2500: Phase I Trial of Thoracic Radiation, Cisplatin and Sirolimus in Non-Small Cell Lung Cancer and Parallel Studies of Drug Effects on Radiation Pneumonitis in Mice

Abstract

Sirolimus is a highly specific inhibitor of the mammalian target of rapamycin (mTOR), and related mTOR inhibitors have demonstrated promising efficacy in lung cancer and other solid malignancies. Preclinical models have demonstrated significant sensitizing effects when sirolimus is combined with either cisplatin or radiation. Thus, the safety and tolerability of sirolimus combined with thoracic radiation and cisplatin was evaluated in lung cancer patients. Because sirolimus monotherapy has been associated with drug-induced pneumonitis, the effects of sirolimus combined with radiation also were evaluated in a murine model for radiation pneumonitis. In a phase I clinical trial, sirolimus was given orally, 5 days per week, in combination with standard 3D-conformal thoracic radiation therapy (60 Gy) and weekly cisplatin (25 mg/m2 IV). The first 3 patients were treated with a daily dose of 2 mg sirolimus, and subsequent patients were treated daily with 5 mg sirolimus. For all but 1 patient, serum sirolimus levels were measured after 3 weeks of drug therapy. In parallel with the clinical study, the effects of sirolimus on radiation pneumonitis were studied in BL6 mice. Mice were randomized into 3 groups of 10 mice each: A) sham RT B) whole thoracic RT (8.9 Gy once per week x 3 fractions) C) RT + sirolimus (1 mg/kg daily). Drug treatment was started with the first dose of radiation and continued for 6 weeks following the completion of RT. The effects of radiation were assessed by breathing rate plethysmography and survival. Seven patients with stage III lung cancer were accrued to the clinical study: 4 women and 3 men. Of the 3 patients treated on dose level 1 (2 mg sirolimus), 1 patient developed Grade 3 pneumonitis that was possibly related to radiation, although he had concomitant diffuse interstitial disease recurrence in the same location. Four patients were accrued to dose level 2 (5 mg sirolimus) and none had pneumonitis. One patient at this dose level had grade 3 toxicities related to therapy including febrile neutropenia, anemia, nausea, vomiting, anorexia, fatigue, dehydration, and dysphagia. Serum levels of sirolimus for all patients were in the therapeutic range: sirolimus levels averaged 3.6 ng/ml (range 3.4 - 3.9) on dose level 1 and 8.8 ng/ml (range 4.7 - 14.2) on dose level 2. In parallel mouse experiments, radiation significantly increased breathing rates by 17 weeks following radiation (p=0.004), and by 41 weeks, mean breathing rates were 370±14, 428±29 and 425±40 breaths per minute for mice treated with sham RT, RT only, or RT + sirolimus. While the breathing rates were significantly different for either RT regimen compared to sham treatment (p≤0.01), there was no difference for irradiated mice treated with or without sirolimus (p=0.8). Mice treated with RT or RT + sirolimus also had a similar mean survival (mean 341 days vs. 346 days, respectively, p=0.8). Combination therapy with sirolimus, radiation and cisplatin was well tolerated in patients and does not appear to increase the risk of radiation pneumonitis.