Study of Miransertib (MK-7075) in Participants With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome (MOSAIC) (MK-7075-002)
Study of Miransertib (MK-7075) in Participants With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome (MOSAIC) (MK-7075-002)
This is an open label, Phase 1/2 study of oral miransertib (MK-7075) administered to
 participants at least 2 years of age with PIK3CA-related Overgrowth Spectrum (PROS) and
 Proteus Syndrome (PS) (MOSAIC).
The study consists of two parts: Part A and Part B. Part A was closed to enrollment under
 Amendment 6. As of Amendment 7, the endpoints for Part A and Part B have been combined to
 assess the safety and tolerability of miransertib in participants with PROS and PS. Previous
 efficacy and pharmacokinetic (PK) objectives and endpoints have been removed.
Inclusion Criteria:

 Part A

 -  Signed informed consent and, when applicable, signed assent

 -  Male or female participants ≥ 2 years old with BSA of ≥ 0.33 m2

 -  Have a clinical diagnosis of PROS or PS with documented somatic PIK3CA or AKT1
 mutations

 -  Archival or fresh overgrowth tissue sample available to be shipped to Sponsor or
 designee

 -  Have poor prognosis, significant morbidity, and/or progressive disease (e.g.,
 worsening of the disease/increase in number or size of the overgrowth lesions in the
 last 12 months)

 -  Have measurable disease (at least one overgrowth lesion that can be accurately
 measured in size by imaging and/or linear or circumference measure)

 -  Adequate organ function based on screening laboratory values

 -  If a female is of child-bearing potential, documentation of a negative pregnancy test
 is required prior to enrollment. Sexually active participants (male and female) must
 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

 -  Ability to complete the Quality of Life (QoL) questionnaires by the participant or
 his/her caregiver

 Part B:

 -  Signed consent form and when applicable, signed assent

 -  Archival or fresh overgrowth tissue sample available to be shipped to Sponsor or
 designee

 -  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

 -  Adequate organ function based on screening laboratory values

 -  Male or female participants 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 miransertib

 -  Ability to complete the study questionnaires by the participant or his/her caregiver

 Cohort 1 (PROS) specific criteria

 -  Male or female participants ≥ 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
 (eligibility to be confirmed by blinded independent central imaging review

 - Cohort 2 (PS) specific criteria

 -  Male or female participants ≥ 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

 -  Cohort 3 specific criteria: Male or female participants ≥2 years old with BSA of
 ≥ 0.33 m2 and who fail to meet the eligibility criteria for Cohorts 1 or 2

 -  Cohort 4 (PROS or PS) specific criteria: participants previously treated with
 miransertib or currently receiving miransertib under Compassionate Use/Expanded
 Access. Participants should meet the age criterion by/on the date of the first
 dose, Cycle 1 Day 1

 Exclusion Criteria

 Part A:

 -  History of Type 1 or 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

 -  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 miransertib (MI occurring > 6 months of the first dose of miransertib
 will be permitted)

 -  Grade 2 (per NCI CTCAE version 4.03) or worse conduction defect (e.g., right or
 left bundle branch block); left ventricular ejection fraction (LVEF) < 50%
 assessed by echocardiogram/multigated acquisition (MUGA) scan

 -  Major surgery, radiotherapy, or immunotherapy within four weeks of the first dose of
 miransertib

 -  Any experimental systemic therapy for the purpose of treating PROS or PS (e.g.,
 sirolimus, everolimus, high dose steroids) 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

 -  Intolerance of or severe toxicity attributed to AKT inhibitors (e.g., miransertib,
 uprosertib, afuresertib, ipatasertib)

 -  Concurrent severe uncontrolled illness not related to PROS or PS (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

 -  Inability to comply with study evaluations or to follow drug administration guidelines

 Part B

 -  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

 -  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 miransertib (MI occurring > 6 months of the first dose of miransertib
 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
 miransertib

 -  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
 miransertib

 -  Intolerance of or severe toxicity attributed to AKT inhibitors (e.g., miransertib,
 uprosertib, afuresertib, ipatasertib)

 -  Concurrent severe uncontrolled illness not related to PROS or PS (e.g. ongoing or
 active infection, known HIV infection, malabsorption syndrome, psychiatric
 illness/substance abuse/social situation that would limit compliance with study
 requirements)

 -  Pregnant or breastfeeding

 -  Inability to comply with study evaluations or to follow drug administration guidelines