PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome (PS). MedDRA version: 20.0 Level: LLT Classification code 10018058 Term: Gene genetic abnormality System Organ Class: 100000004850 MedDRA version: 20.0 Level: LLT Classification code 10069758 Term: Somatic mutation System Organ Class: 100000004867
Conditions
Interventions
Product Name: Miransertib 5 mg
Product Code: ARQ 092
Pharmaceutical Form: Capsule
INN or Proposed INN: Miransertib
CAS Number: 1313881-70-7
Current Sponsor code: ARQ 092•2 methanesulfonic acid (MSA),
Sponsors
ArQule, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion Criteria - Part B 1.Signed informed consent, and when applicable, signed assent 2.Cohort 1 (PROS) specific criteria •Male or female subjects = 2 years and =30 years of age with BSA of = 0.33 m2 •Have clinical diagnosis of PROS per Diagnostic Criteria for PROS and documented somatic PIK3CA variant •Have at least one lesion that can be measured by study- standardized volumetric MRI 3.Cohort 2 (PS) specific criteria •Male or female subjects = 2 years and =18 years of age with BSA of = 0.33 m2 •Have clinical diagnosis of PS per Diagnostic Criteria for PS and documented somatic AKT1 variant •Have at least one plantar CCTN and pre-CCTN lesion that can be measured by standardized photography. 4.Cohort 3 specific criteria •Male or female subjects =2 years old with BSA of = 0.33 m2 and who fail to meet the eligibility criteria for Cohorts 1 or 2 5.Cohort 4 (PROS or PS) specific criteria •Subjects previously treated with ARQ 092 or currently receiving ARQ 092 under Compassionate Use/Expanded Access Note: Subjects should meet the age criterion by/on the date of the first dose, Cycle 1 Day 1. All Cohorts: 6.Archival or fresh overgrowth tissue sample available to be shipped to Sponsor or designee 7.Except for Cohort 4, clinically progressive or worsening disease defined as an increase in number or size of the overgrowth lesion(s) in the last 6 months as assessed by the Investigator 8.Adequate organ function as indicated by the following laboratory values: Hematological a.Hemoglobin (Hgb) depending on age: 2-5 years male and female: = 10.0 g/dL 6-9 years male and female: = 11.5 g/dL 10-17 years female: = 11.0 g/dL 10-17 years male: = 11.5 g/dL =18 years male and female: = 10.0 g/dL b.Glycated hemoglobin (HbA1c): = 8% (= 64 mmol/mol) c.Absolute neutrophil count (ANC): = 1.5 x 10_9/L d.Platelet count = 150 x 10_9/L Hepatic a.Total bilirubin = 1.5 x upper limit of normal (ULN)/L b.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3 x ULN Renal a.Serum creatinine depending on age: 2-5 years male and female: maximum 0.80 mg/dL 6-10 years male and female: maximum 1.0 mg/dL 11-15 years male and female: maximum 1.2 mg/dL > 15 years male and female: maximum 1.5 mg/dL b.Estimated Glomerular Filtration Rate (eGFR): = 60 mL/min/1.73 m2 Metabolic (lipids) a.Cholesterol: = 400 mg/dL (= 10.34 mmol/L) b.Triglyceride: = 500 mg/dL (= 5.7 mmol/L) 9.Male or female subjects of child-producing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after the last dose of ARQ 092 10.Ability to complete the study questionnaires by the subject or his/her caregiver Are the trial subjects under 18? yes Number of subjects for this age range: 60 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 5 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Exclusion Criteria – Part B 1. History of Type 1 diabetes mellitus or Type 2 uncontrolled diabetes mellitus requiring regular medication (other than metformin or other oral hypoglycemic agents) or fasting glucose = 160 mg/dL (if > 12 years old) and = 180 mg/dL (if = 12 years old) at the screening visit 2. History of significant cardiac disorders: • Myocardial infarction (MI) or congestive heart failure defined as Class II-IV per the New York Heart Association (NYHA) classification within 6 months of the first dose of ARQ 092 (MI occurring > 6 months of the first dose of ARQ 092 will be permitted) • Grade 2 (per current version of National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]) or worse conduction defect (e.g., right or left bundle branch block) • Major surgery or locoregional therapy within four weeks of the first dose of ARQ 092 3. Any experimental systemic therapy for the purposes of treating PROS or PS (e.g., sirolimus, everolimus, high dose steroids) within two weeks of the first dose of ARQ 092 4. Intolerance of or severe toxicity attributed to AKT inhibitors (e.g., ARQ 092, uprosertib, afuresertib, ipatasertib) 5. Concurrent severe uncontrolled illness not related to PROS or PS, e.g., • 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 6. Pregnant or breastfeeding 7. Inability to comply with study evaluations or to follow drug administration guidelines
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part B: Primary objective: •To determine the efficacy of ARQ 092 in subjects with PROS and PS ;Secondary Objective: Part B: Secondary objectives: •To estimate the change from baseline in pain score •To estimate change from baseline in physical functioning •To describe the long-term tolerability and safety of ARQ 092 •To determine the duration of response ;Primary end point(s): Part B: Primary endpoint: Change in lesion size from baseline will be used to classify each subject as either a responder or non-responder (binary) in the Treated population. • For Cohort 1 (PROS): The primary endpoint is response rate, as assessed by blinded central imaging review of volumetric MRI • For Cohort 2 (PS): The primary endpoint is response rate, as assessed by blinded central photography review of CCTN lesional area ;Timepoint(s) of evaluation of this end point: The primary efficacy analysis will be conducted for Part B Cohorts 1 and 2 only. Response will be assessed independently at every 6 cycles during the first 24 cycles of treatment, every 12 cycles thereafter, and at the end of treatment (EOT). The primary analysis of the primary endpoint will be performed after the last patient in Cohort 1 or 2 would have completed the 12 month assessment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part B Secondary endpoints: For Cohort 1, 2 and 3 •Change from baseline in pain score and physical functioning. •Duration of response •Safety and tolerability as assessed by frequency, duration and severity of AEs from the first dose of ARQ 092 through 30 days after the last dose of the drug (severity of AEs will be assessed by current CTCAE version) Exploratory endpoints for Cohorts 1, 2 and 3 •Change from baseline in selected disease-related manifestations as evaluated by DXA, MRI, CT or photography •Change from baseline in severity of selected clinical manifestations as assessed by current CTCAE version (subject specific disease related symptom, pre-identified by the Investigator) •Change from baseline in plasma levels of D-dimer and fibrinogen •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 For Cohort 4: •Safety and tolerability of ARQ 092 •Change from baseline in overgrowth lesions as evaluated by imaging ;Timepoint(s) of evaluation of this end point: All subjects who receive at least 1 dose of ARQ 092 will be included in the analysis of safety. Patient-reported pain scores and physical functioning will be analyzed using a mixed model repeated measures to evaluate changes from baseline at each subsequent study assessment visit through the end of the study. Means and medians of questionnaire raw scores will be summarized by time point, overall, and for each domain. The duration of response will be evaluated for each responder and summarized descriptively. The efficacy ARQ 092 for all subjects enrolled in Part B Cohort 4 will be determined on a per subject basis and summarized as a clinical narrative. | — |
Countries
Australia, Brazil, Chile, France, Germany, Italy, Peru, Spain, United Kingdom, United States
Contacts
Public ContactFlorencia Domeniconi
Worldwide Clinical Trials d.o.o.
Outcome results
None listed