Dose Finding Trial of MK-7075 in Children and Adults With Proteus Syndrome

Proteus Syndrome Clinical Trial

Official title: Phase 1 Dose Finding Trial of MK-7075 in Children and Adults With Proteus Syndrome

Status Completed

Clinical Trial Summary

Background:

Proteus syndrome (PS) is caused by a mutation in the AKT1 gene. This gene makes a protein that communicates with other proteins in the body to make cells grow. The AKT1 mutation changes chemical signals in the body and causes overgrowth. PS can be fatal. The drug MK-7075 reduces signals from the AKT1 protein. This may reduce or stabilize some of the overgrowth in people with PS. Researchers want to find the best dose of MK-7075 based on its effect on tissues in people with PS.

Objective:

To determine the safety, tolerability, and recommended dose of MK-7075 in people with PS.

Eligibility:

People ages 6 and older with PS

Design:

Participants will be screened with medical history, physical exam, and blood and urine tests.

Participants will take MK-7075 by mouth once daily for up to 12 28-day cycles.

Participants must stay near the NIH Clinical Center (CC) during the whole first cycle, for weekly visits to the CC. For cycle 2, they will have visits every 2 weeks. They will have 1 visit before cycles 3 and 4, and once before every other cycle for cycles 5 11. The final visit will be at the end of cycle 12. Visits may include:

Small skin samples taken.

ECG: Soft electrodes on the skin record heart signals.

Echocardiogram: A small probe held to the chest takes pictures of the heart.

MRI: Participants will lie in a machine that takes pictures of the body.

Joint and mobility function tests.

Participants will complete surveys by phone and in person.

Participants will keep a daily medication and symptom diary.

...

Clinical Trial Description

Proteus syndrome is a rare segmental overgrowth disorder caused by a somatic gain of function mutation, c.49GA, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase . The disorder is progressive, with high morbidity and mortality - there are very few living adults with this disease. Tissues and cell lines from patients with Proteus syndrome harbor admixtures of mutant alleles that ranged from <1% to approximately 50%. This mutation causes constitutive activation of AKT1, through Ser473 and Thr308 phosphorylation. This activation stimulates the AKT/PI3K pathway, mediating processes including increased cell proliferation and decreased apoptosis. The progressive nature of the disorder and the mechanism of disease (gain of function) make AKT1 an excellent target for therapeutics, specifically repression. The AKT/PI3K pathway is mutated in numerous cancers as well. Because it is commonly mutated in cancer, pharmaceutical companies are interested in targeting this molecule with inhibitors. Indeed, Proteus syndrome can be considered a simple model for cancer therapeutics, as these patients are known to harbor only a single activating mutation instead of the hundreds or thousands that are mutated in cancers. ArQule Inc., a wholly owned subsidiary of Merck & Co., has developed a small molecule, miransertib (MK-7075) that effectively inhibits AKT, with the lowest IC50 for AKT1 (as compared to AKT2 or AKT3, and orders of magnitude lower for other kinases). This agent has undergone significant development with animal toxicity studies and is currently in phase I trials in patients with different types of cancer. In addition, we have performed in vitro testing with miransertib in cells from patients with Proteus syndrome and demonstrated reduction in AKT1 phosphorylation at doses in the range of achievable blood levels in humans with low toxicity. Because Proteus syndrome is a chronic disease, typical approaches to defining the recommended phase II dose by determining the maximum tolerated dose (MTD) are not appropriate it is unreasonable to propose that patients would tolerate significant side effects for prolonged time periods. As an initial trial for this disease, we propose a phase I study to determine a recommended dose for subsequent trials, which will determine the efficacy of miransertib in Proteus syndrome. The recommended phase II dose will be determined based on the tolerability of miransertib in children and adults with Proteus syndrome and measures of drug levels in plasma and affected tissues in patients with Proteus syndrome and measures of tissue phosphorylation of AKT1. We hypothesize that the recommended dose of miransertib will be substantially below that of doses used in patients with cancer and that this will lead to a highly favorable risk-benefit ratio on which we can base future efficacy studies. ;

Related Conditions & MeSH terms

• Proteus Infections
• Proteus Syndrome
• Syndrome

• NCT number: NCT02594215
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 1
• Start date: November 16, 2015
• Completion date: June 24, 2022