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PIK3CA-related Overgrowth Spectrum

Patients with Proteus syndrome (PS) and other overgrowth disorders hypothesized to be in the AKT/PI3K pathway

Julie Sapp

Leslie G Biesecker, M.D.

This study will examine rare congenital disorders that involve malformations and abnormal growth. It will focus on patients with Proteus syndrome, whose physical features are characterized by overgrowth, benign tumors of fatty tissue or blood vessels, asymmetric arms or legs, and large feet with very thick soles. The study will explore the genetic and biochemical cause and course of the disease, the changes in symptoms over time, and the effects of the disease on patients.

Patients with Proteus syndrome and their parents may be eligible for this study. Parents will be studied, when possible, for comparison of molecular findings. Study candidates will have a medical history and physical examination, including X-rays and possibly other imaging tests, such as computerized tomography (CT), magnetic resonance imaging (MRI) and ultrasound. Other tests and examinations may be done if needed.

Those enrolled in the study will have will be interviewed or complete questionnaires, or both, about how their disease affects them. (Parents will be asked about their feelings about having a child with a rare disorder.) Patients will provide a small blood sample for research and may be asked to undergo biopsies from a normal area of skin and from a tumor.

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The purpose of this project is to specifically delineate the phenotype and natural history and genetic etiology of Proteus syndrome (PS) and other overgrowth disorders hypothesized to be in the PI3K/AKT pathway. As we have recently determined the molecular cause of PS and the related disorder of fibroadipose overgrowth, our main objectives moving forward include genotype-phenotype correlations, identifying quantifiable phenotypic characteristics in patients and measuring changes in these characteristics over time, developing potential biomarkers for future therapeutic research, and using our new molecular insights to expand our understanding of both PS and related overgrowth disorders. The natural history and specific phenotypic characteristics of patients with PS and selected other overgrowth disorders will be determined by clinical assessment and longitudinal follow-up of patients, which includes patients who have been exposed to therapeutic agents, such as an AKT inhibitor. Subjects will be screened for eligibility using published diagnostic criteria for PS; screening for AKT1 and other pathway gene mutations may be used in patients with overlapping phenotypes. The discovery of the AKT1 activating mutation in patients with this disease provides an attractive target for directed treatment for this devastating disorder. This protocol aims to aid in identifying individuals with molecularly-confirmed AKT1 mutations who may be candidates for pharmacologic interventional studies. We also propose to expand our clinical ascertainment to determine the full range of PS/AKT1 activating mutation phenotypes and to study other overlapping conditions. The etiology of these disorders will be studied using candidate gene analysis (primarily based on the PI3K/AKT pathway) and possibly exome and whole genome sequencing, performed as part of protocol 10-HG-0065.

Study of Proteus Syndrome and Related Congenital Disorders

The Phenotype and Etiology of Proteus Syndrome

Determine causative genotypes of overgrowth disorders

Determine natural history of a variety of overgrowth disorders

Children's National Research Institute

Uniformed Services University of the Health Sciences

National Human Genome Research Institute (NHGRI)

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

MK-7075 (miransertib) is a small molecule developed by ArQule Inc., a wholly owned subsidiary of Merck Sharp \&amp; Dohme, 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.

MK-7075 (miransertib)

Christopher A Ours, M.D.

For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)

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....

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:

1. To estimate the change from baseline in pain in participants treated with miransertib
2. To estimate change from baseline in physical functioning in participants treated with miransertib
3. To estimate change from baseline in quality of life in participants treated with miransertib
4. To describe the long-term tolerability and safety of miransertib
5. To determine the duration of response in responders with respect to the primary study endpoint

Exploratory Objectives:

1. To describe the effect of miransertib on Proteus syndrome-related overgrowth manifestations assessed by imaging
2. 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
3. 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
4. To describe the effect of miransertib on d-dimer and fibrinogen levels
5. 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:

1. Change from baseline in pain score as assessed by the NRS-11 Pain Rating Scale
2. 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)
3. Change from baseline in quality of life as assessed by the Pediatric Quality of Life Inventory (PedsQL)
4. 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)
5. 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:

1. Change from baseline in selected disease-related manifestations as evaluated by CT, MRI, ultrasound, and/or photography
2. Behavior of the CCTN lesion (+/- confluent papules and nodules) while on continuous treatment with miransertib using historical control data for comparison
3. 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
4. Change from baseline in d-dimer and fibrinogen levels
5. 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

MK-7075 (Miransertib) in Proteus Syndrome

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

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.

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.

Periodic safety (e.g., physical examination, vital sign measurements, clinical laboratory tests, use of concomitant medications and collection of AE information) assessments.

Change from baseline in pain score (NRS-11), physical functioning (PROMIS), and quality of life (PedsQL).

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.

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.

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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.

Dose Finding Trial of MK-7075 in Children and Adults With Proteus Syndrome

Phase 1 Dose Finding Trial of MK-7075 in Children and Adults With Proteus Syndrome

Tissue drug levels are assessed at baseline, cycle 1 /day 14, and cycle 4/day 1.

Tissue tissue phospho-AKT is assessed at baseline, cycle 1/day 14, and cycle 4/day 1.

Tolerability and side effects are assessed on an ongoing basis.

Heart and Blood Diseases

Vascular Malformations

Cardiovascular Abnormalities

Open-label expanded access for ARQ 092 capsules

ARQ 092

ARQ 092 is being investigated for patients with overgrowth diseases and/or vascular anomalies with genetic alterations of the PI3K/AKT pathway and may be available for patients who are ineligible for an ongoing ARQ 092 clinical trial or have other considerations that prevent access to ARQ 092 through an existing clinical trial.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Proteus Syndrome and Related Congenital Disorders	NCT00001403	Proteus Syndrom... PIK3CA Related ...		1 Month - 99 Years	National Institutes of Health Clinical Center (CC)
MK-7075 (Miransertib) in Proteus Syndrome	NCT04316546	Proteus Syndrom...	MK-7075 (mirans...	3 Years - 99 Years	National Institutes of Health Clinical Center (CC)
Dose Finding Trial of MK-7075 in Children and Adults With Proteus Syndrome	NCT02594215	Proteus Syndrom...	MK-7075 (mirans...	6 Years - 65 Years	National Institutes of Health Clinical Center (CC)
Study of Proteus Syndrome and Related Congenital Disorders	NCT00001403	Proteus Syndrom... PIK3CA Related ...		1 Month - 99 Years	National Institutes of Health Clinical Center (CC)
Expanded Access to Provide ARQ 092 for the Treatment of Overgrowth Diseases and/or Vascular Anomalies	NCT03317366	Proteus Syndrom... PIK3CA-Related ... Growth Disorder...	ARQ 092	2 Years -	ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
Dose Finding Trial of MK-7075 in Children and Adults With Proteus Syndrome	NCT02594215	Proteus Syndrom...	MK-7075 (mirans...	6 Years - 65 Years	National Institutes of Health Clinical Center (CC)

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