The safety, tolerability, non-tolerated dosage, maximum tolerated dosage (MTD), and preliminary pharmacokinetic profile of the mammalian target of rapamycin (mTOR) inhibitor CC-223 were assessed in patients with advanced cancer, according to an article published online in the journal Cancer.
In this study, 28 patients with advanced solid tumors or multiple myeloma were administered 7.5 to 60 mg of CC-223 initially, followed by an oral daily dosage in 28-day cycles until disease progression.
Results showed hyperglycemia, fatigue, and rash were the three most common grade 3 adverse effects related to the treatment.
Furthermore, four of the patients experienced dose-limiting toxicities, including hyperglycemia, rash, fatigue, and mucositis.
The MTD was determined to be 45 mg per day and the disease control rate was 32%.
The mean terminal half-life was determined to have a range from 4.86 to 5.64 hours, using the pharmacokinetics of CC-223. Patients who received greater than or equal to 45 mg of CC-223 per day demonstrated a maximum observed plasma concentration of 269 to 480 ng per milliliter.
CC-223 greater than or equal to 30 mg per day inhibited the phosphorylation of mTORC1/mTORC2 pathway biomarkers in blood cells, with an exposure-response relationship.
Patients’ responses included one partial response (breast cancer; response duration 220 days; 30-mg/d cohort), eight with stable disease (across ≥15 mg/d cohorts; response duration range, 36-168 days), and 12 patients with progressive disease.
Bendell, J. C., Kelley, R. K., Shih, K. C., Grabowsky, J. A., Bergsland, E., Jones, S., Martin, T., Infante, J. R., Mischel, P. S., Matsutani, T., Xu, S., Wong, L., Liu, Y., Wu, X., Mortensen, D. S., Chopra, R., Hege, K. and Munster, P. N.