Conditions: Gynecologic Neoplasms Epithelial Ovarian Cancer
Keywords: PLX2853 Ovarian Cancer ARID1A Gynecological Malignancies Carboplatin
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 37
Healthy volunteers: no

Brief summary:
The purpose of this research study is to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of the investigational drug PLX2853 in Advanced Gynecological Malignancies with a Known ARID1A Mutation and PLX2853/Carboplatin Combination Therapy in Platinum-Resistant Epithelial Ovarian Cancer.

Detailed description:

Arms:
arm 1: Subjects with ARID1A mutation-positive advanced gynecological malignancies arm 2: Subjects with platinum-resistant EOC arm 3: Subjects with platinum-resistant EOC arm 4: Subjects with platinum-resistant EOC

Interventions: intervention 1: PLX2853 intervention 2: Carboplatin
Intervention descriptions: intervention 1: PLX2853 tablets intervention 2: Carboplatin IV injection, 5 mg•min/mL

Protocol document:
Prot_SAP_001.pdf: 
PLX2853 
Protocol PLX124-03/Amendment 2 
CONFIDENTIAL/PROPRIETARY 
1 
Plexxikon Inc. 
CLINICAL STUDY PROTOCOL 
Protocol Number: 
PLX124-03 
Title: 
A Multicenter, Open-Label, Parallel, Phase 2a Study of 
PLX2853 Monotherapy in Advanced Gynecological 
Malignancies with a Known ARID1A Mutation and 
Phase 1b/2a Study of PLX2853/Carboplatin Combination 
Therapy in Platinum-Resistant Epithelial Ovarian Cancer 
Indication: 
Advanced gynecological malignancies with a known ARID1A 
mutation and platinum-resistant epithelial ovarian cancer 
Phase: 
2a (PLX2853 monotherapy), 1b/2a (PLX2853 + carboplatin) 
Sponsor: 
Plexxikon Inc. 
329 Oyster Point Boulevard 
South San Francisco, CA 94080, USA 
Telephone:  (510) 647-4000 
IND Number: 
147,651 
EudraCT Number: 
Not Applicable 
Therapeutic Area: 
Antineoplastic Agent 
Medical Monitor: 
Athanasios Tsiatis, MD 
Telephone:  (510) 647-4142 
Mobile:  (510) 590-6443 
Email:  atsiatis@plexxikon.com 
Protocol History: 
 
Date/Version: 
16 April 2020/Original 
29 May 2020/Amendment 1 
03 May 2021/Amendment 2 
Confidentiality Statement 
This document contains information that is confidential and proprietary to the Sponsor. This information is being 
provided to you solely for the purpose of evaluating and/or conducting a clinical study for the Sponsor. You may 
disclose the contents of this document only to study personnel under your supervision, institutional review boards 
(IRBs)/independent ethics committees (IECs), or duly authorized representatives of regulatory agencies for this 
purpose under the condition that they maintain confidentiality. The contents of this document may not be used in 
any other clinical study, disclosed to any other person or entity, and/or published without the prior written 
permission of the Sponsor. The foregoing shall not apply to disclosure required by any regulations; however, you 
will give prompt notice to the Sponsor of any such disclosure. All other nonpublic information provided by the 
Sponsor and any information that may be added to this document also is confidential and proprietary to the Sponsor 
and must be kept in confidence in the same manner as the contents of this document. 
NCT04493619


PLX2853
Protocol
PLX124-03/Amendment
2
SPONSOR SIGNATURE
Protocol PLX124-03:
A Multicenter, Open-Label, Parallel, Phase 2a Study of PLX2853
Monotherapy in Advanced Gynecological
Malignancies with a
Known
ARIDIA
Mutation and Phase 1b/2a Study of
PLX2853/Carboplatin Combination Therapy in Platinum-Resistant
Epithelial Ovarian Cancer
Plexxikon Inc.
329 Oyster Point Boulevard
South San Francisco, CA 94080, USA
Telephone: (510) 647-4000
Sponsor:
I have read and approved this protocol.
2
Plexxikon Inc.
CONFIDENTIAL/PROPRIETARY


PLX2853 
 
Protocol PLX124-03/Amendment 2 
CONFIDENTIAL/PROPRIETARY 
3 
 
Plexxikon Inc. 
INVESTIGATOR AGREEMENT AND SIGNATURE 
Protocol PLX124-03: 
A Multicenter, Open-Label, Parallel, Phase 2a Study of PLX2853 
Monotherapy in Advanced Gynecological Malignancies with a 
Known ARID1A Mutation and Phase 1b/2a Study of 
PLX2853/Carboplatin Combination Therapy in Platinum-Resistant 
Epithelial Ovarian Cancer 
Sponsor: 
Plexxikon Inc. 
329 Oyster Point Boulevard 
South San Francisco, CA 94080, USA 
Telephone:  (510) 647-4000 
I have read and approved this protocol. My signature, in conjunction with the signature of the 
Sponsor, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Council on Harmonisation Guideline for Good Clinical Practice (GCP), the 
Code of Federal Regulations, and the ethical principles that have their origins in the Declaration 
of Helsinki. I agree to inform all who assist me in the conduct of this study of their 
responsibilities and obligations. 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations. 
 
 
Principal Investigator Signature 
 
Date 
 
 
 
 
 
 
Principal Investigator Name and Title (print) 
 
 
 
 
 
 
Investigational site or name of institution and location (printed) 


PLX2853 
 
Protocol PLX124-03/Amendment 2 
CONFIDENTIAL/PROPRIETARY 
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Plexxikon Inc. 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
SPONSOR SIGNATURE ..............................................................................................................2 
INVESTIGATOR AGREEMENT AND SIGNATURE .............................................................3 
TABLE OF CONTENTS ..............................................................................................................4 
LIST OF TABLES ...............................................................................................................8 
LIST OF FIGURES .............................................................................................................8 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS .................................................9 
PROTOCOL SYNOPSIS ............................................................................................................12 
SYNOPSIS TABLE 1:  PHASE 2A PLX2853 MONOTHERAPY SCHEDULE 
OF EVENTS ..........................................................................................................26 
SYNOPSIS TABLE 2:  PHASE 1B PLX2853 + CARBOPLATIN DOSE 
ESCALATION SCHEDULE OF EVENTS ..........................................................30 
SYNOPSIS TABLE 3:  PHASE 2A PLX2853 + CARBOPLATIN DOSE 
EXPANSION SCHEDULE OF EVENTS.............................................................34 
1.0 
BACKGROUND AND STUDY RATIONALE .............................................................37 
1.1 
Background ............................................................................................................37 
1.2 
Evidence of a Role for BET Proteins in Solid Tumors ..........................................37 
1.3 
Role of BET Inhibitors in Platinum-resistant Epithelial Ovarian Cancer ..............38 
1.4 
Role of BET Inhibitors in Advanced Gynecological Malignancies with a 
Known ARID1A Mutation ....................................................................................39 
1.5 
PLX2853 ................................................................................................................40 
1.5.1 
Nonclinical Pharmacology ....................................................................40 
1.5.2 
Nonclinical Pharmacokinetics ...............................................................43 
1.5.3 
Toxicology Studies of PLX2853 ...........................................................45 
1.5.4 
Proposed Starting Dose for Study PLX124-03 .....................................49 
1.6 
Study Rationale ......................................................................................................49 
1.7 
Potential Risks and Benefits ..................................................................................50 
1.8 
Previous Human Experience ..................................................................................51 
1.8.1 
Interim Results of Study PLX124-01 ....................................................51 
1.8.2 
Interim Results of Study PLX124-02 ....................................................53 
2.0 
STUDY OBJECTIVES ....................................................................................................55 
2.1 
Phase 2a (PLX2853 Monotherapy) ........................................................................55 
2.2 
Phase 1b (PLX2853 + Carboplatin Combination) .................................................55 
2.3 
Phase 2a (PLX2853 + Carboplatin Combination) .................................................55 
2.4 
All Phases...............................................................................................................55 
3.0 
STUDY DESIGN ..............................................................................................................56 


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3.1 
Overview of Study Design .....................................................................................56 
3.1.1 
Phase 2a PLX2853 Monotherapy Design .............................................57 
3.1.2 
Phase 1b/2a PLX2853 + Carboplatin Combination ..............................59 
3.2 
Number of Subjects................................................................................................61 
3.3 
Duration of Study ...................................................................................................61 
3.4 
Study Endpoints .....................................................................................................62 
3.4.1 
Primary Endpoints .................................................................................62 
3.4.2 
Secondary Endpoints .............................................................................62 
3.4.3 
Exploratory Endpoints ..........................................................................63 
3.5 
Randomization .......................................................................................................63 
4.0 
STUDY POPULATION ..................................................................................................64 
4.1 
Inclusion Criteria ...................................................................................................64 
4.2 
Exclusion Criteria ..................................................................................................66 
4.2.1 
Effective Methods of Contraception .....................................................68 
5.0 
STUDY TREATMENT ...................................................................................................70 
5.1 
Investigational Product ..........................................................................................70 
5.1.1 
PLX2853 ...............................................................................................70 
5.1.2 
Carboplatin ............................................................................................70 
5.2 
Study Drug Administration ....................................................................................71 
5.2.1 
PLX2853 Administration ......................................................................71 
5.2.2 
Carboplatin Administration ...................................................................71 
5.2.3 
Dosing on Pharmacokinetic Sample Collection Days ..........................71 
5.2.4 
Effect of Food on PLX2853 ..................................................................72 
5.3 
Dose Escalation (Phase 1b PLX2853 + Carboplatin Only) ...................................72 
5.3.1 
Dose Escalation Rules ...........................................................................73 
5.4 
Concomitant Medications (and Procedures) ..........................................................74 
5.5 
Precautions and Restrictions ..................................................................................75 
5.6 
Management of Clinical Events .............................................................................75 
5.7 
Blinding and Unblinding........................................................................................75 
5.8 
Preparation, Reconstitution, and Dispensation ......................................................76 
5.9 
Packaging and Labeling .........................................................................................76 
5.10 
Storage, Handling, and Accountability ..................................................................76 
5.11 
Other Protocol-specified Materials ........................................................................76 
6.0 
DOSE-LIMITING TOXICITIES AND DOSE MODIFICATIONS ...........................77 
6.1 
Definitions of Dose-limiting Toxicity ...................................................................77 
6.2 
Dose Modification Guidelines ...............................................................................78 


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7.0 
STUDY CONDUCT AND ASSESSMENTS .................................................................83 
7.1 
Study Conduct ........................................................................................................83 
7.1.1 
Study Personnel and Organizations ......................................................83 
7.1.2 
Study Committee ...................................................................................83 
7.1.3 
Arrangements for Recruitment of Subjects ...........................................84 
7.1.4 
Treatment Group Assignments .............................................................84 
7.1.5 
Withdrawal of Subjects from Drug Treatment and Study; Subject 
Replacement ..........................................................................................84 
7.1.6 
Study Compliance .................................................................................85 
7.1.7 
Enrollment of Subjects ..........................................................................85 
7.1.8 
Protocol Deviations ...............................................................................85 
7.1.9 
Disease Assessment ..............................................................................86 
7.1.9.1 
Fresh Tumor Biopsy ................................................................87 
7.1.10 
Pharmacokinetic and Pharmacodynamic Assessments .........................87 
7.1.10.1 
Pharmacokinetic Assessments .................................................88 
7.1.10.2 
Biomarker Samples and Pharmacogenomics ...........................88 
7.1.11 
Safety Assessments ...............................................................................90 
7.1.11.1 
Medical and Medication History .............................................90 
7.1.11.2 
ECOG Performance Status Assessment ...................................90 
7.1.11.3 
Physical Examinations .............................................................90 
7.1.11.4 
Vital Signs ................................................................................90 
7.1.11.5 
Height and Weight ...................................................................90 
7.1.11.6 
Electrocardiogram ....................................................................90 
7.1.11.7 
Safety Laboratory Assessments ...............................................91 
7.1.12 
Pregnancy Testing .................................................................................92 
8.0 
STATISTICAL AND QUANTITATIVE ANALYSES ................................................93 
8.1 
Randomization and Stratification ..........................................................................93 
8.2 
Definitions and Populations for Analysis ..............................................................93 
8.2.1 
Evaluable Populations ...........................................................................93 
8.3 
Procedures for Handling Missing, Unused, and Spurious Data.............................93 
8.4 
General Methodology ............................................................................................93 
8.5 
Baseline Comparisons ............................................................................................93 
8.6 
Efficacy Analysis ...................................................................................................93 
8.6.1 
Phase 1b (Dose Escalation) (PLX2853 + Carboplatin) ........................93 
8.6.2 
Phase 2a (PLX2853 Monotherapy) and Phase 2a (PLX2853 + 
Carboplatin Combination) .....................................................................94 
8.6.2.1 
Primary Efficacy Analysis .......................................................94 


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8.6.2.2 
Secondary Efficacy Analyses ..................................................94 
8.7 
Pharmacokinetics, Pharmacodynamics, Biomarkers .............................................95 
8.7.1 
Pharmacokinetic Analysis .....................................................................95 
8.7.2 
Pharmacodynamic and Other Biomarker Analysis ...............................95 
8.8 
Safety Analysis ......................................................................................................95 
8.9 
Interim Analysis .....................................................................................................96 
9.0 
ASSESSMENT OF SAFETY AND ADVERSE EVENTS ...........................................97 
9.1 
Definitions..............................................................................................................97 
9.1.1 
Adverse Event Definition ......................................................................97 
9.1.2 
Serious Adverse Event Definition .........................................................98 
9.2 
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events ......................................................................................................98 
9.3 
Timing of Evaluation of Adverse Events and Serious Adverse Events...............100 
9.3.1 
Adverse Events of Special Interest .....................................................100 
9.3.2 
Worsening of Cancer ..........................................................................101 
9.3.3 
Overdose .............................................................................................101 
9.4 
Monitoring of Adverse Events and Period of Observation ..................................101 
9.5 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ..102 
10.0 
ADMINISTRATIVE REQUIREMENTS ....................................................................103 
10.1 
Good Clinical Practice .........................................................................................103 
10.2 
Data Quality Assurance .......................................................................................103 
10.3 
Electronic Case Report Form Completion ...........................................................103 
10.4 
Study Monitoring .................................................................................................103 
10.5 
Ethical Considerations .........................................................................................104 
10.6 
Subject Information and Informed Consent .........................................................104 
10.7 
Subject Confidentiality ........................................................................................104 
10.8 
Investigator Compliance ......................................................................................104 
10.9 
On-site Audits ......................................................................................................105 
10.10 Investigator and Site Responsibility for Drug Accountability .............................105 
10.11 Product Complaints ..............................................................................................105 
10.12 Closure of the Study.............................................................................................105 
10.13 Record Retention .................................................................................................106 
10.14 Publication and Use of Information .....................................................................106 
11.0 
REFERENCES ...............................................................................................................108 
APPENDIX 1: 
LABORATORY TESTS .............................................................................114 
APPENDIX 2: 
EXAMPLES OF STRONG CYP3A4 AND/OR 2C8 INHIBITORS 
AND INDUCERS ...........................................................................................................117 


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APPENDIX 3: 
RECIST CRITERIA VERSION 1.1 ..........................................................118 
APPENDIX 4: 
DRUGS CLEARLY ASSOCIATED WITH THE RISK OF 
TORSADES DE POINTES (TDP) AND QT PROLONGATION ............................130 
APPENDIX 5: 
ECOG PERFORMANCE STATUS ...........................................................131 
APPENDIX 6: 
EVALUATION OF PROGRESSION ACCORDING TO CA-125 .........132 
 
LIST OF TABLES 
Table 1: 
Kd Values of PLX2853 for Binding to the 8 Bromodomains from 4 BET 
Proteins ..................................................................................................................41 
Table 2: 
Antitumor Effects of PLX2853 in Ovarian Cancer Cell Lines ..............................42 
Table 3: 
Overview of PLX2853 Toxicology Program .........................................................46 
Table 4: 
Study PLX124-01:  Geometric Means of Pharmacokinetic Parameters at 
Day 1 and Day 15 (Steady-state) After Oral Administration of 5, 10, 20, 40, 
80, 120, and 120 (20 mg strength tablet) mg/day PLX2853 to Solid Tumor 
Patients ...................................................................................................................52 
Table 5: 
Study PLX124-02:  Geometric Means of Pharmacokinetic Parameters at 
Day 1 and Day 15 (Steady-state) After Oral Administration of 20, 40, 80, and 
80 (20 mg strength tablet) mg/day PLX2853 to AML Patients .............................54 
Table 6: 
Provisional Dose Escalation Plan ..........................................................................59 
Table 7: 
Recommended PLX2853 Dose Modifications ......................................................80 
Table 8: 
Contact Information ...............................................................................................83 
Table 9: 
Approximate Blood Sample Volumes Collected ...................................................92 
Table 10: 
Time Point Response:  Subjects with Targets (± Non-target) Disease ................127 
Table 11: 
Time Point Response:  Subjects with Non-target Disease Only ..........................127 
Table 12: 
Best Overall Response When Confirmation of CR and PR Required .................128 
Table 13: 
Definition of Progression After First-Line Therapy in Ovarian Cancer as 
Proposed by the GCIG .........................................................................................133 
 
LIST OF FIGURES 
Figure 1: 
Study PLX124-01:  PLX2853 Pharmacodynamic Effect on Peripheral 
Blood Cells.............................................................................................................53 
Figure 2: 
Overview of Study PLX124-03 .............................................................................56 
 


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation or Term 
Definition/Explanation 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve from time zero extrapolated to infinite time 
AUC0-24 
area under the concentration-time curve from time zero to 24 hours postdose 
AUC0-last 
area under the concentration-time curve from time zero to time of last observed 
concentration hours postdose 
BCRP 
breast cancer resistance protein 
BDC 
bile duct-cannulated 
BID 
twice daily 
BET 
bromodomain and extra terminal domain  
BRD 
bromodomain-containing protein 
CA-125 
cancer antigen 125 
CI 
confidence interval 
CI90 
90% confidence interval 
CL 
clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum observed concentration 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CxDx 
Cycle x Day x 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOC 
epithelial ovarian cancer 
ESI+ 
electrospray ionization in positive ion mode 
FU 
follow-up 


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Abbreviation or Term 
Definition/Explanation 
GCP 
Good Clinical Practice 
GERD 
gastroesophageal reflux disease 
GFR 
glomerular filtration rate 
GLP 
Good Laboratory Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HGSOC 
high-grade serous ovarian cancer 
HNSTD 
highest non-severely toxic dose 
HPLC 
high performance liquid chromatography 
HRD 
homologous recombination deficiency 
IBW 
ideal body weight 
IC 
inhibitory concentration 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
intravenous, intravenously 
Kd 
dissociation constant 
LC/MS/MS 
liquid chromatography tandem mass spectrometry 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
N/A 
not applicable 
NCI 
National Cancer Institute  
NGS 
next generation sequencing 
NOAEL 
no-observed-adverse-effect level 
NRG1 
neuregulin-1 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
OCCC 
ovarian clear cell carcinoma 
ORR 
overall response rate 
OS 
overall survival 
PARP 
poly-(ADP-ribose) polymerase 
PD 
progressive disease 
PDx 
pharmacodynamic 
PFS 
progression-free survival 
PG 
pharmacogenomics 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PR 
partial response 
QD 
once daily 


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Abbreviation or Term 
Definition/Explanation 
QD-5/2 
5-day on, 2-day off intermittent dosing 
QTc 
QT interval corrected 
QTcF 
QT interval corrected using Fridericia’s equation 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SD 
stable disease 
SWI/SNF 
switch/sucrose non-fermentable 
T1/2 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TGI 
tumor growth inhibition 
Tmax 
time to maximum observed concentration 
ULN 
upper limit of normal 
US 
United States 
UV 
ultraviolet 
 


PLX2853 
 
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PROTOCOL SYNOPSIS 
Title: 
A Multicenter, Open-Label, Parallel, Phase 2a Study of PLX2853 Monotherapy in 
Advanced Gynecological Malignancies with a Known ARID1A Mutation and Phase 1b/2a 
Study of PLX2853/Carboplatin Combination Therapy in Platinum-Resistant Epithelial 
Ovarian Cancer 
Sponsor: 
Plexxikon Inc. 
Clinical Phase: 
Phase 2a (PLX2853 monotherapy), Phase 1b/2a (PLX2853 + carboplatin) 
Indications: 
• 
Advanced gynecological malignancies with a known ARID1A mutation (with and 
without PIK3CA, PIK3R1, and/or PTEN mutations) 
• 
Platinum-resistant epithelial ovarian cancer (EOC) (including fallopian tube or primary 
peritoneal cancer) 
Objectives: 
Phase 2a (PLX2853 monotherapy) 
Primary objective: 
• 
To evaluate the efficacy of single-agent PLX2853 in subjects with advanced 
gynecological malignancies with a known ARID1A mutation 
Secondary objectives: 
• 
To further characterize the safety and efficacy of single-agent PLX2853 in subjects 
with advanced gynecological malignancies with a known ARID1A mutation 
• 
To further evaluate the pharmacokinetics (PK) of PLX2853 
Phase 1b (PLX2853 + carboplatin combination) 
Primary objective: 
• 
To evaluate the safety and tolerability of PLX2853 + carboplatin combination 
including dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and 
recommended Phase 2 dose (RP2D) in subjects with platinum-resistant EOC 
Secondary objective: 
• 
To characterize the PK and efficacy of PLX2853 when combined with carboplatin in 
subjects with platinum-resistant EOC 
Phase 2a (PLX2853 + carboplatin combination) 
Primary objective: 
• 
To evaluate the efficacy of PLX2853 + carboplatin combination at the RP2D in 
subjects with platinum-resistant EOC 
Secondary objective: 
• 
To further characterize the safety and PK of PLX2853 when combined with 
carboplatin in subjects with platinum-resistant EOC 
All Phases 
Exploratory objectives: 
• 
To assess biomarkers in peripheral blood cells, tumor cells, and tissue biopsies 
• 
To further evaluate the pharmacodynamics (PDx) of PLX2853 


PLX2853 
 
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Study Design: 
This open-label, multicenter, 2-part study will evaluate in parallel PLX2853 monotherapy 
in subjects with advanced gynecological malignancies with a known ARID1A mutation 
(with and without PIK3CA, PIK3R1, and/or PTEN mutations) and PLX2853 and 
carboplatin combination therapy in subjects with platinum-resistant EOC (including 
fallopian tube or primary peritoneal cancer). The study schema and study design are 
presented below. 
PLX2853 Monotherapy Study Design: 
 
 
 
 
 
 
 
 
 


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PLX2853 + Carboplatin Combination Study Design: 
 
a All carboplatin doses are target AUC of 5 mg•min/mL unless otherwise specified. 
Note:  Alternative scheduling of PLX2853 administration may be evaluated. 
 
Phase 2a (PLX2853 Monotherapy) 
The Phase 2a monotherapy part will evaluate the efficacy, safety, PK, and PDx of 
PLX2853 in subjects with advanced gynecological malignancies with a known ARID1A 
mutation using a Simon’s 2-stage design. ARID1A, PIK3CA, PIK3R1, PTEN, and 
homologous recombination repair mutational status and homologous recombination 
deficiency status will be determined based on historical data for all potential subjects from 
a commercially available next generation sequencing (NGS) panel such as FoundationOne® 
CDx or a local NGS panel performed in a Clinical Laboratory Improvement Amendments 
(CLIA)-certified laboratory. 
The safety lead-in will comprise of 6 subjects who will be enrolled at a dose of 80 mg/day 
and assessed for safety by the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0 and for evidence of DLTs. The rules for 
determining DLT are defined further below. After the safety lead-in has been completed, 
the Study Committee will convene to evaluate safety, PK, and PDx data to determine 
which dose to take forward for the remainder of subjects in Phase 2. Response rate for 
subjects in the safety lead-in will be included in the efficacy analysis for the purpose of the 
Simon’s 2 stage design. 
The starting dose level of PLX2853 will be 80 mg/day. In the absence of a DLT and in 
conjunction with review of the PK and PD data from each cohort by the Study Committee, 
the safety lead-in is planned to occur in the following manner: 
• 
The starting dose of PLX2853 will be 80 mg/day 


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• 
DLTs will be assessed in the first 28-day treatment period/cycle 
After dosing has been completed in this cohort of subjects, safety, PK, and PDx data 
(as applicable) will be reviewed, and any dose modification decisions, if applicable, will be 
made by the Study Committee. If ≥33% DLTs are seen during the initial safety lead-in, the 
Safety Committee will convene to consider a dose reduction. If a dose reduction is deemed 
appropriate, the subjects in the initial safety lead-in will need to be replaced and a repeat 
6 subject safety lead-in will need to be conducted at this lower dose. Dose modification 
decisions will also take into consideration safety information beyond the DLT period from 
all enrolled subjects. If no DLT is observed, the recommended dose for further evaluation 
may be established based on safety, PK, and PDx convenience of dosing in subjects treated 
at that dose. If a DLT is seen in ≥33% of subjects in the safety lead-in then the Study 
Committee will convene to consider alternative dose levels and schedule. 
In order to be DLT evaluable a subject must not have missed more than 25% of study drug 
for reasons other than an adverse event (AE) and must not have missed receiving 
carboplatin within 7 days of Cycle 2 Day 1 (if applicable) for reason other than AE. If a 
subject misses more than 25% of the doses for Cycle 1 (e.g., >7 doses of PLX2853 in 
28 days) during the DLT window period for reasons other than an AE, additional subject(s) 
may be enrolled to provide adequate data for safety assessments. 
PLX2853 PK data will be analyzed for peak concentration (Cmax), area under the plasma 
concentration–time curve (AUC), and accumulation ratio at steady state and compared with 
prior dose levels. Dose adjustments may also require increasing the number of subjects at a 
given dose level as a result of the review of safety, observed or anticipated disease activity, 
and PK data. 
A subset of patients may be studied in the monotherapy part of this trial to assess the effect 
of food on PLX2853 exposure. These subjects will receive a single dose of PLX2853 under 
fed conditions 3 or 4 days prior to Cycle 1 Day 1 and have serial PK samples collected. On 
Cycle 1 Day 1, subjects will commence dosing at the same dose level under fasted 
conditions. 
At the discretion of the Sponsor, an additional Phase 2a monotherapy cohort may be 
enrolled using a Simon’s 2 stage design to evaluate the efficacy, safety, PK, and PDx of 
PLX2853 in subjects with advanced gynecological malignancies with a known ARID1A 
mutation and who do not have known pathogenic mutations in the following genes (unless 
allowed with Medical Monitor approval): 
• 
Mutations or amplifications in PIK3CA 
• 
Mutations or amplifications in PIK3R1 
• 
Mutations or deletions in PTEN 
 
Phase 1b/2a (PLX2853 + Carboplatin Combination) 
The Phase 1b/2a combination part of the study will evaluate the safety, PK, PDx, and 
efficacy of PLX2853 in combination with carboplatin in subjects with platinum-resistant 
EOC. 
In Phase 1b (dose escalation), the safety profile, RP2D/MTD, PK, PDx, and preliminary 
efficacy of PLX2853 (administered orally in 28-day treatment cycles) in combination with 
carboplatin (administered intravenously on Day 1 of each 28-day cycle) will be evaluated. 
Each cohort will be enrolled and assessed using a standard “3+3” design. The rules for 
determining DLTs and dose escalation are defined further below. 
 
 
 
 
 


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The provisional dose escalation plan is detailed as follows: 
Dose Level 
Combination PLX2853 Dose 
(mg/day)a 
Carboplatin Dose 
(mg•min/mL)b 
-2 
20 
AUC 4  
-1 
20 
AUC 5  
1 (Starting Dose) 
40 
AUC 5  
2 
80 
AUC 5  
a Once daily dosing schedule unless otherwise specified. 
b Dosed on Day 1 of each 28-day cycle. 
 
In Phase 1b combination, the starting dose level of PLX2853 will be 40 mg/day plus a 
target AUC of 5 mg•min/mL dose of carboplatin (Cohort 1). In the absence of a DLT in the 
first cycle of treatment and in conjunction with review of the PK and available PDx data 
from each cohort by the Study Committee, dose escalation is planned to occur in the 
following manner: 
• 
DLTs will be assessed in the first treatment cycle (up to carboplatin dosing on Cycle 2 
Day 1). 
• 
The starting dose of PLX2853 will be 40 mg/day (Cohort 1), which is 50% below the 
PLX2853 monotherapy RP2D of 80 mg/day. 
• 
Carboplatin will be administered using a target AUC of 5 mg•min/mL on Day 1 of 
each 28-day treatment cycle per label. Carboplatin must be given within 7 days of 
Cycle 2 Day 1 (delays due to reasons other than toxicity will not be assessed as a 
DLT). 
• 
If Dose Level 1 is not tolerated, Dose Level -1 (20 mg/day) will be investigated. If that 
dose level is intolerable, Dose Level -2 (PLX2853 20 mg/day and carboplatin AUC 
4 mg•min/mL) will be studied. If that dose level is intolerable, the study will be halted. 
• 
In the absence of a DLT, a second cohort with a PLX2853 dose of 80 mg/day will be 
investigated (Cohort 2). 
A minimum of 3 to 4 subjects will be initially enrolled in Cohort 1. If a DLT is observed in 
1 subject in a given cohort, up to 6 subjects will be treated at that dose. If DLTs are 
observed in 2 or more of 6 subjects (or ≥33% of the cohort) at a dose level, the dose at 
which this occurs will be considered intolerable and the MTD will have been exceeded. 
The highest dose level at which 0 of 3 subjects or 0 or 1 of 6 subjects experience a DLT 
will be declared the RP2D. If 3 to 4 subjects were initially evaluated at that dose level, an 
additional 2 to 3 subjects may be enrolled to evaluate for DLTs at that dose level for 
confirmation. Up to 6 additional subjects with a known ARID1A mutation (unless 
otherwise approved by the Medical Monitor) may be treated at the RP2D at the discretion 
of the Sponsor for dose confirmation purposes. 
In order to be DLT evaluable a subject must not have missed more than 25% of study drug 
for reasons other than an AE and must not have missed receiving carboplatin within 7 days 
of Cycle 2 Day 1 (if applicable) for reason other than an AE. If a subject misses more than 
25% of the doses for Cycle 1 (e.g., >7 doses of PLX2853 in 28 days) during the DLT 
window for reasons other than an AE, additional subject(s) may be enrolled to provide 
adequate data for dose escalation decision making. Subjects who do not complete Cycle 1 
for reasons other than drug toxicity may be replaced. Subjects must receive their Cycle 2 
Day 1 carboplatin dose to be considered evaluable unless the reason for missing carboplatin 
is due to an AE. 
Once all ongoing subjects in a dose cohort have been treated for at least 2 cycles and the 
safety and tolerability of that dose level has been established, intra-subject dose escalation 
to that dose level may be permitted for subjects enrolled at lower dose levels who have not 
experienced an unresolved Grade 3 or higher treatment-related toxicity and have completed 


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2 cycles. Any intra-subject dose escalation requires a discussion and agreement with the 
Medical Monitor. 
After dosing has been completed in each cohort, safety, PK, and PDx data (if available) 
will be reviewed, and dose escalation decisions will be made by the Study Committee. 
Dose escalation decisions will also take into consideration safety information beyond the 
DLT period from earlier cohorts. If no DLT is observed, the recommended dose for further 
evaluation may be established based on toxicity, PK, convenience of dosing, and PDx (if 
available) in subjects treated at that dose. Dose escalation will only be permitted if 
adequate safety and tolerability have been demonstrated at the previous lower dose for 
28 days. PLX2853 and carboplatin may not be dose escalated in the same cycle. 
PLX2853 PK data will be analyzed in each dosing cohort for Cmax, AUC, and accumulation 
ratio at steady state and compared with prior dose levels. The number of subjects at a given 
dose level may be increased as a result of the review of safety, observed or anticipated 
disease activity, and PK data. Additional dosing schedules may be studied, such as 
alternate day dosing (e.g., every other day) depending on emerging safety and PK data. 
In Phase 2a (dose expansion), efficacy as well as additional safety, PK, and PDx data of 
PLX2853 in combination with carboplatin at the RP2D dose established in Phase 1b by the 
Study Committee will be obtained using a Simon’s 2-stage design.  
Number of Subjects: Total number of subjects:  up to 85 evaluable subjects 
Phase 2a (PLX2853 monotherapy):  Up to 38 evaluable subjects 
There will be up to 2 Simon’s 2-stage design cohort of up to 38 evaluable subjects with 
ARID1A mutation-positive (with and without PIK3CA, PIK3R1, and/or PTEN mutations) 
advanced gynecological malignancies. The safety lead-in of 6 subjects dosed at the level 
selected for Phase 2a will be included in the group of 12 evaluable subjects for Stage 1. 
Phase 1b (PLX2853 + carboplatin combination):  Up to 21 evaluable subjects 
Approximately 9 to 15 evaluable subjects with platinum-resistant EOC will be enrolled, 
depending on the number of escalation cohorts investigated. Up to 6 additional subjects 
with a known ARID1A mutation (unless otherwise approved by the Medical Monitor) may 
be treated at the RP2D at the discretion of the Sponsor for dose confirmation purposes. 
Phase 2a (PLX2853 + carboplatin combination):  Up to 26 evaluable subjects 
There will be 1 Simon’s 2-stage design cohort of between 12 to 26 evaluable subjects with 
platinum-resistant EOC. 
Inclusion Criteria: 
1. Age ≥18 years at the time of signing informed consent 
2. Histologically or cytologically confirmed diagnosis of 1 of the following, and must 
have measurable disease per Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST v1.1): 
• 
Phase 2a (PLX2853 monotherapy):  Any advanced gynecological malignancy 
(cervical, vaginal, vulvar, uterine, ovarian, fallopian tube, or primary peritoneal) with a 
known ARID1A mutation, that is intolerant to or refractory to all standard therapy 
known to confer clinical benefit. 
• 
Subjects must have tumor accessible for sequential biopsy and be willing to 
provide on-study tumor tissue biopsy (core needle biopsy or excision required). 
Tissue collection must not constitute a significant risk procedure. A significant 
risk procedure is generally considered to be one for which the procedure 
associated absolute risk of mortality or major morbidity in the patient’s clinical 
setting and at the institution completing the procedure is 2% or higher. When 
possible, newly obtained tissue should be collected from a non-target lesion. 
• 
Phase 1b and Phase 2a (PLX2853 + carboplatin combination):  Platinum-resistant 
EOC (including fallopian tube or primary peritoneal cancer). Platinum-resistant is 
defined as disease that may have responded to a platinum-containing chemotherapy 


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regimen, but there is documentation of demonstrated recurrence within 6 months 
following the completion of that platinum-containing regimen. 
OR 
Subjects with platinum-refractory EOC are eligible, provided refractory outcome 
was to second line or later repeated platinum regimen (not first line). Refractory is 
defined as disease that failed to achieve at least a partial response (PR) to a 
platinum-containing regimen (i.e., stable disease [SD] or actual disease 
progression). 
Progressive disease (PD) of EOC following platinum-based therapy can be 
documented by physical examination, computed tomography (CT) scans, or a 
doubling of cancer antigen 125 (CA-125) levels from either 1) upper limit of 
normal (ULN) or 2) most recent nadir value (per the Rustin criteria [Rustin 2011] 
[Appendix 6]). For CA-125 to be used as a criterion for PD, the CA-125 level 
nadir must have been above the ULN. In addition, the CA-125 nadir level must 
have been confirmed by a second measurement at least 1 week after the initial 
measurement. 
• 
Subjects in Phase 2a must have tumor accessible for sequential biopsy 
and be willing to provide on-study tumor tissue biopsy (core needle 
biopsy or excision required). Tissue collection must not constitute a 
significant risk procedure. A significant risk procedure is generally 
considered to be one for which the procedure associated absolute risk of 
mortality or major morbidity in the patient’s clinical setting and at the 
institution completing the procedure is 2% or higher. When possible, 
newly obtained tissue should be collected from a non-target lesion. 
3. Eastern Cooperative Oncology Group Performance Status 0 to 1 
4. Adequate organ function as demonstrated by the following laboratory values. All 
Screening laboratory tests should be performed within 10 days of the first PLX2853 
dose. Subjects must meet the following eligibility criteria prior to dosing: 
• 
Hematological: 
– 
Neutrophils ≥1500/µL 
– 
Platelets ≥100,000/µL 
– 
Hemoglobin ≥9 g/dL (transfusion and erythropoietin not permitted within 
14 days prior to blood draw) 
• 
Renal: 
– 
Estimated glomerular filtration rate (GFR) (Chronic Kidney Disease 
Epidemiology Collaboration [CKD-EPI] creatinine calculation [Appendix 1]) 
≥60 mL/min/1.73 m2 
• 
Hepatic: 
– 
Serum total bilirubin ≤1.5 × ULN 
OR 
– 
Direct bilirubin ≤ULN for subjects with total bilirubin >1.5 × ULN 
Exception for elevated bilirubin secondary to Gilbert’s disease, in which case 
it must be ≤2.5 mg/dL. Confirmation of Gilbert’s diagnosis requires:  elevated 
unconjugated (indirect) bilirubin values; normal complete blood count in 
previous 12 months, blood smear, and reticulocyte count; normal 
aminotransferases and alkaline phosphatase in previous 12 months 
– 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 × ULN 
– 
Gamma-glutamyl transferase ≤3 × ULN 
• 
Coagulation: 


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– 
International normalized ratio ≤1.5 × ULN 
– 
Activated partial thromboplastin time ≤1.5 × ULN 
• 
Chemistry: 
– 
Albumin ≥3.0 g/dL 
5. Women of child bearing potential (defined as any female who has experienced 
menarche and who has not undergone successful surgical sterilization [hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy] or is not postmenopausal) must have 
a negative serum pregnancy test within 7 days prior to taking the first dose of study 
drug and, if sexually active, must agree to use a highly effective method of 
contraception (a contraception method with a failure rate <1% per year) and 
1 additional barrier method from the time of the negative pregnancy test to 90 days 
(for subjects in the United States) or 6 months (for subjects in Canada) after the last 
dose of study drug. Women of non-child bearing potential may be included if they are 
either surgically sterile or have been postmenopausal for ≥1 year. 
6. Except as specified above for organ function, all drug-related toxicity from previous 
cancer therapy must be resolved (to Grade ≤1 or baseline per NCI CTCAE version 5.0) 
prior to study treatment administration (Grade 2: alopecia, hot flashes, decreased 
libido, immune-oncology drug induced hypothyroidism controlled with medication, or 
neuropathy is allowed). 
7. Willingness and ability to provide written informed consent prior to any study-related 
procedures and to comply with all study requirements 
Exclusion Criteria: 
1. Prior exposure to a bromodomain inhibitor, such as OTX-015 or CPI-0610 
2. Ongoing systemic infection requiring treatment with antibiotic, antiviral, or antifungal 
treatment 
3. Autoimmune hemolytic anemia or autoimmune thrombocytopenia 
4. Presence of symptomatic or uncontrolled central nervous system or leptomeningeal 
metastases (Note:  Subjects with stable, treated brain metastases are eligible for this 
study. However, subjects must not have required steroid treatment for their brain 
metastases within 30 days of Screening.) 
5. Red blood cell or platelet transfusion within 14 days of Screening blood draw 
6. Known or suspected allergy to the investigational agent or any agent given in 
association with this study 
7. Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily 
adequate intake of 30 µg (NIH-ODS 2020). (Note:  Subjects who switch from a high 
dose to a dose of 30 µg/day or less are eligible for study entry.) Use of herbal, 
alternative, and food supplements (i.e., PC-Spes, Saw Palmetto, St. John’s Wort, etc.) 
and probiotics must be discontinued before treatment start. Daily multi-vitamin 
(provided it does not contain biotin >30 μg/day), calcium, and Vitamin D are 
permitted. 
8. Use of strong inhibitors and inducers of CYP3A4 and 2C8 (Appendix 2) 
9. Clinically significant cardiac disease, defined as any of the following: 
• Clinically significant cardiac arrhythmias including bradyarrhythmias and/or 
subjects who require anti-arrhythmic therapy (excluding beta blockers or digoxin). 
Subjects with controlled atrial fibrillation are not excluded. 
• Congenital long QT syndrome or subjects taking concomitant medications known to 
prolong the QT interval (drugs with a low risk of QTc prolongation that are needed 
for infection control or nausea may be permitted with approval from the Medical 
Monitor). A list of drugs known to prolong the QT interval and risk of Torsades de 
pointes can be found in Appendix 4. 
• QT interval corrected using Fridericia’s equation (QTcF) ≥470 msec at Screening 
(based on average of triplicate electrocardiograms (ECGs) at baseline) 


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• If the QTc is prolonged in a subject with a pacemaker or bundle branch block, the 
subject may be enrolled in the study if confirmed by the Medical Monitor 
• History of clinically significant cardiac disease or congestive heart failure 
>New York Heart Association Class II. Subjects must not have unstable angina 
(anginal symptoms at rest) or new-onset angina within the last 3 months or 
myocardial infarction within the past 6 months. 
• Uncontrolled hypertension, defined as systolic blood pressure >160 mmHg or 
diastolic blood pressure >100 mmHg that has been confirmed by 2 successive 
measurements despite optimal medical management 
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis, or pulmonary 
embolism within the 3 months before start of study medication (except for 
adequately treated catheter-related venous thrombosis occurring >1 month before 
the start of study medication) 
10. Inability to take oral medication or significant nausea and vomiting, malabsorption, or 
significant small bowel resection that, in the opinion of the Investigator, would 
preclude adequate absorption 
11. Poorly controlled known Type 2 diabetes with HbA1C >7.5% 
12. Non-healing wound, ulcer, or bone fracture 
13. Infection with HIV-1 or HIV-2. Exception: subjects with well-controlled HIV 
(e.g., CD4 >350/mm3 and undetectable viral load) are eligible. 
14. Current active liver disease from any cause, including hepatitis A (hepatitis A virus 
immunoglobulin M positive), hepatitis B (hepatitis B virus [HBV] surface antigen 
positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV 
ribonucleic acid). Subjects with HCV with undetectable virus after treatment are 
eligible. Subjects with a prior history of HBV are eligible if quantitative PCR for HBV 
DNA is negative. Note that elevated levels of biotin may interfere with viral serology 
testing. 
15. Active known second malignancy with the exception of any of the following: 
• Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in 
situ cervical cancer 
• Adequately treated Stage I cancer from which the subject is currently in remission 
and has been in remission for ≥2 years 
• Any other cancer from which the subject has been disease-free for ≥3 years 
16. Major surgery or significant traumatic injury within 28 days prior to Cycle 1 Day 1 
17. Hospitalization for subacute bowel obstruction within 28 days prior to Cycle 1 Day 1 
18. Receipt of anti-cancer therapy prior to Cycle 1 Day 1: 
• Chemotherapy, radiation therapy, or small molecule anti-cancer therapy for the 
treatment of cancer within 14 days or 5 half-lives (whichever is shorter) of Cycle 1 
Day 1 
• Immune therapy or other biologic therapy (e.g., monoclonal antibodies, 
antibody-drug conjugates) for the treatment of cancer within 21 days or 5 half-lives 
(whichever is shorter) of Cycle 1 Day 1 
Subjects can receive a stable dose of bisphosphonates for bone metastases, before and 
during the study as long as these were started at least 28 days prior to treatment with 
study drug. 
19. Subject is participating in any other therapeutic clinical study (observational or registry 
studies are allowed) 
20. Subjects who are pregnant or breast-feeding 


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21. Presence of any other medical, psychological, familial, sociological, or geographic 
condition potentially hampering compliance with the study protocol or would interfere 
with the study endpoints or the subject’s ability to participate. 
Duration of Study: 
Screening: 
• 
Up to 28 days prior to the first dose of study drug 
Treatment Period: 
• 
Daily in 28-day treatment cycles until subject discontinuation or withdrawal or study 
termination 
• 
Subjects participating in the optional Food Effect sub-study will take a single dose of 
PLX2853 3 or 4 days prior to Cycle 1 Day1. 
• 
For subjects enrolled in either the monotherapy or combination therapy cohorts, further 
treatment with either PLX2853 and/or carboplatin will depend on tolerability and 
clinical benefit as described in Section 7.1.5. In general, for subjects receiving the 
combination of PLX2853 + carboplatin, it is estimated that subjects will be treated 
with carboplatin for up to 6 cycles. 
30-day Follow-up (FU) Visit: 
• 
Approximately 30 days after the last dose of study drug or prior to starting any new 
anti-cancer therapy, whichever occurs first. 
Long-term Follow-up: 
• 
Subjects will be followed until death, withdrawal of consent, or loss to follow-up  
according to the following schedule: 
- 
First 2 years after the 30-day FU Visit – Every 3 months 
- 
Third year after the 30-day FU Visit and beyond – Every 6 months 
• 
Survival follow-up can be via clinic visit, phone call to the subject or referring 
physician, or other method deemed appropriate by the site and should assess survival, 
progression, subsequent therapy, and response. 
• 
Any subject with a confirmed response who discontinues treatment for reasons other 
than disease progression will continue to be followed per standard of care and no less 
than every 3 months until documented disease progression, initiation of a new 
anti-cancer treatment, or 1 year from discontinuation of study treatment. Radiographic 
scan data will be collected and if scan data are not available, a scan will be obtained 
every 3 months until 6 months of radiographic follow-up after confirmed response has 
been obtained. 
Test Product, Dose, 
and Mode of 
Administration: 
PLX2853 is formulated as 20 mg strength tablets for oral use. Subjects should fast for at 
least 2 hours before and 1 hour after taking PLX2853, except for PK collection days when 
subjects should fast for at least 8 hours (10 hours on fed dosing day for the optional Food 
Effect sub-study) before taking PLX2853 and 1 hour (4 hours on fed dosing day for the 
optional Food Effect sub-study) after taking PLX2853. During the fasting period, subjects 
may have a low-fat snack (e.g., crackers, dry toast, etc.) if they experience gastrointestinal 
symptoms (e.g., nausea, vomiting, etc.) following dosing. Doses will be taken orally with 
water. PLX2853 should be taken at approximately the same time each day. PLX2853 
should be swallowed whole and not crushed, chewed, or dissolved in water. A dosing 
period of up to 30 minutes is permissible if required by the number of tablets to be taken or 
as convenient for the subject. 
Carboplatin is supplied as a sterile, pyrogen-free 10 mg/mL aqueous solution of 
carboplatin, USP for injection. The NCCN 2018 recommendations should be used for 
carboplatin dosing as follows: 
The Calvert equation should be applied to calculate dosage using a target AUC in 
mg•min/mL:  Carboplatin dose (mg) = (target AUC) × (GFR + 25) 


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Target AUC will be 5 mg•min/mL. With the Calvert equation, the total dose of carboplatin 
is calculated in mg not mg/m2. The GFR should be estimated by calculated creatinine 
clearance (CrCl) using the Cockcroft-Gault equation: 
CrCl (male; mL/min) = (140 – age) × (weight in kg) 
 
 
72 × serum creatinine (mg/dL) 
CrCl (female; mL/min) = 0.85 × CrCl (male) 
The dose of carboplatin for desired exposure (AUC) should be capped to avoid potential 
toxicity due to overdosing. The maximum dose is based on a GFR estimate that is capped 
at 125 mL/min for subjects with normal renal function. Based on the Calvert equation, the 
maximum doses can be calculated as follows: 
Maximum carboplatin dose (mg) = Target AUC (mg•min/mL) × (125 mL/min + 25) 
For a target AUC = 5, the maximum dose is 5 × 150 = 750 mg 
For a target AUC = 4, the maximum dose is 4 × 150 = 600 mg 
For overweight or obese subjects (body mass index ≥25 kg/m2), consider using an adjusted 
body weight:   
Adjusted body weight (kg) = ideal body weight (IBW) + 0.4 × (total body weight – IBW) 
For subjects with abnormally low serum creatinine, including elderly or cachectic subjects, 
consider using a minimum creatinine of 0.7 mg/dL to avoid overestimation of CrCl. 
Once the initial dose of carboplatin is calculated, it does not need to be recalculated for 
subsequent cycles unless the subject is experiencing toxicity and requires dose modification 
to a lower dose of carboplatin. 
Definition of 
Dose-limiting 
Toxicity (DLT) 
DLTs are defined as clinically significant AEs or laboratory abnormalities occurring during 
the first cycle of study drug administration that are at least possibly related to either 
PLX2853 or carboplatin and clearly unrelated to disease progression, concurrent illness, or 
concomitant medication, and that meet one of the following CTCAE v5.0 criteria below. 
DLTs will be evaluated for the monotherapy safety lead-in subjects as well as each 
Phase 1b (PLX2853 + carboplatin) escalation cohort. Toxicities occurring in treatment 
Cycle 2 or later will be reviewed and their impact on subsequent dosing levels and 
frequency assessed. 
In Phase 1b (PLX2853 + carboplatin), there will be a 24-hour delay between the first and 
subsequent subjects enrolled in each dose escalation cohort to maximize the safety of 
enrolled subjects. 
Subjects participating in the optional Food Effect sub-study as well as the monotherapy 
safety lead-in will be DLT evaluable from the date of first dose and the DLT window for 
these patients will be 28 days from C1D1. 
DLTs are defined as follows: 
• 
Hematologic Toxicities 
• 
Grade 4 neutropenia lasting >7 days 
• 
Grade ≥3 febrile neutropenia 
• 
Grade 4 thrombocytopenia 
• 
Grade ≥3 thrombocytopenia lasting >7 days or associated with clinically 
significant bleeding 
• 
Grade 4 anemia 
• 
Non-hematologic Toxicities 
• 
Any dose reduction required during Cycle 1 due to an AE 
• 
Any treatment delay of >7 consecutive days during Cycle 1 due to study drug-
related Grade ≥2 AEs that fail to resolve to baseline or Grade ≤1 
• 
Any case of Hy's law defined as AST or ALT >3 × ULN with concurrent total 
bilirubin >2 × ULN, absence of cholestasis (elevated alkaline phosphatase (ALP) 


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>2 × ULN), and no alternative etiology which can explain the combination of 
increased AST or ALT and total bilirubin, such as viral hepatitis A through E, 
other preexisting or acute liver disease, or another drug capable of causing the 
observed injury 
• 
Any Grade ≥3 increase in AST/ALT (only for subjects without hepatic metastasis 
and with baseline values within normal limits) 
• 
AST/ALT >5 × ULN for ≥14 days or any AST/ALT >8 × ULN (only for subjects 
with hepatic metastasis or with abnormal baseline values) 
• 
Grade 3 nausea, vomiting, or diarrhea that does not resolve to Grade ≤2 in 
≤72 hours 
• 
Any Grade 4 vomiting or diarrhea (life-threatening; urgent medical intervention 
indicated) irrespective of duration 
• 
Any non-clinically significant Grade 3 or higher electrolyte imbalance that does 
not correct to Grade ≤1 in ≤5 days 
• 
Any Grade 3 or Grade 4 clinically significant electrolyte imbalance (life-
threatening; urgent medical intervention indicated) irrespective of duration 
• 
Unless specifically noted in other DLT criteria any Grade ≥3 (AE or laboratory 
abnormality) toxicity that does not resolve to Grade ≤2 within 7 days despite 
maximal medical intervention, except for the following: 
 
Grade 3 neuropathy in subjects with pre-existing Grade 2 neuropathy 
• 
Any other Grade ≥3 toxicity (except those noted above) for which either the 
Principal Investigator or Sponsor deems further dose escalation inappropriate 
• 
Carboplatin Cycle 2 Day 1 dose reduction (AUC not total dose) or carboplatin 
Cycle 2 Day 1 dose interruption for >7 days 
 
An allergic reaction to carboplatin or any AEs associated with the allergic 
reaction during Cycle 1 will not be considered a DLT. The subject will be 
noted as inevaluable and will be replaced. 
Any death not clearly due to underlying disease or an extraneous cause 
A subject who experiences a DLT may remain in the study and continue receiving study 
drug(s) at a lower dose if the Investigator deems the potential benefit outweighs the risk 
and that the subject is not eligible for, and/or interested in, an alternative therapy after 
consultation and agreement with the Medical Monitor. 
AEs occurring in treatment Cycle 2 or later will be collected, analyzed, and discussed with 
the Study Committee to help inform the selection of doses for subsequent study cohorts, 
including the option of dose reduction. If cumulative toxicities are observed requiring dose 
reductions in 1 of 3 or more subjects, dose escalation may be halted and more subjects may 
be treated at that or a lower dose level.  
Pharmacokinetic 
Parameters: 
The PK parameters of PLX2853 will be assessed by measuring the AUC from time zero to 
time of last observed concentration hours postdose (AUC0-last), AUC from time zero 
extrapolated to 24 hours (AUC0-24), AUC from time zero extrapolated to infinite time 
(AUC0-∞), Cmax, time to Cmax (Tmax), terminal elimination half-life (T1/2), and accumulation 
ratio at steady state. 
Dose proportionality following study dosing will be explored by analyzing natural 
log-transformed PK variables, AUC0-24, AUC0-∞, and Cmax, with a linear model including 
the natural log-transformed dose as a covariate.  


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Pharmacodynamic 
Parameters: 
Planned biomarker analyses for PDx include, but are not limited to: 
• 
Gene expression, nucleic acid sequencing, histochemical and/or protein analyses of 
plasma, peripheral blood cells, and/or tumor tissue 
• 
Analysis of homologous recombination deficiency (HRD) status 
Exploratory analysis of biomarker samples may also be performed to learn about the drug 
and disease properties. 
Efficacy 
Parameters: 
Response to treatment will be evaluated using investigator-determined RECIST v1.1 
criteria. 
Disease control rate (DCR) will be calculated as the percentage of subjects with confirmed 
complete response (CR), PR, or SD. Progression-free survival (PFS) will be calculated for 
each subject as the number of days from the first day of PLX2853 treatment (Cycle 1 
Day 1) to the date of the first documented disease progression or date of death from any 
cause, whichever occurs first. Duration of response (DOR) will be calculated for each 
subject with a response as the number of days from the date of first response (PR or CR 
confirmed at least 28 days later) to the date of the first documented disease progression or 
date of death from any cause, whichever occurs first. Overall survival (OS) will be 
calculated for each subject as the number of days from the first day of PLX2853 treatment 
(Cycle 1 Day 1) to the date of death from any cause.  
Safety Parameters: 
Safety variables to be assessed will include assessment of AEs, physical examinations 
(including weight), laboratory test results (hematology, clinical chemistry, coagulation, 
serum inflammation marker, and urinalysis), ECG, and vital signs. 
Endpoints: 
Phase 2a (PLX2853 monotherapy): 
Primary endpoint: 
• 
Overall response rate (ORR) as measured by RECIST v1.1 
Phase 1b (PLX2853 + carboplatin combination): 
Primary endpoint: 
• 
Establish the MTD/RP2D for the combination of PLX2853 + carboplatin 
Phase 2a (PLX2853 + carboplatin combination): 
Primary endpoint: 
• 
ORR as measured by RECIST v1.1 
All Phases: 
Secondary endpoints: 
• 
Incidence of treatment-emergent adverse events, changes in safety parameters, and 
unacceptable toxicities 
• 
DOR 
• 
DCR 
• 
PFS 
• 
OS 
• 
PLX2853 PK parameters following single and repeated dosing 
Exploratory endpoint: 
• 
Analysis of peripheral blood and tumors for dose- and exposure-dependent changes in 
the expression of BET target genes 


PLX2853 
 
Protocol PLX124-03/Amendment 2 
CONFIDENTIAL/PROPRIETARY 
25 
 
Plexxikon Inc. 
Statistical 
Considerations: 
Phase 1b (PLX2853 + carboplatin combination): 
The study will employ a standard 3 + 3 design in order to determine the MTD/RP2D taking 
into consideration safety, PK, and PDx data (if applicable). 
Data will be tabulated and evaluated by descriptive statistics. Statistical analyses for the 
primary objectives will be descriptive only, with no hypothesis testing. Summary tables 
will present results for each dose cohort. Descriptive statistics will be presented for 
continuous variables, and frequencies and percentages will be presented for categorical and 
ordinal variables. 
Response to treatment will be evaluated by investigator-determined response using 
RECIST v1.1 criteria. 
Phase 2a (PLX2853 Monotherapy) and Phase 2a (PLX2853 + carboplatin 
combination): 
The primary objectives of the Phase 2a cohorts of the study are to determine the antitumor 
activity (ORR) of PLX2853 monotherapy or PLX2853 + carboplatin combination. 
Response to treatment will be evaluated using investigator-determined RECIST v1.1 
criteria, with a minimum interval for confirmation of CR and PR of 4 weeks. Each Phase 
2a cohort will enroll up to 26 evaluable subjects using a Simon’s 2-stage design in which 
initially 12 evaluable subjects are enrolled. In the monotherapy cohort, the safety lead in of 
6 subjects dosed at the level selected for Phase 2a will be included in the group of 12 
evaluable subjects for stage 1. If ≥33% DLTs are seen during the initial safety lead in, the 
Safety Committee will convene to consider a dose reduction. If a dose reduction is deemed 
appropriate, the subjects in the initial safety lead in will need to be replaced and a repeat 6 
subject safety lead in will need to be conducted at this lower dose. If 2 or more responses 
are observed in 12 evaluable subjects, another 14 evaluable subjects will be enrolled for a 
total of 26 subjects to that cohort. If 6 or more responses are observed, the study has 80% 
power with alpha of 0.05 to reject the ORR of 10% in favor of the ORR of 30%. 
Recruitment will stop within a cohort if no more than 1 response is observed after the 
initial 12 evaluable subjects have been accrued. ORR will be summarized per cohort along 
with their 95% confidence intervals (CIs). A 2-sided 95% CI will be calculated for the true 
response rate based on the Clopper Pearson method. 
 


PLX2853 
 
Protocol PLX124-03/Amendment 2 
CONFIDENTIAL/PROPRIETARY 
26 
Plexxikon Inc. 
SYNOPSIS TABLE 1:  PHASE 2A PLX2853 MONOTHERAPY SCHEDULE OF EVENTS 
ASSESSMENTS▼ 
PROCEDURE▼ 
SCR1 
C1 
C2 
C3+2 
30-day FU3 
LTFU 
 
STUDY DAY► 
-28 to -1 
-4 or -3 
1 
8 
15 
22 
1 
1 
 
WINDOW (days)► 
 
 
 
± 2 
± 2 
± 2 
+ 3 
± 5 
± 7 
± 14 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
History 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Vital 
Vital signs4 
X 
X23 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X23 
X 
X 
X 
X 
X 
X 
X 
 
Safety 
Physical exam5 
X 
X23 
X6 
X 
X 
X 
X 
X 
X 
 
ECOG 
X 
X23 
X6 
X 
X 
X 
X 
X 
X 
 
12-lead ECG7 
X 
X23 
X 
 
X 
 
X 
X 
X 
 
Lab 
PG sample 
X 
 
 
 
 
 
 
 
 
 
Hematology8 
X1 
X23 
X6 
X 
X 
X 
X 
X 
X 
 
Chemistry9 
X1 
X23 
X6 
X 
X 
X 
X 
X 
X 
 
Coagulation tests10 
X1 
X23 
X6 
X 
X 
X 
X 
X 
X 
 
Tumor markers11 
X1 
X23 
X6 
 
 
 
X 
X 
X 
 
Urinalysis12 
X1 
X23 
X6 
X 
X 
X 
X 
X 
X 
 
Serum c-reactive protein 
X1 
X23 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test 
X1 
 
 
 
 
 
 
 
X13 
 
Hepatitis A/B/C & 
HIV testing14 
X 
 
 
 
 
 
 
 
 
 
PK sample15,16,17 
 
X23 
X 
 
X 
 
X 
X 
X 
 
Biomarker (PDx) blood 
sample15 
 
X23 
X 
 
X 
 
X 
X 
X 
 
Medications, 
Non-drug Treatments, 
Radiotherapy 
Prior treatment 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
X 
 
AE 
AE18 
X 
 


PLX2853 
 
Protocol PLX124-03/Amendment 2 
CONFIDENTIAL/PROPRIETARY 
27 
Plexxikon Inc. 
ASSESSMENTS▼ 
PROCEDURE▼ 
SCR1 
C1 
C2 
C3+2 
30-day FU3 
LTFU 
 
STUDY DAY► 
-28 to -1 
-4 or -3 
1 
8 
15 
22 
1 
1 
 
WINDOW (days)► 
 
 
 
± 2 
± 2 
± 2 
+ 3 
± 5 
± 7 
± 14 
Treatment Response 
Archival tissue sample 
X 
 
 
 
 
 
 
 
 
 
Paired biopsy for 
malignant lesion 
(mandatory)19 
X 
 
 
 
 
 
X 
 
 
 
Response assessment20 
X 
 
 
 
 
 
 
Every 2 
cycles 
 
X22 
Study Treatment 
PLX2853 administration17 
 
X24 
Daily administration for 28 days (full cycle) 
 
 
Low fat meal 
 
X24 
 
 
 
 
 
 
 
 
Study drug compliance 
via diary review and 
accountability21 
 
 
 
X 
X 
X 
X 
X 
X 
 
Survival 
Survival follow-up22 
 
 
 
 
 
 
 
 
 
X22 
30-day FU = 30-day follow-up visit; AE = adverse event; C = cycle; CA-125 = cancer antigen 125; D = day; DLT = dose-limiting toxicity; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; LTFU = long-term follow-up; PDx = pharmacodynamics; PG = pharmacogenomics; PK = pharmacokinetic, SCR = screening 
1 
All Screening laboratory tests should be performed within 10 days of C1D1 unless otherwise specified. Screening serum pregnancy test must be negative within 7 days prior to 
C1D1 for women of child-bearing potential. A complete list of required tests is found in Appendix 1 to the protocol. 
2 
If the subject does not have any ongoing Grade 2 or higher treatment-related AEs and following discussion with the Medical Monitor, subjects on treatment longer than 
12 cycles may be given the option to only have study visits on cycles with a response assessment (every 2 cycles). 
3 
The 30-day FU Visit should occur approximately 30 days after the last dose of PLX2853 or prior to starting any new anti-cancer therapy, whichever occurs first. 
4 
Predose vital signs must be obtained on PK days. On non-PK/non-PDx days, vital signs do not need to be predose and subjects may self-administer PLX2853 at home either 
prior to or after their clinic visit (if applicable). 
5 
Complete physical examination at Screening and 30-day FU only. All other physical examinations may be abbreviated and symptom-directed. 
6 
ECOG Performance Status, symptom-directed physical examination, hematology, chemistry, coagulation, urinalysis, and tumor markers do not need to be repeated if these 
assessments from Screening occurred within 3 days of C1D1 unless a change in status is suspected. Subjects must continue to meet all eligibility criteria that are repeated at 
the time of initiation of C1D1 dosing. Subjects participating in the optional Food Effect sub-study must complete all C1D1 assessments on C1D1, however they are not 
required to reconfirm eligibility. 
7 
All ECGs are predose and single tracings on the specified days and only Screening and predose C1D1 should be done in triplicate (approximately 10 seconds per ECG over a 
5-minute period). Standard 12-lead ECG with QTcF calculation. Fridericia’s correction is required. QTcF = (QT)/3√(RR). For subjects participating in the optional Food 
Effect sub-study, single tracings ECGs should be obtained on C1D-4 or -3 at predose and 0.5, 1, 2, 3, and 5 hours postdose. 
8 
Hematology evaluation must include complete blood count with differential and platelet count. A complete list of required tests is found in Appendix 1 to the protocol. 
9 
Chemistry evaluation must include a complete chemistry panel including liver transaminases and gamma-glutamyl transferase. A complete list of required tests is found in 
Appendix 1 to the protocol. 


PLX2853 
 
Protocol PLX124-03/Amendment 2 
CONFIDENTIAL/PROPRIETARY 
28 
Plexxikon Inc. 
10 Coagulation evaluation must include prothrombin time/international normalized ratio, activated partial thromboplastin time, fibrinogen, d-dimer, and Factor VII. A complete 
list of required tests is found in Appendix 1 to the protocol. 
11 To be performed as per institutional practice guidelines. For subjects with ovarian cancer, obtain the 2 most recent CA-125 levels prior to study entry. 
12 Urinalysis with urine dipstick is sufficient; if there is significant proteinuria, hematuria, or pyuria, a microscopic examination should be obtained. A complete list of required 
tests is found in Appendix 1 to the protocol. 
13 Serum or urine pregnancy test to be collected at the 30-day FU visit. 
14 Serology testing for hepatitis A, B, and C, and HIV should be performed within 28 days of C1D1 if the subject is taking ≤30 µg/day biotin. If the subject is taking >30 µg/day 
biotin, the subject must lower their daily biotin intake to ≤30 µg and wait 14 days before hepatitis A, B, and C serology testing can be performed (elevated levels of biotin may 
interfere with viral serology testing). 
15 
Assessment 
C1D-4 or D-3  
(if applicable) 
C1D1 
C1D15 
C2–4 D1 
C5+ D1 
30-day FU 
PK 
Predose and 0.5, 1, 2, 3, 
and 5 hours postdose 
Predose and 0.5, 1, 2, 3, and 
5 hours postdose (prior to second 
daily dose when applicable) 
Predose and 0.5, 1, 2, 3, and 
5 hours postdose (prior to second 
daily dose when applicable) 
Predose and 1 and 
3 hours postdose 
Predose 
Anytime 
PDx 
Predose and 3 and 5 
hours postdose 
Predose and 3 and 5 hours 
postdose 
Predose and 3 hours postdose 
Predose 
Predose 
Anytime 
 
Note:  All PK samples should be collected at the specified time points ±10 minutes at the 0.5- and 1-hour sample and ±30 minutes at subsequent time points. PK samples 
should be collected after the corresponding ECGs have been obtained. Multiple PDx samples and sample types (e.g., serum, whole blood, plasma) may be collected at a given 
timepoint (detailed sample collection information is provided in the Laboratory Manual). 
16 On PK days where a full PK profile is collected (e.g., C1D-3 or C1D-4 (as applicable) C1D1, C1D15), subjects should fast at least 8 hours (10 hours on fed dosing day for the 
Food Effect sub-study) before dose administration and 1 hour (4 hours on fed dosing days for the Food Effect sub-study) after administration of PLX2853. On other PK 
sample collection days, subject should fast for 2 hours prior to their visit.  During the fasting period, subjects may eat a low-fat snack (e.g., crackers, dry toast, etc.) if they 
experience gastrointestinal issues following dosing. 
Additional samples for PK may be collected if a subject experiences a DLT, serious adverse event, AE of special interest, dose modification, or at the Sponsor’s request. The 
time since the last dose of PLX2853 should be noted. Samples for PK collected for any dose modification should be at predose and 0.5, 1, 2, 3, and 5 hours postdose (prior to 
second daily dose when applicable) within 2 weeks of the modification or at the next scheduled clinic visit, whichever occurs closest to the new dosing regimen. 
17 On non-PK days, subjects should fast at least 2 hours before administration and 1 hour after administration of PLX2853, unless otherwise specified. Subjects should be 
instructed not to take their PLX2853 dose at home on PK or PDx collection days. If alternate day dosing is used, subjects will be instructed on which days to take PLX2853 
(e.g., even or odd numbered days). 
18 AE monitoring occurs both predose and postdose on days when PLX2853 is taken in the clinic. All AEs will be monitored for approximately 30 days after the last dose of 
study drug or prior to starting any new anti-cancer therapy, whichever occurs first. 
19 If the archival tissue was collected within 2 months of Screening, a fresh sample does not need to be collected at Screening. 
20 Radiographic assessment of tumor burden will occur at least approximately every 2 cycles, or more frequently as clinically indicated. Screening assessment of tumor burden 
may be within 28 days of scheduled C1D1. 
21 Collection of completed dosing diary and distribution of new diary to occur at the beginning of each cycle. 


PLX2853 
 
Protocol PLX124-03/Amendment 2 
CONFIDENTIAL/PROPRIETARY 
29 
Plexxikon Inc. 
22 Subjects will be followed until death, withdrawal of consent, or loss to follow-up according to the following schedule: every 3 months for the first 2 years after the 30-day 
follow-up visit and every 6 months thereafter. Survival follow-up can be via clinic visit, phone call to the subject or referring physician, or other method deemed appropriate 
by the site, and should assess survival, progression, subsequent therapy, and response. Any subject with a confirmed response who discontinues treatment for reasons other 
than disease progression will continue to be followed per standard of care and no less than every 3 months until documented disease progression, initiation of a new 
anti-cancer treatment, or 1 year from discontinuation of study treatment. Radiographic scan data will be collected and if scan data are not available, a scan will be obtained 
every 3 months until 6 months of radiographic follow-up after confirmed response has been obtained. 
23 For the optional Food Effect sub-study patients only:  Predose assessments for Day -4 or -3 can be completed 1 day prior to fed dosing day. ECOG Performance Status, 
symptom-directed physical examination, hematology, chemistry, coagulation, urinalysis, and tumor markers do not need to be repeated if these assessments from Screening 
occurred within 3 days of Day -4 or -3 unless a change in status is suspected. Subjects must continue to meet all eligibility criteria that are repeated at the time of initiation of 
Day -4 or -3 dosing (or 1 day prior as permitted above). All C1D1 assessments are required for these patients, however they are already considered enrolled and will not be 
required to reconfirm eligibility. 
24 Subjects participating in the optional Food Effect sub-study should present to clinic following an overnight fast of at least 10 hours. The subject will consume a low fat meal 
(see Section 5.2.4 for further details) in 30 minutes or less and complete their dose of PLX2853 within 30 minutes of starting administration with at least 8 ounces of water 
(and no more than 60 minutes from beginning the meal to completion of PLX2853 dose). 
 
 


PLX2853 
 
Protocol PLX124-03/Amendment 2 
CONFIDENTIAL/PROPRIETARY 
30 
Plexxikon Inc. 
SYNOPSIS TABLE 2:  PHASE 1B PLX2853 + CARBOPLATIN DOSE ESCALATION SCHEDULE OF EVENTS 
ASSESSMENTS▼ 
PROCEDURE▼ 
SCR1 
C1 
C2 
C3+2 
30-day FU3 
LTFU 
 
STUDY DAY► 
-28 to -1 
1 
8  
15 
22 
1 
15 
1 
 
WINDOW (days)► 
 
 
± 2 
± 2 
± 2 
+ 3 
± 3 
± 5 
± 7 
± 14 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
History 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Vital 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety 
Physical exam5 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
 
ECOG 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG7,15 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Lab 
PG sample 
X 
 
 
 
 
 
 
 
 
 
Hematology8 
X1 
X6 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry9 
X1 
X6 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation tests10 
X1 
X6 
X 
X 
X 
X 
X 
X 
X 
 
Tumor markers11 
 
X6 
 
 
 
X 
 
X 
X 
 
Urinalysis12 
X1 
X6 
X 
X 
X 
X 
X 
X 
X 
 
Serum c-reactive protein 
 
X 
X 
X 
X 
X 
 
X 
X 
 
Pregnancy test 
X1 
 
 
 
 
 
 
 
X13 
 
Hepatitis A/B/C and HIV testing14 
X 
 
 
 
 
 
 
 
 
 
PK sample15,16,17 
 
X 
 
X 
 
X 
 
X 
X 
 
Biomarker (PDx) blood sample15 
 
X 
 
X 
 
X 
 
X 
X 
 
Medications, Non-drug 
Treatments, Radiotherapy 
Prior treatment 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
X 
 
AE 
AE18 
X 
 


PLX2853 
 
Protocol PLX124-03/Amendment 2 
CONFIDENTIAL/PROPRIETARY 
31 
Plexxikon Inc. 
ASSESSMENTS▼ 
PROCEDURE▼ 
SCR1 
C1 
C2 
C3+2 
30-day FU3 
LTFU 
 
STUDY DAY► 
-28 to -1 
1 
8  
15 
22 
1 
15 
1 
 
WINDOW (days)► 
 
 
± 2 
± 2 
± 2 
+ 3 
± 3 
± 5 
± 7 
± 14 
Treatment Response 
Archival tissue sample 
X 
 
 
 
 
 
 
 
 
 
Paired biopsy for malignant lesion 
(Optional)19 
X 
 
 
 
 
X 
 
 
 
 
Response assessment20 
X 
 
 
 
 
 
 
Every 
2 cycles 
 
X22 
Study Treatment 
PLX2853 administration17 
Daily administration for 28 days (full cycle) 
 
 
Carboplatin administration 
Administration at least 2 hours after PLX2853 dosing using a target AUC of 
5 mg•min/mL on Day 1 of each 28-day treatment cycle per label 
 
 
Study drug compliance via diary 
review and accountability21 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Survival 
Survival follow-up22 
 
 
 
 
 
 
 
 
 
X22 
30-day FU = 30-day follow-up visit; AE = adverse event; AUC = area under the concentration-time curve; C = cycle; CA-125 = cancer antigen 125; D = day; DLT = dose-limiting 
toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; LTFU = long-term follow-up; PDx = pharmacodynamics; PG = pharmacogenomics; 
PK = pharmacokinetic, SCR = screening 
1 
All Screening laboratory tests should be performed within 10 days of C1D1 unless otherwise specified. Screening serum pregnancy test must be negative within 7 days prior to 
C1D1 for women of child-bearing potential. A complete list of required tests is found in Appendix 1 to the protocol. 
2 
If the subject does not have any ongoing Grade 2 or higher treatment-related AEs and following discussion with the Medical Monitor, subjects on treatment longer than 
12 cycles may be given the option to only have study visits on cycles with a response assessment (every 2 cycles). 
3 
The 30-day FU Visit should occur approximately 30 days after the last dose of PLX2853 or prior to starting any new anti-cancer therapy, whichever occurs first. 
4 
Predose vital signs must be obtained on PK days. On non-PK/non-PDx days, vital signs do not need to be predose and subjects may self-administer PLX2853 at home either 
prior to or after their clinic visit (if applicable). 
5 
Complete physical examination at Screening and 30-day FU only. All other physical examinations may be abbreviated and symptom-directed. 
6 
ECOG Performance Status, symptom-directed physical examination, hematology, chemistry, coagulation, and urinalysis do not need to be repeated if these assessments from 
Screening occurred within 3 days of C1D1 unless a change in status is suspected. Subjects must continue to meet all eligibility criteria that are repeated at the time of initiation 
of C1D1 dosing. 
7 
All ECGs are single tracings on the specified days and only Screening and predose C1D1 should be done in triplicate (approximately 10 seconds per ECG over a 5-minute 
period). Standard 12-lead ECG with QTcF calculation. Fridericia’s correction is required. QTcF = (QT)/3√(RR). 
8 
Hematology evaluation must include complete blood count with differential and platelet count. A complete list of required tests is found in Appendix 1 to the protocol. 
9 
Chemistry evaluation must include a complete chemistry panel including liver transaminases and gamma-glutamyl transferase. A complete list of required tests is found in 
Appendix 1 to the protocol. 
10 Coagulation evaluation must include prothrombin time/international normalized ratio, activated partial thromboplastin time, fibrinogen, d-dimer, and Factor VII. A complete 
list of required tests is found in Appendix 1 to the protocol. 


PLX2853 
 
Protocol PLX124-03/Amendment 2 
CONFIDENTIAL/PROPRIETARY 
32 
Plexxikon Inc. 
11 To be performed as per institutional practice guidelines. For subjects with ovarian cancer, obtain the 2 most recent CA-125 levels prior to study entry. 
12 Urinalysis with urine dipstick is sufficient; if there is significant proteinuria, hematuria, or pyuria, a microscopic examination should be obtained. A complete list of required 
tests is found in Appendix 1 to the protocol. 
13 Serum or urine pregnancy test to be collected at the 30-day FU visit. 
14 Serology testing for hepatitis A, B, and C, and HIV should be performed within 28 days of C1D1 if the subject is taking ≤30 µg/day biotin. If the subject is taking >30 µg/day 
biotin, the subject must lower their daily biotin intake to ≤30 µg and wait 14 days before hepatitis A, B, and C serology testing can be performed (elevated levels of biotin may 
interfere with viral serology testing). 
15 
Assessment 
C1D1 
C1D15 
C2+D1 
C2D15 
30-day FU 
ECG  
Predose and at 0.5, 1, 2, 3, and 
5 hours postdose 
Predose and at 0.5, 1, 2, 3, and 
5 hours postdose 
Predose and 1 hour postdose (±30 
minutes) at the start of each cycle 
Predose and 1 hour 
postdose (±30 minutes) 
Anytime 
PK 
Predose and 0.5, 1, 2, 3, and 
5 hours postdose (prior to second 
daily dose when applicable) 
Predose and 0.5, 1, 2, 3, and 
5 hours postdose (prior to second 
daily dose when applicable) 
Predose and 1, and 3 hours 
postdose 
N/A 
Anytime 
PDx 
Predose and 3, and 5 hours 
postdose 
Predose and 3 hours postdose 
Predose 
N/A 
Anytime 
 
Note:  All postdose ECGs should be collected at the specified time point ±30 minutes unless otherwise stated. Multiple PDx samples and sample types (e.g., serum, whole 
blood, plasma) may be collected at a given timepoint (detailed sample collection information is provided in the Laboratory Manual). 
Note:  All PK samples should be collected at the specified time points ±10 minutes at the 0.5- and 1-hour sample and ±30 minutes at subsequent time points. PK samples 
should be collected after the corresponding ECGs have been obtained. 
16 On PK days where a full PK profile is collected (e.g., C1D1, C1D15), subjects should fast at least 8 hours before dose administration and 1 hour after administration of 
PLX2853. On other PK sample collection days, subject should fast for 2 hours prior to their visit. During the fasting period, subjects may eat a low-fat snack (e.g., crackers, 
dry toast, etc.) if they experience gastrointestinal issues following dosing. 
Additional samples for PK may be collected if a subject experiences a DLT, serious adverse event, AE of special interest, dose modification, or at the Sponsor’s request. The 
time since the last dose of PLX2853 should be noted. Samples for PK collected for any dose modification should be at predose and 0.5, 1, 2, 3, and 5 hours postdose (prior to 
second daily dose when applicable) within 2 weeks of the modification or at the next scheduled clinic visit, whichever occurs closest to the new dosing regimen. 
17 On non-PK days, subjects should fast at least 2 hours before administration and 1 hour after administration of PLX2853, unless otherwise specified. Subjects should be 
instructed not to take their PLX2853 dose at home on PK or PDx collection days. If alternate day dosing is used, subjects will be instructed on which days to take PLX2853 
(e.g., even or odd numbered days). 
18 AE monitoring occurs both predose and postdose on days when PLX2853 is taken in the clinic. All AEs will be monitored for approximately 30 days after the last dose of 
study drug or prior to starting any new anti-cancer therapy, whichever occurs first. 
19 If the archival tissue was collected within 2 months of Screening, a fresh sample does not need to be collected at Screening. 
20 Radiographic assessment of tumor burden will occur at least approximately every 2 cycles, or more frequently as clinically indicated. Screening assessment of tumor burden 
may be within 28 days of scheduled C1D1. 
21 Collection of completed dosing diary and distribution of new diary to occur at the beginning of each cycle. 


PLX2853 
 
Protocol PLX124-03/Amendment 2 
CONFIDENTIAL/PROPRIETARY 
33 
Plexxikon Inc. 
22 Subjects will be followed until death, withdrawal of consent, or loss to follow-up according to the following schedule: every 3 months for the first 2 years after the 30-day 
follow-up visit and every 6 months thereafter. Survival follow-up can be via clinic visit, phone call to the subject or referring physician, or other method deemed appropriate 
by the site, and should assess survival, progression, subsequent therapy, and response. Any subject with a confirmed response who discontinues treatment for reasons other 
than disease progression will continue to be followed per standard of care and no less than every 3 months until documented disease progression, initiation of a new anti-
cancer treatment, or 1 year from discontinuation of study treatment. Radiographic scan data will be collected and if scan data are not available, a scan will be obtained every 
3 months until 6 months of radiographic follow-up after confirmed response has been obtained. 
 
 


PLX2853 
 
Protocol PLX124-03/Amendment 2 
CONFIDENTIAL/PROPRIETARY 
34 
Plexxikon Inc. 
SYNOPSIS TABLE 3:  PHASE 2A PLX2853 + CARBOPLATIN DOSE EXPANSION SCHEDULE OF EVENTS 
ASSESSMENTS▼ 
PROCEDURE▼ 
SCR1 
C1 
C2 
C3+2 
30-day FU3 
LTFU 
 
STUDY DAY► 
-28 to -1 
1 
8  
15 
22 
1 
1 
 
WINDOW (days)► 
 
 
± 2 
± 2 
± 2 
+ 3 
± 5 
± 7 
± 14 
Informed Consent 
X 
 
 
 
 
 
 
 
 
History 
Medical history 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Vital 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety 
Physical exam5 
X 
X6 
X 
X 
X 
X 
X 
X 
 
ECOG 
X 
X6 
X 
X 
X 
X 
X 
X 
 
12-lead ECG7 
X 
X 
 
X 
 
X 
X 
X 
 
Lab 
PG sample 
X 
 
 
 
 
 
 
 
 
Hematology8 
X1 
X6 
X 
X 
X 
X 
X 
X 
 
Chemistry9 
X1 
X6 
X 
X 
X 
X 
X 
X 
 
Coagulation tests10 
X1 
X6 
X 
X 
X 
X 
X 
X 
 
Tumor markers11 
 
X6 
 
 
 
X 
X 
X 
 
Urinalysis12 
X1 
X6 
X 
X 
X 
X 
X 
X 
 
Serum c-reactive protein 
 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test 
X1 
 
 
 
 
 
 
X13 
 
Hepatitis A/B/C and HIV testing14 
X 
 
 
 
 
 
 
 
 
PK sample15,16,17 
 
X 
 
X 
 
X 
X 
X 
 
Biomarker (PDx) blood sample15 
 
X 
 
X 
 
X 
X 
X 
 
Medications, Non-drug 
Treatments, Radiotherapy 
Prior treatment 
X 
 
 
 
 
 
 
 
 
Concomitant 
X 
 
AE 
AE18 
X 
 


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ASSESSMENTS▼ 
PROCEDURE▼ 
SCR1 
C1 
C2 
C3+2 
30-day FU3 
LTFU 
 
STUDY DAY► 
-28 to -1 
1 
8  
15 
22 
1 
1 
 
WINDOW (days)► 
 
 
± 2 
± 2 
± 2 
+ 3 
± 5 
± 7 
± 14 
Treatment Response 
Archival tissue sample 
X 
 
 
 
 
 
 
 
 
Paired biopsy for malignant lesion 
(mandatory)19 
X 
 
 
 
 
X 
 
 
 
Response assessment20 
X 
 
 
 
 
 
Every 2 
cycles 
 
X22 
Study Treatment 
PLX2853 administration17 
Daily administration for 28 days (full cycle) 
 
 
Carboplatin administration  
Administration at least 2 hours after PLX2853 dosing using a target AUC of 
5 mg•min/mL on Day 1 of each 28-day treatment cycle per label 
 
 
Study drug compliance via diary 
review and accountability21 
 
 
X 
X 
X 
X 
X 
X 
 
Survival 
Survival follow-up22 
 
 
 
 
 
 
 
 
X22 
30-day FU = 30-day follow-up visit; AE = adverse event; AUC = area under the concentration-time curve; C = cycle; CA-125 = cancer antigen 125; D = day; DLT = dose-limiting 
toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; LTFU = long-term follow-up; PDx = pharmacodynamics; PG = pharmacogenomics; 
PK = pharmacokinetic; SCR = screening 
1 
All Screening laboratory tests should be performed within 10 days of C1D1 unless otherwise specified. Screening serum pregnancy test must be negative within 7 days prior to 
C1D1 for women of child-bearing potential. A complete list of required tests is found in Appendix 1 to the protocol. 
2 
If the subject does not have any ongoing Grade 2 or higher treatment-related AEs and following discussion with the Medical Monitor, subjects on treatment longer than 
12 cycles may be given the option to only have study visits on cycles with a response assessment (every 2 cycles). 
3 
The 30-day FU Visit should occur approximately 30 days after the last dose of PLX2853 or prior to starting any new anti-cancer therapy, whichever occurs first. 
4 
Predose vital signs must be obtained on PK days. On non-PK/non-PDx days, vital signs do not need to be predose and subjects may self-administer PLX2853 at home either 
prior to or after their clinic visit (if applicable). 
5 
Complete physical examination at Screening and 30-day FU only. All other physical examinations may be abbreviated and symptom-directed. 
6 
ECOG Performance Status, symptom-directed physical examination, hematology, chemistry, coagulation, and urinalysis do not need to be repeated if these assessments from 
Screening occurred within 3 days of C1D1 unless a change in status is suspected. Subjects must continue to meet all eligibility criteria that are repeated at the time of initiation 
of C1D1 dosing. 
7 
All ECGs are predose and single tracings on the specified days and only Screening and predose C1D1 should be done in triplicate (approximately 10 seconds per ECG over a 
5-minute period). Standard 12-lead ECG with QTcF calculation. Fridericia’s correction is required. QTcF = (QT)/3√(RR). 
8 
Hematology evaluation must include complete blood count with differential and platelet count. A complete list of required tests is found in Appendix 1 to the protocol. 
9 
Chemistry evaluation must include a complete chemistry panel including liver transaminases and gamma-glutamyl transferase. A complete list of required tests is found in 
Appendix 1 to the protocol. 
10 Coagulation evaluation must include prothrombin time/international normalized ratio, activated partial thromboplastin time, fibrinogen, d-dimer, and Factor VII. A complete 
list of required tests is found in Appendix 1 to the protocol. 


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11 To be performed as per institutional practice guidelines. For subjects with ovarian cancer, obtain the 2 most recent CA-125 levels prior to study entry. 
12 Urinalysis with urine dipstick is sufficient; if there is significant proteinuria, hematuria, or pyuria, a microscopic examination should be obtained. A complete list of required 
tests is found in Appendix 1 to the protocol. 
13 Serum or urine pregnancy test to be collected at the 30-day FU visit. 
14 Serology testing for hepatitis A, B, and C, and HIV should be performed within 28 days of C1D1 if the subject is taking ≤30 µg/day biotin. If the subject is taking >30 µg/day 
biotin, the subject must lower their daily biotin intake to ≤30 µg and wait 14 days before hepatitis A, B, and C serology testing can be performed (elevated levels of biotin may 
interfere with viral serology testing). 
15 
Assessment 
C1D1 
C1D15 
C2–4 D1 
C5+ D1 
30-day FU 
PK 
Predose and 0.5, 1, 2, 3, and 5 hours postdose 
(prior to second daily dose when applicable) 
Predose and 0.5, 1, 2, 3, and 5 hours postdose 
(prior to second daily dose when applicable) 
Predose and 1 and 
3 hours postdose 
Predose 
Anytime 
PDx 
Predose and 3 and 5 hour postdose 
Predose and 3 hours postdose 
Predose 
Predose 
Anytime 
 
Note:  All PK samples should be collected at the specified time points ±10 minutes at the 0.5- and 1-hour sample and ±30 minutes at subsequent time points. PK samples 
should be collected after the corresponding ECGs have been obtained. Multiple PDx samples and sample types (e.g., serum, whole blood, plasma) may be collected at a given 
timepoint (detailed sample collection information is provided in the Laboratory Manual). 
16 On PK days where a full PK profile is collected (e.g., C1D1, C1D15), subjects should fast at least 8 hours before dose administration and 1 hour after administration of 
PLX2853. On other PK sample collection days, subject should fast for 2 hours prior to their visit. During the fasting period, subjects may eat a low-fat snack (e.g., crackers, 
dry toast, etc.) if they experience gastrointestinal issues following dosing. 
Additional samples for PK may be collected if a subject experiences a DLT, serious adverse event, AE of special interest, dose modification, or at the Sponsor’s request. The 
time since the last dose of PLX2853 should be noted. Samples for PK collected for any dose modification should be at predose and 0.5, 1, 2, 3, and 5 hours postdose (prior to 
second daily dose when applicable) within 2 weeks of the modification or at the next scheduled clinic visit, whichever occurs closest to the new dosing regimen. 
17 On non-PK days, subjects should fast at least 2 hours before administration and 1 hour after administration of PLX2853, unless otherwise specified. Subjects should be 
instructed not to take their PLX2853 dose at home on PK or PDx collection days. If alternate day dosing is used, subjects will be instructed on which days to take PLX2853 
(e.g., even or odd numbered days). 
18 AE monitoring occurs both predose and postdose on days when PLX2853 is taken in the clinic. All AEs will be monitored for approximately 30 days after the last dose of 
study drug or prior to starting any new anti-cancer therapy, whichever occurs first. 
19 If the archival tissue was collected within 2 months of Screening, a fresh sample does not need to be collected at Screening. 
20 Radiographic assessment of tumor burden will occur at least approximately every 2 cycles, or more frequently as clinically indicated. Screening assessment of tumor burden 
may be within 28 days of scheduled C1D1. 
21 Collection of completed dosing diary and distribution of new diary to occur at the beginning of each cycle. 
22 Subjects will be followed until death, withdrawal of consent, or loss to follow-up according to the following schedule: every 3 months for the first 2 years after the 30-day 
follow-up visit and every 6 months thereafter. Survival follow-up can be via clinic visit, phone call to the subject or referring physician, or other method deemed appropriate 
by the site, and should assess survival, progression, subsequent therapy, and response. Any subject with a confirmed response who discontinues treatment for reasons other 
than disease progression will continue to be followed per standard of care and no less than every 3 months until documented disease progression, initiation of a new anti-
cancer treatment or 1 year from discontinuation of study treatment. Radiographic scan data will be collected and if scan data are not available, a scan will be obtained every 
3 months until 6 months of radiographic follow -up after confirmed response has been obtained. 


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1.0 
BACKGROUND AND STUDY RATIONALE 
1.1 
Background 
Cancers are biologically heterogeneous diseases that are characterized by a medley of genomic 
aberrations and mutations. Recently, aberrant regulation of epigenetic processes has emerged as 
a common feature underlying many malignancies, with epigenetic regulation of gene expression 
impacting both the initiation and maintenance of these malignancies. Bromodomain and extra 
terminal domain (BET) proteins in particular serve as a common driver of malignancy through 
their effects on the expression of a specific set of genes essential for tumor growth and survival. 
PLX2853 is an orally active, small molecule inhibitor of BET bromodomain-mediated 
interactions. PLX2853 exhibits low nanomolar potency in blocking all 4 BET family members 
(BRD2, BRD3, BRD4, and BRDT). 
1.2 
Evidence of a Role for BET Proteins in Solid Tumors 
Bromodomains are protein interaction modules that recognize acetylated lysine residues on 
target proteins. Bromodomains are present in diverse nuclear proteins and function as epigenetic 
readers for transcriptional regulators and chromatin modifying enzymes (Filippakopoulos 2012). 
Dysfunction of a subset of bromodomain-containing proteins has been strongly associated with 
the development of cancer (Muller 2011). In particular, the BET family bromodomain proteins 
(BRD2, BRD3, BRD4, BRDT) have recently received much attention with the development of 
potent, cell-active inhibitors (Filippakopoulos 2012; Dawson 2011). Pharmacological inhibition 
of BET proteins leads to selective killing of tumor cells across a broad range of malignancies 
(Filippakopoulos 2012; Picaud 2013; Delmore 2011; Zuber 2011; Lockwood 2012; 
Cheng 2013). 
BET proteins facilitate the development of many types of human neoplasms by serving as the 
epigenetic regulators of many genes essential for tumor growth and survival. BET proteins are 
expressed as malignant oncogenic fusions in several rare forms of cancer. In particular, through 
chromosomal translation, BRD4 forms in-frame fusions with the NUT gene to initiate an 
aggressive cancer called NUT midline carcinoma (French 2003). The resulting BRD4NUT 
oncoprotein is an aberrant transcriptional regulator that relies on the bromodomains of BRD4 for 
its oncogenic function (Alekseyenko 2015). Studies using patient-derived NUT midline 
carcinoma xenografts provided the first demonstration of efficacy for a BET inhibitor in a 
preclinical cancer model (Filippakopoulos 2010). BET inhibitors have since shown therapeutic 
effects in other solid tumors (Filippakopoulos 2010; Nicodeme 2010). For non-small cell lung 
cancer, the effects correlate with suppression of FOSL1 expression (Lockwood 2012; 
Shimamura 2013), while the sensitivity of small cell lung cancer appears to be mediated by 
regulation of ASCL1 gene expression (Lenhart 2015). Neuroblastomas that harbor MYCN 
amplifications are also sensitive to BET inhibition, correlating with suppression of MYCN 
transcription (Puissant 2013; Wyce 2013). In addition, BET inhibitors have also shown antitumor 
activity in genetically diverse glioblastomas (Cheng 2013; Pastori 2015), MYC-amplified 


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medulloblastoma (Bandopadhayay 2014; Henssen 2013), castration-resistant prostate cancer 
(Asangani 2014; Cho 2014), basal-like and Her2-positive breast cancer (Shi 2014; 
Stuhlmiller 2015), and melanoma (Ambrosini 2011; Heinemann 2015). 
1.3 
Role of BET Inhibitors in Platinum-resistant Epithelial Ovarian Cancer 
Ovarian cancer, specifically epithelial ovarian cancer (EOC) (nearly 90% of all cases), is the 
leading cause of death from gynecologic malignancies in the United States. In 2018, it was 
estimated that 22,240 new diagnoses and 14,070 deaths had occurred. The incidence of ovarian 
cancer increases with age, and the median age at diagnosis is 63 years. Unfortunately, most cases 
(nearly 70%) present at an advanced stage (NCCN 2020). Ovarian cancer is a diverse and 
genomically complex disease. EOC has been classified into 5 histotypes including high-grade 
serous, low-grade serous, clear cell, endometrioid, and mucinous. 
The primary treatment of advanced ovarian cancer consists of surgical debulking plus systemic 
chemotherapy (usually a combination of a platinum agent and a taxane) in most patients. Some 
patients are refractory to initial therapy, defined as patients who progress after 2 consecutive 
chemotherapy regimens without ever achieving a response. Eventually, even patients who 
respond will relapse. Platinum resistance is defined as progression less than 6 months after the 
last platinum based therapy. Patients who relapse after 6 months are considered to have 
platinum-sensitive disease (NCCN 2020). 
Multiple single-agent and combination therapy strategies have been utilized in the second-line 
(or later) setting with the goal to prolong survival and optimize quality of life. For patients with 
platinum-resistant disease, a number of chemotherapeutic agents are used such as taxanes, 
liposomal doxorubicin, topotecan, and others, and they appear to have similar response rates. 
The addition of anti-angiogenic agents such as bevacizumab (delivered as a maintenance 
strategy) has been shown to improve survival. Several poly-(ADP-ribose) polymerase (PARP) 
inhibitors may also be used in patients whose tumors harbor BRCA1 or BRCA2 mutations 
(NCCN 2020; Coward 2015). Despite these advances, the mortality rate for ovarian cancer 
remains high. Less than 40% of all patients with ovarian cancer are cured. Novel therapies are 
urgently needed to improve patient outcome. 
This study evaluates whether BET inhibitor PLX2853 in combination with platinum represents 
an effective approach for overcoming platinum resistance. This is based on a number of 
preclinical studies that identified BET proteins as potential therapeutic targets in ovarian cancer 
(Baratta 2015; Zhang 2016; Karakashev 2017; Wilson 2018; Rhyasen 2018). Suppression of 
BRD4 using small-molecule BET inhibitors led to robust and broad antitumor effects across all 
subclasses of ovarian cancer (Zhang 2016). In particular, BRD4 is frequently amplified in 
high-grade serous ovarian cancer (HGSOC), the most common and malignant form of EOC 
(Baratta 2015; Ucar 2015). BRD4 amplification is oncogenic; in treatment-naive HGSOC, BRD4 
amplification correlates with poor clinical outcomes (Ucar 2015). Neuregulin-1 (NRG1) 
functions as a critical effector in BRD4-mediated cellular transformation. BRD4 regulation of 
NRG1 expression is mediated by the switch/sucrose non-fermentable (SWI/SNF) nucleosome 


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remodeling complex. BRD4 amplification confers sensitivity to BET inhibition in HGSOC and 
NRG1 suppression represents a specific pharmacodynamics (PDx) marker. The pan-subtype cell-
cycle arrest by BET inhibition, however, is potentially mediated by down regulation of FOXM1 
proto-oncogene, a key driver of EOC. 
A more direct link between BET and platinum-resistant tumors concerns DNA repair 
(Karakashev 2017; Yang 2017; Wilson 2018). DNA repair mechanisms, which are fundamental 
for recognition and removal of platinum adducts, are closely associated with the development of 
drug resistance. Selection for platinum-resistance, thus, enriches tumors with functional DNA 
repairs. This also represents the patient population where none of the current treatments, 
including PARP inhibitors, are effective. In HGSOC, there is a significant enrichment of DNA 
damage repair and cell-cycle checkpoint-regulating genes (e.g., WEE1 and TOPBP1) among 
BRD4 target genes. Combined BET and PARP inhibition increases DNA damage and cell-cycle 
checkpoint defects, leading to mitotic catastrophe. 
1.4 
Role of BET Inhibitors in Advanced Gynecological Malignancies with a Known 
ARID1A Mutation 
Disordered chromatin regulation has emerged as a distinct mechanism contributing to tumor 
development. In particular, genes encoding subunits of ATP-dependent chromatin remodelers, 
especially subunits of the SWI/SNF complex, are frequently mutated in a broad array of cancer 
types (Wilson 2011; Kadoch 2015). Mutually exclusive subunits in the SWI/SNF complex 
include the DNA targeting members ARID1A and ARID1B as well as the ATPases SMARCA2 
and SMARCA4. ARID1A inactivating mutations are the most common alterations of the 
SWI/SNF complex in gynecological malignancies (Wu 2013; Bitler 2015). In particular, nearly 
50% of ovarian clear cell carcinomas (OCCCs) harbor an inactivating mutation in the ARID1A 
gene (Mabuchi 2016). Loss of ARID1A activates major signaling pathways such as increased 
PI3K-AKT-MTOR pathway (Caumanns 2018), that confer an advantage to the tumor cells 
through enhanced proliferation and/or survival. OCCC is a less common form of EOC, 
comprising <10% of all ovarian cancers with a heterogeneous genomic landscape (Murakami 
2017). It is known to be less sensitive to platinum-based chemotherapy (Tan 2013). Once 
patients progress after platinum-based chemotherapy, there are limited options for them. 
Recently, it was shown that loss of ARID1A sensitizes most OCCC to BET inhibition 
(Berns 2018). In a large panel of OCCC cell lines representing the full spectrum of ARID1A 
mutation status, knockdown of BET family member BRD2 resulted in enhanced toxicity 
predominantly in ARID1A mutant cell lines. Small molecule inhibitors of BET (e.g., JQ1 and 
iBET-762) specifically inhibit proliferation of ARID1A mutated OCCCs, both in vitro and in 
ovarian clear cell cancer xenografts and patient-derived xenograft models. BET inhibitors cause 
a reduction in the expression of multiple SWI/SNF members including ARID1B that are 
synthetic lethal targets in ARID1A mutant cells (Berns 2018; Helming 2014; Kelso 2017). 
However, ARID1A mutant cell lines with PIK3CA pathway gene mutations did not show a 
reduction in c-Myc and had a higher half-maximal inhibitory concentration (IC50) for BETi when 
compared to the ARID1A mutant cell lines that did not have PIK3 pathway mutations 


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(Berns 2018). Chromatin immunoprecipitation experiments demonstrated specific BRD2 binding 
to various SWI/SNF member promoter regions. 
Information on ARID1A continues to emerge from comprehensive genome-wide analyses with 
next‑generation sequencers. ARID1A mutations have been found in various types of cancer and 
occur at high frequency at the early stage of canceration from endometriosis to 
endometriosis-associated carcinoma in ovarian cancer and also from atypical endometrial 
hyperplasia to endometrioid adenocarcinoma in endometrial cancer. BET inhibitors such as 
PLX2853 may have broad utilities as a novel therapy for gynecological cancers expressing loss 
of function ARID1A mutations. 
1.5 
PLX2853 
Unlike the first generation BET inhibitors including JQ1 (Filippakopoulos 2010), I-BET762 
(Mirguet 2013), and OTX015 (Boi 2015), PLX2853 is structurally unrelated to the 
benzodiazepines. The nonclinical pharmacology, PK, and toxicology profiles of PLX2853 have 
been characterized in an extensive program of in vitro and in vivo studies. The data from these 
studies supported clinical development of PLX2853 as a novel epigenetic therapy for certain 
cancers. PLX2853 is currently in clinical development for both hematopoietic malignancies 
(Study PLX124-02 [NCT03787498]) and solid tumors (Study PLX124-01 [NCT03297424]). The 
data to date have demonstrated evidence of antitumor activity with manageable toxicity. In 
particular, clinical experience with PLX2853 monotherapy in subjects with heavily pretreated 
ovarian, fallopian, and peritoneal cancers has shown some signs of activity. So far, the dose 
escalation phase of PLX124-01 has enrolled 7 subjects with ovarian cancers, 2 subjects with 
endometrial cancers, 1 subject with primary peritoneal cancer, and 1 subject with cervical cancer. 
Four of these 11 subjects showed initial decreases in the sum of their target lesions after starting 
PLX2853 monotherapy. The subject with peritoneal cancer achieved a 30% reduction in the sum 
of their target lesions and remained on therapy for longer than 9 months. These minor responses 
over a range of doses and in a broad patient segment are encouraging, but suggest that PLX2853 
needs to be explored in combination with other agents or in a genomically defined and sensitive 
population. 
1.5.1 
Nonclinical Pharmacology 
The 4 BET family proteins, BRD2, BRD3, BRD4 and BRDT, share the feature of containing 
2 conserved N-terminal bromodomains (BD1 and BD2), an extra terminal domain, and a 
divergent C-terminal recruitment domain. The dissociation constant (Kd) values of PLX2853 
were determined for the 8 isolated BET bromodomains. Based on the measured Kd values, 
PLX2853 is more potent against isolated bromodomains from the BET proteins BRD2, BRD3, 
and BRD4 than those from the testes-specific BRDT (Table 1). Within these isolated domains 
there is a slight preference for binding to the BD2. Structural analyses of the interactions of BET 
proteins with histone tails suggested that both BD1 and BD2 are involved in the recognition of 
acetyl-lysine epitopes. Thus, potent inhibition of both bromodomains likely contributes to the 
overall pharmacological effects of PLX2853. In biochemical assays that examined the binding of 


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acetylated histone tail to BET proteins containing both bromodomains, PLX2853 displayed 
potent inhibitory activity (IC50 = 4.3 nM for BRD4 and 7.3 nM for BRD2). 
Table 1: 
Kd Values of PLX2853 for Binding to the 8 Bromodomains from 4 BET 
Proteins 
Bromodomaina 
PLX2853 Kd (nM)  
BRD2 (BD1) 
0.32 
BRD2 (BD2) 
0.21 
BRD3 (BD1) 
0.34 
BRD3 (BD2) 
0.21 
BRD4 (BD1) 
0.51 
BRD4 (BD2) 
0.24 
BRDT (BD1) 
1.5 
BRDT (BD2) 
3.9 
Source:  EXP-15-AD5580 
a Each assay used a truncated protein containing a single bromodomain. The 2 bromodomains of each BET protein 
are labeled as BD1 and BD2, respectively. 
 
Binding interactions of PLX2853 to the other 24 isolated bromodomains from 22 different 
proteins were measured using BROMOscan (EXP-15-AD5580). At a 1 μM concentration, 
PLX2853 shows interactions with the bromodomains in 3 non-BET proteins, CREBBP, EP300, 
and TAF1-BD2. The Kd values of PLX2853 were determined for all bromodomains that showed 
>50% binding in the single concentration primary screen. Of the non-BET proteins, only 
CREBBP and EP300 had sub-micromolar potencies with Kd values in the 100 nM range. 
A functional MYC reporter assay was generated by placing a firefly luciferase gene construct 
under the control of a minimal cytomegalovirus promoter and tandem repeats of a MYC binding 
element (E-box) to determine the cellular PDx effect of PLX2853. PLX2853 potently inhibits 
MYC reporter activity in MV4-11 cells with an IC50 of 7.2 nM. 
The antitumor effects of PLX2853 were also evaluated in a panel of 14 ovarian cancer cell lines 
(Table 2). Ovarian cell lines with ARID1Amut cell lines are particularly sensitive to PLX2853. 
This finding provides a rationale for testing PLX2853 as a potential new therapy in the treatment 
of OCCC. OCCC is a distinct histopathologic subtype of ovarian cancer and has a high ARID1A 
mutation frequency (>50%). ARID1A mutations also occur with relatively high frequency in 
other cancers, supporting broader utility of PLX2853 across a broad spectrum of cancers, 
especially clear cell cancers arising from ectopic or eutopic endometrium. 


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Table 2: 
Antitumor Effects of PLX2853 in Ovarian Cancer Cell Lines 
Cell Line 
Type 
Genotype 
IC50 (μM) 
CI95 (μM)a 
SW626 
Ovarian 
ARID1Awt 
0.07 
0.034–0.15 
OVISE (OCCC) 
Ovarian 
ARID1Amut 
0.26 
0.14–0.48 
SKOV3 
Ovarian 
ARID1Amut 
0.49 
0.37–0.66 
OVTOKO (OCCC) 
Ovarian 
ARID1Amut 
0.61 
0.33–1.14 
ES-2 (OCCC) 
Ovarian 
ARID1Amut, MYCAMP 
1.26 
0.68–2.36 
TOV-112D 
Ovarian 
ARID1Awt 
1.31 
0.67–2.57 
COV 644 
Ovarian 
NA 
1.46 
0.70–3.05 
OVCAR-8 
Ovarian 
ARID1Awt 
1.60 
0.85–3.02 
A2780 
Ovarian 
ARID1Amut 
2.41 
1.65–3.53 
COV 504 
Ovarian 
NA 
2.42 
1.02–5.73 
TOV 21G (OCCC) 
Ovarian 
ARID1Amut 
3.13 
1.74–5.63 
OVSAH0 
Ovarian 
ARID1Awt 
>20 
N/A (>20) 
OVCAR-4 
Ovarian 
ARID1Awt 
>20 
N/A (>20) 
PA-1 
Ovarian 
ARID1Awt 
>20 
N/A (>20) 
Source:  EXP-15-AD8492 
CI95 = 95% confidence interval; IC50 = half-maximal inhibitory concentration; N/A = not available 
a 95% confidence interval; individual IC50 values when the number of repeats <3. 
In vitro data also support the combination of BET inhibitors and topoisomerase I/II inhibitors as 
an effective approach to treating ovarian cancer. For example, the combination of PLX2853 with 
irinotecan conferred a synergistic anti-proliferative effect in TOV21G (ovarian) cells. The same 
effect was observed in small cell lung cancer cells. 
The in vivo antitumor activity of PLX2853 was demonstrated in several tumor xenograft models. 
In particular, Study EXP-17-AF3510 examined the effect of PLX2853 with continuous daily 
dosing, as well as 5-days on, 2-days off intermittent dosing (QD-5/2) in the ovarian TOV21G 
xenograft model. Both treatment groups showed significant responses compared to the vehicle 
control group with minimal body weight loss. PLX2853 dosed at 10 mg/kg continuous daily 
dosing resulted in 77% tumor growth inhibition (TGI) by the end of study with a steady state 
area under the concentration-time curve from time zero to 24 hours postdose (AUC0-24) of 
8,710 ng•hr/mL. PLX2853 dosed at 20 mg/kg QD-5/2 performed slightly better (85% TGI). 
Recently, immunotherapies and especially checkpoint inhibitors have shown significant clinical 
benefit in selected patient populations. These therapies can offer broader clinical benefit with 
auxiliary strategies to mitigate the immunosuppressive nature of the tumor microenvironment. A 
selective BET inhibitor holds promise to improve the efficacy of cancer immunotherapies. By 
inhibiting the accumulation of immunosuppressive macrophages and myeloid-derived suppressor 
cells, BET inhibitors have been shown to reprogram the tumor microenvironment to facilitate 
T cell-mediated antitumor immunity (Zhu 2016). Study EXP-16-AF3502 evaluated the potential 
of combining PLX2853 with αCTLA4 in the treatment of colorectal cancer using the MC38 
syngeneic xenograft model. As single agent, PLX2853 at 6 mg/kg once daily (QD) and αCTLA4 


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performed equally well, resulting in 78% and 74% TGI, respectively, by the end of a 21-day 
dosing period. The combined treatment generated stronger efficacy, achieving nearly complete 
(93%) TGI. A similar TGI (95%) and a higher rate of complete response (CR) were observed 
when a higher dose of PLX2853 administered every other day was combined with αCTLA4. The 
5 animals in this group that had achieved sustained CRs rejected the re-implantation of MC38 
tumor cells, illustrating the development of full immunity in these animals (Zhu 2016). 
1.5.2 
Nonclinical Pharmacokinetics 
PLX2853 is an achiral molecule with a molecular weight of 515.6 Da. The absorption, 
distribution, metabolism, and elimination properties of PLX2853 have been characterized 
through a comprehensive panel of nonclinical in vitro and in vivo studies. PLX2853 is lipophilic 
with a logP of 4.15 and a logD (pH 7.4) of 0.93. Because the molecule contains ionizable groups, 
the aqueous solubility of PLX2853 is pH dependent. PLX2853 is more soluble at both low and 
alkaline pH. The presence of bio-relevant media (e.g., simulated intestinal or gastric fluid) 
appears to have minor impact on its aqueous solubility. PLX2853 has a solubility of 94.3 µM 
(48.6 µg/mL) at pH 7 and is stable in simulated intestinal and gastric fluids. PLX2853 shows 
high bidirectional permeability across Caco-2 monolayers with a low efflux ratio. Because of its 
moderate solubility and high permeability, PLX2853 is a Biopharmaceutics Classification 
System class II drug with oral absorption limited by the dissolution rate. 
The preclinical PK of PLX2853 was evaluated in 3 species (mouse, rat, and dog) following 
intravenous (IV) and oral administration of the compound. PLX2853 exhibited low IV clearance 
(CL) in all 3 species (CL = 1.68, 2.71, and 2.69 mL/min/kg in mice, rats, and dogs, respectively) 
with a T1/2 of 2 hours or less. Rat and dog, the 2 species selected for preclinical safety testing, 
were used more extensively to evaluate the PK and bioavailability of oral doses of PLX2853. 
Because of the limited solubility, an immediate-release amorphous formulation using spray-dried 
dispersion technology was developed to enhance bioavailability of PLX2853. In both single-dose 
and repeat-dose PK studies, the Tmax was usually within 2 hours following oral administration. In 
the definitive 28-day Good Laboratory Practice (GLP) rat and dog toxicology studies, PLX2853 
showed near dose-proportional increase in exposure over the dose range evaluated. Because of 
the relatively short T1/2, only modest level of accumulation was observed at steady state. At top 
dose, the exposure, in terms of AUC0-24, was slightly lower in females than in males, though 
differences were less than 2-fold. 
In the IND-enabling toxicology studies, PLX2853 was quantified in plasma using fully-validated 
high performance liquid chromatography (HPLC) tandem mass spectrometry (LC/MS/MS) 
bioanalytical methods. Two GLP-compliant validated LC/MS/MS chromatographic methods in 
positive ion mode (ESI+) were used for quantification of PLX2853 in rat and dog plasma 
samples. A separate method was performed with HPLC coupled with ultraviolet (UV) absorption 
for dosing solution analysis. 
Protein binding of PLX2853 is moderate to high in human (96.1%), monkey (93.4%), dog 
(95.5%), rat (97.9%), and mouse (95.4%) plasma. PLX2853 is stable in the plasma of all 


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5 species. In a single-dose tissue distribution study in rats, the brain penetration of PLX2853 was 
minimal with a brain to plasma ratio of <0.01 two hours after administration of 10 mg/kg oral 
dose of PLX2853. 
PLX2853 is metabolically stable. The metabolic turnover was low for PLX2853 in mouse, rat, 
dog, monkey, and human S9 fractions (S9-based intrinsic clearance <4.9 µL/min/mg in all 
5 species). Liver S9 metabolite profiling identified an oxidation metabolite (labeled M1) in 
human and dog and no major metabolites in rat. Cytochrome P450 (CYP) reaction phenotyping 
indicates that CYP2C8 and CYP3A4 are the major contributors for the formation of the 
PLX2853 oxidative metabolite M1. Their relative contributions to the formation of M1 were 
similar. However, because the rate of metabolism is so low, CYP2C8 and CYP3A4 inhibitors are 
not expected to have a significant effect on the clearance of PLX2853. 
The excretion profiles of PLX2853 in bile duct-cannulated (BDC) male Sprague Dawley rats 
following IV administration were determined. Following IV administration of 1, 10, and 
25 mg/kg PLX2853 to BDC rats, by 24 hours postdose, 4.08%, 5.56%, and 4.56% and 0.118%, 
0.082%, and 0.587% of the administered dose were recovered as PLX2853 in bile and urine, 
respectively. Based on these data, biliary and urinary excretion of untransformed PLX2853 do 
not appear to be major routes of elimination of PLX2853 in rats. 
The drug-drug interaction potential of PLX2853 was further evaluated by measurement of CYP 
inhibition using recombinant enzymes and CYP induction potential in human hepatocytes. 
Studies have also been conducted to assess the potential of PLX2853 as an inhibitor of human 
breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic anion transporter 
(OAT)1, OAT3, OCT2, organic anion transporting polypeptide (OATP)1B1, and OATP1B3 
mediated transport in polarized monolayer of Madin-Darby canine kidney II cells. PLX2853 
demonstrated no potential to cause direct or time-dependent inhibition CYP1A2, 2B6, 2C8, 2C9, 
2C19, 2D6, and 3A4. PLX2853 did not induce any of the respective isoforms of CYP1A, 
CYP2B, and CYP3A genes at all the concentrations tested in human, monkey, dog, and rat 
hepatocytes except CYP3A in monkey (34% to 49% of the positive control). Compared to 
vehicle control, PLX2853 at 10 µM inhibited OCT2, OATP1B1, OATP1B3, BCRP, and P-gp 
mediated transport by 24.4%, 82.4%, 50.7%, 37.2%, and 48.8%, respectively. Considering the 
plasma protein binding of PLX2853 (96.1% in human), the plasma concentration to achieve 
10 µM free fraction is >250 µM, well beyond the anticipated in vivo exposures. Collectively, 
these results suggest that the risk of in vivo drug-drug interactions is low for PLX2853. 
The food effect on the PK of PLX2853 was evaluated following a single oral dose to male beagle 
dogs under fasted or fed (high fat diet) conditions. This was a single-dose, 2-period cross-over 
study where each group received a 40 mg oral dose of PLX2853 (two 20 mg strength tablets) 
while either fasted or fed and then received the alternate treatment (fasted or fed) following a 
washout period of 4 days (96 hours) between doses. 
Dogs receiving the high fat diet had a significant reduction in exposure of PLX2853. The mean 
peak concentration (Cmax) values were 903 and 4870 ng/mL for fed and fasted groups, 


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respectively. The mean AUC0-24 values were 3280 and 14,100 ng•hr/mL for fed vs fasted groups, 
respectively. The geometric mean ratios (fed/fasted) with the calculated 90% confidence 
intervals (CI90) for the ratios for Cmax, AUC0-24, and AUC0-∞ were 17.72% (11.71% to 26.81%), 
and 25.15% (18.34% to 34.548%), and 25.82% (18.92% to 35.24%), respectively. 
1.5.3 
Toxicology Studies of PLX2853 
The PLX2853 toxicology program is consistent with the guidance provided in the International 
Council for Harmonisation (ICH) S9 guideline and is comprised of repeat-dose exploratory 
toxicology studies and definitive 4-week toxicology studies conducted in 2 mammalian species 
(rat and dog) using the clinically-relevant route of administration (oral) and dosing schedule 
(continuous daily administration). Additionally, definitive in vitro genotoxicity studies were 
conducted. Clinically-relevant polymer-based blend formulations of PLX2853 were used in the 
dose-range finding and definitive in vivo studies. Doses/concentrations of test article used in the 
definitive studies were corrected for polymer loading and reflect the dose/concentration of active 
moiety. PLX2853 was administered to rats via oral gavage and to dog via oral capsule. An 
overview of the PLX2853 toxicology program is provided in Table 3. 


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Table 3: 
Overview of PLX2853 Toxicology Program 
Study Type  
(Study Number)  
Species 
and Strain 
Method of 
Administration 
Doses (mg/kg/day)a 
Repeat-dose Toxicity 
 
 
 
14-day dose range-finding 
(EXP-15-AC2093) 
Rat/Crl:CD 
(Sprague-Dawley) 
Oral (gavage) 
0, 1b, 5, 10 
28-day definitive 
(EXP-16-AF1301) 
Rat/Crl:CD 
(Sprague-Dawley) 
Oral (gavage) 
0, 0.5, 1.5, 5c 
14-day dose range-finding 
(EXP-16-AC2095) 
Dog/Beagle 
Oral (capsule) 
0, 1, 3, 6 
28-day definitive 
(EXP-16-AF1302) 
Dog/Beagle 
Oral (capsule) 
0, 0.3, 1c, 3 
Genotoxicity 
 
 
 
Bacterial reverse mutation 
assay 
S. typhimurium, E. coli  
In vitro  
≤5000 μg/plate 
Chromosome aberration 
assay 
Human (peripheral blood 
lymphocytes) 
In vitro 
3 hours without metabolic 
activation:  3.13–250 µg/mL 
3 hours with metabolic  
activation:  0.783–3.13 µg/mL 
22 hours without metabolic 
activation:  0.0061–0.0244 µg/mL  
Other Toxicity Studies 
 
 
 
Phototoxicity assay 
NIH/3T3  
(ATCC® CRL-1658™) 
In vitro 
≤50 µM 
Hepatocyte cytotoxicity assay 
Human 
In vitro 
0.07–50.00 µM 
Cell viability assay 
Human kidney (293T) 
and liver (HepG2) cell 
lines 
In vitro 
≤50 µM 
HNSTD = highest non-severely toxic dose; NOAEL = no-observed-adverse-effect-level 
a Unless otherwise specified. For repeat-dose toxicity, the NOAEL is underlined. 
b NOAEL for females; the NOAEL for males could not be defined. 
c HNSTD for both males and females. A NOAEL could not be determined for either sex. 
 
The rat and dog were selected for the PLX2853 toxicology program as the rodent and nonrodent 
toxicology species, respectively, on the basis of in vitro metabolism studies which indicated that 
metabolism of PLX2853 in rat and dog hepatocytes is qualitatively comparable to that in human 
hepatocytes. 
In both rats and dogs, 14-day exploratory studies were conducted as dose range-finders for 
subsequent 28-day definitive studies. In rats, QD oral administration of PLX2853 at dose levels 
of 1, 5, and 10 mg/kg/day for up to 14 consecutive days resulted in moribundity at 10 mg/kg/day 
in both sexes, resulting in early termination of 10 mg/kg/day animals on Day 7. Adverse test 
article-related microscopic findings noted in PLX2853-treated rats included:  increased minimal 
to moderate thickness of the femoral physis in males at all dose levels; atrophy and lymphoid 
depletion in the thymus and lymphoid depletion in the spleen in both sexes at 5 mg/kg/day; and 


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minimal atretic follicles in the ovary, and an alteration in estrous cyclicity in females at 5 and 
10 mg/kg/day. Under the conditions of this study, the highest non-severely toxic dose (HNSTD) 
of PLX2853 was considered to be 5 mg/kg/day for both sexes. Systemic exposure (AUC0-24 and 
Cmax) at the HNSTD on Day 13 was 9420 ng•hr/mL and 1580 ng/mL, respectively for males and 
2350 ng•hr/mL and 771 ng/mL, respectively, for females. The no-observed-adverse-effect level 
(NOAEL) for PLX2853 in this study was considered to be 1 mg/kg/day for females but could not 
be defined for males. Based on the results of this dose range-finding study, PLX2853 dose levels 
of 0.5, 1.5, and 5 mg/kg/day were selected for evaluation in the subsequent 28-day definitive 
toxicity study. In the 28-day study, QD oral administration of PLX2853 for a minimum of 
28 consecutive days resulted in adverse test article-related effects including reduced body weight 
gain and food consumption in males at 1.5 and 5 mg/kg/day. Adverse microscopic findings in 
lymphoid and hematopoietic tissues at the terminal necropsy included:  hypocellularity of the 
bone marrow at 0.5 (females only), 1.5, and 5 mg/kg/day in both sexes, with clinical pathology 
correlates of decreased mean total white blood cell, absolute lymphocyte, and basophil counts at 
all dose levels, decreased mean absolute eosinophil counts (males only) at 5 mg/kg/day, and 
possibly decreased mean platelet count (males only) at 5 mg/kg/day; atrophy of the thymus in 
males at all dose levels and atrophy and lymphoid necrosis of the thymus in females at 
5 mg/kg/day; and lymphoid depletion of the spleen, mesenteric lymph node (males only), and/or 
thymus in males at all dose levels and in females at 1.5 and 5 mg/kg/day (correlating in males 
with decreased mean absolute lymphocyte counts, decreased mean thymus and spleen weights at 
all dose levels, and macroscopic small thymus at 5 mg/kg/day and in females with decreased 
mean thymus and spleen weights at 1.5 and 5 mg/kg/day). All adverse effects were resolved 
following the 28-day treatment-free recovery period. Under the conditions of this study, the 
HNSTD for PLX2853 was considered to be 5 mg/kg/day. Systemic exposure (AUC0-24 and Cmax) 
at the HNSTD on Day 27 was 1800 ng•hr/mL and 1400 ng/mL, respectively, for males and 
1190 ng•hr/mL and 1370 ng/mL, respectively, for females. A NOAEL could not be determined 
for either sex in this study. 
In dogs, QD oral administration of PLX2853 at dose levels of 1, 3, and 6 mg/kg/day for up to 
14 consecutive days resulted in overt toxicity in both sexes at the 6 mg/kg/day high-dose level. 
Two of 3 high-dose male animals were euthanized in moribund condition on Days 5 and 12. As a 
result, the surviving high-dose animals were scheduled for early termination on Day 13. Adverse 
test article-related findings in PLX2853-treated dogs included:  intestinal mucosal changes, 
lymphoid depletion, necrosis of lymphoid organs, bone marrow hypocellularity and 
prolongations of activated partial thromboplastin time (aPTT) in both sexes; atrophy of the 
thymus, correlating with macroscopic findings and effects on thymic weight in both sexes at 
3 mg/kg/day; and lesions in the male reproductive tract at 3 mg/kg/day. Under the conditions of 
this study, the HNSTD for PLX2853 was considered to be 3 mg/kg/day for both sexes, while the 
NOAEL was considered to be 1 mg/kg/day for both sexes. Systemic exposure (AUC0-24 and 
Cmax) at the HNSTD on Day 13 was 5050 ng•hr/mL and 1900 ng/mL, respectively, for males and 
879 ng•hr/mL and 203 ng/mL, respectively, for females. Systemic exposure (AUC0-24 and Cmax) 
at the NOAEL on Day 13 was 2600 ng•hr/mL and 503 ng/mL, respectively, for males and 
1230 ng•hr/mL and 333 ng/mL, respectively, for females. Based on the results of this dose 


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range-finding study, PLX2853 dose levels of 0.3, 1, and 3 mg/kg/day were selected for 
evaluation in the subsequent 28-day definitive toxicity study. In the 28-day study, all animals 
administered 0.3 or 1 mg/kg/day PLX2853 survived until scheduled termination, whereas 
animals administered 3 mg/kg/day PLX2853 were submitted for early termination on the day of 
the scheduled terminal necropsy. Once daily administration of 3 mg/kg/day PLX2853 resulted in 
adverse clinical observations indicating severe toxicity, body weight loss, reduced food 
consumption, altered organ weights, altered hematology, coagulation, and clinical chemistry 
parameters, and macroscopic and microscopic findings in both males and females. Test 
article-related effects included:  erosion/ulcer and/or hemorrhage in the gastrointestinal tract 
tissues and lung hemorrhage and inflammation, together with concurrent altered serum 
electrolytes, prolonged prothrombin time, and aPTT, and decreased platelet and reticulocyte 
counts at 3 mg/kg/day; tubular degeneration in the testes with associated epididymides and 
prostate changes at 1 and 3 mg/kg/day; hypocellular marrow in both sexes at all dose levels; and 
thymic atrophy, lymphoid depletion of Peyer’s patches and axillary lymph nodes in both sexes at 
3 mg/kg/day. In addition, 1 male in the 0.3 mg/kg/day low-dose group was noted for hemorrhage 
and inflammation in the lung, which was considered adverse. Following 28 days of 
treatment-free recovery, microscopic findings had either completely resolved or were considered 
to be in the process of resolving. Under the conditions of this study, the HNSTD for PLX2853 
was considered to be 1.0 mg/kg/day in both sexes. Systemic exposure (AUC0-24 and Cmax) at the 
HNSTD on Day 27 was 1940 ng•hr/mL and 935 ng/mL, respectively, for males and 
1610 ng•hr/mL and 775 ng/mL, respectively, for females. A NOAEL could not be determined 
for either sex in this study. 
PLX2853 was found to be non-mutagenic in a definitive bacterial reverse mutation assay. In a 
definitive in vitro chromosome aberration assay conducted in human peripheral blood 
lymphocytes, PLX2853 was considered positive for inducing structural aberrations in the 3-hour 
treatment without metabolic activation. In addition, statistically significant increases in 
numerical aberrations (polyploidy or endoreduplication) were noted in PLX2853-treated cultures 
after 3 hours of treatment without metabolic activation. 
In a preliminary assessment of photo safety, PLX2853 did not reduce the viability of 3T3 mouse 
fibroblasts with and without UV A exposure and was therefore concluded to have no phototoxic 
potential. 
In exploratory in vitro studies, PLX2853 was not toxic to human hepatocytes in culture after 
either 24 or 72 hours of exposure (IC50 >50 μM) and did not reduce the viability of human 
HepG2 or 293T cells after either 24 or 72 hours with 10% fetal bovine serum (IC50 >50 μM), 
indicating that the metabolites of PLX2853 are not toxic to liver and kidney cells. 
Additional detailed information regarding the nonclinical pharmacology and toxicology of 
PLX2853 can be found in the Investigator’s Brochure. 


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1.5.4 
Proposed Starting Dose for Study PLX124-03 
As of 22 March 2021, in an ongoing dose escalation study of PLX2853 in subjects with 
advanced solid tumors (Study PLX124-01; NCT03297424), PLX2853 has been generally safe 
and well-tolerated in 46 subjects dosed at up to 120 mg/day with dose limiting toxicities (DLTs) 
experienced by 4 subjects, and evidence of efficacy at doses as low as 5 mg/day (Section 1.8.1). 
As of 22 March 2021, doses of up to 180 mg/day have been evaluated in 22 subjects with 
relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome 
(MDS) in Study PLX124-02 (NCT03787498), with 2 DLTs reported. As of 23 April 2021, 
80 mg/day has been determined to be the recommended Phase 2 dose (RP2D) in both Study 
PLX124-01 and Study PLX124-02. 
Available PLX2853 PK data from the 2 studies (N = 67) showed dose-dependent increases in 
exposures throughout the dose range tested (5 to 180 mg/day). After oral administration, 
PLX2853 exhibited a short terminal half-life and no significant accumulation at steady state. In 
addition, PLX2853 showed dose-dependent pharmacodynamic effect in modulating the 
expression of BET target genes in peripheral blood cells (see Figure 1 below). Significant and 
consistent PDx effect was first observed at 40 mg/day dose. The corresponding daily exposure 
(AUC0-24 = ~2000 ng•hr/mL) defines the pharmacologically active exposure. 
Subjects enrolled in 6 of the 10 cohorts in PLX124-01 and 3 of the 7 cohorts in PLX124-02 were 
administered the 5 mg strength tablets. The 20 mg strength tablet form was introduced later in 
both studies to reduce pill burden. The Day 1 and Day 15 PK for the 2 tablet strength 
formulations were comparable at the 120 mg/day dose (PLX124-01) and 80 mg/day dose 
(PLX124-02). 
The proposed starting dose for PLX2853 monotherapy is 80 mg/day, the highest dose that has 
been cleared of DLTs in both solid tumor (PLX124-01) and AML/MDS (PLX124-02) patients. 
PLX2853 + carboplatin combination may have a different safety profile compared with 
PLX2853 single agent. To ensure adequate safety margin in the combination trial, a starting dose 
of PLX2853 40 mg/day is recommended in combination with carboplatin. Based on the PK, 
PDx, and safety results, the proposed starting doses of 80 mg/day for PLX2853 monotherapy and 
40 mg/day for PLX2853 + carboplatin combination therapy are expected to be 
pharmacologically active and safe. 
1.6 
Study Rationale 
BET inhibitors such as PLX2853 have shown efficacy preclinically in multiple tumor types, 
including ovarian cancer (Yokoyama 2016; Zhang 2016; Zhu 2016). In ovarian cancer, BRD4 is 
often amplified and correlates with worse overall and disease-free survival (Zhang 2016; 
Zhu 2016; Goundiam 2015). Recently BET inhibitors have demonstrated the ability to delay the 
onset of resistance to standard-of-care cisplatin treatment in ovarian cancer cell lines and tumors 
(Yokoyama 2016). BET inhibitors have been shown to overcome chemoresistance by 
suppressing stem cell-like phenotypes. It is likely ovarian cancer stem-like cells contribute to the 
emergence of chemoresistance (Pylvas-Eerola 2016), suggesting that BET inhibition could be 


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used in a combination setting in patients with ovarian cancer to overcome resistance to platinum-
based therapies. 
Inactivating mutations of ARID1A, a core component of the SWI/SNF complex, have been 
found in various types of cancer and occur at high frequency in gynecological malignancies 
including ovarian clear cell adenocarcinoma (OCCC) and endometrioid adenocarcinoma. 
Recently it has been shown that small molecule inhibitors of BET specifically inhibit 
proliferation of ARID1A mutated OCCCs, both in vitro and in vivo due to a lethal interaction 
between BRD2 and ARID1A (Berns 2018; Helming 2014; Kelso 2017). BET inhibition may 
represent a novel treatment strategy for gynecological cancers harboring ARID1A loss of 
function mutations. 
1.7 
Potential Risks and Benefits 
The identified risks of treatment with BET inhibitors from preclinical experience and other 
clinical development programs are hematologic toxicities, including thrombocytopenia, and 
decreased white blood cell and red blood cell counts. Decrease of lymphatic tissue and 
lymphocytes may also contribute to increased risk of infection. Intestinal mucosal atrophy was 
observed with mucosal inflammation and hemorrhage as a possible consequence. Prolongation of 
coagulation times (aPTT, prothrombin time) was also observed nonclinically and lung 
inflammation with hemorrhage was reported. Testicular atrophy was also reported in nonclinical 
studies. In the nonclinical toxicology studies, following 28 days of treatment-free recovery, 
microscopic findings had either completely resolved or were considered to be in the process of 
resolving, demonstrating the potential for reversibility of these findings. Most of these 
parameters can be monitored for their appearance and followed in clinical studies. This study is 
intended to evaluate safety, PK, tolerability, and preliminary efficacy of PLX2853 as a single 
agent and in combination with carboplatin. Subjects with no known treatment options have the 
opportunity to receive an experimental treatment with the hope of clinical benefit. 
As of 22 March 2021, a total of 68 subjects have received PLX2853 at doses ranging from 
5 to 180 mg in Studies PLX124-01 and PLX124-02. No treatment-related deaths have been 
reported. In PLX124-01, 4 treatment-related serious adverse events (SAEs) (thrombocytopenia, 
embolism, ischemic stroke, and subarachnoid hemorrhage) were reported in 1 subject at a dose 
of 120 mg/day. Two additional treatment-related SAEs of vomiting (120 mg/day) and diabetic 
ketoacidosis (60mg twice daily (BID)) were reported (the Sponsor determined that diabetic 
ketoacidosis was unrelated). In PLX124-02, 4 treatment-related SAEs have been reported. One 
subject experienced asymptomatic sinus bradycardia with sinus arrhythmia (80 mg/day) 
requiring overnight observation that resolved without treatment. Three subjects experienced a 
treatment-related SAE of hyperbilirubinemia. All 3 subjects were being treated above the RP2D 
(2 subjects dosed at 140 mg/day; 1 subject dosed at 180 mg/day). 
As of 22 March 2021, the most common adverse events (AEs) associated with PLX2853 
reported in >10% of subjects are nausea, fatigue, diarrhea, decreased appetite, dysgeusia, anemia, 
hyperbilirubinemia, and vomiting. Less common side effects associated with PLX2853 recorded 


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in 5% to 10% of subjects are dehydration, dizziness, dry mouth, gastroesophageal reflux disease, 
decreased platelet count, hyponatremia, increased aspartate aminotransferase, and white blood 
cell count decreased. 
As of 22 March 2021, 1 DLT has been reported in Study PLX124-03:  Grade 3 hyponatremia at 
a dose of 80 mg/day PLX2853 + carboplatin AUC 5 (mg•min/mL). Four DLTs have been 
reported in Study PLX124-01:  2 events of Grade 4 thrombocytopenia at 120 mg/day PLX2853; 
1 dose reduction in Cycle 1 for ≥Grade 2 AE (Grade 3 fatigue, Grade 2 cheilitis, Grade 2 nausea) 
at 40 mg BID (80 mg total/day); and 1 dose reduction in Cycle 1 for ≥Grade 2 AE (Grade 3 
thrombocytopenia) at 60 mg BID (120 mg total/day). Two DLTs have been reported in Study 
PLX124-02:  Grade 3 hyperbilirubinemia at a dose of 180 mg/day; Grade 4 hyperbilirubinemia 
at a dose of 140 mg/day. 
Refer to the Reference Safety Information section of the Investigator’s Brochure for additional 
safety information. 
1.8 
Previous Human Experience 
1.8.1 
Interim Results of Study PLX124-01 
As of 22 March 2021, 46 subjects were enrolled and treated at doses ranging from 5 to 
120 mg/day, all in the dose escalation portion of Study PLX124-01 as an ongoing study of 
PLX2853 in subjects with advanced malignancies and were included in the PK populations. 
Cohort 1 (3 subjects), Cohort 2 (3 subjects), Cohort 3 (4 subjects), Cohort 4 (3 subjects), 
Cohort 5 (4 subjects), and Cohort 6 (3 subjects) have been dosed at 5, 10, 20, 40, 80, and 
120 mg/day PLX2853, respectively, all with the 5 mg strength tablets. Cohort 7 (9 subjects), 
Cohort 8 (6 subjects), Cohort 9 (4 subjects), and Cohort 10 (6 subjects) have been dosed at 
120 mg QD, 40 mg BID (80 mg total/day), 60 mg BID (120 mg total/daily), and 100 mg QD 
PLX2853, respectively, all with the 20 mg strength tablets. The total number of subjects in Study 
PLX124-01 with PK data and included in the PK analysis is 45 subjects. 
The Day 1 and Day 15 geometric mean PK parameters are summarized in Table 4. After oral 
administration up to 120 mg/day PLX2853, rapid absorption was observed with median Tmax 
values ranging from 0.5 to 2 hour. Dose-dependent increases in the geometric mean AUC0-24 
values were observed on Day 1 and Day 15 (steady-state). No significant accumulation of 
PLX2853 was observed, which is consistent with the short terminal T1/2 observed on Day 1 with 
values <3 hours. Subjects enrolled in Cohorts 1–6 were administered the 5 mg strength tablets. 
As dose escalation continued, high pill burden increasingly became a challenge for the subjects, 
which prompted the development of the 20 mg strength tablet. Subjects enrolled in Cohorts 7–10 
were administered the 20 mg strength tablets. The Day 1 and Day 15 PK for the 20 mg strength 
tablets were compared to those for the 5 mg strength tablets at the 120 mg/day dose (Cohorts 6 
and 7). The Day 1 exposures (AUC0-24) are comparable between the 2 tablet formulations. 
Because of the small sample size, the statistical significance of the difference could not be 
assessed. 


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Table 4: 
Study PLX124-01:  Geometric Means of Pharmacokinetic Parameters at 
Day 1 and Day 15 (Steady-state) After Oral Administration of 5, 10, 20, 40, 
80, 120, and 120 (20 mg strength tablet) mg/day PLX2853 to Solid Tumor 
Patients 
Dose a 
(mg/day) Cohort 
N 
Geometric Mean b 
Day 1 
Day 15 
Accumu-
lation 
Ratio c 
Tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-24 
(ng•hr/mL) 
T1/2 
(hr) 
Tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-24 
(ng•hr/mL) 
T1/2 
(hr) 
5 
1 
3 
1.0 
43.9 
65.4 
0.582 0.5 
71.7 
88.6 
0.592 
1.4 
10 
2 
3 
0.5 
157 
207 
0.667 0.5 
204 
264 
0.866 
1.3 
20 
3 
4 
0.5 
364 
701 
1.52 
1.0 
353 
663 
2.06 
0.9 
40 
4 
3 
1.0 
1260 
2330 
1.52 
1.0 
1330 
2630 
2.59 
1.1 
80 
5 
4 
1.0 
1470 
2250 
1.87 
1.0 
1700 
2640 
2.32 
1.2 
120 
6 
3 
0.5 
4400 
6710 
2.48 
0.5 
4390 
5850 
2.67 
0.9 
120 
7 
9/3d 
1.0 
2990 
8770 
2.50 
1.0 
4000 
10500 
4.32 
1.5 
40 BID 
(80 mg 
total) 
8 
6 
1.0 
519 
2140 
1.37 
1.9 
256 
1270 
1.41 
0.6 
60 BID 
(120 mg 
total) 
9 
4 
1 
914 
4260 
1.68 
1.5 
881 
3420 
1.68 
0.8 
100 
10 
6 
1.5 
2210 
6630 
2.02 
2 
1370 
3660 
1.63 
0.6 
AUC0-24 = area under the concentration-time curve from time 0 to 24 hours postdose; BID = twice daily;  
Cmax = maximum observed concentration; Tmax = time to maximum observed concentration; T1/2 = terminal half-life 
a Subjects in Cohorts 1-6 received 5 mg strength tablets; subjects in Cohorts 7-10 received 20 mg strength tablets. 
b Tmax values presented are medians. 
c Accumulation ratio values were calculated by dividing the AUC0-24 on Day 15 by the AUC0-24 on Day 1. 
d N = 9 on Cycle 1 Day 1; N = 3 on Cycle 1 Day 15. 
 
Analysis of peripheral blood cells on Day 1 (before and after a single dose of PLX2853) 
demonstrated dose- and exposure-dependent changes in the expression of BET target genes 
(Figure 1). PDx effect was as measured by a 12-gene BET inhibitor responsive signature (the 
12 genes were:  HEXIM1, WDR47, GLS, G3BP1, CALM11, CIRBP, CCR1, CCR2, TNFRSF8, 
SCIMP, BTN3A2, and KMO). Significant and consistent PDx effect was first observed at 
40 mg/day QD. The corresponding daily exposure at steady-state at 40 mg/day 
(AUC0-24 = 2630 ng•hr/mL) defines the pharmacologically active exposure. 


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Figure 1: 
Study PLX124-01:  PLX2853 Pharmacodynamic Effect on Peripheral 
Blood Cells 
 
 
Of the subjects enrolled as of 22 March 2021, 34 were evaluable for efficacy. One subject with 
diffuse large B-cell lymphoma achieved a CR in the target tumor. Duration of response (DOR) is 
>10 months. One subject with ocular melanoma achieved a partial response (PR) as the best 
response in the target tumor. DOR was 92 days. Nineteen subjects experienced stable disease 
(SD) as the best response in the target tumor. One subject with ARID1A-mutant primary 
peritoneal cancer who had a best response of SD had an unconfirmed PR at Cycle 11 (30 weeks). 
The other 12 subjects experienced progressive disease (PD). 
1.8.2 
Interim Results of Study PLX124-02 
As of 22 March 2021, 22 subjects have enrolled in PLX124-02 at doses ranging from 20 to 
180 mg/day. Cohort 1 (3 subjects), Cohort 2 (4 subjects), and Cohort 3 (3 subjects) received 
20, 40, and 80 mg/day PLX2853, respectively, all with the 5 mg strength tablets. Cohort 4 
(3 subjects), Cohort 5 (3 subjects), Cohort 6 (2 subjects), and Cohort 7 (4 subjects) have been 
dosed at 80, 140, 180, and 140 mg/day PLX2853, respectively, all with the 20 mg strength 
tablets. 
The Day 1 and Day 15 geometric mean PK parameters are summarized in Table 5. After 20, 40, 
80, 140, and 180 mg/day PLX2853, rapid absorption was observed with median Tmax values 
ranging from 0.71 to 1.73 hour (Table 5). Two subjects in the 20 mg/day cohort (Cohort 1) had 
higher exposures on Cycle 1 Day 15 compared to Cycle 1 Day 1; the increases in PLX2853 
concentrations were attributed to patient-specific conditions unrelated to PLX2853. Once these 
conditions improved, PLX2853 plasma concentrations returned to expected levels. 
Dose-dependent increases in the geometric mean AUC0-24 values were observed on Day 1 (from 


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20 to 180 mg/day) and Day 15 (from 40 to 180 mg/day) (steady-state). No significant 
accumulation of PLX2853 was observed from 40 to 180 mg/day, which is consistent with the 
short terminal T1/2 observed on Day 1 with values <3.5 hours (Table 5). The Day 1 and Day 15 
PK parameters for the 2 strength tablet formulations (5 mg and 20 mg strength tablets) were 
compared at the 80 mg/day dose (Cohorts 3 and 4). The geometric mean AUC0-24 values are 
comparable. 
Table 5: 
Study PLX124-02:  Geometric Means of Pharmacokinetic Parameters at 
Day 1 and Day 15 (Steady-state) After Oral Administration of 20, 40, 80, and 
80 (20 mg strength tablet) mg/day PLX2853 to AML Patients 
Dose a 
(mg/day) Cohort 
N 
Geometric Mean b 
Day 1 
Day 15 
Accumu 
-lation 
Ratio c 
Tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-24 
(ng•hr/mL) 
T1/2 
(hr) 
Tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-24 
(ng•hr/mL) 
T1/2 
(hr) 
20 
1 
3 
1 
243 
676 
1.92 
1 
390 
1400 
2.39 
2.1 
40 
2 
4 
0.75 
648 
1080 
1.38 
0.5 
565 
836 
2.08 
0.8 
80 
3 
3 
1 
1530 
2740 
2.07 
1 
1630 
2700 
2.05 
1.0 
80 
4 
3 
1 
1330 
3020 
1.95 
1 
1040 
2450 
2.04 
0.8 
140 
5 
3 
0.71 
1390 
2550 
1.77 
1 
2640 
4990 
1.74 
3.6 
180 
6 
2 
1 
3480 
12000 
3.48 
1 
6190 
11200 
2.20 
0.9 
140 
7 
4/2d 1.68 
1490 
5690 
2.85 
1.73 
1450 
3840 
1.75 
0.7 
AML = acute myeloid leukemia; AUC0-24 = area under the concentration-time curve from time 0 to 24 hours 
postdose; Cmax = maximum observed concentration; Tmax = time to maximum observed concentration;  
T1/2 = terminal half-life 
a Subjects in Cohorts 1-3 received 5 mg strength tablets; subjects in Cohorts 4-7 received 20 mg strength tablets. 
b Tmax values presented are medians. 
c Accumulation ratio values were calculated by dividing the AUC0-24 on Day 15 by the AUC0-24 on Day 1. 
d N = 4 on Cycle 1 Day 1; N = 2 on Cycle 1 Day 15. 
 


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2.0 
STUDY OBJECTIVES 
2.1 
Phase 2a (PLX2853 Monotherapy) 
The primary objective is as follows: 
• To evaluate the efficacy of single-agent PLX2853 in subjects with advanced 
gynecological malignancies with a known ARID1A mutation 
The secondary objectives are as follows: 
• To further characterize the safety and efficacy of single-agent PLX2853 in subjects with 
advanced gynecological malignancies with a known ARID1A mutation 
• To further evaluate the PK of PLX2853 
2.2 
Phase 1b (PLX2853 + Carboplatin Combination) 
The primary objective is as follows: 
• To evaluate the safety and tolerability of PLX2853 + carboplatin combination including 
DLTs, MTD, and RP2D in subjects with platinum-resistant EOC 
The secondary objective is as follows: 
• To characterize the PK and efficacy of PLX2853 when combined with carboplatin in 
subjects with platinum-resistant EOC 
2.3 
Phase 2a (PLX2853 + Carboplatin Combination) 
The primary objective is as follows: 
• To evaluate the efficacy of PLX2853 + carboplatin combination at the RP2D in subjects 
with platinum-resistant EOC 
The secondary objective is as follows: 
• To further characterize the safety and PK of PLX2853 when combined with carboplatin 
in subjects with platinum-resistant EOC 
2.4 
All Phases 
The exploratory objectives are as follows: 
• To assess biomarkers in peripheral blood cells, tumor cells, and tissue biopsies 
• To further evaluate the PDx of PLX2853 


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3.0 
STUDY DESIGN 
3.1 
Overview of Study Design 
This open-label, multicenter, 2-part study will evaluate in parallel PLX2853 monotherapy in 
subjects with advanced gynecological malignancies with a known ARID1A mutation (with and 
without PIK3CA, PI3KR1, and/or PTEN mutations) and PLX2853 + carboplatin combination 
therapy in subjects with platinum-resistant EOC (including fallopian tube or primary peritoneal 
cancer) (Figure 2). 
Figure 2: 
Overview of Study PLX124-03 
PLX2853 Monotherapy Study Design: 
 
 


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PLX2853 + Carboplatin Combination Study Design 
 
AUC = area under the concentration-time curve; DLT = dose-limiting toxicity; EOC = epithelial ovarian cancer; 
QD = once daily; RP2D = recommended Phase 2 dose 
a All carboplatin doses are target AUC of 5 mg•min/mL unless otherwise specified. 
Note: Alternative scheduling of PLX2853 administration may be evaluated 
 
3.1.1 
Phase 2a PLX2853 Monotherapy Design 
The Phase 2a monotherapy part of the study will evaluate the efficacy, safety, PK, and PDx of 
PLX2853 in subjects with advanced gynecological malignancies with a known ARID1A 
mutation using a Simon’s 2-stage design. ARID1A, PIK3CA, PIK3R1, PTEN and homologous 
recombination repair mutational status and homologous recombination deficiency status will be 
determined based on historical data for all potential subjects from a commercially available next 
generation sequencing (NGS) panel such as FoundationOne® CDx or a local NGS panel 
performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. 


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The safety lead-in will comprise 6 subjects who will be enrolled at a dose of 80 mg/day and 
assessed for safety by the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0 and for evidence of DLTs. The rules for determining DLT are 
defined further below. After the safety lead-in has been completed, the Study Committee will 
convene to evaluate safety, PK, and PDx data to determine which dose to take forward for the 
remainder of subjects in Phase 2. Response rate for subjects in the safety lead-in will be included 
in the efficacy analysis for the purpose of the Simon’s 2 stage design. 
The starting dose level of PLX2853 will be 80 mg/day. In the absence of a DLT and in 
conjunction with review of the PK and PDx data from each cohort by the Study Committee, the 
safety lead-in is planned to occur in the following manner: 
• The starting dose of PLX2853 will be 80 mg/day 
• DLTs will be assessed in the first 28-day treatment period/cycle 
After dosing has been completed in this cohort of subjects, safety, PK, and PDx data (as 
applicable) will be reviewed, and any dose modification decisions, if applicable, will be made by 
the Study Committee. If ≥33% DLTs are seen during the initial safety lead-in, the Safety 
Committee will convene to consider a dose reduction. If a dose reduction is deemed appropriate, 
the subjects in the initial safety lead-in will need to be replaced and a repeat 6 subject safety 
lead-in will need to be conducted at this lower dose. Dose modification decisions will also take 
into consideration safety information beyond the DLT period from all enrolled subjects. If no 
DLT is observed, the recommended dose for further evaluation may be established based on 
safety, PK, and PDx convenience of dosing in subjects treated at that dose. If a DLT is seen in 
≥33% of subjects in the safety lead-in then the Study Committee will convene to consider 
alternative dose levels and schedule. 
If a subject misses more than 25% of the doses for Cycle 1 (e.g., >7 doses of PLX2853 in 
28 days) during the DLT window period for reasons other than an AE, additional subject(s) may 
be enrolled to provide adequate data for safety assessments. 
PLX2853 PK data will be analyzed for Cmax, plasma concentration-time curve (AUC), and 
accumulation ratio at steady state and compared with prior dose levels. Dose adjustments may 
also require increasing the number of subjects within a subset of subjects at a given dose level as 
a result of the review of safety, observed or anticipated disease activity, and PK data. 
A subset of patients may be studied in this trial to assess the effect of food on PLX2853 
exposure. These subjects will receive a single dose of PLX2853 under fed conditions 3 or 4 days 
prior to Cycle 1 Day 1 and have serial PK samples collected. On Cycle 1 Day 1, subjects will 
commence dosing at the same dose level under fasted conditions. 
At the discretion of the Sponsor, an additional Phase 2a monotherapy cohort may be enrolled 
using a Simon’s 2 stage design to evaluate the efficacy, safety, PK, and PDx of PLX2853 in 
subjects with advanced gynecological malignancies with a known ARID1A mutation and who do 


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not have known pathogenic mutations in the following genes (unless allowed with Medical 
Monitor approval): 
• Mutations or amplifications in PIK3CA 
• Mutations or amplifications in PIK3R1 
• Mutations or deletions in PTEN 
 
3.1.2 
Phase 1b/2a PLX2853 + Carboplatin Combination 
The Phase 1b/2a combination part of the study will evaluate the safety, PK, PDx, and efficacy of 
PLX2853 in combination with carboplatin in subjects with platinum-resistant EOC. 
In Phase 1b (dose escalation), the safety profile, RP2D/MTD, PK, PDx, and preliminary efficacy 
of PLX2853 (administered orally in 28-day treatment cycles) in combination with carboplatin 
(administered IV on Day 1 of each 28-day cycle) will be evaluated. Each cohort will be enrolled 
and assessed using a standard “3+3” design. The rules for determining DLTs and dose escalation 
are defined in Section 6.1 and Section 5.3.1, respectively. 
The provisional dose escalation plan is detailed in Table 6. 
Table 6: 
Provisional Dose Escalation Plan 
Dose Level 
Combination PLX2853 Dose  
(mg/day)a 
Carboplatin Dose  
(mg•min/mL)b 
-2 
20 
AUC 4  
-1 
20 
AUC 5  
1 (Starting Dose) 
40 
AUC 5  
2 
80 
AUC 5  
AUC = area under the concentration-time curve 
a Once daily dosing schedule unless otherwise specified. 
b Dosed on Day 1 of each 28-day cycle. 
 
In Phase 1b combination, the starting dose level of PLX2853 will be 40 mg/day plus a target 
AUC of 5 mg•min/mL dose of carboplatin (Cohort 1). In the absence of a DLT in the first cycle 
of treatment and in conjunction with review of the PK and available PDx data from each cohort 
by the Study Committee, dose escalation is planned to occur in the following manner: 
• DLTs will be assessed in the first treatment cycle (up to carboplatin dosing on Cycle 2 
Day 1). 
• The starting dose of PLX2853 will be 40 mg/day (Cohort 1), which is 50% below the 
PLX2853 monotherapy RP2D of 80 mg/day. 


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• Carboplatin will be administered using a target AUC of 5 mg•min/mL on Day 1 of each 
28-day treatment cycle per label. Carboplatin must be given within 7 days of Cycle 2 Day 1 
(delays due to reasons other than toxicity will not be assessed as a DLT). 
• If Dose Level 1 is not tolerated, Dose Level -1 (20 mg/day) will be investigated. If that dose 
level is intolerable, Dose Level -2 (PLX2853 20 mg/day and carboplatin AUC 
4 mg•min/mL) will be studied. If that dose level is intolerable, the study will be halted. 
• In the absence of a DLT, a second cohort with a PLX2853 dose of 80 mg/day will be 
investigated (Cohort 2). 
A minimum of 3 to 4 subjects will be initially enrolled in Cohort 1. If a DLT is observed in 
1 subject in a given cohort, up to 6 subjects will be treated at that dose. If DLTs are observed in 
2 or more of 6 subjects (or ≥33% of the cohort) at a dose level, the dose at which this occurs will 
be considered intolerable and the MTD will have been exceeded. The highest dose level at which 
0 of 3 subjects or 0 or 1 of 6 subjects experience a DLT will be declared the RP2D. If 
3 to 4 subjects were initially evaluated at that dose level, an additional 2 to 3 subjects may be 
enrolled to evaluate for DLTs at that dose level for confirmation. Up to 6 additional subjects with 
a known ARID1A mutation (unless otherwise approved by the Medical Monitor) may be treated 
at the RP2D at the discretion of the Sponsor for dose confirmation purposes. 
In order to be DLT evaluable a subject must not have missed more than 25% of study drug for 
reasons other than AE and must not have missed receiving carboplatin within 7 days of Cycle 2 
Day 1 (if applicable) for reason other than AE. If a subject misses more than 25% of the doses 
for Cycle 1 (e.g., >7 doses of PLX2853 in 28 days) during the DLT window for reasons other 
than an AE, additional subject(s) may be enrolled to provide adequate data for dose escalation 
decision making. Subjects who do not complete Cycle 1 for reasons other than drug toxicity may 
be replaced. Subjects must receive their Cycle 2 Day 1 carboplatin dose to be considered 
evaluable unless the reason for missing carboplatin is due to an AE. 
Once all ongoing subjects in a dose cohort have been treated for at least 2 cycles and the safety 
and tolerability of that dose level has been established, intra-subject dose escalation to that dose 
level may be permitted for subjects enrolled at lower dose levels who have not experienced an 
unresolved Grade 3 or higher treatment-related toxicity and have completed 2 cycles. Any 
intra-subject dose escalation requires a discussion and agreement with the Medical Monitor. 
After dosing has been completed in each cohort, safety, PK, and PDx data (if available) will be 
reviewed, and dose escalation decisions will be made by the Study Committee. Dose escalation 
decisions will also take into consideration safety information beyond the DLT period from 
earlier cohorts. If no DLT is observed, the recommended dose for further evaluation may be 
established based on toxicity, PK, convenience of dosing, and PDx (if available) in subjects 
treated at that dose. Dose escalation will only be permitted if adequate safety and tolerability 
have been demonstrated at the previous lower dose for 28 days. PLX2853 and carboplatin may 
not be dose escalated in the same cycle. 


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PLX2853 PK data will be analyzed in each dosing cohort for Cmax, AUC, and accumulation ratio 
at steady state and compared with prior dose levels. The number of subjects at a given dose level 
may be increased as a result of the review of safety, observed or anticipated disease activity, and 
PK data. Additional dosing schedules may be studied, such as alternate day dosing (e.g., every 
other day) depending on emerging safety and PK data. 
In Phase 2a (dose expansion), efficacy as well as additional safety, PK, and PDx data of 
PLX2853 in combination with carboplatin at the RP2D dose established in Phase 1b by the 
Study Committee will be obtained using a Simon’s 2-stage design. 
3.2 
Number of Subjects 
Up to 85 evaluable subjects may be enrolled across the study. 
Phase 2a (PLX2853 monotherapy): 
There will be up to 2 Simon’s 2-stage design cohorts of up to 38 evaluable subjects with 
ARID1A mutation-positive (with and without PIK3CA, PIKR1, and/or PTEN mutations) 
advanced gynecological malignancies. The safety lead-in of 6 subjects dosed at the level selected 
for Phase 2a will be included in the group of 12 evaluable subjects for Stage 1. 
Phase 1b (PLX2853 + carboplatin combination): 
Approximately 9 to 15 evaluable subjects with platinum-resistant EOC will be enrolled, 
depending on the number of escalation cohorts investigated. Up to 6 additional subjects with a 
known ARID1A mutation (unless otherwise approved by the Medical Monitor) may be treated at 
the RP2D at the discretion of the Sponsor for dose confirmation purposes. 
Phase 2a (PLX2853 + carboplatin combination): 
There will be 1 Simon’s 2-stage design cohort of between 12 to 26 evaluable subjects with 
platinum-resistant EOC. 
3.3 
Duration of Study 
The study encompasses the following periods: 
• Screening Period:  Up to 28 days prior to the first dose of study drug 
• Treatment Period:  Daily in 28-day cycles until subject discontinuation or withdrawal or 
study termination (see Section 7.1.5) 
– Subjects participating in the optional Food Effect sub-study will take a single dose of 
PLX2853 3 or 4 days prior to C1D1. 


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– For subjects enrolled in either the monotherapy or combination therapy cohorts, 
further treatment with either PLX2853 and/or carboplatin will depend on tolerability 
and clinical benefit as described in Section 7.1.5. In general, for subjects receiving the 
combination of PLX2853 + carboplatin, it is estimated that subjects will be treated 
with carboplatin for up to 6 cycles. 
• 30-day Follow-up (FU) Visit:  Approximately 30 days after the last dose of study drug 
or prior to starting any new anti-cancer therapy, whichever occurs first 
• Long-term Follow-up Period:  Survival follow-up can be via clinic visit, phone call to 
the subject or referring physician, or other method deemed appropriate by the site and 
should assess survival, progression, subsequent therapy, and response. Subjects will be 
followed until death, withdrawal of consent, or loss to follow-up according to the 
following schedule: 
– First 2 years after the 30-day FU Visit – Every 3 months 
– Third year after the 30-day FU Visit and beyond – Every 6 months 
– Any subject with a confirmed response who discontinues treatment for reasons other 
than disease progression will continue to be followed per standard of care and no less 
than every 3 months until documented disease progression, initiation of a new 
anti-cancer treatment, or 1 year from discontinuation of study treatment. 
Radiographic scan data will be collected and if scan data are not available, a scan will 
be obtained every 3 months until 6 months of radiographic follow-up after confirmed 
response has been obtained. 
 
3.4 
Study Endpoints 
3.4.1 
Primary Endpoints 
The primary endpoints are as follows: 
• Phase 2a (PLX2853 monotherapy):  overall response rate (ORR) as measured by Response 
Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) 
• Phase 1b (PLX2853 + carboplatin combination):  establish the MTD/RP2D for the 
combination of PLX2853 + carboplatin 
• Phase 2a (PLX2853 + carboplatin combination):  ORR as measured by RECIST v1.1 
 
3.4.2 
Secondary Endpoints 
The secondary endpoints are as follows: 
• Incidence of treatment-emergent adverse events (TEAEs), changes in safety parameters, and 
unacceptable toxicities 


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• DOR 
• Disease control rate (DCR) 
• Progression-free survival (PFS) 
• Overall survival (OS) 
• PLX2853 PK parameters following single and repeated dosing 
 
3.4.3 
Exploratory Endpoints 
The exploratory endpoint is as follows: 
• Analysis of peripheral blood and tumors for dose- and exposure-dependent changes in the 
expression of BET target genes  
 
3.5 
Randomization 
None of the subjects in this study will be randomized. 


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4.0 
STUDY POPULATION 
Subjects must meet the following inclusion and exclusion criteria to be enrolled in the study. 
4.1 
Inclusion Criteria 
1. Age ≥18 years at the time of signing informed consent 
2. Histologically or cytologically confirmed diagnosis of 1 of the following and must have 
measurable disease per RECIST v1.1: 
• Phase 2a (PLX2853 monotherapy):  Any advanced gynecological malignancy (cervical, 
vaginal, vulvar, uterine, ovarian, fallopian tube, or primary peritoneal) with a known 
ARID1A mutation, that is intolerant to or refractory to all standard therapy known to 
confer clinical benefit. 
– Subjects must have tumor accessible for sequential biopsy and be willing to provide 
on-study tumor tissue biopsy (core needle biopsy or excision required). Tissue 
collection must not constitute a significant risk procedure. A significant risk 
procedure is generally considered to be one for which the procedure associated 
absolute risk of mortality or major morbidity in the patient’s clinical setting and at the 
institution completing the procedure is 2% or higher. When possible, newly obtained 
tissue should be collected from a non-target lesion. 
• Phase 1b and Phase 2a (PLX2853 + carboplatin combination): 
Platinum-resistant EOC (including fallopian tube or primary peritoneal cancer). 
Platinum-resistant is defined as disease that may have responded to a platinum-containing 
chemotherapy regimen, but there is documentation of demonstrated recurrence within 
6 months following the completion of that platinum-containing regimen. 
 
OR 
 
Subjects with platinum-refractory EOC are eligible, provided refractory outcome was to 
second line or later repeated platinum regimen (not first line). Refractory is defined as 
disease that failed to achieve at least a PR to a platinum-containing regimen (i.e., SD or 
actual disease progression). 
 
Progressive disease of EOC following platinum-based therapy can be documented by 
physical examination, computed tomography (CT) scans, or a doubling of cancer antigen 
125 (CA-125) levels from either 1) upper limit of normal (ULN) or 2) most recent nadir 
value (per the Rustin criteria [Rustin 2011] [Appendix 6]). For CA-125 to be used as a 
criterion for progressive disease, the CA-125 level nadir must have been above the ULN. 
In addition, the CA-125 nadir level must have been confirmed by a second measurement 
at least 1 week after the initial measurement. 


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– Subjects in Phase 2a must have tumor accessible for sequential biopsy and be willing 
to provide on-study tumor tissue biopsy (core needle biopsy or excision required). 
Tissue collection must not constitute a significant risk procedure. A significant risk 
procedure is generally considered to be one for which the procedure associated 
absolute risk of mortality or major morbidity in the patient’s clinical setting and at the 
institution completing the procedure is 2% or higher. When possible, newly obtained 
tissue should be collected from a non-target lesion. 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1 
4. Adequate organ function as demonstrated by the following laboratory values. All Screening 
laboratory tests should be performed within 10 days of the first PLX2853 dose. Subjects 
must meet the following eligibility criteria prior to dosing: 
• Hematological: 
– Neutrophils ≥1500/µL 
– Platelets ≥100,000/µL 
– Hemoglobin ≥9 g/dL (transfusion and erythropoietin not permitted within 14 days 
prior to blood draw) 
• Renal: 
– Estimated glomerular filtration rate (GFR) (Chronic Kidney Disease Epidemiology 
Collaboration [CKD-EPI] creatinine calculation [Appendix 1]) ≥60 mL/min/1.73 m2 
• Hepatic: 
– Serum total bilirubin ≤1.5 × ULN 
OR 
– Direct bilirubin ≤ULN for subjects with total bilirubin >1.5 × ULN 
 
Exception for elevated bilirubin secondary to Gilbert’s disease, in which case it must 
be ≤2.5 mg/dL. Confirmation of Gilbert’s diagnosis requires:  elevated unconjugated 
(indirect) bilirubin values; normal complete blood count in previous 12 months, blood 
smear, and reticulocyte count; normal aminotransferases and alkaline phosphatase in 
previous 12 months 
– Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN 
– Gamma-glutamyl transferase ≤3 × ULN 
• Coagulation: 
– International normalized ratio ≤1.5 × ULN 
– aPTT ≤1.5 × ULN 


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• Chemistry: 
– Albumin ≥3.0 g/dL 
5. Women of child bearing potential (defined as any female who has experienced menarche 
and who has not undergone successful surgical sterilization [hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy] or is not postmenopausal) must have a negative serum 
pregnancy test within 7 days prior to taking the first dose of study drug and, if sexually 
active, must agree to use a highly effective method of contraception (a contraception method 
with a failure rate <1% per year) and 1 additional barrier method from the time of the 
negative pregnancy test to 90 days (for subjects in the United States (US)) or 6 months (for 
subjects in Canada) after the last dose of study drug. Women of non-child bearing potential 
may be included if they are either surgically sterile or have been postmenopausal for 
≥1 year. 
6. Except as specified above for organ function, all drug-related toxicity from previous cancer 
therapy must be resolved (to Grade ≤1 or baseline per NCI CTCAE v5.0) prior to study 
treatment administration (Grade 2:  alopecia, hot flashes, decreased libido, 
immuno-oncology drug induced hypothyroidism controlled with medication, or neuropathy 
is allowed). 
7. Willingness and ability to provide written informed consent prior to any study-related 
procedures and to comply with all study requirements 
 
4.2 
Exclusion Criteria 
1. Prior exposure to a bromodomain inhibitor, such as OTX-015 or CPI-0610 
2. Ongoing systemic infection requiring treatment with antibiotic, antiviral, or antifungal 
treatment 
3. Autoimmune hemolytic anemia or autoimmune thrombocytopenia 
4. Presence of symptomatic or uncontrolled central nervous system or leptomeningeal 
metastases (Note:  Subjects with stable, treated brain metastases are eligible for this study. 
However, subjects must not have required steroid treatment for their brain metastases within 
30 days of Screening.) 
5. Red blood cell or platelet transfusion within 14 days of Screening blood draw 
6. Known or suspected allergy to the investigational agent or any agent given in association 
with this study 
7. Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily 
adequate intake of 30 µg (NIH-ODS 2020). (Note:  Subjects who switch from a high dose to 
a dose of 30 µg/day or less are eligible for study entry.) Use of herbal, alternative, and food 
supplements (i.e., PC-Spes, Saw Palmetto, St. John’s Wort, etc.) and probiotics must be 
discontinued before treatment start. Daily multi-vitamin (provided it does not contain biotin 
>30 μg/day), calcium, and Vitamin D are permitted. 


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8. Use of strong inhibitors and inducers of CYP3A4 and 2C8 (Appendix 2) 
9. Clinically significant cardiac disease, defined as any of the following: 
• Clinically significant cardiac arrhythmias including bradyarrhythmias and/or subjects 
who require anti-arrhythmic therapy (excluding beta blockers or digoxin). Subjects with 
controlled atrial fibrillation are not excluded. 
• Congenital long QT syndrome or subjects taking concomitant medications known to 
prolong the QT interval (drugs with a low risk of QTc prolongation that are needed for 
infection control or nausea may be permitted with approval from the Medical Monitor). 
A list of drugs known to prolong the QT interval and risk of Torsades de pointes can be 
found in Appendix 4. 
• QT interval corrected using Fridericia’s equation (QTcF) ≥470 msec at Screening (based 
on average of triplicate electrocardiograms (ECGs) at baseline) 
• If the QTc is prolonged in a subject with a pacemaker or bundle branch block, the subject 
may be enrolled in the study if confirmed by the Medical Monitor 
• History of clinically significant cardiac disease or congestive heart failure >New York 
Heart Association Class II. Subjects must not have unstable angina (anginal symptoms at 
rest) or new-onset angina within the last 3 months or myocardial infarction within the 
past 6 months. 
• Uncontrolled hypertension, defined as systolic blood pressure >160 mmHg or diastolic 
blood pressure >100 mmHg that has been confirmed by 2 successive measurements 
despite optimal medical management 
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism 
within the 3 months before start of study medication (except for adequately treated 
catheter-related venous thrombosis occurring >1 month before the start of study 
medication) 
10. Inability to take oral medication or significant nausea and vomiting, malabsorption, or 
significant small bowel resection that, in the opinion of the Investigator, would preclude 
adequate absorption 
11. Poorly controlled known Type 2 diabetes with HbA1C >7.5% 
12. Non-healing wound, ulcer, or bone fracture 
13. Infection with HIV-1 or HIV-2. Exception:  subjects with well-controlled HIV  
(e.g., CD4 >350/mm3 and undetectable viral load) are eligible. 


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14. Current active liver disease from any cause, including hepatitis A (hepatitis A virus 
immunoglobulin M positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), 
or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic 
acid). Subjects with HCV with undetectable virus after treatment are eligible. Subjects with 
a prior history of HBV are eligible if quantitative PCR for HBV DNA is negative. Note that 
elevated levels of biotin may interfere with viral serology testing. 
15. Active known second malignancy with the exception of any of the following: 
• Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ 
cervical cancer 
• Adequately treated Stage I cancer from which the subject is currently in remission and 
has been in remission for ≥2 years 
• Any other cancer from which the subject has been disease-free for ≥3 years 
16. Major surgery or significant traumatic injury within 28 days prior to Cycle 1 Day 1 
17. Hospitalization for subacute bowel obstruction within 28 days prior to Cycle 1 Day 1 
18. Receipt of anti-cancer therapy prior to Cycle 1 Day 1: 
• Chemotherapy, radiation therapy, or small molecule anti-cancer therapy for the treatment 
of cancer within 14 days or 5 half-lives (whichever is shorter) of Cycle 1 Day 1 
• Immune therapy or other biologic therapy (e.g., monoclonal antibodies, antibody-drug 
conjugates) for the treatment of cancer within 21 days or 5 half-lives (whichever is 
shorter) of Cycle 1 Day 1 
Subjects can receive a stable dose of bisphosphonates for bone metastases, before and during 
the study as long as these were started at least 28 days prior to treatment with study drug. 
19. Subject is participating in any other therapeutic clinical study (observational or registry 
studies are allowed). 
20. Subjects who are pregnant or breast-feeding 
21. Presence of any other medical, psychological, familial, sociological, or geographic condition 
potentially hampering compliance with the study protocol or would interfere with the study 
endpoints or the subject’s ability to participate.  
 
4.2.1 
Effective Methods of Contraception 
If sexually active, women of child bearing potential must agree to use a highly effective method 
of contraception (a contraception method with a failure rate <1% per year) and 1 additional 
barrier method from the time of the negative pregnancy test to 90 days (for subjects in the US) or 
6 months (for subjects in Canada) after the last dose of study drug. 


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Barrier/Intrauterine Methods 
Hormonal Methods 
Male or female condom with or without spermicide 
Cap, diaphragm, or sponge each with spermicide 
Copper T intrauterine device or levonorgestrel-releasing 
intrauterine system (e.g., Mirena®)a 
Implantsa 
Hormone shot or injectiona 
Combined pilla 
Patcha 
a Highly effective (failure rate of <1% per year). 
 


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5.0 
STUDY TREATMENT 
5.1 
Investigational Product 
5.1.1 
PLX2853 
PLX2853 is formulated as 20 mg strength tablets for oral use. The active drug substance is 
PLX2853, with additional excipients of hypromellose acetate succinate, copovidone, 
microcrystalline cellulose, mannitol, croscarmellose sodium, silicon dioxide, sodium stearyl 
fumarate, sodium bicarbonate, and poloxamer. The drug product presentation is a white to 
off-white solid tablet. The tablets are embossed with “PLX” on one side. 
5.1.2 
Carboplatin 
Carboplatin is supplied as a sterile, pyrogen-free 10 mg/mL aqueous solution of carboplatin, 
USP for injection. 
The NCCN 2018 recommendations should be used for carboplatin dosing as follows: 
The Calvert equation should be applied to calculate dosage using a target AUC in mg•min/mL:  
Carboplatin dose (mg) = (target AUC) × (GFR + 25) 
Target AUC will be 5 mg•min/mL. With the Calvert equation, the total dose of carboplatin is 
calculated in mg not mg/m2. The GFR should be estimated by calculated creatinine clearance 
(CrCl) using the Cockcroft-Gault equation: 
CrCl (male; mL/min) = (140 – age) × (weight in kg) 
72 × serum creatinine (mg/dL) 
CrCl (female; mL/min) = 0.85 × CrCl (male) 
The dose of carboplatin for desired exposure (AUC) should be capped to avoid potential toxicity 
due to overdosing. The maximum dose is based on a GFR estimate that is capped at 125 mL/min 
for subjects with normal renal function. Based on the Calvert equation, the maximum doses can 
be calculated as follows: 
Maximum carboplatin dose (mg) = Target AUC (mg•min/mL) × (125 mL/min + 25) 
For a target AUC = 5, the maximum dose is 5 × 150 = 750 mg 
For a target AUC = 4, the maximum dose is 4 × 150 = 600 mg 
For overweight or obese subjects (body mass index ≥25 kg/m2), consider using an adjusted body 
weight:   
Adjusted body weight (kg) = ideal body weight (IBW) + 0.4 × (total body weight – IBW) 


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For subjects with abnormally low serum creatinine, including elderly or cachectic subjects, 
consider using a minimum creatinine of 0.7 mg/dL to avoid overestimation of CrCl. 
Once the initial dose of carboplatin is calculated, it does not need to be recalculated for 
subsequent cycles unless the subject is experiencing toxicity and requires dose modification to a 
lower dose of carboplatin. 
5.2 
Study Drug Administration 
5.2.1 
PLX2853 Administration 
PLX2853 should be dosed orally with water using a tablet formulation as defined for each 
cohort. Subjects should fast for at least 2 hours before and 1 hour after taking PLX2853, except 
for PK collection days when subjects should fast for at least 8 hours (10 hours on fed dosing day 
for the optional Food Effect sub-study) before taking PLX2853 (see Section 5.2.3). During the 
fasting period, subjects may eat a low-fat snack (e.g., crackers, dry toast, etc.) if they experience 
gastrointestinal symptoms (e.g., nausea, vomiting, etc.) following dosing. PLX2853 should be taken 
at approximately the same time each day. PLX2853 should be swallowed whole and not crushed, 
chewed, or dissolved in water. A dosing period of up to 30 minutes is permissible if required by 
the number of tablets to be taken or as convenient for the subject. Missed doses (generally 
outside of a 2-hour dosing window for BID dosing and a 5-hour dosing window for QD dosing) 
should be skipped and not administered as a double dose at the next administration. Subjects who 
omit their dose should be instructed NOT to make up that dose. Doses that are vomited should 
not be replaced. 
Subjects will be treated with PLX2853 for 28-day cycles. Guidance for dose modification is in 
Section 6.2. 
5.2.2 
Carboplatin Administration 
For subjects enrolled to the Phase 1b/2a PLX2853 + carboplatin cohorts, carboplatin will be 
administered intravenously using a target AUC of 5 mg•min/mL on Day 1 of each 28-day 
treatment cycle per the label. Carboplatin should be administered at least 2 hours after PLX2853 
dosing. Prophylaxis for hypersensitivity reaction and skin testing should be considered per 
institutional standard of care for subjects who have received prior platinum-based regimens. 
Details on carboplatin dosage calculation is in Section 5.1.2. Guidance for dose modification is 
in Section 6.2. 
5.2.3 
Dosing on Pharmacokinetic Sample Collection Days 
Subjects should be instructed not to take their morning dose of PLX2853 at home before the 
clinic visit. The time of dosing will be recorded in the clinic. On PK days where a full PK profile 
is collected (e.g., C1D-3 or C1D-4 (as applicable) C1D1, C1D15), subjects should fast at least 
8 hours (10 hours on fed dosing day for the optional Food Effect sub-study) before dose 
administration and 1 hour (4 hours on fed dosing day for the optional Food Effect sub-study) 


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after administration of PLX2853. On other PK sample collection days, subject should fast for 
2 hours prior to their visit. 
5.2.4 
Effect of Food on PLX2853 
In order to obtain more complete information on the PK profile of PLX2853, PK sampling will 
be performed in an optional Food Effect sub-study in the Phase 2a monotherapy cohort following 
a single dose of PLX2853 given 3 or 4 days prior to the start of continuous dosing. Food effect 
will be examined between test (fed state, Day -4 or -3) and reference (fasted state, Cycle 1 Day 
1) treatments using a 1-way crossover design. On Day -4 or -3 following an overnight fast of at 
least 10 hours, subjects should start the recommended low-fat meal before administration of the 
drug product and complete the meal in 30 minutes or less. A single dose of PLX2853 should be 
taken with 8 ounces (240 mL) of water and within 30 minutes after the low-fat meal. No food is 
allowed for at least 4 hours after the dose. 
The low-fat test meal should be approximately 400–500 calories, with approximated 25% of total 
caloric content coming from fats. An example low-fat test meal is 8 ounces of milk (1% fat), 
1 boiled egg, and 1 packet flavored instant oatmeal made with water. A comparable meal may be 
substituted as long as it contains a similar amount of calories and % fat. The test meal, start and 
completion time of consumption of the meal, and the proportion consumed by the patient will be 
recorded on a case report form (CRF). On Day -4 or -3, PK samples will be collected at predose, 
0.5, 1, 2, 3, and 5 hours postdose. Additional labs and safety assessments will be performed as 
specified in the Schedule of Events (Synopsis Table 1). 
On C1D1 subjects should fast at least 8 hours before dose administration and 1 hour after dose 
administration. All labs and safety assessments specified on C1D1 in the Schedule of Events 
(Synopsis Table 1) must be completed on C1D1. 
The Day -4 or -3 (test) and Day 1 (reference) exposures will be compared. The CI90 of the ratio 
of the test treatment (fed) relative to the reference treatment (fasted) will be obtained. No food 
effect will be confirmed if the CI90 falls between the 80% to 125% interval following the 2-sided 
test procedure. 
5.3 
Dose Escalation (Phase 1b PLX2853 + Carboplatin Only) 
In Phase 1b (PLX2853 + carboplatin combination) dose escalation, cohorts will be enrolled using 
a standard “3+3” design. The starting dose level of PLX2853 will be 40 mg/day plus a target 
AUC of 5 mg•min/mL dose of carboplatin (Cohort 1). In the absence of a DLT in the first cycle 
of treatment and in conjunction with review of the PK and available PDx data from each cohort 
by the Study Committee, dose escalation is planned to occur in the following manner: 
• DLTs will be assessed in the first treatment cycle (up to carboplatin dosing on Cycle 2 
Day 1). 


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• The starting dose of PLX2853 will be 40 mg/day (Cohort 1), which is 50% below the 
PLX2853 monotherapy RP2D of 80 mg/day. 
• Carboplatin will be administered using a target AUC of 5 mg•min/mL on Day 1 of each 
28-day treatment cycle per label. Carboplatin must be given within 7 days of Cycle 2 Day 1 
(delays due to reasons other than toxicity will not be assessed as a DLT). 
• If Dose Level 1 is not tolerated, Dose Level -1 (20 mg/day) will be investigated. If that dose 
level is intolerable, Dose Level -2 (PLX2853 20 mg/day + carboplatin AUC 4 mg•min/mL) 
will be studied. If that dose level is intolerable, the study will be halted. 
• In the absence of a DLT, a second cohort with a PLX2853 dose of 80 mg/day will be 
investigated (Cohort 2). 
 
5.3.1 
Dose Escalation Rules 
Dose escalation will occur in accordance with the following rules: 
• A minimum of 3 to 4 subjects will be initially enrolled in Cohort 1. 
• If a DLT is observed in 1 subject in a given cohort, up to 6 subjects will be treated at that 
dose. 
• If DLTs are observed in 2 or more of 6 subjects (or ≥33% of the cohort) at a dose level, the 
dose at which this occurs will be considered intolerable and the MTD will have been 
exceeded. 
• The highest dose level at which 0 of 3 subjects or 0 or 1 of 6 subjects experience a DLT will 
be declared the RP2D. If 3 to 4 subjects were initially evaluated at that dose level, an 
additional 2 to 3 subjects may be enrolled to evaluate for DLTs at that dose level for 
confirmation. Up to 6 additional subjects with a known ARID1A mutation (unless otherwise 
approved by the Medical Monitor) may be treated at the RP2D at the discretion of the 
Sponsor for dose confirmation purposes. 
• In order to be DLT evaluable a subject must not have missed more than 25% of study drug 
for reasons other than AE and must not have missed receiving carboplatin within 7 days of 
Cycle 2 Day 1 (if applicable) for reason other than AE. If a subject misses more than 25% of 
the doses for Cycle 1 (e.g., >7 doses of PLX2853 in 28 days) during the DLT window for 
reasons other than an AE, additional subject(s) may be enrolled to provide adequate data for 
dose escalation decision making. Subjects who do not complete Cycle 1 for reasons other 
than drug toxicity may be replaced. Subjects must receive their Cycle 2 Day 1 carboplatin 
dose to be considered evaluable unless the reason for missing carboplatin is due to an AE. 


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• Once all ongoing subjects in a dose cohort have been treated for at least 2 cycles and the 
safety and tolerability of that dose level has been established, intra-subject dose escalation to 
that dose level may be permitted for subjects enrolled at lower dose levels who have not 
experienced an unresolved Grade 3 or higher treatment-related toxicity and have completed 
2 cycles. Any intra-subject dose escalation requires a discussion and agreement with the 
Medical Monitor. 
• After dosing has been completed in each cohort, safety, PK, and PDx data (if available) will 
be reviewed, and dose escalation decisions will be made by the Study Committee. Dose 
escalation decisions will also take into consideration safety information beyond the DLT 
period from earlier cohorts. 
• If no DLT is observed, the recommended dose for further evaluation may be established 
based on toxicity, PK, convenience of dosing, and PDx (if available) in subjects treated at 
that dose. Dose escalation will only be permitted if adequate safety and tolerability have been 
demonstrated at the previous lower dose for 28 days. 
• PLX2853 and carboplatin may not be dose escalated in the same cycle. 
 
5.4 
Concomitant Medications (and Procedures) 
Concomitant treatment is permitted if the medication is not expected to interfere with the 
evaluation of safety or efficacy of the study drug. Other antineoplastic therapy for the treatment 
of the cancer for which subject is enrolled onto this study is not permitted (with the exception of 
certain standard of care hormonal therapies in consultation with the Medical Monitor). During 
the study, if the use of any concomitant treatment becomes necessary (e.g., for treatment or 
prophylaxis of an AE), the treatment must be recorded on the electronic case report form 
(eCRF), including the reason for treatment, generic name of the drug, dosage, route, and date of 
administration. 
PLX2853 was stable in human liver S9 fractions with 1 metabolite (M1) detected. CYP2C8 and 
CYP3A4 are the major contributors for the formation of the PLX2853 oxidative metabolite M1. 
Their relative contributions to the formation of M1 were similar. However, because the rate of 
metabolism is very low, CYP2C8 and CYP3A4 inhibitors are not expected to have a significant 
effect on the clearance of PLX2853. Until information regarding exposure-toxicity and exposure-
response relationships are available with PLX2853, concomitant CYP3A4 and CYP2C8 
inhibitors and/or inducers should be avoided and may be administered after study entry with 
Medical Monitor approval, in the event they alter the systemic exposure to PLX2853 (see 
Appendix 2 for an example list of strong CYP3A4/2C8 inhibitors and inducers). 
No routine prophylactic anti-emetic treatment is required at the start of study treatment; however, 
subjects should receive appropriate anti-emetic treatment at the first onset of nausea or vomiting 
and as required thereafter, in accordance with local treatment practice guidelines. 


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As per international guidance on antiemetic use in cancer subjects, generally, a single-agent 
antiemetic should be considered (NCCN 2020; Roila 2016). 
Locally acting antacids may be used for initial presentation of gastroesophageal reflux disease 
(GERD). If locally acting antacids do not properly control GERD, proton pump inhibitors and 
other gastric pH modifiers may be used. All antacids, proton pump inhibitors, and other gastric 
pH modifiers should be administered 2 hours after PLX2853 administration. 
The use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily 
adequate intake of 30 µg is prohibited during the study (NIH-ODS 2020). A total daily dose of 
30 µg or less is allowed. Use of herbal, alternative, and food supplements (i.e., PC-Spes, Saw 
Palmetto, St. John’s Wort, etc.) and probiotics must be discontinued before treatment start. Daily 
multi-vitamin (provided it does not contain biotin >30 μg/day), calcium, and Vitamin D are 
permitted. 
Concomitant medications known to prolong the QT interval (see Appendix 4) are prohibited 
while receiving study drug (drugs with a low risk of QTc prolongation that are needed for 
infection control or nausea may be permitted with approval from the Medical Monitor). 
All ongoing medications and therapies (including herbal products, nutritional supplements, and 
nontraditional medications) at Screening will be considered prior medications. All medications 
and procedures must be recorded on the appropriate eCRFs at the start of Screening until 30-day 
FU Visit procedures are performed or until the initiation of a non-protocol therapy for the 
underlying malignancy, whichever occurs first. 
Palliative radiotherapy may be used for the treatment of pain at the site of bone metastases that 
were present at baseline following the completion of Cycle 1, provided the Investigator does not 
feel that these are indicative of clinical disease progression during the study period. Study 
treatment should be discontinued for a minimum of 3 days before a subject undergoes 
therapeutic palliative radiation treatment and 7 days after completing radiation treatment. Study 
treatment should be restarted within 21 days as long as any bone marrow toxicity has recovered. 
5.5 
Precautions and Restrictions 
There are no non-medication-related restrictions or precautions. 
5.6 
Management of Clinical Events 
All necessary support care shall be available to subjects. For dose modification guidelines, see 
Section 6.2. 
5.7 
Blinding and Unblinding 
Blinding methods will not be employed; PLX2853 and carboplatin (if applicable) will be 
administered in open-label fashion. 


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5.8 
Preparation, Reconstitution, and Dispensation 
PLX2853 is an anti-cancer drug and, as with other potential toxic compounds, caution should be 
exercised when handling PLX2853 (see Section 5.10). Specific instructions on preparation, 
reconstitution, and dispensation will be provided in the Study Pharmacy Manual. 
Carboplatin will be prepared and administered per the label. 
5.9 
Packaging and Labeling 
PLX2853 tablets are manufactured, packaged, and labeled according to Good Manufacturing 
Practice and Good Clinical Practice (GCP) at the following address: 
 
BioDuro LLC (formerly Formex LLC) 
 
11011 Torreyana Road #100 
 
San Diego, CA 92121 
Carboplatin is packaged per the label. 
5.10 
Storage, Handling, and Accountability 
PLX2853 tablets should be stored at room temperature 20°C to 25°C (68°F–77°F); excursions 
are permitted between 15°C and 30°C (59°F and 86°F). Subjects will be requested to store 
PLX2853 at the recommended storage conditions noted on the label. Carboplatin will be stored 
at the recommended storage conditions per the label. 
The study drugs provided in accordance with this protocol will be kept in a secure place and will 
only be supplied to subjects participating in this study. The Principal Investigator is accountable 
for all study drug supplied by the Sponsor in accordance with this protocol. In addition, the 
Principal Investigator must keep accurate and up-to-date dispensation records. Any study drug 
accidently or deliberately destroyed must be recorded in a timely fashion, including an 
explanation for the destruction in writing. Any discrepancies between the amounts of study drug 
dispensed and returned must also be explained in writing. All such records of drug accountability 
must be entered on the corresponding subject eCRFs. 
All unused and partially used study drug must be sealed and returned to the Sponsor or designee 
or destroyed on site in accordance with the established procedures for drug destruction. Details 
of destruction, including, but not limited to, the number of boxes destroyed, batch number, and 
the date and method of destruction must be recorded on the study drug destruction logs. 
5.11 
Other Protocol-specified Materials 
Central laboratory kits will be provided for sample collection, shipment, and storage for PK and 
PDx analyses. 


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6.0 
DOSE-LIMITING TOXICITIES AND DOSE MODIFICATIONS 
6.1 
Definitions of Dose-limiting Toxicity 
DLTs are defined as clinically significant AEs or laboratory abnormalities occurring during the 
first cycle of study drug administration that are at least possibly related to either PLX2853 or 
carboplatin and clearly unrelated to disease progression, concurrent illness, or concomitant 
medication, and that meet one of the following CTCAE v5.0 criteria below. DLTs will be 
evaluated for the monotherapy safety lead-in subjects as well as each Phase 1b (PLX2853 + 
carboplatin) escalation cohort. Toxicities occurring in treatment Cycle 2 or later will be reviewed 
and their impact on subsequent dosing levels and frequency assessed. 
In Phase 1b (PLX2853 + carboplatin), there will be a 24-hour delay between the first and 
subsequent subjects enrolled in each dose escalation cohort to maximize the safety of enrolled 
subjects. 
Subjects participating in the optional  Food Effect sub-study as well as the monotherapy safety 
lead-in will be DLT evaluable from the date of first dose and the DLT window for these patients 
will be 28 days from C1D1. 
Subjects who are withdrawn from the study prior to completing the DLT assessment window for 
any reason other than a DLT will be replaced. Subject numbers must not be re-used. 
DLTs are defined as follows: 
• Hematologic Toxicities 
• Grade 4 neutropenia lasting >7 days 
• Grade ≥3 febrile neutropenia 
• Grade 4 thrombocytopenia 
• Grade ≥3 thrombocytopenia lasting >7 days or associated with clinically significant 
bleeding 
• Grade 4 anemia 
• Non-hematologic Toxicities 
• Any dose reduction required during Cycle 1 due to an AE 
• Any treatment delay of >7 consecutive days during Cycle 1 due to study drug-related 
Grade ≥2 AEs that fail to resolve to baseline or Grade ≤1 
• Any case of Hy's law defined as AST or ALT >3 × ULN with concurrent total bilirubin 
>2 × ULN, absence of cholestasis (elevated alkaline phosphatase (ALP) >2 × ULN), and 
no alternative etiology which can explain the combination of increased AST or ALT and 
total bilirubin, such as viral hepatitis A through E, other preexisting or acute liver disease, 
or another drug capable of causing the observed injury 


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• Any Grade ≥3 increase in AST/ALT (only for subjects without hepatic metastasis and 
with baseline values within normal limits) 
• AST/ALT >5 × ULN for ≥14 days or any AST/ALT >8 × ULN (only for subjects with 
hepatic metastasis or with abnormal baseline values) 
• Grade 3 nausea, vomiting, or diarrhea that does not resolve to Grade ≤2 in ≤72 hours 
• Any Grade 4 vomiting or diarrhea (life-threatening; urgent medical intervention 
indicated) irrespective of duration 
• Any non-clinically significant Grade 3 or higher electrolyte imbalance that does not 
correct to Grade ≤1 in ≤5 days 
• Any Grade 3 or Grade 4 clinically significant electrolyte imbalance (life-threatening; 
urgent medical intervention indicated) irrespective of duration 
• Unless specifically noted in other DLT criteria any Grade ≥3 (AE or laboratory 
abnormality) toxicity that does not resolve to Grade ≤2 within 7 days despite maximal 
medical intervention, except for the following: 
– Grade 3 neuropathy in subjects with pre-existing Grade 2 neuropathy 
• Any other Grade ≥3 toxicity (except those noted above) for which either the Principal 
Investigator or Sponsor deems further dose escalation inappropriate 
• Carboplatin Cycle 2 Day 1 dose reduction (AUC not total dose) or carboplatin Cycle 2 
Day 1 dose interruption for >7 days 
– An allergic reaction to carboplatin or any AEs associated with the allergic reaction 
during Cycle 1 will not be considered a DLT. The subject will be noted as inevaluable 
and will be replaced. 
• Any death not clearly due to underlying disease or an extraneous cause 
A subject who experiences a DLT may remain in the study and continue receiving study drug(s) 
at a lower dose if the Investigator deems the potential benefit outweighs the risk and that the 
subject is not eligible for, and/or interested in, an alternative therapy after consultation and 
agreement with the Medical Monitor. 
AEs occurring in treatment Cycle 2 or later will be collected, analyzed, and discussed with the 
Study Committee to help inform the selection of doses for subsequent study cohorts, including 
the option of dose reduction. If cumulative toxicities are observed requiring dose reductions in 
1 of 3 or more subjects, dose escalation may be halted and more subjects may be treated at that 
or a lower dose level. 
6.2 
Dose Modification Guidelines 
Reduction of dosing may take place for study drug-related AEs in Cycle 2 and beyond for 
subjects enrolled in the Phase 1b PLX2853 + carboplatin dose escalation cohorts or the safety 


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lead-in for the Phase 2a PLX2853 monotherapy part and at any time for subjects enrolled in the 
Phase 2a PLX2853 + carboplatin dose expansion cohorts and for subjects that are not part of the 
safety lead-in of the Phase 2a PLX2853 monotherapy part. Table 7 presents guidelines for 
dosage modification and re-treatment for PLX2853-related toxicities. These parameters are only 
a guide and are not intended to supersede the clinical judgment of the treating physician. Dose 
modifications of carboplatin should follow the label, as well as the guidance below. 
If an allergic reaction to carboplatin occurs after Cycle 1, both PLX2853 and carboplatin should 
be held until a carboplatin desensitization protocol is conducted per institutional standard of care. 
Dosing of study drugs may resume after the subject’s successful completion of a desensitization 
protocol and with approval from the Medical Monitor. 
For the combination parts of the study, if 1 study drug needs to be held due to an AE, then both 
drugs need to be held until the AE resolves per the dose modification guidelines unless Medical 
Monitor approval is granted. If 1 study drug needs to be permanently discontinued, then both 
study drugs must be permanently discontinued and the subject taken off study unless approval 
granted by the Medical Monitor. 
The dose modification/reduction guidelines are for clinically significant toxicities that are at least 
possibly related to PLX2853 administration. Definitions of “clinically significant” and “related” 
will be made based on the judgment of the Investigator, and the case should be discussed with 
the Medical Monitor as needed. All adjustments should be made in consultation with the Medical 
Monitor. 
If there is a PLX2853 dosing hold within a cycle (e.g., due to toxicity), study drug dosing will 
resume on the next appropriate day. For example, if the subject has a study drug hold for 10 days 
beginning on Cycle 2 Day 8 (Day 1 of hold), the subject should resume the schedule of events 
for Cycle 2 Day 18. If study assessments are missed during a hold, those assessments will be 
noted as not done and the next scheduled assessment day procedures will be followed. If the drug 
hold is less than 3 weeks between cycles, the first day of dosing in subsequent cycles should be 
considered Day 1, and all procedures calculated based on that starting day. For example, if the 
subject has a study drug hold on Cycle 2 Day 15 for 15 days, the subject will resume the 
schedule of events for Cycle 3 Day 1. Every attempt should be made to keep to the 28-day cycle. 
In Cycle 2 and beyond, dose interruptions for Grade ≤2 non-hematologic toxicity can be 
implemented for up to 1 week at the discretion of the treating physician to manage clinically 
significant toxicities. No dose reduction is required when resuming treatment. 
Dosing interruptions longer than 2 weeks should generally result in discontinuation from the 
study, unless the subject has demonstrated a clinical benefit from therapy and would like to 
continue dosing with study drug after discussion with the Sponsor and approval by the Medical 
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Table 7: 
Recommended PLX2853 Dose Modifications 
PLX2853-Related 
Toxicities 
Frequency 
When to Hold or Stop 
Dose Adjustments for 
Resumptiona 
Grade 3 or 4 
neutropenia 
1st Appearance 
Interrupt until ANC 
recovers to ≥1.5 × 109/L; 
growth factor support 
permitted 
If recovered to ANC ≥1.5 × 109/L in 
≤7 days, resume at same dose. 
If not recovered to ANC ≥1.5 × 
109/L after 7 days, reduce dose by 
1 dose level. 
2nd Appearance 
Interrupt until ANC 
recovers to ≥1.5 × 109/L; 
growth factor support 
permitted 
If recovered to ANC ≥1.5 × 109/L in 
≤7 days, reduce dose by 1 dose 
level. 
If not recovered to ANC ≥1.5 × 
109/L after 7 days, reduce dose by 
2 dose levels. 
3rd Appearance 
Discontinue permanently; 
growth factor support 
permitted 
N/A 
Grade 3 or 4 
febrile neutropenia 
1st Appearance 
Interrupt until ANC and 
fever recover; provide 
growth factor support 
If recovered to ANC ≥1.5 × 109/L 
and T ≤38°C in ≤7days, reduce dose 
by 1 dose level. 
If not recovered to ANC ≥1.5 × 
109/L after 7 days, discontinue 
permanently. 
2nd Appearance 
Discontinue permanently; 
provide growth factor 
support 
N/A 
Grade 3 or 4 
thrombocytopenia 
without bleeding  
1st Appearance of G3 
Interrupt until PLT 
≥75 × 109/L 
If recovered to PLT ≥75 × 109/L 
≤7 days, resume at same dose. 
If not recovered to PLT ≥75 × 109/L 
after 7 days, reduce dose by 1 dose 
level. 
2nd Appearance of G3 or 
1st Appearance of G4 
Interrupt until PLT 
≥75 × 109/L 
If recovered to PLT ≥75 × 109/L in 
≤7 days, reduce dose by 1 dose 
level. 
If not recovered to PLT ≥75 × 109/L 
after 7 days, reduce dose by 2 dose 
levels. 
3rd Appearance of G3 or 
2nd Appearance of G4 
Discontinue permanently 
N/A 


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PLX2853-Related 
Toxicities 
Frequency 
When to Hold or Stop 
Dose Adjustments for 
Resumptiona 
Grade 3 or 4 
thrombocytopenia 
with clinically 
significant bleeding  
1st Appearance 
Discontinue permanently 
N/A 
Other Grade 3 
toxicities 
(excluding  
transaminase 
increases) 
1st Appearance 
Interrupt until resolved 
(Grade 0–1); start 
symptomatic treatment if 
possible 
If recovered ≤5 days, resume at 
same dose. 
If symptoms persist for >5 days 
despite supportive management, 
reduce by 1 dose level.  
2nd Appearance 
Interrupt until resolved 
(Grade 0–1); start 
symptomatic treatment if 
possible 
If recovered ≤5 days, reduce dose by 
1 dose level. 
If symptoms persist for >5 days 
despite supportive management, 
discontinue permanently. 
3rd Appearance 
Discontinue permanently; 
start symptomatic 
treatment if possible 
N/A 
Grade 3 non-
hematologic 
toxicities 
1st Appearance 
Interrupt until resolved to 
Grade ≤1 or baseline 
If recovered to Grade ≤1 or baseline 
in ≤14 days, restart at a reduced 
dose by 1 dose level. 
If symptoms persist at Grade ≥2 for 
>14 days, discontinue permanently. 
Grade 4 non-
hematologic 
toxicities 
1st Appearance 
Discontinue permanently; 
start symptomatic 
treatment if possible 
N/A 


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PLX2853-Related 
Toxicities 
Frequency 
When to Hold or Stop 
Dose Adjustments for 
Resumptiona 
Transaminase 
increases 
• ALT or AST 
>8 × ULN but 
<20 × ULN 
• ALT or AST 
>5 × ULN for more 
than 2 weeks 
• ALT or AST 
>3 × ULN and total 
bilirubin >2 × ULN or 
INR >1.5 (in absence 
of anticoagulation) 
• ALT or AST 
>3 × ULN with the 
appearance of fatigue, 
nausea, vomiting, right 
upper quadrant pain or 
tenderness, fever, rash, 
and/or eosinophilia 
(>5%) 
Immediately hold dose and 
discuss with Medical 
Monitor. 
Institute close monitoring. 
Any decision to restart 
after transaminases return 
to baseline must be 
discussed with the Medical 
Monitor.  
If clinically indicated, restart at a 
reduced dose. 
• Hy’s Law: AST/ALT 
>3 × ULN and total 
bilirubin >2 × ULN 
and ALP <2 × ULN 
with no alternative 
etiology for the 
observed injury 
• ALT or AST 
>20 × ULN 
Discontinue permanently 
N/A 
QTcF >500 msec 
or 60 msec increase 
from baseline 
verified on repeat 
ECG 
1st Appearance 
Interrupt study drug until 
resolved.  
Upon recovery to QTc ≤500 msec 
(Grade ≤2), restart at a reduced 
dose. 
Permanently discontinue study drug 
if the QTc interval remains 
>500 msec and increased >60 msec 
from pretreatment values (after 
controlling cardiac risk factors for 
QT prolongation, e.g., electrolyte 
abnormalities, congestive heart 
failure, and bradyarrhythmias).b 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; ECG = electrocardiogram; G = grade; INR = International Normalized Ratio; N/A = not 
applicable; PLT = platelet; QTcF = AT interval corrected using Fridericia’s equation; T = temperature; 
ULN = upper limit of normal 
a See Table 6 for dose levels. 
b QTc:  Only 1 dose reduction is permitted per subject. Prior to and following treatment initiation or after dose 
modification of study drugs for QTc prolongation, evaluate ECG and electrolytes (including potassium, 
magnesium, and calcium) after 15 days, and monthly thereafter or more often as clinically indicated. 
 


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7.0 
STUDY CONDUCT AND ASSESSMENTS 
7.1 
Study Conduct 
7.1.1 
Study Personnel and Organizations 
The contact information for the Medical Monitor for this study is presented in Table 8. The 
contact information for the central and any additional clinical laboratories, the coordinating 
investigator for each member state/country, and contract research organization (CRO) can be 
found in the Study Reference Manual. A full list of investigators is available in the Sponsor’s 
investigator database. 
Table 8: 
Contact Information 
Medical Monitor:  
(Emergency Contacts) 
Athanasios Tsiatis, MD 
Vice President, Clinical Development 
Plexxikon Inc.  
329 Oyster Point Boulevard 
South San Francisco, CA 94080, USA 
Phone: 
+1-510-647-4142 
+1-510-590-6443 (after business hours) 
Fax:  +1-510-548-8014 
E-mail:  atsiatis@plexxikon.com 
SAE Reporting Contact 
Report all SAEs, whether related or not to study drug, by emailing 
a completed SAE form within 1 working day of receiving 
knowledge of the event to: 
Email:  Plexxikon.Safety@premier-research.com 
Fax: +1-215-972-8765 
SAE = serious adverse event 
 
7.1.2 
Study Committee 
The Study Committee will include at minimum the Sponsor Medical Monitor and participating 
Principal Investigators. The Study Committee will meet for Phase 1b PLX2853 + carboplatin 
dose escalation decisions and approximately monthly during the Phase 2a PLX2853 
monotherapy and Phase 2a PLX2853 + carboplatin dose expansion portions of the study. Data to 
be evaluated may include (but are not limited to):  deaths, SAEs, AEs (including 
treatment-related AEs), reasons for treatment discontinuation or dose modification/ interruption, 
trends in laboratory evaluations, PK, and efficacy. The Study Committee may also review any 
biomarker data if it becomes available. 


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7.1.3 
Arrangements for Recruitment of Subjects 
Recruitment and enrollment strategies for this study may include recruitment from the 
Investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the Institutional Review Board (IRB) and/or 
Independent Ethics Committee (IEC). 
7.1.4 
Treatment Group Assignments 
This is an open-label, parallel, 2-part study: a Phase 2a PLX2853 monotherapy part in subjects 
with advanced gynecological malignancies with a known ARID1A mutation and a Phase 1b/2a 
PLX2853 + carboplatin dose escalation/dose expansion part in subjects with platinum-resistant 
EOC. In the Phase 2a PLX2853 monotherapy part, subjects will receive PLX2853 80 mg/day. In 
parallel, the initial dose level of PLX2853 in the Phase 1b combination dose escalation will be 
40 mg/day. Thereafter, dose escalation (including alternative dosing schedules) will proceed as 
described in Section 5.3. 
Subjects with a known ARID1A mutation must be enrolled to the Phase 2a PLX2853 
monotherapy cohort unless approved by the Medical Monitor. Once enrollment to this cohort is 
complete, subjects with a known ARID1A mutation may be considered for enrollment to the 
Phase 1b/2a PLX2853 + carboplatin cohorts. 
7.1.5 
Withdrawal of Subjects from Drug Treatment and Study; Subject Replacement 
The Plexxikon Medical Monitor will monitor safety data throughout the course of the study. The 
Medical Monitor will review SAEs within timeframes mandated by company procedures and 
will review trends, laboratory data, and AEs at periodic intervals and provide for interim safety 
analyses if appropriate. 
The reasons a subject may discontinue or be withdrawn from the study include, but are not 
limited to:  AE, clinically significant disease progression, subject request, investigator decision, 
protocol violation, subject noncompliance, and study termination by the Sponsor or IRB/IEC. 
When a subject discontinues or is withdrawn, the Investigator will notify the Sponsor and should 
perform the procedures indicated in the 30-day FU Visit column in the Schedule of Events 
approximately 30 days after discontinuation of study drug or prior to initiation of any new 
anti-cancer therapy, whichever occurs first. Follow-up information may be obtained for subjects 
who discontinue treatment in the study. 
Subjects who discontinue PLX2853 treatment, or miss more than 25% of their expected doses, 
for reasons other than toxicity or clinically significant disease progression (e.g., protocol 
violation or noncompliance) during Cycle 1 may be replaced at the discretion of the Medical 
Monitor. Subjects in the Phase 1b/2a PLX2853 + carboplatin cohorts who miss carboplatin 
dosing on Cycle 1 Day 1 or Cycle 2 Day 1 for reasons other than toxicity will be replaced. 
Study drug administration may be discontinued for an AE or at the discretion of the Investigator. 


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The consequence of withdrawal of all consent by a subject will be that no new information will 
be collected from that subject and added to the existing data or any database. However, every 
effort will be made to follow all subjects for safety. 
7.1.6 
Study Compliance 
The study drugs PLX2853 and carboplatin (if applicable) will be provided only to eligible 
subjects under the supervision of the Investigator or identified sub-investigator(s). The 
appropriate study personnel will maintain records of study drug receipt and dispensing. Any 
discrepancy regarding the dose administered and the reason for the discrepancy will be recorded 
in the eCRF. At each clinic visit, subjects will be questioned about their compliance with study 
drug administration, and their dosing diary should be reviewed. 
7.1.7 
Enrollment of Subjects 
After potential subjects have been identified by the site personnel, the site will inform the 
Sponsor/Sponsor’s representative and a slot may be temporarily reserved for the subject. Once 
informed consent has been obtained and all Screening assessments are completed, the site 
personnel will email the Sponsor/Sponsor’s representative with the enrollment packet. The 
Sponsor’s Medical Monitor or designee will review and approve the enrollment (via email 
typically), inform the Investigator that the subject has been approved for enrollment, and assign 
the appropriate dose level. A subject will be considered enrolled once they have received their 
first dose of PLX2853. Subjects must continue to meet all eligibility criteria that are repeated at 
the time of initiation of C1D1 dosing, except for optional Food Effect subjects who are required 
to meet all eligibility criteria before dosing on D-4 or D-3. 
Subjects who are approved to enroll (signed enrollment form returned by Plexxikon) but do not 
receive study drug will be considered screen fails. 
Further information may be found in the Study Reference Manual. 
7.1.8 
Protocol Deviations 
A protocol deviation is any departure from the protocol. Significant protocol deviations are 
defined as departures from protocol-required processes or procedures that affect subject safety or 
potential benefit or confound assessments of safety or clinical activity. Protocol deviations may 
be grouped into the following categories: 
• Enrollment criteria 
• Study activities (e.g., missed evaluations or visits, data verification issues) 
• Noncompliance with dose or schedule, including dose calculation, administration, 
interruption, reduction, or delay, or discontinuation criteria 
• Use of a prohibited medication 


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• AE not reported/SAE reported late 
• Investigational product handling, including storage and accountability 
• Informed consent and ethical issues 
Significant protocol deviations should be reported to the Sponsor immediately upon awareness 
and submitted to the site’s IRB/IEC per institutional policy. 
All subjects must provide written informed consent. During the consent process, the person 
obtaining consent must inform the subject of all elements of the study. No protocol-specific 
procedures, including Screening procedures, are to be performed until the subject has signed and 
dated an IRB/IEC-approved informed consent form. The study begins with the signing and 
dating of the informed consent form. 
Screening procedures are to be performed within 28 days of Cycle 1 Day 1 unless otherwise 
specified in the Schedule of Events (Synopsis Table 1, Synopsis Table 2, Synopsis Table 3). 
The 30-day FU Visit will take place approximately 30 days after last dose of PLX2853 or prior 
to starting any new anti-cancer therapy, whichever occurs first (see Section 7.1.5 for reasons for 
discontinuation or withdrawal of a subject from the study). 
Survival follow-up can be via clinic visit, phone call to the subject or referring physician, or 
other method deemed appropriate by the site and should assess survival, progression, subsequent 
therapy, and response. Subjects will be followed until death, withdrawal of consent, or loss to 
follow-up according to the following schedule: 
– First 2 years after the 30-day FU Visit – Every 3 months 
– Third year after the 30-day FU Visit and beyond – Every 6 months 
Any subject with a confirmed response who discontinues treatment for reasons other than disease 
progression will continue to be followed per standard of care and no less than every 3 months 
until documented disease progression, initiation of a new anti-cancer treatment, or 1 year from 
discontinuation of study treatment. Radiographic scan data will be collected and if scan data are 
not available, a scan will be obtained every 3 months until 6 months of radiographic follow-up 
after confirmed response has been obtained. Refer to the Schedule of Events (Synopsis Table 1, 
Synopsis Table 2, Synopsis Table 3). 
7.1.9 
Disease Assessment 
Response will be assessed by the Investigator with RECIST v1.1 using imaging appropriate for 
the disease. The same radiographic procedure used to assess disease sites at Screening should be 
used throughout the study (e.g., the same contrast protocol for CT scans). Assessment of tumor 
burden will occur every 2 cycles or more frequently as clinically indicated. Redacted copies of 
pathology, molecular pathology, photography (if applicable) and radiology reports should be sent 


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to the Sponsor as part of the enrollment packet and after each tumor response assessment. In 
addition, redacted copies of radiology scans should be available for an independent review if 
requested by the Sponsor. 
See Appendix 3 for details of RECIST v1.1. 
Subjects without clinically significant radiographic disease progression who are receiving 
clinical benefit may continue on treatment with Medical Monitor approval. 
7.1.9.1 
Fresh Tumor Biopsy 
Archival tissue samples will be collected at Screening. All subjects will be required to permit 
exploratory evaluations of their archival tumor tissue whenever archival tissue is available. If 
>6 months (approximately) have elapsed since the last biopsy, a repeat biopsy(ies) of 
representative lesions (in the judgment of the Investigator) is recommended. Subjects with 
biopsy-accessible tumors may be asked to participate in exploratory evaluations of paired 
biopsies with samples taken at Screening, Cycle 2 Day 1, and any other time per the discretion of 
the Investigator (mandatory for subjects in Phase 2a cohorts, optional for subjects in Phase 1b 
cohorts). If the archival tissue provided was collected within 2 months of Screening, a fresh 
sample does not need to be collected at Screening. The biopsies should be from the same lesion 
if possible/feasible, and preferably from a non-target lesion. 
Further handling/shipping instructions may be found in the Laboratory Manual. 
7.1.10 
Pharmacokinetic and Pharmacodynamic Assessments 
All blood, urine, and tissue samples may be used interchangeably and for multiple types of 
biomarker and PK assays. Because the identification of new biomarkers of disease and treatment 
response is a rapidly developing field, a definitive list of assays remains to be determined. 
Subjects should be instructed not to take their PLX2853 dose at home on PK or PDx collection 
days. 
In addition to scheduled PK assessments, samples for PK should be collected for any dose 
modification at the time points specified in the Schedule of Events (Synopsis Table 1, 
Synopsis Table 2, Synopsis Table 3) within 2 weeks of the modification or at the next scheduled 
clinic visit, whichever occurs closest to the new dosing regimen. Additional samples for PK may 
also be collected if a subject experiences a DLT, SAE, or AE of special interest (AESI). A list of 
protocol-required PK and PDx assessments is provided in Appendix 1. 
A total volume of blood collected in Cycle 1 (28-day cycle) will be approximately 261.5 to 
375 mL and all subsequent cycles will be no more than approximately 76 to112 mL. Further 
information may be found in the Laboratory Manual. 
PK draws should be taken from the opposite arm (not the arm with the IV catheter) whenever 
possible and when not possible from a site below (distal to) the IV site. 


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7.1.10.1 
Pharmacokinetic Assessments 
PLX2853 PK data will be analyzed in each dosing cohort for Cmax, AUC, and accumulation ratio 
at steady state and compared with prior dose levels. The number of subjects at a given dose level 
may be increased as a result of the review of safety, observed or anticipated disease activity, and 
PK data. Additional dosing schedules may be studied, such as alternate day dosing (e.g., every 
other day) depending on emerging safety and PK data. 
In addition, PK analysis may include analysis of PLX2853 metabolites. 
7.1.10.2 
Biomarker Samples and Pharmacogenomics 
Baseline subject blood samples (serum, plasma, whole blood) will be obtained for PDx and 
biomarker assessments. These may be repeated at subsequent time points throughout the study. 
In addition, subjects will be asked to submit archival tumor samples, and may be asked to have 
subsequent tumor biopsies while on the study (optional for subjects in Phase 1b cohort and 
mandatory for subjects in Phase 2a cohorts). These tumor samples may be used for PDx and 
biomarker assessments. While some of the assessments are prospectively described in the 
protocol, new assessment methods may emerge during the study or after it has concluded. Hence 
some samples may be stored and analyzed at a later date as newer technologies emerge. 
PDx and other biomarker samples may be used to identify prognostic or predictive biomarkers. 
In addition, they may be used to improve the understanding of the biology of the disease under 
study, the metabolism of the drug, to help identify subjects who may be more or less likely to 
benefit from the drug, or who may be at risk for potential toxicity from the drug. 
Analyses to be done on the samples (blood and tumor) for this study may include, but are not 
limited to: 
• Genetic analyses (sequencing) of tumor tissues for mutations relevant to bromodomain 
inhibition 
• Histochemical and/or protein analysis of tumor, plasma tissue, peripheral blood cells for 
changes relevant to bromodomain inhibition 
• Genomic analysis and expression arrays may also be performed for exploratory purposes 
• RNA sequencing 
• Serum protein and cytokine analysis 
• Analysis of HRD status 
The science of biomarkers and assays is always evolving and therefore a definitive list of 
biomarkers remains to be determined and may include additional markers suggested by 
preclinical/clinical research or referenced in the literature or other scientific conferences as the 
science and technology evolve. 


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Stored samples will only have the subject study number as an identifier, and will not have any 
subject identifying information such as name, birthdate, etc. Samples will be stored for 3 years 
after the end of the study (defined as execution of the clinical study report), or per local 
guidelines, and then they will be destroyed. 
As part of this study, blood samples will be collected for pharmacogenomics analysis. Where 
required by local regulations, participation in pharmacogenomic sample collection is optional 
and will be addressed in a separate Pharmacogenomics informed consent form at Screening. In 
these regions, subjects who choose not to provide a sample for pharmacogenetic analysis may 
still participate in the study. 
For subjects who participate in pharmacogenetic testing, a blood sample should be collected at 
the Screening Visit or as indicated in the Schedule of Events. This sample may be analyzed only 
for genes suspected to contribute to the safety and efficacy of the study medications. The 
analysis may also include a comprehensive evaluation of genetic information, with a particular 
focus on specific genetic changes considered to potentially predict responsiveness or resistance 
to treatment. 
Results may also provide information on how individuals metabolize and react to the study drug 
or help to identify subjects who are more or less likely to benefit from the study drugs. The 
information may be useful to increase 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 study medications may 
become available in the future, pharmacogenomic samples may also be banked for possible 
future research. In all regions, pharmacogenomic sample banking is optional and will be 
addressed in a separate Pharmacogenomics informed consent form at Screening. 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 protocol requirements and 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 analysis laboratory(ies), 
which has been contracted by the Sponsor to process these samples. 
In order to ensure subject confidentiality, sample tubes will be identified only by a barcode label. 
This barcode will be linked to the subject identification number. Samples will be stored for 
3 years after the end of the study, or per local guidelines, and then they will be destroyed. 
Sample collection, preparation, handling, storage, and shipping instructions are in the Laboratory 
Manual. Blood volume for blood draws is provided in Section 7.1.11.7.1. 


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7.1.11 
Safety Assessments 
Safety and tolerability will be monitored and determined by reported AEs (including deaths, 
other SAEs, and TEAEs), laboratory tests (hematology, clinical chemistry, coagulation, serum 
inflammation marker, and urinalysis), ECG, physical exams (including weight), and vital signs. 
7.1.11.1 
Medical and Medication History 
Medical history includes clinically significant diseases, surgeries, cancer history, and all 
medications (e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, 
nutritional supplements) used by the subject within 28 days prior to the Screening Visit and 
history of treatment for the primary diagnosis, including prior systemic, radiation treatment, and 
surgical treatment. Date of last prior cancer treatment must be documented. Radiographic studies 
performed prior to study entry may be collected for review by the Investigator. 
7.1.11.2 
ECOG Performance Status Assessment 
An assessment of performance status will be performed using the ECOG Performance Status 
scale of 0 to 5 (Appendix 5). 
7.1.11.3 
Physical Examinations 
The Investigator or qualified designee will conduct physical examinations. A complete physical 
examination will be conducted at Screening and 30-day FU Visit, and a symptom-directed 
physical examination (based on interval history and/or AEs) will be conducted at all other visits. 
7.1.11.4 
Vital Signs 
Vital signs will be recorded and will include measurements of body temperature, heart rate, 
respiratory rate, and systolic and diastolic blood pressure. Predose vital signs must be obtained 
on days that PK/PDx samples are taken. On non-PK/non-PDx days, vital signs do not need to be 
predose and subjects may self-administer PLX2853 at home either prior to or after their clinic 
visit (if applicable). 
7.1.11.5 
Height and Weight 
Height (Screening only) in centimeters and body weight in kilograms will be measured. 
7.1.11.6 
Electrocardiogram 
Subjects should rest in the supine or semi-recumbent position for at least 5 minutes before 
12-lead ECG recording is started. The ECGs should be reviewed, signed, and dated by a 
qualified physician (or qualified physician’s assistant or nurse practitioner) and any clinically 
important finding recorded on the appropriate eCRF. The results will include heart rate, PR 
interval, QRS interval, QT interval, and QTcF interval with QTcF calculation. Fridericia’s 
correction is required:  QTcF = (QT)/3√(RR). 


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Triplicate ECGs should be done at Screening and predose Cycle 1 Day 1 (approximately 
10 seconds per ECG over a 5 minute period). All other ECGs are single tracings. Additional 
ECGs should be obtained to evaluate AEs as applicable per standard of care. 
7.1.11.7 
Safety Laboratory Assessments 
The Investigator will monitor the safety laboratory test findings. If any laboratory test is 
abnormal during the course of the study, it will be followed at the discretion of the Investigator. 
Abnormalities of laboratory tests will be evaluated by the Investigator and assessed as either 
clinically significant or not clinically significant. Abnormal laboratory values deemed by the 
Investigator to be clinically significant and, thus, constitute or are associated with an AE, must 
be reported on the AE form. Abnormal laboratory values that require intervention must be 
reported on the Adverse Event form whether or not deemed clinically significant. 
A complete list of required safety laboratory tests is provided in Appendix 1. Additional details 
for specific tests are provided in the Laboratory Manual. 
7.1.11.7.1 
Blood Collection 
The estimated volumes of blood to be collected at each visit of the study are shown in Table 9. 
The quantities of blood are within accepted limits of 10.5 mL/kg or 550 mL (whichever is 
smaller) per National Institutes of Health and other published guidelines (DF/HCC 2012; 
NIHCC 2009; NS LIJ 2013). 


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Table 9: 
Approximate Blood Sample Volumes Collected 
 
Blood Sample Volumes (mL) 
 
SCR 
C1 
C2 
C3–4 
C5+ 
30-day 
FU 
STUDY DAY► 
D-28 
to D-1 
D-4 or 
D-3 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
D1 
WINDOW (days)► 
 
 
 
± 2 
± 2 
± 2 
+ 3 
± 3 
± 5 
± 5 
± 7 
TEST▼ 
 
 
 
 
 
 
 
 
 
 
 
PG blood sample 
6 
 
 
 
 
 
 
 
 
 
 
Hematologya 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
Chemistrya 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
Coagulation testsa 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
C-reactive proteina 
0-5 
5 
5 
5 
5 
5 
5 
 
5 
5 
5 
Tumor markersa 
0-10 
10 
10 
 
 
 
10 
 
10 
10 
10 
Hepatitis A/B/C and 
HIV tests 
9 
 
 
 
 
 
 
 
 
 
 
PDx blood samples 
 
38.5 
38.5 
 
25 
 
31 
 
31 
31 
31 
PK blood samples 
 
36 
36 
 
36 
 
18 
 
18 
6–18 
6 
TOTAL VOLUMEb 
39-54 
113.5 
113.5 
29 
90 
29 
88 
24 
88 
76–88 
76 
30-day FU = 30-day follow-up visit; C = cycle; D = day; PDx= pharmacodynamics; PG = pharmacogenomics; 
PK = pharmacokinetic; SCR = Screening 
a Estimated volume. Actual volume will be per site’s standard of care. 
b The total blood volume drawn over Cycle 1 is approximately 261.5 to 375 mL and in subsequent cycles is 
approximately 76 to 112 mL. 
 
7.1.12 
Pregnancy Testing 
All women of child bearing potential who are being considered for participation in the study will 
be tested for pregnancy with a serum β-human chorionic gonadotropin test within 7 days prior to 
taking the first dose of study drug. Additional pregnancy testing should be scheduled per local 
regulations where applicable. A serum or urine pregnancy test will be completed at the 30-day 
FU Visit. 


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8.0 
STATISTICAL AND QUANTITATIVE ANALYSES 
8.1 
Randomization and Stratification 
No randomization or stratification of subjects is planned for this study. 
8.2 
Definitions and Populations for Analysis 
A screened subject is defined as a subject who signed an informed consent form. 
An enrolled subject is defined as a subject who has received at least 1 dose of study drug. 
A screening failure (screen failure) is defined as a subject who signs consent but is not dosed. 
8.2.1 
Evaluable Populations 
The Efficacy Evaluable Population consists of all subjects who received any treatment with 
PLX2853 and who have at least 1 post-baseline target lesion response assessment or 
discontinued because of clinical progression or drug-related toxicity. The Safety Population 
consists of all subjects who receive any treatment with study drug and have any follow-up data. 
8.3 
Procedures for Handling Missing, Unused, and Spurious Data 
All available efficacy and safety data will be included in the data listings and tabulations. No 
imputation of values for missing data will be performed. 
8.4 
General Methodology 
Summary of tabulations will be presented by cohort displaying the number of observations, 
mean, standard deviation, median, minimum, and maximum for continuous variables, and the 
number and percent per category for categorical data. 
8.5 
Baseline Comparisons 
Demographic and baseline characteristics will be summarized by cohort. The last assessment 
performed prior to the first PLX2853 dose will be considered baseline. 
8.6 
Efficacy Analysis 
8.6.1 
Phase 1b (Dose Escalation) (PLX2853 + Carboplatin) 
Data will be tabulated and evaluated by descriptive statistics. Statistical analyses for the primary 
objectives will be descriptive only, with no hypothesis testing. Summary tables will present 
results for each dose cohort. Descriptive statistics will be presented for continuous variables, and 
frequencies and percentages will be presented for categorical and ordinal variables. 


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Response to treatment will be evaluated using investigator-determined RECIST v1.1 criteria 
(Appendix 3). 
8.6.2 
Phase 2a (PLX2853 Monotherapy) and Phase 2a (PLX2853 + Carboplatin 
Combination) 
8.6.2.1 
Primary Efficacy Analysis 
The primary objectives of the Phase 2a cohorts of the study are to determine the antitumor 
activity (ORR) of PLX2853 monotherapy or PLX2853 + carboplatin combination. Response to 
treatment will be evaluated using investigator-determined RECIST v1.1 criteria (Appendix 3), 
with a minimum interval for confirmation of CR and PR of 4 weeks. Each Phase 2a cohort will 
enroll up to 26 evaluable subjects using a Simon’s 2-stage design in which initially 12 evaluable 
subjects are enrolled. In the monotherapy cohort, the safety lead in of 6 subjects dosed at the 
level selected for Phase 2a will be included in the group of 12 evaluable subjects for stage 1. If 
≥33% DLTs are seen during the initial safety lead in, the Safety Committee will convene to 
consider a dose reduction. If a dose reduction is deemed appropriate, the subjects in the initial 
safety lead in will need to be replaced and a repeat 6 subject safety lead in will need to be 
conducted at this lower dose. If 2 or more responses are observed in 12 evaluable subjects, 
another 14 evaluable subjects will be enrolled for a total of 26 subjects to that cohort. If 6 or 
more responses are observed, the study has 80% power with alpha of 0.05 to reject the ORR of 
10% in favor of the ORR of 30%. Recruitment will stop within a cohort if no more than 
1 response is observed after the initial 12 evaluable subjects have been accrued. ORR will be 
summarized per cohort along with their 95% confidence intervals (CIs). A 2-sided 95% CI will 
be calculated for the true response rate based on the Clopper-Pearson method. 
8.6.2.2 
Secondary Efficacy Analyses 
A 2-sided 95% CI will be calculated for the true response rate based on the Clopper-Pearson 
method for secondary analyses. 
Secondary efficacy analyses include the following: 
• DCR:  The percentage of subjects with confirmed CR, PR, or SD per RECIST criteria 
• PFS:  The number of days from the first day of PLX2853 treatment (Cycle 1 Day 1) to the 
date of the first documented disease progression or date of death from any cause, whichever 
occurs first. The time-to-event secondary efficacy endpoint of PFS will be summarized for 
each cohort using the Kaplan-Meier method. Subjects lost to follow-up or event-free as of the 
data analysis cutoff date will be right-censored. 
• DOR:  The number of days from the date of first response (PR or CR confirmed at least 
28 days later) to the date of the first documented disease progression or date of death from 
any cause, whichever occurs first. 


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• OS:  The number of days from the first day of PLX2853 treatment (Cycle 1 Day 1) to the 
date of death from any cause. The time-to-event secondary efficacy endpoint of OS will be 
summarized for each cohort using the Kaplan-Meier method. Subjects lost to follow-up or 
event-free as of the data analysis cutoff date will be right-censored. 
 
8.7 
Pharmacokinetics, Pharmacodynamics, Biomarkers 
8.7.1 
Pharmacokinetic Analysis 
The PK parameters of PLX2853 will be assessed by measuring AUC from time zero to time of 
last observed concentration hours postdose (AUC0-last), AUC0-24, AUC0-∞, Cmax, Tmax, T1/2, and 
accumulation ratio at steady state. 
Dose proportionality following study dosing will be explored by analyzing natural 
log-transformed PK variables, AUC0-24, AUC0-∞, and Cmax, with a linear model including the 
natural log-transformed dose as a covariate. 
8.7.2 
Pharmacodynamic and Other Biomarker Analysis 
Planned biomarker analyses for PDx include, but are not limited to: 
• Gene expression, nucleic acid sequencing, histochemical and/or protein analyses of plasma, 
peripheral blood cells, and/or tumor tissue 
• Analysis of HRD status 
Exploratory analysis of biomarker samples may also be performed to learn about the drug and 
disease properties. 
No formal statistical analysis of PDx endpoints will be performed. PDx data from each assay will 
be listed, and the possible relationships between clinical response and PDx variables will be 
explored. Any biological activity will be described. 
8.8 
Safety Analysis 
Safety variables to be assessed will include assessment of AEs, physical examinations (including 
weight), laboratory test results (hematology, clinical chemistry, coagulation, serum inflammation 
marker, and urinalysis), ECG, and vital sign measurements. 
AE terms recorded on the eCRFs will be mapped to preferred terms using the Medical 
Dictionary for Drug Regulatory Activities (MedDRA®) version 23 or later. All TEAEs will be 
summarized according to the system organ class and preferred term within the organ class. 
TEAEs will be tallied for overall frequency (number and percentage of subjects), worst reported 
severity, and relationship to study drug for each preferred term per subject. SAEs will be 
similarly summarized. Listings of deaths, SAEs, and AEs leading to early termination of study 
treatment or premature withdrawal from study will also be provided. 


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Laboratory variables will be examined using mean change in value from baseline to scheduled 
time points. Laboratory values will also be categorized according to their CTCAE v5.0 toxicity 
grade and tabulated by worst on-study toxicity grade. The baseline value of a variable is defined 
as the last value obtained on or before the date and time of the first PLX2853 dose. 
ECG, weight, and vital signs will also be summarized by changes from baseline to scheduled 
time points using descriptive statistics. Changes in QTcF will also be evaluated for the 
proportion of subjects with absolute values >500 msec and change from baseline >60 msec. 
8.9 
Interim Analysis 
No formal interim analysis is planned. 


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9.0 
ASSESSMENT OF SAFETY AND ADVERSE EVENTS 
Safety and tolerability will be monitored and determined by serial physical examinations 
(including weight), vital signs, hematology and chemistry laboratory studies (including 
coagulation, serum inflammation marker, and urinalysis), ECGs, and reported AEs (including 
deaths and other SAEs and TEAEs). The Investigator will monitor the laboratory test findings. If 
any laboratory test is abnormal during the course of the study, it will be followed at the 
discretion of the Investigator. Abnormalities of laboratory tests are evaluated by the Investigator 
and assessed as either clinically significant or not clinically significant. Abnormal laboratory 
values deemed by the Investigator to be clinically significant and, thus, constitute or are 
associated with an AE, must be reported on the AE form. Abnormal laboratory values that 
require intervention must be reported on the AE form whether or not deemed clinically 
significant. 
9.1 
Definitions 
9.1.1 
Adverse Event Definition 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product, 
which does not necessarily have a causal relationship with the treatment. An AE can be any 
unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of the study drug, whether or not it is considered to be 
study drug related. This includes any newly occurring event or previous condition that has 
increased in severity or frequency since the administration of study drug. An AE includes, but is 
not limited to, the following: 
• Any clinically significant worsening of a preexisting condition except for events clearly 
consistent with progression of disease under study as described in Section 9.3.2 
• An AE occurring from overdose (i.e., a dose higher than that indicated in the protocol) of a 
study drug, whether accidental or intentional 
• An AE occurring from abuse (e.g., use for nonclinical reasons) of a study drug 
• An AE that has been associated with the discontinuation of the use of a study drug 
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., meeting 
1 or more of the following conditions, should be recorded as a single diagnosis on the AE page 
in the eCRF: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication (e.g., dose modification, interruption, or permanent 
discontinuation) 
• Requiring a change in concomitant therapy (e.g., addition of, interruption of, discontinuation 
of, or any other change in a concomitant medication, therapy, or treatment) 


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AEs will be graded in severity according to CTCAE v5.0 criteria. 
9.1.2 
Serious Adverse Event Definition 
An SAE is any AE occurring at any dose and regardless of causality that: 
• Results in death 
• Is life-threatening. Life-threatening means that the subject was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form. 
• Requires in-subject hospitalization longer than 24 hours or prolongation of existing 
hospitalization (see clarification in the paragraph below on planned hospitalizations). An 
emergency room visit without hospitalization is not considered a hospitalization. 
• Results in persistent or significant disability/incapacity. Disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect 
• Is an important medical event. An important medical event is an event that may not result in 
death, be life-threatening, or require hospitalization but may be considered an SAE when, 
based upon appropriate medical judgment, it may jeopardize the subject and may require 
medical or surgical intervention to prevent 1 of the outcomes listed in the definitions for 
SAEs. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in in-subject hospitalization, or the development of drug dependency or drug abuse. 
Clarification should be made between the terms “serious” and “severe” because they ARE NOT 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be 
of relatively minor medical significance (such as a severe headache). This is NOT the same as 
“serious,” which is based on subject/event outcome or action criteria described above and are 
usually associated with events that pose a threat to a subject’s life or functioning. A severe AE 
does not necessarily need to be considered serious. For example, persistent nausea of several 
hours’ duration may be considered severe nausea but not an SAE. On the other hand, a stroke 
resulting in only a minor degree of disability may be considered mild but would be defined as an 
SAE based on the above noted criteria. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
9.2 
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events 
All AEs spontaneously reported by the subject and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the appropriate page of the CRF. Any clinically relevant deterioration in 


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laboratory assessments or other clinical finding is considered an AE and must be recorded on the 
appropriate pages of the CRF. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as 1 comprehensive event. 
All SAEs, as defined in Section 9.1.2, that occur during the course of the study as defined in 
Section 9.3 must be reported within 1 working day of awareness by using the SAE Report Form. 
All SAEs and deaths must be reported whether or not considered causally related to the study 
drug, except for events clearly consistent with progression of disease under study as described in 
Section 9.3.2. SAEs and deaths will be reported by completing the SAE Report Form and by 
emailing (fax as back-up) the completed SAE Report Form to the designated recipient 
(Section 7.1.1). A sample of the SAE Report Form may be found in the Study Reference Manual. 
Follow-up information on the SAE may be requested by Plexxikon. SAEs reported to Product 
Safety must match the data provided on the eCRF. Contact information will be listed on the SAE 
Report Form. 
Planned hospital admissions or surgical procedures for an illness or disease which existed before 
the subject was enrolled in the study or before study drug was given are not to be considered AEs 
unless the condition deteriorated in an unexpected manner during the study (e.g., surgery was 
performed earlier or later than planned). 
For both serious and non-serious AEs, the Investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. 
Intensity for each AE, including any laboratory abnormality, will be determined by using the 
NCI CTCAE v5.0, as a guideline, wherever possible. The criteria are provided in the Study 
Reference Manual. In those cases where the NCI CTCAE criteria do not apply, intensity should 
be defined according to the following criteria: 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort enough to cause interference with normal daily activities 
Severe 
Inability to perform normal daily activities 
Relatedness to study drug administration will be determined by the Investigator responding to 
the question, ‘Is there a reasonable possibility that the AE is associated with the study drug?’ 
Relatedness to study drug administration will be graded as “probably,” “possibly,” or “not 
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Not  
Related 
Another cause of the event is most plausible; 
OR 
Clinically plausible temporal sequence is inconsistent with the onset of the 
event and the study treatment administration; 
OR, 
A causal relationship is considered biologically implausible. 
Possibly 
Related  
An event that follows a reasonable temporal sequence from administration 
of the study treatment or a known or expected response pattern to the 
suspected drug, but that could readily have been produced by a number of 
other factors.  
Probably 
Related  
An event that follows a reasonable temporal sequence from administration 
of the study treatment, 
AND, 
There is a biologically plausible mechanism for study treatment causing or 
contributing to the AE, 
AND, 
The event could not be reasonably explained by the known characteristics 
of the subject’s clinical state. 
In addition, the relationship may be confirmed by improvement on stopping the study treatment 
and reappearance of the event on repeated exposure. 
9.3 
Timing of Evaluation of Adverse Events and Serious Adverse Events 
All AEs will be recorded from the time the informed consent is signed through 30 days after last 
dose of study drug or prior to initiating new anti-cancer therapy, whichever occurs first. AEs that 
occur after signing informed consent but before first dose of study drug that are not related to a 
protocol-mandated procedure will be recorded as medical history only. AEs occurring as a result 
of a protocol-mandated procedure after signing of informed consent will be recorded as AEs. 
All SAEs will be recorded from the time the informed consent is signed through 30 days after 
last dose of study or prior to starting any new anti-cancer therapy, whichever occurs first. Any 
SAE occurring from time of consent to initiation of study drug that is related to a 
protocol-mandated procedure must be reported to Plexxikon or its designee within 1 working day 
of the knowledge of the event. All SAEs occurring from start of study drug through 30 days after 
administration of the last dose of study drug or prior to the administration of any new anti-cancer 
therapy, whichever occurs first, must be reported to Plexxikon or its designee within 1 working 
day of the knowledge of the event. 
9.3.1 
Adverse Events of Special Interest 
At present, there are no AESIs identified for this study. 


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9.3.2 
Worsening of Cancer 
Clear progression of neoplasia should not be reported as an AE or SAE. Findings that are clearly 
consistent with the expected progression of the underlying cancer should not be reported as an 
AE, and hospitalizations due to the progression of cancer do not qualify for an SAE. Sudden and 
unexplained death should be reported as an SAE. If there is any uncertainty about a finding being 
due solely to progression of neoplasia, the finding should be reported as an AE or SAE as 
appropriate. 
9.3.3 
Overdose 
Certain information, although not considered an AE, must be recorded in the eCRF and followed 
up as indicated for an AE. This may include the following: 
• Overdose 
• Study drug overdose is the accidental or intentional use of PLX2853 in an amount at least 
40% higher than the dose being studied or carboplatin in any amount above the target 
AUC dose. An overdose or incorrect administration of study drug is not an AE unless it 
results in untoward medical effects. Any study drug overdose or incorrect administration 
of study drug should be noted on the appropriate CRF. 
• All AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the adverse event CRF. If the AE also fulfills serious criteria, it should be 
reported as an SAE using the SAE Report Form. 
 
9.4 
Monitoring of Adverse Events and Period of Observation 
AEs, both serious and non-serious, and deaths will be recorded on the CRFs up to and including 
the last visit at approximately 30 days after administration of the last dose of study drug or prior 
to the administration of any new anti-cancer therapy, whichever occurs first. 
Any SAE that occurs at any time after completion of the study and the designated follow-up 
period, which the Investigator considers to be related to study drug, must be reported to 
Plexxikon or designee. 
All SAEs must be followed by the Investigator until one of the following occurs: 
• The event resolves 
• The event stabilizes 
• The event returns to baseline, if a baseline value/status is available 
• The event can be attributed to etiology other than the study drug or to factors unrelated to 
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• 
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts). 
 
9.5 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects she is pregnant while participating in this study or up 
to 90 days (for subjects in the US) or 6 months (for subjects in Canada) after completing study 
treatment, she must inform her treating physician immediately and, if applicable, and 
permanently discontinue study drug. The Sponsor must also be contacted immediately by 
emailing or faxing a completed Pregnancy Form to Plexxikon or designee as described in the 
Study Reference Manual. The pregnancy must be followed through final outcome (i.e., beyond 
delivery) for SAEs. 


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10.0 
ADMINISTRATIVE REQUIREMENTS 
10.1 
Good Clinical Practice 
The study will be conducted in accordance with the ICH Guideline for GCP and the appropriate 
regulatory requirement(s). The Investigator will be thoroughly familiar with the appropriate use 
of the study drug as described in the protocol and the Investigator’s Brochure. 
10.2 
Data Quality Assurance 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study subject. 
Study data will be entered into an eCRF by site personnel using a secure, validated web-based 
electronic data capture (EDC) application. Plexxikon and its CRO designee will have access to 
all data upon entry in the EDC application. 
Study monitors will discuss instances of missing or un-interpretable data with the Investigator 
for resolution. Any changes to study data will be made to the eCRF and documented via an 
electronic audit trail associated with the affected eCRF. 
10.3 
Electronic Case Report Form Completion 
Plexxikon or a CRO designee will provide the study sites with secure access to and training on 
the EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the subjects for which they are responsible. 
eCRFs will be completed for each study subject. Screen failure information will not be collected 
in the eCRFs. It is the Investigator’s responsibility to ensure the accuracy, completeness, clarity, 
and timeliness of the data reported in the subject’s eCRF. 
The Investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected. 
The audit trail entry will show the user’s identification information, and the date and time of the 
correction. The Investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for the 
subjects for which he is responsible. 
Plexxikon or a CRO designee will retain the eCRF data and corresponding audit trails. A copy of 
the final archival eCRF in the form of a compact disk or other electronic media will be placed in 
the Investigator’s study file. 
10.4 
Study Monitoring 
Monitoring and auditing procedures developed or approved by Plexxikon will be followed, in 
order to comply with GCP guidelines. 


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All information recorded on the eCRFs for this study must be consistent with the subject’s 
source documentation. During the course of the study, the Study Monitor will make study site 
visits to review protocol compliance, verify eCRFs against source documentation, assess drug 
accountability, and ensure that the study is being conducted according to pertinent regulatory 
requirements. The review of medical records will be performed in a manner to ensure that 
subject confidentiality is maintained. 
10.5 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The study must fully adhere to the principles outlined in Guideline for Good Clinical 
Practice E6 (R2), November 2016, or with local law if it affords greater protection for the 
subject. The IRB/IEC will review all appropriate study documentation in order to safeguard the 
rights, safety, and well-being of the subjects. The study will only be conducted at sites where 
IRB/IEC approval has been obtained. The protocol, Investigator’s Brochure, informed consent 
form, advertisements (if applicable), written information given to the subjects (including diary 
cards), safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the Investigator or the Sponsor, as allowable by local regulations. 
10.6 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either 
the subject or his/her guardian or legal representative prior to study participation. The method of 
obtaining and documenting the informed consent and the contents of the consent is to comply 
with ICH GCP and all applicable regulatory requirement(s). 
10.7 
Subject Confidentiality 
In order to maintain subject privacy, all eCRFs, study drug accountability records, study reports 
and communications will identify the subject by initials where permitted and/or by the assigned 
subject number. The subject’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 
10.8 
Investigator Compliance 
The Investigator will conduct the study in compliance with the protocol provided by Plexxikon 
and given approval/favorable opinion by the IRB/IEC and the appropriate regulatory 
authority(ies). Modifications to the protocol are not to be made without agreement of both the 
Investigator and Plexxikon. Changes to the protocol will require written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to subjects. Plexxikon, or a CRO designee, will submit all 
protocol modifications to the appropriate regulatory authority(ies) in accordance with the 
governing regulations. 


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When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact Plexxikon, or a CRO designee, if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be documented. 
10.9 
On-site Audits 
Regulatory authorities, the IEC/IRB, and/or Plexxikon may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection. Direct access 
to these documents must be guaranteed by the Investigator, who must provide support at all 
times for these activities. 
10.10 Investigator and Site Responsibility for Drug Accountability 
Accountability for the study drug at the study site is the responsibility of the Investigator. Drug 
accountability records indicating the drug’s delivery date to the site, inventory at the site, use by 
each subject, and amount returned to Plexxikon, or a CRO designee, (or disposal of the drug, if 
approved by Plexxikon) will be maintained by the clinical site. Plexxikon or its CRO designee 
will review drug accountability at the site on an ongoing basis. 
All material containing study drug will be treated and disposed of as hazardous waste in 
accordance with governing regulations. 
10.11 Product Complaints 
A product complaint is any dissatisfaction with a product which 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 Plexxikon quality representative. 
For Product Complaints, refer to the Study Pharmacy Manual for instructions and details. 
10.12 Closure of the Study 
The Sponsor currently has no plans to provide PLX2853 to study subjects after the close of the 
study or earlier subject withdrawal. However, the Sponsor will evaluate the appropriateness of 
continuing to provide PLX2853 to study subjects after evaluating study data pertaining to the 
primary efficacy outcome measure and safety. These analyses may be conducted prior to study 
completion. For subjects who are demonstrating a clinical benefit at the end of this study, the 
possibility of continuing their treatment in this or a roll-over protocol may be considered. Within 
90 days of study closure, the Sponsor will notify the competent authorities and the IECs in all 
member states where the study is being carried out that the study has ended. 
Within 1 year of the end of the study, a summary of the clinical study results will be submitted to 
the competent authorities and IECs in all member states involved in the study. 


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Study participation by individual sites may be prematurely terminated if in the opinion of the 
Investigator there is sufficient reasonable cause. Study participation by individual sites or the 
entire study may be prematurely terminated, if in the opinion of Plexxikon, there is sufficient 
reasonable cause. Written notification documenting the reason for study termination will be 
provided to the Investigator or Plexxikon by the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects 
• Failure to enter subjects at an acceptable rate 
• Insufficient adherence to protocol requirements 
• Insufficient, incomplete, and/or un-evaluable data 
• Determination of efficacy based on interim analysis 
• Plans to modify, suspend, or discontinue the development of the study drug 
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the password 
or access materials once their participation in the study has concluded. In the event that any 
access devices for the EDC application have been provided, these will be returned to Plexxikon 
once the site’s participation in the study has concluded. 
Within 15 days of premature closure, Plexxikon must notify the competent authorities and IECs 
of any member state where the study is being conducted, providing the reasons for study closure. 
10.13 Record Retention 
The Investigator will maintain all study records according to ICH GCP and applicable regulatory 
requirement(s). Records will be retained for at least 2 years after the last marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product or according to applicable regulatory requirement(s). If the Investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility and Plexxikon notified. 
10.14 Publication and Use of Information 
All information regarding PLX2853 supplied by Plexxikon to the Investigator is privileged and 
confidential information. The Investigator agrees to use this information to accomplish the study 
and will not use it for other purposes without consent from Plexxikon. It is understood that there 
is an obligation to provide Plexxikon with complete data obtained during the study. The 
information obtained from the clinical study will be used towards the development of PLX2853 
and may be disclosed to regulatory authority(ies), other investigators, corporate partners, or 
consultants as required. 


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Upon completion of the clinical study and evaluation of results by Plexxikon, the hospital or 
institution and/or Investigator may publish or disclose the clinical study results pursuant to the 
terms contained in the applicable Clinical Trial Agreement. 


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11.0 
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mechanistic insights gained from human genomics. Sci Adv. 2015;1(5):e1500447. 
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APPENDIX 1: 
LABORATORY TESTS 
Hematology 
• Complete blood count with differential (absolute) 
• Platelet count 
 
Chemistry 
• Sodium 
• Potassium 
• Chloride 
• CO2 
• Calcium 
• Phosphorus 
• Magnesium 
• Glucose 
• Blood urea nitrogen 
• Creatininea 
• Uric acid 
• Albumin 
• Total protein 
• Total bilirubin 
• Direct bilirubin 
• Aspartate aminotransferase (AST) 
• Alanine aminotransferase (ALT) 
• Alkaline phosphatase (AP) 
• Lactate dehydrogenase (LDH) 
• Gamma-glutamyl transferase (GGT) 
a 
eGFR calculated using the following formula (CKD-EPI 2009): 
eGFR = 141 × min(SCr/K, 1)α × max(SCr/K, 1)-1.209 × 0.993Age × 1.018 × 1.159 [if Black] 
Abbreviations/Units:  eGFR = estimated glomerular filtration rate (mL/min/1.73 m2); 
SCr = standardized serum creatinine (mg/dL); K = 0.7 (females); α = -0.329 (females); 
min = indicates the minimum of SCr/K or 1; max = indicates the maximum of SCr/K or 1; 
age (years) 
 
Coagulation Tests 
• Prothrombin time (PT)/International normalized ratio (INR) 
• Activated partial thromboplastin time (aPTT) 
• Fibrinogen 
• D-dimer 
• Factor VII 
 
Serum Inflammation Marker 
• C-reactive protein 
 


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Urinalysis (microscopic) 
• pH 
• Protein/albumin 
• Glucose/sugar 
• WBCs 
• Leukocyte esterase 
• Nitrites 
• Ketones/acetone 
• Hemoglobin/blood 
• Casts or other microscopic findings 
Serum or Urine Pregnancy Test (ß-hCG):  women of child-bearing potential 
Serology Tests 
• Hepatitis A (hepatitis a virus immunoglobulin M positive) 
• Hepatitis B (hepatitis B virus [HBV] surface antigen positive) 
• Hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV RNA). 
• Subjects with HCV with undetectable virus after treatment are eligible. Subjects with a 
prior history of HBV are eligible if quantitative PCR for HBV DNA is negative. 
• HIV 
Plasma Samples for PK 
• Area under the plasma concentration-time curve (AUC0-24, AUC0-∞) 
• Maximum observed concentration (Cmax) 
• Time to maximum observed concentration (Tmax) 
• Terminal elimination half-life (T1/2) 
 
Blood Response Biomarkers 
• Genetic analyses (sequencing) of tumor tissues for mutations relevant to bromodomain 
inhibition 
• Histochemical and/or protein analysis of tumor, plasma tissue, peripheral blood cells for 
changes relevant to bromodomain inhibition 
• Genomic analysis and expression arrays may also be performed for exploratory purposes 
• RNA sequencing 
• Serum protein and cytokine analysis 
 


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Paired Biopsy Tissue Response Biomarkers 
• c-Myc 
• DNA or RNA sequencing 
• Gene expression 
• Other response or resistance biomarkers as appropriate 
Because the identification of new response prediction or early response biomarkers of disease 
activity is a rapidly developing field, the definitive list of analyses remains to be determined, and 
may include additional markers of macrophage activity, in addition to antitumor biomarkers that 
may be related to PLX2853 treatment. 


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APPENDIX 2: 
EXAMPLES OF STRONG CYP3A4 AND/OR 2C8 INHIBITORS 
AND INDUCERS  
• Apalutamide 
• Avanafil 
• Boceprevir 
• Carbamazepine 
• Clarithromycin 
• Clopidogrel 
• Cobicistat 
• Conivaptan 
• Danoprevir and ritonavir 
• Ebastine 
• Elvitegravir and ritonavir 
• Enzalutamide 
• Gemfibrozil 
• Grapefruit juice 
• Ibrutinib 
• Idelalisib 
• Indinavir 
• Itraconazole 
• Ketoconazole 
• Lomitapide 
• Lopinavir and ritonavir 
• Mitotane 
• Naloxegol 
• Nefazodone 
• Nelfinavir 
• Paritaprevir and ritonavir and 
ombitasvira and/or dasabuvir 
• Phenytoin 
• Posaconazole 
• Repaglinide 
• Rifampin 
• Ritonavir 
• Saquinavir 
• St. John’s wort 
• Tacrolimus 
• Telaprevir 
• Telithromycin 
• Troleandomycin 
• Voriconazole 
 
 
This list is not comprehensive and subject to change and all medications should be reviewed 
prior to administering. Please refer to https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers for 
further information. 


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APPENDIX 3: 
RECIST CRITERIA VERSION 1.1 
Measurability of Tumor at Baseline 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows. 
Measurable tumor lesions 
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 CT scan (CT scan slice thickness no greater than 5 mm) 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable) 
• 20 mm by chest X-ray 
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 and in follow-up, only the short axis will 
be measured and followed. See also section below on ‘Baseline documentation of target and 
non-target lesions’ for information on lymph node measurement. 
Non-measurable tumor lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include:  leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, peritoneal spread, abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• Bone scan, PET 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. 


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• 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 or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) 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 non-cystic 
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 usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such 
lesions would be considered measurable. 
Specifications by methods of measurements 
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. 
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 done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 


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Chest X-ray:  Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. Still, non-contrast CT is preferred over chest X-ray. 
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. MRI is also acceptable in certain situations (e.g., for body scans). 
If prior to enrollment it is known that a subject is not able to undergo CT scans with IV contrast 
due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI (with 
or without IV contrast) will be used to evaluate the subject at baseline and follow-up, should be 
guided by the tumor type under investigation and the anatomic location of the disease. For 
subjects who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed, 
should also be based on the tumor type, anatomic location of the disease and should be optimized 
to allow for comparison to the prior studies if possible. Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, the 
subject should be considered not evaluable from that point forward. 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from 1 assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a subject to 
be considered in complete response. Because tumor markers are disease specific, instructions for 
their measurement should be incorporated into protocols on a disease specific basis. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup 
has developed CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer. 


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Cytology, histology:  These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g., with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for response 
or stable disease in order to differentiate between response (or stable disease) and progressive 
disease. 
Tumor Response Evaluation 
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. Only subjects with 
measurable disease at baseline should be included in protocols where objective tumor response is 
the primary endpoint. Measurable disease is defined by the presence of at least 1 measurable 
lesion (as detailed above in this Appendix 3). In studies where the primary endpoint is tumor 
progression (either time to progression or proportion with progression at a fixed date), the 
protocol must specify if entry is restricted to those with measurable disease or whether subjects 
having non-measurable disease only are also eligible. 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than 1 measurable lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) 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 (1 site) and 4 lesions (2 sites), respectively, will be recorded. Other lesions in that organ will be 
recorded as non-measurable lesions (even if size is greater than 10 mm by CT scan). 
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 
which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which 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 


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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 which is reported as being 20 mm x 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 non-target lesions. Nodes that have a short axis <10 mm are considered 
non-pathological 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 
non-target 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 non-target lesions involving the same 
organ as a single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
Response criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
Evaluation of target lesions 
• Complete Response (CR):  Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
• 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. 


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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 complete response criteria 
are met, since a normal lymph node is defined as having a short axis of <10 mm. Case report 
forms or other data collection methods may therefore be designed to have target nodal lesions 
recorded in a separate section where, in order to qualify for CR, each node must achieve a short 
axis <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 (e.g., 2 mm). However, sometimes lesions or 
lymph nodes which 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 case 
report form: 
• 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 and BML (below measurable 
limit) should be ticked (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 and BML should also be ticked). 
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 non-reproducible, 
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 and in that case BML should not be ticked. (BML is 
equivalent to a less than sign <) 
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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Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target 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. 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD:  Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions.  
(Note:  the appearance of 1 or more new lesions is also considered progression). 
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target 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 non-target disease, there must be an overall level of 
substantial worsening in non-target disease in a magnitude 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 non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target 
disease will therefore be extremely rare. 
When the subject has only non-measurable disease:  this circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition:  if all lesions 
are truly non-measurable) a useful test that can be applied when assessing subjects for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease:  i.e., an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols 
as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the subject 
should be considered to have had overall PD at that point. While it would be ideal to have 


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objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore, the increase must be substantial. 
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:  i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the subject’s baseline lesions show partial or complete response. 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 brain CT or MRI 
ordered which 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. 
(18)F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up: 
• If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
• If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). 
• If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 


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Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The subject’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of new 
lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in nonrandomized trials where response is 
the primary endpoint, confirmation of PR or CR is needed to deem either 1 the ‘best overall 
response’. This is described further below. 
Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 10 
provides a summary of the overall response status calculation at each time point for subjects who 
have measurable disease at baseline. 
When subjects have non-measurable (therefore non-target) disease only, Table 11 is to be used. 
Missing assessments and not-evaluable designation 
When no imaging/measurement is done 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. 
If 1 or more target lesions were not assessed either because the scan was not done or could not be 
assessed because of poor image quality or obstructed view, the Response for Target Lesions 
should be “Unable to Assess” since the subject is not evaluable. Similarly, if 1 or more 
non-target lesions are indicated as ‘not assessed’, the response for non-target lesions should be 
“Unable to Assess” (except where there is clear progression). Overall response would be 
“Unable to Assess” if either the target response or the non-target response is “Unable to Assess” 
(except where this is clear evidence of progression) as this equates with the case being not 
evaluable at that time point. 


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Best overall response:  all time points 
The best overall response will be determined by statistical programming once all the data for the 
subject is known. 
Table 10: 
Time Point Response:  Subjects with Targets (± Non-target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
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 
 
Table 11: 
Time Point Response:  Subjects with Non-target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial response; SD = stable disease 
a ‘Non-CR/Non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised. 


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Table 12: 
Best Overall Response When Confirmation of CR and PR Required 
Overall Response 
First Time Point 
Overall Response 
Subsequent  
Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, otherwise, NE 
NE 
NE 
NE 
CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial response; SD = stable disease 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). 
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 
 
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 case report form (CRF). 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, 
in most trials it is reasonable to consider a subject with time point responses of PR-NE-PR as a 
confirmed response. 
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 non-target disease as shown in 
Table 10, Table 11, and Table 12. 


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Conditions that define ‘early progression, early death and non-evaluability’ are study specific 
and should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar to 
a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g., 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. 


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APPENDIX 4: 
DRUGS CLEARLY ASSOCIATED WITH THE RISK OF 
TORSADES DE POINTES (TDP) AND QT PROLONGATION 
 
Anti-arrhythmics 
- Amiodarone 
- Disopyramide 
- Dofetilide 
- Dronedarone 
- Flecainide 
- Ibutilide 
- Procainamide (Oral off US Market) 
- Quinidine 
- Sotalol 
- Ritonavir 
- Indinavir 
- Nelfinavir 
Antimicrobials 
- Azithromycin 
- Ciprofloxacin 
- Clarithromycin 
- Erythromycin 
- Grepafloxacin (Off Market worldwide) 
- Levofloxacin 
- Moxifloxacin 
- Sparfloxacin (Removed from US Market) 
- Pentamidine 
- Fluconazole 
Anti-psychotics 
- Haloperidol 
- Mesoridazine (Removed from US Market) 
- Pimozide 
- Thioridazine 
- Chlorpromazine 
- Droperidol 
- Sulpiride (On non US Market) 
Anti-cancers 
- Arsenic trioxide 
- Vandetanib 
Anti-depressants, SSRIs 
- Citalopram 
- Escitalopram 
Antihistamines 
- Astemizole (Removed from US Market) 
- Terfenadine (Removed from US Market) 
Anti-malarials 
- Chloroquine 
- Halofantrine 
Antilipemic 
- Probucol (Removed from US Market) 
- Ondansetron 
Opiates 
- Levomethadyl acetate (Removed from US Market) 
- Methadone 
Anesthetics, general 
- Propofol 
- Sevoflurane 
Others 
- Cisapride (Removed from US Market) 
- Cocaine 
- Anagrelide 
- Bepridil (Removed from US Market) 
- Domperidone (On non US Market) 
 
This list is not comprehensive and all medications should be reviewed prior to administering. 
CredibleMeds® OncoSupport™ can be used as a reference for additional information of drugs 
with known TdP risk. 


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APPENDIX 5: 
ECOG PERFORMANCE STATUS 
These scales and criteria are used by doctors and researchers to assess how a subject's disease is 
progressing, assess how the disease affects the daily living abilities of the subject, and determine 
appropriate treatment and prognosis. They are included here for health care professionals to 
access. 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light housework, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
* As published in Oken 1982. 
 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the scale, 
please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis M.D., Group 
Chair. 
 
All contents copyright © 1998-2000 Eastern Cooperative Oncology Group. 
All rights reserved. 
Revised:  July 27, 2006 
 


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APPENDIX 6: 
EVALUATION OF PROGRESSION ACCORDING TO CA-125 
Progression or recurrence based on serum CA-125 levels will be defined on the basis of a 
progressive serial elevation of serum CA-125 according to the following criteria and Table 13: 
A. Subjects with elevated CA-125 pretreatment and normalization of CA-125 must show 
evidence of CA-125 ≥2 × the upper limit of the reference range on 2 occasions at least 
1 week apart 
OR 
B. Subjects with elevated CA-125 before treatment, which never normalizes, must show 
evidence of CA-125 ≥2 × the nadir value on 2 occasions at least 1 week apart 
OR 
C. Subjects with CA-125 in the reference range before treatment must show evidence of 
CA-125 ≥2 × the upper limit of the reference range on 2 occasions at least 1 week apart. 
CA-125 progression will be assigned the date of the first measurement that meets the criteria 
as noted. Subjects are not evaluable by CA-125 if they have received mouse antibodies 
(unless the assay used has been shown not to be influenced by human anti-mouse antibody) 
or if there has been medical and/or surgical interference with their peritoneum or pleura 
(e.g., paracentesis) during the previous 28 days. 
A subject may be declared to have progressive disease on the basis of either the objective 
RECIST 1.1 criteria or the CA-125 criteria. The date of progression will be the date of the 
earlier of the 2 events if both are documented. 


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Table 13: 
Definition of Progression After First-Line Therapy in Ovarian Cancer as 
Proposed by the GCIG 
GCIG 
Subcategorized 
Group 
RECIST 
Measurable/Nonmeasurable 
Disease 
 
CA-125a 
A 
Compared to baseline (or lowest sum while on 
study if less than baseline), a 20% increase in sum 
of diameters (RECIST 1.1 definition) 
or 
Any new lesions (measurable or nonmeasurable) 
or 
Unequivocal increase in nontarget disease 
Date of PD:  date of documentation of increase or 
new lesions 
A
N
D 
/ 
O
R 
CA-125 ≥2 × ULRR on 2 occasionsb 
Date of PD:  first date of the CA-125 
elevation to ≥2 × ULRR 
B 
As for A 
CA-125 ≥2 × nadir value on 2 occasionsb 
Date of PD:  first date of the CA-125 
elevation to ≥2 × nadir value 
C 
As for A 
As for A 
Source:  Rustin 2011 
CA-125 = cancer antigen 125; GCIG = Gynecological Cancer Intergroup; PD = progressive disease; 
RECIST = Response Evaluation Criteria in Solid Tumors; ULRR = upper limit of response range 
Note:  GCIG Groups A, B, and C defined above. 
a CA-125 levels sampled after subjects received mouse antibodies (unless the assay used has been shown not to be 
influenced by human anti-mouse antibody) or if there has been medical and/or surgical interference with their 
peritoneum or pleura during the previous 28 days should not be taken into account. 
b Repeat CA-125 any time but normally not less than 1 week after the first elevated CA-125 level.