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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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

Brief 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 Summary:

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.


Sponsor: ArQule

Current Primary Outcome: 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


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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


Original Secondary Outcome: Same as current

Information By: ArQule

Dates:
Date Received: March 17, 2017
Date Started: May 2017
Date Completion: June 2020
Last Updated: May 1, 2017
Last Verified: May 2017