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• W1969570939 abstract "Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CABackground: Renal cell carcinoma (RCC) is the most common malignancy of the kidneys. We conducted an NCI-sponsored New York Cancer Consortium phase I/II trial with the combination of sorafenib (SOR) plus the cytotoxic agents gemcitabine (GEM) and capecitabine (CAP).Thymidylate Synthase (TS) is the key enzyme in the catalysis of the methylation from dUMP to dTMP in the DNA synthetic process and high levels may denote poor prognosis, but higher sensitivity to 5-FU in primary cultured RCC cells. In proliferating cells, ribonucleotide reductase (RR) is a key enzyme of de novo nucleotide synthesis pathway; RRM1 expression predicts response to gemcitabine and prognosis in several solid tumors.Methods: 26 patients (pts) with advanced RCC (65% clear cell, 31% papillary; 23% sarcomatoid differentiation) and 0-2 lines of prior therapy were enrolled in the clinical trial (NCI 6981): 15 in the phase I dose-escalation portion which defined toxicity and recommended phase II dose (RP2D): SOR 200 mg BID D1-21,GEM 750 mg/m2 D1 & D8, and CAP 415 mg/m2 BID D1-D14 in 21-day cycles and 11 pts in the phase II portion. Immunohistochemical staining of archival tissue was performed in 13 patients to determine TS and RRM1 status. Response rate (RR) was assessed by RECIST, association between response and marker expression by Fisher's exact test, and overall survival (OS) was calculated by Kaplan-Meier methodology with comparisons using log-rank.Results: Overall, in the phase I/II study (all doses), RR is 16%, progression free survival (PFS) 6.1 mo, OS 18.3 mo [95% CI 10.3, 26.4]. For pts treated at the RP2D, RR is 12.5%, PFS 5.0 mo, OS 18.3. Pts positive for TS (61.5%) or RRM1 (53.8%) expression tended to have higher likelihood of stable disease or better by RECIST (though statistical significance was not reached, likely because of small numbers with progressive disease). Interestingly, the OS analysis demonstrated that pts with TS tumor expression lived longer (57.5 vs 18.1 mo, p=0.002) as did those with TS expression in vasculature (72.5 vs 21.7 mo, p=0.003). RRM1 positive pts also tended to live longer (57.5 vs 18.1 mo, p=0.13).Conclusions: The combination of SOR, GEM, and CAP was tolerated at attenuated doses, but does not appear to have significantly better activity than historical controls. However, TS expression may predict response to capecitabine containing therapy in advanced RCC, which consistent with in-vitro data demonstrating higher sensitivity of cultured RCC cells that express higher TS levels to fluoropyrimidine therapy. These findings are hypothesis-generating and prospective validation is needed.Citation Format: Bishoy Faltas, Gurveen Kaur, Naveed Akhtar, Paul Christos, Brian Robinson, Beerinder Singh, Himisha Beltran, David Nanus, Scott T. Tagawa. Molecular correlates of activity and survival in a phase I/II trial of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT310. doi:10.1158/1538-7445.AM2014-CT310" @default.
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• W1969570939 title "Abstract CT310: Molecular correlates of activity and survival in a phase I/II trial of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma" @default.
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