PMID- 24685058 OWN - NLM STAT- MEDLINE DCOM- 20150330 LR - 20211203 IS - 1938-0682 (Electronic) IS - 1558-7673 (Print) IS - 1558-7673 (Linking) VI - 12 IP - 4 DP - 2014 Aug TI - A phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma. PG - 241-50 LID - S1558-7673(13)00291-7 [pii] LID - 10.1016/j.clgc.2013.11.020 [doi] AB - BACKGROUND: Vatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC). PATIENTS AND METHODS: A phase Ib study of vatalanib and everolimus was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety, and tolerability of the combination. A dose-expansion cohort of 20 patients with metastatic RCC was studied to further define toxicity and preliminary efficacy in patients with RCC. RESULTS: We evaluated 32 patients over 3 dose levels and a dose-expansion cohort. The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Dose-limiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. In all patients, median overall survival (OS) was 16.3 months. In patients with RCC, median progression-free survival (PFS) was 5.8 months, and OS was 16.5 months. OS was significantly better in treatment-naive patients (25.1 months) compared with patients who had received previous vascular endothelial growth factor (VEGF)-targeted therapy (6.3 months). Seven of 24 (29.2%) evaluable patients demonstrated a partial response, and an additional 15 patients exhibited stable disease. Long-term tolerability (> 1 year) was demonstrated in 19% of patients. CONCLUSION: Relevant doses of vatalanib and everolimus were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatment-naive setting, with prolonged tolerability and survival. Further comparative phase II/III studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Bitting, Rhonda L AU - Bitting RL AD - Duke Cancer Institute, Duke University Medical Center, Durham, NC. FAU - Healy, Patrick AU - Healy P AD - Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC. FAU - Creel, Patricia A AU - Creel PA AD - Duke Cancer Institute, Duke University Medical Center, Durham, NC. FAU - Turnbull, James AU - Turnbull J AD - Duke Cancer Institute, Duke University Medical Center, Durham, NC. FAU - Morris, Karla AU - Morris K AD - Duke Cancer Institute, Duke University Medical Center, Durham, NC. FAU - Wood, Sarah Yenser AU - Wood SY AD - Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC. FAU - Hurwitz, Herbert I AU - Hurwitz HI AD - Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC; Duke Cancer Institute, Duke University Medical Center, Durham, NC. FAU - Starr, Mark D AU - Starr MD AD - Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC. FAU - Nixon, Andrew B AU - Nixon AB AD - Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC; Duke Cancer Institute, Duke University Medical Center, Durham, NC. FAU - Armstrong, Andrew J AU - Armstrong AJ AD - Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC; Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC; Duke Cancer Institute, Duke University Medical Center, Durham, NC. FAU - George, Daniel J AU - George DJ AD - Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC; Duke Cancer Institute, Duke University Medical Center, Durham, NC. Electronic address: daniel.george@duke.edu. LA - eng GR - P30 CA014236/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article DEP - 20131114 PL - United States TA - Clin Genitourin Cancer JT - Clinical genitourinary cancer JID - 101260955 RN - 0 (Antineoplastic Agents) RN - 0 (Phthalazines) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridines) RN - 5DX9U76296 (vatalanib) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adult MH - Aged MH - Antineoplastic Agents/therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols MH - Carcinoma, Renal Cell/*drug therapy/metabolism/mortality/secondary MH - Everolimus MH - Female MH - Follow-Up Studies MH - Humans MH - Kidney Neoplasms/*drug therapy/metabolism/mortality/pathology MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Molecular Targeted Therapy MH - Neoplasm Staging MH - Phthalazines/*therapeutic use MH - Prognosis MH - Protein Kinase Inhibitors/*therapeutic use MH - Pyridines/*therapeutic use MH - Receptors, Vascular Endothelial Growth Factor/*antagonists & inhibitors MH - Sirolimus/*analogs & derivatives/therapeutic use MH - Survival Rate MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors PMC - PMC4623321 MID - NIHMS709020 OTO - NOTNLM OT - Clinical trial OT - Renal cell carcinoma OT - VEGFR inhibitor OT - mTOR inhibitor COIS- Disclosure: All other authors have stated that they have no conflicts of interest. EDAT- 2014/04/02 06:00 MHDA- 2015/03/31 06:00 PMCR- 2015/10/28 CRDT- 2014/04/02 06:00 PHST- 2013/09/12 00:00 [received] PHST- 2013/11/01 00:00 [revised] PHST- 2013/11/08 00:00 [accepted] PHST- 2014/04/02 06:00 [entrez] PHST- 2014/04/02 06:00 [pubmed] PHST- 2015/03/31 06:00 [medline] PHST- 2015/10/28 00:00 [pmc-release] AID - S1558-7673(13)00291-7 [pii] AID - 10.1016/j.clgc.2013.11.020 [doi] PST - ppublish SO - Clin Genitourin Cancer. 2014 Aug;12(4):241-50. doi: 10.1016/j.clgc.2013.11.020. Epub 2013 Nov 14.