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

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ClinicalTrials.gov Identifier: NCT03094832
Recruitment Status : Active, not recruiting
First Posted : March 29, 2017
Last Update Posted : March 23, 2021
Sponsor:
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.)

Tracking Information
First Submitted Date  ICMJE March 17, 2017
First Posted Date  ICMJE March 29, 2017
Last Update Posted Date March 23, 2021
Actual Study Start Date  ICMJE May 16, 2017
Estimated Primary Completion Date March 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 19, 2021)
  • Number of participants experiencing an Adverse Event (AE) [ Time Frame: Up to approximately 51 months ]
    An AE is 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.
  • Number of participants discontinuing study treatment due to an Adverse Event (AE) [ Time Frame: Up to approximately 48 months ]
    An AE is 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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 28, 2017)
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
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: March 28, 2017)
  • 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]), C1D8 (t=0 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=0,1,2,4,6,8,24 h), C4D8 (t=0 h), C4D15 (t=0,1,2,4,6,8,24 h), C5D1 (t=0 h), C7D1 (t=0,1,2,4,6,8,24 h), C7D8 (t=0 h), C7D15 (t=0,1,2,4,6,8,24 h), C8D1 (t=0 h).
  • Assess the area under the plasma concentration vs. time curve (AUC) of the pharmacokinetic (PK) profile of ARQ 092 [ Time Frame: C1D1 (t=0,1,2,4,6,8,24 h), C1D8 (t=0 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=0,1,2,4,6,8,24 h), C4D8 (t=0 h), C4D15 (t=0,1,2,4,6,8,24 h), C5D1 (t=0 h), C7D1 (t=0,1,2,4,6,8,24 h), C7D8 (t=0 h), C7D15 (t=0,1,2,4,6,8,24 h), C8D1 (t=0 h).
  • Assess the half life of ARQ 092 [ Time Frame: C1D1 (t=0,1,2,4,6,8,24 h), C1D8 (t=0 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=0,1,2,4,6,8,24 h), C4D8 (t=0 h), C4D15 (t=0,1,2,4,6,8,24 h), C5D1 (t=0 h), C7D1 (t=0,1,2,4,6,8,24 h), C7D8 (t=0 h), C7D15 (t=0,1,2,4,6,8,24 h), C8D1 (t=0 h).
  • Assess phosphatidylinositol 3-kinase (PI3K) / v-Akt murine thymoma viral oncogene homolog (AKT) signaling pathway markers in tissue samples (where feasible) [ Time Frame: Baseline, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
    The PI3K/AKT signaling pathway markers will be assessed to determine the pharmacodynamic activity of ARQ 092
  • Evaluate changes in insulin-like growth factor (IGF)-binding protein 2, fibrinogen, d-dimers, and circulating deoxyribonucleic acid (DNA) for AKT, PIK3CA, and phosphatase and tensin homolog (PTEN) from blood samples [ Time Frame: C1D1, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
    Changes in IGF-binding protein 2, fibrinogen, d-dimers, and circulating DNA will determine the pharmacodynamic activity of ARQ 092
  • Determine the recommended Phase 2 dose (RP2D) of ARQ 092 [ Time Frame: Up to 72 weeks ]
    The ARQ 092 RP2D must be well tolerated, cause reduction from baseline by at least 50% in PI3K/AKT pathway activity, and/or provide clinical benefit (e.g., stabilization of lesions or symptom improvement).
  • Evaluate efficacy measured as evidence of changes to the excess lesion volume [ Time Frame: Baseline, C4D1, C7D1, C10D1, C16D1, and at the end of treatment (up to 18 months) ]
    Disease measurement will occur by bi-dimensional/volumetric MRI, CT scan, or ultrasound, and/or circumferential measurement including photography where applicable
  • 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 assessed by evaluating responses to a Clinical Function Assessment
  • 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 and PedsQL™ Pediatric Pain Questionnaire/short-form McGill Pain Questionnaire
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Miransertib (MK-7075) in Participants With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome (MOSAIC) (MK-7075-002)
Official Title  ICMJE A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects With PIK3CA-related Overgrowth Spectrum (PROS) and Proteus Syndrome (PS) (MOSAIC)
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 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE PIK3CA-Related Overgrowth Spectrum (PROS)/Proteus Syndrome
Intervention  ICMJE Drug: Miransertib
Miransertib capsules administered orally either 1 hour before or 2 hours after a meal
Other Names:
  • MK-7075
  • ARQ 092
Study Arms  ICMJE
  • Experimental: Part A: Miransertib PROS/PS
    Participants with either PROS or PS receive miransertib orally at 15 mg/m^2 once daily (QD) for at least three 28-day cycles with an option to dose increase to 25 mg/m^2.
    Intervention: Drug: Miransertib
  • Experimental: Part B: Miransertib PROS (Cohort 1)
    Participants with PROS who have a measurable lesion by volumetric MRI receive miransertib orally at 15 mg/m^2 QD for at least three 28-day cycles with an option to dose increase to 25 mg/m^2. Treatment will continue for up to 48 cycles or until disease progression, unacceptable toxicity, or discontinuation.
    Intervention: Drug: Miransertib
  • Experimental: Part B: Miransertib PS (Cohort 2)
    Participants with PS who have a measurable lesion by standardized digital photography receive miransertib orally at 15 mg/m^2 QD for at least three 28-day cycles with an option to dose increase to 25 mg/m^2. Treatment will continue for up to 48 cycles or until disease progression, unacceptable toxicity, or discontinuation.
    Intervention: Drug: Miransertib
  • Experimental: Part B: Miransertib PROS/PS (Cohort 3)
    Participants with PROS or PS who do not meet all the eligibility criteria for Cohorts 1 or 2 receive miransertib orally at 15 mg/m^2 QD for at least three 28-day cycles with an option to dose increase to 25 mg/m^2. Treatment will continue for up to 48 cycles or until disease progression, unacceptable toxicity, or discontinuation.
    Intervention: Drug: Miransertib
  • Experimental: Part B: Miransertib Compassionate Use/Expanded Access (Cohort 4)
    Participants previously treated with miransertib or currently receiving miransertib under Compassionate Use/Expanded Access. Participants receive miransertib orally at 15 mg/m^2 QD for at least three 28-day cycles with an option to dose increase to 25 mg/m^2. Participants receiving miransertib at the time of enrollment under Compassionate Use/Expanded Access will continue with their current dose (not to exceed 25 mg/m^2). Treatment will continue for up to 48 cycles or until disease progression, unacceptable toxicity, or discontinuation.
    Intervention: Drug: Miransertib
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: August 15, 2019)
85
Original Estimated Enrollment  ICMJE
 (submitted: March 28, 2017)
16
Estimated Study Completion Date  ICMJE March 30, 2025
Estimated Primary Completion Date March 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Part A

  • Signed informed consent and, when applicable, signed assent
  • Male or female participants ≥ 2 years old with BSA of ≥ 0.33 m2
  • Have a clinical diagnosis of PROS or PS with documented somatic PIK3CA or 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 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 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Italy,   Spain,   United States
Removed Location Countries Brazil,   Chile,   France,   Germany,   Peru,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT03094832
Other Study ID Numbers  ICMJE 7075-002
MOSAIC ( Other Identifier: ArQule )
ARQ 092-103 ( Other Identifier: ArQule )
2016-000558-37 ( EudraCT Number )
MK-7075-002 ( Other Identifier: Merck )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
Study Sponsor  ICMJE ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
Collaborators  ICMJE Worldwide Clinical Trials
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP