3630 - Results of phase 1 clinical trial of high doses of Seleno-L-methionine (SLM) in sequential combination with Axitinib in previously treated and relapsed clear cell renal carcinoma (ccRCC) patients

Background

The overexpression of hypoxia induced factor 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses and schedules of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents.

Methods

This is a phase I (3 + 3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with standard dose axitinib to patients with metastatic ccRCC. Primary endpoint is safety; secondary endpoint is efficacy including overall response rate, progression free survival and overall survival.

Results

Twelve evaluable patients (pts) with metastatic ccRCC who progressed on one or more prior lines of treatment were enrolled. The first 3 pts were treated at 4000 µg, the second and third 3 pts were treated at 2500 and 3000 µg respectively. Additional 3 pts were added to 4000 µg. No dose limiting toxicity was seen. Most common AEs included fatigue, diarrhea, hypertension, nausea, anorexia, cough, proteinuria and weight loss. Of the 4000 µg cohort, 2 pts achieved complete response with ongoing responses at 31 and 29 months, 1 pt had partial response (PR) for 24 months. Of the 2500 µg cohort, 1 pt with ongoing PR for 21 months. The 3000 µg cohort, one pt has ongoing PR for 12 months.

Conclusions

SLM of 4000 µg is safe and the recommended phase 2 dose in combination with standard dose axitinib. The combination has promising efficacy with phase 2 trial is ongoing. Further data to be presented at the meeting.

Clinical trial identification

NCT02535533.

Editorial acknowledgement

NA

Legal entity responsible for the study

Yousef Zakharia.

Funding

Holden Comprehensive Cancer Centre.

Disclosure

Y. Zakharia: Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche Diagnostics; Advisory / Consultancy: Novartis; Advisory / Consultancy: Jansen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Castle Bioscience; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Bayer; Advisory / Consultancy: Array. M. Milhem: Advisory / Consultancy: Amgen; Advisory / Consultancy: Trieza; Advisory / Consultancy: Biontech; Advisory / Consultancy: Blueprint Medicines Corporation; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Array. All other authors have declared no conflicts of interest.