Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors.

Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue. Methods This was a Phase I, open-label, dose-escalation trial in patients with advanced/metastatic solid tumors. A treatment cycle comprised 5 days of oral administration followed by 16 days of rest, for a total of 21 days (3-week cycle). Results Nineteen of 21 enrolled patients with confirmed metastatic disease received study medication. No DLTs occurred at the first 3 dose levels (6, 12, and 24 mg/m2/day). At the subsequent dose level (48 mg/m2/day), 2 of 3 patients developed DLTs. An intermediate level of 36 mg/m2/day was therefore investigated. Four patients were treated and two DLTs were observed. After further cohort expansion, the MTD and recommended phase II dose (RP2D) were determined to be 24 mg/m2/day. Disease stabilization, observed in several patients, was the best treatment response observed. Hematological toxicity (mostly thrombocytopenia and neutropenia) was the major DLT. Systemic exposure to NMS-1286937 increased with dose and was comparable between two cycles of treatment following oral administration of the drug. Conclusions This study successfully identified the MTD and DLTs for NMS-1286937 and characterized its safety profile.

Comparison of two different doses of iodide in the prevention of gestational goiter in marginal iodine deficiency: a longitudinal study.

OBJECTIVE: A prospective randomized trial was performed to assess the usefulness of iodine supplementation in the prevention of goiter in pregnant women living in marginally iodine-deficient areas. DESIGN: Eighty-six pregnant women were recruited and randomized in two groups and treated daily for up to six months after delivery with 200 microg iodide (group A) or 50 microg iodide (group B). Sixty-seven women (32 in group A and 35 in group B) completed the study. METHODS: Thyroid volume (TV), thyroid functional parameters and urinary iodine concentration were determined in all subjects at booking, at the 18th-26th, and the 29th-33rd week of gestation, and at the 3rd and 6th month after delivery. RESULTS: A slight but not significant increase in TV during gestation was observed only in group B. After delivery a progressive decrease in TV was documented in both groups, the final TV being significantly reduced with respect to the initial volume in group A. No significant changes in serum free thyroid hormones and TSH concentrations were found during gestation in either group. Postpartum thyroiditis was observed in 5 women (2 in group A, 3 in group B). No side effects were seen. CONCLUSION: The present data indicate that in marginally iodine-deficient areas, the administration of iodide is recommended in pregnancy and lactation. In the conditions of the present trial a dose of 50 microg iodide/day is a safe and effective measure in preventing an increase in TV during pregnancy but a dose of 200 microg iodide/day appeared to be more effective without inducing side effects and without enhancing the frequency of post-partum thyroiditis.