The epidemiology of myelodysplastic syndromes/neoplasms (MDS) is challenging to define due to inconsistent reporting, complex diagnostic procedures, and evolving diagnostic criteria. Using the National MDS Natural History Study-a prospective cohort with centrally adjudicated histopathology and genetic variant review-we characterized the landscape of MDS across the United States and identified differences across demographics. Among 2115 participants, 64% (1346) had an MDS spectrum condition, including MDS (24%), MDS/myeloproliferative neoplasm (5%) and precursor conditions-clonal cytopenia of undetermined significance (22%) and idiopathic cytopenia/dysplasia of undetermined significance (13%). The median age was 74 years, and participants were predominantly male (66%), White (91%), and Non-Hispanic (92%). Myeloid-associated variants were detected in 68% of participants, most commonly in TET2, DNMT3A, ASXL1, SF3B1, and SRSF2. Black, compared to White, participants were younger at diagnosis (69 vs. 74 years, p = 0.01), had equal or increased prevalence of higher-risk MDS, lower hemoglobin, and higher peripheral blood blasts, yet were less likely to receive MDS-directed therapy (14% vs. 42%, p = 0.008). Black and Hispanic participants had fewer detectable gene mutations than White participants. Females had lower variant allele frequencies and fewer RNA splicing gene mutations than males. After multivariable adjustment, TP53 mutations, MDS diagnosis, and higher-risk disease were associated with worse progression-free and overall survival; age was also associated with overall survival. Black race trended toward improved progression-free survival. These findings highlight the need for enhanced understanding of MDS pathogenesis across patient groups and refined prognostic tools to improve personalized management of MDS spectrum conditions. Trial Registration: ClinicalTrials.gov identifier: NCT02775383.

Abstract G-quadruplexes (G4s) are four-stranded nucleic acid structures that help regulate key cellular processes and are attractive therapeutic targets in oncology. To assess the therapeutic potential of three G4 ligands—pidnarulex, APTO-253, and BRACO-19—we performed a high-throughput drug-combination screen across thirty-one multicellular tumor spheroids derived from patient tumors and established cancer cell lines. These 3D spheroids model salient features of the tumor microenvironment, incorporating malignant, endothelial, and mesenchymal components. Combination partners were selected for mechanistic relevance to G4 biology, including inhibitors of DNA damage response (DDR), replication stress, and chromatin regulation, based on the proposed roles of G4s in replication and genome stability. Responses were quantified using viability assays complemented by longitudinal brightfield imaging to track spheroid morphology and growth. Drug interactions were evaluated by Bliss independence and volume under the viability surface, providing complementary metrics of synergy and global response. Among the ligands, pidnarulex showed the broadest single-agent activity, whereas APTO-253 and BRACO-19 produced more limited effects. Combination screening with PARP inhibitors, DDR-kinase inhibitors (ATM, ATR, DNA-PK), and cell-cycle regulators (WEE1, PIM1) revealed model-specific synergy. Notably, pidnarulex exhibited consistent synergy in one of eight pancreatic adenocarcinoma models (966289-007-R4-J1) across multiple DDR-targeted combinations. Additional interactions were observed with HDAC inhibitors in a subset of models. Brightfield imaging corroborated enhanced suppression of spheroid growth in synergistic combinations. These data highlight the context-dependent activity of G4 ligands and support integrated functional plus imaging-based approaches to define therapeutic combinations in physiologically relevant 3D cancer models. This project was funded with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024. Citation Format: Thomas S. Dexheimer, Nathan P. Coussens, Thomas Silvers, Poorva Juneja, Eric Jones, Steven D. Gore, Mark W. Kunkel, James H. Doroshow, Beverly A. Teicher. Combinatorial profiling of pidnarulex and other G-quadruplex ligands in 3D multicellular tumor spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6504.

INTRODUCTION:Next generation of Theranostics studies are looking at novel combinations with radiation sensitizers to enhance PRRT's efficacy. Here, we present safety and efficacy data from a multi-center phase 1 study of a [¹⁷⁷Lu]lutetium-dotatate -triapine combination in patients with GEP-NETs. METHODS:The study consisted of two phases (dose escalation and expansion) administering the recommended phase 2 doses (RP2D) for the two agents. All patients received 200 mCi of [¹⁷⁷Lu]lutetium-dotatate on day 1 of four 8-week cycles, in combination with oral triapine administered at assigned dose levels (100 mg, 150 mg or 200mg) from days 1 to 14 of each cycle. RESULTS:A total of 31 (A: 15 ; B: 16 ) patients received treatment. Nine patients experienced dose-limiting toxicities; Grade 3 anemia (n=1), Grade 5 cardiac arrest (n=1), and Grade 4 neutropenia (n=7). Based on the overall safety and pharmacokinetics data, a [¹⁷⁷Lu]lutetium-dotatate (200 mCi) plus triapine (150 mg) dose was selected as the RP2D for the expansion phase. Grade ≥3 treatment related adverse events were observed in 77% patients: anemia (23%), nausea and vomiting (3% ), lymphopenia ( 58%), neutropenia ( 35%) and leukopenia ( 39%). The majority of cytopenias were transient and resolved within two weeks. Among the 28 evaluable patients, the objective response rate (ORR) was 21.4% and the median progression-free survival (mPFS) has not been reached (median follow-up period: 23.7 months). CONCLUSIONS:The combination of [¹⁷⁷Lu]lutetium-dotatate (200 mCi) and oral triapine (150 mg D1-14) was well tolerated and demonstrated preliminary activity in patients with well-differentiated GEP-NETs. (NCT04234568).

CDC-like kinases (CLK) and dual-specificity tyrosine-regulated kinases (DYRK) are protein kinases involved in various cellular functions, mRNA splicing, and DNA damage repair. CLK/DYRK kinases have been implicated in many disorders such as diabetes, neurodegenerative diseases, and cancer. Cirtuvivint (SM08502) is an orally bioavailable, first-in-class pan-CLK and pan-DYRK inhibitor that modulates pre-mRNA splicing and has shown the ability to inhibit cancer cell growth in vitro and reduce tumor burden in vivo. This has led to the administration of cirtuvivint in phase I clinical trials. To quantitate cirtuvivint, we have developed and validated an LC-MS/MS method in human plasma. The assay is simple and robust and consists of a protein precipitation, dilute-and-shoot extraction method using 20 μL of plasma, chromatographic separation with a Phenomenex Kinetex C18, and a gradient mobile phase system consisting of 0.1% formic acid in water and acetonitrile. The chromatographic method is followed by mass spectrometric detection with a SCIEX 4500 tandem mass spectrometer. The method has a 5-min run time and is linear from 5 to 1000 ng/mL. The assay met the criteria outlined by the US Food and Drug Administration guidance for bioanalytical method validation and will support ongoing and future clinical studies defining cirtuvivint pharmacokinetics.

Abstract Myelodysplastic syndromes (MDS) are clinically and biologically diverse disorders, emphasizing the need for personalized treatment approaches. The International Working Group for Prognostication of MDS (IWG_PM) recently introduced a molecular classification, referred to as the MDS taxonomy, that categorizes patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at TP53 and TET2 loci. This study sought to validate and enhance the clinical relevance of the MDS taxonomy by analyzing a large retrospective cohort (n = 5136) and transcriptomic data from a prospective cohort (n = 477). The taxonomy successfully identified subgroups with distinct clinical characteristics and disease progression patterns. However, incorporating gene interactions from taxonomy subgroups did not improve the prognostic performance of the Molecular International Prognostic Scoring System (IPSS‐M). We further assessed whether the taxonomy could guide management in patients receiving disease‐modifying therapies. Except for the “TP53‐complex” subgroup, taxonomy classifications were not predictive of hypomethylating agent response or transplant outcomes. Nonetheless, they correlated with overall survival, suggesting that while both IPSS‐M and the taxonomy capture disease biology, other non‐genetic factors may influence treatment response. RNA sequencing confirmed the biological distinctiveness of the taxonomy groups. Transcriptomic profiling of CD34+ bone marrow cells revealed unique, homogeneous gene expression patterns, particularly within the AML‐like, biTET2, SF3B1, and TP53‐complex subgroups. Further integration of multi‐omics data may refine MDS classification, improving clinical decision‐making and guiding the development of targeted therapies.

PURPOSE Inhibition of WEE1, a tyrosine kinase responsible for G2 arrest, results in premature mitotic entry and double-strand DNA breaks. Adavosertib is a selective, ATP-competitive, and small-molecule WEE1 kinase inhibitor. In an adavosertib single-agent, Phase I trial, partial responses (PRs) were observed in patients with solid tumors carrying pathogenic variants (PVs) in BRCA1/2 . In this trial, we further evaluated adavosertib in patients with PV in BRCA1/2 solid tumors. PATIENTS AND METHODS Eligible patients met criteria for the National Cancer Institute-Molecular Analysis for Therapy Choice master protocol and had a diagnosis of advanced BRCA- mutated solid tumor (germline or somatic mutations were accepted); 33 patients were enrolled, and 30 received study treatment. Adavosertib was administered orally, 300 mg once daily, with 5 days on and 2 days off over a 3 week cycle of 2 weeks on and 1 week off, until disease progression or unacceptable toxicity. Radiologic assessment was performed every three cycles. The primary end point was overall response rate (ORR); secondary end points included 6-month overall survival (OS6) and 6-month progression-free survival rate (PFS6). RESULTS The ORR was 3.3% (90% CI, 0.2 to 14.9); the OS6 was 57.3% (90% CI, 41.9 to 72.7); the PFS6 was 23.4% (90% CI, 10.7 to 36.2). One PR (fallopian tube serous carcinoma) and six cases of stable disease (SD, >6 months) were observed. In patients with SD <6 months or progressive disease (nonresponders), significantly increased PI3K/AKT/mTOR signaling pathway gene transcripts suggested activation of this resistance mechanism. The primary reason for treatment discontinuation was disease progression. Common side effects included myelosuppression, fatigue, nausea, anemia, vomiting, and diarrhea. CONCLUSION In heavily pretreated, advanced solid tumor patients with PV in BRCA1/2 , adavosertib treatment resulted in low ORR, and this trial did not meet the primary end point.

Background Ataxia telangiectasia Rad3-related (ATR) protein kinase regulates DNA damage response and is essential for tumor cell survival. Preclinically, ATR inhibition can sensitize tumor cells to radiation and chemotherapy. The authors conducted a phase 1 trial of berzosertib, a selective ATR inhibitor, in combination with definitive radiation and cisplatin in locally advanced head and neck squamous cell cancers (LA-HNSCC). Methods LA-HNSCC patients received daily radiation (2 Gy per fraction to 70 Gy) and weekly intravenous (iv) cisplatin 40 mg/m(2). Berzosertib was administered (iv) once weekly, starting with a pharmacokinetic lead-in dose. Three berzosertib dose levels (DL) were tested: 120 mg/m(2) (DL1), 160 mg/m(2) (DL2), and 200 mg/m(2) (DL3). Results Forty-one of 43 enrolled patients were evaluable for safety and preliminary efficacy assessments. Four patients experienced dose-limiting toxicities (DLTs) in dose-escalation: grade 4 thrombocytopenia (1), grade 4 respiratory failure (1), grade 3 renal injury and hypoxia (1), and inability to receive 90% of the planned radiation dose (1). DL3 was the recommended phase 2 dose, and 15 patients were enrolled at this DL as an expansion cohort. Objective response rates (ORR) in patient cohorts treated with any amount of berzosertib; treated with at least 50% of planned treatment; and in the expansion cohort were 78.8% (26 of 33), 78.8% (26 of 33), and 63.6% (7 of 11), respectively, after excluding eight inevaluable patients without post-treatment imaging assessment. Conclusions Berzosertib (200 mg/m(2) iv weekly) was safe when combined with chemoradiation but did not improve complete response rate in LA-HNSCC.

ABSTRACT:Patients at risk for progression from myeloid precursor states (idiopathic cytopenia of undetermined significance [ICUS] and clonal cytopenia of undetermined significance [CCUS]) to myelodysplastic syndrome (MDS) are not well defined. Epidemiologic risk factors, clonal changes for MDS development, and evolution from one MDS state to another were available in the MDS Natural History Study (NHS), a prospective cohort enrolled at diverse US sites. Extensive clinical data and biospecimens were collected at baseline and follow-up. A total of 1177 (56%) individuals with MDS or MDS-related precursor conditions (ICUS/idiopathic dysplasia of undetermined significance [IDUS], CCUS, and MDS/myeloproliferative neoplasm overlap) were enrolled and diagnosed in the MDS NHS. The median age was 74 years, with 89% aged ≥60 years, and most were male patients. Median follow-up time was 1.6 years and was similar among ICUS/IDUS, CCUS, and MDS. During follow-up period, 68% of participants terminated the study, 35% died, and 38% had disease progression. Using a refined clinical definition of progression, the greatest proportion of progression was observed among higher-risk-MDS (116 [73%]), followed by lower-risk-MDS (170 [52%]); fewer progression events were observed among participants with CCUS (65 [22%]) and ICUS/IDUS (46 [17%]). Predictors of progression are delineated, including female sex, higher quantity of mutations, the presence of TP53 mutation, and poor/very poor cytogenetic score. Based on these prospective data, guidelines for clinical management including monitoring and surveillance are outlined. The MDS NHS provides real-world data to illustrate how clinical and genotypic differences inform the classification, disease course, and approach to therapy, with informed monitoring guidelines for patients. This trial was registered at www.ClinicalTrials.gov as NCT02775383.

Required supplemental table of representativeness of patient population

G-quadruplexes (G4s) are four-stranded nucleic acid structures that regulate key cellular processes and represent promising therapeutic targets in oncology. To investigate the therapeutic potential of three G4 ligands—pidnarulex, APTO-253, and BRACO-19—a high-throughput drug combination screen was conducted in thirty-one multi-cell type tumor spheroids derived from patient tumors and established cancer cell lines. These 3D spheroids mimic key features of the tumor microenvironment, comprising malignant, endothelial, and mesenchymal cell populations. Compounds selected for combination screening included agents with mechanistic relevance to G4 biology, such as inhibitors of DNA damage response (DDR), replication stress, and chromatin regulation, based on the proposed roles of G4s in replication and genome stability. Combination responses were assessed using cell viability assays and supported by longitudinal brightfield imaging to monitor spheroid morphology and growth dynamics. Drug interactions were quantified using Bliss independence scores and the volume under the viability surface, providing complementary metrics of synergy and overall response. Among the G4 ligands, pidnarulex demonstrated the broadest single-agent activity, while APTO-253 and BRACO-19 showed limited effects. Model-specific synergy was observed from combinations with inhibitors of PARP, DDR kinases (ATM, ATR, DNA-PK), and cell cycle regulators (WEE1, PIM1). Interestingly, pidnarulex exhibited consistent synergy in one of eight pancreatic adenocarcinoma models (966289-007-R4-J1) across multiple DDR-targeted combinations. Combination interactions were also observed with HDAC inhibitors in a subset of models. Brightfield imaging corroborated enhanced spheroid growth suppression from synergistic combinations. These findings underscore the context-dependent activity of G4 ligands and support the use of integrated functional and imaging-based approaches to characterize potential therapeutic combinations in physiologically relevant 3D cancer models.

To determine the, safety, tolerability and recommended phase 2 dosing of the combination of navitoclax, a dual Bcl-2/xL inhibitor, and vistusertib, a TORC1/2 inhibitor. Patients with advanced solid tumors received navitoclax plus vistusertib following a 3 + 3 dose escalation design. To mitigate thrombocytopenia, a known toxicity of navitoclax, all patients received lead-in dosing of navitoclax alone at 150 mg orally daily for a minimum of 7 days. In addition to safety and tolerability, pharmacokinetics of navitoclax and vistusertib were evaluated. 14 patients received combination treatment which was well-tolerated at dose level 1 (navitoclax 150 mg orally daily plus vistusertib 35 mg orally twice daily). The main dose-limiting toxicity, grade 3 serum aminotransferase elevation, occurred in two of five patients at dose level 2 (navitoclax 250 mg orally daily plus vistusertib 35 mg orally twice daily). Navitoclax and vistusertib exposures appeared consistent with levels reported in prior studies of each agent. No responses were observed among the 8 response evaluable patients. A tolerable dose of navitoclax at 150 mg orally daily plus vistusertib at 35 mg orally twice daily was identified in patients with advanced solid tumors and established as the recommended phase 2 dose (RP2D). Further efficacy assessment of this combination, in a planned phase 2 expansion in patients with relapsed small cell lung cancer, was terminated due to discontinuation of vistusertib. NCT03366103 (First posted December 8, 2017).

TPS9598 Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer driven by UV mutations or the Merkel cell polyomavirus (MCPyV).It is aggressive, with a high Ki-67 proliferative index.Despite an initial high response rate (~55%) to PD-1 pathway inhibitors, >50% of patients exhibit primary or acquired resistance.ATR (ataxia telangiectasia and Rad3-related) kinase, a critical cell cycle checkpoint regulator, ensures genome fidelity in cancer cells experiencing high replication stress, including MCC.Our preclinical findings suggest anticancer activity of ATR inhibition via transcriptional induction of NF-κB-associated proinflammatory mechanisms.The potent, selective, orally administered ATR inhibitor tuvusertib (M1774) has shown antitumor activity in patients with unresectable solid cancers in Phase I trials, with a recommended Phase II dose of 180 mg daily on an intermittent schedule.We hypothesize that tuvusertib ± anti-PD-(L)1,may induce tumor regression in advanced anti-PD-(L)1-refractory MCC. Methods: The multicenter, randomized Phase II MATRiX trial tests the safety and efficacy of tuvusertib monotherapy (Arm 1) and tuvusertib plus avelumab (Arm 2) in patients with metastatic MCC refractory to PD-(L)1 blockade. Patients with progressive disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 within 120 days of their last anti-PD-(L)1 therapy are eligible. Subjects randomized to Arm 1 receive tuvusertib 180 mg QD on days 1-14 of each 21-day cycle. Subjects in Arm 2 also receive avelumab 1600 mg IV on day 1 of each 21-day cycle. Imaging studies performed 9 weeks after treatment initiation and every 12 weeks thereafter will be assessed per RECIST v1.1. Patients in Arm 1 with progressive disease may receive tuvusertib + avelumab. Treatment-emergent adverse events are graded per Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint is progression-free survival (PFS). Between June 2024 and January 2025, 13 subjects were enrolled across 10 centers. With a targeted enrollment of 50 patients, this trial has 83% power to observe a statistically significant (one-sided level of 10%) difference in PFS if the true hazard ratio for failure is 2.0. A stratified (primary vs. acquired resistance) log-rank test will be used, and binary outcomes will be compared using a Mantel-Haenzel test. A Wieand-like futility rule will be used for an interim analysis after the 23 rd event occurs. Tumor biopsies, blood, and stool specimens will be profiled to gain integrated insight into transcriptomic, proteomic, and metabolic signatures associated with immune-mediated therapeutic outcomes. This orthogonal approach to solid tumor immunotherapy, relevant to analogous cancers, will guide future combination strategies to better harness the anti-tumor immune response. Clinical trial information: NCT05947500 .

Homologous recombination (HR) is a high-fidelity repair mechanism for double-strand breaks. Rad51 is the key enzyme that forms filaments on single-stranded DNA (ssDNA) to catalyze homology search and DNA strand exchange in recombinational DNA repair. In this study, we employed single-particle cryogenic electron microscopy (cryo-EM) to ascertain the density map of the wild-type budding yeast Rad51-ssDNA filament bound to ADP-AlF3, achieving a resolution of 2.35 Å without imposing helical symmetry. The model assigned 6 Rad51 protomers, 24 nt of DNA, and 6 bound ADP-AlF3. It shows 6-fold symmetry implying monomeric building blocks, unlike the structure of the Rad51-I345T mutant filament with three-fold symmetry implying dimeric building blocks, for which the structural comparisons provide a satisfying mechanistic explanation. This image analysis enables comprehensive comparisons of individual Rad51 protomers within the filament and reveals local conformational movements of amino acid side chains. Notably, R293 in Loop 1 adopts multiple conformations to facilitate L296 and V331 in separating and twisting the DNA triplets. We also analyzed the crystal structure of Rad51-I345T and the predicted structure of yeast Rad51-K342E using the Rad51-ssDNA structure from this study as a reference.

Ataxia-telangiectasia and Rad3-related (ATR) protein kinase is an essential regulator of the DNA damage response (DDR) at stalled and collapsed replication forks. Tuvusertib (M1774) is a selective, orally available small molecule ATR inhibitor currently in preclinical and clinical development for cancer treatment. This study presents a robust and simple 5-min assay designed for the quantification of single agent tuvusertib in human plasma utilizing liquid chromatography tandem mass spectrometry (LC-MS/MS). A 20 μL volume of plasma was subjected to protein precipitation, followed by chromatographic separation using a Phenomenex Synergi Polar-RP (4 μm, 2.1 × 50 mm) and a gradient mobile phase system consisting of 0.1% formic acid in both water and acetonitrile during a 4-min run time. Mass spectrometric detection was achieved using a SCIEX 6500+ tandem mass spectrometer with electrospray positive-mode ionization. With a stable isotopic internal standard, our assay met the criteria outlined by the Food and Drug Administration guidance for bioanalytical method validation, demonstrating robust performance within the range from 5 to 5000 ng/mL. This assay will support ongoing and future clinical studies by defining tuvusertib pharmacokinetics.

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.

3089 Background: Pre-clinical data has shown that mutations in isocitrate dehydrogenase (IDH) 1 and 2 can lead to impaired homologous recombination repair. IDH1/2 mutations are frequently present in gliomas and cholangiocarcinomas but also in other solid tumors, such as chondrosarcomas. AZD6738 is an ATR inhibitor, and Olaparib is a PARP inhibitor. Preclinical evidence showed a synergistic effect of this combination in models with DNA damage repair effects. This study aims to evaluate the efficacy of Olaparib and AZD6738 in treating advanced IDH1/2 mutated solid. Methods: NCI 10222 is an open-label Phase II clinical trial performed in the NCI National Clinical Trials Network evaluating olaparib 300 mg twice daily with AZD6738 160 mg daily for IDH mutated solid tumors refractory to standard treatment. The primary endpoint was the overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: From January 2020 until March 2023, a total of 24 patients with IDH1/IDH2 mutant tumors were enrolled in the study across 8 sites. Of these, 14 (58%) had cholangiocarcinoma, 4 (17%) had chondrosarcomas, and 6 (25%) had other tumors. Most tumors had IDH1 mutations (n = 16, 70%). The median age was 59 years (range 29-83), and 15 (63%) participants were male. Patients had received a median of 3 prior lines of therapy (0-6). After a mean follow-up time of 3 months (0.2-ongoing), no objective responses were seen, leading to the closure of enrollment. The median PFS was 2 months (95% CI 2-4), and the median OS was 7 months (95% CI 3-NE). Only three patients had a clinical benefit, defined as PFS > 6 months, with one patient diagnosed with G1 chondrosarcoma still on treatment with stable disease. Combination of Olaparib with AZD6738 resulted in G3 AE in 9 (38%) patients, leading to 4 (17%) discontinuations. Conclusions: Olaparib with AZD6738 did not demonstrate activity in IDH mutant solid tumors. However, the stability seen in the patient with low-grade tumors could suggest that the effect is restricted to lower-grade tumors, still dependent on IDH mutations. Further evaluation of the correlative data is required to elucidate why pre-clinical evidence suggesting potential efficacy did not translate into clinical benefit in IDH mutant solid tumors. Clinical trial information: NCT03878095 .

The alternative splicing of mRNA precursors allows one gene to yield multiple proteins with distinct functions. CDC-like kinases serve as pivotal regulators of alternative splicing. Control of protein expression also occurs at the level of DNA through histone methylation and demethylation. We investigated the activity of two CLK inhibitors, cirtuvivint and CC-671, and the LSD1 inhibitor iadademstat alone and in combination with anticancer drugs or investigational agents. Well-characterized patient-derived cancer cell lines from the PDMR ( https://pdmr.cancer.gov/models/database.htm ) were used along with standard human cancer cell lines. Multi-cell type-tumor spheroids were grown from a ratio of 6:2.5:1.5 malignant cells, endothelial cells, and mesenchymal stem cells. Following three days of growth, the spheroids were exposed to the single agents or combinations at concentrations up to the clinical Cmax value for each agent, if known. After seven days of exposure, cell viability was assessed using the CellTiter-Glo 3D assay and spheroid volume was assessed by bright field imaging. Several of the targeted oncology drugs exhibited additive and greater-than-additive cytotoxicity when combined with a CLK inhibitor, or the LSD1 inhibitor. These agents included the XPO1 inhibitor, eltanexor, and the KRAS G12D specific inhibitor MRTX-1133 which had activity in tumor lines harboring the KRAS G12D mutation. LSD1 inhibition was effective with ubiquitin proteasome pathway inhibitors. Conclusion: These findings may provide guidance for development of clinical trial combination regimens including cirtuvivint, CC-671 or iadademstat. Full data sets are available on PubChem.