Trial reportClinical cancer research : an official journal of the American Association for Cancer Research2022
A Phase Ib/II Randomized Study of RO4929097, a Gamma-Secretase or Notch Inhibitor with or without Vismodegib, a Hedgehog Inhibitor, in Advanced Sarcoma.
Trial report in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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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.
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Who cites it
38 citing papers in PubMed, 41 citations in OpenAlex.
- Cell differentiation-related signaling pathways: biological functions, diseases and therapeutic targets.Signal transduction and targeted therapy · 2026Review
- Inhibiting METTL3 synergizes with Notch blockade to treat ESCC by targeting cancer stemness via m6A-JAG2.Journal of gastroenterology · 2026Article
- Targeting the Notch signaling pathway in digestive system cancers: from bench to bedside.Cancer cell international · 2026Review
- Decoding notch signaling pathway: an updated insight into its role in colorectal cancer progression and therapy.Cancer cell international · 2026Review
- DNMT2-m5C-ACLY Axis Promotes Lenvatinib Resistance in Hepatocellular Carcinoma Through Histone Acetylation-Mediated Notch Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- SMURF2 in Anticancer Therapy: Dual Role in Carcinogenesis and Theranostics.International journal of molecular sciences · 2026Review
- Cancer stem cell-driven drug resistance in colorectal carcinoma: molecular aspects and therapeutic potentials.Molecular cancer · 2026Review
- Resistance to SMO Inhibitors in Advanced Basal Cell Carcinoma: A Case Highlighting the Role of Molecular Tumor Profiling.International journal of molecular sciences · 2025Article
- The Notch signaling pathway in regulating bone and cartilage homeostasis: novel insights into the pathogenesis and therapeutics of osteoarthritis.Cell communication and signaling : CCS · 2025Review
- Towards directed therapy for fusion-positive rhabdomyosarcoma.Pharmacology & therapeutics · 2025Review
- SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics.Genome medicine · 2025Article
- Article
- EZH2 inhibitor and Vismodegib synergistically inhibit the growth and metastasis of medulloblastoma.Medical oncology (Northwood, London, England) · 2025Article
- Emerging strategies in colorectal cancer immunotherapy: enhancing efficacy and survival.Frontiers in immunology · 2025Review
- Chondrosarcoma: Adjuvant Therapeutic Effects of the ASPH Small Molecule Inhibitor, SMI-1182, With Doxorubicin.Japanese journal of cancer and oncology research · 2025Article
- Targeting Fibrosis: From Molecular Mechanisms to Advanced Therapies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Identification of ANXA1 as a Novel Upstream Negative Regulator of Notch1 Function in AML.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Osteosarcoma through the Lens of Bone Development, Signaling, and Microenvironment.Cold Spring Harbor perspectives in medicine · 2024Review
- Notch signaling pathway in cancer: from mechanistic insights to targeted therapies.Signal transduction and targeted therapy · 2024Review
- Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways.International journal of molecular sciences · 2024Review
Corrections and comments
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Authors and funding
20 authors at 3 institutions in 2 countries.
Funding
Abstract
purposeBecause the Hedgehog and Notch pathways are often overexpressed in mesenchymal malignancies, we evaluated the efficacy of concurrent inhibition of Notch and Hedgehog signaling using the gamma-secretase inhibitor (GSI) RO4929097 and the smoothened antagonist vismodegib in unresectable or metastatic sarcoma. PATIENTS AND
methodsIn this investigator-initiated trial, phase Ib used standard 3+3 dose escalation in which patients first received vismodegib once daily for 21 days, followed by the combination of RO4929097 concurrently with vismodegib in 21-day cycles. In phase II, patients were randomized to RO4929097 alone or in combination with vismodegib.
resultsNine patients were treated in phase Ib with no dose-limiting toxicities. RO4929097 at 15 mg daily in combination with 150 mg daily of vismodegib was declared the recommended phase II dose. Most adverse events were grade ≤ 2. In phase II (closed early due to discontinuation of RO4929097 evaluation), 34 patients were randomized to RO4929097 alone and 33 to RO4929097 plus vismodegib. RO4929097 did not interfere with the steady-state concentration of vismodegib, while vismodegib reduced the plasma concentration of RO492909. No patients had an objective response. Neither progression-free nor overall survival differed significantly between treatment arms. Paired tumor biopsies from a subset of patients demonstrated inhibition of cleaved Notch.
conclusionsThe combination of RO4929097 plus vismodegib was generally well tolerated. Although accrual to this study was not completed, vismodegib did not meaningfully enhance the clinical efficacy of RO4929097 in an unplanned analysis. GSIs and GSIs plus vismodegib can inhibit intratumoral Notch and downstream phosphorylated Akt signaling.
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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.