Preliminary Efficacy Data Research Articles

Digital goal management training for cognitive impairment in cervical cancer survivors-a randomized comparison study.

Cognitive impairment (CI) is a common late effect after cancer treatment, for which effective interventions are lacking. Goal management training (GMT) is a validated cognitive training protocol reported to improve cognition, including executive functioning. The purpose of this study was to examine the feasibility and acceptability of digital GMT in cervical cancer survivors (CCS) experiencing CI and compare it to computerized cognitive training (CCT). Thirty-five CCS with significant subjective CI were randomized in a 1:1 ratio between digital GMT (N = 18) and CCT (N = 17). The primary endpoint was attendance, and participants attending ≥ 80% of the sessions were categorized as completers. Acceptability was evaluated post-intervention using the Client Satisfaction Questionnaire-8 (CSQ-8). Secondary outcomes included self-reported and performance-based cognitive functioning. The completion rate in both groups was 88%. Participants in both groups reported high levels of satisfaction (CSQ-8; GMT: M = 25.2, SD 3.7, range 18-31, and CCT: M = 24.6, SD 3.1, range 19-30). Exploratory analyses showed improvements in both groups over time in attention and memory as well as self-reported cognitive functioning. Digital GMT is feasible with a high level of compliance and satisfaction in CCS. Preliminary efficacy data shows promising cognitive improvement over time, and the results are comparable to CCT and warrant further investigation in a larger-scale trial. If deemed effective in a larger study, digital cognitive training, such as GMT, is a low-cost, low-staff intensive intervention that is easily implemented and available to cancer survivors experiencing CI.

CTNI-11. A PHASE 1 OPEN-LABEL STUDY OF BRAF INHIBITOR ABM-1310 IN PATIENTS (PTS) WITH RECURRENT BRAF V600-MUTATED PRIMARY CNS TUMORS

Abstract BACKGROUND ABM-1310 is a blood-brain barrier penetrant BRAF inhibitor. Here we report interim results from our phase 1 study of ABM-1310. METHODS This is a dose-escalation plus expansions trial for adult pts with BRAF V600-mutated primary CNS tumors. In the dose-escalation, ABM-1310 is given at 150 or 200 mg twice a day (bid). In the expansion, ABM-1310 150 mg bid is administered. Study objectives include patient safety, maximum tolerated dose (MTD), preliminary efficacy and pharmacokinetics (PK). Clinical trial information: NCT05892653. RESULTS By May 6, 2024, 15 pts (7 male; median age 39 years old) have been treated. In the dose escalation: 4 pts received ABM-1310 150 mg bid, and another 7-pts received ABM-1310 200 mg bid. In the expansion, all 4 pts were given ABM-1310 at 150 mg bid. Among 14 efficacy evaluable pts, 3 had partial response (PR) (including one each of glioblastoma, WHO grade 2 and 3 pleomorphic xanthoastrocytoma) and 9 pts had stable disease as their best responses. Two pts have PR response for > 8 months and continue study treatment. All pts experienced treatment-related AEs. Common AEs were asymptomatic QT prolongation (n=11) and rash (n=10). Seven pts had grade 3 QT prolongation. There was no drug-related SAE. There was no ABM-1310 related dose limiting toxicity although a few pts had study treatment interruption or dose reduction. One patient discontinued prematurely due to asymptomatic Grade 3 QT prolongation. There were no drug-related deaths. The MTD for ABM-1310 was 200 mg bid, the recommended dose was 150 mg bid. In PK assessment, ABM-1310 drug exposure vs. dosage showed a linear proportional relationship. This trial is ongoing. CONCLUSIONS ABM-1310 was generally safe and tolerated. There were no new safety signals. Preliminary efficacy data demonstrate favorable anti-cancer activity in patients with recurrent BRAF V600-mutated primary CNS tumors.

Supporting emotion regulation in children on the autism spectrum: co-developing a digital mental health application for school-based settings with community partners.

KeepCalm is a digital mental health application, co-designed with community partners, that incorporates wearable biosensing with support for teams to address challenging behaviors and emotion dysregulation in children on the autism spectrum. We followed a user-centered design framework. Before app development, we conducted design workshops, needs assessment interviews, a systematic review, and created an Expert Advisory Board. Once we had a working prototype, we recruited 73 participants to test and help improve the app across five testing cycles. Participants rated the app across testing cycles as highly acceptable, appropriate, feasible, and with good usability. Qualitative data indicated that KeepCalm helped teachers (a) be aware of students' previously unrealized triggers, especially for nonspeaking students; (b) prevent behavioral episodes; (c) communicate with parents about behaviors/strategies; and (d) equipped parents with knowledge of strategies to use at home. We learned that in order to make the app acceptable and appropriate we needed to make the app enjoyable/easy to use and to focus development on novel features that augment teachers' skills (e.g., behavioral pattern and stress detection). We also learned about the importance of maximizing feasibility, through in-person app training/support especially regarding the wearable devices, and the importance of having aides involved. Our findings have informed plans for wider-scale feasibility testing so that we may examine the determinants of implementation to inform adaptations and refinement, and gather preliminary efficacy data on KeepCalm's impact on reducing challenging behaviors and supporting emotion regulation in students on the autism spectrum.

Adapting behavioral activation for patients receiving medications for opioid use disorder in primary care: a pilot study.

Effective adjunctive therapeutic treatments for patients with opioid use disorder (OUD) on medication for OUD (MOUD) in primary care settings are needed to address high rates of mental illness and stress. Behavioral activation (BA) is a brief, evidence-based therapy that has potential to improve quality of life in people with OUD. The purpose of this pilot study was to evaluate the feasibility and acceptability of values-based BA (VBA) as an adjunct treatment for patients receiving MOUD in primary care. Participants were recruited for a single-arm pilot trial of BA in a primary care setting. VBA was adapted for people with OUD and included 4-6 sessions delivered over 12 weeks with a behavioral health consultant, either in-person or virtually. Feasibility was assessed as recruitment percent and pace and retention percent. Acceptability was assessed with the Client Satisfaction Questionnaire-8 (CSQ-8). Participants completed self-report measures of well-being, depression, substance use, and psychological processes of change at baseline, mid-intervention (6-weeks), and post-intervention (12-weeks). Participants engaged in a brief interview about their experiences at the end of the intervention. Twenty-one participants enrolled in the intervention (66.7% female, M age = 44.0 years, 19% of those invited). Participants completed an average of 5.1 BA sessions (SD = 1.6) and most (90%) were retained through 12 weeks. Participants rated the intervention as highly acceptable on the CSQ-8 (M = 30.4/32.0, SD = 1.6). In qualitative interviews, participants reported that working with the therapist and setting values-based goals were helpful, while also recommending more tailoring to patients' needs and offering the program early in MOUD treatment. Preliminary efficacy data suggest the program was associated with small to moderate improvements in life satisfaction (Cohen's d = 0.25) and positive affect (d = 0.62), whereas there were no changes in depression (d = 0.09) or negative affect (d = -0.07) in a group with low depression at baseline. VBA adapted for patients on MOUD in primary care was feasible to deliver and acceptable to participants. Minor modifications to the target population and treatment manual could increase the program's impact. Future studies will test the efficacy of the intervention in improving quality of life and OUD treatment outcomes. https://clinicaltrials.gov/study/NCT05262725, Unique ID: NCT05262725.

Emerging Targets in Non-Small Cell Lung Cancer.

Lung cancer is responsible for a high burden of disease globally. Over the last two decades, the discovery of targetable oncogenic genomic alterations has revolutionized the treatment landscape for early-stage and advanced non-small cell lung cancer (NSCLC). New molecular drivers continue to emerge as promising therapeutic targets, including KRAS non-G12C, RAF/MEK, HER3, Nectin-4, folate receptor alpha, ITGB6, and PRMT5. In this review, we summarize the emerging molecular targets with a potential clinical impact in advanced NSCLC, elaborating on their clinical characteristics and specific mechanisms and molecular pathways for which targeted treatments are currently available. Additionally, we present an aggregate of ongoing clinical trials investigating the available treatment options targeting such alterations, in addition to their current recruitment status and preliminary efficacy data. These advancements may guide further research endeavors and inform future treatment strategies to improve the management of and transform outcomes for patients with advanced NSCLC.

Remote electrical neuromodulation to treat children and adolescents with migraine in the emergency department: Arandomized double-dummy pilot trial.

Using a double-dummy pilot randomized controlled trial design, we aimed to determine the feasibility and acceptability of comparing remote electrical neuromodulation (REN) to typical care intravenous pharmacologic interventions for the treatment of children and adolescents visiting the emergency department (ED) with migraine, and to compare parallel-group versus crossover trial designs. There are limited data to guide the management of migraine in the ED. Children and adolescents are interested in neuromodulation, and specifically REN, for treatment in this setting, but there are no existing data on this approach. We employed a double-dummy, double-blind, pilot randomized controlled trial that tested two designs in two phases: a parallel-group design and a crossover design (ClinicalTrials.gov identifier: NCT05102591). The intervention arms consisted of: (i) active REN stimulation with matched normal saline placebo intravenously, and (ii) matched sham REN stimulation, intravenous metoclopramide (0.15 mg/kg, maximum 10 mg), and intravenous ketorolac (0.5 mg/kg, maximum 30 mg). Youth aged 8.0-<18.0 years visiting a Canadian tertiary care pediatric ED with migraine attacks as per criteria B-E of the International Classification of Headache Disorders third edition were eligible. Primary outcomes were focused on trial feasibility and acceptability, and preliminary efficacy and safety data were also collected. A total of 34% (22/65) of those who screened eligible were enrolled. Three participants (14%) withdrew prior to receiving any study interventions. In all, 10 participants were allocated to typical care, and nine to REN. All treated participants (19/19) completed all assessments. Recruitment was higher during the parallel-group phase: 1.1 participants/month versus 0.6 participants/month, and 36% (17/47) versus 28% (five of 18) of screened eligible were enrolled in the parallel-group and crossover phases, respectively. Participants reported positive impressions of REN use in the ED, e.g., higher mean (standard deviation [SD]) levels of interest in using REN only at 3.7 (1.0) versus 2.8 (1.0) in using intravenous interventions only for a future ED visit. Participants and clinical staff reported overall positive impressions regarding the study protocol. Employing an 11-point pain numerical rating scale, the mean (SD) reduction in pain severity score was 2.1 (1.3) and 2.9 (2.9) from baseline to 1 h, and 2.4 (1.6) and 4.0 (3.5) from baseline to 2 h for REN and intravenous interventions, respectively. One participant in the typical care group and none in the REN group experienced adverse events. We demonstrated the feasibility and acceptability of our trial protocol and of using REN to treat youth presenting to the ED with migraine. The parallel-group design generated a higher recruitment rate than the crossover design. Our preliminary efficacy and safety data suggest that REN could be non-inferior to typical care, but we were not powered for these outcomes. Further research on REN's use in the ED setting is warranted.

Preliminary efficacy data of a mobile app to address dysfunctional beliefs associated with eating disorders in adults

A module has recently been developed within a mobile application (app) with the purpose of addressing dysfunctional beliefs associated with eating disorders (ED). The aim was to conduct a preliminary efficacy study by analyzing changes after use of the app in a general adult population. A quasi-experimental design was used in which 86 people completed a baseline assessment, and of them, 32 used the app daily for 3 minutes over a period of 15 days and completed the post-treatment assessment. Results before and after use of the app showed a decrease in mean scores for dysfunctional beliefs about perfectionism associated with physical appearance, vulnerability to weight gain, and the importance of thought control, as well as an increase in self-esteem. No significant reduction in eating symptomatology or depressive symptoms was observed. The results suggest that the app could be useful in reducing dysfunctional beliefs associated with ED.

ABCL-440 Preliminary Safety and Efficacy Data of Combination Polatuzumab Vedotin Rituximab, Cyclophosphamide Adriamycin, Prednisone (Pola-R-CHP) in Patients With Diffuse Large B-Cell Lymphoma (DLBCL) in the Standard-of-Care Setting: A Single-Center Experience

ABCL-440 Preliminary Safety and Efficacy Data of Combination Polatuzumab Vedotin Rituximab, Cyclophosphamide Adriamycin, Prednisone (Pola-R-CHP) in Patients With Diffuse Large B-Cell Lymphoma (DLBCL) in the Standard-of-Care Setting: A Single-Center Experience

Preliminary Safety and Efficacy Data of Combination Polatuzumab Vedotin, Rituximab, Cyclophosphamide, Adriamycin, Prednisone (Pola-R-CHP) in Patients With Diffuse Large B-Cell Lymphoma (DLBCL) in the Standard-of-Care Setting: A Single-Center Experience

Preliminary Safety and Efficacy Data of Combination Polatuzumab Vedotin, Rituximab, Cyclophosphamide, Adriamycin, Prednisone (Pola-R-CHP) in Patients With Diffuse Large B-Cell Lymphoma (DLBCL) in the Standard-of-Care Setting: A Single-Center Experience

Exercise Therapy to Reduce Anxiety (ExTRA) in mid-life and later-life adults: study protocol

BackgroundAnxiety in mid-life and later-life is highly prevalent and causes significant distress and disability. There is increasing evidence supporting the potential effectiveness of exercise interventions for reducing clinically significant anxiety. Self-directed online interventions can be scalable and thus reach more people. AimsThe Exercise Therapy to Reduce Anxiety (ExTRA) project aims to assess the feasibility and acceptability of an 8-week web-based exercise intervention with the innovation of being self-directed, and facilitated by wearable activity monitors (WAMs) and tailored behaviour change strategies to reduce anxiety in mid-life and later-life adults with clinically significant anxiety. MethodsExTRA will recruit 20-30 community dwelling adults aged 40-79 years with clinically significant anxiety. The self-directed 8-week web-based exercise intervention includes information and strategies to support participants to meet Australian national physical activity guidelines. The intervention is adapted from previous face-to-face trials and includes strategies to support participants living with anxiety. Feasibility will be measured by screening and retention rates. Acceptability will be measured by website usage data, online outcome measure completion, and an evaluation questionnaire. Other outcome measures include anxiety measured by the Depression Anxiety Stress Scales, and physical activity measured by the Global Physical Activity Questionnaire and a WAM. ResultsFindings will demonstrate whether this intervention is feasible and acceptable, and provide preliminary efficacy data. ConclusionsThe findings of this pragmatic real-world study will be valuable in guiding development of future trials, including randomised controlled trials of scalable and accessible exercise interventions to reduce the distress, disability and cost of anxiety.

Repetitive transcranial magnetic stimulation to treat chronic tinnitus: a feasibility study

ABSTRACT This study aimed to evaluate the feasibility, safety and preliminary efficacy of high-frequency repetitive transcranial magnetic stimulation for treating chronic subjective tinnitus. Eleven adults (8 males; age: 56.70 ± 11.42 years, tinnitus duration: 12.43 ± 7.43 years) were recruited to participate in a pre-registered study. Six treatments were provided over two weeks. Feasibility was determined against pre-specified criteria addressing recruitment, adherence (protocol, 2-week follow-up, 4-week follow-up), and perceived usefulness, helpfulness and acceptability. Adverse events were recorded and preliminary efficacy was assessed using the Tinnitus Handicap Inventory. Five out of seven feasibility criteria were met and no serious adverse events occurred. One participant withdrew from the study due to stimulation being uncomfortable. Preliminary efficacy data indicated a significant effect of Time on tinnitus (p < 0.001). Compared to baseline, tinnitus reduced at mid-treatment (t (9) = −3.47, p = 0.028) and 4-weeks post treatment (t (9) = −3.62, p = 0.024). A repetitive transcranial magnetic stimulation protocol to manage chronic subjective tinnitus appears feasible, safe, and may have preliminary evidence of effectiveness. The recommendation is to proceed to trial with minor adjustments to gain further insight into the patient experience.

VAC-Stent in the Treatment of Post-Esophagectomy Anastomotic Leaks: A New "Kid on the Block" Who Marries the Best of Old Techniques-A Review.

Esophagectomy, while a pivotal treatment for esophageal cancer, is not without adverse events. Among these, anastomotic leak (AL) is the most feared complication, threatening patient lives and incurring significant healthcare costs. The management of AL is complex and lacks standardization. Given the high morbidity and mortality rates associated with redo-surgery, which poses risks for already fragile patients, various endoscopic treatments have been developed over time. Self-expandable metallic stents (SEMSs) were the most widely used treatment until the early 2000s. The mechanism of action of SEMSs includes covering the wall defect, protecting it from secretions, and promoting healing. In 2010, endoscopic vacuum therapy (EVT) emerged as a viable alternative for treating ALs, quickly gaining acceptance in clinical practice. EVT involves placing a dedicated sponge under negative pressure inside or adjacent to the wall defect, aiming to clear the leak and promote granulation tissue formation. More recently, the VAC-Stent entered the scenario of endoscopic treatment of post-esophagectomy ALs. This device combines a fully covered SEMS with an integrated EVT sponge, blending the ability of SEMSs to exclude defects and maintain the patency of the esophageal lumen with the capacity of EVT to aspirate secretions and promote the formation of granulation tissue. Although the literature on this new device is not extensive, early results from the application of VAC-Stent have shown promising outcomes. This review aims to synthesize the preliminary efficacy and safety data on the device, thoroughly analyze its advantages over traditional techniques and disadvantages, explore areas for improvement, and propose future directions.

Results from phase 1a/1b analyses of TTX-080, a first in class HLA-G antagonist, in combination with cetuximab in patients (pts) with metastatic colorectal cancer and head and neck squamous cell carcinoma.

2524 Background: TTX-080 is an IgG1 monoclonal antibody targeting HLA-G. This Ph1a/1b study evaluated the safety and preliminary efficacy of TTX-080 alone or in combination with cetuximab (Cetx) or pembrolizumab (Pem) in multiple solid tumor cohorts (NCT04485013). Herein, we report the safety from the Ph1a and preliminary efficacy data from Ph1b cohorts evaluating TTX-080 + Cetx in pts with head and neck squamous cell carcinoma (HNSCC) and WT RAS/BRAF, HER2-Neg metastatic colorectal cancer (mCRC) tumors. Methods: In Ph1a, pts with advanced solid tumors received single agent TTX-080 at escalating doses in a 3+3 design from 0.2-20 mg/kg IV Q3W. In the mCRC and HNSCC arms of Ph1b, pts were treated with RP2D of TTX-080 + Cetx. Patients were followed for safety and anti-tumor activity. Biopsies and blood samples were collected for biomarker analyses. Results: As of 08-Dec-23, 202 pts have received TTX-080 alone or in combination (40 pts in Ph1a and 162 pts in Ph1b). In Ph1a TTX-080 monotherapy dose-escalation, MTD was not reached and no DLT was reported. TTX-080 treatment-related AE (TRAE) of arthralgia, fatigue, and decreased appetite were seen in at least 5% of pts. R2PD for TTX-080 was determined to be 20 mg/kg IV Q3W. In Ph1b of TTX-080 alone or in combination (Cetx or Pem), the most common TRAEs in at least 5% of subjects were fatigue, nausea, anemia, diarrhea, AST increase, headache, vomiting and pruritis. Preliminary efficacy data from the select Ph1b TTX-080 + Cetx subset of pts are shown in Table. Significant HLA-G related immune cell changes in the peripheral blood and in tumors will be presented. Conclusions: TTX-080 is well tolerated alone and in combination with Cetx. TTX-080 + Cetx demonstrates promising activity in pts with HPV-Neg HNSCC and WT RAS/BRAF/Her2-Neg mCRC as manifested by the responses and PFS. These early findings warrant further investigation of TTX-080 + Cetx in a randomized controlled study against standard of care in mCRC and HNSCC. Clinical trial information: NCT04485013 . [Table: see text]

Outstanding safety and efficacy data of IMC002, an autologous CLDN18.2-targeting CAR-T, in CLDN18.2+ advanced solid tumors.

e16012 Background: Claudin 18.2 (CLDN18.2) is a promising therapeutic target for advanced solid tumors with CLDN18.2 expression. IMC002 is an autologous CLDN18.2-targeting CAR-T cell directed by a CLDN18.2-specific VHH, the specificity of which was confirmed by a membrane proteome array assay. Preclinical studies showed that IMC002 exhibited high tumor specificity, anti-tumor efficacy, and excellent safety profile in both cell and animal models. Methods: This is an open label first in human Phase 1 dose escalation study to evaluate the safety and efficacy of IMC002 in advanced solid tumors with CLDN18.2 expression which is defined as CLDN18.2 expression of ≥1+ membrane staining intensity in ≥10% tumor cells. Accelerated titration followed by Bayesian optimal interval design was adopted with a total of 4 dose levels planned at 1, 3, 5 and 7 million (mil) CAR-T cells/kg respectively. All patients (pts) were given a single dose of IMC002 infusion after lymphodepletion chemotherapy. Dose limiting toxicity (DLT) was evaluated during the 28-day period after IMC002 infusion. Safety, anti-tumor activity, pharmacokinetics and pharmacodynamics were explored in this study. Here, we present preliminary safety and efficacy data for the pts dosed with up to 3 mil CAR-T cells/kg. Results: As of January 17, 2024, 3 advanced unresectable gastric cancer pts received IMC002 infusion, 1 patient at 1 mil CAR-T cells/kg and 2 pts at 3 mil CAR-T cells/kg. No DLT or SAE was reported. Manageable CRS (grade 1) was reported in all 3 pts. Other adverse events related to cell therapy included grade 1-2 lipase increase (3/3), diarrhea (1/3), pruritis (1/3) and γ-GGT increase (1/3). All adverse events recovered quickly. Preliminary efficacy data showed that best overall response of the 3 pts was all stable disease as evaluated by RECIST 1.1. The two pts at the dose level of 3 mil CAR-T cells/kg underwent successful radical surgery at week (W) 11 and 44 after IMC002 infusion respectively. Pathological complete response (pCR) was achieved in the patient with surgery at W44. Distinct CAR-T cell expansion in peripheral blood was observed in all 3 pts, with the peak number of CAR+ cells reaching on day 7-11 in the peripheral blood after the infusion. Moreover, CAR-T cell infiltration was detected in the W11 and W44 surgical samples. Significant elevations of serum levels of IFN-γ, IL-10, IP-10, IL-2 and IL-6 were observed in the 3 pts. The trial is ongoing. Conclusions: IMC002 showed a favorable safety profile, encouraging anti-tumor activities with observed pCR and persistent expansion in the tumor tissue at the low dosage levels in pts with advanced CLDN18.2+ gastric cancer. In addition, our trial has successfully provided a surgical treatment opportunity after CAR-T therapy downstaging of unresectable gastric cancers. Clinical trial information: NCT05472857 .

A phase 1 study evaluating the safety, pharmacokinetics, and efficacy of fadraciclib, an oral CDK2/9 inhibitor, in patients with advanced solid tumors and lymphoma.

3125 Background: Fadraciclib (formerly CYC065)is a highly selective inhibitor of CDK2 (IC50= 5 nM) and CDK9 (IC50=26 nM) causing mitotic catastrophe and apoptotic death of cancer cells at sub-micromolar concentrations. In a previous Phase 1 study of intravenous fadraciclib monotherapy, a heavily pretreated endometrial cancer patient with CDNK2A, CDKN2B and PRMT5 loss achieved confirmed CR. This is the first study to evaluate oral fadraciclib monotherapy. Methods: A global Phase 1/2, open-label, dose-escalation study in subjects with advanced solid tumors or lymphoma (NCT04983810). The Phase 1 portion is exploring both schedule and dose of oral fadraciclib monotherapy in 28-day cycles to identify MTD and/or RP2D using a standard 3+3 design. Results: As of January 31, 2024, 45 subjects have received fadraciclib at 8 dose levels (DL1-6a: 50-150 mg, bid given 3-5 days per week for 3-4 out of 4 weeks or DL6b: 125 mg, daily for 4/4 weeks). Heavily pretreated patients with breast, colorectal, gynecological cancers, and T cell lymphoma with ECOG PS 0:1 (9:36) were enrolled. Fadraciclib was well tolerated at dose levels 1 to 5 (up to 100 mg bid). Adverse events reported were nausea (n=31), vomiting (n=23), thrombocytopenia (n=6). Grade 3 DLT of hyperglycemia (1/2 DL6 and 2/6 DL6a) and nausea (1/2 DL6) was observed at doses above 125mg bid M-F, 4/4 weeks. Hyperglycemia was controlled after dose interruption and blood glucose levels returned to normal range after treatment. Preliminary PK analysis suggests dose dependent exposure. At DL5 and above, plasma concentration was above target concentration from CDK2 and CDK9 target engagement studies. Preliminary PD analysis of treated patient samples showed suppression of expression in multiple target genes, including MYC, MCL1, CCNE/cyclin E, CDKN2A, CDKN2B, and PRMT5. Preliminary efficacy data are available for 31 evaluable patients. Two PRs after the first cycle were observed in one patient with CTCL and one with angioimmunoblastic T-Cell Lymphoma (AITL). Twenty patients showed SD. Tumor size reduction was observed in 10 patients. A squamous NSCLC patient harboring a CDK2NB loss of function mutation and prior chemo- and immunotherapy achieved reduction of 22% in the sum of all target lesions after 1 cycle of treatment. Conclusions: Based on data from the CYC065-101 study, fadraciclib appears well tolerated from DL1 to 5. The MTD for the bid dosing schedule is 100mg bid, M-F, 4/4 weeks. The trial is ongoing with evaluation of a daily dosing schedule. Clinical trial information: NCT04983810 .

Preliminary safety and efficacy of oral azacitidine (Oral-AZA) in patients (pts) with low-/Intermediate (Int)-risk myelodysplastic syndromes (MDS): Phase 2 results from the ASTREON trial.

6509 Background: There is an unmet need for new treatment (tx) options in lower-risk MDS (LR-MDS) to address cytopenias and prevent progression to higher-risk MDS and acute myeloid leukemia. Here, we report safety and preliminary efficacy data from phase 2 of the ASTREON study, which evaluated 14-day Oral-AZA regimens in pts with Low-/Int-risk MDS. Methods: ASTREON is a phase 2/3, multicenter study evaluating safety and efficacy of Oral-AZA plus best supportive care (BSC) in pts with Low-/Int-risk MDS (NCT05469737). Phase 2 is an open-label, dose optimization study to determine the recommended phase 3 Oral-AZA dose. Eligible pts (≥ 18 years of age with Revised International Prognostic Scoring System [IPSS-R] Low-/Int-risk MDS and ≥ 1 cytopenia) were randomized 1:1 to receive Oral-AZA 200 mg or 300 mg QD for 14 d per 28-d cycle plus BSC. Primary endpoints are rates of adverse events (AEs) and complete remission (CR) within 6 cycles per International Working Group (IWG) 2006 criteria. Secondary endpoints include achievement of overall response (OR) (including CR, partial remission, marrow CR, hematologic improvement-erythroid response [HI-E], HI-platelet response, and HI-neutrophil response per IWG 2006 criteria); best OR; and OR duration. HI rates within 6 cycles were calculated by investigator assessment per IWG 2006 criteria for pts who received ≥ 75% of the cycle 1 dose and had ≥ 1 post-baseline (BL) efficacy assessment (modified intent-to-treat [mITT] population). Results: As of December 4, 2023, 47 pts were randomized and received ≥ 1 Oral-AZA dose (200 mg, n = 24; 300 mg, n = 23); 6 and 5 pts discontinued tx in the 200 mg and 300 mg arms. The median (range) tx durations were 24.1 (12.1–34.1) and 24.7 (7.7–39.1) wk for the 200 mg and 300 mg arms, respectively. IPSS-R scores and RBC transfusion burden at BL were balanced between tx arms. Most pts (42/47 [89.4%]) had prior MDS tx, including but not limited to erythropoiesis-stimulating agents, lenalidomide, luspatercept, and imetelstat. AE rates were similar between arms: 11/24 (45.8%) vs 12/23 (52.2%) pts in the 200 mg vs 300 mg arms reported ≥ 1 tx-related grade 3 or 4 tx-emergent AE. The most common tx-related AEs in both arms were hematologic and gastrointestinal. Tx-related serious AEs occurred in 1/24 and 3/23 pts in the 200 mg and 300 mg arms, respectively. One death occurred in the 300 mg arm and was considered tx-related. In the mITT population, 8/22 and 7/21 pts achieved any HI in the 200 mg and 300 mg arms, respectively. Six pts in each dose group achieved HI-E. Among mITT pts with anemia at BL, 6/19 (31.6%) pts in the 200 mg and 5/18 (27.8%) pts in the 300 mg arm achieved HI-E. Updated results will be presented. Conclusions: The safety of Oral-AZA 200 mg and 300 mg was consistent with the known Oral-AZA safety profile. Preliminary efficacy data support continued evaluation of Oral-AZA in LR-MDS. Clinical trial information: NCT05469737 .

KPG-121, a novel cereblon modulator, in patients with metastatic castration resistant prostate cancer: Results of a phase I multiple ascending dose study.

e17054 Background: New treatments are needed for prostate cancer patients (pts) reaching the metastatic castration-resistant (mCRPC) stage of the disease. KPG-121 is a novel lenalidomide analogue that binds to CRL4-Cereblon (CRBN) with stronger interaction with CRBN, enhanced immunomodulatory activity, and greater anti-proliferative/anti-angiogenic properties when compared to lenalidomide. KPG-121 demonstrated synergy when combined with abiraterone, enzalutamide, apalutamide, and darolutamide in vitro and in vivo in preclinical studies. The KPG-121 first-in-human Phase 1 study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of KPG-121 plus enzalutamide, abiraterone, or apalutamide in mCRPC pts. Methods: This multicenter, open label, standard 3+3 dose ascending study was conducted in the United States. Eligible male adult pts with CRPC receiving stable doses of enzalutamide or abiraterone were given oral KPG-121 (1.5 mg, 2.5 mg, 5 mg, or 10 mg) once daily in 28-day (d) treatment cycles (21-d on and 7-d off or 10-d on and 4-d off 2 times). The primary endpoint was safety including treatment-emergent adverse events (TEAEs), dose-limiting toxicity, and maximum tolerated dose. Results: A total of 16 adult CRPC pts were enrolled to receive KPG-121. The mean age was 70.4 yrs with 12 pts (75%) being White, 2 pts (12.5%) being Black/African American, and 2 pts (12.5%) being of other races. All pts had mCRPC and received prior stable treatment of abiraterone or enzalutamide. A total of 12 pts (75.0%) had 88 TEAEs that were assessed by the Investigator as related to the study drug. The most commonly reported (≥ 2 pts) related AEs were neutropenia (9 [56.3%]), WBC count decreased (7 [43.8%]), platelet count decreased (6 [37.5%]), anemia (4 [25.0%]), thrombocytopenia (3 [18.8%]), lymphocyte count decreased (2 [12.5%]), electrocardiogram QT prolonged (2 [12.5%]), and muscle spasm (2 [12.5%]). A total of 5 pts (31.3%) who discontinued treatment due to TEAEs (2 in 2.5 mg, 1 in 5 mg, and 2 in 10 mg). One pt died due to COVID-19 assessed by the Investigator as not related to the study drug. Eight Serious Adverse Events (SAEs) were reported in 5 pts (31.3%) of which 1 SAE (neutropenia) was assessed by the Investigator as definitely related to the study drug. Of the 8 pts with RECIST evaluable disease, 3 pts (37.5%) had Partial Response and 3 pts (37.5%) had Stable Disease. Overall, Objective Response Rate and Disease Control Rate was 37.5% (3/8 pts) and 75.0% (6/8 pts), respectively. The PK evaluation of KPG-121 demonstrated dose-proportionality among the cohorts with t1/2 ranging from 2.66 to 2.83 hrs. Conclusions: KPG-121 1.5 mg and 2.5 mg were generally well tolerated and showed meaningful clinical activity based on the preliminary efficacy data in mCRPC pts. Further evaluation of KPG-121 plus abiraterone, enzalutamide or other new hormone therapy is warranted. Clinical trial information: NCT03569280 .

Extended follow-up results beyond 2.5 years from the pivotal NHL-1 EPCORE trial: Subcutaneous epcoritamab monotherapy in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL).

7039 Background: Epcoritamab induces high complete response (CR) and MRD-negativity rates with manageable safety in patients (pts) with challenging-to-treat R/R LBCL as shown in the pivotal phase 2 study (NCT03625037). Here we present long-term data, an additional efficacy analysis from the expansion cohort, and data from the cycle 1 optimization (C1 OPT) part. Methods: Adults with R/R CD20+ LBCL and ≥2 prior systemic therapies received subcutaneous epcoritamab (2 step-up doses, then 48-mg full doses per label) in 28-d Cs. The primary endpoint of the expansion cohort was IRC-assessed overall response rate (ORR). A subgroup analysis evaluated efficacy outcomes by investigator assessment in complete responders with longer follow-up. C1 OPT assessed CRS incidence and severity with hydration and dexamethasone prophylaxis in C1; hospitalization was not required. Results: Overall, 157 LBCL pts were treated in the expansion cohort; 148 had diffuse LBCL (DLBCL) or high-grade B-cell lymphoma (HGBCL). Baseline characteristics were previously reported. As of April 21, 2023, the median follow-up for LBCL was 25.1 mo (range, 0.3+ to 32.7); ORR/CR rates were 63/40% (LBCL) and 61/39% (DLBCL + HGBCL) by IRC. In a subgroup analysis of complete responders with longer follow-up (median, 31.3 mo), median duration of CR was not reached; efficacy outcomes for complete responders are shown in the Table. Long-term safety was consistent with previous reports. CRS remained the most common AE (51% all grade [G]; 32% G1, 16% G2, 3% G3). In C1 OPT, 36 pts were evaluable for CRS with a median follow-up of 1.7 mo. Overall CRS incidence was 22% and events were low grade (14% G1, 8% G2), mostly occurring following the first full dose. All CRS events resolved; none led to treatment discontinuation. Among 60 total pts in C1 OPT, 1 pt experienced ICANS (G1). Additionally, IL-6 levels were lower with C1 OPT and consistent with the observed lower rate and severity of CRS. Preliminary C1 OPT efficacy data were comparable to data observed in the expansion cohort. Conclusions: Epcoritamab monotherapy continues to demonstrate deep and durable responses, with most complete responders remaining in CR and without new safety signals in these long-term follow-up analyses. Implementing simple measures of adequate hydration and prophylactic dexamethasone in C1 markedly reduced the overall incidence and severity of CRS with no impact on efficacy. The continued benefit beyond 2.5 y underlines the long-term efficacy and value of epcoritamab in R/R LBCL. Clinical trial information: NCT03625037 . [Table: see text]

Preliminary safety, efficacy and molecular characterization of emavusertib (CA-4948) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) with FLT3 mutation (FLT3m).

6539 Background: AML is a heterogenous disease and exhibits a dynamic mutational landscape as the disease progresses. Internal tandem duplication (ITD) of FLT3 is considered an acquired late-event mutation and is associated with a poor prognosis in AML. Emavusertib is a potent oral inhibitor of both IRAK4 and FLT3, conferring potential dual efficacy advantages compared to other IRAK4 or FLT3 inhibitors as single agents. IRAK4 is upregulated during anti-FLT3- or other cytotoxic therapies, which drives a resistance pathway of early relapse and progression. Methods: The safety, clinical activity, and potential biomarkers of emavusertib in R/R AML and higher-risk myelodysplastic syndrome are being investigated in the ongoing open-label, Phase 1/2a TakeAim Leukemia trial (NCT04278768). Next generation sequencing (NGS) of 68 genes was performed on genomic DNA from bone marrow or peripheral blood mononuclear cells at baseline and on treatment. Here, we present preliminary safety, efficacy data and molecular characterization in a subset of enrolled AML patients who carried FLT3m at baseline and were treated with emavusertib monotherapy. Results: In this study, we treated 11 R/R AML patients with FLT3m at dose levels of 200-400 mg BID. The median number of prior anti-cancer therapies was 2 (range 1-6). 8 of 11 patients had prior exposure to FLT3 inhibitors. Treatment-related adverse events (TRAEs) Grade ≥ 3 were reported in 2 of 11 (18%) patients. All responders were dosed at the Recommended Phase 2 Dose (RP2D) of 300 mg BID and with &lt; 3 lines of prior therapy. In addition, responders demonstrated more than 90% bone marrow blast reduction compared to baseline. The most common co-mutations in this subset of patients included RUNX1, NRAS, and TET2. Emavusertib treatment significantly decreased the variant allele frequency of these mutations. FLT3-ITD levels were decreased or became undetectable in responders. Additional corelative analysis between bone marrow blast counts and mutation status indicates that AML patients with FLT3m demonstrated increased bone marrow blast reductions (P≤0.05) on emavusertib treatment, when compared to FLT3 WT AML patients. Conclusions: Emavusertib has a favorable safety and tolerability profile in pretreated AML patients with FLT3m and demonstrated monotherapy anti-cancer activity in patients with FLT3m, including patients who have progressed on prior FLT3 inhibitors. Mutational profiles are suggestive of disease-modifying activity of emavusertib. We will present updated safety and efficacy data, including data for patients who proceeded to stem cell transplant. Enrollment in this ongoing trial is continuing at RP2D in patients with &lt; 3 lines of prior anti-cancer therapies. Clinical trial information: NCT04278768 .

Phase I/II first-in-human study to evaluate the safety and efficacy of tissue factor-ADC MRG004A in patients with solid tumors.

3002 Background: Tissue factor (TF) overexpression is associated with thrombosis, metastasis and poor prognosis in solid tumors, including cervical and pancreatic cancer. MRG004A is a novel anti-TF monoclonal antibody conjugated (ADC) to MMAE payload (drug-to-antibody ratio: 3.8), utilizing Glycoconnect site-specific conjugation technology. Herein, we present the preliminary safety and efficacy data from phase I/II MRG004A-001. Methods: This is an interim report (Data cutoff: Dec 15, 2023) of first-in-human, dose-escalation and expansion study ongoing in the USA and China. Pts with ECOG 0-1 with unresectable/metastatic solid tumor with measurable disease per RECIST v1.1 that progressed on prior systemic therapy, received MRG004A monotherapy Q3W intravenously. The primary objectives were to assess the safety, activity, maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D). Baseline tissue was evaluated for the association of TF expression with objective response rate (ORR) and disease control rate (DCR). Results: Sixty-three pts were enrolled with 43 in dose-escalation phase (8 dose levels [0.3-2.6mg/kg]) and 20 in dose-expansion phase (15 at 2.0mg/kg and 5 at 2.4mg/kg). Median age 58 (38-75). ECOG0: 8 (13%) pts. Female: 37 (59%) pts. Median 3 prior lines of therapy: 3 (1-10). MTD was not reached. Sixteen baseline samples were evaluated for overall % membrane positivity by immunohistochemistry. Nineteen were pancreatic cancer (PC) and 68% (13/19) had TF ≥50% and 2 or 3 (+). Five received dose &lt;2 mg/kg Q3W. Significant anti-tumor activity of MRG004A was observed in pts with PC. Among 12 evaluable pts with PC in the 2.0mg/kg cohort, who have received median 3 lines of prior therapy, there were 4 PR and 6 SD. ORR was 33.3% (4/12) and DCR was 83.3% (10/12). Among them, 5 pts with PC of TF expression ≥50% and 3+ intensity and ≤2 prior lines of therapy received MRG004A at 2mg/kg. 4 of 5 TF-overexpressed PC achieved PR and 1 SD. Also, MRG004A showed efficacy in other cancers. In 4 pts with heavily-treated triple-negative breast cancer (TNBC), ORR and DCR were 25% (1/4) and 50% (2/4), respectively. In 2 pts with cervical cancer with four prior therapy lines, 1 PR and 1 SD. Common treatment-related adverse events (TRAE) of any grade include conjunctivitis (27%), anemia (17%), and hypoalbuminemia (13%) and 7.9% (5/63) pts had serious adverse events. One pt with TNBC treated at 1.8mg/kg experienced G3 Steven Johnson Syndrome, a dose-limiting toxicity (DLT), but resolved. No other DLT was observed and dose expansion and matured outcome evaluation is ongoing. Conclusions: MRG004A demonstrated a manageable toxicity and a striking antitumor activity across multiple tumor types with high TF expression in heavily pretreated setting, including pancreatic cancers. These encouraging findings warrant further evaluation of MRG004A, particularly in the context of TF-overexpressed solid tumors. Clinical trial information: NCT03941574 .