Patient case: 54-year-old male with Gastric cancer. Genetic variant: PIK3CA (E545K). Other conditions: Depression.

Clinical trial: Study of ARQ 092 in Patients With Overgrowth Diseases and Vascular Anomalies

Summary: This is an open label, Phase 1/2 study of oral ARQ 092 administered to patients at least 6 years of age with overgrowth diseases and vascular anomalies with genetic alterations of the PI3K/AKT pathway.

Detailed description: This is an open label, Phase 1/2 study of ARQ 092 administered orally. The primary objective of this study is to assess the safety of ARQ 092 in subjects (at least 6 years of age) with overgrowth diseases and vascular anomalies with genetic alterations of the PI3K/AKT pathway.
  The first cohort will receive a dose of 15 mg/m2 of ARQ 092 administered by mouth QD in the morning without food (1 hour prior to or 2 hours after a meal) for 3 cycles. If no drug-related clinically significant toxicity is observed at 15 mg/m2, the cohort will receive 25 mg/m2 QD for 3 more cycles. If no toxicity is observed at 25 mg/m2, and after agreement between the Sponsor and Investigator, the dose may be escalated to 35 mg/m2 for 3 more cycles (but no more than 45 mg total QD).
  For an individual subject, treatment will continue until unacceptable toxicity or another discontinuation criterion is met. Subjects who, in the opinion of the Investigator and in agreement with the Sponsor, are deriving benefit from the experimental therapy by the end of 6 cycles (or 9 cycles for the 35 mg/m2 schedule) will be allowed to remain on therapy for the duration of the benefit for a maximum time of 12 months from the start of their beneficial dose. It is expected that most subjects will receive between 3 to 9 months of treatment.

Eligibility: Inclusion Criteria
  1. Male or female subjects ≥ 6 years old
  2. Overgrowth diseases or vascular anomalies with documented and/or confirmed somatic genetic alterations of PIK3CA, AKT, or PTEN defined/assessed as:
  -  Measureable 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., bi-dimensional/volumetric 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:
  -  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 Kaposiform Hemangioendotheliomas (KHE) or Multifocal Lymphangio-endotheliomatosis with Thrombocytopenia (MLT), platelet count must be ≥ 75 x 109/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:
  -  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 use adequate contraceptive measures 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% 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 PROS (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 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 swallow oral medications

Relevance to patient case: not relevant