subjects (at least 6 years) suffering from diseases overgrowth and vascular anomalies with genetic alterations of the PI3K / AKT pathway. MedDRA version: 20.0 Level: SOC Classification code 10010331 Term: Congenital, familial and genetic disorders System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: ARQ 092
Product Code: ARQ 092 -2 MSA
Pharmaceutical Form: Capsule
Sponsors
ArQule, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Each prospective subject must meet ALL of the following inclusion criteria in order to be eligible for this study: 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 KHE or 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 Are the trial subjects under 18? yes Number of subjects for this age range: 12 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 3 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 1
Exclusion criteria
Exclusion criteria: Potential subjects who meet ANY of the following exclusion criteria are not eligible for enrollment into this study: 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 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE version 4.03]) 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) 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 5. Major surgery, chemotherapy, radiotherapy, or immunotherapy within four weeks of the first dose of ARQ 092 6. No experimental systemic therapy for the purpose of treating PIK3CA Related Overgrowth Spectrum (PROS) (e.g., sirolimus, everolimus, high dose steroids) within two weeks of 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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to assess the safety of ARQ 092 in subjects with overgrowth diseases and vascular anomalies with genetic alterations of the PI3K/AKT pathway.;Secondary Objective: To determine the clinical and biological activity of ARQ 092 in subjects with overgrowth diseases and vascular anomalies • To determine the recommended dose of ARQ 092 in subjects with overgrowth diseases and vascular anomalies • To evaluate the association between markers of the PI3K/AKT signaling pathway, their pharmacodynamic changes, and clinical activity in subjects treated with ARQ 092 • To assess the pharmacokinetic profile of ARQ 092 • To assess the changes while on therapy (change from baseline after 3, 6, and possibly 9 cycles on therapy) of the excess lesion volume at the affected site(s) by imaging (e.g., bi-dimensional/volumetric magnetic resonance imaging [MRI], computed tomography [CT] scan, ultrasound) and/or circumferential measurements including photographs, where applicable • To measure the changes in clinical function assessment while on therapy (change from baseline after 3, 6, and possibly 9 cycles on therapy);Primary end point(s): The primary endpoint of this study is safety and it is measured by safety variables which include the reported adverse events (AEs), laboratory tests, vital signs, ECG, echocardiograms, and physical examination.;Timepoint(s) of evaluation of this end point: for the entire duration of the study and in the three months following the end of the same | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): PK which are measured by maximum plasma drug concentration (Cmax), area under the curve (AUC), and elimination half-life • Pharmacodynamic activity which is measured by evaluating changes in PI3K/AKT signaling pathway markers between baseline and post-dose tissue samples • Pharmacodynamic activity which is measured by evaluating changes in insulin-like growth factor (IGF)-binding protein 2, fibrinogen, d-dimers and circulating DNA for AKT, PIK3CA and PTEN from blood samples collected at baseline and post-dose timepoints • Recommended dose of ARQ 092 in subjects with overgrowth diseases and vascular anomalies will be determined following a review of all safety and pharmacodynamic data generated • Efficacy, measured as evidence of changes to the excess lesion volume by comparing baseline imaging (such as MRI, CT, ultrasound) and/or circumferential measurements to post dose timepoints • Efficacy, measured as changes in the degree of clinical impairment by evaluating responses to Clinical Function Assessment questions from baseline to post-dose timepoints Exploratory endpoints include the following: • Efficacy, measured as quality of life changes by evaluating responses to the PedsQL™ questionnaires and PedsQL™ Pediatric Pain Questionnaire/short-form McGill Pain Questionnaire from baseline to post dose timepoints • Efficacy, measured as changes in performance status by comparing Karnofsky/Lansky scores at baseline to those post-dose;Timepoint(s) of evaluation of this end point: PK: cycles from 1 to 8; pharmacodynamic activity: cycles 1, 4, 7, 10, 16 and at the end of treatment; effectiveness: screening, Cycles 4, 7, 10, 16 and at the end of treatment exploratory endpoint: time points of cycles 1, 4, 7, 10, 16 and EOT | — |
Countries
France, Germany, Italy, Spain, United Kingdom, United States
Contacts
Public ContactPaola Strada
Innopharma Srl
Outcome results
None listed