Phase I trial of sirolimus combined with radiation and cisplatin in non-small cell lung cancer.
OBJECTIVE
The safety and tolerability of sirolimus combined with thoracic radiation and cisplatin was evaluated in patients with lung cancer. In parallel, the effects of sirolimus were studied in a murine model of radiation pneumonitis.


METHODS
The phase I trial evaluated standard three-dimensional conformal thoracic radiation therapy (60 Gy) and weekly cisplatin (25 mg/m2 i.v.) in combination with escalating doses of oral sirolimus. Sirolimus drug levels and inhibition of mTOR signaling to ribosomal S6 protein were assessed in blood. The effects of sirolimus administered during and after whole thoracic radiation of C57BL6/J mice were evaluated by monitoring mouse breathing rates and survival.


RESULTS
Seven patients with stage III lung cancer were accrued to the clinical study. None of the four patients treated with 2 mg/day sirolimus developed dose-limiting toxicities. Three patients were treated with 5 mg/day sirolimus, and one patient at this dose level had dose-limiting toxicity of grade 3 dysphagia. However, the maximally tolerated dose of sirolimus in this regimen was not defined because the study was terminated prematurely because of loss of funding. In the mouse experiments, concomitant sirolimus treatment was not associated with an increase in radiation-associated morbidity or mortality.


CONCLUSIONS
Combination therapy with sirolimus, radiation, and cisplatin was well tolerated in patients.
Sarkaria
Jann N
JN
Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA. sarkaria.jann@mayo.edu
Schwingler
Paul
P
Schild
Steven E
SE
Grogan
Patrick T
PT
Mladek
Ann C
AC
Mandrekar
Sumithra J
SJ
Tan
Angelina D
AD
Kobayashi
Takao
T
Marks
Randolph S
RS
Kita
Hirohito
H
Miller
Robert C
RC
Limper
Andrew H
AH
Leof
Edward B
EB
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011379:Prognosis; D020123:Sirolimus / Q000008:administration & dosage; D015996:Survival Rate
D002945:Cisplatin; D020123:Sirolimus