| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome (PS). |
|
| E.1.1.1 | Medical condition in easily understood language |
| PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome (PS). |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10018058 |
| E.1.2 | Term | Gene genetic abnormality |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10069758 |
| E.1.2 | Term | Somatic mutation |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part B:
Primary objective:
•To determine the efficacy of ARQ 092 in subjects with PROS and PS
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| E.2.2 | Secondary objectives of the trial |
Part B:
Secondary objectives:
•To estimate the change from baseline in pain score
•To estimate change from baseline in physical functioning
•To describe the long-term tolerability and safety of ARQ 092
•To determine the duration of response |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part B
1.Signed informed consent, and when applicable, signed assent. Adults who are unable to consent except by means of a Legally Authorized Representative (LAR) may participate in the study.
2.Cohort 1 (PROS) specific criteria
•Male or female subjects ≥ 2 years and ≤30 years of age with BSA of ≥ 0.33 m2
•Have clinical diagnosis of PROS per Diagnostic Criteria for PROS and documented somatic PIK3CA variant
•Have at least one lesion that can be measured by study- standardized volumetric MRI
3.Cohort 2 (PS) specific criteria
•Male or female subjects ≥ 2 years and ≤18 years of age with BSA of ≥ 0.33 m2
•Have clinical diagnosis of PS per Diagnostic Criteria for PS and documented somatic AKT1 variant
•Have at least one plantar CCTN and pre-CCTN lesion that can be measured by standardized photography.
4.Cohort 3 specific criteria
•Male or female subjects ≥2 years old (there is no upper age limit at the time of enrollment) with BSA of ≥ 0.33 m2
•PROS specific inclusion criterion: Have clinical diagnosis of PROS per Diagnostic Criteria for PROS (see Appendix 1) and documented somatic PIK3CA variant
•PS specific criterion: Have clinical diagnosis of PS per Diagnostic Criteria for PS (see Appendix 1) and documented somatic AKT1 variant
•Subjects must not be eligible for enrollment in Cohort 1 (PROS) or Cohort 2 (PS): Older than 30 years of age (PROS) or 18 years of age (PS) (exceed the upper limit of age allowed for Cohort 1 or Cohort 2 enrollment)
•Do not have measurable disease:
-PROS: do not have at least one lesion that can be measured by study- standardized volumetric MRI or to whom MRI cannot be performed
-PS: no plantar CCTN lesion(s) or the CCTN lesion(s) do not satisfy protocol defined criteria of the measurable lesion
5.Cohort 4 (PROS or PS) specific criteria
•Subjects previously treated with ARQ 092 or currently receiving ARQ 092 under Compassionate Use/Expanded Access
Note: Subjects should meet the age criterion by/on the date of the first dose, Cycle 1 Day 1.
All Cohorts:
6.Archival or fresh overgrowth tissue sample available to be shipped to Sponsor or designee
7.Except for Cohort 4, clinically progressive or worsening disease defined as an increase in number or size of the overgrowth lesion(s) in the last 6 months as assessed by the Investigator
8.Adequate organ function as indicated by the following laboratory values:
Hematological
a.Hemoglobin (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
≥18 years male and female: ≥ 10.0 g/dL
b.Glycated hemoglobin (HbA1c): ≤ 8% (≤ 64 mmol/mol)
c.Absolute neutrophil count (ANC): ≥ 1.5 x 10_9/L
d.Platelet count ≥ 150 x 10_9/L
Hepatic
a.Total bilirubin ≤ 1.5 x upper limit of normal (ULN)/L
b.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN
Renal
a.Serum creatinine depending on age:
2-5 years male and female: maximum 0.80 mg/dL
6-10 years male and female: maximum 1.0 mg/dL
11-15 years male and female: maximum 1.2 mg/dL
> 15 years male and female: maximum 1.5 mg/dL
b.Estimated Glomerular Filtration Rate (eGFR): ≥ 60 mL/min/1.73 m2
Metabolic (lipids)
a.Cholesterol: ≤ 400 mg/dL (≤ 10.34 mmol/L)
b.Triglyceride: ≤ 500 mg/dL (≤ 5.7 mmol/L)
9.Female subjects must be of non-child producing potential or in postmenopausal state. Women of non-child producing potential are defined as those who underwent permanent sterilization (permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy). A postmenopausal state is defined as no menstruation for 12 months without an alternative medical cause, e.g. permanent sterilization.
10. Male subjects should use contraception (e.g., sexual abstinence/refraining from heterosexual intercourse, male condoms)
for the duration of the study from the first dose of ARQ 092 through 90 days after the last dose of the study drug. Female partners of male subjects are encouraged to use the following methods of contraception (these methods are considered to be highly effective with a failure rate less than 1% when used consistently and correctly:
• combined (estrogen and progestogen containing): oral, intravaginal, transdermal.
• progestogen-only hormonal contraception: oral, injectable, implantable
• intrauterine device (IUD)
• intrauterine hormone-releasing system (IUS)
• bilateral tubal occlusion
• sexual abstinence (refraining from heterosexual intercourse during the study: from the Day 1 of dosing through 90 days after the last dose of ARQ 092)
11.Ability to complete the study questionnaires by the subject or his/her caregiver
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| E.4 | Principal exclusion criteria |
Part B
1. History of Type 1 diabetes mellitus or Type 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 current version of National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]) or worse conduction defect (e.g., right or left bundle branch block)
3. Major surgery or locoregional therapy within four weeks of the first dose of ARQ 092
4. Any experimental systemic therapy for the purposes of treating PROS or PS (e.g., sirolimus, everolimus, high dose steroids) within two weeks of the first dose of ARQ 092
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, e.g.,
• 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. Female of child-producing potential, pregnant or breastfeeding. Female subject of child-producing potential is defined as a
premenopausal female capable of becoming pregnant, including women from the onset of menstruation (menarche) until the onset of menopause.
8. Inability to comply with study evaluations or to follow drug administration guidelines
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part B:
Primary endpoint:
Change in lesion size from baseline will be used to classify each subject as either a responder or non-responder (binary) in the Treated population.
• For Cohort 1 (PROS): The primary endpoint is response rate, as assessed by blinded central imaging review of volumetric MRI
• For Cohort 2 (PS): The primary endpoint is response rate, as assessed by blinded central photography review of CCTN lesional area
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary efficacy analysis will be conducted for Part B Cohorts 1 and 2 only. Response will be assessed independently at every 6 cycles during the first 24 cycles of treatment, every 12 cycles thereafter, and at the end of treatment (EOT).
The primary analysis of the primary endpoint will be performed after the last patient in Cohort 1 or 2 would have completed the 12 month assessment |
|
| E.5.2 | Secondary end point(s) |
Part B
Secondary endpoints:
For Cohort 1, 2 and 3
•Change from baseline in pain score and physical functioning.
•Duration of response
•Safety and tolerability as assessed by frequency, duration and severity of AEs from the first dose of ARQ 092 through 30 days after the last dose of the drug (severity of AEs will be assessed by current CTCAE version)
Exploratory endpoints for Cohorts 1, 2 and 3
•Change from baseline in selected disease-related manifestations as evaluated by DXA, MRI, CT, US, (in Germany, ONLY MRI and/or US will be used) or photography
•Change from baseline in severity of selected clinical manifestations as assessed by current CTCAE version (subject specific disease related symptom, pre-identified by the Investigator)
•Change from baseline in plasma levels of D-dimer and fibrinogen
•PK parameters (e.g., maximum plasma drug concentration [Cmax], time to maximum plasma drug concentration [Tmax], and area under the curve [AUC]) which are calculated from plasma concentration- time data
For Cohort 4:
•Safety and tolerability of ARQ 092
•Change from baseline in overgrowth lesions as evaluated by imaging
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All subjects who receive at least 1 dose of ARQ 092 will be included in the analysis of safety.
Patient-reported pain scores and physical functioning will be analyzed using a mixed model repeated measures to evaluate changes from baseline at each subsequent study assessment visit through the end of the study. Means and medians of questionnaire raw scores will be summarized by time point, overall, and for each domain.
The duration of response will be evaluated for each responder and summarized descriptively.
The efficacy ARQ 092 for all subjects enrolled in Part B Cohort 4 will be determined on a per subject basis and summarized as a clinical narrative.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| 4 Cohorts with specific Inc/Exc criteria. Patients will be assigned according to Inc/Exc criteria |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Chile |
| Peru |
| United States |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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