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

CLICCA QUI PER TRADURRE IN ITALIANO CON GOOGLE TRANSLATE

Sponsor: ArQule

Sommario: This is an open label, Phase 1/2 study of oral ARQ 092 administered to patients at least 2 years of age with PIK3CA-related Overgrowth Spectrum (PROS) and Proteus syndrome (PS).


TIPOLOGIA STUDIO

Interventistico

FASE


TRATTAMENTO


OBIETTIVO PRIMARIO

  • Misura: Incidence of adverse events graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) guidelines, version 4.03
  • Tempo: At each visit up to 51 months
  • Descrizione: The incidence of adverse events will be assessed as a measure of the safety and tolerability profile of ARQ 092

OBIETTIVO SECONDARIO

  • Misura: Assess the peak plasma concentration (Cmax) of the pharmacokinetic (PK) profile of ARQ 092
  • Tempo: Cycle 1 Day 1 through Cycle 8 Day 1 (each cycle is 28 days)
  • Descrizione:
  • Misura: Assess the area under the plasma concentration vs. time curve (AUC) of the PK profile of ARQ 092
  • Tempo: Cycle 1 Day 1 through Cycle 8 Day 1 (each cycle is 28 days)
  • Descrizione:
  • Misura: Assess the time to maximum plasma drug concentration (Tmax) of the PK profile of ARQ 092
  • Tempo: Cycle 1 Day 1 through Cycle 8 Day 1 (each cycle is 28 days)
  • Descrizione:
  • Misura: Evaluate changes in fibrinogen and D-dimers from blood
  • Tempo: Baseline, once every cycle for the first year (each cycle is 28 days), and once at study completion, an average of 3 years.
  • Descrizione: Changes in fibrinogen and D-dimers will determine the pharmacodynamic activity of ARQ 092
  • Misura: Evaluate efficacy measured as evidence of changes to the lesion size or volume
  • Tempo: 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
  • Descrizione: 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
  • Misura: Evaluate efficacy measured as changes in the degree of clinical impairment
  • Tempo: Baseline, once at the end of every 3rd cycle (each cycle is 28 days) during 1st year, once every 12 cycles thereafter through study completion, an average of 3 years and once at study completion
  • Descrizione: Clinical impairment will be measured using a functional assessment tool
  • Misura: Evaluate efficacy measured as quality of life changes
  • Tempo: Baseline, once at the end of every 3rd cycle (each cycle is 28 days) during 1st year, once every 12 cycles thereafter through study completion, an average of 3 years and once at study completion
  • Descrizione: Quality of life changes will be measured by evaluating responses to the PedsQL™ questionnaires, PedsQL™ Pediatric Pain Questionnaire, the Face, Legs, Activity, Cry, Consolability (FLACC) scale for children aged 2-4 years, and the short-form McGill Pain Questionnaire
  • Misura: Evaluate efficacy measured as changes in performance status
  • Tempo: Day 1 of each cycle and at the end of treatment (up to 48 months)
  • Descrizione: Changes in performance status will be measured by comparing Karnofsky/Lansky scores

CRITERI DI ELIGIBILITA'

  • Criteri di inclusione e esclusione

    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


SESSO

Tutti


ETA' MINIMA

Età Minima: 2 Years
Età Massima: N/A


LUOGO

Azienda Ospedaliero-Universitaria "Policlinico-Vittorio Emanuele"
Catania,

Fondazione Policlinico Universitario Agostino Gemelli
Roma, 00168

Ospedale Bambino Gesu
Rome,

REFERENTE PER INFORMAZIONI

ArQule, Inc.
781-994-0300
ClinicalTrials@arqule.com