First-in-human phase I study of SOR-C13, a TRPV6 calcium channel inhibitor, in patients with advanced solid tumors

Abstract

Summary Introduction This was an open-label, dose escalation (3 + 3 design), Phase I study of SOR-C13 in patients with advanced tumors of epithelial origin. Primary objectives were to assess safety/tolerability and pharmacokinetics. Secondary goals were to assess pharmacodynamics and efficacy of SOR-C13. Methods SOR-C13 was administered IV QD on days 1–3 and 8–10 of a 21-day cycle. Doses were 2.75 and 5.5 mg/kg (20-min infusion) and 1.375, 2.75, 4.13 and 6.2 mg/kg (90-min infusion). Toxicity was assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose limiting toxicity (DLT) was assessed within the first treatment cycle. Tumors were evaluated, using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, after two cycles. Results Twenty-three patients were treated. No drug-related serious adverse events occurred. DLTs occurred in six patients: asymptomatic, drug-related, transient Grade 2 hypocalcemia (4 patients), and unrelated Grade 3 anemia and Grade 3 atrial fibrillation, 1 patient each. Calcium and vitamin D supplementation eliminated further Grade 2 hypocalcemia. One Grade 3 treatment emergent adverse event, urticaria, was definitely related to SOR-C13. Four possibly drug-related, Grade 3 events (alanine aminotransferase and aspartate aminotransferase elevation, headache, and hypokalemia) were observed. Of 22 evaluable patients, 54.5% showed stable disease ranging from 2.8 to 12.5 months. The best response was a 27% reduction in a pancreatic tumor with a 55% reduction in CA19–9 levels at 6.2 mg/kg. Conclusion SOR-C13 was safe and tolerated up to 6.2 mg/kg. The Maximal Tolerated Dose (MTD) was not established. Stable disease suggested antitumor activity.

TRP Channels in Digestive Tract Cancers

“…While the second study is in the recruiting stage, the results of the first study show that that SOR-C13 was well tolerated. Moreover, of 22 evaluable patients, 54.5% showed stable disease ranging from 2.8 to 12.5 months, which suggests an anti-tumor activity of SOR-C13 [164]. This is a proof of principle, showing that, in the future, drugs targeting TRP channels in cancer could enter clinical use.…”

Transient Receptor Potential Cation Channels in Cancer Therapy

“…The first trial is in the recruiting stage (clinicaltrials.gov accessed 4 November 2019), whereas the data of the second one trial has been recently published. These data show that the administration of SO-C13, up to 6.2 mg/kg, induces in 54.5% of patients (n = 22 patients) a stable disease, ranging from 2.8 to 12.5 months, and the best response was a 27% reduction in PC, with a 55% reduction in CA19-9 marker levels [95]. TRPV6 has been shown to mediate the CPS-induced apoptosis (at 50 µM dose) in GaC cells [96] and, interestingly, GaC cells are more sensitive to CPS-induced apoptosis than normal gastric cells.…”

Peer Review #2 of "Construction and integrated analysis of crosstalking ceRNAs networks in laryngeal squamous cell carcinoma (v0.1)"

“…Targeting calcium signaling is a promising strategy for cancer therapy. Inhibitors of TRPV6, the highly Ca2+ selective ion channel, has now undergone phase Ⅰ clinical trials in patients with advanced tumors (Fu et al 2017). Targeting calcium signaling can reactivate tumor suppressor genes silenced by calciumcalmodulin kinase and increase cell death in colon cancer (Raynal et al 2016).…”