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

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ClinicalTrials.gov Identifier: NCT03094832
Recruitment Status : Recruiting
First Posted : March 29, 2017
Last Update Posted : November 21, 2018
Sponsor:
Information provided by (Responsible Party):
ArQule

Tracking Information
First Submitted Date  ICMJE March 17, 2017
First Posted Date  ICMJE March 29, 2017
Last Update Posted Date November 21, 2018
Actual Study Start Date  ICMJE May 30, 2017
Estimated Primary Completion Date March 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 19, 2018)
Incidence of adverse events graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) guidelines, version 4.03 [ Time Frame: At each visit up to 51 months ]
The incidence of adverse events will be assessed as a measure of the safety and tolerability profile of ARQ 092
Original Primary Outcome Measures  ICMJE
 (submitted: March 28, 2017)
Incidence of adverse events graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) guidelines, version 4.03 [ Time Frame: Up to 84 weeks ]
The incidence of adverse events will be assessed as a measure of the safety and tolerability profile of ARQ 092
Change History Complete list of historical versions of study NCT03094832 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 19, 2018)
  • Assess the peak plasma concentration (Cmax) of the pharmacokinetic (PK) profile of ARQ 092 [ Time Frame: Cycle 1 Day 1 through Cycle 8 Day 1 (each cycle is 28 days) ]
  • Assess the area under the plasma concentration vs. time curve (AUC) of the PK profile of ARQ 092 [ Time Frame: Cycle 1 Day 1 through Cycle 8 Day 1 (each cycle is 28 days) ]
  • Assess the time to maximum plasma drug concentration (Tmax) of the PK profile of ARQ 092 [ Time Frame: Cycle 1 Day 1 through Cycle 8 Day 1 (each cycle is 28 days) ]
  • Evaluate changes in fibrinogen and D-dimers from blood [ Time Frame: Baseline, once every cycle for the first year (each cycle is 28 days), and once at study completion, an average of 3 years. ]
    Changes in fibrinogen and D-dimers will determine the pharmacodynamic activity of ARQ 092
  • Evaluate efficacy measured as evidence of changes to the lesion size or volume [ Time Frame: 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 ]
    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
  • Evaluate efficacy measured as changes in the degree of clinical impairment [ Time Frame: 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 ]
    Clinical impairment will be measured using a functional assessment tool
  • Evaluate efficacy measured as quality of life changes [ Time Frame: 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 ]
    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
  • Evaluate efficacy measured as changes in performance status [ Time Frame: Day 1 of each cycle and at the end of treatment (up to 48 months) ]
    Changes in performance status will be measured by comparing Karnofsky/Lansky scores
Original Secondary Outcome Measures  ICMJE
 (submitted: March 28, 2017)
  • Assess the peak plasma concentration (Cmax) of the pharmacokinetic (PK) profile of ARQ 092 [ Time Frame: Cycle 1 Day 1 (C1D1) (each cycle is 28 days) (time [t]=0,1,2,4,6,8,24 hours [h]), C1D8 (t=0 h), C1D15 (t=0,1,2,4,6,8,24 h), C2D1 (t=0 h). ]
    If dose does not increase, C4D1 and C7D1 (t=0 h). If dose increases, C4D1 (t=0,1,2,4,6,8,24 h), C4D8 (t=0 h), C4D15 (t=0,1,2,4,6,8,24 h), C5D1 (t=0 h), C7D1 (t=0,1,2,4,6,8,24 h), C7D8 (t=0 h), C7D15 (t=0,1,2,4,6,8,24 h), C8D1 (t=0 h).
  • Assess the area under the plasma concentration vs. time curve (AUC) of the pharmacokinetic (PK) profile of ARQ 092 [ Time Frame: C1D1 (t=0,1,2,4,6,8,24 h), C1D8 (t=0 h), C1D15 (t=0,1,2,4,6,8,24 h), C2D1 (t=0 h) ]
    If dose does not increase, C4D1 and C7D1 (t=0 h). If dose increases, C4D1 (t=0,1,2,4,6,8,24 h), C4D8 (t=0 h), C4D15 (t=0,1,2,4,6,8,24 h), C5D1 (t=0 h), C7D1 (t=0,1,2,4,6,8,24 h), C7D8 (t=0 h), C7D15 (t=0,1,2,4,6,8,24 h), C8D1 (t=0 h).
  • Assess the half life of ARQ 092 [ Time Frame: C1D1 (t=0,1,2,4,6,8,24 h), C1D8 (t=0 h), C1D15 (t=0,1,2,4,6,8,24 h), C2D1 (t=0 h) ]
    If dose does not increase, C4D1 and C7D1 (t=0 h). If dose increases, C4D1 (t=0,1,2,4,6,8,24 h), C4D8 (t=0 h), C4D15 (t=0,1,2,4,6,8,24 h), C5D1 (t=0 h), C7D1 (t=0,1,2,4,6,8,24 h), C7D8 (t=0 h), C7D15 (t=0,1,2,4,6,8,24 h), C8D1 (t=0 h).
  • Assess phosphatidylinositol 3-kinase (PI3K) / v-Akt murine thymoma viral oncogene homolog (AKT) signaling pathway markers in tissue samples (where feasible) [ Time Frame: Baseline, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
    The PI3K/AKT signaling pathway markers will be assessed to determine the pharmacodynamic activity of ARQ 092
  • Evaluate changes in insulin-like growth factor (IGF)-binding protein 2, fibrinogen, d-dimers, and circulating deoxyribonucleic acid (DNA) for AKT, PIK3CA, and phosphatase and tensin homolog (PTEN) from blood samples [ Time Frame: C1D1, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
    Changes in IGF-binding protein 2, fibrinogen, d-dimers, and circulating DNA will determine the pharmacodynamic activity of ARQ 092
  • Determine the recommended Phase 2 dose (RP2D) of ARQ 092 [ Time Frame: Up to 72 weeks ]
    The ARQ 092 RP2D must be well tolerated, cause reduction from baseline by at least 50% in PI3K/AKT pathway activity, and/or provide clinical benefit (e.g., stabilization of lesions or symptom improvement).
  • Evaluate efficacy measured as evidence of changes to the excess lesion volume [ Time Frame: Baseline, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
    Disease measurement will occur by bi-dimensional/volumetric MRI, CT scan, or ultrasound, and/or circumferential measurement including photography where applicable
  • Evaluate efficacy measured as changes in the degree of clinical impairment [ Time Frame: Baseline, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
    Clinical impairment will be assessed by evaluating responses to a Clinical Function Assessment
  • Evaluate efficacy measured as quality of life changes [ Time Frame: C1D1, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
    Quality of life changes will be measured by evaluating responses to the PedsQL™ questionnaires and PedsQL™ Pediatric Pain Questionnaire/short-form McGill Pain Questionnaire
  • Evaluate efficacy measured as changes in performance status [ Time Frame: Day 1 of each cycle and at the end of treatment (up to 18 months) ]
    Changes in performance status will be measured by comparing Karnofsky/Lansky scores
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of ARQ 092 in Patients With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome
Official Title  ICMJE A Phase 1/2 Study of ARQ 092 in Patients With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome
Brief Summary 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).
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Proteus Syndrome
  • PIK3CA-Related Overgrowth Spectrum (PROS)
Intervention  ICMJE Drug: ARQ 092
Subjects will receive ARQ 092 orally at 15 mg/m2 QD for the first 3 cycles on a 28 day schedule. 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.
Study Arms  ICMJE Experimental: ARQ 092
All enrolled patients will receive ARQ 092 orally at 15 mg/m2 QD 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.
Intervention: Drug: ARQ 092
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 19, 2018)
40
Original Estimated Enrollment  ICMJE
 (submitted: March 28, 2017)
16
Estimated Study Completion Date  ICMJE June 2020
Estimated Primary Completion Date March 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: ArQule, Inc. 781-994-0300 ClinicalTrials@arqule.com
Listed Location Countries  ICMJE Italy,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03094832
Other Study ID Numbers  ICMJE ARQ 092-103
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party ArQule
Study Sponsor  ICMJE ArQule
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Brian Schwartz, MD ArQule
PRS Account ArQule
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP