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Published on: October 27, 2014
Ridaforolimus for patients with progressive or recurrent malignant glioma: a perisurgical, sequential, ascending-dose
David A Reardon1, Patrick Y Wen, W K Alfred Yung
1Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue-SW G460F, Boston, MA 02215, USA. david_reardon@dfci.harvard.edu
Purpose:
This perisurgical phase 1 study evaluated the pharmacokinetics, pharmacodynamics, and safety of the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus in patients (N = 10) with progressive or recurrent primary grade IV malignant glioma, who failed standard therapy. The primary objective of the study was to determine the maximum tolerated dose (MTD) of ridaforolimus.
Methods:
Treatment was administered intravenously at doses of 12.5 mg (N = 7) or 15 mg (N = 3) once daily for 4 days prior to surgical resection, then resumed for 5 consecutive days every 2 weeks until disease progression or unacceptable toxicity, following a postsurgical recovery period.
Results:
The MTD was not determined because the trial was suspended early due to slower than expected patient accrual and postsurgical drug administration challenges. Pharmacokinetic and pharmacodynamic analyses showed that ridaforolimus concentrations declined slowly during the 24-h dosing interval and remained detectable for 10 days after the last infusion in whole blood samples. In peripheral blood mononuclear cells, median levels of the mTOR downstream effector p4E-BP1 were reduced by >80% compared with baseline by 4 h after dosing. Resected brain specimens showed reduced levels of pS6, another mTOR downstream effector, while nuclear staining for p27(kip1), a protein that functions as a cell cycle inhibitor, increased after treatment. No dose-limiting toxicities were observed, and the reported adverse events were consistent with the previously established safety profile for ridaforolimus. One of 3 patients evaluable for efficacy had stable disease as best response.
Conclusion:
Results suggest that ridaforolimus can cross the blood-brain barrier in areas of tumor involvement, and may inhibit mTOR activity in advanced gliomas based on decreased pS6 levels. This perisurgical trial design should serve as a template for evaluating intratumoral pharmacokinetics and pharmacodynamics of other targeted agents in this patient population.
Insights
Ridaforolimus, an mTOR inhibitor, showed potential in treating malignant glioma by crossing the blood-brain barrier and inhibiting tumor cell growth. Further studies are needed to determine its maximum tolerated dose and efficacy.
Area of Science:
- Oncology
- Pharmacology
- Neuro-oncology
Background:
- Malignant gliomas are aggressive brain tumors with poor prognoses.
- Targeted therapies, such as mTOR inhibitors, offer potential treatment avenues.
- Ridaforolimus is an investigational mTOR inhibitor.
Purpose of the Study:
- Evaluate the pharmacokinetics, pharmacodynamics, and safety of ridaforolimus in patients with recurrent grade IV malignant glioma.
- Determine the maximum tolerated dose (MTD) of ridaforolimus in this patient population.
Main Methods:
- A perisurgical phase 1 study involving 10 patients with recurrent grade IV malignant glioma.
- Intravenous administration of ridaforolimus at 12.5 mg or 15 mg daily for 4 days pre-surgery, then every 2 weeks post-surgery.
- Assessment of pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy.
Main Results:
- The study was suspended early; MTD was not determined.
- Ridaforolimus demonstrated slow elimination and sustained detectable levels in whole blood.
- Significant reduction (>80%) in p4E-BP1 levels and decreased pS6 levels in tumor tissue were observed, indicating mTOR inhibition.
- Increased p27(kip1) expression suggests cell cycle inhibition.
- Adverse events were consistent with the known safety profile; no dose-limiting toxicities were reported.
Conclusions:
- Ridaforolimus can penetrate the blood-brain barrier in gliomas and inhibit mTOR signaling.
- The perisurgical trial design is a valuable model for evaluating targeted agents in brain tumors.
- Further investigation is warranted to establish the MTD and efficacy of ridaforolimus.
