surgery remains the principal treatment option, at the cost of a high rate of tumor recurrence, and risk of damage to the affected joint and surrounding tissues. Systemic treatment options are limited. Emactuzumab is a novel monoclonal antibody, and potent and specific CSF-1 receptor (CSF-1R) antagonist, that causes apoptosis of M2-type macrophages in the tumor micro-environment, thereby inhibiting tumor growth. In a phase Ia/b study, emactuzumab was administered i.v. at doses varying from 900-2000 mg (cycles ranging 1-14) in advanced diffuse TGCT patients (Cassier et al, EJC, 2020). Emactuzumab was well tolerated and showed rapid and pronounced responses with an objective response rate (ORR) of 71%, which was durable with an ORR of 70% and 64% after one or two years, respectively. Clinical activity was associated with symptomatic improvement. The optimal biological dose of emactuzumab, defined as 1000 mg q2w, is under investigation in the Phase 3 trial. Emactuzumab was granted an Orphan Drug Designation by the European Medicines Agency in March 2022. Methods: TANGENT (NCT05417789) is a randomized, double-blind, placebo-controlled trial designed to confirm the efficacy and safety of emactuzumab in TGCT patients not amenable for surgery. The primary endpoint is efficacy, assessed as ORR at 6 months by MRI per RECIST v1.1. Key secondary endpoints include patient-reported outcomes (PROMIS-PF), range of motion, pain and stiffness, and other antitumor activity (e.g. TVS). In Part 1, subjects will be randomized 2:1 to receive either emactuzumab 1000 mg or placebo i.v. q2w for 5 doses over 10 weeks, followed by an observation period of 3 months. Part 2 is a follow-up phase from 6-24 months post randomization during which subjects whose TGCT worsens may be eligible for emactuzumab. The study is actively recruiting. Assessments include tumor evaluation, physical examination, vital signs, electrocardiograms, questionnaires, urinalyses, and blood tests for hematology, biochemistry, and PK of emactuzumab. Safety will be assessed by laboratory assessments and evaluation of adverse events. Clinical trial information: NCT05417789 .

A phase 1a/1b trial in relapsed/refractory T-cell non-Hodgkin lymphoma to determine the safety profile, pharmacology, and maximum tolerated dose of ST-001, an intravenous fenretinide phospholipid suspension (12.5 mg/mL).

TPS7096 Background: N-(4-hydroxyphenyl)retinamide (4-HPR; fenretinide) is a synthetic amide derivative of all-trans retinoic acid. Clinical data from trials of earlier fenretinide formulations indicate that higher plasma levels of fenretinide correlate with improved patient responses. Although fenretinide intravenous emulsion (4-HPR-ILE) increased plasma concentration and yielded complete and partial responses in peripheral T-cell lymphomas, its dose-limiting hypertriglyceridemia mainly related to triglyceride from the soy oil vehicle posed a significant impediment to clinical development (Maurer BJ et al. Clin Cancer Res. 2017). Methods: A new formulation of intravenous fenretinide, designated ST-001 nanoFenretinide, is an innovative dosage form composed of phospholipid nanoparticles in a free-flowing solution (Patent number US 8709379 B2). ST-001 effectively eliminates the risk of vehicle-related hypertriglyceridemia, because it is free of triglycerides. It is also free of adjuvants, non-ionic surfactants, polyoxylated compounds, alkoxylated oils, and animal-derived substances known to cause allergy or hypersensitivity. ST-001 potentially provides a safer form of intravenous fenretinide for achieving therapeutic plasma concentrations. In this Phase 1a/1b clinical trial (NCT04234048), ST-001 is administered via intravenous infusion (IV) to patients with relapsed/refractory T-cell non-Hodgkin’s lymphoma (NHL) following at least one prior treatment, including cutaneous (CTCL) and non-cutaneous T-cell lymphoma subtypes (angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, and follicular T-cell lymphoma). The U.S.-based trial will enroll up to 54 patients across three stages: up to 9 patients (single patient cohorts) for Phase 1a accelerated dose escalation, up to 15 patients (3 patient cohorts) for Phase 1a standard dose escalation and determination of maximum tolerated dose (MTD), and 30 patients for Phase 1b to determine the optimal dose. The primary objectives are to determine the MTD, toxicity profile, adverse events and dose-limiting toxicities (DLTs) based on NCI Common Toxicity Criteria, and anti-tumor activity, when administered over 4 hours daily for 5 consecutive days every 3 weeks, for a maximum of 8 cycles. Secondary objectives include pharmacokinetic profiling and investigating potential mechanisms of action using pharmacodynamic biomarkers. The accelerated stage has completed enrollment, and the standard stage is open for enrollment as of January 2025. This study investigates a novel fenretinide formulation aiming to address treatment challenges in T-cell NHL, with a focus on safety, tolerability, clinical activity, and pharmacology. Clinical trial information: NCT04234048 .

Analysis of genetic mutation profile and CNS pharmacokinetics in relapsed/refractory primary CNS lymphoma patients responding to novel emavusertib (IRAK4i) and BTKi combination.

2085 Background: Primary Central Nervous System Lymphoma (PCNSL) is a rare and aggressive non-Hodgkin lymphoma with no approved treatments for relapsed/refractory (R/R) patients, representing a critical unmet need. MyD88 mutations in ~70% of PCNSL patients drive Interleukin-1 receptor associated kinase 4 (IRAK4) activation, promoting NF-κB signaling, inflammation, and tumor progression. Emavusertib, a potent oral IRAK4 inhibitor, crosses the blood-brain barrier and shows preclinical synergy with Bruton tyrosine kinase inhibitors (BTKi), re-sensitizing BTKi-resistant cell lines. This study evaluates the molecular and pharmacokinetic (PK) data associated with responses to emavusertib + ibrutinib combination therapy in R/R PCNSL patients. Methods: The safety, clinical activity, and potential biomarkers of emavusertib in R/R PCNSL are being investigated in the ongoing open-label, Phase 1/2 TakeAim Lymphoma trial (NCT03328078). Pre-dose and 1.5-hour post-dose plasma samples were collected on Cycle 3 Day 1, Cycle 5 Day 1 and Cycle 7 Day 1. Cerebrospinal fluid (CSF) samples were obtained via a lumbar puncture within 1.5 hrs of collection of the post-dose plasma PK sample on Cycle 3 Day 1. Mutation analysis was based on patients’ molecular pathology reports provided by trial sites. Sequencing of archival tissues, CSF and plasma are in progress. Results: As of 06 December 2024, CSF concentration data were available for 7 PCNSL patients. The mean emavusertib concentration in CSF was 81.3 ng/ml (54.7-104.0) in patients receiving 100 mg emavusertib BID (n = 4). In patients receiving 200 mg emavusertib BID (n = 3), the mean emavusertib concentration in CSF was higher at 175.7 ng/ml (114.8-209.4), which is 2.2X the mean value in patients who received 100 mg emavusertib BID (p-value = 0.02). All 7 patients received 560 mg ibrutinib QD, and the ibrutinib concentrations in the CSF were consistent with findings from previously published clinical studies. MyD88 mutation status was available for 7 patients of which all had prior exposure to BTKi regimens. Among these, 6 patients had MyD88 mutation of which 4 patients had responded (3 complete responses and 1 partial response) to emavusertib + ibrutinib combination with duration of response (DOR) up to 18.9 months with data collection ongoing. Conclusions: Preliminary CNS pharmacokinetic data demonstrates that emavusertib concentration in CSF increases with increasing emavusertib dose. Patients with MyD88 mutations showed expected promising preliminary efficacy to emavusertib + ibrutinib combination and may overcome BTKi resistance. Enrollment in this trial is ongoing. Clinical trial information: NCT03328078 .

Effect of prior treatment (tx) on the clinical activity of imetelstat (IME) in transfusion-dependent (TD) patients (pts) with erythropoiesis-stimulating agent (ESA), relapsed or refractory (R/R)/ineligible lower-risk myelodysplastic syndromes (LR-MDS).

6569 Background: IME, a first-in-class, direct, and competitive inhibitor of telomerase activity, was approved in the US for the tx of red blood cell (RBC)-TD LR-MDS in pts who are R/R or ineligible for ESA based on the results of the pivotal IMerge trial (NCT02598661). IMerge demonstrated significant and durable efficacy of IME (n=118) versus placebo (n=60) for ≥8-week, ≥24-week, and ≥1-year RBC-transfusion independence (TI), with a generally manageable safety profile in this pt population. Here, we pooled data from the 3 parts of the IMerge trial (phase 2, phase 3, and QTc substudy) to investigate the effect of prior txs on the clinical activity of IME. Methods: In IMerge, pts received IME intravenously every 4 weeks at 7.1 mg/kg active dose (7.5 mg/kg IME sodium equivalent). Prior lenalidomide (LEN) and prior hypomethylating agent (HMA) use were exclusion criteria in phase 3 only. In this analysis, pooled data from IME-treated pts (phase 2, phase 3, and QTc substudy) were analyzed by prior tx: ± ESA, luspatercept (LUSP), LEN, and HMA; pts may have received >1 prior tx. Outcomes included ≥8-week, ≥24-week, and ≥1-year RBC-TI, rates of hematologic improvement-erythroid (HI-E) based on the revised International Working Group (IWG) 2018 criteria, transfusion reduction of ≥4 U/8 weeks, and a hemoglobin (Hb) rise of ≥1.5 g/dL for ≥8 weeks. Results: The data cutoff dates were 10/13/2023 (phase 2/3) and 10/13/2024 (QTc substudy). A total of 226 IME-treated pts pooled in IMerge were included in this analysis; most pts (n=188) had a high transfusion burden (TB) per revised IWG 2018 at baseline (vs low TB [n=38]; Table). Of all pts, 39% achieved ≥8-week RBC-TI (median duration of response, 55 weeks), and 28% and 18% achieved ≥24-week and ≥1-year RBC-TI, respectively. Among all IME-treated pts, 204 had prior tx with an ESA and 22 were ineligible for ESAs; 36 had prior LUSP, 26 had prior LEN, and 22 had prior HMA. Pt characteristics and efficacy by prior tx are shown in the table. Conclusions: Pts who were ESA ineligible or who had prior tx with LUSP, LEN, or HMA, and were largely high TB, in IMerge experienced clinical benefit from IME tx, though the number of pts was small. Given the limited efficacy data available in later lines of tx for LR-MDS, these results have important clinical implications, suggesting that IME has clinical activity regardless of prior txs. Clinical trial information: NCT02598661 . ESA ineligible(n=22) Prior ESA(n=204) Prior LUSP(n=36) Prior LEN(n=26) Prior HMA(n=22) TB at baseline, nLow TBHigh TB 319 35169 531 422 319 ≤8-week RBC-TI, %Median duration of RBC-TI for ≥8-week TI responders, weeks 3632 4060 3170 2341 1441 ≥24-week RBC-TI, % 14 29 22 19 9 ≥1-year RBC-TI, % 9 19 14 8 0 HI-E (IWG 2018), % 41 44 31 35 23 Transfusion reduction of ≥4 U/8 weeks (IWG 2006), % 64 64 69 54 50 Hb rise ≥1.5 g/dL for ≥8 weeks (IWG 2006), % 27 34 31 19 14

A phase 1, open-label, dose expansion cohort of the tolerability of tolododekin alfa (ANK-101) in combination with cemiplimab in cutaneous squamous cell carcinoma.

TPS9600 Background: IL-12 stimulates innate and adaptive tumor immunity. Tolododekin alfa (ANK-101) is an anchored drug conjugate that creates a strong link between full-length IL-12 and aluminum hydroxide through an alum-binding protein (ABP) which localizes IL-12 to the tumor microenvironment (TME), resulting in sustained drug release, prolonged antitumor immune activation, increased PD-L1 expression, and minimal systemic adverse events. Cemiplimab is an anti-PD-1 monoclonal antibody approved in several countries worldwide for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or radiation. This phase 1 clinical trial is designed to combine tolododekin alfa and cemiplimab to determine tolerability and initial biologic and clinical activity. Methods: This is an open-label study to evaluate locally administered tolododekin alfa and cemiplimab in patients with advanced CSCC who progressed on, are refractory to, or intolerant of prior SOC treatment. The combination cohort will consist of 15 participants. Participants will be treated with tolododekin alfa in combination with cemiplimab. Treatment will consist of up to eight cycles of tolododekin alfa in combination with cemiplimab followed by cemiplimab alone for up to one year. Follow-up imaging assessments will be performed every 12 weeks. Eligible participants must have histologically confirmed high-risk locally advanced or metastatic CSCC not amenable to surgical management, accessible tumors for injection and biopsy, and measurable disease by RECIST v1.1. Key exclusion criteria include tumors close to vital structures, uncontrolled bleeding disorders, and prior ≥ Grade 3 immune-mediated adverse events (imAEs) following treatment with an agent that blocks the PD-1/ PD-L1 pathway. Primary objectives include safety and tolerability of tolododekin alfa and cemiplimab. Secondary objectives include immunogenicity (ADA), and preliminary clinical activity measured by ORR, DCR, DOR, and PFS by RECIST v1.1. Exploratory objectives include QOL using FACT-G and immune pharmacodynamic (PD) changes. This clinical trial is in progress. Clinical trial information: NCT06171750 .

Patritumab deruxtecan (HER3-DXd) in active brain metastases (BM) from metastatic breast (mBC) and non–small cell lung cancers (aNSCLC), and leptomeningeal disease (LMD) from advanced solid tumors: Results from the TUXEDO-3 phase II trial.

2005 Background: BM and LMD are common and severe complications of solid cancers with high morbidity, poor prognosis, and limited treatment options. Antibody drug conjugates (ADCs) have shown high intracranial overall response rates (IC-ORR) in HER2-positive mBC and EGFR -mutated NSCLC patients (pts). HER3-DXd, an ADC combining an anti-HER3 antibody with a topoisomerase (topo) I inhibitor, has shown promising results in mBC and aNSCLC pts. Since HER3 is highly expressed in aNSCLC and mBC CNS metastases, we hypothesized HER3-DXd may have clinical activity in BM from mBC and aNSCLC pts, and LMD from any solid tumor. Methods: TUXEDO-3 (NCT05865990) is an international, multicenter, multicohort, single-arm, phase II trial enrolling pts with BM from mBC (cohort 1), aNSCLC (cohort 2), and LMD from any solid tumor (cohort 3). Key inclusion criteria were: Pts ≥18 years old, histologically documented disease, ECOG PS 0-2, and left ventricular ejection fraction ≥50% in all cohorts; newly diagnosed/progressing BM with ≥1 brain lesions ≥10mm by MRI, and ≥1 line of prior systemic treatment, in cohorts 1 and 2; LMD per EANO-ESMO in cohort 3. Pts received HER3-DXd 5.6 mg/kg IV Q3W until disease progression, unacceptable toxicity or withdrawal for any reason. Primary endpoint was IC-ORR per local investigator according to RANO-BM in cohorts 1 and 2, and 3-month OS in cohort 3. Sample size was based on Simon’s two-stage design. Primary endpoint was met if ≥3 IC responses (H0: ≤5%; H1: ≥25%) in cohort 1 and 2; and if ≥3 pts with 3-month OS (H0: ≤5%; H1: ≥25%) in cohort 3. Overall sample size was 60 pts with a target population of 20 pts per cohort. Results: Between December 2023 and July 2024, 61 evaluable pts were enrolled from 8 Austrian and Spanish sites. Median age (min; max) was 57.0 (35.0; 75.0), 59.5 (37.0; 72.0) and 51.5 (40.0; 66.0) years in cohorts 1, 2 and 3, respectively. At data cut-off, median follow-up (min; max) was 4.4 (1.4; 10.1), 4.3 (0.2; 11.0) and 3.5 (0.8; 8.6) months in cohorts 1, 2 and 3, respectively. Primary endpoints were met in all three cohorts. In cohort 1, 5/21 (23.8%) pts had IC response irrespective of BC subtype; 2 (40.0%) responders had received previous topo I based ADCs. In cohort 2, 5/20 (25.0%) pts had IC response. In cohort 3, 11/20 (55.0%) pts achieved 3-month OS irrespective of the LMD type. No new signals of toxicity were observed and neurological symptoms, QoL and neurocognitive function remained stable or improved over the treatment period. Tumoral HER3 expression did not correlate with treatment response. Conclusions: TUXEDO-3 is the first trial evaluating efficacy and safety of HER3-DXd in pts with BM or LMD. HER3-DXd showed substantial CNS activity in parenchymal metastases and LMD, and may be a potential novel treatment for CNS disease in cancer pts. Clinical trial information: NCT05865990 .

Major trauma coordinators in the UK: A survey of demographics and role functions.

Major trauma coordinators in the UK: A survey of demographics and role functions.

Suboptimal suppression of serum androgen levels among men treated with apalutamide and abiraterone acetate plus prednisone compared with abiraterone acetate plus prednisone alone.

5065 Background: Phase III studies of dual therapy with an androgen receptor (AR) antagonist, apalutamide (Apa) or enzalutamide (Enza) with abiraterone acetate (AA) plus (+) prednisone (P) in metastatic castration resistant prostate cancer (mCRPC) have not shown a survival benefit vs single agent therapy. Apa and Enza induce CYP3A4 activity, resulting in decreases in serum AA and P levels. The decrease in AA levels has not been considered clinically significant, but the potential impact of AR antagonist-mediated CYP3A4 induction on serum steroid levels, in context of clinical studies combining an AR antagonist with AA, has not been previously reported. Methods: We measured levels of AA, its metabolites and androgens using LC/MS-MS in available serum samples obtained at baseline and at 4 weeks of therapy in the PANTHER phase II study (n=86) of Apa (240 mg daily) and AA (1000mg daily) + P (10mg daily), and in the Abi Race phase II study (n=75) of AA (1000mg daily) + P (10mg daily) among men with mCRPC. Samples were batched and all sera assessed contemporaneously. Comparison of metabolite levels between studies used the Mann-Whitney test, and within study the Wilcoxon matched-pairs signed rank test. Results: At 4 weeks, median (med) levels of AA and its primary metabolites delta-4 and keto-Abi in PANTHER vs Abi Race were 13.1 vs 39.6 ng/ml, 0.49 vs 1.93 ng/ml, and 0.75 vs 8.98 ng/ml (p=<0.0001 for all), equating to 66%, 75%, and 92% lower levels with Apa and AA + P vs AA + P. Baseline steroid levels did not differ between the studies, but steroids downstream of CYP17A were suppressed markedly less effectively in the dual therapy PANTHER study: DHEAS was detectable in 80% vs 14% of samples (med 1.23 vs 0.49 ng/ml, p=<0.0001), DHEA in 90% vs 26% (med 0.44 vs 0.01 ng/ml, p=<0.0001), AED in 70% vs 11% (med 0.017 vs 0.010 ng/ml, p=<0.0001), and testosterone in 50% vs 17% (med 0.006 vs 0.005 ng/ml, p=0.0005). Despite the decrease in AA levels, steroids upstream of CYP17A in PANTHER were markedly elevated vs treatment with AA + P alone: pregnenolone (4.1 vs 0.79ng/ml, p=<0.0001), consistent with a suboptimal prednisone-mediated suppression of ACTH. Conclusions: Serum AA levels at week 4 are substantially lower, and androgen levels substantially higher, among men with mCRPC treated with Apa and AA + P vs AA + P. Our data suggest that Apa decreased P levels to the point that circulating ACTH remained sufficient to mediate ongoing basal adrenal androgen synthesis. Suboptimal suppression of steroids may explain why AA and AR antagonist combination studies have not been more effective. The clinical activity when both treatment strategies are at full efficacy remains to be fully tested, and will likely require use of dexamethasone or higher than standard dosing of prednisone. This may be particularly important for treatment of prostate cancers with greater dependence on AR signaling.

FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers.

TPS2091 Background: Plixorafenib (FORE8394; PLX8394) is a novel, oral, small-molecule BRAF inhibitor highly selective for BRAF V600 monomers and BRAF-containing dimers. Plixorafenib binding disrupts RAF dimerization, targeting both BRAF V600 mutations and fusions, thereby preventing paradoxical activation and avoiding the need for combination with a MEK inhibitor. In a phase 1/2a study, plixorafenib demonstrated promising safety and clinical activity across a range of doses tested in tumors with BRAF V600 mutations or fusions. The most common adverse events (AEs) included predominantly low-grade liver function test changes and grade 1 fatigue, nausea, diarrhea, and vomiting. Methods: The FORTE Phase 2 basket study is currently enrolling patients ≥10 years of age into 4 sub-protocols. Study details are shown in theTable. Eligible patients have received prior therapy for advanced disease, have measurable disease, and have a Karnofsky (≥16 years) or Lansky (<16 years) Performance Score of ≥60 at study entry. All patients receive plixorafenib continuous dosing, in some cohorts coadministered with cobicistat, a pharmacokinetic (PK) booster. Prior MAPK inhibitor therapy is excluded unless otherwise specified below. As of January 2025, the trial is recruiting participants in 9 countries globally, with 54 sites activated. Clinical trial information: NCT05503797 . Sub-Protocol A Sub-Protocol B Sub-Protocol C Sub-Protocol D Patient Population Advanced solid and primary CNS tumors harboring BRAF fusions BRAF V600-mutated recurrent primary CNS tumors Rare 1 BRAF V600-mutated advanced solid tumors BRAF V600-mutated melanoma 2 or thyroid cancer without anaplastic or undifferentiated components Planned Enrollment ~100 ~50 ~75 ~12 Design Single-arm, open-label, Bayesian optimal phase 2 design 1:1 randomized, open-label crossover design to compare plixorafenib administered alone and with PK booster Planned Efficacy Interim Analyses N=25N=50 N=25 N=25N=50 None Primary Endpoint ORR 3 Intra-patient PK Key Secondary Endpoints DOR, DCR, PFS, OS, PK, Safety Safety, ORR, DOR, DCR, PFS, OS, Safety Key Exploratory Endpoint Longitudinal ctDNA assessments 4 1 BRAF V600-mutated tumors occurring in ≤40,000 US patients annually (eg, ovarian/gynecologic cancers, cholangiocarcinoma, small intestinal/gastrointestinal cancers other than colorectal adenocarcinoma, neuroendocrine cancers). 2 Patients with melanoma should have received and not tolerated a prior BRAF inhibitor. 3 Response assessed by BICR using RECIST v1.1 for solid tumors or RANO HGG or LGG for primary CNS tumors. ORR for primary CNS tumors using RANO 2.0 is an exploratory endpoint. Tumors assessed at cycle 1 day 1, every 9 weeks for 48 weeks, then every 12 weeks. 4 Plasma for all patients; plasma and CSF for patients with primary CNS tumors.

Induction of neoantigen-specific immune responses by VB10.NEO in combination with atezolizumab in heavily pretreated patients with advanced solid tumors: Final analysis of the phase 1b VB N-02 trial.

2639 Background: VB10.NEO, a personalized DNA-based neoantigen vaccine, was evaluated with atezolizumab in a Phase 1b trial to assess safety, clinical activity, and immune responses in heavily pretreated patients with advanced solid tumors. The NeoSELECT platform enriches for clonal neoantigens by analyzing RNA and circulating tumor DNA, incorporating frameshift antigens and single nucleotide variants. Methods: This open-label, dose-escalation trial investigated VB10.NEO across three dose levels (3, 6 and 9 mg) combined with atezolizumab (1200 mg Q3W). Eligible patients had advanced or metastatic solid tumors, sufficient tumor material for vaccine manufacturing, at least 10 identified tumor neoantigens, and measurable disease. Immune responses were assessed using ELISpot assays (in vitro stimulation and ex vivo), T cell receptor sequencing, and flow cytometry. Endpoints included safety, immune response, and antitumor activity per RECIST v1.1. Results: At study completion (October 2024), 26 patients (median age 61 years, range 28–72; 62% female) received at least one dose of VB10.NEO. Median prior therapy lines for advanced disease were three (range 1–6), and 54% had prior immunotherapy, including checkpoint inhibitors. Tumor types included head and neck squamous cell carcinoma (15%), triple-negative breast cancer (15%), and others (31%; most were tumors with low tumor mutational burden). The majority (69%) of evaluable patients had low or negative PD-L1 expression. Injection site reactions (15%) and fatigue (12%), mainly Grades 1–2, were the most common adverse events. A dose-limiting Grade 3 transient blood pressure increase occurred in the 9 mg cohort. No treatment-related serious events or deaths occurred. Across all dose levels, VB10.NEO induced robust and durable neoantigen-specific immune responses. In vitro stimulated ELISpot assays detected vaccine-induced T cell responses in 85% (11/13) of evaluable patients and in 58% of evaluated neoantigens, while ex vivo ELISpot demonstrated responses in 22% (4/18) of patients and 5% of evaluated neoantigens. T cell receptor sequencing showed persistent T cell clone expansion in 9/11 patients, indicating durable immune responses. Putative neoantigen-specific clones were detected in 6/7 analyzed patients, with persistent expansion in 4. All patients achieving stable disease (34.8%, 8/23) exhibited neoantigen-specific immune responses. Conclusions: VB10.NEO combined with atezolizumab demonstrated a favorable safety profile while eliciting robust, durable immune responses across all dose levels, even in heavily pretreated patients with advanced solid tumors. The potential correlation between immunogenicity and clinical benefit supports further exploration in earlier treatment settings. Clinical trial information: NCT05018273 .

Phase 2 trial of dual EGFR inhibition with cetuximab and afatinib in patients with recurrent/metastatic head and neck squamous cell cancers (HNSCC).

6023 Background: Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) but its clinical activity is limited by resistance mechanisms. Our previous HNSCC trial of chemotherapy, cetuximab and erlotinib demonstrated a 62.5% objective response rate (ORR) including 2 durable complete responses (CR), with greater inhibition of phosphorylated EGFR in post-treatment biopsies. Because human epidermal growth factor receptor (HER)-2 and HER3 are overexpressed in cetuximab-resistant HNSCC, we postulated that the combination of cetuximab and afatinib, an irreversible, pan-HER inhibitor, would overcome resistance by inhibiting EGFR/HER dimers and inhibiting nuclear translocation and resulting non-canonical EGFR activities in R/M HNSCC. Methods: The primary objective of this single-arm phase II trial was ORR to the combination of cetuximab and afatinib in patients with R/M HNSCC refractory to platinum-based chemotherapy and/or immune checkpoint therapy. Cetuximab was administered at standard doses weekly/bi-weekly. Afatinib was initially dosed at 40 mg orally daily, amended to 30 mg orally daily after 25 patients, to improve tolerability. Key secondary endpoints were median progression-free survival (mPFS), median overall survival (mOS) and toxicity. Radiographic tumor assessment was performed, using RECIST version 1.1 every 8 weeks. Biopsy was obtained at baseline, 4 weeks after treatment initiation and at end of treatment, where medically feasible. Results: The study protocol was approved by the institutional review board and written informed consent was obtained from all participants. Fifty patients were enrolled between 7/3/2017 and 10/16/2024 at Yale Cancer Center, 47 were evaluable for response. Median age was 63 years (range 43-81 years), 39 (83%) were male, 21 (44.7%) had p16 positive tumors, 26 (55.3%) were p16 negative. Most common primary tumor location was oropharynx (n, %: 21, 44.7). ORR was 23.4% (2 complete responses, 9 partial responses, 95% CI: 12.3%-38%) for the entire population, 10 responses were in p16- patients (ORR 38.5%) and 1 response (4.8%) in a patient with p16+ disease. Median PFS was 3.8 months (95% CI: 2.1-not reached) for p16- patients and 1.8 months (95% CI: 1.7-8.9) for p16+ patients. Median OS was 7.5 months (95% CI: 4.8-12). Commonest adverse events (n, %) were diarrhea (19, 40), anemia (17, 36) rash (14, 30) and fatigue (13, 28). Correlative analyses are underway. Conclusions: This trial of dual EGFR targeting demonstrated high clinical efficacy, especially in the p16- population. Adverse events were consistent with those associated with EGFR inhibitor treatment. Clinical trial information: NCT02979977 .

First-in-human study of 177 Lu-JH020002 in patients with metastatic castration-resistant prostate cancer.

5055 Background: 177 Lu-JH020002 is a novel radioligand therapy that delivers beta-particle radiation to PSMA-expressing tumor cells and the surrounding microenvironment, demonstrating high affinity and antitumor activity in preclinical studies. JH020002-01C is an ongoing, multicenter, open-label phase I/II study investigating the safety, tolerability, pharmacokinetics, dosimetry and preliminary antitumor activity of 177 Lu-JH020002 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Here, we reported the preliminary safety and efficacy results of phase I. Methods: Eligible pts for phase I had mCRPC, were refractory to or had progressed following at least one androgen receptor pathway inhibitor (ARPI) and chemotherapy, and had at least one PSMA-positive tumoral lesion (PET imaging). Pts received an intravenous dose of 177 Lu-JH020002 at the beginning of each 6-week cycle, up to a maximum of 6 cycles. Dose escalation and determination of the maximum tolerated dose (MTD) in phase I were based on an accelerated titration and 3+3 dose-escalation design, including 5 dose cohorts. The primary objective of phase I is to evaluate the safety and tolerability of 177 Lu-JH020002 and determine the recommended phase 2 dose. Secondary objectives are dosimetry, pharmacokinetics, efficacy and safety. Tumor response is assessed per PCWG3 criteria. Results: As of Jan 22, 2025, 12 pts received 177 Lu-JH020002 with a median cumulative dose of 18.06 GBq. 91.7% pts with bone, 33.3% nodal, 8.3% peritoneal metastases. 100% with ≥1 prior ARPI therapy, 50% ≥ 1 prior chemo regimen, 16.7% 223 Ra, 33.3% PARPi. No DLT was reported and MTD was not reached. The most common treatment related adverse events (TRAEs) were Grade1-2. No grade 4/5 AEs were reported. TRAEs of note were hematologic TRAEs, including lymphocyte count decreased (91.7%), platelet count decreased (50.0%), anaemia (66.7%) and white blood cell count decreased (16.7%). With follow-up ongoing, across cohorts 2-5, 63.6% with ≥ 50% PSA decline; 27.3% with ≥ 90% PSA decline. Seven pts were evaluated per PCWG3. None of them had progressive disease, and all of them remain under treatment follow-up. Among all pts, 1 was with measurable disease and had a partial response. Conclusions: 177 Lu-JH020002 exhibited excellent antitumor activity in heavily pre-treated pts with mCRPC. Toxicity was well tolerated and generally manageable. Further clinical trials are under planning. Clinical trial information: NCT06139575 . Exposure and clinical activity (cohorts 2~5, at doses ≥ 3.70 GBq). Parameter,median (range) or n (%) 3.70 GBq 5.90 GBq 7.40 GBq 8.88 GBq Total No. of patients 2 3 3 3 11 Cumulative dose (GBq) 11.20(4.2-18.2) 24.58 (5.4-35.2) 22.8(22.1-29.1) 17.29 (17.28-17.9) 18.21 (4.2-35.2) PSA decline 2 (100) 2 (66.7) 3 (100) 2 (66.7) 9 (81.8) ≥ 50% PSA decline 1 (50) 2 (66.7) 2 (66.7) 2 (66.7) 7 (63.6)

IMMUNONET: A multicenter, open-label, proof-of-concept phase II trial evaluating NP137 as add-on therapy in advanced/metastatic solid tumors treated with standard immunotherapies.

TPS3177 Background: PD-1/PD-L1 blockade has transformed oncology by offering durable responses in various cancers. However, many patients develop resistance, highlighting the need for novel therapeutic strategies. Epithelial-to-Mesenchymal Transition (EMT) plays a pivotal role in immune checkpoint inhibitor efficacy, with epithelial tumors exhibiting greater immunoreactivity than mesenchymal ones. NP137, a first-in-class anti-Netrin-1 monoclonal antibody, has shown in phase I study the ability to inhibit EMT, potentially overcoming resistance (Cassier et al., Nature , 2023). This phase I data demonstrated NP137’s ability to shift tumors toward an epithelial phenotype, supporting its combination with immune checkpoint inhibitor to sensitize tumors and alleviate resistance. The goal of IMMUNONET study (NCT05605496) is to evaluate NP137’s ability to re-sensitize advanced solid tumors to anti-PD-1/PD-L1 therapy. Methods: This proof-of-concept study assess NP137 (14 mg/kg, IV, Q3W) as add-on therapy to standard PD-1/PD-L1 inhibitors across three independent cohorts of patients with advanced/metastatic solid tumors of any histological types: Cohort 1 (Stable Disease [SD]): Radiological SD after ≥12 weeks of anti-PD-1/PD-L1 therapy. Cohort 2 (Primary Refractory): Radiological progressive disease (PD) and no response under anti-PD-1/PD-L1 therapy. Cohort 3 (Secondary Refractory): Radiological PD following initial response under anti-PD-1/PD-L1 therapy. Treatment continues until progression, unacceptable toxicity, or consent withdrawal. The primary endpoint is clinical activity: objective response rate (ORR)-12W for cohort 1 and progression-free rate (PFR)-12W for cohorts 2 and 3. Secondary endpoints include ORR-12W (cohorts 2 and 3), Time to Objective Response (ToR), Duration of Response (DoR) and safety for all cohorts. Evolution of EMT, Netrin-1, and receptor expression will be analysed and correlated with clinical outcomes. An adaptive 2-stage design is being used for this study (Lin and Shih, Biometrics 2004). The target levels of clinical activity are set at 20% (relevant) and 25% (high). In stage 1, 18 patients will be enrolled at 1-sided alpha of 5%. Depending on the observed success rate, additional 11 patients (if 1 or 2 successes) or 5 patients (if > 2 successes) could be recruited into stage 2. Null hypotheses will be rejected if ≥4 successes are observed in 29 [test p 0 = 0.05 vs. 0.20, 80% power] or 23 patients [test p 0 = 0.05 vs. 0.25, 90% power], respectively. Current Status: Cohort 1 has been closed due to non-feasibility. Prespecified goals for the first stage were met, stage 2 enrolment is underway. Cohort 2 has enrolled 21 patients, and cohort 3 has enrolled 19 of 23 planned evaluable patients. Clinical trial information: NCT05605496 .

Concerns about data integrity across 263 papers by one author

Comprehensive investigation of published work by authors suspected of academic misconduct can reveal further concerns. We aimed to test for data integrity concerns in papers published by an author with eight retracted articles. We investigated the integrity of all papers reporting on prospective clinical studies by this author. We assessed the feasibility of study methods, baseline characteristics, and outcomes. We plotted the author's clinical research activity over time. We conducted pairwise comparisons of text, tables, and figures to identify duplicate publications, and checked for consistency between conference abstracts, interim analyses, trial registrations, and final papers. Where indicated, we recalculated p-values from the reported summary statistics. We identified 263 papers claiming to have enrolled 74,667 participants between January 2009 and July 2022, 190 (72 %) of which reported on studies that recruited from the Assiut Women's Health Hospital in Assiut, Egypt. The number of active studies per month was greatest between 2016 and 2019, with 88 ongoing studies in May 2017. We found evidence of data integrity concerns in 130 (49 %) papers, 43 (33 %) of which contained concerns sufficient to suggest that they could not be based on data reliably collected from human participants. Our investigation finds evidence of widespread integrity concerns in the collected work of one author. We recommend that the involved journals collaborate in a formal investigation.

Forty-one Cytokine Profile and Interferon-I Score in Juvenile Dermatomyositis: A Case Series Study

Aim: To analyze a broad spectrum of cytokine in the serum of patients with JDM. Background: Juvenile dermatomyositis (JDM) is the most common subtype of idiopathic inflammatory myopathies characterized by muscle and skin involvement. The etiology of JDM is unclear. A variety of cytokines play a role in the pathogenesis of JDM. Interferons, galectin-9, CLCX10, and neopterin are the most promising biomarkers. Objective: This study describes the associations between clinical symptoms, cytokine, and interferon profiles in children with JDM. Materials and Methods: Ten patients (6 girls and 4 boys) with JDM were included in the study. The clinical symptoms, disease activity (CMAS, CAT), laboratory parameters, and treatment were assessed. Forty-one cytokines levels and IFN-I scores in the serum were measured. The levels of cytokines were compared with a group of healthy controls (n=25). Results: Significant differences were observed in 21 of 41 analyzed cytokines between JDM patients and healthy controls. Patients with active disease (n=8) have higher levels of fractalkine (p = 0.036), IFNa (p = 0.037), IFNg (p = 0.037), GRO (p = 0.037), IL-10 (p = 0.037), IL-12p40 (p = 0.037), IL-12p70 (p = 0.048), IL-17a (p = 0.048), IL-1RA (p = 0.037), IL-1a (p = 0.037), compared to patients with inactive disease (n=2). A strong positive association was found between aCAT activity and eotaxin (r=0.753, p =0.012), GRO (r=0.735, p =0.015), IP-10 (r=0.805, p =0.005), and MCP-1 (r=0.734, p =0.016). A strong negative correlation association was observed between CMAS and eotaxin (r= -0.714, p =0.020), GRO (r= -0.727, p =0.017), IL-10 (r= -0.786, p =0.007), IP-10 (r= - 0.719, p =0.019), and MCP-1 (r= -0.800, p =0.005). IFN-I scores showed a positive correlation with IFNa (r=0.790, p =0.007), GRO (r=0.736, p =0.015) and IL-1RA (r=0.930, p <0.001). Conclusion: Among the spectrum of 41 cytokines, GRO, eotaxin, IP-10, and MCP-1 have shown the strongest association with JDM activity.

Classification criteria of joint activity using joint index vector for patients with rheumatoid arthritis: An evaluation and verification.

Classification criteria of joint activity using joint index vector for patients with rheumatoid arthritis: An evaluation and verification.