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MK-7075 (Miransertib) in Proteus Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04316546
Recruitment Status : Recruiting
First Posted : March 20, 2020
Last Update Posted : January 28, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )

Brief Summary:

Background:

Proteus syndrome is a rare overgrowth disorder. Most people begin to have symptoms between 6 months and 2 years of age. There are very few living adults with this disease. There is also no known treatment for it. Researchers want to see if a new drug can slow down or stop overgrowth in people with Proteus syndrome.

Objective:

The learn if miransertib is a safe and effective treatment for Proteus syndrome.

Eligibility:

People ages 3 and older with Proteus syndrome

Design:

Participants will be screened with a medical checkup. They will answer questions about their medical history and current health. They will have a physical exam with vital signs. They will have an electrocardiogram to measure their heartbeat. They will give blood and urine samples. They will repeat the screening tests during the study.

Participants will take a miransertib pill once a day. They will bring their empty pill bottles with them to the NIH when they visit. If they can t swallow a pill, researchers will try to find other ways for them to take the drug.

Participants will have X-rays, ultrasounds, and imaging scans. Photos may be taken of their feet and other parts of the body that have or develop signs of Proteus syndrome.

Participants will have lung function tests to measure how much and how fast air moves out of their lungs.

Participants will complete surveys about their levels of pain, physical functioning, and quality of life.

Participants may have additional tests performed to assess their individual disease. They may have consultations with other specialists.

Participation lasts about 4 years. Participants will have 20-30 visits at the NIH.

...


Condition or disease Intervention/treatment Phase
Proteus Syndrome Drug: MK-7075 (miransertib) Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multi-Cohort Phase 2 Dose-Escalation Study of MK-7075 (Miransertib) in Proteus Syndrome
Estimated Study Start Date : February 2, 2022
Estimated Primary Completion Date : March 31, 2025
Estimated Study Completion Date : March 31, 2028

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: MK-7075 (miransertib)
This is a single-arm study. All study participants will be taking the experimental drug, MK-7075 (miransertib).
Drug: MK-7075 (miransertib)
MK-7075 (miransertib) is a small molecule developed by ArQule Inc., a wholly owned subsidiary of Merck & Co., that effectively inhibits AKT. Proteus syndrome is caused by mosaic activating mutations in AKT1. This is a Phase 2 trial investigating the efficacy of miransertib as a treatment for adult and pediatric patients with Proteus syndrome.




Primary Outcome Measures :
  1. CCTN [ Time Frame: baseline, two years ]
    Change in CCTN involvement of the plantar surface from baseline will be used to classify each subject as either a responder or non-responder (binary) in the treated population. The primary endpoint is response rate (defined as (=< 5% increase in plantar involvement from baseline over two years). This will be assessed by blinded central photography review.


Secondary Outcome Measures :
  1. Quality of life [ Time Frame: Periodically throughout the study (described in schedule of activities) ]
    Change from baseline in pain score (NRS-11), physical functioning (PROMIS), and quality of life (PedsQL)

  2. Long-term safety and tolerability [ Time Frame: Periodically throughout the study (described in schedule of activities) ]
    Periodic safety (e.g., physical examination, vital sign measurements, clinical laboratory tests, use of concomitant medications and collection of AE information) assessments.

  3. Duration of response [ Time Frame: Periodically throughout the study (described in schedule of activities) ]
    Duration of response is defined as the amount of time from first response signal to progression of CCTN involvement >5% over rolling two year intervals.



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Ages Eligible for Study:   3 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

All participants in all Cohorts must meet the criteria below:

  • Signed informed consent, and when applicable, signed assent
  • Have a molecular diagnosis of Proteus syndrome with documented somatic AKT1 mutation from a CLIA-certified laboratory.
  • Have progressive and measurable disease (e.g., a measurable manifestation of Proteus syndrome with evidence or report of worsening of manifestation(s)/ in the last 12 months)
  • Adequate organ function as indicated by the following laboratory values:

Hematological:

  • Hemoglobin (Hgb) depending on age:

    • 2-5 years male and female: greater than or equal to 10.0 g/Dl
    • 6-9 years male and female: greater than or equal to 11.5 g/dL
    • 10-17 years female: greater than or equal to 11.0 g/dL
    • 10-17 years male: greater than or equal to 11.5 g/dL
    • >17 years male and female: greater than or equal to 10.0 g/dL
  • Glycated hemoglobin (HbA1c): less than or equal to 8% (less than or equal to 64 mmol/mol)
  • Absolute neutrophil count (ANC): greater than or equal to 1.5 x 10^9/L
  • Platelet count greater than or equal to 150 x 10^9/L

Hepatic:

  • Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN)/L
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to x ULN

Renal:

-Serum creatinine depending on age:

  • 2-5 years male and female: less than or equal to 0.50 mg/dL
  • 6-10 years male and female: less than or equal to 0.59 mg/dL
  • 11-15 years male and female: less than or equal to 1.2 mg/dL
  • >15 years male and female: less than or equal to 1.5 mg/dL

Metabolic (lipids):

  • Cholesterol: less than or equal to 400 mg/dL (less than or equal to 10.34 mmol/L)
  • Triglyceride: less than or equal to 500 mg/dL (less than or equal to 5.7 mmol/L)

    • If a female is of child-bearing potential, documentation of a negative pregnancy test is required prior to enrollment. Sexually active participants (male and female) must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse while on study and for up to 90 days after ending treatment
    • Ability to complete the questionnaires by the participant and/or his/her caregiver

The following specific criteria will be used to assign participants to Cohorts:

Cohort 1 (Proteus syndrome with plantar CCTN) specific criteria:

  • Have at least one plantar CCTN that can accurately be measured by standardized photography. The CCTN is defined as a nevus with at least two gyri and three sulci affecting 10% - 70% of the total surface area of the foot.
  • Male or female participants age greater than or equal to 3 and less than or equal to 16 years old and BSA of greater than or equal to 0.33 m^2

Cohort 2 (Proteus syndrome without plantar CCTN) specific criteria:

  • Does not meet the eligibility criteria for Cohorts 1 or 3
  • Male or female participants age greater than or equal to 3 years old and BSA of greater than or equal to 0.33 m^2

Cohort 3 (Proteus syndrome previously treated with miransertib) specific criteria:

  • Participants previously treated with miransertib or currently receiving miransertib under Compassionate Use/Expanded Access or an existing trial (i.e., 16-HG-0014)
  • Male or female participants greater than or equal to 3 years old and BSA of greater than or equal to 0.33 m^2

Note: All participants must meet Cohort-related age criteria by/on the date of the first dose, Cycle 1 Day 1

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

  • History of Type 1 or Type 2 uncontrolled diabetes mellitus requiring regular medication (other than metformin or other oral hypoglycemic agents) or fasting glucose greater than or equal to 160 mg/dL ( if >12 years old) and greater than or equal to 180 mg/dL (if less than or equal to 12 years old) at the baseline/screening visit
  • History of significant cardiac disorders:

    • Myocardial infarction (MI) or congestive heart failure defined as Class II-IV per the New York Heart Association (NYHA) classification within six months of the first dose of miransertib (MI occurring >6 months of the first dose of miransertib will be permitted)
    • Grade 2 (per National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] current version) or worse conduction defect (e.g., right or left bundle branch block).
  • Major surgery, radiotherapy, or immunotherapy within four weeks of the first dose of miransertib
  • Any experimental systemic therapy for the purpose of treating Proteus syndrome (e.g., sirolimus, everolimus, high dose steroids, alpelisib) within two weeks of the first dose of miransertib, except for participants who were previously or are currently treated with miransertib under a Compassionate Use/Expanded Access program or existing protocol

    --Participants who were previously treated with or currently are receiving miransertib will be enrolled and treated according to the Schedule of Assessments/Study Visits defined in this protocol

  • Intolerance of, or severe toxicity attributed to, AKT inhibitors (e.g., miransertib, uprosertib, afuresertib, ipatasertib)
  • Concurrent severe uncontrolled illness not related to Proteus syndrome

    • Ongoing or active infection
    • Known human immunodeficiency virus (HIV) infection malabsorption syndrome
    • Psychiatric illness/substance abuse/social situation that would limit compliance with study requirements
  • Pregnant or breastfeeding (contraception requirements can be found above and in the informed consent form)
  • Inability to comply with study evaluations or to follow drug administration guidelines
  • Concomitant use of a prohibited medication
  • Regular tobacco use and/or use of cannabidiol/tetrahydrocannabidiol (CBD/THC), and/or vaping products

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04316546


Contacts
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Contact: Christopher A Ours, M.D. (301) 443-8750 chris.ours@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Contact: Research Assistant    Not Listed    proteustrial@nih.gov   
Sponsors and Collaborators
National Human Genome Research Institute (NHGRI)
Investigators
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Principal Investigator: Leslie G Biesecker, M.D. National Human Genome Research Institute (NHGRI)
Additional Information:
Publications:
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Responsible Party: National Human Genome Research Institute (NHGRI)
ClinicalTrials.gov Identifier: NCT04316546    
Other Study ID Numbers: 200034
20-HG-0034
First Posted: March 20, 2020    Key Record Dates
Last Update Posted: January 28, 2022
Last Verified: January 24, 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) ):
AKT1
CCTN
Mosaic Overgrowth Disorder
Additional relevant MeSH terms:
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Proteus Infections
Proteus Syndrome
Syndrome
Disease
Pathologic Processes
Enterobacteriaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Hamartoma Syndrome, Multiple
Hamartoma
Neoplasms
Neoplasms, Multiple Primary
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Limb Deformities, Congenital
Musculoskeletal Abnormalities
Abnormalities, Multiple
Congenital Abnormalities