PMID- 25649370 OWN - NLM STAT- MEDLINE DCOM- 20150825 LR - 20211203 IS - 1097-0142 (Electronic) IS - 0008-543X (Linking) VI - 121 IP - 11 DP - 2015 Jun 1 TI - Phase 1b study of the mammalian target of rapamycin inhibitor sirolimus in combination with nanoparticle albumin-bound paclitaxel in patients with advanced solid tumors. PG - 1817-26 LID - 10.1002/cncr.29254 [doi] AB - BACKGROUND: The optimal weekly oral dose of sirolimus and intravenous nanoparticle albumin-bound paclitaxel (nab-paclitaxel) were evaluated. METHODS: A phase 1b study was performed to evaluate escalating doses of oral sirolimus (5-60 mg) on days 2, 9, and 16 with intravenous nab-paclitaxel (100 mg/m(2) ) on days 1, 8, and 15 in a 28-day cycle. A run-in treatment of nab-paclitaxel (day -14) and sirolimus (day -7) was administered for pharmacokinetic and pharmacodynamic assessments. Clinical trial endpoints included dose-limiting toxicities (DLTs), maximum tolerated doses, and response rates. Pharmacodynamics included immunohistochemistry for phosphatase and tensin homolog, mammalian target of rapamycin (mTOR), AKT, phosphorylated AKT, S6K1, and phosphorylated S6K1; exploratory gene expression analysis; and [(18) F]fludeoxyglucose (FDG) positron emission tomography. RESULTS: Twenty-three patients with advanced solid tumors were treated. Fifteen patients had prior taxane therapy. Twenty-two patients were evaluable for responses. One patient had a complete response, and 5 patients had a partial response (3 confirmed). DLTs were seen in 1 patient each at 10 (grade 3 dyspnea/hypoxia) and 40 mg (grade 4 leukopenia/neutropenia) and in 2 patients at 60 mg (grade 3 fatigue and grade 4 pericardial effusion). Patients with higher expression of posttreatment AKT and a greater decline in FDG activity were more likely to have a treatment response or stable disease. CONCLUSIONS: Sirolimus showed an acceptable safety profile at a weekly dose of 40 mg with weekly intravenous nab-paclitaxel at 100 mg/m(2) on days 1, 8, and 15 every 28 days. The posttreatment AKT score and changes in FDG activity may have roles as early predictors of responses to mTOR inhibitors. CI - (c) 2015 American Cancer Society. FAU - Abu-Khalaf, Maysa M AU - Abu-Khalaf MM AD - Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut. FAU - Baumgart, Megan A AU - Baumgart MA AD - Department of Medical Oncology, University of Rochester, Rochester, New York. FAU - Gettinger, Scott N AU - Gettinger SN AD - Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut. FAU - Doddamane, Indukala AU - Doddamane I AD - Department of Diagnostic Imaging, Yale University School of Medicine, New Haven, Connecticut. FAU - Tuck, David P AU - Tuck DP AD - EMD Serono, Billerica, Massachusetts. FAU - Hou, Shihe AU - Hou S AD - Celgene Corporation, Berkeley Heights, New Jersey. FAU - Chen, Nianhang AU - Chen N AD - Celgene Corporation, Berkeley Heights, New Jersey. FAU - Sullivan, Catherine AU - Sullivan C AD - Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut. FAU - Lezon-Geyda, Kimberly AU - Lezon-Geyda K AD - Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut. FAU - Zelterman, Daniel AU - Zelterman D AD - Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut. FAU - Hatzis, Christos AU - Hatzis C AD - Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut. FAU - Deshpande, Hari AU - Deshpande H AD - Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut. FAU - Digiovanna, Michael P AU - Digiovanna MP AD - Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut. FAU - Azodi, Masoud AU - Azodi M AD - Department of Gynecologic Oncology, Yale University School of Medicine, New Haven, Connecticut. FAU - Schwartz, Peter E AU - Schwartz PE AD - Department of Gynecologic Oncology, Yale University School of Medicine, New Haven, Connecticut. FAU - Harris, Lyndsay N AU - Harris LN AD - Department of Medical Oncology, Case Western University, Cleveland, Ohio. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150203 PL - United States TA - Cancer JT - Cancer JID - 0374236 RN - 0 (Albumin-Bound Paclitaxel) RN - 0 (Albumins) RN - 0Z5B2CJX4D (Fluorodeoxyglucose F18) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - P88XT4IS4D (Paclitaxel) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adult MH - Aged MH - Albumin-Bound Paclitaxel MH - Albumins/administration & dosage/pharmacokinetics MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/pharmacokinetics MH - Cohort Studies MH - Female MH - Fluorodeoxyglucose F18 MH - Humans MH - Male MH - Middle Aged MH - Nanoparticles/administration & dosage MH - Neoplasms/diagnostic imaging/*drug therapy/metabolism MH - Paclitaxel/administration & dosage/pharmacokinetics MH - Positron-Emission Tomography/methods MH - Sirolimus/administration & dosage/pharmacokinetics MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors MH - Treatment Outcome OTO - NOTNLM OT - [18F]fludeoxyglucose positron emission tomography (FDG-PET) OT - mammalian target of rapamycin (mTOR) OT - nanoparticle albumin-bound paclitaxel (nab-paclitaxel) OT - sirolimus OT - solid tumors EDAT- 2015/02/05 06:00 MHDA- 2015/08/26 06:00 CRDT- 2015/02/05 06:00 PHST- 2014/11/10 00:00 [received] PHST- 2014/12/18 00:00 [revised] PHST- 2014/12/22 00:00 [accepted] PHST- 2015/02/05 06:00 [entrez] PHST- 2015/02/05 06:00 [pubmed] PHST- 2015/08/26 06:00 [medline] AID - 10.1002/cncr.29254 [doi] PST - ppublish SO - Cancer. 2015 Jun 1;121(11):1817-26. doi: 10.1002/cncr.29254. Epub 2015 Feb 3.