Study of Miransertib (MK-7075) in Participants With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome (MOSAIC) (MK-7075-002) (MOSAIC)

• ClinicalTrials.gov Identifier: NCT03094832
• Recruitment Status: Terminated
• First Posted: March 29, 2017
• Results First Posted: March 31, 2023
• Last Update Posted: April 13, 2023
• Sponsor: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Collaborator: Worldwide Clinical Trials
• Information provided by (Responsible Party): ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Study Description

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).

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

Expanded Access : An investigational treatment associated with this study is no longer available outside the clinical trial.   More info ...

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome
• Actual Study Start Date: May 16, 2017
• Actual Primary Completion Date: April 11, 2022
• Actual Study Completion Date: April 11, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part A: Miransertib PROS/PS; During Cycles 1-3, participants with either PROS (phosphatidylinositol- 4,5-bisphosphate 3-kinase, catalytic subunit alpha [PIK3CA]-related Overgrowth Spectrum) or PS (Proteus syndrome) received miransertib 15 mg/m^2 once daily (QD) (each cycle length = 28 days). From Cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 and then titrated to 35 mg/m^2 orally QD at the investigator's discretion.	Drug: Miransertib; Miransertib capsules administered orally at an initial dose of 15 mg/m^2 or 25 mg/m^2 QD and then titrated up to 25 mg/m^2 or 35 mg/m^2 QD at the investigator's discretion.; Other Names: MK-7075; ARQ 092
Experimental: Part B: Miransertib PROS (Cohort 1); During Cycles 1-3, participants with PROS who have a measurable lesion by volumetric magnetic resonance imaging (MRI) received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.	Drug: Miransertib; Miransertib capsules administered orally at an initial dose of 15 mg/m^2 or 25 mg/m^2 QD and then titrated up to 25 mg/m^2 or 35 mg/m^2 QD at the investigator's discretion.; Other Names: MK-7075; ARQ 092
Experimental: Part B: Miransertib PS (Cohort 2); During Cycles 1-3, participants with PS who have a measurable lesion by standardized digital photography received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.	Drug: Miransertib; Miransertib capsules administered orally at an initial dose of 15 mg/m^2 or 25 mg/m^2 QD and then titrated up to 25 mg/m^2 or 35 mg/m^2 QD at the investigator's discretion.; Other Names: MK-7075; ARQ 092
Experimental: Part B: Miransertib PROS/PS (Cohort 3); During Cycles 1-3, participants with PROS or PS who do not meet all the eligibility criteria for Cohorts 1 or 2 received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.	Drug: Miransertib; Miransertib capsules administered orally at an initial dose of 15 mg/m^2 or 25 mg/m^2 QD and then titrated up to 25 mg/m^2 or 35 mg/m^2 QD at the investigator's discretion.; Other Names: MK-7075; ARQ 092
Experimental: Part B: Miransertib Compassionate Use/Expanded Access (Cohort 4); During cycles 1-48 (each cycle length = 28 days) or until disease progression, unacceptable toxicity, or discontinuation, participants previously treated with miransertib or currently receiving miransertib under Compassionate Use/Expanded Access continued to receive the current dose of miransertib (did not exceed 25 mg/m^2).	Drug: Miransertib; Miransertib capsules administered orally at an initial dose of 15 mg/m^2 or 25 mg/m^2 QD and then titrated up to 25 mg/m^2 or 35 mg/m^2 QD at the investigator's discretion.; Other Names: MK-7075; ARQ 092

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to approximately 48 months ]
   An AE was defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product and does not imply any judgment about causality.
2. Number of Participants Who Discontinued Study Treatment Due to an AE [ Time Frame: Up to approximately 45 months ]
   An AE was defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product and does not imply any judgment about causality.

Eligibility Criteria

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

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

Contacts and Locations

Locations

United States, Georgia

Children's Hospital of Atlanta ( Site 0107)

Atlanta, Georgia, United States, 30342

United States, Illinois

Ann & Robert H. Lurie Children's Hospital of Chicago ( Site 0101)

Chicago, Illinois, United States, 60611

United States, Massachusetts

Boston Children's Hospital ( Site 0089)

Boston, Massachusetts, United States, 02115

United States, Ohio

Cincinnati Children's Hospital Medical Center ( Site 0102)

Cincinnati, Ohio, United States, 45229

United States, Texas

Texas Children's Hospital ( Site 0104)

Houston, Texas, United States, 77030

United States, Washington

Seattle Childrens Hospital ( Site 0103)

Seattle, Washington, United States, 98105

Australia, New South Wales

Hunter Genetics ( Site 0201)

Waratah NSW, New South Wales, Australia, 2298

Italy

Ospedale Pediatrico Bambino Gesu ( Site 0087)

Rome, Roma, Italy, 00165

Universita di Catania ( Site 0088)

Catania, Italy, 95123

Fondazione Policlinico Universitario A. Gemelli ( Site 0052)

Roma, Italy, 00168

Spain

Hospital Sant Joan ( Site 0601)

Esplugues de Llobregat, Barcelona, Spain, 08950

Sponsors and Collaborators

ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Worldwide Clinical Trials

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

  Study Documents (Full-Text)

Documents provided by ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.):

Study Protocol  [PDF] March 5, 2021

Statistical Analysis Plan  [PDF] May 9, 2022

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• ClinicalTrials.gov Identifier: NCT03094832
• Other Study ID Numbers: 7075-002; MOSAIC ( Other Identifier: ArQule ); ARQ 092-103 ( Other Identifier: ArQule ); MK-7075-002 ( Other Identifier: Merck ); 2016-000558-37 ( EudraCT Number )
• First Posted: March 29, 2017
• Results First Posted: March 31, 2023
• Last Update Posted: April 13, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.):

ARQ 092; ArQule; AKT; PIK3CA; Overgrowth; Congenital malformations; Miransertib; MOSAIC

Additional relevant MeSH terms:

Proteus Infections; Proteus Syndrome; Syndrome; Disease; Pathologic Processes; Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; 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