Proteus Syndrome Clinical Trial
Official title:
A Multi-Cohort Phase 2 Dose-Escalation Study of MK-7075 (Miransertib) in Proteus Syndrome
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 cerebriform connective tissue nevus (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 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 45 mg/dose 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 lesion proportion of the plantar surface 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 26 cycles) 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 26 cycle 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 ;
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