Phase I Studies of Sirolimus Alone or in Combination with Pharmacokinetic Modulators in Advanced Cancer Patients

Abstract

Purpose Sirolimus is the eponymous inhibitor of the mammalian target of rapamycin (mTOR); however, only its analogues have been approved as cancer therapies. Nevertheless, sirolimus is readily available, has been well-studied in organ transplant patients, and demonstrates efficacy in several preclinical cancer models. Experimental Design Three simultaneously conducted phase I studies in advanced cancer patients utilized an adaptive escalation design to find the dose of oral, weekly sirolimus alone or in combination with either ketoconazole or grapefruit juice that achieves similar blood concentrations as its intravenously administered and approved prodrug, temsirolimus. Additionally, the effect of sirolimus on inhibition of p70S6 kinase phosphorylation in peripheral T cells was determined. Results Collectively, the three studies enrolled 138 subjects. The most commonly observed toxicities were hyperglycemia, hyperlipidemia, and lymphopenia in 52%, 43%, and 41% of subjects, respectively. The target sirolimus area under the concentration curve (AUC) of 3810 ng-hr/ml was achieved at sirolimus doses of 90 mg, 16 mg, and 25 mg in the sirolimus alone, sirolimus plus ketoconazole, and sirolimus plus grapefruit juice studies, respectively. Ketoconazole and grapefruit juice increased sirolimus AUC approximately 500% and 350%, respectively. Inhibition of p70 S6 kinase phosphorylation was observed at all doses of sirolimus and correlated with blood concentrations. One partial response was observed in a patient with epithelioid hemangioendothelioma. Conclusion Sirolimus can be feasibly administered orally, once weekly with a similar toxicity and pharmacokinetic profile compared to other mTOR inhibitors and warrants further evaluation in studies of its comparative effectiveness relative to recently approved sirolimus analogues.

Weekly nab-Rapamycin in Patients with Advanced Nonhematologic Malignancies: Final Results of a Phase I Trial

“…At the MTD of 100 mg/m 2 , the C max of nab -rapamycin was 3227.61 ng/mL, which is significantly higher than C max of rapamycin levels achieved in other studies: the C max of 15.5 ng/mL reported with 5 mg oral rapamycin (45), C max of 37.9 ng/mL reported with 9 mg oral rapamycin (46), C max of 57.72 ng/mL reported with 60 mg oral rapamycin (47), and day 5 rapamycin C max of 133.9 ng/mL after 5 days of IV daily administration of temsirolimus at 19.1 mg/m 2 (48). As expected, the half-life of rapamycin from nab -rapamycin was relatively long at 40–91 hours across the tested dose range and was 63 hours at the MTD of 100 mg/m 2 , similar to the half-life of 61–69 hours for oral rapamycin and IV temsirolimus and 45–52 hour for deferolimus given by weekly IV infusion (35, 36, 49, 50).…”

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218

“…We did not demonstrate a significant reduction in phospho‐p70S6K in circulating PBMCs at 2 hours after temsirolimus or predose on day 36 of cycles 1 to 3, although as noted above, temsirolimus‐related toxicity meant that the majority of patients were dosed inconsistently with consequent reduction in drug exposure. Reduction in p70S6K phosphorylation in PBMCs is seen with single‐agent sirolimus at 48 hours after dose and in PBMCs and tumor biopsies after temsirolimus therapy . However, p70S6K was not consistently reduced in the temsirolimus single‐agent pediatric study, in which only two dose levels (25 and 150 mg/m 2 ) showed a reduction at 8 hours after dose but not at other time points (1, 2, 24, and 168 hours after dose) .…”

“…Reduction in p70S6K phosphorylation in PBMCs is seen with single-agent sirolimus at 48 hours after dose and in PBMCs and tumor biopsies after temsirolimus therapy. 31,32 However, p70S6K was not consistently reduced in the temsirolimus single-agent pediatric study, in which only two dose levels (25 and 150 mg/m 2 ) showed a reduction at 8 hours after dose but not at other time points (1, 2, 24, and 168 hours after dose). 5 The preceding pediatric vinblastine/sirolimus phase I study also did not show significant reduction of p70S6K at 28 days after dose.…”

Therapeutic Drug Monitoring on the Safety of Sirolimus in Transplant Patients

“…Sirolimus is an immunosuppressive agent that blocks the molecular target of rapamycin (mTOR inhibitor) [2]. This blockade leads to the inhibition of T-and B-cell proliferation and immunoglobulin production.…”