Pharmacodynamic-Guided Modified Continuous Reassessment Method–Based, Dose-Finding Study of Rapamycin in Adult Patients With Solid Tumors
| العنوان: | Pharmacodynamic-Guided Modified Continuous Reassessment Method–Based, Dose-Finding Study of Rapamycin in Adult Patients With Solid Tumors |
|---|---|
| المؤلفون: | Heather A. Jacene, Michelle A. Rudek, Antonio Jimeno, Ming Zhao, Sharyn D. Baker, Daniel A. Laheru, Peter Kulesza, Ross C. Donehower, Manuel Hidalgo, Wells A. Messersmith, Jenna Wheelhouse, Anna Howard, Yasmin Khan, Elizabeth Garrett-Mayer, Wen Wee Ma |
| المصدر: | Journal of Clinical Oncology. 26:4172-4179 |
| بيانات النشر: | American Society of Clinical Oncology (ASCO), 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Maximum Tolerated Dose, Pharmacology, Drug Administration Schedule, Dose finding, Pharmacokinetics, Neoplasms, Internal medicine, medicine, Humans, Aged, Aged, 80 and over, Sirolimus, Antibiotics, Antineoplastic, Dose-Response Relationship, Drug, medicine.diagnostic_test, Adult patients, business.industry, Middle Aged, Phase I and Clinical Pharmacology, Clinical trial, Positron emission tomography, Positron-Emission Tomography, Pharmacodynamics, Toxicity, Leukocytes, Mononuclear, Female, business, medicine.drug |
| الوصف: | Purpose Pharmacodynamic studies are frequently incorporated into phase I trials, but it is uncommon that they guide dose selection. We conducted a dose selection study with daily rapamycin (sirolimus) in patients with solid tumors employing a modified continuous reassessment method (mCRM) using real-time pharmacodynamic data as primary dose-estimation parameter. Patients and Methods We adapted the mCRM logit function from its classic toxicity-based input data to a pharmacodynamic-based input. The pharmacodynamic end point was skin phospho-P70 change after 28 days. Pharmacodynamic effect was defined as at least 80% inhibition from baseline. The first two dose levels (2 and 3 mg) were evaluated before implementing the mCRM, and the data used to estimate the next dose level based on statistical modeling. Toxicity-based boundaries limited the escalation steps. Other correlates analyzed were positron emission tomography (PET) and computed tomography, pharmacokinetics, phospho-P70 in peripheral-blood mononuclear cells, and tumor biopsies in patients at the maximum-tolerated dose (MTD). Results Twenty-one patients were enrolled at doses between 2 and 9 mg. Pharmacodynamic effect occurred across dose levels, and toxicity boundaries ultimately drove dose selection. The MTD of daily oral rapamycin was 6 mg. Toxicities in at least 20% were hyperglycemia, hyperlipidemia, elevated transaminases, anemia, leucopenia, neutropenia, and mucositis. Pharmacokinetics were consistent with prior data, and exposure increased with dose. No objective responses occurred, but five previously progressing patients received at least 12 cycles. PET showed generalized stable or decreased glucose uptake unrelated to antitumor effect. Conclusion mCRM-based dose escalation using real-time pharmacodynamic assessment was feasible. However, the selected pharmacodynamic end point did not correlate with dose. Toxicity ultimately drove dose selection. Rapamycin is a well-tolerated and active oral anticancer agent. |
| تدمد: | 1527-7755 0732-183X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0dcf93edeccc653c1c35cd2ed31ce9e8 https://doi.org/10.1200/jco.2008.16.2347 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....0dcf93edeccc653c1c35cd2ed31ce9e8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15277755 0732183X |
|---|