A phase I study of vorinostat (suberoylanilide hydroxamic acid) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC)
| العنوان: | A phase I study of vorinostat (suberoylanilide hydroxamic acid) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC) |
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| المؤلفون: | M. G. Fakih, L. Pendyala, P. Smith, P. Creaven, K. Toth, J. Zwiebel, S. Frankel, A. Litwin, L. Huffman, M. Egorin |
| المصدر: | Journal of Clinical Oncology. 25:4088-4088 |
| بيانات النشر: | American Society of Clinical Oncology (ASCO), 2007. |
| سنة النشر: | 2007 |
| مصطلحات موضوعية: | Cancer Research, Oncology |
| الوصف: | 4088 Background: At 5μM, vorinostat decreases thymidilate synthase (TS) expression by ∼ 40 fold, which translates into synergistic antitumor activity when added to 5-FU. We conducted a phase I study of vorinostat plus FOLFOX in patients with CRC to determine the recommended dose of this combination. Methods: Vorinostat was escalated in a standard 3+3 design with a planned expansion of the maximum tolerated dose (MTD) cohort to 10 patients (pts). Vorinostat (100mg, 200mg, 300mg, 400 mg dose levels) was given twice daily for 1 week followed by 1 week break. FOLFOX was administered at a fixed standard dose every 2 weeks on the 4th day of vorinostat. Tumor biopsies were obtained from liver metastases before and on the 4th day of vorinostat (prior to FOLFOX) to assess TS expression. Results: 19 pts were treated on study (M/F: 12/7; median age: 58; ECOG 0/1: 6/13). All pts had failed prior FOLFOX therapy. Dose-limiting toxicities (DLT) were noted in 3 pts: 2/4 pts at dose level (DL)4 (vorinostat 400mg BID) consisting of grade (G) 3 fatigue, & diarrhea in 1 pt and G3 fatigue in the other; 1/8 pts at DL3 (MTD, vorinostat 300mg BID) consisting of G3 fatigue, anorexia, nausea, and dehydration. 8 pts have been treated at the MTD for a total of 38 cycles. “All Cycles” G3–4 toxicities at the MTD consisted of 2 pts with G3 neutropenia and 2 pts with G3 thrombocytopenia along with the above described DLT. Responses were evaluable in 17 pts: 0 Objective Response, 8 Stable Disease (4 confirmed). TS expression by IHC and by RT-PCR showed modest decreases in 2/6 patients after vorinostat treatment. Cmax of SAHA was < 2μM at all investigated DL, which could explain the lack of adequate TS down-regulation. Conclusions: vorinostat 300mg PO BID × 1 week every 2 weeks in combination with FOLFOX is the established recommended dose. The lack of significant TS down-regulation may be due to the suboptimal serum vorinostat concentrations. Alternate shorter vorinostat schedules may allow for further daily dose escalations and hence for better likelihood of TS down-regulation. This study was partly supported by CTEP, NCI. No significant financial relationships to disclose. |
| تدمد: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2007.25.18_suppl.4088 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::1172852eba93add32708982a00628e82 https://doi.org/10.1200/jco.2007.25.18_suppl.4088 |
| رقم الانضمام: | edsair.doi...........1172852eba93add32708982a00628e82 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15277755 0732183X |
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| DOI: | 10.1200/jco.2007.25.18_suppl.4088 |