Clinical trial NCT05012397
Conditions: Solid Tumors Head and Neck Carcinoma Cholangiocarcinoma Sarcoma Lung Adenocarcinoma Bladder Urothelial Carcinoma Stomach Adenocarcinoma Breast Cancer Invasive Ovarian Carcinoma Cervical Cancer Non Small Cell Lung Cancer Gastric Cancer Biliary Tract Cancer Melanoma Pancreas Cancer MDM2 Gene Amplification Testicular Germ Cell Tumor Adrenocortical Carcinoma
Keywords: MDM2 Milademetan Basket Study
Sponsor: Rain Oncology Inc
Start date: 2021-11-01; Completion date: 2023-10-15
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase 2, multicenter, single-arm, open-label basket study designed to evaluate the safety and efficacy of milademetan in patients with advanced or metastatic solid tumors refractory or intolerant to standard-of-care therapy that exhibit wild-type (WT) TP53 and MDM2 copy number (CN) ≥ 8 using prespecified biomarker criteria.

Detailed description:
Approximately 65 patients will be enrolled to receive milademetan.

Patients will receive the study drug until reaching unequivocal disease progression (per Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\]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). 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 the study drug, whichever comes first.

Arms: arm 1: 260 mg once dailly orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle
Interventions: intervention 1: RAIN-32
Intervention descriptions: intervention 1: 260 mg once daily orally on Days 1 to 3 and Days 15 to 17 of each 28-day cycle

Protocol documents:
Prot_000.pdf: 
 
 
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A Phase 2 Basket Study of Milademetan in Advanced/Metastatic Solid Tumors  
(MANTRA-2) 
Sponsor: 
Rain Therapeutics Inc. 
8000 Jarvis Avenue 
Suite 204 
Newark, CA 94560 
USA 
Sponsor Protocol No.: 
RAIN-3202 
EU CT No.:  
2022-502564-20-00 
Investigational Drug Name: 
Milademetan (RAIN-32)  
Phase: 
2 
Date of Protocol: 
 
Version Number: 
 
Version History/Date: 
 
 
21 November 2022 
 
2.0 
 
Version 1.0 (16 June 2021) 
 
 
 
 
This study will be conducted according to the protocol and in compliance with Good Clinical 
Practice, the Declaration of Helsinki, and 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 Phase 2 Basket Study of Milademetan in Advanced/Metastatic Solid 
Tumors 
 
 
 
This study was designed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and is consistent with Good Clinical Practice 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 supports 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 
document. 
 
 
 


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PROTOCOL VERSION HISTORY 


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SYNOPSIS 
Study Number  
RAIN-3202 
Sponsor  
Rain Therapeutics Inc. 
Phase  
2 
Study Duration  
Estimated to be 3 years 
Objectives 
Primary Objective 
The primary objective is to determine the objective response rate (ORR) of treatment 
with milademetan in patients with advanced/metastatic solid tumors with murine double 
minute 2 (MDM2) gene amplification.  
Secondary Objectives 
 
To assess treatment with milademetan for the following efficacy parameters:  
o 
Duration of response (DOR) 
o 
Progression-free survival (PFS) 
o 
Growth modulation index (GMI) 
o 
Disease control rate (DCR) 
o 
Overall survival (OS)  
 
To assess the safety profile of milademetan 
 
To evaluate patient-reported health-related quality of life with the European 
Organisation for Research and Treatment of Cancer Quality-of Life Questionnaire, 
Core 30 (QLQ-C30) 
Exploratory Objectives 
-1) 
Study Design  
This is a Phase 2, multicenter, single-arm, open-label basket study designed to evaluate 
the safety and efficacy of milademetan in patients with advanced or metastatic solid 
tumors refractory or intolerant to standard-of-care therapy that exhibit wild-type (WT) 
tumor protein 53 (TP53) gene and MDM2 copy number (CN) ≥ 8 using prespecified 
biomarker criteria. 
Approximately 65 patients will be enrolled to receive milademetan. 
Patients will receive the study drug until reaching unequivocal disease progression (per 
Response Evaluation Criteria in Solid Tumors [RECIST] version [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 


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they are experiencing clinical benefit based on the assessment of the Investigator in 
discussion with the Sponsor’s Medical Monitor. 
All patients will be followed for documentation of disease progression and survival 
information (i.e., date and cause of death). 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 after the first dose of study drug for the last patient, whichever comes first. 
Investigational 
Treatment 
(Milademetan) 
Dose and Mode of Administration: 260 mg administered orally once daily (QD) on Days 1 
to 3 and Days 15 to 17 of each 28-day cycle. 
 
Eligibility  
Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in the study: 
1. Is a patient ≥ 18 years old 
2. Has signed and dated an informed consent form prior to the start of any study-
specific qualification procedures 
3. Has histologically and/or cytologically confirmed diagnosis of a cancer that is a 
locally advanced or metastatic solid tumor 
4. Has measurable tumor lesion(s) in accordance with RECIST v1.1 
5. Must have received all standard therapy appropriate for their tumor type and 
stage of disease or, in the opinion of the Investigator, would be unlikely to 
tolerate or derive clinically meaningful benefit from appropriate standard-of-
care therapy 


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6. Has resolution of any clinically relevant toxic effects of prior chemotherapy, 
surgery, radiotherapy, or hormonal therapy 
8. Has an Eastern Cooperative Oncology Group (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: 


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a. Alanine aminotransferase and aspartate aminotransferase ≤ 3 × the upper 
limit of normal (ULN) if no liver metastases are present or ≤ 5 × ULN if liver 
metastases are present  
b. Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of liver metastases. 
Patients with Gilbert’s disease who have serum bilirubin levels > 3 × ULN may 
be enrolled 
12. Is willing and able to comply with the protocol requirements 
13. If requiring anticoagulation medication, should be on a stable regimen, defined 
as being on the same dose for at least 4 weeks 
14. If a woman of childbearing potential (WOCBP), they must have a negative serum 
pregnancy test at Screening and a negative urine pregnancy test on Cycle 1 Day 1 
before receiving the first dose of study drug or within 72 hours of the first dose 
of study drug 
15. If a male patient, is surgically sterile, willing to use a condom, or remain 
abstinent upon enrollment through the Treatment Period and until at least 90 
days after the final dose of the study drug 
Exclusion Criteria 
A patient who meets any of the following criteria will not be eligible to participate in the 
study: 
1. Has had prior treatment with an MDM2 inhibitor 
-
2. Has well-differentiated/dedifferentiated liposarcoma or intimal sarcoma/cardiac 
sarcoma 
3. Has other primary malignancies that 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 cervix or breast) and will not interfere with the study 
outcomes 
4. Has a primary malignant brain tumor of any grade or histology  
5. Has untreated brain metastases 


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6. Has gastrointestinal conditions that could affect the absorption of milademetan, 
in the opinion of the Investigator 
7. Has a clinically significant uncontrolled infection within the last 7 days requiring 
intravenous antibiotics, antivirals, or antifungals 
8. Has known HIV infection or active hepatitis B or C infection 
9. Has not met the minimum washout period before enrollment, defined as:  
a. Cytochrome P450 (CYP)3A4 isozyme strong inhibitor: 5 elimination half-lives 
of the inhibitor 
b. CYP3A4 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 a checkpoint inhibitor: 4 weeks 
10. Has had major surgery ≤ 3 weeks from Cycle 1 Day 1 
11. 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 Cycle 1 Day 1 
12. Has uncontrolled or significant cardiovascular disease, including: 
a. Corrected QTc interval as calculated according to Fridericia’s formula (QTcF) 
at rest, where the mean QTcF interval is > 480 ms (average of triplicate 12-
lead electrocardiograms [ECGs]) in the absence of an offending medication 
that can be safely discontinued 
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 mm Hg or 
diastolic blood pressure > 100 mm Hg) on repeat measurements and despite 
adequate medical management 
13. Is a woman who is pregnant or breastfeeding or intends to become pregnant 
during the study 
14. 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 ORR, and the secondary efficacy endpoints are DOR, PFS, 
GMI, DCR, and OS. Health-related quality-of-life evaluations include the QLQ-C30. 


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The ORR is defined as the percentage of patients who have achieved a confirmed 
complete response (CR) or partial response (PR). 
Tumor assessments via imaging (computed tomography scans or magnetic resonance 
imaging) will be performed by the Investigator; the evaluation of tumor response will be 
based on RECIST v1.1.  
Tumor response evaluations will be performed at Screening and then every 8 weeks 
(± 7 days) while the patient remains on the 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 secondary efficacy endpoints DOR, PFS, GMI, DCR, and OS are defined as:  
 
The DOR is defined as the time from the date of first response to the date of 
disease progression or death  
 
The PFS is defined as the time from the date of first dose to the earliest date of the 
first objective documentation of radiographic disease progression or death due to 
any cause 
 
The GMI will be determined using the ratio of time to progression (TTP) with nth 
line of therapy (TTPn; here defined as milademetan) to the most recent prior line of 
therapy (TTPn-1)  
 
The DCR is defined as the percentage of patients who have achieved confirmed CR, 
PR, or stable disease (SD) lasting for ≥ 16 weeks 
 
OS, as measured from the date of the first dose of the study drug to the date of 
death due to any cause 
Health-related quality-of-life endpoints include QLQ-C30. 
Criteria for Safety 
Evaluation 
Safety endpoints include the incidence of treatment-emergent AEs (TEAEs); including 
serious AEs, TEAEs leading to dose reductions, TEAEs leading to discontinuation of the 
study drug, and TEAEs leading to study withdrawal); changes in clinical laboratory 
parameters (hematology, serum or plasma chemistry, and urine pregnancy test), deaths, 
vital signs, and ECG parameters (especially QT intervals); physical examination results; 
and use of concomitant medications. 
Criteria for 
Pharmacokinetic 
Evaluation 
Exploratory 
Evaluations 


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e 
Statistical 
Methods  
 
 
r 
 
ll 
 
n 
e 


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TABLE OF CONTENTS 
STATEMENT OF THE SPONSOR ................................................................................................2 
PROTOCOL VERSION HISTORY ................................................................................................3 
SYNOPSIS 5 
TABLE OF CONTENTS ...............................................................................................................16 
LIST OF TABLES .........................................................................................................................19 
LIST OF FIGURES .......................................................................................................................20 
LIST OF ABBREVIATIONS ........................................................................................................21 
1. 
INTRODUCTION ......................................................................................................24 
2. 
BACKGROUND INFORMATION ...........................................................................25 
2.1. 
Milademetan ...............................................................................................................25 
2.1.1. 
Summary of Nonclinical Studies Using Milademetan ...............................................25 
2.1.2. 
Nonclinical Toxicology ..............................................................................................26 
2.1.3. 
Absorption, Distribution, Metabolism, and Excretion ................................................27 
2.2. 
Summary of Clinical Studies Using Milademetan .....................................................28 
2.2.1. 
Efficacy .......................................................................................................................28 
2.2.2. 
Safety ..........................................................................................................................28 
2.3. 
Rationale for Selection of the Study Population .........................................................28 
2.4. 
Rationale for Dose Selection ......................................................................................31 
2.5. 
Benefit/Risk Assessment ............................................................................................32 
3. 
STUDY OBJECTIVES AND PURPOSE ..................................................................33 
3.1. 
Primary Objective .......................................................................................................33 
3.2. 
Secondary Objectives .................................................................................................33 
3.3. 
Exploratory Objectives ...............................................................................................33 
4. 
STUDY DESIGN .......................................................................................................33 
4.1. 
Study Design Overview ..............................................................................................33 
4.2. 
Endpoints and Criteria for Evaluation ........................................................................34 
4.2.1. 
Primary Endpoint ........................................................................................................34 
4.2.2. 
Secondary Endpoints ..................................................................................................34 
4.2.3. 
Exploratory Endpoints ................................................................................................35 
4.3. 
Measures Taken to Minimize/Avoid Bias ..................................................................35 


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4.4. 
Duration of Study Treatment ......................................................................................35 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................35 
5.1. 
Inclusion Criteria ........................................................................................................35 
5.2. 
Exclusion Criteria .......................................................................................................37 
5.3. 
Patient Withdrawal Criteria ........................................................................................39 
6. 
TREATMENT OF PATIENTS ..................................................................................40 
6.1. 
Patient Enrollment ......................................................................................................40 
6.2. 
Milademetan Administration ......................................................................................41 
6.3. 
Milademetan Dose Modifications ...............................................................................41 
6.4. 
Treatment Beyond Progression ...................................................................................45 
6.5. 
Compliance .................................................................................................................45 
6.6. 
Study Visits .................................................................................................................46 
6.7. 
Prescreening ................................................................................................................46 
6.8. 
Screening Period/Baseline Assessments.....................................................................46 
6.9. 
Treatment Period ........................................................................................................48 
6.10. 
EOT Visit ....................................................................................................................48 
6.11. 
Long-Term Follow-up ................................................................................................49 
6.12. 
Concomitant Medications and Treatments .................................................................49 
6.12.1. 
Prohibited Medications ...............................................................................................49 
6.12.2. 
Concomitant Medications that Should be Avoided or Used with Caution .................50 
7. 
ASSESSMENT OF EFFICACY ................................................................................50 
7.1. 
Primary Efficacy Endpoint .........................................................................................51 
7.2. 
Secondary Efficacy Endpoints ....................................................................................51 
8. 
ASSESSMENT OF SAFETY AND EXPLORATORY VARIABLES .....................51 
8.1. 
Definitions ..................................................................................................................51 
8.1.1. 
Adverse Event Definitions ..........................................................................................51 
8.1.2. 
Serious Adverse Events ..............................................................................................52 
8.2. 
AE Reporting ..............................................................................................................52 
8.2.1. 
AE Collection Period ..................................................................................................52 
8.2.2. 
AE Term .....................................................................................................................53 
8.2.3. 
AE Severity .................................................................................................................53 
8.2.4. 
AE Duration ................................................................................................................54 


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8.2.5. 
AE Causality ...............................................................................................................54 
8.3. 
SAE Reporting ............................................................................................................54 
8.5. 
Reporting Disease Progression and Death ..................................................................55 
8.6. 
Special Situation Reporting ........................................................................................55 
8.7. 
ECG Monitoring .........................................................................................................56 
8.8. 
Vital Sign Assessments...............................................................................................56 
8.9. 
Clinical Laboratory Assessments ...............................................................................56 
8.10. 
Contraception, Pregnancy Testing and Reporting ......................................................57 
8.11. 
Physical Examinations ................................................................................................58 
8.12. 
ECOG Performance Status Scale ................................................................................59 
8.13. 
Pharmacokinetics ........................................................................................................59 
8.14. 
Tumor Tissue ..............................................................................................................59 
8.15. 
Biomarkers ..................................................................................................................60 
9. 
STATISTICS ..............................................................................................................60 
9.1. 
Determination of Sample Size ....................................................................................60 
9.2. 
General Considerations ...............................................................................................61 
9.3. 
Patient Disposition ......................................................................................................61 
9.3.1. 
Disposition of Patients ................................................................................................61 
9.3.2. 
Protocol Deviations ....................................................................................................61 
9.3.3. 
Analysis Sets ...............................................................................................................61 
9.4. 
Baseline Characteristics and Concomitant Medications .............................................61 
9.5. 
Prior and Concomitant Medications ...........................................................................61 
9.6. 
Treatment Compliance ................................................................................................61 
9.7. 
Efficacy Analysis ........................................................................................................62 
9.7.1. 
Primary Efficacy Analysis ..........................................................................................62 
9.7.2. 
Secondary Efficacy Analysis ......................................................................................62 
9.8. 
Safety Analyses ..........................................................................................................63 
9.9. 
Other Analyses ............................................................................................................63 
9.9.1. 
PK Analyses ................................................................................................................63 
9.9.2. 
Biomarker Analyses ....................................................................................................63 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................63 


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10.1. 
Data Quality Assurance ..............................................................................................63 
10.1.1. 
Database Management and Quality Control ...............................................................63 
11. 
ETHICS ......................................................................................................................64 
11.1. 
Prescreening Informed Consent ..................................................................................64 
11.2. 
Informed Consent .......................................................................................................64 
11.3. 
Protocol Approval and Amendment ...........................................................................65 
11.4. 
Duration of the Study ..................................................................................................65 
11.5. 
Premature Termination of the Study ...........................................................................65 
11.6. 
Confidentiality ............................................................................................................65 
12. 
DATA HANDLING AND RECORD KEEPING ......................................................66 
12.1. 
CRFs and Source Documentation ...............................................................................66 
12.1.1. 
Data Collection ...........................................................................................................67 
12.2. 
Access to Source Data ................................................................................................67 
12.3. 
Data Processing ..........................................................................................................67 
12.4. 
Archiving Study Records ............................................................................................68 
13. 
PUBLICATION POLICY ..........................................................................................68 
14. 
REFERENCES ...........................................................................................................69 
APPENDIX A. EXAMPLES OF PROHIBITED MEDICATIONS OR 
CONCOMITANT MEDICATIONS THAT SHOULD BE AVOIDED OR 
USED WITH CAUTION ...........................................................................................71 
APPENDIX B. DECLARATION OF THE INVESTIGATOR ..................................................72 
 
LIST OF TABLES 


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LIST OF FIGURES 


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LIST OF ABBREVIATIONS 
Abbreviation or Specialist Term 
Definition 
(3/14 × 2) 
3 days on, 11 days off every 2 weeks 
AE 
adverse event 
AUC 
area under the curve  
BCRP 
breast cancer resistance protein 
CCP 
Centrally Confirmed Population 
CFU-GM 
colony-forming unit granulocyte/macrophage 
CI 
confidence interval 
Cmax 
maximum peak plasma concentration 
Cmin 
minimum plasma concentration 
CN 
copy number 
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 
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 
EOT 
end of treatment  
FAP 
Full Analysis Population 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FSH 
follicle-stimulating hormone 
GMI  
growth modulation index 
HNSTD 
highest non severely toxic dose 
IB 
Investigator’s Brochure 
IC50 
concentration causing 50% inhibition 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
MDM2 
murine double minute 2 gene  


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Abbreviation or Specialist Term 
Definition 
MDM2 
murine double minute 2 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC-1 
macrophage inhibitory cytokine-1 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute  
NOAEL 
no-observed-adverse-effect level 
ORR 
objective response rate 
OS 
overall survival 
p21 
cyclin-dependent kinase inhibitor 1 
p53 
Tumor suppressor protein 53 
P-gp 
P-glycoprotein 
PD 
progressive disease 
PDX 
patient-derived xenograft 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PUMA 
p53 upregulated modulator of apoptosis 
QD 
once daily 
QLQ-C30 
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire, Core 30 
QTc 
corrected QT interval 
QTcF 
corrected QTc interval as calculated according to Fridericia’s 
formula 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease  
SJSA-1 
osteosarcoma cell line 
TEAE 
treatment-emergent adverse event 
TP53 
tumor protein p53 gene 
TTP 
time to progression 
TTPn 
time to progression with the nth line of therapy 
TTPn-1 
time to progression to the most recent prior line of therapy 
ULN 
upper limit of normal 
US 
United States 
v 
version 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
WT 
wild type 


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1. 
INTRODUCTION 
The tumor suppressor protein p53 plays an essential role in preventing neoplasia by inducing cell 
cycle arrest or apoptosis in cells undergoing various types of physiological stress. However, 
inactivation of TP53 by mutation occurs in a significant percentage of human tumors, resulting 
in a loss of tumor suppressor activity and thereby removing a pivotal barrier to neoplastic 
development. In human tumors that retain WT p53 protein, its activity is frequently inhibited by 
intermolecular interactions between p53 and MDM2. MDM2 and p53 form a regulatory 
feedback loop in which MDM2 maintains low levels of p53 activity in normal, unstressed cells 
by promoting export of p53 out of the nucleus and proteasome-mediated degradation of p53 
through its E3 ubiquitination ligase activity (Shangary 2009). In the presence of stress, p53 
becomes activated and subsequently acts as a transcription factor that modulates the expression 
of a variety of genes, including MDM2 (Levine 2009). The MDM2 binding domain on p53 
overlaps with the transcriptional activation domain of p53, thereby inhibiting the activity of p53. 
Thus, in human tumors, disruption of MDM2/p53 balance through overexpression and/or 
oncogenic activation of MDM2 allows tumorigenesis and tumor growth by preventing p53 
function. 
In patients with cancers that do not harbor TP53 mutations, MDM2 gene amplification or 
increased MDM2 activity represent an alternate path for loss of p53 function. Alterations, such 
as gene amplification, are associated with tumorigenic potential (Fakharzadeh 1991) and thus, 
may serve as a predictive biomarker of antitumor activity with MDM2 inhibitors. MDM2 gene 
amplification is found across solid tumors at varying frequencies and with varying levels of gene 
amplification. Pharmacologic inhibition of the interaction between MDM2 and WT p53 in tumor 
cells could result in sustained increases in p53 activity and subsequent antitumor effects 
(Vassilev 2004, Shangary 2008). Therefore, pharmacologic restoration of the p53 pathway could 
be an effective strategy for cancer therapy targeting the wide array of human cancers that retain 
WT p53 (Vassilev 2007). 
Milademetan (RAIN-32) is a small-molecule inhibitor of MDM2 that disrupts the interactions 
between MDM2 and the tumor suppressor protein p53 (Noguchi 2019). MDM2 expression 
and/or activity can be upregulated by multiple mechanisms in cancer cells including MDM2 gene 
amplification (Tirunagaru 2021), cyclin-dependent kinase inhibitor 2A gene (CDKN2A) loss 
(Sherr 2000), and Merkel cell polyomavirus-encoded small T antigen (Park 2021) among other 
mechanisms, leading to potential MDM2-dependency and sensitivity to milademetan. 
This is a Phase 2 multicenter, single-arm, open-label basket study designed to evaluate the safety 
and efficacy of milademetan in patients with advanced or metastatic solid tumors refractory or 
intolerant to standard-of-care therapy and that exhibit WT TP53 and MDM2 CN ≥ 8 using 
prespecified biomarker criteria. The primary objective of the study is to determine the ORR of 
treatment with milademetan in these patients. 


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2. 
BACKGROUND INFORMATION 
2.1. 
Milademetan 
Milademetan is a novel, specific, small-molecule inhibitor of MDM2 that disrupts the 
interactions between MDM2 and the tumor suppressor protein p53 in tumor cells, preventing 
excessive degradation of p53 (Noguchi 2019). In normal cells, the balance of MDM2 and p53 
levels are maintained by a feedback mechanism in which p53 induces MDM2 expression, and 
the MDM2-p53 interaction promotes nuclear export of p53 and its proteasome-mediated 
degradation through the E3 ubiquitin ligase activity of MDM2 (Vassilev 2004). Mutational 
inactivation of p53 occurs in a significant percentage of human tumors, resulting in the loss of 
tumor suppressor activity in tumor cells. In human tumors that harbor WT TP53, MDM2 levels 
or activity are frequently elevated by MDM2 gene amplification or other mechanisms of 
overexpression, resulting in increased MDM2-p53 interaction and loss of p53 tumor suppressor 
function due to its degradation. Pharmacologic disruption of the interaction between MDM2 and 
p53 by milademetan in animal models of tumors that harbor WT TP53 have demonstrated 
sustained increases in p53 activity with a resultant antitumor effect (Vassilev  2007). 
2.1.1.1. 
In Vitro Pharmacology Studies 


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2.4. 
Rationale for Dose Selection 


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2.5. 
Benefit/Risk Assessment 
Current evidence supports the continued study of milademetan in clinical studies. 
Preclinical and preliminary clinical data support the development of milademetan in patients 
with advanced or metastatic solid tumors that are refractory or intolerant to standard-of-care 
therapy and exhibit WT TP53 and MDM2 CN ≥ 8. The mechanism of action of milademetan, the 
inhibition of MDM2 which increases p53 activity with a resultant antitumor effect, suggests a 
potential benefit in this patient population. 
Overall, milademetan was generally well tolerated, with an acceptable benefit/risk assessment. 


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3. 
STUDY OBJECTIVES AND PURPOSE 
The purpose of the study is to evaluate the safety and efficacy of milademetan in patients with 
advanced/metastatic solid tumors with WT TP53 and MDM2 gene amplification. To be eligible, 
patients must have progressed on 1 or more prior systemic therapies. 
3.1. 
Primary Objective 
The primary objective of the study is to determine the ORR of treatment with milademetan in 
patients with advanced/metastatic solid tumors with MDM2 gene amplification. 
3.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To assess treatment with milademetan for the following efficacy parameters: 
 DOR 
 PFS 
 GMI 
 DCR 
 OS 
 To assess the safety profile of milademetan 
 To evaluate patient-reported quality-of-life questionnaire (QLQ-C30) 
4. 
STUDY DESIGN 
4.1. 
Study Design Overview 
This is a Phase 2, multicenter, single-arm, open-label basket study designed to evaluate the 
safety and efficacy of milademetan in patients with advanced or metastatic solid tumors 
refractory or intolerant to standard-of-care therapy that exhibit WT TP53 and MDM2 CN ≥ 8 
using prespecified biomarker criteria. Local lab results for determination of TP53 mutation status 


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and MDM2 amplification may be used for eligibility; verification of MDM2 CN should be 
performed using a central laboratory as outlined under Section 5.1 Inclusion Criteria. 
Approximately 65 patients will be enrolled to receive milademetan. 
Patients will receive the study drug until reaching unequivocal disease progression (per RECIST 
v1.1), as determined by the Investigator; experiencing unmanageable toxicity; or until other 
treatment discontinuation criteria are met. Patients may be treated beyond tumor progression if 
patients are experiencing clinical benefit based on the assessment of the Investigator in 
discussion with the Sponsor’s Medical Monitor.  
All patients will be followed for documentation of disease progression and survival information 
(i.e., date and cause of death). Long-term follow-up (LTFU) will continue every 12 weeks 
(± 7 days) until the endpoint of death, the patient is lost to follow-up, or for 24 months after the 
first dose of the study drug for the last patient, whichever comes first. 
4.2. 
Endpoints and Criteria for Evaluation 
4.2.1. 
Primary Endpoint 
The primary efficacy endpoint is ORR. The ORR is defined as the percentage of patients who 
have achieved a confirmed CR or PR. Tumor response will be assessed in accordance with 
RECIST v1.1. 
4.2.2. 
Secondary Endpoints  
Secondary efficacy endpoints include:  
 The DOR, defined as the time from the date of first response to the date of disease 
progression or death 
 The PFS, defined as the time from the date of first dose to the earliest date of the first 
objective documentation of radiographic disease progression or death due to any 
cause  
 The GMI will be determined using the ratio of TTP with TTPn (here defined as 
milademetan) to TTPn-1  
 The DCR, defined as the percentage of patients who have achieved confirmed CR, 
PR, or SD for ≥ 16 weeks 
 OS, as measured from the date of the first dose of the study drug to the date of death 
due to any cause 
Health-related quality-of-life endpoints include the QLQ-C30. 
Safety endpoints include the incidence of TEAEs (including SAEs, TEAEs leading to dose 
reductions, TEAEs leading to discontinuation of study drug, and TEAEs leading to study 
withdrawal); changes in clinical laboratory parameters (hematology, serum or plasma chemistry, 
and urine pregnancy test), deaths, vital signs, and ECG parameters (especially QT intervals); 
physical examination results; and use of concomitant medications. 


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4.3. 
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 v1.1, by site 
radiologists. All responses will be source verified; copies of tumor assessment scans will be 
collected and stored for future potential evaluation.  
4.4. 
Duration of Study Treatment 
Patients will continue to receive the study drug until reaching unequivocal disease progression 
(per RECIST v1.1), as determined by the Investigator, or experiencing unmanageable toxicity. 
See Section 6.4 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 ≥ 18 years of age at the time of signing informed consent 
2. Has signed and dated an informed consent form prior to the start of any study-specific 
qualification procedures 
3. Has histologically and/or cytologically confirmed diagnosis of a cancer that is a locally 
advanced or metastatic solid tumor 
4. Has measurable tumor lesion(s) in accordance with RECIST v1.1 
5. Must have received all standard therapy appropriate for their tumor type and stage of 
disease or, in the opinion of the Investigator, would be unlikely to tolerate or derive 
clinically meaningful benefit from appropriate standard-of-care therapy 


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6. Has resolution of any clinically relevant toxic effects of prior chemotherapy, surgery, 
radiotherapy, or hormonal therapy 
7. Presence of WT TP53 and MDM2 gene amplification by tumor tissue/blood testing, 
defined as: 
a.  ≥ 8 copies in tumor tissue by central laboratory or 
b.  ≥ 8 copies or 4-fold increase in tumor tissue or blood by local testing  
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: 


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a. Alanine aminotransferase and aspartate aminotransferase ≤ 3 × the ULN if no liver 
metastases are present or ≤ 5 × ULN if liver metastases are present  
b. Total bilirubin ≤ 1.5 × ULN or ≤ 3 ×ULN in the presence of liver metastases. Patients 
with Gilbert’s disease who have serum bilirubin levels of > 3 × ULN may be enrolled 
12. Is willing and able to comply with the protocol requirements 
13. If requiring anticoagulation medication, should be on a stable regimen, defined as being 
on the same dose for at least 4 weeks 
14. If a WOCBP, they must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on Cycle 1 Day 1 before receiving the first dose of study 
drug or within 72 hours of the first dose of study drug 
15. If a male patient is surgically sterile and willing to use a condom or remain abstinent 
upon enrollment through the Treatment Period and until at least 90 days after the final 
dose of the 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 had prior treatment with a murine double minute 2 (MDM2) inhibitor 
2. Has well-differentiated/dedifferentiated liposarcoma or intimal sarcoma/cardiac sarcoma 
3. Has other primary malignancies that 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 cervix 
or breast) and will not interfere with the study outcomes 
4. Has a primary malignant brain tumor of any grade or histology 
5. Has untreated brain metastases 


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6. Has gastrointestinal conditions that could affect the absorption of milademetan, in the 
opinion of the Investigator. 
7. Has a clinically significant uncontrolled infection within the last 7 days requiring 
intravenous antibiotics, antivirals, or antifungals 
8. Has known HIV infection or active hepatitis B or C infection 
9. Has not met the minimum washout period before enrollment, defined as:  
a. CYP3A4 isozyme strong inhibitor: 5 elimination half-lives of the inhibitor 
b. CYP3A4 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 a checkpoint inhibitor: 4 weeks 
10. Has had major surgery ≤ 3 weeks from Cycle 1 Day 1 
11. 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 Cycle 1 Day 1 
12. Has uncontrolled or significant cardiovascular disease, including: 
a. QTcF at rest, where the mean QTcF interval is > 480 ms (average of triplicate 12-lead 
ECGs) in the absence of an offending medication that can be safely discontinued 
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 mm Hg or diastolic 
blood pressure > 100 mm Hg) on repeat measurements and despite adequate medical 
management 
13. Is a woman who is pregnant or breastfeeding or intends to become pregnant during the 
study 
14. Has a concomitant medical condition that would interfere with the assessment of efficacy 
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5.3. 
Patient Withdrawal Criteria  
All patients are free to discontinue the study drug or withdraw from the study at any time. All 
patients wishing to discontinue from the 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 withdrawal of consent, 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 the study drug or 
until the initiation of a new anticancer treatment, whichever comes first, with documented patient 
agreement.  
Patients will be discontinued from the study drug if any of the following events occur:  
 PD according to RECIST v1.1 at any time during the study (unless approved by the 
Sponsor’s Medical Monitor [see Section 6.4]) 
 Clinical progression (e.g., symptomatic deterioration) not meeting the RECIST v1.1 
criterion for PD but considered by the Investigator to require discontinuation of the 
study drug 
 Patient is unable to tolerate dosing after dose reductions per Table 4  
 Significant deviation from the protocol or eligibility criteria. These patients may 
continue dosing with the study drug after discussion and agreement between the 
Investigator and Sponsor’s Medical Monitor and subsequent approval by the IRB or 
IEC. 
 Pregnancy  
 Patient withdrawal of consent and/or election to discontinue the study drug 
 Termination of the study by the Sponsor 
 Any other reason which, in the opinion of the Investigator, would justify 
discontinuing the patient from the study drug  
A patient may also be discontinued from the study drug by the Sponsor, Regulatory Authorities, 
or IECs/IRBs.  
If a patient discontinues from the study drug due to the ongoing COVID-19 global pandemic, 
information should be captured in the eCRF so this information can be summarized in the 
clinical study report at the end of the study. 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 
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Patients who are discontinued from the study drug for reasons other than PD by RECIST v1.1 
should undergo scans for tumor assessments according to the original tumor assessment schedule 
(every 8 weeks [± 7 days] from Cycle 1 Day 1) until any of the following occur, whichever 
comes first:  
 PD by RECIST v1.1 
 Initiation of new anticancer treatment 
 Discontinuation from the study (death, withdrawal of consent, or loss to follow-up) 
After discontinuation from study drug, all patients will have an EOT Visit. The EOT Visit will 
occur 30 days (±7 days) after the last dose of the study drug administration or before starting 
new anticancer therapy. 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 Visit assessments prior to 
commencing the new anticancer 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 Visit, will be performed every 
12 weeks (± 7 days) until the endpoint of death, the patient is lost to follow-up, or for 24 months 
after the first dose of study drug for the last patient, whichever comes first. 
Withdrawal from the study should be in a stepwise fashion. As mentioned above, patients may 
discontinue or be discontinued from the study drug. Any patient who discontinues or is 
discontinued from the 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 to have any direct 
follow-up, permission should be requested to conduct periodic medical record review and/or 
contact the patient’s medical care provider for LTFU. 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 
Selected patients may require central verification of TP53 mutation status and /or MDM2 
amplification which can be performed under prescreening consent as outlined in the inclusion 
section. 
Prior to any study-related assessments, all potential patients will provide written informed 
consent. After written informed consent has been obtained and eligibility has been confirmed, 
the study site will obtain the patient’s identification number from the Interactive Response 
Technology System. Once a patient identification number has been assigned, it will be used to 
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Investigational sites will provide the Sponsor’s Medical Monitor with a completed Eligibility 
Checklist for Sponsor review. Patients who meet the eligibility criteria may be enrolled. Patients 
will be considered enrolled upon their first dose of the study drug.  
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 drug administration and compliance. 
6.2. 
Milademetan Administration 
Refer to the Pharmacy Manual for milademetan packaging, labeling, and storage instructions. 
Milademetan 260 mg QD will be administered orally QD on Days 1 to 3 and Days 15 to 17 of 
each 28-day cycle after all predose procedures have been performed. Clinical laboratory 
assessments must be resulted and evaluated prior to administration of study drug on the day of 
day. 
6.3. 
Milademetan Dose Modifications 


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6.4. 
Treatment Beyond Progression 
Patients with PD who meet the following criteria may continue to receive the study drug if, in the 
opinion of the Investigator, the patient is still benefiting (e.g., asymptomatic systemic 
progression or local symptomatic progression), after discussion with and approval by the 
Sponsor’s Medical Monitor (or designee): 
 Absence of symptoms and signs indicating clinically significant progression of 
disease 
 No decline in ECOG performance status 
 Absence of symptomatic rapid disease progression requiring urgent medical 
intervention (e.g., symptomatic pleural effusion or spinal cord compression) 
The Investigator should periodically discuss ongoing treatment with the study drug with the 
Sponsor’s 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, after discussion with and approval by the Sponsor’s 
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 study drug. 
6.5. 
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 
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 Eligibility 
 Study drug administration, including dose modification 
 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 the eligibility 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.  
If a deviation impacts the safety of a patient, the Investigator must contact the Sponsor 
immediately. The Investigator will also ensure that deviations meeting IRB/IEC and applicable 
regulatory authorities’ criteria are documented and communicated appropriately. All 
documentation and communications to the IRB/IEC and applicable regulatory authorities may be 
provided to the Sponsor and maintained within the Trial Master File. 
Study staff will receive additional training as needed to prevent noncompliance.  
6.6. 
Study Visits  
Protocol-required assessments scheduled for each study visit are summarized in the Schedule of 
Events (Table 1) and described in the following sections. In exceptional circumstances with prior 
Sponsor approval, study visits may be performed by a local provider. 
6.7. 
Prescreening 
Potential patients who meet any of the criteria on local testing specified in Inclusion Criterion #7 
(Section 5.1) may be asked to consent to prescreening. 
During prescreening the patient will authorize the study personnel to obtain previously collected 
tumor tissue and have it processed at a central laboratory. Prescreening eligibility does not 
guarantee study enrollment and the patient must consent to the main study before any Screening 
activities may commence. 
6.8. 
Screening Period/Baseline Assessments 
Patients may be screened at any time during the 21 days prior to the first dose of the study drug. 
Unless otherwise specified, Screening/baseline assessments may be done any time after consent 
and prior to the first dose of the study drug. Physical examination, ECOG, and clinical laboratory 
assessments on Cycle 1 Day 1 can be performed within 72 hours before the first dose of study 
drug. Patients who are determined not to meet eligibility criteria at any time prior to the first dose 
of the study drug will not be enrolled. The following will be assessed or measured at 
Screening/baseline: 
 Informed consent  


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 Eligibility (including tumor assessment) 
 Medical/disease history 
 Smoking history: Smoking history should be documented on the eCRF page as 
“never,” “former” (with quit date), or “current” (document pack years) 
 Demographics 
 Physical examination focused on major organ systems that are clinically relevant as 
determined by the Investigator and including symptom directed findings and vital 
signs (taken 5 minutes after sitting), including height and weight  
 ECOG Performance Status Scale 
 ECG (12-lead) in triplicate 
 Blood samples for laboratory assessments (see Table 1); ensure a serum pregnancy 
test is conducted for WOCBP 
 Patient-reported outcomes: QLQ-C30  
 Tissue as newly obtained biopsy or archived tissue ≤ 5 years old for central diagnostic 
laboratory verification of WT TP53 and MDM2 CN. Tissue may be submitted as 
either: 
 FFPE block, or  
 at least 15 unstained, unbaked, positively charged slides with ≥20% tumor tissue 
in 5-micron sections per slide as confirmed by a local pathologist  
Note: Patients who have central testing of TP53 and MDM2 gene status performed 
under prescreening consent can forego this tissue submission requirement. 
 In patients who provide consent to the optional procedure:  
 Tumor biopsy consisting of sufficient tissue to generate at least 15 slides of 
adequate quality 
 Prior and concomitant medications: 
 Record all concomitant medication use after 21 days prior to Cycle 1 Day 1 
 Special attention should be accorded to medications that are known to cause 
prolongation of QTc or deplete potassium 
 Baseline radiographic tumor assessment per RECIST v1.1: 
 Perform according to institutional practice and/or disease type; include CT or 
MRI of the chest and abdomen; baseline radiographic tumor assessment is 
required within 28 days prior to the first dose of study drug. 
 Baseline brain scan to exclude occult central nervous system metastases is 
required for all patients with lung cancer, breast cancer, melanoma, testicular 
cancer, or renal cell cancer and is strongly recommended in other appropriate 


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clinical settings at the discretion of the Investigator. Brain scans do not need to be 
repeated for patients without central nervous system metastases at baseline. 
Patients with a history of brain metastasis should be followed per standard 
institutional practice. 
 Bone scan during baseline radiographic tumor assessment is only required for 
patients with a primary tumor diagnosis in the prostate, breast, kidney, lung, or 
thyroid. Additional tumor types may have baseline bone scans at the discretion of 
the Principal Investigator if there is suspicion of bone metastasis.  
 For patients where baseline brain and/or bone scans are required, the tumor 
assessment must be performed within 28 days prior to the first dose of study drug.  
 Brain and bone scans do not need to be repeated for patients with no brain or bone 
metastases at baseline, unless clinically indicated. 
 If brain and/or bone metastases are identified at the baseline visit, brain, and/or 
bone scans must be repeated and aligned with the protocol-specified tumor 
assessment schedule. These lesions should be followed per RECIST v1.1 
guideline using the same modalities at each assessment.  
6.9. 
Treatment Period  
See the Schedule of Events for the timing of procedures during the Treatment Period (Table 1). 
 Please refer to the Pharmacy Manual for further information on 
treatment continuation after dose holds. 
Physical and radiographic tumor assessments will be performed every 8 weeks (± 7 days) while 
the patient remains on the study drug and any other time during the study as clinically indicated. 
In accordance with RECIST v1.1, 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 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). 
6.10. 
EOT Visit  
The EOT Visit will occur 30 days (± 7 days) after the last dose of the study drug administration 
or before starting a new anticancer therapy. If the patient begins another anticancer therapy 
before the end of the 30-day period, every effort will be made to complete all the EOT Visit 
assessments prior to commencing the new anticancer therapy. If there is an AE in need of 
monitoring beyond the EOT Visit, patients will be followed until resolution or confirmed 
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 ECOG Performance Status Scale  
 Physical examination focused on major organ systems that are clinically relevant as 
determined by the Investigator and including symptom directed findings, and vital 
signs, including weight 
 Urine pregnancy test for WOCBP 
 Record AEs 
 Record concomitant medications 
 Patient-reported outcomes: QLQ-C30  
 Blood samples for laboratory assessments (see Table 1) 
 Serum samples for exploratory biomarkers 
 In patients who provide consent to the optional procedure: tumor biopsy consisting of 
sufficient tissue to generate an FFPE block or at least ≥ 15 slides of adequate quality 
 Survival follow-up 
6.11. 
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., the date 
and cause of death) and subsequent treatment information (i.e., the 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 
after the first dose of study drug for the last patient, whichever comes first. Unless the patient 
withdraws consent, all patients enrolled in the study will be followed for LTFU assessments after 
EOT. 
6.12. 
Concomitant Medications and Treatments 
All concomitant medications (prescription and over-the-counter) and blood products taken from 
Screening 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 the 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 
to each patient to manage disease-related symptoms (e.g., antiemetics, antibiotics, transfusions, 
nutritional support, and pain control) according to institutional guidelines. 
Use of filgrastim is allowed in accordance with ASCO/ESMO guidelines (Klastersky 2016, 
Smith 2015). 
6.12.1. 
Prohibited Medications  


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7. 
ASSESSMENT OF EFFICACY 
Tumor assessments via imaging (CT scans or MRIs) will be performed by the Investigator; the 
evaluation of tumor response will be based on RECIST v1.1. The primary objective is to 
determine the ORR of treatment with milademetan in patients with advanced/metastatic solid 
tumors with MDM2 gene amplification. The decision to discontinue the study drug for disease 
progression will be determined locally by the Investigator. 


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Tumor response evaluations will be performed at Screening and then every 8 weeks (±7 days) 
while the patient remains on the study drug, and any other time during the study as clinically 
indicated. 
In accordance with RECIST v1.1, 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 collected and filed for transmission to the Sponsor (or designee) for 
future independent review. 
7.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is ORR, as determined by Investigator assessment. 
7.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following according to the Investigator’s assessment: 
 DOR 
 PFS 
 GMI 
 DCR 
 OS 
Health-related quality-of-life evaluations, including QLQ-C30, are additional secondary 
endpoints. 
8. 
ASSESSMENT OF SAFETY AND EXPLORATORY VARIABLES 
8.1. 
Definitions 
8.1.1. 
Adverse Event Definitions 
An AE is defined as 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., off-label use or use in combination with another drug) and with any route of 
administration, formulation, or dose, including an overdose. 
8.1.1.1. 
Events Not Considered to Be AEs 
AEs do not include the following events: 
 Preexisting diseases, conditions, or laboratory abnormalities present or detected 
before the Screening Visit that do not worsen after the initiation of study drug 


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 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. 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 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 medical 
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 or SAE. 
8.1.2. 
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 
 is life-threatening (i.e., immediate risk of death at the time of event) 
 inpatient hospitalization or prolongation of existing hospitalization 
 persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 a congenital anomaly/birth defect 
Based upon appropriate medical judgment, an AE that may jeopardize the patient or require 
medical or surgical intervention to prevent one of the aforesaid outcomes should be reported as 
an SAE. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency department or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
8.2. 
AE Reporting 
8.2.1. 
AE Collection Period  
After signing the informed consent, but before the initiation of study drug, an event must be 
collected and reported on the AE CRF, IF it is related to protocol-required procedures (e.g., 
biopsy); otherwise, the event must be reported as medical history. 
After 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. 


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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. 
AE 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 that 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. 
AE Severity 
AE severity will be graded according to NCI CTCAE v5.0. 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, according to the NCI CTCAE); the event 
itself may be of relatively minor medical significance (e.g., severe headache without any further 
findings). 
Events not listed in NCI CTCAE will be graded according to the criteria described in Table 5. 
Table 5: 
Severity Grading Guideline for AEs Not Listed in NCI CTCAE  
AE Not Listed in NCI CTCAE v5.0 
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 selfcare activities of daily livingb 
4 
 
Life-threatening consequences 
 
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5 
 
Death related to adverse event 
Abbreviations: AE = adverse event; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; 
v = version. 
Note: A semicolon indicates “or” within the description of the grade. 
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.  
8.2.4. 
AE Duration 
The start date (the date that the event/condition was first noticed or diagnosed) and end date (the 
date that the event/condition had completely resolved, returned to baseline, or changed in 
severity grade) will be recorded. If the exact date is not known, the best estimate should be 
reported. 
All AEs will be followed until stabilization or resolution.  
8.2.5. 
AE Causality 
Where the determination of the relationship of the AE to the 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 
 The time sequence between the onset of the AE and study drug administration is 
consistent with the event being related to the study drug; and/or  
 There is a possible biologic mechanism for the 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 
 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. 
SAE Reporting 
Investigators must report all SAEs regardless of causality immediately (within 24 hours of 
awareness) on the AE CRF. If the EDC system is unavailable, SAEs must be reported by 
completing the back-up paper SAE report form and emailing the completed form to: 
‑
An event that results in hospitalization or prolongs existing hospitalization will not be considered 
an SAE if the only reason for that hospitalization or prolongation is: 


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 To administer the study drug 
 To conduct protocol-specified study procedures 
 For placement of a permanent intravenous catheter 
 Hospice placement due to PD 
 Respite care 
 
8.5. 
Reporting Disease Progression and Death 
Progressive disease, also referred to as disease progression, and death due to disease progression 
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 AEs/SAEs unless 
the Investigator feels that they are accelerated, atypical, or related to the study drug. All deaths 
must be communicated as soon as possible to the appropriate IRB/IEC and 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 expedited reporting and/or safety evaluations. These include, but 
are not limited to: 
 Overdose of the 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 of the study drug – persistent or sporadic, intentional excessive use of a 
medicinal product, which is accompanied by harmful physical or psychological 
effects. 
 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 
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 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 eCRF. 
8.7. 
ECG 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 healthcare professional in accordance with institutional standard of care.  
ECGs will be performed at the time points indicated in the Schedule of Events (Table 1). The 
Screening ECG will be performed in triplicate.  
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 as indicated in the Schedule of Events 
(Table 1). 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 the study drug. The laboratory variables in 
Table 6 will be collected in accordance with the Schedule of Events (Table 1).  


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Table 6: 
Clinical Laboratory Assessments 
Serum or Plasma 
Chemistry: 
Sodium 
Potassium 
Chloride 
Calcium 
Magnesium 
Phosphorous 
Glucose 
Total Bilirubin 
Aspartate aminotransferase  
Alanine aminotransferase 
Alkaline phosphatase 
Albumin 
Total protein  
Creatinine  
Hematology: 
Red blood cell count  
Hemoglobin  
Hematocrit  
Platelet counts 
White blood cell count with differential (reported as absolute counts), where possible  
Total neutrophils  
 
Lymphocytes  
 
Monocytes  
 
Eosinophils  
 
Basophils  
Coagulation: 
International normalized ratio 
Partial thromboplastin time 
Activated partial thromboplastin time 
Pregnancy Test: 
In women of childbearing potential only: serum β-human chorionic gonadotropin pregnancy 
test, urine, or urine dipstick 
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, Pregnancy Testing and Reporting 
Patients who are WOCBP will have a serum pregnancy test performed at Screening and urine 
pregnancy test performed on Day 1 (before dosing) of every cycle and 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. 
WOCBP participating in the study must use a highly effective method of contraception during 
the study 
Highly effective 
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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 
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.  
Note: For this study, abstinence is defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments. Periodic abstinence, withdrawal (coitus 
interrupts), 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 within the timeline specified above after the last dose of study drug. 
The Investigator must report the pregnancy by completing the exposure in utero (EIU) form and 
emailing the completed form to 
ithin 24 hours of 
awareness. 
The Investigator must obtain permission from a patient’s pregnant partner before collecting 
further information regarding 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 eCRF. 
8.11. 
Physical Examinations 
Complete physical examinations focused on major organ systems that are clinically relevant as 
determined by the Investigator and including system directed findings, vital signs (taken 5 
minutes after sitting), height and weight will be performed at the visits indicated in the Schedule 
of Events (Table 1). Height will be recorded at Screening. Weight will be recorded at all time 


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points indicated in the Schedule of Events. Clinically significant findings observed during the 
physical examination will be reported as medical history (pretreatment) or AEs (posttreatment).  
8.12. 
ECOG Performance Status Scale 
All patients will be assessed on Days 1 and 15 in Cycles 1 to 3, Day 1 only in Cycles 4 and 
beyond, and at the EOT Visit using the ECOG Performance Status Scale (Table 7). 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 7: 
ECOG Performance Status Scale 
ECOG Performance Status Scale 
Grade 
Description 
0 
Fully active, able to continue 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 
Abbreviation: ECOG = Eastern Cooperative Oncology Group. 
Source: Oken 1982 
8.13. 
Pharmacokinetics 
l 
8.14. 
Tumor Tissue 


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r 
 
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10. 
 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1. 
Data Quality Assurance 
The Sponsor or Sponsor’s 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 patient. 
All information recorded in the EDC system for the 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 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. 
Prescreening Informed Consent 
Potential patients who meet the any of the criteria on local testing specified in Inclusion Criteria 
#7 (Section 5.1) may be asked to consent to prescreening. 
By signing the prescreening consent, the patient will authorize the study personnel to obtain 
archival tumor tissue and have it processed at a central laboratory. Prescreening eligibility does 
not guarantee study enrollment and the patient must consent to the main study before any 
Screening activities may commence. Patients who have central testing of TP53 and MDM2 gene 
status performed under prescreening consent may use the same tissue for submission 
requirement. 
11.2. 
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 dated and retained by the Investigator or designee (designee must be listed 
on the Delegation of Authority Log or equivalent) as part of the study records. The Investigator 
will not undertake any investigation specifically required only for the clinical study 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 and dated 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 for analysis and correlative studies. 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. 


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11.3. 
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 Sponsor’s 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, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to 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. 
11.4. 
Duration of the Study 
The total study duration is estimated to be 3 years, including approximately 12 months for 
accrual and approximately 5 months for follow--up after the last patient is enrolled. Patients are 
expected to receive up to 12 months of treatment. The end of the study is defined as the last 
patient visit or contact, including telephone contacts, for collection of any study-related data.  
11.5. 
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 
study drug 
11.6. 
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 IB 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/IEC is expressly permitted, the IRB/IEC members having the same obligation of 
confidentiality. 


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The Investigator shall consider as confidential and 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 Sponsor’s designee by their 
patient number, initials, and/or birth date, not by name. Documents not to be submitted to the 
Sponsor or Sponsor’s designee that identify the patient (e.g., the signed informed consent) 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 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 the 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. 
CRFs and Source Documentation 
All data obtained during the 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 Sponsor’s 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. 


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12.1.1. 
Data Collection 
The Investigators (and appropriately authorized staff) will be given access to an online 
web-based EDC system that is compliant with the ICH guidelines for Good Clinical Practice 
(ICH E6). This system is specifically designed for the collection of clinical data in electronic 
format. Access and rights 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. 
The eCRF should be completed for each patient included in the study and reflect the latest 
observations on the patient. 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 online. All discrepancies will be solved online 
directly by the Investigator or authorized staff. Offline 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 in the eCRF.  
12.2. 
Access to Source Data 
Patients are informed about 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 and 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 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 


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study monitors for resolution with the Investigator. The database will be updated based on signed 
corrections.  
Concomitant medications will be coded using the WHO Drug Global dictionary, which employs 
the Anatomical Therapeutic Chemical classification system. Medical history, current medical 
conditions, and AEs will be coded using MedDRA terminology. The versions of the 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 
The Investigator shall retain study drug disposition records and all source documentation (such 
as original ECG tracings and laboratory reports, in subject or office subject records) for the 
maximum period required by the country and institution where the study will be conducted or for 
the period specified by Rain, whichever is longer. The investigator must contact Rain prior to 
destroying any records associated with the study. If the investigator withdraws from the study 
(due to relocation, retirement, etc.), the records shall be transferred to a mutually agreed upon 
designee, such as another investigator or IRB/IEC. Notice of such transfer will be provided in 
writing to Rain. 
Rain Therapeutics Inc. 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 
Fakharzadeh SS, Trusko SP, George DL. Tumorigenic potential associated with enhanced 
expression of a gene that is amplified in a mouse tumor cell line. EMBO J. 1991;10(6):1565-9. 
Flørenes VA, Maelandsmo GM, Forus A, et al. MDM2 gene amplification and transcript levels 
in human sarcomas: relationship to TP53 gene status. J Natl Cancer Inst. 1994;86(17):1297-302. 
Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia: ESMO Clinical 
Practice Guidelines. Ann Oncol. 2016;27(suppl 5):v111-v118. doi:10.1093/annonc/mdw325 
Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 
2009 Oct; 9(10):749-58. 
National Cancer Institute. Genomic Data Commons Data Portal. https://portal.gdc.cancer.gov/ 
National Cancer Institute; Surveillance, Epidemiology, and End Results Program. Cancer Stat 
Facts. Cited November 2022. Available from: https://seer.cancer.gov/statfacts. 
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. 
Park SY, Doolittle-Amieva C, Moshiri Y, Akaike T, Parvathaneni U, Bhatia S, et al. How we 
treat Merkel cell carcinoma: within and beyond current guidelines. Future Oncol. 2021 
Apr;17(11):1363-1377. doi: 10.2217/fon-2020-1036. 
Pugh TJ, Bell JL, Bruce JP, et al. AACR Project GENIE: 100,000 Cases and Beyond. Cancer 
Discov. 2022;12(9):2044-2057. doi:10.1158/2159-8290.CD-21-1547 
Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S, et al. Temporal activation of p53 by 
a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth 
inhibition. Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3933-8. 
Shangary S, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to 
reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol. 
2009; 49:223-41. 
Sherr CJ, Weber JD. The ARF/p53 pathway. Curr Opin Genet Dev. 2000 Feb;10(1):94-9. 
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth Factors: 
American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 
2015;33(28):3199-3212. doi:10.1200/JCO.2015.62.3488 
Tirunagaru VG, Gounder MM, Kumar P, Hong D, Doebele RC. MDM2 gene amplification as a 
predictive biomarker for the MDM2 inhibitor milademetan. Poster presented at: AACR-NCI-
EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 
Oct 7-10. 
Vassilev LT. MDM2 inhibitors for cancer therapy. Trends Mol Med. 2007;13(1):23-31.  


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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):844-8. 
 


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APPENDIX B. DECLARATION OF THE INVESTIGATOR 
All documentation for the study that is supplied to me and has not been previously published will 
be kept in the strictest confidence. This documentation includes the study protocol, milademetan 
Investigator's Brochure, electronic data capture system, and other scientific data. I have read and 
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 study drug is 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 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 study 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 the requirements of 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 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 the submission 
Responsible Investigator 
 
 
 
Signature 
 
Date 
Name (Printed) 
 
 
Title (Printed) 
 

SAP_001.pdf: 
 
Statistical Analysis Plan RAIN-3202  
28 Oct 2023  
Rain Oncology, Inc.  
Confidential and Proprietary 
 
 
 
 
 
 
Statistical Analysis Plan 
 
A Phase 2 Basket Study of Milademetan in Advanced/Metastatic Solid Tumors 
 
Sponsor: 
Rain Oncology, Inc. 
8000 Jarvis Avenue 
Suite 204 
Newark, CA 94560 
USA 
 
Protocol No.: 
 
RAIN-3202 
 
Investigational Drug Name: 
 
Milademetan (RAIN-32)  
Phase: 
2 
Date of Plan: 
 
 
V1.0   28 October 2023 
 
 
 
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 Oncology, Inc. 
Do not copy or distribute without written permission from Rain Oncology, Inc. 
CONFIDENTIAL 


 
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APPROVAL & SIGNATURE PAGE 
 
Protocol No.: RAIN-3202 
Version:  v1.0 
The Statistical Analysis Plan has been reviewed and approved by:  
 
 


 
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Table of Contents 
LIST OF ABBREVIATIONS ............................................................................................. 4 
1. 
INTRODUCTION .................................................................................................... 6 
2. 
STUDY OBJECTIVES ............................................................................................ 6 
2.1 
Primary Objective .......................................................................................... 6 
2.2 
Secondary Objectives .................................................................................... 6 
2.3 
Exploratory Objectives ................................................................................... 6 
3. 
STUDY DESIGN OVERVIEW ................................................................................ 7 
3.1 
Overall Design ............................................................................................... 7 
3.2 
Sample Size Considerations .......................................................................... 7 
4. 
STUDY ENDPOINTS AND COVARIATES ............................................................. 7 
4.1 
Primary Endpoint ........................................................................................... 8 
4.2 
Secondary Endpoints ..................................................................................... 8 
4.3 
Exploratory Endpoints .................................................................................... 8 
5. 
ANALYSIS POPULATIONS ................................................................................... 9 
5.1 
Full Analysis Population ................................................................................. 9 
5.2 
Centrally Confirmed Population ..................................................................... 9 
5.3 
Pharmacokinetics (PK) Population ................................................................. 9 
6. 
STATISTICAL METHODS OF ANALYSIS .............................................................. 9 
6.1 
General Principles and Reporting Conventions .............................................. 9 
6.2 
Subject Accountability .................................................................................. 10 
6.3 
Demographic and Baseline Characteristics ................................................. 10 
6.4 
Efficacy Analyses......................................................................................... 11 
6.5 
Safety Analysis ............................................................................................ 12 
6.6 
Pharmacokinetics Analysis .......................................................................... 15 
6.7 
Exploratory Biomarker Analysis ................................................................... 15 
7. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ....................... 15 
8. 
LIST OF PLANNED TABLES ............................................................................... 16 
9. 
LIST OF PLANNED FIGURES ............................................................................. 18 
10. 
LIST OF PLANNED DATA LISTINGS .................................................................. 19 
11. 
REFERENCES ..................................................................................................... 20 
 


 
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LIST OF ABBREVIATIONS  
  
Abbreviation  
Term  
AE  
Adverse Event  
BMI  
Body Mass Index  
CCP 
Centrally Confirmed Population 
CR  
Complete Response  
CRF  
Case Report Form  
CSR  
Clinical Study Report  
CTCAE  
Common Terminology Criteria for Adverse Events  
DOR  
Duration of Response  
ECOG  
Eastern Cooperative Oncology Group  
ECG  
Electrocardiogram  
EORTC QLQ-C30  
European Organization for the Research and Treatment of Cancer 
Quality of Life Questionnaire  
EOS  
End of Study  
FAP 
Full Analysis Population 
GMI  
Growth Modulation Index  
MedDRA  
Medical Dictionary for Regulatory Activities  
MDM2 
Mouse Double Minute 2 
ORR  
Objective Response Rate  
OS  
Overall Survival  
PD  
Progressive Disease  
PFS  
Progression-Free Survival  
PK  
Pharmacokinetics  
PR  
Partial Response  
PT  
Preferred Term  
QoL  
Quality of Life  
RECIST  
Response Evaluation Criteria in Solid Tumors  
SAE  
Serious Adverse Event  
SAP  
Statistical Analysis Plan  
SD  
Stable Disease  
SOC  
System Organ Class  
TEAE  
Treatment-Emergent Adverse Event  


 
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TP53 
Tumor Protein 53 
TTP 
Time to Progression 
WHODrug  
World Health Organization Drug Reference List  
   


 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) outlines the statistical methods to be implemented within the 
scope of Protocol RAIN-3202 entitled “A Phase 2 Basket Study of Milademetan in 
Advanced/Metastatic Solid Tumors”. 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 
data base lock. Results of the proposed 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 determine the objective response rate (ORR) of treatment with 
milademetan in patients with advanced/metastatic solid tumors with murine double minute 2 
(MDM2) gene amplification. 
2.2 
Secondary Objectives  
The secondary objectives are: 
 
To assess treatment with milademetan for the following efficacy parameters: 
o Duration of response (DOR) 
o Progression-free survival (PFS) 
o Growth modulation index (GMI) 
o Disease control rate (DCR) 
o Overall survival (OS) 
 
To assess the safety profile of milademetan 
 
To evaluate patient-reported health-related quality of life with the European Organisation 
for Research and Treatment of Cancer Quality-of-Life Questionnaire, Core 30 (QLQ-
C30) 
2.3 
Exploratory Objectives 


 
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3. 
STUDY DESIGN OVERVIEW 
3.1 
Overall Design 
This is a Phase 2, multicenter, single-arm, open-label basket study designed to evaluate the 
safety and efficacy of milademetan in patients with advanced or metastatic solid tumors 
refractory or intolerant to standard-of-care therapy that exhibit wild-type (WT) tumor protein 53 
(TP53) gene and MDM2 copy number (CN) ≥ 8 using prespecified biomarker criteria. 
Approximately 65 patients will be enrolled to receive milademetan. 
Patients will receive the study drug until reaching disease progression (per Response 
Evaluation Criteria in Solid Tumors [RECIST] version [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). Long-term follow-up will continue every 8 weeks (± 7 days) until 
the endpoint of death, the patient is lost to follow-up, or for 24 months following the final dose of 
the study drug, whichever comes first.  
3.2 
Sample Size Considerations  
4. 
STUDY ENDPOINTS AND COVARIATES 


 
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4.1 
Primary Endpoint 
The primary efficacy endpoint is ORR. The ORR is defined as the percentage of patients who 
have achieved a confirmed CR or PR. Tumor response will be assessed in accordance with 
RECIST v1.1. 
4.2 
Secondary Endpoints  
Secondary efficacy endpoints include:  
 
The DOR, defined as the time from the date of first response to the date of disease 
progression or death for patients with an objective response 
 
The PFS, defined as the time from the date of first dose to the earliest date of the first 
objective documentation of radiographic disease progression or death due to any cause  
 
The GMI will be determined using the ratio of time to progression (TTP) with nth line of 
therapy (TTPn; here defined as milademetan) to the most recent prior line of therapy 
(TTPn-1)  
 
The DCR, defined as the percentage of patients who have achieved confirmed CR, PR, 
or stable disease (SD) for ≥ 16 weeks 
 
Overall survival, as measured from the date of the first dose of the study drug to the date 
of death due to any cause 
Health-related quality-of-life endpoints include the QLQ-C30. 
Safety endpoints include the incidence of TEAEs (including SAEs, TEAEs leading to dose 
reductions and TEAEs leading to discontinuation of study drug); changes in clinical laboratory 
parameters (hematology, serum or plasma chemistry), deaths, vital signs, and ECG parameters 
(especially QT intervals); physical examination results; and use of concomitant medications. 
4.3 
Exploratory Endpoints  
 
t 


 
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5. 
ANALYSIS POPULATIONS 
5.1 
Full Analysis Population  
5.2 
Centrally Confirmed Population  
5.3 
Pharmacokinetics (PK) Population  
The pharmacokinetics population consists of all patients who have evaluable PK data. 
Exploratory pharmacokinetics analyses will be performed using the PK population. 
6. 
STATISTICAL METHODS OF ANALYSIS 
6.1 
General Principles and Reporting Conventions 
In general, efficacy and safety analysis in this study will be summarized across all tumor types. 
Analysis may be performed for specific tumor types when appropriate.  


 
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If departures from these general conventions are present in the specific evaluations section of 
this SAP, then those conventions will take precedence over these general conventions.   
6.2 
Subject Accountability 
6.2.1 
Disposition of Patients  
The number and percentage of patients who were enrolled and treated with study drug will be 
tabulated. End of treatment and end of study will be summarized by reasons.  
6.3 
Demographic and Baseline Characteristics 
Demographic data, medical history, concomitant disease, and concomitant medication will be 
summarized by means of descriptive statistics or frequency tables for the FAP.      
6.3.1 
Demographic Characteristics  
The following demographic variables will be summarized:  
 
age (years)  
 
age group (<65, ≥ 65 years)   
 
sex  
 
race (Asian, American Indian or Alaska Native, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Other) 
 
ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 
height (cm)  
 
weight (kg)  
 
body mass index (BMI) calculated as: BMI (kg/m2) = Weight (kg)/ (Height(cm) * 
0.01)2  
6.3.2 
Baseline Disease Characteristics  
The following baseline disease characteristics will be summarized:  
 
ECOG  
 
Number of prior lines of therapy  
 
Tumor type 
 
Stage at initial diagnosis 
 
Stage at study entry 
 
TNM stage 
 
MDM2 copy number (central and local) 
 
Time from initial diagnosis 
 
Time from metastatic diagnosis 


 
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 
Tumor status 
 
Brain metastases (Present/Absent) 
6.3.3 
Prior Cancer Therapy 
Prior radiation, cancer related surgy, cancer therapy will be summarized with indication. Number 
of prior lines of therapy for metastatic disease, best response of each line of therapy will be 
summarized.  
6.3.4 
Medical History  
Medical history data will be summarized in frequency table.   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/ 
Day1 in accordance with the Schedule of Procedures included in the protocol.  
6.3.5 
Prior and 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 
(WHODrug) dictionary B3 Global March 2021 and summarized in a frequency table.  
6.4 
Efficacy Analyses 
The efficacy analysis of the study will be performed in the CCP.  The analysis of ORR and other 
RECIST endpoints will be according to the investigator’s tumor assessments. 
6.4.1 
Objective Response Rate (ORR) 
Objective response rate is defined as the proportion of patients demonstrating an objective 
response during the study. Objective response includes complete responses (CR) and partial 
responses (PR) as defined in the RECIST 1.1 criteria and must be subsequently confirmed at 
least 4 weeks later.  
 
6.4.2 
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 progressive disease (PD) or 
death is objectively documented. Patient is censored at the last valid tumor assessment if PD or 
death has not been documented.   


 
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6.4.3 
Progression Free Survival (PFS)  
The PFS is defined as the time from the date of the first dose of the study drug to the earliest 
date of the first objective documentation of radiographic disease progression or death due to 
any cause according to Investigator assessment. Patients without documented 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 first dose 
date.   
6.4.5 
Disease Control Rate (DCR)  
The DCR is defined as the percentage of patients with confirmed CR, PR, or SD for at least 16 
weeks (+/- 1 week window) according to RECIST v1.1 recorded in the period between the date 
of first study drug dose and disease progression or death due to any cause. 
6.5 
Safety Analysis  
6.5.1 
Overview of Safety Analysis Methods  
All safety analysis will be performed for all patients in the Full Analysis Population. The following 
assessments will be used to evaluate the safety of milademetan:   
• 
Adverse events (AEs)  
• 
Medical history  
• 
Vital sign measurements  
• 
Physical examination findings  
• 
Electrocardiogram (ECG)   
• 
Liver Function Tests results (Hy’s law) 
• 
Eastern Cooperative Oncology Group (ECOG) performance status  
• 
Laboratory assessments   


 
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6.5.2 
Extent of Exposure  
Extent of exposure to milademetan will be summarized by total dose, number of cycles, number 
of dose interruptions and number of dose reductions.  
Dose intensity and relative dose intensity for milademetan will also be summarized. 
Dose intensity will be calculated as the cumulative dose of the drug divided by total number of 
scheduled dosing days during the treatment. 
 
6.5.1 
Concomitant Medications  
Concomitant medications will be defined as medications documented on the Concomitant 
Medications CRF and started on or after the C1D1.  Concomitant medications will be coded 
using the World Health Organization (WHODrug) dictionary B3 Global March 2021 version and 
summarized in a table.  
6.5.2 
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 MedDRA v24.0 or later and graded by the Investigator according to the NCI CTCAE v5.0 
or later. 
Summaries of adverse event will in general focus on treatment emergent adverse events 
(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.  
Subject incidence of the following events will be tabulated: 
 
All TEAEs 
 
SAEs 
 
SAEs not associated with transfusion 
 
Treatment-related TEAEs  


 
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 
Treatment-related SAEs 
 
Grade 3 or 4 TEAEs 
 
TEAE leading to treatment discontinuation, dose reduction, dose interruption 
Listings of TEAEs leading to IP discontinuation, and SAEs will be provided. Listings will be 
sorted by patient ID and study day; All AE listings will include patient ID, study day, SOC, PT, 
reported term, AE onset date, AE end date, outcome, duration, relationship to drug, action 
taken, and severity.    
The incidence of death will be summarized by cause of death 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.  
6.5.3 
Clinical Laboratory Evaluation  
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 value and the change from 
baseline.  Additionally, clinically significant abnormalities in laboratory results will be 
summarized for the post-baseline cycles/visits using frequencies and percentages. Shifts in 
CTCAE grade between baseline and subsequent visits will be summarized as well. 
6.5.4 
Vital Signs and Physical Examinations  
Vital signs, including systolic and diastolic blood pressure, heart rate, and body temperature, as 
well as respiration rate will be collected each visit.  
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 value and the change from baseline. 
Physical examination results will be summarized, and the frequency of clinically significant 
changes will be tabulated.  
6.5.5 
Electrocardiograms  
The ECG will include heart rate, RR, PR, QRS, and QT intervals. The ECG will be read and 
interpreted at the investigational site for patient safety monitoring.  


 
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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 using descriptive statistic.  
6.5.6 
Liver Function Test Results  
A listing will be generated for patients potentially meeting Hy’s Law criteria (total bilirubin >= 
(2xULN) and AST or ALT > (3xULN) 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.  
6.5.7 
ECOG Performance Status  
ECOG performance status will be assessed at Day 1 and Day 15 in Cycles 1 to 3, Day 1 only in 
Cycles 4 and beyond, 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. 
6.6 
Pharmacokinetics Analysis 
Standard PK parameters will be estimated for milademetan based on available drug 
concentration data. PK data will be summarized in tables using descriptive statistics at each 
time point. 
6.7 
Exploratory Biomarker Analysis  
7. 
 CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL  
 


 
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8. 
LIST OF PLANNED TABLES  
Category  
Title  
Disposition 
Summary of Subject Disposition  
Demography and 
Baseline Characteristics 
Summary of Demographics  
 
Summary of Baseline Disease Characteristics 
Medical History  
Summary of Medical History   
Prior Cancer Therapy 
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  
Study Medication  
Summary of Treatment Exposure  
  
Summary of Treatment Dose Reduction  
  
Summary of Treatment Dose Hold  
Efficacy  
Summary of Objective Response Rate  
 
Summary of PFS 
  
Summary of Disease Control Rate  
 
Summary of GMI 
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 Serious 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 Preferred Term 
  
Incidence of Grade 3 or 4 TEAE by System Organ Class, and 
Preferred Term  


 
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Summary of Death  
Laboratory  
Mean and Mean Change from Baseline in Numeric Laboratory Data:  
Hematology/ Clinical Chemistry/Coagulation/Urinalysis  
  
Frequency Table of Clinically Significant Laboratory Data:  
Hematology/ Clinical Chemistry Coagulation//Urinalysis  
  
Shift from Baseline in Laboratory Data:  Hematology/ Clinical 
Chemistry/ Coagulation/Urinalysis  
PK 
Summary of Plasma Concentration of Milademetan by Scheduled 
Time Point 
 
Summary of PK parameters of Milademetan  
Vital Signs  
Mean and Mean Change from Baseline in of Vital Signs Data  
  
Frequency Table of Clinically Significant Vital Signs Data   
Physical Exam  
Summary of Physical Examination  
ECG 
Mean and Mean Change from Baseline in ECG Data  
 
Frequency Table of Clinically Significant Values in ECG 
Liver Function  
Summary of Liver Function Parameters for Potential Hy’s Law 
ECOG 
Summary of ECOG by Visit 
 


 
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9. 
LIST OF PLANNED FIGURES  
Category 
Title  
  


 
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10. 
LIST OF PLANNED DATA LISTINGS  
Category 
Title  
 Safety 
Listing of Serious Adverse Events  
  
Listing of Adverse Events Leading to Treatment Discontinuation  
  
Listing of Deaths  
  
Listing of Potential Hy’s Law Cases  
  


 
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11. 
REFERENCES  
 
RECIST Guidelines version 1.1. EJC 45 (2009) 228-247 
 
FDA Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs 
and Biologics.  
 
EORTC QLQ-C30 Scoring Manual; European Organisation for Research and Treatment 
of Cancer, Brussels 2001 
 
Fairclough D.  Design and Analysis of Quality of Life Studies in Clinical Trials.  Chapman 
& Hall.  2002. 
 
Brookmeyer R, Crowley J.  A Confidence Interval for the Median Survival Time.  
Biometrics 1982;38:29-41 
 
Allison PD.  Survival Analysis Using the SAS System: A Practical Guide.  SAS Institute 
Inc.  1997 
 
R Core Team (2023). R: A Language and Environment for Statistical Computing. R 
Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/.