Dose Finding Trial of MK-7075 in Children and Adults With Proteus Syndrome
Condition: Proteus Syndrome
MeSH terms: Proteus Infections; Proteus Syndrome; Syndrome
Study type: Interventional
Phase: Phase 1

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.

      ...
    

Detailed 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.
    

Intervention name(s): MK-7075 (miransertib)
Intervention type(s): Drug
Intervention description(s): MK-7075 or miransertib (formerly ARQ 092) is small molecule that effectively inhibits AKT. Proteus syndrome is caused by mosaic activating mutations in AKT1. This is a phase I study to determine a recommended dose for subsequent trials, which will determine the efficacy of miransertib in Proteus syndrome.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: AKT1; Overgrowth