PIK3CA-Related Overgrowth Spectrum (PROS)/Proteus Syndrome
Conditions
Keywords
ARQ 092, ArQule, AKT, PIK3CA, Overgrowth, Congenital malformations, Miransertib, 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 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.
Interventions
DRUGMiransertib
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.
Sponsors
Worldwide Clinical Trials
ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced an Adverse Event (AE) | 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. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | 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. |
Countries
Australia, Italy, Spain, United States
Participant flow
Pre-assignment details
50 participants were enrolled in the study of which 49 participants received at least one dose of treatment and was used for safety analysis.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 17 |
| 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. | 22 |
| 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. | 1 |
| 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. | 8 |
| 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). | 2 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Other | 13 | 20 | 1 | 7 | 1 |
| Overall Study | Withdrawal by Parent/Guardian | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part B:Miransertib Compassionate Use/Expanded Access(Cohort 4) | Total | Part A: Miransertib PROS/PS | Part B: Miransertib PROS (Cohort 1) | Part B: Miransertib PS (Cohort 2) | Part B: Miransertib PROS/PS (Cohort 3) |
|---|---|---|---|---|---|---|
| Age, Continuous | 20.0 years STANDARD_DEVIATION 1.4 | 10.2 years STANDARD_DEVIATION 8.3 | 8.2 years STANDARD_DEVIATION 9.9 | 9.9 years STANDARD_DEVIATION 6.7 | 12.0 years | 12.5 years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 46 Participants | 15 Participants | 20 Participants | 1 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 6 Participants | 0 Participants | 5 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 39 Participants | 17 Participants | 13 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Female | 1 Participants | 23 Participants | 9 Participants | 10 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 27 Participants | 8 Participants | 12 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 17 | 0 / 22 | 0 / 1 | 0 / 8 | 0 / 2 |
| other Total, other adverse events | 17 / 17 | 18 / 22 | 0 / 1 | 6 / 8 | 1 / 1 |
| serious Total, serious adverse events | 4 / 17 | 3 / 22 | 0 / 1 | 1 / 8 | 0 / 1 |
Outcome results
Primary
Number of Participants Who Discontinued Study Treatment Due to an AE
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.
Time frame: Up to approximately 45 months
Population: All participants who have received at least one dose of study treatment were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Miransertib PROS/PS | Number of Participants Who Discontinued Study Treatment Due to an AE | 2 Participants |
| Part B: Miransertib PROS (Cohort 1) | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| Part B: Miransertib PS (Cohort 2) | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| Part B: Miransertib PROS/PS (Cohort 3) | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| Part B:Miransertib Compassionate Use/Expanded Access(Cohort 4) | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
Primary
Number of Participants Who Experienced an Adverse Event (AE)
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.
Time frame: Up to approximately 48 months
Population: All participants who have received at least one dose of study treatment were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Miransertib PROS/PS | Number of Participants Who Experienced an Adverse Event (AE) | 17 Participants |
| Part B: Miransertib PROS (Cohort 1) | Number of Participants Who Experienced an Adverse Event (AE) | 20 Participants |
| Part B: Miransertib PS (Cohort 2) | Number of Participants Who Experienced an Adverse Event (AE) | 0 Participants |
| Part B: Miransertib PROS/PS (Cohort 3) | Number of Participants Who Experienced an Adverse Event (AE) | 6 Participants |
| Part B:Miransertib Compassionate Use/Expanded Access(Cohort 4) | Number of Participants Who Experienced an Adverse Event (AE) | 1 Participants |