Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer.
OBJECTIVE
In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated.


METHODS
Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus.


RESULTS
Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%).


CONCLUSIONS
In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.
Chan
Stephen
S
Department of Clinical Oncology, Nottingham City Hospital, Hucknall Rd, Nottingham N65 1PB, United Kingdom. schan2@ncht.trent.nhs.uk
Scheulen
Max E
ME
Johnston
Stephen
S
Mross
Klaus
K
Cardoso
Fatima
F
Dittrich
Christian
C
Eiermann
Wolfgang
W
Hess
Dagmar
D
Morant
Rudolph
R
Semiglazov
Vladimir
V
Borner
Markus
M
Salzberg
Marc
M
Ostapenko
Valerijus
V
Illiger
Hans-Joachim
HJ
Behringer
Dirk
D
Bardy-Bouxin
Nathalie
N
Boni
Joseph
J
Kong
Steven
S
Cincotta
Maria
M
Moore
Laurence
L
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019540:Area Under Curve; D001859:Bone Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011494:Protein Kinases / Q000187:drug effects*; D012449:Safety; D016879:Salvage Therapy; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012983:Soft Tissue Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus