Ridaforolimus for patients with progressive or recurrent malignant glioma: A perisurgical, sequential, ascending-dose trial

摘要: This perisurgical phase 1 study evaluated the pharmacokinetics, pharmacodynamics, and safety of mammalian target rapamycin (mTOR) inhibitor ridaforolimus in patients (N = 10) with progressive or recurrent primary grade IV malignant glioma, who failed standard therapy. The objective was to determine maximum tolerated dose (MTD) ridaforolimus. Treatment administered intravenously at doses 12.5 mg (N = 7) 15 mg (N = 3) once daily for 4 days prior surgical resection, then resumed 5 consecutive days every 2 weeks until disease progression unacceptable toxicity, following a postsurgical recovery period. MTD not determined because trial suspended early due slower than expected patient accrual drug administration challenges. Pharmacokinetic pharmacodynamic analyses showed that concentrations declined slowly during 24-h dosing interval remained detectable 10 days after last infusion whole blood samples. In peripheral mononuclear cells, median levels mTOR downstream effector p4E-BP1 were reduced by >80% compared baseline 4 h dosing. Resected brain specimens pS6, another effector, while nuclear staining p27kip1, protein functions as cell cycle inhibitor, increased treatment. No dose-limiting toxicities observed, reported adverse events consistent previously established profile One 3 evaluable efficacy had stable best response. Results suggest can cross blood–brain barrier areas tumor involvement, may inhibit activity advanced gliomas based on decreased pS6 levels. design should serve template evaluating intratumoral pharmacokinetics pharmacodynamics other targeted agents this population.