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

• Published in: Cancer chemotherapy and pharmacology 2012-04, Vol.69 (4), p.849-860
• Main Authors: Reardon, David A., Wen, Patrick Y., Alfred Yung, W. K., Berk, Lori, Narasimhan, Narayana, Turner, Christopher D., Clackson, Timothy, Rivera, Victor M., Vogelbaum, Michael A.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antibiotics, Antineoplastic - adverse effects; Antibiotics, Antineoplastic - pharmacokinetics; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic agents; Biological and medical sciences; Cancer Research; Cohort Studies; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Glioma - drug therapy; Glioma - metabolism; Glioma - pathology; Glioma - surgery; Humans; Immunohistochemistry; Male; Maximum Tolerated Dose; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Neurology; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Sirolimus - adverse effects; Sirolimus - analogs & derivatives; Sirolimus - pharmacokinetics; Sirolimus - therapeutic use; Tumors of the nervous system. Phacomatoses
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-011-1773-y

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.