The methylenetetrahydrofolate reductase C677T mutation, factor V G1691A (factor V Leiden) mutation, prothrombin G20210A mutation and 8 other laboratory values associated with increased thrombotic risk were analyzed in 40 patients with sudden sensorineural hearing loss (SSHL). The results were compared with those obtained from 120 controls not affected by SSHL. We found a statistically significant higher frequency of hyperhomocysteinemia in the SSHL group compared with controls, and that this was also associated with the presence of homozygosity for the MTHFR C677T mutation. The study results suggest that SSHL might be caused, among other factors, by a combination of these 2 variables. We suggest that this analysis of the MTHFR C677T mutation should be further investigated to establish the etiology of SSHL, and that the same analysis should be taken into account in those patients with high levels of homocysteine.
e15091 Background: CDK 8 /CDK19 are kinases involved in transcriptional control of embryonic development and cellular homeostasis via the mediator complex. They are also described to maintain tumor dedifferentiation and stem cell properties. A variety of cancer cells hijack the mediator complex and targeting cancer-specific gene transcription via CDK8/19 inhibition has potential for treatment of solid tumors. RVU120 (SEL120) is a selective CDK8/19 inhibitor with preclinical efficacy in hematologic malignancies and a variety of solid tumor types (Rzymski et al. 2017). RVU120 showed strong anticancer activity in preclinical triple-negative breast cancer (TNBC) models, especially in the mesenchymal stem-like (MSL) molecular subtype (Rzymski et al SABCS 2021). Methods: A Phase I/II clinical trial of RVU120 in solid tumors is currently ongoing (NCT05052255). Patients with metastatic or advanced solid tumors without available treatments receive increasing doses of RVU120 as a single oral dose every other day (QOD) for a total of 7 doses on Days 1, 3, 5, 7, 9, 11 and 13, in a 3-week treatment cycle. Primary objectives of the study are safety / tolerability of RVU120 as single agent and determination of the recommended Phase II dose (RP2D) via a 3+3 dose escalation design. Secondary objectives include objective response rate (ORR) (RECIST criteria v1.1) and PK of RVU120. Results: As of 11FEB 2022, 5 pts have been enrolled into the trial: 3 into cohort 1, 75 mg dose, 2 into cohort 2, 100 mg. None of the pts experienced a DLT, SAEs or > Grade 3 AE. Treatment-related AEs were all G1 except for G2 diarrhea and weakness. Cohort 1 patients had at least 1 post-baseline tumor assessment. A 62 YO patient, stage IV esophago-gastric junction carcinoma, metastases to the liver, retroperitoneum, adrenal gland and portocaval lymph nodes, progressing after 4 lines of previous therapy, achieved a SD with a +4% change of target lesion size and progressed in cycle 6. A 65 YO patient, stage IV adenoid cystic carcinoma of the trachea, metastases to the lung and refractory to antiandrogens and radiotherapy, achieved a SD with -4% change of target lesion size after 3 cycles and is currently ongoing in cycle 5. A 43 YO pt stage IV thymic carcinoma, metastases to the lung, mediastinum, pleura and lymph nodes, progressing under cisplatin/etoposide, stopped study drug at the end of cycle 3 for PD in non-target lesions, target lesions increased by 11%. Cohort 2 patients, a 65 YO pt with pancreatic cancer stage IV, metastases to liver and lung, and a 55 YO pt with TNBC stage IV, metastases to the lung, will be evaluated end of cycle 3. Conclusions: In the first dose escalation level with single agent RVU120, no DLTs or ≥G3 AEs were observed in patients with previously progressive solid tumors. Initial assessments in 3 pts demonstrated stable disease in 2 patients. Collection of further data at higher doses is ongoing with 2 patients enrolled at 100 mg. Clinical trial information: NCT05052255.
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Background: Myelodysplastic syndromes (MDS) are a group of malignant blood disorders characterized by ineffective hematopoiesis and cytopenias and frequent evolution to acute myeloid leukemia (AML). MDS results from the expansion of genetically and epigenetically changed clones with impaired differentiation and maturation. Primary clinical goals in MDS are to achieve remissions, alleviate symptoms associated with cytopenias, and minimize the transfusion burden. While supportive red blood cell transfusions, erythropoiesis-stimulating agents and novel targeted agents may lead to clinical improvement, an allogeneic bone marrow transplant (BMT) remains the only potential curative option for patients with MDS. RVU120 (SEL120) is a specific, selective inhibitor of CDK8 and its paralog CDK19. A first-in-human Phase Ib clinical trial with RVU120 in patients with AML or high risk (HR)-MDS is currently ongoing. Preclinical studies indicated the strong antileukemic potential of RVU120 that was often associated with the multilineage commitment of CD34+ AML cells. Moreover, RVU120 could improve proliferation and induce erythroid differentiation of CD34+ cells derived from Diamond-Blackfan anemia (DBA) patients. Aims: Primary aim was to evaluate the erythroid differentiation potential of RVU120 in primary MDS and transformed cord blood CD34+ blood cells characterized with an early block in erythroid differentiation. Methods: Efficacy and mechanism of action of RVU120 and other CDK8 inhibitors were investigated in cord blood (CB) cells transduced with TLS-ERG, a fusion gene generated from t(16;21)(p11;q22). Transformed cells displayed an increased capacity for self-renewal, proliferation, and altered erythroid differentiation. Efficacy was further tested in CD34+ cells isolated from BM of MDS patients and established MDS cell lines. Cells were treated with RVU120 and global transcriptional changes and chromatin status were analyzed by RNA-seq, ATAC-seq, and ChIP-seq. Cell cycle, proliferation, and lineage-specific markers were studied by flow cytometry in liquid and semi-solid methylcellulose-based media. Results: RVU120 treatment leads to transcriptional reprogramming of transformed CD34+ CB cells. The most profound changes included decreased CDK8 occupancy followed by increased STAT5 and RNA Polymerase II loading at transcription start site and gene bodies. RVU120 treatment transcriptionally represses multiple genes associated with hematopoietic and leukemia stem cells such as CD34, FLI1, ENG and RGS18 and importantly induce the expression of genes involved in erythroid commitment, including regulators of erythroid/megakaryocytic fate, such as RGS18, KLF1, FLI1, INHBA, GATA1/2 and hemoglobin genes. Detailed analysis of transformed CB and MDS CD34+ cells by flow cytometry at early and late time points reflected sequential changes in the expression of lineage-specific surface markers, leading to erythroid differentiation. Conclusions: Presented results indicate strong erythroid differentiation potential of RVU120 in CD34+ cells that acquired genetic abnormalities leading to arrested erythroid commitment, characteristics of many MDS and AML subtypes. Observed differentiation phenotype strikingly resembles effects of RVU120 in DBA cells caused by disruption of genes encoding ribosomal proteins. Detailed transcriptomic profiling strongly links the differentiation with enrichment of genes representing regulators of erythroid commitment and hemoglobin metabolism. Further studies are warranted to investigate the efficacy of RVU120 in chronic anemias associated with bone marrow failures in AML and MDS patients. Figure 1 Figure 1. Disclosures Pakulska: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Obacz: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Goller: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Combik: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Keska: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mazan: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Juszczynski: Ryvu Therapeutics: Current equity holder in publicly-traded company. Brzozka: Ardigen: Current Employment, Membership on an entity's Board of Directors or advisory committees; Selvita SA: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Dziedzic: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Angelosanto: Ryvu Therapeutics: Current Employment. Shamsili: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rzymski: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company.
Background: CDK8 and its paralog CDK19 are part of the kinase module of the mediator complex, which functions as a bridge between enhancers and core promoters. The CDK8 module functions as a master regulator of transcription and lineage development, including regulation of various oncogenic programs and importantly also hematopoiesis and differentiation. The CDK8/CDK19 inhibitor RVU120 (SEL120) is being investigated in a Phase Ib clinical study (NCT04021368) in AML and HR-MDS patients. Preclinical data indicate the high efficacy of RVU120 in AML models, particularly in cells with stem cell-like characteristics, where the treatment leads to lineage commitment and eventually cell death. Results from the patient cohorts of the dose-escalation phase indicate signs of clinical efficacy, including a complete response (CR) in a relapsed/refractory (R/R) AML patient. Aim: It is now critical to establish the relationship between preclinical and clinical efficacy results and molecular characteristics to identify actionable biomarkers predicting response to CDK8/CDK19 inhibitors. Methods: Association between gene mutations and gene expression patterns with responses to RVU120 has been analyzed on 27 genetically annotated AML patient-derived cells (PDCs). The activity and efficacy of RVU120 were assessed in both non-differentiating and differentiating media followed by flow cytometry and bioinformatics analysis. DNMT3A mutant PDCs were implanted intravenously into NSG-SGM3 mice and after disease onset, animals were treated orally with RVU120. Profiling of transcriptional response to RVU120 in DMNT3A mutant cells has been performed by RNA-seq. The first-in-human Phase1b study CLI120-001 (NCT04021368) of RVU120 is currently enrolling R/R AML and HR-MDS patients, in a dose-escalation design aimed at exploring safety/tolerability and identifying the randomized Phase II dose (RPD2). RVU120 is administered orally, every other day (EOD), 7 total doses per cycle, in 21-day treatment cycles until disease progression/unacceptable toxicity. Local assessment of Bone Marrow (BM) and Peripheral Blood (PB) are performed at different time points according to investigator guidelines to define response to study drug according to Dohner 2017 response criteria. Results: Screening of 27 AML PDCs against RVU120 and other non-related CDK8/CDK19 inhibitors indicated high anti-cancer efficacy in >40% of tested samples (12 out of 27). Correlation of efficacy with the genetic profile of samples showed specific enrichment of DNMT3A mutants (8 out of 12) in the responder group (p=0.015). Notably, efficacy results were further corroborated in vivo in a disseminated PDX AML model, showing complete clearance of blasts positive for DNMT3A mutation and recovery of normal murine BM in animals treated with RVU120. Molecular profiling of responder cells indicated transcriptional reprogramming and lineage commitment. At the date of this abstract submission, 7 patients have been enrolled into the Phase 1b CLI120-001 trial: 5 AML and 2 HR-MDS patients, median age 73 years, failing 2 median previous lines of therapy. Notably, a 62 YO R/R AML patient that has achieved a CR was positive for DNMT3A R882C mutation. At study entry, this patient had progressed after venetoclax/decitabine, with pancytopenia and >50% BM monocytic blasts and skin leukemia. At the end of the first cycle of the study drug, BM showed complete clearance of blasts with hematological recovery and strong monocytic differentiation starting in cycle 2. Skin leukemia lesions improved gradually during treatment with a complete resolution in cycle 7, resulting in CR. After 1 month from CR patient progressed with 65% BM blasts with the same phenotype as at the study entry. Conclusion: AML PDCs with DNMT3 mutations show increased sensitivity to RVU120 treatment both in vitro and in vivo. The anti-cancer efficacy of RVU120 was strongly associated with transcriptomic reprogramming and lineage commitment. Preliminary evidence of response to RVU120 has also been shown in a R/R AML patient positive for DNMT3A mutation that has achieved a CR. Further molecular studies in more patients treated with RVU120 are ongoing and could provide evidence for predictive biomarkers of response to RVU120 in AML. Figure 1 Figure 1. Disclosures Rzymski: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Pakulska: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Burris: Boehringer Ingelheim: Consultancy, Other: research grant ; AstraZeneca: Consultancy, Other: research grant ; Bayer: Consultancy, Other: research grant ; Daiichi Sankyo: Consultancy; Grail: Consultancy; Incyte: Consultancy, Other: research support; Novartis: Consultancy, Other: research grant, Expert Testimony; Pfizer: Consultancy, Other: research grant ; Vincerix Pharma: Consultancy; Abbvie: Other: research grant ; Agios: Other: research grant ; ARMO Biosciences: Other: research grant ; Array BioPharma: Other: research grant ; BioAtla: Other: research grant ; BioMed Valley Discoveries: Other: research grant ; Boehringer Ingelheim: Other: research grant ; Bristol Myers Squibb: Other: research grant ; CALGB: Other: research grant ; CicloMed: Other: research grant ; eFFECTOR Therapeutics: Other: research grant ; Lilly: Other: research grant ; EMD Serono: Other: research grant ; Roche/Genetech: Other: research grant ; GlaxoSmithKline: Other: research grant ; Harpoon: Other: research grant ; Hengrui Therapeutics: Other: research grant ; Infinity Pharmaceuticals: Other: research grant ; Janssen: Other: research grant ; Jounce: Other: research grant ; Kymab: Other: research grant ; MacroGenics: Other: research grant ; MedImmune: Other: research grant ; Merck: Other: research grant ; Millennium Pharmaceuticals: Other: research grant ; Moderna: Other: research grant ; Foundation Medicine: Other: research grant ; Revolution Medicine: Other: research grant ; Seattle Genetics: Other: research grant ; Tesaro: Other: research grant ; TG Therapeutics: Other: research grant ; Verastem: Other: research grant ; Vertex Pharmaceuticals: Other: research grant ; XBiotech: Other: research grant ; Zymeworks: Other: research grant ; Arch Oncology: Other: research grant ; Arvinas: Other: research grant ; Coordination Pharmaceuticals: Other: research grant ; NGM Biopharmaceuticals: Other: research grant ; Gossamer Bio: Other: research grant ; Ryvu Therapeutics: Other: research grant ; BioTheryX: Other: research grant ; HCA Healthcare: Other: stock ownership. Obacz: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Goller: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Combik: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mazan: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Juszczynski: Ryvu Therapeutics: Current equity holder in publicly-traded company. Zawadzka: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Brzozka: Selvita SA: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Ardigen: Current Employment, Membership on an entity's Board of Directors or advisory committees; Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Shamsili: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Angelosanto: Ryvu Therapeutics: Current Employment.
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