NIH Clinical Center Search the Studies: Study Number, Study Title

Protocol Details

A Multi-Cohort Phase 2 Dose-Escalation Study of MK-7075 (Miransertib) in Proteus Syndrome

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

20-HG-0034

Sponsoring Institute

National Human Genome Research Institute (NHGRI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 3 Years
Max Age: 99 Years

Referral Letter Required

No

Population Exclusion(s)

None

Keywords

AKT1;
CCTN;
Mosaic Overgrowth Disorder

Recruitment Keyword(s)

None

Condition(s)

Proteus Syndrome

Investigational Drug(s)

mk-7075 (miransertib)

Investigational Device(s)

None

Intervention(s)

Drug: MK-7075 (miransertib)

Supporting Site

National Human Genome Research Institute

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:

To 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.

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Eligibility

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 or international equivalent.

-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:

a. Total bilirubin <=2 x upper limit of normal (ULN)

b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=3 x ULN

Renal:

a. 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:

-Individuals without an evaluable plantar CCTN

-No prior exposure to miransertib

-Male or female participants age >=3 years old and BSA of >=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 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 clinically 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]) or worse conduction defect (e.g., right or left bundle branch block).

-Major surgery, radiotherapy, chemotherapy, 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 on Cohort 3 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


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Citations:

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.

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.

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.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Leslie G. Biesecker, M.D.
National Human Genome Research Institute (NHGRI)
NIHBC 50 BG RM 5140
50 SOUTH DR
BETHESDA MD 20892
(301) 402-2041
lesb@mail.nih.gov

Christopher A. Ours, M.D.
National Human Genome Research Institute (NHGRI)
NIHBC 10 - CLINICAL CENTER BG RM 8D47B
10 CENTER DR
BETHESDA MD 20892
(301) 443-8750
chris.ours@nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1
ccopr@nih.gov

Clinical Trials Number:

NCT04316546

--Back to Top--

NIH Clinical Center Search the Studies: Study Number, Study Title

Protocol Details

A Multi-Cohort Phase 2 Dose-Escalation Study of MK-7075 (Miransertib) in Proteus Syndrome

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

20-HG-0034

Sponsoring Institute

National Human Genome Research Institute (NHGRI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 3 Years
Max Age: 99 Years

Referral Letter Required

No

Population Exclusion(s)

None

Keywords

AKT1;
CCTN;
Mosaic Overgrowth Disorder

Recruitment Keyword(s)

None

Condition(s)

Proteus Syndrome

Investigational Drug(s)

mk-7075 (miransertib)

Investigational Device(s)

None

Intervention(s)

Drug: MK-7075 (miransertib)

Supporting Site

National Human Genome Research Institute

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:

To 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.

--Back to Top--

Eligibility

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 or international equivalent.

-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:

a. Total bilirubin <=2 x upper limit of normal (ULN)

b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=3 x ULN

Renal:

a. 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:

-Individuals without an evaluable plantar CCTN

-No prior exposure to miransertib

-Male or female participants age >=3 years old and BSA of >=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 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 clinically 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]) or worse conduction defect (e.g., right or left bundle branch block).

-Major surgery, radiotherapy, chemotherapy, 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 on Cohort 3 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


--Back to Top--

Citations:

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.

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.

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.

--Back to Top--

Contacts:

Principal Investigator

Referral Contact

For more information:

Leslie G. Biesecker, M.D.
National Human Genome Research Institute (NHGRI)
NIHBC 50 BG RM 5140
50 SOUTH DR
BETHESDA MD 20892
(301) 402-2041
lesb@mail.nih.gov

Christopher A. Ours, M.D.
National Human Genome Research Institute (NHGRI)
NIHBC 10 - CLINICAL CENTER BG RM 8D47B
10 CENTER DR
BETHESDA MD 20892
(301) 443-8750
chris.ours@nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1
ccopr@nih.gov

Clinical Trials Number:

NCT04316546

--Back to Top--