{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:34:29Z","timestamp":1789194869718,"version":"build-2803163510"},"reference-count":21,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"25","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[2008,9,1]]},"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p> 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). <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec>","DOI":"10.1200\/jco.2008.16.2347","type":"journal-article","created":{"date-parts":[[2008,11,26]],"date-time":"2008-11-26T20:13:24Z","timestamp":1227730404000},"page":"4172-4179","source":"Crossref","is-referenced-by-count":62,"title":["Pharmacodynamic-Guided Modified Continuous Reassessment Method\u2013Based, Dose-Finding Study of Rapamycin in Adult Patients With Solid Tumors"],"prefix":"10.1200","volume":"26","author":[{"given":"Antonio","family":"Jimeno","sequence":"first","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle A.","family":"Rudek","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Kulesza","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen Wee","family":"Ma","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna","family":"Wheelhouse","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Howard","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin","family":"Khan","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zhao","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Jacene","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wells A.","family":"Messersmith","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Laheru","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross C.","family":"Donehower","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Garrett-Mayer","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharyn D.","family":"Baker","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Hidalgo","sequence":"additional","affiliation":[{"name":"From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00117-3"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(97)80078-6"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/93.20.1517"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1096\/fj.01-0658com"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-1345(02)03906-4"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-200101270-00019"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1997.tb04318.x"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1007\/s002800050763"},{"key":"R9","unstructured":"Peralba JM, DeGraffenried L, Friedrichs W, et al: Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res 9:2887,2003-2892,"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-8049(99)00229-4"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/92.3.205"},{"key":"R12","doi-asserted-by":"crossref","unstructured":"Gibaldi M, Perrier D: Pharmacokinetics  (ed 2nd). New York, NY, Dekker, 1982","DOI":"10.1201\/b14095"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.04.5245"},{"key":"R14","unstructured":"Gibbons JJ, Discafani C, Peterson R, et al: The effect of CCI-779, a novel macrolide anti-tumor agent, on the growth of human tumor cells in vitro and in nude mouse xenograft in vivo. Proc Am Assoc Cancer Res 40,1999,  (abstr 301)"},{"key":"R15","unstructured":"Dudkin L, Dilling MB, Cheshire PJ, et al: Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 7:1758,2001-1764,"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6603419"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.23.622"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.22195"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-1560"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0050008"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3800995"}],"container-title":["Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascopubs.org\/doi\/pdfdirect\/10.1200\/JCO.2008.16.2347","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T20:22:25Z","timestamp":1653510145000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascopubs.org\/doi\/10.1200\/JCO.2008.16.2347"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,9,1]]},"references-count":21,"journal-issue":{"issue":"25","published-print":{"date-parts":[[2008,9,1]]}},"alternative-id":["10.1200\/JCO.2008.16.2347"],"URL":"https:\/\/doi.org\/10.1200\/jco.2008.16.2347","relation":{},"ISSN":["0732-183X","1527-7755"],"issn-type":[{"value":"0732-183X","type":"print"},{"value":"1527-7755","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,9,1]]}}}