Abstract: Despite a recent increase in therapeutic options, patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) eventually require novel therapies. We conducted a phase 1 trial of blinatumomab and lenalidomide in R/R B-NHL. Three dose levels representing 2 schedules were explored. The primary end points were adverse events (AEs) and determining the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). Thirty-five patients were enrolled, and 34 patients initiated treatment with a median number of prior regimens of 3 (range, 2-8). There were no dose-limiting toxicities (DLTs) in the first 2 dose levels. Dose level 3, 20 mg of lenalidomide daily on days 1 to 21 and days 29 to 49 of a 56-day induction cycle plus blinatumomab 9 μg/d continuous IV infusion (CIVI) on days 1 to 7, 28 μg/d CIVI on days 8 to 14, and 112 μg/d CIVI on days 15 to 56 was determined to be the MTD/RP2D. The most common grade ≥2 AE was neurotoxicity in 11 of 34 patients (32%), with 4 of 16 patients (25%) at the RP2D. At the RP2D, there was 1 DLT, a patient with grade 2 tremor and word-finding difficulty. For all patients completing induction, the overall response rate was 80% (95% confidence interval, 56-94) with a complete response rate of 70%, and 8 of 34 patients (24%) had durable remissions lasting >2 years. GranB+ CD56bright CD16dim CD11b+ natural killer cells and memory regulatory T cells in the peripheral blood at baseline were predictive of response. Concomitant administration of lenalidomide appeared to reduce blinatumomab-mediated T-cell exhaustion. In conclusion, encouraging activity was seen with blinatumomab and lenalidomide in heavily pretreated R/R B-NHL (NCI Protocol no. 9924).

BACKGROUND:The prognosis for patients with unresectable or metastatic soft tissue sarcomas remains poor. Evidence shows that a combination of antiangiogenic agents and chemotherapy inhibit tumour growth. We aimed to investigate the dual targeting of VEGF and MET pathways with cabozantinib and temozolomide in patients with unresectable or metastatic leiomyosarcoma and other soft tissue sarcomas. METHODS:This multicentre, single-arm, lead-in phase 2 trial was conducted at five academic Sarcoma Centers of Excellence of the Midwest Sarcoma Trials Partnership in the USA. Eligible patients were aged 18 years or older, had histologically-confirmed unresectable or metastatic uterine and non-uterine leiomyosarcoma (cohort 1) and other soft tissue sarcomas (cohort 2; exploratory), an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, up to five previous chemotherapy regimens, adequate organ and bone marrow function, and measurable disease as per Response Evaluation Criteria in Solid Tumors (version 1.1). Patients received oral cabozantinib 40 mg (as a starting dose) once per day and temozolomide 150 mg/m2 on days 1-5 of a 28-day cycle for cycle one. Starting from cycle two, temozolomide was escalated to 200 mg/m2 on days 1-5 of each cycle, if the absolute neutrophil count was more than 1·5 × 109/L and platelet count was more than 100·0 × 109/L, and treatment continued until disease progression or unacceptable drug-related adverse events. The primary endpoint in cohort 1 was progression-free survival at 12 weeks, assessed in the intention-to-treat population (defined as all enrolled patients). This study is registered with ClinicalTrials.gov, NCT04200443 (completed accrual). FINDINGS:Between Jan 17, 2020, and Feb 6, 2023, 96 patients were assessed for eligibility, 24 were ineligible, and 72 were enrolled. The median age at enrolment was 59 years (IQR 52-66) in cohort 1 (n=42) and 63 years (50-69) in cohort 2 (n=30), with a median follow-up of 18·0 months (17·5-20·7). 42 (58%) of 72 patients were female and 30 (42%) were male. In cohort 1, progression-free survival at 12 weeks was reached by 31 (74%) of 42 patients who were still receiving cabozantinib and temozolomide. The Kaplan-Meier estimate of progression-free survival was higher due to censoring and not requiring patients to be receiving treatment at 12 weeks (79·4% [95% CI 68·6-86·8]). 20 (48%) patients in cohort 1 and 23 (77%) in cohort 2 had died due to disease progression at the end of the study. 71 (99%) of 72 patients had grade 1 or higher treatment-related adverse events. The most common grade 3-4 adverse events attributed to either one or both drugs were platelet count decrease (22 [30%]), neutrophil count decrease (13 [18%]), hypertension (seven [10%]), and diarrhoea (six [8%]). There were no treatment-related deaths. INTERPRETATION:Cabozantinib with temozolomide showed a meaningful clinical benefit and could potentially be a viable treatment option for patients with unresectable or metastatic leiomyosarcoma. Treatment was tolerable and did not reveal any new safety signals. FUNDING:Exelixis.

Tumor heterogeneity and evolution constrain NSCLC immunotherapy, leading to variable and often short-lived responses. This commentary discusses the ARPA-H ADAPT program and IMMUNO-BIOMAP trial, which longitudinally profile tumors and the microenvironment to identify resistance mechanisms in real time and enable adaptive, biomarker-guided, personalized treatment strategies.

Background: We have utilized 64Cu-DOTA-Trastuzumab-PET to image patients with advanced HER2+ breast cancer. In our experience, uptake on 64Cu-DOTA-Trastuzumab-PET correlated with the qualitative assessment of HER2 by IHC. In women treated with the antibody-drug conjugate (ADC), ado-Trastuzumab emtansine (TDM1), we identified a threshold level of 64Cu-DOTA-Trastuzumab-PET uptake that predicted for lack of response to TDM1. The ADC, Trastuzumab-deruxtecan (TDXd), has demonstrated activity in patients with metastatic HER2 positive breast cancer with brain metastases. The DESTINY 04 trial included patients with HER2 1+ and 2+ disease and demonstrated superior survival compared to standard of care. Only 5% of patients enrolled had CNS metastases making efficacy of TDXd difficult to assess. As it is not always feasible to biopsy brain metastases to determine tumor markers, we initiated a pilot study to determine if functional imaging could predict response or lack of response to TDXd in patients with HER2 low and HER2 positive breast cancers that have metastasized to the brain. We hypothesize that uptake on pretreatment 64Cu-DOTA-Trastuzumab PET/MRI would predict response of brain metastases in patients treated with TDXd. Primary Endpoint: 64Cu-DOTA-Trastuzumab PET/MRI will identify tumor heterogeneity in patients with HER2 low and HER2+ brain metastases. 1. The level of uptake of 64Cu-DOTA-Trastuzumab on PET/MRI will predict for CNS response to TDXd. Secondary Endpoint: 1. Uptake of 64Cu-DOTA-Trastuzumab on PET/MRI will be predictive of response duration to TDXd. Eligibility: Patients with recurrent HER2 1+, 2+ or 3+ breast cancer that has metastasized to the brain as detected by CT or MRI, and are to undergo treatment with TDXd. Methods: Pretreatment staging workup included the following: pathologic review of HER2 status, disease staging with 18FDG-PET or CT of the chest/abdomen/pelvis and bone scan, and 64Cu-DOTA-Trastuzumab PET/MRI of the brain. TDXd was administered every 3 weeks per standard of care. After initiation of TDXd, MRI of the brain and systemic staging were repeated every 6 weeks for the first 24 weeks and every 9 weeks thereafter. Post-contrast MRI scans were used to delineate tumors for analysis of 64Cu-DOTA-Trastuzumab uptake and tumor perfusion. SUVmax on the PET, as well as the Ktrans (volume transfer constant) and vp (plasma volume fraction) on the brain MRI were analyzed. Progress: We have enrolled 5 patients, with 4 having HER2+ cancer by IHC and 1 HER2 1+; 3 having cancer confined to the brain, and 2 having additional systemic disease. Three patients demonstrating tumor regression on post-treatment MRI had higher uptake of 64Cu-DOTA-Trastuzumab (SUVmax: 6.1 +/- 1.5, Ktrans: 0.12 +/- 0.049, vp: 0.016 +/- 0.0038). Two patients with lower 64Cu-DOTA-Trastuzumab (SUVmax: 1.8 +/- 0.1, Ktrans: 0.13 +/- 0.028, vp: 0.020 +/- 0.0041) did not respond to therapy. An SUVmax greater than 2 was predictive of tumor response to TDXd in the initial cohort. To date, the responding patients continue therapy for 8-10 months. Non-responding patients experienced disease progression within 2 to 3 months. On average, responding tumors had lower plasma volume fraction as measured by DCE-MRI (n=5, not significant). The goal is to accrue 10 patients to this pilot study, to investigate the combined value of brain MRI perfusion parameters and 64Cu-DOTA-Trastuzumab uptake values. Citation Format: Joanne Mortimer, Beth Chen, Erasmus Poku, Jessica Liu, Irene Kang, Thanh Nga Doan, Paul Frankel, Russell Rockne, Ryan Woodall, Vikram Adhikarla. 64Cu-DOTA Trastuzumab -PET to predict CNS response to Trastuzumab-deruxtecan (TDXd) in patients with metastatic HER2 low and HER2 positive breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-03-07.

Hematopoietic cell transplantation (HCT) and CAR-T cell therapy patients face increased risks from SARS-CoV-2 due to immunosuppression and limited vaccine responsiveness. In a phase 2 trial of hematologic malignancy (HM) patients post-HCT/CAR-T, we assessed the immunogenicity of the MVA-(modified vaccinia Ankara) based COVID-19 vaccine COH04S1 (licensed as GEO-CM04S1 by GeoVax, Inc.), which co-expresses spike (S) and nucleocapsid (N) antigens. Thirteen patients vaccinated 3–12 months post-HCT/CAR-T with 2–4 doses of COH04S1 displayed robust S- and N-specific humoral and cellular responses, including cross-neutralizing antibodies effective against variants of concern such as Omicron XBB.1.5. T-cell responses, predominantly CD4+, remained elevated at six months post-vaccination. Immune responses in HCT/CAR-T patients were superior or comparable to those in healthy volunteers (HV) and healthcare workers (HCW) vaccinated with Comirnaty®. Parallel studies revealed COH04S1’s potential cross-protection against MPXV (monkeypox virus). In human volunteers and non-human primates (NHPs), COH04S1 elicited orthopoxvirus-specific and MPXV cross-reactive immune responses, including MPXV cross-neutralizing antibodies comparable to JYNNEOS. In mpox-susceptible mice, COH04S1 and its sMVA backbone protected against lung infection following MPXV challenge. These findings highlight COH04S1’s dual potential as a SARS-CoV-2 vaccine for immunocompromised patients and cross-protection against mpox. Funding was provided by the Carol Moss Foundation, donors Julie and Roger Baskes, Judd Malkin and Michael Zweig. Vaccines and Immunotherapy (VAC)

Required supplemental table of representativeness of patient population

Background: Radiation therapy (RT) is an essential component of definitive treatment for cancers of the prostate, rectum, cervix, and other pelvic malignancies. Despite its proven efficacy, pelvic RT is associated with a constellation of adverse effects, collectively referred to as pelvic radiation disease (PRD). Several clinical and preclinical studies have shown that dietary interventions, including time-restricted eating (TRE), may represent a novel approach to mitigate radiation and chemotherapy toxicity and, in some cases, promote oncologic efficacy, thereby enhancing quality of life, reducing morbidity and mortality, and improving disease outcomes. Objectives: This trial was designed to evaluate TRE feasibility/tolerability and test the hypothesis that TRE during RT or chemoradiation could reduce DNA damage accumulation in peripheral blood mononuclear cells over the course of treatment, as quantified by γH2AX foci. Secondary objectives include reduction in clinically observed toxicities, improvements in urinary or blood biomarkers of DNA damage, mitigation of microbiome dysbiosis and cytokine response during radiation, and improved metabolic parameters. Methods: A total of 48 individuals with prostate, cervical, or rectal cancer aged ≥18 years with a BMI ≥21 kg/m2 receiving pelvic radiation will be randomized to either TRE or nutritional counseling. Both groups of participants will receive dietary consultation with a registered dietician before and during RT, and the TRE group participants will be asked to restrict their caloric intake to a specific timeframe (fast at least 6-8 hours before and at least 4-6 hours after RT). Biospecimens (blood, urine, stool), quality-of-life surveys, physician-reported toxicities (CTCAEv5.0), and food intake and fasting logs will be collected biweekly during the study intervention and every 3-6 months up to one year follow-up. Results: Accrual was completed in August 2025. Follow-up and biospecimen collection are ongoing, and correlative analyses are in progress. Final outcomes will be reported upon study completion. Trial registration: ClinicalTrials.gov [NCT05722288][1]; https://clinicaltrials.gov/study/[NCT05722288][1] ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT05722288 ### Funding Statement This study was supported by generous funding from the NIH/NCI Paul Calabresi K12 Career Development Award (YRL, 5K12CA001727; PI: Joanne Mortimer), NIH Directors Common Fund DP5 Early Independence Award (YRL, 1DP5OD033424) and the Cherng Family Center for Integrative Oncology Pilot Award (YRL, 2025). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of City of Hope gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05722288&atom=%2Fmedrxiv%2Fearly%2F2025%2F12%2F02%2F2025.11.28.25340848.atom

Background:Cancer Centers offer a comprehensive approach to cancer prevention, diagnosis, and treatment through tertiary services and by providing coordinated, personalized care. We investigated whether this approach results in significantly better patient outcomes at an NCI-designated Comprehensive Cancer Center (NCI-CCC), City of Hope (COH), versus the U.S. Surveillance, Epidemiology, and End Results (SEER) national database. Methods:Patient-level data were abstracted from the COH Cancer Registry and SEER*Stat software, respectively. The cohort included patients diagnosed with incident cancer from 2004 to 2020. Overall survival was analyzed using multivariable Cox proportional hazards models. To reduce confounding from baseline differences, propensity score matching (PSM) methods were employed in a 1:5 ratio between COH and SEER, respectively, using age group at diagnosis category, gender, race, ethnicity, stage (for solid tumors), and diagnosis year. Findings:Patients treated at COH had significantly superior overall survival (OS) compared with those in the SEER cohort across all examined cancer types after multivariable adjustment for key baseline characteristics and in the PSM analyses. Median OS (when reached) was uniformly longer in the COH cohort compared with the SEER cohort in the full population adjusted model and in the PSM analyses. For the PSM analyses: non-small cell lung cancer (NSCLC) hazard ratio (HR) 0.73 (95% confidence interval [CI]: 0.70-0.76), breast cancer HR 0.83 (95% CI: 0.78-0.86), prostate cancer HR 0.62 (95% CI: 0.58-0.65), colorectal cancer HR 0.74 (95% CI: 0.69-0.79), pancreatic cancer HR 0.75 (95% CI: 0.70-0.81), acute myeloid leukemia HR 0.79 (95% CI: 0.75-0.84), acute lymphoid leukemia HR 0.7 (95% CI: 0.69-0.87), and multiple myeloma HR 0.70 (95% CI: 0.66-0.76) (all p <0.001). In addition, notable findings included substantially lower mortality risk for patients with any of the studied advanced solid cancers, including stage IV NSCLC (HR 0.71, 95% CI: 0.67-0.75, p <0.001) and stage IV breast cancer (HR 0.78, 95% CI: 0.69-0.87, p <0.001). Conclusions:Our results revealed patient care at an individual NCI-CCC employing state-of-the-art therapies and modern care is associated with survival benefits for cancer patients. Patients had significantly superior OS in the COH cohort compared with the SEER cohort for most of the analyzed solid tumors assessed for each stage (I-IV) and for 3 major hematologic malignancies assessed by age group.Until randomized comparisons studies are possible and the SEER data becomes more comprehensive, the specific causes of the observed benefit and identifying patients that benefit most may be subject to considerable debate. Additional research can help determine with greater granularity the drivers of the survival benefit and highlight an opportunity to make adjusted survival outcomes more accessible to patients, complementing the data currently available because of price transparency mandates. Such efforts may help ensure that all patients benefit from precision medicine approaches.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) transformed from indolent B-cell lymphomas, including Richter transformation, have a poor prognosis. PD-1/PD-L1 antibodies produce modest objective and complete response rates in B-cell non-Hodgkin lymphoma as monotherapy but may synergize with immunogenic chemotherapies such as gemcitabine and oxaliplatin (GemOx). Thus, we evaluated the safety and efficacy of atezolizumab plus rituximab and GemOx (R-GemOx+Atezo) in R/R transformed DLBCL, including Richter transformation. We conducted a phase I trial including patients with transformed DLBCL after ≥1 prior therapy. Patients received up to four cycles of R-GemOx+Atezo. Patients in complete remission could then proceed to R-Atezo maintenance until progression. A safety lead-in with evaluation of dose-limiting toxicity was performed to confirm the recommended phase II dose; subsequently the treatment was administered to two expansion cohorts: one with transformed follicular lymphoma (FL) and the other with non-FL transformed DLBCL, including Richter transformation. Twenty-seven patients were enrolled. One of the six patients in the safety lead-in had a dose-limiting toxicity attributed to atezolizumab, a grade 4 Stevens-Johnson syndrome. The most common grade ≥3 events were neutropenia (18.5%), lymphopenia (18.5%), and thrombocytopenia (14.8%). The overall and complete response rates were 59% and 33%, respectively. The overall and complete response rates in transformed FL were 79% and 43%, respectively, and 38% and 23% in transformed non-FL, respectively. The median progression-free survival and overall survival of the total population were 4.2 and 7.7 months, respectively. R-GemOx+Atezo was well tolerated and demonstrated promising preliminary efficacy in patients with relapsed/refractory transformed DLBCL.

Nociceptive pain, resulting from tissue injury or inflammation, affects a large portion of the global population. This type of pain is commonly treated by small molecules that are associated with a variety of drawbacks, including addiction and potential liver or kidney damage, highlighting the need for new therapeutic strategies. Here, we report the design, synthesis, and characterization of EG01449 (12h), a quinoline-based neuropilin-1 (NRP1) antagonist with analgesic effects in vascular endothelial growth factor (VEGF)-induced pain models. Neuropilin-1 is a critical coreceptor mediating VEGF signaling. In models of VEGF-induced pain, the VEGFA165a isoform increases currents through voltage-gated sodium and calcium channels in dorsal root ganglia sensory neurons. Notably, this effect was mitigated upon the inhibition of NRP1 by 12h, while 12h alone showed no discernible impact on sodium currents. Compound 12h also attenuated sensitivity to mechanical stimuli and cold-induced allodynia. Unlike the previously reported NRP1-targeting compounds that may activate intracellular signaling, 12h did not activate p38 mitogen-activated protein kinase and exhibited a purely inhibitory pharmacological profile. Structural comparison using X-ray crystallography revealed an additional hydrogen bond that contributes to the increased stabilization of the 12h/NRP1 complex. These findings demonstrate that the NRP1 inhibitor 12h elicits an antinociceptive effect and highlight the impact of subtle structural modifications on biological outcomes. NRP1 antagonism thus represents a promising new modality for the treatment of chronic pain conditions.

Background: Based on preclinical data demonstrating a synergistic effect of combining immune checkpoint inhibitors (ICIs) with CDK4/6 inhibitors, we conducted a phase I/II study of palbociclib, endocrine therapy, and pembrolizumab in patients (pts) with HR+/HER2- MBC. We previously reported that the gut microbiome can predict clinical response to this ICI combination. Emerging evidence also suggests that the gut microbiome is closely linked to the development of immune-related adverse events (irAE), and that the onset of irAE may be associated with improved ICI response. Here, we explore the role of the gut microbiome on the onset of severe irAE in this cohort of pts with HR+/HER2- MBC treated with palbociclib, endocrine therapy, and pembrolizumab. Methods: Pts with stage IV HR+/HER2- MBC were enrolled and treated with palbociclib, endocrine therapy, and pembrolizumab. Baseline stool samples were collected at Day -28 to C1D1 (N=28 pts). Next on-treatment sample was used if baseline unavailable. Gut microbiota composition was assessed using deep metagenomic sequencing. Taxonomic profiling was conducted using MetaPhlAn4. Functional profiling was performed using HUMAnN3. Correlative studies assessed the association between the gut microbiome and severe (grade >3) irAE. Results: Between March 2017 and May 2022, 40 pts (39 female/1 male) were accrued, with a median age of 51 (range 39-75). With a median follow-up of 35.8 months (mos) (95% CI: 26.1, 63.5), the median progression-free survival (PFS) was 27.8 mos (95% CI: 11.2, NR). The incidence of severe irAE was 11/40 (27.5%). There was no difference in PFS between pts with and without severe irAE (P=0.6). The median PFS was 27.8 mos (95% CI: 6.7, NR) and 27.1 mos (95% CI: 8.7, NR) in pts with and without severe irAE, respectively. ANCOM-BC (Analysis of compositions of microbiomes with bias correction) identified Dialister invisus (log fold change [LFC] 2.45 [P=0.02]), Blautia caecimuris (LFC 2.43 [P=0.01]), Flavonifractor plautii (LFC 2.40 [P=.01]), and Eisenbergiella massiliensis (LFC 2.12 [P=0.001]) in greater abundance in pts without severe irAE, while Coprococcus eutactus (LFC -3.94 [P=0.0009]) was in greater abundance in pts with severe irAE. Beta diversity using Bray-Curtis analysis showed significant differences in gut microbiome composition between irAE groups (P=0.04). Although alpha diversity using the Shannon diversity analysis showed no differences across irAE groups (P=0.3), Shannon diversity analysis showed significant differences in functional genetic pathways between irAE groups (P=0.03). ANCOM-BC identified several distinguishing metabolic pathways between irAE groups, including the CMP-pseudoaminate biosynthesis pathway which was enriched in pts without severe irAE (LFC 2.37 [P=0.0002]). Conclusions: Certain gut bacteria can predict the development of severe irAE in a cohort of pts with HR+/HER- MBC treated with palbociclib, endocrine therapy, and pembrolizumab. Several metabolic pathways were enriched between irAE groups, which suggests differences in immune activation that can lead to the onset of irAE. This study suggests that the gut microbiome can serve as a risk factor and biomarker of severe irAE in breast cancer pts, which warrants further evaluation. Citation Format: Alexis LeVee, Keehoon Lee, Colt Egelston, Susan Yost, Nora Ruel, Paul Frankel, Christopher Ruel, Daniel Schmolze, Peter Lee, Christina Yeon, Yuan Yuan, James Waisman, Sumanta Pal, Joanne Mortimer. Impact of the gut microbiome on immune-related adverse events (irAE) in HR+/HER2- locally advanced or metastatic breast cancer (MBC) patients (pts) receiving palbociclib, endocrine therapy, and pembrolizumab [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-05-24.

Purpose: The ataxia telangiectasia and Rad3-related kinase inhibitor elimusertib synergizes with cisplatin preclinically. We evaluated the clinical feasibility of combining elimusertib with cisplatin. Patients and Methods: Patients with advanced solid tumors who had received <300 mg/m(2) of prior cisplatin, and for whom cisplatin-based treatment was deemed appropriate, were enrolled according to a standard 3 + 3 design, starting elimusertib at 20 mg orally twice daily on days 2 and 9, with cisplatin 60 mg/m(2) intravenously on day 1 of a 21-day cycle. Primary objectives were the determination of the maximum tolerated dose and safety. Secondary objectives included the assessment of elimusertib pharmacokinetics and preliminary efficacy. Results: Fifteen patients were enrolled. Dose level -2 (elimusertib 20 mg once on day 2 and cisplatin 30 mg/m(2) on days 1 and 8) was deemed the maximum tolerated dose; dose-limiting toxicities (DLT) including creatinine increase, hypokalemia, febrile neutropenia, neutropenia, syncope, and thrombocytopenia, required dose de-escalation. Although the four patients with the highest elimusertib exposure all experienced hematologic DLTs within 1 week, they also received a higher day 1 cisplatin dose, precluding a definitive association of elimusertib exposure with DLT occurrence. Of 10 evaluable patients, one (10%) with clear-cell ovarian cancer had a partial response, whereas five (50%) had stable disease. Conclusions: Cisplatin combined with elimusertib was associated with hematologic toxicity requiring significant dose de-escalation. Elimusertib pharmacokinetics was consistent with prior studies. Only modest activity was observed. Further clinical evaluation of elimusertib plus cisplatin is not warranted. Significance: Preclinical data suggest synergy between cisplatin and the ataxia telangiectasia and Rad3-related inhibitor elimusertib, leading to this phase Ib trial in advanced solid tumors evaluating feasibility. The results do not support further examination of the combination due to DLTs observed in the absence of robust efficacy.

5569 Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with improved overall survival in Stage III epithelial ovarian cancer (EOC) patients. We set out to evaluate the gene signatures associated with HIPEC response in EOC patients. Methods: Ninety-one EOC patients who underwent HIPEC with pre-operative tumor samples at City of Hope (51) and CHU Lyon (40) were identified between 2014 and 2022. RNA isolation was performed from formalin-fixed paraffin-embedded samples, followed by Whole-transcriptome library construction. Following exclusion of non-high grade serous (HGS) samples, and quality control steps, twenty-four samples were excluded. Progression-free survival (PFS) was used to define HIPEC response. Cut-off PFS values were used to distinguish good vs poor responders in primary EOC patients (18 months, based on KGOG, CARCINO-HIPEC trials), and recurrent EOC patients (12 months, based on MSK, CHIPOR HIPEC trials). Differential Gene Expression Analysis comparing good and poor HIPEC responders identified significantly changed genes. Pathway analysis was conducted using gene set enrichment analysis (GSEA) against Hallmark. Results: A total of sixty HGS tumor samples with available survival data were analyzed. 63.3% were primary EOC, 36.7% recurrent EOC. Germline BRCA mutations affected 21.7% of patients. With a median follow up of 31.9 months, median PFS was 29.3 (95%CI: 15.3, 63.5) months in primary EOC patients and 26.0 (95%CI: 14.7, 37.1) months in recurrent patients. Median OS was not reached in either group. 60.0% had a recurrence. Thirty-eight patients were identified as good responders, with a median PFS of 37.1 mos. (95%CI: 26.4, NR); 18 patients were identified as poor responders, with median PFS of 11.4 months (95%CI: 7.5, 14.2). Differential gene expression analysis between good and poor responders revealed 29 significantly upregulated 35 downregulated genes in HIPEC responders. Top upregulated genes in HIPEC responders include MAPK signaling pathway genes (RIB2, ETV5, CAPN8, IGFR1), in addition to CCND1 and CEACAM1. In HIPEC responders, the top-ranking gene sets in the transcriptional signature included Notch, KRAS, and Wnt/beta-catenin signaling pathways. In poor HIPEC responders, the DNA damage repair associated pathways E2F targets and G2M checkpoint, were activated. Similar transcriptomic pathway signatures were observed in Non-recurrent versus Recurrent HIPEC patients: Non-recurrent tumors were enriched with Notch signaling, while Recurrent tumors were enriched with E2F target and G2M checkpoint pathways. Conclusions: Good HIPEC response is characterized by transcriptional signatures consistent with Type I EOC characteristics of PI3K/RAS/Notch signaling. Recurrence after HIPEC in HGS ovarian cancer is higher in patients with E2F/G2M transcriptional signatures.

Abstract Background: Outcomes for relapsed or refractory (R/R) acute myeloid leukemia (AML) remain poor despite advances in the treatment of AML. MEC, consisting of mitoxantrone, etoposide (ETOP), and cytarabine, is an established regimen for the treatment of R/R AML. Peposertib is a potent, selective, and oral DNA-PK inhibitor that disrupts DNA-PK mediated non-homologous end joining and repair of double-strand DNA breaks induced by anthracyclines (AC) and ETOP. Peposertib synergizes with AC and ETOP in preclinical studies. Peposertib inhibits CYP3A4, which is predicted to increase ETOP levels by up to 2-fold depending on the peposertib dose and could lead to increased toxicity. Thus, we tested the safety, pharmacokinetics (PK), and antileukemia activity of peposertib combined with MEC in patients with R/R AML. Methods: This is a multicenter Phase I trial of peposertib in combination with MEC in patients with R/R AML (NCT03983824). A modified 3+3 design with a PK-based dose-escalation schema was used to determine the recommended phase 2 dose (RP2D), followed by a dose expansion part at the RP2D. Key eligibility criteria included age ≥18 years, AML diagnosis by WHO criteria, relapsed and/or refractory disease, and eligibility for AC. Patients received one cycle of treatment with peposertib plus MEC. There were up to 6 dose levels planned, 3 dose levels with MEC with a reduced ETOP dose of 50mg/m2 D1-5, and peposertib dosed at 100mg, 200mg, or 400mg PO BID D2-21 (Dose Levels A1, A2, and A3) and 3 dose levels with ETOP at the standard dose of 100mg/m2, with peposertib at either 100mg, 200mg, or 400mg PO BID D2-21 (Levels A4, A5, and A6). Peposertib was given D2-21 to allow for MEC only PK analysis. Bone marrow biopsies, PK, and pharmacodynamic (PD) testing were obtained pre- and post-treatment. The primary objective was to determine safety and tolerability. Adverse events (AE) were monitored throughout treatment, and dose-limited toxicities (DLT) assessed up to day 28. Secondary and exploratory objectives were to evaluate PK and preliminary efficacy and PD, respectively. Responses were per European LeukemiaNet (ELN) 2017 criteria. Results: Enrollment was completed, with 37 patients enrolled (Levels A1 n=3, A2 n=13, A3 n=3, A4 n=12, and A5 n= 6). Median age was 58 years (range 23-74). Of the patients enrolled, 62% (n=22) were male, 5% (n=2) were Asian, 5% (n=2) were Black, and 49% (n=18) identified as Hispanic or Latino. All patients had an ECOG PS of 0-1. Per ELN 2022 criteria, risk was adverse in 62% (n=23), while 65% (n=24) and 35% (n=13) had relapsed and refractory AML, respectively. Median prior lines of therapy received was 2 (range 1-6), including prior venetoclax in 78% (n=29) of patients. During dose escalation, there were no DLT on A1 (0/3) or A2 (0/6), 2 DLT on A3 (2/3, both grade 3 mucositis), 1 DLT on A4 (1/6, grade 3 rash maculo-papular), and 2 DLT on A5 (2/3, 1 grade 3 mucositis and 1 grade 5 sepsis). Dose level A6 was not explored due to DLT in A3 and A5. As a result, both A2 (lower ETOP/higher peposertib) and A4 (standard ETOP/lower peposertib) were expanded, with a total of 13 patients treated on A2 and 12 patients treated on A4. The majority of patients on both dose levels were able to receive the full treatment without interruption. On cohorts A2 and A4, the 30-day mortality was 1/12 and 0/12, and 60-day mortality was 3/12 and 1/12, respectively, with 1 unknown on A2. To date, all patients are off treatment. Among the 37 patients started on protocol therapy, 27% (n=10) had an antileukemia response, including 3 complete remission (CR), 6 CR with incomplete count recovery (CRi), and 1 partial remission (PR). The CR/CRi rate was 24.3% (n=9). On level A2, 5/13 patients responded (2 CR, 2 CRi, and 1 PR), and on dose level A4, 3/12 responded (1 CR and 2 CRi). PK analyses from dose levels A1, A2, A3, A4, and A5 showed no increase in ETOP area under the curve with the addition of peposertib. Conclusions: Overall, combining peposertib with MEC was feasible and did not significantly affect ETOP PK. Despite the high risk and heavily pretreated study population, including 78% with prior venetoclax, activity was seen on multiple dose levels, including A2 and A4, which were both expanded and remain RP2D candidates after expansion. Additional PK and PD analyses, follow-up, and evaluation of duration of remission, event-free survival, and overall survival, will aid in selecting the final RP2D and informing future studies.

e13146 Background: Despite recent FDA approval of immune checkpoint inhibitor (ICI) and antibody-drug conjugates (ADCs), therapeutic options for metastatic triple negative breast cancer (mTNBC) remain limited. Preclinical data showed that ivermectin induces robust T cell infiltration into breast tumors and turning “cold” tumors “hot” in mouse model of TNBC. Balstilimab is a fully humanized IgG4 anti-PD-1 agent with proven safety and efficacy in metastatic cervical cancer. The current phase I/II trial is designed to test the safety and efficacy of the combination of ivermectin and balstilimab in patients with mTNBC. Methods: Key eligibility criteria include patients with unresectable or metastatic TNBC; progressed on 1-2 prior chemotherapies including an ICI-containing regimen; ECOG 0-1; RECIST 1.1 measurable disease. Eligible patients receive balstilimab 450 mg, IV, on Day 1 and ivermectin (30, 45 or 60 mg po daily), PO, Days 1-3, 8-10, 15-17 of each 21 days cycle till disease progression or intolerance. The primary objective of the phase 1 portion of the study is to determine the recommended phase 2 dose of ivermectin in combination with balstilimab using NCI-CTCAE v5.0. The primary objective of the phase II portion of the study is to determine the efficacy of the combination using the objective response rate (ORR). Secondary objectives are progression free survival (PFS), overall survival (OS), clinical benefit rate (CBR), and patients’ quality of life (QOL) by EORTC QLQ-C30. Results: This study has accrual 9 patients to-date. Median age was 52 years (IQR 47-56, range 38-68), 4 (44.4%) were non-Hispanic white, 3 (33.3%) were Hispanic, and 2 were other (22.2%). Median lines of metastatic chemo or targeted therapy prior to the start of trial registration was 5 (IQR 2-5, range 1-7). Dose level 1 and 2 were completed with only 1 serious adverse event (AE) attributed to disease related anemia. All grades treatment related AEs are: 2 maculo-papular rash (grade 1), 1 patient each for anemia (grade 3), diarrhea (grade 1), dysgeusia (grade 1), generalized muscle weakness (grade 1), hypothyroidism (grade 2), and vomiting (grade 1). The initial ECOG value was 0 among 8 patients and 1 patient had ECOG of 1. Six (66.7%) patients had prior immune checkpoint inhibitors, 6 (66.7%) had positive tumor PD-L1 expression. The study will continue to accrual of dose level 3. Of 8 evaluable patients, 1 had SD, 6 had PD, and 1 had PR. The median PFS was 2.5 month (95% CI 66 – Not reached). The 4-monthclinical benefit rate was 37.5% (95% CI 15.3%-91.7%). OS is too early to be assessed. Conclusions: The combination of ivermectin and balstilimab is safe and well tolerated. Encouraging CBR was observed in this heavily pretreated population, which warranted continued investigation. Clinical trial information: NCT05318469 .