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

NCT02594215 | Completed Phase 1 FDA Drug

• 2 other identifiers: 16001416-HG-0014
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief 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. ...

Conditions

Proteus Syndrome

Keywords

AKT1; Overgrowth

Outcome Measures

Primary Outcomes (3)

• Tissue drug levels

  Tissue drug levels are assessed at baseline, cycle 1 /day 14, and cycle 4/day 1.

  End of cycle 3

• Tissue phospho-AKT level

  Tissue tissue phospho-AKT is assessed at baseline, cycle 1/day 14, and cycle 4/day 1.

  End of cycle 3

• Tolerabilty/Side Effects

  Tolerability and side effects are assessed on an ongoing basis.

  Ongoing

Secondary Outcomes (1)

• Tolerability and side effects

  Ongoing

Study Arms (1)

Experimental

EXPERIMENTAL

Experimental

Drug: MK-7075 (miransertib)

Interventions

MK-7075 (miransertib) DRUG

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.

Experimental

Eligibility Criteria

• Age: 6 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Meets published clinical criteria for PS.
• Measurable disease: Patients must have at least one measurable lesion for volumetric MRI or photographic CCTN.
• Has a CLIA-validated report demonstrating presence of a mosaic AKT1 c.49G\>A mutation.
• years of age or older. The age limits including children and adolescents were chosen because childhood and puberty are considered to be the greatest risk for disease progression, and MK-7075 may provide the most benefit to this young group of patients. In addition, an important objective of this study is to characterize the pharmacokinetics of MK-7075 in the pediatric population since it has been better studied in adults.
• Not using nor has used within the past 6 months any medication known to affect the AKT/PI3K pathway (e.g., everolimus), reviewed by NIHCC pharmacist.
• Performance status: Patients greater than or equal to 16 years of age must have a Karnofsky performance level of greater than or equal to 40%, and adolescents 6 - 16 years old must have a Lansky performance of greater than or equal to 40%.
• Is willing to identify and allow us to communicate with an outside medical provider if needed.
• Hepatic function: Bilirubin must be less than or equal to 1.5 x the upper limit of normal and the SGPT (ALT) must be less than or equal to 2.5 x the upper limit of normal.
• Cardiac function: Must have an ejection fraction with normal limits for age by echocardiogram.
• Must have cognitive abilities to complete patient surveys/QOL assessments as appropriate for age or have an appropriate surrogate decision-maker or guardian able to complete these measures in the case of intellectually impaired adults.
• Renal function: Age-adjusted normal serum creatinine (see Table below) OR a creatinine clearance greater than or equal to 60 mL/min/1.73 m\^2.
• Age (Years): less than or equal to 15; Serum Creatinine (mg/dl): less than or equal to1.2
• Age (Years): \> 15; Serum Creatinine (mg/dl): less than or equal to 1.5
• Body surface area of at least 0.5 m\^2

You may not qualify if:

• Pregnant or breast-feeding females are excluded due to potential risks of fetal and teratogenic adverse events of an investigational agent. Pregnancy tests must be obtained prior to enrollment on this study in all females. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Abstinence is an acceptable method of birth control.
• Patients who anticipate the need for surgical intervention within the first three cycles (3 months), as surgical intervention during the period of DLT evaluation may affect analysis of adherence and/or make the subject unevaluable.
• An investigational agent within the past 6 months.
• Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the disease, immunotherapy, or biologic therapy.
• Clinically significant unrelated systemic illness, such as serious infections, hepatic, renal or other organ dysfunction, which in the judgment of the Principal or Associate Investigator would compromise the patient s ability to tolerate the agents used in this trial or are likely to interfere with the study procedures or results.
• Type I or II diabetes mellitus or is being treated with insulin or an oral hypoglycemic agent.
• Abnormal LVEF on echocardiogram.
• Patients with known extensive intestinal involvement of the disease or evidence of malabsorption that, in the investigator s opinion could compromise drug absorption.
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
• Inability to undergo MRI/CT and/or contraindication for MRI examinations following the MRI protocol. Prosthesis or orthopedic or dental braces that would interfere with volumetric analysis of target lesion on MRI.
• Evidence of a tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.
• Patients with baseline (pre-treatment) QTcF\>470ms on ECG.
• Absence of an approved legal guardian or approved surrogate decision-maker in the case of intellectually impaired adults.

Sponsors & Collaborators

• National Human Genome Research Institute (NHGRI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (2)

• Ours CA, Sapp JC, Hodges MB, de Moya AJ, Biesecker LG. Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome. Cold Spring Harb Mol Case Stud. 2021 Dec 9;7(6):a006134. doi: 10.1101/mcs.a006134. Print 2021 Dec.

  PMID: 34649967 DERIVED

• Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, Darling TN, Burton-Akright J, Bagheri M, Dombi E, Gruber A, Jarosinski PF, Martin S, Nathan N, Paul SM, Savage RE, Wolters PL, Schwartz B, Widemann BC, Biesecker LG. Pharmacodynamic Study of Miransertib in Individuals with Proteus Syndrome. Am J Hum Genet. 2019 Mar 7;104(3):484-491. doi: 10.1016/j.ajhg.2019.01.015. Epub 2019 Feb 22.

  PMID: 30803705 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Proteus Syndrome

Interventions

Miransertib

Condition Hierarchy (Ancestors)

Hamartoma Syndrome, Multiple; Hamartoma; Neoplasms; Neoplasms, Multiple Primary; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Limb Deformities, Congenital; Musculoskeletal Abnormalities; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Leslie G Biesecker, M.D.

  National Human Genome Research Institute (NHGRI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 31, 2015
• First Posted: November 3, 2015
• Study Start: November 16, 2015
• Primary Completion: December 31, 2017
• Study Completion: June 24, 2022
• Last Updated: June 30, 2022

Record last verified: 2022-06

Locations

US (1)