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Developmental therapeutics

1965 - A Phase I pharmacokinetic study of metronomic vinorelbine and sorafenib using two schedules in Asian non-small cell lung cancer (NSCLC) patients (136O)

Date

18 Nov 2017

Session

Developmental therapeutics

Topics

Cytotoxic Therapy;  Clinical Research;  Thoracic Malignancies

Presenters

Sylvia Chen

Citation

Annals of Oncology (2017) 28 (suppl_10): x39-x41. 10.1093/annonc/mdx658

Authors

S. Chen1, N. Sutiman2, V. Shih2, D. Tan3, M.K. Ang3, C.K. Toh1, D. Lim3, Q.S. Ng3, E.H. Tan3, B. Chowbay1

Author affiliations

  • 1 Division Of Medical Sciences, National Cancer Centre Singapore, 169610 - Singapore/SG
  • 2 Clinical Pharmacology, SingHealth, 169856 - Singapore/SG
  • 3 Department Of Medical Oncology, National Cancer Centre Singapore, 169610 - Singapore/SG
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Abstract 1965

Background

A recent Phase I study of metronomic oral vinorelbine (60mg, 90mg and 120mg) per week and 200mg BID sorafenib in Asian NSCLC patients performed by our group showed that the combination of 60mg/week vinorelbine and 200mg BID sorafenib correlated with better survival and response. We herein report the pharmacokinetics (PK) profile of metronomic vinorelbine at these three doses in combination with 200mg BID sorafenib in Asian NSCLC patients to better understand the pharmacology of this low dose combination treatment.

Methods

Thirty-five NSCLC patients were randomly allocated into two treatment schedules S1 (N = 19) and S2 (N = 16) and sub-grouped to receive either oral vinorelbine at three dose levels on Day 1 followed by 200mg sorafenib BID on Day 17 (S1) and vice-versa (S2). PK analysis of samples collected at steady-state on Days 15 and 29 from each group were quantified using LC-MS/MS. PK parameters were derived using non-compartmental analysis. Statistical analyses were performed on GraphPad Prism 6.0c.

Results

Higher exposure of vinorelbine as determined by these PK parameters (average vinorelbine concentrations (Cav), area under the plasma-concentration curve (AUC0-∞) and vinorelbine clearance (CL/F)) was observed in 60mg/week cohort compared to that of 90mg/week group in S1 on Day 15. [60mg/week vs 90mg/week respectively Cav: 2.62 ng/mL vs 0.57 ng/mL, P=0.016; AUC0-∞: 277.7 h.ng/mL vs 41.2 h.ng/mL, P=0.06; CL/F: 158.77 L/h vs 1094.0 L/h, P=0.016]. Similar trends in Cav, AUC0-∞ and CL/F were also observed from steady-state samples collected at Day 29 in both schedules; probably suggesting a lack of drug-drug interactions between vinorelbine and sorafenib. Due to insufficient sampling collection, analysis could not be performed for the 120mg/week cohort. No significant changes in sorafenib PK parameters were discernible in either S1 or S2.

Conclusions

This pilot study illustrates that 60mg/week vinorelbine confers a more superior PK profile and improved clinical response compared to 90mg/week or 120mg/week. Future studies should investigate the combined therapeutic effect of 60mg/week vinorelbine and 200mg BID sorafenib in a Phase II efficacy trial.

Legal entity responsible for the study

National Cancer Centre Singapore

Clinical trial identification

Legal entity responsible for the study

National Cancer Centre Singapore

Funding

National Medical Research Council

Disclosure

All authors have declared no conflicts of interest.

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