A phase 1b study of oral rapamycin (sirolimus) in patients with advanced malignancies

Abstract

3510 Background: Rapamycin (R) analogues are being studied as cancer therapies since mTOR is recognized as a relevant target in several cancer types. However, R is readily available, has been well-studied in organ transplant patients, was the first recognized mTOR inhibitor, and demonstrates efficacy in preclinical cancer models. The aims of this study were to define R’s maximum tolerated dose (MTD), observed toxicities, dose-limiting toxicities (DLT), pharmacokinetics and effect on inhibition of phosphorylation of p70 S6 kinase (S6K) in peripheral T-cells (PTL). Methods: R was administered orally once weekly to successive cohorts of patients using an adaptive escalation design based on whole blood concentrations ([R]), using a validated HPLC procedure. S6K was assessed by stimulating CD3+ cells ex-vivo with PMA and ionomycin for 1 hour, followed by Western blot analysis using antibodies directed against phospho-Thr389 of S6K versus total S6K as a loading control. Results: 24 subjects have been enrolled in dose cohorts of 10 mg, 20 mg, 30 mg, and 60 mg. The mean [R] observed on day 2 of week 1 (24 hr after 1 st dose) was 5.5±2.7, 11.6±6.0 and 22.6±10.7 ng/mL, for dose levels 10 mg, 20 mg and 30 mg, respectively. [R] decreased by ∼50% by day 4 of week 1 (2.7±1.0, 6.9±4.0 and 11.0±7.7 ng/mL, respectively). By day 1 of week 2 (prior to the next dose of R), [R] had decreased below the limit of quantitation (2 ng/mL) for all subjects at 10 mg, 3 of 7 at 20 mg, and 4 of 6 at 30 mg. Preliminary analysis suggests that sustained phospho-S6K inhibition was achieved in some patients at 30 mg. The most common toxicities observed included nausea (50%), diarrhea (42%), asthenia (38%), hyperglycemia (58%), anemia (46%), and lymphopenia (33%). DLTs observed include 1 patient with grade 3 pneumonia at 20 mg, 1 patient with grade 3 dehydration at 30 mg, and 1 patient with grade 3 asthenia at 60 mg. Stable disease has been observed in 46% of evaluable patients. Conclusions: R can be feasibly administered orally on a once weekly schedule with a similar toxicity and pharmacokinetic profile compared with other mTOR inhibitors. Preliminary evidence suggests that prolonged suppression of phospho-S6K in PTL is possible at well-tolerated doses. No significant financial relationships to disclose.