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Published on: June 9, 2016
Phase II multicenter trial of imatinib in 10 histologic subtypes of sarcoma using a bayesian hierarchical statistical
Rashmi Chugh1, J Kyle Wathen, Robert G Maki
11500 E Medical Center Dr, C407 Med Inn, SPC 5843, Ann Arbor, MI 48109-5843, USA. rashmim@umich.edu
Abstract:
PURPOSE The purpose of this trial was to assess the efficacy of imatinib in patients with one of 10 different subtypes of advanced sarcoma. PATIENTS AND METHODS Eligible patients were treated daily with imatinib dosed at 300 mg twice a day (for body-surface area > or = 1.5 m(2)). The primary end point was response (clinical benefit response [CBR]), defined as complete (CR) or partial response (PR) at 2 months, or stable disease, CR, or PR at 4 months. Rules for early termination within each disease type were based on a Bayesian hierarchical probability model (BHM) accounting for correlation of the responses of the 10 subtypes. Available tissue samples were analyzed for molecules within the KIT/platelet-derived growth factor receptor (PDGFR) signal transduction pathway. Results One hundred eighty-five assessable patients with one of 10 subtypes of sarcoma were treated. One CR and three PRs were achieved. A CBR was achieved in 28 patients treated overall and by subtype: two angiosarcomas (n = 16), 0 Ewing (n = 13), one fibrosarcoma (n = 12), six leiomyosarcomas (n = 29), seven liposarcomas (n = 31), three malignant fibrous histiocytomas (n = 30), five osteosarcomas (n = 27), one malignant peripheral-nerve sheath tumor (n = 7), 0 rhabdomyosarcoma (n = 2), and three synovial sarcomas (n = 22). Variable expression and mutations within the KIT/PDGFR pathway were observed. CONCLUSION This is the first phase II study of a new agent in sarcoma to include sufficient patients with each of the common histologic subtypes to permit generalizable conclusions. The BHM is an effective method for studying rare diseases and their subtypes, when it is reasonable to assume that their response rates are exchangeable. Although rare dramatic responses were seen, imatinib is not an active agent in advanced sarcoma in these subtypes.
Insights
This phase II trial assessed imatinib in advanced sarcoma subtypes. Imatinib showed limited efficacy across 10 sarcoma subtypes, with rare dramatic responses observed.
Area of Science:
- Oncology
- Medical Research
- Clinical Trials
Background:
- Advanced sarcoma comprises diverse histologic subtypes, necessitating subtype-specific treatment evaluations.
- Imatinib, a tyrosine kinase inhibitor, has shown efficacy in certain cancers, prompting investigation in various sarcoma types.
Purpose of the Study:
- To evaluate the efficacy of imatinib in patients with 10 different subtypes of advanced sarcoma.
- To determine response rates and identify potential predictive biomarkers within the KIT/PDGFR pathway.
Main Methods:
- A phase II clinical trial involving 185 assessable patients with advanced sarcoma subtypes.
- Daily administration of imatinib at 300 mg twice daily.
- Bayesian hierarchical probability model (BHM) for early termination rules and response correlation across subtypes.
- Analysis of KIT/platelet-derived growth factor receptor (PDGFR) pathway molecules in tissue samples.
Main Results:
- A clinical benefit response (CBR) was achieved in 28 out of 185 patients.
- Response rates varied by sarcoma subtype, with no responses in Ewing sarcoma or rhabdomyosarcoma.
- Variable expression and mutations within the KIT/PDGFR pathway were observed, but not strongly correlated with response.
Conclusions:
- Imatinib demonstrated limited overall efficacy in advanced sarcoma across the studied subtypes.
- The Bayesian hierarchical probability model (BHM) proved effective for studying rare diseases and their subtypes.
- Further research may be needed to identify specific sarcoma subtypes or patient populations that could benefit from imatinib or similar targeted therapies.