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MK-7075 (Miransertib) in Proteus Syndrome

Primary Purpose

Proteus Syndrome

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
MK-7075 (miransertib)
Sponsored by
National Human Genome Research Institute (NHGRI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Proteus Syndrome focused on measuring AKT1, CCTN, Mosaic Overgrowth Disorder

Eligibility Criteria

3 Years - 99 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • 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): >=10.0 g/dL
  • Glycated hemoglobin (HbA1c): <=8% (<=64 mmol/mol)
  • Absolute neutrophil count (ANC): >=1.5 x 10^9/L
  • Platelet count >=150 x 10^9/L

Hepatic:

  1. Total bilirubin <=2 x upper limit of normal (ULN)
  2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=3 x ULN

Renal:

  1. Serum creatinine depending on age:

    2-5 years male and female: <=0.50 mg/dL

    6-10 years male and female: <=0.59 mg/dL

    11-15 years male and female: <=1.2 mg/dL

    >15 years male and female: <=1.5 mg/dL

    Metabolic (lipids):

    • Cholesterol: <=400 mg/dL (<=10.34 mmol/L)
    • Triglyceride: <=500 mg/dL (<=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 v 5.0] 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

Sites / Locations

  • National Institutes of Health Clinical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

MK-7075 (miransertib)

Arm Description

This is a single-arm study. All study participants will be taking the experimental drug, MK-7075 (miransertib).

Outcomes

Primary Outcome Measures

CCTN
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

Quality of life
Change from baseline in pain score (NRS-11), physical functioning (PROMIS), and quality of life (PedsQL)
Long-term safety and tolerability
Periodic safety (e.g., physical examination, vital sign measurements, clinical laboratory tests, use of concomitant medications and collection of AE information) assessments.
Duration of response
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.

Full Information

First Posted
March 19, 2020
Last Updated
September 15, 2023
Sponsor
National Human Genome Research Institute (NHGRI)
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1. Study Identification

Unique Protocol Identification Number
NCT04316546
Brief Title
MK-7075 (Miransertib) in Proteus Syndrome
Official Title
A Multi-Cohort Phase 2 Dose-Escalation Study of MK-7075 (Miransertib) in Proteus Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
September 14, 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 20, 2022 (Actual)
Primary Completion Date
March 31, 2025 (Anticipated)
Study Completion Date
March 31, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Human Genome Research Institute (NHGRI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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. ...
Detailed Description
Study Description: The primary objective of this study is to determine the response rate of miransertib as measured by the change in CCTN involvement of the plantar surface from baseline, using blinded independent central review of lesional photography in individuals with Proteus syndrome (Cohort 1). Cohorts 2 and 3 will enroll up to 30 additional patients whose non-plantar CCTN Proteus syndrome-associated lesions will be evaluated to address the secondary and exploratory study objectives. All participants will be treated with miransertib in continuous, 28-day cycles. Participants in Cohorts 1 and 2 will receive miransertib at the starting dose of 15 mg/m^2 daily for the first three cycles, and then the dose will be increased to 25 mg/m^2 daily, provided no clinically significant drug-related toxicity is observed. Participants in Cohort 3 will receive miransertib at the dose they were on at the time of enrollment if continuing use of miransertib or at the starting dose for Cohorts 1 and 2, not to exceed 25 mg/m^2 daily. Safety and toxicity data will be gathered on all participants. Participants will stay on treatment for up to 52 cycles. The final clinical safety follow-up will be performed 30 days after the last dose. Objectives: Primary Objective: To determine the response to treatment with miransertib as measured by the growth of plantar CCTN in individuals with Proteus syndrome. Secondary Objectives: To estimate the change from baseline in pain in participants treated with miransertib To estimate change from baseline in physical functioning in participants treated with miransertib To estimate change from baseline in quality of life in participants treated with miransertib To describe the long-term tolerability and safety of miransertib To determine the duration of response in responders with respect to the primary study endpoint Exploratory Objectives: To describe the effect of miransertib on Proteus syndrome-related overgrowth manifestations assessed by imaging To describe the effect of miransertib on the rate of growth of the CCTN lesion and the total lesional area (CCTN and confluent papules and nodules (pre-CCTN)) as compared to historical data from untreated participants To determine if the clinical gestalt status of participants with Proteus syndrome improves on/after treatment with miransertib by comparing baseline pre-treatment gestalt to available gestalt data on/after treatment To describe the effect of miransertib on d-dimer and fibrinogen levels To describe the PK profile of miransertib Endpoints: Primary Endpoint (assessed in Cohort 1): Change in lesional size as a proportion of the plantar surface from baseline will be used to classify each participant as either a responder or non- responder (binary) in the treated population. The primary endpoint is the response rate (defined as a <= 5% increase in the proportion of plantar involvement from baseline after two years) as assessed by blinded central photography review. Secondary Endpoints: Change from baseline in pain score as assessed by the NRS-11 Pain Rating Scale Change from baseline in physical functioning as assessed by PROMIS (Pediatric Upper Extremity Short Form 8a, Parent Proxy Upper Extremity Short Form 8a, Pediatric Mobility Short Form 8a, Parent Proxy Mobility Short Form 8a, Physical Function Short Form 8b, Parent Proxy Pain Behavior Short Form 8a) Change from baseline in quality of life as assessed by the Pediatric Quality of Life Inventory (PedsQL) Safety and tolerability as assessed by frequency, duration and severity of AEs from the first dose of miransertib through 30 days after the last dose of the drug (severity of AEs will be assessed by CTCAE version 5.0) Time from response to failure to respond defined as having a > 5% increase in the proportion of plantar involvement over a rolling two year period Exploratory Endpoints: Change from baseline in selected disease-related manifestations as evaluated by CT, MRI, ultrasound, and/or photography Behavior of the CCTN lesion (+/- confluent papules and nodules) while on continuous treatment with miransertib using historical control data for comparison Change in clinical gestalt status in treated participants using a blinded review panel and a set of pre-selected and customized endpoints for each participant Change from baseline in d-dimer and fibrinogen levels PK parameters (e.g., maximum plasma drug concentration [Cmax], time to maximum plasma drug concentration [Tmax], and area under the curve [AUC]) which are calculated from plasma concentration time data

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Proteus Syndrome
Keywords
AKT1, CCTN, Mosaic Overgrowth Disorder

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
45 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
MK-7075 (miransertib)
Arm Type
Experimental
Arm Description
This is a single-arm study. All study participants will be taking the experimental drug, MK-7075 (miransertib).
Intervention Type
Drug
Intervention Name(s)
MK-7075 (miransertib)
Intervention Description
MK-7075 (miransertib) is a small molecule developed by ArQule Inc., a wholly owned subsidiary of Merck &amp; 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 Measure Information:
Title
CCTN
Description
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.
Time Frame
baseline, two years
Secondary Outcome Measure Information:
Title
Quality of life
Description
Change from baseline in pain score (NRS-11), physical functioning (PROMIS), and quality of life (PedsQL)
Time Frame
Periodically throughout the study (described in schedule of activities)
Title
Long-term safety and tolerability
Description
Periodic safety (e.g., physical examination, vital sign measurements, clinical laboratory tests, use of concomitant medications and collection of AE information) assessments.
Time Frame
Periodically throughout the study (described in schedule of activities)
Title
Duration of response
Description
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.
Time Frame
Periodically throughout the study (described in schedule of activities)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility 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): >=10.0 g/dL Glycated hemoglobin (HbA1c): <=8% (<=64 mmol/mol) Absolute neutrophil count (ANC): >=1.5 x 10^9/L Platelet count >=150 x 10^9/L Hepatic: Total bilirubin <=2 x upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=3 x ULN Renal: Serum creatinine depending on age: 2-5 years male and female: <=0.50 mg/dL 6-10 years male and female: <=0.59 mg/dL 11-15 years male and female: <=1.2 mg/dL >15 years male and female: <=1.5 mg/dL Metabolic (lipids): Cholesterol: <=400 mg/dL (<=10.34 mmol/L) Triglyceride: <=500 mg/dL (<=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 v 5.0] 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Christopher A Ours, M.D.
Phone
(301) 443-8750
Email
chris.ours@nih.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Leslie G Biesecker, M.D.
Phone
(301) 402-2041
Email
lesb@mail.nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Leslie G Biesecker, M.D.
Organizational Affiliation
National Human Genome Research Institute (NHGRI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Phone
800-411-1222
Ext
TTY8664111010
Email
prpl@cc.nih.gov

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
26657992
Citation
Lindhurst MJ, Yourick MR, Yu Y, Savage RE, Ferrari D, Biesecker LG. Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome. Sci Rep. 2015 Dec 11;5:17162. doi: 10.1038/srep17162.
Results Reference
background
PubMed Identifier
30803705
Citation
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.
Results Reference
background
PubMed Identifier
29042227
Citation
Nathan NR, Patel R, Crenshaw MM, Lindhurst MJ, Olsen C, Biesecker LG, Keppler-Noreuil KM, Darling TN. Pathogenetic insights from quantification of the cerebriform connective tissue nevus in Proteus syndrome. J Am Acad Dermatol. 2018 Apr;78(4):725-732. doi: 10.1016/j.jaad.2017.10.018. Epub 2017 Oct 16.
Results Reference
background
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2020-HG-0034.html
Description
NIH Clinical Center Detailed Web Page

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MK-7075 (Miransertib) in Proteus Syndrome

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