Clinical trial NCT03094832: Study of Miransertib (MK-7075) in Participants With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome (MOSAIC) (MK-7075-002)
Official title: A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: PIK3CA-Related Overgrowth Spectrum (PROS)/Proteus Syndrome
Keywords: ARQ 092
ArQule
AKT
PIK3CA
Overgrowth
Congenital malformations
Miransertib
MOSAIC
Lead sponsor: ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
Sponsor class: INDUSTRY
Collaborators: name: Worldwide Clinical Trials
First posted: 2017-03-29
Enrollment: 50
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is an open label, Phase 1/2 study of oral miransertib (MK-7075) administered to participants at least 2 years of age with phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA)-related Overgrowth Spectrum (PROS) and Proteus Syndrome (PS) (MOSAIC).

Detailed description: The study consists of two parts: Part A and Part B. Part A was closed to enrollment under Amendment 6. As of Amendment 7, the endpoints for Part A and Part B have been combined to assess the safety and tolerability of miransertib in participants with PROS and PS. Previous efficacy and pharmacokinetic (PK) objectives and endpoints have been removed. Amendment 7 will complete the final enrollment into the MOSAIC study and Compassionate Use/Expanded Access Program.

Eligibility criteria: Inclusion Criteria:

Part A

* Signed informed consent and, when applicable, signed assent
* Male or female participants ≥ 2 years old with body surface area (BSA) of ≥ 0.33 m\^2
* Have a clinical diagnosis of PROS or PS with documented somatic PIK3CA or serine-threonine protein kinase (AKT1) mutations
* Archival or fresh overgrowth tissue sample available to be shipped to Sponsor or designee
* 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)
* Have measurable disease (at least one overgrowth lesion that can be accurately measured in size by imaging and/or linear or circumference measure)
* Adequate organ function based on screening laboratory values
* If a female is of child-bearing potential, documentation of a negative pregnancy test is required prior to enrollment. Sexually active participants (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
* Ability to complete the Quality of Life (QoL) questionnaires by the participant or his/her caregiver

Part B:

* Signed consent form and when applicable, signed assent
* Archival or fresh overgrowth tissue sample available to be shipped to Sponsor or designee
* 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
* Adequate organ function based on screening laboratory values
* Male or female participants of child-producing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after the last dose of miransertib
* Ability to complete the study questionnaires by the participant or his/her caregiver

Cohort 1 (PROS) specific criteria

* Male or female participants ≥ 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 (eligibility to be confirmed by blinded independent central imaging review

  - Cohort 2 (PS) specific criteria
* Male or female participants ≥ 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 cerebriform connective tissue nevus (CCTN) and pre-CCTN lesion that can be measured by standardized photography

  * Cohort 3 specific criteria: Male or female participants ≥2 years old with BSA of ≥ 0.33 m2 and who fail to meet the eligibility criteria for Cohorts 1 or 2
  * Cohort 4 (PROS or PS) specific criteria: participants previously treated with miransertib or currently receiving miransertib under Compassionate Use/Expanded Access. Participants should meet the age criterion by/on the date of the first dose, Cycle 1 Day 1

Exclusion Criteria

Part A:

* 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
* 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 miransertib (MI occurring \> 6 months of the first dose of miransertib 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
* Major surgery, radiotherapy, or immunotherapy within four weeks of the first dose of miransertib
* 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 miransertib, except for participants who were previously or are currently treated with miransertib under a Compassionate Use/Expanded Access program
* Intolerance of or severe toxicity attributed to v-Akt murine thymoma viral oncogene homolog (AKT) inhibitors (e.g., miransertib, uprosertib, afuresertib, ipatasertib)
* 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)
* Pregnant or breastfeeding
* Inability to comply with study evaluations or to follow drug administration guidelines

Part B

* 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
* 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 miransertib (MI occurring \> 6 months of the first dose of miransertib 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)
  * Major surgery or locoregional therapy within four weeks of the first dose of miransertib
* 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 miransertib
* Intolerance of or severe toxicity attributed to AKT inhibitors (e.g., miransertib, uprosertib, afuresertib, ipatasertib)
* Concurrent severe uncontrolled illness not related to PROS or PS (e.g. ongoing or active infection, known HIV infection, malabsorption syndrome, psychiatric illness/substance abuse/social situation that would limit compliance with study requirements)
* Pregnant or breastfeeding
* Inability to comply with study evaluations or to follow drug administration guidelines

Primary outcomes:
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 48 months
measure: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to approximately 45 months
Secondary outcomes:
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Children's Hospital of Atlanta ( Site 0107)
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago ( Site 0101)
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital ( Site 0089)
state: Massachusetts
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center ( Site 0102)
state: Ohio
city: Houston
country: United States
facility: Texas Children's Hospital ( Site 0104)
state: Texas
city: Seattle
country: United States
facility: Seattle Childrens Hospital ( Site 0103)
state: Washington
city: Waratah NSW
country: Australia
facility: Hunter Genetics ( Site 0201)
state: New South Wales
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesu ( Site 0087)
state: Roma
city: Catania
country: Italy
facility: Universita di Catania ( Site 0088)
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario A. Gemelli ( Site 0052)
city: Esplugues de Llobregat
country: Spain
facility: Hospital Sant Joan ( Site 0601)
state: Barcelona
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Forde K, Resta N, Ranieri C, Rea D, Kubassova O, Hinton M, Andrews KA, Semple R, Irvine AD, Dvorakova V. Clinical experience with the AKT1 inhibitor miransertib in two children with PIK3CA-related overgrowth syndrome. Orphanet J Rare Dis. 2021 Feb 27;16(1):109. doi: 10.1186/s13023-021-01745-0.