Phase I study of cediranib, an oral VEGFR inhibitor, in combination with selumetinib, an oral MEK inhibitor, in patients with advanced solid malignancies
| Autor: | Grace Lin, Carrie Strand, Charles Erlichman, Alex A. Adjei, Jack Fiskum, Michael Menefee, Brian A. Costello, Joleen M. Hubbard, Rui Qin, Paul Haluska, Erin L. Schenk, Joel M. Reid, Jun Yin, Percy Ivy, L. Austin Doyle |
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| Rok vydání: | 2021 |
| Předmět: |
Oncology
Adult Male medicine.medical_specialty Disease Response Maximum Tolerated Dose VEGF receptors Antineoplastic Agents Drug Administration Schedule Article Cediranib chemistry.chemical_compound Internal medicine Neoplasms Antineoplastic Combined Chemotherapy Protocols Medicine Humans Pharmacology (medical) Progression-free survival Aged Pharmacology Aged 80 and over Mitogen-Activated Protein Kinase Kinases biology Dose-Response Relationship Drug business.industry Vascular Endothelial Growth Factors MEK inhibitor Middle Aged Vascular endothelial growth factor Tolerability chemistry Selumetinib biology.protein Quinazolines Benzimidazoles Female business medicine.drug |
| Zdroj: | Invest New Drugs |
| ISSN: | 1573-0646 |
| Popis: | Purpose. Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response. Methods. Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length. Results. Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients. Conclusions. Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib. |
| Databáze: | OpenAIRE |
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