- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02594215
Dose Finding Trial of MK-7075 in Children and Adults With Proteus Syndrome
Phase 1 Dose Finding Trial of MK-7075 in Children and Adults With Proteus Syndrome
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.
...
Study Overview
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Maryland
-
Bethesda, Maryland, United States, 20892
- National Institutes of Health Clinical Center, 9000 Rockville Pike
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
- INCLUSION CRITERIA:
- 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.
- 6 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
EXCLUSION CRITERIA:
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Other
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Experimental
|
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.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Tissue drug levels
Time Frame: End of cycle 3
|
Tissue drug levels are assessed at baseline, cycle 1 /day 14, and cycle 4/day 1.
|
End of cycle 3
|
Tissue phospho-AKT level
Time Frame: End of cycle 3
|
Tissue tissue phospho-AKT is assessed at baseline, cycle 1/day 14, and cycle 4/day 1.
|
End of cycle 3
|
Tolerabilty/Side Effects
Time Frame: Ongoing
|
Tolerability and side effects are assessed on an ongoing basis.
|
Ongoing
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Tolerability and side effects
Time Frame: Ongoing
|
Tolerability and side effects are assessed on an ongoing basis.
|
Ongoing
|
Collaborators and Investigators
Publications and helpful links
General Publications
- 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.
- 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.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Infections
- Neoplasms
- Disease
- Congenital Abnormalities
- Musculoskeletal Diseases
- Gram-Negative Bacterial Infections
- Bacterial Infections
- Bacterial Infections and Mycoses
- Bone Diseases
- Musculoskeletal Abnormalities
- Abnormalities, Multiple
- Enterobacteriaceae Infections
- Bone Diseases, Developmental
- Limb Deformities, Congenital
- Hamartoma Syndrome, Multiple
- Hamartoma
- Neoplasms, Multiple Primary
- Syndrome
- Proteus Infections
- Proteus Syndrome
Other Study ID Numbers
- 160014
- 16-HG-0014
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Proteus Syndrome
-
Merck Sharp & Dohme LLCActive, not recruitingPIK3CA-Related Overgrowth Spectrum (PROS)/Proteus Syndrome (PS)United States, Australia, Brazil, Italy, United Kingdom
-
ArQule, Inc. (a wholly owned subsidiary of Merck...Worldwide Clinical TrialsTerminatedPIK3CA-Related Overgrowth Spectrum (PROS)/Proteus SyndromeUnited States, Australia, Italy, Spain
-
National Human Genome Research Institute (NHGRI)Recruiting
-
National Human Genome Research Institute (NHGRI)Children's National Research Institute; Uniformed Services University of the...RecruitingProteus Syndrome | PIK3CA Related Overgrowth SpectrumUnited States
-
Hamad Medical CorporationCompletedEscherichia Coli Bacteremia | Klebsiella Bacteraemia | Enterobacter Bacteraemia | Serratia Bacteraemia | Citrobacter Bacteraemia | Proteus BacteraemiaQatar, Turkey, Bahrain, Kuwait
-
ArQule, Inc. (a wholly owned subsidiary of Merck...No longer availableGrowth Disorders | Proteus Syndrome | PIK3CA-Related Overgrowth Spectrum (PROS)
-
National Human Genome Research Institute (NHGRI)CompletedCoronary Artery Disease | Proteus Syndrome | Familial Isolated Hyperparathyroidism | Coffin - Sins Syndrome | Dubouitz SyndromeUnited States
-
University of PittsburghCompletedInfection | Proteus Infections | Klebsiella Infections | E Coli InfectionsUnited States
-
Neumedicines Inc.Department of Health and Human ServicesCompletedHematopoietic Syndrome Due to Acute Radiation SyndromeUnited States
-
Ministry of Public Health, Democratic Republic...National Institutes of Health (NIH); Oregon Health and Science University; National... and other collaboratorsCompletedNeurotoxicity Syndrome, Cassava | Neurotoxicity Syndrome, Cyanate | Neurotoxicity Syndrome, Cyanide | Neurotoxicity Syndrome, ThiocyanateCongo, The Democratic Republic of the
Clinical Trials on MK-7075 (miransertib)
-
National Human Genome Research Institute (NHGRI)Recruiting
-
Merck Sharp & Dohme LLCActive, not recruitingPIK3CA-Related Overgrowth Spectrum (PROS)/Proteus Syndrome (PS)United States, Australia, Brazil, Italy, United Kingdom
-
ArQule, Inc. (a wholly owned subsidiary of Merck...Worldwide Clinical TrialsTerminatedPIK3CA-Related Overgrowth Spectrum (PROS)/Proteus SyndromeUnited States, Australia, Italy, Spain
-
Merck Sharp & Dohme LLCTerminated
-
Merck Sharp & Dohme LLCCompletedType 2 Diabetes Mellitus
-
Merck Sharp & Dohme LLCCompletedHypertension | Isolated Systolic Hypertension (ISH)
-
Merck Sharp & Dohme LLCCompleted
-
Merck Sharp & Dohme LLCCompleted
-
Merck Sharp & Dohme LLCCompletedHepatitis C Virus Infection