Proteus SyndromePhase 1NCT02594215
Dose Finding Trial of MK-7075 in Children and Adults With Proteus Syndrome
A Phase 1 study testing MK-7075 (miransertib) in people with Proteus Syndrome, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 6 to 65 years
- Conditions the study is for
- Proteus Syndrome
- What is being tested?
- MK-7075 (miransertib)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- 16 Nov 2015to 24 Jun 2022
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 to 65 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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%.
Show all 14Show fewer
- 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
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: 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.
Read more
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.
...
Read the detailed description
Proteus syndrome is a rare segmental overgrowth disorder caused by a somatic gain of function mutation, c.49GA, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase . The disorder is progressive, with high morbidity and mortality - there are very few living adults with this disease. Tissues and cell lines from patients with Proteus syndrome harbor admixtures of mutant alleles that ranged from <1% to approximately 50%. This mutation causes constitutive activation of AKT1, through Ser473 and Thr308 phosphorylation. This activation stimulates the AKT/PI3K pathway, mediating processes including increased cell proliferation and decreased apoptosis. The progressive nature of the disorder and the mechanism of disease (gain of function) make AKT1 an excellent target for therapeutics, specifically repression. The AKT/PI3K pathway is mutated in numerous cancers as well. Because it is commonly mutated in cancer, pharmaceutical companies are interested in targeting this molecule with inhibitors. Indeed, Proteus syndrome can be considered a simple model for cancer therapeutics, as these patients are known to harbor only a single activating mutation instead of the hundreds or thousands that are mutated in cancers. ArQule Inc., a wholly owned subsidiary of Merck \& Co., has developed a small molecule, miransertib (MK-7075) that effectively inhibits AKT, with the lowest IC50 for AKT1 (as compared to AKT2 or AKT3, and orders of magnitude lower for other kinases). This agent has undergone significant development with animal toxicity studies and is currently in phase I trials in patients with different types of cancer. In addition, we have performed in vitro testing with miransertib in cells from patients with Proteus syndrome and demonstrated reduction in AKT1 phosphorylation at doses in the range of achievable blood levels in humans with low toxicity. Because Proteus syndrome is a chronic disease, typical approaches to defining the recommended phase II dose by determining the maximum tolerated dose (MTD) are not appropriate it is unreasonable to propose that patients would tolerate significant side effects for prolonged time periods. As an initial trial for this disease, we propose a phase I study to determine a recommended dose for subsequent trials, which will determine the efficacy of miransertib in Proteus syndrome. The recommended phase II dose will be determined based on the tolerability of miransertib in children and adults with Proteus syndrome and measures of drug levels in plasma and affected tissues in patients with Proteus syndrome and measures of tissue phosphorylation of AKT1. We hypothesize that the recommended dose of miransertib will be substantially below that of doses used in patients with cancer and that this will lead to a highly favorable risk-benefit ratio on which we can base future efficacy studies.
- Conditions
- Proteus Syndrome
- Being tested
- MK-7075 (miransertib)
- Keywords
- AKT1, Overgrowth
- Medical subject headings
- Proteus Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
| Study group | Role | What they receive |
|---|---|---|
| Experimental | Experimental | Experimental Receives: Drug: MK-7075 (miransertib) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Tissue drug levels
Tissue drug levels are assessed at baseline, cycle 1 /day 14, and cycle 4/day 1.
Measured: 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.
Measured: End of cycle 3
Tolerabilty/Side Effects
Tolerability and side effects are assessed on an ongoing basis.
Measured: Ongoing
Secondary outcomes (1)
Tolerability and side effects
Tolerability and side effects are assessed on an ongoing basis.
Measured: Ongoing
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Nov 2015 (estimated)
- Study start16 Nov 2015
- Primary completion31 Dec 2017
- Study completion24 Jun 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Proteus SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Human Genome Research Institute (NHGRI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Leslie G Biesecker, M.D., Principal investigator, National Human Genome Research Institute (NHGRI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02594215
- Sponsor's protocol ID
- 160014
- Other IDs
- 16-HG-0014
- Status last verified
- Jun 2022
- First submitted
- 31 Oct 2015
- Last updated
- 30 Jun 2022
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
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.
PubMed 34649967Keppler-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.
PubMed 30803705
Study at a glance
From the registry record, last updated by the sponsor on 30 Jun 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 1 Dose Finding Trial of MK-7075 in Children and Adults With Proteus Syndrome
- ClinicalTrials.gov ID
- NCT02594215
- Acronym / sponsor ID
- 160014
- Conditions
- Proteus Syndrome
- Keywords
- AKT1, Overgrowth
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 6 participants (actual)
- Lead sponsor
- National Human Genome Research Institute (NHGRI)US National Institutes of Health
- Study start
- 16 Nov 2015 (actual)
- Primary completion
- 31 Dec 2017 (actual)
- Study completion
- 24 Jun 2022 (actual)
- First posted
- 3 Nov 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
...
Detailed description
Proteus syndrome is a rare segmental overgrowth disorder caused by a somatic gain of function mutation, c.49GA, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase . The disorder is progressive, with high morbidity and mortality - there are very few living adults with this disease. Tissues and cell lines from patients with Proteus syndrome harbor admixtures of mutant alleles that ranged from <1% to approximately 50%. This mutation causes constitutive activation of AKT1, through Ser473 and Thr308 phosphorylation. This activation stimulates the AKT/PI3K pathway, mediating processes including increased cell proliferation and decreased apoptosis. The progressive nature of the disorder and the mechanism of disease (gain of function) make AKT1 an excellent target for therapeutics, specifically repression. The AKT/PI3K pathway is mutated in numerous cancers as well. Because it is commonly mutated in cancer, pharmaceutical companies are interested in targeting this molecule with inhibitors. Indeed, Proteus syndrome can be considered a simple model for cancer therapeutics, as these patients are known to harbor only a single activating mutation instead of the hundreds or thousands that are mutated in cancers. ArQule Inc., a wholly owned subsidiary of Merck \& Co., has developed a small molecule, miransertib (MK-7075) that effectively inhibits AKT, with the lowest IC50 for AKT1 (as compared to AKT2 or AKT3, and orders of magnitude lower for other kinases). This agent has undergone significant development with animal toxicity studies and is currently in phase I trials in patients with different types of cancer. In addition, we have performed in vitro testing with miransertib in cells from patients with Proteus syndrome and demonstrated reduction in AKT1 phosphorylation at doses in the range of achievable blood levels in humans with low toxicity. Because Proteus syndrome is a chronic disease, typical approaches to defining the recommended phase II dose by determining the maximum tolerated dose (MTD) are not appropriate it is unreasonable to propose that patients would tolerate significant side effects for prolonged time periods. As an initial trial for this disease, we propose a phase I study to determine a recommended dose for subsequent trials, which will determine the efficacy of miransertib in Proteus syndrome. The recommended phase II dose will be determined based on the tolerability of miransertib in children and adults with Proteus syndrome and measures of drug levels in plasma and affected tissues in patients with Proteus syndrome and measures of tissue phosphorylation of AKT1. We hypothesize that the recommended dose of miransertib will be substantially below that of doses used in patients with cancer and that this will lead to a highly favorable risk-benefit ratio on which we can base future efficacy studies.
Study design
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Experimental | Experimental | Drug: MK-7075 (miransertib)Experimental |
Who may qualify
- Ages
- 6 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (14 listed)
- 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.
Key exclusion criteria (13 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MK-7075 (miransertib)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. | Drug | Experimental |
Primary outcome
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.
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.
Tolerabilty/Side Effects
Time frame: Ongoing
Tolerability and side effects are assessed on an ongoing basis.
1 secondary outcome
Tolerability and side effects
Time frame: Ongoing
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jun 2022.
- Derived from this study: PubMed 34649967Ours 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.
- Derived from this study: PubMed 30803705Keppler-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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
Related trials for Proteus Syndrome
RecruitingObservational study
Study of Proteus Syndrome and Related Congenital Disorders
Proteus Syndrome, PIK3CA Related Overgrowth Spectrum
Active, not recruitingPhase 2
MK-7075 (Miransertib) in Proteus Syndrome
Proteus Syndrome
Active, not recruitingPhase 2
A Study of the Safety and Tolerability in Participants With PIK3CA-related Overgrowth Spectrum or Proteus Syndrome Who Are Being Treated With Miransertib (MK-7075) in Other Studies (MK-7075-006)
PIK3CA-Related Overgrowth Spectrum (PROS)/Proteus Syndrome (PS)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Leslie G Biesecker, M.D. principal investigator
National Human Genome Research Institute (NHGRI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing MK-7075 (miransertib) in people with Proteus Syndrome, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Tissue drug levels (time frame: End of cycle 3). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02594215, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jun 2022.