Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma Journal Article


Authors: Molina, A. M.; Feldman, D. R.; Voss, M. H.; Ginsberg, M. S.; Baum, M. S.; Brocks, D. R.; Fischer, P. M.; Trinos, M. J.; Patil, S.; Motzer, R. J.
Article Title: Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma
Abstract: BACKGROUND: Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor targeting VEGF, are standard agents in the management of metastatic RCC. METHODS: Sequential cohorts of 3 to 6 patients with advanced RCC received doseescalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on/2 weeks off) with everolimus (2.5-5 mg daily or 20-30 mg weekly). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine maximum tolerated dose (MTD). Pharmacokinetic profiles were obtained. RESULTS: Twenty patients (13 clear cell and 7 nonclear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the second cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1 to 28 of a 42-day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, and 3 had nonclear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was observed. CONCLUSIONS: The combination of everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in nonclear cell and clear cell RCC. © 2011 American Cancer Society.
Keywords: adult; clinical article; human tissue; treatment response; aged; middle aged; human cell; constipation; drug tolerability; fatigue; neutropenia; sunitinib; advanced cancer; area under the curve; cancer combination chemotherapy; diarrhea; drug withdrawal; hypertension; hypophosphatemia; side effect; treatment duration; cancer patient; drug eruption; multiple cycle treatment; pain; sensory neuropathy; anemia; bleeding; leukopenia; mucosa inflammation; nausea; thrombocytopenia; antineoplastic combined chemotherapy protocols; cohort analysis; weight reduction; creatinine; renal cell carcinoma; kidney carcinoma; kidney neoplasms; asthenia; drug dose escalation; drug fever; dyspnea; febrile neutropenia; hyperglycemia; lymphocytopenia; pneumonia; lung embolism; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; chemotherapy induced emesis; dysphagia; gastrointestinal toxicity; hyperkalemia; hypoalbuminemia; hypokalemia; hyponatremia; malaise; disease severity; drug accumulation; carcinoma, renal cell; hypoglycemia; open study; targeted therapy; hyperbilirubinemia; maximum plasma concentration; time to maximum plasma concentration; metastasis potential; drug metabolism; maximum tolerated dose; phase 1 clinical trial; hypercholesterolemia; drug half life; hypothyroidism; drug dose increase; indoles; pyrroles; dry skin; lethargy; everolimus; sirolimus; lung infiltrate; hypertriglyceridemia; hypernatremia; partial thromboplastin time; dysgeusia; skin allergy; triacylglycerol lipase; diaphoresis; bacterial endocarditis; international normalized ratio; hyperamylasemia; combination drug therapy; n deethylsunitinib; herpetic stomatitis; streptococcus viridans infection
Journal Title: Cancer
Volume: 118
Issue: 7
ISSN: 0008-543X
Publisher: Wiley Blackwell  
Date Published: 2012-04-01
Start Page: 1868
End Page: 1876
Language: English
DOI: 10.1002/cncr.26429
PROVIDER: scopus
PUBMED: 21898375
PMCID: PMC3609026
DOI/URL:
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 11 May 2012" - "CODEN: CANCA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Sujata Patil
    386 Patil
  2. Robert Motzer
    769 Motzer
  3. Michael S Baum
    20 Baum
  4. Michelle S Ginsberg
    159 Ginsberg
  5. Darren Richard Feldman
    172 Feldman
  6. Martin Henner Voss
    128 Voss
  7. Ana Maria Luisa Molina
    45 Molina
  8. Patricia Marie Russ Fischer
    19 Fischer
  9. Michael Joseph Trinos
    7 Trinos