Clinical trial NCT03094832
Conditions: PIK3CA-Related Overgrowth Spectrum (PROS)/Proteus Syndrome
Keywords: ARQ 092 ArQule AKT PIK3CA Overgrowth Congenital malformations Miransertib MOSAIC
Sponsor: ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
Start date: 2017-05-16; Completion date: 2022-04-11
Enrollment: 50 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: 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. arm 3: 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. arm 4: 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. arm 5: 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).
Interventions: intervention 1: Miransertib
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects with
PIK3CA-related Overgrowth Spectrum and Proteus Syndrome
05-MAR-2021
NCT03094832


PRODUCT: ARQ 092 / MK-7075
1
PROTOCOL/AMENDMENT NO.: 002-07
05-MAR-2021
STUDY TITLE
A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects with 
PIK3CA-related Overgrowth Spectrum and Proteus Syndrome
Study Number:
ARQ 092-103 / MK-7075-002
Study Phase:
1 / 2
Product Name:
ARQ 092 (miransertib)
IND Number:
130784
EudraCT Number:
2016-000558-37
Sponsor:
ArQule, Inc. (A Wholly Owned Subsidiary of Merck, Sharp and 
Dohme, a subsidiary of Merck & Co., Inc., hereafter referred to 
as the Sponsor or MSD)
One Merck Drive
PO Box 100
Whitehouse Station, New Jersey, 08889-0100, USA
Medical Monitor:
Date of Protocol:
Original: 25 August 2016
Amendment 1: 21 October 2016
Amendment 2: 18 May 2017
Amendment 3: 25 September 2017
Amendment 4: 01 August 2018
Amendment 5: 14 December 2018
Amendment 6: 07 March 2019
Amendment 7: 05 March 2021
CONFIDENTIALITY STATEMENT
The information contained in this document is confidential and the proprietary property of 
ArQule, Inc., a wholly owned subsidiary of Merck, Sharp and Dohme, a subsidiary of Merck 
& Co., Inc. Any unauthorized use or disclosure of such information without the prior written 
authorization of ArQule, Inc., a wholly owned subsidiary of Merck, Sharp and Dohme, is 
prohibited.
PPD
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Summary of Changes from Amendment 6 to Amendment 7
Type of change
Rationale
Sections affected
Administrative changes to 
replace ArQule contact 
personnel and contact 
information with Merck 
address, compound number, 
personnel, and contact 
information
ArQule now part of Merck

Title page

All headers and footers

8.4 Serious Adverse 
Event Reporting

Sponsor Signature Page
Redacted potentially 
identifiable patient 
information; deleted Section 
1.3.2.2 Expanded Access 
Program/Compassionate Use
To maintain patient 
privacy

Throughout the document

Removed patient 
narratives from 1.3.2.1 A 
Phase 1 Dose-Finding 
Trial of ARQ 092 in 
Children and Adults with 
Proteus Syndrome.
Removal of primary 
objectives related to 
efficacy, removal of 
secondary and tertiary 
endpoints
Accurate assessment of 
efficacy no longer 
considered possible from 
the data set, only 
evaluation of safety and 
tolerability achievable

Synopsis table

2.1 Study Objectives

2.2 Overall Study Design

2.3 Study Endpoints

9 Planned Statistical 
Methods
Updated primary objective 
of the entire study to reflect 
safety and tolerability of 
miransertib; endpoints for 
Part A and Part B have been 
combined.
Safety and tolerability 
(originally secondary 
endpoints) remain a valid 
assessment

Synopsis table

2.1 Study Objectives

9.3 Study Endpoints
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PROTOCOL/AMENDMENT NO.: 002-07
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Type of change
Rationale
Sections affected
Removal of imaging-based 
efficacy assessments
Procedures that will not be 
used for safety and may 
pose additional risk to 
patients will not be 
assessed and should not be 
performed (eg, MRI used 
for comparison for 
efficacy on treatment)
have been removed

Synopsis table

2.2 Overall Study Design

2.3 Study Endpoints

4.1 Informed Consent

5.1 Medical History

Table 3 Schedule of 
Events Part B, Cohorts 1, 
2, and 3

Table 4 Schedule of 
Events Part B, Cohort 4
Removal of PK sample 
collections
PK assessments to assess 
efficacy will no longer be 
performed as there will not 
be efficacy assessments to 
support.

2.2 Overall Study Design

2.3 Study Endpoints

5.4 Pharmacokinetic 
Assessments

Table 3 Schedule of 
Events Part B, Cohorts 1, 
2, and 3

Table 4 Schedule of 
Events Part B, Cohort 4

9.5 Pharmacokinetic 
Analysis
Removal of preclinical 
efficacy data
Efficacy assessment is no 
longer an objective for this 
study, so this efficacy data 
is no longer relevant

1 Introduction
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Type of change
Rationale
Sections affected
Removal of functional 
assessments, including 
deletion of the following: 
Section 5.6 Pain Assessment 
(Part B Cohorts 1, 2, and 3),
Section 5.7 Physical 
Function Assessment (Part B 
Cohorts 1, 2, and 3)
Appendix 2: Wong-Baker 
FACES® Pain Rating Scale 
/ Numerical Rating Scale, 
Appendix 3: Physical 
Function Assessment by 
PROMIS, 
Appendix 7: Study Visits for 
Part B
Efficacy no longer a study
objective

2.3 Study Endpoints

5.5 Other Assessments

Table 3 Schedule of 
Events, Cohorts 1, 2, and 
3

Table 4 Schedule of 
Events, Cohort 4
Assessment of response 
modified based on removal 
of efficacy assessments, 
including deletion of the 
following;
Section 9.4 Efficacy 
Analysis
No longer relevant; 
efficacy no longer assessed

8 Assessment of 
Response

8.1 Measurable Disease

8.2 Response Evaluation
Deleted statistical analysis 
of efficacy data and 
exploratory endpoints, 
including deletion of the 
following:
Section 9.3.1 Primary 
Endpoint,
Section 9.3.2 Secondary 
Endpoints,
Section 9.3.3 Exploratory 
Endpoints,
Section 9.3.4 Part A Study 
Endpoints;
Subsequent sections 
renumbered.
Efficacy no longer a study
objective.

9 Planned Statistical 
Methods
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Type of change
Rationale
Sections affected
Removed discussion of AKT 
signaling and preclinical 
data
Streamlined the 
Introduction for focus to 
issues of clinical 
importance

Synopsis table

1 Introduction

Figures 1-5 removed

Table 1 revised

8 Assessment of 
Response
Copied details regarding 
study population including 
inclusion and exclusion 
criteria from Section 3 to the 
synopsis
Makes information more 
accessible. No new 
information added.

Synopsis table
Moved description of 
inactive Part A to Annex 1
Information on the closed 
Part A is left only for 
reference. Changes to 
Annex 1 are not described 
in detail.

Annex 1
Replaced the name “ARQ 
092” with “miransertib”
Miransertib is the 
approved generic name for 
the compound
Throughout the document
Addressed issued related to 
spelling, grammar, and 
formatting. These changes 
had no impact on the content 
of the document
Improved document 
quality and readability
Throughout the document
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Table of Contents
SYNOPSIS........................................................................................................................10
LIST OF ABBREVIATIONS .........................................................................................17
1
INTRODUCTION....................................................................................................21
1.1
Nonclinical Effects of Miransertib on Overgrowth Syndromes In Vitro .22
1.2
Toxicology of Miransertib in Animals .........................................................23
1.3
Effects of Miransertib in Humans................................................................23
1.3.1
EFFECTS OF MIRANSERTIB IN ONCOLOGY................................23
1.3.1.1
ARQ 092-101...............................................................................23
1.3.1.2
ARQ 092-101 Pharmacokinetics .................................................24
1.3.1.3
ARQ 092-102...............................................................................25
1.3.2
Effects of Miransertib in Overgrowth Diseases.....................................25
1.3.2.1
A Phase 1 Dose-Finding Study of Miransertib in Children and 
Adults With Proteus Syndrome ...................................................25
1.4
Conclusion ......................................................................................................25
2
INVESTIGATIONAL PLAN .................................................................................26
2.1
Study Objectives.............................................................................................26
2.2
Overall Study Design .....................................................................................26
2.3
Study Endpoints.............................................................................................28
3
SELECTION OF STUDY POPULATION ...........................................................28
3.1
Inclusion Criteria...........................................................................................28
3.1.1
Part B: ....................................................................................................28
3.2
Exclusion Criteria – Part B...........................................................................30
4
STUDY VISITS........................................................................................................31
4.1
Informed Consent ..........................................................................................32
4.2
Participant Discontinuation..........................................................................32
4.2.1
Discontinuation From Treatment...........................................................32
4.2.2
Discontinuation From the Study ............................................................33
4.3
Study Discontinuation ...................................................................................33
5
STUDY PROCEDURES .........................................................................................34
5.1
Medical History..............................................................................................34
5.2
12-Lead Electrocardiogram..........................................................................34
5.3
Clinical Laboratory Tests..............................................................................35
5.4
Pharmacokinetic Assessments ......................................................................35
5.5
Other Assessments .........................................................................................36
5.6
Additional Tests .............................................................................................37
5.7
Home Blood Glucose Monitoring .................................................................37
5.8
Schedule of Events .........................................................................................37
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5.8.1
Cohorts 1, 2, and 3.................................................................................37
5.8.2
Cohort 4 .................................................................................................39
6
TREATMENT..........................................................................................................40
6.1
Miransertib.....................................................................................................40
6.2
Miransertib Accountability...........................................................................40
6.3
Miransertib Administration..........................................................................40
6.4
Missed or Vomited Doses ..............................................................................41
6.5
Dose Modifications.........................................................................................41
6.6
Treatment Compliance..................................................................................43
6.7
Blinding...........................................................................................................44
6.8
Concomitant Medication and Procedures ...................................................44
6.8.1
Permitted Treatment...............................................................................44
6.8.2
Prohibited Treatment .............................................................................44
6.8.3
Medications to be Avoided While on Study..........................................45
6.8.4
Potential of Drug-Drug Interaction When Miransertib and Warfarin Are 
Coadministered ......................................................................................45
6.9
Potential Risks................................................................................................46
7
SAFETY ASSESSMENTS......................................................................................46
7.1
Definitions.......................................................................................................47
7.1.1
Adverse Event........................................................................................47
7.1.2
Adverse Reaction...................................................................................47
7.1.3
Suspect Adverse Reaction......................................................................47
7.1.4
Unexpected ............................................................................................47
7.1.5
Serious....................................................................................................47
7.1.6
Suspected Unexpected Serious Adverse Reaction (SUSAR)................48
7.1.7
Hospitalization.......................................................................................48
7.1.8
Study Medication-related Adverse Event or Serious Adverse Event ....48
7.1.9
Further Adverse Event and Serious Adverse Event Defining ...............48
7.2
Responsibilities and Procedures ...................................................................48
7.3
Adverse Event and Serious Adverse Event Criteria...................................49
7.4
Serious Adverse Event Reporting.................................................................49
7.5
Posttreatment Safety Follow-up ...................................................................50
7.6
Grading of Severity........................................................................................50
7.7
Assessment of Causality ................................................................................51
7.7.1
Related ...................................................................................................51
7.7.2
Not Related ............................................................................................51
8
ASSESSMENT OF RESPONSE ............................................................................51
8.1
Measurable Disease........................................................................................51
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8.2
Response Evaluation......................................................................................51
9
PLANNED STATISTICAL METHODS...............................................................51
9.1
General Considerations.................................................................................51
9.2
Analysis Populations......................................................................................52
9.3
Study Endpoints.............................................................................................52
9.3.1
Determination of Sample Size ...............................................................52
9.3.2
Data Handling Rules for Efficacy Endpoint Analyses...........................52
9.4
Safety Analysis ...............................................................................................52
9.5
Pharmacokinetic Analysis.............................................................................53
9.6
Data Monitoring Committee.........................................................................53
10
COMPLIANCE WITH GOOD CLINICAL PRACTICE AND ETHICAL 
CONSIDERATIONS...............................................................................................53
10.1
Institutional Review Board or Independent Ethics Committee Approval
..........................................................................................................................53
10.2
Compliance With Good Clinical Practice and Ethical Considerations ....54
10.3
Participant Information and Consent/Assent .............................................54
11
STUDY MANAGEMENT AND MATERIALS....................................................55
11.1
Monitoring, Verification of Data, Audit, and Inspection...........................55
11.2
Data Recording and Retention of Study Data.............................................55
11.3
Electronic Case Report Forms......................................................................56
11.4
Confidentiality, Publication, and Disclosure Policy....................................56
12
REFERENCE LIST.................................................................................................57
APPENDIX 1
CLINICAL DIAGNOSTIC CRITERIA CLINICAL DIAGNOSTIC 
CRITERIA FOR PROS ..........................................................................................60
APPENDIX 2
DOSING NOMOGRAM .....................................................................63
APPENDIX 3
EXAMPLES OF IN VIVO SUBSTRATES, INHIBITORS, AND 
INDUCERS FOR SPECIFIC ENZYMES.............................................................64
APPENDIX 4
EXAMPLES OF IN VIVO SUBSTRATES, INHIBITORS, AND 
INDUCERS OF P-GLYCOPROTEIN ..................................................................65
ANNEX 1 ..........................................................................................................................66
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List of In-Text Tables
Table 1
ARQ 092-101 Drug-Related TEAE Reported by More Than 1 Participant 
With QOD/QD Dosing ..............................................................................24
Table 2
Part B: PK Sampling Schedule (Cohorts 1, 2, and 3)................................36
Table 3
Schedule of Events Part B Cohorts 1, 2 and 3...........................................38
Table 4
Schedule of Events Part B Cohort 4 ..........................................................39
Table 5
Miransertib Dose Reduction Schedule.......................................................42
Table 6
Dose Interruptions/Reductions for Drug-Related Toxicity Except 
Hyperglycemia...........................................................................................42
Table 7
Dose Modification for Drug-Related Hyperglycemia and Suggested 
Clinical Treatment and Management of Hyperglycemia...........................43
List of In-Text Figures
No table of figures entries found.
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SYNOPSIS
Study Title:
A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects with 
PIK3CA-related Overgrowth Spectrum and Proteus Syndrome
Study Number:
ARQ 092-103 / MK-7075-002
Study Phase:
1/2
IND Number:
130784
EudraCT Number:
2016-000558-37
Rationale for the 
Study
Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit 
alpha / v-Akt murine thymoma viral oncogene homolog 
(PIK3CA/AKT) genetic alterations have been identified in many
solid and hematologic malignancies as well as in overgrowth 
diseases and vascular anomalies, including PIK3CA-related 
Overgrowth Spectrum (PROS) and Proteus Syndrome (PS). In 
contrast to cancer, which is characterized by multiple genetic 
aberrations, a single activating mutation has been identified in both 
PROS and PS. This single postzygotic PIK3CA or serine-threonine 
protein kinase (AKT1) mutation leads to cellular overgrowth 
characterized by somatic mosaicism. The severity of the disease 
varies from patient to patient and ranges from a single overgrowth 
lesion to life-threatening, progressively debilitating multiorgan 
disorders. Both PROS and PS are very rare disorders with no 
specific treatment and, in general, a poor survival rate.
Many PI3K/AKT inhibitors, including miransertib, are being 
evaluated in cancers that are driven by PI3K/AKT pathway 
activation. Miransertib is an oral, allosteric, selective pan-AKT 
inhibitor that potently inhibits both active and inactive forms of 
AKT. In in vitro and in vivo experiments, it showed
antiproliferative activity in cancer and in cells derived from PROS 
and PS patients.
Safety, tolerability, and preliminary efficacy data of miransertib at 
doses ranging from 10 mg up to 350 mg at varying frequencies (ie, 
qod, qd, bid, and qw) have been evaluated in more than 150 adult 
participants with advanced solid tumors and recurrent malignant 
lymphoma (NCT#01473095; NCT#02476955). In this oncology 
patient population, miransertib at doses up to 60 mg qd showed a 
manageable safety profile.
The National Institutes of Health / National Human Genome 
Research Institute (NIH / NHGRI) has conducted the first clinical 
study of miransertib in patients with PS (“Dose Finding Trial of 
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ARQ 092 in Children and Adults with Proteus Syndrome”; 
NCT02594215). The primary endpoint of the study was to 
determine the biological effect of miransertib measured by changes 
of phosphorylated AKT (pAKT) levels in the affected tissue. 
Secondary endpoints included safety, tolerability, and disease 
specific evaluations (volumetric magnetic resonance imaging 
[MRI], photography of the cerebriform connective tissue nevus
[CCTN], quality of life [QoL], and functional assessments). The 
study initially enrolled 3 adult patients. Once miransertib was
shown to be well tolerated, additional 3 younger patients (<18 years 
of age) were enrolled. All participants were treated at a daily dose 
of 5 mg/m2 and were expected to complete 12 cycles of treatment, 
with a cycle being defined as a 28-day period. Of the 6 enrolled 
participants, 2 discontinued treatment after 8 cycles (due to 
withdrawalof consent and an adverse event of transaminase 
increase), 3 participants completed 12 cycles, and 1 participant
continues treatment after completion of 12 cycles. In 5 participants, 
a reduction of 50% or greater of tissue pAKT levels was reported, 
and the primary endpoint of the study was met. The clinical 
efficacy measurements showed reduction in size of the CCTN at 
Cycle 12 by quantitative standardized photography. The 3 younger 
participants reported an improvement in pain as assessed by a 
standardized pain scale. The drug was well tolerated with most
adverse events (AEs) being mild to moderate in severity.
Study Objective:
Originally, the ARQ 092-103 study was entitled “A Phase 1/2 
Study of ARQ 092 in Patients with Overgrowth Diseases and/or 
Vascular Anomalies with Genetic Alterations of the PI3K/AKT 
Pathway” (NCT03094832) and was initiated as a dose-finding, 
safety, and tolerability study. Subsequently, this study was 
amended to enroll only patients with PROS or PS with PIK3CA or 
AKT1 mutations (“A Phase 1/2 Study of ARQ 092 in Subjects with 
PIK3CA-related Overgrowth Spectrum and Proteus Syndrome”).
The current protocol (Amendment 6) was designed to assess safety 
of miransertib in patients with PROS and PS. The study consists of 
2 parts: Part A that includes all participants enrolled before
Amendment 6 and Part B that enrolled participants after
Amendment 6.
Enrollment in Part A was closed on approval of Amendment 6. Part 
B consists of 4 cohorts. Cohort 1 enrolled patients with PROS; 
Cohort 2 enrolled patients with PS; Cohort 3 enrolled patients with 
either PROS or PS who did not meet the eligibility criteria for 
Cohorts 1 or 2; and Cohort 4 enrolled patients previously treated 
with miransertib or currently receiving miransertib under 
Compassionate Use/Expanded Access.
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Amendment 7 will complete the final enrollment into the MOSAIC 
study and Compassionate Use/Expanded Access Program. In the 
future, patients will be transitioned to new miransertib programs.
Study Design and 
Treatment:
Global, multicenter open-label, two-part Phase 1 /2 study testing 
miransertib in PROS and PS patients.
All participants enrolled in Part B Cohorts 1, 2, and 3 will receive
miransertib at the starting dose of 15 mg/m2 qd for the first 
3 cycles, (a cycle of therapy is 28 days), and then the dose will be
increased to 25 mg/m2 qd, provided no clinically significant drug-
related toxicity is observed.
Study Endpoints:
Under this amendment, 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 based on the frequency, duration, 
and severity of AEs from the first dose of the drug through 90 days
after the last dose of the drug.
Study Population:
Participants diagnosed with PROS or PS with documented PIK3CA 
or AKT1 somatic mutation will be enrolled.
Participants who are eligible for enrollment must meet ALL of the 
inclusion and NONE of the exclusion criteria.
Enrollment in Part A was closed on approval of Amendment 6.
Inclusion Criteria - Part B
•
Signed informed consent, and when applicable, signed assent
Cohort 1 (PROS) 
•
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 standardized 
volumetric MRI
Cohort 2 (Proteus) 
•
Male or female participants ≥2 years and ≤18 years of age with 
body surface area (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 evaluated by standardized digital photography.
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Cohort 3 specific criteria
Male or female PROS or PS patients ≥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
•
Note: Participants should meet the age criterion by/on the date 
of the first dose, Cycle 1 Day 1.
All Cohorts:
1. Archival or fresh overgrowth tissue sample available to be 
shipped to Sponsor or designee
2. 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
3. Adequate organ function as indicated by the following laboratory 
values:
Hematological
•
Hemoglobin (hgb) depending on age: 2 to 5 years male and 
female: ≥10.0 g/dL, 6 to 9 years male and female: ≥11.5 g/dL,
10 to 17 years female: ≥11.0 g/dL, 10 to 17 years male: 
≥11.5 g/dL, ≥18 years male and female: ≥10.0 g/dL
•
HbA1c: ≤8% (≤64 mmol/mol)
•
Absolute neutrophil count (ANC): ≥1.5 x 109/L
•
Platelet count ≥150 x 109/L
Hepatic
•
Total bilirubin ≤1.5 x ULN
•
AST and ALT ≤3 x ULN
Renal
•
Serum creatinine depending on age: 2 to 5 years male and 
female: maximum 0.80 mg/dL, 6 to 10 years male and female: 
maximum 1.0 mg/dL, 11 to 15 years male and female: 
maximum 1.2 mg/dL, >15 years male and female: maximum 
1.5 mg/dL
•
Estimated glomerular filtration rate (eGFR):
≥60 mL/min/1.73 m2
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Metabolic (lipids)
•
Cholesterol: ≤400 mg/dL (≤10.34 mmol/L)
•
Triglyceride: ≤500 mg/dL (≤5.7 mmol/L)
4. 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.
5. Ability to complete the study questionnaires by the participant or 
his/her caregiver
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
3. Myocardial infarction (MI) or congestive heart failure defined as 
Class II to 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)
4. Grade 2 (per current version of National Cancer Institute
Common Terminology Criteria for Adverse Events [NCI CTCAE]) 
or worse conduction defect (eg, right or left bundle branch block)
5. Major surgical procedures or locoregional therapy within 
4 weeks of the first dose of miransertib
6. Any experimental systemic therapy for the purposes of treating 
PROS or PS (eg, sirolimus, everolimus, high dose steroids) within 
2 weeks of the first dose of miransertib
7. Intolerance of or severe toxicity attributed to AKT inhibitors (eg, 
miransertib, uprosertib, afuresertib, ipatasertib)
8. Concurrent severe uncontrolled illness not related to PROS or 
PS, (eg, ongoing or active infection, known human 
immunodeficiency virus [HIV] infection)
9. Malabsorption syndrome
10. Psychiatric illness/substance abuse/social situation that would 
limit compliance with study requirements
11. Pregnant or breastfeeding
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12. Inability to comply with study evaluations or to follow drug 
administration guidelines
Study Drug, Doses, 
and Administration:
Miransertib is an orally administered pan-AKT inhibitor.
Miransertib is supplied as 5-mg or 10-mg capsules and will be 
administered either 1 hour before or 2 hours after a meal. The 
capsules should be swallowed whole but, when medically 
necessary, can be opened and sprinkled onto a small amount of 
sweetened semiliquid food (eg, apple sauce, chocolate syrup, or ice 
cream).
Participants will be administered miransertib at 15 mg/m2 daily for 
3 cycles and then 25 mg/m2 daily for the remainder of the study 
unless unacceptable toxicity is observed.
Participants in Cohort 4 will receive miransertib at the same dose 
they were on at the time of enrollment, the dose should not exceed 
25 mg/m2. For participants who previously received miransertib but 
at the time of the enrollment were not receiving the drug, 
miransertib administration will follow Part B miransertib
administration schedule. Independent from the dose the participant
is on, the actual dose should be evaluated at each study visit and 
adjusted when necessary based on BSA, since it is expected to 
change over the course of treatment due to the normal growth of 
the participant.
Criteria for Dose 
Escalation/ 
Reduction:
For participants enrolled in Part B Cohorts 1, 2, and 3 dose 
escalation to 25 mg/m2 qd will be performed after 3 cycles of 
treatment at the initial dose of 15 mg/m2 qd provided no clinically 
significant drug-related toxicity was observed (as assessed by the 
investigator and agreed on by the investigator and the Sponsor).
When a miransertib-related toxicity is observed, dose delays and/or 
reductions are allowed. Dose re-escalation will not be permitted.
Duration of 
Treatment:
For an individual participant, treatment will continue for up to 
48 cycles or until disease progression, unacceptable toxicity, or 
another discontinuation criterion is met.
It is expected that most participants will receive between 3 and
48 cycles of treatment.
Data Monitoring 
Committee:
The DMC will monitor participants’ safety by reviewing and 
evaluating study data, reviewing study conduct and progress, and
making recommendations concerning the continuation, 
modification, or termination of the study. Data Monitoring 
Committee (DMC) meetings will take place at least 2 times per 
year.
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Statistical Analysis:
All participants who receive at least 1 dose of miransertib will be 
included in the analysis of safety.
For Part A and Part B: The safety and tolerability of miransertib for 
all participants enrolled in Part A and Part B will be determined 
and summarized as a clinical narrative.
Further details including data handling rules will be provided in the 
Statistical Analysis Plan (SAP).
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LIST OF ABBREVIATIONS
Note: The terms subject, patient, or study participant may be used interchangeably.
AE
adverse event
AKT
v-Akt murine thymoma viral oncogene homolog
AKT1
serine-threonine protein kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-24
area under the curve from time 0 to 24 hours after dose administration
AVM
arteriovenous malformation
bid
twice daily
BSA
body surface area
BUN
blood urea nitrogen
C
cycle (eg, C1 = Cycle 1)
CBC
complete blood count
CCTN
cerebriform connective tissue nevus
CFR
Code of Federal Regulations
CLOVES
Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal 
Nevis, Spinal/Skeletal Anomalies/Scoliosis syndrome
Cmax
maximum plasma drug concentration
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome
D
day (eg, D1 = Day 1)
DDI
drug-drug interaction
DIC
disseminated intravascular coagulation
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DVT
deep vein thrombosis
ECG
electrocardiogram
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eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated Glomerular Filtration Rate
EOT
end of treatment
FAO
fibroadipose hyperplasia or overgrowth
FDA
Food and Drug Administration
FOB
Functional Observational Battery
GCP
Good Clinical Practice
GDPR
General Data Protection Regulation
GI
gastrointestinal
HbA1C
glycated hemoglobin
HDL
high-density lipoprotein
Hgb
hemoglobin
HHML
Hemihyperplasia Multiple Lipomatosis
HIPAA
Health Information Portability and Accountability Act
HIV
human immunodeficiency virus
HNSTD
highest non-severely toxic dose
IB
Investigator’s Brochure
IC50
inhibitor concentration required for 50% inhibition
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
Institutional Review Board
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
MCAP
megalencephaly-capillary malformation
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
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mTOR
mammalian target of rapamycin
mTORC2
mammalian target of rapamycin complex 2
NCI
National Cancer Institute
NHGRI
National Human Genome Research Institute
NIH
National Institutes of Health
NYHA
New York Heart Association
pAKT
phosphorylated AKT
PD
pharmacodynamic(s)
PDK1
phosphoinositide-dependent kinase 1
PE
pulmonary embolism
P-gp
P-glycoprotein 1
PH
pleckstrin homology
PI3K
phosphatidylinositol 3-kinase
PIK3CA
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
PIP3
phosphatidylinositol 3,4,5-triphosphate
PK
pharmacokinetic(s)
PND
postnatal day
pPRAS40
phospho-PRAS40
PR
partial response
PRAS40
proline-rich AKT substrate of 40 kilodaltons
PROS
PIK3CA-related Overgrowth Spectrum
PS
Proteus Syndrome
PT
prothrombin time
PTEN
phosphatase and tensin on chromosome 10
PTT
partial thromboplastin time
qd
once daily
qd-qow
one dose every other week (Q2W)
qod
every other day
QoL
quality of life
qow
every other week
qw
once per week
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SAE
serious adverse event
SAP
statistical analysis plan
SAR
serious adverse reaction
SCC
single cell clone
Ser473
serine 473
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
Thr308
threonine 308
Tmax
time to maximum plasma drug concentration
ULN
upper limit of normal
US
ultrasound
VA
vascular anomalies
VM
vascular malformations
WMA
World Medical Association
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1
INTRODUCTION
The PI3K/AKT/mTOR signaling pathway plays a major role in the physiological processes 
regulating cellular growth, proliferation, angiogenesis, survival, and metabolism [Brazil DP, 
Yang ZZ, Hemmings BA 2004] [Bellacosa, A., et al 2005] [Engelman JA, Luo J, Cantley LC 
2006]. In the last 2 decades, the PI3K/AKT/mTOR signaling pathway has been extensively 
studied in cancer due to its critical role in tumor growth, survival, metabolism, and the 
development of metastases [Khan, K. H., et al 2013]. In addition, somatic activating 
mutations in PI3K and AKT1 (serine-threonine protein kinase) have been shown to cause 
abnormal segmental overgrowth phenotypes [Lindhurst, M. J., et al 2011] [Keppler-Noreuil
KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ 2015]. The umbrella term of 
“phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA)-Related 
Overgrowth Spectrum (PROS)” is intended to encompass both the known conditions, 
including macrodactyly, FAO, HHML, CLOVES and related megalencephaly conditions, 
and the emerging clinical entities associated with somatic PIK3CA mutations [Keppler-
Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ 2015]. A consensus on 
diagnostic criteria, testing eligibility and evaluation of patients with PIK3CA-associated 
somatic overgrowth disorders was reached at a NIH workshop and reported by Keppler-
Noreuil, et al in 2015 [Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ 
2015].
Proteus Syndrome is another rare segmental overgrowth disorder caused by a somatic gain of 
function mutation in the oncogene AKT1 (AKT1-E17K). AKT serves a range of cellular 
functions with effects on metabolism and cell survival, and through indirect activation of 
mTOR controls cell proliferation, protein translation, and autophagy [Keppler-Noreuil, K. 
M., et al 2016]. Tissues and cell lines from patients with PS harbor admixtures of mutant 
alleles that ranged from <1% to approximately 50%. This mutation causes constitutive 
activation of AKT1, through Ser473 and Thr308 phosphorylation [Lindhurst, M. J., et al 
2011] [Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ 2015] 
[Biesecker LG, Lindhurst MJ, Yourick MR, Dransfield DT 2014].
In contrast to cancer, which is characterized by multiple genetic aberrations, a single 
activating mutation has been identified in both PROS and PS. In general, clinical 
presentation is characterized by a mosaic distribution, sporadic occurrence, progressive 
course of the overgrowth lesions that can affect any tissue or organ in the human body 
(connective tissue or bone hyperplasia, vascular malformation, etc.). Onset usually occurs at 
birth or early in life (the first 6-18 months of life). Affected areas generally keep growing 
throughout the life, but at a slower pace after the patient reaches their third decade of life
[Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ 2015] [Martinez-
Lopez, A., et al 2017] [Biesecker, L. G. 2019]. Currently there is no drug therapy for PROS 
or PS; the treatment consists of symptom management, mainly surgical management of 
overgrowth lesions, that ultimately leads to severe physical disabilities with unsatisfactory 
QoL. The potential to modify and control disease progression is greatest during the rapid
disease progression stage which occurs in early childhood. Later treatment may be beneficial,
but it will likely have a limited effect.
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Miransertib is a novel, potent, and selective allosteric pan-AKT inhibitor with activity against 
both the active and inactive forms of AKT. AKT1, 2, and 3 are inhibited with IC50 values of 
5.0, 4.5, and 16 nM, respectively. Biochemical and cellular analysis showed that miransertib
inhibited AKT activation not only by dephosphorylating the membrane associated active 
form of AKT but also by preventing the inactive form from localizing into the plasma 
membrane [Yu Y, Savage RE, Eathiraj S, Meade J, Wick MJ, et al. 2015].
1.1
Nonclinical Effects of Miransertib on Overgrowth Syndromes In Vitro
Antiproliferative activity of miransertib was assessed in 6 fibroblast cell lines derived from 
PROS patients with HHML (PIK3CA H1047R), CLOVES (PIK3CA H1047R), Macrodactyly
(PIK3CA H1047R), and MCAP (PIK3CA H1047R, or PIK3CA E81K). These PROS
fibroblast cell lines showed elevated AKT activity. Miransertib very potently inhibited 
proliferation of PROS fibroblasts in a dose- and time-dependent manner with less 
cytotoxicity as compared with rapamycin (mTOR inhibitor) and wortmannin (PI3K 
inhibitor). Treatment with miransertib markedly suppressed AKT and its downstream targets
[Ranieri, C., et al 2018]. In addition, fibroblasts from the skin of a patient with FAO 
(PIK3CA H1047R) were evaluated and the results showed that miransertib inhibited both 
pAKT and pPRAS40 in a dose-dependent manner [Biesecker LG, Lindhurst MJ, Yourick 
MR, Dransfield DT 2014].
Miransertib was further evaluated in skin fibroblasts isolated from several patients with PS
harboring the activating mutant of AKT1, AKT1 E17K mutation [Lindhurst, M. J., et al 
2015]. pAKT levels were 7- to 29-fold higher and pPRAS40 levels were 9- to 20-fold higher 
in the mutation-positive SCC compared with mutation-negative SCC. Phosphorylation of 
AKT1 and its substrate PRAS40 and other AKT downstream targets was markedly reduced 
on treatment of miransertib for 24 hours at the concentration range of 31 to 500 nM. With as
little as 30 nM of miransertib, pAKT levels were reduced to approximately half compared 
with the levels in untreated fibroblasts. At 500 nM of miransertib, all pAKT levels were 
nearly zero.
In an ex vivo study, pAKT levels were assessed in skin biopsies from 2 affected toes of one 
patient that were incubated in a culture medium for 96 hours at 37°C with or without serum in
the presence or absence of miransertib at 125 nM [Lindhurst, M. J., et al 2015]. 
Phosphorylation of AKT was reduced from 4- to 7-fold for tissues incubated with serum and 
9- to 27-fold for those in serum-free medium when miransertib was added. pPRAS40 levels 
were also reduced, though not as dramatically as pAKT.
In vitro antiproliferative activity of miransertib was also conducted in skin fibroblast cells 
from patients with PS (AKT1-E17K) and unaffected cells with wild type AKT1 were used as 
comparison [Lindhurst, M. J., et al 2015]. In both high (10%) and low (0.5%) serum, the 
mutation-positive cells were more sensitive to increased levels of miransertib than mutation-
negative cells.
In summary, the PI3K/AKT pathway, which is dysregulated in overgrowth diseases such as
PROS and PS, is frequently activated through mutations in PIK3CA or AKT. AKT1 
mutation-positive cells and PROS cells treated with 625 nM of miransertib had 25% to 40% 
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reduction in cell viability (measured by AKT phosphorylation) compared with untreated 
cells, whereas in mutation-negative cells the reduction was 0% to 20% [Lindhurst, M. J., et al 
2011]. A similar effect on PIK3CA-mutant cells was observed at miransertib concentrations 
of 1000 nM or below. The target tissue concentration required for adequate (50%-75%) 
inhibition of AKT phosphorylation is between 500 and 1000 nM; when concentrations were 
above 2500 nM, no additional effect on cellular proliferation was noted [Loconte DC, Grossi 
V, Bozzao C, Forte G, Bagnulo R 2015]. Thus, inhibition of AKT by miransertib is a rational 
approach for the therapeutic intervention in such diseases.
1.2
Toxicology of Miransertib in Animals
Miransertib was generally well tolerated in rats and monkeys up to doses of about 
10 mg/kg/day. The toxicity profile in juvenile rats was not different from that of adult rats 
and there was no effect on male or female fertility in the juvenile toxicology study.
Based on the 4-week rat study, the STD10 of miransertib was determined to be 15 mg/kg/day 
when given daily via oral gavage. This correlates to a human equivalent dose of 
90 mg/m2/day. Based on the 4-week monkey study, the HNSTD of miransertib was 
determined to be 10 mg/kg/day when given via oral gavage daily. This correlates to a human 
equivalent dose of 120 mg/m2/day. Hence, based on the ICH S9 guidance document, the 
Phase 1 starting dose was thus calculated to be 9 mg/m2/day or 13.5 mg/day. The initial
starting dose of miransertib in humans was suggested to be 10 mg/day. The actual starting
dose in the first-in-human study, ARQ 092-101, was 10 mg qod.
Dosing in the juvenile toxicity study in rats started on PND 21, correlating with a 2-year old
child. Therefore, the results support the safe use of miransertib in pediatric patients down to 
2 years of age. The weight of evidence indicates that miransertib is not mutagenic or 
aneugeic but is weakly clastogenic. Additional details can be found in the IB.
1.3
Effects of Miransertib in Humans
1.3.1
EFFECTS OF MIRANSERTIB IN ONCOLOGY
Safety, tolerability and preliminary efficacy of miransertib have been tested in more than
150 adult participants with advanced solid tumors and recurrent malignant lymphoma
(ARQ 092-101 [NCT# 01473095] and ARQ 092-102 [NCT# 02476955]).
1.3.1.1
ARQ 092-101
ARQ 092-101, A Phase 1 Dose Escalation Study of Miransertib in Adult Subjects with 
Advanced Solid Tumors and Recurrent Malignant Lymphoma, was an open-label, first-in-
human of miransertib. A total of 120 participants were treated with miransertib monotherapy. 
miransertib was initially administered at 10 mg qod and dose escalated from 10 mg qd to 
350 mg bid qw. Fifteen dose levels and 3 dosing schedules (continuous [up to 80 mg qd], 
intermittent [up to 270 mg qd one week on and one week off], and weekly [up to 350 mg bid
qw]) were explored in this study. The MTD in adult cancer patients was determined to be 
60 mg qd (approximately 30 mg/m2).
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The most common reason for treatment discontinuation was radiological disease progression 
(76/120, 63.3%). Safety and PK details for the 28 participants who received continuous, daily 
dosing of miransertib are summarized below. This subset of ARQ 092-101 participants’ data 
are the most relevant for Study ARQ 092-103. Additional details can be found in the IB.
The drug-related TEAEs at continuous dosing are shown in Table 1.
Table 1
ARQ 092-101 Drug-Related TEAE Reported by More Than 1 Participant
With QOD/QD Dosing
Preferred Term
10 mg
QOD (n=4)
10 mg
QD (n=3)
20 mg
QD (n=3)
40 mg
QD (n=4)
60 mg
QD (n=7)
80 mg
QD (n=7)
Total 
(n=28)
Diarrhoea
1 (33.3)
1 (33.3)
1 (25.0)
1 (14.3)
2 (28.6)
6 (21.4)
Dry Mouth
1 (25.0)
1 (33.3)
1 (14.3)
3 (10.7)
Nausea
2 (66.7)
1 (25.0)
2 (28.6)
4 (57.1)
9 (32.1)
Stomatitis
1 (14.3)
1 (14.3)
2 (7.1)
Fatigue
1 (25.0)
1 (25.0)
1 (14.3)
1 (14.3)
4 (14.3)
Decreased Appetite
1 (25.0)
2 (28.6)
3 (10.7)
Hyperglycaemia
1 (14.3)
4 (57.1)
5 (17.9)
Dermatitis Acneiform
2 (28.6)
2 (7.1)
Dry Skin
1 (14.3)
2 (28.6)
3 (10.7)
Palmar-Plantar 
Erythrodysaesthesia Syndrome
1 (14.3)
1 (14.3)
2 (7.1)
Pruritus
1 (33.3)
2 (28.6)
2 (28.6)
5 (17.9)
Rash Maculo-Papular
2 (28.6)
3 (42.9)
5 (17.9)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; QD=once daily; QOD=every other day
Final study data; 07 Aug 2017
In Cohort 5, 80 mg qd, one of the first 3 participants experienced 2 DLTs (Grade 3 cardiac 
failure congestive and Grade 4 cardiomyopathy) and the Cohort was expanded to enroll 
3 additional participants. After 2 more DLTs (Grade 3 maculopapular rash and Grade 3 
hyperglycemia) were experienced by 2 other participants, qd dosing was reduced to 60 mg 
for Cohort 6. In Cohort 6, one of the first 3 participants experienced a DLT (Grade 3 
increased AST) and the Cohort was expanded with no additional DLTs reported. The MTD 
was declared as 60 mg qd for the continuous dosing schedule.
1.3.1.2
ARQ 092-101 Pharmacokinetics
Miransertib PK data for this study are available for all 28 participants treated with the
continuous dosing. The mean Cmax of miransertib ranged from 11 nM (10 mg qod dose) to
166 nM (60 mg qd dose) on Day 1 and from 29 nM (10 mg qod dose) to 787 nM (80 mg qd
dose) on Day 15. The mean AUC0-24 of miransertib ranged from 163 h*nM (10 mg qod dose) 
to 2217 h*nM (60 mg qd dose) on Day 1 and from 489 h*nM (10 mg qod dose) to 15212
h*nM (80 mg qd dose) on Day 15. Miransertib accumulates with accumulation ratios ranging 
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from 2.9 (10 mg qd dose) to 7.2 (80 mg qd dose) for Cmax, and from 3.0 (10 mg qd dose) to 
8.6 (80 mg qd dose) for AUC0-24. Due to the long elimination phase, the half-life of 
miransertib could not be accurately determined; however, it is estimated that the half-life of 
miransertib is in the range of 40 to 60 hours. Additional details can be found in the IB.
1.3.1.3
ARQ 092-102
ARQ 092-102 is an open-label, Phase 1b study of miransertib in combination with 
carboplatin plus paclitaxel, paclitaxel alone, or anastrozole for the treatment of selected solid 
tumors. As of the data cutoff date, 34 participants have been treated with miransertib. The 
most common miransertib-related TEAEs (≥20%) seen were diarrhea (35.3%), nausea 
(32.4%), fatigue (26.5%), maculopapular rash (26.5%), and decreased appetite (20.6%). 
Additional details can be found in the IB.
1.3.2
Effects of Miransertib in Overgrowth Diseases
1.3.2.1
A Phase 1 Dose-Finding Study of Miransertib in Children and Adults With 
Proteus Syndrome
Study 16-HG-0014 is an investigator sponsored study conducted under NIH IND 126197 
[NCT02594215]). The primary endpoint of the study was to determine the biological effect 
of miransertib as measured by changes in pAKT levels in the affected tissue. Results from 
the study have been reported and are summarized below [Keppler-Noreuil, K. M., et al 
2019].
In 5 of 6 participants, a reduction of 50% or greater of tissue pAKT levels was reported, and 
the primary endpoint of the study was met. The clinical efficacy measurements showed 
significant reduction in size of the CCTN in 2 participants at Cycle 12 by quantitative 
standardized photography. Three participants reported an improvement in pain as assessed by 
a standardized pain scale.
Overall, the drug was well tolerated with most AEs considered mild or moderate in severity. 
The most common drug-related AEs (observed in ≥3 participants) were headache (66.7%) 
increase bone formation (66.7%), exostosis (66.7%), and pain in extremity (66.7%). Detailed 
summary of the safety data as reported by NHGRI Investigators’ can be found in the IB.
1.4
Conclusion
Based on the nonclinical data and observed activity in patients with PS treated with
miransertib, this Phase 1/2 study was initiated to further explore the single agent activity of 
miransertib in patients with PROS and PS with known PI3KCA and AKT1 somatic 
activating mutations.
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2
INVESTIGATIONAL PLAN
PROS and PS are characterized by overlapping clinical features, but caused by different 
somatic activating mutations, PIK3CA and AKT1, respectively. The overgrowth can affect 
any organ and cause multiple disabling complications. The significant morbidity and 
mortality associated with these progressive disorders, together with their unique, single 
genetic mutations, make themgood candidates for AKT/PIK3CA targeted therapies that were 
initially developed for oncology indications [Keppler-Noreuil KM, Rios JJ, Parker VE, 
Semple RK, Lindhurst MJ 2015] [Keppler-Noreuil, K. M., et al 2016].
As of 31-JAN-2019, a total of 15 PROS and PS patients with PIK3CA or AKT1 mutations have 
been enrolled and treated in Study 092 103.
The study includes 2 parts:
Part A: All participants enrolled before Amendment 6. Part A was designed to enroll 25 to
40 participants with PROS and PS.
Part B: All participants enrolled under Amendment 6 or higher. Cohort 1 will enroll PROS 
patients; Cohort 2 will enroll PS patients; Cohort 3 will enroll either PROS or PS patients
who do not meet the eligibility criteria for Cohorts 1 or 2; and Cohort 4 will enroll patients
previously treated with miransertib or currently receiving miransertib under Compassionate 
Use/Expanded Access.
Cohorts 1 and 2 were originally designed to determine the response rate of miransertib in a 
selected participant population, as measured by a change in target lesion size from baseline,
using blinded independent central imaging review: volumetric MRI in PROS or cerebriform 
CCTN photography in PS.
2.1
Study Objectives
Under this amendment, the primary study objective for both Part A and Part B is to describe the
safety and tolerability of miransertib in patients with PROS and PS, and further efficacy 
assessments have been removed. Part A was closed to enrollment after the approval of 
Amendment 6.
Amendment 7 will complete the final enrollment into the MOSAIC study and Compassionate 
Use/Expanded Access Program. In the future, patients will be transitioned to new miransertib 
programs.
2.2
Overall Study Design
This is an open-label, multicenter Phase 1/2 study of oral miransertib administered daily to
patients with PROS and PS. The study will be conducted at up to 20 sites globally.
Part B will enroll approximately 65 participants with clinical diagnosis of PROS or PS with 
documented somatic PIK3CA or AKT1 mutations. Part B will be comprised of 4 Cohorts: 
Cohort 1 will enroll 20 participants with PROS with a measurable lesion by the study-
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standardized volumetric MRI. Cohort 2 will enroll 10 participants with PS with measurable 
CCTN and pre-CCTN lesional area by the study-standardized photography. Cohort 3 will 
enroll approximately 25 PROS or PS patients who do not meet the eligibility criteria for 
enrollment in Cohort 1 or Cohort 2. Cohort 4 will enroll participants previously treated with 
miransertib or currently receiving miransertib Compassionate Use/Expanded Access.
In Part B (except Cohort 4), participants will receive miransertib at the 15 mg/m2 qd dose 
level during the first 3 cycles, (a cycle of therapy is considered to 28 days). The dose will be 
increased to 25 mg/m2 qd provided no clinically significant drug-related toxicity is observed. 
Participants who experienced miransertib-related toxicity or are unable to tolerate study 
medication during the first 3 cycles may be treated at lower doses.
Participants enrolled in Cohort 4 will continue treatment at the dose they were on at the time 
of enrollment, but their dose should not exceed the 25 mg/m2.
For all participants, actual dose will be calculated using BSA, per the DuBois formula.
Participants will stay on treatment for up to 48 cycles.
To better understand the natural history of the disease of each individual participant, all 
participants will be asked to provide a detailed history of their disease, including prenatal and
postnatal evaluations, and surgical operations, results of any functional tests performed 
before the study enrollment, and, when possible, imaging scans (eg, CT, MRI, US), 
photographs, and/or video recordings collected before study enrollment.
PIK3CA or AKT1 somatic mutations must be documented before enrollment. If the status is 
unknown, an archival or fresh tissue biopsy must be collected and tested for PIK3CA or 
AKT1 somatic mutations. For all enrolled participants, archival or fresh tissue biopsy should 
be collected and sent to the Sponsor or designee.
For Part B Cohort 1, 2, and 3, safety (eg, physical examination, vital sign measurements,
clinical laboratory tests, use of concomitant medications, and collection of AE information) 
assessments will be performed at baseline, twice during the first cycle, and at each study visit 
thereafter. All clinical assessments and laboratory tests will be performed per the Schedule of 
Events [Table 3]
For Cohort 4, safety (eg, physical examination, vital sign measurements, clinical laboratory
tests, use of concomitant medications, and collection of AE information) assessments will be
performed every 3 months (Table 4). If clinically indicated, unscheduled laboratory tests and 
any clinical assessments or evaluations may be performed per the discretion of the 
investigator.
A single blood sample will be collected for CYP2D6 genotyping. The final clinical safety 
follow-up will be performed 30 days after the last dose of miransertib.
Miransertib is supplied as 5- and 10-mg capsules and should be swallowed whole (1 hour
before or 2 hours after a meal). When medically necessary, the capsules can be opened and 
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sprinkled onto a small amount of sweetened semiliquid food (eg, apple sauce, chocolate 
syrup, or ice cream).
The study data and endpoints were reviewed by the Sponsor in 2020. It was concluded that
the current data from this study would not be sufficient to establish efficacy for either the 
PROS or PS patients. As a consequence, Amendment 7 was written to remove all efficacy 
assessments, including the volumetric MRIs for the PROS patients, the CCTN photography 
for the PS patients, as well as to remove the functional assessments, among others.
2.3
Study Endpoints
Under this amendment, 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 based on the 
frequency, duration, and severity of AEs from the first dose of the drug through 90 days after 
the last dose of the drug.
3
SELECTION OF STUDY POPULATION
Participants with PROS or PS with a documented PIK3CA or AKT1 somatic mutation will be
enrolled in this study. It is expected that the study will be conducted at up to 10 sites 
globally. Part A is closed to enrollment. Part B will enroll approximately 65 participants.
Participant accrual will occur over a period of approximately 24 months.
Participants must meet ALL of the inclusion criteria and NONE of the exclusion criteria to 
be enrolled.
3.1
Inclusion Criteria
Part A is closed to enrollment after the approval of Amendment 6. See Annex 1 for 
inclusion/exclusion criteria for Part A.
3.1.1
Part B:
1. Signed informed consent, and when applicable, signed assent
2. Cohort 1 (PROS) specific criteria
•
Male or female participants ≥2 years and ≤30 years of age with BSA of ≥0.33 m2. 
Participants should meet the age criterion by/on the date of the first dose Cycle 1 
Day 1.
•
Have clinical diagnosis of PROS per Diagnostic Criteria for PROS (Appendix 1) and 
documented somatic PIK3CA variant.
•
Have at least one lesion that can be accurately measured by study-standardized 
volumetric MRI (eligibility to be confirmed by blinded central imaging review).
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3. Cohort 2 (PS) specific criteria
•
Male or female participants ≥2 years and ≤18 years of age with BSA of ≥0.33 m2. 
Participants should meet the age criterion by/on the date of the first dose Cycle 1 
Day 1.
•
Have clinical diagnosis of PS per Diagnostic Criteria for PS (Appendix 1) and 
documented somatic AKT1 variant.
•
Have at least one plantar CCTN and pre-CCTN lesion that can accurately be 
measured by standardized photography. The CCTN is defined as a nevus with at least 
2 gyri and 3 sulci and should affect between 10% and 70% of the total surface area of 
the foot (eligibility to be confirmed by blinded independent central photo review).
4. Cohort 3 specific criteria
•
Male or female PROS or PS patients ≥2 years old with BSA of ≥0.33 m2 and who fail 
to meet the eligibility criteria for Cohorts 1 or 2. Participants should meet the age 
criterion by/on the date of the first dose Cycle 1 Day 1.
5. Cohort 4 (PROS or PS) specific criteria
•
Participants previously treated with miransertib or currently receiving miransertib
under Compassionate Use/Expanded Access
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:
a.
Hematological
1. Hgb depending on age:
•
2 to 5 years male and female: ≥10.0 g/dL
•
6 to 9 years male and female: ≥11.5 g/dL
•
10 to 17 years female: ≥11.0 g/dL
•
10 to 17 years male: ≥11.5 g/dL
•
≥18 years male and female: ≥10.0 g/dL
2. HbA1c: ≤8% (≤64 mmol/mol)
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3. ANC: ≥1.5 x 109/L
4. Platelet count ≥150 109/L
b.
Hepatic
1. Total bilirubin ≤1.5 x ULN
2. AST and ALT ≤3 x ULN
c.
Renal
1. Serum creatinine depending on age:
•
2 to 5 years male and female: maximum 0.80 mg/dL
•
6 to 10 years male and female: maximum 1.0 mg/dL
•
11 to 15 years male and female: maximum 1.2 mg/dL
•
>15 years male and female: maximum 1.5 mg/dL
2. Estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2
d. Metabolic (lipids)
1. Cholesterol: ≤400 mg/dL (≤10.34 mmol/L)
2. Triglyceride: ≤500 mg/dL (≤5.7 mmol/L)
9. 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
10. Ability to complete the study questionnaires by the participant or his/her caregiver
3.2
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 (>12 years old) and ≥180 mg/dL (if ≤12 years old) at the Screening 
Visit
2. History of significant cardiac disorders
3. MI or congestive heart failure defined as Class II to IV per the NYHA classification 
within 6 months of the first dose of miransertib (MI occurring >6 months of the first dose 
of miransertib will be permitted)
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4. Grade 2 (per current version of NCI CTCAE) or worse conduction defect (eg, right or left 
bundle branch block)
5. Major surgical procedures or locoregional therapy within 4 weeks of the first dose of 
miransertib
6. Any experimental systemic therapy for the purposes of treating PROS or PS 
(eg, sirolimus, everolimus, high dose steroids) within 2 weeks of the first dose of
miransertib
7. Intolerance of or severe toxicity attributed to AKT inhibitors (eg, miransertib, uprosertib, 
afuresertib, ipatasertib)
8. Concurrent severe uncontrolled illness not related to PROS or PS, including:
•
Ongoing or active infection
•
Known HIV infection
•
Malabsorption syndrome
•
Psychiatric illness/substance abuse/social situation that would limit compliance with 
study requirements
9. Pregnant or breastfeeding
10. Inability to comply with study evaluations or to follow drug administration guidelines
4
STUDY VISITS
Before the start of any study required procedures, the investigator or designee must obtain a
signed written ICF and, when applicable, signed assent for the study from each prospective 
participant or his/her parent or legal guardian.
For Part A, all ongoing participants will continue treatment and will follow the Schedule of 
Eventsin Annex 1.
For Part B Cohorts 1, 2 and 3, study visits will consist of a Screening Visit, (during which the 
participant’s eligibility for the study and baseline disease state will be evaluated), 2 visits 
during the first and fourth cycles, one visit per cycle for Cycles 2 and 3, and 5, then once
every 2 cycles for Visits 7, 9, 11, and 13, and then one visit per every 3 cycles until EOT,
during which the participant’s clinical status will be evaluated, and a 30-Day Safety Follow-
up (Table 3).
For participants enrolled in Cohort 4, study visits will consist of a Screening Visit, (during 
which the participant’s eligibility for the study and baseline disease state will be evaluated), 
Cycle 1 Day 1visit and then one visit per every 3 cycles (eg, Cycle 4 Day 1, Cycle 7 Day 1, 
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Cycle 10 Day 1, Cycle 13 Day 1, etc.) until EOT, during which the participant’s clinical
status will be evaluated, and a 30-Day Safety Follow-up (Table 4).
After the Screening Visit and a determination by the investigator and with Sponsor approval 
that the participant meets all inclusion criteria and none of the exclusion criteria, the 
participant will be considered entered into the study.
Participants enrolled in Part B, Cohorts 1 and 2, must also meet eligibility requirements 
according to applicable central imaging criteria.
4.1
Informed Consent
A sample ICF and Assent Form with core information will be provided to each study site.
Before study initiation at a given study site, each site/investigator must obtain a written
approval/favorable opinion from its respective IRB/IEC for the ICF, assent form, and any
other written information to be provided to participants. All ICFs and assent forms must be 
compliant with the ICH GCP guidelines and local regulations and must be approved by the 
Sponsor before submission to the IRB/IEC. The written approval of the IRB/IEC, together 
with the approved participant information, ICF, and assent forms, must be maintained in the 
study masterfiles.
Written informed consent and/or assent must be obtained from a prospective participant and 
his/her parent/legal guardian before any study-specific procedures are performed on that 
individual. Participants who agree to participate in the study will sign the most recently 
approved ICF and/or Assent Form and will be provided with a copy of the fully executed 
document(s). The original, executed ICF and Assent Form will be maintained in the 
respective participant’s clinical study file.
The ICF can be signed greater than 45 days before dosing and does not need to be re-signed
before dosing unless specific reasons or local regulations apply (eg, a new consent version 
has been issued and approved by the IRB/IEC).
All screening imaging assessments must be performed within 21 days of C1D1, unless rescan 
by MRI or repeat photography is required.
4.2
Participant Discontinuation
Participants in the study will be removed from treatment or the study at any time if they meet 
any of the following criteria:
4.2.1
Discontinuation From Treatment
•
Participant experiences, in the opinion of the investigator, an acceleration of the 
overgrowth disease.
•
Miransertib-related clinically significant toxicities that do not recover despite optimal 
treatment or dose reduction.
•
Participant needs to take or elects to take another investigational agent.
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•
Development of any concurrent medical condition that might preclude or 
contraindicate the further administration of miransertib.
•
Serious protocol violations such as noncompliance with treatment or required
follow-up and evaluation as determined by the investigator.
•
Investigator’s decision (in agreement with the Sponsor’s Medical Monitor or 
designee).
•
Participant, or guardian, refusal of further treatment/withdrawal of consent. Reasons
for refusal of further treatment/withdrawal of consent should be noted in that 
participant’s medical record.
•
Death.
4.2.2
Discontinuation From the Study
•
Participant and/or guardian refusal of further examinations (follow-up visits) and/or 
communications with the site/withdrawal of consent. Reasons for refusal/withdrawal 
of consent should be noted in that participant’s medical record.
•
Lost to follow-up.
•
Death.
4.3
Study Discontinuation
The Sponsor reserves the right to temporarily or permanently discontinue the study at any 
investigative site and at any time. Reasons for study discontinuation may include, but are not 
limited to, the following:
•
Safety concerns
•
Poor enrollment
•
Investigator noncompliance with the protocol, GCP guidelines, or other regulatory 
requirements
•
Request to discontinue the study by a regulatory or health authority
•
Discontinuation of product development
•
Manufacturing difficulties/concerns
The Sponsor and/or designee will promptly inform all Investigators and the appropriate
regulatory authorities if the study is suspended or terminated for safety reasons. In the case of 
such termination, the investigator will notify their IRB/IEC.
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5
STUDY PROCEDURES
5.1
Medical History
Medical history will include but not be limited to the following:
•
Demography: date of birth, sex, race and ethnicity
•
Clinically significant prior diagnoses and surgical operations (not related to PROS or
PS)
•
Medications used within 45 days before the first dose of miransertib and throughout 
the treatment period should be reported
•
Natural history of the disease (up to the study enrollment):

Perinatal history; prenatal and postnatal evaluations; family history; intellectual 
and psychomotor developmental milestones; disease-related manifestations 
(anatomical location, severity, frequency); management of the disease, 
including prophylactic and symptomatic therapies, hospitalizations, surgical 
operations; results of the clinical function assessments
•
Genetic testing results: AKT1 or PIK3CA mutation status in the affected tissue must 
be confirmed before dosing. The AKT1 or PIK3CA mutation (dependent on clinical
diagnosis) results will be captured in the EDC database and copies of the genetic report
will be forwarded to the Sponsor or designee. If mutational status is unknown, 
archival or fresh tissue biopsy must be collected and tested for mutation status to 
confirm eligibility for the study.

An archival tissue sample is to be sent to the Sponsor or designee for central 
confirmation of mutation analysis, if required.

When possible, imaging scans (eg, MRI, CT, US), photography, video recordings, 
and/or other assessments of size such as linear and/or circumference measurements 
performed before study enrollment will be collected and forwarded to the Sponsor or
designee.
5.2
12-Lead Electrocardiogram
A 12-lead ECG will be conducted at specific timepoints (see Table 3 and Table 4).
Additional ECGs may be conducted if clinically indicated or required per standard of care
(triplicate if possible). The ECG parameters will be captured in the EDC database and copies of
ECG tracings will be collected and forwarded for future analyses by the Sponsor or its
designee.
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5.3
Clinical Laboratory Tests
Safety laboratory determinations will include hematology, blood chemistry, and urinalysis. 
Refer to the Schedule of Events (Table 3 and Table 4) of the protocol for testing frequency. 
All laboratory tests required for scheduled visits during the study must be obtained at the 
local laboratory at the investigational site. If laboratory tests need to be performed to assess 
an AE in between scheduled study visits, these tests can be performed at a laboratory close to 
the participant’shome after agreement with theSponsor.
Chemistry samples should be taken in a fasting state (fasting for at least 4 hours for children 
<6 years of age and at least 8 hours for children ≥6 years of age). If, in error, the participant
has eaten ahead of testing, this should be documented as a fed rather than a fasting sample on 
theeCRF.
•
Hematology: CBC including Hgb, hematocrit, white blood cell count with 5-part 
differential, red blood cell, platelet, and reticulocyte count
•
HbA1c (screening only)
•
Coagulation tests (screening only): PT, PTT, and INR, D-dimer and fibrinogen
•
Blood chemistry: alkaline phosphatase, bicarbonate, calcium, phosphorus,
magnesium, albumin, glucose, serum creatinine, and insulin
•
Liver function tests: AST, ALT, LDH, alkaline phosphatase, total and direct bilirubin, 
uric acid, total protein, and BUN
•
Electrolytes: sodium, potassium, and chloride
•
Lipids: cholesterol, HDL, LDL, and triglycerides
•
Routine urinalysis: dipstick and microscopy including protein, specific gravity, 
glucose and blood
•
Serum pregnancy test for female participants of child-bearing potential, if applicable
•
Clinical laboratory tests can be collected within 24 hours of CXDX clinic visit for all 
visits except C1D1.
5.4
Pharmacokinetic Assessments
With Amendment 7, PK analyses will be limited to data already collected, as additional PK 
samples will not be collected.
PK variables measured will include Cmax, Tmax, and AUC.
For Part A, blood samples for PK analysis will be collected during Cycle 1 on Day 1 and 
Day 15 and on Cycle 2 Day 1 (Annex 1). Blood samples for PK analysis will also be 
collected during Cycles 4 and 7. If the dose did not increase during Cycle 4 or Cycle 7, a 
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single PK sample will be collected on Day 1 of these cycles. If the dose did increase during 
Cycle 4 or Cycle 7, blood samples for PK analysis will be collected on Day 1 and Day 15, 
and a single PK sample will be collected on Cycle 5 Day 1 and Cycle 8 Day 1. The blood 
sampling date and time and the time of dosing of miransertib administration on the days of 
PK collection must be recorded on the eCRF.
For Part B (Cohorts 1, 2, and 3), blood samples for PK analysis will be collected during 
Cycles 1 and 4 according to the schedule in Table 2. The blood sampling date and time and 
the time of dosing of miransertib administration on the days of PK collection must be 
recorded on the eCRF.
Table 2
Part B: PK Sampling Schedule (Cohorts 1, 2, and 3)
Day
Procedure
Collection Timepoint
Permitted Window for
blood draw
CYCLE 1 and CYCLE 4 Day 1
1
Draw blood sample
0 hour
(before the first dose of 
miransertib)
NA
1
Draw blood sample
3 hours
(± 15 minutes)
1
Draw blood sample
8 hours
(± 1 hour)
CYCLE 1 and CYCLE 4 Day 15
1
Draw blood sample
0 hour (before dosing)
NA
1
Draw blood sample
4 hours
(± 15 minutes)
1
Draw blood sample
6 hours
(± 1 hour)
NA=not applicable
Detailed instructions for collection and shipment of plasma PK samples will be provided in 
the Laboratory Manual. Samples for PK assessments will be labeled by personnel from the
institution with the participants’ study ID; the participants’ identity will not be made known 
to employees from the Sponsor, additional collaborators, or other Investigators. Samples will 
only be used for the purposes of the protocol and will only be used by the Sponsor’s 
personnel or by an external laboratory chosen by the Sponsor to outsource the analyses 
according to internal guidelines. Samples will be kept until all protocol-related analyses are 
completed, for a period not exceeding 10 years or as required by local law.
5.5
Other Assessments
A single blood sample will be collected from all participants for detecting polymorphism of
CYP2D6. The goal will be to explore the impact of these variants on study endpoints as well 
as on PK. This may only be explored for participants enrolled before Amendment 7.
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5.6
Additional Tests
No longer applicable with the adoption of Amendment 7.
5.7
Home Blood Glucose Monitoring
At home, fasting glucose measurements may be performed as necessary in case of symptoms
or as determined by the investigator.
5.8
Schedule of Events
5.8.1
Cohorts 1, 2, and 3
Table 3 is intended as a list of visits and associated assessments. Please refer to relevant 
protocol sections for detailed information.
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Table 3
Schedule of Events Part B Cohorts 1, 2 and 3
Phase
Screening
Treatment (Year 1) 1
Treatment (Years 2-4)
Follow-Up
Tests & Procedures /
Visit Name
Screening
C1D1
C1D15 C4D15
C2, C3, C5, C9, 
C11,
C4D1
C7, C13
C16, C19, C22, C25, 
C28, C31, C34, C37, 
C40, C43, C46
EOT (C48)
30-day 
Safety 
Follow-up
Window (days)
-14 to 0
-1 to 0
± 3
± 5
± 5
± 5
Within 7 days
30+
Days
Written informed consent
X
Medical history
X
Physical examination
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Calculate BSA / dose
X
X
X
X
X
Dose increase to 25 mg/m2
X
12-lead ECG
X
X
X
X
X
Fasting clinical blood tests
X
X
X
X
X
X
X
Insulin/glucose blood tests
X
X
X (C19, C25, C37)
X
Urinalysis
X
X
X
X
X
X
X
Serum pregnancy test (if 
applicable)
X
X
X
Dispense study medication 2
X
X
X
X
X
Collect and count returned 
miransertib capsules
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
BSA=body surface area; C=cycle; D=day; ECG=electrocardiogram; EOT=end of treatment.
1
The following CXDX visit assessments may be performed within a 24-hour window of dosing (Physical Examination, ECG)
2
Dispense monthly allotments at C1, C2, C3, C4; 2-month allotments at C5, C7, C9, C11; 3-month allotments at C13, C16, C19, C22, C25, C28, C31, C34, C37, C40, C43;
2-month allotment at C46
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5.8.2
Cohort 4
Table 4 is intended as a list of visits and associated assessments. Please refer to relevant protocol sections for detailed information.
Table 4
Schedule of Events Part B Cohort 4
Phase
Screening
Treatment (year 1)
Treatment (years 2-4)
Follow-Up
Tests & Procedures /
Visit Name
Screening
C1
C4
C7, C10, C13
C16, C19, C22, C25, C28, C31, 
C34, C37, C40, C43, C46
EOT (C48)
30-day 
Safety 
Follow-up
Window (days)
-14 to 0
-1 to 0
± 5
± 5
± 5
Within 7 days
30+ Days
Written informed consent
X
Medical history
X
Physical examination
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
Calculate BSA / dose
X
X
X
X
12-Lead ECG
X
X
X
X
Fasting clinical blood tests
X
X
X
X
X
X
Insulin/glucose blood tests
X
X
X (C19, C25, C37)
X
Urinalysis
X
X
X
X
X
X
Serum pregnancy test (if applicable)
X
X
X
Tissue biopsy
X
Blood for CYP2D6
X
Lesion measurement by imaging (e.g. DXA)
X
Dispense miransertib1
X
X
X
X
Collect and count returned miransertib capsules
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
BSA=body surface area; C=cycle; DXA=dual-energy X-ray absorptiometry ECG=electrocardiogram; EOT=end of treatment.
1
Dispense 3-month allotments from C1 through C43; dispense 2-month allotment at C46.
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6
TREATMENT
6.1
Miransertib
Miransertib capsules will be supplied to the pharmacy at the clinical site in bottles containing 
30 capsules each. Study medication will be labeled as an investigational agent, limited by 
federal and other applicable laws, as required. The appropriate number of bottles will be 
dispensed to the participantto ensure that they have sufficient drug at the prescribed dose 
level until their next drug dispensing visit. Miransertib should be stored according to the 
instructions provided on the bottle label.
6.2
Miransertib Accountability
The Sponsor will provide all study medication required for completion of this study. The 
recipient will acknowledge receipt of the drug indicating shipment content and condition.
Damaged supplies will be replaced. Until dispensed to the participants, the study medication
will be stored in a secure locked area, accessible to authorized personnel only. Drug 
accountability records will be maintained. The clinical site’s pharmacy records should record 
quantities of study medication received and quantities dispensed to participants, including the 
lot number, date received and dispensed, participant identifier number, participant initials 
(when applicable), protocol number, dose, quantity returned, balance remaining, and the 
initials of the person dispensing the drug. Accurate records of all study medication dispensed
from and returned to the clinical site are to be maintained. The clinical site must supply a 
copy of their drug destruction policy to the Sponsor before authorization for destruction will 
be granted. Product accountability will be monitored throughout the study. On completion or 
termination of the study, and after inventory by the Sponsor’s monitor or designee, all 
unopened drug is to be returned to the Sponsor or designee in the original containers.
6.3
Miransertib Administration
In Part A, the first 6 participants (all with PROS) were enrolled in the dose escalation cohort 
and treated at 15 mg/m2 qd for 3 cycles, with a cycle defined as 28 days. They were allowed 
to have 2 dose escalations (25 mg/m2, 35 mg/m2 qd). Only the first participant had the dose
increased to 35 mg/m2. Subsequently, based on nonclinical and clinical data from the NHGRI,
and data from the 6 participants in this study, 15 mg/m2 qd for at least 3 cycles with an option 
to dose increaseto 25 mg/m2 was determined to be safe. All subsequently enrolled 
participants received miransertib at 15 mg/m2, with a dose increase to 25 mg/m2 permitted 
after either 3 or 6 cycles oftherapy.
For Part B (Cohorts 1, 2, and 3), participants will receive miransertib at the starting dose of 
15 mg/m2 qd for the first 3 cycles, (a cycle of therapy is 28 days), and then the dose will be 
increased to 25 mg/m2 qd, provided no clinically significant drug-related toxicity is observed.
Participants in Cohort 4 receiving miransertib at the time of enrollment under Compassionate 
Use/Expanded Access will continue with their current dose, but their dose should not exceed 
25 mg/m2. Participants who previously received miransertib but were not on the study 
medication at the time of enrollment, will receive miransertib at the starting dose of 
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15 mg/m2 qd for the first 3 cycles with a potential dose increase to 25 mg/m2 qd, provided no 
clinically significant drug-related toxicity is observed. Actual dose will be calculated using 
BSA, per the DuBois formula.
Miransertib will be supplied as 5 and 10-mg capsules, which should be taken either 1 hour 
before or 2 hours after a meal. Capsules should be swallowed whole. The preferred beverage 
for administration is water. However, in cases where there is a medical problem affecting the
participant’s ability to swallow (eg, the participant has an enlarged tongue), the capsules can 
be opened, and the powder contents sprinkled onto a small amount of sweetened semiliquid 
food (eg, apple sauce, chocolate syrup, or ice cream) and administered in its entirety to the
participant. The same type of semiliquid food should be used, if possible, for the duration of
the study. Refer to the Pharmacy Manual for specific instructions on opening the capsules.
To maximize safety and avoid unnecessary exposure to the drug by caregivers, it is 
recommended that gloves and a facemask be worn by the caregiver when handling opened 
capsules and that the gloves and facemask are discarded along with the empty capsule shells 
after use. Pregnant women should not open the capsules.
Miransertib will be administered once daily. Dose will be calculated based on BSA, and
actual dose level will be rounded to the nearest 5 mg using a dosing nomogram 
(Appendix 2). Miransertib will be capped at a BSA >1.77 m2. During site visits, miransertib
dosing will be adjusted for changes in BSA according to the dosing nomogram.
Participants and/or their guardians must use the diary card provided to keep a record of daily
intake of each dose of miransertib and the method of administration (capsules swallowed 
whole or opened and swallowed with semiliquid).
6.4
Missed or Vomited Doses
A missed or vomited dose should not be replaced. The participant will be instructed to take 
the next scheduled dose at the regularly scheduled time.
6.5
Dose Modifications
When a drug-related toxicity is observed, dose interruptions and/or reductions in miransertib
administration are allowed. In general, once the dose of miransertib has been modified for a
participant, all subsequent doses should be administered to that participant at the modified 
dose level. A drug-related toxicity is any toxicity considered related, probably related, or 
possibly related to miransertib.
Dose reduction should occur according to Table 5. Guidelines for dose interruptions for drug-
related toxicities and hyperglycemia are detailed in Table 6 and Table 7, respectively.
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Table 5
Miransertib Dose Reduction Schedule
Administered Dose
Dose Reduction
25 mg/m2 qd:
15 mg/m2 qd
10 mg/m2 qd
5 mg/m2 qd
15 mg/m2 qd (during first 3 cycles)
10 mg/m2 qd
5 mg/m2 qd
qd=once per day
Dose reduction is allowed and should be performed per Table 5. If the dose reduction is 
indicated, the participant should be assigned to the lower dose and it should be agreed on by 
the investigator and the Sponsor. Dose re-escalation will not be permitted.
Treatment will be permanently discontinued in case of Grade 2 drug-related toxicity that 
doesnot recover within 21 days after holding miransertib, or Grade 3 drug-related toxicity at
the lowest dose (5 mg/m2), or if another discontinuation criterion listed in the protocol is met.
Table 6
Dose Interruptions/Reductions for Drug-Related Toxicity Except 
Hyperglycemia
Event Grade 
(CTCAE)
Action
Grade 1
Continue current dose level.
Grade 2
Withhold miransertib until recovery to Grade 1 or baseline. If recovery 
occurs within 21 days of holding miransertib, restart miransertib at the same 
dose level, unless further dose reduction is required.
If a participant experienced a Grade 2 drug-related toxicity that does not 
recover within 21 days of holding miransertib at a higher dose level 
(25 mg/m2 or 15 mg/m2), they will be allowed to reduce the dose to the next 
lower level once the event has recovered to Grade 1 or baseline.
Grade 3-4
Withhold miransertib until recovery to Grade 1 or baseline. If recovery 
occurs within 21 days of holding miransertib, restart miransertib at the next 
lower dose level for subsequent doses, unless further dose reduction is 
required.
If recovery occurs after more than 21 days on drug hold, permanently 
discontinue miransertib.
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Table 7
Dose Modification for Drug-Related Hyperglycemia and Suggested 
Clinical Treatment and Management of Hyperglycemia
Event Grade 
(CTCAE)
Miransertib Dose Modification
Suggested Clinical Treatment 
and Management of 
Hyperglycemia
Grade 1
Continue treatment with the current dose 
level and schedule.
Start once per day home glucose 
monitoring (alternate between 
before breakfast and dinner, 
preferably fasting). No treatment 
needed.
Grade 2
Withhold miransertib until recovery to 
Grade 1 or baseline.
If recovery occurs within 21 days of 
holding miransertib, restart miransertib
at the next lower dose level for 
subsequent doses, unless further dose 
reduction is required.
If recovery does not occur within 
21 days of drug hold at the lowest dose 
permanently discontinue miransertib.
Start home glucose monitoring 
twice per day (before breakfast and 
dinner, preferably fasting).
Treat hyperglycemia per the 
institutional standard of care.
Grade 3 or 4
Withhold miransertib until recovery to 
Grade 1 or baseline. If recovery occurs 
within 21 days of holding miransertib, 
restart miransertib at the next lower dose 
level for subsequent doses, unless 
further dose reduction is required.
If recovery does not occur within 
21 days of drug hold, permanently 
discontinue miransertib.
Treat hyperglycemia per the 
institutional standard of care.
6.6
Treatment Compliance
A participant is considered compliant with the study protocol when study medication is 
administered at a compliance level of ≥80% (excluding dose holds for surgical operations or 
drug-related AEs).
Compliance will be calculated using the following equation:
([Number of capsules ingested] / [Number of capsules that should have been ingested]) 
*100%
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6.7
Blinding
This is an open-label study. Neither the participant nor the investigator or site staff will be 
blinded to the treatment administered.
6.8
Concomitant Medication and Procedures
6.8.1
Permitted Treatment
The following treatments are permitted while on study:
•
Standard therapies, including sclerotherapy, for concurrent medical conditions
•
Oral hypoglycemic treatment or insulin for elevated blood glucose
•
Topical or low dose systemic steroid treatment
•
High dose steroid treatment is permitted when used intermittently for acute 
exacerbation of disease
•
Factor Xa inhibitors (fondaparinux, rivaroxaban, apixaban, and edoxaban) are 
preferred to warfarin if anticoagulation therapy is needed
•
Surgical procedures are allowed, provided that in the opinion of the investigator, the 
participant does not meet criteria for treatment discontinuation
•
A minor surgical operation or procedure generally does not require extensive
resection (eg, biopsy, tooth extraction, etc.) and hospitalization (eg, day 
surgical operation), presents low risk of complications, and may not require 
treatment interruption. If drug hold is required, the investigator and the Sponsor
should discuss the duration of drug hold before and after the surgical 
operation.
•
A major surgical operation requires a more extensive resection (eg, 
appendectomy, tumor excision), prolonged hospitalization with higher risk of 
complications, and treatment interruption for at least 2 weeks before and 
1 week after the surgical operation. If a surgery is required, the investigator 
and the Sponsor should discuss the duration of drug hold before and after the 
surgical operation.
6.8.2
Prohibited Treatment
The following treatments are prohibited while on study:
•
Other investigational agents
•
Inhibitors of the mTOR pathway (eg, sirolimus, everolimus)
•
Immunosuppressive therapies
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•
Continuous high dose steroids
6.8.3
Medications to be Avoided While on Study
Miransertib is metabolized by CYP2D6, CYP2C9, and CYP3A4. Additionally, miransertib
has been shown to inhibit CYP2C19, CYP2C9, and CYP2D6 with IC50 values of 4.0, 3.0, 
and 10.2 µM, respectively.
A preliminary assessment of the effect of CYP450 inhibitors on miransertib exposure was 
performed using available data from the ARQ 092-101 clinical study. A subset of 
32 participants with normal CYP2D6 expression who received doses of miransertib ranging 
from 10 mg qd to 270 mg qd-qow were evaluated. The majority of these participants (28/32) 
were taking one or more known CYP450 inhibitors (2D6, 3A4, 2C19, 2C9) concurrently 
with miransertib. The average AUC0-24 divided by dose for participants taking CYP 
inhibitors (17/32 2D6, 21/32 3A4, 13/32 2C19, and 12/32 2C9) was within 30% of the AUC0-
24 of all participants regardless of inhibitor combination, with the lowest average AUC0-24
observed in participants taking no known inhibitors (4/32). Moreover, AEs known to be 
associated with miransertib such as hyperglycemia and rash were not observed more 
frequently in any subgroup. However, this analysis was conducted on a limited sample of 
participants, and to date, no formal DDI studies have been performed for miransertib.
Therefore, the following strong CYP inhibitors, inducers, and substrates are not permitted 
during the study:
•
Strong CYP2D6 inhibitors and inducers
•
Strong CYP3A4 inhibitors and inducers
•
Strong CYP2C9 inhibitors and inducers
•
Strong CYP2C19 substrates and inducers
•
Grapefruit juice
See Appendix 3 for details.
6.8.4
Potential of Drug-Drug Interaction When Miransertib and Warfarin Are 
Coadministered
Warfarin is the standard treatment for participants at risk for developing DVT or PE. To date, 
no formal clinical studies have been conducted to assess the potential for DDI of miransertib
with warfarin. Hence, the following assessment is based on in vitro CYP450 studies with 
miransertib, clinical experience of miransertib (monotherapy) in Phase 1 oncology studies, 
and literature data available for warfarin.
Miransertib is metabolized by CYP2D6, CYP2C9, and CYP3A4. Additionally, miransertib
has been shown to inhibit CYP2C19, CYP2C9, and CYP2D6 with IC50 values of 4.0, 3.0, 
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and 10.2 µM, respectively. Warfarin is also metabolized by CYP2C9, CYP3A4, and
CYP1A2.
Because both agents are metabolized by CYP2C9 and CYP3A4, and miransertib is a 
moderate to strong inhibitor of CYP2C9, the continued use of warfarin for participants taking 
miransertib is not recommended. Also, sensitive substrates for CYP2C19 should be avoided 
or used with caution. See Appendix 3 for details.
For participants who show a clinical need for an antithrombolic agent, there are alternative 
therapies that do not have a high DDI risk based on CYP metabolism. Possible options 
include thrombin inhibitors such as argatroban that is minimally involved in CYP3A4/5 
metabolism (in vitro) or dabigatran (not metabolized by any CYP450 enzymes). Dabigatran 
is a P-glycoprotein 1 (P-gp) substrate/inhibitor (Appendix 4); it should be noted that while
miransertib is not a P-gp substrate, it has not been tested in P-gp inhibition studies.
6.9
Potential Risks
Based on data from oncology and nononcology clinical studies, participants should be 
monitored for signs and symptoms of hyperglycemia, skin toxicities (rash maculopapular, 
rash, pruritus, dermatitis, etc.), stomatitis/mucosal inflammation, transaminase (ALT and 
AST) elevation, and diarrhea. These potential risks are generally consistent with the 
PI3K/AKT/mTOR pathway inhibitor class. The current safety information for miransertib
can be found in the IB.
Also, based on nonclinical data it has been suggested that miransertib may cause a phototoxic 
reaction in some participants exposed to the drug and sunlight. The amount of miransertib
that may be required to cause such reaction is unknown. All participants should be instructed
to avoid exposure to sunlight, to use sunscreen to protect exposed areas of the body (eg, 
forehead, nose, lips, and hands), and to report symptoms that may be associated with 
phototoxic reaction (eg, redness, pruritus, swelling, blister formation).
There can be other drug-related risks factors that have not yet been reported.
7
SAFETY ASSESSMENTS
Adverse events will be assessed throughout study and categorized by the current version of 
CTCAE. Participants will be evaluated according to the Schedule of Events in Table 3 and 
Table 4. If clinically indicated, unscheduled laboratory tests and any clinical assessments or 
evaluations may be performed per the discretion of the investigator.
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7.1
Definitions
7.1.1
Adverse Event
AE means any untoward medical occurrence associated with the use of a drug in humans,
whether 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.
7.1.2
Adverse Reaction
An adverse reaction is defined as any event for which there is a reasonable possibility that the
drug caused the event.
7.1.3
Suspect Adverse Reaction
A suspected adverse reaction is defined as any AE for which there is a reasonable possibility 
that the drug caused the AE. Reasonable possibility means that there is evidence to suggest a 
causal relationship between the drug and the AE. Suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any AE caused by a 
drug.
7.1.4
Unexpected
An AE or SAR is considered “unexpected” if it is not listed in the IB or is not listed at the 
specificity or severity that has been observed. “Unexpected” also refers to AEs or SARs that
are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug but are not specifically mentioned as occurring with 
the particular drug under investigation.
7.1.5
Serious
An AE or SAR is considered “serious” (an SAE) if, in the view of either the investigator or
Sponsor, it results in any of the following outcomes: death, a life-threatening AE, in-patient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be
life-threatening, or require hospitalization may be considered serious when, based on 
appropriate medical judgment, they may jeopardize the participant and may require medical
or surgical intervention to prevent one of the outcomes listed. An AE or SAR is considered
“life-threatening” if, in the view of either the investigator or Sponsor, its occurrence places the 
participant at immediate risk of death.
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7.1.6
Suspected Unexpected Serious Adverse Reaction (SUSAR)
All AEs that are determined by the investigator or by the Sponsor as having a reasonable
suspected causal relationship (possibly, probably, or definitely related) to a study medication
including placebo and that are both unexpected and serious are considered to be SUSAR and 
are subject to expedited regulatory reporting.
7.1.7
Hospitalization
Hospitalization is defined as a hospital admission that lasts more than 24 hours.
7.1.8
Study Medication-related Adverse Event or Serious Adverse Event
Study medication-related AE or SAE is defined as an AE or SAE that is related to the 
treatment with miransertib. A related AE or SAE is any AE or SAE considered related,
probably related, or possibly related to miransertib.
7.1.9
Further Adverse Event and Serious Adverse Event Defining
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified. However, if an observed or reported sign or symptom is not 
considered a component of a specific disease or syndrome by the investigator, it should be
recorded as a separate AE.
Laboratory data are to be collected as stipulated in this protocol. Clinical syndromes 
associated with laboratory abnormalities are to be recorded as appropriate (eg, diabetes 
mellitus instead of hyperglycemia).
Scheduled hospitalizations or elective surgical procedures will not be considered as AEs or
SAEs. Prolongation of a scheduled hospitalization can be considered an SAE.
Complications associated with scheduled procedures are considered AEs or SAEs.
Treatment-emergent AEs, including SAEs are events with the onset or the worsening of the 
severity that occurred at or any time after administration of the first dose and through 90 days
after the administration of the last dose of the study medication.
Any AEs, including SAEs which are observed before administration of the study medication
should be reported as medical history.
7.2
Responsibilities and Procedures
The responsibility for the safety of an individual participant lies in all cases with the
investigator. This includes the timely review of all safety data obtained during the course of 
the study.
An investigator must instruct his/her participants to report any AE and SAEs they experience. 
Investigators must capture, evaluate, and document all AEs and SAEs occurring during a
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participant’s participation in the study, commencing with the first day of treatment and 
including the protocol-defined 30-day post-treatment follow-up period as source documents 
and on designated eCRF pages. These AEs/SAEs must be recorded in the EDC system of this
study.
Investigators should assess AEs at each scheduled and nonscheduled visit, by the use of 
open-ended questioning, physical examination, and review of laboratory results. It is important
to record all AEs and SAEs that result in temporary and permanent discontinuation of study
medication, regardless of severity.
Investigators must report all SAEs, whether they are considered study medication related, to 
the Sponsor or designee within 24 hours from knowledge of the event (see Section 8.4).
In cases of SUSARs, Investigators are responsible for reporting to their local IRB/IEC as
required by regulation; and the Sponsor or designee is responsible for notifying regulatory 
authorities and all relevant Investigators of SUSARs.
7.3
Adverse Event and Serious Adverse Event Criteria
AEs and SAEs are evaluated and graded using current NCI CTCAE guidelines.
7.4
Serious Adverse Event Reporting
In the event of any new SAE occurring during the study, the investigator must notify the
Sponsor or designee within 24 hours of becoming aware of the event by telephone, or by 
email. When an event is reported by telephone, a written report must be sent immediately 
thereafter by email. For names, addresses, telephone numbers for SAE reporting, see 
information included on the SAE Report Form. All written reports should be transmitted 
using the SAE Report Form, which must be completed by the investigator after specific 
completion instructions. The AE section of the eCRF must be completed. Relevant pages 
from the eCRF may be provided in parallel. Additional documents may be provided by the 
investigator, if available (for ex; laboratory results, hospital report, autopsy report). In all 
cases, the information provided on the SAE Report Form must be consistent with the data on 
the event that is recorded in the corresponding sections of the eCRF. The investigator must 
respond to any request for follow-up information or to any question the Sponsor or designee 
may have on the AE within the same timelines as described for initial reports.
The information provided on the SAE Report Form should be as complete as possible but 
contain a minimum of:
•
A short description of the AE (diagnosis) and the reason why the AE was categorized 
as serious
•
Participant identification and treatment (if applicable)
•
Investigator’s name and phone number (if applicable)
•
Name of the suspect medicinal product and dates of administration
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•
Assessment of causality
If all information about the SAE is not yet known, the investigator will be required to report 
any additional information within 24 hours as it becomes available.
All SAEs will be evaluated by the Sponsor’s Medical Monitor or designee. The Sponsor will
make an assessment of the expectedness of an SAE based on the criteria outlined in Section
8.1.4. In the case of a SUSAR, once all of the relevant information is compiled on the event, 
the Sponsor or designee will report the event to all pertinent regulatory authorities having 
jurisdiction over ongoing miransertib studies in an expedited manner (within 7 days or 
15 days of knowledge) and to all Investigators involved in miransertib clinical studies.
The Investigators must in turn notify their governing IRB/IEC as required by regulation.
7.5
Posttreatment Safety Follow-up
In this study, the posttreatment safety follow-up period is defined as 30 days after the last
dose of miransertib. All AEs occurring during the study period from the time of the first dose
to the last day of the 30-day posttreatment follow-up period will be captured.
All participants will be followed for a minimum of 30 days after discontinuation of 
miransertib. All participants should be instructed to report AEs or SAEs occurring during the 
30-day posttreatment safety follow-up period.
Unresolved study medication-related (see Section 8.1.8 for definition) AEs and SAEs at the 
time of treatment discontinuation or new study medication-related AEs and SAEs that occur 
during the 30-day safety follow-up period will be followed until they have, in opinion of the 
Investigator, resolved to baseline, have stabilized, or are deemed to be irreversible.
7.6
Grading of Severity
Each AE or SAE will be graded for severity according to the current NCI CTCAE version. 
The criteria can be found at http://ctep.cancer.gov/reporting/ctc.html.
For AEs not listed in the NCI CTCAE, a similar grading system should be used as follows:
•
Grade 1 Mild AE
•
Grade 2 Moderate AE
•
Grade 3 Severe AE
•
Grade 4 Life-threatening or disabling AE
•
Grade 5 Death related to AE
For AEs that can be described by the NCI CTCAE guidelines, the current NCI CTCAE 
version Grade 4 (life-threatening or disabling AE) is assessed based on unique clinical 
descriptions of severity for each AE and these criteria may be different from those used for 
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the assessment ofAE seriousness. An AE assessed as Grade 4 based on the NCI CTCAE 
Grades may or may not be assessed as serious based on the seriousness criteria.
7.7
Assessment of Causality
The relationship between an AE and miransertib will be determined by the investigator by
his/her clinical judgment and the following definitions:
7.7.1
Related
•
The AE follows a reasonable temporal sequence from study medication
administration and cannot be reasonably explained by the participant’s clinical state 
or other factors (eg, disease under study, concomitant diseases, concomitant
medications).
•
The AE follows a reasonable temporal sequence from study medicationadministration
and is a known reaction to the drug under study or its chemical group or is predicted 
by known pharmacology as a known reaction to agent or chemical group or predicted 
by known pharmacology.
•
A related AE is any AE considered related, probably related, or possibly related to 
miransertib.
7.7.2
Not Related
•
The AE does not follow a reasonable sequence from study product administration or
can be reasonably explained by the participant’s clinical state or other factors (eg,
disease under study, concurrent diseases, and concomitant medications).
8
ASSESSMENT OF RESPONSE
Efficacy assessments are no longer being conducted in this protocol with the adoption of 
Amendment 7. Analyses of previously collected responses may be performed by the Sponsor.
8.1
Measurable Disease
No longer applicable with the adoption of Amendment 7.
8.2
Response Evaluation
No longer applicable with the adoption of Amendment 7.
9
PLANNED STATISTICAL METHODS
9.1
General Considerations
Details of the statistical analyses presented below will be provided in the study’s SAP. The 
SAP will be finalized before database lock. Any changes to the methods described in the plan 
will be described and justifiedin the final clinical study report.
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All data listings, summaries, figures and statistical analyses will be generated using SAS 
version 9.4 or higher. Summaries will be presented by Part (A/B), Cohort (and by dose 
within, Cohort for AEs), and overall. Continuous variables will be summarized by the 
number of nonmissing observations, mean, median, standard deviation, minimum and 
maximum. Categorical variables will be summarized by presenting the frequency and 
percent. Percentages will be based on the number of nonmissing observations or the
participant population unless otherwise specified. For each variable, all categories will be 
shown. Zero frequencies (but not the percent) within a category will be presented.
9.2
Analysis Populations
Safety Population: all patients who have received a dose of study medication.
9.3
Study Endpoints
Under this amendment, 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 based on the 
frequency, duration, and severity of AEs from the first dose of the drug through 90 days after 
the last dose of the drug.
9.3.1
Determination of Sample Size
Part B of this study is designed to determine the efficacy in PROS and PS patients treated 
with a daily dose of miransertib. The primary endpoint for Cohort 1 and Cohort 2 is response
rate as assessed by blinded reviewers (with adjudication) using protocol response criteria. 
Sample size is justified based on the precision of a 95% confidence interval on the response 
rate. To exclude a clinically irrelevant response rate of 5%, the lower limit of the 95% 
confidence interval should be higher than 5%.
•
Cohort 1, PROS: A sample size of n=20 participants will provide a two-sided exact 
Clopper-Pearson 95% confidence interval of (6%, 44%) on an observed response rate of
30%.
•
Cohort 2, PS: A sample size of n=10 participants will provide a two-sided exact Clopper-
Pearson 95% confidence interval of (7%, 65%) on an observed response rate of 30%.
9.3.2
Data Handling Rules for Efficacy Endpoint Analyses
With Amendment 7, efficacy assessments will no longer be collected, and the primary 
objective is the evaluation of safety and tolerability of miransertib. Therefore, data handling 
rules for efficacy endpoint analyses are no longer applicable with the adoption of 
Amendment 7.
9.4
Safety Analysis
All participants who receive at least one dose of study treatment will be evaluated for safety. 
The incidence rates of TEAEs, treatment-related adverse events, and serious adverse events 
(SAEs will be described, as identified with preferred terms and MedDRA system organ class. 
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The frequency of occurrence of overall toxicity, categorized by the maximum toxicity grades 
(severity), will also be described. Listings of laboratory test results and CTCAE grades will 
be generated, and descriptive statistics summarizing the changes in laboratory tests over time 
will be presented.
The safety analyses will be presented by dose and overall using the Safety Population. Safety 
assessments include AEs, 12-lead ECGs, physical examination, clinical laboratory, and home 
fasting glucose measurements.
Adverse events will be graded according to the current version of CTCAE.
Exploratory analyses will also be performed on other safety parameters, as deemed 
appropriate, and within subgroups defined by age, sex, race, mutation status, prior therapies, 
medical history, and other prognostic factors. Exploratory analyses may also be performed on 
previously collected laboratory analytes, including PK samples.
Exposure to study treatment over time will be summarized with time on treatment, total 
amount of administered treatment, dose intensity and relative dose intensity.
9.5
Pharmacokinetic Analysis
Summary statistics for steady-state trough (predose) levels may be computed from previously 
collected samples. PK data may be used in an exposure-response analysis for safety and 
efficacy. Details will be provided in the SAP.
9.6
Data Monitoring Committee
The DMC will monitor patients’ safety by reviewing and evaluating study data, reviewing
study conduct and progress, and making recommendations concerning the continuation, 
modification, or termination of the study. DMC meetings will take place at least 2 times per 
year. There will be a formal charter outlining DMC membership and responsibilities.
10
COMPLIANCE WITH GOOD CLINICAL PRACTICE AND ETHICAL 
CONSIDERATIONS
10.1
Institutional Review Board or Independent Ethics Committee Approval
The protocol, any protocol modifications, the ICF, and, if applicable, permission to use 
private health information must be approved by the investigator’s IRB/IEC before study 
initiation. Documentation of this approval must be provided to the Sponsor or designee and 
made available during an inspection by the FDA or other regulatory agency inspectors. The 
investigator will also provide the Sponsor with the General Assurance Number documenting 
that the IRB/IEC is duly constituted, as well as a list of the names, occupations, and 
affiliations of the members of the IRB/IEC when available.
Before initiating a study, the investigator/Institution should have written and dated 
approval/favorable opinion from the IRB/IEC and where applicable, competent 
authorities/regulatory bodies for the protocol/amendment(s), written ICF, participant
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recruitment procedures (eg, advertisements), and written information to be provided to 
participants.
10.2
Compliance With Good Clinical Practice and Ethical Considerations
This study must be conducted in compliance with IRB/IEC informed consent regulation and 
the ICH GCP guidelines. In addition, all local regulatory requirements will be adhered to, in
particular those affording greater protection to the safety of the study participants.
This study will also be conducted according to the current revision and all subsequent
revisions of the WMA Declaration of Helsinki – Ethical Principles for Medical Research
Involving Human Subjects and with local laws and regulations relevant to the use of new 
therapeutic agents in the country of conduct.
Changes to the protocol will require written IRB/IEC and, where applicable, competent 
authorities/regulatory bodies approval/favorable opinion before implementation, except when
the modification is needed to eliminate an immediate hazard(s) to participants.
10.3
Participant Information and Consent/Assent
The investigator, or designee, is responsible for the content of the ICF and Assent Form, but 
the original and any updated versions must be approved by the Sponsor before submission to 
the IRB/IEC. The ICF and Assent Form should also include any additional information 
required by local laws relating to institutional review.
Before the start of any study-related procedures are undertaken, the investigator or designee 
must obtain written, informed consent and/or assent from each study participant (or his/her 
legal guardian) in accordance with the ICH document “Guidance for Industry – E6 Good 
Clinical Practice: Consolidated Guidance” and country specific regulations (eg, 21 CFR Part 
50). Informed consent/assent will be obtained by discussing with the participant and his/her 
legal guardian the purpose of the study, the risks and benefits, the study procedures, and any 
other information relevant to the participant.
The investigator or designee must explain to the participant and his/her legal guardian that 
for purposes of evaluating the study results, the participant’s private health information 
obtained during the study may be shared with the study Sponsor, regulatory agencies, and 
IRBs/IECs, before enrolling that participant into the study. It is the investigator’s (or 
designee’s) responsibility to obtain permission to use private health information per HIPAA 
or GDPR and/or other applicable laws from each participant or, if appropriate, the 
participant’s legal guardian.
The participant or his/her legal guardian will document his/her informed consent/assent by
signing the current version of the written, IRB/IEC-approved ICF and/or Assent Form. The 
person who conducted the informed consent/assent discussion with the participant and/or 
participant’s legalguardian must also sign the ICF and Assent Form. The participant or 
his/her legal guardian is given a fully executed copy of the ICF and/or Assent Form bearing 
all appropriate signatures; the original(s) must be maintained in the clinical master files at the
site.
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All active participants participating on the protocol must be reconsented each time the 
ICF/Assent Form is updated and re-approved by the IRB/IEC.
11
STUDY MANAGEMENT AND MATERIALS
11.1
Monitoring, Verification of Data, Audit, and Inspection
A Sponsor monitor or designee will periodically visit each clinical study site to discuss the
progress of the clinical study and to review eCRFs and source documents for accuracy of 
data recording, study medication accountability, and correspondence. When requested, the 
investigator must be available to the study monitor for personal, one-to-one consultation.
Periodically, some or all of the facilities used in the study may be reviewed or inspected by 
the IRB/IEC and/or regulatory authorities. An audit or inspection may include, for example, a 
review of all source documents, drug records, and original clinical medical notes.
The investigator is to ensure that the study participants are aware of and consent to the 
review of personal information during the data verification process, as part of the 
monitoring/auditing process conducted by properly authorized agents of the Sponsor or be 
subject to inspection by regulatory authorities. In addition, participation and personal 
information is treated as strictly confidential to the extent of applicable law and is not 
publicly available.
11.2
Data Recording and Retention of Study Data
In compliance with GCP, the medical records/medical notes, and other study-related 
materials should be clearly marked and permit easy identification of participation by an 
individual in a specified clinical study.
The investigator is to record all data with respect to protocol procedures, drug administration, 
laboratory data, safety, and efficacy on the eCRFs.
If the investigator relocates or retires, or otherwise withdraws his/her responsibility for 
maintenance and retention of the master clinical study records, the Sponsor must be notified 
in writing so that adequate provision can be made concerning the study documents.
Study documents should be retained for at least 2 years after the approval of a marketing 
application in an ICH region and until there are no pending or planned marketing 
applications in an ICH region, or until at least 2 years have elapsed since the formal 
discontinuation ofclinical development of miransertib by the Sponsor. The documents should 
be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the Sponsor that it will inform the investigator, in
writing, as to when the retention of these documents is no longer necessary.
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11.3
Electronic Case Report Forms
An EDC system will be used to collect the data in this study. The EDC system provides 
functionality for the clinical sites to enter the data directly into the eCRFs and respond to data 
discrepancies. Once the data are entered, the information is encrypted and transmitted over 
the Internet to a clinical study server where it is electronically reviewed. Any resulting data 
queriesare immediately sent back to the site for resolution. The system automatically keeps a 
full audit trail of all data changes that occur. The clinical team will undertake additional 
manual review of the data, but all resulting data queries or clarifications will be entered into 
the EDC system for resolution. All eCRFs will be completed according to instructions 
provided in the eCRF Completion Guidelines and ICH/GCP guidelines.
11.4
Confidentiality, Publication, and Disclosure Policy
The investigator understands that the Sponsor will use the information developed in the 
clinical study in connection with the development of miransertib. This information may be
disclosed to other clinical Investigators, the FDA, and other government agencies, including 
publication on public websites, such as www.clinicaltrials.gov.
All information disclosed to the investigator by the Sponsor for the purpose of having the 
investigator conduct the clinical study described in this protocol, or information generated by 
the investigator as results in the clinical study shall be treated by the investigator as strictly
confidential. The investigator shall not use such information other than for the purpose of
conducting the clinical study and may not disclose such information to others, except when 
such disclosure is made to colleagues and/or employees who reasonably require the 
information to assist incarrying out the clinical study and who are bound by like-obligations 
of confidentiality. Notwithstanding, the investigator may use or disclose to others any 
information which: (i) was known to the investigator before the date of its disclosure; (ii) is 
now, or becomes in the future, publicly available; or (iii) is lawfully disclosed to the 
investigator on a nonconfidential basis by a third party who is not obligated to the Sponsor or 
any other party to retain such information in confidence.
The Sponsor acknowledges that the investigator has certain professional responsibilities to 
report to the scientific community on findings made in the clinical investigations they 
conduct. The investigator shall have the right to publish the results of research performed 
under this protocol, provided that such publication does not disclose any Confidential 
Information or trade secrets of the Sponsor (other than the data). If the study is conducted as 
part of a multicenter protocol, the investigator agrees not to independently publish the 
findings except as part of an overall multicenter publication, unless specifically approved in 
writing by the Sponsor or unless more than 12 months have elapsed since the last participant
in the study has completed his/her study designed treatment.
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12
REFERENCE LIST
[Bellacosa, A., et al 
2005]
Bellacosa A, Kumar CC, Di Cristofano A, Testa 
JR. Activation of AKT kinases in cancer: 
implications for therapeutic targeting. Adv 
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[Biesecker LG, 
Lindhurst MJ, Yourick 
MR, Dransfield DT 
2014]
Biesecker LG, Lindhurst MJ, Yourick MR, 
Dransfield DT. Inhibition of AKT signaling in 
Proteus and PROS cells: A simple model for 
cancer therapeutics targeting the AKT/PI3K 
pathway. Poster presented at: The American 
Society of Human Genetics Annual Meeting; 
2014 October 18-22;  San Diego, CA USA.
[05GMDH]
[Biesecker, L. 2006]
Biesecker L. The challenges of Proteus 
syndrome: diagnosis and management. Eur J 
Hum Genet. 2006;14:1151-7.
[05NZK2]
[Biesecker, L. G. 2019]
Biesecker LG, Sapp JC. GeneReviews 
[Internet]. Adam MP, Ardinger HH, Pagon RA, 
et al., editors. Seattle (WA): University of 
Washington; c1993-2020. Proteus syndrome; 
2012 Aug 9 [updated 2019 Jan 10; cited 2020 
Dec 18]; 15 p. Available from: 
https://www.ncbi.nlm.nih.gov/books/NBK9949
5/.
[05NZM7]
[Brazil DP, Yang ZZ, 
Hemmings BA 2004]
Brazil DP, Yang ZZ, Hemmings BA. Advances 
in protein kinase B signalling: AKTion on 
multiple fronts. Trends Biochem Sci. 2004 
May;29(5):233-42.
[05FPFQ]
[Engelman JA, Luo J, 
Cantley LC 2006]
Engelman JA, Luo J, Cantley LC. The 
evolution of phosphatidylinositol 3-kinases as 
regulators of growth and metabolism. Nat Rev 
Genet. 2006 Aug;7(8):606-19.
[05FPFW]
[Keppler-Noreuil KM, 
Rios JJ, Parker VE, 
Semple RK, Lindhurst 
MJ 2015]
Keppler-Noreuil KM, Rios JJ, Parker VE, 
Semple RK, Lindhurst MJ, Sapp JC, et al. 
PIK3CA-related overgrowth spectrum (PROS): 
diagnostic and testing eligibility criteria, 
differential diagnosis, and evaluation. Am J 
Med Genet A. 2015 Feb;167A(2):287-95.
[05FPFZ]
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[Keppler-Noreuil, K. 
M., et al 2016]
Keppler-Noreuil KM, Parker VER, Darling TN, 
Martinez-Agosto JA. Somatic overgrowth 
disorders of the PI3K/AKT/mTOR pathway & 
therapeutic strategies. Am J Med Genet C 
Semin Med Genet. 2016;172C:402-21.
[05MQQG]
[Keppler-Noreuil, K. 
M., et al 2019]
Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, 
Darling TN, Burton-Akright J, Bagheri M, et al. 
Pharmacodynamic study of miransertib in 
individuals with Proteus syndrome. Am J Hum 
Genet. 2019 Mar 7;104:484-91.
[05MQP3]
[Khan, K. H., et al 2013]
Khan KH, Yap TA, Yan L, Cunningham D. 
Targeting the PI3K-AKT-mTOR signaling 
network in cancer. Chin J Cancer. 
2013;32(5):253-65.
[05MQQH]
[Lindhurst, M. J., et al 
2011]
Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, 
Finn EM, Peters K, et al. A mosaic activating 
mutation in AKT1 associated with the Proteus 
syndrome. N Engl J Med. 2011 Aug 
18;365(7):611-9.
[05MYY8]
[Lindhurst, M. J., et al 
2015]
Lindhurst MJ, Yourick MR, Yu Y, Savage RE, 
Ferrari D, Biesecker LG. Repression of AKT 
signaling by ARQ 092 in cells and tissues from 
patients with Proteus syndrome. Sci Rep. 2015 
Dec 11;5:17162.
[05MQQJ]
[Loconte DC, Grossi V, 
Bozzao C, Forte G, 
Bagnulo R 2015]
Loconte DC, Grossi V, Bozzao C, Forte G, 
Bagnulo R, Stella A, et al. Molecular and 
Functional Characterization of Three Different 
Postzygotic Mutations in PIK3CA-Related 
Overgrowth Spectrum (PROS) Patients: Effects 
on PI3K/AKT/mTOR Signaling and Sensitivity 
to PIK3 Inhibitors. PLoS One. 2015 Apr 
27;10(4):e0123092.
[05FPG5]
[Martinez-Lopez, A., et 
al 2017]
Martinez-Lopez A, Blasco-Morente G, Perez-
Lopez I, Herrera-Garcia JD, Luque-Valenzuela 
M, Sanchez-Cano D, et al. CLOVES syndrome: 
review of a PIK3CA-related overgrowth 
spectrum (PROS). Clin Genet. 2017;91:14-21.
[05NZMM]
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[Ranieri, C., et al 2018]
Ranieri C, Di Tommaso S, Loconte DC, Grossi 
V, Sanese P, Bagnulo R, et al. In vitro efficacy 
of ARQ 092, an allosteric AKT inhibitor, on 
primary fibroblast cells derived from patients 
with PIK3CA-related overgrowth spectrum 
(PROS). Neurogenetics. 2018;19:77-91.
[05MQQR]
[Yu Y, Savage RE, 
Eathiraj S, Meade J, 
Wick MJ, et al. 2015]
Yu Y, Savage RE, Eathiraj S, Meade J, Wick 
MJ, et al. Targeting AKT1-E17K and the 
PI3K/AKT Pathway with an Allosteric AKT 
Inhibitor, ARQ 092. PLoS One. 2015 Oct 
15;10(10):e0140479.
[05FQ5Q]
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APPENDIX 1
CLINICAL DIAGNOSTIC CRITERIA CLINICAL DIAGNOSTIC 
CRITERIA FOR PROS
Required:
Congenital or Early Childhood Onset
Overgrowth Sporadic and Mosaic (Other terms: Patchy,
Irregular)
Presence of PIK3CA mutation in overgrowth lesion
Features described in either A or B
A.
Spectrum (2 or more)
Overgrowth: Adipose, Muscle, Nerve, Skeletal
Vascular Malformations: Capillary Venous, Arteriovenous
Malformation, Lymphatic
Epidermal Nevus
B.
Isolated Features
Large Isolated Lymphatic Malformation
Isolated Macrodactyly OR Overgrown Splayed Feet/Hands,
Overgrown Limbs
Truncal Adipose Overgrowth
Hemimegalencephaly
Epidermal Nevus
Seborrheic Keratoses
Benign Lichenoid Keratoses
Keppler-Noreuil KM, et al. Am J Med Genet A. 2015 Feb;167A(2):287-95 [Keppler-Noreuil KM, Rios JJ, Parker VE, 
Semple RK, Lindhurst MJ 2015]
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Clinical Diagnostic Criteria for Proteus Syndrome
To make a diagnosis of PS, one must have all the general criteria, and various specific 
criteria
General Criteria
Specific Criteria
All the following:
Either
Mosaic distribution of lesions
Category A or,
Sporadic occurrence
Two from category B or,
Progressive course
Three from category C
Specific criteria categories
Plus AKT1 mutation in overgrowth lesion
Category A.
Category C
Cerebriform connective tissue nevus
1. Dysregulated adipose tissue
Category B.
Either one:
1. Linear epidermal nevus
a) Lipomas
2. Asymmetric, disproportionate 
overgrowth
b) Regional lipohypoplasia
One or more:
2. Vascular malformations
a) Limbs
One or more:
b) Hyperostosis of the skull
a) Capillary malformation
c) Hyperostosis of the external 
auditory canal
b) Venous malformation
d) Megaspondylodysplasia
c) Lymphatic malformation
e) Viscera:
3. Lung cysts
f) Spleen/thymus
4. Facial phenotype (all of the following)
3. Specific tumors before 2nd decade
a) Dolichocephaly
One of the following:
b) Long face
a) Bilateral ovarian cystadenoma
c) Down slanting palpebral fissures and/or 
minor ptosis
b) Parotid monomorphic adenoma
d) Low nasal bridge
e) Wide or anteverted nares
f) Open mouth at rest
Biesecker L. Eur J Hum Genet. 2006 Nov;14(11):1151-7 [Biesecker, L. 2006].
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Definition of the Total Cerebriform Connective Tissue Nevus (CCTN) Lesional Area:

The plantar surface of the foot is defined as CCTN, pre-CCTN and nonaffected 
area. The percentage of the affected area (total CCTN lesional area) is calculated
based on the size of the sole, excluding toes

Total lesional area is defined as the space encompassing CCTN and 
noncerebriform affected area

The CCTN is defined as a nevus with at least 2 gyri and 3 sulci and should 
affect between 10% and 70% of the total surface area of the sole.
The pre-CCTN is defined as an area characterized by a confluent growth with visible papules
and nodules but without typical nevus growths
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APPENDIX 2
DOSING NOMOGRAM
15 mg/m2 Dose Level
BSA range (m2)
0.33-0.49
0.5-
0.82
0.83-
1.16
1.17-
1.49
1.50-
1.83
1.84-
2.16
2.17-
2.49
2.50-
2.83
≥2.84
Target range 
(mg/day)
4.95-7.35
7.5-
12.3
12.45-
17.40
17.55-
22.35
22.50-
27.45
27.60-
32.40
32.55-
37.35
37.50-
42.45
≥42.60
Actual Dose 
(mg qd)
5
10
15
20
25
30
35
40
45
25 mg/m2 Dose Level
BSA range (m2)
0.33-0.49
0.5-0.69
0.70-
0.89
0.90-
1.09
1.1-1.29
1.30-
1.49
1.50-
1.69
≥1.70
Target range 
(mg/day)
8.25-
12.25
12.5-17.25
17.5-
22.25
22.5-
27.25
27.5-
32.25
32.5-
37.25
37.5-
42.25
≥42.5
Actual Dose 
(mg qd)
10
15
20
25
30
35
40
45
Target mg/day range = Desired dose level (eg, 15 mg/m2 or 25 mg/m2) x BSA range(m2)
Actual mg/m2 dose range = Actual dose (mg) / BSA range(m2)
Generally, a child of BSA 0.5 m2 (the average BSA for a 2-year-old child) should receive 1/4 to 1/3 the dose in mg of that 
of an adult of BSA ~ 1.7 m2. Hence, if the adult gets a 40-mg dose, the child should get a 10-mg dose.
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APPENDIX 3
EXAMPLES OF IN VIVO SUBSTRATES, INHIBITORS, AND 
INDUCERS FOR SPECIFIC ENZYMES
CYP
Substrate (sensitive)
Inhibitor (strong)
Inducer (strong)
2D6
atomoxetine, desipramine,
dextromethorphan, eliglustat, 
nortriptyline, tolterodine, 
nebivolol, perphenazine,
venlafaxine
bupropion, fluoxetine, paroxetine,
quinidine, terbinafine
none identified
3A4/
3A5
remifentanil, avanafil, buspirone, 
conivaptan, darifenacin, darunavir, 
ebastine, everolimus, ibrutinib, 
lomitapide, lovastatin, midazolam, 
naloxegol, nisoldipine, saquinavir, 
simvastatin, sirolimus, tacrolimus,
tipranavir, triazolam, vardenafil
boceprevir, cobicistat, conivaptan, 
grapefruit juice, itraconazole, 
ketoconazole, ritonavir, 
clarithromycin, diltiazem, idelalisib,
nefazodone, nelfinavir
carbamazepine,
enzalutamide, mitotane,
phenytoin, rifampin, 
St. John’s wort
2C9
celecoxib
none identified
none identified
2C19
S-mephenytoin, omeprazole
fluconazole, fluoxetine, fluvoxamine, 
ticlopidine
rifampin, ritonavir
2C8
repaglinide
clopidogrel, gemfibrozil
none identified
Source: https://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm093664.htm
(accessed 5 March 2019)
Note: This is not an exhaustive list.
Sensitive substrates are drugs that show an increase in AUC of ≥5-fold with strong index 
inhibitors of a given metabolic pathway in clinical DDI studies.
Strong, moderate, and weak inhibitors are drugs that increase the AUC of sensitive index
substrates of a given metabolic pathway ≥5-fold.
Strong inducers are drugs that decreases the AUC of sensitive index substrates of a given
metabolic pathway by ≥80%.
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APPENDIX 4
EXAMPLES OF IN VIVO SUBSTRATES, INHIBITORS, AND 
INDUCERS OF P-GLYCOPROTEIN
Transporter
Clinical Substrates
Clinical Inhibitors
P-gp (Gene ABCB1)
dabigatran, digoxin, 
fexofenadine
amiodarone, carvedilol, clarithromycin, dronedarone, 
itraconazole, lapatinib, propafenone, quinidine, ranolazine, 
ritonavir, telaprevir, verapamil
Source: Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and 
Labeling Recommendations. 
(http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf) Not 
an exhaustive list. For an updated list, see the following link: 
http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499
htm.
Criteria for selecting clinical substrates for P-gp are those which (1) result in AUC fold-
increase ≥2 with verapamil or quinidine coadministration and (2) in vitro transport by P-gp 
expression systems, but not extensively metabolized.
Criteria for selecting in vivo inhibitors for P-gp are those which (1) AUC fold-increase of 
digoxin ≥2 with coadministration and (2) in vitro inhibitor.
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ANNEX 1
PART A: ELIGIBILITY
Patients (≥2 years old) with PROS or PS with documented PIK3CA or AKT1 somatic 
mutation will be enrolled in this study.
Patient accrual will occur over a period of approximately 30 months.
Patients must meet ALL of the inclusion criteria and NONE of the exclusion criteria to be 
enrolled.
INCLUSION CRITERIA
1. Signed informed consent, and when applicable, signed assent
2. Male or female patients ≥2 years old with BSA of ≥0.33 m2
3. Have a clinical diagnosis of PROS or PS with documented somatic PIK3CA or AKT1
mutations
4. Archival or fresh overgrowth tissue sample available to be shipped to Sponsor or 
designee
5. Have poor prognosis, significant morbidity, and/or progressive disease (eg, worsening of
the disease/increase in number or size of the overgrowth lesions in the last 12 months)
6.
Have measurable disease (at least one overgrowth lesion that can be accurately 
measured in size by imaging and/or linear or circumference measure)
7. Adequate organ function as indicated by the following laboratory values:
a.
Hematological
1. 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
•
>17 years male and female: ≥10.0 g/dL
2. HbA1c: ≤8% (≤64 mmol/mol)
3. ANC: ≥1.5 x 109/L
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4. Platelet count ≥150 x 109/L
b. Hepatic
1. Total bilirubin ≤1.5 x ULN
2. AST and ALT ≤3 x ULN
c.
Renal
3.
Serum creatinine depending on age:
•
2-5 years male and female: maximum 0.50 mg/dL
•
6-10 years male and female: maximum 0.59 mg/dL
•
11-15 years male and female: maximum 1.2 mg/dL
•
>15 years male and female: maximum 1.5 mg/dL
d.
Metabolic (lipids)
1. Cholesterol: ≤400 mg/dL (≤10.34 mmol/L)
2. Triglyceride: ≤500 mg/dL (≤5.7 mmol/L)
8. If a female is of child-bearing potential, documentation of a negative pregnancy test is 
required before enrollment. Sexually active patients (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
9. Ability to complete the QoL questionnaires by the patient or his/hercaregiver
EXCLUSION CRITERIA
1. 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
2. History of significant cardiac disorders:
•
Myocardial infarction or congestive heart failure defined as Class II to IV per the 
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 the current version of the NCI CTCAE) or worse conduction defect (eg, 
right or left bundle branch block).
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3. Major surgical operation, radiotherapy, or immunotherapy within 4 weeks of the first 
dose of miransertib
4. Any experimental systemic therapy for the purpose of treating PROS or PS (eg, 
sirolimus, everolimus, high dose steroids) within 2 weeks of the first dose of miransertib, 
except for patients who were previously or are currently treated with miransertib under a 
Compassionate Use/Expanded Access program
•
Patients, who were previously treated with or currently are receiving miransertib, will 
be enrolled and treated according to the Schedule of Events/Study Visits defined in 
this protocol
5. Intolerance of or severe toxicity attributed to AKT inhibitors (eg, miransertib, uprosertib, 
afuresertib, ipatasertib)
6. Concurrent severe uncontrolled illness not related to PROS or PS
•
Ongoing or active infection
•
Known HIV infection
•
Malabsorption syndrome
•
Psychiatric illness/substance abuse/social situation that would limit compliance with 
study requirements
7. Pregnant or breastfeeding
8. Inability to comply with study evaluations or to follow drug administrationguidelines
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Schedule of Events Part A
This table is intended as a cumulative list of visits and associated assessments.
Phase
Screening
Treatment (Year 1)
Treatment (Years 2-4)
Follow-Up
Tests & Procedures / 
Visit Name
Screening
C1D1
C1D15 
C4D15 
C7D15
C2, C3, C5, C6, 
C8, C9, C11, 
C12
Day 1
C4D1 
C7D1 
C10D1 
C13D1
C16, C19, C22, 
C28, C31, C34, 
C40, C43, C46
Day 1
C25D1 
C37D1
EOT
30-day Safety 
Follow-up
3 Month Follow-up
Window (days)
-14 to 0
-1 to 0
± 3
± 5
± 5
± 5
± 5
Within 7 days
30+ days
±14 days
Written informed 
consent
X
Medical history
X
Physical examination
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
Calculate BSA / dose
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
X
Fasting clinical blood 
tests
X
X
X
X
X
X
X
Insulin/glucose blood 
tests
X
Urinalysis
X
X
X
X
X
X
Serum pregnancy test 
(if applicable)
X
X
X
Disease Measurement
X
X
Dispense miransertib
X
X
X
X
X
Collect and count 
returned miransertib
X
X
X
X
X
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PRODUCT: ARQ 092 / MK-7075
70
PROTOCOL/AMENDMENT NO.: 002-07
05-MAR-2021
Phase
Screening
Treatment (Year 1)
Treatment (Years 2-4)
Follow-Up
Tests & Procedures / 
Visit Name
Screening
C1D1
C1D15 
C4D15 
C7D15
C2, C3, C5, C6, 
C8, C9, C11, 
C12
Day 1
C4D1 
C7D1 
C10D1 
C13D1
C16, C19, C22, 
C28, C31, C34, 
C40, C43, C46
Day 1
C25D1 
C37D1
EOT
30-day Safety 
Follow-up
3 Month Follow-up
Window (days)
-14 to 0
-1 to 0
± 3
± 5
± 5
± 5
± 5
Within 7 days
30+ days
±14 days
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
1 C4D15 visit will only occur if the dose (mg/m2) increases at Cycle 4. C7D15 visit will only occur if the dose (mg/m2) increases at Cycle7.
2 CYP2D6 at C1D15 ONLY. If not collected at C1D15 for previously enrolled participants, it will be collected at the next Cycle visit after reconsenting under the amended 
protocol.
3 ECG and PK are tested at C2D1 for all participants and at C5D1 and C8D1 only if the dose was increased at Cycle 4 and Cycle 7,respectively.
4 Blood for PK ONLY collected at C4D1 and C7D1.
5 Disease Measurement by US, photography and/or video recording only on C4D1 if no dose increase.
6 Dispense 3-cycle supply of drug at C13D1 if participant is continuing beyond the first 12 cycles oftherapy.
7 ECGs will only be performed if clinically indicated or if required per standard ofcare.
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PRODUCT: ARQ 092 / MK-7075
71
PROTOCOL/AMENDMENT NO.: 002-07
05-MAR-2021
Study Visits – Screening Visit, Cycle 1 Day 1, and Cycle 1 Day 15 at 15 mg/m2 Of Miransertib
Screening visit (-14 – 0 days)
Cycle 1 Day 1
(15 mg/m2)
Cycle 1 Day 15 (± 3 days)
(15 mg/m2)
•
Written Informed consent – can be obtained >14 days before
the first dose.
•
Medical history.
•
Physical examination, including skin.
•
Vital signs (height, weight, temperature, blood pressure, 
respiration rate, and heart rate).
•
12-lead ECG.
•
Fasting Clinical Blood Tests Urinalysis.
•
Serum pregnancy test, if applicable.
•
Biopsy of overgrowth tissue to confirm eligibility (if a prior 
biopsy sample is not available to confirm genetic alteration)
or if archival tissue is not available to ship to the Sponsor or 
designee (for previously enrolled participants, it will be 
collected after re consenting under the amended protocol). 
The biopsy can be performed >14 days before the first dose
but must meet the requirements for this protocol.
•
Disease measurement by imaging (eg, MRI, CT, US, 
photography, video recording) and/or by other 
circumference measurements within 28 days before the first 
dose of miransertib.
•
Record concomitant medication.
•
Physical examination, including (If Screening Visit 
was within 3 days of C1D1, physical examination
does not have to be repeated)
•
Vital signs (height, weight, temperature, blood 
pressure, respiration rate, and heart rate)
•
Calculate BSA using the DuBois formula
•
Blood sample for potential biomarkers, including 
fibrinogen and D-dimers
•
Dispense miransertib and administer the first dose 
after all assessments listed above are completed 
(other than postdose blood draws)
•
Record concomitant medication 
•
Assess AEs after the first dose
•
Physical examination, including
skin
•
Vital signs (temperature, blood 
pressure, respiration rate, and heart
rate)
•
Blood sample for insulin/glucose
•
Record concomitant medication
•
Assess AEs
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PRODUCT: ARQ 092 / MK-7075
72
PROTOCOL/AMENDMENT NO.: 002-07
05-MAR-2021
Study Visits – Cycle 2 Day 1 to Cycle 13 Day 1
Cycles 2, 3, 5, 6, 8, 9, 11 and 12 - Day 1 (± 5 days)
(*when dose did not change either at C4 or at C7 
respectively)
Cycles 4 and 10 - Day 1 (± 5 days) 
(C4 dose not changed)
Cycles 7 and 13 - Day 1 (± 5 days) 
(C7 dose not changed)
•
Physical examination, including skin
•
Vital signs (height, weight, temperature, blood 
pressure, respiration rate, and heart rate)
•
Calculate BSA using the DuBois formula
•
12-lead ECG, predose (ONLY Cycle 2 Day 1)
•
Fasting Clinical Blood Tests
•
Where relevant, additional functional test(s) to 
evaluate individual participant disease status –
frequency as per standard of care
•
Dispense miransertib
•
Collect and count returned miransertib
•
Record concomitant medication
•
Assess AEs
•
Physical examination, including skin 
•
Vital signs (height, weight, temperature, blood 
pressure, respiration rate, and heart rate)
•
Calculate BSA using the DuBois formula
•
12-lead ECG, predose
•
Fasting Clinical Blood Tests Urinalysis
•
Fibrinogen and D-dimers
•
Dispense miransertib
•
Collect and count returned miransertib
•
Record concomitant medication 
•
Assess AEs
•
Physical examination, including skin
•
Vital signs (height, weight, temperature, blood 
pressure, respiration rate, and heart rate)
•
Calculate BSA using the DuBois formula
•
12-lead ECG, predose
•
Fasting Clinical Blood Tests Urinalysis
•
Optional lesion biopsy (ONLY Cycle 13)
•
Fibrinogen and D-dimers
•
Where relevant, additional functional test(s) to 
evaluate individual participant disease status –
frequency as per standard of care
•
Dispense miransertib (dispense 3-cycle supply 
at C13 if participant is continuing beyond first 
12 cycles of treatment)
•
Collect and count returned miransertib
•
Record concomitant medication
•
Assess AEs
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PRODUCT: ARQ 092 / MK-7075
73
PROTOCOL/AMENDMENT NO.: 002-07
05-MAR-2021
Study Visits – C4D1, C4D15, C5D1, C7D1, C7D15, and C8D1 When Dose Increased to 25 mg/m2 of Miransertib
Cycles 4 and 7 - Day 1 (± 5 days) 
(dose increase to 25 mg/m2)
Cycles 4 and 7 - Day 15 (± 3 days) (dose 
increase to 25 mg/m2on C4D1 or C7D1 
respectively)
Cycles 5 and 8 - Day 1 (± 5 days) (dose increase 
to 25 mg/m2 on C4D1 or C7D1 respectively)
•
Physical examination, including skin
•
Vital signs (height, weight, temperature, blood pressure, 
respiration rate, and heart rate)
•
Calculate BSA using the DuBois formula
•
12-lead ECG, predose
•
Fasting Clinical Blood Tests
•
Urinalysis
•
Fibrinogen and D-dimers 
•
Where relevant, additional functional test(s) to evaluate 
individual participant disease status – frequency as per
standard of care
•
Dispense miransertib
•
Collect and count returned miransertib
•
Record concomitant medication
•
Assess AEs
•
Physical examination, including skin
•
Vital signs (temperature, blood pressure, 
respiration rate, and heart rate)
•
Blood sample for insulin/glucose
•
Record concomitant medication
•
Assess AEs
•
Physical examination, including skin
•
Vital signs (height, weight, temperature, blood 
pressure, respiration rate, and heart rate)
•
Calculate BSA using the DuBois formula
•
12-lead ECG, predose
•
Fasting Clinical Blood Tests
•
Blood samples for PK
•
Where relevant, additional functional test(s) to 
evaluate individual participant disease status, 
frequency as per standard of care
•
Dispense miransertib
•
Collect and count returned miransertib
•
Record concomitant medication
•
Assess AEs
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PRODUCT: ARQ 092 / MK-7075
74
PROTOCOL/AMENDMENT NO.: 002-07
05-MAR-2021
Study Visits – After 12 Cycles of Treatment
Cycles* 16, 19, 22, 28, 31, 34, 40, 43 and 46 - Day 1
(± 5 days)
Cycles* 25 and 37 - Day 1
(± 5 days)
•
Physical examination, including skin
•
Vital signs (height, weight, temperature, blood pressure, respiration rate, 
and heart rate)
•
Calculate BSA using the DuBois formula
•
12-lead ECG, predose, if clinically indicated or required per standard of 
care
•
Fasting Clinical Blood Tests Urinalysis
•
Urinalysis
•
Dispense miransertib
•
Collect and count returned miransertib
•
Record concomitant medication
•
Assess AEs
•
Physical examination, including skin
•
Vital signs (height, weight, temperature, blood pressure, respiration rate, 
and heart rate)
•
Calculate BSA using the DuBois formula 
•
12-lead ECG, predose
•
Fasting Clinical Blood Tests
•
Urinalysis
•
Dispense miransertib
•
Collect and count returned miransertib
•
Record concomitant medication
•
Assess AEs
*After the initial 12 months of treatment, the participant may continue receiving treatment and will be seen at the study site once every 3 months per the schedule outlined above.
086YC6


PRODUCT: ARQ 092 / MK-7075
75
PROTOCOL/AMENDMENT NO.: 002-07
05-MAR-2021
Study Visits – End of Treatment, 30 Day Safety Follow-Up
End of treatment/EOT*
(within 7 days of decision to permanently discontinue)
30-day Safety Follow-up* (30+ days after last dose)
•
Physical examination, including skin
•
Vital signs (height, weight, temperature, blood pressure, respiration rate, and 
heart rate)
•
12-lead ECG
•
Fasting Clinical Blood Tests Urinalysis
•
Serum pregnancy test, if applicable
•
Collect and count returned miransertib
•
Record concomitant medication
•
Assess AEs
•
Record concomitant medication
•
Assess AEs
* EOT visit, 30-day safety follow-up and 3-cycle safety follow-up assessments to be performed whenever the participant permanently discontinues miransertib (whether during the 
first 12 cycles or after the first 12 cycles)
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PRODUCT: ARQ 092 / MK-7075
76
PROTOCOL/AMENDMENT NO.: 002-07
05-MAR-2021
SPONSOR SIGNATURE
Study Title:
A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects with PIK3CA-
related Overgrowth Spectrum and Proteus Syndrome
Study Number:
ARQ 092-103 / MK-7075-002
This clinical study protocol was subject to critical review and has been approved by the 
Sponsor. The following personnel contributed to writing and/or approving this protocol:
Signed:___________________________________________
Date:______________
Project Director, Merck & Co.
PPD
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PRODUCT: ARQ 092 / MK-7075
77
PROTOCOL/AMENDMENT NO.: 002-07
05-MAR-2021
INVESTIGATOR’S SIGNATURE
Study Title:
A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects with PIK3CA-related Overgrowth 
Spectrum and Proteus Syndrome
Study Number:
ARQ 092-103 / MK-7075-002
I have read the protocol described above. I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.
Signed by:
Printed Name of Investigator
Signature:
Date:
Investigator
DD/MMM/YYYY
086YC6

SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects with
PIK3CA-related Overgrowth Spectrum and Proteus Syndrome
09-May-2022
NCT03094832


Merck & Co., Inc. 
MK-7075-002/ARQ 092-103 
Statistical Analysis Plan 
Amendment 1 
Final Version 2.0 
Issue Date: 09May2022 
Template: WCT-TP-ST-005-005 
Page 1 of 24 
Effective Date: 15-Apr-2016 
Confidential 
Statistical Analysis Plan Amendment 1 
Title: A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects with PIK3CA-related 
Overgrowth Spectrum and Proteus Syndrome 
Protocol Number: MK-7075-002/ARQ 092-103 
Final Version 2.0 
Issue Date: 09May2022 
Previous Versions  
Version 1.0 09Nov2021 
PPD
086YC0


 
 
Merck & Co., Inc. 
 
MK-7075-002/ARQ 092-103 
 
Statistical Analysis Plan 
Amendment 1 
 
Final Version 2.0 
 
Issue Date: 09May2022 
 
Template: WCT-TP-ST-005-005 
 
Page 2 of 24 
Effective Date: 15-Apr-2016 
 
Confidential 
 
 
SAP Amendments before database lock 
 
Version  Issue Date 
Section 
Revision/Addition 
Rationale 
2.0 
xxMay2022 
4.6 
A listing of participants by 
Investigator name and 
treatment 
group 
was 
added. 
Added 
per 
Sponsor’s 
request. 
 
 
 
 
086YC0


 
 
Merck & Co., Inc. 
 
MK-7075-002/ARQ 092-103 
 
Statistical Analysis Plan 
Amendment 1 
 
Final Version 2.0 
 
Issue Date: 09May2022 
 
Template: WCT-TP-ST-005-005 
 
Page 3 of 24 
Effective Date: 15-Apr-2016 
 
Confidential 
 
Table of Contents 
1 
INTRODUCTION ............................................................................................... 5 
2 
STUDY DESIGN ................................................................................................. 5 
2.1 
Study objectives .............................................................................................................. 6 
2.1.1 
Primary Objective ..................................................................................................... 6 
2.2 
Endpoints ........................................................................................................................ 6 
2.2.1 
Part A and Part B Endpoints ...................................................................................... 6 
2.3 
Sample size ...................................................................................................................... 7 
3 
RANDOMIZATION ............................................................................................ 7 
4 
PLANNED ANALYSES ........................................................................................ 8 
4.1 
Analysis Sets .................................................................................................................... 8 
4.1.1 
Screened Population ................................................................................................. 8 
4.1.2 
Safety Population ...................................................................................................... 8 
4.2 
Derived Data ................................................................................................................... 8 
4.2.1 
Race ........................................................................................................................... 8 
4.2.2 
Baseline ..................................................................................................................... 8 
4.2.3 
Duration/Study day/Time ......................................................................................... 9 
4.3 
Conventions for Missing and Partial Dates ..................................................................... 9 
4.3.1 
Missing/Partial Start/Stop Date of Adverse Events and Concomitant Medications 9 
4.3.2 
Missing Last Dates of Study Drug Dosing ................................................................ 10 
4.3.3 
Missing Diagnosis Dates .......................................................................................... 10 
4.3.4 
Exposure to Study Drug .......................................................................................... 11 
4.3.5 
Inexact Values ......................................................................................................... 11 
4.3.6 
Electrocardiogram Data .......................................................................................... 11 
4.3.7 
Unscheduled Visits .................................................................................................. 11 
4.4 
Conventions .................................................................................................................. 11 
4.5 
Decimal Places .............................................................................................................. 12 
4.6 
Disposition .................................................................................................................... 12 
4.7 
Protocol Deviations ....................................................................................................... 13 
4.8 
Baseline Comparability ................................................................................................. 13 
086YC0


Merck & Co., Inc. 
MK-7075-002/ARQ 092-103 
Statistical Analysis Plan 
Amendment 1 
Final Version 2.0 
Issue Date: 09May2022 
Template: WCT-TP-ST-005-005 
Page 4 of 24 
Effective Date: 15-Apr-2016 
Confidential 
4.9 
Demographics ............................................................................................................... 13 
4.10 
Medical History ............................................................................................................. 14 
4.11 
Prior and Concomitant Medications ............................................................................. 14 
4.12 
Exposure to Study Drug ................................................................................................ 15 
4.13 
Treatment Compliance ................................................................................................. 15 
4.14 
Pharmacokinetic Analyses (Part A and B) ..................................................................... 16 
4.15 
Safety Analyses ............................................................................................................. 16 
4.16 
Adverse Events .............................................................................................................. 17 
4.17 
Laboratory Data ............................................................................................................ 18 
4.18 
Vital Signs ...................................................................................................................... 20 
4.19 
Electrocardiogram Data ................................................................................................ 20 
4.20 
Physical Examination .................................................................................................... 21 
5
INTERIM ANALYSIS ......................................................................................... 21
6
DATA MONITORING COMMITTEE ANALYSIS .................................................. 21
7
CHANGES TO PLANNED PROTOCOL ANALYSIS ............................................... 21
8
REFERENCES .................................................................................................. 22
9
APPENDIX 1: CTCAE GRADES FOR SELECT LABORATORY PARAMETERS ......... 23
086YC0


 
 
Merck & Co., Inc. 
 
MK-7075-002/ARQ 092-103 
 
Statistical Analysis Plan 
Amendment 1 
 
Final Version 2.0 
 
Issue Date: 09May2022 
 
Template: WCT-TP-ST-005-005 
 
Page 5 of 24 
Effective Date: 15-Apr-2016 
 
Confidential 
 
1 INTRODUCTION 
This document details the planned statistical analyses for the ArQule, Inc., (a wholly owned 
subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.), protocol “MK-7075-
002/ARQ 092-103” study titled “A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects with 
PIK3CA-related Overgrowth Spectrum and Proteus Syndrome”. 
2  STUDY DESIGN 
This is an open label, multi-center Phase 1/2 study of oral miransertib administered daily to 
patients with phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA)-
related Overgrowth Spectrum (PROS) and Proteus Syndrome (PS). This is a two-part study (Part 
A and Part B) that will be conducted at approximately 20 sites globally.  
Part A includes all participants enrolled in the study prior to Protocol Amendment 6. Part A was 
designed to enroll 25 to 40 participants with PROS and PS. These participants will continue 
treatment according to the schedule of drug administration/assessments they have been on at 
the time of the amendment 6 approval.   
 
Part B includes all participants enrolled under Protocol Amendment 6 or higher. Part B will enroll 
approximately 65 participants with clinical diagnosis of PROS or PS with documented somatic 
PIK3CA or v-Akt murine thymoma viral oncogene homolog (AKT1) mutations. Part B is comprised 
of four cohorts.  
• Cohort 1 will enroll 20 participants with PROS with a measurable lesion by the study-
standardized volumetric magnetic resonance imaging (MRI).  
• Cohort 2 will enroll 10 participants with PS with measurable cerebriform connective tissue 
nevus (CCTN) and pre-CCTN lesional area by the study-standardized photography.  
• Cohort 3 will enroll approximately 25 PROS or PS patients who do not meet the eligibility 
criteria for enrollment in Cohort 1 or Cohort 2.  
• Cohort 4 will enroll participants previously treated with miransertib or currently receiving 
miransertib under Compassionate Use/Expanded Access. 
086YC0


 
 
Merck & Co., Inc. 
 
MK-7075-002/ARQ 092-103 
 
Statistical Analysis Plan 
Amendment 1 
 
Final Version 2.0 
 
Issue Date: 09May2022 
 
Template: WCT-TP-ST-005-005 
 
Page 6 of 24 
Effective Date: 15-Apr-2016 
 
Confidential 
 
Cohorts 1 and 2 were originally designed to determine the response rate of miransertib in a 
selected participant population, as measured by a change in target lesion size from baseline, 
using blinded independent central imaging review: volumetric MRI in PROS or cerebriform 
connective tissue nevus (CCTN) photography in PS. 
 
In Part B (except Cohort 4), participants will receive miransertib at the 15 mg/m2 qd dose level 
during the first 3 cycles (a cycle of therapy is considered to 28 days). The dose will be increased 
to 25 mg/m2 qd provided no clinically significant drug-related toxicity is observed. Participants 
who experienced miransertib-related toxicity or are unable to tolerate study medication during 
the first 3 cycles may be treated at lower doses. 
 
Participants enrolled in Cohort 4 will continue treatment at the dose they were on at the time 
of enrollment, but their dose should not exceed the 25 mg/m2. 
Participants will stay on treatment for up to 48 cycles. 
The study data and endpoints underwent an internal review by the Sponsor in 2020. It was 
concluded that the current data from this study would not be sufficient to establish efficacy for 
either the PROS or PS patients. As a consequence, Protocol Amendment 7 was written to 
remove all efficacy assessments, including the volumetric MRIs for the PROS patients, the CCTN 
photography for the PS patients, as well as to remove the functional assessments, among 
others. 
 
2.1 Study objectives 
2.1.1 
Primary Objective 
The primary study objective for both Part A and Part B is to describe the safety and tolerability 
of miransertib in patients with PROS and PS.  
 
 
2.2 Endpoints 
2.2.1 
Part A and Part B Endpoints 
086YC0


 
 
Merck & Co., Inc. 
 
MK-7075-002/ARQ 092-103 
 
Statistical Analysis Plan 
Amendment 1 
 
Final Version 2.0 
 
Issue Date: 09May2022 
 
Template: WCT-TP-ST-005-005 
 
Page 7 of 24 
Effective Date: 15-Apr-2016 
 
Confidential 
 
Under Protocol 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 based on the 
frequency, duration, and severity of AEs from the first dose of the drug through 90 days after 
the last dose of the drug. 
 
2.3 Sample size 
Part A:   
Enrollment in Part A was stopped upon approval of Protocol Amendment 6. 25 to 40 participants 
were planned to be enrolled. 
Part B: Cohorts 1 and 2 
Part B of this study was originally designed to determine the efficacy in PROS and PS patients 
treated with a daily dose of miransertib. The primary endpoint for Cohort 1 and Cohort 2 was 
response rate as assessed by blinded reviewers (with adjudication) using protocol response 
criteria. The sample size was justified based on the precision of a 95% confidence interval (CI) 
on the response rate. To exclude a clinically irrelevant response rate of 5%, the lower limit of 
the 95% CI should be higher than 5%. 
• Cohort 1, PROS: A sample size of n=20 participants will provide a two-sided exact 
Clopper-Pearson 95% CI of (6%, 44%) on an observed response rate of 30%. 
• Cohort 2, PS: A sample size of n=10 participants will provide a two-sided exact Clopper- 
Pearson 95% CI of (7%, 65%) on an observed response rate of 30%. 
With Protocol Amendment 7, efficacy assessments will no longer be collected, and the primary 
objective of the study is the evaluation of safety and tolerability of miransertib. 
Part B: Cohorts 3 and 4 
Approximately 25 and 10 patients will be enrolled in Cohorts 3 and 4, respectively. 
3 RANDOMIZATION 
This is an open label study, with all participants receiving miransertib, so randomization is not 
applicable. 
086YC0


 
 
Merck & Co., Inc. 
 
MK-7075-002/ARQ 092-103 
 
Statistical Analysis Plan 
Amendment 1 
 
Final Version 2.0 
 
Issue Date: 09May2022 
 
Template: WCT-TP-ST-005-005 
 
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Effective Date: 15-Apr-2016 
 
Confidential 
 
4 PLANNED ANALYSES 
No statistical analysis plan (SAP) prepared in advance of the data can be absolutely definitive and 
the final clinical study report (CSR) may contain additional tables or statistical tests if warranted 
by the data obtained.  The justification for any such additional analyses will be fully documented 
in the final CSR. 
 
4.1 Analysis Sets 
Participants excluded from the analysis sets and the reason for their exclusion will be listed. 
4.1.1 
Screened Population 
The Screened Population includes all participants who were screened and who signed informed 
consent.  
4.1.2 
Safety Population 
The Safety Population includes all participants who received at least one dose of study 
medication. 
4.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
4.2.1 
Race 
Where more than one race category has been selected for a participant, these race categories 
will be combined into a single category labeled “Multiple Race” in the summary tables. The 
listings will reflect the original selected categories.  
4.2.2 
Baseline 
Unless otherwise defined, baseline is defined as the last non-missing value (either scheduled, 
unscheduled or repeat) before the participant receives the first dose of miransertib.  
086YC0


 
 
Merck & Co., Inc. 
 
MK-7075-002/ARQ 092-103 
 
Statistical Analysis Plan 
Amendment 1 
 
Final Version 2.0 
 
Issue Date: 09May2022 
 
Template: WCT-TP-ST-005-005 
 
Page 9 of 24 
Effective Date: 15-Apr-2016 
 
Confidential 
 
4.2.3 
Duration/Study day/Time 
Study day will be calculated as the number of days from first dose of miransertib.  
• date of event – date of first dose of miransertib + 1, for events on or after first dose  
• date of event – date of first dose of miransertib, for events before first dose.   
4.3 Conventions for Missing and Partial Dates 
All rules explained below for partial/missing dates will be followed unless contradicted by any 
other data recorded on the electronic Case Report Form (eCRF). 
All dates presented in the individual participant listings will be as recorded on the eCRF (i.e., not 
completed as per the below rules). 
4.3.1 
Missing/Partial Start/Stop Date of Adverse Events and Concomitant 
Medications 
Missing and partial start and stop date will be imputed for analysis purposes as follows. 
Partial or missing stop date will be imputed as follows: 
If the stop date is completely missing and the event has resolved or the participant has stopped 
taking the concomitant medication, the stop date will be imputed as the date of the participant’s 
last clinic visit in the study. 
• If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the 
date of the participant’s last clinic visit in the study if in the same year. 
• If the month and year are known, the stop date will be imputed as the last day of that 
month unless the stop date corresponds to the same month as the participant’s last clinic 
visit in which case the date of participant’s last clinic visit in the study will be used instead. 
Missing start date will be imputed as follows: 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of study 
drug.  
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• If the stop date occurs before the start of study drug, the start date of the 
event/concomitant medication will be imputed as the participant’s screening date or the 
stop date of the event/concomitant medication whichever the earlier. 
Partial start date (year present, but month and day missing) 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, and the year is the same as the year of first dosing the start date 
will be imputed as “01-Jan” of the same year or the date of the first dose of study drug 
whichever is latest. If the year is different from the year of first dosing “01-Jan” will be 
used. 
• If the stop date occurs before the start of study drug, the start date of the 
event/concomitant medication will be imputed as the “01-Jan” of the same year. 
Partial start date (month and year present, but day missing) 
• If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, the start date will be imputed as the first day of the same month 
and year unless this partial start date is in same month as the first dose of study drug in 
which case the date of first dose of study drug will be used.  
• If the stop date occurs before the start of study drug, the start date will be imputed as the 
first day of the month and year of the partial stop date. 
4.3.2 
Missing Last Dates of Study Drug Dosing 
If the date of last dose of study drug is completely missing, then the date of last dose of study 
drug will be taken for analysis purposes as the date when the participant would have run out of 
study drug assuming full compliance from the date the study drug was last dispensed or the date 
of participant’s last clinic visit in the study or early withdrawal or death whichever the earlier. 
If only the month and year of the last dose was recorded, then the date of last dosing will be 
taken for analysis purposes as the date the participant would have run out of study drug assuming 
full compliance from the date the study drug was last dispensed, the last day of the month of the 
recorded last dose or the date of participant’s last clinic visit in the study or early withdrawal or 
death whichever the earlier. 
4.3.3 
Missing Diagnosis Dates   
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If the month and year are present but the day is missing, the diagnosis date will be set to first day 
of the relevant month. If only the year is recorded the diagnosis date will be set as “01-Jan” for 
that year.  
4.3.4 
Exposure to Study Drug  
Exposure to miransertib will be calculated as follows: date of last dosing minus the first day of 
dosing + 1. The exposure calculation will not take into account breaks in therapy. 
4.3.5 
Inexact Values 
In the case where a laboratory variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value of x will 
be taken for analysis purposes. 
4.3.6 
Electrocardiogram Data 
For electrocardiogram (ECG) data recorded on continuous scales, if more than one value is 
recorded at a time point, the mean value rounded to the integer will be presented. For overall 
interpretation if more than one value is recorded, the most severe (worst case) of the respective 
readings will be taken. 
4.3.7 
Unscheduled Visits 
Only scheduled post-baseline laboratory, vital signs, and ECG values will be tabulated. Post-
baseline repeat/unscheduled assessments will be disregarded, although these post-baseline 
assessments will be listed in the relevant appendices to the CSR.   
4.4 Conventions 
All data listings, summaries, and figures will be generated using SAS version 9.4 or higher1. 
Summaries will be presented by Part (A/B), Cohort (and by dose within Cohort for adverse events 
[AEs]), and overall. Treatment group labels will be displayed as follows:  
Part A 
  
Part B 
  
Overall 
  
Cohort 1 
 
Cohort 2 
  
Cohort 3 
  
Cohort 4 
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Listings will be sorted in the following order: Part, Cohort, participant ID, parameter, and cycle 
unless otherwise stated. 
Continuous variables will be summarized by the number of non-missing observations, mean, 
median, standard deviation, minimum and maximum.  
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the participant population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented.  
4.5 Decimal Places 
Decimal places for derived data described in section 4.2 will be determined by the scale of 
measurement unless otherwise stated. No decimal places will be displayed if the smallest 
calculated value is ≥ 100; 1 decimal place will be displayed when the smallest value is within the 
interval (10, 100), with 10 being inclusive; 2 decimal places will be displayed when the smallest 
value is within (1, 10), with 1 being inclusive; and so on for even smaller scales of measurement.  
Derived data where it is known in advance the result will be an integer for example day, month, 
year, number of days and total scores (for rating scales) will be presented with zero decimal 
places.  
Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the 
minimum and maximum will be displayed to the same number of decimal places as reported in 
the raw data. Percentages will be displayed with one decimal place.  
4.6 Disposition 
Participant disposition will be summarized as follows:  
• The number of participants included in the Screened Population and the Safety 
Population will be summarized by Part, Cohort and overall for the Screened Population.  
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• The number of participants who failed screening and the reasons for failure will be 
tabulated by Part, Cohort and overall for the Screened Population.  
• The number of participants who completed the treatment period, completed the study, 
and who prematurely withdrew along with the reasons for withdrawal will be tabulated 
by Part, Cohort and overall for the Safety Population. Early withdrawals will also be 
summarized by the dose the participant was on at the time of withdrawal. 
• The number of participants who completed each treatment cycle of the study will be 
summarized by Part, Cohort and overall for the Safety Population.  
• A listing of participant disposition will be produced for the Enrolled Population. 
• A listing of participants by Investigator name and treatment group will be produced for 
the Screened Population. 
4.7 Protocol Deviations 
Important protocol deviations and protocol deviations related to COVID-19 will be listed using 
the Safety Population.  
4.8 Baseline Comparability 
Demographics and baseline variables will be summarized by Part, Cohort and overall using the 
Safety Population. 
The comparability of treatment Part and Cohorts with respect to participant demographics and 
baseline characteristics will be assessed in a descriptive manner, but no formal statistical testing 
will be performed.  
 
4.9 Demographics 
The following baseline demographic variables will be summarized using standard continuous or 
categorical variable summaries: age at Informed Consent (years) both continuous and 
categorized as <18 years, ≥18 years), sex, race, ethnicity, height, weight, and body surface area 
(BSA). Additionally, a summary of participant characteristics for disclosure to public databases 
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(gender, race, ethnicity, age) will be produced for the Safety Population. The following age 
categories will be summarized: 
• Newborns (0-27 days) 
• Infants and toddlers (28 days – 23 months) 
• Children (2-11 years) 
• Adolescents (12-17 years) 
• Adults (between 18 and 64 years) 
• From 65 to 84 years 
• 85 years and older 
A listing of baseline demographic variables will be produced for the Safety Population. 
4.10 Medical History 
Previous and ongoing medical history conditions and previous surgical and medical procedures 
reported at screening will be presented together in a single table by Medical Dictionary of 
Regulated Activities (MedDRA) v24.0 primary System Organ Class (SOC) and Preferred Term (PT) 
and summarized by Part, Cohort and overall for the Safety Population. A listing of these data will 
also be produced. 
Baseline disease characteristics related to PROS and PS (life stage overgrowth reported, any 
significant family history, disease diagnosis, and time since diagnosis [years]) will be summarized 
in a separate table and listing using the Safety Population. 
 
The pathological diagnosis (genetic testing results) will be summarized in listing format only using 
the Safety Population. 
 
A listing of all non-drug procedures related to PROS or PS will be produced using the Safety 
Population. 
4.11 Prior and Concomitant Medications 
Separate tabulations will be produced for prior and concomitant medications presented by Part, 
Cohort and overall for the Safety Population. Prior medications are defined as all medications 
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taken within 45 days of the first dose of miransertib. Concomitant medications are defined as 
medications taken on or after the date of first dose of study drug. Concomitant medications will 
be coded using the World Health Organization (WHO) Drug Dictionary, version B3 WHO Drug 
Global – March 2021, and will be summarized using ATC Level 2 and PT.  
A listing of these data will also be produced. 
 
4.12 Exposure to Study Drug 
Duration of exposure is defined as the total number of days of study drug administration, ignoring 
any temporary drug interruption. Duration of exposure will be presented by Part, Cohort, and 
overall for the Safety Population.     
Additionally, the total (cumulative) amount of administered treatment, dose intensity, and 
relative dose intensity will be summarized for the Safety Population. The amount of administered 
treatment will be calculated for each capsule strength as follows: 
• Total amount of 5 mg dose received per cycle = 5 * [(total # of 5 mg capsules dispensed) 
- (total # of 5 mg capsules lost + total # of 5 mg capsules returned) 
• Total amount of 10 mg dose received per cycle = 10 * [(total # of 10 mg capsules 
dispensed) - (total # of 10 mg capsules lost + total # of 10 mg capsules returned) 
The total (cumulative) amount of administered treatment will be calculated as the sum of the 
total amount of 5 mg and 10 mg doses received across all cycles and for the entire study duration. 
Relative dose intensity (expressed in mg/m2) will be summarized using descriptive statistics and 
will present the number and percentage of participants receiving at least one dose at each level 
(i.e., 5 mg/m2 daily, 10 mg/m2 daily, etc.). Dose intensity (expressed in mg) is defined as the total 
dose received, calculated using relative dose intensity and BSA. Total dose received will be 
summarized using descriptive statistics. 
Exposure data will also be listed using the Safety Population. 
4.13 Treatment Compliance 
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A participant is considered compliant with the study protocol when study medication is 
administered at a compliance level of ≥80% (excluding dose holds for surgical operations or drug-
related AEs). Treatment compliance will be calculated overall as follows: 
(Total [cumulative] amount of treatment actually taken [mg])/Total [cumulative] amount of 
treatment that should have been taken [mg]) x 100 
The total (cumulative) amount of treatment actually taken (mg) will be calculated as described in 
Section 4.12. The total (cumulative) amount of treatment that should have been taken (mg) will 
be calculated for each dose strength received as dose strength * (end date at that dose level – 
start date at that dose level) + 1 day, summed across all dosing records available for a participant. 
Compliance will be summarized by Part, Cohort, and overall using the Safety Population. A listing 
of this data will also be provided. 
   
4.14 Pharmacokinetic Analyses (Part A and B) 
Pharmacokinetic analyses will be analyzed and reported in a separate report.  
4.15 Safety Analyses 
All participants who receive at least one dose of study treatment will be evaluated for safety.  
Safety and tolerability will be assessed by clinical review of all relevant parameters including AEs, 
SAEs, 12-lead electrocardiogram (ECGs), physical examination, vital signs, and clinical laboratory 
tests. 
Descriptive summary statistics such as counts and percentages will be provided for safety 
analysis. 
Exploratory analyses will also be performed on other safety parameters, as deemed appropriate, 
within subgroups defined by age at enrollment (<12 years, ≥12 to <18 years, ≥18 years) and 
disease (PROS, PS). Further details regarding these subgroup analyses are provided in the 
following sections. concomitant use of pain relief medications. Age subgroups to be considered 
will be less than 5, 5 to 7; 8 to 11; 12 to 18 subject to number of patients available within each of these 
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groups. Where an age group category has less than 5 patients then this category will  be merged with the 
previous one.  
4.16 Adverse Events 
AEs will be assessed by the frequency, duration and severity from the first dose of miransertib 
through 90 days after the last dose of the drug. Severity of AEs will be assessed by the current 
version of Common Terminology Criteria for Adverse Events (CTCAE). A treatment emergent 
adverse event (TEAE) is defined as follows: 
• Any AE that has an onset on or after the first dose of study drug and before last dose of 
study drug + 90 days. 
• Any pre-existing AE that has worsened in severity on or after the first dose of study drug 
and before the last dose of study drug + 90 days.  
A treatment-related AE (TRAE) is defined as an AE as being related to miransertib.  
The following tables will be presented for AEs: 
• Overall incidence and the number of TEAEs, ≥ grade 3 TEAEs, serious AEs (SAEs), TRAEs, 
serious TRAEs, TEAEs leading to early study withdrawal, and deaths (TEAEs leading to 
death and AEs leading to death). 
• TEAEs by SOC and PT, incidence and number of events 
• TRAEs by SOC and PT, incidence and number of events 
• Serious TEAEs by SOC and PT, incidence and number of events 
• Serious TRAEs by SOC and PT, incidence and number of events 
• Serious TRAEs resulting in death by SOC and PT, incidence and number of events 
• Serious non-TRAEs by SOC and PT, incidence and number of events 
• Non-serious TEAEs by SOC and PT, incidence and number of events 
• Non-serious TEAEs by SOC and PT, incidence >5% in one or more cohorts and number of 
events 
• TEAEs by SOC, PT, and maximum toxicity, incidence 
• TEAEs leading to early study withdrawal by SOC and PT, incidence 
• TEAEs reported in ≥10% of participants by PT, sorted by decreasing incidence of PT 
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• TRAEs reported in ≥10% of participants by PT, sorted by decreasing incidence of PT 
• Serious TEAEs reported in ≥5% of participants by PT, sorted by decreasing incidence of PT 
• All AEs resulting in death by PT, sorted by decreasing incidence of PT 
• Listing of TEAEs 
• Listing of SAEs 
• Listing of TEAEs leading to early study withdrawal 
• Listing of subjects with TEAEs resulting in treatment interruption 
• Listing of subjects with TEAEs resulting in treatment discontinuation 
• Listing of AEs leading to death  
In counting the number of AEs reported, a continuous event (i.e. reported more than once and 
which did not cease), will be counted only once; non-continuous AE reported several times by 
the same subject will be counted as multiple events. 
Additionally, the following tables will be produced by grade (<3, ≥3) and separately by the 
subgroups of age at enrollment (<12 years, ≥12 to <18 years, ≥18 years) and disease (PROS, PS): 
• TEAEs by SOC and PT, incidence and number of events 
• TRAEs by SOC and PT, incidence and number of events; overall and separately by grade 
category (<3, ≥3) 
• Serious TEAEs by SOC and PT, incidence and number of events; overall and separately by 
grade category (<3, ≥3) 
• Serious TRAEs by SOC and PT, incidence and number of events; overall and separately by 
grade category (<3, ≥3) 
• Serious non-TRAEs by SOC and PT, incidence and number of events; overall and separately 
by grade category (<3, ≥3) 
TEAE duration by SOC and PT: 
The duration of each AE for each participant will be calculated in days by subtracting the date of 
the start of the AE from the date of the end of the AE + 1 day. The AE duration will be summarized 
in the AE listings. 
4.17  Laboratory Data 
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Descriptive statistics of the observed values and change from baseline (continuous data) will be 
presented by Part, Cohort,  and treatment cycle for the following laboratory parameters: 
• Hematology: complete blood count (CBC) including hemoglobin, hematocrit, white blood cell 
count with 5-part differential, red blood cell, platelet, and reticulocyte count 
• Hemoglobin A1c (HbA1c) 
• Coagulation tests (screening only): prothrombin time (PT), partial thromboplastin time (PTT), 
international normalized ratio (INR), D-dimer, and fibrinogen  
• Blood chemistry: alkaline phosphatase, bicarbonate, calcium, phosphorus, magnesium, 
albumin, glucose, serum creatinine, and insulin  
• Liver function tests: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
lactate dehydrogenase (LDH), alkaline phosphatase, total and direct bilirubin, uric acid, total 
protein, and blood urea nitrogen (BUN) 
• Electrolytes: sodium, potassium, and chloride  
• Lipids: cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and 
triglycerides 
Each blood chemistry and liver function test parameter will be classed as below, within, or above 
normal range, based on ranges supplied by the laboratory used. Shift tables from baseline to the 
minimum post-baseline value and separately to the maximum post-baseline value will be 
presented by Part, Cohort, and overall. 
The incidence of post-baseline ALT, AST, ALP, and total bilirubin values meeting CTCAE criteria 
will be summarized by Part, Cohort, and overall. Refer to Appendix 1 of this SAP for CTCAE 
definitions for these parameters. Additionally, the incidence of participants meeting Hy’s law 
criteria will be summarized. Hy’s law criteria are defined as follows: 
• ALT ≥5xULN or  
• ALP ≥2xULN or  
• ALT ≥3xULN and total bilirubin ≥2xULN 
For the third criterion which requires both an elevated ALT and elevated total bilirubin value, 
both lab values must be elevated at the same visit in order to be counted. 
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The following laboratory parameters will be listed only: 
• Serum pregnancy test for female patients of childbearing potential, if applicable  
• Routine urinalysis: dipstick and microscopy including protein, glucose, and blood; pH, and 
specific gravity 
A listing of all post-baseline clinically significant ALT, AST, ALP, or total bilirubin measurements, 
defined as measurements meeting ≥CTCAE grade 3 criteria, recorded throughout the treatment 
period will be presented. 
4.18  Vital Signs 
Vital signs will be collected at all treatment cycles. Descriptive statistics for observed values and 
changes from baseline in the following vital signs will be presented by Part, Cohort, overall and 
for each cycle: 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Heart rate (bpm)  
• Respiration rate (breaths/min) 
• Body temperature (degrees Celsius) 
4.19  Electrocardiogram Data 
Descriptive statistics for observed values and changes from baseline in the following ECG 
variables will be tabulated at each follow-up:  
• PR interval (ms) 
• RR interval (ms)  
• QRS duration (ms)   
• QT interval (ms)  
• QTc interval (ms)  
 
Additionally, the overall interpretation (Normal/Abnormal) and corresponding clinical 
significance for the interpretation will be summarized at each visit. All ECG data will be listed. 
 
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4.20  Physical Examination 
All physical examination data will be listed.  
5 INTERIM ANALYSIS 
There will be no interim analysis for this study.   
 
6 DATA MONITORING COMMITTEE ANALYSIS 
The data monitoring committee (DMC) will monitor patients’ safety by reviewing and evaluating 
study data, review study conduct and progress, and making recommendations concerning the 
continuation, modification, or termination of the study. DMC meetings will take place at least 2 
times per year. There will be a formal charter outlining DMC membership and responsibilities.  
A subset of the outputs defined as part of this SAP will form the DMC output reviewed at each 
DMC meeting. 
 
7 CHANGES TO PLANNED PROTOCOL ANALYSIS 
 
General changes: 
Under Protocol Amendment 7, the primary study objective for both Part A and Part B was 
updated to describe the safety and tolerability of miransertib in patients with PROS and PS, and 
further efficacy assessments were removed. Part A was closed to enrollment after the approval 
of Amendment 6. Amendment 7 will complete the final enrollment into the MOSAIC study and 
Compassionate Use/Expanded Access Program. In the future, patients will be transitioned to 
new miransertib programs. 
 
Specific changes: 
Protocol section 6.6 states that study drug compliance is to be calculated using the following 
formula:  
• ([Number of capsules ingested] / [Number of capsules that should have been 
ingested])*100%.  
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Compliance is unable to be calculated using this formula. Subjects have the option of being 
administered capsules as either 5mg or 10mg, and it is not possible to determine from the data 
collected on the eCRF the actual number of capsules that should have been ingested. Because 
of this, an alternative method to calculate compliance has been specified in this SAP. 
 
8 REFERENCES 
1. SAS Institute Inc.  The SAS System, Version 9.4.  Cary, NC, SAS Institute Inc. 2014. 
 
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9 APPENDIX 1: CTCAE GRADES FOR SELECT LABORATORY PARAMETERS 
Parameter 
Unit 
Definition 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT 
U/L 
High 
>ULN-3.0xULN 
if 
baseline was normal; 
1.5-3.0x baseline if 
baseline 
was 
abnormal  
>3.0-5.0x 
ULN 
if 
baseline was normal; 
>3.0-5.0x baseline if 
baseline 
was 
abnormal  
>5.0-20.0xULN if 
baseline 
was 
normal; >5.0-20.0x 
baseline if baseline 
was abnormal  
>20.0xULN if baseline 
was 
normal; 
>20.0x 
baseline if baseline was 
abnormal  
AST 
U/L 
High 
>ULN-3.0xULN 
if 
baseline was normal; 
1.5-3.0x baseline if 
baseline 
was 
abnormal  
>3.0-5.0xULN 
if 
baseline was normal; 
>3.0-5.0x baseline if 
baseline 
was 
abnormal  
>5.0-20.0xULN if 
baseline 
was 
normal; >5.0-20.0x 
baseline if baseline 
was abnormal  
>20.0xULN if baseline 
was 
normal; 
>20.0x 
baseline if baseline was 
abnormal  
Alkaline 
phosphatase 
U/L 
High 
>ULN-2.5xULN 
if 
baseline was normal; 
2.0-2.5x baseline if 
baseline 
was 
abnormal 
>2.5-5.0xULN 
if 
baseline was normal; 
>2.5-5.0x baseline if 
baseline 
was 
abnormal 
>5.0-20.0xULN if 
baseline 
was 
normal; >5.0-20.0x 
baseline if baseline 
was abnormal  
>20.0xULN if baseline 
was 
normal; 
>20.0x 
baseline if baseline was 
abnormal  
Total 
bilirubin 
mg/dL 
High 
>ULN-1.5xULN 
if 
baseline was normal; 
>1.0-1.5x baseline if 
>1.5-3.0xULN 
if 
baseline was normal; 
>1.5-3.0x baseline if 
>3.0-10.0xULN if 
baseline 
was 
normal; >3.0-10.0x 
>10.0xULN if baseline 
was 
normal; 
>10.0x 
baseline if baseline was 
abnormal 
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Parameter 
Unit 
Definition 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
baseline 
was 
abnormal 
baseline 
was 
abnormal 
baseline if baseline 
was abnormal 
ULN=Upper limit of normal 
Values in table are based on CTCAE v5.0. 
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