Efficacy and safety of imatinib mesylate (Gleevec) and immunohistochemical expression of c-Kit and PDGFR-beta in a Gynecologic Oncology Group Phase Il Trial in women with recurrent or persistent carcinosarcomas of the uterus.
OBJECTIVE
This multi-institutional phase II trial assessed the activity and toxicity of imatinib mesylate and explored c-Kit and platelet-derived growth factor receptor (PDGFR)-beta in recurrent or persistent uterine carcinosarcoma.


METHODS
Women with measurable uterine carcinosarcoma, who had a performance status of 0, 1, or 2 and had received up to two prior treatment regimens, were eligible and treated with a 600-mg daily oral dose of imatinib mesylate until disease progression or unacceptable toxicity. Endpoints included progression-free survival (PFS) >or=6 months, overall toxicity, PFS, overall survival (OS), and response. c-Kit and PDGFR-beta were evaluated by immunohistochemistry in archival tumor.


RESULTS
Twenty-six women were enrolled, 23 were eligible/evaluable, 1 was ineligible (wrong primary), and 2 were inevaluable (never treated). One subject had a PFS time >or=6 months, yielding the only patient with stable disease. All other patients had progressive disease (n=17) or were inevaluable for tumor response (n=5). Adverse events included grade 4 hypocalcemia (n=1) and grade 3 fatigue, dehydration and anorexia, genitourinary/renal, lymphatic, metabolic, and ocular toxicity (n=1 each, 4%). Positive expression of c-Kit or PDGFR-beta was observed in 88% (14/16) or 40% (6/15) and in 56% (9/16) or 73% (11/15) of cases in the sarcoma and carcinoma component of the tumor, respectively. Expression of c-Kit in the carcinoma component appeared to be associated with worse OS. No other associations were notable.


CONCLUSIONS
Imatinib mesylate was generally well tolerated but had minimal activity as a single agent in unscreened patients. The potential association between carcinomatous c-Kit and OS requires validation.
Huh
Warner K
WK
Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
Sill
Michael W
MW
Darcy
Kathleen M
KM
Elias
Kevin M
KM
Hoffman
James S
JS
Boggess
John F
JF
Alvarez
Ronald D
RD
Long
Harry J
HJ
O'Malley
David M
DM
Birrer
Michael J
MJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D002296:Carcinosarcoma / Q000188:drug therapy* / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis*; D016896:Treatment Outcome; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt