Study of ARQ 092 in Patients With Overgrowth Diseases and/or Vascular Anomalies

Study Description

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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 overgrowth diseases and/or vascular anomalies with genetic alterations of the PI3K/AKT pathway.

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

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 2 years of age) with overgrowth diseases and/or vascular anomalies with documented 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	16 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 1/2 Study of ARQ 092 in Patients With Overgrowth Diseases and/or Vascular Anomalies With Genetic Alterations of the PI3K/AKT Pathway
Actual Study Start Date :	May 30, 2017
Estimated Primary Completion Date :	March 2020
Estimated Study Completion Date :	June 2020

Arms and Interventions

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Arm

Intervention/treatment

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.

Outcome Measures

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Primary Outcome Measures :

1. 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 :

1. 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]), 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 h), C4D15 (t=0,1,2,4,6,8 h), C5D1 (t=0 h), C7D1 (t=0,1,2,4,6,8 h), C7D15 (t=0,1,2,4,6,8 h), C8D1 (t=0 h).
2. Assess the area under the plasma concentration vs. time curve (AUC) of the PK profile of ARQ 092 [ Time Frame: C1D1 (t=0,1,2,4,6,8,24 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 h), C4D15 (t=0,1,2,4,6,8 h), C5D1 (t=0 h), C7D1 (t=0,1,2,4,6,8 h), C7D15 (t=0,1,2,4,6,8 h), C8D1 (t=0 h).
3. Assess the time to maximum plasma drug concentration (Tmax) of the PK profile of ARQ 092 [ Time Frame: C1D1 (t=0,1,2,4,6,8,24 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 h), C4D15 (t=0,1,2,4,6,8 h), C5D1 (t=0 h), C7D1 (t=0,1,2,4,6,8 h), C7D15 (t=0,1,2,4,6,8 h), C8D1 (t=0 h).
4. Evaluate changes in fibrinogen, D-dimers, and deoxyribonucleic acid (DNA) for AKT and PIK3CA mutations from blood and/or tissue samples [ Time Frame: C1D1, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
   Changes in fibrinogen, D-dimers, and DNA will determine the pharmacodynamic activity of ARQ 092
5. Determine the recommended Phase 2 dose (RP2D) of ARQ 092 [ Time Frame: Up to 72 weeks ]
   The ARQ 092 RP2D must be well tolerated and must provide clinical benefit (e.g., stabilization of overgrowths or symptom improvement).
6. Evaluate efficacy measured as evidence of changes to the overgrowths and/or vascular anomalies [ Time Frame: Baseline, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
   Disease measurement will occur by radiographic imaging (e.g., MRI, CT scan, ultrasound) and/or other assessments of size of overgrowths and/or vascular anomalies such as circumferential measurements and/or photographs where applicable
7. 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 measured using a functional assessment tool
8. 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, 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
9. 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

Eligibility Criteria

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Ages Eligible for Study:	2 Years and older (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria

1. Male or female subjects ≥ 2 years of age with BSA of ≥ 0.33 m2

2. Overgrowth diseases and/or vascular anomalies with documented and/or confirmed somatic genetic alterations of PIK3CA or AKT defined/assessed as:

   • Measurable 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., 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:

   • 2-5 years male and female: ≥ 11.0 g/dL
   • 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 Multifocal Lymphangio-endotheliomatosis with Thrombocytopenia (MLT), platelet count must be ≥ 75 x 10^9/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:

    • 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
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 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.

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% (or > 64 mmol/mol) 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 the overgrowth disease and/or vascular anomalies (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 ongoing 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 comply with study evaluations or come to follow up appointments

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

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

Locations

United States, Massachusetts
Boston Children's Hospital	Recruiting
Boston, Massachusetts, United States, 02115
Contact: ArQule 781-994-0300 ClinicalTrials@arqule.com
Italy
Azienda Ospedaliero-Universitaria "Policlinico-Vittorio Emanuele"	Recruiting
Catania, Italy
Contact: ArQule 781-994-0300 ClinicalTrials@arqule.com
Fondazione Policlinico Universitario Agostino Gemelli	Recruiting
Roma, Italy, 00168
Contact: ArQule 781-994-0300 ClinicalTrials@arqule.com
Ospedale Bambino Gesu	Recruiting
Rome, Italy
Contact: ArQule 781-994-0300 ClinicalTrials@arqule.com

Sponsors and Collaborators

ArQule

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	ArQule
ClinicalTrials.gov Identifier:	NCT03094832 History of Changes
Other Study ID Numbers:	ARQ 092-103
First Posted:	March 29, 2017
Last Update Posted:	March 29, 2018
Last Verified:	March 2018
Individual Participant Data (IPD) Sharing Statement:
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