A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects with PIK3CA-related Overgrowth Spectrum (PROS) and Proteus Syndrome (PS)

Phase 1

Conditions: PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome (PS).
MedDRA version: 20.0Level: LLTClassification code 10018058Term: Gene genetic abnormalitySystem Organ Class: 100000004850
MedDRA version: 22.0Level: LLTClassification code 10069758Term: Somatic mutationSystem Organ Class: 100000004850
Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Registration Number: EUCTR2016-000558-37-DE

Lead Sponsor: Merck Sharp & Dohme Corp

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 65

Inclusion Criteria

Part B
1.Signed informed consent, and when applicable, signed assent. Adults who are unable to consent except by means of a Legally Authorized Representative (LAR) may participate in the study.

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 (there is no upper age limit at the time of enrollment) with BSA of = 0.33 m2
•PROS specific inclusion criterion: Have clinical diagnosis of PROS per Diagnostic Criteria for PROS (see Appendix 1) and documented somatic PIK3CA variant
•PS specific criterion: Have clinical diagnosis of PS per Diagnostic Criteria for PS (see Appendix 1) and documented somatic AKT1 variant
•Subjects must not be eligible for enrollment in Cohort 1 (PROS) or Cohort 2 (PS): Older than 30 years of age (PROS) or 18 years of age (PS) (exceed the upper limit of age allowed for Cohort 1 or Cohort 2 enrollment)
•Do not have measurable disease:
-PROS: do not have at least one lesion that can be measured by study- standardized volumetric MRI or to whom MRI cannot be performed
-PS: no plantar CCTN lesion(s) or the CCTN lesion(s) do not satisfy protocol defined criteria of the measurable lesion

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.Female subjects must be of non-child producing potential or in postmenopausal state. Women of non-child producing potential are defined as those who underwent permanent sterilization (permanent ster

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)

3. Major surgery or locoregional therapy within four weeks of the first dose of ARQ 092

4. 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

5. Intolerance of or severe toxicity attributed to AKT inhibitors (e.g., ARQ 092, uprosertib, afuresertib, ipatasertib)

6. 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

7. Female of child-producing potential, pregnant or breastfeeding. Female subject of child-producing potential is defined as a
premenopausal female capable of becoming pregnant, including women from the onset of menstruation (menarche) until the onset of menopause.

8. Inability to comply with study evaluations or to follow drug administration guidelines

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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