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

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 PIK3CA-related Overgrowth Spectrum (PROS) and Proteus syndrome (PS).

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

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	40 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 PIK3CA-related Overgrowth Spectrum and Proteus Syndrome
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; 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.

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.

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: 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

Secondary Outcome Measures :

1. 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) ]
2. 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) ]
3. 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) ]
4. 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
5. 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
6. 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
7. 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
8. 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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

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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"	Withdrawn
Catania, Italy
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

Investigators

Study Director:	Brian Schwartz, MD	ArQule

More Information

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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:	November 21, 2018
Last Verified:	November 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:

Syndrome; Proteus Infections; Proteus Syndrome; Disease; Pathologic Processes; Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Hamartoma Syndrome, Multiple; Hamartoma	Neoplasms; Neoplasms, Multiple Primary; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Limb Deformities, Congenital; Musculoskeletal Abnormalities; Abnormalities, Multiple; Congenital Abnormalities