Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT02594215 |
Other study ID # |
160014 |
Secondary ID |
16-HG-0014 |
Status |
Completed |
Phase |
Phase 1
|
First received |
|
Last updated |
|
Start date |
November 16, 2015 |
Est. completion date |
June 24, 2022 |
Study information
Verified date |
June 2022 |
Source |
National Institutes of Health Clinical Center (CC) |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
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.
...
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.