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Trial record 1 of 1 for:    092-103
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Study of ARQ 092 in Patients With Overgrowth Diseases and Vascular Anomalies

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified March 2017 by ArQule
Sponsor:
Information provided by (Responsible Party):
ArQule
ClinicalTrials.gov Identifier:
NCT03094832
First received: March 17, 2017
Last updated: March 28, 2017
Last verified: March 2017
  Purpose
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.

Condition Intervention Phase
Proteus Syndrome
PIK3CA-Related Overgrowth Spectrum (PROS)
Growth Disorders
Drug: ARQ 092
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of ARQ 092 in Patients With Overgrowth Diseases and Vascular Anomalies With Genetic Alterations of the PI3K/AKT Pathway

Resource links provided by NLM:


Further study details as provided by ArQule:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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


Estimated Enrollment: 16
Anticipated Study Start Date: March 2017
Estimated Study Completion Date: June 2020
Estimated Primary Completion Date: March 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ARQ 092
Subjects will receive ARQ 092 orally at the dose level and administration schedule specified for their respective dose cohort on a 28 day cycle. Subjects will receive treatment with ARQ 092 until unacceptable toxicity or another discontinuation criterion is met. It is expected that most subjects will receive between 3 and 9 cycles of ARQ 092 for a treatment period of 12 to 36 weeks.
Drug: ARQ 092
Subjects will receive ARQ 092 orally at the dose level and administration schedule specified for their respective dose cohort on a 28 day schedule.

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

Ages Eligible for Study:   6 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03094832

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

Locations
Italy
Not yet recruiting
Catania, Italy
Contact    781-994-0300    ClinicalTrials@arqule.com   
Not yet recruiting
Rome, Italy
Contact    781-994-0300    ClinicalTrials@arqule.com   
Sponsors and Collaborators
ArQule
  More Information

Responsible Party: ArQule
ClinicalTrials.gov Identifier: NCT03094832     History of Changes
Other Study ID Numbers: ARQ 092-103
Study First Received: March 17, 2017
Last Updated: March 28, 2017
Individual Participant Data  
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by ArQule:
ARQ 092
ArQule
AKT
PIK3CA
Overgrowth
Congenital malformations

Additional relevant MeSH terms:
Growth Disorders
Vascular Malformations
Proteus Syndrome
Pathologic Processes
Cardiovascular Abnormalities
Cardiovascular Diseases
Congenital Abnormalities
Hamartoma Syndrome, Multiple
Hamartoma
Neoplasms
Neoplasms, Multiple Primary
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Limb Deformities, Congenital
Musculoskeletal Abnormalities
Abnormalities, Multiple

ClinicalTrials.gov processed this record on April 25, 2017