Clinical trial NCT01877382
Conditions: Advanced Solid Tumor Lymphoma
Sponsor: Daiichi Sankyo
Start date: 2013-07-11; Completion date: 2020-12-03
Enrollment: 107 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This will be a Phase 1, open-label study of milademetan to assess its safety and tolerability, identify a maximum tolerated dose (MTD)/tentative recommended phase 2 dose (RP2D), and assess its pharmacokinetic (PK)/ pharmacodynamic (PDy) properties in participants with advanced solid tumors or lymphomas.

Approximately 5 US sites are planned for Part 1 (Dose Escalation) and Part 2 (Dose Expansion). The same sites are planned to participate for both parts.

Detailed description:

Arms: arm 1: Participants receive milademetan alone with different dose schedules. arm 2: Participants with advanced melanoma and diffuse large B cell lymphoma (DLBCL) receive milademetan alone with different dose schedules.
Interventions: intervention 1: Milademetan intervention 2: Milademetan
Intervention descriptions: intervention 1: DS-3032b will be administered as an oral capsule. It will be supplied in 5, 20, 80, and/or 200 mg capsules individually packaged in desiccant-embedded aluminum blisters. intervention 2: Milademetan will be administered as a single oral capsule or as a combination of multiple oral capsules containing 5, 20, 80, and/or 200 mg. An alternate combination of 30 and/or 100 mg capsules of milademetan may be utilized.

Protocol documents:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
Page 1 
CLINICAL STUDY PROTOCOL 
 
A PHASE 1 MULTIPLE ASCENDING DOSE STUDY OF 
MILADEMETAN, AN ORAL MDM2 INHIBITOR, IN 
SUBJECTS WITH ADVANCED SOLID TUMORS OR 
LYMPHOMAS 
 
PROTOCOL NUMBER: DS3032-A-U101 
IND NUMBER: 118125 
 
VERSION 4.0, 04 FEB 2020 
VERSION 3.0, 29 SEP 2015 
VERSION 2.0, 03 MAR 2015 
VERSION 1.0, 25 MAR 2013 
 
DAIICHI SANKYO, INC. 
211 Mt. Airy Road 
Basking Ridge, NJ 07920-2311 
United States 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo, Inc.  The information is 
provided to you in confidence which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement.  Do not give this document or any copy of it or reveal 
any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
Daiichi Sankyo, Inc. 


PPD
PPD


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SUMMARY OF CHANGES 
Amendment Rationale: 
This amendment was prepared to allow evaluation of less frequent dosing schedules of once 
daily for 7 out of 28 days (QD 7/28) and QD for 3 out of 14 days (QD 3/14) repeated twice in a 
28-day cycle; remove restrictions on the timing of meal relative to the drug administration, 
remove the restriction of concomitant use of medications that are strong inhibitors of 
cytochrome P450 (CYP) 3A. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.   
Changes to the Protocol: 
Please refer to the comparison document for protocol Version 4.0 (dated, 04 Feb 2020) vs. 
protocol Version 3.0 (dated, 29 Sep 2015) for actual changes in-text.  The summary of changes 
below is a top-line summary of major changes in the current DS3032-A-U101 clinical study 
protocol (Version 4.0) by section. 
CONVENTIONS USED IN THIS SUMMARY OF CHANGES 
All locations (Section numbers and/or paragraph/bullet numbers) refer to the current protocol version, 
which incorporates the items specified in this Summary of Changes. 
Minor edits, such as updates to language that do not alter original meaning, update to version numbering, 
formatting, change in font color, corrections to typographical errors, use of abbreviations, moving 
verbiage within a section or table, change in style, or changes in case, are not noted in the table below. 
Section # and Title 
Description of Change 
Brief Rationale 
General 
Changed DS-3032b to 
milademetan. 
International nonproprietary 
name provided. 
Cover Page 
Company name and address 
changed. 
Company name changed and 
moved to new location. 
Sponsor Approval 
Approver changed to Prasanna 
Kumar, PhD. 
Change in personnel. 
Protocol Synopsis (Part 1 
Secondary Objectives)  
Section 3.1.2.1 Part 1 (Dose 
Escalation) 
Part 1 Secondary Objectives: 
moved from exploratory to 
secondary objective:  
To evaluate the response of solid 
tumors and lymphoma and their 
subtypes to milademetan using 
the Response Evaluation Criteria 
in Solid Tumors (RECIST) v 1.1 
or International Working Group 
(IWG) criteria.  
To include efficacy signals as 
one of the criteria to select the 
most optimal dosing schedule 
during dose escalation. 


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Section # and Title 
Description of Change 
Brief Rationale 
Protocol Synopsis (Part 1 
Exploratory Objectives)  
Protocol Synopsis (Part 2 Dose 
Expansion, Exploratory 
Objectives) 
Section 3.1.3.1 Part 1 (Dose 
Escalation) 
Section 3.1.3.2 Part 2 (Dose 
Expansion) 
Added assessment of blood and 
tumor samples for 
deoxyribonucleic acid (DNA) and 
ribonucleic acid (RNA) analysis. 
For molecular analysis of tumor 
DNA and RNA and circulating 
free DNA to identify predictors 
of response, resistance and 
toxicity to milademetan. 
Protocol Synopsis (Part 1 
Exploratory Objectives) 
Protocol Synopsis (Part 2 Dose 
Expansion, Exploratory 
Objectives) 
Section 3.1.3.1 Part 1 (Dose 
Escalation)  
Section 3.1.3.2 Part 2 (Dose 
Expansion) 
Deleted specifics of assessing 
pharmacodynamic (PDy) effect 
on reticulocyte and absolute 
neutrophil count and added if 
samples are available. 
Language edited for flexibility, 
since post-treatment tumor 
samples are not always 
available. 
Protocol Synopsis (Part 2 Dose 
Expansion, Secondary Objectives) 
Section 3.1.2.2 Part 2 (Dose 
Expansion) 
Deleted evaluation of relationship 
of tumor response to milademetan 
and predictive biomarkers. 
Moved to exploratory objective 
because validated predictive 
biomarkers are not available 
yet. 
Protocol Synopsis (Part 2 Dose 
Expansion, Exploratory 
Objectives) 
Protocol Synopsis (Study Design) 
Protocol Synopsis (Study Design-
Part 2 Dose Expansion in Subjects 
with Advanced Melanoma or 
DLBCL) 
Figure 2: Flow Diagram of Food 
SubStudy Part 2  
Section 3.1.3.2 Part 2 (Dose 
Expansion) 
Section 7.3.2.2. Part 2 (Dose 
Expansion), Cycle 1/Day 1) 
Section 7.3.2.7. Part 2 (Dose 
Expansion), Cycle 2/Day 1) 
Section 7.3.2.8. Part 2 (Dose 
Expansion), Cycle 2/Day 2) 
Deleted food effect component of 
study; deleted from objective, 
study design. 
A separate food effect study on 
milademetan pharmacokinetic 
(PK) (DS3032-A-U115) has 
been completed.  
Protocol Synopsis (Part 2 Dose 
Expansion, Exploratory 
Objectives) 
Added evaluation of relationship 
between tumor response to 
milademetan and predictive 
Moved from secondary 
objective to exploratory 
objective; the biomarkers are 


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Section # and Title 
Description of Change 
Brief Rationale 
Section 3.1.3.2 Part 2 (Dose 
Expansion) 
biomarkers in tumor samples. 
still under exploration. 
Protocol Synopsis (Primary and 
Secondary outcome measure) 
Section 3.2 Outcome Measures 
Section 3.2.1 Primary Outcome 
Measures 
Section 3.2.2 Secondary Outcome 
Measures 
Added outcome measures and 
corresponding details for each; 
timeframe from start of study for 
approximately 6 years for all; end 
differs as detailed).  Outcome 
measures are: 
Primary: number of subjects with 
treatment-emergent adverse 
events (TEAEs) during study 
until last subject last visit, 
maximum tolerated dose until 
final data base lock, number of 
subjects with dose-limiting 
toxicities (DLTs) until the DLT 
evaluation of the last subject in 
dose escalation part, response 
rates in melanoma and diffuse 
large B-cell lymphoma (DLBCL) 
in dose expansion cohorts until 
last subject last tumor assessment 
in Dose Expansion. 
Secondary: PK parameters and 
pharmacodynamic effect of 
milademetan until final database 
lock. 
New Daiichi Sankyo, Inc. 
requirement to comply with 
CTgov and EudraCT disclosure 
guidelines. 
Protocol Synopsis (Study Design) 
Added schedule for dose 
escalation: 
(eg, QD 28/28, QD 7/28, QD 3/14 
× 2). 
Clarification. 
Protocol Synopsis (Study Design-
Part 1 Dose Escalation) 
 
Revised maximum tolerated dose 
(MTD) model: removed modified 
continuous reassessment method 
(mCRM) throughout; kept 
Bayesian logistic regression 
model (BLRM). 
Replaced mCRM with BLRM 
throughout. 
Clarification that the escalation 
is essentially based on BLRM. 


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Section # and Title 
Description of Change 
Brief Rationale 
Protocol Synopsis (Study Design-
Part 1 Dose Escalation-Dose 
escalation using alternative drug 
administration schedule) 
Section 4.1.2.1 Part 1 (Dose 
Escalation) 
Added less frequent dosing 
schedule to be evaluated with a 
starting dose of 120 mg that was 
the MTD determined in the 
QD × 21/28-day schedule: 
QD for 7 out of 28 days (QD × 
7/28 days) 
QD for 3 out of 14 days (QD × 
3/14 days) repeated twice in a 
28-day cycle 
Alternative less frequent dosing 
schedule to optimize 
milademetan treatment in dose 
escalation. 
Protocol Synopsis (Study Design-
Part 2 Dose Expansion in Subjects 
with Advanced Melanoma or 
DLBCL) 
Section 4.1.2.2 Part 2 (Dose 
Expansion in Subjects With 
Advanced Melanoma or DLBCL) 
Revised text for definition of 
when dose expansion will begin 
to the establishment of 
MTD/tentative recommended 
Phase 2 dose (RP2D) and drug 
administration schedule in Part 1.  
Revised text from PDy response 
to PDy signals. 
Added assessment will be in 
approximately 20 subjects and 
added that tumors tested positive 
for wild type gene encoding p53 
(TP53) genotype. 
Clarification. 
Protocol Synopsis (Study Design-
Part 2 Dose Expansion in Subjects 
with Advanced Melanoma or 
DLBCL) 
Section 4.1.2.2 Part 2 (Dose 
Expansion in Subjects With 
Advanced Melanoma or DLBCL) 
Modified sentence: 
If the incidence of adverse events 
fulfilling the criteria of a DLT has 
exceeded that predicted by the 
escalation with overdose control 
(EWOC) principle, after the 
initial 4 DLT-evaluable subjects 
or after further enrollment, no 
further testing at the 
MTD/tentative RP2D level 
established in Part 1 will be done 
and dose de-escalation or 
treatment at alternative dose 
schedules may be considered for 
further evaluation of safety and 
efficacy. 
Clarification. 
Protocol Synopsis (Study Design-
Part 2 Dose Expansion in Subjects 
with Advanced Melanoma or 
DLBCL) 
Edited the language to clarify that 
20 subjects each of melanoma and 
DLBCL with wild type TP53 will 
be enrolled in Part 2 classifier 
criteria. 
Clarification. 
Protocol Synopsis (Study Design-
Added to include dose expansion. 
Clarified who needs to be 


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Section # and Title 
Description of Change 
Brief Rationale 
Part 2 Dose Expansion TP53 
genotyping, subject enrollment 
and early discontinuation 
criteria)- 
Modified language that only the 
investigator will be informed if 
the test confirms the presence of 
inactivating TP53 mutations. 
Removed allowing subject to 
continue if genotyping 
indeterminate. 
Removed details of methodology 
of TP53 genotyping, 
specifications of type of samples, 
handling of results, and re-testing. 
informed and the result that 
should be shared with the 
investigator as it pertains to the 
study conduct.  
Protocol Synopsis (Part 2 [Dose 
Expansion in Subjects with 
Advanced Melanoma or 
DLBCL]) 
Section 4.1.2.2. Part 2 (Dose 
Expansion in Subjects With 
Advanced Melanoma or DLBCL)  
Added to end of section:  
“for further evaluation of safety 
and efficacy.” 
Clarification. 
Protocol Synopsis (Dose-Limiting 
Toxicity Definition) 
Section 4.1.5.2 Dose-limiting 
Toxicities 
Deleted Grade ≥ 3 for febrile 
neutropenia. 
Febrile neutropenia is already 
Grade ≥ 3. 
Protocol Synopsis (Study Design-
Part 2 Dose Expansion TP53 
genotyping, subject enrollment, 
and early discontinuation 
criteria)- 
Protocol Synopsis (Subject 
Eligibility Criteria) 
Section 5.1.2 Exclusion Criteria 
Section 5.2 Removal of Subjects 
from Therapy 
Section 5.2.1 Reasons for 
Withdrawal/Early Discontinuation 
Section 9.2.1. TP53 Status 
In synopsis: deleted redundant 
text and added inclusion criterion 
14, applicable to Part 2 only: 
subject willing to undergo pre-
treatment tumor biopsies.  
Exclusion criteria header revised 
to indicate criteria apply to both 
Part 1 and Part 2. 
Deleted “contains a 
nonsynonymous mutation” 
Added “contains an inactivating 
mutation” 
Added “contains an inactivating 
mutation” to Part 1 and Part 2 
exclusion criteria. 
Added clarification that whenever 
subject withdraws, they will be 
followed for 30 days or beyond 
until resolution of toxicity. 
“Containing an inactivating 
mutation” or “contain an 
inactivating mutation” added 
for further clarity. 
Protocol Synopsis (Study 
Duration) 
Changed from 3 to 6 years. 
Update of study duration. 
Protocol Synopsis (Study Sites 
Modified that 5 sites to be used 
Clarification that the same sites 


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Section # and Title 
Description of Change 
Brief Rationale 
and Location) 
for both escalation and expansion. to be used for both parts. 
Protocol Synopsis (Planned 
Sample Size) 
Changed text to potentially 
evaluate multiple dosing 
schedules. 
Added that sample size is not 
known because of the multiple 
dosing schedules to be evaluated 
to determine the most optimal 
schedule. 
Defined subject population 
further as advanced melanoma 
and DLBCL. 
Removed details on obtaining 10 
biomarker positive subjects. 
Update on sample size 
Protocol Synopsis (Planned 
Sample Size) 
Section 12.10 Sample size 
Determination 
Removed: 
“with biomarker-positive tumors” 
from paragraph: 
For the Dose Expansion phase 
(Part 2), approximately 
20 subjects (each of subjects with 
advanced melanoma and DLBCL) 
will be enrolled.   
Clarification. 
Protocol Synopsis (Subject 
Eligibility Criteria) 
 
Section 5.1.1 Inclusion Criteria 
For Part 2 Inclusion Criteria, 
removed text indicating additional 
inclusion criteria for solid 
tumor/lymphoma expansion; 
revised to melanoma/DLBCL. 
For Part 1 and Part 2: 
Added bullet under criteria 1 that 
subjects with certain tumor types 
(eg, well-differentiated 
(WD)/dedifferentiated (DD) 
liposarcoma) may be 
preferentially enrolled in Part 1. 
Clarification. 
Protocol Synopsis (Statistical 
Analysis) 
Added for tumor response that 
additional efficacy analyses, 
including progression free 
survival and spider plots, will be 
detailed in the statistical analysis 
plan (SAP). 
Clarification. 
Section 2.1.1.5. Nonclinical 
Studies 
Deleted nonclinical sections for 
pharmacology, safety 
pharmacology, absorption, 
distribution, metabolism, 
Clinical data are now available 
and this information moved to 
the current Investigator’s 
Brochure (IB). 


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Section # and Title 
Description of Change 
Brief Rationale 
excretion, toxicokinetics, 
toxicology, and phototoxicity. 
Section 2.1.1.5.1 Human Starting 
Dose 
Section 2.1.1.6 Clinical 
Experience 
Section 2.3.1 Potential Risks 
Associated with Milademetan 
2.3.2 Potential Risk of Drug-Drug 
Interaction 
Text added for reader to refer to 
current IB. 
Clinical data are now available 
in the current IB. 
Protocol Synopsis (Dosage Form, 
Dose and Route of 
Administration) 
Section 2.4 Population, Route, 
Dosage, Dosage Regimen, 
Treatment Period 
Section 6.1 Investigational 
Products 
Two other capsule strengths of 30 
and 100 mg added. 
Additional strengths now 
available. 
2.3.2 Potential Risk of Drug-Drug 
Interaction 
Data added detailing completed 
Phase 1 study in healthy subjects 
evaluating the effect of co-
administration of strong CYP3A4 
inhibitors and instructing the 
investigator to reduce dose of 
milademetan to half when 
concomitantly administered with 
strong CYP3A4 inhibitors. 
Important safety data for 
CYP3A4 inhibitors available 
and the summary needed to be 
highlighted in the protocol.  
Section 3.3 Study Hypothesis 
Revised to solid tumors and 
lymphomas vs. melanoma and 
DLBCL. 
Clarification. 
Section 4.1.1 Study Type 
New header and text added 
describing study and number of 
sites. 
New template. 
Section 4.1.2 Treatment Groups 
Section revised.  Text added that 
safety and tolerability will be 
determined by the PDy response 
in tumor samples and preliminary 
efficacy will be determined in 
advanced melanoma or DLBCL. 
Dosing schedule specified as 
QD × 21/28 days but option based 
on results to use an alternative 
dosing schedule if there is clinical 
benefit. 
Clarification. 


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Section # and Title 
Description of Change 
Brief Rationale 
Section 4.1.2.1 Part 1 (Dose 
Escalation) 
Added text that the MTD will be 
guided by a BLRM following 
EWOC principle after an initial 
accelerated titration design (ATD) 
and that this will minimize the 
number of subject treated at sub-
therapeutic doses. 
Toxicity levels for decision 
making for enrollment of next 
dose and defining DLT for the 
ATD were specified. 
EWOC principle requirements for 
BLRM recommended dose for the 
next cohort of subjects added. 
Identification of Sponsor’s 
clinical team and investigators as 
determining the selection of the 
dose to be tested in the next 
cohort of subjects. 
Defined that safety, PK and PDy 
data collected using 
QD × 21/28-day schedule 
determines the alternative drug 
administration schedule.  Also 
added that if the alternative 
dosing schedule provides less 
toxicity and more benefit, this 
alternative dosing schedule will 
be used in lieu of or in parallel 
with the QD × 21/28-day 
schedule. 
Scenarios defining the situations 
where this would apply were 
defined; Case 1 (starting dose less 
frequent than QD × 21/28-day 
schedule) added. 
For Case 3, added that the first 
cohort to be evaluated will begin 
treatment with milademetan at 90 
mg QD × 21/28 days, 
preferentially in subjects with 
liposarcoma. 
Added criteria for dose reduction 
in the case of platelet decrease or 
thrombocytopenia.  
Added less frequent dosing 
schedules to be considered if the 
Clarification. 


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Section # and Title 
Description of Change 
Brief Rationale 
starting dose of 120 mg is the 
MTD. 
Both the original 
QD × 21/28 days and alternative 
dosing schedules are explored in 
parallel. 
The final MTD for each dosing 
schedule will be decided based on 
considerations of the respective 
MTDs estimated by the BLRM, 
and on an overall assessment of 
safety data from subsequent 
cycles and PK/PDy information 
collected at all different doses 
tested.  Upon determining the 
final MTD of the original 
QD × 21/28 days and/or 
alternative dosing schedules, one 
dosing regimen will be selected 
for further evaluation in Part 2 
(Dose Expansion) and as the 
tentative RP2D.   
Section 4.1.2.2 Part 2 (Dose 
Expansion in Subjects With 
Advanced Melanoma or DLBCL) 
Added:  
Upon establishing MTD/tentative 
RP2D and drug administration 
schedule in Part 1, the Dose 
Expansion part will begin with 
the intention of confirming the 
safety and tolerability of 
milademetan, determining the 
PDy signals in tumor samples, 
and evaluating preliminary 
efficacy of milademetan in 
approximately 20 subjects each 
with advanced melanoma and 
DLBCL whose tumors are tested 
positive for wild-type TP53 
genotype.   
Clarification. 
Section 4.1.2.2 Part 2 (Dose 
Expansion in Subjects With 
Advanced Melanoma or DLBCL) 
Tumor re-biopsy added:  
To search for possible 
mechanisms of acquired 
resistance to milademetan, an 
optional tumor re biopsy may be 
performed within 30 days 
following the last dose of 
milademetan treatment for 
subjects who have achieved an 
Clarification. 


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Section # and Title 
Description of Change 
Brief Rationale 
initial complete response 
(CR)/partial response (PR) or 
stable disease for at least 6 
months by standard response 
criteria but later developed 
progressive disease (PD) while on 
therapy (both in Dose Escalation 
and Dose Expansion), preferably 
prior to initiating new therapy. 
Section 4.1.2.2 Part 2 (Dose 
Expansion in Subjects With 
Advanced Melanoma or DLBCL) 
Section 9.2.1. TP53 Status 
Added to TP53 genotyping, 
subject enrollment, and early 
discontinuation criteria: 
During Dose Escalation and Dose 
Expansion, tumor TP53 
genotyping will be performed in 
archived formalin-fixed paraffin-
embedded and, if available, fresh 
tumor biopsies in all enrolled 
subjects.  Confirmation of TP53 
wild-type status is NOT required 
prior to milademetan dosing.  The 
investigator will be informed if 
the genotyping confirms the 
presence of inactivating TP53 
mutations: testing result shows 
that a subject’s malignant cells 
contain an inactivating mutation, 
insertion, or deletion in the TP53 
gene.  If study treatment has 
already begun, the subject may 
choose to discontinue study drug 
or continue study drug as long as 
clinical benefit is noted per the 
investigator’s judgment.  
Deleted text as there is not an 
established sensitive gene 
expression signature, nor do all 
TP53 wild type represent a 
sensitive population. 
Section.9.2.1. TP53 Status 
Revised during dose expansion 
that tumor samples may be 
analyzed for DNAseq and by 
RNAseq.  
 
Protocol Synopsis 
Section.9.2.1. TP53 Status 
Deleted “Nonmutant PT53 
genotype and/or presence of a 
sensitive gene expression 
signature constitute the 
“biomarker positive” population. 
 
Section 5.2.2 Withdrawal 
Procedures 
Deleted: Protocol-specified 
withdrawal procedures are the 
same as those to be performed at 
Clarification. 


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Section # and Title 
Description of Change 
Brief Rationale 
the End-of-Treatment Visit. 
Section 5.2.4 Subject Re-
Screening Procedures 
Added to end of paragraph: 
… re-screened subjects, except 
for those that were not repeated 
during re-screening (eg, tumor 
biopsies) or other tests that are 
still valid within the screening 
window per the medical monitor 
Clarification. 
Section 6.2.1. Prohibited 
Concomitant 
Medications/Activities 
Added that if drugs that are strong 
inhibitors of CYP3A need to be 
taken concomitantly, then 
milademetan dose must be 
reduced to half the assigned dose. 
Added Seville oranges as 
prohibited. 
Clarification. 
Section 7.3.1.5. Part 1 (Dose 
Escalation), Cycle 1/Days 18 to 
21 
Added:  
(For subjects enrolled in the 
QD × 7/28 days schedule, this 
visit is needed only if there are 
unresolved Grade ≥ 3 adverse 
events (AEs) or Grade ≥ 2 
thrombocytopenia on Day 15 that 
need follow up). 
Clarification (because there is 
no drug administration or other 
assessments at this time point in 
the QD × 7/28 day schedule) 
Section 7.3.1.11. Part 1 (Dose 
Escalation), Cycle 4 and All 
Subsequent Cycles, Day 1 
Added:  
For Cycle 4 Day 1 and beyond: 
subjects who completed more 
than 1 year of treatment with 
continued clinical benefit and no 
ongoing Grade ≥ 3 TEAEs or risk 
thereof in the judgment of the 
investigator are allowed to 
continue on with the subsequent 
visits at every other cycle, and 
may have additional visits as 
clinically needed. 
To allow less frequent visits for 
subjects after confirmation of 
safety, tolerance, and benefit for 
more than 1 year on treatment. 
Section 7.3.2.12. Part 2 (Dose 
Expansion), Cycle 4 and All 
Subsequent Cycles, Day 1 
Added: 
For Cycle 4 Day 1 and beyond: 
subjects who completed more 
than 1 year of treatment with 
continued clinical benefit and no 
ongoing Grade ≥ 3 TEAEs or risk 
thereof in the judgment of the 
investigator are allowed to 
continue on with the subsequent 
visits at every other cycle, and 
To allow less frequent visits for 
subjects after confirmation of 
safety, tolerance, and benefit for 
more than 1 year on treatment. 


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Section # and Title 
Description of Change 
Brief Rationale 
may have additional visits as 
clinically needed. 
Section 7.3.1.5. Part 1 (Dose 
Escalation), Cycle 1/Days 18 to 
21 
Added:  
(For subjects receiving study drug 
under the QD 7/28  days or 
QD 3/14 days schedules, the 
blood sample collection 
[exploratory blood samples, PK 
samples, ad macrophage 
inhibitory cytokine-1 (MIC-1) 
induction] on Cycle 1 Days 18 to 
21 is not required) 
Clarification that the sample 
collection in the said schedules 
are not need at this time point 
due to time lag after the last 
dose. 
Section 8.1. Efficacy Variable(s) 
Added: 
As a complementary approach to 
the exploratory objective #2 in 
Part 1 (Section 3.1.3.1), 
particularly in WD/DD 
liposarcoma that are preferentially 
enrolled in the study due to high 
prevalence of murine double 
minute 2 amplification, the 
growth rates of the target tumors 
before starting milademetan 
versus on-treatment with 
milademetan may be analyzed by 
capturing the target tumor 
measurements by local reading in 
2 or more prior scans from the 
medical records, if available. 
Additionally, a digital or 
electronic copy of the computed 
tomography (CT)/magnetic 
resonance imaging (MRI) scans 
performed for RECIST v 1.1 
assessment may be collected by 
the sponsor for centralized 
analysis by sponsor-appointed 
radiologist(s) as a post-hoc 
exploration of the effect of 
milademetan on specific tumor 
histologies (eg, WD/DD 
liposarcoma).  
Deleted: 
If feasible, multiple pre-screening 
CT/MRI scans may be collected 
and included in the analysis to 
Additional exploratory analysis 
of the tumor responses in solid 
tumor subpopulations (WD/DD 
liposarcoma). 


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Section # and Title 
Description of Change 
Brief Rationale 
compare the progression rate 
before milademetan treatment vs 
tumor response after starting 
milademetan.  Any additional 
results will also be data protected 
for privacy. 
Section 9.1 Pharmacokinetic 
Assessment(s) 
Revised blood samples collected 
for PK analysis of milademetan. 
Added table 
Description of PK parameter 
analyses moved to Section 12.5.1. 
Clarification of the PK sample 
collections for the different 
dosing schedules with a table 
and footnotes. 
Section 9.2.1. TP53 Status 
Revised to DNAseq and RNAseq 
vs sensitive gene expression 
signature.  
Revised to the exploratory 
analysis by DNAseq and 
RNAseq, because a sensitivity 
gene expression signature was 
not available. 
Section 10.4.3 Grade Assessment 
Added National Cancer Institute 
Common Terminology Criteria 
for Adverse Events guidelines for 
certain AEs and clarification that 
for each episode, the highest 
severity grade attained should be 
reported. 
Life-threatening definition 
modified to include urgent 
intervention indicated. 
Clarification. 
Section 12.2. 3 Biomarker 
Positive Analysis Set 
Deleted. 
Deleted because of the absence 
of a validated sensitivity 
biomarker. 
Section 12.2.4. Dose-Limiting 
Toxicity Evaluable Set 
Added to further define as 
milademetan doses during the 
first 3 weeks (21 days). 
Clarification. 
Section 12.2.6.  Pharmacokinetic 
Analysis Set 
Added that subjects in this 
analysis set had any amount of 
milademetan and had measurable 
plasma concentrations of 
DS-3032a (the free form of 
milademetan). 
Clarification. 
Section 12.2.7. Biomarker 
Analysis Set 
New text:  
The PDy biomarker analysis set 
will include all subjects in the 
enrolled analysis set who received 
any amount of milademetan and 
who had the baseline assessment 
Definition of PDy biomarker 
analysis set added. 


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Section # and Title 
Description of Change 
Brief Rationale 
and where applicable, at least 
1 post-baseline assessment for 
biomarkers. 
Section 12.4.1. Primary Efficacy 
Analyses 
Added: 
Change in tumor size comparing 
to pretreatment/historical data 
will be presented graphically.  
Additional details will be 
presented in the SAP. 
Additional exploratory analysis 
of tumor response. 
Section 12.4.2. Secondary 
Efficacy Analyses 
Added:  
In addition, the growth rates of 
the target tumors before starting 
milademetan based on prior scans 
from subjects’ medical records 
versus on-treatment with 
milademetan may be summarized. 
Additional analyses will be 
described in the SAP. 
Additional exploratory analysis 
of tumor response. 
Section 12.5.1. Pharmacokinetic 
Analyses 
Revised section that plasma 
concentration data will be 
summarized using descriptive 
statistics, and a table was added 
for the parameters to be analyzed 
in the dose escalation and 
expansion phases using non-
compartmental analyses. 
Added that Population 
pharmacokinetic (PopPK) and 
exposure response may be 
developed but will be provided 
separately along with results.  
Clarification with the table and 
footnotes to explain the PK 
sample collections for the 
different dosing schedules. 
Protocol Synopsis (Predictive 
Biomarker Parameters) 
Section 9.2.3. Exploratory 
Biomarker Analysis 
Section 12.5.3. Biomarker and 
Exploratory Analyses 
Added that pre-treatment, on-
treatment, and end-of-treatment 
tumor samples will be examined. 
Deleted: 
“in the form of multi-gene and/or 
protein signature “ and p14, p16, 
and CDKN2A.   
Clarified the biomarker analysis 
of tumor samples and removed 
the multigene and/or protein 
signature that is not available 
yet. 
Section 12.11. Specification of 
Bayesian Logistic Regression 
Model with Escalation with 
Overdose Control 
Removed mCRM throughout. 
Clarification by replacing 
mCRM with BLRM. 
Table 18.2 Schedule of Events 
Part 1 (Dose Escalation)  
Added to sampling for 
exploratory blood samples, PK 
Updates of the schedule of 
events and footnotes for all the 


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Section # and Title 
Description of Change 
Brief Rationale 
collection and MIC-1 induction, 
that these samples are not 
required of subjects receiving 
study drug under the 
QD 7/28 days or QD 3/14 days 
schedules, the blood sample 
collection on Cycle 1 Days 18 to 
21. 
different dosing schedules. 
Table 18.2 Schedule of Events 
Part 1 (Dose Escalation) 
Table 18.3 Schedule of Events 
Part 2 (Dose Expansion) 
Abbreviations added and updated. 
Text added to electrocardiogram 
footnote regarding subjects 
enrolled per Case 3. 
PK sampling schedule updated. 
Updated to match updates in 
text. 
Table 18.4 Schedule of Events 
(Extension Phase) 
New footnote added: 
For subjects who completed more 
than 1 year of study drug with 
continued clinical benefit and no 
ongoing clinically significant 
TEAEs or at risk of clinically 
significant TEAEs in the 
judgment of the investigator, the 
subsequent visits every other 
cycle, and additional visits as 
clinically indicated, is allowed. 
Footnote modified from every 
other cycle to every 3 cycles and 
as clinically indicated. 
To allow less frequent visits for 
subjects after confirmation of 
safety, tolerance, and benefit for 
more than 1 year on treatment. 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Protocol Synopsis 
IND Number: 
118125 
Protocol Number: 
DS3032-A-U101 
Investigational Product: 
Milademetan (DS-3032b) 
Active Ingredient(s)/INN: 
(3'R,4'S,5'R)-N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-
yl]-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-
2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide mono(4-methylbenzenesulfonate) 
monohydrate 
Study Title: 
A Phase 1 Multiple Ascending Dose Study of Milademetan, an 
Oral MDM2 Inhibitor, in Subjects with Advanced Solid Tumors 
or Lymphomas 
Study Phase: 
Phase 1 
Indication Under Investigation: Milademetan will be evaluated in subjects with advanced solid 
tumors or lymphomas that are refractory to standard therapy or 
for which no standard therapy is available. 
Study Objectives: 
Part 1 (Dose Escalation) 
Primary Objectives: 
To assess the safety and tolerability of milademetan in subjects 
with advanced solid tumors or lymphomas who have relapsed 
from or are refractory to standard therapy or for whom no 
standard therapy is available. 
To determine the maximum tolerated dose (MTD) or tentative 
recommended Phase 2 dose (RP2D) of milademetan in subjects 
with advanced solid tumors or lymphomas. 
Secondary Objectives: 
1. To determine the plasma pharmacokinetics (PK) of 
DS-3032a (the free form of milademetan). 
2. To determine the pharmacodynamic (PDy) effect of 
milademetan on macrophage inhibitory cytokine-1 
(MIC-1) levels in serum. 
3. To evaluate the response of solid tumors and lymphoma 


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and their subtypes to milademetan using the 
corresponding standard response criteria (Response 
Evaluation Criteria in Solid Tumors [RECIST] v 1.1 or 
revised International Working Group [IWG] criteria, 
respectively). 
Exploratory Objectives: 
1. To compare progression free survival (PFS) between that 
observed with milademetan treatment and that observed 
from the most recent therapeutic regimen. 
2. To bank blood samples for deoxyribonucleic acid (DNA) 
analysis for the assessment of potential biomarkers 
(eg, murine double minute 2 [MDM2] single-nucleotide 
polymorphism [SNP] 309) that may be predictive of 
benefit or toxicity from milademetan. 
3. To assess blood and tumor samples for DNA or 
ribonucleic acid (RNA) analysis that may be predictive 
of benefit or toxicity from milademetan. 
4. To evaluate the relationship between tumor response to 
milademetan and potential predictive biomarkers studied 
in archived tumor samples, pre-treatment tumor biopsies, 
if available, and/or blood samples. 
5. To assess the PDy effect of milademetan on the 
expression levels of p53, p21, MDM2, murine double 
minute 4 (MDM4), Ki67, apoptosis markers, and/or 
other biomarkers in pre- and post-treatment solid 
tumor/lymphoma samples, if available.  
6. To characterize the plasma metabolites of DS-3032a. 
Part 2 (Dose Expansion) 
Primary Objectives: 
1. To confirm the safety and tolerability of milademetan at 
the MTD/tentative RP2D in subjects with advanced 
melanoma or diffuse large B-cell lymphoma (DLBCL) 
who have relapsed from or are refractory to standard 
therapy or for whom no standard therapy is available.  
2. To assess tumor response in subjects with melanoma 
using RECIST v 1.1 and in subjects with DLBCL using 
the revised IWG criteria. 
Secondary Objectives: 
1. To determine the PK profile of DS-3032a at the 


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MTD/tentative RP2D. 
To determine the PDy effect of milademetan on MIC-1 levels in 
serum. 
Exploratory Objectives: 
1. To compare PFS between that observed with 
milademetan treatment and that observed from the most 
recent therapeutic regimen. 
2. To bank blood samples for DNA analysis for the 
assessment of potential biomarkers (eg, MDM2 
SNP 309) that may be predictive of benefit or toxicity 
from milademetan. 
3. To assess blood and tumor samples for DNA or RNA 
analysis that may be predictive of benefit or toxicity 
from milademetan. 
4. To assess the PDy effect of milademetan on the 
expression levels of p53, p21, MDM2, MDM4, Ki67, 
apoptosis markers, and/or other biomarkers in pre- and 
post-treatment solid tumor/lymphoma samples, if 
available. 
5. To characterize the plasma metabolites of DS-3032a. 
6. To evaluate the relationship between tumor response to 
milademetan and biomarkers studied in archived tumor 
samples and pretreatment, on-treatment, and 
end-of-treatment tumor biopsies. 
Primary Outcome Measure 
Title: Number of subjects with treatment-emergent adverse 
events (TEAEs) during the study  
Details: Number of subjects with TEAEs by frequency and 
grade in each cohort of dose and dosing schedule and the 
total number of subjects with the TEAEs 
Timeframe: From start of study until last subject last visit 
(approximately 6 years). 
Title: Maximum tolerated dose(s)  
Details: MTD(s) identified at different dosing schedules 
Time frame: From start of study until final database lock 
(approximately 6 years) 


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Title: Number of subjects with dose-limiting toxicities 
(DLTs) 
Details: Number of subjects with DLTs at each dose [level 
/cohort] and the total number of subjects with DLTs 
Time frame: From start of study until the DLT evaluation of 
the last subject in dose escalation part (approximately 6 years 
or less) 
Title: Response rates in melanoma and DLBCL in dose 
expansion cohorts 
Details: Number and percentage of subjects with melanoma 
and DLBCL in dose expansion cohorts who achieved 
objective response per RECIST v 1.1 and IWG, respectively 
Time frame: From start of study until last subject last tumor 
assessment in Dose Expansion (approximately 6 years) 
Secondary Outcome Measure 
Title: PK parameters of milademetan 
Details: Determination of milademetan PK parameters 
(maximum plasma concentration [Cmax], time to reach 
maximum plasma concentration [Tmax], AUC, apparent 
clearance [CL/F], and half-life [T1/2]). 
Timeframe: From start of study until final database lock 
(approximately 6 years) 
Title: Pharmacodynamic effect of milademetan 
Details: Pharmacodynamic effect of milademetan assessed 
by increase in serum MIC-1 levels over baseline. 
Time frame: From start of study until final database lock 
(approximately 6 years) 
Study Design 
This will be a Phase 1, open-label study of milademetan to 
assess its safety and tolerability, identify an MTD/tentative 
RP2D, and assess its PK/PDy properties in subjects with 
advanced solid tumors or lymphomas. 
Dose regimen 
Milademetan will be administered once daily on Days 1 to 21 
of a 28-day cycle (once a day [QD] × 21/28 days).  An 


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alternative drug administration schedule for dose escalation 
may be considered based on safety, PK, and PDy data 
collected during Dose Escalation using the above schedule, 
and upon review by the Principal Investigators and Sponsor 
(eg, QD 28/28, QD 7/28, QD 3/14 × 2). 
Part 1 (Dose Escalation) 
Dose escalation of milademetan to determine the MTD will be 
guided by a Bayesian logistic regression model (BLRM) 
following escalation with overdose control (EWOC) principle 
following an initial accelerated titration design (ATD).  
Accelerated titration design for determining initial dose for 
escalation by BLRM with EWOC. 
Before starting BLRM, initial dose escalation will proceed 
following an ATD in order to minimize the number of subjects 
treated at sub-therapeutic doses of the drug.  The proposed 
human starting dose of milademetan is 15 mg/day.  Single 
subjects will be enrolled into sequential dose levels with a 
dose increment of 100% from the previous dose.  
Over-enrollment in ATD up to 3 subjects per cohort is 
permitted.  The dose for ending ATD will be the dose level in 
which one of the following occurs: 
 One Grade 2 or higher milademetan-related toxicity 
according to National Cancer Institute Common 
Terminology Criteria for Adverse Events v 4 
(NCI-CTCAE v4) during Cycle 1, 3 to 6 subjects will be 
enrolled at the next dose level, which will be guided by 
BLRM1; or 
 If a DLT is observed during Cycle 1, the cohort will first 
be expanded to 3 DLT-evaluable subjects and the next 
2 subjects in the expanded cohort will receive milademetan 
treatment starting at least 1 week apart.  If no further DLT 
is reported, the cohort will be expanded to include up to 3 
additional DLT-evaluable subjects prior to initiation of 
BLRM in the next dose level. 
The information from the accelerated titration stage will be 
included in the Bayesian model for dose escalation. 
Dose level increment during dose escalation by BLRM with 
                                                 
1 For isolated NCI-CTCAE v4 Grade ≥ 2 laboratory abnormalities that are not associated with signs or symptoms, 
transition from ATD to BLRM will be at the discretion of the Investigator. 


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EWOC 
The dose increment during BLRM will be as follows: 
 The dose level increment should be no less than 30% in 
order to have distinction among dose levels considering 
the inter-subject variability in exposure, but flexibility may 
be applied in selecting the dose to accommodate the 
available dosage form strengths. 
 The dose level increment should be no more than 100% 
even if the model suggested a higher dose than 100% for 
the next cohort. 
 In the event of a DLT, the next 2 subjects in the expanded 
cohort will receive milademetan treatment starting at least 
1 week apart. 
The dose escalation will be based on a BLRM with EWOC 
principle.  The logistic regression model for the dose-toxicity 
(DLT rate) relationships will include 2 parameters: the 
intercept and the slope.  After the first 3 subjects of each 
cohort complete DLT evaluation during Cycle 1, the posterior 
distributions of the DLT rate will be derived for all dose levels 
based on the BLRM using the DLT outcome data from all 
assessed exposure levels and a pre-specified prior distribution 
for the model parameters.  The posterior probability of the 
DLT rate in the following 4 intervals at each dose level: [0%, 
16%] as the DLT rate interval for under-dosing, [16%, 33%] 
as the target DLT rate interval, [33%, 60%] as the DLT rate 
interval for excessive toxicity, and [60%, 100%] as the DLT 
rate interval for unacceptable toxicity will then be calculated, 
and used for dose recommendation for the next cohort 
according to the EWOC principle.  
The EWOC principle requires that the BLRM recommended 
dose for the next cohort of subjects is the one with the highest 
posterior probability of the DLT rate in the target DLT rate 
interval of [16%, 33%] among all dose levels fulfilling the 
overdose control constraint: there is less than 25% of 
probability for the DLT rate  33% (probability for excessive 
or unacceptable toxicity). 
The dose to be tested in the next cohort of subjects chosen by 
the Sponsor’s clinical team and the investigator(s) involved in 
the clinical study will be based on the dose recommended by 
the BLRM, clinical assessment of toxicity profiles, and 
PK/PDy information observed thus far. 
Cohorts of 3 to 6 subjects will be enrolled and assessed for 


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DLT before escalation to a new higher dose.  As an exception, 
the model will be reevaluated before enrollment of any 
additional subjects to the cohort if 2 evaluable subjects in the 
cohort experience DLT before the enrollment of the next 
subject.  Enrollment of subjects to a new cohort requires 
completion of DLT evaluation of at least 3 subjects treated in 
the current cohort.  Subjects who have neither completed DLT 
evaluation nor experienced DLT will be censored and not 
included in the BLRM update.  In the event that subjects in the 
previous cohort experience DLT after the enrollment of 
subjects to a new cohort has begun, dose level assignment of 
the next subject in the new cohort will be based on an updated 
BLRM using DLT outcome data from all assessed doses. 
For a subject to be considered evaluable for dose escalation 
decisions, the subject must have received 75% of the doses 
(ie, 16 days) during Cycle 1, or experienced a DLT in Cycle 1.  
The final MTD will be decided based on considerations of the 
respective MTD estimated by the BLRM, and on an overall 
assessment of safety data from subsequent cycles and PK/PDy 
information collected at all different doses tested.  For dose 
determination, the following stopping rules will be 
implemented for the Dose Escalation part: (a) at least 
6 evaluable subjects at MTD level with at least 21 evaluable 
subjects in total enrolled in the Dose Escalation part, or (b) at 
least 9 evaluable subjects have been enrolled at a dose level 
that is the model’s recommendation for the next dose cohort 
and for which the posterior probability of targeted toxicity is at 
least 50%, or (c) dose level -1 is too toxic. 
Cohorts may be expanded at any dose level or at the MTD for 
further elaboration of safety, PK, or PDy parameters as 
required. 
Dose escalation using alternative drug administration schedule 
Based on safety, PK, and PDy data collected during Dose 
Escalation using the QD × 21/28-day schedule of 
milademetan, an alternative drug administration schedule for 
dose escalation may be considered following review by the 
Principal Investigators and Sponsor.  Modeling and simulation 
will be performed to evaluate DS-3032a exposure relationship 
to PDy and toxicity.  If the results indicate that using an 
alternative dosing schedule may provide less toxicity (eg, 
myelosuppression) while offering pharmacodynamic benefits 
based on available biomarkers or a better PK profile, dose 
escalation using this recommended alternative dosing schedule 
will be performed in lieu of, or in parallel with the 


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QD × 21/28-day schedule.  For example: 
 Case 1: If the recommended dosing schedule is less 
frequent than QD × 21/28 days, the starting daily dose of 
the new schedule will be same as the highest daily dose 
tested for the QD × 21/28-day schedule that showed DLT 
in less than one-third of evaluable subjects.   
 Case 2: If the recommended dosing schedule is more 
frequent than QD × 21/28 days (eg, QD continuous 
× 28 days), the starting daily dose will be ≤ 75% of the 
highest daily dose tested for the QD × 21/28-day schedule 
that showed DLT in less than one-third of evaluable 
subjects.  This starting dose of the new schedule will 
provide the same 4-week cumulative dose while reducing 
daily exposure by ≥ 25%. 
 Case 3: If additional testing is suggested to optimize the 
dosing regimen (to maintain sufficient dose density over 
time without requiring frequent dose interruptions as a 
result of delayed toxicities) after the MTD is identified, 
then dosing may initiate at a dose level lower than MTD in 
that dosing regimen.  Subject enrollment may be limited to 
one or a small number of cancer types or molecular sub-
types depending on available clinical data for milademetan 
with the dosing regimen and investigator experience with 
this class of compound.  Up to 15 subjects may be enrolled 
in the cohort and enrollment may be conducted in parallel 
with Part 2 of the study.  
The first cohort to be evaluated will begin treatment with 
milademetan at 90 mg QD × 21/28 days, preferentially in 
subjects with liposarcoma considering the existing data in 
this patient population at 120 mg QD × 21/28 days and 
90 mg QD × 28/28 days for comparison of safety.  
The dose of 90 mg QD × 21/28 days is evaluated to define 
a hematologically safe and tolerable regimen based on the 
safety data at the doses previously evaluated (15 mg 
through 30, 60, 120, 160 and 240 mg QD × 21/28 days, 
with the determination of MTD at 120 mg) in this dosing 
schedule.  Most DLTs arose from myelosuppression, 
particularly thrombocytopenia, which also resulted in dose 
delays and dose reductions in the subjects who continued 
in Cycle 2 and subsequent cycles.  Therefore to reduce the 
risk of progressing to more severe bone marrow toxicities 
and dose interruptions during continued treatment, the 
following dose adjustment rules will be followed for 


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Cycle 2 and subsequent cycles: 
 If platelets decrease to < 50% of baseline (the 
platelets measured at Cycle 1 Day 1) or 
Grade ≥ 2 thrombocytopenia 
(Platelets < 75 × 109/L) at the end of Cycle 1, 
then: 
o If platelets decrease by > 50% from 
baseline, but are ≥ 75 × 109/L, do not 
interrupt milademetan dosing, but reduce 
the dose of milademetan to 60 mg 
QD × 21/28 days. 
o If Grade ≥ 2 thrombocytopenia, hold 
dosing of milademetan.  When the 
platelets recover to ≥ 75 × 109/L, resume 
milademetan at a reduced dose of 60 mg 
QD × 21/28 days. 
 Dose interruptions and further dose reductions 
due to toxicity will be allowed.  
After an initial cohort of 3 subjects has completed treatment 
in Cycle 1, the dose may be adjusted based on the safety 
results and discussion between the investigators and the 
Sponsor. 
In addition to the above dose dense schedules, the following 
less frequent dosing schedules will be evaluated in dose 
escalation with a starting dose of 120 mg that was the MTD 
determined in the QD × 21/28 days schedule: 
 QD for 7 out of 28 days (QD × 7/28 days) 
  QD for 3 out of 14 days (QD × 3/14 days) repeated twice 
in a 28-day cycle 
Both the original QD × 21/28 days and alternative dosing 
schedules are explored in parallel. 
The final MTD for each dosing schedule will be decided based 
on considerations of the respective MTDs estimated by the 
BLRM, and on an overall assessment of safety data from 
subsequent cycles and PK/PDy information collected at all 
different doses tested.  Upon determining the final MTD of the 
original QD × 21/28 days and/or alternative dosing schedules, 
one dosing regimen will be selected for further evaluation in 
Part 2 (Dose Expansion), which may also be the tentative 
RP2D. 


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Dose-Limiting Toxicity Definition 
A DLT is defined as any TEAE not attributable to disease or 
disease-related processes that occurs during the observation 
period (Cycle 1) in each dose-level cohort and is Grade 3 or 
higher according to NCI-CTCAE v4, with the exceptions as 
defined below: 
For hematologic events, a DLT is defined as follows: 
 Grade 4 neutropenia lasting > 7 days 
 Febrile neutropenia  
 Grade 4 anemia 
 Grade 4 thrombocytopenia or Grade ≥ 3 thrombocytopenia 
lasting more than 7 days or associated with bleeding 
 Dose delay > 7 days secondary to myelosuppression 
For elevations in hepatic function enzymes, a DLT is defined 
as follows: 
 Grade 4 aspartate aminotransferase (AST)/alanine 
aminotransferase (ALT) levels 
 AST/ALT > 5  upper limit of normal (ULN) lasting 
> 3 days without liver metastases 
 AST/ALT > 5  ULN if accompanied by ≥ Grade 2 
elevation in bilirubin 
 AST/ALT > 5  ULN lasting > 3 days, if the baseline level 
was ≤ 3  ULN in subjects with liver metastases 
 AST/ALT > 8  ULN lasting > 3 days, if the baseline level 
was > 3  ULN in subjects with liver metastases 
The following adverse events are NOT considered DLTs: 
 Grade 3 fatigue lasting < 3 days 
 Grade 3 nausea or vomiting that has resolved to Grade ≤ 2 
within 48 hours after standard antiemetic therapies 
 Grade 3 diarrhea that has resolved to Grade ≤ 2 within 48 
hours after standard antidiarrheal therapies 
 Isolated laboratory findings not associated with signs or 
symptoms including Grade 3/4 alkaline phosphatase, uric 
acid, amylase, and lipase elevations, and Grade 3 
hyponatremia lasting < 72 hours developed from Grade 1 
at baseline 


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 Grade 3/4 lymphopenia 
Subjects who are unable to complete at least 75% of the 
prescribed dose of milademetan in the first 21 days as a result 
of nondisease-related ≥ Grade 2 adverse events will be 
considered to have a DLT. 
 A delay of ≥ 1 week in initiating Cycle 2 secondary to a 
nondisease-related ≥ Grade 2 adverse event will be 
considered a DLT. 
Part 2 (Dose Expansion in Subjects with Advanced 
Melanoma or DLBCL) 
Upon establishing MTD/tentative RP2D and drug 
administration schedule in Part 1, the Dose Expansion part 
will begin with the intention of confirming the safety and 
tolerability of milademetan, determining the PDy signals in 
tumor samples, and evaluating preliminary efficacy of 
milademetan in approximately 20 subjects each with advanced 
melanoma and DLBCL whose tumors are tested positive for 
wild-type TP53 genotype.   
Four subjects of each tumor type will initially be treated.  
Following the completion of the first cycle, a safety analysis 
will be conducted to allow the reevaluation of the 
appropriateness of the dosing level.  If the incidence of 
adverse events fulfilling the criteria of a DLT has exceeded 
that predicted by the EWOC principle, after the initial 
4 DLT-evaluable subjects or after additional enrollment, no 
further testing at the MTD/tentative RP2D level established in 
Part 1 will be done, and dose de-escalation or treatment at 
alternative dose schedules may be considered for further 
evaluation of safety and efficacy. 
Tumor assessment (Part 1 and Part 2) 
Tumor assessment will be performed according to the study 
schedule at baseline, every 2 cycles while the subject remains 
on study for the first 8 cycles and then every 3 cycles 
thereafter (start of Cycles 3, 5, 7, and 9, then Cycles 12, 15, 
etc.). 
Tumor re-biopsy 
To search for possible mechanisms of acquired resistance to 
milademetan, an optional tumor re-biopsy may be performed 
within 30 days following the last dose of milademetan 
treatment for subjects who have achieved an initial complete 
response (CR)/partial response (PR) or stable disease for at 


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least 6 months by standard response criteria but later 
developed progressive disease (PD) while on therapy (both in 
Dose Escalation and Dose Expansion), preferably prior to 
initiating new therapy. 
TP53 genotyping, subject enrollment, and early 
discontinuation criteria 
 During Dose Escalation and Dose Expansion, tumor 
TP53 genotyping will be performed in archived 
formalin-fixed paraffin-embedded (FFPE) and, if 
available, fresh tumor biopsies in all enrolled 
subjects.  Confirmation of TP53 wild-type status is 
NOT required prior to milademetan dosing.  The 
investigator will be informed if the genotyping 
confirms the presence of inactivating TP53 mutations 
testing result shows that a subject’s malignant cells 
contain an inactivating mutation, insertion, or 
deletion in the TP53 gene.  If study treatment has 
already begun, the subject may choose to discontinue 
study drug or continue study drug as long as clinical 
benefit is noted per the investigator’s judgment.  
TP53 re-testing can be considered.  
Study Duration: 
The study duration is expected to last approximately 6 years 
from the time the first subject is enrolled in Part 1 of the study.  
The number of treatment cycles is not fixed in this study.  
Subjects who continue to derive clinical benefit from treatment 
in the absence of withdrawal of subject consent, progression, or 
unacceptable toxicity may continue treatment.  Subjects in Part 1
and Part 2 who are still on study at least 6 months after 
enrollment is completed in both the parts will be eligible to 
continue receiving study drug in a separate extension phase of 
the protocol.  Data collected from those subjects may be 
captured in a separate database. 
Study Sites and Location: 
Approximately 5 United States sites are planned for Part 1 (Dose 
Escalation) and for Part 2 (Dose Expansion).  The same sites are 
planned to participate for both parts. 
Planned Sample Size: 
The Dose Escalation phase of this study (Part 1) consists of an 
ATD followed by BLRM + EWOC design with at least 3 DLT-
evaluable subjects per dose level.  At least 21 DLT-evaluable 
subjects are needed to reach an accurate estimate of the MTD.  
However, to better define an RP2D that will be clinically 
beneficial to the subjects as well as hematologically safe and 
tolerable for prolonged treatment without dose delays, subjects 


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in additional cohorts and multiple dosing schedules may be 
added. 
Sample size for the dose escalation part of the study is not 
known because of the multiple dosing schedules to be 
evaluated to determine the most optimal schedule.  No formal 
statistical assessment has been performed. 
For the Dose Expansion part (Part 2), approximately 
20 subjects (each of subjects with advanced melanoma and 
DLBCL) will be enrolled.  If response rate is more than 25% 
(null hypothesis: response rate ≤ 0.25, alternative hypothesis: 
response rate > 0.25), then the probability of no response out of 
10 subjects will be less than 10%.  The probability that 4 or 
more responders out of 10 subjects are observed will be less 
than 25% under the null hypothesis but more than 80% under 
alternative hypothesis with response rate = 0.50. 
The probability values for the sample size are derived based on 
binomial distribution using SAS Version 9.2. 
Subject Eligibility Criteria: 
Inclusion Criteria 
1a. Dose Escalation Cohorts (Part 1) 
Has a histologically or cytologically documented 
advanced solid tumor or lymphoma that has relapsed 
from or is refractory to standard treatment, or for which 
no standard treatment is available.  
 Subjects with melanoma who are ineligible to receive 
or have declined ipilimumab treatment, or who are 
refractory or intolerant to ipilimumab may enroll. 
 Subjects with certain tumor types such as those with 
high prevalence of MDM2 amplification or 
overexpression (eg, well-differentiated 
(WD)/dedifferentiated (DD) liposarcoma) may be 
preferentially enrolled in Part 1. 
1b. Dose Expansion Cohort (Part 2) 
Has a histologically or cytologically documented 
advanced melanoma or DLBCL, with measurable 
disease that is refractory to standard treatment or for 
which no standard treatment is available. 
Subjects with melanoma who are ineligible to receive or 
have declined ipilimumab treatment, or who are 
refractory or intolerant to ipilimumab may enroll. 
Subjects with DLBCL who have failed, been deemed 


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ineligible for, or refused autologous stem cell 
transplantation may enroll. 
2. Male or female ≥ 18 years old. 
3. Has an Eastern Cooperative Oncology Group (ECOG) 
performance status 0 to 1. 
4. Has adequate bone marrow function, defined as: 
 Platelet count ≥ 100  109/L 
 Hemoglobin ≥ 9.0 g/dL 
 Absolute neutrophil count ≥ 1.5  109/L 
5. Has adequate renal function, defined as: 
 Creatinine clearance ≥ 60 mL/min, as calculated using 
the modified Cockcroft-Gault equation, ([140 - age (in 
years)] × weight (in kg) / [serum creatinine (in mg/dL) × 
72]; multiply by 0.85 if female), OR 
creatinine ≤ 1.5  ULN 
6. Has adequate hepatic function, defined as: 
 AST/ALT ≤ 3  ULN (if liver metastases are present, ≤ 5 
 ULN) 
 Bilirubin ≤ 1.5  ULN 
7. Has adequate blood clotting function, defined as: 
 International normalized ratio (INR) and activated partial 
thromboplastin time (aPTT) ≤ 1.5  ULN 
8. Subject should be able to provide written informed consent, 
comply with protocol visits and procedures, be able to take 
oral medication, and not have any active infection or 
comorbidity that would interfere with therapy. 
9. Subject (male and female) of childbearing/reproductive 
potential must agree to use double-barrier contraceptive 
measures or avoid intercourse during the study and for 90 
days after the last dose of study drug. 
10. Subject must be fully informed about their illness and the 
investigational nature of the study protocol (including 
foreseeable risks and possible side effects) and must sign 
and date an Institutional Review Board-approved informed 
consent form (including Health Insurance Portability and 
Accountability Act authorization, if applicable) before 
performance of any study-specific procedures or tests. 
11. Is willing to provide and there is confirmed availability of 


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pre-existing diagnostic or resected tumor samples, such as 
paraffin-embedded sections.  Providing fresh tumor biopsy 
is optional for subjects in Dose Escalation cohorts.  
12. Is willing to undergo tumor genotyping for TP53 mutation, 
insertion, or deletion at screening.  Confirmation of TP53 
nonmutant status is encouraged, but not required prior to 
milademetan dosing. 
13. Is willing to provide additional archived samples for 
comprehensive genomic and/or proteomic analyses if the 
subject has a partial response (PR)/complete response (CR) 
to milademetan treatment. 
14. (Applicable to Part 2 only) Is willing to undergo pre-
treatment tumor biopsies (post-treatment biopsies are 
requested). 
Exclusion Criteria 
Part 1 and Part 2: Dose Escalation and Dose Expansion 
1. Has a tumor that contains an inactivating mutation, 
insertion, or deletion in the TP53 gene determined 
previously or at screening.   
2. Has a history of primary central nervous system 
malignancy. 
3. Has gastrointestinal conditions that could affect the 
absorption of milademetan in the opinion of the 
investigator. 
4. Has an uncontrolled infection requiring intravenous 
antibiotics, antivirals, or antifungals, known human 
immunodeficiency virus infection, or active hepatitis B 
or C infection. 
5. Has received an allogeneic bone marrow or allogeneic 
stem cell transplant. 
6. Has a concomitant medical condition that would increase 
the risk of toxicity, in the opinion of the investigator or 
Sponsor. 
7. Has clinically active brain metastases, defined as 
untreated and symptomatic, or requiring therapy with 
steroids or anticonvulsants to control associated 
symptoms.  Subjects with treated brain metastases that 
are no longer symptomatic and who require no treatment 
with steroids may be included in the study if they have 
recovered from the acute toxic effect of radiotherapy.  A 


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minimum of 4 weeks must have elapsed between the end 
of whole brain radiotherapy and study enrollment 
(2 weeks for stereotactic radiotherapy). 
8. Has unresolved toxicities from previous anticancer 
therapy, defined as toxicities (other than alopecia) not 
yet resolved to NCI-CTCAE v4, Grade ≤ 1 or baseline.  
Subjects with chronic Grade 2 toxicities may be eligible 
per the discretion of the investigator and Sponsor (eg, 
Grade 2 chemotherapy-induced neuropathy).   
9. Had an autologous transplant within 3 months of starting 
study drug treatment. 
10. Is receiving concomitant treatment with a strong inducer 
of cytochrome P450 (CYP) 3A. 
11. Had systemic treatment with anticancer therapy, 
antibody-based therapy, retinoid therapy, or hormonal 
therapy within 3 weeks before study drug treatment; or 
treatment with nitrosoureas or mitomycin C within 
6 weeks before study drug treatment; or treatment with 
small-molecule targeted agents within 2 weeks before 
study drug treatment.  Previous and concurrent use of 
hormone replacement therapy, the use of 
gonadotropin-releasing hormone modulators for prostate 
cancer, and the use of somatostatin analogs for 
neuroendocrine tumors are permitted if such therapy has 
not been changed within 8 weeks before study drug 
treatment. 
12. Had therapeutic radiation therapy or major surgery 
within 4 weeks before study drug treatment or palliative 
radiation therapy within 2 weeks before study drug 
treatment. 
13. Participated in a clinical study within 3 weeks before 
study drug treatment, or current participation in other 
therapeutic investigational procedures. 
14. Prolongation of corrected QT interval by Fridericia’s 
method (QTcF) at rest, where the mean QTcF interval is 
> 450 ms for males and > 470 ms for females based on 
triplicate electrocardiogram (ECG). 
15. Pregnant or breastfeeding. 
16. Substance abuse or medical, psychological, or social 
conditions that, in the opinion of the investigator, may 
interfere with the subject’s participation in the clinical 


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study or evaluation of the clinical study results. 
17. Prior treatment with an MDM2 inhibitor. 
Dosage Form, Dose and Route 
of Administration: 
Milademetan will be administered as an oral capsule.  It will be 
supplied in 5, 20, 80, and 200 mg capsules individually 
packaged in desiccant-embedded aluminum blisters.  Two other 
capsule strengths of 30 and 100 mg will also be supplied in 
high-density polyethylene bottles.  
Study Endpoints: 
Safety Endpoints: 
Safety parameters will include serious adverse events, TEAEs, 
physical examination findings (including ECOG performance 
status), vital sign measurements, standard clinical laboratory 
parameters (serum chemistry, hematology, urinalysis), and ECG 
parameters.  Adverse events will be graded according to the 
NCI-CTCAE v4.  Dose escalation will be determined by plasma 
drug concentrations and rate of DLTs. 
Pharmacokinetic and Pharmacodynamic Endpoints: 
Plasma PK and standard non-compartmental PK parameters will 
be assessed.  Plasma samples for PK assessments will be taken 
at multiple time points in the study.  Additionally, PK samples 
may also be obtained outside of the specified time points during 
the study if deemed clinically necessary.   
Induction of serum MIC-1 will be the primary PDy biomarker.  
Whole blood samples will be collected at multiple time points in 
the study to assess the effect of milademetan treatment on 
MIC-1 induction.  Other exploratory PDy biomarkers including, 
but not limited to, expression levels of p53, p21, MDM2, 
MDM4, Ki67, apoptosis markers, and/or other biomarkers will 
also be assessed, if available. 
Efficacy Endpoints: 
In solid tumor subjects with measurable disease, tumor response 
will be evaluated using RECIST v 1.1.  In subjects with 
lymphomas, treatment response will be evaluated using the 
revised IWG criteria. 
Statistical Analyses 
The primary analysis will occur either after all subjects in Part 1 
and Part 2 have discontinued the study or at least 6 months after 
enrollment of the last subject.  After the primary analysis, the 
main study will be closed.  Subjects in Part 1 and Part 2 who are 
still on study drug at the time of the primary analysis will be 
eligible to continue receiving study drug in a separate extension 
phase of the protocol, and data collected from those subjects 


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may be captured in a separate database.  
Descriptive statistics will be provided for selected demographic, 
safety, PK, and PDy data by dose and time as appropriate.  
Descriptive statistics on continuous data will include means, 
medians, standard deviations, and ranges, while categorical data 
will be summarized using frequency counts and percentages.  
Graphical summaries of the data may be presented. 
Safety Endpoints: 
The safety profile will be based on serious adverse events, 
TEAEs, physical examination findings (including ECOG 
performance status), vital sign measurements, standard clinical 
laboratory endpoints (serum chemistry, hematology, urinalysis), 
and ECG endpoints.  All subjects receiving at least 1 dose of 
milademetan will be included in the safety analyses. 
Tumor Response: 
Response assessment will be performed according to the 
Schedule of Events or if disease progression is suspected.  
Radiographic assessment should include computed tomography 
(CT) of all affected sites.  In addition, subjects with lymphoma 
should undergo a (18F) fluorodeoxyglucose-positron emission 
tomography (FDG-PET) scan.  Tumor responses will be 
assessed by the investigator according to RECIST v 1.1 criteria 
for subjects with solid tumors and revised IWG criteria for 
subjects with lymphoma.  Descriptive statistics for the greatest 
percent change in the sum of longest dimensions (SLD) of 
measurable tumors will be provided.  A waterfall plot of the 
greatest percent change from screening in the SLD for each 
subject will be presented for subjects with advanced solid 
malignancies and lymphomas.  Additional efficacy analyses, 
including PFS and spider plots, will be detailed in the Statistical 
Analysis Plan (SAP).  In addition, descriptive statistics for 
FDG-PET scans will be provided for lymphoma subjects 
according to revised IWG criteria. 
Pharmacokinetic Endpoints: 
Plasma concentrations of milademetan will be listed and 
summarized using descriptive statistics by dose cohort at each 
time point.  A non-compartmental analysis will be performed to 
estimate PK endpoints, which include Cmax, time to Cmax 
[Tmax], minimum plasma concentration (Cmin), area under the 
curve until 8 hours [AUC0-8h] and 24 hours [AUC0-24h], 
accumulation index [AI], as well as any other endpoints deemed 
appropriate. 


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A Population pharmacokinetic [PopPK] analysis and exposure-
response analysis for various endpoints may be developed.  The 
analysis plan and the Technical Report will be provided 
separately.   
Pharmacodynamic Endpoints: 
Changes in MIC-1 levels in serum and other PDy markers, if 
available, will be listed and summarized using descriptive 
statistics by dose level cohort. 
Predictive Biomarker Endpoints: 
Archived or pre-treatment, on-treatment, and end-of-treatment 
biopsied tumor samples will be examined for components of the 
p53 pathway, which may include, but are not limited to, 
expression of p53, p21, MDM2, MDM4, and MDM2 copy 
number, and TP53 mutations.  Additional biomarkers outside of 
the p53 pathway may be included in order to better understand 
the responsiveness to therapy.  These may include protein, 
metabolite, gene expression, or genetic biomarkers. 
Analyses for potential biomarkers that may be predictive of 
benefit from milademetan will be graphed and/or listed and 
summarized using descriptive statistics by dose level cohort.  


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1.2. 
Study Schema 
Figure 1.1: 
Flow Diagram of Dose Escalation Phase 
 
BLRM = Bayesian logistic regression model; DLT = dose-limiting toxicity; EWOC = escalation with overdose 
control; MTD = maximum tolerated dose; QD = once daily 
a Continue single subject cohort, 100% dose escalation until a non-DLT adverse event of Grade ≥ 2 or a DLT is 
observed. 
b Over-enrollment in ATD up to 3 subjects per cohort is permitted. 
c In total, there should be at least 21 DLT-evaluable subjects before claiming the MTD. 
d Refer to Section 4.1.5.1 for stopping criteria.  
Note: Alternative dosing schedules will be evaluated after reaching MTD at QD × 21/28-day schedule 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
SUMMARY OF CHANGES ...........................................................................................................3 
1. 
PROTOCOL SUMMARY ............................................................................................18 
1.1. 
Protocol Synopsis ..........................................................................................................18 
1.2. 
Study Schema ................................................................................................................37 
LIST OF ABBREVIATIONS ........................................................................................................48 
2. 
INTRODUCTION AND BACKGROUND INFORMATION .....................................51 
2.1. 
Data Summary ...............................................................................................................51 
2.1.1. 
Investigational Product(s) .............................................................................................51 
2.1.1.1. 
Name .............................................................................................................................51 
2.1.1.2. 
Description ....................................................................................................................51 
2.1.1.3. 
Intended Use Under Investigation .................................................................................51 
2.1.1.4. 
Pharmacological Target(s) ............................................................................................51 
2.1.1.5. 
Nonclinical Studies .......................................................................................................52 
2.1.1.6. 
Clinical Experience .......................................................................................................53 
2.2. 
Study Rationale .............................................................................................................53 
2.3. 
Risks and Benefits for Study Subjects ..........................................................................53 
2.3.1. 
Potential Risks Associated with Milademetan ..............................................................53 
2.3.2. 
Potential Risk of Drug-Drug Interaction .......................................................................54 
2.3.3. 
Potential Benefit Associated with Milademetan ...........................................................54 
2.4. 
Population, Route, Dosage, Dosage Regimen, Treatment Period.................................54 
2.4.1. 
Part 1 (Dose Escalation) ................................................................................................55 
2.4.2. 
Part 2 (Dose Expansion)................................................................................................55 
3. 
STUDY OBJECTIVES AND HYPOTHESES .............................................................56 
3.1. 
Study Objectives ...........................................................................................................56 
3.1.1. 
Primary Objectives ........................................................................................................56 
3.1.1.1. 
Part 1 (Dose Escalation) ................................................................................................56 
3.1.1.2. 
Part 2 (Dose Expansion)................................................................................................56 
3.1.2. 
Secondary Objectives ....................................................................................................56 
3.1.2.1. 
Part 1 (Dose Escalation) ................................................................................................56 
3.1.2.2. 
Part 2 (Dose Expansion)................................................................................................56 


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3.1.3. 
Exploratory Objectives..................................................................................................57 
3.1.3.1. 
Part 1 (Dose Escalation) ................................................................................................57 
3.1.3.2. 
Part 2 (Dose Expansion)................................................................................................57 
3.2. 
Outcome Measures ........................................................................................................58 
3.2.1. 
Primary Outcome Measure ...........................................................................................58 
3.2.2. 
Secondary Outcome Measure .......................................................................................58 
3.3. 
Study Hypothesis ..........................................................................................................59 
3.4. 
Study Endpoints ............................................................................................................59 
4. 
STUDY DESIGN ..........................................................................................................60 
4.1. 
Overall Plan ...................................................................................................................60 
4.1.1. 
Study Type ....................................................................................................................60 
4.1.2. 
Treatment Groups..........................................................................................................60 
4.1.2.1. 
Part 1 (Dose Escalation) ................................................................................................60 
4.1.2.2. 
Part 2 (Dose Expansion in Subjects With Advanced Melanoma or Diffuse 
Large B-cell Lymphoma) ..............................................................................................64 
4.1.2.3. 
Intrasubject Dose Escalation .........................................................................................65 
4.1.3. 
Duration of the Study ....................................................................................................65 
4.1.4. 
Duration of Subject Participation ..................................................................................65 
4.1.5. 
Stopping Rules ..............................................................................................................65 
4.1.5.1. 
Stopping Rule for Maximum Tolerated Dose Determination .......................................65 
4.1.5.2. 
Dose-limiting Toxicities................................................................................................66 
4.1.6. 
Maximum Tolerated Dose and Tentative Recommended Phase 2 
Dose Definition .............................................................................................................67 
4.1.7. 
Management of Subjects with Adverse Events .............................................................67 
4.1.8. 
Guidelines for Dose Delays ..........................................................................................67 
4.2. 
Selection of Doses .........................................................................................................68 
4.2.1. 
Experimental Treatments ..............................................................................................68 
4.2.1.1. 
Part 1 (Dose Escalation) ................................................................................................68 
4.2.1.2. 
For the Study .................................................................................................................68 
4.2.1.3. 
For Individual Subjects .................................................................................................68 
4.2.2. 
Control Treatments........................................................................................................68 
5. 
STUDY POPULATION ...............................................................................................69 
5.1. 
Enrollment .....................................................................................................................69 


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5.1.1. 
Inclusion Criteria ...........................................................................................................70 
5.1.2. 
Exclusion Criteria..........................................................................................................71 
5.2. 
Removal of Subjects from Therapy ..............................................................................72 
5.2.1. 
Reasons for Withdrawal/Early Discontinuation............................................................72 
5.2.2. 
Withdrawal Procedures .................................................................................................73 
5.2.3. 
Subject Replacement .....................................................................................................73 
5.2.4. 
Subject Re-screening Procedures ..................................................................................73 
6. 
TREATMENTS ADMINISTERED .............................................................................74 
6.1. 
Investigational Products ................................................................................................74 
6.1.1. 
Method of Assigning Subjects to Treatments and Blinding .........................................74 
6.1.1.1. 
Randomization ..............................................................................................................74 
6.1.1.2. 
Blinding .........................................................................................................................74 
6.1.2. 
Method of Assessing Treatment Compliance ...............................................................74 
6.1.3. 
Labeling and Packaging ................................................................................................74 
6.1.4. 
Preparation ....................................................................................................................75 
6.1.5. 
Storage...........................................................................................................................75 
6.1.6. 
Drug Accountability ......................................................................................................75 
6.1.7. 
Retention Samples .........................................................................................................75 
6.2. 
Concomitant Medications .............................................................................................75 
6.2.1. 
Prohibited Concomitant Medications/Activities ...........................................................76 
7. 
STUDY PROCEDURES ..............................................................................................77 
7.1. 
Screening .......................................................................................................................77 
7.1.1. 
Part 1 (Dose Escalation), Screening (Pre-cycle) ...........................................................77 
7.2. 
Randomization ..............................................................................................................78 
7.3. 
Treatment Period ...........................................................................................................78 
7.3.1. 
Treatment Period, Part 1 (Dose Escalation) ..................................................................78 
7.3.1.1. 
Part 1 (Dose Escalation), Cycle 1/Day 1 .......................................................................78 
7.3.1.2. 
Part 1 (Dose Escalation), Cycle 1/Day 2 .......................................................................79 
7.3.1.3. 
Part 1 (Dose Escalation), Cycle 1/Day 8 .......................................................................80 
7.3.1.4. 
Part 1 (Dose Escalation), Cycle 1/Day 15 .....................................................................80 
7.3.1.5. 
Part 1 (Dose Escalation), Cycle 1/Days 18 to 21 ..........................................................81 
7.3.1.6. 
Part 1 (Dose Escalation), Cycle 2/Day 1 .......................................................................81 


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7.3.1.7. 
Part 1 (Dose Escalation), Cycle 2/Day 8 .......................................................................82 
7.3.1.8. 
Part 1 (Dose Escalation), Cycle 2/Day 15 .....................................................................82 
7.3.1.9. 
Part 1 (Dose Escalation), Cycle 3/Day 1 .......................................................................83 
7.3.1.10. Part 1 (Dose Escalation), Cycle 3/Day 15 .....................................................................83 
7.3.1.11. Part 1 (Dose Escalation), Cycle 4 and All Subsequent Cycles, Day 1..........................84 
7.3.1.12. Part 1 (Dose Escalation), End-of-Treatment (Post-cycle).............................................84 
7.3.1.13. Part 1 (Dose Escalation) End-of-Study Follow-up .......................................................85 
7.3.1.14. Part 1 (Dose Escalation) Tumor Re-biopsy ..................................................................86 
7.3.2. 
Treatment Period, Part 2 (Dose Expansion) ..................................................................86 
7.3.2.1. 
Part 2 (Dose Expansion), Screening (Pre-cycle) ...........................................................86 
7.3.2.2. 
Part 2 (Dose Expansion), Cycle 1/Day 1 ......................................................................87 
7.3.2.3. 
Part 2 (Dose Expansion), Cycle 1/Day 2 ......................................................................88 
7.3.2.4. 
Part 2 (Dose Expansion), Cycle 1/Day 8 ......................................................................88 
7.3.2.5. 
Part 2 (Dose Expansion), Cycle 1/Day 15 ....................................................................88 
7.3.2.6. 
Part 2 (Dose Expansion), Cycle 1/Days 18 to 21 ..........................................................89 
7.3.2.7. 
Part 2 (Dose Expansion), Cycle 2/Day 1 ......................................................................89 
7.3.2.8. 
Part 2 (Dose Expansion), Cycle 2/Day 8 ......................................................................90 
7.3.2.9. 
Part 2 (Dose Expansion), Cycle 2/Day 15 ....................................................................90 
7.3.2.10. Part 2 (Dose Expansion), Cycle 3/Day 1 ......................................................................91 
7.3.2.11. Part 2 (Dose Expansion), Cycle 3/Day 15 ....................................................................91 
7.3.2.12. Part 2 (Dose Expansion), Cycle 4 and All Subsequent Cycles, Day 1 .........................92 
7.3.2.13. Part 2 (Dose Expansion), End-of-Treatment (Post-Cycle) ...........................................92 
7.3.2.14. Part 2 (Dose Expansion) End-of-Study Follow-up .......................................................93 
7.3.2.15. Part 2 (Dose Expansion) Tumor Re-biopsy ..................................................................93 
8. 
EFFICACY ASSESSMENTS .......................................................................................94 
8.1. 
Efficacy Variable(s) ......................................................................................................94 
9. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ........................95 
9.1. 
Pharmacokinetic Assessment(s) ....................................................................................95 
9.2. 
Pharmacodynamic/Predictive Biomarker Variable(s)...................................................96 
9.2.1. 
TP53 Status ...................................................................................................................96 
9.2.2. 
Pharmacodynamic Variables .........................................................................................96 
9.2.3. 
Exploratory Biomarker Analysis...................................................................................96 


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9.3. 
Pharmacogenomics .......................................................................................................97 
10. 
SAFETY EVALUATION AND REPORTING ...........................................................98 
10.1. 
Adverse Event Collection and Reporting ......................................................................98 
10.2. 
Safety Endpoints ...........................................................................................................98 
10.3. 
Adverse Events of Special Interest ...............................................................................98 
10.4. 
Adverse Event ...............................................................................................................99 
10.4.1. 
Definition of Adverse Event .........................................................................................99 
10.4.2. 
Serious Adverse Event ..................................................................................................99 
10.4.3. 
Grade Assessment .......................................................................................................100 
10.4.4. 
Causality Assessment ..................................................................................................100 
10.4.5. 
Action Taken Regarding the Study Product ...............................................................101 
10.4.6. 
Other Action Taken for Event .....................................................................................101 
10.4.7. 
Adverse Event Outcome .............................................................................................101 
10.5. 
Serious Adverse Event Reporting Procedure For Investigators ..................................102 
10.6. 
Notifying Regulatory Authorities, Investigators, IRB, and Competent 
Authorities ...................................................................................................................102 
10.7. 
Exposure In Utero During Clinical Studies ................................................................102 
10.8. 
Clinical Laboratory Evaluations .................................................................................103 
10.9. 
Vital Signs ...................................................................................................................104 
10.10. 
Electrocardiograms .....................................................................................................104 
10.11. 
Physical Examinations ................................................................................................104 
10.12. 
Other Safety Assessments ...........................................................................................104 
11. 
OTHER ASSESSMENTS ...........................................................................................105 
12. 
STATISTICAL METHODS .......................................................................................106 
12.1. 
General Statistical Considerations ..............................................................................106 
12.2. 
Analysis Sets ...............................................................................................................106 
12.2.1. 
Enrolled Analysis Set ..................................................................................................106 
12.2.2. 
Full Analysis Set .........................................................................................................106 
12.2.3. 
Biomarker Positive Analysis Set .................................................................................107 
12.2.4. 
Dose-Limiting Toxicity Evaluable Set .......................................................................107 
12.2.5. 
Safety Analysis Set .....................................................................................................107 
12.2.6. 
Pharmacokinetic Analysis Set .....................................................................................107 
12.2.7. 
Biomarker Analysis Set...............................................................................................107 


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12.3. 
Study Population Data ................................................................................................107 
12.4. 
Efficacy Analyses........................................................................................................107 
12.4.1. 
Primary Efficacy Analyses ..........................................................................................107 
12.4.2. 
Secondary Efficacy Analyses ......................................................................................108 
12.4.3. 
Exploratory Efficacy Analyses ...................................................................................108 
12.5. 
Pharmacokinetic/Pharmacodynamic Analyses ...........................................................108 
12.5.1. 
Pharmacokinetic Analyses ..........................................................................................108 
12.5.2. 
Pharmacodynamic Analyses .......................................................................................109 
12.5.3. 
Biomarker and Exploratory Analyses .........................................................................109 
12.6. 
Safety Analyses ...........................................................................................................110 
12.6.1. 
Adverse Event Analyses .............................................................................................110 
12.6.2. 
Clinical Laboratory Evaluation Analyses ...................................................................110 
12.6.3. 
Vital Signs Analyses ...................................................................................................110 
12.6.4. 
Electrocardiogram Analyses .......................................................................................111 
12.6.5. 
Physical Finding Analyses ..........................................................................................111 
12.6.6. 
Other Safety Analyses .................................................................................................111 
12.7. 
Other Analyses ............................................................................................................111 
12.8. 
Interim Analyses .........................................................................................................111 
12.9. 
Data and Safety Monitoring Board .............................................................................111 
12.10. 
Sample Size Determination .........................................................................................111 
12.11. 
Specification of Bayesian Logistic Regression Model with Escalation with 
Overdose Control ........................................................................................................112 
12.11.1. Bayesian Logistic Regression Model for Modified Continuous Reassessment 
Method ........................................................................................................................112 
12.11.2. Prior Specification for Bayesian Logistic Regression Model Parameters ..................112 
12.11.3. Escalation with Overdose Control Principle ...............................................................113 
13. 
DATA INTEGRITY AND QUALITY ASSURANCE ..............................................114 
13.1. 
Monitoring and Inspections ........................................................................................114 
13.2. 
Data Collection............................................................................................................114 
13.3. 
Data Management .......................................................................................................115 
13.4. 
Study Documentation and Storage ..............................................................................115 
13.5. 
Record Keeping ...........................................................................................................116 
13.6. 
Product Complaints .....................................................................................................116 


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14. 
FINANCING AND INSURANCE .............................................................................117 
14.1. 
Finances.......................................................................................................................117 
14.2. 
Reimbursement, Indemnity, and Insurance .................................................................117 
15. 
PUBLICATION POLICY ...........................................................................................118 
16. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION ..............................119 
16.1. 
Compliance Statement, Ethics, and Regulatory Compliance......................................119 
16.2. 
Subject Confidentiality................................................................................................119 
16.3. 
Informed Consent ........................................................................................................119 
16.4. 
Regulatory Compliance ...............................................................................................120 
16.5. 
Protocol Deviations .....................................................................................................120 
16.6. 
Supply of New Information Affecting the Conduct of the Study ...............................121 
16.7. 
Protocol Amendments .................................................................................................121 
16.8. 
Study Termination .......................................................................................................122 
16.9. 
Data and Safety Monitoring Board .............................................................................122 
16.10. 
Address List ................................................................................................................122 
17. 
REFERENCES ............................................................................................................123 
18. 
APPENDICES ............................................................................................................124 
18.1. 
Eastern Cooperative Oncology Group Performance Status Scale ..............................124 
18.2. 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4 .....................................................................................................................124 
18.3. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 ......................................125 
18.3.1. 
Measurability of Tumor at Baseline ............................................................................125 
18.3.1.1. Definitions ...................................................................................................................125 
18.3.1.2. Specifications by Methods of Measurements .............................................................126 
18.3.2. 
Tumor Response Evaluation .......................................................................................126 
18.3.2.1. Assessment of Overall Tumor Burden and Measurable Disease ................................126 
18.3.2.2. Baseline Documentation of “Target” and “Nontarget” Lesions .................................127 
18.3.2.3. Response Criteria ........................................................................................................127 
18.3.2.4. Evaluation of Best Overall Response ..........................................................................130 
18.3.2.5. Frequency of Tumor Reevaluation..............................................................................131 
18.4. 
International Working Group Criteria .........................................................................132 
18.5. 
Cytokine P450 3A Inducers and Inhibitors .................................................................132 
18.6. 
Schedule of Events ......................................................................................................135 


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18.7. 
Extension Phase ..........................................................................................................141 
18.7.1. 
Extension Phase Synopsis ...........................................................................................141 
 


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LIST OF TABLES 
Table 9.1: Blood Sample Collection for Milademetan Pharmacokinetics ...................................95 
Table 12.1: Pharmacokinetic Parameters for Non-Compartmental Analysis ..............................109 
Table 18.1: Overall Response ......................................................................................................130 
Table 18.2: Schedule of Events Part 1 (Dose Escalation) ...........................................................135 
Table 18.3: Schedule of Events Part 2 (Dose Expansion) ...........................................................138 
Table 18.4: Schedule of Events (Extension Phase) .....................................................................143 
 


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LIST OF FIGURES 
Figure 1.1: Flow Diagram of Dose Escalation Phase ....................................................................37 
Figure 2.1: Targeted Mechanism of Milademetan Antitumor Activity ........................................52 
 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
Adverse events 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATD 
Accelerated titration design 
AUC0-8h 
Area under the plasma concentration- time curve from time 0 to 8 hours 
AUC0-24h 
Area under the plasma concentration- time curve from time 0 to 24 hours 
BLRM 
Bayesian logistic regression model 
Cmax 
Maximum plasma concentration 
Cmin 
Minimum plasma concentration 
CFR 
Code of Federal Regulations 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DD 
Dedifferentiated 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DNAseq 
Deoxyribonucleic acid sequence 
DS-3032a 
The free form of milademetan 
DSI 
Daiichi Sankyo, Inc. 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 


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ABBREVIATION 
DEFINITION 
EIU 
Exposure in utero 
EWOC 
Escalation with overdose control 
FDG-PET 
(18F) fluorodeoxyglucose-positron emission tomography 
FFPE 
Formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
HNSTD 
Highest nonseverely toxic dose 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Council of Medical Journal Editors 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWG 
International Working Group 
MDM2 
Murine double minute 2 
MDM4 
Murine double minute 4 
MIC-1 
Macrophage inhibitory cytokine-1 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
PD 
Progressive disease 
PDy 
Pharmacodynamic 
PFS 
Progression free survival 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetic(s) 
PopPK 
Population pharmacokinetic 
PR 
Partial response 
QD 
Once daily 
QTcB 
Corrected QT interval using Bazett’s formula 
QTcF 
Corrected QT interval using Fridericia’s formula 
RNA 
Ribonucleic acid 
RNAseq 
Ribonucleic acid sequence 
RP2D 
Recommended phase 2 dose 


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ABBREVIATION 
DEFINITION 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAVER 
Serious adverse event report 
SD 
Stable disease 
SID 
Subject identification number 
SLD 
Sum of longest dimensions 
SNP 
Single-nucleotide polymorphism 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse event reaction 
t1/2 
Terminal elimination half-life 
Tmax 
Time to reach maximum plasma concentration 
TEAE 
Treatment-emergent adverse event 
TP53 
The gene encoding p53 
TTR 
Time-to-response 
ULN 
Upper limit of normal 
US 
United States 
WD 
Well-differentiated 


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2. 
INTRODUCTION AND BACKGROUND INFORMATION 
2.1. 
Data Summary 
2.1.1. 
Investigational Product(s) 
2.1.1.1. 
Name 
Milademetan 
Chemical Name: (3'R,4'S,5'R)-N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6''-chloro-4'-
(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-indole]-5'-carboxamide mono(4-methylbenzenesulfonate) monohydrate 
2.1.1.2. 
Description 
Milademetan is an orally available and highly selective inhibitor of the murine double minute 2 
(MDM2)-p53 interaction. 
2.1.1.3. 
Intended Use Under Investigation 
Milademetan will be evaluated in subjects with advanced solid tumors or lymphomas refractory 
to standard treatment or for which no standard treatment is available.  
2.1.1.4. 
Pharmacological Target(s) 
Milademetan, a novel, specific, small-molecule inhibitor of MDM2, disrupts interactions 
between MDM2 and the tumor suppressor protein p53 in tumor cells and is being developed as 
an oral drug for the treatment of cancer.  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 p53 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. 
The mechanism of action of milademetan is summarized in Figure 2.1. 


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Figure 2.1: 
Targeted Mechanism of Milademetan Antitumor Activity 
 
Bax = Bcl-2–associated X protein; MDM2 = murine double minute 2;  
p21 = cyclin-dependent kinase inhibitor 1; puma = p53 upregulated modulator of apoptosis; Ub = ubiquitin. 
Note: Schematic of p53/MDM2 interactions and impact on cell signaling pathways altered in certain 
malignancies.  Milademetan exerts antitumor activity by inhibiting interactions between MDM2 and p53 and 
preventing p53 degradation.  The resulting increase in wild-type p53 activity activates signal transduction pathways 
important in inducing cell cycle arrest, apoptosis, and/or senescence in tumor cells. 
Source: Data on File 
In human tumors that retain wild-type 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 ubiquitinization ligase activity.1 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 MDM2.2 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.  Pharmacologic inhibition of 
the interaction between MDM2 and wild-type p53 in tumor cells could result in sustained 
increases in p53 activity and subsequent antitumor effects.3,4 Therefore, pharmacologic 
restoration of the p53 pathway could be an effective strategy for cancer therapy targeting the 
wide array of human cancers that retain wild-type p53.5 
2.1.1.5. 
Nonclinical Studies 
Please refer to the current milademetan Investigator's Brochure (IB)6 for nonclinical data 
supporting its use in clinical studies.6   


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2.1.1.5.1. Human Starting Dose 
Based on the rat and dog repeat-dose toxicity studies, the dog proved to be the most sensitive 
species to milademetan-induced myelotoxicity.  The highest nonseverely toxic dose (HNSTD) in 
dog was found to be 3 mg/kg/day (60 mg/m2/day; human equivalent dose 1.62 mg/kg or 
~ 100 mg in a 60-kg patient).  Applying a safety factor of 6, these data supported a starting dose 
of 10 mg/m2 (~15 mg in a 60-kg patient).  The nonclinical pharmacology data suggested that 
pharmacologically active exposures were likely to be achieved through dose escalation.  To 
mitigate the risk of untoward toxicity, the use of a continuous reassessment method coupled with 
a dose-exposure model is proposed to guide dose escalation.  Additional details are provided in 
the current IB.6 
2.1.1.6. 
Clinical Experience 
This is the first-in-human study of milademetan.  No prior clinical experience of milademetan 
was available when the study was initiated.  Additional details of ongoing clinical studies are 
provided in the current IB.6  
2.2. 
Study Rationale 
The tumor suppressor p53 is a transcription factor that plays a central role in preventing tumor 
development and progression by inducing cell cycle arrest, apoptosis, or senescence.  The gene 
encoding p53 (TP53) suffers disabling somatic mutations or deletions in about 50% of all 
malignant tumors.  In tumors expressing wild-type protein, the tumor suppressor function of p53 
may be attenuated by other mechanisms, such as over-expression of MDM2, a negative regulator 
of p53.  MDM2 binds p53 with high affinity and negatively modulates the transcriptional activity 
and stability of the tumor suppressor.  In tumors with functional p53, inhibition of the 
MDM2-p53 interaction can restore p53 activity and is expected to offer a novel strategy for 
cancer therapy. 
Milademetan is an orally available and highly selective inhibitor of the MDM2-p53 interaction.  
It shows antitumor efficacy against tumors with wild-type p53 via activation of the tumor 
suppressor in a variety of cell culture and xenograft models.  This ongoing Phase 1 
first-in-human study will be conducted to assess the safety and tolerability of milademetan, as 
well as to determine the pharmacokinetic (PK)/pharmacodynamic (PDy) profile and preliminary 
efficacy of the drug. 
2.3. 
Risks and Benefits for Study Subjects 
2.3.1. 
Potential Risks Associated with Milademetan 
Investigators in the milademetan program must be aware of the potential for hematologic and 
gastrointestinal toxicities and properly monitor for these toxicities and promptly manage subjects 
who experience these adverse events (AEs).  Please refer to the current IB6 for updated safety 
and risk/benefit assessment. 


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2.3.2. 
Potential Risk of Drug-Drug Interaction 
Nonclinical studies indicate that DS-3032a (the free form of milademetan) is metabolized by 
cytochrome P450 (CYP) 3A4 and CYP3A5 by using microsomes containing individual 
recombinant human CYP isoforms.  Drugs that are strong inducers of CYP3A may alter the 
pharmacokinetics of milademetan and, therefore, should be avoided until formal drug-drug 
interaction studies have been conducted. 
A Phase 1 study in healthy subjects was conducted to evaluate the effect of co-administration of 
the strong CYP3A4 inhibitors (itraconazole and posaconazole) on milademetan PK 
(Study U107).  Co-administration of milademetan 100 mg with itraconazole 200 mg at steady 
state increased milademetan geometric mean Cmax and AUCinf by 8% and 115%, respectively.  
Similarly, posaconazole 200 mg at steady state increased milademetan geometric mean Cmax by 
approximately 19% and AUCinf by approximately 149%.  Therefore, dose of milademetan is 
recommended to be reduced to half when it is concomitantly administered with strong CYP3A4 
inhibitors. 
Milademetan showed direct inhibition on CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, and CYP3A, but not on CYP1A2 and CYP2E1 (half maximal inhibitory concentration  
range: 7.8 µM to 27.0 µM).  Milademetan also showed metabolism-dependent inhibition on 
CYP3A (both testosterone 6β-hydroxylase and midazolam 1’-hydroxylase).  The concentration 
required for half maximal inactivation (KI) and maximal rate of inactivation at saturation (kinact) 
values were calculated to be 60.5 µM and 0.0619 min-1 for CYP3A (midazolam 1’-hydroxylase), 
respectively.  However, these levels of milademetan are much higher than those expected to be 
achievable in humans.  Therefore concomitant use of CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, and CYP3A substrates will be permitted.  Please refer to the current IB for additional 
details on drug-drug interactions with milademetan.6  
2.3.3. 
Potential Benefit Associated with Milademetan 
Milademetan is a novel, specific, small-molecule inhibitor of MDM2 that disrupts interactions 
between MDM2 and p53 in tumor cells.  Nonclinical data demonstrated in human tumor cell 
lines expressing wild-type p53 that milademetan inhibited cell growth in a 
concentration-dependent manner and induced apoptosis, and was more potent than the 
well-characterized MDM2 inhibitor Nutlin-3a.  In vivo studies in mouse xenografts 
demonstrated that multiple doses of milademetan produced statistically significant dose-related 
antitumor responses.  The highest dose of milademetan yielded a 93% tumor reduction relative to 
the control group.  These data demonstrate that in tumors with wild-type p53, inhibition of 
MDM2-p53 interaction can restore p53 activity and is expected to offer a novel strategy for 
cancer therapy. 
2.4. 
Population, Route, Dosage, Dosage Regimen, Treatment Period 
Milademetan will be administered as an oral capsule.  It will be supplied in 5, 20, 80, and 
200 mg capsules individually packaged in desiccant-embedded aluminum blisters.  Two other 
capsule strengths of 30 and 100 mg are also supplied in high density polyethylene (HDPE) 
bottles. 


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2.4.1. 
Part 1 (Dose Escalation) 
This study will enroll adult subjects with advanced solid tumors or lymphomas that are refractory 
to standard therapy or for which no standard therapy is available.  See Section 5.1.1 and 
Section 5.1.2 for a detailed description of all inclusion and exclusion criteria, respectively. 
2.4.2. 
Part 2 (Dose Expansion) 
Although the subjects in the Dose Escalation and Dose Expansion parts of the study will have 
common inclusion and exclusion criteria, subjects with advanced melanomas or with diffuse 
large B-cell lymphomas (DLBCLs) in the Dose Expansion part of the study will have additional 
inclusion criteria, as described in Section 5.1.1.   
See Section 4.1 for a detailed description of the study drug administration schedule, treatment 
cycle duration, and follow-up after discontinuation. 


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3. 
STUDY OBJECTIVES AND HYPOTHESES  
3.1. 
Study Objectives 
3.1.1. 
Primary Objectives 
3.1.1.1. 
Part 1 (Dose Escalation) 
The primary objectives are as follows: 
1. To assess the safety and tolerability of milademetan in subjects with advanced solid 
tumors or lymphomas who have relapsed from or are refractory to standard therapy or for 
whom no standard therapy is available.  
To determine the maximum tolerated dose (MTD) or tentative recommended Phase 2 dose 
(RP2D) of milademetan in subjects with advanced solid tumors or lymphomas. 
3.1.1.2. 
Part 2 (Dose Expansion) 
The primary objectives are as follows: 
1. To confirm the safety and tolerability of milademetan at the MTD/tentative RP2D in 
subjects with advanced melanoma or DLBCL who have relapsed from or are refractory to 
standard therapy or for whom no standard therapy is available.  
2. To assess tumor response in subjects with melanoma using Response Evaluation Criteria 
in Solid Tumors (RECIST) v 1.1 and in subjects with DLBCL using the revised 
International Working Group (IWG) criteria. 
3.1.2. 
Secondary Objectives 
3.1.2.1. 
Part 1 (Dose Escalation) 
The secondary objectives are as follows: 
1. To determine the plasma PK of DS-3032a (the free form of milademetan). 
2. To determine the PDy effect of milademetan on macrophage inhibitory cytokine-1 
(MIC-1) levels in serum. 
3. To evaluate the response of solid tumors and lymphoma and their subtypes to 
milademetan using the corresponding standard response criteria (Response Evaluation 
Criteria in Solid Tumors [RECIST] v 1.1 or revised IWG criteria, respectively). 
3.1.2.2. 
Part 2 (Dose Expansion) 
The secondary objectives are as follows: 
1. To determine the PK profile of DS-3032a at the MTD/tentative RP2D. 
2. To determine the PDy effect of milademetan on MIC-1 levels in serum. 


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3.1.3. 
Exploratory Objectives 
3.1.3.1. 
Part 1 (Dose Escalation) 
The exploratory objectives are as follows: 
1. To compare progression free survival (PFS) between that observed with milademetan 
treatment and that observed from the most recent therapeutic regimen. 
To bank blood samples for deoxyribonucleic acid (DNA) analysis for the assessment of potential 
biomarkers (eg, MDM2 single-nucleotide polymorphism [SNP] 309) that may be predictive of 
benefit or toxicity from milademetan. 
To assess blood and tumor samples for DNA or ribonucleic acid (RNA) analysis that may be 
predictive of benefit or toxicity from milademetan. 
To evaluate the relationship between tumor response to milademetan and potential predictive 
biomarkers studied in archived tumor samples, pre-treatment tumor biopsies, if available, and/or 
blood samples. 
To assess the PDy effect of milademetan on the expression levels of p53, p21, MDM2, murine 
double minute 4 (MDM4), Ki67, apoptosis markers, and/or other biomarkers in pre- and 
post-treatment solid tumor/lymphoma samples, if available. 
To characterize the plasma metabolites of DS-3032a. 
3.1.3.2. 
Part 2 (Dose Expansion) 
The exploratory objectives are as follows: 
1. To compare PFS between that observed with milademetan treatment and that observed 
from the most recent therapeutic regimen.  
To bank blood samples for DNA analysis for the assessment of potential biomarkers (eg, MDM2 
SNP 309) that may be predictive of benefit or toxicity from milademetan. 
To assess blood and tumor samples for DNA or RNA analysis that may be predictive of benefit 
or toxicity from milademetan. 
To assess the PDy effect of milademetan on the expression levels of p53, p21, MDM2, MDM4, 
Ki67, apoptosis markers, and/or other biomarkers in pre- and post-treatment solid 
tumor/lymphoma samples, if available. 
To characterize the plasma metabolites of DS-3032a. 
To evaluate the relationship between tumor response to milademetan and biomarkers studied in 
archived tumor samples and pretreatment, on-treatment, and end-of-treatment tumor biopsies. 


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3.2. 
Outcome Measures 
3.2.1. 
Primary Outcome Measure 
Title: Number of subjects with TEAEs during the study 
Details: Number of subjects with TEAEs by frequency and grade in each cohort of dose and 
dosing schedule and the total number of subjects with the TEAEs 
Timeframe: From start of study until last subject last visit (approximately 6 years) 
 
Title: Maximum tolerated dose(s)  
Details: MTD(s) identified at different dosing schedules 
Time frame: From start of study until final database lock (approximately 6 years) 
 
Title: Number of subjects with dose-limiting toxicities (DLTs) 
Details: Number of subjects with DLTs at each dose [level /cohort] and the total number of 
subjects with DLTs 
Time frame: From start of study until the DLT evaluation of the last subject in dose escalation 
part (approximately 6 years or less)  
 
Title: Response rates in melanoma and DLBCL in dose expansion cohorts 
Details: Number and percentage of subjects with melanoma and DLBCL in dose expansion 
cohorts who achieved objective response per RECIST v 1.1 and IWG, respectively 
Time frame: From start of study until last subject last tumor assessment in Dose Expansion 
(approximately 6 years) 
3.2.2. 
Secondary Outcome Measure 
Title: PK parameters of milademetan 
Details: Determination of milademetan PK parameters (Cmax, Tmax, AUC, CL/F, and T½). 
Timeframe: From start of study until final database lock (approximately 6 years) 
 
Title: Pharmacodynamic effect of milademetan 
Details: Pharmacodynamic effect of milademetan assessed by increase in serum MIC-1 levels 
over baseline. 
Time frame: From start of study until final database lock (approximately 6 years) 


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3.3. 
Study Hypothesis 
Milademetan will be safe and well tolerated and will exhibit acceptable PK/PDy properties in 
subjects with advanced solid tumors or lymphomas who have relapsed from or are refractory to 
standard therapy or for which no standard therapy is available.  Milademetan will manifest 
activity as evidenced by objective response in subjects with solid tumors and lymphomas. 
3.4. 
Study Endpoints 
The endpoints for the study include the following: 
 Safety endpoints: 
Serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), physical 
examination findings (including Eastern Cooperative Oncology Group [ECOG] performance 
status), vital signs measurements, standard clinical laboratory parameters (serum chemistry, 
hematology, urinalysis), and electrocardiogram (ECG) parameters.  Adverse events will be 
graded according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) v4.  Dose escalation will be determined by plasma drug concentrations 
and rate of DLTs.  
 Pharmacokinetic and pharmacodynamic endpoints: 
Plasma PK and standard non-compartmental PK parameters will be assessed.  Plasma samples 
for PK assessments will be taken at multiple time points in the study.  Additionally, a PK sample 
may also be obtained outside of the specified time points during the study if deemed clinically 
necessary.   
Induction of serum MIC-1 will be the primary PDy biomarker.  Whole blood samples will be 
collected at multiple time points in the study to assess the effect of milademetan treatment on 
MIC-1 induction.  Other exploratory PDy biomarkers including, but not limited to, expression 
levels of p53, p21, MDM2, MDM4, Ki67, apoptosis markers, and/or other biomarkers will also 
be assessed, if available. 
 Efficacy endpoints: 
In solid tumor subjects with measurable disease, tumor response will be evaluated using RECIST 
v 1.1.  In subjects with lymphomas, treatment response will be evaluated using the revised IWG 
criteria.7 


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4. 
STUDY DESIGN 
4.1. 
Overall Plan 
4.1.1. 
Study Type 
This will be a Phase 1, open-label study of milademetan to assess its safety and tolerability, 
identify an MTD/tentative RP2D, and assess its PK/PDy properties in subjects with advanced 
solid tumors or lymphomas. 
Approximately 5 United States (US) sites are planned for Part 1 (Dose Escalation) and Part 2 
(Dose Expansion).  The same sites are planned to participate for both parts. 
4.1.2. 
Treatment Groups 
This 2-part study will include both a Dose Escalation portion, to identify the MTD/tentative 
RP2D, and a Dose Expansion portion, to confirm the safety and tolerability of milademetan, by 
determining the PDy response in tumor samples and evaluating the preliminary efficacy of 
milademetan in subjects with advanced melanoma or DLBCL. 
Milademetan will be administered once daily on Days 1 to 21 of a 28-day cycle 
(QD × 21/28 days).  An alternative drug administration schedule for dose escalation may be 
considered to evaluate the DS-3032a exposure relationship to PDy, toxicity, and efficacy.  If the 
results indicate that using an alternative dosing schedule may provide less toxicity 
(eg, myelosuppression) while offering PDy benefits based on available biomarkers, or better PK 
profile, dose escalation using this recommended alternative dosing schedule will be performed in 
lieu of or in parallel with the QD × 21/28-day schedule.   
After discontinuation of the study drug, subjects will be contacted for an End-of-Study 
Follow-up Visit 30 (± 2) days after the last dose of study drug. 
4.1.2.1. 
Part 1 (Dose Escalation) 
Dose escalation of milademetan to determine the MTD will be guided by a Bayesian logistic 
regression model (BLRM) following escalation with overdose control (EWOC) principle 
following an initial accelerated titration design (ATD).   


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Accelerated titration design for determining the initial dose for escalation by BLRM with 
EWOC 
Before starting BLRM, initial dose escalation will proceed following an ATD in order to 
minimize the number of subjects treated at sub-therapeutic doses of the drug.  The proposed 
human starting dose of milademetan is 15 mg/day.  Single subjects will be enrolled into 
sequential dose levels with a dose increment of 100% from the previous dose.  Over-enrollment 
in ATD up to 3 subjects per cohort is permitted.  The dose for ending ATD will be the dose level 
in which one of the following occurs: 
 One Grade 2 or higher milademetan-related toxicity according to NCI-CTCAE v4 
during Cycle 1, in which case, 3 to 6 subjects will be enrolled at the next dose level, 
which will be guided by BLRM2; or 
 If a DLT is observed during Cycle 1, the cohort will first be expanded to 
3 DLT-evaluable subjects, and the next 2 subjects in the expanded cohort will receive 
milademetan treatment starting at least 1 week apart.  If no further DLT is reported, 
the cohort will be expanded to include up to 3 additional DLT-evaluable subjects 
prior to initiation of BLRM in the next dose level. 
The information from the accelerated titration stage will be included in the Bayesian model for 
dose escalation. 
Dose level increment during dose escalation by BLRM with EWOC 
The dose increment during the BLRM will be as follows: 
 The dose level increment should be no less than 30% in order to have distinction 
among dose levels considering the inter-subject variability in exposure, but flexibility 
may be applied in selecting the dose to accommodate the available dosage form 
strengths. 
 The dose level increment should be no more than 100% even if the model suggested a 
higher dose than 100% for the next cohort. 
 In the event of a DLT, the next 2 subjects in the expanded cohort will receive 
milademetan treatment starting at least 1 week apart. 
The dose escalation will be based on a BLRM with EWOC principle.  The logistic regression 
model for the dose-toxicity (DLT rate) relationships will include 2 parameters: the intercept and 
the slope.  After the first 3 subjects of each cohort complete DLT evaluation during Cycle 1, the 
posterior distributions of the DLT rate will be derived for all dose levels based on the BLRM 
using the DLT outcome data from all assessed exposure levels and a pre-specified prior 
distribution for the model parameters.  The posterior probability of the DLT rate in the following 
4 intervals at each dose level will then be calculated and used for dose recommendation for the 
next cohort according to the EWOC principle [0%, 16%] as the DLT rate interval for 
                                                 
2 For isolated NCI-CTCAE v4 Grade ≥ 2 laboratory abnormalities that are not associated with signs or symptoms, 
transition from ATD to BLRM will be at the discretion of the Investigator. 


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under-dosing, [16%, 33%] as the target DLT rate interval, [33%, 60%] as the DLT rate interval 
for excessive toxicity, and [60%, 100%] as the DLT rate interval for unacceptable toxicity. 
The EWOC principle requires that the BLRM recommended dose for the next cohort of subjects 
is the one with the highest posterior probability of the DLT rate in the target DLT rate interval of 
[16%, 33%] among all dose levels fulfilling the overdose control constraint: there is less than 
25% of probability for the DLT rate  33% (probability for excessive or unacceptable toxicity). 
The dose to be tested in the next cohort of subjects chosen by the Sponsor’s clinical team and the 
investigator(s) involved in the clinical study will be based on the dose recommended by the 
BLRM, clinical assessment of toxicity profiles, and PK/PDy information observed thus far. 
Cohorts of 3 to 6 subjects will be enrolled and assessed for DLT before escalation to a new 
higher dose.  As an exception, the model will be reevaluated before enrollment of any additional 
subjects to the cohort if 2 evaluable subjects in the cohort experience DLT before the enrollment 
of the next subject.  Enrollment of subjects to a new cohort requires completion of DLT 
evaluation of at least 3 subjects treated in the current cohort.  Subjects who have neither 
completed DLT evaluation nor experienced DLT will be censored and not included in the BLRM 
update.  In the event that subjects in the previous cohort experience a DLT after the enrollment 
of subjects to a new cohort has begun, dose level assignment of the next subject in the new 
cohort will be based on an updated BLRM using DLT outcome data from all assessed doses. 
Cohorts may be expanded at any dose level or at the MTD for further elaboration of safety, PK, 
or PDy parameters as required. 
Dose escalation using alternative drug administration schedules 
Based on safety, PK, and PDy data collected during Dose Escalation using the QD × 21/28-day 
schedule of milademetan, an alternative drug administration schedule for dose escalation may be 
considered following review by the Principal Investigators and Sponsor.  Modeling and 
simulation will be performed to evaluate DS-3032a exposure relationship to PDy and toxicity.  If 
the results indicate that using an alternative dosing schedule may provide less toxicity 
(eg, myelosuppression) while offering pharmacodynamic benefits based on available biomarkers 
or a better PK profile, dose escalation using this recommended alternative dosing schedule will 
be performed in lieu of or in parallel with the QD × 21/28-day schedule.  For example: 
 Case 1: If the recommended dosing schedule is less frequent than QD × 21/28 days, 
the starting daily dose of the new schedule will be the same as the highest daily dose 
tested for the QD × 21/28-day schedule that showed DLT in less than one-third of 
evaluable subjects. 
 Case 2: If the recommended dosing schedule is more frequent than QD × 21/28 days 
(eg, QD continuous × 28 days), the starting daily dose will be ≤ 75% of the highest 
daily dose tested for the QD × 21/28-day schedule that showed DLT in less than 
one-third of evaluable subjects.  This starting dose of the new schedule will provide 
the same 4-week cumulative dose while reducing daily exposure by ≥ 25%. 
 Case 3: If additional testing is suggested to optimize the dosing regimen (to maintain 
sufficient dose density over time without requiring frequent dose interruptions as a 
result of delayed toxicities) after the MTD is identified, then dosing may initiate at a 


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dose level lower than MTD in that dosing regimen.  Subject enrollment may be 
limited to one or a small number of cancer types or molecular sub-types depending on 
available clinical data for milademetan with the dosing regimen and investigator 
experience with this class of compound.  Up to 15 subjects may be enrolled in the 
cohort, and enrollment may be conducted in parallel with Part 2 of the study.  
The first cohort to be evaluated will begin treatment with milademetan at 90 mg QD 
× 21/28 days, preferentially in subjects with liposarcoma considering the existing data 
in this patient population at 120 mg QD × 21/28 days and 90 mg QD × 28/28 days for 
comparison of safety.  
The dose of 90 mg QD × 21/28 days is evaluated to define a hematologically safe and 
tolerable regimen based on the safety data at the doses previously evaluated (15 mg 
through 30, 60, 120, 160, and 240 mg QD × 21/28 days, with the determination of 
MTD at 120 mg) in this dosing schedule.  Most DLTs arose from myelosuppression, 
particularly thrombocytopenia, which also resulted in dose delays and dose reductions 
in subjects who continued in Cycle 2 and subsequent cycles.  Therefore, to reduce the 
risk of progressing to more severe bone marrow toxicities and dose interruptions 
during continued treatment, the following dose adjustment rules will be followed for 
Cycle 2 and subsequent cycles: 
 If platelets decrease to <50% of baseline (the platelets measured at Cycle 1 Day 1) 
or Grade ≥2 thrombocytopenia (Platelets < 75 × 109/L) at the end of Cycle 1, 
then: 
o If platelets decrease by >50% from baseline, but are ≥ 75 × 109/L, do not 
interrupt milademetan dosing, but reduce the dose of milademetan to 
60 mg QD × 21/28 days. 
o If Grade ≥2 thrombocytopenia, hold dosing of milademetan.  When the 
platelets recover to ≥ 75 × 109/L, resume milademetan at a reduced dose of 
60 mg QD × 21/28 days. 
 Dose interruptions and further dose reductions due to toxicity will follow the 
same guidelines provided in Section 4.1.8. 
After an initial cohort of 3 subjects has completed treatment in Cycle 1, the dose may be 
adjusted based on the safety results and discussion between the investigators and the 
Sponsor. 
In addition to the above dose dense schedules, the following less frequent dosing 
schedules will be evaluated in dose escalation with a starting dose of 120 mg that was the 
MTD determined in the QD 21/28-day schedule: 
 QD for 7 out of 28 days (QD × 7/28 days)  
 QD for 3 out of 14 days (QD × 3/14 days) repeated twice in a 28-day cycle 


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Notes: 
1. The QD 7/28 and QD 3/14 days schedules were initiated by a memo to the 
institutional review boards (IRBs) by referring to the above section in 
Protocol v 3.0 allowing alternative dosing schedules.  
2. These alternative dose schedules were initiated in dose escalation after the dose 
expansion in the dose schedule QD 21/28 was evaluated in subjects with 
melanoma and DLBCL and found that the QD 21/28 schedule was not tolerated 
well for further development of the drug. 
Both the original QD × 21/28 days and alternative dosing schedules can be explored in parallel. 
The final MTD for each dosing schedule will be decided based on considerations of the 
respective MTDs estimated by the BLRM and on an overall assessment of safety data from 
subsequent cycles and PK/PDy information collected at all different doses tested.  Upon 
determining the final MTD of the original QD × 21/28 days and/or alternative dosing schedules, 
one dosing regimen will be selected for further evaluation in Part 2 (Dose Expansion) and as the 
tentative RP2D.   
4.1.2.2. 
Part 2 (Dose Expansion in Subjects With Advanced Melanoma or Diffuse Large 
B-cell Lymphoma)  
Upon establishing the MTD/tentative RP2D and drug administration schedule in Part 1, the Dose 
Expansion part will begin with the intention of confirming the safety and tolerability of 
milademetan, determining the PDy signals in tumor samples, and evaluating the preliminary 
efficacy of milademetan in approximately 20 subjects each with advanced melanoma and 
DLBCL whose tumors tested positive for wild-type TP53 genotype.   
Four subjects of each tumor type will initially be treated.  Following the completion of the first 
cycle, a safety analysis will be conducted to allow the reevaluation of the appropriateness of the 
dosing level.  If the incidence of AEs fulfilling the criteria of a DLT has exceeded that predicted 
by the EWOC principle after the initial 4 DLT-evaluable subjects or after further enrollment, no 
further testing at the MTD/tentative RP2D level established in Part 1 will be done, and dose 
de-escalation or treatment at alternative dose schedules may be considered for further evaluation 
of safety and efficacy. 
Tumor assessment (Part 1 and Part 2) 
Tumor assessment will be performed according to the study schedule at baseline, every 2 cycles 
while the subject remains on study for the first 8 cycles and then every 3 cycles thereafter (start 
of Cycles 3, 5, 7, and 9, then Cycles 12, 15, etc.). 
Tumor re-biopsy  
To search for possible mechanisms of acquired resistance to milademetan, an optional tumor 
re-biopsy may be performed within 30 days following the last dose of milademetan treatment for 
subjects who have achieved an initial complete response (CR)/partial response (PR) or stable 
disease (SD) for at least 6 months by standard response criteria but later developed progressive 
disease (PD) while on therapy (both in Dose Escalation and Dose Expansion), preferably prior to 
initiating new therapy. 


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TP53 genotyping, subject enrollment, and early discontinuation criteria 
 During Dose Escalation and Dose Expansion, tumor TP53 genotyping will be 
performed in archived formalin-fixed paraffin-embedded (FFPE) and, if available, 
fresh tumor biopsies in all enrolled subjects.  Confirmation of TP53 wild-type status 
is NOT required prior to milademetan dosing.  The investigator will be informed if 
the genotyping confirms the presence of inactivating TP53 mutations testing result 
shows that a subject’s malignant cells contain an inactivating mutation, insertion, or 
deletion in the TP53 gene. If study treatment has already begun, the subject may 
choose to discontinue study drug or continue study drug as long as clinical benefit is 
noted per the investigator’s judgment.  TP53 re-testing can be considered. 
4.1.2.3. 
Intrasubject Dose Escalation 
No intrasubject dose escalation will be permitted. 
4.1.3. 
Duration of the Study 
The study duration is expected to last approximately 6 years from the time the first subject is 
enrolled in Part 1 of the study. 
4.1.4. 
Duration of Subject Participation 
The number of treatment cycles is not fixed in this study.  Subjects who continue to derive 
clinical benefit from treatment in the absence of withdrawal of subject consent, progression, or 
unacceptable toxicity may continue treatment.  Subjects in Part 1 and Part 2 who are still on 
study at least 6 months after enrollment is completed in both parts will be eligible to continue 
receiving study drug in a separate extension phase of the protocol (see Section 18.7).  Data 
collected from those subjects may be captured in a separate database. 
4.1.5. 
Stopping Rules 
The study may be terminated at any time at Daiichi Sankyo, Inc.’s (DSI’s) discretion. 
4.1.5.1. 
Stopping Rule for Maximum Tolerated Dose Determination 
The final MTD will be decided based on considerations of the respective MTD estimated by the 
BLRM and on an overall assessment of safety data from subsequent cycles and PK/PDy 
information collected at all different doses tested.  For MTD determination, the following 
stopping rules will be implemented for the Dose Escalation part: (a) at least 6 evaluable subjects 
at MTD level with at least 21 evaluable subjects in total enrolled in the Dose Escalation part, or 
(b) at least 9 evaluable subjects have been enrolled at a dose level that is the model’s 
recommendation for the next dose cohort and for which the posterior probability of targeted 
toxicity is at least 50%, or (c) dose level -1 is too toxic. 
Cohorts may be expanded at any dose level or at the MTD for further elaboration of safety, PK, 
or PDy parameters as required. 


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4.1.5.2. 
Dose-limiting Toxicities 
A DLT is defined as any TEAE not attributable to disease or disease-related processes that 
occurs during the observation period (Cycle 1) in each dose-level cohort and is Grade 3 or higher 
according to NCI-CTCAE, v 4, with the exceptions as defined below: 
For hematologic events, a DLT is defined as follows: 
 Grade 4 neutropenia lasting > 7 days 
 Febrile neutropenia  
 Grade 4 anemia 
 Grade 4 thrombocytopenia or Grade ≥ 3 thrombocytopenia lasting more than 7 days 
or associated with bleeding 
 Dose delay > 7 days secondary to myelosuppression 
For elevations in hepatic function enzymes, a DLT is defined as follows: 
 Grade 4 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels 
 AST/ALT > 5  upper limit of normal (ULN) lasting > 3 days without liver 
metastases 
 AST/ALT > 5  ULN if accompanied by ≥ Grade 2 elevation in bilirubin 
 AST/ALT > 5  ULN lasting > 3 days, if the baseline level was ≤ 3  ULN in 
subjects with liver metastases 
 AST/ALT > 8  ULN lasting > 3 days, if the baseline level was > 3  ULN in 
subjects with liver metastases 
The following adverse events are NOT considered DLTs: 
 Grade 3 fatigue lasting < 3 days 
 Grade 3 nausea or vomiting that has resolved to Grade ≤ 2 within 48 hours after 
standard antiemetic therapies 
 Grade 3 diarrhea that has resolved to Grade ≤ 2 within 48 hours after standard 
antidiarrheal therapies 
 Isolated laboratory findings not associated with signs or symptoms including 
Grade 3/4 alkaline phosphatase, uric acid, amylase, and lipase elevations, and Grade 3 
hyponatremia lasting < 72 hours developed from Grade 1 at baseline 
 Grade 3/4 lymphopenia 
Subjects who are unable to complete at least 75% of the prescribed dose of milademetan in the 
first 21 days as a result of nondisease-related ≥ Grade 2 adverse events will be considered to 
have a DLT. 
 A delay of ≥ 1 week in initiating Cycle 2 secondary to a nondisease-related ≥ Grade 2 
adverse event will be considered a DLT. 


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4.1.6. 
Maximum Tolerated Dose and Tentative Recommended Phase 2 Dose Definition 
Once the stopping criteria are met, the MTD estimated by BLRM + EWOC is the dose with the 
highest posterior probability of the DLT rate in the target DLT rate interval of [16%, 33%] 
among all doses fulfilling the overdose control constraint: there is less than 25% probability for 
the DLT rate > 33% (probability for excessive or unacceptable toxicity) (Section 4.1.2.1).  Since 
an alternative drug administration schedule may be explored in lieu of or in parallel with the 
original QD × 21/28 days schedule, separate MTDs may be identified for each regimen.  The 
final MTD for each dosing schedule will be decided based on considerations of the respective 
MTDs estimated by the BLRM and on an overall assessment of safety data from subsequent 
cycles and PK/PDy information collected at all different doses tested.  Upon determining the 
final MTD of the original QD × 21/28 days and/or alternative dosing schedules, one dosing 
regimen will be selected for further evaluation in Part 2 (Dose Expansion), which may also be 
the tentative RP2D.   
4.1.7. 
Management of Subjects with Adverse Events 
Treatment-related toxicities meeting the DLT definition (see Section 4.1.5.2 for DLT definitions) 
occurring after Day 28 (ie, outside the DLT observation period) or occurring in Part 2 of the 
study will result in interruption and/or discontinuation of therapy.  For subjects deriving clinical 
benefit from treatment, an option to resume the therapy at 1 dose level below that at which the 
toxicity occurred may be considered after the toxicity returns to NCI-CTCAE v4 Grade ≤ 1 or to 
baseline values.  However, subjects requiring more than 4 weeks to recover from acute toxicities 
will be withdrawn from the treatment.  If a subject experiences NCI-CTCAE v4 Grade 3 or 4 
toxicity or an SAE that is unequivocally attributable to the underlying malignancy, milademetan 
treatment may be postponed until the toxicity has resolved to NCI-CTCAE v4 Grade ≤ 1 or 
returns to baseline values. 
The window for recommencing treatment may be extended to up to 8 weeks, if subject has 
obtained clinical benefit from milademetan treatment that continued during the recovery period 
of the AEs.  
4.1.8. 
Guidelines for Dose Delays 
Dosing of milademetan should be interrupted if the following adverse events develop any time 
during treatment: 
 Absolute neutrophil count < 1 × 109/L (1000/mm3). 
 Platelet count < 75 × 109/L. 
 All other NCI-CTCAE v4 Grade ≥ 2 nonhematological, nondisease-related toxicities, 
except alopecia and Grade ≥ 2 fatigue lasting < 48 hours. 
 For other NCI-CTCAE v4 Grade ≥ 2 laboratory abnormalities that are not DLTs, 
treatment continuation with milademetan will be at the discretion of the investigator. 
Commencing rules for milademetan administration are: 
 Absolute neutrophil count ≥ 1 × 109/L (1000/mm3). 
 Platelet count ≥ 75 × 109/L. 


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 All other NCI-CTCAE v4 Grade ≥ 2 nonhematological toxicities (excluding alopecia) 
must have resolved to Grade ≤ 1 or baseline values. 
These parameters should be seen as guidelines and are not intended to supersede the clinical 
judgment of the treating physician.  All adjustments should be made in consultation with the 
Sponsor’s Medical Monitor. 
In the event of a dose delay occurring prior to completion of the PK/PDy sampling in the study, 
investigators should contact DSI for guidance regarding rescheduling these procedures. 
In the event of a dose delay due to noncompliance, the study site should notify DSI at the earliest 
possible time.  Subjects missing more than 25% of the scheduled doses in Cycle 1 for 
nontoxicity-related reasons may be removed from the study. 
4.2. 
Selection of Doses 
4.2.1. 
Experimental Treatments 
4.2.1.1. 
Part 1 (Dose Escalation) 
The study will enroll subjects into cohorts with dose escalation by BLRM with EWOC principle 
as outlined in Section 4.1.2.1.  The starting dose will be 15 mg/day (see Section 2.1.1.5.1 for 
justification of the human starting dose).  In the event of a DLT, the next 2 subjects in the 
expanded cohort will receive milademetan treatment starting at least 1 week apart. 
Upon completion of Part 1 (Dose Escalation) and determination of the MTD/tentative RP2D, 
Part 2 (Dose Expansion) will immediately begin.  Subjects will receive milademetan at the 
MTD/tentative RP2D defined in Section 4.1.2.1. 
4.2.1.2. 
For the Study 
Please see Section 2.2 for further details. 
4.2.1.3. 
For Individual Subjects 
Please see Section 2.4 for further details. 
4.2.2. 
Control Treatments 
Not applicable. 


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5. 
STUDY POPULATION 
The study population will comprise male and female subjects aged 18 years and older with a 
pathologically documented advanced solid tumor or lymphoma that has relapsed from or is 
refractory to standard treatment, or for which no standard treatment is available.  Specific 
inclusion and exclusion criteria are available in Section 5.1.1 and Section 5.1.2. 
5.1. 
Enrollment 
Investigators will maintain a confidential screening log of all potential study candidates that 
includes limited information of the subjects (initials, age, sex), date, and outcome of screening 
process (eg, enroll in the study, reason for ineligibility, refused to participate). 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the study 
indicating their assigned study number. 
Investigators will maintain a confidential subject identification code list.  This confidential list of 
names of all subjects who have been allocated to a subject identification number (SID) upon 
enrolling in the study allows the investigator to reveal the identity of any subject when necessary. 
Each subject or legally acceptable representative will be provided with information about the 
study, will have all questions answered to their satisfaction, and will sign and date an informed 
consent form (ICF).  This will be completed before any study-specific procedures are performed.  
Additional information about informed consent procedures is provided in Section 16.3. 
A subject is considered enrolled in the study upon the Investigator or designee obtaining written 
informed consent from the subject or the subject’s legally acceptable representative 
(Section 16.3) and upon determination that all inclusion and exclusion criteria have been 
satisfied.  After assigning a SID to each subject at the timing of screening, investigators will 
assess the eligibility of a subject based on the inclusion and exclusion criteria after obtaining 
written informed consent from the subject.  After assessment by investigators, the inclusion 
criteria/exclusion criteria form will be completed for registration.  The Sponsor will perform 
registration after verifying that the subject meets the inclusion/exclusion criteria provided by the 
Investigator.  If the Sponsor has any questions regarding the information sent by the investigator, 
he or she will immediately contact the investigator to check the details.  Directly after 
registration, the Sponsor will forward the results of registration to the investigator.  At this time, 
the subject will be assigned to study drug treatment.  
The Investigator must not prescribe or administer the study drug until the subject has completed 
registration.  If the Sponsor disqualifies a subject from participation in the clinical study, the 
investigator will be notified.  The investigator will then explain this outcome to the relevant 
subject. 
Data for all study visits will be recorded on the electronic case report form (eCRF) for subjects 
who receive study drug treatment.  Only minimal data (ie, demography and reason for 
withdrawal) will be recorded on the eCRF for subjects who fail the inclusion/exclusion criteria 
and/or do not receive study drug.  Further data, such as adverse events, will not be collected from 
subjects once they are considered screen failures or have decided to withdraw prior to receiving 
study drug. 


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5.1.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study: 
1a. Dose Escalation Cohorts (Part 1) 
Has a histologically or cytologically documented advanced solid tumor or lymphoma that 
has relapsed from or is refractory to standard treatment, or for which no standard 
treatment is available.  
 Subjects with melanoma who are ineligible to receive or have declined ipilimumab 
treatment or who are refractory or intolerant to ipilimumab may enroll. 
 Subjects with certain tumor types such as those with high prevalence of MDM2 
amplification or overexpression (eg, well-differentiated [WD]/dedifferentiated [DD] 
liposarcoma) may be preferentially enrolled in Part 1. 
1b. Dose Expansion Cohort (Part 2) 
Has a histologically or cytologically documented advanced melanoma or DLBCL, with 
measurable disease that is refractory to standard treatment or for which no standard 
treatment is available.  
 Subjects with melanoma who are ineligible to receive or have declined ipilimumab 
treatment or who are refractory or intolerant to ipilimumab may enroll.  
 Subjects with DLBCL who have failed, been deemed ineligible for, or refused 
autologous stem cell transplantation may enroll. 
2. Male or female ≥ 18 years old. 
3. Has an ECOG performance status of 0 to 1. 
4. Has adequate bone marrow function, defined as: 
 Platelet count ≥ 100  109/L 
 Hemoglobin ≥ 9.0 g/dL 
 Absolute neutrophil count ≥ 1.5  109/L. 
5. Has adequate renal function, defined as: 
 Creatinine clearance ≥ 60 mL/min, as calculated using the modified Cockcroft-Gault 
equation, ([140 - age (in years)] × weight (in kg) / [serum creatinine (in mg/dL) × 72]; 
multiply by 0.85 if female), OR creatinine ≤ 1.5  ULN. 
6. Has adequate hepatic function, defined as: 
 AST/ALT levels ≤ 3  ULN (if liver metastases are present, ≤ 5  ULN) 
 Bilirubin ≤ 1.5  ULN. 
7. Has adequate blood clotting function, defined as: 
 International normalized ratio (INR) and activated partial thromboplastin time (aPTT) 
≤ 1.5  ULN. 


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8. Subject should be able to provide written informed consent, comply with protocol visits 
and procedures, be able to take oral medication, and not have any active infection or 
comorbidity that would interfere with therapy. 
9. Subject (male and female) of childbearing/reproductive potential must agree to use 
double-barrier contraceptive measures or avoid intercourse during the study and for 
90 days after the last dose of study drug. 
10. Subject must be fully informed about their illness and the investigational nature of the 
study protocol (including foreseeable risks and possible side effects) and must sign and 
date an IRB-approved ICF (including Health Insurance Portability and Accountability 
Act authorization, if applicable) before performance of any study-specific procedures or 
tests. 
11. Is willing to provide and there is confirmed availability of pre-existing diagnostic or 
resected tumor samples, such as paraffin-embedded sections.  Providing fresh tumor 
biopsy is optional for subjects in Dose Escalation cohorts.  
12. Is willing to undergo tumor genotyping for TP53 mutation, insertion, or deletion at 
screening.  Confirmation of TP53 nonmutant status is encouraged but not required prior 
to milademetan dosing. 
13. Is willing to provide additional archived samples for comprehensive genomic and/or 
proteomic analyses if the subject has a PR/CR to milademetan treatment. 
14. (Applicable to Part 2 only) Is willing to undergo pre-treatment tumor biopsies 
(post-treatment biopsies are requested). 
5.1.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study: 
1. Has a tumor that contains an inactivating mutation, insertion, or deletion in the 
TP53 gene determined previously or at screening.   
2. Has a history of primary central nervous system malignancy. 
3. Has gastrointestinal conditions that could affect the absorption of milademetan in the 
opinion of the investigator. 
4. Has an uncontrolled infection requiring intravenous antibiotics, antivirals, or antifungals, 
known human immunodeficiency virus infection, or active hepatitis B or C infection. 
5. Has received an allogeneic bone marrow or allogeneic stem cell transplant. 
6. Has a concomitant medical condition that would increase the risk of toxicity, in the 
opinion of the investigator or Sponsor. 
7. Has clinically active brain metastases, defined as untreated and symptomatic, or requiring 
therapy with steroids or anticonvulsants to control associated symptoms.  Subjects with 
treated brain metastases that are no longer symptomatic and who require no treatment 
with steroids may be included in the study if they have recovered from the acute toxic 
effect of radiotherapy.  A minimum of 4 weeks must have elapsed between the end of 
whole brain radiotherapy and study enrollment (2 weeks for stereotactic radiotherapy). 


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8. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other 
than alopecia) not yet resolved to NCI-CTCAE v4, Grade ≤ 1 or baseline.  Subjects with 
chronic Grade 2 toxicities may be eligible per the discretion of the investigator and 
Sponsor (eg, Grade 2 chemotherapy-induced neuropathy).   
9. Had an autologous transplant within 3 months of starting study drug treatment. 
10. Is receiving concomitant treatment with a strong inducer of CYP3A. 
11. Had systemic treatment with anticancer therapy, antibody-based therapy, retinoid 
therapy, or hormonal therapy within 3 weeks before study drug treatment; or treatment 
with nitrosoureas or mitomycin C within 6 weeks before study drug treatment; or 
treatment with small-molecule targeted agents within 2 weeks before study drug 
treatment.  Previous and concurrent use of hormone replacement therapy, use of 
gonadotropin-releasing hormone modulators for prostate cancer, and use of somatostatin 
analogs for neuroendocrine tumors are permitted if such therapy has not been changed 
within 8 weeks before study drug treatment. 
12. Had therapeutic radiation therapy or major surgery within 4 weeks before study drug 
treatment or palliative radiation therapy within 2 weeks before study drug treatment. 
13. Participated in a clinical study within 3 weeks before study drug treatment or current 
participation in other therapeutic investigational procedures. 
14. Prolongation of corrected QT interval by Fridericia’s method (QTcF) at rest, where the 
mean QTcF interval is > 450 milliseconds (ms) for males and > 470 ms for females based 
on triplicate ECG. 
15. Pregnant or breastfeeding. 
16. Substance abuse or medical, psychological, or social conditions that, in the opinion of the 
investigator, may interfere with the subject’s participation in the clinical study or 
evaluation of the clinical study results. 
17. Prior treatment with an MDM2 inhibitor. 
5.2. 
Removal of Subjects from Therapy 
Any subject may withdraw from the treatment or study at any time.  Subjects will be followed 
for a 30-day safety follow-up or beyond if there are unresolved drug-related toxicities. 
5.2.1. 
Reasons for Withdrawal/Early Discontinuation 
Any subject who discontinues from the study drug for any reason will have their study drug 
discontinuation recorded.   
Subjects may be withdrawn from the study after signing informed consent for the following 
reasons: 
 Adverse event 
 Lost to follow-up 
 Death 


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 Protocol violation 
 Withdrawal of consent by subject 
 TP53 contain an inactivating mutation, insertion, or deletion detected  
 Study terminated by Sponsor 
 PD (radiographic progression)  
 Other (eg, discretion of the investigator or clinical progression or start of new 
therapy) 
If a subject withdraws from the study, the investigator will complete and report the observations 
as thoroughly as possible up to the date of withdrawal, including the date of last treatment and 
the reason for withdrawal. 
If the subject is withdrawn due to an adverse event, the investigator will follow the subject until 
the adverse event has resolved or stabilized. 
All subjects who are withdrawn from the study should complete protocol-specified withdrawal 
procedures (Section 5.2.2). 
5.2.2. 
Withdrawal Procedures 
Protocol-specified withdrawal procedures will involve an End-of-Treatment Visit and an 
End-of-Study Follow-up Visit 30 (± 2) days later (Sections 7.3.1.12 and Section 7.3.1.13). 
5.2.3. 
Subject Replacement 
During Part 1 of the study, any subject who discontinues study participation before completing 
the first cycle of treatment and is not evaluable for DLT may be replaced.  See Section 4.1.5.2 
for definitions of DLTs. 
5.2.4. 
Subject Re-screening Procedures 
The study will allow re-screening for any subject who failed to meet eligibility criteria upon 
initial screening.  The Principal Investigator will consult with the Sponsor before making the 
re-screen decision.  For both Parts 1 and 2, the SID must remain the same at the time of 
re-screening.  The initial screening information and the reason why the subject is ineligible for 
the initial evaluation will be recorded on the Screening Log.  No data from the initial evaluation 
will be entered into the clinical database for re-screened subjects, except for those that were not 
repeated during re-screening (eg, tumor biopsies) or other tests that are still valid within the 
screening window per the medical monitor. 


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6. 
TREATMENTS ADMINISTERED 
6.1. 
Investigational Products 
The investigator must ensure that the investigational product will be used only in accordance 
with the protocol. 
Milademetan will be administered as an oral capsule.  It will be supplied in 5, 20, 80, and 
200 mg capsules individually packaged in desiccant-embedded aluminum blisters.  Two other 
capsule strengths of 30 and 100 mg will also be supplied in HDPE bottles. 
6.1.1. 
Method of Assigning Subjects to Treatments and Blinding 
6.1.1.1. 
Randomization 
Not applicable because this is a single-arm study. 
6.1.1.2. 
Blinding 
Both parts of the study are open label, and no blinding will be performed. 
6.1.2. 
Method of Assessing Treatment Compliance 
The following measures will be employed to ensure treatment compliance during dosing at the 
clinical site:  
 Milademetan only to subjects participating in the study and complying with the 
instructions from the clinical study personnel.  
 Doses on the visit days of Cycle 1 should be administered to subjects under the 
supervision of clinical study personnel at the site.  A mouth and hand check of all 
subjects should be completed to ensure that all capsules have been swallowed. 
 Milademetan may be dispensed in amounts exceeding the minimum amount required 
for the period of time until the next visit.  Subjects will be instructed to return all 
unused milademetan at the next visit.  Alternatively, to ensure compliance, the site 
personnel may choose to dispense only the adequate amount of study drug required 
until the next scheduled visit.  Compliance with the study drug regimen will be 
determined by counting unused capsules and needs to be ≥ 75% in the DLT 
evaluation period.   
 Milademetan administration that occurs at clinic visits will be supervised by a 
member of the site staff.  
6.1.3. 
Labeling and Packaging 
Milademetan will be supplied in individually packaged desiccant-embedded aluminum blisters. 
The clinical site will dispense take-home medication with labels and instructions. 


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6.1.4. 
Preparation 
Procedures for proper handling and disposal of anticancer drugs should be followed in 
accordance with the standard operating procedures (SOPs) of the study site. 
6.1.5. 
Storage 
Drug supplies must be stored in a secure, limited access storage area under the recommended 
storage conditions listed below: 
 Stored at 2°C to 8°C (36°F to 46°F). 
If storage conditions are not maintained per specified requirements, Medpace or DSI should be 
contacted. 
6.1.6. 
Drug Accountability 
When a drug shipment is received, the investigator or designee will check the amount and 
condition of the drug, check for appropriate local language in the label and drug expiration date, 
and sign the Receipt of Shipment Form provided.  The Receipt of Shipment Form should be 
faxed as instructed on the form.  The original will be retained at the site.  In addition, the 
investigator or designee shall contact DSI as soon as possible if there is a problem with the 
shipment. 
A Drug Accountability Record will be provided for the investigational product.  The record must 
be kept current and should contain the dates and quantities of drug received, subject 
(identification number and/or initials or supply number as applicable) for whom the 
investigational product was dispensed, the date and quantity of investigational product dispensed 
and remaining, if from individual subject drug units, as well as the initials of the dispenser. 
At the end of the study, or as directed, all milademetan capsules including unused, partially used, 
or empty containers will be returned to a designee as instructed by DSI.  Investigational product 
will be returned only after the study monitor has completed a final inventory to verify the 
quantity to be returned.  The return of investigational product must be documented and the 
documentation included in the shipment.  At the end of the study, a final investigational product 
reconciliation statement must be completed by the investigator or designee and provided to the 
Sponsor.  Unused drug supplies may be destroyed by the investigator when approved in writing 
by DSI/delegate, and DSI/delegate has received copies of the site’s drug handling and disposition 
SOPs. 
All investigational product inventory forms must be made available for inspection by a DSI 
authorized representative or designee and regulatory agency inspectors.  The investigator is 
responsible for the accountability of all used and unused study supplies at the site. 
6.1.7. 
Retention Samples 
Not applicable. 
6.2. 
Concomitant Medications 
Medications used within 30 days before screening will be recorded.  All concomitant 
medications will be recorded on the eCRF. 


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6.2.1. 
Prohibited Concomitant Medications/Activities 
The following medications and products will be prohibited: 
 Other anticancer therapy, including cytotoxic, antibody, retinoid, or hormonal 
treatment and small-molecule tyrosine kinase inhibitors.  Concurrent use of hormone 
replacement therapy, the use of gonadotropin releasing hormone modulators for 
prostate cancer, and the use of somatostatin analogs for neuroendocrine tumors are 
permitted if such therapy has not been changed within 8 weeks before study drug 
treatment.  Megestrol acetate as supportive care is also permitted. 
 Other investigational agents. 
 Nonclinical studies indicate that milademetan is metabolized by CYP3A.  Drugs that 
are strong inducers of these enzymes may alter the PK of milademetan and should 
therefore be avoided (Section 18.5).  If drugs that are strong inhibitors of CYP3A 
need to be taken concomitantly, then milademetan dose must be reduced to half the 
assigned dose. 
 Milademetan is metabolized by CYP3A.  St. John’s Wort (hypericin) therefore will 
not be permitted for 30 days before and during participation in the study. 
 Because milademetan is a substrate for CYP3A and grapefruit juice and Seville 
oranges contain CYP3A inhibitors, foods or beverages containing grapefruit or 
Seville oranges should be avoided within 48 hours before initial dose of study drug 
and throughout the duration of the study. 


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7. 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided in Section 18.6. 
7.1. 
Screening 
7.1.1. 
Part 1 (Dose Escalation), Screening (Pre-cycle) 
The screening (Pre-cycle) period occurs within 14 days prior to starting study therapy.   
The following procedures will be performed during the Part 1 screening period: 
 Obtain written (ie, signed and dated) informed consent. 
 Assign an SID number. 
 Record demographic, medical history information including PFS post the most recent 
prior therapy, and prior medication history information for cancer. 
 Perform a complete physical examination and record weight and height. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain blood samples for safety laboratories (Section 10.8). 
 Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential. 
 Obtain a urine sample for urinalysis (Section 10.8). 
 Perform a 12-lead ECG in triplicate: 
 For subjects enrolled per Case 3 (Section 4.1.2.1), 4 sets of triplicate ECGs should 
each be taken approximately 1 hour apart. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Obtain archived tumor samples for TP53 testing (approximately 25 FFPE sections or 
blocks) (Section 9.2.1). 
 Perform a tumor biopsy (optional) within 21 days prior to the first dose of study drug 
(Section 9.2). 
 Perform a tumor assessment within 4 weeks before the administration of the first dose 
of study drug (Section 8.1). 
 For all subjects with lymphoma, perform a (18F) fluorodeoxyglucose-positron 
emission tomography (FDG-PET) scan under fasting conditions at baseline.  
Assess bone marrow by aspirate and/or biopsy per investigator decision. 


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 Complete the Inclusion/Exclusion Criteria Form for subject registration. 
 The Sponsor will perform registration after verifying that the subject meets the 
inclusion/exclusion criteria (Section 5.1) provided by the investigator.  If the 
Sponsor has any questions regarding the information sent by the investigator, he 
or she will immediately contact the investigator to check the details.  Directly 
after registration, the Sponsor will forward the results of registration to the 
investigator.  At this time, the subject will be assigned to study drug treatment. 
 The investigator must not prescribe or administer the study drug until the subject 
has completed registration.  If the Sponsor disqualifies a subject from 
participation in the clinical study, the investigator will be notified.  The 
investigator will then explain this outcome to the relevant subject. 
7.2. 
Randomization 
Not applicable because this is a single-arm study. 
7.3. 
Treatment Period 
7.3.1. 
Treatment Period, Part 1 (Dose Escalation) 
Unless otherwise stated, an activity occurs before drug administration. 
7.3.1.1. 
Part 1 (Dose Escalation), Cycle 1/Day 1 
The following procedures will be completed predose during the Part 1, Cycle 1/Day 1 visit.  If 
the screening visit for Part 1 is completed within 24 hours of Cycle 1/Day 1, the assessments do 
not need to be repeated. 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry) both before administration of 
study drug and at 2 hours postdose. 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1).  
 Obtain blood samples for safety laboratories (Section 10.8). 
 Obtain a PK blood sample. 
 Obtain a blood sample for tumor markers as appropriate for the tumor type. 
 Obtain a blood sample for pharmacogenomics (PGx).  Instructions for handling and 
shipping the PGx blood sample are included in the Study Manual. 
 Obtain MIC-1 serum sample. 
 Obtain blood samples for exploratory analysis (Section 10.8). 
 Obtain a urine sample for urinalysis (Section 10.8). 
 Perform a 12-lead ECG in triplicate. 


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 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
The following procedures will be completed postdose during the Part 1, Cycle 1/Day 1 visit: 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry) at 2 hours postdose. 
 Obtain PK blood samples at the following time points: 0.5, 1, 2, 3, and 6 to 8 hours 
postdose. 
 Obtain MIC-1 serum samples 6 to 8 hours postdose. 
 Obtain blood samples for exploratory analyses 6 to 8 hours postdose (Section 10.8). 
 Perform a 12-lead ECG at 2 hours postdose in triplicate:  
 For subjects enrolled per Case 3 (Section 4.1.2.1), triplicate ECGs will be taken at 
predose, 0.5, 1, 2, 3, and 8 hours postdose, corresponding to the PK time points.  
The time points for the ECG and PK sample collection should be as close as 
possible within a 10-minute window. 
7.3.1.2. 
Part 1 (Dose Escalation), Cycle 1/Day 2 
The following procedures will be performed during the Part 1, Cycle 1/Day 2 visit.   
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain a predose PK blood sample. 
 Obtain a predose MIC-1 serum sample. 
 Perform a 12-lead ECG in triplicate. 
 For subjects enrolled per Case 3 (Section 4.1.2.1), triplicate ECGs will be taken at 
predose, corresponding to the PK time point.  The time point for the ECG and PK 
sample collection should be as close as possible within a 10-minute window. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense a pill diary with dose administration instructions to assess treatment 
compliance. 


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7.3.1.3. 
Part 1 (Dose Escalation), Cycle 1/Day 8 
The following procedures will be performed during the Part 1, Cycle 1/Day 8 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain a predose PK blood sample. 
 Obtain a predose MIC-1 serum sample. 
 Obtain a predose urine sample for urinalysis (Section 10.8). 
 Perform a 12-lead ECG in triplicate. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Obtain an optional tumor biopsy 6 hours postdose. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 
7.3.1.4. 
Part 1 (Dose Escalation), Cycle 1/Day 15 
The following procedures will be performed during the Part 1, Cycle 1/Day 15 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain a predose PK blood sample. 
 Obtain a predose MIC-1 serum sample. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 


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7.3.1.5. 
Part 1 (Dose Escalation), Cycle 1/Days 18 to 21 
The following procedures will be completed predose during the Part 1, Cycle 1/Days 18 to 21 
visit: 
(For subjects enrolled in the QD × 7/28 days schedule, this visit is needed only if there are 
unresolved Grade ≥3 AEs or Grade ≥2 thrombocytopenia on Day 15 that need follow up). 
(For subjects receiving study drug under the QD 7/28 days or QD 3/14 days schedules, the blood 
sample collection [exploratory blood samples, PK samples, ad MIC-1 induction] on Cycle 1 
Days 18 to 21 is not required) 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain PK blood samples at the following time points: predose, 0.5, 1, 2, 3, and 6 to 
8 hours postdose. 
 Obtain a predose MIC-1 serum sample. 
 Obtain predose blood samples for exploratory analysis (Section 10.8). 
 Obtain a predose urine sample for urinalysis (Section 10.8). 
 For subjects enrolled per Case 3 (Section 4.1.2.1), perform a 12-lead ECG in 
triplicate. 
 Triplicate ECGs will be taken at predose and 3 hours postdose, corresponding to 
the PK time points.  The time points for the ECG and PK sample collection 
should be as close as possible within a 10-minute window. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
 Review pill diary to assess treatment compliance. 
7.3.1.6. 
Part 1 (Dose Escalation), Cycle 2/Day 1 
The following procedures will be performed during the Part 1, Cycle 2/Day 1 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry) before administration of study 
drug. 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 


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 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain PK blood samples at the following time points: predose and at 1, 3, and 6 to 
8 hours postdose. 
 For subjects enrolled per Case 3 (Section 4.1.2.1), obtain a predose MIC-1 serum 
sample. 
 Obtain a blood sample for tumor markers as appropriate for the tumor type. 
 Obtain a predose urine sample for urinalysis (Section 10.8). 
 Perform a 12-lead ECG in triplicate. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 
7.3.1.7. 
Part 1 (Dose Escalation), Cycle 2/Day 8 
The following procedures will be performed at the Part 1, Cycle 2/Day 8 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 
7.3.1.8. 
Part 1 (Dose Escalation), Cycle 2/Day 15 
The following procedures will be performed at the Part 1, Cycle 2/Day 15 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 


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 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 
7.3.1.9. 
Part 1 (Dose Escalation), Cycle 3/Day 1 
The following procedures will be performed at the Part 1, Cycle 3/Day 1 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential. 
 Obtain a blood sample for tumor markers as appropriate for the tumor type. 
 Obtain a predose urine sample for urinalysis (Section 10.8). 
 Perform a 12-lead ECG in triplicate. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Perform a tumor assessment (Section 8.1). 
 If the subject has a lymphoma that is FDG-PET avid, post-treatment FDG-PET 
scans will be performed under fasting conditions.  If baseline bone marrow 
aspirate and/or biopsy was positive, it may be repeated at this time. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 
7.3.1.10. Part 1 (Dose Escalation), Cycle 3/Day 15 
The following procedures will be performed at the Part 1, Cycle 3/Day 15 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 


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 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 
7.3.1.11. Part 1 (Dose Escalation), Cycle 4 and All Subsequent Cycles, Day 1 
The following procedures will be performed at the Part 1, Cycle 4/Day 1 visit and all additional 
Cycle Day 1 visits: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain a blood sample for tumor markers as appropriate for the tumor type. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Perform a tumor assessment at the time points outlined in the Schedule of Events; 
every 2 cycles of treatment for the first 8 cycles and then every 3 cycles thereafter 
(ie, at start of Cycles 3, 5, 7, and 9, then Cycles 12, 15, etc.). (Section 8.1). 
 If the subject has a lymphoma that is FDG-PET avid, post-treatment FDG-PET 
scans will be performed under fasting conditions.  If baseline bone marrow 
aspirate and/or biopsy was positive, it may be repeated at the same time as 
subsequent tumor assessments.  
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 
For Cycle 4 Day 1 and beyond: subjects who completed more than 1 year of treatment with 
continued clinical benefit and no ongoing Grade ≥3 TEAEs or risk thereof in the judgment of the 
investigator are allowed to continue on with the subsequent visits at every other cycle and may 
have additional visits as clinically needed. 
7.3.1.12. Part 1 (Dose Escalation), End-of-Treatment (Post-cycle)  
This End-of-Treatment Visit should occur at the earliest day possible within 30 (± 2) days after 
the last administration of milademetan but before beginning any other form of anticancer 


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therapy.  The same procedures will be performed when subjects roll over to the Extension Phase 
(Section 18.7). 
The following assessments will be performed at this visit: 
 Perform a complete physical examination and record weight and height. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain blood samples for safety laboratories (Section 10.8). 
 Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential. 
 Obtain a blood sample for tumor markers as appropriate for the tumor type. 
 Obtain PK blood sample. 
 Obtain blood samples for exploratory analyses (Section 10.8). 
 Obtain a urine sample for urinalysis (Section 10.8). 
 Perform a 12-lead ECG in triplicate. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Review pill diary to assess treatment compliance. 
 Record reason for treatment discontinuation. 
 Tumor re-biopsy (optional) (Section 7.3.1.14). 
7.3.1.13. Part 1 (Dose Escalation) End-of-Study Follow-up 
The End-of-Study Follow-up should occur 30 (± 2) days after the last administration of 
milademetan.  Follow-up information will be collected via a phone call or site visit.  If the 
subject begins another form of anticancer therapy before the end of the 30 (± 2)-day period, 
every effort will be made to complete all the End-of-Study assessments prior to commencing the 
new therapy.  The investigator should follow subjects with adverse events until the event has 
resolved or the condition has stabilized.  In case of unresolved adverse events, including 
significant abnormal laboratory values at the End-of-Treatment assessment, these events will be 
followed up until resolution or until they become clinically irrelevant. 
The following information will be collected at this follow-up: 
 Assessment of adverse events 
 Current medications 
 Subject survival status 


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If the End-of-Study Follow-up is not performed (ie, due to death, lost to follow-up, etc.), record 
the reason. 
7.3.1.14. Part 1 (Dose Escalation) Tumor Re-biopsy 
To search for possible mechanisms of acquired resistance to milademetan, an optional tumor 
re-biopsy may be performed in subjects who have achieved an initial CR/PR or SD for at least 
6 months by RECIST v 1.1 or revised IWG criteria to milademetan but later develop PD while 
on therapy.  Tumor re-biopsy would be performed within 30 days following the last dose of 
milademetan treatment, preferably prior to initiating new therapy. 
7.3.2. 
Treatment Period, Part 2 (Dose Expansion) 
Unless otherwise stated, an activity occurs before study drug administration. 
7.3.2.1. 
Part 2 (Dose Expansion), Screening (Pre-cycle) 
The screening (Pre-cycle) period is within 14 days before starting study therapy.   
The following assessments will be performed during the Part 2 screening period: 
 Obtain written (ie, signed and dated) informed consent. 
 Record demographic, medical history information including PFS post the most recent 
prior therapy, and prior medication history information for cancer. 
 Perform a complete physical examination and record weight and height. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain blood samples for safety laboratories (Section 10.8). 
 Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential. 
 Obtain a urine sample for urinalysis (Section 10.8). 
 Perform a 12-lead ECG in triplicate. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Obtain archived tumor samples for TP53 testing (approximately 25 FFPE sections or 
blocks) (Section 9.2.1). 
 Perform a pre-treatment tumor biopsy (Section 9.2).  
 Perform a tumor assessment within 4 weeks before the administration of the first dose 
of study drug (Section 8.1). 
 For all subjects with DLBCL, perform a FDG-PET scan under fasting conditions 
at baseline.  Assess bone marrow by aspirate and/or biopsy per investigator 
decision.   
 Complete the Inclusion/Exclusion Criteria Form for subject registration. 


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 The Sponsor will perform registration after verifying that the subject meets the 
inclusion/exclusion criteria provided by the investigator.  If the Sponsor has any 
questions regarding the information sent by the investigator, he or she will 
immediately contact the investigator to check the details.  Directly after 
registration, the Sponsor will forward the results of registration to the investigator.  
At this time, the subject will be assigned to study drug treatment. 
 The investigator must not prescribe the study drug until the subject has completed 
registration.  If the Sponsor disqualifies a subject from participation in the clinical 
study, the investigator will be notified.  The investigator will then explain this 
outcome to the relevant subject. 
7.3.2.2. 
Part 2 (Dose Expansion), Cycle 1/Day 1 
The following will be completed during the Part 2, Cycle 1/Day 1 visit.  If the screening visit for 
Part 2 is completed within 24 hours of Cycle 1/Day 1, the assessments do not need to be 
repeated. 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry) both before administration of 
study drug and at 2 hours postdose. 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain a blood sample for tumor markers as appropriate for the tumor type. 
 Obtain PK blood samples at the following time points: predose, and then at 0.5, 1, 2, 
3, 4, 6, and 8 hours postdose.  All samples should be collected within ±5 minutes of 
specified time points. 
 Obtain a blood sample for PGx.  Instructions for handling and shipping the PGx 
blood sample are included in the Study Manual. 
 Obtain MIC-1 serum samples predose and another sample between 6 and 8 hours 
postdose. 
 Obtain blood samples for exploratory analyses predose and at 8 hours postdose 
(Section 10.8). 
 Obtain a predose urine sample for urinalysis (Section 10.8). 
 Perform a 12-lead ECG both predose and at 2 hours postdose in triplicate. 
 Administer mildemetan per protocol (at the site). 
 Record concomitant medications. 
 Assess subjects for adverse events. 


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7.3.2.3. 
Part 2 (Dose Expansion), Cycle 1/Day 2 
The following procedures will be performed during the Part 2, Cycle 1/Day 2 visit: 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain a predose PK blood sample. 
 Obtain a predose MIC-1 serum sample. 
 Perform a 12-lead ECG predose and 2 hours postdose in triplicate. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense a pill diary with dose administration instructions to assess treatment 
compliance. 
7.3.2.4. 
Part 2 (Dose Expansion), Cycle 1/Day 8 
The following procedures will be performed during the Part 2, Cycle 1/Day 8 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1).  
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain a predose PK blood sample. 
 Obtain a predose MIC-1 serum sample. 
 Obtain a predose urine sample for urinalysis (Section 10.8). 
 Perform a 12-lead ECG in triplicate. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Perform a tumor biopsy (requested) 6 hours postdose (optional). 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 
7.3.2.5. 
Part 2 (Dose Expansion), Cycle 1/Day 15 
The following procedures will be performed during the Part 2, Cycle 1/Day 15 visit: 
 Perform a complete physical examination and record weight. 


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 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain a predose PK blood sample. 
 Obtain a predose MIC-1 serum sample. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 
7.3.2.6. 
Part 2 (Dose Expansion), Cycle 1/Days 18 to 21 
The following procedures will be performed during the Part 2, Cycle 1/Days 18 to 21 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain PK blood samples at the following time points: predose, 0.5, 1, 2, 3, 4, 6, and 
8 hours postdose.  All samples should be collected within ± 5 minutes of specified 
time points.  
 Obtain a predose MIC-1 serum sample. 
 Obtain predose blood samples for exploratory analyses (Section 10.8). 
 Obtain a predose urine sample for urinalysis (Section 10.8). 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
 Review pill diary to assess treatment compliance. 
7.3.2.7. 
Part 2 (Dose Expansion), Cycle 2/Day 1 
The following procedures will be performed during the Part 2, Cycle 2/Day 1 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry) before administration of study 
drug. 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 


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  Obtain a blood sample for tumor markers as appropriate for the tumor type. 
 Obtain a predose urine sample for urinalysis (Section 10.8). 
 Perform a 12-lead ECG in triplicate. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Obtain PK blood samples at the following time points: predose, and then at 0.5, 1, 2, 
3, 4, 6, and 8 hours postdose. 
 Administer mildemetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 
7.3.2.8. 
Part 2 (Dose Expansion), Cycle 2/Day 8 
The following procedures will be performed during the Part 2, Cycle 2/Day 8 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 
7.3.2.9. 
Part 2 (Dose Expansion), Cycle 2/Day 15 
The following procedures will be performed during the Part 2, Cycle 2/Day 15 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 


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7.3.2.10. Part 2 (Dose Expansion), Cycle 3/Day 1 
The following procedures will be performed at the Part 2, Cycle 3/Day 1 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential. 
 Obtain a blood sample for tumor markers as appropriate for the tumor type. 
 Obtain a predose urine sample for urinalysis (Section 10.8). 
 Perform a 12-lead ECG in triplicate. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Perform a tumor assessment (Section 8.1). 
 If the subject has DLBCL that is FDG-PET avid, post-treatment FDG-PET scans 
will be performed under fasting conditions.  If baseline bone marrow aspirate 
and/or biopsy was positive, it may be repeated at this time. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 
7.3.2.11. Part 2 (Dose Expansion), Cycle 3/Day 15 
The following procedures will be performed during the Part 2, Cycle 3/Day 15 visit: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 


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7.3.2.12. Part 2 (Dose Expansion), Cycle 4 and All Subsequent Cycles, Day 1 
The following procedures will be performed at the Part 2, Cycle 4/Day 1 visit and all additional 
Cycle Day 1 visits: 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain predose blood samples for safety laboratories (Section 10.8). 
 Obtain a blood sample for tumor markers as appropriate for the tumor type. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Perform a tumor assessment at the time points outlined in the Schedule of Events; 
every 2 cycles of treatment for the first 8 cycles and then every 3 cycles thereafter 
(ie, at start of Cycles 3, 5, 7, and 9, then Cycles 12, 15, etc.). (Section 8.1). 
 If the subject has DLBCL that is FDG-PET avid, post-treatment FDG-PET scans 
will be performed under fasting conditions.  If baseline bone marrow aspirate 
and/or biopsy was positive, it may be repeated at the same time as subsequent 
tumor assessments. 
 Administer milademetan per protocol (at the site). 
 Dispense milademetan per protocol (to take home). 
 Dispense and review pill diary to assess treatment compliance. 
For Cycle 4 Day 1 and beyond: subjects who completed more than 1 year of treatment with 
continued clinical benefit and no ongoing Grade ≥ 3 TEAEs or risk thereof in the judgment of 
the investigator are allowed to continue on with the subsequent visits at every other cycle and 
may have additional visits as clinically needed. 
7.3.2.13. Part 2 (Dose Expansion), End-of-Treatment (Post-Cycle)  
This End-of-Treatment Visit should occur at the earliest day possible within 30 (±2) days after 
the last administration of milademetan, but before beginning any other form of anticancer 
therapy.  The same procedures will be performed when subjects roll over to the Extension Phase 
(Section 18.7). 
The following assessments will be performed at this visit: 
 Perform a complete physical examination and record weight and height. 
 Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, and pulse oximetry). 
 Assess functional status using the ECOG Performance Status Scale (Section 18.1). 
 Obtain blood samples for safety laboratories (Section 10.8). 
 Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential. 


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 Obtain a blood sample for tumor markers as appropriate for the tumor type. 
 Obtain blood samples for exploratory analyses (Section 10.8). 
 Obtain a urine sample for urinalysis (Section 10.8). 
 Perform a 12-lead ECG in triplicate. 
 Record concomitant medications. 
 Assess subjects for adverse events. 
 Review pill diary to assess treatment compliance. 
 Record reason for treatment discontinuation. 
 Tumor re-biopsy (optional) (Section 7.3.2.15). 
7.3.2.14. Part 2 (Dose Expansion) End-of-Study Follow-up 
The End-of-Study Follow-up should occur 30 (± 2) days after the last administration of 
milademetan.  Follow-up information will be collected via a phone call or site visit.  If the 
subject begins another form of anticancer therapy before the end of the 30 (± 2)-day period, 
every effort will be made to complete all the End-of-Study assessments prior to commencing the 
new therapy.  The investigator should follow subjects with adverse events until the event has 
resolved or the condition has stabilized.  In case of unresolved adverse events, including 
significant abnormal laboratory values at the End-of-Treatment assessment, these events will be 
followed up until resolution or until they become clinically not relevant. 
The following information will be collected at this follow-up: 
 Assessment of adverse events 
 Current medications 
 Subject survival status 
If the End-of-Study Follow-up is not performed (ie, due to death, lost to follow-up, etc.), record 
the reason. 
7.3.2.15. Part 2 (Dose Expansion) Tumor Re-biopsy 
Please see Section 7.3.1.14 for details regarding performing tumor re-biopsy in Part 2.  
Re-biopsy in Part 2 will follow the same procedures used in Part 1. 


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8. 
EFFICACY ASSESSMENTS 
8.1. 
Efficacy Variable(s) 
Efficacy assessments will be based on tumor assessments to be performed at screening and every 
2 cycles of treatment for the first 8 cycles and then every 3 cycles thereafter (ie, at start of 
Cycles 3, 5, 7, and 9, then Cycles 12, 15, etc.) while the subject remains on study drug.  The 
clinical activity of milademetan will be assessed by evaluating tumor response.  In subjects with 
solid tumors, tumor response will be evaluated using RECIST v 1.1 (Section 18.3).  In subjects 
with lymphomas, tumor response will be evaluated using the revised IWG criteria 
(Section 18.4).7 
Computed tomography (CT) and/or magnetic resonance imaging (MRI) (spiral CT or MRI with 
≤ 5 mm cuts) of the chest, abdomen, and pelvis should be used for tumor assessment unless 
another modality of disease assessment is necessary for the lesions.  Every effort should be made 
to use the same assessment modality for all assessments for each subject. 
Subjects with lymphoma require an FDG-PET scan at baseline.  Subjects with lymphoma who 
are FDG-PET avid require FDG-PET scanning at each tumor assessment.  Bone marrow will be 
assessed at baseline by aspirate and/or biopsy per the investigator’s decision.  If positive, bone 
marrow assessments may be repeated with subsequent tumor assessments. 
As a complementary approach to the exploratory objective #2 in Part 1 (Section 3.1.3.1), 
particularly in WD/DD liposarcoma that are preferentially enrolled in the study due to the high 
prevalence of MDM2 amplification, the growth rates of the target tumors before starting 
milademetan versus on-treatment with milademetan may be analyzed by capturing the target 
tumor measurements by local reading in 2 or more prior scans from the medical records, if 
available. 
Additionally, a digital or electronic copy of the CT/MRI scans performed for RECIST v 1.1 
assessment may be collected by the sponsor for centralized analysis by sponsor-appointed 
radiologist(s) as a post-hoc exploration of the effect of milademetan on specific tumor 
histologies (eg, WD/DD liposarcoma). 


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9. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
9.1. 
Pharmacokinetic Assessment(s) 
Blood samples for PK analyses will be collected for the measurement of plasma concentrations 
of milademetan as shown in Table 9.1.  Additionally, PK samples may be obtained at any time 
during the study if deemed clinically necessary.  At each time point, approximately 5 mL of 
blood will be collected for DS-3032a analysis.  Instructions for the handling of blood samples 
and shipping of plasma samples for PK analyses are included in a separate document 
(eg, laboratory manual).  The actual time of study drug administration and the exact time of 
blood sampling for PK analysis must be recorded on the case report form (CRF).   
The PK samples will be shipped to a central laboratory for forwarding to a Sponsor-designated 
bioanalytical laboratory.  Plasma concentrations of DS-3032a will be measured using a validated 
assay at the bioanalytical laboratory.   
The PK parameters (eg, Cmax, area under the plasma concentration-time curve from time 0 to 
24 hours [AUC0-24h], etc.) will be estimated by non-compartmental analysis as described in 
Section 12.5.1. 
Table 9.1: 
Blood Sample Collection for Milademetan Pharmacokinetics 
Part 
Dose Escalation 
Cycle/Days 
Cycle 1/ Days 1, 18 to 21 and 
Cycle 2/ Day 1e 
Cycle 1/ 
Days 2, 8, 
15 
 
End-of-Treatment 
Hour 
0a,d 0.5b 
1b 
2b 
3b 
6 to 8c 
0a 
0a 
Part 
Dose Expansion 
Cycle/Days 
Cycle 1/ Days 1, 18 to 21 and 
Cycle 2/ Day 1 
Cycle 1/ 
Days 2, 8, 
15 
 
End-of-Treatment 
Hour 
0a,d 0.5b 
1b 
2b 
3b 
4b 
6b 
8b 
0a 
0a 
eCRF = electronic case report form; PK = pharmacokinetics; QD = once daily 
a Predose within 2 hours prior to drug administration. 
b ± 15% of nominal time. 
c PK sample will be collected between time window of 6 and 8 hours postdose.  Actual time of sample collection 
must be recorded in eCRF.  
d 24-hour PK on Cycle 1 Days 18 to 21 and Cycle 2 Day 1 will be imputed to its predose PK.   
e Cycle 1 Days 18 to 21 PK sample collection is not needed for subjects in QD x 7/28 days and QD 3/14 days dose 
schedules. 


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9.2. 
Pharmacodynamic/Predictive Biomarker Variable(s) 
9.2.1. 
TP53 Status 
 During Dose Escalation, tumor TP53 genotyping will be performed in archived FFPE 
and, if available, fresh tumor biopsies in all enrolled subjects.  Confirmation of TP53 
wild-type status is NOT required prior to milademetan dosing.  The investigator will 
be informed if the genotyping confirms the presence of inactivating TP53 mutations 
(ie, if the testing result shows that a subject’s malignant cells contain an inactivating 
mutation, insertion, or deletion in the TP53).  If the testing result shows that a 
subject’s tumor contains an inactivating mutation, insertion, or deletion in the 
TP53 gene after milademetan has begun, the subject may choose to discontinue from 
the study or continue treatment as long as the subject is deriving clinical benefit (SD 
or objective response) in the absence of unacceptable toxicities per investigator 
assessment.  TP53 re-testing can be considered. 
 During Dose Expansion, TP53 genotyping will be performed in both fresh 
pre-treatment tumor biopsies and archived samples from subjects with sarcoma and 
DLBCL.  In addition to TP53 genotyping, tumor samples may be analyzed for 
DNAseq and RNAseq.  Confirmation of TP53 wild-type status is NOT required prior 
to milademetan dosing, but the investigator will be informed if the genotyping 
confirms the presence of inactivating TP53 mutations.  If the testing result shows that 
a subject’s tumor contains an inactivating mutation, insertion, or deletion in the 
TP53 gene after milademetan has begun, the subject may choose to discontinue from 
the study or continue treatment as long as the subject is deriving clinical benefit (SD 
or objective response) in the absence of unacceptable toxicities per investigator 
assessment.  TP53 re-testing can be considered. 
9.2.2. 
Pharmacodynamic Variables 
Induction of serum MIC-1 will be the primary PDy biomarker.  Serum samples will be collected 
at multiple time points in the study to assess the effect of milademetan treatment on MIC-1 
induction.  Other exploratory PDy biomarkers including, but not limited to, expression levels of 
p53, p21, MDM2, MDM4, Ki67, apoptosis markers, and/or other biomarkers will also be 
assessed, if available. 
9.2.3. 
Exploratory Biomarker Analysis 
Archived or pre-treatment, on-treatment, and end-of-treatment biopsied tumor samples will be 
examined for components of the p53 pathway, which may include, but are not limited to, 
expression of p53, p21, MDM2, MDM4, and MDM2 copy number, and TP53 mutations.  
Additional biomarkers outside of the p53 pathway may be included in order to better understand 
the responsiveness to therapy.  These may include protein, metabolite, gene expression, or 
genetic biomarkers. 
Subjects should be willing to provide archived tumor samples.  During Part 1 (Dose Escalation), 
subjects will have the option to provide pre- and post-treatment biopsies (baseline and 6 hours 
postdose [± 2 hours] on Cycle 1 Day 8 [± 2 days]).  During Part 2 (Dose Expansion), subjects are 


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required to provide a pre-treatment biopsy (baseline).  Post-treatment tumor biopsies will be 
requested to be obtained 6 hours postdose [± 2 hours] on Cycle 1 Day 8.  Tumor biopsies may be 
obtained by skin punch biopsies (for melanoma), Tru-cut technique, or core needle biopsies 
under imaging guidance. 
Optional tumor re-biopsy will be performed within 30 days of the last dose of milademetan in 
subjects who have achieved an initial CR/PR or SD for at least 6 months to milademetan but 
later developed PD while on therapy. 
9.3. 
Pharmacogenomics 
As part of this study, a blood sample will also be banked for possible future PGx analysis in 
DNA.  All participants should be presented with the PGx ICF at screening.  Participation in this 
portion of the study is optional for all subjects.  Thus, those who choose not to provide a sample 
for PGx analysis may still participate in the main portion of the study. 
In all parts of the study, on Day 1 of Cycle 1 prior to study drug administration, the blood PGx 
sample should be collected for subjects who sign the PGx ICF.  This sample may be analyzed 
only for genes suspected to contribute to the safety and efficacy of the study drug (milademetan).   
Results will provide information on how individuals metabolize and/or react to the study drug or 
help to identify subjects who are more likely or less likely to benefit from the study drug.  The 
information may be useful in increasing the knowledge of differences among individuals in the 
way they metabolize the study drug, as well as helping in the development of new drugs or 
improvement of existing drugs. 
Because emerging information regarding the safety and efficacy of milademetan may become 
available in the future, samples will be retained for possible future analysis.  Samples will be 
retained until the DNA has been exhausted or until the Sponsor instructs the genotyping 
contractor to destroy the sample (in accordance with laboratory procedures).  During the period 
of storage, the DNA sample will not be immortalized or sold to anyone.  Subjects will have the 
right to withdraw consent and have their sample destroyed at any time. 
The samples will be shipped to a central laboratory for forwarding to Gentris Clinical Genetics, 
Inc., which has been contracted by the Sponsor to process these blood samples. 
To ensure subject confidentiality, sample tubes will be identified only by a barcode label.  This 
barcode will be linked to the subject’s SID number. 
Refer to a separate document for instructions for sample collection, preparation, handling, 
storage, and shipment. 


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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Adverse Event Collection and Reporting 
All clinical adverse events occurring after the subject signs the ICF and up to 30 (±2) days after 
the last dose of study drug, whether observed by the investigator or reported by the subject, will 
be recorded on the adverse event eCRF page.  Medical conditions (including laboratory 
values/vital signs that are out of range) that were diagnosed or known to exist prior to informed 
consent will be recorded as part of medical history.  All SAEs are to be reported according to the 
procedures in Section 10.5.  Investigators should report diagnosis as the adverse event or SAE 
term; when the diagnosis is unavailable, they should report signs and symptoms as individual 
entries of adverse event or SAE until the diagnosis becomes available.  For events that are 
serious due to hospitalization, the reason for hospitalization must be reported as the SAE 
(diagnosis or symptom requiring hospitalization).  A procedure is not an adverse event or SAE, 
but the reason for the procedure may be an adverse event or SAE.  Pre-planned (prior to signing 
the ICF) procedure or treatment requiring hospitalization for pre-existing conditions that do not 
worsen in severity should not be reported as SAEs (see Section 10.4.2 for definitions).  For 
deaths, the underlying or immediate cause of death should always be reported as an SAE.  
Disease progression is a study endpoint and consequently should not be reported as an adverse 
event/SAE.  However, when a subject dies from disease progression with no other immediate 
causes, “disease progression” should be reported as an SAE.  In addition, any serious, untoward 
event that may occur subsequent to the reporting period that the investigator assesses as related 
to study drug should also be reported and managed as an SAE. 
At each visit, the investigator will determine whether any adverse events have occurred by 
evaluating the subject.  Adverse events may be directly observed, reported spontaneously by the 
subject, or by questioning the subject at each study visit.  Subjects should be questioned in a 
general way, without asking about the occurrence of any specific symptoms.  All laboratory 
values must be appraised by the investigator as to clinical significance.  All post-baseline 
abnormal laboratory values considered clinically significant by the investigator must be recorded 
as an adverse event on the eCRF and, if serious, reported as an SAE following the procedures in 
Section 10.5. 
The investigator should follow subjects with adverse events until the event has resolved or the 
condition has stabilized.  In case of unresolved adverse events including significant abnormal 
laboratory values at the End-of-Treatment assessment, these events will be followed up until 
resolution or until they become clinically irrelevant. 
10.2. 
Safety Endpoints 
Safety endpoints include SAEs, TEAEs, physical examination findings (including ECOG 
performance status), vital signs measurements, standard clinical laboratory parameters (serum 
chemistry, hematology, urinalysis), and ECG parameters.   
10.3. 
Adverse Events of Special Interest 
Not applicable. 


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10.4. 
Adverse Event 
10.4.1. 
Definition of Adverse Event 
An adverse event is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment.  An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product (International Council for Harmonisation 
[ICH] E2A Guideline.  Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting, Oct 1994). 
It is the responsibility of investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings that should be considered adverse events. 
10.4.2. 
Serious Adverse Event 
Any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is an important medical event 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe (ICH E2A Guideline.  Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting, Oct 1994). 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the definition above.  
Examples include allergic bronchospasm, convulsions, and blood dyscrasias, or development of 
drug dependency or drug abuse. 
Note: 
 A procedure is not an adverse event or SAE, but the reason for the procedure may be 
an adverse event. 
 Pre-planned (prior to signing the ICF) procedures or treatment requiring 
hospitalizations for pre-existing conditions that do not worsen in severity are not 
SAEs. 


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10.4.3. 
Grade Assessment 
The severity of AEs will be graded using NCI-CTCAE, v 4.0.  For each episode, the highest 
severity grade attained should be reported. 
The NCI-CTCAE guidelines do not allow certain grades for certain AEs.  For example, pain can 
be Grade 1 to 3 only (ie, cannot be life-threatening or fatal), whereas sepsis can only be Grade 4 
or 5 (ie, can only be life-threatening or fatal).  In addition, alopecia can only be Grade 1 or 2.  
The NCI-CTCAE guidelines should be followed closely. 
 Grade 1 Mild adverse event 
 Grade 2 Moderate adverse event 
 Grade 3 Severe adverse event 
 Grade 4 Life-threatening consequences; urgent intervention indicated 
 Grade 5 Death related to adverse event 
Severity vs. Seriousness: Severity is used to describe the intensity of a specific event while the 
event itself, however, may be of relatively minor medical significance (such as severe headache).  
This is not the same as “seriousness,” which is based on subject/event outcome at the time of the 
event.  For example, the NCI-CTCAE Grade 4 (life-threatening or disabling adverse event) is 
assessed based on unique clinical descriptions of severity for each adverse event, and these 
criteria may be different from those used for the assessment of adverse event seriousness.  An 
adverse event assessed as Grade 4 based on the NCI-CTCAE grades may or may not be assessed 
as serious based on the seriousness criteria. 
10.4.4. 
Causality Assessment 
The investigator should assess causal relationship between an adverse event and milademetan on 
the basis or his/her clinical judgment and the following definitions.  The causality assessment 
should be made based on the available information and can be updated as new information 
becomes available. 
 1 = Related: 
 The adverse event follows a reasonable temporal sequence from study drug 
administration and cannot be reasonably explained by the subject’s clinical state 
or other factors (eg, disease under study, concurrent diseases, and concomitant 
medications). 
Or 
 The adverse event follows a reasonable temporal sequence from study drug 
administration and is a known reaction to the drug under study or its chemical 
group or is predicted by known pharmacology. 


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 2 = Not Related: 
 The adverse event does not follow a reasonable sequence from study product 
administration or can be reasonably explained by the subject’s clinical state or 
other factors (eg, disease under study, concurrent diseases, and concomitant 
medications). 
10.4.5. 
Action Taken Regarding the Study Product 
 1 = Dose Not Changed: No change in study drug dosage was made. 
 2 = Drug Withdrawn: The study drug was permanently stopped. 
 3 = Dose Reduced: The dosage of study drug was reduced. 
 4 = Drug Interrupted: The study drug was temporarily stopped. 
 5 = Dose Increased: The dosage of study drug was increased.  
10.4.6. 
Other Action Taken for Event 
 None 
 No treatment was required 
 Medication required 
 Prescription and/or over-the counter (OTC) medication was required to treat the 
adverse event. 
 Hospitalization or prolongation of hospitalization required 
 Other 
10.4.7. 
Adverse Event Outcome 
 1 = Recovered/Resolved 
 The subject fully recovered from the adverse event with no residual effect 
observed. 
 2 = Recovered/Resolved with Sequelae 
 The residual effects of the adverse event are still present and observable. 
 Include sequelae/residual effects. 
 3 = Not Recovered/Not Resolved 
 The adverse event itself is still present and observable. 
 4 = Fatal 
 Fatal should be used when death is a direct outcome of the adverse event. 
 5 = Unknown 


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10.5. 
Serious Adverse Event Reporting Procedure For Investigators 
All AEs and SAEs will be reported in the eCRF.  Additionally, SAEs should be reported by the 
investigator on a serious adverse event report (SAVER) form within 24 hours of awareness.  
Call Medpace study personnel immediately once notified of an SAE. 
Medpace SAE hotline - USA: 
Phone: 
 
Fax: 
 
E-mail: 
 
All events (serious and non-serious) must be reported with the investigator's assessment of the 
event's seriousness, severity, and causality to the study drug.  A detailed narrative summarizing 
the course of the event, including its evaluation, treatment, and outcome, should be provided.  
Specific or estimated dates of event onset, treatment, and resolution should be included when 
available.  Medical history, concomitant medications, and laboratory data that are relevant to the 
event should also be summarized in the narrative.  For fatal events, the narrative should state 
whether an autopsy was or will be performed and include the results if available.  Source 
documents (including medical reports) will be retained at the study site and should not be 
submitted to the Sponsor for SAE reporting purposes. 
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
10.6. 
Notifying Regulatory Authorities, Investigators, IRB, and Competent 
Authorities 
DSI and/or Medpace will inform investigators, IRBs, and regulatory authorities of any suspected 
unexpected serious adverse event reactions (SUSARs) occurring in other study sites or other DSI 
studies of the investigational product, as appropriate per local reporting requirements. 
In the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the study 
drug, unless delegated to the Sponsor, it is the investigator’s responsibility to inform the IRB per 
Sponsor’s instruction. 
10.7. 
Exposure In Utero During Clinical Studies 
DSI must be notified of any subject who becomes pregnant while receiving study drug or up to 
the End-of-Study Follow-up (at least 30 [± 2] days after the last administration of study drug) or 
withdrawal from the study, whichever occurs later.   
Although pregnancy is not technically an adverse event, all pregnancies must be followed to 
conclusion to determine their outcome.  This information is important for both drug safety and 
public health concerns.  It is the responsibility of the investigator, or designee, to report any 
pregnancy in a subject using the Exposure In Utero (EIU) Reporting form.  Please contact your 
study monitor to receive the EIU Reporting Form upon learning of a pregnancy.  The 
investigator should make every effort to follow the subject until completion of the pregnancy.  If 
the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
PPD
PPD
PPD


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(ie, post-partum complications, spontaneous abortion, stillbirth, neonatal death, or congenital 
anomaly, including that in an aborted fetus), the investigator should follow the procedures for 
reporting SAEs as outlined in Section 10.5. 
The potential for milademetan to affect fertility and embryo-fetal development has not been 
tested.  Women of childbearing potential should be informed of the potential risk, have periodic 
pregnancy tests, and use highly effective methods of birth control during treatment and for an 
additional 90 days after the end of treatment.  Women should not breastfeed during the study and 
for an additional 90 days after the end of treatment. 
The potential of milademetan to be transferred by semen and its effect on sperm is unknown.  
Male subjects with partners of childbearing potential should inform their partners of their 
participation in the clinical study and use highly effective methods of birth control during 
treatment and for an additional 90 days after the end of treatment. 
10.8. 
Clinical Laboratory Evaluations 
The following clinical laboratory tests will be measured.  For clinical laboratory parameters, the 
reference range of the institution that performs the measurements will be used. 
Information will be entered in the eCRF on whether or not measured, date of measurement, and 
measurement results for the following items. 
 Hematology tests 
 red blood cell count, hemoglobin, hematocrit, platelet count, and white blood cell 
count with 5-part differential, including absolute neutrophil count and reticulocyte 
count. 
 Serum chemistry tests 
 sodium, potassium, bicarbonate, chloride, calcium, phosphorus, albumin, glucose, 
serum creatinine, uric acid, total protein, blood urea nitrogen, AST, ALT, alkaline 
phosphatase, and total and direct bilirubin. 
 Urinalysis  
 Creatinine clearance (screening only), protein, glucose, blood, microscopy 
assessments, and specific gravity. 
 Coagulation: INR and aPTT. 
 Serum or urine beta-human chorionic gonadotropin pregnancy test. 
 Tumor markers. 
All laboratory values must be appraised by the investigator as to clinical significance.  All 
abnormal laboratory values considered clinically significant by the investigator must be recorded 
in the adverse event page of the eCRF.  Abnormal laboratory values (NCI-CTCAE Grade 3 or 4) 
occurring during the clinical study will be followed until repeat test results return to normal (or 
baseline), stabilize, or are no longer clinically significant. 


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10.9. 
Vital Signs 
Vital sign measurements will include systolic blood pressure, diastolic blood pressure, 
respiratory rate, pulse rate, body temperature, and pulse oximetry. 
Blood pressure and pulse rate will be measured after the subject has rested in a recumbent 
position for 5 minutes or more. 
Whether or not measured, information will be entered in the eCRF on date of measurement and 
measurement results for the following items: systolic blood pressure, diastolic blood pressure, 
pulse rate, respiratory rate, body temperature, and pulse oximetry. 
10.10. 
Electrocardiograms 
Twelve-lead ECGs (in triplicate) will be measured after the subject has rested in a recumbent 
position for 5 minutes or more.  Whether or not measured, date performed, results, and findings 
will be recorded in the eCRF. 
Standard supine 12-lead ECGs will be performed by qualified technicians in triplicate as noted in 
the schedule of events.  ECGs will be reviewed at the site for treatment of any urgent issues.  The 
clinical significance of any ECG change must be assessed by the investigator in the context of 
the subject’s medical history, physical examination, and concomitant medications.  The 
investigator or delegated physician will review, sign, and date all ECGs.  Please refer to 
Table 18.2 and Table 18.3 for timing of ECG assessments and specific instructions for subjects 
enrolled per Case 3 (Section 4.1.2.1). 
10.11. 
Physical Examinations 
Physical examinations will evaluate the following body systems/organs: general appearance; 
dermatological; head and eyes; ears, nose, mouth, and throat; pulmonary; cardiovascular; 
abdominal; genitourinary (optional); lymphatic; musculoskeletal/extremities; and neurological.  
Weight and height will also be recorded in kilograms and centimeters, respectively, and BMI 
calculated.  Clinically significant changes from baseline must be reported as AEs.  ECOG 
performance status will also be assessed as part of the physical examinations. 
10.12. 
Other Safety Assessments 
Not applicable. 


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11. 
OTHER ASSESSMENTS 
Not applicable. 


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12. 
STATISTICAL METHODS 
12.1. 
General Statistical Considerations 
The primary analysis is to summarize DLT during the Dose Escalation part; efficacy in the Dose 
Expansion part; and safety, PK, and PDy data in both study parts. 
The primary analysis will occur either after all subjects in Part 1 and Part 2 have discontinued the 
study or at least 6 months after enrollment of the last subject.  After the primary analysis, the 
main study will be closed.  Subjects in Part 1 and Part 2 who are still on study drug at the time of 
the primary analysis may be eligible to continue receiving study drug in a separate extension 
phase of the protocol (see Section 18.7), and data collected from those subjects may be captured 
in a separate database. 
Descriptive statistics will be provided for selected demographic, safety, PK, and PDy data by 
dose and time as appropriate.  Descriptive statistics on continuous data will include means, 
medians, standard deviations, and ranges, while categorical data will be summarized using 
frequency counts and percentages.  Graphical summaries of the data may be presented. 
Assessments of change from baseline to post-treatment or the ratio of post-treatment to baseline 
will include only those subjects with both baseline and post-treatment measurements.  The last 
nonmissing value of a variable taken before the first dose of study drug will be used as the 
baseline value, unless otherwise specified.  In general, missing or dropout data will not be 
imputed for the purpose of data analysis, unless otherwise specified.   
Safety analyses will be performed based on the safety analysis set.  Analysis of PK parameters 
will be based on the PK analysis sets, and biomarker analyses will be based on the PDy 
biomarker analysis sets.  Efficacy endpoints will be analyzed based on the full analysis set and 
the primary analysis set.  Data from the Dose Escalation part will be summarized by dose level 
and overall. 
A detailed SAP describing the methodology to be used in the final analysis will be prepared and 
finalized before database lock.  Statistical methods described within this document may be 
changed based on advances in research. 
12.2. 
Analysis Sets 
12.2.1. 
Enrolled Analysis Set 
The enrolled analysis set will include all subjects who signed an ICF and were enrolled in either 
the Dose Escalation part or the Dose Expansion part of the study.  
12.2.2. 
Full Analysis Set 
The full analysis set will include all subjects enrolled in the Dose Escalation part or the Dose 
Expansion part who received any amount of milademetan. 


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12.2.3. 
Biomarker Positive Analysis Set 
The Biomarker Positive analysis set will include all subjects in the full analysis set who were 
biomarker positive. 
12.2.4. 
Dose-Limiting Toxicity Evaluable Set  
The DLT-evaluable set will include all subjects enrolled in the Dose Escalation part who had a 
DLT within the first 4 weeks (28 days) on study, or without DLT but received at least 75% of 
scheduled Cycle 1 (28 days) milademetan doses and completed Cycle 1 safety assessments.  
12.2.5. 
Safety Analysis Set 
The safety analysis set will include all subjects enrolled who received any amount of 
milademetan.  Subjects will be summarized according to treatment actually received.  
Three groups of subjects will be identified within the safety analysis set: (1) subjects in the Dose 
Escalation part, (2) subjects in the Dose Expansion part, and (3) all subjects in the study. 
12.2.6. 
Pharmacokinetic Analysis Set 
The PK analysis set will include all subjects in the enrolled analysis set who received any 
amount of milademetan and had measurable plasma concentrations of milademetan.  
12.2.7. 
Biomarker Analysis Set 
The PDy biomarker analysis set will include all subjects in the enrolled analysis set who received 
any amount of milademetan and who had the baseline assessment and, where applicable, at least 
1 post-baseline assessment for biomarkers. 
12.3. 
Study Population Data 
Disposition and reasons for ending the treatment and discontinuing from the study will be 
summarized and listed for subjects in the enrolled analysis sets. 
Demographic and baseline characteristics such as age, sex, race, baseline ECOG performance 
status, histology, cancer stage, best response to prior chemotherapy, lines of prior regimens, and 
prior treatment type will be summarized for the enrolled analysis sets, full analysis sets, primary 
analysis sets, and safety analysis sets.  If 2 analysis sets within a part of the study are identical to 
each other, the table will be presented only once. 
Study drug exposure, treatment duration, and compliance with study therapy will be summarized 
using descriptive statistics for the safety analysis sets. 
12.4. 
Efficacy Analyses 
12.4.1. 
Primary Efficacy Analyses 
Not applicable for Part 1.  
For Part 2 (Dose Expansion), primary efficacy variables will include objective response rate (the 
sum of CR and PR rates); disease control rate (DCR) (the sum of CR rate, PR rate, and SD rate 


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for a minimum of 8 weeks from the first dosing date), response duration, duration of SD, and 
time-to-response (TTR), using RECIST v 1.1 or the revised IWG criteria. 
The primary efficacy variables will be listed and summarized using descriptive statistics based 
on the full analysis set and the primary analysis set for the Dose Expansion part of the study.  For 
both objective response rate and DCR, point estimates and 95% exact binomial confidence 
intervals will be provided.  Time to event variables including PFS, response duration, and 
duration of SD will be summarized descriptively using the Kaplan-Meier method.  PFS is 
defined as the time from the date of the first dose to the earlier of the dates of the first objective 
documentation of radiographic disease progression, death due to any cause, or the last 
radiographic assessment if no progression assessment occurs.  Censoring rules for the PFS 
analysis will be specified in the SAP. 
In addition to the above analysis, descriptive statistics for the percent change in the sum of 
longest dimensions (SLD) in measurable tumors will be provided for solid tumors.  A waterfall 
plot of the greatest percent decreases from screening in the SLD will be presented for each 
subject with an advanced solid malignancy.  In addition, the percent change in the SLD at each 
of the first 3 post-baseline assessments will be presented.  Change in tumor size comparing to 
pretreatment/historical data will be presented graphically.  Additional details will be presented in 
the SAP. 
12.4.2. 
Secondary Efficacy Analyses 
For Part 1 (if feasible), objective response rate, DCR, response duration, duration of SD, TTR, 
PFS, and percent change in SLD of measurable tumors may also be analyzed using the same 
method as described above for the primary efficacy analyses. 
In addition, the growth rates of the target tumors before starting milademetan based on prior 
scans from subjects’ medical records versus on-treatment with milademetan may be summarized. 
Additional analyses will be described in the SAP. 
12.4.3. 
Exploratory Efficacy Analyses 
For both Part 1 and Part 2, the growth modulation indices (the intrasubject ratio of PFS 
post-study drug versus PFS post the most recent prior therapeutic regimen) will be summarized 
by dose level. 
12.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
12.5.1. 
Pharmacokinetic Analyses 
Plasma concentration data for milademetan will be summarized using descriptive statistics 
(number of subjects [n], mean, coefficient of variance [CV%], standard deviation, median, 
geometric mean, geometric CV%, minimum and maximum) by dose cohort at each time point.  
The last PK time point for Cycle 1 Day 1 (24 hr) is the predose sample for Cycle 1 Day 2.  
For Dose Escalation and Dose Expansion, the PK parameters listed in Table 12.1 will be 
summarized descriptively by dose and cancer type calculated using non-compartmental analysis.  
The PK parameters will be listed and summarized using descriptive statistics (same as above) by 


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dose cohort and visit, except Tmax, where only n, median, minimum, and maximum will be 
presented. 
Table 12.1: 
Pharmacokinetic Parameters for Non-Compartmental Analysis 
PK Parameter 
Definition of PK Parameter 
Cmax 
Maximum plasma concentration 
Cmin 
minimum plasma concentration  
Tmax 
Time to reach maximum plasma concentration 
t1/2 
Terminal elimination half-life 
t1/2,eff 
Effective half-lifea 
AUCinf 
Area under the plasma concentration-time curve up to infinity 
AUC0-8h 
Area under the plasma concentration-time curve from time 0 to 8 hours 
AUC0-24h 
Area under the plasma concentration-time curve from time 0 to 24 hours 
AUClast 
Area under the plasma concentration-time curve up to the last recorded time point 
CL/F 
Apparent clearance 
Vd/F 
Apparent volume of distribution 
AI 
Accumulation indexa 
a AI and steady-state exposures will be calculated using the PK data from the 21/28- and 28/28-day dosing 
schedules. 
The dose proportionality of milademetan will be assessed for Cmax, area under the plasma 
concentration-time curve from time 0 to 8 hours (AUC0-8h), and AUC0-24h on Cycle 1 Day 1. 
A PopPK analysis and exposure-response analysis for various endpoints may be developed.  The 
analysis plan and the technical report will be provided separately. 
12.5.2. 
Pharmacodynamic Analyses 
Increase in MIC-1 levels over baseline in serum will be listed and summarized using descriptive 
statistics by dose level cohort. 
12.5.3. 
Biomarker and Exploratory Analyses 
Archived or pre-treatment, on-treatment, and end-of-treatment biopsied tumor samples will be 
examined for components of the p53 pathway, which may include, but are not limited to, 
expression of p53, p21, MDM2, MDM4, and MDM2 copy number, and TP53 mutations.  
Additional biomarkers outside of the p53 pathway maybe included in order to better understand 
the responsiveness to therapy.  These may include protein, metabolite, gene expression, or 
genetic biomarkers. 
Analyses for potential biomarkers that may be predictive of benefit from milademetan will be 
graphed and/or listed and summarized using descriptive statistics by dose level cohort. 
Change in post-treatment biomarker expression from pre-treatment expression will be 
summarized by dose and cancer type if data warrant. 


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12.6. 
Safety Analyses 
Safety parameters will include SAEs, TEAEs, physical examination findings (including ECOG 
performance status), vital sign measurements, standard clinical laboratory parameters (serum 
chemistry, hematology, urinalysis), and ECG parameters.  Adverse events will be graded 
according to the NCI-CTCAE v4.  In the Dose Escalation part, the incidence of DLTs will also 
be evaluated. 
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics.  In the Dose Escalation part, the number of DLTs identified 
among the DLT-evaluable subjects in the DLT-evaluable set will be listed and summarized for 
each dose of milademetan.   
12.6.1. 
Adverse Event Analyses 
A TEAE is defined as an adverse event that emerges during the treatment period (from first dose 
date until 30 days after the last dosing date), having been absent at pre-treatment; or reemerges 
during treatment, having been present at baseline but stopped prior to treatment; or worsens in 
severity after starting treatment relative to the pre-treatment state, when the adverse event is 
continuous. 
The number and percentage of subjects reporting TEAEs will be tabulated by the worst 
NCI-CTCAE grade, system organ class (SOC), and preferred term.   
Similarly, the number and percentage of subjects reporting treatment-emergent SAEs will be 
tabulated, as well as TEAEs/SAEs considered related to milademetan.  
A by-subject adverse event (including TEAE) data listing will be provided, including, but not 
limited to, verbatim term, preferred term, SOC, NCI-CTCAE grade, and relationship to study 
drug. 
Deaths, other SAEs, and other significant AEs, including those leading to permanent 
discontinuation from milademetan, will be listed. 
12.6.2. 
Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for selected clinical laboratory test results (hematology 
and blood chemistry) and changes from baseline by scheduled time of evaluation, including the 
End-of-Treatment Visit, maximum post-treatment value, and minimum post-treatment value.  
Abnormal laboratory results will be graded according to NCI-CTCAE, v4, if applicable.  A shift 
table, presenting the 2-way frequency tabulation for baseline and the worst post-treatment value 
according to the NCI-CTCAE grade, will be provided for selected clinical laboratory tests.  
Abnormal clinical laboratory test results that are deemed of clinical significance or of Grade 3 or 
4 will be listed. 
12.6.3. 
Vital Signs Analyses 
Descriptive statistics will be provided for the vital signs measurements and changes from 
baseline by scheduled time of evaluation, including the End-of-Treatment Visit and the 
maximum and minimum post-treatment values. 


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12.6.4. 
Electrocardiogram Analyses 
ECG parameters (PR, RR, QRS, QT, corrected QT interval using Bazett’s formula [QTcB], and 
QTcF) will be summarized using descriptive statistics for actual values and for changes from 
baseline by scheduled time of evaluation, including the End-of-Treatment Visit and the 
maximum post-treatment value.  The corrected QT intervals using Bazett’s and Fridericia’s 
formula will be calculated as follows: QTcB = QT/(RR)1/2 and QTcF = QT/(RR)1/3. 
The incidence of notable ECG changes in maximum absolute QT, QTcF, and QTcB intervals 
(> 450, > 480, and > 500 ms) over all post-treatment evaluations, as well as in QT, QTcF, and 
QTcB maximum changes from baseline (> 30 and > 60 ms) over all post-treatment evaluations 
will be summarized.  A listing of ECG data will be provided. 
The concentration-delta QTc relationship will be characterized by a linear mixed-effect model, 
and the slope and 90% CI will be estimated. 
12.6.5. 
Physical Finding Analyses 
Physical examination findings will be listed for the safety analysis sets. 
12.6.6. 
Other Safety Analyses 
The ECOG performance status at baseline will be summarized for the safety analysis sets.  A 
shift table, presenting the 2-way frequency tabulation for baseline and End-of-Treatment Visit, 
will be provided for ECOG performance status. 
12.7. 
Other Analyses 
Not applicable. 
12.8. 
Interim Analyses 
No formal interim analysis is planned, except for the assessment of the MTD after each 
escalation cohort in the Dose Escalation part. 
12.9. 
Data and Safety Monitoring Board 
Not applicable. 
12.10. 
Sample Size Determination 
Cohorts of 3 to 6 subjects will be enrolled and assessed for DLT before escalation to a new 
higher dose.  As an exception, the model will be reevaluated before enrollment of any additional 
subjects to the cohort if 2 evaluable subjects in the cohort experience a DLT before the 
enrollment of the next subject.  For a subject to be considered evaluable for dose escalation 
decisions, the subject must have received 75% of the prescribed doses within the DLT 
observation period in Cycle 1 or experienced a DLT in Cycle 1.  Subjects who are unable to 
complete at least 75% of the prescribed doses of milademetan within the DLT observation period 
as a result of unequivocal progression of disease may be replaced. 


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In total, there should be (a) at least 6 evaluable subjects at the MTD dose level with at least 
21 evaluable subjects in total enrolled in the Dose Escalation part, or (b) at least 9 evaluable 
subjects have been enrolled at a dose level that is the model’s recommendation for the next dose 
cohort and for which the posterior probability of targeted toxicity is at least 50%, or (c) dose 
level -1 is too toxic.  At least 21 DLT-evaluable subjects are needed to reach an accurate estimate 
of the MTD.8,9,10  However, to better define an RP2D that will be clinically beneficial to the 
subjects as well as hematologically safe and tolerable for prolonged treatment without dose 
delays,  subjects in additional cohorts and multiple dosing schedules may be added. 
For the Dose Expansion part (Part 2), approximately 20 subjects (each for advanced melanoma 
and DLBCL) will be enrolled.  If the response rate is more than 25% (null hypothesis: response 
rate ≤ 0.25, alternative hypothesis: response rate > 0.25), then the probability of no response out 
of 10 subjects will be less than 10%.  The probability that 4 or more responders out of 10 
subjects are observed will be less than 25% under the null hypothesis but more than 80% under 
alternative hypothesis with response rate = 0.50. 
The probability values for the sample size are derived based on binomial distribution using SAS 
v 9.2. 
12.11. 
Specification of Bayesian Logistic Regression Model with Escalation 
with Overdose Control 
12.11.1. 
Bayesian Logistic Regression Model for Modified Continuous Reassessment 
Method 
The dose-toxicity relationship for BLRM with EWOC principle will be described by a 
2-parameter BLRM: 
logit(π(d)) = log(α) + β log(d/d*),  
α>0, β>0 
where logit(π(d))= ln (π(d)/(1-π(d))), π(d) is the probability of a DLT or the DLT rate at dosed.  
Doses are rescaled as d/d* with the reference dose d* = 90 mg/day.  As a consequence, α is equal 
to the odds of toxicity at d*.  Note that for a dose equal to zero, the probability of toxicity is zero. 
12.11.2. 
Prior Specification for Bayesian Logistic Regression Model Parameters 
The Bayesian approach requires the specification of a prior distribution for the BLRM 
parameters.  A minimally informative bivariate normal prior11 for the model parameters (log(α), 
log(β)) is obtained as follows: 
 Based on extrapolation of nonclinical toxicology studies in dogs, the MTD is 
projected to be greater than 90 mg/day in humans (the HNSTD of dogs is 
3 mg/kg/day [60 mg/m2/day], and assuming humans and dogs are equally sensitive, 
the MTD is projected to be greater than 90 mg/day in humans).  The median prior 
probabilities of DLT are set to be approximately 8.0% and 24.5% at 15 mg/day 
(10 mg/m2/day) (projected starting dose for dose escalation using BLRM) and at 
90 mg/day (60 mg/m2/day), respectively. 
 For the remaining doses, the prior medians of probability of DLT are assumed linear 
in log-dose on the logit-scale. 


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 Based on the above medians for the probability of DLT at each dose and wide prior 
credible intervals (obtained from minimally informative Beta distributions11), the 
optimal parameters of the bivariate normal distribution can be obtained as follows:  
Parameters 
Means 
Standard Deviations 
Correlation 
log(α), log(β) 
(-1.1286, -0.4947) 
(2.0244, 1.0595) 
-0.4831 
12.11.3. 
Escalation with Overdose Control Principle 
Dose recommendation for the next cohort will be based on summaries of the posterior 
probability of the DLT rate for provisional doses: 15, 30, 60, 90, 130, 200, 300, 440, 680, and 
900 mg/day.  After each cohort of subjects completes DLT evaluation during Cycle 1, the 
posterior distributions of the DLT rate are derived for all provisional dose levels based on the 
BLRM using the DLT outcome data from all assessed doses and a prespecified prior distribution 
for the model parameters.  The posterior probability of the DLT rate in the following 4 intervals 
at each dose level: [0%, 16%] as the DLT rate interval for underdosing, [16%, 33%] as the target 
DLT rate interval, [33%, 60%] as the DLT rate interval for excessive toxicity, and [60%, 100%] 
as the DLT rate interval for unacceptable toxicity will then be calculated and used for dose 
recommendation for the next cohort according to the EWOC principle.  The above provisional 
doses are based on an initial estimate of the human MTD of 90 mg/day using the HNSTD of 
dogs in nonclinical toxicology studies (3 mg/kg/day).  Of note, the HNSTD of rats was 
considerably higher (1000 mg/kg/day), and dog bone marrow cells were approximately 6-fold to 
7-fold more sensitive to milademetan-induced myelotoxicity than human in the colony-forming 
unit-granulocyte/macrophage assay (see current IB).  It is therefore conceivable that the posterior 
probability of DLT rate for dose recommendation may be generated using alternative provisional 
doses as long as the predicted exposure increments are between 30% and 100% (Section 4.1.2.1). 
The EWOC principle requires that the BLRM recommended dose for the next cohort of subjects 
is the one with the highest posterior probability of the DLT rate in the target DLT rate interval of 
[16%, 33%] among all doses fulfilling the overdose control constraint: there is less than 25% of 
probability for the DLT rate > 33% (probability for excessive or unacceptable toxicity). 


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13. 
DATA INTEGRITY AND QUALITY ASSURANCE 
13.1. 
Monitoring and Inspections 
The DSI and Medpace monitor and regulatory authority inspectors are responsible for contacting 
and visiting the investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the study (eg, eCRFs, source data, and other pertinent 
documents). 
Verification of adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to ICH Good Clinical Practice (GCP) and local regulations on the conduct of 
clinical research will be accomplished through a combination of onsite visits by the monitor and 
review of study data remotely.  The frequency of the monitoring visit will vary based on the 
activity at each study site.  The monitor is responsible for visiting site(s) at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to ICH GCP and local regulations on the conduct of 
clinical research.  The monitor is responsible for inspecting the eCRFs and ensuring 
completeness of the study essential documents.  The monitor should have access to subject 
medical records and other study-related records needed to verify the entries on the eCRFs.  
Detailed information is provided in the monitoring plan. 
The monitor will communicate deviations from the protocol, SOPs, GCP, and applicable 
regulations to the investigator and will ensure that appropriate action(s) designed to prevent 
recurrence of the detected deviations is taken and documented. 
The investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are addressed to the satisfaction of the sponsor and 
documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor.  Audit of study site facilities (eg, pharmacy, drug storage 
areas, laboratories) and review of study-related records will occur in order to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory requirements.  
The investigator should respond to audit findings.  In the event that a regulatory authority 
informs the investigator that it intends to conduct an inspection, the Sponsor shall be notified 
immediately. 
13.2. 
Data Collection 
An eCRF must be completed for each subject who signs an ICF and undergoes any screening 
procedure.  If a subject is not treated, the reason must be recorded on the eCRF.  
All data collected during the study will be recorded in this individual, subject-specific eCRF.  
Instructions will be provided for the completion of the eCRF, and any corrections made will be 
automatically documented via an “audit trail.” 
The eCRF should be kept current to enable the monitor to review the subject’s status throughout 
the course of the study.  Upon completion of the subject’s eCRF, it will be reviewed and signed 
off by the investigator via the electronic data capture (EDC) system’s electronic signature.  This 


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signature will indicate that the investigator reviewed the data in the eCRF, the data queries, and 
the site notifications, and agrees with the eCRF content.  Instructions for completion of the 
eCRFs will be provided.  Corrections to electronic forms will be automatically documented by 
using the software’s “audit trail.” 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 
The extent or frequency of data collection during the extension period of the study may be the 
same as during the main period of the study or may be reduced at the Sponsor’s discretion 
considering the number of PFS and OS events, the number of subjects on study drug, and the 
value of additional data collection for evaluation of study endpoints.   
Refer to Schedule of Assessments, Extension Phase, for details (Table 18.4). 
13.3. 
Data Management 
This is an open-label study.  Each subject will be identified in the database by a unique subject 
identifier as defined by DSI. 
To ensure the quality of clinical data across all subjects and sites, a Clinical Data Management 
review will be performed on subject data according to specifications given to Sponsor/or 
designee.   
Each subject will be identified in the database by a unique subject identifier as defined by the 
sponsor. 
To ensure the quality of clinical data across all subjects and study sites, a Clinical Data 
Management review will be performed on subject data according to specifications given to 
Sponsor/or designee.  Data will be vetted both electronically and manually for eCRFs, and the 
data will be electronically vetted by programmed data rules within the application.  Queries 
generated by rules and raised by reviewers will be generated within the EDC application.  During 
this review, subject data will be checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data will be reviewed for adherence to the protocol and GCP.  To 
resolve any questions arising from the Clinical Data Management review process, eCRF queries 
will be raised and resolved within the EDC application. 
Data received from external sources such as central labs will be reconciled to the clinical 
database. 
SAEs in the clinical database will be reconciled with the safety database. 
All prior cancer therapy and prior/concomitant medications entered into the database will be 
coded by using the latest version of World Health Organization Drug Dictionary.  All adverse 
events will be coded using the latest version of Medical Dictionary for Regulatory Activities. 
13.4. 
Study Documentation and Storage 
The investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties.  All persons authorized to make entries and/or corrections on 
eCRFs will be included on the Signature List. 


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Source documents are original documents, data, and records from which the subject’s eCRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, X-rays, and correspondence. 
Records of subjects, source documents, monitoring visit logs, data correction forms, eCRFs, 
inventory of study drug, regulatory documents (eg, protocol and amendments, IRB/ethics 
committee (EC) correspondence and approvals, approved and signed ICFs, Investigator’s 
Agreement, clinical supplies receipts, distribution and return records), and other sponsor 
correspondence pertaining to the study must be kept in appropriate study files at the study site 
(Trial Master File).  Source documents include all recordings and observations or notations of 
clinical activities and all reports and records necessary for the evaluation and reconstruction of 
the clinical study.  These records will be retained in a secure file for the period required by the 
institution or study site policy.  Prior to transfer or destruction of these records, the Sponsor must 
be notified in writing and be given the opportunity to further store such records. 
13.5. 
Record Keeping 
The investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (Trial Master File) of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable regulatory 
authorities.  Essential documents include: 
 Subject files containing completed eCRFs, ICFs, and supporting copies of source 
documentation (if kept). 
 Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of relevant essential documents required prior to commencing a clinical study, 
and all correspondence to and from the EC/IRB and the Sponsor. 
 Records related to the study drug(s) including acknowledgment of receipt at study 
site, accountability records and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the eCRFs must be maintained 
and be readily available. 
No study document should be destroyed without prior written agreement between Sponsor and 
the investigator.  Should the investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor in writing of the new responsible 
person and/or the new location. 
13.6. 
Product Complaints 
A product complaint is any dissatisfaction with a product that may be attributed to the identity, 
quality, durability, reliability, or safety of the product.  Individuals who identify a potential 
product complaint situation should immediately report the event.  Whenever possible, the 
associated product should be maintained in accordance with the label instructions pending 
further guidance from a quality representative form from the Sponsor.  For product complaints, 
refer to the Study Manual for instructions and details. 


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14. 
FINANCING AND INSURANCE 
14.1. 
Finances 
Prior to starting the study, the Principal Investigator and/or institution will sign a clinical study 
agreement with DSI.  This agreement will include the financial information agreed upon by the 
parties. 
14.2. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case of 
study-related injury. 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 


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15. 
PUBLICATION POLICY 
The Sponsor is committed to meeting the highest standards of publication and public disclosure 
of information arising from clinical studies sponsored by the company.  The Sponsor will 
comply with US, European Union, and Japanese policies for public disclosure of the clinical 
study protocol and clinical study results and for sharing of clinical study data.  The Sponsor will 
follow the principles set forward in “Good Publication Practice for Communicating 
Company- Sponsored Medical Research (GPP3)”, and publications will adhere to the 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” established by the International Council of Medical Journal Editors (ICMJE). 
In order to ensure compliance with the public disclosure policies and the ICMJE 
recommendations, and to protect proprietary information generated during the study, all 
publications (manuscripts, abstracts, or other public disclosure) based on data generated in this 
study must be reviewed and approved in writing by the Sponsor prior to submission. 


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16. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
16.1. 
Compliance Statement, Ethics, and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the ICH consolidated Guideline E6 for GCP 
(CPMP/ICH/135/95), and applicable regulatory requirement(s) including the following: 
 US Food and Drug Administration GCP Regulations: Code of Federal Regulations 
(CFR) Title 21, parts 11, 50, 54, 56, and 312, as appropriate, and 
 other applicable local regulations. 
16.2. 
Subject Confidentiality 
The investigators and the Sponsor, DSI, will preserve the confidentiality of all subjects taking 
part in the study, in accordance with GCP and local regulations. 
The investigator must ensure that the subject’s anonymity is maintained.  On the CRFs or other 
documents submitted to DSI or the contract research organization (CRO), subjects should be 
identified by a unique subject identifier as designated by DSI.  Documents that are not for 
submission to DSI and/or Medpace (eg, signed ICFs) should be kept in strict confidence by the 
investigator. 
In compliance with ICH GCP guidelines, it is required that the investigator and institution permit 
authorized representatives of the company, of the regulatory agency(s), and the IRB direct access 
to review the subject’s original medical records for verification of study-related procedures and 
data.  The investigator is obligated to inform the subject that his/her study-related records will be 
reviewed by the above-named representatives without violating the confidentiality of the subject. 
16.3. 
Informed Consent  
Before a subject’s participation in the study, it is the investigator’s responsibility to obtain freely 
given consent, in writing, from the subject or legally acceptable representative after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards of the study and 
before any protocol-specific screening procedures or any study drugs are administered.  Subjects 
should be given the opportunity to ask questions and receive satisfactory answers to their 
inquiries, and should have adequate time to decide whether or not to participate in the study.  
The written ICF should be prepared in the local language(s) of the potential subject population. 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirements and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  The consent form and any revision(s) should be 
approved by the IRB prior to being provided to potential subjects. 
The subject’s written informed consent should be obtained prior to his/her participation in the 
study and should be documented in the subject’s medical records, as required by 
21 CFR Part 312.62.  The ICF should be signed and personally dated by the subject or a legally 
acceptable representative and by the person who conducted the informed consent discussion (not 


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necessarily the investigator).  The original signed ICF should be retained in accordance with 
institutional policy, and a copy of the signed consent form should be provided to the subject.  
The date and time (if applicable) that informed consent was given should be recorded on the 
eCRF. 
If the subject cannot read, then according to ICH GCP Guideline, Section 4.8.9, an impartial 
witness should be present during the entire informed consent discussion.  This witness should 
sign the ICF after the subject has consented to the subject’s participation and, if possible, signed 
the ICF.  By signing the ICF, the witness attests that the information in the ICF and any other 
written information was adequately explained to and apparently understood by the subject or the 
legally acceptable representative and that informed consent was freely given by the subject. 
Suggested model text for the ICF for the study and any applicable subparts (genomic, 
pharmacokinetic, etc) and assent forms for pediatric subjects (if applicable) are provided in the 
DSI ICF template for the investigator to prepare the documents to be used at his or her site.  
Updates to applicable forms will be communicated via letter from the Sponsor. 
The consent for PGx sampling for banking and tumor biopsies should be documented in the 
subject’s written informed consent.  The consent form should be signed and personally dated by 
the subject or the subject's legal representative prior to his/her participation in the study.  
Participation for PGx sampling for banking is optional for all subjects.  Participation for pre- and 
post-treatment tumor biopsies is optional for all subjects in Part 1, but for pre-treatment is 
mandatory in Part 2.  Participation for tumor re-biopsy upon progression is optional for all 
subjects.  Those subjects who choose not to provide a sample for PGx sampling for banking or 
optional tumor biopsies may still participate in the main portion of the study. 
16.4. 
Regulatory Compliance 
The study protocol, subject information and consent form, the investigator Brochure, any subject 
diary card or written instructions to be given to the subject, available safety information, subject 
recruitment procedures (eg, advertisements), information about payments and compensation 
available to the subjects, and documentation evidencing the investigator’s qualifications should 
be submitted to the IRB for ethical review and approval according to local regulations prior to 
the study start.  The written approval should identify all documents reviewed by name and 
version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the Statistical Analysis Plan (SAP). 
In addition, the investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard and of any 
suspected/actual serious GCP non-compliance that the investigator becomes aware of.   
16.5. 
Protocol Deviations 
The investigator should conduct the study in compliance with the protocol agreed to by DSI and, 
if required, by the regulatory authority(ies), and which was given approval/favorable opinion by 
the IRBs/ECs. 


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A deviation to any protocol procedure or waiver to any stated criteria will not be allowed in this 
study except where necessary to eliminate immediate hazard(s) to the subject.  The Sponsor must 
be notified of all intended or unintended deviations to the protocol (eg, inclusion/exclusion 
criteria, dosing, missed study visits) on an expedited basis. 
The investigator, or person designated by the investigator, should document and explain any 
deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or investigational treatment, and had at 
least 1 administration of investigational product, data should be collected for safety purposes. 
The investigator should notify the IRB of deviations from the protocol in accordance with local 
procedures. 
16.6. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects or the 
conduct of the study, the Sponsor will inform all investigators involved in the clinical study, 
IRBs/ECs, and regulatory authorities of such information, and, when needed, will amend the 
protocol and/or subject information. 
The investigator should immediately inform the subject whenever new information becomes 
available that may be relevant to the subject’s consent or may influence the subject’s willingness 
to continue participation in the study.  The communication should be documented on medical 
records, for example, and it should be confirmed whether the subject is willing to remain in the 
study. 
If the subject information is revised, it must be re-approved by the IRB/EC.  The investigator 
should obtain written informed consent to continue participation with the revised written 
information even if subjects were already informed of the relevant information.  The investigator 
or other responsible personnel who provided explanations and the subject should sign and date 
the revised ICFs. 
16.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses will 
be communicated to the investigator by DSI.  Also, the Sponsor will ensure the timely 
submission of amendments to regulatory authorities. 
A global protocol amendment will affect study conduct at all study sites in all regions of the 
world.  Such amendments will be incorporated into a revised protocol document.  Changes made 
by such amendments will be documented in a Summary of Changes document.  These protocol 
amendments will undergo the same review and approval process as the original protocol. 
A local protocol amendment will affect study conduct at a particular study site(s) and/or in a 
particular region/country.  Sponsor approval of local amendments will be clearly documented. 
A protocol amendment may be implemented after it has been approved by the IRB/EC and by 
regulatory authorities where appropriate, unless immediate implementation of the change is 
necessary for subject safety.  


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16.8. 
Study Termination 
The Sponsor has the right to terminate the study at any time, and the study termination may also 
be requested by (a) competent authority/ies. 
Stopping criteria are noted in Section 5.2.1. 
16.9. 
Data and Safety Monitoring Board 
Not applicable. 
16.10. 
Address List 
A list of key study personnel (including personnel at the sponsor, CRO, laboratories, and other 
vendors) and their contact information (address, telephone, fax, email) will be kept on file and 
updated in study reference materials. 


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17. 
REFERENCES 
1. 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;49:223-241. 
2. Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev 
Cancer. 2009;9:749-758. 
3. Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-
molecule antagonists of MDM2. Science. 2004;303:844-848. 
4. Shangary S, Qin D, McEachern D, et al. Temporal activation of p53 by a specific MDM2 
inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. 
PNAS. 2008;105:3933-3938. 
5. Vassilev LT. MDM2 inhibitors for cancer therapy. Trends Mol Med 2007;13:23-31. 
6. Milademetan Investigator’s Brochure (v. 6.0, dated 29 Jul 2019) 
7. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol. 2007;25:579-586. 
8. O'Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for 
Phase 1 clinical trials in cancer. Biometrics. 1990;46:33-48. 
9. O'Quigley J, Shen LZ. Continual reassessment method: a likelihood approach. 
Biometrics. 1996;52:673-684. 
10. Iasonos A, Wilton AS, Riedel ER, et al. A comprehensive comparison of the continual 
reassessment method to the standard 3 + 3 dose escalation scheme in Phase I dose-finding 
studies. Clin Trials. 2008;5:465-477. 
11. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Stat Med. 2008;27:2420-2439. 
12. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 


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18. 
APPENDICES 
18.1. 
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0  
Fully active, able to carry on all predisease performance without restriction 
1  
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2  
Ambulatory and capable of all self-care, but unable to carry out any work activities, up and 
about more than 50% of waking hours 
3  
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4  
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
5  
Dead 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:649-655.12  
18.2. 
National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4 
1. Toxicity grade should reflect the most severe degree occurring during the evaluated 
period, not an average. 
2. When 2 different criteria grades might be applicable for rating a particular toxicity, or 
similar toxicities, the more severe grade should be used. 
3. Any toxicity resulting in death is defined as Grade 5. 
4. The evaluator must attempt to discriminate between disease/treatment and related 
signs/symptoms. 
5. For links to the National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 4, please refer to 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40  


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18.3. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
18.3.1. 
Measurability of Tumor at Baseline 
18.3.1.1. Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or nonmeasurable as 
follows: 
Measurable 
 Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of: 
 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater 
than 5 mm) 
 10-mm caliper measurement by clinical exam (lesions that cannot be accurately 
measured with calipers should be recorded as nonmeasurable) 
 20 mm by chest X-ray 
 Measurable malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm).  At baseline 
(ie, screening for this study) and in follow-up (ie, all measurements past screening for 
this study), only the short axis will be measured and followed.  See also notes below 
on “Baseline documentation of target and nontarget lesions” for information on 
lymph node measurement 
Nonmeasurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis), as well as truly nonmeasurable lesions.  Lesions 
considered truly nonmeasurable include leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
18.3.1.1.1. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment. 
Bone Lesions 
 Bone scan, positron emission tomography scan, or plain films are not considered 
adequate imaging techniques to measure bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT 


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or magnetic resonance imaging (MRI) can be considered as measurable lesions if the 
soft tissue component meets the definition of measurability described above. 
 Blastic bone lesions are nonmeasurable. 
Cystic Lesions 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they 
are, by definition, simple cysts. 
 “Cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions if they meet the definition of measurability described above.  
However, if noncystic lesions are present in the same subject, these are preferred for 
selection as target lesions. 
Lesions with Prior Local Treatment 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion.  
18.3.1.2. Specifications by Methods of Measurements 
18.3.1.2.1. Measurement of Lesions 
All measurements should be recorded in metric notation using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and NEVER 
more than 4 weeks before the beginning of the treatment. 
18.3.1.2.2. Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation 
should always be performed rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
An MRI is also acceptable in certain situations (eg, for body scans).  
18.3.2. 
Tumor Response Evaluation 
18.3.2.1. Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements.  In this study, only 
subjects with measurable disease at baseline should be included in the study. 


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18.3.2.2. Baseline Documentation of “Target” and “Nontarget” Lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (representative of all involved organs) should be identified as target lesions and 
will be recorded and measured at baseline (this means in instances where subjects have only 1 or 
2 organ sites involved a maximum of 2 and 4 lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion that 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor.  As noted above, pathological nodes that are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of  ≥ 15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum.  The short axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumor.  Nodal size is normally reported as 2 dimensions in the plane in 
which the image is obtained (for CT scan, this is almost always the axial plane; for MRI, the 
plane of acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the 
short axis.  For example, an abdominal node that is reported as being 20 mm × 30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with short axis 
≥ 10 mm but < 15 mm) should be considered nontarget lesions.  Nodes that have a short axis 
< 10 mm are considered nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as 
nontarget lesions and should also be recorded at baseline.  Measurements are not required, and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression.”  In addition, it is possible to record multiple nontarget lesions involving the same 
organ as a single item on the case record form (eg, “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”).  
18.3.2.3. Response Criteria 
This section provides the definitions of the criteria used to determine the objective tumor 
response for target lesions. 
18.3.2.3.1. Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or nontarget) must have reduction in short axis to < 10 mm. 


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Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note: the appearance of 1 or more new lesions is also 
considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
18.3.2.3.2. Special Notes on the Assessment of Target Lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study.  This means that when lymph nodes are 
included as target lesions, the “sum” of lesions may not be zero even if CR criteria are met, since 
a normal lymph node is defined as having a short axis of < 10 mm.  For PR, SD, and PD, the 
actual short axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become “too small to measure”: While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
“too small to measure.”  When this occurs, it is important that a value be recorded on the eCRF.  
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned (Note: It is less likely that this rule 
will be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well).  This default value is derived from the 5-mm 
CT slice thickness (but should not be changed with varying CT slice thickness).  The 
measurement of these lesions is potentially nonreproducible; therefore, providing this default 
value will prevent false responses or progressions based upon measurement error.  To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even if 
it is below 5 mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum.  
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the “coalesced lesion.” 


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18.3.2.3.3. Evaluation of Nontarget Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of nontarget lesions.  While some nontarget lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.  
CR: Disappearance of all nontarget lesions and normalization of tumor marker level.  All lymph 
nodes must be nonpathological in size (< 10 mm short axis). 
NonCR/NonPD: Persistence of 1 or more nontarget lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
PD: Unequivocal progression (see comments below) of existing nontarget lesions (Note: the 
appearance of 1 or more new lesions is also considered progression). 
18.3.2.3.4. Special Notes on Assessment of Progression of Nontarget Disease 
The concept of progression of nontarget disease requires additional explanation as follows, when 
the subject also has measurable disease.  In this setting, to achieve “unequivocal progression” on 
the basis of the nontarget disease, there must be an overall level of substantial worsening in 
nontarget disease such that, even in presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy.  A modest “increase” in the 
size of 1 or more nontarget lesions is usually not sufficient to quality for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in nontarget disease 
in the face of SD or PR of target disease will therefore be extremely rare.  
18.3.2.3.5. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, ie, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (eg, some “new” bone 
lesions may be simply healing or flare of preexisting lesions).  This is particularly important 
when the subject’s baseline lesions show PR or CR.  For example, necrosis of a liver lesion may 
be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of this is 
the subject who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered that reveals metastases.  The subject’s brain metastases are considered to be evidence of 
PD even if he/she did not have brain imaging at baseline.  
If a new lesion is equivocal, for example, because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan.  


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18.3.2.4. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study drug until the 
end of treatment.  No confirmatory measurement for CR, PR, or SD is required in the study. 
The subject’s best overall response assignment will depend on the findings of both target and 
nontarget disease and will also take into consideration the appearance of new lesions. 
18.3.2.4.1. Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table 18.1 provides a summary of the overall response status calculation at each time point for 
subjects who have measurable disease at baseline. 
Table 18.1: 
Overall Response 
Time point Response: Subjects with Target (± Nontarget) Disease 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
NonCR/NonPD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
NonPD or not all evaluated 
No 
PR 
SD 
NonPD or not all evaluated 
No 
SD 
Not all evaluated 
NonPD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial response;  
SD = stable disease. 
18.3.2.4.2. Missing Assessments and Inevaluable Designation 
When no imaging/measurement is performed at all at a particular time point, the subject is not 
evaluable at that time point.  If only a subset of lesion measurements are made at an assessment, 
usually the case is also considered not evaluable at that time point, unless a convincing argument 
can be made that the contribution of the individual missing lesion(s) would not change the 
assigned time point response.  This would be most likely to happen in the case of PD.  For 
example, if a subject had a baseline sum of 50 mm with 3 measured lesions and at follow-up 
only 2 lesions were assessed, but those gave a sum of 80 mm, the subject will have achieved PD 
status, regardless of the contribution of the missing lesion.  
18.3.2.4.3. Best Overall Response: All Time Points 
The best overall response is determined once all the data for the subject are known. 
Best response determination in studies where confirmation of CR or PR IS NOT required: Best 
response in these studies is defined as the best response across all time points (eg, a subject who 


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has SD at first assessment, PR at second assessment, and PD on last assessment has a best 
overall response of PR).  When SD is believed to be best response, it must also meet the 
protocol-specified minimum time from baseline, 6 weeks.  If the minimum time is not met when 
SD is otherwise the best time point response, the subject’s best response depends on the 
subsequent assessments.  For example, a subject who has SD at first assessment, PD at second, 
and does not meet minimum duration for SD will have a best response of PD.  The same subject 
lost to follow-up after the first SD assessment would be considered inevaluable. 
18.3.2.4.4. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that subjects with CR may 
not have a total sum of “zero” on the eCRF. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of 
such subjects is to be determined by evaluation of target and nontarget disease. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at 
the next scheduled assessment progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
18.3.2.5. Frequency of Tumor Reevaluation 
In this study, tumor measurement will be conducted every 2 cycles while the subject remains on 
study for the first 8 cycles and then every 3 cycles thereafter (start of Cycles 3, 5, 7, and 9, then 
Cycles 12, 15, etc.) until progression of disease, withdrawal of consent, death, or loss to 
follow-up.  Scan dates should not be adjusted or rescheduled due to dose interruption of any 
type. 
Baseline tumor assessments must be performed within 4 weeks (28 days) prior to the first dose of 
treatment.  
All efforts should be made to ensure consistency between the baseline measurements and all 
subsequent measurements in reference to utilization of scanning method, equipment, technique 
(including slice thickness and field of view), and radiographic interpreter. 
The radiographic evaluation must include CT or MRI scanning of the chest, abdomen, and 
pelvis.  Any additional suspected sites of disease should also be imaged.  All evaluations should 
meet the standard of care for imaging of lesions in the respective organ(s) and should conform to 
the image acquisition guidelines according to institutional standards. 
All target and nontarget sites are evaluated at each time point of tumor assessment. 


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18.4. 
International Working Group Criteria 
 
Source: Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 
2007;25:579-586.7 
18.5. 
Cytokine P450 3A Inducers and Inhibitors 
This table is created using information from the hyperlinked source below.  Please refer to those 
sites for additional information. 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM292362.pdf 
CYP3A Inhibitors 
CYP3A Inducers 
HIV Antivirals: Indinavira 
Nelfinavira 
Ritonavira 
 
Boceprevira 
Clarithromycina 
Conivaptana 
Grapefruit Juicea 
Itraconazolea 
Ketoconazolea 
Lopinavira 
Nefazodonea 
HIV Antivirals: 
Efavirenze 
Nevirapine 
 
Avasimibed 
Carbamazepined 
Phenytoind 
Rifampind 
St. John's Wortd 
 
Bosentane 
Etravirinee 
Modafinile 


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CYP3A Inhibitors 
CYP3A Inducers 
Posaconazolea 
Saquinavira 
Telaprevira 
Telithromycina 
 
Voriconazolea 
Amprenavirb 
Aprepitantb 
Atazanavirb 
Ciprofloxacinb 
Crizotinibb 
Darunavirb 
Dilitiazemb 
Erythromycinb 
Fluconazoleb 
Fosamprenavirb 
Grapefruit Juiceb 
Imatinibb 
Verapamilb 
Alprazolamc 
Amiodaronec 
Amlodipinec 
Atorvastatinc 
Bicalutamidec 
Cilostazolc 
Cimetidinec 
Cyclosporinec 
Fluoxetinec 
Fluvoxaminec 
Ginkgoc 
Goldensealc 
Isoniazidc 
Lapatinibc 
Nilotinibc 
Oral Contraceptivesc 
Pazopanibc 
Ranitidinec 
Ranolazinec 
Nafcilline 
 
Amprenavirf 
Aprepitantf 
Armodafinilf 
Clobazamechinaceaf 
Pioglitazonef 
Prednisonef 
Rufinamidef 
Vemurafenibf 
 
Barbiturates  
Glucocorticoids 
Modafinil 
Oxcarbazepine 
Phenobarbital 
Rifabutin 
Troglitazone 


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CYP3A Inhibitors 
CYP3A Inducers 
Tipranavirc 
Ticagrelorc 
Zileutonc 
Not Azithromycin 
Chloramphenicol 
Delavirdine 
Diethyl-Dithiocarbamate 
Gestodene 
Mibefradil 
Mifepristone 
Norfloxacin 
Norfluoxetine 
Starfruit 
AUC = area under the plasma concentration-time curve; CYP = cytochrome P450; HIV = human immunodeficiency 
virus 
a Strong inhibitor: causes a ≥ 5-fold increase in the plasma AUC values or more than 80% decrease in clearance.  
b Moderate inhibitor: causes a ≥ 2-fold increase in the plasma AUC values or 50% to 80% decrease in clearance. 
c Weak inhibitor: causes a ≥ 1.25-fold but < 2-fold increase in the plasma AUC values or 20% to 50% decrease in 
clearance. 
d Strong inducer: causes a ≥ 80% decrease in the plasma AUC values. 
e Moderate inducer: causes a 50% to 80% decrease in the plasma AUC values.  
f Weak inducer: causes a 20% to 50% decrease in the plasma AUC value. 


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18.6. 
Schedule of Events 
Table 18.2: 
Schedule of Events Part 1 (Dose Escalation) 
Cyclea 
Pre-
Cycle 
1 
2 
3 
4 and 
Beyond 
Post-
Cycle 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 and 
Beyond 
TBD 
Visit Description 
Screen-
ing 
Exam and 1st Dose 
Exam Exam Exam 
Exam 
Exam 
Exam Exam Exam Exam Exam 
EOTb 
Cycle Day(s) 
-14 to 0 
1 
2 
8 
15 
18-21 
1 
8 
15 
1 
15 
1 
ND 
Visit Window (days) 
± 2 
± 2 
0 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
Time Postdose (hours) 
Pre
dose 0.5 1 
2 
3 
6-8 
Pre
dose 0.5 1 
2 
3 
6-8 
Pred
ose 1 
3 
6-8  
Informed consent 
X 
 
Demographics 
X 
 
Medical history 
X 
 
Archive tumor sample 
X 
 
Inclusion/exclusion criteria 
X 
 
Pregnancy testc 
X 
 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
ECOG  
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical examination  
and vital signsd 
X 
X 
@ 
@ 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Safety laboratorye 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysisf 
X 
X 
X 
X 
 
X 
 
X 
X 
Tumor markersg 
X 
 
X 
 
X 
X 
X 
ECG (12-lead)h 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Tumor assessmenti 
X 
 
 
X 
X 
Tumor biopsy (optional)j 
X 
X 
 
 
PGx blood samplek 
X 
 
 


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Table 18.2: 
Schedule of Events Part 1 (Dose Escalation) (Continued) 
Cyclea 
Pre-
Cycle 
1 
2 
3 
4 and 
beyond 
Post-
Cycle 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 and 
beyond 
TBD 
Visit Description 
Screen-
ing 
Exam and 1st Dose 
Exam Exam Exam 
Exam 
Exam 
Exam Exam Exam Exam Exam 
EOTb 
Cycle Day(s) 
-14 to 0 
1 
2 
8 
15 
18-21 
1 
8 
15 
1 
15 
1 
ND 
Visit Window (days) 
± 2 
± 2 
0 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
Time Postdose (hours) 
Pre
dose 0.5 1 
2 
3 
6-8 
Pre
dose 0.5 1 
2 
3 
6-8 
Pred
ose 1 
3 
6-8  
Exploratory blood samplel 
X 
X 
X 
 
 
X 
Milademetan administrationm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK blood samplen 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
 
 
 
 
X 
MIC-1 serum sampleo 
X 
X 
X 
X 
X 
X 
Xp 
 
Dispense milademetan 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pill diaries dispensed/reviewed 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optional tumor re-biopsyq 
 
X 
DLT = dose-limiting toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FDG-PET = (18F) fluorodeoxyglucose-positron emission tomography; 
IWG = International Working Group; MIC-1 = macrophage inhibitory cytokine-1; ND = not determined; PGx = pharmacogenomic; PK = pharmacokinetic(s); QD = once daily; RECIST = Response 
Evaluation Criteria in Solid Tumors Version 1.1; TBD = to be determined 
Note: The End-of-Study Follow-up will occur 30 (±2) days after the last administration of milademetan.  If the subject begins another form of anticancer therapy before the end of the 30 (±2)-day period, 
every effort will be made to complete all the End-of-Study assessments prior to commencing the new therapy. 
a Each cycle will last 28 days.  Cohort safety assessment for DLTs will be performed after Day 28 of Cycle 1. 
b The EOT Visit will occur 30 (± 2) days after the last administration of milademetan.  If the subject begins another form of anticancer therapy before the end of the 30 (±2)-day period, every effort will 
be made to complete all the EOT assessments prior to commencing the new therapy.  If there is an abnormality in need of monitoring beyond the EOT Visit, subjects will be followed until resolution 
or confirmed stability of the abnormality. 
c Pregnancy test (urine or serum) will be performed in female subjects of childbearing potential at screening, Cycle 3 Day 1, and EOT Visit. 
d Physical examination including vital signs will be performed on visit days indicated by X.  Height and weight will be recorded at Screening and EOT Visits.  Weight will be recorded at all other visits.  
Vital signs will be performed on visit days indicated by X or @. 
e Safety laboratory samples for Day 1 predose (complete blood count with differential and reticulocyte count, serum chemistry, urinalysis, and coagulation profile) can be collected within 72 hours 
before the first dose.  Creatinine clearance will be performed at screening. 
f Urinalysis will be performed for the indicated visits up to Cycle 3 Day 1 and at EOT Visit.   
g Tumor markers will be obtained as appropriate for the tumor type at each cycle. 
h Twelve-lead ECGs (in triplicate) will be measured after the subject has rested in a recumbent position for 5 minutes or more. ECGs will be performed predose except at additional 2 hours postdose on 
Day 1.  Procedure window is ± 1 hour.  For subjects enrolled per Case 3 (Section 4.1.2.1), at Screening 4 sets of triplicate ECGs should each be taken approximately 1 hour apart, then triplicate ECGs 
will be taken at predose, 0.5, 1, 2, 3, 8, and 24 hours on Cycle 1 Days 1 to 2, and at predose and 3 hours post-dose on Days 18 to 21, corresponding to the PK time points on Day 1, Day 2, and Days 
18-21, respectively.  The time points for the ECG and PK sample collection should be as close as possible within a 10-minute window. 


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i Tumor assessment by physical examination and RECIST v 1.1 or revised IWG criteria will be performed at baseline within 4 weeks of the first dose of milademetan and after every 2 cycles of 
treatment for the first 8 cycles and then every 3 cycles thereafter (ie, at start of Cycles 3, 5, 7, and 9, then Cycles 12, 15, etc.).  Pre-treatment FDG-PET scans will be performed in all subjects with 
lymphoma under fasting conditions at baseline within 4 weeks of the first dose of milademetan.  In subjects with lymphoma that are FDG-PET avid, FDG-PET scans will be performed every 2 cycles 
of treatment for the first 8 cycles and then every 3 cycles thereafter (ie, at start of Cycles 3, 5, 7, and 9, then Cycles 12, 15, etc.).  Bone marrow will be assessed at baseline by aspirate and/or biopsy 
per the investigator’s decision.  If positive, bone marrow assessments may be repeated with the subsequent tumor assessment. 
j Optional paired tumor biopsies will be obtained by skin punch biopsies (for melanoma), Tru-cut technique, or core needle biopsies under imaging guidance. 
k Informed consent specifically allowing optional PGx testing must be obtained before collecting sample. 
l Exploratory blood samples drawn at Cycle 1 Day 1 predose and 6-8 hours postdose, Cycle 1 Days 18-21 predose, and EOT Visit for future analysis of circulating biomarkers.  For subjects receiving 
study drug under the QD 7/28 days or QD 3/14 days schedules, the blood sample collection on Cycle 1 Days 18-21 is not required. 
m Milademetan is administered per protocol at the clinical site at the indicated visit days.  Subjects in the alternative dosing schedules will receive milademetan according to their assigned schedule (QD 
7/28 days or QD 3/14 days). 
n Pharmacokinetic samples will be collected predose at the indicated visit days (Cycle 1 Days 1, 2, 8, 15, 18-21 and Cycle 2 Day 1) and as detailed in Table 9.1.  Subjects will be instructed not to take 
their dose until after sample has been collected on clinic days.  Additional PK samples will be collected at the indicated time points.  On Cycle 1 Day 8, a predose PK sample will be collected, and if 
tumor biopsy is performed, one additional PK sample will be taken right before (-1 hour) the tumor biopsy.  For subjects receiving study drug under the QD 7/28 days or QD 3/14 days schedules, PK 
sample collection on Cycle 1 Days 18-21 is not required.  The window for PK sample collection will be ± 15% unless otherwise specified in Section 9.1.  Based on the PK profile established from the 
initial subjects treated in the study, PK sample collection time points may be modified upon notification by the Sponsor. 
o Serum for MIC-1 induction will be obtained at the indicated time points (predose on Cycle 1 Days 1, 2, 8, 15, and 18 to 21).  For subjects receiving study drug under the QD 7/28 days or QD 3/14 
days schedules, MIC-1 sample collection on Cycle 1 Days 18-21 is not required. 
p For subjects enrolled per Case 3 (Section 4.1.2.1), an additional sample at Cycle 2 Day 1 predose will be collected. 
q An optional tumor re-biopsy may be performed within 30 days of the last dose of milademetan in subjects who have achieved an initial complete response/partial response or stable disease for at least 
6 months by RECIST v 1.1 or revised IWG criteria to milademetan but later developed progressive disease while on therapy. 


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Table 18.3: 
Schedule of Events Part 2 (Dose Expansion) 
Cyclea 
Pre-
Cycle 
1 
2 
3 
4 and 
Beyond 
Post-
Cycle 
Visit Number 
1 
 
2 
3 
4 
5 
 
6 
7 
 
7b 
8 
9 
10 11 
12 and 
Beyond TBD 
Visit Description 
Screening 
Exam and 1st Dose 
Exam 
Exam 
Exam 
Exam 
Exam 
Exam 
Exam 
Exam 
Exam 
Exam 
Exam EOTb 
Cycle Day(s) 
-14 to 0 
1 
2 
8 
15 
18-21 
1 
2 
8 
15 
1 15 
1 
ND 
Visit Window (days) 
 
± 2 ± 2 
0 
± 2 
 
± 2 ± 2 ± 2 ± 2 
± 2 
± 2 
Time Postdose 
(hours) 
Pred
ose 0.5 1 
2 
3 
4 
6 8 
Pred
ose 
0.5 
1 
2 
3 
4 
6 
8 
Predo
se 
0.
5 
1 
2 
3 
4 
6 
8 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archive tumor sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Adverse events 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X X 
X 
X 
Concomitant 
medications 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X X 
X 
X 
ECOG  
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X X 
X 
X 
Physical examination 
and vital signsd 
X 
X 
@ 
 
 
@ X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X X 
X 
X 
Safety laboratorye 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X X 
X 
X 
Urinalysisf 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Tumor markersg 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
ECG (12-lead)h 
X 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Tumor assessmenti 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


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Table 18.3: 
Schedule of Events Part 2 (Dose Expansion) (Continued) 
Cyclea 
Pre-
Cycle 
1 
2 
3 
4 and 
beyond 
Post-
Cycle 
Visit Number 
1 
 
2 
3 
4 
5 
 
6 
7 
 
7b 
8 
9 
10 11 
12 and 
beyond TBD 
Visit Description 
Screening 
Exam and 1st Dose 
Exam 
Exam 
Exam 
Exam 
Exam 
Exam 
Exam 
Exam 
Exam 
Exam 
Exam EOTb 
Cycle Day(s) 
-14 to 0 
1 
2 
8 
15 
18-21 
1 
2 
8 
15 
1 15 
1 
ND 
Visit Window (days) 
 
± 2 ± 2 
0 
± 2 
 
± 2 ± 2 ± 2 ± 2 
± 2 
± 2 
Time postdose 
(hours) 
Pred
ose 0.5 1 
2 
3 
4 
6 8 
Pred
ose 
0.5 
1 
2 
3 
4 
6 
8 
Predo
se 
0.
5 
1 
2 
3 
4 
6 
8 
 
 
Tumor biopsyj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx blood samplek 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory blood 
samplel 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Milademetan 
administration in 
clinicm 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X X 
X 
PK blood samplen 
X 
X X X X X X X X 
X 
X 
X 
X 
X X X X X X 
X 
X 
X X X X X X 
Xp 
 
MIC-1 serum sampleo 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense milademetan 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X X 
X 
Pill diaries 
dispensed/reviewed 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X X 
X 
X 
Optional tumor re-
biopsy  
 
 
Xq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xt 
DLBCL = diffuse large B-cell lymphoma; DLT = dose-limiting toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; 
FDG-PET = (18F) fluorodeoxyglucose-positron emission tomography; IWG = International Working Group; MIC-1 = macrophage inhibitory cytokine-1; ND = not determined; 
PGx = pharmacogenomic; PK = pharmacokinetic(s); QD = once daily; RECIST = Response Evaluation Criteria in Solid Tumors; TBD = to be determined 
Note: The End-of-Study Follow-up will occur 30 (± 2) days after the last administration of milademetan.  If the subject begins another form of anticancer therapy before the end of the 30 (±2)-day 
period, every effort will be made to complete all the End-of-Study assessments prior to commencing the new therapy. 
a Each cycle will last 28 days.  Cohort safety assessment for DLTs will be performed after Day 28 of Cycle 1. 


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b End-of-Treatment Visit will occur 30 (± 2) days after the last administration of milademetan.  If the subject begins another form of anticancer therapy before the end of the 30 (±2)-day period, every 
effort will be made to complete all the End-of-Treatment assessments prior to commencing the new therapy.  If there is an abnormality in need of monitoring beyond the End-of-Treatment Visit, 
subjects will be followed until resolution or confirmed stability of the abnormality. 
c Pregnancy test will be performed in female subjects of childbearing potential at screening, Cycle 3 Day 1, and End-of-Treatment Visit. 
d Physical examination including vital signs will be performed on visit days indicated by X.  Height and weight will be recorded at Screening and End-of-Treatment Visits.  Weight will be recorded at 
all other visits.  Vital signs will be performed on visit days indicated by X or @. 
e Safety laboratory samples for Day 1 predose (complete blood count with differential and reticulocyte counts, serum chemistry, urinalysis, and coagulation profile) can be collected within 72 hours 
before the first dose.  Creatinine clearance will be calculated at screening.   
f Urinalysis will be performed for the indicated visits up to Cycle 3 Day 1 and at End-of-Treatment Visit. 
g Tumor markers will be obtained as appropriate for the tumor type at each cycle. 
h Twelve-lead ECGs (in triplicate) will be measured after the subject has rested in a recumbent position for 5 minutes or more.  ECGs will be performed predose except at additional 2 hours postdose on 
Day 1 and Day 2.  Procedure window is ± 1 hour.   
i Tumor assessment by physical examination and RECIST v 1.1 or revised IWG criteria will be performed at baseline within 4 weeks of the first dose of milademetan, and after every 2 cycles of 
treatment for the first 8 cycles and then every 3 cycles thereafter (ie, at start of Cycles 3, 5, 7, and 9, then Cycles 12, 15, etc.).  Pre-treatment FDG-PET scans will be performed in all subjects with 
DLBCL under fasting conditions at baseline within 4 weeks of the first dose of milademetan.  In subjects with DLBCL that are FDG-PET avid, FDG-PET scans will be performed every 2 cycles of 
treatment for the first 8 cycles and then every 3 cycles thereafter (ie, at start of Cycles 3, 5, 7, and 9, then Cycles 12, 15, etc.).  Bone marrow will be assessed at baseline by aspirate and/or biopsy per 
the investigator’s decision.  If positive, bone marrow assessments may be repeated with the subsequent tumor assessment. 
j Mandatory pre-treatment tumor biopsies will be obtained by skin punch biopsies (for melanoma), Tru-cut technique, or core needle biopsies under imaging guidance at baseline. 
k Informed consent specifically allowing optional PGx testing must be obtained before collecting sample. 
l Exploratory blood samples drawn at Cycle 1 Day 1 predose and 6-8 hours postdose, Cycle 1 Days 18-21 predose, and End-of-Treatment Visit for future analysis of circulating biomarkers.  
m Milademetan is administered per protocol at the clinical site at the indicated visit days.  If an alternative dosing schedule than QD 21/28 is used for dose expansion, the subjects will receive 
milademetan according to their assigned schedule (eg, QD 3/14 days). 
n Pharmacokinetic samples will be collected predose at the indicated visits (Cycle 1 Days 1, 2, 8, 15, 18-21 and Cycle 2 Day 1) and as detailed in Table 9.1.  Subjects will be instructed not to take their 
dose until after sample has been collected on clinic days.  Additional PK samples will be collected at the indicated time points.  On Cycle 1 Day 8, a predose PK sample will be collected, and if tumor 
biopsy is performed, one additional PK sample will be taken right before (-1 hour) the tumor biopsy.  The window for PK sample collection will be ± 15% unless otherwise specified in Section 9.1.  
Based on the PK profile established from the initial subjects treated in the study, PK sample collection time points may be modified upon notification by the Sponsor. 
o Serum for MIC-1 induction will be obtained at the indicated time points (predose on Cycle 1 Days 2, 8, 15, and 18-21). 
p Cycle 1 Day 8 (± 2 days) requested post-treatment re-biopsy should be obtained 6 hours postdose (± 2 h). 
q An optional tumor re-biopsy may be performed within 30 days of the last dose of milademetan in subjects who have achieved an initial complete response/partial response or stable disease for at least 
6 months by RECIST v 1.1 or revised IWG criteria to milademetan but later developed progressive disease while on therapy. 


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18.7. 
Extension Phase 
18.7.1. 
Extension Phase Synopsis 
Objective of the Extension 
Phase: 
The primary objective of the Extension Phase is to allow 
continuation of milademetan treatment for those subjects in the 
milademetan Phase 1 study who have tolerated the drug and 
whose disease has not progressed (ie, stable disease [SD] or 
better) at least 6 months after enrollment is completed in both 
parts. 
Design of the Extension Phase: This is an open-label, nonrandomized extension phase of the 
main study phase, which is designed to allow subjects who have 
tolerated milademetan and demonstrated clinical benefit (SD or 
better) at the time of study closure during the main study phase 
to continue with milademetan monotherapy. 
Subjects will continue with the same dose of milademetan 
monotherapy treatment as in the main study phase until they 
commence new cancer therapy, experience unacceptable 
toxicity, withdraw consent, or have progressive disease. 
If study drug is withheld for toxicity, periodic visits should 
continue to occur as clinically indicated.  These visits should 
include any procedures needed to ensure subject safety. 
Subjects enrolled in the Extension Phase will be assessed as 
outlined in Table 18.4.   
Data collected will be recorded in the individual, 
subject-specific electronic case report form (eCRF).  The extent 
or frequency of data collection into the eCRFs may be reduced 
for the Extension Phase. 
Duration of the Extension 
Phase: 
The start of the Extension Phase is at least 6 months after 
enrollment is completed in both Part 1 and Part 2.  Subjects who 
are receiving clinical benefit (SD or better) and have tolerated 
milademetan will continue to receive the drug.  It is not possible 
to predict the duration of the Extension Phase because subjects 
may continue treatment until disease progression, unacceptable 
toxicity, starting of new cancer therapy, or withdrawal of 
consent. 
Subject Eligibility: 
Subjects must have tolerated milademetan and demonstrated 
clinical benefit (SD or better) at the time of closure of the main 
study phase (Part 1 and Part 2) in order to be eligible for this 
extended use phase of the study. 


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Safety Evaluations: 
Safety evaluations include adverse events, serious adverse 
events, clinical laboratory evaluations, physical examinations, 
vital signs, as needed.  ECGs may be done at investigator 
discretion, as clinically indicated. 
Dose: 
Subjects who participate in the Extension Phase will continue to 
take milademetan at the same dose as was taken in the main 
study phase. 
Statistical Analyses: 
Data collected during the Extension Phase will be listed and 
appended to the Clinical Study Report. 
 


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Table 18.4: 
Schedule of Events (Extension Phase) 
Assessment 
All Cycles, Day 1a 
End-of-Treatment Visitb 
Visit Window (Days) 
28 Days ± 3 Days from Day 1 of 
Previous Cyclec 
30 to 45 Days After Last Dose 
Physical examination 
X 
X 
Vital signsd 
X 
X 
Adverse events 
X 
X 
CBC (with differential and 
platelet count)  
Xd 
X 
Serum chemistries  
Xd 
X 
Milademetan administratione 
X 
 
Tumor assessment  
Xf 
 
CBC = complete blood count; TEAE = treatment-emergent adverse event 
a Assessments and laboratory tests indicated on Day 1 will occur before administration of milademetan.   
b End-of-Treatment Visit will occur 30 to 45 days after the last administration of milademetan in the Extension 
Phase.  If there is a clinically significant laboratory abnormality in need of monitoring beyond the 
End-of-Treatment Visit, subjects will be followed until resolution of the abnormality or until it is considered 
stable. 
c For subjects who completed more than 1 year of study drug with continued clinical benefit and no ongoing 
clinically significant TEAEs or at risk of clinically significant TEAEs in the judgment of the investigator, the 
subsequent visits every 3 cycles and additional visits as clinically indicated are allowed. 
d Clinical safety laboratory tests include hematology, chemistry, CBC, and platelet count.  The tests described in 
Section 10.8 will be conducted on Day 1 of all cycles and as clinically indicated by the investigator.  The subject’s 
weight will be recorded as part of the vital signs assessment 
e Milademetan is to be administered at the same dosing schedule that the individual subject was using as during the 
main study phase.  
f Tumor assessment will be performed every 3 cycles.