Study of ARQ 092 in Patients With Overgrowth Diseases and/or Vascular Anomalies

Status: Recruiting
Phase:
DFCI Protocol ID:

This is an open label, Phase 1/2 study of oral ARQ 092 administered to patients at least 2 years of age with overgrowth diseases and/or vascular anomalies with genetic alterations of the PI3K/AKT pathway.

Conducting Institutions:

Dana-Farber Cancer Institute, Children's Hospital Boston

Overall PI:

Denise Adams, MD, Boston Children's Hospital

Site-responsible Investigators:

Contacts:

Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, ctip@partners.org

Eligibility Criteria

Inclusion Criteria

  1. Male or female subjects ≥ 2 years of age with BSA of ≥ 0.33 m2

  2. Overgrowth diseases and/or vascular anomalies with documented and/or confirmed somatic
     genetic alterations of PIK3CA or AKT defined/assessed as:

       -  Measurable segmental overgrowth, currently experiencing growth, or with clinical
  history of overgrowth progression

       -  Vascular and/or lymphatic overgrowth diseases as determined by clinical (such as
  dermatological), imaging (e.g., MRI, CT, ultrasound), and
  histological/cytological criteria

  3. Subjects with significant morbidity, poor quality of life, or with disease
     characterized by poor prognosis

  4. No standard systemic therapeutic option available or no satisfactory response to prior
     experimental or local therapies

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

  6. Hemoglobin (Hgb) depending on age:

       -  2-5 years male and female: ≥ 11.0 g/dL

       -  6-9 years male and female: ≥ 11.5 g/dL

       -  10-17 years female: ≥ 12.0 g/dL

       -  10-17 years male: ≥ 12.5 g/dL

       -  > 17 years male and female: ≥ 10.0 g/dL

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

  8. Platelet count ≥ 150 x 109/L (for subjects with Multifocal
     Lymphangio-endotheliomatosis with Thrombocytopenia (MLT), platelet count must be ≥ 75
     x 10^9/L)

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

 10. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN

 11. 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

 12. If a female is of child-bearing potential, documentation of a negative pregnancy test
     is required prior to enrollment. Sexually active subjects (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.

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) and ≥ 180 mg/dL (if ≤ 12 years) at the screening visit

  2. Grade 2 per NCI CTCAE version 4.03 or worse hypercholesterolemia or
     hypertriglyceridemia or > 8% (or > 64 mmol/mol) glycated Hgb (HbA1C)

  3. Malabsorption syndrome

  4. History of myocardial infarction (MI) or New York Heart Association (NYHA) Class II-IV
     congestive heart failure within 6 months of the administration 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 conduction defect (e.g., right or left bundle
     branch block); left ventricular ejection fraction (LVEF) < 50% assessed by
     echocardiogram/multigated acquisition (MUGA) scan

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

  6. Any experimental systemic therapy for the purpose of treating the overgrowth disease
     and/or vascular anomalies (e.g., sirolimus, everolimus, high dose steroids) within two
     weeks of the first dose of ARQ 092

  7. Previous treatment with AKT inhibitors

  8. Concurrent severe uncontrolled illness not related to overgrowth diseases

  9. Ongoing or active known infection, including human immunodeficiency virus (HIV)
     infection or ongoing bleeding

 10. Psychiatric illness/substance abuse/social situation that would limit compliance with
     study requirements

 11. Pregnant or breastfeeding

 12. Severe hypersensitivity reactions to mammilian target of rapamycin (mTOR) inhibitors
     (e.g., sirolimus, everolimus)

 13. Insufficient language proficiency of the subject (or legal guardian) to complete the
     informed consent and quality of life questionnaires

 14. Inability to comply with study evaluations or come to follow up appointments

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