- Part A - Assess the peak plasma concentration (Cmax) of the pharmacokinetic (PK) profile of ARQ 092 [ Time Frame: Cycle 1 Day 1 through Cycle 8 Day 1 (each cycle is 28 days) ]
- Part A - Assess the area under the plasma concentration vs. time curve (AUC) of the PK profile of ARQ 092 [ Time Frame: Cycle 1 Day 1 through Cycle 8 Day 1 (each cycle is 28 days) ]
- Part A - Assess the time to maximum plasma drug concentration (Tmax) of the PK profile of ARQ 092 [ Time Frame: Cycle 1 Day 1 through Cycle 8 Day 1 (each cycle is 28 days) ]
- Part A - Evaluate changes in fibrinogen and D-dimers from blood [ Time Frame: Baseline, once every cycle for the first year (each cycle is 28 days), and once at study completion, an average of 3 years. ]
Changes in fibrinogen and D-dimers will determine the pharmacodynamic activity of ARQ 092
- Part A - Evaluate efficacy measured as evidence of changes to the lesion size or volume [ Time Frame: Baseline, once at end of every 3rd cycle (each cycle is 28 days) during 1st year, once every 6 cycles thereafter through study completion, an average of 3 years, and once at study completion ]
Disease measurement will occur by imaging examination (e.g., MRI, CT, US), photography, video recording, and/or change in body measurements (e.g., linear or circumference measurements) as performed by a tape measure
- Part B (cohorts 1, 2, 3) - Change from baseline in pain score [ Time Frame: Screening,Cycle 1 Day 1, Cycle 7, Cycle 13, Cycle 19, Cycle 25, Cycle 37, End of Trial ]
Change from baseline in pain score will be assessed by Wong-Baker FACES® Pain Rating Scale
- Part B (cohorts 1, 2, 3) - Change from baseline in physical functioning [ Time Frame: Screening,Cycle 1 Day 1, Cycle 7, Cycle 13, Cycle 19, Cycle 25, Cycle 37, End of Trial ]
Change from baseline in physical functioning will be 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)
- Part B (cohorts 1, 2, 3) - duration of response [ Time Frame: The time period from when subject first achieve a response to the next assessment, and all subsequent assessments ]
- Part B (cohorts 1, 2, 3) - safety and tolerability [ Time Frame: Safety and tolerability will be 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) ]
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- Assess the peak plasma concentration (Cmax) of the pharmacokinetic (PK) profile of ARQ 092 [ Time Frame: Cycle 1 Day 1 (C1D1) (each cycle is 28 days) (time [t]=0,1,2,4,6,8,24 hours [h]), C1D8 (t=0 h), C1D15 (t=0,1,2,4,6,8,24 h), C2D1 (t=0 h). ]
If dose does not increase, C4D1 and C7D1 (t=0 h). If dose increases, C4D1 (t=0,1,2,4,6,8,24 h), C4D8 (t=0 h), C4D15 (t=0,1,2,4,6,8,24 h), C5D1 (t=0 h), C7D1 (t=0,1,2,4,6,8,24 h), C7D8 (t=0 h), C7D15 (t=0,1,2,4,6,8,24 h), C8D1 (t=0 h).
- Assess the area under the plasma concentration vs. time curve (AUC) of the pharmacokinetic (PK) profile of ARQ 092 [ Time Frame: C1D1 (t=0,1,2,4,6,8,24 h), C1D8 (t=0 h), C1D15 (t=0,1,2,4,6,8,24 h), C2D1 (t=0 h) ]
If dose does not increase, C4D1 and C7D1 (t=0 h). If dose increases, C4D1 (t=0,1,2,4,6,8,24 h), C4D8 (t=0 h), C4D15 (t=0,1,2,4,6,8,24 h), C5D1 (t=0 h), C7D1 (t=0,1,2,4,6,8,24 h), C7D8 (t=0 h), C7D15 (t=0,1,2,4,6,8,24 h), C8D1 (t=0 h).
- Assess the half life of ARQ 092 [ Time Frame: C1D1 (t=0,1,2,4,6,8,24 h), C1D8 (t=0 h), C1D15 (t=0,1,2,4,6,8,24 h), C2D1 (t=0 h) ]
If dose does not increase, C4D1 and C7D1 (t=0 h). If dose increases, C4D1 (t=0,1,2,4,6,8,24 h), C4D8 (t=0 h), C4D15 (t=0,1,2,4,6,8,24 h), C5D1 (t=0 h), C7D1 (t=0,1,2,4,6,8,24 h), C7D8 (t=0 h), C7D15 (t=0,1,2,4,6,8,24 h), C8D1 (t=0 h).
- Assess phosphatidylinositol 3-kinase (PI3K) / v-Akt murine thymoma viral oncogene homolog (AKT) signaling pathway markers in tissue samples (where feasible) [ Time Frame: Baseline, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
The PI3K/AKT signaling pathway markers will be assessed to determine the pharmacodynamic activity of ARQ 092
- Evaluate changes in insulin-like growth factor (IGF)-binding protein 2, fibrinogen, d-dimers, and circulating deoxyribonucleic acid (DNA) for AKT, PIK3CA, and phosphatase and tensin homolog (PTEN) from blood samples [ Time Frame: C1D1, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
Changes in IGF-binding protein 2, fibrinogen, d-dimers, and circulating DNA will determine the pharmacodynamic activity of ARQ 092
- Determine the recommended Phase 2 dose (RP2D) of ARQ 092 [ Time Frame: Up to 72 weeks ]
The ARQ 092 RP2D must be well tolerated, cause reduction from baseline by at least 50% in PI3K/AKT pathway activity, and/or provide clinical benefit (e.g., stabilization of lesions or symptom improvement).
- Evaluate efficacy measured as evidence of changes to the excess lesion volume [ Time Frame: Baseline, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
Disease measurement will occur by bi-dimensional/volumetric MRI, CT scan, or ultrasound, and/or circumferential measurement including photography where applicable
- Evaluate efficacy measured as changes in the degree of clinical impairment [ Time Frame: Baseline, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
Clinical impairment will be assessed by evaluating responses to a Clinical Function Assessment
- Evaluate efficacy measured as quality of life changes [ Time Frame: C1D1, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
Quality of life changes will be measured by evaluating responses to the PedsQL™ questionnaires and PedsQL™ Pediatric Pain Questionnaire/short-form McGill Pain Questionnaire
- Evaluate efficacy measured as changes in performance status [ Time Frame: Day 1 of each cycle and at the end of treatment (up to 18 months) ]
Changes in performance status will be measured by comparing Karnofsky/Lansky scores
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Inclusion Criteria for Part A
- Signed informed consent and, when applicable, signed assent
- Male or female patients ≥ 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)
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Adequate organ function as indicated by the following laboratory values:
Hematological
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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
- > 17 years male and female: ≥ 10.0 g/dL
- Glycated hemoglobin (HbA1c): ≤ 8% (≤ 64 mmol/mol)
- Absolute neutrophil count (ANC): ≥ 1.5 x 109/L
- Platelet count ≥ 150 x 109/L
Hepatic
- Total bilirubin ≤ 1.5 x upper limit of normal (ULN)/L
- AST and ALT ≤ 3 x ULN
Renal
a. Serum creatinine depending on age:
- 2-5 years male and female: maximum 0.50 mg/dL
- 6-10 years male and female: maximum 0.59 mg/dL
- 11-15 years male and female: maximum 1.2 mg/dL
- > 15 years male and female: maximum 1.5 mg/dL
Metabolic (lipids)
- Cholesterol: ≤ 400 mg/dL (≤ 10.34 mmol/L)
- Triglyceride: ≤ 500 mg/dL (≤ 5.7 mmol/L)
- If a female is of child-bearing potential, documentation of a negative pregnancy test is required prior to enrollment. Sexually active patients (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 QoL questionnaires by the patient or his/her caregiver
Exclusion Criteria for 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
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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 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 ARQ 092
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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 ARQ 092, except for patients who were previously or are currently treated with ARQ 092 under a Compassionate Use/Expanded Access program
- Patients, who were previously treated with or currently are receiving ARQ 092, 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., ARQ 092, uprosertib, afuresertib, ipatasertib)
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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
Inclusion criteria for Part B:
- Signed consent form and when applicable, signed assent
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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 (eligibility to be confirmed by blinded independent central imaging review
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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.
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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
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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:
- 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.
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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
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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 109/L d. Platelet count ≥ 150 x 109/L Hepatic
- Total bilirubin ≤ 1.5 x upper limit of normal (ULN)/L
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN Renal
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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
- Estimated Glomerular Filtration Rate (eGFR):
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60 mL/min/1.73 m2 Metabolic (lipids)
- Cholesterol: ≤ 400 mg/dL (≤ 10.34 mmol/L)
- Triglyceride: ≤ 500 mg/dL (≤ 5.7 mmol/L)
- 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
- Ability to complete the study questionnaires by the subject or his/her caregiver
Exclusion Criteria for 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
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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
- 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
- Intolerance of or severe toxicity attributed to AKT inhibitors (e.g., ARQ 092, uprosertib, afuresertib, ipatasertib)
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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
- Pregnant or breastfeeding
- Inability to comply with study evaluations or to follow drug administration guidelines
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