Phase II trial of S-1 plus leucovorin in patients with advanced gastric cancer and clinical prediction by S-1 pharmacogenetic pathway.

Abstract

BACKGROUND:

The first one-arm phase II trial aimed to evaluate and predict efficacy and safety of S-1 plus oral leucovorin (S-1/LV) as first-line chemotherapy for patients with advanced gastric cancer (AGC), using S-1 pharmacogenetic pathway approach.

PATIENTS AND METHODS:

A total of 39 patients orally took S-1 at conventional dose and LV simultaneously at a dose of 25 mg twice daily for a week, within a 2-week cycle. The primary endpoint was overall response rate (ORR), while the secondary endpoints were progression-free survival (PFS), time to failure (TTF), overall survival (OS), disease control rate (DCR), and adverse events (AEs). Peripheral blood was sampled prospectively for baseline expression of dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and thymidylate synthase (TS), CYP2A6 gene polymorphisms, and 5-FU pharmacokinetics.

RESULTS:

The ORR and DCR were 41.0 and 76.9%. The median PFS, TTF, and OS were 4.13, 3.70, and 11.40 months. Grade 3-4 AEs occurred in only 13 patients, and grade 4 AEs occurred in only 1 of them. High OPRT/TS and peritoneal metastasis (vs. liver metastasis) independently predicted responding. High OPRT/DPD independently predicted grade 3-4 AEs. High AUC0-24h of 5-FU and metastatic/recurrent sites ≤2 (vs. >3) independently predicted prolonged PFS. Low baseline plasmic DPD independently predicted prolonged OS.

CONCLUSIONS:

Two-week, oral S-1/LV regimen demonstrated promising efficacy and safety as first-line chemotherapy for AGC. CLINICALTRIALS.

GOV IDENTIFIER:

NCT02090153.

• Authors: Ming-Ming He, Dong-Sheng Zhang, Feng Wang, Zi-Xian Wang, Shu-Qiang Yuan, Zhi-Qiang Wang, Hui-Yan Luo, Chao Ren, Miao-Zhen Qiu, Ying Jin, De-Shen Wang, Dong-Liang Chen, Zhao-Lei Zeng, Yu-Hong Li, Yang-Yang He, Yuan-Tao Hao, Pi Guo, Feng-Hua Wang, Yi-Xin Zeng, Rui-Hua Xu
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 79 Issue 1 Pg. 69-79 (Jan 2017) ISSN: 1432-0843 [Electronic] Germany
• PMID: 27913881 (Publication Type: Clinical Trial, Phase II, Journal Article)

Chemical References

• Drug Combinations
• S 1 (combination)
• Tegafur
• Oxonic Acid
• CYP2A6 protein, human
• Cytochrome P-450 CYP2A6
• Orotate Phosphoribosyltransferase
• Leucovorin
• Fluorouracil

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cytochrome P-450 CYP2A6 (genetics)
• Disease-Free Survival
• Drug Combinations
• Female
• Fluorouracil (pharmacokinetics)
• Humans
• Leucovorin (administration & dosage, adverse effects)
• Male
• Middle Aged
• Orotate Phosphoribosyltransferase (blood)
• Oxonic Acid (administration & dosage, adverse effects, metabolism)
• Pharmacogenomic Testing
• Stomach Neoplasms (drug therapy, genetics, mortality)
• Tegafur (administration & dosage, adverse effects, metabolism)