A phase I trial of sorafenib plus gemcitabine and capecitabine for patients with advanced renal cell carcinoma: New York Cancer Consortium Trial NCI 6981.

Abstract

OBJECTIVE:

To define the safety [dose limiting toxicity (DLT)] and recommended phase II dose of the combination of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma (RCC).

METHODS:

In this phase I dose-escalation study, cohorts of 3 to 6 patients with metastatic RCC received sorafenib (200 or 400 mg po BID), gemcitabine (750 or 1000 mg/m(2) intravenous on days 1 and 8), and capecitabine (415 or 622 mg/m(2) po BID days 1-14) every 21 days using a standard 3+3 design.

RESULTS:

Fifteen patients with advanced RCC (93% with clear cell histology and 87% treatment naive) received treatment. The recommended phase II doses for the combination were sorafenib 200 mg/m(2) BID continuously plus gemcitabine 750 mg/m(2) intravenous days 1 and 8 and capecitabine 415 mg/m(2) BID days 1 to 14, every 21 days. Of the 15 patients, 3 developed dose-limiting hand-foot syndrome during the first 2 cycles; 2 additional DLT's were grade 3 mucositis and transaminase elevation. Four of 14 evaluable patients had a partial response by response evaluation criteria in solid tumors (29%; 95% confidence interval (CI): 8, 58%). Median progression-free survival was 7.5 months (95% CI-0, 18.7), and median overall survival has not been reached at a median follow-up of 28.8 months. The median number of treatment cycles given was 7 (range, 2-38+).

CONCLUSIONS:

The combination of sorafenib plus gemcitabine and capecitabine is tolerable, but requires attenuation of sorafenib and capecitabine dosing because of the overlapping toxicity of hand-foot syndrome. Antitumor activity was observed leading to an ongoing phase II trial.

• Authors: Scott T Tagawa, Matthew I Milowsky, Stephanie Jeske, Madhu Mazumdar, Sophia Kung, Max Sung, Deborah Lehrer, Daniel Matulich, Jodi Selzer, John J Wright, David M Nanus
• Journal: American journal of clinical oncology (Am J Clin Oncol) Vol. 34 Issue 5 Pg. 443-8 (Oct 2011) ISSN: 1537-453X [Electronic] United States
• PMID: 20881475 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Benzenesulfonates
• Phenylurea Compounds
• Pyridines
• Deoxycytidine
• Niacinamide
• Capecitabine
• Sorafenib
• Fluorouracil
• Gemcitabine

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Benzenesulfonates (administration & dosage)
• Bone Neoplasms (drug therapy, secondary)
• Capecitabine
• Carcinoma, Renal Cell (drug therapy, secondary)
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Female
• Fluorouracil (administration & dosage, analogs & derivatives)
• Follow-Up Studies
• Humans
• Kidney Neoplasms (drug therapy, pathology)
• Liver Neoplasms (drug therapy, secondary)
• Lung Neoplasms (drug therapy, secondary)
• Lymphatic Metastasis
• Male
• Maximum Tolerated Dose
• Middle Aged
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Pyridines (administration & dosage)
• Sorafenib
• Survival Rate
• Treatment Outcome
• Gemcitabine