Clinical trial NCT04979442
Conditions: Dedifferentiated Liposarcoma
Keywords: sarcoma MDM2 pleomorphic liposarcoma
Sponsor: Rain Oncology Inc
Start date: 2021-07-14; Completion date: 2023-10-01
Enrollment: 175 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Randomized, multicenter, open-label, Phase 3 registration study designed to evaluate the safety and efficacy of milademetan compared to trabectedin in patients with unresectable (i.e., where resection is deemed to cause unacceptable morbidity or mortality) or metastatic DD liposarcoma that progressed on 1 or more prior systemic therapies, including at least 1 anthracycline-based therapy.

Detailed description:
Approximately 160 patients will be randomly assigned in a 1:1 ratio to receive milademetan or trabectedin. Randomization will be stratified by the ECOG performance status (0 or 1) and number of prior treatments (≤ 2 or \> 2) for the patient's liposarcoma.

Patients will receive study drug (i.e., milademetan or trabectedin) until reaching unequivocal disease progression (RECIST v.1.1) as determined by the Investigator, experiencing unmanageable toxicity, or until other treatment discontinuation criteria are met. Patients may be treated beyond tumor progression if they are experiencing clinical benefit based on the assessment of the Investigator in discussion with the Medical Monitor. All patients will be followed for documentation of disease progression and survival information (i.e., date and cause of death) and subsequent treatment information (i.e., date/duration of treatment, response, and subsequent disease progression). Long-term follow-up will continue every 12 weeks (± 7 days) until the endpoint of death, the patient is lost to follow-up, or for 24 months following the final dose of study drug, whichever comes first.

Arms: arm 1: 260 mg once daily orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle. arm 2: 1.5 mg/m2 body surface area as a 24-hour IV infusion, every 3 weeks.
Interventions: intervention 1: RAIN-32 intervention 2: Trabectedin
Intervention descriptions: intervention 1: 260 mg once daily orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle intervention 2: 1.5 mg/m2 body surface area as a 24-hour IV infusion, every 3 weeks

Protocol documents:
Prot_000.pdf: 
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STUDY RAIN-3201 
A Randomized Multicenter Phase 3 Study of Milademetan Versus Trabectedin in Patients 
with Dedifferentiated Liposarcoma 
Sponsor: 
Rain Therapeutics, Inc. 
8000 Jarvis Avenue 
Suite 204 
Newark, CA 94560 
USA 
Sponsor Protocol No.: 
RAIN-3201 
U.S. IND No.: 
EudraCT No.: 
2021-001394-23 
Investigational Drug Name: 
Milademetan (RAIN-32) 
Phase: 
3 
Date of Protocol: 
18 March 2022 
Version Number: 
 
Version History/Date: 
 
 
3.1 
 
Original (27 April 2021) 
Version 1.0 (17 May 2021) 
Version 2.0 (20 May 2021) 
Version 2.1 United Kingdom (11 August 2021) 
Version 2.1 Germany (26 August 2021) 
Version 2.1 Spain (01 September 2021) 
Version 3.0 (19 January 2022) 
 
This study will be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), with the Declaration of Helsinki and with other applicable regulatory 
requirements. 
This document contains confidential information of Rain Therapeutics, Inc. 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 


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STATEMENT OF THE SPONSOR 
 
Protocol Title: 
A Randomized Multicenter Phase 3 Study of Milademetan Versus 
Trabectedin in Patients with Dedifferentiated Liposarcoma 
 
This study was designed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and is consistent with GCP and applicable regulatory requirements. 
Foreseeable risks and inconveniences have been weighed against the anticipated benefit for the 
individual study patient and society. Review of the available nonclinical and clinical information 
support this study and the anticipated benefits justify the risks.  
The rights, safety, and well-being of the study patients are the most important consideration. 
While foreseeable risks have been identified, strategies are included to help mitigate both 
anticipated and unanticipated risks.  
This clinical study is scientifically sound, and the study design is clearly described in this 


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PROTOCOL REVISION HISTORY 


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3.0 
 


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3.1 


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SYNOPSIS 
Study Number  
RAIN-3201 
Sponsor  
Rain Therapeutics, Inc. 
Phase  
3 
Study Duration  
Estimated to be 4 Years 
Objectives 
Primary Objective 
The primary objective is to compare progression-free survival (PFS) between the 
milademetan treatment arm and trabectedin control arm, as determined by blinded 
independent central review (BICR), in patients with unresectable or metastatic 
dedifferentiated (DD) liposarcoma, with or without a well-differentiated (WD) 
component, who progressed on 1 or more prior systemic therapies including at least 
1 anthracycline-based therapy. 
Secondary Objectives 
 
To compare the milademetan treatment arm versus the trabectedin control arm 
for the following efficacy measures: 
o 
Overall survival (OS) 
o 
Disease control rate (DCR) by BICR and Investigator assessment 
o 
Objective response rate (ORR) by BICR and Investigator assessment  
o 
Duration of response (DOR) by BICR and Investigator assessment 
o 
PFS by Investigator assessment 
 
To assess the safety profile of milademetan 
 
To evaluate patient-reported outcomes of quality of life 
Study Design  
This is a randomized, multicenter, open-label, Phase 3 registration study designed to 
evaluate the safety and efficacy of milademetan compared to trabectedin in patients 
with unresectable (i.e., where resection is deemed to cause unacceptable morbidity or 
mortality) or metastatic DD liposarcoma that progressed on 1 or more prior systemic 
therapies, including at least 1 anthracycline-based therapy. Trabectedin is the chosen 
active control treatment because it has been approved as a second-line therapy by the 
United States Food and Drug Administration for patients with liposarcoma or 
leiomyosarcoma who received a prior anthracycline-containing regimen. Trabectedin 
was approved for liposarcoma based on improved PFS. In the current study, the 
primary endpoint is to compare PFS, as determined by BICR, between patients 
receiving milademetan versus trabectedin. 
An independent data monitoring committee (IDMC) will review unblinded safety data 
during the course of the study and make recommendations to the Sponsor as applicable 
and outlined in the IDMC charter.  
Approximately 160 patients will be randomly assigned in a 1:1 ratio to receive 
milademetan or trabectedin (Figure S1). Randomization will be stratified by Eastern 
Cooperative Oncology Group (ECOG) performance status (0 or 1) and number of prior 
treatments (≤ 2 or > 2) for the patient’s liposarcoma. 


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Patients will receive study drug (i.e., milademetan or trabectedin) until reaching 
unequivocal disease progression (per Response Evaluation Criteria in Solid Tumors 
[RECIST] version 1.1) as determined by the Investigator, experiencing unmanageable 
toxicity, or until other treatment discontinuation criteria are met. Patients may be 
treated beyond tumor progression if they are experiencing clinical benefit based on the 
assessment of the Investigator in discussion with the Medical Monitor. All patients 
will be followed for documentation of disease progression and survival information 
(i.e., date and cause of death) and subsequent treatment information (i.e., date/duration 
of treatment, response, and subsequent disease progression). Long-term follow-up will 
continue every 12 weeks (± 7 days) until the endpoint of death, the patient is lost to 
follow-up, or for 24 months following the first dose of study drug of the last patient 
enrolled, whichever comes first. 
 
BICR = blinded independent central review; DCR = disease control rate; DD = dedifferentiated; DOR = duration of 
response; HRQoL = health-related quality of life; ORR = objective response rate; OS = overall survival; PFS = progression-
free survival; RECIST = Response Evaluation Criteria in Solid Tumors; WD = well-differentiated 
Intensive ECG and 
PK Evaluation in a 
Subgroup of 
Milademetan-
Treated Patients 
A subset of approximately 25 patients enrolled across several milademetan (RAIN-32) 
studies, including the current study, will undergo intensive ECG and PK evaluation at 
selected study centers. 
Patients in the ECG/PK subgroup must meet the following criteria to participate in the 
additional ECG and PK evaluation (if these criteria are not met patients can still 
participate in the study but will not participate in intensive ECG and PK evaluation): 
 
Has a corrected QT interval (QTc) as calculated according to Fridericia’s 
formula (QTcF) ≤ 450 ms 
 
Does not have atrial fibrillation or atrial flutter 
 
Does not have complete left bundle branch block 
 
Does not have an implanted pacemaker or defibrillator 
 
Does not have a history of Long QT Syndrome, Brugada Syndrome, Wolff 
Parkinson White Syndrome, or aborted sudden cardiac death 
In this subset of patients, PK blood samples will be collected on Cycle 1 Day 1 
(predose and at 1, 2, 3, 4, 6, 8, and 24 hours after dosing) and Cycle 1 Day 3 (predose 
and at 1, 2, 3, 4, 6, 8, and 24 hours after dosing). Patients will wear continuous 12-lead 
Holter recorders from 1 hour before their milademetan dose through 24 hours after 
their dose on Cycle 1 Day 1 and Cycle 1 Day 3. Each ECG will be extracted from a 
supine rest period of at least 10 minutes. The PK samples will be collected 
immediately after the supine rest period.  


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Investigational 
Treatment 
(Milademetan) 
Dose and Mode of Administration: 260 mg once daily (QD) on Days 1 to 3 and 
Days 15 to 17 of each 28-day cycle. 
Reference Therapy 
(Trabectedin) 
Formulation and Packaging: 1 mg sterile lyophilized powder in single-dose glass 
vials. Trabectedin will be procured locally and prepared for intravenous (IV) infusion 
per manufacturer’s instructions. 
Dose and Mode of Administration: Trabectedin administered at 1.5 mg/m2 body 
surface area as a 24-hour IV infusion, every 3 weeks through a central venous line.  
Dose Modification due to Toxicity: Follow dose modification guidelines for 
trabectedin as described in the approved label. 
Eligibility  
Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in the study: 
1. Is a male or female patient ≥ 18 years old 
2. Has a signed and dated informed consent form prior to the start of any study 
specific qualification procedures 
3. Has histologically confirmed DD liposarcoma, with or without a WD 
component (WD/DD liposarcoma), by local pathologic review; central 
pathologic review will also be performed but is not required for inclusion 
 
d 
4. Has documented advanced unresectable (i.e., where resection is deemed to cause 
unacceptable morbidity or mortality) and/or metastatic WD/DD liposarcoma 
5. 
6. 
7. Has resolution of any clinically relevant toxic effects of prior chemotherapy, 
surgery, radiotherapy, or hormonal therapy 
8. Has an ECOG performance status of 0 or 1 
9. Has adequate bone marrow function, defined as: 
a. 
Platelet count ≥ 100 × 109/L 
b. Hemoglobin ≥ 9.0 g/dL 
c. 
Absolute neutrophil count ≥ 1.5 × 109/L 
10. Has adequate renal function, defined as creatinine clearance ≥ 30 mL/min, as 
calculated using the modified Cockcroft-Gault equation (or equivalent 
glomerular filtration rate calculated using the Chronic Kidney Epidemiology 
Collaboration formula) 
11. Has adequate hepatic function, defined as: 
a. 
Alanine aminotransferase and aspartate aminotransferase ≤ 3 × upper limit 
of normal (ULN) if no liver metastases are present; ≤ 5 × ULN if liver 
metastases are present 


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b. Total bilirubin ≤ 1.5 × ULN. Patients with Gilbert’s disease who have 
serum bilirubin level ≤ 3x ULN, may be enrolled 
12. Is willing and able to comply with the protocol requirements 
13. Patients requiring anticoagulation medication should be on a stable regimen, 
defined as at least 4 weeks on the same dose 
14. Patients requiring antihypertensive medication should be on a stable regimen, 
defined as at least 4 weeks on the same dose 
15. If a woman of childbearing potential, must have a negative serum pregnancy test 
at screening and a negative urine pregnancy test on Cycle 1 Day 1 before 
receiving her first dose of study drug or within 72 hours of the first dose of study 
drug  
16. If a male patient, is surgically sterile, willing to use a condom, or remain 
abstinent upon randomization through the Treatment Period and for 5 months 
after the final dose of study drug.  
 
Exclusion Criteria 
A patient who meets any of the following criteria will not be eligible to participate in 
the study: 
1. Has received prior treatment with any mouse double minute 2 (MDM2) inhibitor 
or trabectedin  
2. Has other primary malignancies that have required systemic antineoplastic 
treatment within the previous 2 years, except for localized cancers that have 
apparently been cured (e.g., nonmelanoma skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast) and will not 
interfere with the study outcomes 
3. Has gastrointestinal conditions that could affect the absorption of milademetan, 
in the opinion of the Investigator 
4. Has an uncontrolled infection within the last 7 days from randomization 
requiring IV antibiotics, antivirals, or antifungals 
5. Has known HIV infection or active hepatitis B or C infection 
6. Has untreated brain metastases 


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7. Has not met the minimum washout period before randomization, defined as: 
a. 
Cytochrome P450 (CYP) 3A4 isozyme strong inhibitor: 5 elimination half-
lives of the inhibitor 
b. CYP3A strong or moderate inducers (e.g., St. John’s wort and modafinil): 
4 weeks 
c. 
Systemic anticancer therapy (chemotherapy; small molecules, including 
antibody drug therapy; retinoid therapy; or hormonal therapy) or 
investigational therapy: 3 weeks or 5 half-lives, whichever is shorter 
d. Immunotherapy with checkpoint inhibitor: 4 weeks  
8. Has had major surgery ≤ 3 weeks from randomization 
9. Has had curative-intent radiation therapy ≤ 4 weeks or palliative radiation 
therapy, defined as ≤ 30 Gy in ≤ 10 fractions (e.g., 20 Gy in 5 fractions or 8 Gy 
in 1 fraction) ≤ 2 weeks from randomization 
10. Has uncontrolled or significant cardiovascular disease, including: 
a. QTcF at rest, where the mean QTcF interval is > 480 milliseconds (average 
of triplicate electrocardiograms [ECGs]) 
b. Myocardial infarction within 6 months prior to screening 
c. Uncontrolled angina pectoris within 6 months prior to screening 
d. New York Heart Association Class 3 or 4 congestive heart failure 
e. Uncontrolled hypertension (resting systolic blood pressure > 150 mmHg or 
diastolic blood pressure > 100 mmHg) 
11. Is a female who is pregnant or breastfeeding or intends to become pregnant 
during the study 
12. Has a concomitant medical condition that would interfere with the assessment of 
efficacy or increase the risk of toxicity, in the opinion of the Investigator or 
Sponsor 
Criteria for Efficacy 
Evaluation  
The primary efficacy endpoint is PFS defined as the time from randomization to the 
earliest date of the first objective documentation of radiographic disease progression as 
determined by BICR or death due to any cause. The results of the BICR will  provide 
data for statistical analysis of the primary endpoint of PFS and the secondary endpoints 
of DCR, ORR, and DOR. Investigator’s assessment will also be applied for the 
secondary efficacy endpoints of PFS, DCR, ORR, and DOR. Additional secondary 
efficacy endpoints include OS and health-related quality of life (HRQoL). 
Tumor assessments via imaging (computed tomography scans or magnetic resonance 
imaging) will be performed by both the Investigator and a blinded central review 
committee; the evaluation of tumor response will be based on RECIST version 1.1. 
The primary efficacy endpoint is to compare PFS, as determined by BICR, between 
patients receiving milademetan versus trabectedin. However, the decision to 
discontinue study drug for disease progression will be determined locally by the 
Investigator. 
Tumor response evaluations will be performed at screening; at the end of Week 8, 
Week 16, Week 24, and Week 32; and then every 12 weeks (± 1 week [7 days]) while 
the patient remains on study drug and any other time during the study as clinically 
indicated. In accordance with RECIST version 1.1, response (partial response [PR] and 
complete response [CR]) must be confirmed by a subsequent tumor assessment at least 
4 weeks after the initial observed response. 
The secondary endpoints OS, DCR (BICR and Investigator), ORR (BICR and 
Investigator), and DOR (BICR and Investigator) and PFS by Investigator assessment 
are defined as: 
 
OS: as measured from the date of randomization to the date of death by any 
cause 


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 
DCR: the percentage of patients who achieve CR, PR, or stable disease (SD) for 
≥ 16 weeks 
 
ORR: the percentage of patients who achieve a confirmed CR or PR 
 
DOR: the time from date of first response to date of disease progression or death 
 
PFS: the time from randomization to the earliest date of the first objective 
documentation of radiographic disease progression or death due to any cause 
HRQoL will be evaluated using: 
 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire, Core 30 (QLQ-C30) 
Criteria for PK 
Evaluation 
Exploratory 
Evaluations 
Criteria for Safety 
Evaluation 
Safety assessments include treatment-emergent AEs (TEAEs) (including serious AEs, 
TEAEs leading to discontinuation of study drug, and TEAEs leading to study 
withdrawal); changes in clinical laboratory parameters (hematology, serum chemistry, 
coagulation, and serum and urine pregnancy tests), deaths, vital signs, and ECG 
parameters; physical examination results (including ECOG performance status); and 
use of concomitant medications.  
All AEs will be graded according to NCI CTCAE version 5.0. 
Statistical Methods  


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SCHEDULES OF EVENTS  


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Table 2: 
Blood Sample Collection Schedule for Laboratory Assessments — Milademetan Arm 


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TABLE OF CONTENTS 
Statement of the Sponsor.............................................................................................................. 2 
Protocol Revision History............................................................................................................. 3 
Synopsis .......................................................................................................................................... 8 
Schedules of Events ..................................................................................................................... 16 
Table of Contents ........................................................................................................................ 25 
List of Tables ............................................................................................................................... 29 
List of Figures .............................................................................................................................. 29 
List of Abbreviations .................................................................................................................. 30 
1. 
Introduction ...................................................................................................................... 33 
2. 
Background Information ................................................................................................ 34 
2.1 
Investigational Product: Milademetan ........................................................................... 34 
2.2 
Dedifferentiated Liposarcoma ........................................................................................ 35 
2.3 
Summary of Nonclinical and Clinical Studies Using Milademetan .............................. 36 
2.3.1 
Nonclinical Studies ................................................................................................. 36 
2.3.2 
Clinical Studies ....................................................................................................... 43 
2.4 
Rationale for Selection of the RAIN-3201 Study Population ........................................ 46 
2.5 
Rationale for Dose Selection .......................................................................................... 46 
2.6 
Potential Risks ................................................................................................................ 47 
3. 
Study Objectives and Purpose ........................................................................................ 47 
3.1 
Primary Objective .......................................................................................................... 47 
3.2 
Secondary Objectives ..................................................................................................... 48 
3.3 
Exploratory Objectives ................................................................................................... 48 
4. 
Study Design ..................................................................................................................... 48 
4.1 
Study Design Overview ................................................................................................. 48 
4.2 
Imaging Assessments by Blinded Independent Central Review .................................... 49 
4.2.1 
Intensive Electrocardiogram and Pharmacokinetics Evaluation in a Subgroup of 
Milademetan-Treated Patients ................................................................................ 49 
4.3 
Endpoints and Criteria for Evaluation ............................................................................ 50 
4.3.1 
Primary Endpoint .................................................................................................... 50 
4.3.2 
Secondary Endpoints .............................................................................................. 50 
4.3.3 
Exploratory Endpoints ............................................................................................ 51 


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4.4 
Measures Taken to Minimize/Avoid Bias ...................................................................... 51 
4.5 
Duration of Study Treatment.......................................................................................... 51 
5. 
Selection and Withdrawal of Patients ............................................................................ 51 
5.1 
Inclusion Criteria ............................................................................................................ 51 
5.2 
Exclusion Criteria ........................................................................................................... 53 
5.3 
Study Completion ........................................................................................................... 54 
5.4 
Patient Withdrawal Criteria ............................................................................................ 54 
6. 
Treatment of Patients ...................................................................................................... 56 
6.1 
Patient Enrollment .......................................................................................................... 56 
6.2 
Milademetan Administration ......................................................................................... 57 
6.2.1 
Milademetan Dose Modifications ........................................................................... 57 
6.3 
Trabectedin Administration............................................................................................ 60 
6.3.1 
Trabectedin Dose Calculation ................................................................................. 60 
6.3.2 
Trabectedin Infusion Duration ................................................................................ 60 
6.3.3 
Trabectedin Dose Modifications ............................................................................. 60 
6.4 
Premedication ................................................................................................................. 61 
6.5 
Treatment Beyond Progression ...................................................................................... 61 
6.6 
Compliance..................................................................................................................... 61 
6.7 
Study Visits .................................................................................................................... 62 
6.7.1 
Screening Period/Baseline Assessments ................................................................. 62 
6.7.2 
Treatment Period ..................................................................................................... 63 
6.7.3 
End-of-Treatment Visit ........................................................................................... 64 
6.7.4 
Long-Term Follow-Up............................................................................................ 64 
6.8 
Concomitant Medications and Treatments ..................................................................... 64 
6.8.1 
Prohibited Medications ........................................................................................... 65 
6.8.2 
Concomitant Medications That Should Be Avoided or Used with Caution ........... 65 
7. 
Assessment of Efficacy ..................................................................................................... 66 
7.1 
Primary Efficacy Endpoint ............................................................................................. 66 
7.2 
Secondary Efficacy Endpoints ....................................................................................... 66 
8. 
Assessment of Safety and Exploratory Variables ......................................................... 66 
8.1 
Definitions ...................................................................................................................... 66 
8.1.1 
Adverse Event Definitions ...................................................................................... 66 


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8.2 
Adverse Events Reporting .............................................................................................. 68 
8.2.1 
Adverse Event Collection Period ............................................................................ 68 
8.2.2 
Adverse Event Term ............................................................................................... 68 
8.2.3 
Adverse Event Severity........................................................................................... 68 
8.2.4 
Adverse Event Duration .......................................................................................... 69 
8.2.5 
Adverse Event Causality ......................................................................................... 69 
8.3 
Serious Adverse Events Reporting ................................................................................. 70 
8.4 
8.5 
Reporting Disease Progression and Death ..................................................................... 71 
8.6 
Special Situation Reporting ............................................................................................ 71 
8.7 
Electrocardiogram Monitoring ....................................................................................... 72 
8.7.1 
Subgroup of Patients Undergoing Intensive Electrocardiogram Monitoring at 
Selected Study Centers ........................................................................................... 72 
8.8 
Vital Sign Assessments .................................................................................................. 73 
8.9 
Clinical Laboratory Assessments ................................................................................... 73 
8.10 Contraception and Pregnancy Testing and Reporting .................................................... 74 
8.11 Physical Examinations ................................................................................................... 75 
8.12 Eastern Cooperative Oncology Group ........................................................................... 76 
8.13 Pharmacokinetics ........................................................................................................... 76 
8.13.1 
Subgroup of Patients Undergoing Intensive Pharmacokinetic Assessments at 
Selected Study Centers ........................................................................................... 76 
8.14 Tumor Tissue.................................................................................................................. 77 
8.15 Biomarkers ..................................................................................................................... 77 
9. 
Statistics ............................................................................................................................ 77 
9.1 
Determination of Sample Size........................................................................................ 77 
9.2 
General Considerations .................................................................................................. 78 
9.3 
Patient Disposition ......................................................................................................... 78 
9.3.1 
Disposition of Patients ............................................................................................ 78 
9.3.2 
Protocol Deviations ................................................................................................. 78 
9.3.3 
Analysis Sets ........................................................................................................... 79 
9.4 
Baseline Characteristics and Concomitant Medications ................................................ 79 
9.5 
Prior and Concomitant Medications ............................................................................... 79 
9.6 
Treatment Compliance ................................................................................................... 79 


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9.7 
Efficacy Analyses ........................................................................................................... 79 
9.7.1 
Primary Efficacy Analysis: Progression-Free Survival per Blinded Independent  
Central Review ....................................................................................................... 79 
9.7.2 
Secondary Efficacy Analyses ................................................................................. 79 
9.8 
Safety Analyses .............................................................................................................. 80 
9.9 
Other Analyses ............................................................................................................... 81 
9.9.1 
Pharmacokinetic Analyses ...................................................................................... 81 
9.9.2 
Biomarker Analyses ................................................................................................ 81 
10. 
Quality Control and Quality Assurance ........................................................................ 81 
10.1 Data Quality Assurance .................................................................................................. 81 
10.1.1 
Database Management and Quality Control ........................................................... 81 
11. 
Ethics ................................................................................................................................. 82 
11.1 Informed Consent ........................................................................................................... 82 
11.2 Protocol Approval and Amendment ............................................................................... 82 
11.3 Duration of the Study ..................................................................................................... 83 
11.4 Premature Termination of the Study .............................................................................. 83 
11.5 Confidentiality ................................................................................................................ 83 
12. 
Data Handling and Record Keeping .............................................................................. 84 
12.1 Case Report Forms and Source Documentation ............................................................ 84 
12.1.1 
Data Collection ....................................................................................................... 84 
12.2 Access to Source Data .................................................................................................... 85 
12.3 Data Processing .............................................................................................................. 85 
12.4 Archiving Study Records ............................................................................................... 86 
13. 
Publication Policy............................................................................................................. 86 
14. 
References ......................................................................................................................... 87 
Appendix A: Examples of Prohibited Medications or Concomitant Medications That 
Should Be Avoided or Used with Caution ................................................................................ 88 
Declaration of the Investigator .................................................................................................. 89 
 
 
 


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LIST OF TABLES 
 
LIST OF FIGURES 


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LIST OF ABBREVIATIONS 
Abbreviation or 
Specialist Term 
Definition 
5-AZA 
5-azacitidine 
AE 
Adverse event 
AML 
Acute myeloid leukemia 
ATC 
Anatomical Therapeutic Chemical 
AUC0-24h 
Area under the curve from time 0 to 24 hours after dosing 
BCRP 
Breast cancer resistance protein 
BICR 
Blinded independent central review 
BSA 
Body surface area 
CFU-GM 
Colony-forming unit granulocyte/macrophage 
CFR 
Code of Federal Regulations 
Cmax 
Maximum peak plasma concentration 
COVID-19  
Coronavirus disease 2019  
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DD 
Dedifferentiated 
DDI 
Drug-drug interaction 
DOR 
Duration of response 
EC50 
Half-maximal response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EIU 
Exposure in utero 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
End-of-treatment 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin embedded 
FSH 
Follicle stimulating hormone 
GLP 
Good Laboratory Practice 
HNSTD 
Highest non-severely toxic dose 


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Abbreviation or 
Specialist Term 
Definition 
HRQoL 
Health-related quality of life 
IC50 
50% inhibitory concentration 
IC75 
75% inhibitory concentration 
IC90 
90% inhibitory concentration 
ICH 
International Council for Harmonisation 
IDMC 
Independent data monitoring committee 
IEC 
Independent ethics committee 
IRB 
Institutional review board 
IRR 
Infusion-related reactions 
IV 
Intravenous 
Ki 
Inhibition constant 
MIC-1  
Macrophage inhibitory cytokine 1 
MDM2 
Mouse double minute 2 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger RNA 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NOAEL 
No-observed-adverse-effect level 
NOD SCID 
Nonobese diabetic/severe combined immunodeficiency 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
QD 
Once daily 
QLQ-C30 
Quality of Life Questionnaire, Core 30 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval as calculated according to Fridericia’s 
formula 
QWBA 
Quantitative whole-body autoradiography 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease  


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Abbreviation or 
Specialist Term 
Definition 
TEAE 
Treatment-emergent adverse event 
TP53 
Tumor protein 53 
ULN 
Upper limit of normal 
WD 
Well-differentiated 
WOCBP 
Women of childbearing potential 
WT 
Wild-type 


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1. INTRODUCTION 
Milademetan (RAIN-32) is an orally bioavailable small-molecule inhibitor of mouse double 
minute 2 (MDM2) that disrupts the interactions between MDM2 and the tumor suppressor 
protein p53. Milademetan is currently being developed by Rain Therapeutics, Inc. (hereafter 
referred to as Rain) for the treatment of patients with liposarcoma and advanced/metastatic solid 
tumors with MDM2 gene amplification. Milademetan was initially developed by Daiichi Sankyo 
as an oral oncology therapeutic agent for use alone or in combination with other agents. 
The current study is a randomized, multicenter, open-label, Phase 3 registration study designed 
to evaluate the safety and efficacy of milademetan in patients with unresectable and/or metastatic 
well-differentiated (WD)/dedifferentiated (DD) liposarcoma. Liposarcoma is a malignant life-
threatening mesenchymal tumor accounting for almost 20% of adult mesenchymal tumors. It can 
be found anywhere in the body, but most commonly in the extremities and retroperitoneum; WD 
and DD liposarcomas comprise the largest subgroups (60%-66%) of liposarcomas. 
Milademetan disrupts the MDM2-p53 interaction and prevents excessive degradation of p53, a 
tumor suppressor protein (Noguchi 2019). The mechanism of action is distinct from other 
chemotherapeutic agents that are currently approved for liposarcoma (trabectedin and eribulin). 
Trabectedin (an alkylating agent) and eribulin (a microtubule inhibitor), have received full 
approval from the Food and Drug Administration (FDA) for an indication inclusive of that being 
sought for milademetan (patients with unresectable or metastatic liposarcoma who progressed on 
at least 1 prior systemic therapy including at least 1 anthracycline-containing regimens). Notably, 
no drugs are specifically approved for the WD or DD subtypes of liposarcoma, distinct subtypes 
of liposarcoma with unique molecular features (MDM2 amplification) not prevalent in the other 
subtypes of liposarcoma (myxoid/round cell, and pleomorphic). WD and DD liposarcomas are 
biologically distinct from other subtypes of liposarcoma in that they are characterized by MDM2 
amplification in up to 100% of cases (Abeshouse 2017). 


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2. BACKGROUND INFORMATION  
2.1 
Investigational Product: Milademetan 
Milademetan is provided as 30-mg and 100-mg, immediate-release capsules for oral 
administration. A dosing regimen of 2 capsules of each strength is orally administered to obtain 
total daily dosage of 260 mg QD administered on Days 1 to 3 and Days 15 to 17 of each 28-day 
cycle. 
Information on the milademetan packaging, labeling, accountability, and storage instructions will 
be provided in the Pharmacy Manual.  


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3. STUDY OBJECTIVES AND PURPOSE  
The purpose of this study is to evaluate the safety and efficacy of milademetan compared to 
trabectedin in patients with unresectable or metastatic DD liposarcoma. To be eligible, patients 
must have progressed on 1 or more prior systemic therapies, including at least 
1 anthracycline-based therapy. 
3.1 
Primary Objective 
The primary objective is to compare PFS between the milademetan treatment arm and 
trabectedin control arm, as determined by blinded independent central review (BICR), in patients 
with unresectable or metastatic DD liposarcoma, with or without a WD component, who 
progressed on 1 or more prior systemic therapies including at least 1 anthracycline-based 
therapy. 


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3.2 
Secondary Objectives 
Secondary objectives are: 
 To compare the milademetan treatment arm versus the trabectedin control arm for the 
following efficacy measures: 
o Overall survival (OS) 
o DCR by BICR and Investigator assessment 
o ORR by BICR and Investigator assessment 
o Duration of response (DOR) by BICR and Investigator assessment 
o PFS by Investigator assessment 
 To assess the safety profile of milademetan versus trabectedin 
 To evaluate patient-reported outcomes of quality of life 
4. STUDY DESIGN  
4.1 
Study Design Overview 
This is a randomized, multicenter, open-label, Phase 3 registration study designed to evaluate the 
safety and efficacy of milademetan compared to trabectedin in patients with unresectable 
(i.e., where resection is deemed to cause unacceptable morbidity or mortality) or metastatic DD 
liposarcoma that progressed on 1 or more prior systemic therapies, including at least 1 
anthracycline-based therapy. Trabectedin is the chosen active control treatment because it has 
been approved as a second-line therapy by the US FDA for patients with liposarcoma or 
leiomyosarcoma who received a prior anthracycline-containing regimen. Trabectedin was 
approved for liposarcoma based on improved PFS. In the current study, the primary objective is 
to compare PFS, as determined by BICR, between patients receiving milademetan versus 
trabectedin. 
An independent data monitoring committee (IDMC) will review unblinded safety data during the 
course of the study and make recommendations to the Sponsor as applicable and outlined in the 
IDMC charter.  
Approximately 160 patients will be randomly assigned in a 1:1 ratio to receive milademetan or 
trabectedin. Randomization will be stratified based on Eastern Cooperative Oncology Group 


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(ECOG) performance status (0 or 1) and number of prior therapies (≤ 2 or > 2) for the patient’s 
liposarcoma. 
Patients will receive study drug (i.e., milademetan or trabectedin) until reaching unequivocal 
disease progression (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) as 
determined by the Investigator, experiencing unmanageable toxicity, or until other treatment 
discontinuation criteria are met. Patients may be treated beyond tumor progression if they are 
experiencing clinical benefit based on the assessment of the Investigator in discussion with the 
Medical Monitor. All patients will be followed for documentation of disease progression and 
survival information (i.e., date and cause of death) and subsequent treatment information (i.e., 
date/duration of treatment, response, and subsequent disease progression). Long-term follow-up 
will continue every 12 weeks (± 7 days) until the endpoint of death, the patient is lost to 
follow-up, or for 24 months following the first dose of study drug of the last patient enrolled, 
whichever comes first. 
The study design is illustrated in Figure 5. 
Figure 5: 
RAIN-3201 Study Design Diagram 
 
BICR = blinded independent central review; DCR = disease control rate; DD = dedifferentiated; DOR = duration of response; EU 
= European Union; HRQoL = health-related quality of life; ORR = objective response rate; OS = overall survival; PFS = 
progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; TP53 = tumor protein p53; WD = well-
differentiated 
4.2 
Imaging Assessments by Blinded Independent Central Review 
4.2.1 
Intensive Electrocardiogram and Pharmacokinetics Evaluation in a Subgroup of 
Milademetan-Treated Patients 


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4.3 
Endpoints and Criteria for Evaluation 
4.3.1 
Primary Endpoint 
The primary efficacy endpoint is PFS defined as the time from randomization to the earliest date 
of the first objective documentation of radiographic disease progression as determined by BICR 
or death due to any cause. Tumor response will be assessed in accordance with RECIST 
version 1.1.  
4.3.2 
Secondary Endpoints  
Secondary efficacy endpoints include: 
 OS as measured from the date of randomization to the date of death by any cause 
 DCR defined as the percentage of patients who have achieved CR, PR, or SD for 
≥ 16 weeks by BICR and Investigator assessment 
 ORR defined as the percentage of patients who achieve a confirmed CR or PR by 
BICR and Investigator assessment 
 DOR defined as the time from date of first response to date of disease progression or 
death by BICR and Investigator assessment 
 PFS defined as the time from randomization to the earliest date of the first objective 
documentation of radiographic disease progression or death due to any cause, based 
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Health-related quality of life (HRQoL) endpoints include: 
 European Organisation for Research and Treatment of Cancer (EORTC) Quality of 
Life Questionnaire, Core 30 (QLQ-C30) 
Safety endpoints include the incidence of treatment-emergent AEs (TEAEs) (including SAEs, 
TEAEs leading to discontinuation of study drug, and TEAEs leading to study withdrawal); 
changes in clinical laboratory parameters (hematology, serum chemistry, coagulation, and serum 
and urine pregnancy test), deaths, vital signs, and electrocardiogram (ECG) parameters 
(especially QT intervals); physical examination results (including ECOG performance status); 
and use of concomitant medications. 
4.3.3 
Exploratory Endpoints  
4.4 
Measures Taken to Minimize/Avoid Bias  
If a patient withdraws from the study, the data (including tested and untested samples) collected 
to the point of withdrawal will remain part of the study database and will not be removed.  
Response criteria are based on objective measurements as defined in RECIST version 1.1 by site 
radiologists. All responses will be source verified; copies of tumor assessment scans will be 
collected and provided for evaluation by BICR (Section 4.2).  
Biometrics representatives from the Sponsor team and BICR will remain blinded throughout the 
conduct of the study and described in a separate trial integrity document.  
 
4.5 
Duration of Study Treatment 
Patients will continue to receive study drug (i.e., either milademetan or trabectedin) until 
documented disease progression or unacceptable toxicity. See Section 6.5 for treatment beyond 
progression.  
5. SELECTION AND WITHDRAWAL OF PATIENTS  
5.1 
Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in the study: 
1. Is a male or female patient ≥ 18 years old 
2. Has a signed and dated informed consent form prior to the start of any study-specific 
qualification procedures 


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3. Has histologically confirmed WD/DD liposarcoma, by local pathologic review; central 
pathologic review will also be performed, but is not required for inclusion 
4. Has documented advanced unresectable (i.e., where resection is deemed to cause 
unacceptable morbidity or mortality) and/or metastatic WD/DD liposarcoma 
5. 
6. 
7. Has resolution of any clinically relevant toxic effects of prior chemotherapy, surgery, 
radiotherapy, or hormonal therapy 
8. Has an ECOG performance status of 0 or 1 
9. Has adequate bone marrow function, defined as: 
a. 
Platelet count ≥ 100 × 109/L 
b. 
Hemoglobin ≥ 9.0 g/dL 
c. 
Absolute neutrophil count ≥ 1.5 × 109/L 
10. Has adequate renal function, defined as creatinine clearance ≥ 30 mL/min, as calculated 
using the modified Cockcroft-Gault equation (or equivalent glomerular filtration rate 
calculated using the Chronic Kidney Disease Epidemiology Collaboration formula) 
11. Has adequate hepatic function, defined as: 
a. 
Alanine aminotransferase and aspartate aminotransferase ≤ 3 × upper limit of normal 
(ULN) if no liver metastases are present; ≤ 5 × ULN if liver metastases are present 
b. 
Total bilirubin ≤ 1.5 × ULN. Patients with Gilbert’s disease who have serum bilirubin 
level ≤ 3 × ULN, may be enrolled 
12. Is willing and able to comply with the protocol requirements 
13. Patients requiring anticoagulation medication should be on a stable regimen, defined as at 
least 4 weeks on the same dose 
14. Patients requiring antihypertensive medication should be on a stable regimen, defined as at 
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15. If a woman of childbearing potential (WOCBP), must have a negative serum pregnancy test 
at screening and a negative urine pregnancy test on Cycle 1 Day 1 before receiving her first 
dose of study drug or within 72 hours of the first dose of study drug  
16. If a male patient, is surgically sterile, willing to use a condom, or remain abstinent upon 
randomization through the Treatment Period and for 5 months after the final dose of study 
drug 
5.2 
Exclusion Criteria 
A patient who meets any of the following criteria will not be eligible to participate in the study: 
1. Has received prior treatment with any MDM2 inhibitor or trabectedin 
2. Has other primary malignancies that have required systemic antineoplastic treatment within 
the previous 2 years, except for localized cancers that have apparently been cured (e.g., 
nonmelanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, 
cervix, or breast) and will not interfere with the study outcomes 
3. Has gastrointestinal conditions that could affect the absorption of milademetan, in the 
opinion of the Investigator 
4. Has an uncontrolled infection within the last 7 days from randomization requiring IV 
antibiotics, antivirals, or antifungals 
5. Has known HIV infection or active hepatitis B or C infection 
6. Has untreated brain metastases 
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a. CYP3A4 strong inhibitor: 5 elimination half-lives of the inhibitor 
b. CYP3A strong or moderate inducers (e.g., St. John’s wort and modafinil): 4 weeks 
c. Systemic anticancer therapy (chemotherapy; small molecules, including antibody drug 
therapy; retinoid therapy; or hormonal therapy) or investigational therapy: 3 weeks or 
5 half-lives, whichever is shorter 
d. Immunotherapy with checkpoint inhibitor: 4 weeks  
8. Has had major surgery ≤ 3 weeks from randomization 
9. Has had curative-intent radiation therapy ≤ 4 weeks or palliative radiation therapy, defined as 
≤ 30 Gy in ≤ 10 fractions (e.g., 20 Gy in 5 fractions or 8 Gy in 1 fraction) ≤ 2 weeks from 
randomization 
10. Has uncontrolled or significant cardiovascular disease, including: 
a. QTcF at rest, where the mean QTcF interval is > 480 milliseconds (average of triplicate 
ECGs) 
b. Myocardial infarction within 6 months prior to screening 
c. Uncontrolled angina pectoris within 6 months prior to screening 
d. New York Heart Association Class 3 or 4 congestive heart failure 
e. Uncontrolled hypertension (resting systolic blood pressure > 150 mmHg or diastolic 
blood pressure > 100 mmHg) 
11. Is a female who is pregnant or breastfeeding or intends to become pregnant during the study 
12. Has a concomitant medical condition that would interfere with the assessment of efficacy or 
increase the risk of toxicity, in the opinion of the Investigator or Sponsor 
5.3 
Study Completion 
Patient study “completion” refers to completion of study procedures and follow-up assessments 
or the patient has died, is lost to follow-up, or withdrawn consent before end of study. 
5.4 
Patient Withdrawal Criteria  
All patients are free to discontinue study drug or withdraw from the study at any time. All 
patients wishing to discontinue from study drug or withdraw from the study will be queried to 
determine the reason for withdrawal while respecting the privacy of the patient. The reason a 
patient decided to withdraw from study drug will be recorded.  
In the event of consent withdrawal, the Investigator should make every effort to ensure that the 
patient is followed for AEs for a minimum of 30 days after their last dose of study drug or until 
the initiation of a new anticancer treatment, whichever comes first, with documented patient 
agreement.  
Patients will be discontinued from study drug if any of the following events occur: 
 PD according to RECIST version 1.1 at any time during the study (unless approved 
by the Medical Monitor [See Section 6.5]) 


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 Clinical progression (e.g., symptomatic deterioration) not meeting the RECIST 
version 1.1 criterion for PD but considered by the Investigator to require withdrawal 
from study drug 
 Patient is unable to tolerate dosing after 3 dose reductions (for the milademetan arm) 
or is unable to maintain treatment with trabectedin following the dose modification 
guidelines provided in the local package insert/label (for the trabectedin arm) 
 Patient is unable to restart trabectedin after a dosing delay of > 3 weeks due to a 
persistent adverse reaction 
 Significant deviation from the protocol or eligibility criteria. These patients may 
continue study drug following a discussion and agreement between the Investigator 
and the Medical Monitor and subsequent approval by the institutional review board 
(IRB) or independent ethics committee (IEC). 
 Pregnancy  
 Patient withdrawal of consent and/or election to discontinue study drug 
 Termination of the study by the Sponsor 
 Any other reason which, in the opinion of the Investigator, would justify removing 
the patient from the study drug  
A patient may also be withdrawn from study drug by the Sponsor, Regulatory Authorities, or 
IECs/IRBs.  
If a patient discontinues study drug due to the ongoing coronavirus disease 2019 (COVID-19) 
global pandemic, information should be captured in the electronic case report form (eCRF) so 
this information can be summarized in the clinical study report at the end of the study, in line 
with the FDA guidance (FDA 2020). The reason for discontinuation should be recorded in the 
eCRF as COVID-19, if applicable, and include as many details as possible. For example, specific 
reasons may include, but are not limited to: 
 The patient exhibits symptoms consistent with COVID-19. 
 The patient has a positive test result for COVID-19. 
 The patient has neither symptoms nor a positive test for COVID-19 but has decided to 
discontinue treatment due to personal choice related to COVID-19 concerns. 
Patients who discontinue study drug for reasons other than PD by RECIST version 1.1 should 
undergo scans for tumor assessment according to the original tumor assessment schedule (every 
8 to 12 weeks [± 1-week window (7 days)] from Cycle 1 Day 1) until any of the following 
occurs, whichever comes first: 
 PD by RECIST version 1.1 
 Initiation of new anticancer treatment 
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After discontinuation from study drug, all patients will have an EOT Visit. The EOT Visit should 
take place 30 days (± 7 days) after the last study drug administration or before starting new 
anticancer treatment. If the patient begins another form of anticancer therapy before the end of 
the 30-day period, every effort will be made to complete all EOT assessments before 
commencing the new therapy. If there is an AE in need of monitoring beyond the EOT Visit, 
patients will be followed until resolution or confirmed stability of the AE. Long-term follow-up 
visits, to obtain survival information, after the EOT will be performed every 12 weeks (± 7 days) 
until the endpoint of death, the patient is lost to follow-up, or for 24 months following the first 
dose of study drug of the last patient enrolled, whichever comes first. 
Withdrawal from the study should be in a step-wise fashion. As mentioned above, patients may 
withdraw or be withdrawn from study drug. Any patient who withdraws or is withdrawn from 
study drug should be encouraged to complete all planned safety and follow-up assessments. If 
the patient wishes to withdraw from all study assessments, permission should be requested to 
contact the patient, a designated contact person, or the patient’s primary care provider for long-
term survival follow-up. If the patient does not wish any direct follow-up, permission should be 
requested to conduct periodic medical record review and/or contact the patient’s medical care 
provider for long-term follow-up. If the patient withdraws from the study and also withdraws 
consent for disclosure of future information, no further evaluations should be performed, and no 
additional data should be collected. Where allowed by local regulations, public records may still 
be consulted for the patient’s survival status. 
6. TREATMENT OF PATIENTS  
6.1 
Patient Enrollment  
Before any study related assessments, all potential patients will provide written informed 
consent. After written informed consent has been obtained and eligibility has been established, 
the study site will obtain the patient’s identification number and treatment assignment from the 
Interactive Response Technology System. Once a patient identification number has been 
assigned, it will be used to identify the patient throughout the study, and it cannot be reassigned 
to another patient. 
Investigational sites will provide the Medical Monitor with a completed Eligibility Checklist and 
relevant redacted source documents for medical history and concomitant medications for 
Sponsor review. Patients who meet the eligibility criteria may be enrolled. Patients will be 
considered enrolled upon randomization.  
Patients who cannot complete the procedures within the Screening window or are not initially 
eligible may be rescreened. In this situation, a new patient identification number will be 
assigned. For rescreening within the original Screening window, certain Screening procedures 
may not need to be repeated. Reconsent is required for rescreening outside the original Screening 
window.  
An investigational drug accountability log must be used for drug accountability. For additional 
details on investigational study drug management, please refer to the Pharmacy Manual. Patients 
will be provided with a patient diary to record study product administration and compliance. 


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6.2 
Milademetan Administration 
Milademetan 260 mg QD will administered orally on Days 1 to 3 and Days 15 to 17 of each 
28-day cycle. Milademetan will be administered at the clinical site on the indicated visit days 
(Cycle 1: Days 1, 3, and 15, Cycles 2 and 3: Days 1 and 15, and Cycles 4+: Day 1 only; Table 1) 
6.2.1 
Milademetan Dose Modifications 


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6.3 
Trabectedin Administration 
Trabectedin will be administered at 1.5 mg/m2 BSA as a 24-hour IV infusion, every 3 weeks 
through a central venous line. Clinical laboratory assessments must be resulted and evaluated 
prior to administration of study drug on the day of administration. 
6.3.1 
Trabectedin Dose Calculation 
The dose administered will be based on the patient’s BSA determined on Day 1 (± 7 days) of 
each cycle. The DuBois and DuBois formula for BSA calculation is: 
BSA = (W 0.425 × H 0.725) × 0.007184 
Investigational sites are instructed to use the DuBois and DuBois formula but may also use the 
formula/method in current institutional practice if accurate dose calculation can be assured.  
6.3.2 
Trabectedin Infusion Duration 
Reconstituted, diluted trabectedin solution should be infused over a 24-hour period through a 
central venous line using an infusion set with a 0.2 micron polyethersulfone in-line filter to 
reduce the risk of exposure to adventitious pathogens that may be introduced during solution 
preparation. 
Infusion must be completed within 30 hours of initial reconstitution. Discard any unused portion 
of the reconstituted product or infusion solution. 
6.3.3 
Trabectedin Dose Modifications 


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6.4 
Premedication 
Administer dexamethasone (or equivalent) and antiemetics per institution’s standard-of-care 30 
minutes before each dose of trabectedin. 
6.5 
Treatment Beyond Progression 
Patients with disease progression who meet the following criteria: 
a. Absence of symptoms and signs indicating clinically significant progression of disease. 
b. No decline in ECOG or Karnofsky performance status. 
c. Absence of symptomatic rapid disease progression requiring urgent medical 
intervention (e.g., symptomatic pleural effusion, spinal cord compression) 
may continue to receive study drug if, in the opinion of the Investigator, the patient is still 
benefiting (e.g., asymptomatic systemic progression or local symptomatic progression) following 
discussion with and approval by the Medical Monitor (or designee). The Investigator should 
periodically discuss the ongoing treatment with study drug with the Medical Monitor. Where 
applicable the IRB/IEC will be notified of any planned treatment beyond progression. Patients 
may receive palliative radiation to disease sites of progression, including brain metastases, 
following discussion with and approval by the Medical Monitor (or designee).  
At the time of radiographic progression of disease, patients should be informed of treatments 
with known clinical benefit they may be foregoing in order to continue receiving the 
investigational product. 
6.6 
Compliance 
Investigators are required to conduct the study in compliance with the protocol. Compliance with 
the protocol will be closely monitored. Important aspects of compliance with this clinical study 
include: 


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 Eligibility 
 Study drug administration, including: 
o Dose calculation, for the trabectedin arm 
o Dose modification 
o Infusion duration, for the trabectedin arm 
 Performance of protocol-specified assessments 
 ECG monitoring 
 AE reporting 
Protocol deviations are defined as any departure from the protocol or associated instructions and 
will be monitored. Deviations from the protocol, including violations of inclusion/exclusion 
criteria, will be assessed as “minor” or “major”. Protocol deviations at investigational sites will 
be discussed with the Investigator and additional training will be provided as needed to secure 
Investigator compliance.  
Study staff will receive additional training as needed to prevent noncompliance.  
6.7 
Study Visits  
Protocol-required assessments scheduled for each study visit are summarized in the Schedule of 
Events (Table 1 [milademetan arm] and Table 4 [trabectedin arm]) and described below. In 
exceptional circumstances with prior Sponsor approval, study visits may be performed by local 
provider.  
6.7.1 
Screening Period/Baseline Assessments 
Patients may be screened anytime during the 21 days prior to randomization. Unless otherwise 
specified, baseline assessments may be done anytime following consent and prior to 
randomization. Patients who are determined not to meet eligibility criteria at any time prior to 
randomization will not be enrolled. The following will be assessed or measured at 
screening/baseline: 
 Informed consent  
 Eligibility (including tumor assessment) 
 Medical/Disease history including all anticancer treatment  
 Demographics  
 Physical examination and vital signs, including height and weight 
 ECOG 
 ECG (12-lead) in triplicate 


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 Collect blood samples for laboratory assessments (see Table 2 [milademetan arm] and 
Table 5 [trabectedin arm]); ensure a serum pregnancy test is collected within 21 days 
of Cycle 1 Day 1 for WOCBP 
 Patient-reported outcome questionnaire (EORTC QLQ-C30) 
 Tumor tissue 
o Formalin-fixed paraffin embedded (FFPE) block from newly obtained biopsy or 
archival tissue of approximately 25 FFPE sections. Two sections will be used for 
eligibility confirmation after enrollment (enrollment is based on local pathology). 
The remaining 23 sections will be used for future genetic testing. 
 In patients who provide consent to the optional procedure: 
o Tumor biopsy consisting of sufficient tissue to generate an FFPE block of 
approximately 25 sections. Refer to the study Laboratory Manual for details.  
 Concomitant medications 
o Record all concomitant medications used after 21 days prior to Cycle 1 Day 1 
o Special attention should be accorded to medications that are known to cause 
prolongation of QTc or deplete potassium 
 Baseline physical and radiographic tumor assessment 
o Perform physical examination and radiological assessments per RECIST version 
1.1; include a computed tomography (CT) scan or magnetic resonance imaging 
(MRI) of the chest, abdomen, and pelvis, unless otherwise clinically indicated. 
The baseline radiographic tumor assessment is required within 28 days (± 1week 
window [7 days]) prior to the first dose of study drug.  
6.7.2 
Treatment Period  
See the Schedule of Events for the timing of procedures during the Treatment Period (Table 1 
[milademetan arm] and Table 4 [trabectedin arm]). Blood samples will be collected at the time 
points indicated in Table 2 (milademetan arm) and Table 5 (trabectedin arm). If screening 
laboratory assessments were performed within 72 hours of Cycle 1 Day 1 dosing, these screening 
laboratory assessments can be used as Cycle 1 Day 1 safety laboratory assessments. 
Physical and radiographic tumor assessments will be performed at the end of Week 8, Week 16, 
Week 24, and Week 32; and then every 12 weeks (± 1 week [7 days]) until treatment 
discontinuation, and any other time during the study as clinically indicated. In accordance with 
RECIST version 1.1, response (PR and CR) must be confirmed by a subsequent tumor 
assessment at least 4 weeks after the initial observed response. The same imaging modality used 
for baseline imaging (i.e., CT or MRI) must be used for subsequent radiographic tumor 


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assessments. Any dose interruption after starting study treatment will not cause adjustment to the 
tumor assessment schedule. Additional tumor assessments may be performed as clinically 
indicated (e.g., if disease progression is suspected). 
6.7.3 
End-of-Treatment Visit  
The EOT Visit should take place 30 days (± 7 days) after the last study drug administration or 
before starting new anticancer treatment. If the patient begins another form of anticancer therapy 
before the end of the 30-day period, every effort will be made to complete all EOT assessments 
before commencing the new therapy. If there is an AE in need of monitoring beyond the EOT 
Visit, patients will be followed until resolution or confirmed stability of the AE. The following 
will be performed at the EOT Visit: 
 Collect blood samples for laboratory assessments (see Table 2 [milademetan arm] and 
Table 5 [trabectedin arm] 
 Urine pregnancy test in WOCBP 
 ECOG 
 Physical examination and vital signs, including height and weight 
 Record AEs 
 Record concomitant medications 
 Patient-reported outcomes questionnaire (EORTC QLQ-C30) 
 In patients who provide consent to these optional procedures: tumor biopsy consisting 
of sufficient tissue to generate an FFPE block of approximately 25 sections. Refer to 
the study Laboratory Manual for details. 
 
6.7.4 
Long-Term Follow-Up 
Once a patient has completed the EOT Visit, they will enter the follow-up phase. All patients 
will be followed for documentation of disease progression and survival information (i.e., date 
and cause of death) and subsequent treatment information (i.e., date/duration of treatment, 
response, and subsequent disease progression). Long-term follow-up will continue every 12 
weeks (± 7 days) until the endpoint of death, the patient is lost to follow-up, or for 24 months 
following the first dose of study drug of the last patient enrolled, whichever comes first.  
6.8 
Concomitant Medications and Treatments  
All concomitant medications (prescription and over -the -counter) and blood products taken from 
the Screening Visit until the EOT Visit will be recorded. The reason(s) for treatment, dose, and 
dates of treatment will be recorded. In addition, concomitant medications used to treat AEs 
occurring up to 30 days after the last dose of study drug will be recorded.  
See Appendix A for a list of prohibited medications and those medications that are permitted but 
should be used with caution during the study. Supportive care should be provided as appropriate 


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to each patient to manage disease-related symptoms (e.g., antiemetics, antibiotics, transfusions, 
nutritional support, and pain control) according to institutional guidelines. 
6.8.1 
Prohibited Medications  


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7. ASSESSMENT OF EFFICACY  
Tumor assessments via imaging (CT scans or MRIs) will be performed by both the Investigator 
and a blinded central review committee; the evaluation of tumor response will be based on 
RECIST version 1.1. The primary efficacy objective is to compare PFS, as determined by BICR, 
between patients receiving milademetan versus trabectedin. However, the decision to discontinue 
study drug for disease progression will be determined locally by the Investigator. 
Tumor response evaluations will be performed at screening; at the end of Week 8, Week 16, 
Week 24, and Week 32; and then every 12 weeks (± 1 week [7 days]) while the patient remains 
on study drug, and any other time during the study as clinically indicated. 
In accordance with RECIST version 1.1, response (PR and CR) must be confirmed by a 
subsequent tumor assessment at least 4 weeks after the initial observed response. The scheduling 
of subsequent tumor assessments may be adjusted based on the date of the most recent imaging. 
Investigators are instructed to ensure that original images (or high-quality copies) of all baseline 
and on-study scans are filed and available for transmission to the Sponsor (or designee) for 
central reading.  
7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is PFS, as determined by BICR. 
7.2 
Secondary Efficacy Endpoints 
Secondary efficacy variables include: 
 OS 
 DCR by BICR and Investigator assessment 
 ORR by BICR and Investigator assessment 
 DOR by BICR and Investigator assessment 
 PFS by Investigator assessment 
 HRQoL evaluations: 
o EORTC QLQ-C30 
8. ASSESSMENT OF SAFETY AND EXPLORATORY VARIABLES 
8.1 
Definitions 
8.1.1 
Adverse Event Definitions 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug-related. An AE can be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
and does not imply any judgment about causality. An AE can arise with any use of the drug (e.g., 
use in combination with another drug) and with any route of administration, formulation, or 
dose, including an overdose. 


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8.1.1.1 Events Not Considered to be Adverse Events 
AEs do not include the following events: 
 Medical procedures, such as surgery, endoscopy, tooth extraction, or transfusion; 
however, the condition that led to the procedure may be an AE and must be reported 
 Preexisting diseases, conditions, or laboratory abnormalities present or detected 
before the Screening visit that do not worsen after the initiation of study drug 
 Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery or social and/or convenience admissions) 
 Overdose without clinical sequelae, as overdose is a special situation that should be 
reported using the Special Situation Report Form 
 Any medical condition or clinically significant laboratory abnormality with an onset 
date of on or after the informed consent form is signed but before the first dose of 
study drug and not related to a protocol-associated procedure. In this case, the 
condition or clinically significant laboratory abnormality is not an AE but should be 
considered preexisting and should be documented as medical history. 
 An event that is part of the natural course of the disease under study (i.e., disease 
progression, death due to disease progression) should not be recorded as an AE or 
SAE; however, signs and symptoms of clinical sequelae resulting from disease 
progression will be reported if they fulfill the definition of AE or SAE. If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an AE. 
8.1.1.2 Serious Adverse Events 
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results in 
any of the following outcomes: 
 Death 
 Life-threatening (immediate risk at the time of the event) 
 Inpatient hospitalization or prolongation of existing hospitalization 
 Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 Congenital anomaly/birth defect 
Any other important medical event, as defined as an AE that may jeopardize the patient or 
require medical or surgical intervention to prevent one of the outcomes listed above, based upon 
appropriate medical judgement, should be reported as an SAE. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. 


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8.2 
Adverse Events Reporting  
8.2.1 
Adverse Event Collection Period 
After signing the informed consent, but before the initiation of study drug, an event must be 
collected and entered on the AE case report form (CRF), IF it is related to protocol-required 
procedures (e.g., biopsy); otherwise, the event must be reported as medical history.  
Following initiation of study drug, all AEs, regardless of causality, will be collected and entered 
on the AE CRF until 30 days after the last administration of study drug or until initiation of 
another anticancer therapy, whichever comes first.  
All AEs should be followed until resolution or until the AE is stable, if possible. The Sponsor 
may request that certain AEs be followed beyond the protocol-defined follow-up period.  
8.2.2 
Adverse Event Term  
AEs must be reported using standard medical terminology. The use of abbreviations (standard 
and nonstandard) should be avoided to help ensure a clear understanding of the event. An 
example of a standard abbreviation that may have several meanings is “MI” which could mean 
“myocardial infarction” or “mitral insufficiency.” All AE terms will be coded using a 
standardized dictionary (i.e., Medical Dictionary for Regulatory Activities [MedDRA]). 
Generally, when reporting a well-known and understood condition, it is preferable to report the 
overall diagnosis rather than the individual signs and symptoms. The term “intermittent” should 
be avoided as the duration and incidence of events helps in understanding the safety profile of 
the study drug.  
8.2.3 
Adverse Event Severity  
AEs will be reported at the highest experienced severity. AE severity will be graded according to 
NCI CTCAE version 5.0. A copy of the document will be provided to investigational sites and an 
electronic version is available at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf  
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an 
adverse event (e.g., rated as mild, moderate, or severe, or according to the NCI CTCAE); the 
event itself may be of relatively minor medical significance (e.g., severe headache without any 
further findings).  
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Table 13: 
Severity Grading Guideline for Adverse Events Not Listed in NCI 
CTCAE  
Adverse Events Not Listed in NCI CTCAE Version 5.0 
Grade 
Description 
1 
 
Mild 
 
Asymptomatic or mild symptoms 
 
Clinical or diagnostic observations only 
 
Intervention not indicated 
2 
 
Moderate 
 
Minimal, local or noninvasive intervention indicated 
 
Limiting age-appropriate instrumental activities of daily livinga 
3 
 
Severe or medically significant but not immediately life-threatening 
 
Hospitalization or prolongation of hospitalization indicated 
 
Disabling 
 
Limiting self-care activities of daily livingb 
4 
 
Life-threatening consequences 
 
Urgent intervention indicated 
5 
 
Death related to adverse event 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b Self-care activities of daily living refer to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, 
and not bedridden.  
Note: A semicolon indicates “or” within the description of the grade. 
8.2.4 
Adverse Event Duration  
The start date (the date that the event was first noticed) and the end date (the date that the event 
had completely resolved, returned to baseline, or improved in severity grade) will be recorded. If 
the exact date is not known, the best estimate should be reported.  
8.2.5 
Adverse Event Causality  
Where the determination of the relationship of the AE to study drug rests on medical judgment, 
the determination must be made with the appropriate involvement of the Investigator, or, if the 
Investigator is not a physician, a designated Sub-investigator who is a physician. 
Using the following criteria, Investigators will assess whether there is a reasonable possibility 
that the study drug caused or contributed to the AE. 
Related (Possibly, Probably, or Definitely Related) 
 The time sequence between the onset of the AE and study drug administration is 
consistent with the event being related to study drug; and/or  


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 There is a possible biologic mechanism for study drug causing or contributing to the 
AE; and the AE may or may not be attributed to concurrent/underlying illness, other 
drugs, or procedures. 
Not Related (Unlikely Related) 
 Another cause of the AE is most likely; and/or 
 The time sequence between the onset of the AE and study drug administration is 
inconsistent with a causal relationship; and/or 
 A causal relationship is considered biologically unlikely. 
8.3 
Serious Adverse Events Reporting  
Error! Reference source not found.Investigators must report all SAEs regardless of causality 
immediately (within 24 hours of learning of the event without undue delay) on the AE CRF. If 
the EDC system is unavailable, SAEs must be reported by completing the back-up paper on the 
SAE report form and emailing the completed form to: 
An event that results in hospitalization or prolongs an existing hospitalization will not be 
considered an SAE, if the only reason for that hospitalization or prolongation is: 
 To administer study drug 
 To conduct protocol-specified study procedures 
 For placement of permanent IV catheter 
 Hospice placement due to PD 
 Respite care 
 


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Table 14: 
Severity Grading Guideline for Infusion-Related Reactions  
Infusion-Related Reactions 
Grade 
Description 
1 
 
Mild transient reaction; 
 
Infusion interruption not indicated; 
 
Intervention not indicated  
2 
 
Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (e.g., 
antihistamines, nonsteroidal anti-inflammatory drugs, narcotics, and intravenous fluids); 
 
Prophylactic medications indicated for ≤ 24 hours 
3 
 
Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of 
infusion); 
 
Recurrence of symptoms following initial improvement; 
 
Hospitalization indicated for clinical sequelae 
4 
 
Life-threatening consequences; 
 
Urgent intervention indicated  
5 
 
Death 
Adapted from National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 
Note: A semicolon indicates “or” within the description of the grade. 
8.5 
Reporting Disease Progression and Death 
PD, also referred to as disease progression, and death due to any cause are study endpoints and 
information related to these events will be collected in eCRFs specifically designed to collect 
these data. These events will not be reported as AE/SAEs unless the Investigator feels that they 
are accelerated, atypical, or related to study drug. All deaths must be communicated as soon as 
possible to the appropriate IRB/IEC and/or reported in accordance with local laws and 
regulations. 
If an autopsy is performed, a copy of the report will be requested and provided to the Sponsor, if 
available.  
8.6 
Special Situation Reporting 
Special situations may require immediate reporting and/or safety evaluations, and these 
situations must be reported without undue delay. These include, but are not limited to: 
 Overdose of any study drug – administration of a quantity of study drug above the 
recommended dose according to the protocol. In cases of a discrepancy in the drug 
accountability, overdose is established only when it is clear that the patient has taken 
additional doses or the Investigator has a reason to suspect that the patient has taken 
additional doses. 
 Abuse – persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 


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 Misuse of a study drug – situations where the medicinal product is intentionally and 
inappropriately used in a way that is not in accordance with the protocol instructions 
or local prescribing information and may be accompanied by harmful physical and/or 
psychological effects. 
 Medication error – unintentional error in the prescribing, dispensing, or 
administration of the medicinal product. 
 Product complaint – any written, electronic, or oral communication alleging 
deficiencies related to the identity, quality, durability, reliability, safety, or 
effectiveness of a drug after it is released for distribution. This situation should be 
reported by completing the specific Product Complaint Form (See Pharmacy Manual 
forms for details). If also associated with an AE, report the AE on the AE CRF. 
All special situations must be reported by completing the Special Situation Report Form except 
for a product complaint (see above). The completed form should be sent via email to: 
If the special situation is associated with an AE, the 
AE must also be recorded on the AE CRF. 
8.7 
Electrocardiogram Monitoring  
Standard 12-lead ECGs will be performed locally using a calibrated digital ECG machine 
capable of providing automated measurements. All ECG tracings will be acquired with the 
patient in the supine position after the patient has been resting for at least approximately 
10 minutes. ECG tracings will be measured and interpreted locally by a cardiologist or other 
qualified health care professional in accordance with institutional standard-of-care.  
ECGs will be performed at the time points indicated in the Schedule of Events (Table 1 
[milademetan arm] and Table 4 [trabectedin arm]). Screening ECGs should be performed in 
triplicate in all patients.  
8.7.1 
Subgroup of Patients Undergoing Intensive Electrocardiogram Monitoring at 
Selected Study Centers 
A subset of milademetan-treated patients (see Section 4.2.1) will undergo intensive ECG and PK 
assessments. ECGs will be collected digitally using an ECG continuous 12-lead digital recorder 
on the day of dosing. Holter monitoring will commence 60 minutes before the administration of 
milademetan and will continue through 24 hours following the administration of milademetan on 
Day 1 and Day 3 of Cycle 1. The Holter flash cards will be sent to an established clinical 
research organization with ECG experience (hereafter referred to as the “ECG core laboratory”) 
where replicate ECGs will be extracted at time points matching the PK sample collection 
schedule. Each ECG will be extracted from a supine rest period of at least 10 minutes of supine 
rest; PK sample collection will be performed immediately following the ECG supine rest 
periods. Triplicate ECGs and plasma concentration will be sampled before dosing (3 sets of 
triplicate ECGs collected before dosing on Cycle Day 1 at -45, -30, and -15 minutes to serve as 
baseline (e.g., 3 supine resting windows in the hour before dosing); and 1 set of predose ECGs 
will be collected on Day 3). Triplicate ECGs will be extracted at 1, 2, 3, 4, 6, 8, and 24 hours 
after dosing on Cycle 1 Days 1 and 3 (last treatment of first 3 doses) during Cycle 1. Safety 
ECGs will be reviewed by the Investigator, and continuous ECG recordings will be uploaded to 


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the ECG core laboratory for cardiologist over-reading. ECGs will be measured and have 
cardiologist evaluation in a blinded manner using the ECG core laboratory’s validated data 
management system (Table 3).  
All clinically significant ECG readings should be manually verified by a qualified individual. If 
the Investigator has any question regarding the local automated read, a local cardiologist should 
be consulted.  
8.8 
Vital Sign Assessments  
The following vital signs will be assessed after the patient has been sitting for approximately 
5 minutes. Vital signs will be obtained at each visit indicated in the Schedule of Events (Table 1 
[milademetan arm] and Table 4 [trabectedin arm]). Vital signs to be measured include: 
 Blood pressure (systolic and diastolic; mmHg) 
 Heart rate (beats per minute) 
 Body temperature (°C) 
 Respiration rate (breaths per minute) 
8.9 
Clinical Laboratory Assessments  
Clinical laboratory assessments will be performed by each institution’s local laboratory and must 
be resulted and evaluated prior to administration of study drug on the day of administration. The 
following laboratory variables (Table 155) will be collected at the time points indicated in 
Table 2 (milademetan arm) and Table 5 (trabectedin arm). 


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Table 15: 
Clinical Laboratory Assessments 
Serum Chemistrya: Sodium 
Potassium 
Chloride 
Bicarbonate 
Calcium 
Magnesium 
Phosphorous 
Glucose 
Blood urea nitrogen  
Bilirubin 
Aspartate aminotransferase  
Alanine aminotransferase 
Alkaline phosphatase 
Albumin 
Total protein  
Creatinine 
Hematology: 
Red blood cell count with differential and reticulocyte count 
Hemoglobin  
Hematocrit  
Platelet count  
Reticulocyte count 
White blood cell count with differential (reported as absolute counts)  
 
Total neutrophils  
 
Lymphocytes  
 
Monocytes  
 
Eosinophils  
 
Basophils  
Coagulation: 
International normalized ratio 
Activated partial thromboplastin time 
Pregnancy Test: 
In women with childbearing potential only: serum β-human chorionic gonadotropin 
pregnancy test, urine, or urine dipstick 
a If screening laboratory assessments were performed within 72 hours of Cycle 1 Day 1 dosing, the same screening laboratory 
assessments can be used as Cycle 1 Day 1 safety laboratory assessments. If the site cannot perform serum chemistry analysis, 
then the test may be performed with plasma (blood). 
All clinically significant unscheduled laboratory results will be recorded and all clinically 
significant laboratory results (scheduled and unscheduled) obtained during the study period will 
be reported as AEs (e.g., Grade ≥ 2 aspartate aminotransferase, alanine aminotransferase, or 
serum bilirubin). 
8.10 
Contraception and Pregnancy Testing and Reporting 
Patients who are WOCBP will have a serum pregnancy test performed at Screening and a urine 
pregnancy test performed on Day 1 (before dosing) of every cycle and at the EOT Visit. If a 
patient’s serum pregnancy test at screening is within 72 hours of their first dose of study drug, a 
negative urine pregnancy test on Cycle 1 Day 1 is not required. Additional pregnancy testing 
may be performed according to institutional practice.  
Patients who are WOCBP and male patients whose partners are WOCBP will be counseled on 
the importance of avoiding pregnancy during the study and after the final dose of study drug.  
WOCBP must use a highly effective method of contraception during the study and for at least 
3 months after the last dose of study drug. Highly effective contraceptive measures include, but 
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 Combined (estrogen and progestogen containing) hormonal contraception (oral, etc.) 
associated with inhibition of ovulation 
 Progestogen-only hormonal contraception (oral, etc.) associated with inhibition of 
ovulation 
 Intrauterine device  
 Intrauterine hormone-releasing system  
 Bilateral tubal occlusion 
 Vasectomized partner  
 For this study, male abstinence is defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments. Periodic abstinence, withdrawal (coitus interruptus), or the use of spermicides only 
are not acceptable methods of contraception. 
All patients will be instructed to report any suspected pregnancies in themselves or their female 
partners during the study. The Investigator must report the pregnancy by completing the EIU 
form and emailing the completed form to
within 24 
hours of awareness.  
If a female patient becomes pregnant, she should immediately discontinue the study drug and 
receive appropriate monitoring and care until the conclusion of the pregnancy. 
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons. However, the pregnancy should be followed until the 
outcome is known. Once the outcome of the pregnancy is known, the EIU form should be 
completed within 24 hours of awareness and emailed to 
If the pregnancy outcome is spontaneous abortion, stillbirth, neonatal death, infant with 
congenital anomaly, or a postpartum complication, the Investigator must also report the outcome 
as an SAE by completing the required information on the AE CRF. 
 
8.11 
Physical Examinations  
Complete physical examinations, including a review of all body systems, will be performed at 
the visits indicated in the Schedule of Events (Table 1 [milademetan arm] and Table 4 
[trabectedin arm]). Height and weight will be recorded at the Screening and EOT Visits. Weight 
will be recorded at all other visits. Clinically significant findings observed during the physical 
examination will be reported as medical history (pretreatment) or AEs (post-treatment).  


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8.12 
Eastern Cooperative Oncology Group 
All patients will be assessed at screening, Day 1 of each Cycle, and EOT using the ECOG 
Performance Status Scale (Table 166). An ECOG performance score of 0 to 1 is required for 
study entry but is not a criterion for retreatment or study drug discontinuation.  
Table 16: 
ECOG Performance Status Scale 
ECOG Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about > 50% 
of waking hours 
3 
Capable of only limited self-care; confined to bed or chair > 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
ECOG = Eastern Cooperative Oncology Group 
Source: Oken 1982 
8.13 
Pharmacokinetics 
8.13.1 
Subgroup of Patients Undergoing Intensive Pharmacokinetic Assessments at 
Selected Study Centers 


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8.14 
Tumor Tissue 


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10. QUALITY CONTROL AND QUALITY ASSURANCE  
10.1 
Data Quality Assurance 
The Sponsor (or designee) will conduct a site visit to verify the qualifications of each 
Investigator, inspect the site facilities, and inform the Investigator of the responsibilities and 
procedures for ensuring adequate and correct documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. All information recorded in the electronic data capture (EDC) system for this study 
must be consistent with the patients’ source documentation (i.e., medical records). 
10.1.1 
Database Management and Quality Control 
All data generated by the site personnel will be captured electronically at each study center using 
an EDC system. Data from external sources, such as laboratory data, will be entered into the 
database. Once the EDC clinical data have been submitted to the central server at the 


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independent data center, corrections to the data fields will be captured in an audit trail. The 
reason for the change and name of the person who performed the change, together with the time 
and date, will be logged to provide an audit trail.  
If additional corrections are needed, the responsible monitor or data manager will raise a query in 
the EDC application. The appropriate staff at the study site will answer queries sent to the 
Investigator. The name of the staff member responding to the query and time and date stamp will 
be captured to provide an audit trail. Once all source data verification is complete and all queries 
are closed, the monitor will freeze the EDC. 
The specific procedures to be used for data entry and query resolution using the EDC system will 
be provided to study sites in a training manual. In addition, site personnel will receive training on 
the EDC system. 
11. ETHICS  
11.1 
Informed Consent 
Before each patient is admitted to the study, written informed consent will be obtained from the 
patient according to the regulatory and legal requirements of the participating country. This 
consent form must be signed, dated, and retained by the Investigator or designee (designee must 
be listed on the Delegation of Authority Log) as part of the study records. The Investigator will 
not undertake any study-specific procedures until valid consent has been obtained. The terms of 
the consent and when it was obtained must also be documented in the EDC system. A copy of 
each signed informed consent form must be provided to the patient at the time it is signed by the 
patient. 
Patients may elect to provide optional tumor biopsies. These samples will be collected only if the 
patient provides additional consent. 
If a protocol amendment is required, the informed consent form may need to be revised to reflect 
the changes to the protocol. If the consent form is revised, it must be reviewed and approved by 
the appropriate IEC/IRB and signed by all patients subsequently enrolled in the study as well as 
those currently enrolled in the study. 
11.2 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. The 
Sponsor (or designee) must ensure that all ethical and legal requirements have been met before 
the first patient provides consent to participate in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written and 
approvals received from the appropriate personnel and IRB/IEC/Competent Authority before 
implementation (if appropriate).  
Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients with 
appropriate instructions. 


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11.3 
Duration of the Study 
The total study duration is estimated to be 4 years, including approximately 12 months for 
accrual of patients, up to 12 months of treatment for each patient, and up to 24 months of long-
term follow-up following the first dose of study drug of the last patient enrolled. The end of the 
study is defined as the last patient visit or contact, including telephone contacts, for collection of 
any study-related data.  
11.4 
Premature Termination of the Study 
If the Investigator, Sponsor, or Medical Monitor become aware of conditions or events that 
suggest a possible hazard to patients if the study continues, the study may be terminated after 
appropriate consultation between the relevant parties. The study may also be terminated early at 
the Sponsor’s discretion in the absence of such a finding. 
Conditions that may warrant termination include, but are not limited to: 
 The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study 
 Failure to enroll patients at an acceptable rate 
 A decision on the part of the Sponsor to suspend or discontinue development of the 
drug 
11.5 
Confidentiality 
All goods, materials, information (oral or written), and unpublished documentation provided to 
the Investigator (or any company acting on their behalf), inclusive of this protocol; the patient 
eCRFs; and the milademetan Investigator's Brochure are the exclusive property of the Sponsor. 
Documents and information provided to the Investigator by the Sponsor may not be given or 
disclosed by the Investigator or by any person within his authority in part or in totality to any 
unauthorized person without the prior written formal consent of the Sponsor. 
It is specified that the submission of this protocol and other necessary documentation to the IRB 
or IEC is expressly permitted, with the IRB or IEC members having the same obligation of 
confidentiality. 
The Investigator shall consider as confidential and shall take all necessary measures to ensure 
that there is no breach of confidentiality in respect of all information accumulated, acquired or 
deduced during the study, other than that information to be disclosed to a third party mandated 
by applicable law.  
Any language relating to these issues appearing in the Clinical Trial Agreement will supersede 
that outlined in this section. 
The anonymity of participating patients must be maintained. Patients will be identified in the 
EDC system and other documents submitted to the Sponsor (or designee) by their patient 
number, initials, and/or birth date, not by name. Documents not to be submitted to the Sponsor 


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(or designee) that identify the patient (e.g., the signed informed consent form) must be 
maintained in confidence by the Investigator.  
Information on maintaining patient confidentiality in accordance with individual local and 
national patient privacy regulations must be provided to each patient as part of the informed 
consent process either as part of the informed consent form or as a separate signed document (for 
example, in the US, a site-specific Health Insurance Portability and Accountability Act of 1996 
consent may be used). The Investigator or designee must explain to each patient that for the 
evaluation of study results, the patient’s protected health information obtained during the study 
may be shared with the Sponsor and its designees, regulatory agencies, and IRBs/research ethics 
boards/IECs. The study Sponsor will not use the patient’s protected health information or 
disclose it to a third party without applicable authorization. It is the Investigators or designee’s 
responsibility to obtain written permission to use protected health information from each patient. 
If a patient withdraws permission to use protected health information, it is the Investigator’s 
responsibility to obtain the withdrawal request in writing from the patient and to ensure that no 
further data will be collected from the patient. Any data collected on the patient before 
withdrawal will be used in the analysis of study results. 
During the review of source documents by the monitors or auditors, the confidentiality of the 
patient will be respected with strict adherence to professional standards and regulations. 
12. DATA HANDLING AND RECORD KEEPING  
12.1 
Case Report Forms and Source Documentation 
All data obtained during this study should be entered in the EDC system promptly. All source 
documents from which EDC entries are derived should be placed in the patient’s medical 
records. Measurements for which source documents are usually available include laboratory 
assessments, ECG recordings, CT scans, MRI, and X-rays. EDC entries may be checked against 
source documents at the study site or remotely by the Sponsor (or designee) site monitor. After 
review by the site monitor, completed EDC entries will be uploaded and forwarded to the 
Sponsor (or designee). Instances of missing or uninterpretable data will be discussed with the 
Investigator for resolution.  
The specific procedures to be used for data entry and query resolution using the EDC system will 
be provided to study sites in a training manual. In addition, site personnel will receive training on 
the EDC system. 
12.1.1 
Data Collection  
The Investigators (and appropriately authorized staff) will be given access to an online 
web-based EDC system which is compliant with the International Council for Harmonisation 
guidelines on Good Clinical Practice (ICH E6). This system is specifically designed for the 
collection of the clinical data in electronic format. Access and right to the EDC system will be 
carefully controlled and configured according to everyone’s role throughout the study. In 
general, only the Investigator and authorized staff will be able to enter data and make corrections 
in the eCRFs. 


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The eCRF should be completed for each patient included in the study and reflect the latest 
observations on the patients participating in the study. Therefore, the eCRFs are to be completed 
as soon as possible during or immediately after the patient’s visit or assessment. The Investigator 
must verify that all data entries in the eCRF are accurate and correct. 
Computerized data-check programs and manual checks will identify any clinical data 
discrepancies for resolution. Corresponding queries will be loaded into the system and the site 
will be informed about new issues to be resolved on-line. All discrepancies will be solved on-line 
directly by the Investigator or by authorized staff. Off-line edit checks will be done to examine 
relationships over time and across panels to facilitate quality data. 
After completion, the Investigator will be required to electronically sign off the clinical data.  
Data about all study drug dispensed or administered to the patient and any dosage changes will 
be tracked on the eCRF.  
12.2 
Access to Source Data 
Patients are informed who may have access to their medical records and study data. During the 
study, a monitor will make site visits or conduct remote monitoring to review protocol 
compliance, compare EDC entries with individual patient’s medical records, and ensure that the 
study is being conducted according to pertinent regulatory requirements. EDC entries will be 
verified with source documentation. The review of medical records will be performed in a 
manner to ensure that patient confidentiality is maintained. Appropriate access controls will be in 
place to ensure that access to confidential research information is restricted to those who need 
access. 
Checking of the EDC entries for completeness and clarity and cross-checking with source 
documents will be required to monitor the progress of the study. Moreover, Regulatory 
Authorities of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or on-site audit inspections. Direct 
access to source data will be required for these inspections and audits; they will be carried out 
giving due consideration to data protection and medical confidentiality. The Investigator assures 
the Sponsor (or designee) the necessary access at all times. 
12.3 
Data Processing 
All data will be entered by site personnel into the EDC system. The data -review and 
data -handling document, to be developed during the initiation phase of the study, will include 
specifications for consistency and plausibility checks on data and will also include data -handling 
rules for obvious data errors. Query/correction sheets for unresolved queries will be sent to the 
study monitors for resolution with the Investigator. The database will be updated based on signed 
corrections.  
Concomitant medications will be coded using the WHODrug Global dictionary, which employs 
the ATC classification system. Medical history including all anticancer treatment, current 
medical conditions, and AEs will be coded using MedDRA terminology. The versions of the 


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coding dictionaries will be provided in the clinical study report. When personal data is 
transferred electronically, data will be encrypted during transfer. 
12.4 
Archiving Study Records 
Per 21 CFR 312.62(c), Investigators shall retain records required to be maintained under this part 
for a period of 2 years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated, or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified. However, documents may be retained for a longer period if 
required by the applicable legal requirements. 
The Sponsor will maintain archive copies of all records for a period of no less than 25 years.  
13. PUBLICATION POLICY 
By signing the study protocol, the Investigator agrees with the use of results of the study for the 
purposes of national and international registration, publication, and information for medical and 
pharmaceutical professionals. If necessary, Regulatory Authorities will be notified of the 
Investigator's name, address, qualifications, and extent of involvement. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without discussion with 
and approval by the Sponsor. 
 


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14. REFERENCES 
Abeshouse A, Adebamowo C, Adebamowo SN, et al. Comprehensive and integrated genomic 
characterization of adult soft tissue sarcomas. Cell. 2017;171(4):950-965.  
Demetri GD, Von Mehren M, Jones RL, et al. Efficacy and safety of trabectedin or dacarbazine 
for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: 
results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2016;34(8):786-793.  
Demetri GD, Schöffski P, Grignani G, et al. Activity of eribulin in patients with advanced 
liposarcoma demonstrated in a subgroup analysis from a randomized phase III study of eribulin 
versus dacarbazine. J Clin Oncol. 2017;35(30):3433-3439.  
European Medicines Agency (EMA). European public assessment report (EPAR) for Yondelis 
(trabectedin). August 2021. 
Food and Drug Administration. In vitro Drug Interaction Studies — Cytochrome P450 Enzyme- 
and Transporter-Mediated Drug Interactions. Guidance for Industry [cited 30 December 2020]. 
Available from: https://www.fda.gov/media/134582/download 
Gounder MM, Bauer TM, Schwartz GK, et al. Milademetan, an oral MDM2 inhibitor, in well-
differentiated/dedifferentiated liposarcoma: results from a phase 1 study in patients with solid 
tumors or lymphomas. Eur J Cancer. 2020;138:S3-4. 
Kang D, Kumar P, Zernovak O, Song S, Xiong Y, Bergsma T, Lovern M, Yin O. Population 
pharmacokinetics and exposure-response analyses of an MDM2 inhibitor milademetan. J 
Pharmacokinet Pharmacodyn 2018 Oct 1;45: S24-S24. 
Noguchi S, Seki T, Adachi N, et al. PF225 azacitidine (AZA) enhances antileukemic activity of 
the MDM2 inhibitor milademetan in TP53 wild-type acute myeloid leukemia (AML). 
HemaSphere. 2019;3(S1):65. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
US Department of Health and Human Services (DHHS). Food and Drug Administration. 
Guidance for industry and investigators: Safety reporting requirements for INDs and BA/BE 
studies. December 2012. [cited 02 February 2021]. Available from: 
https://www.fda.gov/media/79394/download. 
United States prescribing information (USPI). Yondelis (trabectedin). Janssen Products, LP. 
Horsham, PA. June 2020. 
Vassilev LT. MDM2 inhibitors for cancer therapy. Trends Mol Med. 2007;13(1):23-31.  
Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule 
antagonists of MDM2. Science. 2004;303(5659):844-848.  
 


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DECLARATION OF THE INVESTIGATOR 
All documentation for this study that is supplied to me and that has not been previously published 
will be kept in the strictest confidence. This documentation includes this study protocol, 
milademetan Investigator’s Brochure, electronic data capture system, and other scientific data. I 
have read, understood, and agree to abide by all the conditions and instructions contained in this 
protocol, including the following statements: 
  I will conduct the study in accordance with the relevant, current protocol and will only make 
changes in a protocol after notifying the Sponsor, except when necessary to protect the safety, 
rights, or welfare of patients.  
 I will personally, conduct or supervise the described investigation.  
 I will inform any patients, or any persons used as controls, that the drugs are being used for 
investigational purposes and I will ensure that the requirements relating to obtaining informed 
consent in Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
approval provided in the International Council for Harmonisation (ICH) guidelines on Good 
Clinical Practice (ICH E6) and local requirements are met.  
 I will report to the Sponsor adverse experiences that occur in the course of the investigation(s) 
in accordance with ICH E6 and local requirements. I have read and understand the information 
in the protocol and milademetan Investigator’s Brochure, including the potential risks and side 
effects of the drug.  
 I will ensure that all associates, colleagues, and employees assisting in the conduct of the study 
are informed about their obligations in meeting the above commitments.  
 I will maintain adequate and accurate records in accordance with the ICH E6 and local 
requirements including making these records available for inspection.  
 I will ensure that an IRB/IEC that complies with ICH E6 and local requirements will be 
responsible for the initial and continuing review and approval of the clinical investigation. I will 
also promptly report to the IRB/IEC all changes in the research activity and all unanticipated 
problems involving risks to patients or others. Additionally, I will not make any changes in the 
research without IRB/IEC approval, except where necessary to eliminate apparent immediate 
hazards to patients. 
 I will comply with all other requirements regarding the obligations of clinical investigators and 
all other pertinent requirements in accordance with ICH E6 and local requirements. 
I understand that before I publish any findings from this study in scientific journals or present 
these at scientific meetings, I must first provide the Sponsor with ample opportunity to review 
the intended use of the study data. The Sponsor must authorize the disclosure of study data for 
any proposed abstract, manuscript, or meeting materials prior to their submission. 
 


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Responsible Investigator 
 
 
 
Signature 
 
Date 
Name (Printed) 
 
 
Title (Printed) 
 

SAP_001.pdf: 
Page 1 of 29 
 
 
 
Statistical Analysis Plan 
 
A Randomized Multicenter Phase 3 Study of Milademetan Versus Trabectedin in Patients 
with Dedifferentiated Liposarcoma 
 
Sponsor: 
Rain Therapeutics, Inc. 
8000 Jarvis Avenue 
Suite 204 
Newark, CA 94560 
USA 
Sponsor Protocol No.: 
RAIN-3201 
Investigational Drug Name: 
Milademetan (RAIN-32)  
Phase: 
3 
Date of Statistical Analysis Plan: 
18 August 2022 
Version Number: 
1.0 (Original) 
 
 
 
This study will be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), with the Declaration of Helsinki and with other applicable regulatory 
requirements. 
This document contains confidential information of Rain Therapeutics, Inc. 
Do not copy or distribute without written permission from Rain Therapeutics Inc. 
CONFIDENTIAL 
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APPROVAL & SIGNATURE PAGE 
 
Protocol No.: RAIN-3201 
Version: Original v1.0 
The Statistical Analysis Plan has been reviewed and approved by:  
 
 
 
 
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TABLE OF CONTENTS 
APPROVAL & SIGNATURE PAGE .............................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
1. 
INTRODUCTION ........................................................................................................7 
2. 
STUDY OBJECTIVES ................................................................................................7 
2.1. 
Primary Objective .........................................................................................................7 
2.2. 
Secondary Objectives ...................................................................................................7 
2.3. 
Exploratory Objectives .................................................................................................7 
3. 
STUDY DESIGN OVERVIEW ...................................................................................8 
3.1. 
Overall Design ..............................................................................................................8 
3.2. 
Sample Size Considerations .........................................................................................8 
4. 
STUDY ENDPOINTS AND COVARIATES ..............................................................9 
4.1. 
Primary Endpoint ..........................................................................................................9 
4.2. 
Secondary Endpoints ....................................................................................................9 
4.3. 
Exploratory Endpoints ................................................................................................10 
4.4. 
Baseline Covariates ....................................................................................................10 
5. 
ANALYSIS POPULATIONS ....................................................................................10 
5.1. 
Intent-to-treat (ITT) Population ..................................................................................10 
5.2. 
Safety Population ........................................................................................................11 
5.3. 
Pharmacokinetics (PK) Population .............................................................................11 
5.4. 
Quality of Life (QoL) Population ...............................................................................11 
5.5. 
Centrally Confirmed Dedifferentiated Liposarcoma (CCDD) Population .................11 
5.6. 
MDM2 Amplification by ctDNA Population .............................................................11 
5.7. 
Per Protocol Population ..............................................................................................11 
6. 
INTERIM ANALYSIS AND DATA MONITORING ..............................................12 
7. 
STATISTICAL METHODS OF ANALYSIS ............................................................12 
7.1. 
General Principles and Reporting Conventions ..........................................................12 
7.2. 
Subject Accountability ................................................................................................13 
7.3. 
Demographic and Baseline Characteristics ................................................................13 
7.4. 
Efficacy Analyses .......................................................................................................15 
7.5. 
Efficacy Analysis Methods .........................................................................................17 
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7.6. 
Safety Analysis ...........................................................................................................20 
7.7. 
Exploratory Biomarker Analysis ................................................................................23 
7.8. 
Pharmacokinetics Analysis .........................................................................................24 
8. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .....................24 
LIST OF PLANNED TABLES, FIGURES, AND LISTINGS .....................................................25 
List of Planned Tables ...................................................................................................................25 
List of Planned Figures ..................................................................................................................27 
List of Planned Data Listings .........................................................................................................28 
REFERENCES ..............................................................................................................................29 
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LIST OF ABBREVIATIONS 
Abbreviation  
Term  
AE  
Adverse event  
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BICR 
Blinded independent central review 
BMI  
Body mass index  
CCDD 
Centrally confirmed dedifferentiated 
CDK4 
Cyclin dependent kinase 4 
CDKN2A 
cyclin-dependent kinase inhibitor 2A 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenzel  
CR 
Complete response  
CSR 
Clinical Study Report  
CTCAE 
Common Terminology Criteria for Adverse Events  
ctDNA 
Circulating rumor DNA 
DCR 
Disease control rate 
DOR 
Duration of response  
ECOG 
Eastern Cooperative Oncology Group  
ECG 
Electrocardiogram  
eCRF 
Electronic case report form 
EORTC QLQ-C30 
European Organization for the Research and Treatment of Cancer 
Quality of Life Questionnaire  
FDA 
United States Food and Drug Administration 
IDMC 
Independent data monitoring committee  
ITT 
Intent to treat  
IRT 
Interactive response technology 
MDM2 
Mouse double minute 2 
ORR  
Objective response rate  
OS  
Overall survival  
PD  
Progressive disease  
PFS  
Progression-free survival  
PK  
Pharmacokinetics  
PR  
Partial response  
PRO 
Patient reported outcomes 
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PT 
Preferred term  
QoL  
Quality of life  
RECIST 
Response Evaluation Criteria in Solid Tumors 
RMST 
Restricted mean survival time 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan  
SD 
Stable disease  
SOC 
System organ class  
TEAE  
Treatment-emergent adverse event  
TP53 
Tumor protein 53 
ULN 
Upper limit of normal 
 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) outlines the statistical methods to be implemented for study 
RAIN-3201 entitled “A Randomized Multicenter Phase 3 Study of Milademetan Versus 
Trabectedin in Patients with Dedifferentiated Liposarcoma”. The purpose of the SAP is to ensure 
the credibility of the study findings by pre-specifying the statistical approaches to the analysis of 
study data prior to the primary analysis. Results of the planned analyses in this SAP will become 
the basis of the clinical study report (CSR) for this protocol. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is to assess the effect of milademetan versus trabectedin on progression-
free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as 
determined by blinded independent central review (BICR) in patients with unresectable or 
metastatic dedifferentiated (DD) liposarcoma, with or without a well-differentiated (WD) 
component, who progressed on 1 or more prior systemic therapies including at least 1 
anthracycline-based therapy. 
2.2. 
Secondary Objectives 
The secondary objectives are: 
 To compare the milademetan treatment arm versus the trabectedin control arm for the 
following efficacy measures: 
 Overall survival (OS)  
 Disease control rate (DCR) by BICR and by Investigator 
 Objective response rate (ORR) by BICR and by Investigator 
 Duration of response (DOR) by BICR and by Investigator 
 PFS by Investigator assessment 
 To assess the safety profile of milademetan 
 To evaluate patient-reported outcomes of milademetan 
2.3. 
Exploratory Objectives 
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3. 
STUDY DESIGN OVERVIEW 
3.1. 
Overall Design 
This is a randomized, multicenter, open-label, Phase 3 registration study designed to evaluate the 
safety and efficacy of milademetan compared to trabectedin in patients with unresectable (i.e., 
where resection is deemed to cause unacceptable morbidity or mortality) or metastatic DD 
liposarcoma that progressed on 1 or more prior systemic therapies, including at least 1 
anthracycline-based therapy.  
Approximately 160 patients will be randomly assigned in a 1:1 ratio to receive milademetan or 
trabectedin. Randomization will be stratified by Eastern Cooperative Oncology Group (ECOG) 
performance status (0 or 1) and number of prior treatments (≤ 2 or > 2) for the patient’s 
liposarcoma.  
Patients will receive study drug (i.e., milademetan or trabectedin) until reaching disease 
progression per RECIST 1.1 as determined by the Investigator, experiencing unmanageable 
toxicity, or until other treatment discontinuation criteria are met. Patients may be treated beyond 
tumor progression if they are experiencing clinical benefit based on the assessment of the 
Investigator in discussion with the Medical Monitor. All patients will be followed for 
documentation of disease progression and survival information (i.e., date and cause of death) and 
subsequent treatment information (i.e., date/duration of treatment, response, and subsequent 
disease progression). Long-term follow-up will continue every 12 weeks (± 7 days) until the 
endpoint of death, the patient is lost to follow-up, or for 24 months following the final dose of 
study drug, whichever comes first.  
3.2. 
Sample Size Considerations  
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4. 
STUDY ENDPOINTS AND COVARIATES 
4.1. 
Primary Endpoint 
The primary efficacy endpoint is PFS defined as the time from the date of randomization to the 
date of documented disease progression as determined per RECIST 1.1 by BICR or death due to 
any cause, whichever comes first.  
4.2. 
Secondary Endpoints  
Secondary efficacy endpoints include:  
 OS defined as the time measured from the date of randomization to the date of death 
by any cause  
 DCR defined as the percentage of patients who have achieved complete response 
(CR), partial response (PR), or stable disease (SD) for ≥ 16 weeks as determined by 
BICR/Investigator using RECIST 1.1. 
 ORR defined as the percentage of patients who achieve a confirmed CR or PR as 
determined by BICR/Investigator using RECIST 1.1. 
 DOR defined as the time from date of first objective response (CR or PR) to date of 
disease progression as determined by BICR/Investigator using RECIST 1.1. or death, 
whichever comes first  
 PFS defined as the time from the date of randomization to the documented disease 
progression based on Investigator assessments as determined per RECIST 1.1 or 
death due to any cause  
Health-related quality of life (HRQoL) endpoints include:  
 European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-
Life Questionnaire, Core 30 (QLQ-C30)  
Safety endpoints include: 
 Incidence of treatment-emergent adverse events (TEAEs) including serious adverse 
events (SAEs) 
 Incidence of TEAEs leading to discontinuation of study drug 
 Incidence of TEAEs leading to study withdrawal 
 Incidence of deaths 
 Changes in clinical laboratory parameters (hematology, serum chemistry, 
coagulation, urinalysis, and serum and urine pregnancy test), vital signs, and 
electrocardiogram (ECG) parameters (especially QT intervals); physical examination 
results (including ECOG performance status); and use of concomitant medications.  
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4.3. 
Exploratory Endpoints  
 
4.4. 
Baseline Covariates 
The following covariates will be used to examine efficacy in subgroups or in multivariate 
analyses: 
 ECOG performance status: 0 vs. 1  
 Number of prior anti-cancer treatments: ≤ 2 vs. >2  
 Prior therapy for advanced/metastatic disease: Yes vs. No 
 Region: North America, Europe, and Rest of World 
 Age: < 65 vs. ≥ 65 years 
 Sex: male vs. female 
 Race: white and other categories depending on frequency observed 
 Well differentiated liposarcoma component: yes vs. no 
Covariate values may be discordant if collected via electronic case report form (eCRF) and 
interactive response technology (IRT) (ECOG performance status, number of prior treatments). 
For subgroup and multivariate model analyses, the source verified eCRF value will be used to 
reflect the true clinical relevance of the covariate. For stratified treatment comparisons, however, 
the IRT value will be used to be consistent with the randomization scheme. 
5. 
ANALYSIS POPULATIONS 
5.1. 
Intent-to-treat (ITT) Population 
The intent-to-treat (ITT) population is defined as all subjects who are randomized into the study. 
Patients will be analyzed according to treatment arm to which they were randomized regardless 
of treatment received.  
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5.2. 
Safety Population 
The Safety Population is defined as all randomized patients who received at least one dose of 
investigational product. Patients will be analyzed based on the treatment actually received 
regardless of the treatment to which they were randomized.  
All safety analyses will be performed using the Safety Population. 
5.3. 
Pharmacokinetics (PK) Population 
The pharmacokinetics population consists of all randomized patients who received at least one 
dose of milademetan for whom data on concentrations of study treatment is available.  
5.4. 
Quality of Life (QoL) Population 
The QoL population consists of all patients in the ITT population for who have a baseline and at 
least one post baseline QoL assessment.  
5.5. 
Centrally Confirmed Dedifferentiated Liposarcoma (CCDD) 
Population 
The Centrally Confirmed Dedifferentiated Liposarcoma Population is defined as all patients with 
centrally confirmed dedifferentiated liposarcoma disease.  
5.7. 
Per Protocol Population 
The Per Protocol Population consists of all randomized patients who have no important protocol 
deviations thought to impact the efficacy analysis.  
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6. 
INTERIM ANALYSIS AND DATA MONITORING 
No interim PFS analysis is planned. One OS interim analysis is planned at the time of the 
primary PFS analysis. The final OS analysis will be performed at the end of the study when all 
patients complete the 24-month long-term follow-up.  
An independent data monitoring committee (IDMC) will review accumulating data periodically 
throughout the study and to make recommendations to the Sponsor regarding the conduct of the 
study in order to safeguard the interests of trial participants while preserving the integrity and 
credibility of the study. The Sponsor will implement guidelines to provide internal access of 
unblinded data on a strictly as required basis for the purpose of data capture, cleaning and 
analysis of this study. An independent biostatistician external to the Sponsor will prepare 
analyses for the IDMC. 
7. 
STATISTICAL METHODS OF ANALYSIS 
7.1. 
General Principles and Reporting Conventions 
The primary goal of the statistical analysis of the study is to demonstrate whether there is an 
increase in PFS in subjects treated with milademetan versus trabectedin in ITT population. The 
timing of the primary analyses of PFS will be event-driven based on corresponding pre-specified 
goals for the target number of 105 PFS events in the ITT population. The primary analysis of 
PFS and other RECIST endpoints will be according to BICR. Sensitivity analyses using 
investigator assessed tumor response or disease progression will be performed, using similar 
analysis sets of local review. 
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7.2. 
Subject Accountability 
7.2.1. 
Disposition of Patients  
The number and percentage of patients who were screened, randomized and treated with study 
drug, randomized but not treated with study drug will be tabulated by treatment arm. The number 
and percentage of patients in each analysis population will be tabulated by treatment arm.  
Screen failures will be summarized with reasons. The number and percentage of patients entering 
and completing each phase of the study will be presented by treatment. End of treatment and end 
of study will be summarized by reasons.  
7.2.2. 
Protocol Deviations  
Protocol deviations will be classified and monitored regularly during the duration of the study. 
Among other reasons, failure to meet any of the protocol inclusion or exclusion criteria will be 
considered a protocol deviation. All protocol deviations will be listed and summarized by type 
and treatment group. Important protocol deviations, thought to potentially impact the study 
conclusions, will be listed and tabulated using incidence and percentage by deviation type and 
treatment arm. 
7.3. 
Demographic and Baseline Characteristics 
Descriptive statistics will be provided for all demographic and baseline disease characteristics 
based on the ITT population. Demographic data, medical history, concomitant disease, and 
concomitant medication will be summarized by means of descriptive statistics or frequency 
tables, overall and stratified by treatment. 
7.3.1. 
Demographic Characteristics  
The following demographic variables will be summarized by treatment group: 
 age (years)  
 age group (<65, ≥ 65 years; <65, 65 – 85, ≥ 85 years) 
 sex  
 race & ethnicity  
 region (North America, Europe, and Rest of World) 
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 height (cm)  
 weight (kg)  
 body mass index (BMI) calculated as: BMI (kg/m2) = Weight (kg)/ (Height(cm) × 
0.01)2  
7.3.2. 
Randomization Stratification Factors 
7.3.3. 
Baseline Disease Characteristics  
The following baseline disease characteristics will be summarized by treatment group:  
 Stage at initial diagnosis 
 Stage at study entry 
 Tumor differentiation 
 Mitotic count 
 Tumor necrosis 
 FNCLCC grade 
 TNM stage at study entry 
 Time from initial diagnosis to randomization 
 Time from metastatic diagnosis to randomization 
 Tumor status 
 Metastatic sites 
7.3.4. 
Prior Cancer Therapy 
Prior radiation, cancer related surgery, cancer therapy will be summarized with indication and by 
treatment arm. Number of prior lines of therapy for metastatic disease, best response and reason 
for treatment discontinuation of each therapy will be summarized by treatment arm. 
7.3.5. 
Medical History  
Medical history data including chronic conditions, relevant surgical procedures, symptoms, any 
medical conditions that require medication and cancer history will be collected at screening, 
within 14 days before Cycle 1 Day 1. Medical history data will be summarized and listed by 
treatment arm. 
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7.4. 
Efficacy Analyses 
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7.4.1. 
Progression Free Survival (PFS) 
Progression free survival (PFS) is defined as the time interval from the date of randomization 
until the first date on which progression (per RECIST v1.1) or death due to any cause, is 
documented, whichever comes first. Assessment of PFS will be performed for all patients at 
baseline, at the end of W8, W16, W24, W32, and then every 12 weeks (± 1 week), regardless of 
treatment schedule modification (e.g., dose delay), until documented disease progression, 
initiation of new anticancer therapy, or discontinuation from the study (death, withdrawal of 
consent, or loss to follow-up). Subjects without documented progressive disease (PD) or death, 
including those who dropped out, will be censored at their last tumor assessment. Patients who 
did not have any tumor assessments after the screening visit will be censored on the 
randomization date. 
7.4.2. 
Overall Survival (OS) 
Overall survival is defined as the time from the date of randomization to the date of death due to 
any cause, censored at the last date known alive on or prior to the data cutoff date. Patients who 
had PD and started new anticancer therapy will continue to be followed for the OS assessment.  
7.4.3. 
Disease Control Rate (DCR) 
Disease control rate is the proportion of patients who achieve overall tumor response (confirmed 
CR or PR) or SD as assessed by RECIST 1.1 at least 16 (-1 week tumor assessment window) 
weeks from randomization. 
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7.4.4. 
Objective Response Rate (ORR)  
Objective response rate is defined as the proportion of patients demonstrating an objective 
response during the study. Objective response includes CR and PR as defined in the RECIST 1.1 
criteria and must be subsequently confirmed at least 4 weeks later. 
7.4.5. 
Duration of Response (DOR) 
Duration of response is measured from the time at which measurement criteria are first met for 
CR or PR (whichever status is recorded first) until the first date of PD is objectively documented 
or death. It is censored at the last valid tumor assessment if PD or death has not been 
documented. 
7.5. 
Efficacy Analysis Methods 
7.5.1. 
Primary Analysis of PFS 
7.5.2. 
Sensitivity Analyses of PFS 
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7.5.3. 
Secondary Efficacy Endpoints Analyses 
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7.6. 
Safety Analysis 
7.6.1. 
Overview of Safety Analysis Methods 
All safety analysis will be performed for all patients in the Safety population. The following 
assessments will be used: 
 Adverse events (AEs) 
 Medical history 
 Physical examination findings 
 Vital sign measurements 
 Laboratory assessments 
 ECOG performance status 
 ECG 
 Liver Function Tests results 
All safety endpoints will be summarized by treatment group and visit when appropriate. 
7.6.2. 
Extent of Exposure  
Extent of exposure to each investigational product will be summarized by total dose, number of 
cycles, treatment duration, dose intensity, relative dose intensity, number of missed doses, 
number of dose delays and number of dose reductions.  
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7.6.3. 
Concomitant Medications 
Concomitant medications will be defined as medications documented on the Concomitant 
Medications CRF. Concomitant medications will be coded using the World Health Organization 
Drug Reference List (WHODrug) dictionary 2021 version and summarized in a table and a data 
listing.  
7.6.4. 
Adverse Events, Serious Adverse Events, and Deaths 
All AEs and SAEs will be reported until 30 days after the last dose of investigational product(s) 
and will be followed until resolution or until condition stabilizes. AEs and SAEs will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) 24.1 and graded by the 
Investigator according to the NCI CTCAE v5.0 or later. 
Summaries of adverse event will, in general, focus on TEAEs which is defined as adverse event 
that occurs or worsens on or after first dose of investigational product and up to 30 days after the 
last dose. Missing data for safety endpoints will not be imputed. If dates are missing or 
incomplete for adverse event therefore TEAE status cannot be determined, then this AE will be 
included as an TEAE in the safety analysis. 
Subject incidence of the following events will be tabulated in two formats: 1) system organ class 
(SOC), preferred term (PT), and grade by treatment group; 2) PT only and by treatment group. 
 All TEAEs 
 SAEs 
 Treatment-related TEAEs 
 Treatment-related SAEs 
 Grade 3 or 4 TEAEs 
 TEAE leading to treatment discontinuation, dose reduction, dose interruption 
 TEAEs with an incidence >10% 
 TEAEs with at least a 5% difference in incidence rates between treatment groups 
Listings of TEAEs, TEAEs leading to IP discontinuation, TEAEs related to study treatment, and 
SAEs will be provided. Listings will be sorted by treatment, patient ID and study day; SAEs will 
be flagged. All AE listings will include treatment arm, patient ID, study day, SOC, PT, reported 
term, dose, Cycle/day, AE onset date, AE end date, outcome, duration, relationship to drug, 
action taken, and severity.  
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The incidence of death will be summarized by cause of death, treatment arm, and on-study status 
at time of death (within 30 days of last dose vs. more than 30 days after last dose). Patient death 
listings will include all death data available including date of death, cause of death and any AEs 
resulting in death.  
AE of special interest may be identified and summarized.  
7.6.5. 
Clinical Laboratory Evaluation 
Samples for clinical chemistry, hematology, and other lab parameters will be collected during 
screening, before study drug administration, on day 1 (and day 15 in milademetan arm) of each 
treatment cycle and at the treatment discontinuation visit.  
Laboratory data will be summarized in tables using descriptive statistics for baseline and each 
cycle/visit. Descriptive statistics will be calculated on both the actual score and the change from 
baseline score. Additionally, clinically significant abnormalities in laboratory results will be 
summarized for the post-baseline cycles/visits using frequencies and percentages. Shifts from 
baseline to minimum post-baseline and baseline to maximum post-baseline value (according to 
NCI Common Toxicity Criteria version 5.0 grading) will be presented for each treatment group. 
7.6.6. 
Vital Signs and Physical Examinations 
Vital signs, including systolic and diastolic blood pressure, pulse, and body temperature, as well 
as weight will be collected during screening and on day 1 (and day 15 in milademetan arm) of 
each cycle.  
Summary tables will include descriptive statistics (number of patients, mean, std, median, Q1, 
Q3, min, and max) for baseline and each cycle/visit. Descriptive statistics will be calculated on 
both the actual score and the change from baseline score. 
Physical examinations will be collected during screening, before study drug administration, on 
day 1 (and day 15 in milademetan arm) of each treatment cycle and at the Treatment 
Discontinuation Visit. Physical examination results will be summarized, and the frequency of 
clinically significant changes will be tabulated by treatment. 
7.6.7. 
Electrocardiograms 
Single standard 12 lead digital ECG will be performed during screening, at Cycle 1 Day 1 (and 
Day 15 in milademetan arm), and on the treatment discontinuation visit. For the triplicates at 
baseline, the average will be included in the summary.  
The ECG (measured after resting in a supine position for 10 minutes) will include heart rate, 
rhythm, and RR, PR, QRS, QT and QTc intervals. The ECG will be read and interpreted at the 
investigational site for patient safety monitoring, and documentation stored with the source 
documents.  
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All ECG parameters, their change from baseline, and the frequency of abnormal ECG events will 
be summarized across study time points by treatment arm using descriptive statistic. All ECG 
values will be listed by patient. 
7.6.9. 
Liver Function Test Results 
A listing will be generated for patients potentially meeting Hy’s Law criteria (total bilirubin ≥ 2× 
upper limit of normal [ULN] and aspartate aminotransferase [AST] or alanine aminotransferase 
[ALT] > 3×ULN at any time during the study). Plots or tables of on therapy peak total bilirubin 
vs. peak AST (or ALT) will also be generated to help identify potential Hy’s Law cases. 
7.6.10. 
ECOG Performance Status 
ECOG performance status will be assessed at screening, Day 1 of every cycle (and Day 15 in 
milademetan arm), and at treatment discontinuation. 
The ECOG status will be included in the baseline and demographic variables. The number and 
percentages of patients in each ECOG category will be presented by treatment. 
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8. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
This section is to be filled out if there are any changes to the analyses prior to finalization of the 
SAP. 
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LIST OF PLANNED TABLES, FIGURES, AND LISTINGS 
List of Planned Tables 
Category 
Title 
Disposition 
Summary of Randomization 
 
Summary of Analysis Population 
 
Summary of Subject Disposition  
 
Summary of Protocol Deviations  
 
Summary of Follow-up Time 
Demography and Baseline 
Characteristics 
Summary of Demographics  
 
Summary of Baseline Characteristics 
Medical History 
Summary of Medical History 
Cancer History 
Summary of Prior Cancer History 
 
Summary of Prior Anticancer Medications 
 
Summary of Prior Anticancer Radiotherapy 
 
Summary of Prior Anticancer Surgical Therapy 
 
Summary of Biomarkers 
Concomitant Medications 
Summary of Concomitant Medications 
 
Summary of Concomitant Surgery 
Study Medication 
Summary of Treatment Exposure  
 
Summary of Treatment Dose Reduction 
 
Summary of Treatment Dose Hold 
Efficacy 
Summary of Progression-Free Survival by Central Review 
 
Summary of Progression-Free Survival by Investigator 
 
Summary of PFS in Subgroups 
 
Summary of Objective Response Rate 
 
Summary of Duration of Response 
 
Summary of Disease Control Rate 
 
Summary of Overall Survival 
 
Summary of Overall Survival in Subgroups 
 
Concordance of Central PFS and Local PFS 
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Category 
Title 
 
Summary of Subsequent Anti-cancer Treatment 
Health Outcomes 
Summary of EORTC QLQ-C30 Observed Results and Change from 
Baseline 
 
Summary of EORTC QLQ-C30 Mixed Model Between Treatment 
Comparison 
 
Summary of Time to EORTC QLQ-C30 Deterioration 
Safety 
Summary of Overall Safety 
 
Incidence of TEAE by Preferred Term 
 
Incidence of TEAE by System Organ Class, Preferred Term, and Grade 
 
Incidence of Serious Adverse Events by Preferred Term 
 
Incidence of Serious Adverse Events by System Organ Class, Preferred 
Term, and Grade 
 
Incidence of TEAE Related to Study Treatment 
 
Incidence of TEAE Leading to Study Discontinuation 
 
Incidence of TEAE Leading to Study Drug Reduction 
 
Incidence of TEAE Leading to Study Drug Hold 
 
Incidence of Grade 3 or 4 TEAE by System Organ Class, and Preferred 
Term 
 
Summary of TEAE with Incidence >= 10% by Preferred Term 
 
Summary of Death 
 
Summary of TEAE of Special Interest 
Laboratory  
Mean and Mean Change from Baseline in Numeric Laboratory Data: 
Hematology/ Clinical Chemistry  
  
Shift from Baseline in Laboratory Data: Hematology/ Clinical Chemistry 
Vital Signs  
Mean and Mean Change from Baseline in of Vital Signs Data 
 
Frequency Table of Potentially Clinically Significant Vital Signs Data 
Physical Exam  
Summary of Physical Examination 
ECG 
Mean and Mean Change from Baseline in ECG Data 
 
Summary of Abnormality in ECG 
Liver Function  
Summary of Liver Function Parameters for Potential Hy’s Law 
ECOG 
Summary of ECOG by Visit 
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List of Planned Figures 
Category 
Title  
Efficacy  
Kaplan-Meier Plot of Progression-free Survival by Central Review 
 
Kaplan-Meier Plot of Progression-free Survival by Investigator  
 
Forest Plot of Progression-free Survival by Central Review 
 
Forest Plot of Progression-free Survival by Investigator  
  
Kaplan-Meier Plot of Overall Survival  
 
Forest Plot of Overall Survival  
 
Kaplan-Meier Plot of Duration of Response by Central Review 
 
Kaplan-Meier Plot of Duration of Response by Investigator 
QoL 
Mean Plot of Observed EORTC QLQ-C30 by Visit 
 
Mean Plot of EORTC QLQ-C30 Change from Baseline by Visit 
Safety 
Hy’s Law Plot 
 
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List of Planned Data Listings 
Category 
Title  
Disposition 
Listing of Protocol Deviations  
 
Listing of Enrollment by Country 
Safety 
Listing of Serious Adverse Events 
 
Listing of Adverse Events Leading to Treatment Discontinuation 
 
Listing of Adverse Events Leading to Hospitalization 
 
Listing of Adverse Events Leading to Dose Reduction 
 
Listing of Adverse Events Leading to Dose Hold 
 
Listing of Treatment Related Adverse Events 
 
Listing of Deaths  
 
Listing of Potential Hy’s Law Cases 
Study Drug 
Listing Study Drug Lot Numbers  
 
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