![]() ![]() Incidence and severity of Adverse Events were coded according to NCI Common Terminology Criteria (NCI CTCAE, Version 3.0). Routine anti-emetic prophylaxis was not given. The starting dose was 45 mg/m 2, targeted to administer 1/10 th of the exposure at MTD in the dog, the most sensitive species in toxicology studies. Danusertib was administered via central line as a 24-h IV infusion on Day 1 of a 14-day treatment cycle. The drug product was stored at 2–8☌, protected from light and brought to room temperature shortly before use. Each vial contained 15 mL of solution (10 mg/mL) corresponding to 150 mg of danusertib. (Nerviano, Italy) and supplied as 1% (w/v) sterile solution in 20/26 mL type I glass vials. ![]() Danusertib was manufactured by Nerviano Medical Sciences S.r.l. I DOSER DOSES FOR FREE TRIALThis was a Phase I, open-label, non-randomized, dose-escalation trial conducted at 2 USA sites. All patients were adults (age >18 yrs) and gave written informed consent according to local IRB and Federal guidelines. Patients with previous high-dose chemotherapy requiring hematopoietic stem cell rescue, known brain or leptomeningeal metastasis, active inflammatory bowel disease, partial or complete bowel obstruction or chronic diarrhea, abnormal left ventricular function, severe cardiovascular disease, cardiac dysrhythmias ≥Grade 2, and active infections were excluded. Eligibility criteria also included Eastern Cooperative Oncology Group performance status ≤ 1 prior radiation completed ≥2 weeks prior to enrollment and no more than 25% of bone marrow irradiated life expectancy ≥12 weeks normal blood pressure (≤140/90 mmHg) with or without treatment and baseline laboratory data indicating acceptable bone marrow, liver and kidney function. Patients with histological or cytological evidence of advanced refractory cancer lacking options for established curative or life-prolonging therapy were eligible. To the best of our knowledge danusertib was the first Aurora kinase inhibitor in the clinic. In addition an increase in peripheral blood pressure was observed after IV bolus and 6-h infusion in rats, but not in dogs.īased on this broad spectrum of preclinical activity and favorable toxicology profile, we performed a phase I study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of danusertib in patients with refractory solid tumors. ![]() Renal effects, however, are only seen at high drug exposure. Danusertib also has significant antitumor activity in transgenic tumor models with a favorable preclinical safety profile( 16) principal target organs of danusertib are the hemolymphopoietic system, GI tract, male reproductive organs and kidneys. Thus, inhibition of histone H3 phosphorylation may be a potential biomarker of danusertib biological activity. Danusertib inhibits Aurora-B phosphorylation at serine 10 of histone H-3, a protein implicated in chromosome condensation. In vitro studies have shown that danusertib causes a failure of cell division, resulting in polyploidy and reduction in viability. Danusertib shows dominant Aurora B Kinase inhibition( 16) with additional activity against bcr-abl, including the T315I mutation. Several AK inhibitors with diverse pharmacological properties are in clinical trials( 8– 15).ĭanusertib is active in vitro against a wide range of cancer cell lines with sub-micromolar IC 50 values for inhibition of proliferation. Aurora B is a chromosome passenger protein required for histone H3 phosphorylation, chromosome segregation and cytokinesis( 5– 7). Aurora A, required for spindle assembly, localizes to centrosomes. AKs are essential for mitosis( 1) and cytokinesis with upregulation in many malignancies, including pancreatic( 2), colorectal( 3), ovarian( 3) and esophageal cancer( 4). Danusertib is a small molecule 3-aminopyrazole derivative that potently inhibits all Aurora Kinase (AK) family members (A, -B & -C). ![]()
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