Miransertib for Proteus Syndrome

Overseen By Leslie G Biesecker, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: National Human Genome Research Institute (NHGRI)

Must not be taking: Experimental therapies, AKT inhibitors

Disqualifiers: Uncontrolled diabetes, Cardiac disorders, Major surgery, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 21

Duration: Up to 52 cycles (approximately 4 years)

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if the experimental drug miransertib (also known as ARQ092 or MK-7075) can safely and effectively slow or stop the overgrowth caused by Proteus syndrome, a rare disorder that leads to abnormal tissue growth. Participants will take a daily dose of miransertib and undergo various health checks, imaging scans, and surveys to monitor their condition and quality of life. Individuals aged 3 and older with Proteus syndrome, who show signs of worsening symptoms, may be eligible to join. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those using certain experimental therapies or those with uncontrolled diabetes requiring regular medication. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that miransertib is likely to be safe for humans?

Research has shown that miransertib is generally safe and well-tolerated in people with Proteus syndrome. In one study, most participants did not experience severe side effects, indicating a good safety record. The treatment has been used for over five years and has helped reduce symptoms like pain and slow the growth of affected areas.

These findings suggest that while some side effects may occur, they are usually not serious for most people. For those considering joining a trial for miransertib, these results indicate that the treatment has been well-tolerated in past studies. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard of care for Proteus Syndrome, which typically involves symptom management through surgery and other supportive treatments, miransertib targets the underlying cause of the condition. Most treatments don't address the genetic mutations driving the disease. However, miransertib is designed to inhibit the AKT1 protein, which is involved in cell growth and division, thereby potentially controlling the abnormal tissue growth at its source. Researchers are excited because miransertib could offer a more precise approach to managing Proteus Syndrome, potentially improving quality of life for patients by addressing the root cause rather than just the symptoms.

What evidence suggests that miransertib might be an effective treatment for Proteus syndrome?

Research has shown that miransertib could be a promising treatment for Proteus syndrome. One study found that miransertib slowed the growth of affected areas and reduced symptoms like pain in patients with this condition. Another study confirmed that miransertib was safe and well-tolerated, which is important for long-term use. This drug targets specific processes in the body that control cell growth, a major issue in Proteus syndrome. These findings suggest that miransertib could help manage symptoms and slow the disorder's progression. In this trial, all participants will receive the experimental drug, MK-7075 (miransertib). ^{1 2 6 7 8}

Who Is on the Research Team?

Leslie G Biesecker, M.D.

Principal Investigator

National Human Genome Research Institute (NHGRI)

Are You a Good Fit for This Trial?

This trial is for people aged 3 and older with Proteus syndrome, a rare overgrowth disorder. Participants must have specific blood values within normal ranges, not use tobacco or certain drugs, and agree to contraception if of childbearing potential. They can't join if they have uncontrolled diabetes, significant heart issues, active infections, or intolerance to AKT inhibitors like miransertib.

Inclusion Criteria

I am between 3 and 16 years old with a measurable foot tumor and a body surface area of at least 0.33 m^2.

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

I am over 3 years old, have used or am using miransertib, and my body surface area is at least 0.33 m^2.

Exclusion Criteria

I do not have any severe illnesses unrelated to Proteus syndrome.

I have diabetes that is not well-controlled with medication other than metformin.

I haven't had serious heart problems in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive miransertib in continuous, 28-day cycles, with dose escalation based on tolerance

Up to 52 cycles (approximately 4 years)

20-30 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with a final clinical safety follow-up 30 days after the last dose

30 days

Long-term monitoring

Participants may continue to be monitored for long-term safety and effectiveness

Ongoing

What Are the Treatments Tested in This Trial?

Interventions

• Miransertib (ARQ092)
• MK-7075 (Miransertib)

Trial Overview

The trial tests the safety and effectiveness of MK-7075 (miransertib) in slowing down or stopping overgrowth in Proteus syndrome patients. It involves taking daily pills of miransertib for about four years with regular checkups at NIH including medical exams, imaging scans, lung function tests and surveys on pain and quality of life.

How Is the Trial Designed?

Group I: MK-7075 (miransertib) Experimental Treatment 1 Intervention

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

Who Is Running the Clinical Trial?

National Human Genome Research Institute (NHGRI)

Lead Sponsor

Trials

273

Recruited

299,000+

Published Research Related to This Trial

Cancer cells, particularly in multiple myeloma, rely heavily on the ubiquitin proteasome pathway for survival, making proteasome inhibitors like carfilzomib important therapeutic targets.

Carfilzomib, a second-generation proteasome inhibitor, irreversibly binds to the proteasome and has been developed to reduce the toxicities and resistance issues seen with the first-generation inhibitor bortezomib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib: A Promising Proteasome Inhibitor for the Treatment of Relapsed and Refractory Multiple Myeloma. Jayaweera, SPE., Wanigasinghe Kanakanamge, SP., Rajalingam, D., et al.[2021]

In a study of 66 patients with recurrent malignant glioma, the maximum tolerated dose (MTD) of bortezomib was found to be 1.70 mg/m² for those not taking enzyme-inducing anti-seizure drugs, while the dose could not be escalated beyond 2.5 mg/m² for those who were, indicating that these drugs affect bortezomib's tolerability.

The study showed that bortezomib effectively inhibited the 20S proteasome, achieving a plateau of around 79% inhibition in patients not on anti-seizure drugs, and some clinical activity was observed with two partial responses, suggesting potential efficacy in treating high-grade gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 clinical trial of bortezomib in adults with recurrent malignant glioma. Phuphanich, S., Supko, JG., Carson, KA., et al.[2018]

Proteasome inhibitors, starting with bortezomib, have been a significant advancement in cancer therapy over the past 20 years, particularly for treating multiple myeloma.

Bortezomib received FDA approval in 2003, and subsequent proteasome inhibitors like carfilzomib and ixazomib have also been developed, showcasing the ongoing evolution of this treatment class.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CCR 20th anniversary commentary: In the beginning, there was PS-341. Teicher, BA., Anderson, KC.[2019]

Bortezomib, the first proteasome inhibitor approved for clinical use in 2003, has shown significant efficacy in treating advanced multiple myeloma, with about one third of patients experiencing clinical benefits in trials.

The drug works by inhibiting the proteasome, leading to apoptosis of cancer cells and reduced tumor growth through mechanisms like nuclear factor-kappa B inhibition and activation of c-Jun N-terminal kinase.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proteasome inhibition as a novel therapeutic target in human cancer. Rajkumar, SV., Richardson, PG., Hideshima, T., et al.[2015]

In a phase II study involving 12 patients with metastatic breast cancer, PS-341 (bortezomib) showed no objective tumor responses, indicating it was ineffective for this condition.

All patients in the study experienced disease progression while on PS-341 treatment, leading to the early termination of the trial due to lack of efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of single agent bortezomib in patients with metastatic breast cancer: a single institution experience. Engel, RH., Brown, JA., Von Roenn, JH., et al.[2015]

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