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Report for Clinical Trial NCT04316546

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Multi-Cohort Phase 2 Dose-Escalation Study of ARQ 092 (Miransertib) in Proteus Syndrome

Study Description: The primary objective of this study is to determine the response rate of miransertib as measured by a change in CCTN lesion size relative to total plantar area from baseline, using blinded independent central review of lesional photography in at least 10 patients 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 QD for the first three cycles, and then the dose will be increased to 25 mg/m^2 QD, 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 if resuming use of miransertib, not to exceed 25 mg/ m^2 QD. 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 relative growth of plantar CCTN in participants with Proteus syndrome. Secondary Objectives: - To estimate the change from baseline in pain in participants treated with miransertib - To estimate change from baseline in physical functioning in participants treated with miransertib - To estimate change from baseline in quality of life in participants treated with miransertib - To describe the long-term tolerability and safety of miransertib. - To determine the duration of response in responders with respect to the primary study endpoint Exploratory Objectives: - To describe the effect of miransertib on Proteus syndrome-related overgrowth manifestations assessed by imaging - To describe the effect of miransertib on selected CTCAE categorized Proteus syndrome-related symptoms - To describe the effect of miransertib on d-dimer and fibrinogen levels - To describe the PK profile of miransertib - To describe tolerability and safety of miransertib in participants who previously were treated with miransertib - To describe the effect of miransertib on the rate of growth of the CCTN lesion as compared to historical data from untreated participants - To describe the effect of miransertib on the rate of growth of the total lesional area (CCTN and confluent papules and nodules (pre-CCTN)) as compared to historical data from untreated participants - 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 (N of 1 design). Endpoints: Primary Endpoint (assessed in Cohort 1): Change in relative lesional size 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 response rate (defined as (less than or equal to 5% relative increase from baseline) in the CCTN lesional area relative to the total plantar area as assessed by blinded central photography review. Secondary Endpoints (assessed in Cohorts 1 and 2): - Change from baseline in pain score as assessed by Wong-Baker FACES Pain Rating Scale - 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) - Change from baseline in quality of life as assessed by the Pediatric Quality of Life Inventory (PedsQL) - Time from response to relative growth of plantar CCTN greater than or equal to 5% from baseline - 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 current CTCAE version) Exploratory Endpoints (assessed in Cohorts 1 and 2): - Change from baseline in selected disease-related manifestations as evaluated by DXA, CT, MRI, ultrasound, and/or photography - Change from baseline in severity of selected clinical manifestations as assessed by current CTCAE version (participant-specific disease- related symptoms, pre-identified by the Investigator) - Change from baseline in plasma levels of d-dimer and fibrinogen - PK parameters (e.g., maximum plasma drug concen...

NCT04316546 Proteus Syndrome
MeSH:Proteus Infections Proteus Syndrome Syndrome

1 Interventions

Name: Miransertib (ARQ092)

Description: ARQ 092 (miransertib) is a small molecule developed by ArQule Inc. 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.
Type: Drug
Group Labels: 1

ARQ 092 (miransertib)


Primary Outcomes

Description: Change in relative lesional size 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% relative increase from baseline) in the CCTN lesional area relative to the total plantar area as assessed by blinded central photography review.

Measure: CCTN

Time: baseline, one year

Secondary Outcomes

Description: Duration of response is defined as the amount of time from first response signal to annual progression of CCTN relative to sole greater than 5% or EQT.

Measure: Duration of Response

Time: Periodically throughout the study

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

Measure: Long-term safety and tolerability

Time: Periodically throughout the study

Description: Change from baseline in pain score (Wong-Baker FACES scale), physical functioning (PROMIS), and quality of life (PedsQL)

Measure: Quality of life

Time: Periodically throughout the study

Purpose: Treatment

Allocation: N/A

Single Group Assignment


There is one SNP

SNPs


1 E17K

- Major surgery, radiotherapy, 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 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 Proteus Syndrome Proteus Infections Proteus Syndrome Syndrome Proteus syndrome is a rare mosaic overgrowth disorder caused by a somatic gain of function variant, c. 49G>A, p.(Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase. --- Glu17Lys ---



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