Abstract P1-18-03: Phase I trial to assess the safety, pharmacokinetics and pharmacodynamics of receptor activator of nuclear factor-κB ligand inhibitor (TK006) in patients with bone metastases from breast cancer
Authors: Mei YY , Hai TJ , Wei L , Xiang H , Hao W , Ming ZX , An LX 
Published: May 2019

Abstract
Background
Within the bone microenvironment, tumor cells secrete factors that stimulate osteoblasts to express and secrete receptor activator of nuclear factor-κB ligand (RANKL), which binds to its receptor RANK on the surface of osteoclasts, thus enhancing the osteoclast-mediated bone resorption and promoting skeletal complications.TK006 is a fully human monoclonal antibody that binds and inhibits RANKL, thus inhibiting osteoclast-mediated bone destruction.
Objective
To investigate the safety, pharmacokinetics and pharmacodynamics of TK006 in patients with bone metastases from breast cancer.
Patients and methods
In this dose-escalating study, patients were sequentially enrolled into 60 mg, 120 mg, 180 mg single-dosing and 120 multiple-dosing cohorts. Before making dose escalation decision, the safety of TK006 during the 14-day period after dosing in the prior cohort must be confirmed. In the three single-dosing cohorts, patients were followed up for 16 weeks after dosing. In the 120 mg multiple-dosing cohort, patents were treated with 120 mg TK006 every 4 weeks for 3 times totally, and followed up for 20 weeks after the first dosing. The primary outcome was safety profile, and the secondary outcomes were pharmacokinetics, pharmacodynamics and immunogenicity. Pharmacodynamics was measured by level of serum bone alkaline phosphatase (BALP) and urine creatinine corrected cross-linked N-telopeptides of type I collagen (uNTX/Cr).
Patients aged 18 to 65 years with breast cancer related bone metastasis were eligible. It was planned to enroll 10 subjects in each cohort for a total sample size of 40 subjects.
Result
As of May 24 2018, the common adverse events (AEs) related to treatment (≥10%) included: hypocalcemia (25.0%), limbs pain (20.0%), gamma-glutamyl transferase increased (17.5%), lactate dehydrogenase increased (12.5%), alpha-hydroxybutyric dehydrogenase increased (12.5%), aspertate aminotransferase increased (12.5%), alanine aminotransferase (10.0%),osphyalgia (10.0%) toothache (10.0%) and hypertriglyceridemia (10%). Most adverse reactions were mild or moderate except one case of grade 3 hypertriglyceridemia and two cases of grade 3 gamma-glutamyl transferase increasement. No esteonecrosis of the jaw or treatment-related SAE was reported.
In the 60 mg single-dosing cohort, a significant reduction in median uNTX/Cr was observed as early as day 1, the nadir of median uNTX/Cr was reach at day 28 and started to return towards the baseline level at day 112 (Table 1).
Only modest decreasing from baseline in median bone-specific alkaline phosphatase was observed.
Table 1.Effects of 60 mg TK006 therapy on bone turnover markers uNTX/Cr, % change from baseline, medianBALP , % change from baseline, medianD1-38.6-4.7D7-63.01.7D14-55.30.2D28-69.2-0.2D56-57.9-12.1D84-33.4-0.4D1121.3-18.7
Ostalgia was measured by visual analogue scale (VAS). In the 60 mg single-dosing cohort, scores were reduced to 2 from 5 and 3 in two patients individually. No increasing in pain was observed in the remaining 8 patients.
Conclusion
These results suggested a potential therapeutic role for TK006 in patients with bone metastases from breast cancer.
Citation Format: Mei YY, Hai TJ, Wei L, Xiang H, Hao W, Ming ZX, An LX. Phase I trial to assess the safety, pharmacokinetics and pharmacodynamics of receptor activator of nuclear factor-κB ligand inhibitor (TK006) in patients with bone metastases from breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-18-03.