Trial reportCancer chemotherapy and pharmacology2017
A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS-FLI1 fusion transcript.
Trial report in Cancer chemotherapy and pharmacology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01610570 (Phase I/II Trial of Mithramycin in Children and Adults With Refractory Extracranial Solid Tumors), which is not on this map. Cited by 55 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Phase I/II Trial of Mithramycin in Children and Adults With Refractory Extracranial Solid Tumors (Phase I) or Ewing Sarcoma and EWSFLI1 Fusion Transcript (Phase II)
Who cites it
55 citing papers in PubMed, 1 synthesis or guideline pooled it, 75 citations in OpenAlex.
- Systematic review of phase-I/II trials enrolling refractory and recurrent Ewing sarcoma: Actual knowledge and future directions to optimize the research.Cancer medicine · 2021Pooled it
- Trabectedin and low-dose irinotecan to target EWS::FLI1 in Ewing sarcoma: a phase 1/2 trial.Nature medicine · 2026Trial
- Physiologically based pharmacokinetic modeling to predict human pharmacokinetics of a novel mithramycin analog for Ewing sarcoma.Cancer chemotherapy and pharmacology · 2026Article
- Targeting fusion proteins in solid tumors: from oncogenic mechanisms to clinical interventions.Acta pharmacologica Sinica · 2026Review
- Physiologically Based Pharmacokinetic Modeling to Predict Human Pharmacokinetics of a Novel Mithramycin Analog for Ewing Sarcoma.Research square · 2026Article
- Mithramycin alters EWS::FLI1 DNA binding and RNA polymerase II processivity to inhibit nascent transcription.Nature communications · 2026Article
- The SP1-SuperEnhancer-SPHK1 Axis Mediates Niraparib Resistance in TNBC.Pharmaceuticals (Basel, Switzerland) · 2025Article
- New Approaches to Investigate Novel Agents in Ewing Sarcoma: A Report From the Children's Oncology Group Bone Tumor Committee.Pediatric blood & cancer · 2025Review
- Screening FDA-Approved Oncology Drugs with Three-Dimensional Spheroids Identifies Romidepsin as a Therapeutic Candidate for Osteosarcoma.Cancer research communications · 2025Article
- Evaluation of Mithramycin in Combination with Chemotherapeutic Agents Against Ewing Sarcoma Cell Lines.Cancers · 2025Article
- Preclinical Pharmacokinetic Evaluation of Mithramycin and Mithramycin SA Tryptophan-Conjugated Analog.Pharmaceutics · 2025Article
- The Position of Indole Methylation Controls the Structure, DNA Binding, and Cellular Functions of Mithramycin SA-Trp Analogues.Chembiochem : a European journal of chemical biology · 2025Article
- Targeted inactivation of EWSR1 : : FLI1 gene in Ewing sarcoma via CRISPR/Cas9 driven by an Ewing-specific GGAA promoter.Cancer gene therapy · 2025Article
- Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer.Experimental hematology & oncology · 2025Article
- Druggable upregulated proteins in EWS-FLI-driven Ewing sarcoma as emerging new therapeutic targets.American journal of translational research · 2025Review
- Enhancing Standard of Care Chemotherapy Efficacy Using DNA-Dependent Protein Kinase (DNA-PK) Inhibition in Preclinical Models of Ewing Sarcoma.Molecular cancer therapeutics · 2024Article
- Differential Expression of SRY-Related HMG-Box Transcription Factor 2, Oligodendrocyte Lineage Transcription Factor 2, and Zinc Finger E-Box Binding Homeobox 1 in Serum-Derived Extracellular Vesicles: Implications for Mithramycin Sensitivity and Targeted Therapy in High-Grade Glioma.ACS pharmacology & translational science · 2024Article
- ELK4 Promotes Colorectal Cancer Progression by Activating the Neoangiogenic Factor LRG1 in a Noncanonical SP1/3-Dependent Manner.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Article
- Poly(ADP-ribose) Polyremase-1 (PARP-1) Inhibition: A Promising Therapeutic Strategy for ETS-Expressing Tumours.International journal of molecular sciences · 2023Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
purposeIn a preclinical drug screen, mithramycin was identified as a potent inhibitor of the Ewing sarcoma EWS-FLI1 transcription factor. We conducted a phase I/II trial to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of mithramycin in children with refractory solid tumors, and the activity in children and adults with refractory Ewing sarcoma. PATIENTS AND
methodsMithramycin was administered intravenously over 6 h once daily for 7 days for 28 day cycles. Adult patients (phase II) initially received mithramycin at the previously determined recommended dose of 25 µg/kg/dose. The planned starting dose for children (phase I) was 17.5 µg/kg/dose. Plasma samples were obtained for mithramycin PK analysis.
resultsThe first two adult patients experienced reversible grade 4 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation exceeding the MTD. Subsequent adult patients received mithramycin at 17.5 µg/kg/dose, and children at 13 µg/kg/dose with dexamethasone pretreatment. None of the four subsequent adult and two pediatric patients experienced cycle 1 DLT. No clinical responses were observed. The average maximal mithramycin plasma concentration in four patients was 17.8 ± 4.6 ng/mL. This is substantially below the sustained mithramycin concentrations ≥50 nmol/L required to suppress EWS-FLI1 transcriptional activity in preclinical studies. Due to inability to safely achieve the desired mithramycin exposure, the trial was closed to enrollment.
conclusionsHepatotoxicity precluded the administration of a mithramycin at a dose required to inhibit EWS-FLI1. Evaluation of mithramycin in patients selected for decreased susceptibility to elevated transaminases may allow for improved drug exposure.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.