Phase II multicenter trial of imatinib in 10 histologic subtypes of sarcoma using a bayesian hierarchical statistical model.
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.
Chugh
Rashmi
R
1500 E Medical Center Dr, C407 Med Inn, SPC 5843, Ann Arbor, MI 48109-5843, USA. rashmim@umich.edu
Wathen
J Kyle
JK
Maki
Robert G
RG
Benjamin
Robert S
RS
Patel
Shreyaskumar R
SR
Meyers
Paul A
PA
Myers
Paul A
PA
Priebat
Dennis A
DA
Reinke
Denise K
DK
Thomas
Dafydd G
DG
Keohan
Mary L
ML
Samuels
Brian L
BL
Baker
Laurence H
LH
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
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate