title: Phase II multicenter trial of imatinib in 10 histologic subtypes of sarcoma using a bayesian hierarchical statistical model.
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.
authors.affiliation: 1500 E Medical Center Dr, C407 Med Inn, SPC 5843, Ann Arbor, MI 48109-5843, USA. rashmim@umich.edu
authors.forename: Rashmi
authors.initials: R
authors.lastname: Chugh
authors.forename: J Kyle
authors.initials: JK
authors.lastname: Wathen
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
authors.forename: Robert S
authors.initials: RS
authors.lastname: Benjamin
authors.forename: Shreyaskumar R
authors.initials: SR
authors.lastname: Patel
authors.forename: Paul A
authors.initials: PA
authors.lastname: Meyers
authors.forename: Paul A
authors.initials: PA
authors.lastname: Myers
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Priebat
authors.forename: Denise K
authors.initials: DK
authors.lastname: Reinke
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.forename: Mary L
authors.initials: ML
authors.lastname: Keohan
authors.forename: Brian L
authors.initials: BL
authors.lastname: Samuels
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Baker
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001499:Bayes Theorem; D001549:Benzamides; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000627:therapeutic use*; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate