Study of ARQ 092 in Patients With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome

This is an open label, Phase 1/2 study of ARQ 092 administered orally. The study objectives
are:

- To assess the safety and tolerability of ARQ 092 in patients with PROS and PS

- To assess the clinical activity of ARQ 092

- To evaluate the dosing schedule of ARQ 092

- To determine the pharmacokinetic (PK) profile of ARQ 092.

All enrolled patients will receive ARQ 092 at the 15 mg/m2 QD dose level during the first
three cycles. A study cycle is defined as 28 days. Actual dose will be calculated using body
surface area (BSA), per the DuBois formula. The dose may be increased to 25 mg/m2 provided no
clinically significant drug-related toxicity is observed and upon agreement between the
Investigator and the Sponsor. The intra-patient dose escalation can be implemented after
completion of 3 or 6 treatment cycles.

For an individual patient, treatment will continue until disease progression, unacceptable
toxicity, or another discontinuation criterion is met. It is expected that most patients will
receive between 3 to 48 cycles of treatment.

Inclusion Criteria

1. Signed informed consent and, when applicable, signed assent

2. Male or female patients ≥ 2 years old with BSA of ≥ 0.33 m2

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

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

5. 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)

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

7. Adequate organ function as indicated by the following laboratory values:

Hematological

1. 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

2. Glycated hemoglobin (HbA1c): ≤ 8% (≤ 64 mmol/mol)

3. Absolute neutrophil count (ANC): ≥ 1.5 x 109/L

4. Platelet count ≥ 150 x 109/L

Hepatic

1. Total bilirubin ≤ 1.5 x upper limit of normal (ULN)/L

2. 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)

1. Cholesterol: ≤ 400 mg/dL (≤ 10.34 mmol/L)

2. Triglyceride: ≤ 500 mg/dL (≤ 5.7 mmol/L)

8. 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

9. Ability to complete the QoL questionnaires by the patient or his/her caregiver

Exclusion Criteria:

1. 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

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 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

3. Major surgery, radiotherapy, or immunotherapy within four weeks of the first dose of
ARQ 092

4. 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

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

- 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. Pregnant or breastfeeding

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