Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma.
OBJECTIVE
To evaluate the efficacy, safety, and pharmacokinetics of multiple doses of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma (RCC).


METHODS
Patients (n = 111) were randomly assigned to receive 25, 75, or 250 mg CCI-779 weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, survival, and adverse events. Blood samples were collected to determine CCI-779 pharmacokinetics.


RESULTS
CCI-779 produced an objective response rate of 7% (one complete response and seven partial responses) and minor responses in 26% of these advanced RCC patients. Median time to tumor progression was 5.8 months and median survival was 15.0 months. The most frequently occurring CCI-779-related adverse events of all grades were maculopapular rash (76%), mucositis (70%), asthenia (50%), and nausea (43%). The most frequently occurring grade 3 or 4 adverse events were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%). Neither toxicity nor efficacy was significantly influenced by CCI-779 dose level. Patients were retrospectively classified into good-, intermediate-, or poor-risk groups on the basis of criteria used by Motzer et al for a first-line metastatic RCC population treated with interferon alfa. Within each risk group, the median survivals of patients at each dose level were similar.


CONCLUSIONS
In patients with advanced RCC, CCI-779 showed antitumor activity and encouraging survival and was generally well tolerated over the three dose levels tested.
Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, E Campus, Kirstein 158, Boston, MA 02215, USA. matkins@bidmc.harvard.edu
Michael B
MB
Atkins
Manuel
M
Hidalgo
Walter M
WM
Stadler
Theodore F
TF
Logan
Janice P
JP
Dutcher
Gary R
GR
Hudes
Young
Y
Park
Song-Heng
SH
Liou
Bonnie
B
Marshall
Joseph P
JP
Boni
Gary
G
Dukart
Matthew L
ML
Sherman
D000368:Aged; D000369:Aged, 80 and over; D001682:Biological Availability; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009367:Neoplasm Staging; D011336:Probability; D011379:Prognosis; D018570:Risk Assessment; D016879:Salvage Therapy; D020123:Sirolimus / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D016019:Survival Analysis; D016896:Treatment Outcome
C401859:temsirolimus; D020123:Sirolimus