Conditions: Urothelial Carcinoma Urothelial Cancer Lung Neoplasms Small Cell Lung Cancer Prostate Cancer
Keywords: PARP Inhibitor Topoisomerase I (Top1) Camptothecins Nanoparticle Drug Conjugate Solid Tumors
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 45
Healthy volunteers: no

Brief summary:
Background: EP0057 (formerly CRLX101) consists of a sugar molecule cyclodextrin linked to a chemotherapy drug called camptothecin. The combined molecule or "nanoparticle drug conjugate" travels through the blood. Once inside cancer cells, the chemotherapy drug is released from the molecule. Olaparib is a drug that may stop cancer cells from repairing the deoxyribonucleic acid (DNA) damage caused by chemotherapy. Researchers want to see how safe it is to give EP0057 and olaparib together and to see how well the combination treats a specific type of lung cancer called small cell lung cancer (SCLC).

Objectives:

To test the safety and maximum dose of EP0057 and olaparib together. To test how well they treat small cell lung cancer.

Eligibility:

Adults 18 and older with small cell lung cancer.

Design:

Participants will be screened with standard cancer care tests.

Participants will get the 2 study drugs in 28-day cycles. EP0057 will be given every 2 weeks, through a small plastic tube in an arm vein. Olaparib will be taken by mouth twice a day most days. Participants will keep a pill diary.

For Cycle 1, participants will have 3 visits. All other cycles will have 2 visits.

At study visits, participants may have:

* Blood and hair samples taken
* History and Physical exam
* Questions about health and side effects
* Pregnancy test
* Optional tumor biopsy where a piece of tumor is removed by needle after numbing the skin.
* Computed tomography (CT) scan
* Injection of EP0057 (twice per cycle)
* Olaparib prescription

Participants will have a follow-up visit 4 weeks after finish taking the drugs. They will have a physical exam and blood tests. They may have a tumor biopsy. The study team will call the patient every 3 months for follow up after completing the study treatment.

Detailed description:
Background:

* Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis.
* Although highly responsive to chemotherapy initially, SCLC relapses quickly and becomes refractory to treatment within a few months.
* Urothelial Carcinoma (UC) of the Bladder is the fourth most common malignancy in men and the ninth most common in women.
* Prostate cancer is the most common cancer among men in the United States. While prostate cancer is initially responsive to androgen deprivation therapy (ADT), the median duration of sensitivity is 24-36 months. Moreover, patients develop resistance to current treatment options.
* The use of poly adenosine diphosphate ribose polymerase (PARP) inhibitors in combination with chemotherapy builds upon pre-clinical data in lung cancer and other cancers supporting the notion that PARP inhibitors potentiate the effect of deoxyribonucleic acid (DNA) damaging therapies.
* Despite their highly synergistic activity in preclinical models, human studies combining PARP inhibitors and camptothecins have not translated into clinical benefit due to enhanced toxicity with the combination.
* One approach to improve ability to combine camptothecins with agents that sensitize their activity like PARP inhibitors is to use alternative formulations that minimize toxicity to the normal tissues.
* EP0057 (formerly CRLX101) is a nanoparticle drug conjugate composed of 20 (S)-camptothecin (a potent and highly selective topoisomerase I inhibitor) conjugated to a linear, cyclodextrin polyethylene glycol-based polymer.
* Olaparib is a PARP inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germline breast cancer gene (BRCA) mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Olaparib has an established safety profile, and it is under investigation in a number of different cancers.

Objectives:

* Phase I: To determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of EP0057 in combination with olaparib in patients with refractory cancers.
* Phase II: To determine the antitumor activity of olaparib plus EP0057 with respect to progression free survival at 16 weeks in SCLC patients with resistant or sensitive relapse.
* Expansion Cohorts: To determine overall response rate of EP0057 plus olaparib in patients with mCRPC and urothelial carcinoma.

Eligibility:

Phase I

* Adult patients \>=18 years of age
* Histologically or cytologically confirmed, advanced solid tumor that is refractory to standard therapy and/or for whom no further standard therapy is available
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2

Phase II

* Adult patients \>= 18 years old
* Have a pathologically (histology or cytology) confirmed diagnosis of SCLC
* Disease progression on or after at least one platinum-based standard chemotherapy regimen and/or an immune-checkpoint inhibitor for either limited or extensive stage disease.
* Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
* ECOG performance status of 0, 1 or 2

Phase II Expansion Cohorts

* Have a pathologically (histology or cytology) confirmed diagnosis of urothelial carcinoma or metastatic, progressive, castrate resistant prostate cancer (mCRPC)
* Disease progression on or after at least one platinum-based standard chemotherapy regimen and/or an immune-checkpoint inhibitor (except prostate cohort)
* Have measurable disease per RECIST 1.1 (except prostate cohort)
* Prior treatment with enzalutamide and/or abiraterone (prostate cancer cohort only)
* Patients must have castrate levels of testosterone (\<50 ng/dl \[1.74 nmol/l\]) (Prostate cohort only)

Design:

* Patients meeting eligibility criteria will receive EP0057 (intravenous (IV) every (Q) 2weeks) plus olaparib (by mouth (PO) twice a day (BID), days 3-13 and days 17-26 administered in 28-day cycles, until disease progression or development of intolerable side effects. The maximum tolerated dose (MTD) of the combination will be used in Phase II.
* Patients in Phase II will receive, the recommended phase 2 dose (RP2D) at DL4R EP0057 12 mg/m\^2 and olaparib 250 mg twice a day (BID).
* Blood, tumor and hair samples will be collected at multiple time points for pharmacokinetics (PK), pharmacodynamics (PD) analyses. Hair sample collection is optional. Tumor biopsies are optional for SCLC and ulcerative colitis (UC) patients and mandatory for metastatic castration-resistant prostate cancer (mCRPC) patients (only baseline biopsy is mandatory).
* Toxicity will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
* Tumor assessments will be made using computed tomography (CT) scans (chest, abdomen and pelvis) at baseline and after every 2 cycles (3 cycles for metastatic castration-resistant prostate cancer (mCRPC) according to RECIST version 1.1.
* After discontinuation of study treatment, follow-up for survival will be carried out every 3 months.

Arms:
arm 1: EP0057 + olaparib arm 2: EP0057 (formerly CRLX101) + olaparib at maximum tolerated dose/recommended phase 2 dose (MTD/RP2D)

Interventions: intervention 1: EP0057 intervention 2: olaparib intervention 3: CT scan intervention 4: CT chest, abdomen, and pelvis intervention 5: Bone scan intervention 6: ECG intervention 7: Echocardiogram intervention 8: Biopsy
Intervention descriptions: intervention 1: EP0057 (formerly CRLX101) intravenous (IV) every (Q) 2weeks Day 1 and Day 15, administered in 28-day cycles, until disease progression or development of intolerable side effects.

Plus olaparib (by mouth (PO) days 3-13\* and days 17-26\*) administered in 28-day cycles, until disease progression or development of intolerable side effects. Phase (P)1: Dose Escalation P2: recommended phase 2 dose (RP2D).

(\* On days 13 and 26, only one dose of olaparib will be administered in the morning) intervention 2: Olaparib (by mouth (PO) days 3-13\* and days 17-26\* administered in 28-day cycles, until disease progression or development of intolerable side effects Plus EP0057 (formerly CRLX101) (intravenous (IV) every (Q) 2 weeks, Day 1 and Day 15) administered in 28-day cycles, until disease progression or development of intolerable side effects. Phase (P)1: Dose Escalation P2: recommended phase 2 dose (RP2D).

(\* On days 13 and 26, only one dose of olaparib will be administered in the morning). intervention 3: Screening and baseline. intervention 4: Metastatic castration-resistant prostate cancer (mCRPC) participants only at screening, baseline, cycle 2 Day 1, and end of treatment/disease progression. intervention 5: Metastatic castration-resistant prostate cancer (mCRPC) participants only at screening, baseline, cycle 2 Day 1, and end of treatment/disease progression. intervention 6: Screening, baseline, Day 1, Day 15 and cycle 2, Day 1. intervention 7: At screening. intervention 8: Baseline Day 4 and end of treatment/disease progression.

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
1
Abbreviated Title: EP0057 in Advanced Cancers
NIH Protocol #: 16-C-0107 
Version Date: 08/16/2024
NCT Number: NCT02769962
Title: A Phase I/II Trial of EP0057, a Nanoparticle Camptothecin with Olaparib in Patients with 
Relapsed/Refractory Small Cell Lung, Bladder and Prostate Cancers 
NCI Principal Investigator:
Anish Thomas, MBBS, M.D. 
Developmental Therapeutics Branch (DTB)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
10 Center Drive, Room 4-5330
Bethesda, MD 20892
Phone: 240-760-7343
E-mail: anish.thomas@nih.gov
Drug Name:
EP0057 (formerly CRLX101)
Olaparib
IND Number:
130102
130102
Sponsor:
Center for Cancer Research
Center for Cancer Research
Manufacturer:
Ellipses Pharma Limited
AstraZeneca
Supplier:
Ellipses Pharma Limited
AstraZeneca


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
2
PRÉCIS 
Background:
•
Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis.
•
Although highly responsive to chemotherapy initially, SCLC relapses quickly and 
becomes refractory to treatment within a few months.
•
Urothelial Carcinoma (UC) of the Bladder is the fourth most common malignancy in men 
and the ninth most common in women.
•
Prostate cancer is the most common cancer among men in the United States. While 
prostate cancer is initially responsive to androgen deprivation therapy (ADT), the median 
duration of sensitivity is 24-36 months. Moreover, patients develop resistance to current 
treatment options. 
•
The use of PARP inhibitors in combination with chemotherapy builds upon pre-clinical 
data in lung cancer and other cancers supporting the notion that PARP inhibitors 
potentiate the effect of DNA damaging therapies. 
•
Despite their highly synergistic activity in preclinical models, human studies combining 
PARP inhibitors and camptothecins have not translated into clinical benefit due to 
enhanced toxicity with the combination.
•
One approach to improve ability to combine camptothecins with agents that sensitize 
their activity like PARP inhibitors is to use alternative formulations that minimize 
toxicity to the normal tissues.
•
EP0057 is a nanoparticle drug conjugate composed of 20 (S)-camptothecin (a potent and 
highly selective topoisomerase I inhibitor) conjugated to a linear, cyclodextrin-
polyethylene glycol-based polymer.
•
Olaparib is a PARP inhibitor indicated as monotherapy in patients with deleterious or 
suspected deleterious germline BRCA mutated advanced ovarian cancer who have been 
treated with three or more prior lines of chemotherapy. Olaparib has an established safety 
profile and it is under investigation in a number of different cancers.
Objectives:
•
Phase I: To determine the MTD/recommended Phase 2 dose (RP2D) of EP0057 in 
combination with olaparib in patients with refractory cancers.
•
Phase II: To determine the antitumor activity of olaparib plus EP0057 with respect to 
progression free survival at 16 weeks in SCLC patients with resistant or sensitive relapse.
•
Expansion Cohorts: To determine overall response rate of EP0057 plus olaparib in 
patients with mCRPC and urothelial carcinoma.
Eligibility:
Phase I
•
Adult patients ≥18 years of age


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
3
•
Histologically or cytologically confirmed, advanced solid tumor that is refractory to 
standard therapy and/or for whom no further standard therapy is available
•
ECOG Performance Status of 0, 1 or 2
Phase II
•
Adult patients ≥ 18 years old
•
Have a pathologically (histology or cytology) confirmed diagnosis of SCLC
•
Disease progression on or after at least one platinum-based standard chemotherapy 
regimen and/or an immune-checkpoint inhibitor for either limited or extensive stage 
disease. 
•
Have measurable disease per RECIST 1.1 
•
ECOG performance status of 0, 1 or 2
Phase II Expansion Cohorts
•
Have a pathologically (histology or cytology) confirmed diagnosis of urothelial 
carcinoma or metastatic, progressive, castrate resistant prostate cancer (mCRPC)
•
Disease progression on or after at least one platinum-based standard chemotherapy 
regimen and/or an immune-checkpoint inhibitor (except prostate cohort)
•
Have measurable disease per RECIST 1.1 (except prostate cohort)
•
Prior treatment with enzalutamide and/or abiraterone (prostate cancer cohort only)
•
Patients must have castrate levels of testosterone (<50 ng/dl [1.74 nmol/l]) (Prostate 
cohort only)
Design:
•
Patients meeting eligibility criteria will receive EP0057 (IV Q 2weeks) plus olaparib (PO 
BID days 3-13 and days 17-26 administered in 28-day cycles, until disease progression or 
development of intolerable side effects. The MTD of the combination will be used in 
Phase II. 
•
Patients in Phase II will receive, the RP2D at DL4R EP0057 12 mg/m2 and olaparib 250 
mg BID. 
•
Blood, tumor and hair samples will be collected at multiple time points for PK, PD 
analyses. Hair sample collection is optional. Tumor biopsies are optional for SCLC and 
UC patients and mandatory for mCRPC patients (only baseline biopsy is mandatory).
•
Toxicity will be graded according to CTCAE version 4.0. 
•
Tumor assessments will be made using CT scans (chest, abdomen and pelvis) at baseline 
and after every 2 cycles (3 cycles for mCRPC) according to RECIST version 1.1. 
•
After discontinuation of study treatment, follow-up for survival will be carried out every 
3 months. 


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
4
Trial schema and dose escalation
Provisional Dose levels
EP0057, mg/m2
(IV q 2 weeks D1 and D15)
Olaparib tablet, mg
(PO BID Days 3-13* and 17-
26*) 
1
12
100
2
12
150
3
12
200
4
12
300**
4R(educed) (MTD/RP2D)
12
250
5 (Not explored)
15
300
5B (Not explored)
15
300
28-day cycles; biopsies pre-treatment and on day 4 (24 hours post- olaparib) and at disease 
progression. 
* There should be a minimum 48-hour window between EP0057 and olaparib except dose 
level 5B which allows the interval to be abbreviated to 24 hours. 
The recommended phase 2 dose (RP2D) may be lower than, or equal to, the MTD. Phase II 
portion of this study may start with RP2D, and/or at MTD.
** An additional dose level (4R) of 250 mg has been evaluated with DLTs in 1 of 6 patients as 
there were 2 or more DLTs among 6 patients treated at dose level 4.


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
5


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
6
TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS.................................................................................................................6
STATEMENT OF COMPLIANCE...............................................................................................12
1
INTRODUCTION..................................................................................................................13
1.1
Study Objectives .............................................................................................................13
1.1.1
Primary Objectives...................................................................................................13
1.1.2
Secondary Objectives...............................................................................................13
1.1.3
Exploratory Objectives ............................................................................................13
1.2
Background and Rationale..............................................................................................13
1.2.1
Small Cell Lung Cancer...........................................................................................13
1.2.2
Urothelial Carcinoma (UC) of the Bladder..............................................................14
1.2.3
Castrate resistant prostate cancer (mCRPC)............................................................16
1.2.4
PARP as a Therapeutic Target in Small Cell Lung Cancer.....................................18
1.2.5
PARP Inhibitors and DNA Damaging Chemotherapy are Synergistic ...................19
1.2.6
Safely combining PARP Inhibitors with Camptothecins.........................................19
1.2.7
EP0057 Preclinical Toxicology ...............................................................................21
1.2.8
EP0057 phase I clinical trial ....................................................................................21
1.2.9
Adverse Events with EP0057 (CRLX101) Monotherapy........................................22
1.2.10
Adverse Events Associated with EP0057 (CRLX101) Combination Therapy .......28
1.2.11
EP0057 (CRLX101) Clinical Development Overview............................................33
1.2.12
Preclinical Data of EP0057 (CRLX101) plus Olaparib...........................................34
1.2.13
Hypothesis................................................................................................................35
1.2.14
Rationale ..................................................................................................................36
1.2.15
Rationale for Amendment C....................................................................................36
1.2.16
Rationale for Amendment E ....................................................................................36
1.2.17
Rationale for mCRPC cohort accrual closure (amendment version date: 
07/27/2021)............................................................................................................................37
1.2.18
Rationale for urothelial carcinoma cohort accrual closure (amendment version date: 
08/17/22)................................................................................................................................37
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT ........................................................37
2.1
Eligibility Criteria ...........................................................................................................37
2.1.1
Inclusion Criteria - Phase I ......................................................................................37


Abbreviated Title: EP0057 in Advanced Cancers
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2.1.2
Inclusion Criteria - Phase II SCLC..........................................................................39
2.1.3
Inclusion Criteria for Urothelial Carcinoma Expansion Cohort (accrual to the 
cohort ended with amendment version 08/17/2022)..............................................................40
2.1.4
Inclusion Criteria for mCRPC Expansion Cohort (accrual to the mCRPC cohort 
ended with amendment version 7/27/2021)...........................................................................42
2.1.5
Exclusion Criteria - Phase I and II SCLC and UC Expansion Cohort (note: accrual 
to the UC cohort ended with amendment version 08/17/2022).............................................43
2.1.6
Exclusion Criteria - mCRPC Expansion Cohort (accrual to the mCRPC cohort 
ended with amendment version 7/27/2021)...........................................................................44
2.2
Recruitment Strategies ....................................................................................................46
2.3
Screening Evaluation ......................................................................................................47
2.3.1
Screening activities performed prior to obtaining informed consent.......................47
2.3.2
Screening activities performed after a consent for screening has been signed........47
2.4
Participant Registration and Status Update Procedures..................................................48
2.4.1
Screen Failures.........................................................................................................48
2.4.2
Treatment Assignment Procedures ..........................................................................48
2.5
Baseline Evaluation.........................................................................................................48
3
STUDY IMPLEMENTATION ..............................................................................................49
3.1
Study Design...................................................................................................................49
3.1.1
Dose Limiting Toxicity............................................................................................50
3.1.2
Dose Escalation........................................................................................................51
3.2
Drug Administration .......................................................................................................52
3.2.1
EP0057.....................................................................................................................52
3.2.2
Olaparib....................................................................................................................53
3.3
Dose Modifications.........................................................................................................53
3.3.1
General Recommendation for Dose Modification...................................................53
3.3.2
Dosing Delays/Dose Modifications and Management of Toxicities.......................54
3.3.3
General Recommendations for Dose Modification and Management of Non-
Hematologic Adverse Events.................................................................................................57
3.3.4
Management of the hypersensitivity/infusion reactions ..........................................58
3.3.5
Dose Modification for Surgical Procedures or Palliative Radiation........................59
3.3.6
Laboratory safety assessment ..................................................................................59
3.4
Study Calendar................................................................................................................60
3.5
Cost and Compensation ..................................................................................................63


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
8
3.5.1
Costs.........................................................................................................................63
3.5.2
Compensation ..........................................................................................................63
3.5.3
Reimbursement ........................................................................................................63
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................63
3.6.1
Criteria for Removal from Protocol Therapy...........................................................63
3.6.2
Off-Study Criteria....................................................................................................63
4
CONCOMITANT MEDICATIONS/MEASURES................................................................64
4.1
Supportive Care...............................................................................................................65
4.1.1
Other Concomitant Medications..............................................................................65
4.1.2
Palliative radiotherapy .............................................................................................66
4.1.3
Administration of other anti-cancer agents..............................................................66
4.1.4
Medications that may NOT be administered ...........................................................66
4.1.5
Overdose ..................................................................................................................66
4.2
Highly Effective methods of birth control ......................................................................66
4.2.1
Acceptable non-hormonal birth control methods ....................................................67
4.2.2
Acceptable hormonal methods.................................................................................67
5
CORRELATIVE STUDIES FOR RESEARCH ....................................................................68
5.1
Biospecimen Collection ..................................................................................................68
5.1.1
Phase I and Phase II Cohorts ...................................................................................68
5.1.2
UC Expansion Cohort..............................................................................................74
5.1.3
mCRPC Expansion Cohort ......................................................................................85
5.2
Sample Storage, Tracking and Disposition.....................................................................87
5.2.1
DTB Clinical Translational Unit..............................................................................87
5.2.2
Clinical Pharmacology Program (Figg Lab)............................................................88
5.2.3
Redon (Aladjem) Lab ..............................................................................................89
5.2.4
Paul Meltzer Lab......................................................................................................89
5.2.5
Laboratory of Genitourinary Cancer Pathogenesis (Kathleen Kelly Siebenlist).....89
5.2.6
Urologic Oncology Branch Molecular Therapeutics Facility (Donald Bottaro) .....89
5.2.7
Laboratory of Pathology ..........................................................................................90
5.2.8
Laboratory of Pathology NCI COMPASS Program................................................90
5.2.9
Future Use/IRB Reporting/Protocol Completion/Sample Destruction....................90
5.3
Samples for Genetic/Genomic Analysis .........................................................................91
5.3.1
Description of the scope of genetic/genomic analysis.............................................91


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
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5.3.2
Certificate of Confidentiality...................................................................................91
5.3.3
Management of Results............................................................................................91
6
DATA COLLECTION AND EVALUATION ......................................................................92
6.1
Data Collection ...............................................................................................................92
6.2
Data Sharing Plans..........................................................................................................92
6.2.1
Human Data Sharing Plan........................................................................................92
6.2.2
Genomic Data Sharing Plan.....................................................................................93
6.3
Response Criteria ............................................................................................................93
6.3.1
Definitions................................................................................................................93
6.3.2
Disease Parameters ..................................................................................................93
6.3.3
Methods for Evaluation of Measurable Disease......................................................94
6.3.4
Response Criteria.....................................................................................................96
6.3.5
Response Criteria for mCRPC Cohort.....................................................................98
6.3.6
Duration of Response...............................................................................................99
6.3.7
Progression-Free Survival........................................................................................99
6.3.8
Response Review.....................................................................................................99
6.4
Toxicity Criteria..............................................................................................................99
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN..100
7.1
Definitions.....................................................................................................................100
7.2
OHSRP Office of Compliance and Training / IRB Reporting......................................100
7.2.1
Expedited Reporting ..............................................................................................100
7.2.2
IRB Requirements for PI Reporting at Continuing Review ..................................100
7.3
NCI Clinical Director Reporting...................................................................................100
7.4
NIH Required Data and Safety Monitoring Plan..........................................................100
7.4.1
Principal Investigator/Research Team...................................................................100
8
SPONSOR PROTOCOL/SAFETY REPORTING...............................................................101
8.1
Definitions.....................................................................................................................101
8.1.1
Adverse Event........................................................................................................101
8.1.2
Serious Adverse Event (SAE)................................................................................101
8.1.3
Life-threatening......................................................................................................101
8.1.4
Severity ..................................................................................................................101
8.1.5
Relationship to Study Product ...............................................................................102
8.2
Assessment of Safety Events ........................................................................................102


Abbreviated Title: EP0057 in Advanced Cancers
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8.3
Reporting of Serious Adverse Events ...........................................................................102
8.4
Waiver of expedited reporting to CCR/OSRO .............................................................103
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators....................................103
8.5.1
Ellipses Reporting Requirements...........................................................................103
8.5.2
AstraZeneca Reporting Requirements...................................................................103
8.6
Reporting Pregnancy.....................................................................................................105
8.6.1
Maternal exposure ................................................................................................105
8.6.2
Paternal exposure...................................................................................................105
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND.................105
8.8
Sponsor Protocol Deviation Reporting .........................................................................106
9
CLINICAL MONITORING.................................................................................................106
10 STATISTICAL CONSIDERATIONS .................................................................................107
10.1
Phase I and Phase II...................................................................................................107
10.2
Phase II Expansion Cohorts ......................................................................................109
10.2.1
Expansion Cohort (Urothelial Carcinoma)............................................................109
10.2.2
Expansion Cohort (mCRPC) .................................................................................109
10.3
Sample Size Determination.......................................................................................111
11 COLLABORATIVE AGREEMENTS.................................................................................111
11.1
Cooperative Research and Development Agreement (CRADA)..............................111
11.1.1
BlueLink (CRADA #03049)..................................................................................111
11.1.2
Astra Zeneca (CRADA #02299)............................................................................111
12 HUMAN SUBJECTS PROTECTIONS...............................................................................111
12.1
Rationale For Subject Selection ................................................................................111
12.2
Participation of Children ...........................................................................................111
12.3
Evaluation of Benefits and Risks/Discomforts .........................................................111
12.3.1
Risks.......................................................................................................................111
12.3.2
Benefits ..................................................................................................................112
12.4
Consent Process and Documentation ........................................................................112
12.4.1
Request for Waiver of Consent for Screening Activities.......................................113
13 REGULATORY AND OPERATIONAL CONSIDERATIONS.........................................113
13.1
Study Discontinuation and Closure...........................................................................113
13.2
Quality Assurance and Quality Control ....................................................................114
13.3
Conflict of Interest Policy .........................................................................................114


Abbreviated Title: EP0057 in Advanced Cancers
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11
13.4
Confidentiality and Privacy.......................................................................................114
14 PHARMACEUTICAL INFORMATION ............................................................................115
14.1
EP0057 (IND#130102)..............................................................................................115
14.1.1
Description.............................................................................................................115
14.1.2
Supplier/How Supplied..........................................................................................115
14.1.3
Handling and Dispensing.......................................................................................116
14.1.4
Preparation.............................................................................................................116
14.1.5
Storage and Stability..............................................................................................116
14.1.6
Dosage and Administration....................................................................................117
14.1.7
Premedication and Hydration ................................................................................117
14.1.8
Return and Retention of EP0057 ...........................................................................117
14.1.9
Toxicity..................................................................................................................117
14.2
Olaparib (AZD2281; Olaparib; IND#130102)..........................................................117
14.2.1
Source ....................................................................................................................117
14.2.2
Pre-clinical experience...........................................................................................118
14.2.3
Toxicology and safety pharmacology summary....................................................118
14.2.4
Approved indications and clinical experience.......................................................118
14.2.5
Indications and Usage............................................................................................118
14.2.6
Dosage and Administration....................................................................................118
14.2.7
Tablet Dosage Forms and Strengths ......................................................................118
14.2.8
Warnings and Precautions......................................................................................119
14.2.9
Adverse Reactions .................................................................................................119
14.2.10 Drug Interactions ...................................................................................................121
15 REFERENCES .....................................................................................................................122
16 APPENDICES......................................................................................................................128
16.1
Appendix A: Performance Status Criteria.................................................................128
16.2
Appendix B : List of drugs that may have potential CYP3A4 interactions ..............129
16.2.1
CYP3A4 Substrates ...............................................................................................129
16.2.2
CYP3A4 Inhibitors ................................................................................................130
16.2.3
CYP3A4 Inducers..................................................................................................135
16.3
Appendix C : Patient’s Pill Diary: Olaparib..............................................................140


Abbreviated Title: EP0057 in Advanced Cancers
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12
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.


Abbreviated Title: EP0057 in Advanced Cancers
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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objectives
1.1.1.1
Phase I: To determine the MTD/recommended Phase 2 dose (RP2D) of EP0057 plus 
olaparib in patients with refractory cancers.
1.1.1.2
Phase II: To determine the antitumor activity of olaparib plus EP0057 with respect to 
progression free survival 16 weeks in SCLC patients with resistant or sensitive relapse
1.1.1.3
Phase II Expansion Cohorts: To determine overall response rate of EP0057 plus 
olaparib in patients with mCRPC and urothelial carcinoma
1.1.2
Secondary Objectives
Phase I and Phase II Cohorts:
1.1.2.1
To evaluate the pharmacokinetic profile of EP0057 (both the total drug and released 
camptothecin) and olaparib in plasma. 
1.1.2.2
To evaluate the pharmacodynamic (PD) activity of EP0057 in blood, surrogate tissue 
and tumor biopsy specimens.
1.1.2.3
To determine the duration of response (DOR), overall survival (OS), and progression-
free survival (PFS) of the combination.
1.1.2.4
To further explore safety for combination.
Phase II Expansion Cohorts:
1.1.2.5
To determine safety and progression-free survival (PFS) in patients with mCRPC and 
urothelial carcinoma.
1.1.2.6
To determine duration of response and PSA responses in patients with mCRPC.
1.1.3
Exploratory Objectives
Phase I and Phase II Cohorts:
1.1.3.1
To explore possible correlations between clinical response and biomarkers
Phase II Expansion Cohorts:
1.1.3.2
To determine correlation between molecular markers and clinical outcomes (ORR and 
PFS) in urothelial carcinoma patients. 
1.1.3.3
To explore pharmacodynamic changes in immune characteristics in tumor, circulating 
tumor cells (CTCs), and PBMCs in response to treatment of patients with mCRPC
1.2
BACKGROUND AND RATIONALE
1.2.1
Small Cell Lung Cancer
Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. Annually there are 
approximately 34,000 new cases in the United States alone. SCLC is characterized by rapid 
doubling time, high growth fraction and early and widespread metastatic involvement. 
Approximately two thirds of patients present with extensive-stage disease with tumor 


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14
involvement of contralateral lung, liver, adrenal glands, brain, bones and/or bone marrow. The 
median survival of patients with extensive-stage SCLC (ES-SCLC) ranges from 8 to 13 months. 
Less than 5% of patients survive two years and less than 2% of patients survive five years after 
diagnosis.
Standard therapy for patients with ES-SCLC consists of platinum and etoposide followed by 
prophylactic cranial irradiation in patients with a response (2). Although highly responsive to 
chemotherapy initially, SCLC relapses quickly and becomes refractory to treatment within a few 
months. There is only one FDA approved treatment for patients with relapsed SCLC after first-
line chemotherapy: topotecan, a camptothecin which inhibits relegation of topoisomerase I-
mediated single-strand DNA breaks leading to lethal double-strand DNA breaks. In patients with 
disease that is refractory to or relapsed after first-line chemotherapy, the median survival ranges 
from 2 to 6 months. 
Patients with disease progression during or after their initial treatment are classified into 
categories based on the treatment free intervals from the initial chemotherapy. Sensitive relapse 
is tumor progression that occurs 90 days or more after the last day of initial chemotherapy. 
Resistant relapse is tumor progression that occurs within 90 days of the last day of initial 
chemotherapy. Refractory relapse is when tumor progresses during the initial therapy or did not 
respond to initial therapy. These parameters have been found to be independent predictors of 
probability of responding to second-line chemotherapy (3).
The standard treatment of ES-SCLC today reflects the prevailing state-of-the-art from the early 
1980s. Among the many strategies that have been evaluated unsuccessfully over the last three 
decades are dose-dense chemotherapy regimens, addition of a third drug to standard two drug 
chemotherapies, alternating non-cross resistant chemotherapy regimens, maintenance therapy 
and more recently targeted therapies. Not unexpectedly, the outcomes for these patients have not 
significantly changed over this time. Clearly there is a critical need for newer therapeutic 
approaches for patients with SCLC. 
1.2.2
Urothelial Carcinoma (UC) of the Bladder
In the United States, urothelial carcinoma (UC) of the bladder is the fourth most common 
malignancy in men and the ninth most common in women, with 76,960 new cases and 31,540 
deaths estimated for 2016 (4). Although UC is a chemo-sensitive malignancy, there is no FDA-
approved second-line therapy that have demonstrated a survival benefit in patients who have 
progressed after first-line platinum-based chemotherapy. Second-line trials with cytotoxic agents 
have generally yielded discouraging response rates with a median progression-free survival 
(PFS) of 2–3 months and a median overall survival (OS) of 6–9 months (5-9). 
Two immune-checkpoint inhibitors have been FDA-approved as second-line therapy for patients 
with metastatic UC after disease progression following or during platinum-containing 
chemotherapy. Atezolizumab, an anti-programmed death-ligand 1 (PD-L1) humanized 
monoclonal antibody, showed an overall response rate (ORR) confirmed by independent review 
of 14.8% (95% CI: 11.1-19.3) in all treated patients (10) and nivolumab, a PD-1 humanized 
monoclonal antibody, that has demonstrated ORR of 19.6% (95% CI, 15.1 - 24.9). The estimated 
median duration of response was 10.3 months with nivolumab (11). Unfortunately, only a subset 
of patients with metastatic UC benefit from immune-checkpoint inhibitors highlighting the need 
to develop novel therapies to treat such population. 


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Specific genes involved in the DNA damage response (DDR) are mutated in UC increasing the 
genomic instability of cancer cells. Nickerson and colleagues at the National Cancer Institute, the 
TCGA, and other investigators have recognized that a marked number of somatic and germline 
mutations in genes encoding proteins involved in the DNA-repair pathway are present in UC 
(roughly 30% of cases) (Table 1) (12-14) These events may render UC particularly sensitive to 
inhibition of PARP in homologous recombination DNA repair, creating opportunities for 
synthetic lethality or synergistic cytotoxicity (potentiate the effect of other DNA damaging 
therapies).
Table 1. Summary of observed somatic/germline mutations frequencies in UC of the bladder
Yap, K.L.; et al.
(Whole-exome sequencing)
Somatic Mutations % (n)
Nickerson, M.; et 
al.
(Exome and Sanger 
sequencing of 
tumor-normal DNA)
Somatic Mutations 
% (n)
Nickerson, M.; et 
al.
(Exome and 
Sanger 
sequencing of 
tumor-normal 
DNA)
Germline 
Mutations % (n)
TP53
40.7% (33/81)
9.2% (5/54)
-
KDM6A
17% (21/81)
22.2% (12/54)
3.7% (2/54)
BAP1
NA
15% (8/54)
1.8% (1/54)
TSC1
12.3% (10/81)
3.7% (2/54)
-
ATM
12.3% (10/81)
7.4% (4/54)
1.8% (1/54)
UNC5C
9.9% (8/81)
NA
-
BRCA2
8.6% (7/81)
1.8% (1/54)
9.2% (5/54)
ERCC2
6.2% (5/81)
NA
-
FANCD2
4.9% (4/81)
NA
-
PALB2
4.9% (4/81)
3.7% (2/54)
5.5% (3/54)
BRAC1
3.7% (3/81)
3.7% (2/54)
1.8% (1/54)
PARP inhibitors (PARPi) such as olaparib are highly effective in combination with 
camptothecins in tumors with and without defects in homologous recombination. (15-17) In the 
case of UC, studies of human xenograft in vivo models and clinical studies have confirmed 
activity of irinotecan (CPT) and its combinations in human urothelial tumors. In the clinical 
setting, gemcitabine combined CPT has demonstrated to be with manageable toxicities in 
cisplatin-ineligible patients with locally-advanced or metastatic UC(18). Other clinically 
evaluated combination with irinotecan includes mitomycin, fluorouracil, and CPT in cisplatin-
pretreated and cisplatin-ineligible metastatic UC patients. This regimen demonstrated modest 
activity with an overall response rate of 19%(19).
EP0057 is a novel nanoparticle consisting of camptothecin (10% by weight) conjugated to a 
biocompatible copolymer of cyclodextrin and polyethylene glycol designed to maximize CPT 
efficacy without problematic hematologic toxicity. This offers a unique opportunity to revisit the 
use of topoisomerase-1 inhibitors for urothelial carcinoma treatment. 
The observation that the administration of an agent that acts to inhibit the repair of single strand 
DNA damage, such as olaparib, will potentiate DNA damage and increase the potency of 


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topoisomerase-1 inhibitors (10, 12, 20) provided rational for EP0057 being assessed in 
combination with olaparib at the National Institute of Health (NCT02769962). Initial safety 
results are favorable at dose level 2 in this Phase I study.
Given the high proportion of DNA-repair abnormalities and sensitivity to CPT of UC, our intent 
is to examine the clinical activity of EP0057 in combination with olaparib in patients with UC.
1.2.2.1
Rationale for expansion cohort in patients with metastatic/advanced urothelial 
carcinoma
As of Amendment C we propose an expansion to our current study protocol # 16-C-0107 
[NCT02769962] for 34 additional patients with metastatic or advanced UC. The expansion 
would enroll patients with metastatic or unresectable locally advanced UC who must have 
received prior treatment with at least one platinum-based chemotherapy and/or an immune-
checkpoint inhibitor. To be eligible for this expansion cohort, patients must have histologically 
confirmed diagnosis of UC and at least one measurable site of disease (according per RECIST 
criteria v 1.1).
This study will provide further insight into the potential increased efficacy of EP0057 in 
combination with olaparib in UC patients with manageable toxicity. Primary end-point is ORR. 
Secondary end-points are PFS and safety. Exploratory end-point include correlation between 
molecular markers and clinical outcomes (ORR and PFS).
1.2.3
Castrate resistant prostate cancer (mCRPC)
Prostate cancer is the most common cancer among men in the United States with an estimated 
161,360 new cases and 26,730 deaths in 2017 (21). While prostate cancer is initially responsive 
to androgen deprivation therapy (ADT), the median duration of sensitivity is 24-36 months,(22) 
and a majority of men will go on to develop castration-resistant disease. Over the last several 
years, the landscape of treatment in metastatic castration-resistant prostate cancer (mCRPC) has 
heralded new treatment options including potent hormonal agents abiraterone(23, 24) and 
enzalutamide(25, 26). Both abiraterone and enzalutamide have shown overall survival (OS) 
benefits in mCRPC, but unfortunately, men will develop resistance to these agents and to 
chemotherapeutic agents such as docetaxel. Furthermore, emerging data suggests that DNA 
repair mutations are present in 25-30% of tumors(27) and up to ~12% of patients with mCRPC 
may have germline mutations (28). Therefore, therapies that can exploit this target may improve 
clinical outcomes in advanced prostate cancer.
1.2.3.1
DNA Damage Repair
Next generation sequencing (NGS) techniques have been used to characterize recurrent 
mutations and genomic alterations in advanced prostate cancer (29) which include alterations in 
key genes important for DNA repair such as BRCA2. An international consortium of 8 medical 
center clinical sites conducted prospective whole-exome and trascriptome sequencing of bone or 
soft tissue tumor biopsies in 150 patients with mCRPC (27). Informative mutations were 
frequent, with clinically actionable alterations often seen in the DNA repair pathway (19%). 
Aberrations of BRCA2 and BRCA1 were observed with BRCA2 alterations in 19/150 (12.7%) 
of cases. Pathogenic germline BRCA2 mutations were found in 8 patients (5.3%) with a 
subsequent somatic event that resulted in biallelic loss. Events were also noted in BRCA1. 
Overall, 19.3% of patients harbored aberrations in DNA repair pathway involving BRCA2, 
BRCA1, and ATM. 


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Early clinical data has supported DNA repair defects as a target in mCRPC. In the phase II 
TOPARP-A study, fifty patients with mCPRC were treated with a single agent PARP inhibitor, 
olaparib(30). All patients had been treated previously with docetaxel, 49 patients (98%) had been 
previously treated with abiraterone or enzalutamide, and 29 patients (58%) with cabazitaxel. In 
33% (16/49) of evaluable patients, NGS revealed homozygous deletions and/or deleterious 
mutations in DNA repair genes, with the majority in BRCA2 and ATM. Of these 16 patients, 14 
(88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic 
somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of 
the biomarker suite was 94%. In the 7 patients with BRCA2 loss, 57% (4/7) were somatic 
aberrations and 43% (3/7) were germline. Targeting genetic defects in DNA repair genes in 
mCRPC offer possibilities for treatment options in heavily pre-treated patients and larger 
confirmatory trials are underway.
Recent data shows DNA damage plays an important role in priming the type I interferon (INF) 
system, where DNA damage results in enhanced production of type I IFNs via the cystolic DNA 
sensor STING (stimulator of interferon genes) which can prime the innate immune system for an 
amplified response (31). STING is a signaling molecule which is involved in controlling the 
transcription of host defense genes including Type I IFNs following recognition of aberrant 
DNA species and also self-DNA as a result of DNA damage (32). Instigating DNA damage can 
lead to nuclear DNA leakage into the cytosol and trigger STING-dependent cytokine activity 
(32). Loss of DNA repair mechanisms, via PARP inhibition, may enable DNA to leak into the 
cytoplasm to activate STING leading to production of Type I IFNs which exert potent effects on 
the priming of anti-tumor T cells (32).
1.2.3.2
Camptothecin Derivatives Investigated in Prostate Cancer
Camptothecin (CPT) is a potent Top1 inhibitor that failed clinical development due to poor 
solubility and high systemic toxicity. CPT derivatives such as irinotecan and topotecan have 
clinical utility for the treatment of a limited subset of advanced solid tumors. Both irinotecan and 
topotecan demonstrated improvements in plasma solubility but decreased target affinity 
compared to CPT. The primary cellular target of CPT is the Top1-DNA cleavage complex. CPT 
stabilizes the Top1-DNA cleavage complex during DNA replication and prevents Top1-mediated 
DNA relegation, leading to double strand breaks. The accumulation of double-strand breaks via 
CPT leads to apoptosis.
Camptothecin has shown activity in several prostate cancer cell lines (e.g. PC3, DU145, 
LNCaP).(33-35) The administration of CPT in LNCaP cells was shown to down-regulate 
expression of the AR and PSA.(36) Camptothecin was shown to suppress the expression of 
matrix-metalloproteinase-9 (MMP-9) and VEGF through inhibition of NF-κB activity in DU145 
cells.(37)
Synergistic activity between camptothecin and olaparib has been shown in DU145 prostate 
cancer cells. The combination’s activity is independent of defects in homologous recombination 
(e.g. BRCA1, BRCA2, etc.) and is due to catalytic PARP inhibitory activity.(1)
1.2.3.3
Rationale for the expansion cohort in patients with mCRPC
The rationale for combination of a PARP inhibitor, olaparib, and EP0057, is based upon the 
potential complementary mechanisms of action of the two therapies. Synergy between 
camptothecin and PARP inhibitors has been established.(38) PARP1 plays a role in the repair of 
topoisomerase I-induced DNA damage. By inhibiting PARP, via olaparib, the potency of 


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18
topoisomerase I inhibitors may be increased and thus olaparib plus EP0057 offers a potential 
treatment option in patients with heavily pre-treated advanced prostate cancer.
The purpose of the expansion cohort is to test the hypothesis that the EP0057 in combination 
with olaparib could yield durable responses in mCRPC. Increased DNA damage should 
complement the activity of topoisomerase I inhibitor EP0057 in mCRPC.
1.2.4
PARP as a Therapeutic Target in Small Cell Lung Cancer
Poly-(ADP)-ribose polymerases (PARPs) are a large family comprising of proteins that are 
critical regulatory components in DNA damage repair, maintenance of genomic integrity and 
other cellular processes (39). PARP-1 and PARP-2 are activated by single-strand DNA breaks 
(SSB). When SSBs are formed, PARP binds at the end of broken DNA strands, activating its 
enzymatic activity. Activated PARP catalyzes addition of long polymers of ADP-ribose (PAR). 
This lengthening PAR chain (PARylation) builds up a large negatively charged structure at the 
SSB which recruits other DNA repair enzymes that collectively repair DNA breaks via base 
excision repair (BER). PARP inhibition by inhibiting BER leads to the conversion of SSB to 
DNA double-strand breaks (DSB). The activity of PARP inhibitors are best established in 
cancers with mutations in BRCA1/2 and other DNA repair genes that result in synthetic lethality 
in the setting of PARP inhibition (which provides a second “hit” to the DNA repair machinery). 
Olaparib monotherapy was recently FDA-approved for patients with advanced, BRCA-mutated 
ovarian cancer who have received three or more lines of chemotherapy.
Drugs that target DNA damage response (DDR), including PARP inhibitors, have shown 
promising activity against SCLC in pre-clinical models and in early clinical trials. Proteomic 
profiling of a large panel of SCLC cell lines led to the observation that PARP1, Chk1, and 
several other DNA repair proteins are expressed at high levels in SCLC (40). These studies also 
confirmed PARP1 overexpression in patient tumors at the protein level by 
immunohistochemistry and at the mRNA level. Based on this finding, several PARP inhibitors 
were tested in pre-clinical models of SCLC. Olaparib, rucaparib, and talazoparib (previously 
BMN-673) all demonstrated striking single agent activity in a majority of SCLC cell lines tested. 
Furthermore, the addition of a PARP inhibitor to standard chemotherapies (e.g., cisplatin, 
etoposide and/or topotecan) and radiation further potentiated their effect (41). In animal models 
including xenografts and patient-derived xenografts (PDXs), talazoparib has demonstrated 
significant anti-tumor activity as a single agent, comparable or superior to cisplatin (42). 
Following these observations, several clinical trials were initiated to investigate the effects of 
PARP inhibition in SCLC patients. The first two studies to complete enrollment investigated the 
use of PARP inhibitors in relapsed SCLC. In the first study, single-agent talazoparib (BMN-673) 
was tested in an expansion cohort of patients with platinum-sensitive SCLC relapse 
(NCT01286987). Preliminary data from this trial demonstrated 2/23 patients with RECIST 
confirmed partial responses and 3/23 with stable disease lasting more than 24 weeks (clinical 
benefit rate of 25%). More than half of patients treated had some tumor volume reduction as 
their best response (43). In the second study, the oral alkylating drug temozolomide with or 
without veliparib (ABT-888) was studied in 100 patients with sensitive or refractory relapse 
(NCT01638546). This trial recently completed enrollment and analysis of the results are 
ongoing.


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19
1.2.5
PARP Inhibitors and DNA Damaging Chemotherapy are Synergistic 
The use of PARP inhibitors in combination with chemotherapy builds upon prior pre-clinical 
data in lung cancer and other malignancies supporting the notion that PARP inhibitors potentiate 
the effect of other DNA damaging therapies. Supporting this hypothesis, PARP inhibition has 
been reported to down regulate key components of the DNA repair machinery and enhanced the 
efficacy of chemotherapy in preclinical SCLC models (40). PARP inhibition sensitizes cancer 
cells both to cytotoxic chemotherapy, such as alkylators (temozolomide, cyclophosphamide) or 
camptothecins (irinotecan, topotecan) and to ionizing radiation- all of which induce DNA 
damage requiring BER (44). PARP inhibitors are highly effective in combination with 
camptothecins in tumors with and without defects in homologous recombination (1, 15, 16, 45). 
The Pommier laboratory has demonstrated highly synergistic activity of olaparib in combination 
with camptothecins (Figure 1) (1). They observed that the synergistic activity is due to its 
catalytic PARP inhibitory activity rather than due to trapping of PARP-DNA complexes. 
 
Despite their highly synergistic activity in preclinical models, human studies combining PARP 
inhibitors and camptothecins have not translated into clinical benefit due to enhanced toxicity 
with the combination (46, 47). In combination with chemotherapy, olaparib and veliparib 
enhanced the myelosuppression of their chemotherapy partners. In these studies, unacceptable 
toxicity necessitated dose reductions to sub-therapeutic levels. 
1.2.6
Safely combining PARP Inhibitors with Camptothecins
One approach to safely combine camptothecins with agents that sensitize their activity like 
PARP inhibitors is to use alternative formulations that could minimize toxicity to the normal 
tissues.
EP0057 (formerly named CRLX101 and IT-101) is a nanoparticle-drug conjugate (NDC) 
composed of 20(S) -camptothecin conjugated to a linear, cyclodextrin-polyethylene glycol-based 
polymer (Poly-CD-PEG-Camptothecin) (EP0057 Investigators Brochure) In solution, EP0057 
self-assembles into nanoparticles and releases CPT over prolonged periods of time (48) (49).
Figure 1: Synergistic activity of 
camptothecins and olaparib in DT40 
cells with a synergistic combination 
index (<0.3), even when the doses of 
individual agents are low (1).


Abbreviated Title: EP0057 in Advanced Cancers
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20
Camptothecin (CPT) is a potent topoisomerase I (Top1) inhibitor that failed clinical development 
due to poor solubility and high systemic toxicity. CPT derivatives such as irinotecan and 
topotecan demonstrate clinical utility for the treatment of advanced solid tumors. The primary 
cellular target of CPT, the Top1–DNA cleavage complex, is stabilized, preventing Top1-
mediated DNA relegation. Exposure of cancer cells to CPT leads to replication-mediated 
accumulation of DNA double-strand breaks and subsequent apoptosis. 
EP0057 localizes to the tumor and is retained for a prolonged duration by a mechanism referred 
to as enhanced permeability and retention (EPR) wherein macromolecules penetrate and are 
trapped in tumor tissue due to the abnormally leaky vasculature of tumors. EP0057 provides 
sustained release of CPT from polymer in the tumor for prolonged periods while sustaining low 
unconjugated (released) CPT concentrations in the blood. Animal xenograft models of cancer 
indicate that EP0057 accumulates in solid tumors and releases CPT over a period of several days 
to give sustained inhibition of its target (49). Sustained release of camptothecin from polymer in 
the tumor and low unconjugated camptothecin concentrations in the blood could optimize the 
cell cycle specific antitumor activity associated with the prolonged drug exposure in tumor tissue 
and improve tolerability associated with low systemic exposure. Drug localization analyses have 
been conducted in tumor from subjects with HER-2 negative gastric cancer who enrolled in a 
clinical trial of EP0057. Pre- and post- treatment biopsies involving tumor tissue and healthy 
adjacent tissue were collected from 10 subjects, 9 of whom had evaluable biopsies. Biopsies 
from all subjects were analyzed for differential drug accumulation between tumor and normal 
tissue using immunofluorescence techniques. Post-treatment biopsies were obtained between 24 
and 48 hours after a single dose of EP0057 and CPT was visualized by direct fluorescent 
excitation of tissues. Of the 9 patients with evaluable biopsies, 7 showed clear evidence of CPT 
within the post-treatment tumor while only one patient showed potential evidence of CPT in the 
post-treatment normal tissue. Images show bright, punctuate CPT signal specific to tumor tissue 
following treatment with EP0057 and rare events of CPT signal co-localized with anti-PEG 
signal as demonstrated in Figure 2.
Figure 2: Immunofluorescence Visualization in Gastric Cancer Tumor and Adjacent Normal Tissue after 
First Dose with EP0057 in Subjects on the Gastric Investigator-Sponsored Trial
 
Left: Tumor pre-treatment; Middle: Tumor 24 hour post-treatment; Right: Healthy adjacent tissue 24 hours pos
Green dots = CPT from nanoparticles


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21
1.2.7
EP0057 Preclinical Toxicology
Dose-limiting toxicity in rat and dog were largely body weight losses. Reductions in neutrophil 
and platelet counts were observed in the acute dog toxicity study and reversible reductions in 
neutrophil and platelet counts were observed at the mid dose in the sub-acute multi-dose dog 
toxicity study (EP0057 Investigators Brochure). Reversible reductions in neutrophil and 
increases in platelet counts were observed at the high dose in the sub-acute multi-dose rat 
toxicity study.
1.2.8
EP0057 phase I clinical trial
Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-
escalation study, in which EP0057 was administered intravenously over 60 min among two 
dosing schedules, initially weekly at 6, 12, and 18 mg/m2 and later bi-weekly at 12, 15, and 18 
mg/m2. The MTD was determined at 15 mg/m2 bi-weekly, and an expansion phase 2a study was 
completed. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. 
Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting 
toxicity. Among all phase 1/2a patients receiving the MTD (n=44), most common grade 3/4 
adverse events were neutropenia (Grade 3 neutropenia = 9% and no grade 4) and fatigue (Grade 
3 fatigue = 9%, no grade 4). Evidence of systemic plasma exposure to both the polymer-
conjugated and unconjugated CPT was observed in all treated patients. Mean elimination 
unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma 
concentrations and areas under the curve were generally proportional to dose for both polymer-
conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 
%) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free 
survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC 
patients was 4.4 months. 


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22
1.2.9
Adverse Events with EP0057 (CRLX101) Monotherapy
Table 2. Treatment-emergent AEs Related to EP0057 (CRLX101) Monotherapy in Cerulean-sponsored Studies (as of 12 March 2016)
15 mg/m2 Q2W 
(MTD)
(N=141)
6 mg/m2 QW
(N=6)
12 mg/m2 QW
(N=10)
15 mg/m2 QW
(N=5)
18 mg/m2 QW
(N=3)
12 mg/m2 Q2W
(N=3)
18 mg/m2 Q2W
(N=3)
Total
(N=171)
MedDRA Preferred 
Terma
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
At Least 1 TEAE Related 
to Study Drug
88 (62.4)
21 
(14.9)
5 (83.3) 3 (50.0)
10 
(100.0)
5 (50.0) 5 (100.0) 1 (20.0) 3 (100.0) 3 (100.0) 2 (66.7)
0
3 (100.0) 2 (66.7)
116 
(67.8)
35 
(20.5)
Anaemia
25 (17.7) 1 ( 0.7) 1 (16.7)
0
1 (10.0)
0
0
0
3 (100.0) 1 (33.3)
0
0
1 (33.3) 1 (33.3) 31 (18.1) 3 ( 1.8)
Fatigue
17 (12.1) 4 ( 2.8) 3 (50.0) 2 (33.3) 6 (60.0) 1 (10.0) 2 (40.0)
0
2 (66.7) 1 (33.3)
0
0
1 (33.3)
0
31 (18.1) 8 ( 4.7)
Cystitis
19 (13.5) 1 ( 0.7) 1 (16.7)
0
3 (30.0)
0
2 (40.0)
0
1 (33.3)
0
0
0
1 (33.3)
0
27 (15.8) 1 ( 0.6)
Nausea
20 (14.2) 1 ( 0.7)
0
0
3 (30.0)
0
2 (40.0)
0
1 (33.3)
0
1 (33.3)
0
0
0
27 (15.8) 1 ( 0.6)
Haematuria
11 ( 7.8) 1 ( 0.7) 2 (33.3)
0
3 (30.0)
0
0
0
2 (66.7) 1 (33.3)
0
0
0
0
18 (10.5) 2 ( 1.2)
Neutropenia
9 ( 6.4)
6 ( 4.3)
0
0
0
0
0
0
3 (100.0) 3 (100.0)
0
0
1 (33.3) 1 (33.3) 13 ( 7.6) 10 ( 5.8)
Diarrhoea
8 ( 5.7)
0
0
0
0
0
2 (40.0) 1 (20.0)
0
0
0
0
2 (66.7)
0
12 ( 7.0) 1 ( 0.6)
Vomiting
5 ( 3.5)
1 ( 0.7) 1 (16.7)
0
4 (40.0)
0
0
0
1 (33.3)
0
1 (33.3)
0
0
0
12 ( 7.0) 1 ( 0.6)
Dysuria
6 ( 4.3)
0
3 (50.0) 1 (16.7) 1 (10.0)
0
0
0
1 (33.3)
0
0
0
0
0
11 ( 6.4) 1 ( 0.6)
Constipation
3 ( 2.1)
0
1 (16.7)
0
2 (20.0)
0
3 (60.0)
0
0
0
0
0
0
0
9 ( 5.3)
0
Thrombocytopenia
4 ( 2.8)
1 ( 0.7)
0
0
0
0
1 (20.0)
0
2 (66.7) 2 (66.7)
0
0
2 (66.7) 2 (66.7) 9 ( 5.3)
5 ( 2.9)
Alopecia
7 ( 5.0)
0
0
0
0
0
0
0
0
0
0
0
1 (33.3)
0
8 ( 4.7)
0
Decreased appetite
3 ( 2.1)
0
1 (16.7)
0
2 (20.0)
0
0
0
2 (66.7)
0
0
0
0
0
8 ( 4.7)
0
Leukocyturia
4 ( 2.8)
0
2 (33.3)
0
1 (10.0)
0
0
0
1 (33.3)
0
0
0
0
0
8 ( 4.7)
0
Leukopenia
4 ( 2.8)
0
0
0
1 (10.0)
0
0
0
3 (100.0) 2 (66.7)
0
0
0
0
8 ( 4.7)
2 ( 1.2)
Neuropathy peripheral
5 ( 3.5)
1 ( 0.7)
0
0
0
0
1 (20.0)
0
0
0
0
0
0
0
6 ( 3.5)
1 ( 0.6)
Proteinuria
3 ( 2.1)
0
1 (16.7)
0
0
0
1 (20.0)
0
1 (33.3)
0
0
0
0
0
6 ( 3.5)
0
Pyrexia
4 ( 2.8)
0
0
0
2 (20.0)
0
0
0
0
0
0
0
0
0
6 ( 3.5)
0
Dyspnoea
3 ( 2.1)
1 ( 0.7)
0
0
0
0
1 (20.0)
0
0
0
0
0
1 (33.3) 1 (33.3) 5 ( 2.9)
2 ( 1.2)


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
23
15 mg/m2 Q2W 
(MTD)
(N=141)
6 mg/m2 QW
(N=6)
12 mg/m2 QW
(N=10)
15 mg/m2 QW
(N=5)
18 mg/m2 QW
(N=3)
12 mg/m2 Q2W
(N=3)
18 mg/m2 Q2W
(N=3)
Total
(N=171)
MedDRA Preferred 
Terma
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
Urinary tract infection
3 ( 2.1)
0
1 (16.7)
0
0
0
0
0
0
0
1 (33.3)
0
0
0
5 ( 2.9)
0
Alanine aminotransferase 
increased
4 ( 2.8)
0
0
0
0
0
0
0
0
0
0
0
0
0
4 ( 2.3)
0
Dehydration
2 ( 1.4)
1 ( 0.7) 1 (16.7)
0
1 (10.0) 1 (10.0)
0
0
0
0
0
0
0
0
4 ( 2.3)
2 ( 1.2)
Haemoglobin decreased
2 ( 1.4)
0
0
0
0
0
0
0
0
0
1 (33.3)
0
1 (33.3)
0
4 ( 2.3)
0
Neutrophil count 
decreased
3 ( 2.1)
3 ( 2.1)
0
0
0
0
0
0
0
0
0
0
1 (33.3) 1 (33.3) 4 ( 2.3)
4 ( 2.3)
Pain in extremity
3 ( 2.1)
0
1 (16.7)
0
0
0
0
0
0
0
0
0
0
0
4 ( 2.3)
0
White blood cell count 
decreased
3 ( 2.1)
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
1 (33.3) 1 (33.3) 4 ( 2.3)
2 ( 1.2)
Abdominal pain
3 ( 2.1)
0
0
0
0
0
0
0
0
0
0
0
0
0
3 ( 1.8)
0
Aspartate 
aminotransferase 
increased
3 ( 2.1)
0
0
0
0
0
0
0
0
0
0
0
0
0
3 ( 1.8)
0
Asthenia
2 ( 1.4)
1 ( 0.7) 1 (16.7)
0
0
0
0
0
0
0
0
0
0
0
3 ( 1.8)
1 ( 0.6)
Blood creatinine increased 3 ( 2.1)
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
3 ( 1.8)
1 ( 0.6)
Chills
2 ( 1.4)
0
0
0
0
0
0
0
0
0
0
0
1 (33.3)
0
3 ( 1.8)
0
Dizziness
2 ( 1.4)
0
0
0
0
0
0
0
1 (33.3)
0
0
0
0
0
3 ( 1.8)
0
Micturition urgency
2 ( 1.4)
0
0
0
1 (10.0)
0
0
0
0
0
0
0
0
0
3 ( 1.8)
0
Abdominal distension
1 ( 0.7)
0
0
0
1 (10.0)
0
0
0
0
0
0
0
0
0
2 ( 1.2)
0
Bladder spasm
2 ( 1.4)
0
0
0
0
0
0
0
0
0
0
0
0
0
2 ( 1.2)
0
Blood alkaline 
phosphatase increased
2 ( 1.4)
0
0
0
0
0
0
0
0
0
0
0
0
0
2 ( 1.2)
0
Bone pain
2 ( 1.4)
0
0
0
0
0
0
0
0
0
0
0
0
0
2 ( 1.2)
0
Cough
2 ( 1.4)
0
0
0
0
0
0
0
0
0
0
0
0
0
2 ( 1.2)
0


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
24
15 mg/m2 Q2W 
(MTD)
(N=141)
6 mg/m2 QW
(N=6)
12 mg/m2 QW
(N=10)
15 mg/m2 QW
(N=5)
18 mg/m2 QW
(N=3)
12 mg/m2 Q2W
(N=3)
18 mg/m2 Q2W
(N=3)
Total
(N=171)
MedDRA Preferred 
Terma
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
Cystitis haemorrhagic
0
0
1 (16.7)
0
1 (10.0) 1 (10.0)
0
0
0
0
0
0
0
0
2 ( 1.2)
1 ( 0.6)
Dysgeusia
1 ( 0.7)
0
0
0
1 (10.0)
0
0
0
0
0
0
0
0
0
2 ( 1.2)
0
Dyspepsia
0
0
1 (16.7)
0
1 (10.0)
0
0
0
0
0
0
0
0
0
2 ( 1.2)
0
Flatulence
0
0
1 (16.7)
0
0
0
1 (20.0)
0
0
0
0
0
0
0
2 ( 1.2)
0
Hyperglycaemia
2 ( 1.4)
0
0
0
0
0
0
0
0
0
0
0
0
0
2 ( 1.2)
0
Hypersensitivity
1 ( 0.7)
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
1 (33.3) 1 (33.3) 2 ( 1.2)
2 ( 1.2)
Hypokalaemia
1 ( 0.7)
0
0
0
0
0
0
0
1 (33.3)
0
0
0
0
0
2 ( 1.2)
0
Infusion related reaction
1 ( 0.7)
1 ( 0.7)
0
0
0
0
1 (20.0)
0
0
0
0
0
0
0
2 ( 1.2)
1 ( 0.6)
Insomnia
1 ( 0.7)
0
0
0
0
0
0
0
1 (33.3)
0
0
0
0
0
2 ( 1.2)
0
Lymphocyte count 
decreased
0
0
0
0
2 (20.0) 2 (20.0)
0
0
0
0
0
0
0
0
2 ( 1.2)
2 ( 1.2)
Myalgia
2 ( 1.4)
0
0
0
0
0
0
0
0
0
0
0
0
0
2 ( 1.2)
0
Nocturia
1 ( 0.7)
0
1 (16.7)
0
0
0
0
0
0
0
0
0
0
0
2 ( 1.2)
0
Oedema peripheral
0
0
1 (16.7)
0
0
0
0
0
0
0
0
0
1 (33.3)
0
2 ( 1.2)
0
Pollakiuria
0
0
0
0
2 (20.0)
0
0
0
0
0
0
0
0
0
2 ( 1.2)
0
Rash
2 ( 1.4)
0
0
0
0
0
0
0
0
0
0
0
0
0
2 ( 1.2)
0
Urinary retention
2 ( 1.4)
0
0
0
0
0
0
0
0
0
0
0
0
0
2 ( 1.2)
0
Abdominal pain upper
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Acute kidney injury
0
0
0
0
0
0
1 (20.0)
0
0
0
0
0
0
0
1 ( 0.6)
0
Acute respiratory distress 
syndrome
1 ( 0.7)
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
1 ( 0.6)
Adrenal insufficiency
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Angina pectoris
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Anxiety
0
0
0
0
0
0
0
0
1 (33.3)
0
0
0
0
0
1 ( 0.6)
0


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
25
15 mg/m2 Q2W 
(MTD)
(N=141)
6 mg/m2 QW
(N=6)
12 mg/m2 QW
(N=10)
15 mg/m2 QW
(N=5)
18 mg/m2 QW
(N=3)
12 mg/m2 Q2W
(N=3)
18 mg/m2 Q2W
(N=3)
Total
(N=171)
MedDRA Preferred 
Terma
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
Atrial flutter
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Back pain
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Bacteriuria
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Bladder discomfort
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Bladder pain
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Bronchospasm
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Candida infection
0
0
0
0
0
0
1 (20.0)
0
0
0
0
0
0
0
1 ( 0.6)
0
Cystitis noninfective
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Cytokine release 
syndrome
1 ( 0.7)
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
1 ( 0.6)
Dry mouth
0
0
1 (16.7)
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Dysphagia
0
0
0
0
0
0
0
0
1 (33.3)
0
0
0
0
0
1 ( 0.6)
0
Dysphonia
0
0
0
0
0
0
0
0
1 (33.3)
0
0
0
0
0
1 ( 0.6)
0
Dyspnoea exertional
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Electrocardiogram qt 
prolonged
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Epistaxis
0
0
0
0
1 (10.0)
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Febrile neutropenia
0
0
0
0
1 (10.0) 1 (10.0)
0
0
0
0
0
0
0
0
1 ( 0.6)
1 ( 0.6)
Gait disturbance
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Gastric haemorrhage
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Gastrointestinal disorder
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Gastrointestinal pain
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Glucose tolerance 
impaired
0
0
0
0
1 (10.0)
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
26
15 mg/m2 Q2W 
(MTD)
(N=141)
6 mg/m2 QW
(N=6)
12 mg/m2 QW
(N=10)
15 mg/m2 QW
(N=5)
18 mg/m2 QW
(N=3)
12 mg/m2 Q2W
(N=3)
18 mg/m2 Q2W
(N=3)
Total
(N=171)
MedDRA Preferred 
Terma
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
Headache
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Herpes zoster
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Hiccups
0
0
0
0
1 (10.0)
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Hypercreatininaemia
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Hyperkalaemia
0
0
0
0
0
0
0
0
1 (33.3)
0
0
0
0
0
1 ( 0.6)
0
Hypertension
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Hypoglycaemia
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Hypomagnesaemia
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Hypotension
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Hypoxia
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Lip swelling
0
0
0
0
0
0
0
0
1 (33.3)
0
0
0
0
0
1 ( 0.6)
0
Lymphadenopathy
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Lymphopenia
1 ( 0.7)
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
1 ( 0.6)
Mucosal inflammation
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Musculoskeletal 
discomfort
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Nitrituria
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Ocular discomfort
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Pancytopenia
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Paraesthesia
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Pelvic pain
1 ( 0.7)
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
1 ( 0.6)
Penile pain
0
0
0
0
1 (10.0) 1 (10.0)
0
0
0
0
0
0
0
0
1 ( 0.6)
1 ( 0.6)
Platelet count decreased
0
0
0
0
1 (10.0) 1 (10.0)
0
0
0
0
0
0
0
0
1 ( 0.6)
1 ( 0.6)


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
27
15 mg/m2 Q2W 
(MTD)
(N=141)
6 mg/m2 QW
(N=6)
12 mg/m2 QW
(N=10)
15 mg/m2 QW
(N=5)
18 mg/m2 QW
(N=3)
12 mg/m2 Q2W
(N=3)
18 mg/m2 Q2W
(N=3)
Total
(N=171)
MedDRA Preferred 
Terma
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
All 
Grades
n (%)
Grade 
3/4
n (%)
Polydipsia
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Polyuria
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Pyelonephritis chronic
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Rash generalised
0
0
0
0
0
0
0
0
0
0
0
0
1 (33.3) 1 (33.3) 1 ( 0.6)
1 ( 0.6)
Rash maculo-papular
0
0
0
0
0
0
1 (20.0)
0
0
0
0
0
0
0
1 ( 0.6)
0
Rash papular
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Right ventricular 
dysfunction
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Sinus tachycardia
0
0
1 (16.7)
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Stomatitis
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Tachycardia
0
0
0
0
0
0
0
0
0
0
0
0
1 (33.3)
0
1 ( 0.6)
0
Upper respiratory tract 
infection
0
0
0
0
0
0
0
0
1 (33.3)
0
0
0
0
0
1 ( 0.6)
0
Urethritis
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Urine flow decreased
0
0
0
0
1 (10.0)
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Urobilinogen urine 
increased
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Urticaria
0
0
0
0
0
0
0
0
0
0
0
0
1 (33.3)
0
1 ( 0.6)
0
Ventricular extrasystoles
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Vertigo
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0
Vision blurred
0
0
0
0
0
0
0
0
1 (33.3)
0
0
0
0
0
1 ( 0.6)
0
Weight decreased
1 ( 0.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 ( 0.6)
0


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
28
1.2.10
Adverse Events Associated with EP0057 (CRLX101) Combination Therapy
Table 3. Treatment-Emergent AEs Related to EP0057 (CRLX101) + bevacizumab combination therapy in Cerulean-sponsored Studies (as of 12 March 
2016)
12 mg/m2 QW +
bevacizumab Q2W
(N=7)
15 mg/m2 QW +
bevacizumab Q2W
(N=4)
15 mg/m2 Q2W +
bevacizumab Q2W
(N=55)
Total
(N=66)
MedDRA Preferred Terma
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
At Least 1 TEAE Related to Study Drug
3 (42.9)
0
1 (25.0)
0
47 (85.5)
13 (23.6)
51 (77.3)
13 (19.7)
Fatigue
2 (28.6)
0
1 (25.0)
0
23 (41.8)
4 ( 7.3)
26 (39.4)
4 ( 6.1)
Nausea
2 (28.6)
0
0
0
16 (29.1)
0
18 (27.3)
0
Constipation
0
0
0
0
10 (18.2)
0
10 (15.2)
0
Anaemia
2 (28.6)
0
0
0
5 ( 9.1)
2 ( 3.6)
7 (10.6)
2 ( 3.0)
Decreased appetite
0
0
0
0
7 (12.7)
0
7 (10.6)
0
Cystitis noninfective
1 (14.3)
0
0
0
5 ( 9.1)
0
6 ( 9.1)
0
Diarrhoea
1 (14.3)
0
0
0
5 ( 9.1)
1 ( 1.8)
6 ( 9.1)
1 ( 1.5)
Headache
0
0
0
0
6 (10.9)
1 ( 1.8)
6 ( 9.1)
1 ( 1.5)
Cystitis
0
0
0
0
5 ( 9.1)
1 ( 1.8)
5 ( 7.6)
1 ( 1.5)
Dysuria
0
0
0
0
5 ( 9.1)
0
5 ( 7.6)
0
Haematuria
1 (14.3)
0
0
0
3 ( 5.5)
0
4 ( 6.1)
0
Vomiting
2 (28.6)
0
0
0
2 ( 3.6)
1 ( 1.8)
4 ( 6.1)
1 ( 1.5)
Weight decreased
0
0
0
0
4 ( 7.3)
0
4 ( 6.1)
0
Aspartate aminotransferase increased
0
0
0
0
3 ( 5.5)
0
3 ( 4.5)
0
Asthenia
0
0
0
0
3 ( 5.5)
1 ( 1.8)
3 ( 4.5)
1 ( 1.5)
Chills
0
0
0
0
3 ( 5.5)
0
3 ( 4.5)
0
Dizziness
0
0
0
0
3 ( 5.5)
0
3 ( 4.5)
0
Dyspepsia
0
0
0
0
3 ( 5.5)
0
3 ( 4.5)
0
Dyspnoea
0
0
0
0
3 ( 5.5)
0
3 ( 4.5)
0
Epistaxis
0
0
0
0
3 ( 5.5)
0
3 ( 4.5)
0
Hypersensitivity
0
0
0
0
3 ( 5.5)
0
3 ( 4.5)
0


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
29
12 mg/m2 QW +
bevacizumab Q2W
(N=7)
15 mg/m2 QW +
bevacizumab Q2W
(N=4)
15 mg/m2 Q2W +
bevacizumab Q2W
(N=55)
Total
(N=66)
MedDRA Preferred Terma
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
Hypokalaemia
1 (14.3)
0
0
0
2 ( 3.6)
0
3 ( 4.5)
0
Hyponatraemia
0
0
0
0
3 ( 5.5)
0
3 ( 4.5)
0
Insomnia
0
0
0
0
3 ( 5.5)
0
3 ( 4.5)
0
Onychoclasis
0
0
0
0
3 ( 5.5)
0
3 ( 4.5)
0
Stomatitis
0
0
0
0
3 ( 5.5)
0
3 ( 4.5)
0
Urinary tract infection
0
0
0
0
3 ( 5.5)
0
3 ( 4.5)
0
Abdominal pain
1 (14.3)
0
0
0
1 ( 1.8)
0
2 ( 3.0)
0
Flushing
0
0
0
0
2 ( 3.6)
0
2 ( 3.0)
0
Hiccups
0
0
0
0
2 ( 3.6)
0
2 ( 3.0)
0
Hypertension
0
0
0
0
2 ( 3.6)
2 ( 3.6)
2 ( 3.0)
2 ( 3.0)
Infusion related reaction
0
0
0
0
2 ( 3.6)
0
2 ( 3.0)
0
Mucosal inflammation
0
0
0
0
2 ( 3.6)
0
2 ( 3.0)
0
Myalgia
0
0
0
0
2 ( 3.6)
0
2 ( 3.0)
0
Neutropenia
0
0
0
0
2 ( 3.6)
1 ( 1.8)
2 ( 3.0)
1 ( 1.5)
Neutrophil count decreased
0
0
0
0
2 ( 3.6)
1 ( 1.8)
2 ( 3.0)
1 ( 1.5)
Night sweats
0
0
0
0
2 ( 3.6)
0
2 ( 3.0)
0
Oedema peripheral
0
0
0
0
2 ( 3.6)
0
2 ( 3.0)
0
Proteinuria
0
0
0
0
2 ( 3.6)
0
2 ( 3.0)
0
Acidosis
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Acute kidney injury
1 (14.3)
0
0
0
0
0
1 ( 1.5)
0
Alanine aminotransferase increased
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Arthralgia
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Asymptomatic bacteriuria
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Blood alkaline phosphatase increased
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Blood bilirubin increased
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
30
12 mg/m2 QW +
bevacizumab Q2W
(N=7)
15 mg/m2 QW +
bevacizumab Q2W
(N=4)
15 mg/m2 Q2W +
bevacizumab Q2W
(N=55)
Total
(N=66)
MedDRA Preferred Terma
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
Blood phosphorus decreased
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Blood urine present
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Cheilitis
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Cognitive disorder
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Confusional state
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Cough
1 (14.3)
0
0
0
0
0
1 ( 1.5)
0
Dysgeusia
1 (14.3)
0
0
0
0
0
1 ( 1.5)
0
Dysphonia
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Gingival bleeding
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Hyperkeratosis
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Hypoaesthesia
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Hypoalbuminaemia
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Hypocalcaemia
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Hypomagnesaemia
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Hypophosphataemia
0
0
0
0
1 ( 1.8)
1 ( 1.8)
1 ( 1.5)
1 ( 1.5)
Influenza like illness
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Leukopenia
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Lung infection
0
0
0
0
1 ( 1.8)
1 ( 1.8)
1 ( 1.5)
1 ( 1.5)
Micturition urgency
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Musculoskeletal discomfort
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Nail infection
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Oedema
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Pain
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Palmar-plantar erythrodysaesthesia 
syndrome
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
31
12 mg/m2 QW +
bevacizumab Q2W
(N=7)
15 mg/m2 QW +
bevacizumab Q2W
(N=4)
15 mg/m2 Q2W +
bevacizumab Q2W
(N=55)
Total
(N=66)
MedDRA Preferred Terma
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
Paronychia
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Peripheral sensory neuropathy
1 (14.3)
0
0
0
0
0
1 ( 1.5)
0
Pollakiuria
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Procedural headache
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Pyrexia
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Rash
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Retching
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Sinus congestion
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Skin irritation
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Thrombocytopenia
1 (14.3)
0
0
0
0
0
1 ( 1.5)
0
Tongue ulceration
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Upper gastrointestinal haemorrhage
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Urine analysis abnormal
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
Visual impairment
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
White blood cell count decreased
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0
White blood cells urine positive
0
0
0
0
1 ( 1.8)
0
1 ( 1.5)
0


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
32
Table 4. Treatment-emergent AEs Related to EP0057 (CRLX101) + paclitaxel combination therapy in Cerulean-sponsored Studies (as of 12 March 
2016)
12 mg/m2 Q2W +
paclitaxel QW
(3 out of 4 weeks)
(N=3)
15 mg/m2 Q2W +
paclitaxel QW
(3 out of 4 weeks)
(N=6)
Total
(N=9)
MedDRA Preferred Terma
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
All Grades
n (%)
Grade 3/4
n (%)
Subjects With at Least 1 TEAE Related to 
Study Drug
3 (100.0)
2 ( 66.7)
6 (100.0)
3 ( 50.0)
9 (100.0)
5 ( 55.6)
Fatigue
3 (100.0)
0
3 ( 50.0)
0
6 ( 66.7)
0
Neutrophil count decreased
3 (100.0)
2 ( 66.7)
3 ( 50.0)
2 ( 33.3)
6 ( 66.7)
4 ( 44.4)
Nausea
2 ( 66.7)
0
2 ( 33.3)
0
4 ( 44.4)
0
Infusion related reaction
1 ( 33.3)
0
2 ( 33.3)
0
3 ( 33.3)
0
Alopecia
1 ( 33.3)
0
1 ( 16.7)
0
2 ( 22.2)
0
Headache
0
0
2 ( 33.3)
0
2 ( 22.2)
0
Urinary tract infection
1 ( 33.3)
0
1 ( 16.7)
0
2 ( 22.2)
0
Vomiting
1 ( 33.3)
0
1 ( 16.7)
0
2 ( 22.2)
0
Alanine aminotransferase increased
0
0
1 ( 16.7)
0
1 ( 11.1)
0
Anemia
1 ( 33.3)
0
0
0
1 ( 11.1)
0
Aspartate aminotransferase increased
0
0
1 ( 16.7)
0
1 ( 11.1)
0
Constipation
1 ( 33.3)
0
0
0
1 ( 11.1)
0
Cystitis noninfective
1 ( 33.3)
0
0
0
1 ( 11.1)
0
Dizziness
0
0
1 ( 16.7)
0
1 ( 11.1)
0
Dyspnea
1 ( 33.3)
0
0
0
1 ( 11.1)
0
Hypertension
0
0
1 ( 16.7)
1 ( 16.7)
1 ( 11.1)
1 ( 11.1)
Insomnia
0
0
1 ( 16.7)
0
1 ( 11.1)
0
Peripheral sensory neuropathy
1 ( 33.3)
0
0
0
1 ( 11.1)
0
Sinusitis
0
0
1 ( 16.7)
0
1 ( 11.1)
0


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
33
1.2.11
EP0057 (CRLX101) Clinical Development Overview
As of 12 March 2016, there have been 5 clinical trials sponsored by Cerulean: CRLX-001, 
CRLX-002, CRLX101-208, CRLX101-209, and CRLX101-102. 
•
Studies CRLX-001 and CRLX-002 have been completed; studies CRLX101-208, 
CRLX101-209, and CRLX101-102 are ongoing. 
•
246 subjects received CRLX101/EP0057 at doses ranging from 6 to 18 mg/m2 in the 
5 cerulean-sponsored trials.
There have been 7 Investigator-sponsored trials (ISTs) with EP0057 (named CRLX101 at the 
time), (see Table 4 for details); as of 12 March 2016, 138 subjects received at least 1 dose of 
EP0057 in the ISTs at doses ranging from 12 to 15 mg/m2. 
•
A total of 384 subjects across all studies have received at least 1 dose of CRLX101. 
When tested in the QOW schedule, the MTD/RP2D of EP0057 monotherapy was 
determined to be 15 mg/m2. 
•
EP0057 has been generally well-tolerated, and has shown preliminary antitumor 
activity in subjects with solid tumors such as with gastroesophageal, lung, and 
ovarian cancers.
As of 12 March 2020, there have been 6 clinical trials sponsored by Cerulean Pharma (prior to 
17 April 2017) and BlueLink Genetics (as of 17 April 2017). Overall, 286 subjects received at 
least 1 dose of EP0057 at doses ranging from 6 to 18 mg/m2 in these 6 BlueLink Genetics-
sponsored studies. There have been 8 Investigator-sponsored trials with EP0057 in which 193 
subjects received at least 1 dose of EP0057 at starting doses ranging from 12 to 15 mg/m2. When 
tested in the every-other-week schedule, the MTD/recommended phase 2 dose (RP2D) of 
EP0057 monotherapy was determined to be 15 mg/m2. EP0057 has been generally well-
tolerated, and has shown preliminary antitumor activity in subjects with solid tumors.
Overall Safety Assessment from these trials indicated:
•
Infusion-related reactions, cystitis, hematologic toxicity, and gastrointestinal disorders 
have been recognized as the risks associated with EP0057. 
•
Infusion-related hypersensitivity reactions have been well managed with the mandatory 
premedication and slower rate of infusion. 
•
Cystitis symptoms have been well managed with IV hydration before and after the 
EP0057 infusion. In addition, the impact of urine alkalization (oral and/or IV) on the 
incidence and severity of cystitis in subjects treated with EP0057 continue to be 
evaluated. 
EP0057 is contraindicated for subjects who have a history of infusion-related hypersensitivity 
reactions to a topo-1 inhibitor or any EP0057 excipients. The effects of EP0057 on the 
developing human fetus or concentration in breast milk with respect to nursing mothers are 
unknown. Olaparib
Olaparib is a PARP inhibitor indicated as monotherapy in patients with deleterious or suspected 
deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian 


Abbreviated Title: EP0057 in Advanced Cancers
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34
cancer who have been treated with three or more prior lines of chemotherapy. Olaparib has an 
established safety profile and it is under investigation in a number of different cancers. 
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP 
ribose] polymerisation (PARP) inhibitor (PARP-1, -2 and -3) that is being developed as an oral 
therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy 
and other anti-cancer agents.
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair 
mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). 
Inhibiting PARPs leads to the persistence of SSBs, which are then converted to the more serious 
DNA double strand breaks (DSBs) during the process of DNA replication. During the process of 
cell division, DSBs can be efficiently repaired in normal cells by homologous recombination 
repair (HR). Tumors with HR deficiencies (HRD), such as serous ovarian cancers and SCLC 
cannot accurately repair the DNA damage, which may become lethal to cells as it accumulates. 
In such tumor types, olaparib may offer a potentially efficacious and less toxic cancer treatment 
compared with currently available chemotherapy regimens. 
Olaparib has been shown to inhibit selected tumor cell lines in vitro and in xenograft and primary 
explant models as well as in genetic BRCA knock-out models, either as a stand-alone treatment 
or in combination with established chemotherapies. Cells deficient in homologous recombination 
DNA repair factors, notably BRCA1/2, are particularly sensitive to olaparib treatment. 
PARP inhibitors such as olaparib may also enhance the DNA damaging effects of chemotherapy 
(50-52). For further information, please refer to the current version of the olaparib Investigator 
Brochure.
1.2.12
Preclinical Data of EP0057 (CRLX101) plus Olaparib
In vivo studies (conducted by Astra Zeneca) show that concurrent combination of EP0057 and 
olaparib resulted in a dose-dependent decrease in hematological parameters in preclinical rat 
bone marrow model (53). However, combination with delay (24h+) between EP0057 and 
olaparib provided sparing effect on peripheral blood cells (nadir and recovery) (Figure 3). 
The combination of EP0057 with olaparib (starting 24 hours after EP0057) administered for 14 
days had significantly more anti-tumor activity than olaparib administered for 2 days and 
provided greater efficacy than EP0057 alone (Figure 4). The combination was also significantly 
more efficacious than topotecan (standard-of-care for SCLC). 


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Figure 3: Hematological response to sequenced 
versus concurrent combination schedule in Wistar 
rat. Animals were treated with a single dose of 
EP0057 and either simultaneously or with 24h and 
48h delay with daily olaparib. Peripheral blood was 
collected from tail vain and analysis was performed 
on the Siemens Advia 2120i hematology analyzer.
Figure 4: In vivo efficacy of 
EP0057 combination with 
various duration of 
olaparib dosing in SCLC 
xenograft model. Mice 
implanted with NCI-H417a 
tumor cells were dosed with 
single dose of EP0057 + 
olaparib for 2 days or 14 
days starting 24h after the 
EP0057. 
1.2.13
Hypothesis
Despite their highly synergistic activity in preclinical models, human studies combining PARP 
inhibitors and camptothecins have not translated into clinical benefit due to enhanced toxicity 
with the combination. EP0057 (and free camptothecin) is cleared out more slowly from tumor 
cells compared to plasma/bone marrow and induces sustained activation of DNA damage 
response in tumor. Of note, in preclinical models, most EP0057 is cleared from the bone marrow 
by 24 hours; in contrast, durable topoisomerase 1 inhibition in the tumor is apparent. This effect 
combined with low systemic exposure lends EP0057 to combinations with PARP inhibitors 
where both drugs can potentially be used at effective doses. Based on preclinical studies, PARP 
inhibitors used 48 hours after EP0057 administration will provide synergy while minimizing risk 
of myelosuppression.


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1.2.14
Rationale
PARP inhibitors are highly synergistic in combination with camptothecins in preclinical models. 
However, this has not translated to clinical effectiveness, primarily due to enhanced toxicity 
which precludes administration of effective doses of either the PARP inhibitor or chemotherapy. 
Major dose limiting toxicity of this combination is myelosuppression. EP0057 is a nanoparticle 
drug conjugate with a camptothecin payload that provides durable inhibition of topoisomerase I 
(Top1) specifically in the tumor. EP0057 is cleared from the bone marrow relatively quickly. 
These properties allow combination of EP0057 with PARP inhibitors where both drugs can 
potentially be used at doses close to the MTD of each. Based on preclinical studies, PARP 
inhibitors used 48 hours after EP0057 and continued for 11 days will provide maximum synergy 
while minimizing risk of myelosuppression. 
Since the safety of this combination is not established, we propose a phase I trial where 
escalating doses of olaparib will be combined with EP0057 administered at 80% of its MTD (12 
mg/kg IV q2 weeks). The starting dose of olaparib is 100 mg bid which is a third of its single-
agent maximum tolerated dose (MTD; 300 mg tablet BID). 
1.2.15
Rationale for Amendment C
This is a phase I/II trial of EP0057, a nanoparticle drug conjugate plus olaparib. The goal of 
phase I this to determine the MTD/recommended Phase 2 dose (RP2D) of EP0057 in 
combination with olaparib in patients with refractory cancers. The goal of the existing phase II 
trial is to determine the antitumor activity of olaparib plus EP0057 with respect to progression 
free survival at 16 weeks separately in SCLC patients with resistant and
sensitive relapse. 
Between May 2016 and April 2017, 13 patients enrolled on phase 1 portion of this trial. No 
DLTs were observed among the first 3 patients who enrolled at dose level 1 (EP0057 12 mg/m2 
IV q2weeks plus olaparib 100 mg tablet PO BID). At dose level 2 (EP0057 12 mg/m2 plus 
olaparib 150 mg), five patients were enrolled. Two patients in this cohort were not evaluable due 
to early and rapid disease progression prior to completion of DLT assessment period. At dose 
level 3 (EP0057 12 mg/m2 plus olaparib 200 mg), three patients enrolled with no DLTs. Two 
patients started on dose level 4 (EP0057 12 mg/m2 plus olaparib 300 mg), on 4/4/2017 and are 
currently in the DLT evaluation period. 
Adverse event profile of the combination is consistent with what is expected from the AEs of 
both EP0057 and olaparib and consists mostly of myelosuppression. These events have not been 
dose-limiting and managed with dose delays/ growth factors. One patient at dose level 3 required 
dose delays for ANC not recovering to 1500 prior to the next cycle. Two patients treated at dose 
level 3 and two patients who recently enrolled at dose level 4 remain on treatment. Among 8 
evaluable patients with multiple histologies, 6 patients had progressive disease, one patient with 
cervical cancer had stable disease with -17% reduction in target tumor lasting 6 months, and 
another patient with refractory small cell lung cancer has ongoing stable disease at 3 months.
1.2.16
Rationale for Amendment E
Summary of Dose Escalation and Determination of MTD/Recommended Phase II Dose
Twenty-four patients were enrolled between May 2016 and December 2017. All patients had 
received one or more lines of prior systemic therapy and had evidence of disease progression at 
enrollment. 


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Patients across different dose levels received the same dose of EP0057 (EP0057 12mg/m2 Q2W) 
and increasing doses of olaparib. There were no DLTs at DL1 (n=3; olaparib 100 mg BID), DL2 
(n=5, 2 patients were not evaluable for DLT; olaparib 150 mg BID), or DL3 (n=3; olaparib 200 
mg BID). One patient at DL4 (olaparib 300 mg BID) experienced a DLT- grade 4 neutropenia 
not recovering within 7 days. This cohort was expanded with 5 additional patients. One 
additional patient had a DLT at this dose level- inability to begin subsequent treatment course 
within 28 days of the scheduled date, due to neutropenia. Therefore, DL4 was considered too 
toxic and 3 patients were enrolled at DL4R with lower dose of olaparib 250 mg BID. One of the 
3 patients enrolled at DL4R with lower dose of olaparib had a DLT- grade 4 neutropenia that did 
not resolve within 7 days. This cohort was expanded with 3 additional patients. No DLTs were 
observed in the additional patients, which established DL4R (EP0057 12 mg/m2 and olaparib 
250 mg) as the MTD/RP2D. 
1.2.17
Rationale for mCRPC cohort accrual closure (amendment version date: 07/27/2021)
Accrual to the mCRPC cohort is to cease with amendment version date 7/27/2021. Accrual to 
this cohort has been slow given the recent FDA approval of olaparib for prostate cancer. 
Additionally, underlying conditions such as history of pelvic irradiation or surgery predispose the 
prostate cancer cohort to cystitis and hematuria.
1.2.18
Rationale for urothelial carcinoma cohort accrual closure (amendment version date: 
08/17/22)
Accrual to this cohort has been slow due to currently active protocols competing for the same 
patient population. There are also protocols in development which the team believes are better 
suited for these patients. The decision was made to close cohort accrual on this trial to prioritize 
current and upcoming studies.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria - Phase I
2.1.1.1
Patients must have histologically or cytologically confirmed advanced solid tumor that 
is resistant or refractory to standard therapy. 
2.1.1.2
A minimum of 2 weeks will be required from any prior therapy, including 
chemotherapy, immunotherapy and/or radiation. In addition, recovery to Grade ≤ 1 
from all reversible toxicities related to prior therapy is required at study entry.
2.1.1.3
Patients do not need to have measurable disease to enroll on phase I. 
2.1.1.4
Age >18 years. 
2.1.1.5
ECOG performance status ≤2 (Appendix A, Section 16.1).
2.1.1.6
Patients with treated brain metastases (surgery, whole or stereotactic brain radiation) are 
allowed provided the lesions have been stable for at least 2 weeks and the patient is off 
steroids or is on a stable dose of steroids. Patients with brain metastases should not 
require use of enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, or 
phenobarbital) within 14 days before first dose and during study. Use of newer 


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antiepileptics that do not produce enzyme induction drug-drug interactions (DDIs) is 
allowed.
2.1.1.7
Patients must have normal organ and marrow function as defined below: 
leukocytes
>3,000/mcL
absolute neutrophil count
>1,500/mcL without growth factor support
platelets
>100,000/mcL without growth factor 
support
hemoglobin
≥9 g/dL, and no blood transfusion within 4 
weeks.
OR
hemoglobin
>10 g/dL, and no blood transfusion within 2 
weeks.
total bilirubin
≤1.5 x ULN (unless Gilbert’s Disease)
AST(SGOT)/ALT(SGPT)
<2.5 X institutional upper limit of normal (≤ 
5X ULN if liver mets)
creatinine
≤ ULN
OR
creatinine clearance
>51 mL/min (calculated using the Cockroft-
Gault formula) for patients with creatinine 
levels above institutional normal.
2.1.1.8
Individuals who can father children and their partners must agree to use highly effective 
contraception (refer to section 4.2 for details) prior to study entry, for the duration of 
study participation and for 3 months following last dose of study drugs. Individuals who 
are of childbearing potential and sexually active must agree to the use of 1 highly 
effective form of contraception, and their partners, if they can father children, must use 
a condom, or they must totally/truly abstain from any form of sexual intercourse, 
throughout their participation in the study and for at least 6 months after last dose of 
study drugs. Individuals should not donate sperm throughout the period of taking 
olaparib and for 3 months following the last dose of olaparib. Individuals of 
childbearing potential (IOCBP) are defined as being physically capable of becoming 
pregnant unless unable have children because of surgery or other medical reasons 
(effective tubal ligation, ovaries or the uterus removed, or are post-menopausal). Post-
menopausal is defined as:
o
Amenorrheic for 1 year (12 months in a row) or more following 
cessation of exogenous hormonal treatments,
o
LH and FSH levels in the post-menopausal range for individuals 
under 50,
o
radiation-induced oophorectomy with last menses >1 year ago,
o
chemotherapy-induced menopause with >1 year interval since last 
menses,
o
or surgical sterilization of participant (bilateral oophorectomy or 
hysterectomy) and/or partner.


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2.1.1.9
Negative urine pregnancy test ≤3 days prior to C1D1 (IOCBP)
2.1.1.10 Patient is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including follow 
up. 
2.1.2
Inclusion Criteria - Phase II SCLC 
2.1.2.1
Age >18 years. 
2.1.2.2
Patients must have histologically or cytologically confirmed diagnosis of SCLC from a 
CLIA-certified laboratory. 
2.1.2.3
Have received and progressed during or after a platinum-based standard chemotherapy 
regimen and/or an immune-checkpoint inhibitor 
2.1.2.4
Patients could have received any number of therapies for relapsed or progressive 
disease, including re-treatment with original frontline regimen. A minimum of 2 weeks 
will be required from any prior therapy, including chemotherapy, immunotherapy 
and/or radiation. In addition, recovery to Grade ≤ 1 from all reversible toxicities related 
to prior therapy is required at study entry. No previous irradiation to the site of 
measurable or evaluable disease, unless that site had subsequent evidence of 
progression.
2.1.2.5
Patients must have measurable disease as per Response Evaluation Criteria in Solid 
Tumors, version (RECIST 1.1). See Section 6.3 for the evaluation of measurable 
disease.
2.1.2.6
Radiographic evidence of disease progression after initial therapy should have been 
documented.
2.1.2.7
ECOG performance status ≤2 (see Appendix A, Section 16.1).
2.1.2.8
Patients with treated brain metastases (surgery, whole or stereotactic brain radiation) are 
allowed provided the lesions have been stable for at least 2 weeks and the patient is off 
steroids or is on a stable dose of steroids. Patients with brain metastases should not 
require use of enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, or 
phenobarbital) within 14 days before first dose and during study. Use of newer 
antiepileptics that do not produce enzyme induction drug-drug interactions (DDIs) is 
allowed. 
2.1.2.9
Patients must have normal organ and marrow function as defined below: 
leukocytes
>3,000/mcL
absolute neutrophil count
>1,500/mcL without growth factor support
platelets
>100,000/mcL without growth factor 
support
hemoglobin
≥9 g/dL, and no blood transfusion within 4 
weeks.
OR
hemoglobin
>10 g/dL, and no blood transfusion within 2 
weeks.


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total bilirubin
≤1.5 x ULN (unless Gilbert’s Disease)
AST(SGOT)/ALT(SGPT)
<2.5 X institutional upper limit of normal (≤ 
5X ULN if liver mets)
creatinine
≤ ULN
OR
creatinine clearance
>51 mL/min (calculated using the Cockroft-
Gault formula) for patients with creatinine 
levels above institutional normal.
2.1.2.10 Individuals who can father children and their partners must agree to use highly effective 
contraception (refer to section 4.2 for details) prior to study entry, for the duration of 
study participation and for 3 months following last dose of study drugs. Individuals who 
are of childbearing potential and sexually active must agree to the use of 1 highly 
effective form of contraception, and their partners, if they can father children, must use 
a condom, or they must totally/truly abstain from any form of sexual intercourse, 
throughout their participation in the study and for at least 6 months after last dose of 
study drugs. Individuals should not donate sperm throughout the period of taking 
olaparib and for 3 months following the last dose of olaparib. Individuals of 
childbearing potential (IOCBP) are defined as being physically capable of becoming 
pregnant unless unable to have children because of surgery or other medical reasons 
(effective tubal ligation, ovaries or the uterus removed, or are post-menopausal). Post-
menopausal is defined as:
o
Amenorrheic for 1 year (12 months in a row) or more following 
cessation of exogenous hormonal treatments,
o
LH and FSH levels in the post-menopausal range for individuals 
under 50,
o
radiation-induced oophorectomy with last menses >1 year ago,
o
chemotherapy-induced menopause with >1 year interval since last 
menses,
o
or surgical sterilization of participant (bilateral oophorectomy or 
hysterectomy) and/or partner.
2.1.3
Inclusion Criteria for Urothelial Carcinoma Expansion Cohort (accrual to the cohort 
ended with amendment version 08/17/2022)
2.1.3.1
Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the 
bladder, urethra, ureter, or renal pelvis from a CLIA-certified laboratory, with 
measurable disease by RECIST (version 1.1) including lymphadenopathy and visceral 
metastatic disease
2.1.3.2
Adult patients ≥ 18 years of age. 
2.1.3.3
Patient must have received at least one platinum based regimen of chemotherapy and/or 
an immune-checkpoint inhibitor if appropriate with progressive disease.
2.1.3.4
Prior antiangiogenic and radiation therapy are permitted (2-week washout from therapy 
is required). 
2.1.3.5
Bisphosphonates and denosumab are permitted if on a stable dose for ≥4 weeks. 


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41
2.1.3.6
ECOG 0–2 
2.1.3.7
Patients must have normal organ and marrow function as defined below: 
leukocytes
>3,000/mcL
absolute neutrophil count
>1,500/mcL without growth factor support
platelets
>100,000/mcL without growth factor 
support

hemoglobin
≥9 g/dL, and no blood transfusion within 4 
weeks.
OR

hemoglobin
>10 g/dL, and no blood transfusion within 2 
weeks.
total bilirubin
≤1.5 x ULN (≤ 3 × ULN for subjects with 
Gilbert’s Disease)
AST(SGOT)/ALT(SGPT)
<2.5 X institutional upper limit of normal (≤ 
5X ULN if liver mets)
creatinine
≤ ULN
OR
creatinine clearance
>51 mL/min (calculated using the Cockroft-
Gault formula) for patients with creatinine 
levels above institutional normal.
PT/INR and aPTT
  within 1.25 X ULN institutional limits, except 
where a lupus anti-coagulant has been 
confirmed
2.1.3.8
Individuals who can father children and their partners must agree to use highly effective 
contraception (refer to section 4.2 for details) prior to study entry, for the duration of 
study participation and for 3 months following last dose of study drugs. Individuals who 
are of childbearing potential and sexually active must agree to the use of 1 highly 
effective form of contraception, and their partners, if they can father children, must use 
a condom, or they must totally/truly abstain from any form of sexual intercourse, 
throughout their participation in the study and for at least 6 months after last dose of 
study drugs. Individuals should not donate sperm throughout the period of taking 
olaparib and for 3 months following the last dose of olaparib. Individuals of 
childbearing potential (IOCBP) are defined as being physically capable of becoming 
pregnant unless unable have children because of surgery or other medical reasons 
(effective tubal ligation, ovaries or the uterus removed, or are post-menopausal). Post-
menopausal is defined as:
o
Amenorrheic for 1 year (12 months in a row) or more following 
cessation of exogenous hormonal treatments,
o
LH and FSH levels in the post-menopausal range for individuals 
under 50,
o
radiation-induced oophorectomy with last menses >1 year ago,


Abbreviated Title: EP0057 in Advanced Cancers
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42
o
chemotherapy-induced menopause with >1 year interval since last 
menses,
o
or surgical sterilization of participant (bilateral oophorectomy or 
hysterectomy) and/or partner.
2.1.3.9
Patients must be able to tolerate oral medications and not have gastrointestinal illnesses 
that would preclude absorption of olaparib. 
2.1.3.10 Ability to understand and the willingness to sign a written informed consent document. 
2.1.3.11 Willingness to release archival tissue sample for research purposes, if available
2.1.4
Inclusion Criteria for mCRPC Expansion Cohort (accrual to the mCRPC cohort ended 
with amendment version 7/27/2021)
2.1.4.1
Patients must have metastatic, progressive, castrate resistant prostate cancer (mCRPC).
2.1.4.2
Documented histopathological confirmation of prostate cancer from a CLIA-certified
laboratory.
2.1.4.3
All patients must have at least one lesion deemed safe to biopsy and be willing to 
undergo a mandatory baseline biopsy.
2.1.4.4
Patients must have received prior treatment with enzalutamide and/or abiraterone with 
the exception of patients who were treated with docetaxel and androgen deprivation 
therapy for metastatic castrate-sensitive prostate cancer and progressed on docetaxel 
treatment or who progress within one month of the last docetaxel dose.
2.1.4.5
Patients must have castrate levels of testosterone (<50 ng/dl [1.74 nmol/l])
2.1.4.6
Patients must have undergone bilateral surgical castration or must agree to continue on 
GnRH agonists/antagonists for the duration of the study.
2.1.4.7
ECOG performance status ≤ 2
2.1.4.8
Patients must have adequate bone marrow, hepatic, and renal function with: 
leukocytes
>3,000/mcL
absolute neutrophil count
>1,500/mcL without growth factor support
platelets
>100,000/mcL without growth factor 
support
hemoglobin
≥9 g/dL, and no blood transfusion within 4 
weeks.
OR
hemoglobin
>10 g/dL, and no blood transfusion within 2 
weeks.
total bilirubin
≤1.5 x ULN (≤ 3 × ULN for subjects with 
Gilbert’s Disease)
AST(SGOT)/ALT(SGPT)
<3 X institutional upper limit of normal (≤ 
5X ULN if liver mets)


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creatinine
≤ ULN
OR
creatinine clearance
>51 mL/min (calculated using the Cockroft-
Gault formula) for patients with creatinine 
levels above institutional normal.
2.1.4.9
Men must be at least 18 years of age.
2.1.4.10 Patient must be capable of understanding and complying with protocol requirements 
and is willing to give informed consent.
2.1.4.11 Individuals who can father children and their partners must also agree to use adequate 
contraception (refer to section 4.2 for details) prior to the study and for the duration of 
study participation and for 3 months after last dose of study drugs. Individuals should 
not donate sperm throughout the period of taking olaparib and for 3 months following 
the last dose of olaparib 
2.1.4.12 Patients who were treated for metastatic castrate-sensitive prostate cancer with 
docetaxel and androgen deprivation therapy who progress on docetaxel treatment or 
who progress within one month of the last docetaxel dose are eligible. 
2.1.5
Exclusion Criteria - Phase I and II SCLC and UC Expansion Cohort (note: accrual to the 
UC cohort ended with amendment version 08/17/2022)
2.1.5.1
Patients who are receiving any other investigational agents.
2.1.5.2
Persistent toxicities (≥ CTCAE grade 2) with the exception of alopecia and neuropathy, 
caused by previous cancer therapy
2.1.5.3
Patients who have had prior treatment with olaparib or other camptothecin inhibitors 
(UC expansion Cohort Only).
2.1.5.4
Patients with myelodysplastic syndrome/acute myeloid leukemia or active pneumonitis; 
or baseline features suggestive of myelodysplastic syndrome or acute myelogenous 
leukemia on peripheral blood smear or bone marrow biopsy, if clinically indicated.
2.1.5.5
Hypersensitivity to study therapies and its excipients
2.1.5.6
Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication.
2.1.5.7
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to EP0057 and/or olaparib or other agents used in study.
2.1.5.8
Patients receiving any medications or substances that are strong and moderate inhibitors 
or inducers of CYP3A are ineligible. Lists including medications and substances known 
or with the potential to interact with the CYP3A isoenzymes are provided in Appendix 
B, Section 16.2.
2.1.5.9
Pregnant individuals are excluded from this study because EP0057 and/or olaparib are 
agents with the potential for teratogenic or abortifacient effects. Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment 
of the mother with EP0057 and/or olaparib, breastfeeding should be discontinued if the 


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mother is treated with EP0057 and/or olaparib. These potential risks may also apply to 
other agents used in this study.
2.1.5.10 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with EP0057 and/or olaparib. In addition, 
these patients are at increased risk of lethal infections when treated with marrow-
suppressive therapy. Appropriate studies will be undertaken in patients receiving 
combination antiretroviral therapy when indicated. 
2.1.5.11 Prolongation of QT/QTc interval (QTc interval >500 msec) using the Fredericia method 
of QTc analysis or family history of long QT syndrome. If single reading is above these 
minimum ranges, then repeat test in triplicate and evaluate eligibility based on average 
value
2.1.5.12 Any chronic or concurrent acute liver disease.
2.1.5.13 History of stroke, transient ischemic attack (TIA), or myocardial infarction, within 6 
months prior to C1D1
2.1.5.14 Uncontrolled concurrent disease or illness including but not limited to:
•
symptomatic congestive heart failure, unstable angina pectoris, clinically significant 
cardiac arrhythmia
•
unstable or untreated cardiac conditions or ejection fraction of <50% as determined by 
echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)
•
uncontrolled diabetes mellitus
•
psychiatric illness that would limit compliance with study requirements, as determined by 
the Investigator 
2.1.5.15 Other severe, acute, or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study drug 
administration or that may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for the study.
2.1.6
Exclusion Criteria - mCRPC Expansion Cohort (accrual to the mCRPC cohort ended 
with amendment version 7/27/2021)
2.1.6.1
Patients who have had prior treatment with olaparib or other camptothecin inhibitors.
2.1.6.2
The patient has received chemotherapy, radiotherapy, biologic agents or enzalutamide 
within 3 weeks before the first dose of study treatment (nitrosoureas or mitomycin 
within 6 weeks). However, for patients receiving abiraterone, they must discontinue the 
medication at least 14 days before the first dose of study treatment. 
2.1.6.3
The patient has received any other type of investigational agent within 28 days before 
the first dose of study treatment. 
2.1.6.4
The patient has received radionuclide treatment within 6 weeks prior to the first dose of 
the study treatment
2.1.6.5
Patients with evidence of CNS metastasis or leptomeningeal disease within 1 year prior 
to enrollment will be excluded from this clinical trial because of their poor prognosis 


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and because they often develop progressive neurologic dysfunction that would 
confound the evaluation of neurologic and other adverse events. Patients with a remote 
history of brain metastases may be considered if they received sterilizing therapy to the 
CNS (resection or radiation) and have been CNS progression-free for the 1-year period. 
Baseline imaging to rule out brain metastases is not required for screening, but should 
be performed prior to study enrollment if clinically indicated.
2.1.6.6
Patients receiving any medications or substances that are strong and moderate inhibitors 
or inducers of CYP3A are ineligible. Lists including medications and substances known 
or with the potential to interact with the CYP3A isoenzymes are provided in Appendix 
B, Section 16.2.
2.1.6.7
The patient has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all 
prior therapies, including surgery, except alopecia and other non-clinically significant 
AEs.
2.1.6.8
Uncontrolled concurrent disease or illness including but not limited to:
•
symptomatic congestive heart failure, unstable angina pectoris, clinically significant 
cardiac arrhythmia
•
unstable or untreated cardiac conditions or ejection fraction of <50% as determined 
by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)
•
uncontrolled diabetes mellitus
•
psychiatric illness that would limit compliance with study requirements, as 
determined by the Investigator 
2.1.6.9
Any of the following within 6 months before the first dose of study treatment:
•
unstable angina pectoris
•
stroke (including TIA, or other ischemic event)
•
myocardial infarction
2.1.6.10 Other clinically significant disorders such as:
•
active infection requiring intravenous treatment within 7 days of starting protocol 
treatment
•
serious non-healing wound/ulcer/bone fracture (excluding stable compression 
fracture) within 28 days before the first dose of study treatment
2.1.6.11 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with the study agent. 
2.1.6.12 HBV-or HCV-positive patients are ineligible
2.1.6.13 Prolongation of QT/QTc interval (QTc interval >500 msec) using the Fredericia method 
of QTc analysis or family history of long QT syndrome. If single reading is above these 


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minimum ranges, then repeat test in triplicate and evaluate eligibility based on average 
value
2.2
RECRUITMENT STRATEGIES
It is expected that participants for this single site study will be enrolled from across the United 
States though there is no exclusion for participants from foreign countries. 
Recruitment strategies that can be used for this study may include:
1. The study will be publicized on 
a.
NIH official websites; (e.g., www.clinicaltrials.gov, NCI cancer clinical trial 
listing (PDQ), and CCR)
b. NIH moderated social media platforms [e.g., Facebook, X, Instagram]. These 
sites comply with government terms of service per the NIH Social Media 
Guidelines)
c.
Research Match https://www.researchmatch.org/about/
d. Newsletters
The protocol may be abstracted into a plain language announcement-information to be abstracted 
includes-study title; purpose of the study; protocol summary; basic eligibility criteria; study site 
location(s); and how to contact the site for further information) and posted/distributed on the above 
media without IRB approval. Should we add additional descriptive information about the study to 
these announcements, we will seek IRB approval.
2. Television advertisements/radio advertisements
a.
Clinical Center TV (CCTV) – Clinical Center Television - CCTV | NIH Clinical 
Center - America's Research Hospital TVs placed all around the NIH Clinical 
Center will rotate through various messages including one for this study.
3. Newspaper advertisements
4. Videos
5. Publicly posted recruitment flyers and posters
6. Brochures
7. Clinical Center Office of Patient Recruitment Services (OPR) including OPR 
a.
Listservs (Email list of those interested in receiving study recruitment updates.) 
Includes the OPR Protocols and OPR Healthy Volunteers listservs and 3 NIH 
listservs (NIH Post bac, NIH Clinical Fellows & NIH Study Volunteers)
8. Recruitment Letters 
a.
Doctor to patient informational letter: distribution of letters to private health 
care physicians who will then share the letters with potential participants. This 
information will be made available in electronic and/or a hard copy as needed. 
(Note: if material is not to be shared with participants, these are not submitted 
to the IRB)
b. Investigator to potential participant letters.
Prior to the distribution of any individual recruitment materials not included in item #1, 
such materials will be submitted for IRB review, as appropriate. 


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2.3
SCREENING EVALUATION
2.3.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 
•
Email, written, in person or telephone communications with prospective participants 
•
Review of existing medical records to include H&P, laboratory studies, etc.  
•
Review of existing MRI, x-ray, or CT images, etc.
•
Review of existing photographs or videos
•
Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
A waiver of consent for these activities has been requested in Section 12.4.1.
2.3.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the participant has signed the study consent 
OR the consent for study 01-C-0129 (provided the procedure is permitted on that study) on 
which screening activities may also be performed. Assessments performed at outside facilities or 
on another NIH protocol within the timeframes below may also be used to determine eligibility 
once a participant has signed the consent.
Screening must be completed within 2 weeks prior to C1D1. 
•
History and physical exam (including height, weight, vital signs and performance status)
•
Blood tests (for organ function)
o
Complete blood count (CBC/Diff)
o
Acute care panel (sodium, potassium, chloride, total CO2 (Bicarbonate), 
creatinine, glucose, urea nitrogen)
o
Hepatic panel (alkaline phosphatase, ALT/GPT, AST/GOT, total bilirubin, direct 
bilirubin)
o
Prothrombin time (PT)
o
Partial thromboplastin time (PTT)
o
Viral Markers Protocol Screen (HBsAg, anti-HCV, anti-HIV) within 3 months of 
C1D1.
•
Collection of pathology reports from any certified laboratory for confirmation of 
diagnosis (may be done prior to the two week screening window).
•
CT chest/abdomen/pelvis (mCRPC patients will have baseline CT scans and technetium-
99 bone scan imaging within 30 days prior to initiation of therapy)
•
Electrocardiogram
•
Echocardiogram within 4 weeks prior to C1D1
•
Urine or serum HCG for IOCBP (to be performed within 3 days prior to C1D1)
•
Serum testosterone level (mCRPC patients only)


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2.4
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.4.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details and eligibility criteria.
2.4.2
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Phase I
Phase I subjects
2
Phase II SCLC expansion
Phase II expansion cohort of subjects with SCLC 
3
Phase II urothelial carcinoma 
expansion
Phase II expansion cohort of subjects with urothelial carcinoma
4
Phase II mCRPC expansion
Phase II expansion cohort of subjects with mCRPC
Arms
Number
Name
Description
1
Phase I
EP0057 + olaparib
2
Phase II
EP0057 + olaparib at MTD/RP2D
Arm Assignment
All subjects in cohort 1 will be enrolled on arm 1. All subjects in cohorts 2-4 will be enrolled on 
arm 2. There is no randomization.
Note: Accrual to cohort 4 (mCRPC) ended with amendment version 7/27/2021. Accrual to 
cohort 3 (urothelial carcinoma) ended with amendment version 8/17/2022.
2.5
BASELINE EVALUATION
Please refer to the Study Calendar (Section 3.4).


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3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is a phase I / II open label single center trial. Patients will be enrolled to the phase I portion 
of the study to determine the maximum tolerated dose (MTD) or recommended phase 2 dose 
(RP2D). The RP2D is EP0057 12mg/m2 and olaparib 250 mg BID. In phase II, up to 27 
evaluable patients with SCLC will be enrolled (Amendment H). To further evaluate clinical 
response rate to EP0057, up to 34 evaluable patients will be enrolled into a urothelial carcinoma 
cohort and 25 evaluable patients enrolled into an mCRPC expansion cohort as described in 
section 10. 
Patients meeting the eligibility criteria will receive EP0057 (IV Q 2weeks) plus olaparib (PO 
BID days 3-13* and days 17-26* administered in 28-day cycles, until disease progression or 
development of intolerable side effects. 
* There should be at least a 48-hour window between EP0057 and olaparib with the exception of 
dose level 5B in which the window is reduced to 24 hours.
Blood, tumor and hair samples will be collected at multiple time points for PK, PD analyses as 
described in Section 5.1.1. Tumor biopsies are optional for SCLC and UC patients. mCRPC must 
have a mandatory baseline biopsy. If an SCLC patient opts for a biopsy, it will be performed at 
the following time points: pre-treatment, on cycle 1 day 4 and at disease progression. Patients 
will be asked to consent to the optional biopsy at the time of the procedure. If patients choose not 
to have the biopsy, that will be documented in the medical record and noted in the research 
record. 
Toxicity will be graded according to CTCAE version 4.0. Tumor assessments will be made using 
CT scans (chest, abdomen and pelvis) at baseline and after every 2 cycles according to RECIST 
version 1.1. Tumor assessments will be discontinued at the time of progression. Subsequently 
follow-up for survival will be carried out every 3 months. 
Between May 2016 and November 2016, 8 patients enrolled on this trial. No DLTs were 
observed among the first 3 patients who enrolled at dose level 1. At dose level 2, three patients 
did not have DLTs. Patients 6 and 7 at dose level 2 were not evaluable due to early and rapid 
disease progression prior to completion of DLT assessment period. In the patients enrolled to 
date at 2 dose levels, we have not seen dose limiting toxicities, specifically myelosuppression. 
With amendment A, we would like to dose escalate olaparib from 200 mg to 300 mg between 
dose levels 3 and 4. This represents a 50% increase in the dose of olaparib (compared with 25% 
increase proposed in the earlier schema from 200 to 250 mg). If olaparib 300 mg is not tolerated 
(2 or more DLTs), dose escalation will be stopped and 250 mg dose level will be explored. 
Additionally, with amendment A, if the highest dose level (dose level 5) is well tolerated, the 
interval between EP0057 and olaparib will be abbreviated at the next dose level (dose level 5B) 
from 48 hours to 24 hours. 
With amendment E, patients are to be enrolled at RP2D (DL 4R, EP0057 at 12 mg/m2 and 
olaparib at 250 mg) in Phase II part of the trial as Phase I part of the study is now completed; it 
was determined that olaparib at the dose level 4R, 250 mg, is well tolerated. 


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Provisional Dose levels
EP0057, mg/m2
(IV q 2 weeks
D1 and D15)
Olaparib tablet, mg
(PO BID Days 3-13* and 17-26*) 
1
12
100
2
12
150
3
12
200
4
12
300**
4R(educed) (MTD/RP2D)
12
250
5 (Not explored)
15
300
5B (Not explored)
15
300
28-day cycles; biopsies pre-treatment and on day 4 (24 hours post- olaparib) and at disease 
progression; 
* There should be a minimum 48-hour window between EP0057 and olaparib except dose 
level 5B which allows the interval to be abbreviated to 24 hours. 
The recommended phase 2 dose (RP2D) may be lower than, or equal to, the MTD. Phase II 
portion of this study may start with RP2D, and/or at MTD.
** An additional dose level (4R) of 250 mg has been evaluated with DLTs in 1 of 6 patients as 
there were 2 or more DLTs among 6 patients treated at dose level 4.
With amendment version 07/27/2021, accrual to the mCRPC cohort is to cease given the 
incidence and possibly the severity of hematuria/cystitis in participants with GU malignancies 
and slow cohort accrual following FDA approval of Olaparib for prostate cancer.
Accrual to the urothelial carcinoma cohort ended with amendment version 08/17/2022.
3.1.1
Dose Limiting Toxicity
During the phase 1 portion of the study subjects will be monitored for DLTs during the first 
cycle unless otherwise indicated. DLTs will be defined using the National Cancer Institute (NCI) 
CTCAE (Version 4). The following events, occurring during cycle 1 of the study combination, 
will be considered DLTs if deemed drug-related:
•
Grade 4 neutropenia complicated by fever ≥ 38.5 °C (i.e. febrile neutropenia) and/or 
documented infection; 
•
Grade 4 neutropenia that does not resolve within 7 days* 
•
Grade 4 thrombocytopenia that does not resolve within 7 days* or any grade 3-4 
thrombocytopenia complicated with hemorrhage; 


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•
Grade 4 anemia that does not resolve within 7 days despite optimal therapy (withholding 
study drug and red blood cell transfusions); 
•
Inability to begin subsequent treatment course within 28 days of the scheduled date, due 
to study drug toxicity; 
•
Any grade 3-4 non-hematologic toxicity (except fatigue/asthenia < 2 weeks in duration; 
mucositis in subjects who have not received optimal therapy for mucositis; vomiting or 
diarrhea lasting less than 72 hours whether treated with an optimal anti-emetic or anti-
diarrheal regimen or not; or alkaline phosphatase changes). 
*Note: In the event of a Grade 4 neutropenia or thrombocytopenia, a full blood count must be 
performed no more than 7 days after the onset of the event to determine if a DLT has occurred. 
The subject will be closely monitored until resolution to Grade 3 or less.
3.1.2
Dose Escalation
Dose escalation will proceed in groups of 3–6 patients. The MTD is the dose level at which no 
more than 1 of up to 6 patients experience DLT during the DLT evaluation period, and the dose 
below that at which at least 2 (of ≤6) patients have DLT as a result of the drug. If a patient did 
not experience DLT and did not finish cycle 1 of treatment, he or she will not be evaluable for 
toxicity and will be replaced in the dose level. Patients who do not complete the DLT evaluation 
period and do not have a DLT will be replaced. 
The theoretical maximum number of subjects required to determine the MTD in the phase 1 
portion of the study is 30 subjects (6 per dose level), although it is expected that as few as 15 
subjects in 4 dose levels would be required to reach an MTD.
The recommended phase 2 dose (RP2D) may be lower than, or equal to, the MTD. Phase II 
portion of this study may start with RP2D, and/or at MTD.
Dose escalation will follow the rules outlined in the Table 5 below.
Table 5. Dose Escalation Guidelines 
Number of Patients with 
DLT
at a Given Dose Level
Escalation Decision Rule
0 out of 3
Enter up to 3 patients at the next dose level
> 2
Dose escalation will be stopped. This dose level will 
be declared the maximally administered dose 
(highest dose administered). Up to three (3) 
additional patients will be entered at the next lowest 
dose level if only 3 patients were treated previously 
at that dose.


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1 out of 3
Enter up to 3 more patients at this dose level.
•
If 0 of these 3 patients experience DLT, proceed 
to the next dose level.
•
If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared 
the maximally administered dose. UP to three (3) 
additional patients will be entered at the next 
lowest dose level if only 3 patients were treated 
previously at that dose.
<1 out of 6 at highest dose 
level below the maximally 
administered dose
This is the MTD and is generally the recommended 
phase 2 dose. At least 6 patients must be entered at 
the recommended phase 2 dose.
3.2
DRUG ADMINISTRATION
3.2.1
EP0057
EP0057 will be diluted with 5% dextrose for injection (D5W) to a total volume of 500 mL and 
should be infused intravenously as described in section 14.1.6 over 60-75 minutes. Nothing else 
should be added to the bag.
The EP0057 infusion should begin immediately after preparation and diluted EP0057 infusion 
solution not used within 6 hours should be destroyed following institutional practices. 
3.2.1.1
Premedication Prior to EP0057 Treatment and Pre and Post Hydration
Subjects will receive up to 1,000 ml of 0.9% normal saline solution IV hydration before and after 
administration of EP0057 to reduce risk of cystitis adverse reaction. Hydration levels should be 
adjusted as needed by the Investigator based on any underlying health conditions of the subject.
Hypersensitivity reaction (HSR) have been observed in a small number of subjects treated with 
EP0057. Most HSR associated with EP0057 are mild and moderate, reversible upon study drug 
interruption. In general, subjects restarted EP0057 infusion at a slower infusion rate without 
recurrence. In addition to the mandatory premedication to prevent HSR, the duration of EP0057 
infusion must be prolonged from 1 hour to approximately 2 hours. 
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of study drug infusion.
Subjects should be pre-medicated with the following 3 drug classes 30-120 minutes* prior to 
start of EP0057 infusion to reduce likelihood of hypersensitivity adverse reactions:
▪
a corticosteroid (dexamethasone 20 mg IV) 30-120 minutes prior to start of EP0057 
▪
an antihistamine (diphenhydramine 50 mg PO)
▪
an H2 antagonist (ranitidine 50 mg IV) 


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Premedication with antiemetics such as a 5-HT3 receptor antagonist are to be administered to 
reduce the potential for nausea. Suggested antiemetics include dolasetron (PO), granisetron (PO 
or IV) or ondansetron (PO or IV) 30-120 minutes prior to starting EP0057 infusion.
The example medications, route of administration, and dose indicated should be the medication-
of-choice if clinically feasible. It is acknowledged that the premedication regimen may be altered 
for patient safety during the study (for example, if a patient experiences a 
hypersensitivity/infusion reaction related to study drug, the premedication regimen may be 
altered for subsequent cycle dosing based on the investigator’s discretion).
* Contact study team if the time after pre-medications exceeds 120 minutes.
3.2.2
Olaparib
Olaparib tablet at the appropriate dose level will be given orally on days 3-13* and days 17-26* 
twice daily (*there should be at least a 48-hour window between olaparib and EP0057 except 
dose level 5B which allows the window to be abbreviated to 24 hours). The correct number of 25 
mg, 100 mg, 150 mg or 200 mg tablets comprising the appropriate dose should be taken at the 
same times each day with approximately 240 mL of water. A light snack (biscuits/ toast) is 
advised at the time of dosing to help alleviate nausea but no specific timing needs to be observed. 
The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or divided.
Olaparib will be dispensed at the start of each cycle. Patients will be provided with a pill diary 
(Appendix C, Section 16.3), instructed in its use, and asked to bring it with them to each 
appointment.
For Phase II, it is recommended, but not required, that growth factors be given prophylactically 
starting cycle 1 on the phase II part of the study. Please note that G-CSF should not be used 
within at least 24 hours of the last dose of EP0057 administration. 
If vomiting occurs shortly after the olaparib capsules are swallowed, the dose should only be 
replaced if all of the intact capsules can be seen and counted. Should any patient enrolled on the 
study miss a scheduled dose, the patient will be allowed to take the scheduled dose up to a 
maximum of 2 hours after that scheduled dose time. If greater than 2 hours after the scheduled 
dose time, the missed dose should not be taken, and the patient should take their allotted dose at 
the next scheduled time.
Olaparib can be taken continuously in cases where EP0057 is missed for any reason. 
3.3
DOSE MODIFICATIONS
The dose levels and the general approach to dose modification of EP0057 and olaparib are 
shown below. AEs should be treated with the appropriate maximum intervention, and dose 
reductions should be clearly documented in the note. 
3.3.1
General Recommendation for Dose Modification 
Table 6. Olaparib Dosage Schedule
Olaparib dosage schedule
Dose Level
Starting dose
First dose reduction
Second dose 
reduction


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-1 
100 mg twice daily
75 mg twice daily
50 mg twice daily
1
100 mg twice daily
75 mg twice daily
50 mg twice daily
2 
150 mg twice daily
100 mg twice daily
75 mg twice daily
3
200 mg twice daily 
150 mg twice daily
100 mg twice daily
4 and 5
300 mg twice daily
250 mg twice daily
200 mg twice daily
4R (RP2D)
250 mg twice daily
200 mg twice daily
150 mg twice daily
Table 7. EP0057 Dosage Schedule
EP0057 dosage schedule
Dose Level
Starting dose
First dose reduction
Second dose 
reduction
-1 
9 mg/m2 q 2weeks
6 mg/m2 q 2weeks
4 mg/m2 q 2weeks
1-4 & 4R
12 mg/m2 q 2weeks
9 mg/m2 q 2weeks
6 mg/m2 q 2weeks
5
15 mg/m2 q 2weeks
11 mg/m2 q 2weeks
7 mg/m2 q 2weeks
3.3.2
Dosing Delays/Dose Modifications and Management of Toxicities
•
In the case of toxicity, appropriate medical treatment should be used (including anti-emetics, 
anti-diarrheals, etc.). 
•
Once a patient has a dose reduction for toxicity, the dose will not be increased. 
•
A maximum of 2 dose reductions is permitted 
•
If either agent is discontinued due to toxicity, the patient may continue on the other agent.
•
Participants continuing to experience toxicity at the off treatment visit will be contacted for 
additional assessments until the toxicity has resolved or is deemed irreversible. Patients must 
remain on the study to have additional assessment.
•
For AEs that are unrelated to the study drugs, study drug may be held for up to 21 days at the 
discretion of the PI. 
•
The associate investigator and/or PI will determine whether one or both drugs are responsible 
for an observed toxicity and will manage that toxicity as described below.


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3.3.2.1
Hematologic toxicities
Table 8. Dose Modification and Management of Hematologic Adverse Events
Observation 
Action
On day 1 and 15 
Absolute neutrophil count (ANC) ≥ 
1500/mcL
AND
Platelets ≥ 75,000/mcL
AND
Hemoglobin ≥ 8 g/dL
No interruption.
On day 1 and 15 
ANC < 1500/mcL
OR
Platelets < 75,000/mcL
OR
Hemoglobin < 8 g/dL
If any weekly evaluation demonstrates grade ≥ 3 
neutropenia or grade ≥ 2 thrombocytopenia, a repeat 
hematology assessment will be obtained 2-4 days 
later.
On first occurrence, hold the drug(s) causing the 
toxicity for up to 21 days until ANC ≥ 1500/mcL, 
platelets ≥ 75,000/mcL, and hemoglobin ≥ 9 g/dL.
The associate investigator and/or PI will determine 
whether one or both drugs are responsible for an 
observed toxicity and will initiate appropriate 
medical therapy and no change in dose upon re-
initiation.
On second occurrence, hold the drug(s) causing the 
toxicity for up to 21 days until ANC ≥ 1500/mcL, 
platelets ≥ 75,000/mcL, and hemoglobin ≥ 9 g/dL. 
Initiate appropriate medical therapy. Treatment with 
olaparib or EP0057 may be restarted at one dose 
level (DL) lower. 
Patients whose counts have not recovered to ANC ≥ 
1500/mcL, platelets ≥ 75,000/mcL, and hemoglobin 
≥ 9 g/dL after 21 days should be removed from the 
drug causing the toxicity. 
At any time during cycle 
Grade 4 hematologic AE 
On first occurrence, hold the drug(s) causing the 
toxicity for up to 21 days until ANC ≥ 1500/mcL, 
platelets ≥ 75,000/mcL, and hemoglobin ≥ 9 g/dL. 
Initiate appropriate medical therapy. Treatment with 
olaparib or EP0057 may be restarted at one DL 
lower. 
On second occurrence, discontinue the drug(s) 
causing the toxicity. Follow patient until 


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Table 8. Dose Modification and Management of Hematologic Adverse Events
Observation 
Action
resolution/stabilization of toxicity. 
Patients whose counts have not recovered to ANC ≥ 
1500/mcL, platelets ≥ 75,000/mcL, and hemoglobin 
≥ 9 g/dL after 21 days should be removed from the 
drug causing the toxicity. See section 3.3.2.1 for 
exceptions.
Toxicities requiring more than 2 dose 
reductions
Remove patient from the drug causing the toxicity.
•
Treatment may be delayed for a maximum of 21 days after holding the treatment for 
toxicities that develop and do not resolve as defined above (the following AE’s are exempt 
from hold: lymphopenia, or leukopenia in the absence of grade 3 or higher neutropenia).
•
Weekly blood counts will be obtained during the first cycle, and then at day 1 and 15 of 
subsequent cycles.
•
Management of prolonged hematological toxicities while on study treatment
If a patient develops prolonged hematological toxicity such as:
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anemia 
and/or development of blood transfusion dependence
≥3 week interruption/delay in study treatment due to CTC grade 3 or worse neutropenia 
(ANC < 1,000/mcL)
≥3 week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia (Platelets < 50,000/mcL)
Weekly differential blood counts including reticulocytes (calculate reticulocyte index 
(RI), RI = reticulocyte count x hematocrit (Hct)/normal Hct; a value of 45 is usually used 
for normal Hct) and peripheral blood smear should be performed. If any blood parameters 
remain clinically abnormal after 4 weeks of dose interruption, the patient should be 
referred to hematologist for further investigations. Bone marrow analysis and/or blood 
cytogenetic analysis should be considered at this stage according to standard 
hematological practice. 
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder 
should be reported as an SAE. Study treatment should be discontinued if diagnosis of 
myelodysplastic syndrome is confirmed. 
3.3.2.2
Neutropenia
•
Phase I: Growth factors to prevent neutropenia will not be administered during the DLT 
period in phase I but may be used thereafter to prevent/treat neutropenia. Please note that G-
CSF should not be used within at least 24 hours of the last dose of EP0057 administration.


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3.3.2.3
Thrombocytopenia
•
Thrombocytopenia will be treated conservatively. In the absence of bleeding, or a necessary 
invasive procedure, platelet transfusions should be given for a platelet count ≤ 10,000/mcL.
•
If invasive procedure(s) is (are) planned, or the patient develops bleeding, platelet 
transfusions should be administered in accordance with the standard of practice, usually 
maintaining a platelet count above 50,000/mcL.
3.3.2.4
Anemia
•
Symptomatic anemia should be treated with red blood cell transfusion and is recommended if 
the hemoglobin falls below 8 g/dL or the patient is symptomatic.
3.3.3
General Recommendations for Dose Modification and Management of Non-
Hematologic Adverse Events 
•
The management of general AEs not otherwise specified in the following sections should be 
as per Table 9. 
•
At the discretion of the investigator, the study drugs may be held or dose modified 
independently if the observed toxicity is attributed to only one of the drugs, while the patient 
continued to receive the drug not associated with the observed toxicity. 
•
Dose modifications for nausea, vomiting, and diarrhea will be made only if they are 
refractory to treatment. The time a given drug is held should not exceed 21 days.
Table 9. General Management of Adverse Events (Non-Hematologic)
Observation
Action
Grade 1 or 2 AEs resolves promptly (within 
48 hours) with supportive care 
Maintain dose level (DL)
Any ≥ grade 3 non-hematologic* 
Hold study drug(s) causing the toxicity for up 
to 21 days until toxicity resolves to ≤ grade 1. 
Treatment with olaparib or EP0057 may be 
restarted at one DL lower, as per the dose 
reduction guidelines. 
Grade 3 or 4 non-hematologic AE related to 
drugs that does not resolve to grade 1 or less 
within 21 days despite maximum supportive 
care after treating patient at the lowest 
reduced DL
Remove patient from the drug causing the 
toxicity.
Toxicities requiring more than 2 dose 
reductions 
Remove patient from the drug causing the 
toxicity.


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*Except fatigue/asthenia < 2 weeks in duration; mucositis in subjects who have not received 
optimal therapy for mucositis; vomiting or diarrhea lasting less than 72 hours whether treated 
with an optimal anti-emetic or anti-diarrheal regimen or not; or alkaline phosphatase changes
•
Management of new or worsening pulmonary symptoms
If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormality occurs, an 
interruption in olaparib dosing is recommended and a diagnostic workup (including a high 
resolution CT scan) should be performed, to exclude active pneumonitis. Following 
investigation, if no evidence of abnormality is observed on CT imaging and symptoms resolve, 
then olaparib treatment can be restarted, if deemed appropriate by the investigator. 
3.3.4
Management of the hypersensitivity/infusion reactions
Table 10. Management of the hypersensitivity/infusion reactions
Hypersensitivity reaction
Grade 1 or 2 
Stop infusion immediately, continue hydration fluids and provide 
medications as indicated per institutional guidelines. 
If symptoms resolve within 1-2 hours, at Investigator’s discretion may 
re-start study drug administration at slower rate (i.e. 2x slower rate) 
and increase rate slowly to complete administration of full dose.
OR
Hold dose administration on day of event, and resume treatment at 
next scheduled day at same dose level.
At Investigator’s discretion may administer subsequent dose using a 
desensitization protocol as per institutional guidelines.
Grade 3 or 4 
Stop infusion immediately and administer medical support as 
indicated per institutional guidelines. 
Hold dose administration on day of event.
Review with study Principal Investigator to determine whether to 
discontinue from study drug treatment. Confirm that rate of 
administration was appropriate and premeds were given as suggested.
Administration of EP0057 should be over 2 hours (using the following infusion schedule) with 
additional pre-medications (dexamethasone 20mg IV, ranitidine 50mg IV, acetaminophen 
650mg PO, ondansetron 16mg PO or IV and Benadryl 50mg PO). 
 EP0057 in 500ml 5% dextrose IV infusion
15mL/hr for 15 minutes, then increase to
30mL/hr for 15 minutes, then increase to
60mL/hr for 15 minutes, then increase to
120mL/hr for 15 minutes, then increase to


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240mL/hr for 15 minutes, then increase to
480mL/hr for 15 minutes, then increase to
528mL/hr for 30 minutes to complete infusion
3.3.5
Dose Modification for Surgical Procedures or Palliative Radiation
•
Olaparib should be stopped 3 days before surgery and re-started after wound has healed 
following recovery. 
•
No stoppage of olaparib is required for any biopsy procedures.
•
Olaparib should be discontinued for a minimum of 3 days before a patient undergoes 
therapeutic palliative radiation treatment.
3.3.6
Laboratory safety assessment
Full hematology assessments for safety (hemoglobin, red blood cells [RBC], platelets, mean cell 
volume [MCV], mean cell hemoglobin concentration [MCHC], mean cell hemoglobin [MCH], 
white blood cells [WBC], absolute differential white cell count (neutrophils, lymphocytes, 
monocytes, eosinophils and basophils) and absolute neutrophil count or segmented neutrophil 
count and Band forms should be performed weekly during Cycle 1, at each subsequent visit, and 
when clinically indicated. If absolute differentials are not available, percentage differentials are 
acceptable. Coagulation [activated partial thromboplastin time (APTT) and international 
normalized ratio (INR)] will be performed at baseline and if clinically indicated. Patients taking 
warfarin may participate in this study; however, it is recommended that prothrombin time (INR 
and APTT) be monitored carefully at least once per week for the first month, then monthly if the 
INR is stable.
Biochemistry assessments for safety include an acute care panel and hepatic panel. These tests 
should be performed weekly during Cycle 1, at each subsequent visit, and when clinically 
indicated. The mCRPC cohort will have additional assessments specified in 3.4.
Urine or serum HCG for IOCBP (to be performed within 3 days of C1D1) is to be performed at 
screening only. 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
hematological toxicities.
Additional analyses may be performed if clinically indicated.
Any clinically significant abnormal laboratory values should be repeated as clinically indicated.


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3.4
STUDY CALENDAR
On study assessments can be performed within ±7 days of the specified time, unless otherwise indicated. Treatments may be delayed 
up to 7 days to accommodate scheduling. 
Cycles = 28 days1
Procedure
Screening
Baseline2
Day 1
2
3
4
5
7
1528
21
28
Cycle 222 
Day 1
End of 
Treatment/ 
Disease 
Progression 
13
Post Therapy 
Follow-up4
History
X
X
X
Physical exam3
X
X
X
X
PTT/PT 23
X
X
Viral Markers Protocol 
Screen17
X
CBC diff 5, 20
X
X
X14
X
X
X
X
Acute Care Panel6,20
X
X
X14
X
X
X
X
Hepatic Panel7, 20
X
X
X14
X
X
X
X
Mineral Panel (mCRPC 
only) 24
X
X
LDH, Creatine kinase, 
Uric Acid, Total Protein 
(mCRPC only)
X
X
Pregnancy test8
X
X
X
CT scan12
X15
X
X
CT c/a/p and bone scan 
(mCRPC only)
X
X
X25
X
PSA (mCRPC only)
X
X25
X
Clinical disease 
assessment
X
X
X
ECG
X
X
X27
X27
X27
Echocardiogram21
X
Whole blood, plasma, 
hair26 and saliva for 
correlative studies9, 29
Refer to tables in section 5. Table 11– Phase 1 and Phase 2 SCLC; Table 13 – UC 
expansion; Table 14 – mCRPC expansion


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Cycles = 28 days1
Procedure
Screening
Baseline2
Day 1
2
3
4
5
7
1528
21
28
Cycle 222 
Day 1
End of 
Treatment/ 
Disease 
Progression 
13
Post Therapy 
Follow-up4
PK16, 29 
X
X
X
X19
Biopsies10 
X
X
X
EP0057
X
X
X
Olaparib11
X
X
X
X
X
Follow-up phone call
X
1 Number of cycles depends on disease progression and development of intolerable side effects
2 Baseline procedures are performed within 2 weeks of initiation of study therapy with the exception of pregnancy test which must be performed 
within 3 days prior to the initiation of study therapy. If the procedure was performed during the appropriate timeframe at screening, it is not 
necessary to repeat at baseline.
3 Symptom-directed physical examinations will be performed as clinically indicated in the investigator’s judgment
4 Follow-up for survival will be carried out every 3 months
5 Includes Neutrophils, Lymphs, Monos, Eos, Basos, WBC, RBC, Hemoglobin, Hematocrit, RBC Indices, MCV, RDW, Platelet. Results should 
be available prior to administration of study drugs
6 Includes Sodium (NA), Potassium (K), Chloride (CL), Total CO2 (Bicarbonate), Creatinine, random Glucose, Urea or blood urea nitrogen 
[BUN], eGFR.
7 Includes Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin
8 Only for IOCBP; may be obtained up to 3 days prior to Day 1 of each cycle.
9 Blood, plasma, hair and saliva samples will be collected at multiple time points during cycles 1,2 and each cycle thereafter for hair collection (for 
specific timepoints on correlative samples collection please refer to section 5.1.1 for Phase I and Phase II cohorts, section 5.1.2 for UC expansion 
cohort and section 5.1.3 for mCRPC expansion cohort). C1D15 timepoint for correlative studies will only be done for Phase II SCLC cohort. Only 
whole blood will be drawn for that cohort at that timepoint. 
10 Optional biopsies will be obtained at baseline, during the first treatment cycle (approximately 24 hours after the first dose of olaparib) and at 
disease progression. In the mCRPC cohort, biopsy at baseline is mandatory. 
11 PO days 3-13 and days 17-26, as indicated in Section 3.2. There should be at least a 48-hour window between EP0057 and olaparib except dose 
level 5B which allows the interval to be abbreviated to 24 hours. Olaparib can be taken continuously if EP0057 is missed for any reason. 
12 Performed after every 2 cycles
13 Approximately 4 weeks after treatment discontinuation
14 Only done in cycle 1
15 Only done in phase 2
16 Phase 1 portion of the study in cycles 1 and 6 only.


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17 Within 3 months of C1D1.
19 D15 PKs can be obtained +/- 5 days.
20 Weekly during C1, at every visit for subsequent cycles, and whenever clinically indicated
21 Within 4 weeks
22 C2 and all subsequent cycles, Day 1
23 All patients should get tested at screening. Patients taking warfarin will be monitored at least weekly for C1, then monthly if the INR is stable.
24 Includes Albumin, Calcium, Magnesium and Phosphorus
25 PSA is to be analyzed along with measurable lesions evaluated by CT scan of chest/abdomen/pelvis and technetium 99 bone scan every 3 cycles 
(every 12 weeks).
26 Hair collection will only be done for Phase I cohorts. 
27 ECG required within 60 -180 minutes post-infusion for first two cycles of EP0057 for patients with any conduction abnormality on baseline 
ECG.
28 Day 15 assessments not required for patients on olaparib only.
29. This protocol targets patients with aggressive tumors and, historically, minimal tissue is available (majority of patients are unresectable at 
diagnosis). Hence, the priority is to perform biopsies followed by treatment initiation as quickly as possible. In instances where research labs 
including PKs cannot be obtained due to scheduling conflicts, samples may be omitted or collected in a delayed fashion. 


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3.5
COST AND COMPENSATION 
3.5.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs. 
Medicines that are not part of the study treatment will not be provided or paid for by the NIH 
Clinical Center.  
3.5.2
Compensation
Participants will not be compensated on this study.
3.5.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation. Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate. The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy. 
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from protocol, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy.
3.6.1
Criteria for Removal from Protocol Therapy
•
Progressive disease 
•
Participant requests to be withdrawn from active therapy
•
Unacceptable Toxicity as defined in Sections 3.1.1 and 3.3
•
Toxicity related dose delay lasting longer than 21 days in which case patient will be 
removed from the drug causing the toxicity.
•
Investigator discretion
•
Requirement for any of the prohibited study drugs as described in Appendix B, 
Section 16.2 (Strong and moderate Inhibitors and Inducers of CYP3A)
•
The subject becomes pregnant
•
Active pneumonitis
3.6.2
Off-Study Criteria
•
Participant requests to be withdrawn from study
•
Investigator decision to end study
•
Death
•
Permanent loss of capacity to consent
•
Screen failure


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4
CONCOMITANT MEDICATIONS/MEASURES
•
No other chemotherapy, hormonal therapy (HRT is acceptable) or other novel agent is to be 
permitted during the course of the study for any patient (the patient can receive a stable dose 
of corticosteroids during the study as long as these were started at least 4 weeks prior to 
treatment, as per exclusion criteria above). For the mCRPC cohort, patients may receive 
hormonal therapy in the form of GnRH agonists/antagonists as per eligibility criteria above 
and corticosteroids are permissible. 
•
Live virus and bacterial vaccines should not be administered whilst the patient is receiving 
study medication and during the 30 day follow up period. An increased risk of infection by 
the administration of live virus and bacterial vaccines has been observed with conventional 
chemotherapy drugs and the effects with olaparib are unknown.
•
No concomitant use of alternative, complementary therapies or over-the-counter agents will 
be allowed without approval of the PI. All medications must be recorded in the case report 
form and be reviewed by the treating physician at each visit. 
•
Caution should be exercised in the concomitant use of any medication that may markedly 
affect renal function. Such medications may be used with caution as deemed essential for 
treatment, or if already in use prior to entry in the study without any effect on renal function. 
•
Caution should be exercised in concomitant use of any medication that may significantly 
affect hepatic CYP450 drug metabolizing activity by way of enzyme induction (e.g. 
Phenytoin) or inhibition (e.g. ketoconazole, ritonavir, erythromycin) within 2 weeks before 
the first dose of olaparib and throughout the study period.
•
Given this data, potent inhibitors or inducers of CYP3A4 (as outlined in Appendix B, 
Section 16.2 must not be used during this study. 
•
CYP3A4 known potent inhibitors: wash-out period 1 week, or at least 4.5x elimination half-
lives for drugs and metabolites known to inhibit CYP3A subfamily enzymes: Ketoconazole, 
itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir
•
CYP3A4 inducers (potential reduction in efficacy of olaparib) a wash-out period for 3 weeks 
for Phenytoin, rifampicin, rifapentin, rifabutin, carbamazepine, phenobarbital, nevirapine, 
modafinil and St John’s Wart.
•
Patients should avoid concomitant use of drugs, herbal supplements and/or ingestion of foods 
known to modulate CYP3A4 enzyme activity from the time they enter the screening period 
until 30 days after the last dose of study medication. In vitro data have shown that the 
principal enzyme responsible for the formation of the 3 main metabolites of olaparib is 
CYP3A4 and consequently, this restriction is required to ensure patient safety.
•
Olaparib inhibits CYP3A4 in vitro and is predicted to be a mild CYP3A inhibitor in vivo. 
Therefore, caution should be exercised when sensitive CYP3A substrates or substrates with a 
narrow therapeutic margin (e.g. simvastatin, cisapride, cyclosporine, ergot alkaloids, 
fentanyl, pimozide, sirolimus, tacrolimus and quetiapine) are combined with olaparib. 
•
Substrates of UGT1A1 should also be given with caution in combination with olaparib (e.g. 
irinotecan, nintedanib, ezetimibe, raltegravir or buprenorphine).


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•
Induction of CYP1A2, 2B6 and 3A4 has been shown in vitro with CYP3A4 CYP2B6 being 
most likely to be induced to a clinically relevant extent. The potential for olaparib to induce 
CYP2C9, CYP2C19 and P-gp is unknown. It cannot be excluded that olaparib upon co 
administration may reduce the exposure to substrates of these metabolic enzymes and 
transport protein. The efficacy of hormonal contraceptives may be reduced if co administered 
with olaparib.
•
In vitro olaparib has been shown to be an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, 
MATE1 and MATE2K and is a weak inhibitor of BRCP. It cannot be excluded that olaparib 
may increase the exposure to substrates of P-gp (e.g. statins, digoxin, dabigatran, colchicine), 
OATP1B1 (e.g. bosentan, glibenclamide, repaglinide, statins, and valsartan), OCT1 (e.g. 
metformin), OCT2 (e.g. serum creatinine), OAT3, MATE1 and MATE2K. In particular, 
caution should be exercised if olaparib is administered in combination with any statin.
4.1
SUPPORTIVE CARE
Patient should receive general concomitant and supportive care medications based on best 
medical practice. 
The use of any natural/herbal products or other “folk remedies” should be discouraged.
Olaparib is an investigational drug for which no data on in vivo interactions are currently 
available. Based on in vitro data and clinical exposure data, olaparib is considered unlikely to 
cause clinically significant drug interactions through inhibition or induction of cytochrome P450 
enzyme activity. In vitro data have, however, also shown that the principal enzyme responsible 
for the formation of the 3 main metabolites of olaparib is CYP3A4 and consequently, to ensure 
patient safety, the following potent inhibitors of CYP3A4 must not be used during this study for 
any patient receiving olaparib.
While this is not an exhaustive list, it covers the known potent inhibitors, which have most often 
previously been reported to be associated with clinically significant drug interactions:
•
ketoconazole, itraconazole, ritonavir, idinavir, saquinavir, telithromycin, clarithromycin 
and nelfinavir 
For patients taking any of the above, the required wash-out period prior to starting olaparib is 
one week.
In addition, to avoid potential reductions in exposure due to drug interactions and therefore a 
potential reduction in efficacy, the following CYP3A4 inducers should be avoided:
•
Phenytoin, rifampicin, rifapentine, rifabutin, carbamazepine, phenobarbitone, nevirapine, 
modafinil and St John’s Wort (Hypericum perforatum) 
For patients taking any of the above, the required wash-out periods prior to starting olaparib are:
•
phenobarbitone 5 weeks, and for any of the others, 3 weeks.
4.1.1
Other Concomitant Medications
All medications (prescriptions or over-the-counter medications) continued at the start of the trial 
or started during the study or until 30 days from the end of the last protocol treatment and 
different from the study medication must be documented.
Anticoagulant Therapy: Subcutaneous heparin is permitted.


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4.1.2
Palliative radiotherapy 
Palliative radiotherapy may be used for the treatment of pain at the site of bony metastases that 
were present at baseline, 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 the patient undergoes palliative radiation treatment. Study treatment 
should be restarted within 28 days from the scheduled date as long as any bone marrow toxicity 
has recovered.
4.1.3
Administration of other anti-cancer agents
Patients must not receive any other concurrent anti-cancer therapy, including investigational 
agents, while on study treatment. Patients may continue the use of bisphosphonates for bone 
disease and corticosteroids for the symptomatic control of brain metastases provided the dose is 
stable before and during the study
4.1.4
Medications that may NOT be administered
•
No other chemotherapy, immunotherapy, hormonal therapy or other novel agent is to be 
permitted while the patient is receiving study medication. For the mCRPC cohort, patients 
may receive hormonal therapy in the form of GnRH agonists/antagonists as per eligibility 
criteria above. 
4.1.5
Overdose 
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established. 
Olaparib must only be used in accordance with the dosing recommendations in this protocol. 
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol 
should be reported as an overdose.
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately.
4.2
HIGHLY EFFECTIVE METHODS OF BIRTH CONTROL
The study drugs used in the study are regarded as having with medium/high fetal risk.
Individuals of childbearing potential and their partners, who are sexually active, must agree to 
the use of one highly effective form of contraception and their partner must use a condom [as 
listed below]. This should be started from the signing of the informed consent and continue 
throughout the period of taking study treatment and for at least 6 months after last dose of study 
drug(s), or they must totally/truly abstain from any form of sexual intercourse (see below).
Individuals who can father children must use a condom during treatment and for 3 months after 
the last dose of olaparib when having sexual intercourse with a pregnant woman or with a 
woman of childbearing potential. Their partners should also use a highly effective form of 
contraception if they are of childbearing potential (as listed below). Individuals who can father 
children should not donate sperm throughout the period of taking olaparib and for 3 months 
following the last dose of olaparib.


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4.2.1
Acceptable non-hormonal birth control methods
•
Total/true abstinence: When the patient refrains from any form of sexual intercourse and 
this is in line with their usual and/or preferred lifestyle; this must continue for the total 
duration of the study treatment and for at least 6 months (for individuals able to bear 
children) or at least 3 months (for individuals able to father children) after the last dose of 
study treatment. Periodic abstinence (eg, calendar ovulation, symptothermal, post-
ovulation methods, or declaration of abstinence solely for the duration of a trial) and 
withdrawal are not acceptable methods of contraception.
•
Vasectomised sexual partner PLUS condom (with participant assurance that partner 
received post-vasectomy confirmation of azoospermia).
•
Tubal occlusion PLUS condom.
•
Intrauterine device (provided coils are copper-banded) PLUS condom.
4.2.2
Acceptable hormonal methods
•
Mini pill PLUS condom: Progesterone-based oral contraceptive pill using desogestrel. 
Cerazette (Merck Sharp & Dohme) is currently the only highly efficacious progesterone-
based pill available.
•
Combined pill PLUS condom: Normal and low-dose combined oral pills.
•
Injection PLUS condom: Medroxyprogesterone injection (eg, Depo-Provera [Pfizer]).
•
Implants PLUS condom: Etonorgestrel-releasing implants (eg, Nexplanon [Merck Sharp 
& Dohme]).
•
Patch PLUS condom: Norelgestromin/ethinyl estradiol transdermal system (eg, Xulane).
•
Intravaginal device (eg, ethinyl estradiol-/etonogestrel-releasing intravaginal devices such 
as NuvaRing [Merck Sharp & Dohme]) PLUS condom.
•
Levonorgestrel-releasing intrauterine system (eg, Mirena [Bayer]) PLUS condom.


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5
CORRELATIVE STUDIES FOR RESEARCH
5.1
BIOSPECIMEN COLLECTION
5.1.1
Phase I and Phase II Cohorts
Table 11. Correlative studies 
Phase I
Sample
Assay
Time points
Type of 
tube/sample a
Amount of blood
gH2AX
(1) Pre-treatment on C1D1
(2) Pre-treatment C1D4 
(24hr after olaparib)
(3) At disease progression 
NA
NA
SLFN11 IHC
SLFN11 gene expression
NA
NA
Optional Tumor 
(only in patients with 
SCLC)
Exome/RNAseq/ droplet digital 
PCR
NA
NA
Germline DNA
(1) Pre-treatment
Purple top EDTA
5 ml
Circulating tumor
DNA mutation analyses
(1) Pre-treatment
Lavender top tubes
Three 10-ml
Immune subsets (Peripheral 
blood mononuclear cells)
(1) Pre-treatment on C1D1
(2) Pre-treatment C1D3 
(pre-olaparib)
(3) C1D4 (24hr after 
olaparib)
(4) Pre-treatment C2D1
CPT citrate 
blue/black tubes
Two 8-ml tubes
Whole blood
(only in patients with 
SCLC)
Circulating tumor cells 
enumeration RAD51 foci
(1) Pre-treatment on C1D1 
(2) Pre-treatment C2D1 
(3) At disease progression
Lavender top tubes
Two 10-ml


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Sample
Assay
Time points
Type of 
tube/sample a
Amount of blood
Nanostring immune panel (770 
genes)
(1) Pre-treatment on C1D1
(2) Pre-treatment C2D1
(3) At disease progression
PAXgene RNA
One 2.5 ml
Nanostring DNA damage 
response panel (180 genes) 3,4
(1) Pre-treatment on C1D1
(2) Pre-treatment C2D1
(3) At disease progression
PAXgene RNA
One 2.5 ml
Whole Blood 
(in all phase I 
patients)
gH2AX
(1) Pre-treatment on C1D1 
(2) Pre-treatment C1D3 
(pre-olaparib) 
(3) C1D4 (24hr after 
olaparib)
green top
One 6-ml tube
Hair
(optional)
gH2AX
(1) Pre-treatment on C1D1
(2) Pre-treatment on C1D3 
(pre-olaparib)
(3) C1D4 (24hr after 
olaparib)
(4) End of each cycle (any 
time after the last dose of 
olaparib but prior to the next 
dose of EP0057)
12 follicles
12 follicles
Plasma
PK
Refer to Table 12
Refer to Table 12
a.
Please note that tubes and media may be substituted based on availability with the permission of the PI or laboratory 
investigator.


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Phase II SCLC only
Sample
Assay
Time points
Type of tube a
Amount 
of blood
Lab/
Instruction
gH2AX
(1) Pre-treatment C1D1
(2) Pre-treatment C1D4
 (24hr after olaparib)
NA
NA
SLFN11 IHC
SLFN11 gene expression
(3) At disease progression
NA
NA
Tumor 
(Optional)
Exome/RNAseq/droplet 
digital PCR
NA
NA
Germline DNA
Pre-treatment
Lavender top 
EDTA
5 ml
Immune subsets 
(Peripheral blood 
mononuclear cells)
(1) Pre-treatment on C1D1
(2) Pre-treatment on C1D15
(3) Pre-treatment on C2D1
(4) At disease progression
CPT citrate 
blue/black 
tubes
Two 8-ml 
tubes
Circulating tumor cells 
enumeration
(1) Pre-treatment C1D1
(2) Pre-treatment C2D1
(3) At disease progression
CellSave tubes
One 10 ml
Nanostring immune panel 
(770 genes)
(1) Pre-treatment C1D1
(2) Pre-treatment C2D1
(3) At disease progression
PAXgene RNA
One 2.5 
ml
Whole Blood
Nanostring DNA Damage 
and Repair panel (180 
genes)
(1) Pre-treatment C1D1
(2) Pre-treatment C2D1
(3) At disease progression
PAXgene RNA
One 2.5 
ml
Please call DTB 
Clinical 
Translational Unit 
when the samples 
are ready for pick-
up at 240-760-6330
10/12C208
Keep all tubes at 
room temperature
a.
Please note that tubes and media may be substituted based on availability with the permission of the PI or laboratory 
investigator.


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5.1.1.1
γ-H2AX
Phosphorylated H2AX (γ-H2AX) plays an important role in the recruitment and/or retention of 
DNA repair and checkpoint proteins such as BRCA1, MRE11/RAD50/NBS1 complex, MDC1 
and 53BP1. DNA damage has been shown to increase H2AX phosphorylation in cancer cells 
following exposure to camptothecins. If olaparib is able to increase the degree of DNA damage 
due to EP0057, it may be detectable by measurement of H2AX phosphorylation. We plan to 
study patient PBMCs, hair follicles, and tumor biopsies if obtained. Tumor tissue (optional) and 
hair follicles will be obtained if patients are suitable candidates and willing to allow such 
sampling. The ideal biomarker would confirm that there was increased DNA damage following 
addition of olaparib relative EP0057 alone. This analysis will be exploratory only and data will 
be used in planning biomarker endpoints in subsequent trials with the combination of EP0057and 
olaparib.
Hair follicles will be collected at multiple time points per Table 11. At least 24 hours prior to the 
start of the study, the research nurse will contact Dr. Redon in Dr. Aladjem’s lab (DTB-
LMP/CCR/NCI, Bldg 37/ Rm 5056) to inform him when samples will be taken (Tel: 240-760-
7338 (L); 301-760-6275 (Cell); redonc@mail.nih.gov). Dr. Redon will provide tubes for 
collecting the plucked hairs. The tubes contain ice cold PBS labeled with the date/time of 
sampling, the protocol, and the unique identifier. Dr. Redon will also provide forceps for 
plucking. Dr. Redon should be notified of when the samples should be picked up. 
Single hairs are plucked from the scalp with forceps. Plucked hairs from eyebrows will be 
collected only if scalp hairs cannot be provided. The aim is to acquire 12 hairs that contain a full 
intact follicle and sheath. All the hairs from a patient are placed in microfuge tubes containing 
cold PBS and stored on ice. Upon delivery in Dr. Aladjem’s lab, hairs will be fixed with 
paraformaldehyde and analyzed under a dissection microscope to select those containing a full 
intact follicle and sheath. Plucked hairs will be fluorescently stained for γ-H2AX and images will 
be recorded by using a confocal microscope. 
Blood will be collected per Table 11. When the patient is scheduled, the DTB Clinical 
Translational Unit will be contacted [by email to leesun@mail.nih.gov]. Blood from heparinized 
syringe will be mixed with a 1:1 ratio of room temperature PBS and layered over a 1:1 blood-
PBS/Ficoll ratio in a conical centrifuge tube. The conical centrifuge tube should be centrifuged 
25 minutes at room temperature at approximately 1000 rpm. The cell layer resting above the 
Ficoll and containing the peripheral blood mononuclear cells (PBMCs) will be aspirated and 
transferred to a 15 ml conical tube for washing in 15 ml PBS. PBMCs will be fixed with 
paraformaldehyde, spun onto a microscope slide and stain for γH2AX detection. Images from γ-
H2AX-stained PBMCs will be recorded by using a confocal microscope.
5.1.1.2
SLFN11
Expression of the gene SLFN11 has been found to correlate with the activity of topoisomerase 
inhibitors in studies using the National Cancer Institute cell line panel (NCI60) and the Cancer 
Cell Line Encyclopedia (CCLE) (54, 55). SLFN11 expression predicted sensitivity to DNA 
damaging chemotherapy including Top1 and Top2 inhibitors, alkylating agents, platinum 
derivatives, DNA synthesis and PARP inhibitors (54-56). In experiments using cells with 
endogenously high and low SLFN11 expression and siRNA- and Crispr-mediated silencing, 


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SLFN11 was found to be causative in determining cell cycle arrest and cell death in response to 
DNA damaging agents in cancer cells (56). Data from the CCLE, the NCI60 and The Cancer 
Genome Atlas (TCGA) indicate a broad range of SLFN11 expression in lung cancers, raising the 
possibility that high SLFN11 expression might enrich for tumors that are more likely to respond 
to DNA damaging chemotherapy; conversely low SLFN11 expression may predict tumors that 
are likely resistant. Pre-treatment SLFN11 expression in tumor samples will be assessed (IHC 
and RNA) to assess in an exploratory manner, the potentially role of SLFN11 as a predictor of 
response to EP0057 plus olaparib. 
5.1.1.3
Tumor biopsies and genomic DNA 
Biopsies will be done only in phase II part of the study and in SCLC patients in the phase I part 
of the study.
Paired tumor biopsies will be obtained by minimally invasive methods such as CT guided 
percutaneous biopsies before and after treatment [C1D4 (24hr after olaparib)] and at disease 
progression per Table 11. The site of biopsy will be determined in discussion with interventional 
radiologist. If it can be safely obtained, 4 cores of tumor tissue will be collected. Two cores will 
be sent to pathology- one for confirmation of diagnosis and another will be used for making an 
FFPE block. The other 2 cores will be flash frozen at the time of biopsy. When the patient is 
scheduled, the DTB Clinical Translational Unit lab will be contacted [by email to Sunmin Lee 
leesun@mail.nih.gov]. Interventional Radiology will call the lab at 240-760-6330 when the 
patient arrives in IR and a lab member will be present at Interventional Radiology for the 
procedure. The cores will be flash frozen, 2D barcoded, and stored in liquid nitrogen.
Formalin fixed paraffin embedded tumor tissue (FFPE) from the new biopsies and or from 
archived FFPE tissue from prior biopsies/surgical procedures will be sent to the DTB Clinical 
Translational Unit as described above. Genomic DNA and RNA will be extracted from the tumor 
and archived for genomic analysis. Tumor tissue when obtained before start of treatment will be 
used for the following assessments: γ-H2AX, SLFN11, and POLQ expression; post-treatment 
biopsy samples will be assessed for γ-H2AX expression. 
5.1.1.4
Immune Subsets 
Little is known of the immunomodulatory effects of DNA damage-inducing cytotoxic therapy. 
Peripheral blood mononuclear cells (PBMC) will be obtained per Table 11 and will be assessed 
by the DTB Clinical Translational Unit using multiparameter flow cytometry for immune subsets 
including but not necessarily limited to Tregs, myeloid-derived suppressor cells, effector and 
exhausted CD4+ and CD8+ T-cells, and CD14+ monocytes. Assessment will include functional 
markers, i.e. PD-1, Tim-3, CTLA-4, CD40, HLA-DR, and/or PD-L1. Members of the lab will 
procure the peripheral blood samples, enter the samples in a secure patient database, process the 
samples for viable cell storage, label each sample with a unique 2D barcode, and viably store the 
samples. They will prepare the samples for staining, stain and run the samples by 
multiparametric flow cytometry (MACSQuant, Miltenyi Biotec, Bergisch Gladbach, DE), the 
data will be analyzed by FlowJo v.X.0.6. Peripheral blood will be drawn into two 8-ml CPT 
citrate blue/black tubes for each time point. These assessments will be performed by the DTB 
Clinical Translational Unit.
Accumulating evidence has revealed the interplay between the host immune system and 
anticancer therapies.(57, 58) Several classical chemotherapeutics and molecular-targeted 


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therapies have been reported to stimulate tumor-specific immune responses either by inducing 
immunogenic cell death (ICD) or by engaging immune effector mechanisms. We propose to 
study the impact of combination therapy of EP0057 with olaparib on immune subsets and test for 
clinical relevance. These analyses offer the opportunity to obtain new insights into the 
immunomodulatory action of these combination therapies.
5.1.1.5
Circulating Tumor Cells and Circulating Tumor DNA
Circulating tumor cells (CTCs), which can be prevalent in SCLC, present a readily accessible 
'liquid biopsy'. Peripheral blood will be collected per Table 11 to correlate circulating tumor cell 
(CTC) levels at baseline or levels pre- and post-therapy with clinical response and survival. 
CTCs will be assessed using ferrofluidic enrichment and multiparameter flow cytometric 
detection. CTCs will be identified as viable, nucleated cells, that positively express one or more 
epithelial or tumor markers and are negative for expression of hematopoietic markers. CTCs will 
be enumerated and if sufficient, additional characterization performed included RAD51 foci, 
gene expression by droplet digital PCR, NanoString, whole transcriptome by Illumina or another 
platform as appropriate to the sample. Peripheral blood will be drawn into two 10-ml lavender 
top tubes and one 2.5 ml PAXgene RNA tube for each time point. These assessments will be 
performed by the DTB Clinical Translational Unit. 
Circulating tumor DNA will be isolated from plasma separated from peripheral blood. Mutations 
identified by analysis of patient tumor samples may be included as personalized tumor markers 
in the circulating nucleic acid analysis. Mutations will be assessed by the appropriate technology. 
A multiplexed gene expression approach to profiling immune gene and DNA damage response 
signatures 
Peripheral immune and DNA damage response transcriptional signatures will be evaluated by the 
DTB Clinical Translational Unit using the NanoString nCounter® platform (NanoString 
Technologies, Seattle, WA). We will use the nCounter 770 gene PanCancer Immune Profiling 
Panel and the newly released 170 gene DNA Damage & Repair panel, built in collaboration with 
the Developmental Therapeutics Branch. Peripheral blood will be collected in a PAXgene tube 
(PreAnalytix; 2.5 cc peripheral blood per tube) per the manufacturer’s instructions. RNA will be 
isolated using the PAXgene Blood RNA Kit according to the manufacturer’s instructions. The 
peripheral gene signatures will be evaluated at baseline and post-therapy to look for correlates of 
clinical response.
5.1.1.6
PK (Phase I only)
In Phase I only, blood samples for the determination of EP0057 and olaparib plasma levels will 
be obtained from participating patients via 6mL sodium heparin tube (BD, Franklin Lakes, NJ) 
per the table below. Samples will be obtained following the first dose on Cycle 1, day 1, and 
again on Cycle 6, day 1 in order to assess the extent of accumulation from repeated dosing at the 
time points specified below:


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Table 12. Phase I PK Sample Collection Timeline
sample
cycle
day
time 
(approx.)
hr post-EP0057 start
post-olaparib
1
1
1
8:00a
0 hr (predose, may be drawn 24 hrs prior 
start of dosing)
-
2
1
1
8:30a
0.5 hr [+/- 5 minutes] (mid-infusion)
-
3
1
1
9:00a
1 hr [+/- 5 minutes] (end of infusion 
(EIO))
-
4
1
1
10:00a
2 hr [+/- 5 minutes] (1 hr post EOI)
-
5
1
1
11:00a
3 hr [+/- 5 minutes] (1 hr post EOI)
-
6
1
1
9:00p
13 hr [+/- 60 minutes] (12 hr post EOI)
-
7
1
2
9:00a
25 hr [+/- 60 minutes] (24 hr post EOI)
-
8
1
3
10:00a
50 hr [+/- 120 minutes] (49 hr post EOI)
2 hr
9
1
15
8:00a
360 hr [+/- 5 days] (359 hr post EOI)
-
10
6
1
8:00a
0 hr (predose, may be drawn 24 hrs prior 
start of dosing)
-
11
6
1
8:30a
0.5 hr [+/- 5 minutes] (mid-infusion)
-
12
6
1
9:00a
1 hr [+/- 5 minutes] (end of infusion 
(EIO))
-
13
6
1
10:00a
2 hr [+/- 5 minutes] (1 hr post EOI)
-
14
6
1
11:00a
3 hr [+/- 5 minutes] (1 hr post EOI)
-
15
6
1
9:00p
13 hr [+/- 60 minutes] (12 hr post EOI)
-
16
6
2
9:00a
25 hr [+/- 60 minutes] (24 hr post EOI)
-
17
6
3
10:00a
50 hr [+/- 120 minutes] (49 hr post EOI)
2 hr
18
6
15
8:00a
360 hr [+/- 5 days] (359 hr post EOI)
-
The PK samples will be placed immediately on wet ice and refrigerated. The date and exact time 
of each blood draw should be recorded on the sample tube and the PK sheet. Please e-mail the 
Blood Processing Core) BPC at NCIBloodcore@mail.nih.gov at least 24 hours before 
transporting samples (the Friday before is preferred). For sample pick up, please page 102-
11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no 
answer, 240-760-6190 (main clinical pharmacology lab number). 
Bioanalytical measurements of EP0057 and olaparib will be measured by individual ultra HPLC-
MS/MS assays optimized for each drug by the Clinical Pharmacology Program (CPP). This data 
will be used to assess any drug-drug interactions are present between olaparib and EP0057, as 
well as to correlate adverse events and efficacy to each drug’s exposure. Neither olaparib nor 
camptothecin are extensively metabolized into pharmacologically active metabolites, therefore 
there are no relevant pharmacogenomic considerations regarding drug metabolizing enzymes or 
transporters with this combination.
5.1.2
UC Expansion Cohort
Tumor biopsies and blood samples will be obtained at the time points as described below. Archival 
tissue and blood or saliva will be collected at baseline and will be stored under uniform conditions 
or, preferably, processed immediately for DNA. Tumor biopsies (nodal or visceral) will be 
optional for molecular analyses and will be obtained at baseline, on-treatment (timing at the 
discretion of PI) and at disease progression. 


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In the case of tumor biopsy and limited material, tissue distribution should be prioritized as 
follows:
1. Storage and diagnosis confirmation (Dr. Maria Merino)
2. MET analysis (Dr. Don Bottaro) 
3. RNA sequencing (Dr. Michael Nickerson)
4. Genetic/Genomic Analysis (Dr. Michael Nickerson)


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Table 13. UC Expansion Cohort Sample Collection Guideline
Test Description
Amount/ 
Type/Tube/Handling
Collection 
Time
Contact
Special Instructions
Fresh Tumor Biopsy at
NIH CCR
(voluntary)
3-4 cores
Baseline (Pre-
Treatment),
On-treatment,
At Disease 
Progression
Email: Rene Costello, 
rene.costello@nih.gov 
24 hours prior to anticipated collection
Call Rene Costello at 301-443-6975 
immediate pick-up of sample collection
day.
3-4 cores will be flash frozen at the time 
of biopsy.
When the patient is scheduled for 
biopsy will call, Dr. Bottaro/Rene 
Costello (tech) (301-443-6975), and Dr. 
Figg’s lab (pager 102-11964).
The cores will be flash frozen, 2D 
barcoded, and stored in liquid nitrogen. 
The tumor tissue will be divided among 
three laboratories for storage and will 
be batched:
1.1 core: Laboratory of pathology 
(Maria Merino) will perform diagnosis 
confirmation.
2. 1-2 cores: Genitourinary 
Malignancies Branch. Molecular 
Pharmacology Section (Figg 
Laboratory) will store 1-2 core of fresh 
tumor per patient (for Dr. Nickerson 
WES/RNA seq)
3. 1 core will be stored with Dr. Don 
Bottaro (MET protein)
Samples will be sent in batches of 10 to 
Dr. Nickerson lab.
When the samples will be shipped, the 
Nickerson lab will be contacted by 
email to 
NCICGFDESLReceiving@mail.nih.gov 
about the timing of the shipment and the 


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Test Description
Amount/ 
Type/Tube/Handling
Collection 
Time
Contact
Special Instructions
number and type of samples with typed 
sample IDs.
Nickerson laboratory:
DNA Extraction and Staging 
Laboratory (DESL)
ATTN: Amy Hutchinson 8717 
Grovemont Circle
ATC, Room 149
Gaithersburg, MD 20877
 Phone: 240-760-6496
Saliva
3ml Oragene saliva 
collection kits
(DNA Genotek)
Baseline (or any 
time after consent 
is signed but 
preferably at 
baseline)
Email: BPC 
NCIBloodcore@mail.nih.gov
24 hours prior to collection
For sample pickup, page 102-11964 - 
Figg lab
Store at room temperature 
Will be stored in Dr. Figg’s Lab
Plasma and urine HGF 
and MET
One 4mL EDTA tube and 
collect at least 20 mL of 
urine specimen container 
Baseline,
Day 1 Each 
Cycle
E-mail BPC 
NCIBloodcore@mail.nih.gov at least 24 
hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964 -
Figg lab
Invert EDTA tube 2-4 times, place on 
wet ice and store at 4°C in the 
refrigerator until processing for a 
maximum of 30-60 min. Should be 
centrifuged within 30 min. 
Mix urine sample well by inverting 5-8 
times. Take 20ml of urine from the 
center of the container and put into a 
50ml tube. sMET analysis requires 1-
2ml urine HGF analysis requires 10-
20ml urine. Adjust urine to pH 7.5 with 
2 mol/L, ph 7.5 Trizma-HCL (Sigma, 
St. Louis, MO) using 50uL per 2 mL 


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Test Description
Amount/ 
Type/Tube/Handling
Collection 
Time
Contact
Special Instructions
urine volume. Centrifuge the conical at 
3000xg for 10 min at room temperature 
to remove cells and debris. Make as 
many 2 mL aliquots as possible. Store 
at -80C until requested by Dr. Don 
Bottaro’s lab
Comprehensive 
cytokine/chemokine 
study
One 10mL EDTA tube
Baseline
C2D1
C3D1
NIH CCR: E-mail BPC 
NCIBloodcore@mail.nih.gov at least 24 
hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964 - 
Figg lab
Invert EDTA tube 2-4 times, place on 
wet ice and store at 4°C in the 
refrigerator until processing for a 
maximum of 30-60 min.
Immunologic Subsets
Two 8 ml BD Vacutainer 
Cell
Preparation Tubes (CPT) 
citrate
(blue/black tiger top 
closure)
C1D1 (Pre-
treatment)
C2D1 (Pre-
treatment)
Disease 
Progression 
NIH CCR:
When scheduled email
Sunmin Lee
(leesun@mail.nih.gov),
Min-Jung Lee
(leemin@mail.nih.gov)
and when samples are ready call 240-
760-6330
Invert several times and leave at room 
temperature for DTB Clinical 
Translational Unit member pick up 
within NIH
Nanostring immune
panel (770 genes)
PAXgene tube 2.5 cc 
peripheral
blood per tube
C1D1 (Pre-
treatment)
C2D1 (Pre-
treatment)
NIH CCR:
When scheduled email
Sunmin Lee
(leesun@mail.nih.gov),
Min-Jung Lee
(leemin@mail.nih.gov)
and when samples are ready call 240-
760-6330
Invert several times and place at room 
temp or refrigerate Store up to 3 days at 
room temperature (15–25°C); up to 5 
days at 2–8°C and 8 years at –20°C or –
70°C
Nanostring DNA
damage response
panel (180 genes)
PAXgene tube 2.5 cc 
peripheral blood per tube
Pretreatment on 
C1D1
Pretreatment on 
C2D1
NIH CCR:
When scheduled email
Sunmin Lee
(leesun@mail.nih.gov),
Min-Jung Lee
(leemin@mail.nih.gov)
Invert several times and place at room 
temp or refrigerate
Store up to 3 days at room temperature 
(15–25°C); up to 5 days at 2–8°C and 8 
years at –
20°C or –70°C


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Test Description
Amount/ 
Type/Tube/Handling
Collection 
Time
Contact
Special Instructions
and when samples are ready call 240-
760-6330
CTC (DTB Clinical 
Translational Unit)
CellSave tube 7.5 cc
C1D1 (Pre-
treatment)
C2D1 (Pre-
treatment)
Disease 
Progression
NIH CCR:
When scheduled email
Sunmin Lee
(leesun@mail.nih.gov),
Min-Jung Lee
(leemin@mail.nih.gov)
and when samples are ready call 240-
760-6330
Invert several times and leave at room 
temperature for DTB Clinical 
Translational Unit member pick up 
within NIH.
CTC (Epic Science)
10mL Streck Cell-Free 
DNA BCT
C1D1 (Pre-
treatment)
C3D1 (Pre-
treatment) 
Have patient bring sample to clinic. 
Contact Katie Graap, 240-506-8634, for 
pick-up of specimen
Send notification to:
partners@epicsciences.com
Ship to:
Epic Science
Attn: (Partner Protocol #/Epic
internal ID)
9381 Judicial Dr. Suite 200
Sand Diego, CA 92121
Contact phone number is:
1-858-356-6610
Confirm blood tube is not expired. 
Expired tubes should not be used for 
blood collection. 
•
Ensure first 5ml blood is discarded 
or the blood for CTC analysis is not 
the first tube to be collected
•
Draw whole blood sample into 10 
mL
Streck Cell-Free DNA BCT tube (*see 
note regarding prevention of backflow).
Fill tube until blood low stops. NOTE: 
Epic requires a minimum of 4 mL blood 
per sample, but a full 10 mL tube of 
blood should be provided when 
possible.


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Test Description
Amount/ 
Type/Tube/Handling
Collection 
Time
Contact
Special Instructions
Cell-free DNA
One 10mL lavender top 
(EDTA) Tube (minimum 
of blood required 3 cc)
Every 2weeks
E-mail BPC 
NCIBloodcore@mail.nih.gov at least 24 
hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964 -
Figg lab
When the samples will be shipped, the 
Nickerson lab will be contacted by 
email to
NCICGFDESLReceiving@mail.nih.gov
about the timing of the shipment and the 
number and type of samples with typed 
sample IDs
After the tube has been filled with 
blood, immediately invert the tube 
several times to prevent coagulation.
Process within 2 hours following a 
double-spin protocol.


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5.1.2.1
MET studies for UC expansion cohort
Prior work from our group showed that MET overexpression in cancer cells is associated with 
increased proteolytic release of soluble MET (sMet) protein from the cell surface into blood and 
urine, a potentially useful biomarker of tumor aggressiveness and progression. (59)We also 
found that urinary sMET levels differentiated urothelial bladder cancer (N=141) and benign 
bladder pathology (N=64), (P=0.0093) and non-muscle-invasive (N=110) from muscle-invasive 
(N=31) disease (P<0.0001) (60). In an independent cohort of patients with metastatic (N=23) and 
muscle-invasive (N=8) (not metastatic) urothelial cancer, we found that sMET levels in urine 
samples from ileal conduits and neobladders were significantly higher than in normally voided 
urine, regardless of stage (N=31) (P=0.0489), and in patients with visceral metastasis (N=14) 
(P=0.0111) (data not shown). Serum sMET levels showed a trend toward higher values in 
patients with metastatic versus non-metastatic disease. The process that increases MET shedding 
in the urine and blood of patients with UC are likely multi-factorial and not fully understood. 
However, there is great excitement for the potential of MET as a potential biomarker of disease 
status and progression. We plan to analyze plasma and urine sMET during treatment and 
correlate the results with baseline clinical parameters and response to therapy. We also plan to 
analyze cMET by real time PCR (RT-PCR).
5.1.2.2
Circulating Tumor Cells (DTB Clinical Translational Unit)
Blood will be collected per Table 13 to correlate baseline or changes in CTCs with clinical 
outcome. CTCs will be investigated using ferrofluidic enrichment and multi-parameter flow 
cytometric analysis. CTCs will be identified by positivity for epithelial markers including but not 
limited to EpCAM and negative for expression of hematopoetic markers including but not limited 
to the panhematopoietic marker CD45.
5.1.2.3
Circulating Tumor Cells (Epic Science)
The patients on the bladder expansion cohort will also have CTC’s measured using fee-for-
service Epic Science’s “no cell left behind” platform. 
CTC Samples should be collected in the 10 mL Streck Cell-Free DNA BCT at timepoints per 
Table 13 baseline and day 1 of cycle 2 and 3. These tubes are commercially available through 
Streck (Omaha, NE). 
IMPORTANT: The first 5 mL of blood collected from the fresh venipuncture cannot be used for 
the collection into the Streck tubes due to possibility of contaminating epithelial cells during 
venipuncture. Please ensure that at least one blood tube of 5 mL or more is collected prior to 
collection of the CTC sample to avoid adversely affecting the test results. 
Prevention of Backflow: 
Since Streck Cell-Free DNA BCT tubes contain chemical additives, it is important to avoid 
possible backflow from the tube. To guard against backflow, observe the following precautions: 
•
Keep patient’s arm in the downward position during the collection procedure. 
•
Hold the tube with the stopper uppermost. 
•
Release tourniquet once the blood starts to flow into the tube, or within 2 minutes of 
application. 


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•
Tube contents should not touch stopper or the end of the needle during the collection 
procedure. 
Blood Collection Instructions: 
**Arrange for the same day shipment! 
•
Confirm blood tube is not expired. Expired tubes should not be used for blood collection. 
•
Draw whole blood sample into 10 mL Streck Cell-Free DNA BCT tube (*see note 
regarding prevention of backflow). Fill tube until blood flow stops. NOTE: Epic requires 
a minimum of 4 mL blood per sample, but a full 10 mL tube of blood should be provided 
when possible. 
•
Remove tube from adapter and immediately mix by gentle inversion 8 to 10 times. Tube 
inversion prevents clotting. Inadequate or delayed mixing may result in inaccurate test 
results. 
•
Label the tube with subject’s identification and date and time of blood draw. Unlabeled 
blood tubes may not be processed. 
•
Keep sample at room temperature and ship on day of collection in shipper with ambient 
gel packs. 
Specimen Shipment Logistics 
All shipments must include requisition forms that contain Patient ID, Collection Date and time, 
Collection Site (including address), Time Point (if applicable), and the appropriate trial code 
(CTEP # 9681/ Epic Internal ID: NE-003). Clinical sites should provide email notification of 
sample shipment to Epic Sciences on the day of collection. The email should contain: 
•
Trial codes (CTEP # 9681/ Epic Internal ID: NE-003) 
•
Patient ID 
•
Collection date and time* 
•
Time point/Visit 
•
Tracking information 
If possible, include a scanned copy of the completed sample requisition form. Partner will be 
responsible for all blood collection supplies, shipping materials, and shipping expenses. 
* When collection time is not provided, Epic Sciences will assume the sample was collected at 
8:00AM (local time) on the date of collection.
Send notification to: partners@epicsciences.com 
Ship to: Epic Science
Attn: (CTEP # 9681/Epic internal ID: NE-003)
9381 Judicial Dr. Suite 200
Sand Diego, CA 92121
Contact phone number is: 1-858-356-6610
Holiday Outages 
In observance of the following holidays, Epic Sciences sample processing locations will be closed, 
and samples will be processed on the next business day. Epic holidays are reviewed regularly and 
are subject to change. Notification of any changes to the holiday schedule will be communicated 
promptly via email to the project stakeholders.
Epic Sciences (USA) Holidays


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New Year’s Day or Business Day after New Year’s Day
President’s Day 
Memorial Day 
Business day before Independence Day 
Independence Day 
Labor Day 
Thanksgiving Day 
Day after Thanksgiving Day 
Business day before Christmas or Christmas Day 
5.1.2.4
Nanostring immune panel & Nanostring DNA damage response panel (UC Expansion 
Cohort)
Peripheral immune and DNA damage response transcriptional signatures will be evaluated by the 
DTB Clinical Translational Unit using the NanoString nCounter® platform (NanoString 
Technologies, Seattle, WA). We will use the nCounter 770 gene PanCancer Immune Profiling 
Panel and the newly released 170 gene DNA Damage & Repair panel, built in collaboration with 
the Developmental Therapeutics Branch. Peripheral blood will be collected in a PAXgene tube 
(PreAnalytix; 2.5 cc peripheral blood per tube) per the manufacturer’s instructions. RNA will be 
isolated using the PAXgene Blood RNA Kit according to the manufacturer’s instructions. The 
peripheral gene signatures will be evaluated at baseline and post-therapy to look for correlates of 
clinical response.
5.1.2.5
Whole exome sequencing and RNA sequencing for UC expansion cohort
Recent data indicate that subsets of bladder cancer have dysfunctions in genes related to DNA 
damage repair pathways. Analysis of DNA copy number and mutation status of UC by The 
Cancer Genome Atlas Research Network has revealed that up to 30% (germline or somatic 
mutations) of the cases included had BRCA pathway alterations (12). Nickerson and colleagues 
also found multiple germline and somatic mutations in genes encoding BRCA pathway proteins 
in bladder cancer, including BRCA1, BRCA2, ATM, BAP1, and PALB2. (14) Based on these 
data, exome sequencing will be done for bladder cancer cohort to investigate potential predictive 
biomarkers with particular focus on abnormalities in DNA-repair genes. Molecular finding will 
be correlate with response and time-to-event outcomes.
Inhibition of PARP1 could lead to an increase in SSBs, and if left unrepaired or additional DNA 
damaged is conferred – for example adding chemotherapy- these SSBs would lead to the 
formation of increased DSBs and in turn increased cell death.(61, 62) However, cells contain 
alternative mechanism for DNA damage repair in the absence of PARP activity. In this regard, 
differential expression of proteins involved in such alternative DNA repair mechanisms would 
further enhance the efficacy of PARP inhibitors. We propose to analyze DNA damage response 
transcriptional signatures in peripheral blood of our cohort of patients to correlate with response 
to olaparib. We hypothesize that differential expression of genes involved in DNA damage 
response and repair processes influence the response to olaparib. This part will be performed in 
collaboration with Michael Nickerson in the Genetics Branch/CCR/NCI.
5.1.2.6
Circulating Tumor Cell DNA
FM panel and targeted sequencing results will be used to identify germline and somatic cancer-
gene alterations associated with tumor cells. This data will be used to design a patient-specific 
targeted sequencing panel to detect and monitor mutation load based on sequencing read counts in 


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blood before, during and after treatment using whole blood DNA and Illumina and Ion Torrent 
sequencing.
Peripheral blood will be collected in EDTA-containing (lavender tops) tube at designated time 
points (see Table 13). Blood samples for isolation of DNA containing circulating tumor cell DNA 
will be processed per guidelines in Table 13 and stored at 40C at Dr. Figg’s laboratory (Section 
5.2.2). 
DNA will be shipped to Dr. Nickerson’s Laboratory for analysis in batches of 5-10 samples. 
5.1.2.7
Blood Serum for Cytokine Analysis by Liang Cao: UC Cohort 
Blood Serum will be collected for cytokine analysis by Liang Cao (to be stored in Figg’s lab) at 
baseline and Day 1 of every cycle. Page 102-11964 for Dr. Figg’s lab to pick up.
i. Blood Serum: Collect 7-10 mLs blood in one (1) serum separator tube (SST) or red top 
tube with no preservatives. 
ii. Allow the blood to clot by standing at room temperature for 30 minutes.
iii. Separate serum from cells by centrifuging at 4 degrees C for 10 minutes at 1200 x g.
iv. Pipette two (2) aliquots of serum 1.5mLs each into two 2mL cryovials.
v. Freeze immediately at -20 or lower.
vi. Maintain in -80 freezer for storage until shipment to Dr. Cao’s lab.
5.1.2.8
Urine Cytology Tumor DNA (in patients with intact primary tumors only) by Mark 
Raffeld: UC Cohort
Urine will be collected for urine cytology tumor DNA by Mark Raffeld (to be stored in Figg’s 
lab). Page 102-11964 for Dr. Figg’s lab to pick up.
Urine Cytology tumor DNA Standard Operating Procedure
Objective: To identify 10 urines morphologically positive for HG transitional cell carcinoma 
with tumor available in surgical pathology for parallel 50 CGMP +Tert analysis
1. Urine samples with clinical information suggesting the presence of a HG transitional cell 
carcinoma will be divided in the cytology laboratory into two aliquots. 
a.
One aliquot will be processed for routing laboratory cytomorphologic evaluation 
(i.e., Thin Prep)
b. A second aliquot will be stored in the refrigerator (-4 C)
c.
The cytotechologist will make a note on the request form that a second aliquot 
exists/ has been saved
2. If routine cytologic evaluation confirms the presence of a HG transitional cell carcinoma
a.
The cytopathologist will check whether the Pt’s tumor exists in surgical pathology 
b. If surgical pathology material exists – the cytopathologist will notify the 
cytotechnologist that the second aliquot should be centrifuged per laboratory 
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i.
Up to 5 ml of supernatant should be pipetted into a conical tube labelled 
with the case number 
ii.
The tube with the remaining cell pellet should also be labelled with the 
case number
3. Both tubes should be stored at -20 C (freezer to be determined)
4. When ten samples with corresponding surgical pathology material have been collected, 
these will be transferred to the Molecular Pathology Section for DNA extraction and 
CGMP50 +Tert analysis. 
5.1.2.9
Tissue: UC Cohort 
Patient must be able to provide either archival tumor samples (H&E slides and one paraffin 
block or 15 unstained slides) or undergo tumor biopsy. If tissue was already collected for another 
CCR study run by Dr. Apolo, no additional tissue is needed. Biopsies are encouraged but 
voluntary.
o
10 unstained slides and 1 H&E for Dr. Paul Meltzer’s laboratory
o
5 unstained slides and 1 H&E for DTB Clinical Translational Unit’s laboratory
Biopsies obtained by surgery or interventional radiology will be processed immediately by Don 
Bottaro and DTB Clinical Translational Unit’s laboratory. Three cores will be collected when 
possible (1-2 cores for pathology and 1 core for Don Bottaro). Fresh tumor obtained at NCI CCR 
will also be divided among the above 3 labs and additionally Dr. Bottaro will use one core to 
perform the MET tumor assay. Biospecimens will be collected and processed using validated 
SOPs that will ensure both specimen quality and patient confidentiality. Using a computerized 
inventory system and a backup hardcopy process, all specimen collection and processing steps 
will be documented and the specific location of each specimen will be tracked. 
•
Please contact Dr. Bottaro to notify of biopsy date and time at 240-858-3967 (or Rene 
Costello at 301-443-6915) and to arrange for pick-up of sample during biopsy (1 core)
•
1-2 biopsy cores will be submitted to pathology
•
Tissue blocks and slides from outside pathology departments will be stored in the NIH 
pathology department with attention to Dr. Maria Merino. 
5.1.3
mCRPC Expansion Cohort
Correlative Studies: mCRPC cohort 
Patients will undergo one mandatory pretreatment biopsy and two optional research biopsies 
(timepoints assessed at PI discretion) to assess the effect of response to olaparib plus EP0057.
Table 14. mCRPC Sample Collection Guidelines
Test
Amount/Type/Tube
Collection 
Timing
Contact
Special Instruction
Chemokine and 
cytokine analysis
Purple, Tube size: 10 
cc, 2 tubes, Draw 
volume: 20 cc
Baseline, 
C4D1, and 
progression
CPC pickup at 
102-11964
Immediately pack 
on wet ice


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Test
Amount/Type/Tube
Collection 
Timing
Contact
Special Instruction
Immune subsets 
PBMC
Black/Blue, Tube 
size: 8 cc, 2 tubes, 
Draw volume: 16 cc
Baseline,
C2D1, and 
C3D1 
DTB Clinical 
Translational 
Unit at 240-760-
6330
Invert blood tubes 
3-4 times keep at 
room temperature 
Circulating Tumor 
Cells (CTC)
Purple (LVV), Tube 
size: 7.5 cc Draw 
volume: 7.5 cc
Baseline,
C2D1, and
progression 
DTB Clinical 
Translational 
Unit at 240-760-
6330
Invert blood tubes 
3-4 times keep at 
room temperature
Nanostring 
Immune Panel
PAX red, Tube size, 
2.5 cc, Draw volume 
2.5 cc
Baseline,
C2D1, and 
progression 
DTB Clinical 
Translational 
Unit at 240-760-
6330
Invert blood tubes 
3-4 times keep at 
room temperature 
or refrigerate
Nanostring DNA 
damage response 
panel 
PAXgene tube, Draw 
volume 2.5 cc
Baseline, 
C2D1, and 
progression
DTB Clinical 
Translational 
Unit at 240-760-
6330
Invert blood tubes 
3-4 times keep at 
room temperature 
or refrigerate
CTC (Epic 
Science)
Brown/Black Streck 
tube, 10 cc, Draw 
volume 10 cc
Baseline, 
C4D1
Page 102-11964 
for Dr. Figg’s lab 
to pick up
Keep at room 
temperature
5.1.3.1
Tumor biopsies on mCRPC expansion cohort
Biopsy will be performed at the following time: mandatory-prior to treatment on cycle 1 day 1. 
Optional tumor biopsies may be obtained at 2 additional time points as determined by the 
investigator(s) and/or the PI. 
Biopsies may be not performed on the specific dates and times due to the following reasons, 
including but not limited to, delayed recovery of hematologic toxicities, delayed clinic schedule, 
or national holidays.
At least 1 core biopsy specimen will be obtained via Interventional Radiology and members of 
the Kelly lab will be on call to receive the biopsies: Dr. Kelly’s lab representative: 240-760-
7121. 
5.1.3.2
Exome sequencing for mCRPC expansion cohort
Exome sequencing will be done for mCRPC cohort on tumor tissue to investigate potential 
predictive biomarkers in responders and non-responders in collaboration with Dr. Paul Meltzer 
in the Genetics Branch/CCR/NCI. Additionally, culturing of patient-derived organoids (cell 
lines) will be performed in collaboration with Kathleen Kelly Siebenlist in the Laboratory of 
Genitourinary Cancer Pathogenesis/CCR/NCI, if there is biopsy core specimen available.


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5.1.3.3
Saliva sample collection for mCRPC expansion cohort
A one-time saliva sample will be collected anytime during the study as a source of normal tissue 
for genomics comparison. Saliva sample will be collected in one Oragene Saliva Kit at room 
temperature and page Dr. Figg’s lab for pick up at 102-11964. Dr. Figg’s lab will barcode the 
sample, remove patient identifier, and send the sample to Dr. Meltzer’s lab via courier. Patients 
will be instructed not to eat, drink, smoke or chew gum for 30 minutes before giving their saliva 
sample. Sequencing of DNA will be performed by the Genetics Branch/CCR/NCI.
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION
All samples [except PK samples- which will be sent to Doug Figg’s lab; one core of research 
biopsy- which will be stored in the Laboratory of Pathology; hair samples which will be 
collected and processed by Dr. Redon, Developmental Therapeutics Branch] will be sent to and 
stored in DTB Clinical Translational Unit at NCI, Bldg 10, Bethesda, MD. Place all samples at 
room temperature, phone the Lab at 240-760-6330 and a laboratory member will come to pick up 
the sample. 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. 
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required. Any transfer of materials to other NIH or non-NIH investigators will occur following 
NIH Intramural Research Program guidelines. If the subject withdraws consent the participant’s 
data will be excluded from future distributions, but data that have already been distributed for 
approved research use will not be able to be retrieved.
5.2.1
DTB Clinical Translational Unit 
Tracking and disposition of samples will conform to the NCI CCR Biospecimen Guidelines.
All samples will be barcoded and data entered and stored in the Labmatrix system utilized by the 
NIH Clinical Center. This is a secure system with access limited to defined personnel. 
Labmatrix creates a unique barcode ID for every sample which cannot be traced back to subjects 
without Labmatrix access. The data recorded for each sample may include the subject ID, name, 
trial name/protocol number, date/time drawn, as well as box and freezer location. Subject 
demographics associated with the clinical center patient number are provided in the system. For 
each sample, there are notes associated with the processing method (delay in sample processing, 
storage conditions on the ward, etc.). Access to personally identifiable information (PII) is 
limited to the PI and associate investigators. 
An additional layer of encryption will be added for samples undergoing genetic analysis in the 
DTB Clinical Translational Unit where a separate clinically annotated unique sample ID will be 
generated linked with the sample ID in Labmatrix. As additional clinical information is 
generated and linked to the unique patient ID, it is also electronically linked via Labmatrix to the 
sample ID. The DTB Clinical Translational Unit will proceed with sample analysis and record 
data under the unique sample ID. 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C or in 
liquid nitrogen according to stability requirements. These freezers are located onsite, and access 
to stored clinical samples is restricted. Samples will be stored until requested by a researcher 
named on the protocol. All requests are monitored and tracked in the Labmatrix System. All 


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researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the NCI. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval.
Samples will be stored in a freezer at either -4° C or -70° C behind a door locked after working 
hours. Samples will be tracked by a designated member of the laboratory who is responsible for 
notifying the PI about requests for use of the material, for allocating the material to other 
members of the laboratory, for recording the disposition of the allocated material. 
5.2.2
Clinical Pharmacology Program (Figg Lab)
Upon arrival in the Clinical Pharmacology Program, samples will be centrifuged and the plasma 
transferred into cryovials for storage at -80 C until the time of analysis. In addition, samples will 
be barcoded.
All PK samples will be bar-coded, with data entered and stored in the Patient Sample Data 
Management System (PSDMS, aka Labmatrix) utilized by the CPP. This is a secure program, 
with access to PSDM System limited to defined CPP personnel, who are issued individual user 
accounts. The program creates a unique barcode ID for every sample and sample box, which 
cannot be traced back to patients with PSDMS access. The data recorded for each sample may 
include the patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, 
material type, as well as box and freezer locations. Patient demographics associated with the 
clinical center patient number are provided in the system. For each sample, there are notes 
associated with the processing method (e.g. delay in sample processing, storage conditions on the 
ward, etc.).
Bar-coded samples are stored in bar-coded boxes in locked freezers at either -20 C or -80 C 
according to stability requirements. These freezers are located onsite in the CPP and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Samples will be stored until 
requested by a researcher named on the protocol. All requests are monitored and tracked in 
PSDMS. All researchers are required to sign a form stating that the samples are only to be used 
for research purposes associated with this trial (as per IRB approved protocol) and that any 
unused samples must be returned to the CPP.
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested). The PI will record any loss 
or unanticipated destruction of samples as a deviation. Reporting will be per the requirements of 
section 7.2.
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
PSDMS. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
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5.2.3
Redon (Aladjem) Lab
At least 24 hours in advance, the research nurse will contact Dr. Redon in Dr. Aladjem’s lab 
(DTB-LMP/CCR/NCI, Bldg 37/ Rm 5056) to inform him when samples will be taken (Tel: 240-
760-7338 (L); 301-760-6275 (Cell); redonc@mail.nih.gov). Dr. Redon will provide tubes for 
collecting the plucked hairs which contain ice cold PBS, and are labeled with the date/time of 
sampling, the protocol, and the unique identifier. Dr. Redon should be notified of when the 
samples should be picked up. 
All of the hairs from a patient will be placed in microfuge tubes containing cold PBS and stored 
on ice. Upon delivery in Dr. Aladjem’s lab, hairs will be fixed with paraformaldehyde and 
analyzed under a dissection microscope to select those containing a full intact follicle and sheath. 
Plucked hairs will be fluorescently stained for γ-H2AX and images will be recorded by using a 
confocal microscope.
5.2.4
Paul Meltzer Lab
All samples will be stored in monitored freezers/refrigerators in the Meltzer laboratory at 
specified temperatures with alarm systems in place. All samples will be tracked by unique 
sample identifiers with bar code labeling, using the Labmatrix software and the Genologic 
Clarity LIMS system. Secure computer database systems (Labmatrix and Clarity LIMS) will be 
used to track all samples collected on this protocol. The system will contain data that includes, 
but is not limited to the unique sample identifiers, storage locations and conditions, biologic 
study results, clinical information, and corresponding records of all derivatives generated from 
samples/tissues collected on this protocol. The system will employ mechanisms for restricting 
users to viewing only the level of data appropriate for each individual user, will provide the 
capability to audit any data modification, and will be maintained and backed up according to 
established standards.
5.2.5
Laboratory of Genitourinary Cancer Pathogenesis (Kathleen Kelly Siebenlist)
All samples will be assigned a unique barcode ID and entered into the Labmatrix system. Tissue 
will be processed immediately after biopsy and placed into organoid culture. Organoids that fail 
to grow will be destroyed. Organoids that are cultured successfully will be maintained in the 
Kelly lab. Viably frozen stocks of organoids will be stored in liquid nitrogen in the Kelly lab and 
tracked by the unique ID. DNA and RNA derivatives will be added into the Labmatrix system, 
The system will contain data that includes, but is not limited to the unique sample identifiers, 
storage locations (freezer and box identifiers) and conditions, and corresponding records of all 
derivatives generated from samples/tissues collected on this protocol. Access to the tracking 
system is limited to appropriate personnel. Material will be stored in a monitored -80° C freezer, 
and access to material will be restricted to appropriate lab personnel.
5.2.6
Urologic Oncology Branch Molecular Therapeutics Facility (Donald Bottaro)
Each patient research sample will be assigned a unique patient identifier and relevant sample 
characteristics (such as timing of sample collection, treatment cycle and day identifiers) will be 
recorded. The location of all samples will be carefully tracked in the secure UOB database. All 
stored samples will be coded and no identifying patient information will be on placed on sample 
containers. Stored samples will be kept in freezers / refrigerators or secure containers located in 
the Urologic Oncology Branch research laboratories or in the laboratories of collaborators.


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Samples will be stored until requested by an authorized researcher(s). All researchers are 
required to use the samples for research purposes associated with this trial (as per the NIH IRB 
approved protocol). Subjects will be given the option of consenting to future use of their research 
samples per the informed consent process with their option declared in the consent document. 
Samples from those patients who consent to this will be stored permanently. However, these 
samples will be used only for research studies on active NIH IRB approved protocols covered by 
a valid informed consent document. Samples will be destroyed at the completion of the study 
from those subjects who decline future use of their samples. Once primary research objectives 
for the protocol are achieved, intramural researchers can request access to remaining samples 
provided they have an IRB approved protocol and patient consent. Any unused samples must be 
returned to the UOB laboratories as appropriate. 
5.2.7
Laboratory of Pathology
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation. Unutilized excess tissue that is not placed in 
paraffin blocks is stored in formalin for up to three months, in accordance with College of 
American Pathologists/Joint Commission on Accreditation of Healthcare Organizations 
(CAP/JCAHO) guidelines, and then discarded. Following completion of the diagnostic workup, 
the slides and tissue blocks are stored indefinitely in the LP’s clinical archives. All specimens are 
catalogued and retrieved utilizing the clinical laboratory information systems, in accordance with 
CAP/JCAHO regulations. The use of any stored specimens for research purposes is only allowed 
when the appropriate IRB approval has been obtained. In some cases, this approval has been 
obtained via the original protocol on which the patient was enrolled.
5.2.8
Laboratory of Pathology NCI COMPASS Program
Participants may undergo genetic analysis through the NCI COMPASS program for tumor-
normal exome and transcriptome. For additional information on consenting, ordering and results, 
refer to CCR SOP ADGC-5, Tumor/Normal Whole Exome Sequencing: Consenting, Ordering, 
and Obtaining Results found at 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
5.2.9
Future Use/IRB Reporting/Protocol Completion/Sample Destruction
Blood and tissue specimens collected in the course of this research project may be banked and 
used in the future to investigate new scientific questions related to this study, including 
gene/protein expression and germline analysis. However, this research may only be done if the 
risks of the new questions were covered in the consent document and the proposed research has 
undergone prospective IRB review and approval. If new risks are associated with the research 
(e.g., analysis of germ line genetic mutations.) the Principal Investigator must amend the protocol 
and obtain informed consent from all research subjects.
Following completion of this study, samples will remain in storage as detailed above only for those 
subjects that agreed to future use in the Optional Studies section of the consent form. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting the 
rights to use the material. Currently, there is no plan to use these samples outside of the use 
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All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are 
remaining at the completion of the protocol will be stored in the conditions described below. The 
study will remain open so long as sample or data analysis continues. Samples from consenting 
subjects will be stored until they are no longer of scientific value or if a subject withdraws consent 
for their continued use, at which time they will be destroyed. 
If the patient withdraws consent the participants data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved.
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 7.2. 
5.3
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.3.1
Description of the scope of genetic/genomic analysis
One of the exploratory endpoints of this protocol is to characterize genetic alterations which 
predict response and changes associated with the development of chemoresistance. To this end, 
whole and targeted genome sequencing may be performed on banked tumor samples collected 
pre-treatment and/or post-progression. Since analysis of germline variants is essential to fully 
characterize the somatic mutations identified in genome sequencing, these assays will involve 
both somatic and germline DNA. 
5.3.2
Certificate of Confidentiality
Refer to section 13.4.
5.3.3
Management of Results
The analyses that we perform in our laboratory are for research purposes only; they are not 
nearly as sensitive as the tests that are performed in a laboratory that is certified to perform 
genetic testing. Changes that we observe unrelated to our research may or may not be valid. 
Therefore, we do not plan to inform participants of the results of testing on the tissue and blood 
that is performed in our research lab. However, in the unlikely event that a clinically actionable 
gene variant is discovered, subjects will be contacted. Clinically actionable findings for the 
purpose of this study are defined as disorders appearing in the American College of Medical 
Genetics and Genomics recommendations for the return of incidental findings that is current at 
the time of primary analysis. (A list of current guidelines is maintained on the CCR intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists) Subjects will 
be contacted at this time with a request to provide a sample to be sent to a CLIA certified 
laboratory. If the research findings are verified in the CLIA certified lab, the subject will be 
referred to the NCI CCR Genetics Branch for the disclosure of the results. 
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
For samples undergoing analysis through the NCI COMPASS, results will be reported per CCR 
SOP ADGC-5, Tumor/Normal Whole Exome Sequencing: Consenting, Ordering, and Obtaining 
Results found at https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 


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6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
Document AEs from the first study intervention, Study Day 1, through 30 days after the last 
study drug administration. Adverse events that are serious need to be recorded through 30 days 
after the last study drug administration. Beyond 30 days after the last study drug administration 
and through the end of study participation, only adverse events which are serious and related to 
the study intervention need to be recorded.
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:
•
Results in discontinuation from the study
•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is associated with death or another serious adverse event, including hospitalization. 
•
Is judged by the Investigator to be of significant clinical impact
If any abnormal laboratory result is considered clinically significant, the investigator will provide 
details about the action taken with respect to the test drug and about the patient’s outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1. 
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows (check all that 
apply):
_x__ Coded and linked data in an NIH-funded or approved public repository. 
_x__ Coded and linked data in BTRIS (automatic for activities in the Clinical Center)
_x__ Coded and linked or identified data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through (check all that apply):
_x__ An NIH-funded or approved public repository: clinicaltrials.gov; dbGaP.


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_x__ BTRIS (automatic for activities in the Clinical Center)
_x__ Approved outside collaborators under appropriate individual agreements.
_x__ Publication and/or public presentations.
When will the data be shared? 
_x__ Before publication.
_x__ At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.3
RESPONSE CRITERIA
For the purposes of this study, patients should be re-evaluated for response every 2 cycles (every 
3 cycles for patients on mCRPC cohort as per section 6.3.5). In addition to a baseline scan, 
confirmatory scans should also be obtained 4 weeks (8 weeks for mCRPC) following initial 
documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (61). Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria.
6.3.1
Definitions
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with EP0057.
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.)
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
6.3.2
Disease Parameters
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as: 
•
By chest x-ray: >20 mm; 
•
By CT scan: 
o
Scan slice thickness 5 mm or under as >10 mm with CT scan


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o
Scan slice thickness >5 mm: double the slice thickness 
•
With calipers on clinical exam: >10 mm. 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
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.
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable.
Note: Cystic 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 patient, these are preferred for selection as target lesions.
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. 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. 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 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.
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
6.3.3
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
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 is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.


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Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If 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). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible.
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
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 one 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, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 


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PSA response (in recurrent prostate cancer) have been published (62-64). 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 (65).
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
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: 
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
b. 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.
c.
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.
 Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
6.3.4
Response Criteria
6.3.4.1
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 the diameters of target lesions, 
taking as reference the baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the 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 


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absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study.
6.3.4.2
Evaluation of Non-Target Lesions
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).
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator).
6.3.4.3
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-
CR/Non-PD
No
PR
CR
Not 
evaluated
No
PR
PR
Non-
CR/Non-
PD/not 
evaluated
No
PR
>4 wks. Confirmation**


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SD
Non-
CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks. from baseline**
PD
Any
Yes or 
No
PD
Any
PD***
Yes or 
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**
Only for non-randomized trials with response as primary endpoint.
***
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression.
Note:
Patients 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 the objective progression even after 
discontinuation of treatment.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
6.3.5
Response Criteria for mCRPC Cohort
Changes in PSA and measurable lesions will be analyzed for efficacy according to the Prostate 
Cancer Clinical Trials Working Group 2 recommendations (63). PSA alone will not be utilized 
as a means to take a patient off-treatment. 
Patients will be assessed primarily by CT scan of the chest, abdomen and pelvis and by 
technetium 99 bone scan at baseline and every 12 weeks (66). Response and progression will be 
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
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evaluated in this study using the new international criteria proposed by the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) (67) and Prostate Cancer 
Clinical Trials Working Group criteria (PCWG2) (66). Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria.
Metastatic Bone Lesions
Disease progression is considered if a minimum of two new lesions is observed on bone scan. 
New lesions seen by the end of cycle 3 or before cycle 4 (after the first staging bone scan) may 
represent disease that was not detected on the pre-study scan, and a confirmatory scan will be 
required at the next scheduled staging bone scan. If confirmed, progression should be dated by 
the initial time when the lesions are first detected. If new lesions are seen after cycle 3 but no 
additional lesions are seen on confirmatory scans, the scans from after cycle 3 would serve as the 
baseline scan to evaluate for disease progression (66).
6.3.6
Duration of Response
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
6.3.7
Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first.
6.3.8
Response Review
Tumor measurements will be performed in consultation with the Center for Cancer Research 
Radiology and Imaging Sciences image processing service. 
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 


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7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
Note: Only IND Safety Reports that meet the definition of an unanticipated problem or present 
new information that might affect the willingness of participants to enroll or remain on the study 
will need to be reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease. 
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
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8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2)).
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
•
Death (except if from progressive disease, see 8.4)
•
A life-threatening adverse event (see 8.1.3)
•
Inpatient hospitalization or prolongation of existing hospitalization
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.
•
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
•
A congenital anomaly/birth defect.
•
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32).
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.


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8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms: related or not 
related. 
•
Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.
•
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship. AEs will be followed through resolution.
SAEs will be:
•
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.
•
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.
•
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited 
reporting requirements are found in section 8.4.
All SAE reporting must include the elements described in 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and 
instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible.


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8.4
WAIVER OF EXPEDITED REPORTING TO CCR/OSRO 
As death/hospitalization due to disease progression is part of the study objectives (DOR, OS and 
PFS), and captured as endpoints in this study, they will not be reported in expedited manner to 
the sponsor. However, if there is evidence suggesting a causal relationship between the study 
drug and the event, report the event in an expedited manner according to section 8.3.
The Sponsor might request case summaries for those events if, upon review, the Sponsor 
determines that an aggregate safety report is required (21CFR312.32(c)(1)(iv)).
8.5
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
8.5.1
Ellipses Reporting Requirements
The study team will report every SAE, regardless of suspected causality, occurring after the 
patient begins taking study drug and until 30 days after the patient has stopped study treatment to 
Ellipses within 24 hours of learning of its occurrence. The MedWatch 3500A or equivalent form 
will be used to report all SAEs. The study team will report any SAE experienced after this 30 
day period only if there is a causal relationship to the study drug. 
Recurrent episodes, complications, or progression of the initial SAE will be reported by the study 
team as follow-up to the original episode within 24 hours of follow-up information receipt. An 
SAE occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one will be reported separately as a new event. The investigator will assess 
and record the relationship of each SAE to each specific study drug (if there is more than one 
study drug).
SAEs will be reported to: 
-
Ellipses pharmacovigilance vendor, Simbec-Orion: 
pharmacovigilance@simbecorion.com (Or alternatively by fax to +1 609 514 1000 or 
Back-up SAE fax: +1 609 452 7888)
-
Ellipses contacts: Rina Patel at rina@ellipses.life Other Adverse Events of Special 
Interest
For all subjects, the following adverse events are categorized as Adverse Events of Special 
Interest (AESI) for EP0057:
•
infusion-related hypersensitivity reaction(s) of any Grade
•
any newly developed cystitis (including grade 1) in subjects without cystitis at baseline
The study team will report any occurrence of cystitis or patient hypersensitivity/allergic reactions 
a patient experiences associated with EP0057 to Ellipses (via Simbec-Orion) within 24 hours of 
learning of its occurrence using MedWatch 3500A or equivalent form. 
8.5.2
AstraZeneca Reporting Requirements
8.5.2.1
To be performed by Sponsor
The Sponsor shall report any adverse events or adverse reactions (each as defined in the 
protocol) that arise in relation to the study to (i) the relevant regulatory authorities in accordance 
with the applicable laws; and (ii) any overseeing ethics committee in accordance with its 
policies. 


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Adverse events will be collected from the time consent is given, throughout the treatment period 
and up to and including the 30 day follow-up period. After withdrawal from treatment, subjects 
will be followed-up for all existing and new AEs for 30 calendar days after the last dose of trial 
drug and/or until event resolution. All new AEs occurring during that period will be recorded (if 
SAEs, then they will be reported to the FDA and AstraZeneca). All study-related toxicities/ 
SAEs will be followed until resolution, unless in the Investigator’s opinion, the condition is 
unlikely to resolve due to the patient’s underlying disease.
The Sponsor will report to the Company per the following guidelines:
•
The Sponsor will notify the Company of all Suspected Unexpected Serious Adverse 
Reactions (SUSARs) subject to expedited reporting under the Applicable Laws at the 
same time that the reports are sent to the FDA using a medwatch 3500A form or 
equivalent.
•
The Sponsor will notify the company within 30 days of all other SAEs [non-expedited 
reports], plus any AE reports relating to topics of special interest [MDS/AML, new 
primary malignancy and pneumonitis] using a medwatch 3500A form or equivalent.
•
The Sponsor will inform the Company of any other matter relating to safety, quality or 
efficacy of the Company’s medicinal product or which might affect the conduct of the 
study or the safety of subjects as soon as possible and at least in parallel with 
correspondence to regulators, IECs/IRBs and investigators.
•
The Sponsor will provide the Company all adverse events (AEs and SAEs) on the Final 
Study Report upon completion of the Study.
•
The Sponsor will respond to any query from the Company relating to SAEs, as part of the 
Company’s pharmacovigilance processes.
The sponsor will send reports described above to:
 AEMailboxClinicalTrialTCS@astrazeneca.com. 
Tata Consultancy Services (TCS) will be responsible for processing all SAEs onto the AZ 
Patient Safety Database. Reports can also be sent via FAX to 1-302-886-4114.
Overdose 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the sponsor 
will inform appropriate AstraZeneca representatives within one day, i.e., immediately but no 
later than the end of the next business day of when he or she becomes aware of it. 
For overdoses associated with SAE, standard reporting timelines apply. For other overdoses, 
reporting should be done within 30 days.
Pregnancies
If any pregnancy occurs in the course of the study, then the Sponsor will inform appropriate 
AstraZeneca and Ellipses representatives within one day i.e., immediately but no later than the 
end of the next business day of when he or she becomes aware of it. 
All outcomes of pregnancy should be reported to AstraZeneca and Ellipses.


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8.5.2.2
To be Performed by Study Team
The PI and Research Team will be responsible for reporting the AEs that are not specifically 
listed above including:
•
Providing the Company with line listing of all adverse events reported in the study. These 
line listings will be sent when the investigator receives an e-mail from Company.
•
A summary report of other AEs and SARs will also be sent at a frequency no less than 
once a year and in a format agreed upon at Study Start-up. Instructions on sending these 
additional reports will be agreed upon at Study Start-up.
8.6
REPORTING PREGNANCY 
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. 
Forms and instructions can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 
8.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy become known,
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (8.1.2) should be reported as SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.6.2
Paternal exposure
Patients should refrain from fathering a child or donating sperm during the study and for (3 
months) after the last dose of EP0057 or olaparib.
Pregnancy of the patient’s partner is not considered to be an AE. The outcome of all pregnancies 
occurring from the date of the first dose until (3 months) after the last dose should, if possible, be 
followed up and documented. Pregnant partners may be offered the opportunity to participate in 
an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry study) to 
provide data about the outcome of the pregnancy for safety reporting purposes.
8.7
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.


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8.8
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual 
of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the 
Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online 
application. The entries into the PDTS online application should be timely, complete, and 
maintained per CCR PDTS user requirements. 
In addition, any deviation to the protocol should be documented in the participant’s source 
records and reported to the reviewing IRB per their guidelines. OSRO required protocol 
deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 
Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol 
deviations.
9
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure:
•
that the rights of the participants are protected; 
•
that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and, 
•
the quality and integrity of study data and data collection methods are maintained. 
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) and Regulatory Oversight Support (SROS) Services contractor. Clinical site 
monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) Good Clinical 
Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable regulatory 
requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study 
site(s). Monitoring visit reports will describe visit activities, observations, and associated action 
items or follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring 


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reports will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, 
coordinating center (if applicable), and the Sponsor regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR 
Protocol Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as 
applicable per institutional and IRB guidance. 
10 STATISTICAL CONSIDERATIONS 
•
Phase I: To determine the MTD/ recommended Phase 2 dose (RP2D) of EP0057 in 
combination with olaparib in patients with refractory cancers
•
Phase II: To determine the antitumor activity of olaparib plus EP0057 with respect to 
progression free survival at 16 weeks in SCLC patients with resistant or sensitive relapse
•
Expansion: To determine overall response rate of EP0057 plus olaparib in patients with 
mCRPC and urothelial carcinoma
10.1 PHASE I AND PHASE II
For the phase I portion of the trial, a standard 3+3 design will be used, to determine the 
RP2D/MTD of EP0057 in combination with olaparib. The theoretical maximum number of 
subjects required to determine the MTD in the phase I portion of the study is 30 subjects (6 per 
dose level), although it is expected that as few as 15 subjects in 4 dose levels would be required 
to reach an MTD.
Sensitivity to first-line chemotherapy has been considered as the main driver of second-line 
therapy outcome in SCLC. For this reason, relapsed SCLC has been traditionally classified into 
sensitive and resistant disease according to the type of response to first-line therapy and to 
treatment-free interval (treatment-free interval longer or shorter than 60–90 days) (68). Although 
this definition was derived many years ago and based on a small patient series (69), first-line 
chemotherapy sensitivity has since been confirmed to be a prognostic factor to predict response 
to second line and further therapy in meta-analyses (3) and randomized studies (70, 71). 
Published results suggest that the median PFS for single agent therapy with topotecan (currently 
the only approved second line therapy) for previously treated patients which included a 
combination of sensitive and resistant /refractory SCLC patients was approximately 3 months 
(median 3.0-4.3 months for sensitive and 1.5-2.6 months for refractory; (68, 70-73) (refer to 
Table 15). 
A recent randomized study of PARP inhibitor plus chemotherapy in relapsed SCLC patients 
(both platinum-sensitive and resistant patients were included) found no significant difference in 
4-month PFS between temozolomide/veliparib (20 of 55; 36%) and temozolomide /placebo (13 
of 49; 27%; P = .19) (74). Median PFS was 3.8 months and 2.0 months in the temozolomide 
/veliparib and temozolomide /placebo arms, respectively (log-rank P = .39; hazard ratio, 0.84; 
95% CI, 0.56 to 1.25). 
Patients with both sensitive and resistant SCLC will be enrolled in the phase II study and 
analyzed together. The phase II trial will be conducted using an optimal two-stage design in 
order to rule out an unacceptably low success rate of 25% (p0=0.25) in favor of an improved 
success rate of 45% (p1=0.45). With alpha=0.10 (probability of accepting a poor treatment=0.10) 


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and beta = 0.20 (probability of rejecting a good treatment=0.20), this first stage will enroll 15 
evaluable patients, and if 0 to 4 of the 15 have a success (that is, 0 to 4 make it to 16 weeks 
without progression), then no further patients will be accrued. If 5 or more of the first 15 patients 
have success, then accrual would continue until a total of 27 evaluable resistant/refractory 
patients have been enrolled. As it may take up to 4 months to determine if a patient has 
experienced a success at 16 weeks, a temporary pause in the accrual may be necessary to ensure 
that enrollment to the second stage is warranted. If there are 5 to 9 patients with a success out of 
27 patients, this would be an uninterestingly low success rate. If there were 10 or more of 27 
(37%) who experienced a success, this would be sufficiently interesting to warrant further study 
in later trials. Under the null hypothesis (25% success rate), the probability of early termination 
is 68.7%. 
Patients who receive at least one dose of the study drug will be evaluable for safety. Patients who 
complete at least one cycle of treatment and have a follow up imaging study will be evaluable for 
efficacy. The maximum number of patients on the phase I portion of the trial is 30 and phase II 
SCLC may accrue up to 27 evaluable patients. Thus, the maximum number of evaluable patients 
which may enroll on the phase I and II cohorts is 57. In order to allow for a small number of in-
evaluable patients, the accrual ceiling will be set at 60 for these cohorts. It is anticipated that 
approximately 1 to 2 patients per month may enroll onto these cohorts.
Table 15. Selected randomized studies of cytotoxic agents for SCLC
No. 
Patients 
Treatment
s
Primary 
endpoint
Median 
PFS- 
topotecan
Median 
OS- 
topotecan
Reference
1
Sensitive 
SCLC
Topotecan 
(N=107) 
vs. CAV 
(N=104) 
ORR
3.3 months 
(sensitive)
6.3 months 
(sensitive)
(68)
2
Refractory or 
sensitive 
SCLC; 2nd 
line
Topotecan 
(N=213) 
vs. 
amrubicin 
(N=424)
OS
4.3 months 
(sensitive)
2.6 months
(refractory) 
9.9 months 
(sensitive)
5.7 months 
(refractory)
(71)
3
Sensitive 
SCLC 
2:1
Topotecan 
(N=26) vs. 
amrubicin 
(N=50)
ORR
3.3 months
(sensitive)
7.6 months 
(sensitive)
(73)
4
Refractory or 
sensitive 
SCLC
Topotecan 
(N=30) vs. 
amrubicin 
(N=29)
ORR
3.0 months 
(sensitive)
1.5 months
(refractory) 
NA 
(70)
5
Sensitive 
SCLC; 2nd 
line
PO 
(N=153) 
vs. IV 
ORR
3.7 months 
(sensitive)
8.7 months 
(sensitive)
(72)


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No. 
Patients 
Treatment
s
Primary 
endpoint
Median 
PFS- 
topotecan
Median 
OS- 
topotecan
Reference
(N=151) 
topotecan 
10.2 PHASE II EXPANSION COHORTS
10.2.1
Expansion Cohort (Urothelial Carcinoma)
The primary objective of this cohort is to determine the clinical response rate to EP0057 and 
olaparib in patients with bladder cancer. Data from a single trial of 310 patients with metastatic 
bladder cancer receiving atezolizumb alone demonstrated an ORR of 15%. To establish at least 
slightly improved efficacy of this treatment combination compared to single agent atezolizumab, 
the primary objective would be to determine if using the proposed agents would rule out a 10% 
response rate and result in a response rate consistent with 25%. As such, this cohort of the trial 
will be conducted using a Simon optimal two-stage phase II trial design (75) to rule out an 
unacceptably low PR+CR rate of 10% (p0=0.10) in favor of an improved response rate of 25% 
(p1=0.25). With alpha=0.10 (probability of accepting a poor treatment=0.15) and beta = 0.20 
(probability of rejecting a good treatment=0.20), the first stage will enroll 13 evaluable patients, 
and if 0 to 1 of the 13 have a clinical response, then no further patients will be accrued in this 
cohort. If 2 or more of the first 13 patients have a response, then accrual would continue until a 
total of 34 evaluable patients have been treated. As it may take up to several months to determine 
if a patient has experienced a response, a temporary pause in the accrual may be necessary to 
ensure that enrollment to the second stage is warranted. If there are 2 to 5 patients with a 
response out of 34 patients, this would be an uninterestingly low response rate. If there were 6 or 
more of 34 (17.6%) who experienced a response, this would be sufficiently interesting to warrant 
further study in later trials. Under the null hypothesis (10% response rate), the probability of 
early termination is 62.1%.
It is expected that approximately 1 to 2 patients per month may enroll onto this cohort in the 
trial. Thus, it is expected that 2 to 3 years may be required to enroll up to 34 evaluable patients. 
To allow for a small number of inevaluable patients, the accrual ceiling for this cohort will be set 
at 36 patients. Analysis of correlative studies will be exploratory.
10.2.2
Expansion Cohort (mCRPC)
The primary objective of this exploratory cohort is to determine the clinical response rate to 
EP0057 and olaparib in patients with prostate cancer who are identified as having one of several 
possible genetic mutations.
In a published study of 16 patients with prostate cancer who have one of a set of specified 
mutations, 14 (87.5%) had experienced a clinical response when treated with olaparib alone. 
While it is unlikely that this could be improved upon, it would be of interest to explore if a 
similarly high response rate could be seen in patients treated at the NCI with EP0057 and 
olaparib.
Patients with prostate cancer will be enrolled onto this cohort and biopsied, and the patients who 
are found to have any of a set of defined genetic mutations (in the DNA damage repair 
pathways), will receive EP0057 and olaparib and be evaluated for clinical response by PSA and 
RECIST criteria. It is anticipated that 25-30% of patients will be found to possess one of the 


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mutations of interest. To obtain at least 5 patients who could be evaluated for response, 25 total 
patients will undergo procedures necessary to determine if they possess the appropriate 
mutations. If the true probability of a mutation were 30%, then with 25 patients, there is a 91.0% 
probability of identifying 5 or more with mutations, including a 32.3% probability of identifying 
9 or more patients with mutations. If the true probability of a mutation were 25%, with 25 
patients, there is a 78.6% probability of identifying 5 or more with mutations, and a 14.9% 
probability of obtaining 9 or more with mutations. Thus, by enrolling 25 patients, there should be 
between 79% and 91% probability of identifying 5 or more patients with mutations, and between 
15% and 32% probability of potentially identifying 9 or more with mutations. 
For however many patients are identified with mutations, expected to be between 5 and 9 out of 
25, these patients will receive treatment with EP0057 and olaparib, and will have their responses 
evaluated using PSA and RECIST criteria. The fraction with responses obtained will be reported 
along with 80% and 95% two-sided confidence intervals, and the results compared, at least 
informally, to those from the published study with similar patients treated with olaparib alone. 
While the actual number of these patients to receive EP0057 and olaparib is likely to between 5 
and 9, the trial will continue to enroll and evaluate up to the ceiling of 25 patients with prostate 
cancer, unless an early stopping rule is invoked. If among the first 5 treated patients with prostate 
cancer who have DNA damage repair pathway mutations, only 1 of 5 responds, then no further 
patients will be enrolled since the upper one-sided 90% CI bound on 1/5 = 58.4%, which would 
be below the lower one sided 90% CI bound on 14/16 from the published study (70.0%), and 
thus be inconsistent with the prior results.
The remaining patients without a mutation in their DNA damage repair pathway will also receive 
the combination of EP0057 and olaparib. It is expected that out of 25 evaluable patients enrolled 
on the trial, between 16 and 20 will not have these mutations. For these patients, it would be 
desirable to determine if their response rate would exceed 5% and be consistent with 25% or 
greater. Using that as a guideline, if there are 16 patients without the proper mutations who 
receive the combination treatment, 3 responses in 16 would be associated with a two-sided 80% 
exact confidence interval of 7.1-37.1%, and 4 responses in 16 would be associated with a two-
sided 80% exact confidence interval of 11.4 to 43.9%. With 20 patients without the proper 
mutations, 3 responses in 20 is associated with the same confidence interval of 5.6 to 30.4%, and 
4 responses in 20 would have a confidence interval of 9.0-36.1%. The values for 17 to 19 
patients have similar confidence intervals. Thus, in the expected range of 16 to 20 patients 
without mutations, a minimum of 3 responses, but preferably 4 or more, would be the lowest 
numbers of responses obtained which could be considered sufficiently interesting to allow the 
treatment to be evaluated further in these patients. As these patients are being accrued and treated 
while aiming to attain the greatest number of patients with the DNA damage repair pathway 
mutations, there will be no early stopping rule based on poor response in this group of 16 to 20 
patients.
It is expected that approximately 1 patient per month may enroll onto this cohort in the trial. 
Thus, it is expected that 2 years may be required in order to enroll up to 25 evaluable patients. To 
allow for a small number of inevaluable patients, the accrual ceiling for this cohort will be set at 
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10.3 SAMPLE SIZE DETERMINATION
With up to 30+27+34+25= 116 evaluable participants needed for the phase 1 dose escalation and 
expansion phases, as well as planning for a small number of inevaluable participants (10), we 
intend to initiate intervention in up to 126 participants.  Note:  To allow for screen failures (10), a 
total of 136 will be set for the purposes of the NIH accrual ceiling.
Overall, 1 – 2 patients per month are expected to enroll across all of the cohorts. It is expected 
that enrollment will be completed in 6 – 8 years.
11 COLLABORATIVE AGREEMENTS 
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)
11.1.1
BlueLink (CRADA #03049)
The investigational study agent formerly named CRLX101 was being provided by the company, 
BlueLink under a Collaborative Agreement [Cooperative Research and Development Agreement 
(CRADA)].
As of March 2020, the CRADA has been amended to switch the manufacturer from BlueLink to 
Ellipses and drug name from CRLX101 to EP0057. 
11.1.2
Astra Zeneca (CRADA #02299)
The investigational study agent, olaparib is provided by the company, Astra Zeneca under a 
Collaborative Agreement [Cooperative Research and Development Agreement (CRADA)].
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
As previously described, the subjects for this study will include all subjects who meet the 
eligibility criteria outlined in section 2.1. No gender, racial, or ethnic groups will be excluded 
from participation in this trial. 
The effects of EP0057 and olaparib on the developing human fetus are unknown.  For this 
reason, participants will be required to use contraception
12.2 PARTICIPATION OF CHILDREN
Because no dosing adverse event data are currently available on the use of EP0057 in 
combination with olaparib in subjects <18 years of age, children are excluded from this study.
12.3 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
12.3.1
Risks 
12.3.1.1 Study drug risks
The risks associated with the specific study agents are described in sections 14.1.9 and 14.2.9. 
Subjects will be adequately monitored for the occurrence of any possible side effects. 


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12.3.1.2 Biopsy risks
The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize 
pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site. CT 
guidance may be used in obtaining biopsies.
12.3.1.3 Conscious sedation risks
There is a possibility that conscious sedation may be used for the procedure. The common side 
effects of conscious sedation include drowsiness, delayed reflexes, hypotension, headache, and 
nausea. These are generally mild and last no more than a few hours.
12.3.1.4 Radiation risks
Subjects will be exposed to radiation from 3 CT guided biopsies and up to 9 CTs. The amount of 
radiation exposure is equal to approximately up to 12.3 rem. 
Note: As accrual to cohort 4 (mCRPC) ended with amendment version 7/27/2021, CT c/a/p and 
bone scan every 3 weeks are not included in the calculated radiation dose above.
12.3.1.5 Risks from CT scans
There is a chance of developing an allergic reaction from the contrast material, which may cause 
symptoms ranging from mild itching or a rash to severe difficulty breathing, shock or rarely, 
death. The contrast material may also cause kidney problems. Patients may feel discomfort when 
the contrast material is injected. 
12.3.1.6 Risks related to blood sampling
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. Up 
to 225 mL of blood may be drawn at any given visit, with a maximum of 529 mL in an 8-week 
period.
12.3.1.7 Risk related to hair collection
The only risk associate with hair collection is pain. 
12.3.2
Benefits
The benefits include a possible decrease in the size of the tumor and the scientific knowledge 
that could be acquired through this trial.
12.4 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant for review prior to consenting. A designated study investigator will carefully explain 
the procedures and tests involved in this study, and the associated risks, discomforts and benefits. 
In order to minimize potential coercion, as much time as is needed to review the document will 
be given, including an opportunity to discuss it with friends, family members and/or other 
advisors, and to ask questions of any designated study investigator. A signed informed consent 
document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant. Whether in person or remote, the privacy of the subject will be 


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maintained. Consenting investigators (and participant, when in person) will be located in a 
private area (e.g., clinic consult room). When consent is conducted remotely, the participant will 
be informed of the private nature of the discussion and will be encouraged to relocate to a more 
private setting if needed. 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic signature) on the electronic document. When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures:
•
Adobe platform (which is not 21 CFR Part 11 compliant); or, 
•
iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location, but is not required. 
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) found https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
12.4.1
Request for Waiver of Consent for Screening Activities
Prior to the participant signing the consent for this study pre-screening activities listed in Section 
2.3.1 may be performed. 
We request a waiver of consent for these activities as they involve only minimal risk to the 
participants.  A waiver will not adversely affect the rights and welfare of the participants given 
that the activities are only intended to determine suitability for screening for participation in 
research protocols.  These activities could not practicably be carried out without the wavier as 
central recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities 
for multiple studies and obtaining consent for each one is beyond their resources.  The 
participants will be provided with additional pertinent information after participation as they will 
be informed whether or not they are eligible to sign a consent for additional screening.
13  REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 


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will provide the reason(s) for the termination or suspension. Study participants will be contacted, 
as applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping  
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe the site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council for 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The study leadership in conjunction with the National Cancer Institute has 
established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest.
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 


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held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by the clinical site(s) and by NCI CCR research staff will be secured and password 
protected. At the end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
14 PHARMACEUTICAL INFORMATION 
14.1 EP0057 (IND#130102)
14.1.1
Description 
EP0057 is a polymer drug conjugate composed of 20 (S)-camptothecin conjugated to a 
biocompatible polymer. The compound self assembles into soluble nanoparticles composed of 
several molecules when dissolved in aqueous solution. Camptothecin (CPT) is an antineoplastic 
that inhibits topoisomerase I resulting in cell death during the S phase of the cell cycle. EP0057 
nanoparticles are believed to be taken up by tumor cells followed by release of the active 
pharmaceutical ingredient 20(S)-camptothecin.
14.1.2
Supplier/How Supplied
The EP0057 is provided by the company, Ellipses, the manufacturer of the drug under a 
Collaborative Agreement [Cooperative Research and Development Agreement (CRADA)].


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EP0057 will be provided at no cost to the study patient. It is supplied as a lyophilized cakein 30 
mL single-use vial containing 35 mg of CPT equivalents (approximately 350 mg of polymer 
drug conjugate). 
14.1.3
Handling and Dispensing 
EP0057 is a sterile injectable and must be handled under appropriate controls, conditions, and 
aseptic techniques to maintain product sterility. EP0057, a cytotoxic, should be prepared in a 
class II biological safety cabinet using standard precautions for the safe handling of 
antineoplastic agents. Latex gloves are recommended. It must be dispensed only from official 
study sites by authorized personnel according to local regulations, and stored in a secure area 
according to local regulations. It is the responsibility of the Investigator to ensure that study drug 
is only dispensed to eligible study patients. 
14.1.4
Preparation
Vials of EP0057 should be removed from the refrigerator and warmed to room temperature for 
approximately one hour prior to preparation. Concentrated EP0057 solution is prepared by 
adding 14 mL of SWFI to each 35 mg vial. The required volume of SWFI is to be aseptically 
withdrawn into a sterile calibrated syringe and the syringe needle inserted through the vial 
septum. The SWFI should be slowly added along the inside of the vial wall and not directly onto 
the lyophilized product cake to minimize foaming. The product is dissolved by gentle swirling 
(do not shake) until a clear homogenous solution is achieved. The majority of the product cake 
will dissolve quickly, however complete dissolution to a clear, homogenous solution will take 
longer and may require up to 30 minutes. The EP0057 concentrated solution should be inspected 
visually for particulate matter prior to further preparation. Visually inspect for completion of 
reconstitution every 2‐3 minutes. Reconstitution is complete when (i) foam head has dissipated 
down to a thin bubble ring along inner wall of vial, (ii) solids in solution and foam head are no 
longer visible, and (iii) translucent polymer “vapors” are no longer visible in solution and the 
solution is clear and uniform in appearance. Complete reconstitution of the vial may take up to 
30 minutes.
Each milliliter of concentrated solution contains 2.5 mg of camptothecin equivalents. 
Concentrated EP0057 solution is diluted to the recommended dose with 5% dextrose in water for 
injection (D5W) to a total volume of 500 mL. After determining the amount of EP0057 
concentrated solution required for dosing, an equivalent volume is aseptically withdrawn from a 
500 mL infusion bag or bottle of D5W with a calibrated syringe. The measured volume of 
concentrated EP0057 solution is then withdrawn with a calibrated syringe and injected into the 
prepared 500 mL D5W infusion bag or bottle. The solution is thoroughly mixed by gentle 
manual rotation.
14.1.5
Storage and Stability
EP0057 vials should be stored at refrigerated conditions (2° - 8°C) and should only be accessible 
to authorized individuals. EP0057 is stable for at least 3 years when stored at refrigerated 
conditions (2° - 8°C). The reconstituted solution is stable for 24 hours when stored at room 
temperature. Any unused product solution from the reconstituted vials should be destroyed per 
the site’s standard operating procedures.
Formulated EP0057 (i.e., IV bag) should be used within 6 hours of reconstituting the drug 
product vials. 


Abbreviated Title: EP0057 in Advanced Cancers
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14.1.6
Dosage and Administration
See Sections 3.2 and 3.3 for the dose levels and administration of EP0057 to be evaluated in this 
study.
See Section 3.3.4 for management of any EP0057 infusion related/hypersensitivity reactions. 
The second and subsequent dose of EP0057 may be delayed if related AEs have not resolved to 
grade 1 or better. If a dose of EP0057 is delayed, then the subsequent dose should be 
administered 2 weeks later to avoid significant carry-over of unconjugated plasma CPT from one 
dose to the next (see Section 3.3). However, the maximum delay for AEs to resolve is 21 days 
beyond which the patient will be taken off treatment. 
14.1.7
Premedication and Hydration
The premedication prior to EP0057 treatment and pre and post hydration and additional 
prevention measurements to prevent hypersensitivity/infusion reaction have been described in 
Section 3.2.1.1.
14.1.8
Return and Retention of EP0057
Any used study drug vials, or partially used vials, remaining after trial is complete will be 
destroyed per institution drug destruction policy. Unused study drug vials may be destroyed in 
the same manner or returned if requested to Ellipses. 
14.1.9
Toxicity
Possible toxicities from EP0057 include: neutropenia, thrombocytopenia, anemia, nausea, vomiting, 
diarrhea, mucositis, anorexia, and cystitis. Commonly reported toxicities in clinical trials with 
EP0057 are anemia, fatigue, cystitis, nausea, hematuria, neutropenia, diarrhea, vomiting, dysuria, 
constipation, thrombocytopenia, decreased appetite, and infusion-related reaction.
For additional details, refer to section 1.2 and investigator brochure.
14.2 OLAPARIB (AZD2281; OLAPARIB; IND#130102) 
(Please refer to the Investigator’s Brochure and the package insert for further details)
14.2.1
Source 
The olaparib is provided by the company, Astra Zeneca under a Collaborative Agreement 
[Cooperative Research and Development Agreement (CRADA)].
Olaparib (AstraZeneca Pharmaceuticals LP) has been commercially Food and Drug 
Administration approved as monotherapy for the treatment of patients with deleterious or 
suspected deleterious germline BRCA mutated (gBRCAm) (as detected by an FDA-approved 
test) advanced ovarian cancer who have been treated with three or more prior lines of 
chemotherapy. 
As of 20 March 2015, >3800 patients with ovarian, breast, pancreatic, gastric and a variety of 
other solid tumors are estimated to have received treatment with olaparib in clinical studies as 
either monotherapy or in combination with other chemotherapy/anti-cancer agents. Most new 
clinical studies are investigating the tablet formulation which delivers the therapeutic dose of 
olaparib in fewer dose units than the capsule.


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118
14.2.2
Pre-clinical experience
The pre-clinical experience is fully described in the current version of the olaparib Investigator’s 
Brochure (IB). 
14.2.3
Toxicology and safety pharmacology summary
Olaparib has been tested in a standard range of safety pharmacology studies e.g. dog 
cardiovascular and respiratory function tests, and the rat Irwin test. There were no noticeable 
effects on the cardiovascular or respiratory parameters in the anaesthetized dog or any 
behavioral, autonomic or motor effects in the rat at the doses studied.
The toxicology studies indicate that the target organ of toxicity is the bone marrow. 
Further information can be found in the current version of the olaparib Investigator’s Brochure
14.2.4
Approved indications and clinical experience
Clinical experience with olaparib is fully described in the current version of the olaparib 
Investigator’s Brochure.
AstraZeneca is planning to voluntarily withdraw olaparib for the treatment of adult patients with 
deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian 
cancer who have been treated with three or more prior lines of chemotherapy (Dear ESR Sponsor 
Letter dated 8/10/22). This is currently an approved indication in the US. 
A recent subgroup analysis indicated a potential detrimental effect on overall survival (OS) for 
olaparib as a line of treatment compared to the chemotherapy control arm in patients who had 
received three or more prior lines of chemotherapy in the randomized Phase III study, SOLO3 
(D0816C00010; NCT02282020). SOLO3 met its primary endpoint of ORR and the key 
secondary endpoint of progression-free survival (PFS). Safety data, other than OS, reported for 
olaparib in the SOLO3 study were consistent with that reported in other clinical trials with 
olaparib, and no new safety signals were identified.
14.2.5
Indications and Usage
Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy in 
patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an 
FDA-approved test) advanced ovarian cancer who have been treated with three or more prior 
lines of chemotherapy.
The indication is approved under accelerated approval based on objective response rate and 
duration of response. Continued approval for this indication may be contingent upon verification 
and description of clinical benefit in confirmatory trials. 
14.2.6
Dosage and Administration
Please refer to section 3.2.2 for administration instructions. Dose will be according to assigned 
dose level (see section 3.1).
14.2.7
Tablet Dosage Forms and Strengths
Olaparib is presented for oral administration as a green, film-coated tablet containing 25 mg, 100 
mg, 150 mg or 200 mg of drug substance. 


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14.2.8
Warnings and Precautions
• Myelodysplastic syndrome/Acute Myeloid Leukemia: (MDS/AML) occurred in patients 
exposed to olaparib, and some cases were fatal. Monitor patients for hematological toxicity at 
baseline and monthly thereafter. Discontinue if MDS/AML is confirmed. 
• Pneumonitis: occurred in patients exposed to olaparib, and some cases were fatal. Interrupt 
treatment if pneumonitis is suspected. Discontinue if active pneumonitis is confirmed. 
• Embryo-Fetal toxicity: olaparib can cause fetal harm. Advise individuals of reproductive 
potential of the potential risk to a fetus and to avoid pregnancy. 
14.2.9
Adverse Reactions 
Table 16. Adverse Drug Reactions Reported in Clinical Trials
MedDRA SOC
MedDRA term
CIOMS descriptor/ 
overall frequency 
(All CTCAE grades)
Frequency of CTCAE 
Grade 3 and above
Neoplasms benign, 
malignant and 
unspecified (including 
cysts and polyps)
Myelodysplastic 
syndrome/acute myeloid 
leukaemia
Uncommon
Uncommon
Anaemiaa
Very common
Very common
Neutropeniaa
Very common
Common
Leukopeniaa
Very common
Common
Thrombocytopeniaa
Common
Common
Blood and lymphatic 
system disorders
Lymphopeniaa
Common
Common
Hypersensitivitya
Uncommon
Rare
Immune system 
disorders
Angioedemab
Uncommon
-
Metabolism and 
nutrition disorders
Decreased appetite
Very common
Uncommon
Dizziness
Very common
Uncommon
Headache
Very common
Uncommon
Nervous system 
disorders
Dysgeusiaa
Very common
-
Cougha
Very common
Uncommon
Respiratory, thoracic 
and mediastinal 
disorders
Dyspnoeaa
Very common
Common
Vomiting
Very common
Common
Diarrhoea
Very common
Uncommon
Nausea
Very common
Common
Dyspepsia
Very common
Rare
Stomatitisa
Common
Uncommon
Gastrointestinal 
disorders
Upper abdominal pain
Common
Rare
Rasha
Common
Uncommon
Dermatitisa
Uncommon
Rare
Skin and 
subcutaneous tissue 
disorders
Erythema nodosumb
Rare
-


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120
General disorders
Fatigue (including 
asthenia)
Very common
Common
Blood creatinine 
increased
Common
Rare
Investigations
Mean cell volume 
increased
Uncommon
-
Vascular disorders
Venous 
thromboembolisma
Common
Common
a
Anaemia includes preferred terms (PTs) of anaemia, anaemia macrocytic, erythropenia, haematocrit 
decreased haemoglobin decreased, normocytic anaemia and red blood cell count decreased; Cough includes 
PTs of cough and productive cough; Dermatitis includes PTs of dermatitis and dermatitis allergic; 
Dysgeusia includes PTs of dygeusia and taste disorder; Dyspnoea includes PTs of dyspnoea and dyspnoea 
exertional; Hypersensitivity includes PTs of drug hypersensitivity and hypersensitivity; Leukopenia 
includes PTs of leukopenia and white blood cell count decreased; Lymphopenia includes PTs of 
lymphocyte count decreased and lymphopenia; Neutropenia includes PTs of febrile neutropenia, 
neutropenia, neutropenic infection, neutropenic sepsis, and neutrophil count decreased; Rash includes PTs 
of exfoliative rash, generalized erythema, rash, rash erythematous, rash macular, rash maculo-papular, rash 
papular and rash pruritic; Stomatitis includes PTs of aphthous ulcer, mouth ulceration and stomatitis; 
Thrombocytopenia includes PTs of platelet count decreased, and thrombocytopenia; Venous 
thromboembolism includes PTs of deep vein thrombosis, embolism, pulmonary embolism, thrombosis, 
vena cava thrombosis and venous thrombosis.
b
Observed in the post-marketing setting.
CIOMS = Council for International Organizations of Medical Sciences; CTCAE = Common Terminology 
Criteria for Adverse Events; MedDRA = Medical Dictionary for Regulatory Activities; PT = Preferred term; 
SOC = System organ class.
MedDRA version 24.0.
Table 17. Serious Adverse Reactions for Olaparib Considered Expected for Safety Reporting 
Safety Reporting Purposes 
Number of patients exposed 
(N) = 4098
MedDRAa SOC
Preferred Term
CIOMS frequency indicator
Acute myeloid leukaemia
Uncommon
Neoplasms benign, malignant and 
unspecified (including cysts and 
polyps)
Myelodysplastic syndrome
Uncommon
Anaemia
Common
Anaemia macrocytic
Rare
Febrile neutropenia
Uncommon
Leukopenia
Rare
Neutropenia
Uncommon
Blood and lymphatic system disorders
Thrombocytopenia
Uncommon
Diarrhoea
Rare
Nausea
Uncommon
Gastrointestinal disorders
Vomiting
Uncommon
General disorders
Fatigue
Rare


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121
Asthenia
Rare
Blood creatinine increased
Rare
Haematocrit decreased
Rare
Haemoglobin decreased
Uncommon
Lymphocyte count decreased
Rare
Neutrophil count decreased
Uncommon
Platelet count decreased
Uncommon
Red blood cell count decreased
Rare
Investigations
White blood cell count decreased
Uncommon
Metabolism and nutrition disorders
Decreased appetite
Rare
Nervous system disorders
Dizziness
Rare
Cough
Rare
Respiratory, thoracic and mediastinal 
disorders
Dyspnoea
Uncommon
Embolism
Uncommon
Vascular disorders
Pulmonary embolism
Uncommon
a
MedDRA version 24.0.
CIOMS = Council for International Organizations of Medical Sciences; DCO = Data cut-off;
MedDRA = Medical Dictionary for Regulatory Activities; PT = Preferred term; SAE = Serious adverse event.
For additional information, refer to investigator brochure.
14.2.10 Drug Interactions
• CYP3A Inhibitors: Avoid concomitant use of strong and moderate CYP3A inhibitors. If the 
inhibitor cannot be avoided, reduce the dose.
• CYP3A Inducers: Avoid concomitant use of strong and moderate CYP3A inducers. If a 
moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy. 


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16 APPENDICES
16.1
 APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory. 
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).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
2
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, 
hospitalization indicated. Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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16.2 APPENDIX B : LIST OF DRUGS THAT MAY HAVE POTENTIAL CYP3A4 INTERACTIONS
16.2.1
CYP3A4 Substrates
Albuterol 
Alfentanil 
Alprazolam 
Amiodarone 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
BortezomibBosentan 
Bromazepam 
Bromocriptine 
Budesonide 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazepine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cilostazol 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Dasatinib 
Delavirdine 
Diazepam 
Dihydroergotamine 
Diltiazem 
Disopyramide 
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., 
synthetic 
Estrogens, conj., equine 
Estrogens, conj., 
esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestane 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fluticasone 
Fosamprenavir 
Gefitinib 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine 
Itraconazole 
Ketamine 
Ketoconazole 
Lansoprazole 
Letrozole 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Pipotiazine 
Primaquine 
Progesterone 
Quetiapine 
Quinidine 
Rabeprazole 
Ranolazine 
Repaglinide 
Rifabutin 
Ritonavir 
Salmeterol 
Saquinavir 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Spiramycin 
Sufentanil 
Sunitinib 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tipranavir 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamide 
Zopiclone 


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16.2.2
CYP3A4 Inhibitors
In Vivo Inhibitors of CYP3A Probes
Inhibitor
Therapeutic Class
Inhibitor dosing (oral)
Object1 
(oral, unless 
otherwise 
specified)
AUCratio PMID or NDA # Published
Potent CYP3A Inhibitors (yielding substrate AUCr > 5)
VIEKIRA PAK2
Antivirals
See note2
tacrolimus2
55.76
25708713
2015 May
indinavir /RIT
Protease Inhibitors
800/100 mg BID (1 day)
alfentanil
36.5
19225389
2009 Mar
tipranavir/RIT
Protease Inhibitors
500/200 mg BID (2 days)
midazolam
26.91
20147896
2010 Jun
ritonavir
Protease Inhibitors
3 doses of 100 mg over 24 h
midazolam
26.41
20002087
2009 Dec
cobicistat (GS-9350) None
200 mg QD (14 days)
midazolam
19.03
20043009
2010 Mar
indinavir
Protease Inhibitors
800 mg TID (7 days)
vardenafil
16.25
NDA # 021400 2003 Aug
ketoconazole
Antifungals
400 mg QD (4 days)
midazolam
15.9
8181191
1994 May
troleandomycin
Antibiotics
500 mg single dose
midazolam
14.8
15536460
2004 Dec
telaprevir
Antivirals
750 mg TID (16 days)
midazolam
13.5
22162542
2012 Oct
danoprevir / RIT
Antivirals
200/100 mg QD (14 days)
midazolam
13.42
23872824
2013 Nov
elvitegravir / RIT
Treatments of AIDS
150/100 mg QD (10 days)
midazolam
12.8
NDA # 203100 2012
saquinavir / RIT
Protease Inhibitors
1000/100 mg BID (14 days)
midazolam
12.48
19792991
2009 Oct
lopinavir / RIT
Protease Inhibitors
400/100 mg BID (2 days)
alfentanil
11.47
24067429
2013 Dec
itraconazole
Antifungals
200 mg QD (4 days)
midazolam
10.8
8181191
1994 May
voriconazole
Antifungals
200 mg BID (9 days)
midazolam
9.63
21937987
2011 Nov
mibefradil
Calcium Channel Blockers 100 mg single dose
midazolam
8.86
14517191
2003 Oct


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Inhibitor
Therapeutic Class
Inhibitor dosing (oral)
Object1 
(oral, unless 
otherwise 
specified)
AUCratio PMID or NDA # Published
LCL161
Cancer Treatments
600 mg single dose
midazolam
8.8
23585187
2013 Jun
clarithromycin
Antibiotics
500 mg BID (7 days)
midazolam
8.39
16432272
2006 Feb
posaconazole
Antifungals
400 mg BID (7 days)
midazolam
6.23
19302901
2009 Feb
telithromycin
Antibiotics
800 mg QD (6 days)
midazolam
6.2
NDA# 021144 2004
grapefruit juice DS3 Food Products
240 mL TID (2 days) and 90 min, 
60min, 30 min prior to midazolam
midazolam
5.95
12953340
2003 Aug
conivaptan
Diuretics
40 mg BID (5 days)
midazolam
5.76
NDA # 021697 2005
nefazodone
Antidepressants
100-200 mg BID (12 days)
midazolam
5.44
14551182
2003 Nov
nelfinavir
Protease Inhibitors
1250 mg BID (14 days)
midazolam
5.29
21406602
2011 Jun
saquinavir
Protease Inhibitors
1200 mg TID (5 days)
midazolam
5.18
10430107
1999 Jul
idelalisib
Kinase Inhibitors
150 mg BID (8 days)
midazolam
5.15
NDA # 206545 2014
boceprevir
Antivirals
800 mg TID (6 days)
midazolam
5.05
NDA # 202258 2011
Moderate CYP3A Inhibitors (AUCr ≥ 2 and < 5)
erythromycin
Antibiotics
1000 mg single dose
midazolam
4.99
25139487
2014 Dec
fluconazole
Antifungals
400 mg single dose
midazolam
4.93
16172184
2005 Oct
atazanavir / RIT
Protease Inhibitors
300/100 mg BID
maraviroc
4.9
18333863
2008 Apr
darunavir
Protease Inhibitors
1200 mg BID (14 days)
saquinavir
4.9
NDA # 021976 2006
diltiazem
Calcium Channel Blockers 60 mg TID (2 days)
midazolam
4.06
21209240
2011 Nov
darunavir / RIT
Protease Inhibitors
400/100 mg BID (8 days)
sildenafil
4.0
NDA # 021976 2006
dronedarone
Antiarrhythmics
400 mg BID (14 days)
simvastatin
3.66
NDA # 022425 2009
crizotinib
Kinase Inhibitors
250 mg BID (28 days)
midazolam
3.65
NDA # 202570 2011
atazanavir
Protease Inhibitors
400 mg QD (7 days)
maraviroc
3.57
18333863
2008 Apr
aprepitant
Antiemetics
80-125 mg QD (5 days)
midazolam
3.29
12891225
2003 Aug
casopitant
Antiemetics
120 mg QD (14 days)
midazolam
3.13
20840445
2010 Oct
amprenavir
Protease Inhibitors
1200 mg BID (10 days)
rifabutin
2.93
11158747
2001 Feb


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Inhibitor
Therapeutic Class
Inhibitor dosing (oral)
Object1 
(oral, unless 
otherwise 
specified)
AUCratio PMID or NDA # Published
faldaprevir
Antivirals
240 mg BID (14 days)
midazolam IV
2.92
25449227
2015 Apr
imatinib
Antineoplastic Agents
400 mg QD (7 days)
simvastatin
2.92
14612892
2003 Nov
verapamil
Calcium Channel Blockers 80 mg TID (2 days)
midazolam
2.92
8198928
1994 Mar
netupitant
Antiemetics
300 mg single dose
midazolam
2.44
23729226
2013 Oct
nilotinib
Kinase Inhibitors
400 mg BID (12 days)
midazolam
2.4
25418605
2015 Apr
grapefruit juice
Food Products
240 mL QD (4 days)
midazolam
2.39
10546919
1999 Oct
tofisopam
Benzodiazepines
100 mg TID (9 days)
midazolam
2.36
17989974
2008 Jan
cyclosporine
Immunosuppressants
Not provided (1-5 years)
midazolam
2.21
21753749
2011 Sep
ACT-178882
Renin Inhibitors
300 mg QD (14 days)
midazolam
2.19
22849770
2013 Dec
ciprofloxacin4
Antibiotics
500 mg single dose
sildenafil
2.12
16372380
2005 Dec
schisandra 
Herbal Medications
3 capsules (= 11.25 mg 
midazolam
2.05
19552749
2009 May
isavuconazole
Antifungals
clinical dose (detail not provided)
midazolam
2.03
NDA # 207500 2015
cimetidine
H-2 Receptor Antagonists 200-400 mg QID (1.5 days)
midazolam
2.02
6152615
1984 Sep
FK1706
Central Nervous System 
60 mg QD (14 days)
midazolam
2.01
19889885
2010 Feb
Weak CYP3A Inhibitors (AUCr ≥ 1.25 and < 2)
tabimorelin
Hormone Replacement
2.86-3.21 mg QD (7 days)
midazolam
1.93
12610745
2003 Feb
ranolazine
Cardiovascular Drugs
1000 mg BID (7 days)
simvastatin
1.89
NDA # 021526 2006
amlodipine
Calcium Channel Blockers 10 mg QD (9 days)
simvastatin
1.8
23965645
2014 Apr
lomitapide
Other Antilipemics
60 mg QD (7 days)
simvastatin
1.77
24734312
2014 Mar
fosaprepitant (IV)
Antiemetics
150 mg single 30-min infusion
midazolam
1.76
21209230
2011 Dec
Seville orange juice Food Products
240 mL single dose
felodipine
1.76
11180034
2001 Jan
amiodarone
Antiarrhythmics
400 mg QD (4 days)
simvastatin 
1.76
17301736
2007 May
chlorzoxazone
Muscle Relaxants
250 mg single dose (part of a 6-drug midazolam
1.68
11736864
2001 Nov
M100240
Antihypertensive Agents
50 mg single dose
midazolam
1.66
15051745
2004 Apr
fluvoxamine
Antidepressants
50-00 mg BID (12 days)
midazolam
1.66
14551182
2003 Nov


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Inhibitor
Therapeutic Class
Inhibitor dosing (oral)
Object1 
(oral, unless 
otherwise 
specified)
AUCratio PMID or NDA # Published
ranitidine
H-2 Receptor Antagonists 150 mg BID (1.5 days)
midazolam
1.66
6135440
1983 Jun
fostamatinib5
Anti-inflammatory Drugs
100 mg BID (7 days)
simvastatin
1.64
26748647
2016 Mar
goldenseal
Herbal Medications
1,323 mg (= 24.1 mg isoquinoline 
midazolam
1.63
17495878
2008 Jan
clotrimazole
Antifungals
10 mg TID (5 days)
midazolam
1.61
20233179
2010 Feb
tacrolimus
Immunosuppressants
Not provided (1-5 years)
midazolam
1.61
21753749
2011 Sep
palbociclib
Kinase Inhibitors
125 mg QD (8 days)
midazolam
1.58
NDA # 207103 2015
cilostazol
Antiplatelets
100 mg BID (7 days)
lovastatin
1.56
10702889
1999
ticagrelor
Antiplatelets
180 mg bid (7 days)
simvastatin
1.56
NDA # 022433 2011
peppermint oil
Food Products
600 mg (= 300 uL peppermint oil) 
felodipine
1.55
12235445
2002 Sep
ivacaftor
Cystic fibrosis treatments 150 mg BID (6 days)
midazolam
1.54
NDA # 203188 2012
GSK2248761
Transcriptase Inhibitors
100 mg QD (12 days)
midazolam
1.54
22288567
2012 Aug
Guan Mai Ning
Herbal Medications
3 tablets TID (7 days)
simvastatin
1.51
25801058
2015 Sep
AZD2327
Depression Treatments
15 mg QD (7 days)
midazolam
1.49
26081137
2015 Nov
resveratrol
Food Products
500 mg QD (10 days)
carbamazepin
1.48
25624269
2015 May
roxithromycin
Antibiotics
300 mg QD (6 days)
midazolam
1.47
7995324
1994
suvorexant
Hypnotics - Sedatives
80 mg QD (14 days)
midazolam
1.47
NDA # 204569 2014
propiverine
Anticholinergics
15 mg BID (7 days)
midazolam
1.46
16183781
2005 Dec
isoniazid
Antibiotics
90 mg BID (4 days)
triazolam
1.46
6140941
1983 Dec
berberine
Herbal Medications
300 mg TID (14 days)
midazolam
1.45
21870106
2012 Feb
oral contraceptives Oral contraceptives
OC with low doses of estrogen (< 35 triazolam
1.44
6149030
1984 Nov
delavirdine
NNRTIs
400 mg TID (9 days)
indinavir
1.44
9665503
1998 Jul
daclatasvir
Antivirals
60 mg QD (7 days)
simeprevir
1.44
NDA # 205123 2013
simeprevir
Protease Inhibitors
150 mg QD (11 days)
midazolam
1.43
NDA # 205123 2013
atorvastatin
HMG CoA Reductase 
10-40 mg/day (chronic treatment)
midazolam IV
1.41
12911366
2003 Sep
tolvaptan
Vasopressin Antagonists
60 mg single dose
lovastatin
1.41
NDA # 022275 2009


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Inhibitor
Therapeutic Class
Inhibitor dosing (oral)
Object1 
(oral, unless 
otherwise 
specified)
AUCratio PMID or NDA # Published
almorexant
Hypnotics - Sedatives
200 mg QD (9 days)
midazolam
1.37
22990330
2013 Mar
GSK1292263
Other Antilipemics
300 mg BID (9 days)
simvastatin
1.36
23256625
2013 Jun
evacetrapid
CETP inhibitors
300 mg QD (15 days)
midazolam
1.35
26264702
2015 Dec
linagliptin
Dipeptidyl Peptidase 
10 mg QD (6 days)
simvastatin
1.34
20497745
2010 Jun
lacidipine
Calcium Channel Blockers 4 mg QD (8 days)
simvastatin
1.33
11259986
2001 Feb
cranberry juice
Food Products
240 mL double strength juice, 1 glass midazolam
1.33
19114462
2009 Mar
pazopanib
Kinase Inhibitors
800 mg QD (17 days)
midazolam
1.32
20881954
2010 Nov
everolimus
Immunosuppressants
10 mg QD (5 days)
midazolam
1.31
23426978
2013 Apr
blueberry juice
Food Products
two doses of 300 mL, separated by 16 
hours
buspirone
1.31
22943633
2013 Apr
AMD070
Fusion Inhibitors
200 mg BID (8 days)
midazolam
1.29
18362694
2008 Apr
alprazolam
Benzodiazepines
1 mg TID (7 days)
buspirone
1.29
8300893
1993 Nov
Tong Xin Luo
Herbal Medications
4 capsules TID (7 days)
simvastatin
1.29
25801058
2015 Sep
bicalutamide
Antiandrogens
150 mg QD (>3 months)
1.27
15509184
2004
sitaxentan
Endothelin Receptor 
100 mg QD (7 days)
1.27
20078609
2010 Jan
azithromycin
Antibiotics
500 mg QD (3 days)
1.27
8720318
1996 Feb
ginkgo
Herbal Medications
120 mg TID (28 days)
1.25
17050793
2006 Nov
teriflunomide
Other Immunomodulators 14-70 mg QD (14 days)
1.25
NDA # 202992 2012
1 To allow better comparability, DDI studies with the probe substrate midazolam were selected first.
When no study with midazolam was available, the AUCratio of another probe or sensitive substrate is presented.
2 VIEKIRA PAK = 150/100 mg paritaprevir/ritonavir + 25 mg ombitasvir + 800 mg dasabuvir for 28 days. Tacrolimus is also a substrate of 
3 240 mL GFJ double-strength administered TID for 3 days
4 Of note, co-administration of ciprofloxacin (750 mg BID for 7 days) did not affect plasma concentrations of ivacaftor, which is also a 
5 Fostamatinib also inhibits BCRP, and BCRP inhibition likely participates to the increase in exposure of simvastatin


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
135
Inhibitor
Therapeutic Class
Inhibitor dosing (oral)
Object1 
(oral, unless 
otherwise 
specified)
AUCratio PMID or NDA # Published
M and T Drug Interaction Database® - Copyright 2016
www.druginteractioninfo.org
Database Searched in April 2016
16.2.3
CYP3A4 Inducers
In Vivo CYP3A Inducers
Inducers
Therapeutic class
Object (oral, 
unless 
otherwise 
specified)
% ↓ AUC % ↑ oral CLPrecipitant Dose (oral)
PMID or NDA # Published
Potent Inducers (AUC decreased by ≥ 80% or CL increased by more than 5 fold (400%))
rifampin
Antibiotics
budesonide
99.7
36904.5
600 mg QD (7 days)
15726657
2005 Mar
mitotane
Other 
midazolam
94.5
Not Provided maximum of 3.5 g TID 
21220434
2011 Apr
avasimibe
Other Antilipemics midazolam
93.5
Not Provided 750 mg/day (7 days)
12766253
2003 Sep
phenytoin
Anticonvulsants
nisoldipine
89.5
Not Provided 200-450 mg/day (chronic 
treatment)
8917062
1996 Nov
carbamazepine
Anticonvulsants
quetiapine
86.6
643.1
200 mg TID (26 days)
16390352
2006 Jan
enzalutamide
Antiandrogens
midazolam
85.9
Not Provided 160 mg QD (85±3 days)
NDA # 203415 2012
St John's Wort xtract
Herbal Medicationsmidazolam
80.0
Not Provided 300 mg TID (14 days)
16341856
2006 Jan
rifabutin
Antibiotics
delavirdine
Not Provided
458.0
300 mg QD (14 days)
9224961
1997 Jun


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
136
Inducers
Therapeutic class
Object (oral, 
unless 
otherwise 
specified)
% ↓ AUC % ↑ oral CLPrecipitant Dose (oral)
PMID or NDA # Published
phenobarbital
Anticonvulsants verapamil
76.6
400.9
100 mg QD (21 days)
3392664
1988 Jul
Moderate Inducers (AUC decreased by 50-80% or CL increased by 2-5 fold (100-400%))
ritonavir and St. Johns 
wort
None
midazolam
77.2
Not Provided ritonavir: 300 mg BID and 
SJW: 300 mg T ID (14 days)
19924124
2010 Feb
semagacestat
Alzheimer's 
Treatments
midazolam
76.4
324.6
140 mg QD (10 days)
22789530
2012 Oct
efavirenz
NNRTIs
alfentanil
76
369.4
600 mg QD (20 days)
22398970
2012 Apr
tipranavir and ritonavir
Protease Inhibitors saquinavir
75.6
Not Provided tipranavir: 500 mg and 
ritonavir: 200 mg BID (14 
18176328
2008 Apr
bosentan
Endothelin 
sildenafil
69.0
239.8
62.5-125 mg BID (8 weeks)
15963102
2005 Jul
genistein
Food Products
midazolam
13.7
136.9
1000 mg QD (14 days)
21943317
2012 Feb
thioridazine
Antipsychotics
quetiapine
68.7
104.5
100-300 mg QD (15 days)
22569350
2012 Jun
nafcillin
Antibiotics
nifedipine
62.6
145.1
500 mg 4 times daily (5 
days)
12814453
2003 Jun
talviraline
NNRTIs
indinavir
61.7
181.2
500 mg TID (14 days)
10516944
1999 Oct
lopinavir
Protease Inhibitors amprenavir
59.7
Not Provided 400 mg BID (4 weeks)
15060509
2004 Apr
modafinil
Psychostimulants
triazolam
57.6
35.7
200-400 mg QD (28 days)
11823757
2002 Jan
etravirine
NNRTIs
sildenafil
56.7
Not Provided 800 mg BID (13.5 days)
NDA# 022187 2008
lersivirine
NNRTIs
midazolam
51.4
105.5
1000 mg BID (14 days)
22527351
2012 Nov
Weak Inducers (AUC decreased by 20-50% or CL increased by 20-100% (less than 2 fold))
eslicarbazepine
Anticonvulsants
simvastatin
49.4
98.4
800 mg QD (14 days)
23726291
2013 Sep
telaprevir
Antivirals
darunavir
48.4
Not Provided 1125 mg BID (4 days)
NDA# 201917 2011
garlic
Food Products
saquinavir
44.7
Not Provided caplet of GarliPure BID (20 
days)
11740713
2002 Jan


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
137
Inducers
Therapeutic class
Object (oral, 
unless 
otherwise 
specified)
% ↓ AUC % ↑ oral CLPrecipitant Dose (oral)
PMID or NDA # Published
bexarotene
Other 
Antineoplastics
atorvastatin
45.3
Not Provided 400 mg/m2 QD (at least 
two 4-week cycles)
22057855
2012 Feb
amprenavir
Protease Inhibitors lopinavir
43.0
Not Provided 700 mg BID (2-4 weeks)
15668539
2005 Jan
raltegravir
HIV-Integrase 
darunavir
42.0
Not Provided 400 mg BID
21958880
2012 Feb
lesinurad
Antigout and 
Uricosuric Agents
amlodipine
41.9
72.5
400 mg QD (24 days)
NDA # 207988 2015
vemurafenib
Kinase Inhibitors
midazolam
39.4
Not Provided 960 mg BID (15 days)
NDA # 202429 2011
troglitazone
Thiazolidinediones simvastatin
37.7
Not Provided 400 mg QD (24 days)
11361054
2001 May
sorafenib
Kinase Inhibitors
sirolimus
36.9
Not Provided 200 mg BID (11 days)
21045832
2010 Nov
rufinamide
Anticonvulsants
triazolam
36.7
53.4
400 mg BID (11.5 days)
NDA # 021911 2008
sirukumab***
Immunomodulator
s Biologics
midazolam
35.7
Not Provided 300 mg single dose 
subcutaneously
26054042
2015 Dec
pleconaril
Antivirals
midazolam
34.6
52.8
400 mg TID (6 days)
16467135
2006 May
ginseng
Herbal Medicationsmidazolam
34.2
50.7
500 mg BID (28 days)
21646440
2012 Jun
boceprevir
Antivirals
darunavir
34.2
41.0
800 mg every 8 hrs (6 days)
23155151
2013 Mar
sulfinpyrazone
Antigout and 
Uricosuric Agents
cyclosporine
33.9
(change in 
Cavg)
200 mg/day
11124491
2000 Dec
ginkgo
Herbal Medicationsmidazolam
33.7
52.6
120 mg BID (28 days)
18205997
2008 Feb
vinblastine
Vinca Alkaloids
midazolam IV
33.2
48.8
not provided (4 cycles)
20959500
2010 Nov
nevirapine
NNRTIs
indinavir
32.5
Not Provided 200 mg QD (14 days), then 
BID (19 days)
10191212
1999 May
armodafinil (R-modafinil) Psychostimulants
midazolam
32.2
54.7
100-250 mg/day (31 days)
18076219
2008
ticagrelor
Anticoagulants and midazolam
31.7
46.5
400 mg QD (6 days)
23870610
2013 Jul
LCL161
Cancer Treatments midazolam
29.8
34.0
600 mg single dose
23585187
2013 Jun


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
138
Inducers
Therapeutic class
Object (oral, 
unless 
otherwise 
specified)
% ↓ AUC % ↑ oral CLPrecipitant Dose (oral)
PMID or NDA # Published
vicriviroc and ritonavir
Treatments of AIDSethinyl 
estradiol
29.4
Not Provided 30 mg vicriviroc and 100 mg 
ritonavir QD (10 days)
22015327
2011 Oct
ritonavir
Protease Inhibitors ethinyl 
29.2
Not Provided 100 mg QD (10 days)
22015327
2011 Oct
prednisone
Corticosteroids
tacrolimus
29.0
Not Provided 1.5 mg/kg/day
15787787
2005 Apr
oxcarbazepine
Anticonvulsants
felodipine
28.1
Not Provided 450 mg BID (7 days)
8451779
1993 Feb
danshen
Herbal Medicationsmidazolam
27.9
32.8
4 g TID (14 days)
20565457
2010 Jun
clobazam
Benzodiazepines
midazolam
27.7
Not Provided 40 mg QD (15 days)
22422635
2012 Apr
echinacea
Herbal Medicationsmidazolam
27.3
37.5
500 mg TID (28 days)
20653355
2010 Aug
ticlopidine
Anticoagulants and alfentanil
27.0
50.0
250 mg BID (4 days)
23361846
2013 Mar
brivaracetam
Anticonvulsants
ethinyl 
26.8
37.3
200 mg BID (21 days)
24386664
2013 Dec
Stribild*
Treatments of AIDSethinyl 
estradiol
26.2
31.3
150 mg ELV + 150 mg COB 
+ 200 mg EMT+ 300 mg 
NDA # 203100 2012
pioglitazone
Thiazolidinediones midazolam
26.0
Not Provided 45 mg QD 7 days
Actos® Product 2004 Aug
VIEKIRA PAK**
Antivirals
darunavir
25.7
Not Provided See note**
NDA # 206619 2014
dexamethasone
Corticosteroids
aprepitant
25.0
Not Provided 8 mg/day (5 days)
NDA # 021549 2003
terbinafine
Antifungals
midazolam
24.5
Not Provided 250 mg QD (4 days)
8527290
1995 Sep
quercetin
Food Products
midazolam
23.6
Not Provided 500 mg QD (13 days)
21680781
2012 Jun
glycyrrhizin
Herbal Medicationsmidazolam
23.0
Not Provided 150 mg BID (15 days)
20393696
2010 Aug
aprepitant
Neurokinin-1 
midazolam IV
22.1
28.5
125/80 mg QD (3 days)
14973304
2004 Mar
pretomanib (PA-824)
Antibiotics
midazolam
22.1
20.7
400 mg QD (14 days)
23689718
2013 Aug
oritavancin
Antibiotics
midazolam
18.7
23.9
1200 mg IV single infusion
NDA # 206334 2014
AZD 7325
Anxiolytics
midazolam
18.7
22.6
10 mg QD (12 days)
22122233
2012 Jul
methylprednisolone
Corticosteroids
cyclosporine
15.8
35.0
16 mg/day (12 days) then 8 
mg/day (6 months)
12164891
2002 Sep
topiramate
Anticonvulsants
ethinyl 
12.0
20.2
50 mg/day (21 days)
12681003
2003 Apr


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
139
Inducers
Therapeutic class
Object (oral, 
unless 
otherwise 
specified)
% ↓ AUC % ↑ oral CLPrecipitant Dose (oral)
PMID or NDA # Published
1- Ritonavir has dual effects of simultaneous CYP3A inhibition and induction, and the net pharmacokinetic outcome during chronic 
2- All the substrates presented in the table are sensitive CYP3A substrates (see definition in FDA guidance) except verapamil, 
cyclosporine, ethinyl estradiol, and delavirdine.
* Stribild is a combination of elvitegravir, cobicistat, emtricitabine and tenofovir DF
** VIEKIRA PAK = paritaprevir/ritonavir/ombitasvir 150/100/25 mg QD + dasabuvir 250 mg BID for 14 days
 *** Sirukumab is not a CYP inducer per se. It reverses the IL-6 mediated suppression of CYP3A activity in patients with active rheumatoid 
h
M and T Drug Interaction Database® - Copyright 2016
www.druginteractioninfo.org
Database Searched in April 2016


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
140
16.3 APPENDIX C : PATIENT’S PILL DIARY: OLAPARIB 
Today’s date ________________________________ 
Patient Name_______________________________ Patient Study ID ______________________ 
Cycle #__________ Days 1-14
(initials acceptable for patient’s name) 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each cycle (28 days). 
2. You will take each dose twice a day 12 hours apart on days 3 – 13* and days 17 -26*. Each dose is 
___150mg tablets and ___ 100mg tablets. You must take the tablets with a large glass of water. A light snack 
(biscuits/ toast) is also recommended to help reduce nausea.
3. Record the date, the number of tablets you took, and when you took them. (*You will be given additional 
instructions about the timing of the doses on Days 13 and 26 each cycle.)
4. If you have any comments or notice any side effects, please record them in the Comments column. 
5. Please bring your pill bottle and this form to your physician when you go for your next appointment. 
DAY
DATE
# TABLETS 
AND WHEN 
TAKEN: 
OLAPARIB 
AM PM
12 HOURS 
APART
COMMENTS (side effects or missed doses)
1
Do not take 
olaparib
2
Do not take 
olaparib
3
_________AM 
_________PM
4
_________AM 
_________PM
5
_________AM 
_________PM
6
_________AM 
_________PM


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
141
7
_________AM 
_________PM
8
_________AM 
_________PM 
9
_________AM 
_________PM 
10
_________AM 
_________PM
11
_________AM 
_________PM 
12
_________AM 
_________PM 
13
_________AM 
14
Do not take 
olaparib
Patient’s Signature: ________________________________________ Date: _________________________ 
The Study Team will complete this section: 
1. Date patient started protocol treatment______________ Date patient was removed from study _____________
2. Patient’s planned daily dose___________________ Total number of pills taken Days 1-14 __________________
Physician/Nurse Signature ____________________________________________________________________ 


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
142
Appendix C: Patient’s Pill Diary: Olaparib
Today’s date ________________________________ 
Patient Name_______________________________ Patient Study ID ______________________
Cycle #__________ Days 15-28
(initials acceptable for patient’s name) 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each cycle (28 days). 
2. You will take ___ tablets twice a day 12 hours apart on days 3 – 13* and days 17 -26*. Each dose is 
___150mg tablets and ___ 100mg tablets. You must take the tablets with a large glass of water. A light snack 
(biscuits/ toast) is also recommended to help reduce nausea. (*You will be given additional instructions about 
the timing of the doses on Days 13 and 26 each cycle.)
3. Record the date, the number of tablets you took, and when you took them. 
4. If you have any comments or notice any side effects, please record them in the Comments column. 
5. Please bring your pill bottle and this form to your physician when you go for your next appointment. 
DAY
DATE
# TABLETS 
AND WHEN 
TAKEN: 
OLAPARIB 
AM PM
12 HOURS 
APART
COMMENTS (side effects or missed doses)
15
Do not take 
olaparib
16
Do not take 
olaparib
17
_________AM 
_________PM 
18
_________AM 
_________PM
19
_________AM 
_________PM
20
_________AM 
_________PM 


Abbreviated Title: EP0057 in Advanced Cancers
Version Date: 08/16/2024
143
21
_________AM 
_________PM 
22
_________AM 
_________PM 
23
_________AM 
_________PM
24
_________AM 
_________PM 
25
_________AM 
_________PM
26
_________AM 
27
Do not take 
olaparib
28
Do not take 
olaparib
Patient’s Signature: ________________________________________ Date: _________________________ 
The Study Team will complete this section: 
1. Date patient started protocol treatment______________ Date patient was removed from study _____________
 
2. Patient’s planned daily dose___________________ Total number of pills taken Days 15-28 _______________
3. Total number of pills taken this cycle (Days 1-28)___________
Physician/Nurse Signature ____________________________________________________________________ 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 09/26/2024
Page 1 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: Anish Thomas, MD
STUDY TITLE:
A Phase I/II Trial of EP0057, a Nanoparticle Camptothecin 
with Olaparib in Patients with Relapsed/Refractory Small 
Cell Lung, Bladder and Prostate Cancers
STUDY SITE: 
NIH Clinical Center
Cohort: 
Affected Patient
Consent Version:  
09/26/2024
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Anish Thomas, MD, by phone at 240-760-7343 or email anish.thomas@nih.gov
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive. Take the time needed to ask any questions and 
discuss this study with NIH staff, and with your family, friends, and personal health care 
providers. Taking part in research at the NIH is your choice.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may 
change your mind and stop participating in the study at any time and for any reason. In either 
case, you will not lose any benefits to which you are otherwise entitled. However, to be seen at 
the NIH, you must be taking part in a study or are being considered for a study. If you do choose 
to leave the study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
The use of EP0057 (formerly known as CRLX101) in this study is experimental. EP0057 is a 
sugar molecule called cyclodextrin that is linked to a chemotherapy drug called camptothecin. 
Linked together, the combined molecule or “nanoparticle drug conjugate” travels through the 
bloodstream. Once inside the cancer cells, the chemotherapy drug is released from the combined 
carrier molecule. 
Olaparib is a drug that may stop the cancer cells from repairing the DNA damage caused by 
chemotherapy. Olaparib has been approved by the FDA for use in some types of breast cancers, 
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 09/26/2024
Page 2 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
prostate cancers, ovarian cancers and pancreatic cancers. This drug is considered 
investigational in this study.
This study is divided into three parts, Phase I, Phase II and Expansion cohorts (groups). The 
Phase I portion of the study is being done to test the safety of the combination of EP0057 and 
olaparib, and to determine the highest doses of these two drugs that can be given in 
combination safely in participants with a variety of cancers. During Phase II and in the 
Expansion cohorts, this study will analyze how effective this drug combination is in treating 
specific cancers: small cell lung cancer (SCLC) in Phase II and urothelial carcinoma and 
metastatic castrate resistant prostate cancer.  As of August 2021, we are no longer enrolling 
participants with prostate cancer as treatment being commercially available for this type of 
cancer has slowed down accrual to the current study. We also stopped enrolling participants 
with urothelial carcinoma as of August 2022 due to low past accrual and availability of other 
more current treatment protocols.
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You have been asked to take part in this study because you have been diagnosed with 
SCLC, urothelial carcinoma or another type of cancer that does not currently have an 
approved treatment.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
About 126 people may receive study drugs at the NIH.
DESCRIPTION OF RESEARCH STUDY
What will happen if you take part in this research study? 
Before you begin the study
Before you begin this study, you will have several exams and tests to make sure you are 
eligible for this study. If you have had these tests done recently on another NIH protocol or 
outside of NIH, we will collect the records instead.
The following tests may be done or records collected:
-
A medical history and physical exam  
-
Routine blood tests to check on your health status
-
As part of this study, we will do blood tests to check for infections with HIV (the virus 
that causes AIDS), Hepatitis B and C (viruses that infect the liver). If you are infected 
with any of these viruses, you will be able to take part in this study if you are getting 
treatment for these diseases and if the virus cannot be found through blood tests. We will 
tell you what the results of blood tests mean, how to find care, how to avoid infecting 
others, how we report these infections, and the importance of informing your partners at 
possible risk because of your HIV or hepatitis infection.
-
A pregnancy test for individuals who can have children (by blood or urine) 
-
Imaging to include:
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 09/26/2024
Page 3 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
o
Computed Tomography (CT): The CT scanner is a donut-shaped machine that 
uses x-rays to make computer pictures of the inside of your body.  During the 
procedure, you will need to lie still on a table inside the CT machine. An MRI 
makes pictures of the inside of your body using strong magnets instead of x-ray 
energy.  
o
Technetium-99 bone scan (only for participants with metastatic castrate resistant 
prostate cancer): The bone scan is a test using a special camera to check for any 
issues in your bones. It involves the injection of a radioactive substance 
(Technetium-99) which is detected by the camera.
o
Echocardiogram: An echocardiogram is a painless test using sound waves to take 
a picture of your heart.  During this test, we will put some jelly on your chest.  We 
will then put the ultrasound probe on your chest and take the picture.  We may ask 
you to lay on your side to get a better picture.  For some pictures, we may put the 
probe on the upper part of your abdomen and push down firmly.  This can be 
uncomfortable.  The scan takes about 30 minutes to complete.  
-
Electrocardiogram (EKG): An electrocardiogram (EKG) is a test that looks at electrical 
activity of your heart. You will need to lie still for about 5 minutes.  We will place 
electrodes on your chest, arms, and legs.  Electrodes are small stickers that are attached 
to wires that go to the machine.  The signals are recorded by the machine.  If you have a 
lot of hair on your chest, it may hurt a little bit to remove the stickers.
-
We will confirm your diagnosis through medical records. 
If we find you are not eligible, we will remove you from the study.
DURING THE STUDY
You will receive EP0057 intravenously (through a small plastic tube inserted into your vein) 
every 2 weeks (days 1 and 15) and olaparib by mouth twice daily on days 3-13 and days 17-26 
(You will be given additional instructions about the timing of the doses on Days 13 and 26 
each cycle) administered in 28-day cycles. You will continue to receive treatment until your 
disease no longer responds or you are no longer able to tolerate the drug.
You should take the olaparib at the same time each day with a large glass of water. A light 
snack (biscuits/ toast) is also recommended to help reduce nausea. You should swallow the 
tablets whole. You will be given a pill diary at the beginning of each cycle to fill out and bring 
back to the study nurse at the end of the cycle.
In the Phase I part of the protocol, the EP0057 and olaparib will be tested a lower dose level in 
the first group of participants. If none or only one of the participants experience intolerable side 
effects, the next group will be enrolled at the next highest dose level. This will continue until 
more than one person in a group has intolerable side effects or until the highest pre-planned 
dose has been reached. The maximum safe dose is set at the highest dose level in which no 
more than one of six participants experienced an intolerable side effect.
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 09/26/2024
Page 4 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The maximum safe dose is now determined, and in the phase II and expansion portions of the 
study, up to 94 participants will be enrolled at that dose to evaluate the anti-cancer activity of 
EP0057 and olaparib in small cell lung cancer, urothelial cancer and prostate cancer.
If you experience side effects (described later in this consent) when taking EP0057 and/or 
olaparib, the dosage of these drugs may be adjusted to reduce the severity of your side effects. 
Also, subsequent doses may be delayed until you have time to recover. If the side effects are 
too severe, the doctor may decide to stop all further doses of EP0057 and/or olaparib.
During treatment, the health care provider will monitor you every 2 weeks. If your doctor 
believes that it is necessary, based on your symptoms, the physical exam will be performed 
more often than indicated. You may have blood drawn to assess blood counts, liver and kidney 
functions (about one and a half tablespoon at each timepoint). Please see the study chart for the 
schedule of the tests.
ADDITIONAL RESEARCH STUDIES
An important part of the research is to determine how your body and tumor responds to the 
combination of drugs. This will also include the genetic analysis of the tumor cells and your 
normal cells. To understand this, we will collect your blood (about 10 tablespoons over the 
course of the study), hair samples (if you are in the phase I cohort), saliva (if you are enrolled 
on expansion cohort) and tumor at different time points. Hair sampling is optional. Single hairs 
will be plucked from the scalp with forceps. Plucked hairs from eyebrows will be collected only 
if we cannot get hair from your scalp.
Biopsies will be performed only in SCLC participants who enroll in phase I and all participants 
in phase II and expansion cohorts. All biopsies are optional. If you agree to have the biopsies, 
these will be performed before you start treatment, on day 4 of cycle one, and if you stop 
responding to the drug or your disease worsens.   If your doctor determines it is safe, we will 
obtain a piece of your tumor (biopsy) using a needle. This process will be guided by a CT scan. 
You will be given local anesthesia (numbing medicine). The biopsy will be taken through a 
needle put through the skin into your tumor. After the procedure the nurses will watch your 
blood pressure and other vital signs. The biopsy to be performed is exclusively for research 
purposes and will not benefit you. It might help other people in the future.
You may receive conscious sedation before undergoing a biopsy, if needed. Conscious sedation 
is usually given to help someone relax and minimize discomfort. It can be given as a pill, a shot, 
an IV (intravenous catheter, a small plastic tube that is put into a vein, usually in your arm) or 
even inhaled. You may have to wait up to an hour to start feeling the effects depending on how it 
is given. Once it takes effect, you will be mostly awake, though relaxed or drowsy. You will be 
monitored throughout the procedure.
WHEN YOU ARE FINISHED TAKING THE DRUGS (TREATMENT)
In the case that you have to stop receiving treatment, you will have a clinic visit approximately 
4 weeks after you discontinue taking the study drugs, in which the health care provider will 
perform a physical exam and blood will be drawn. You will then receive follow-up phone calls 
from the study team every three months.
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


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STUDY CHART
Day
What to do and what will happen to you
Before 
starting
Medical history and physical exam. 
Blood samples
Echocardiogram and CT scan 
Pregnancy test if you can become pregnant.
Tumor biopsy if you agree 
Cycle 1
Day 1
Physical exam 
Blood samples
Pregnancy test if you can become pregnant (may be obtained up to 3 
days prior to Day 1).
Hair samples (Phase I cohort only) 
First dose of EP0057 intravenously.
EKG if your first study EKG was abnormal. *
Day 2
Blood samples (Phase I cohort only)
Day 3
Blood (Phase I cohort)
Hair samples (Phase I cohort only)
First dose of olaparib orally, starting today until day 13 (You will be given 
additional instructions about the timing of the doses on Day 13).
Day 4
Tumor biopsy if you agree.
Blood samples (Phase I cohort only)
Hair samples (Phase I cohort only)
Day 7
Blood samples for assessing blood counts (can be performed at local health 
care provider)
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Day 15
Recording of any health problems, including side effects from the study 
drugs; 
Physical exam.
Blood samples for assessing blood counts, liver and kidney functions 
Blood samples (Phase II SCLC cohort only)
Second dose of EP0057 intravenously.
EKG if your first study EKG was abnormal.
Day 17
Start olaparib orally, starting today until day 26 (You will be given 
additional instructions about the timing of the doses on Day 26).
Day 21
Blood samples for assessing blood counts (can be performed at local health 
care provider)
Day 28
Recording of any health problems, including side effects from the study 
drugs; 
Physical exam.
Hair samples (Phase I cohort only) *
Cycle 2 and beyond
Day 1
Recording of any health problems, including side effects from the study 
drugs; 
Physical exam.
Blood samples.
Pregnancy test if can become pregnant (may be obtained up to 3 days 
prior to Day 1).
EP0057 intravenously.
EKG if your first study EKG was abnormal.
Day 3
You will receive a dose of olaparib orally, starting today until day 13 (You 
will be given additional instructions about the timing of the doses on Day 
13).
Day 15
Recording of any health problems, including side effects from the study 
drugs.
Blood samples will be collected for assessing blood counts, liver and kidney 
functions
EP0057 intravenously.
EKG if your first study EKG was abnormal.
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


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Day 17
Olaparib orally, starting today until day 26 (You will be given additional 
instructions about the timing of the doses on Day 26).
Day 28
A CT scan will be performed after every 2 cycles
Day 28
Recording of any health problems, including side effects from the study 
drugs;
Physical exam.
Hair samples (Phase I cohort only) **
End of Treatment/ Follow up
Recording of any health problems, including side effects from the study 
drugs.; 
Physical exam. 
Blood samples 
Tumor biopsy if you agree. 
Follow-up phone calls every 3 months
* The EKG will be done 1-3 hours after the EP0057. It will only be required for the first 2 
cycles.
** Hair samples may be collected any time after the last dose of olaparib but before the next 
dose of EP0057 between days 26-28.
BIRTH CONTROL
If you can bear children: If you are breast feeding or pregnant, you may not take part in the 
study because we do not know how these medicines would affect your baby or your unborn 
child. If you can become pregnant, you will need to use a highly effective form of birth 
control and your partner must use a condom before starting study treatment, during study 
treatment, and for 6 months after you finish study treatment.   
You must have a negative pregnancy test prior to enrolling in the study. 
Highly effective forms of birth control include:
•
Total abstinence (when this is the preferred and usual lifestyle of the participant). 
Withdrawal and periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) are not acceptable methods of contraception.
•
Sterilization: 
o
defined as having had surgical bilateral oophorectomy with or without 
hysterectomy, total hysterectomy, or tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the 
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reproductive status of the participant has been confirmed by follow up hormone 
level assessment.
o
Vasectomy for at least 6 months prior to screening. The vasectomized partner 
should be the sole partner for that participant.
•
Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. In case of use of oral 
contraception individual should have been stable on the same pill for a minimum of 3 
months before taking study treatment
If you can father children: We do not know if using EP0057 or olaparib will affect sperm, but 
reproductive organ effects were observed in animal studies. Therefore, due to this potential 
risk, you should not get your partner pregnant during the study drug period and for 3 months 
following the last dose of study drug. Even if you are surgically sterilized (i.e. have had a 
vasectomy) you must use condoms and avoid sperm donation from the time of signing the 
informed consent form, and throughout the entire study drug treatment period, and for 3 
months following the last dose of study drug.
If you or your partner become pregnant while you are receiving study drug or within 3 months 
(for participants who can father children) or 6 months (for participants who can bear children) 
after your last dose of study drug, you should notify the study doctor right away. The study 
doctor will ask to follow your pregnancy, or your partner’s pregnancy to its outcome. 
RISKS OR DISCOMFORTS OF PARTICIPATION
What side effects or risks can I expect from being in this study?
During the study you may have risks and/or discomforts from the study drugs and procedures 
as described below. You may experience some, none, or all of these risks and/or discomforts, 
and they may be mild, moderate, or severe. There is always the chance of a very rare or 
previously unknown risks and/or discomfort occurring. There is also the risk of death.
If you experience any risks and/or discomforts, whether they are listed below or not, you must 
tell your study doctor who may be able to give you medicine to ease the discomfort. In 
addition, if a severe reaction to a study drug occurs, your doctor may decide to reduce the 
amount of study drug you take, or maybe even withdraw you from the study. You will be 
monitored closely for all risks and/or discomforts.
RISKS FROM EP0057
One risk is that you may get a drug that does not help treat your disease or that makes your 
condition or disease worse. The investigational study drug, EP0057, contains a cancer 
chemotherapy drug known as camptothecin. The very common, severe risk from camptothecin 
alone is inflammation and bleeding in the bladder. This risk has occurred with EP0057, but has 
been reported as mild to moderate and has resolved within a few weeks. EP0057 may cause 
other risks or discomforts similar to other cancer chemotherapy because the drug affects 
rapidly dividing cells in your body, which can include both cancer cells and other normal cells. 
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


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The risks or discomforts from EP0057 can range from mild and reversible to severe, long 
lasting and possibly life-threatening. EP0057 is an investigational drug, so not all of the risks 
or discomforts are known at this time. You need to tell your doctor or a member of the study 
team immediately about any symptoms that you experience while taking part in the study.
The following risks and discomforts have been reported from previous and ongoing studies of 
EP0057.
VERY COMMON (>10% OF PATIENTS REPORTED):
•
Low number of red blood cells that can cause tiredness and shortness of breath (anemia) 
If this becomes severe, you may need to come into the clinic or hospital to have a 
transfusion of red blood cells.
•
Feeling tired or lacking energy (fatigue)
•
Nausea
•
Inflammation of the bladder (cystitis)
•
Blood in the urine (hematuria)
COMMON (3-10% OF PATIENTS REPORTED):
•
A decrease in white blood cells (specific type called neutrophils), which can lead to 
infection requiring antibiotic treatment and possibly hospitalization (neutropenia)
•
Diarrhea
•
Vomiting
•
Dysuria (painful or uncomfortable urination, typically a sharp, burning sensation)
•
Difficulty passing stool (constipation)
•
Fever or chills
•
A decrease in white blood cells (not specified by type) in blood (leukopenia)
•
A reduction in platelets (blood cells that help the blood to clot), which can lead to bleeding 
requiring one or more platelet transfusions (thrombocytopenia)
•
Numbness, tingling or weakness in hands or feet (peripheral neuropathy)
•
Loss of hair (alopecia)
•
Decreased appetite
•
Presence of white blood cells in the urine (leukocyturia)
•
Presence of protein in the urine, which may cause fluid retention (proteinuria)
UNCOMMON (1-2% OF PATIENTS REPORTED):
•
Swelling or build-up of fluids in the extremities (peripheral edema)
•
Muscle discomfort or pain (myalgia), joint pain (arthralgia)
•
Altered taste
•
Bladder spasm
•
Blood in the urine and painful voiding (hemorrhagic cystitis)
•
Increased need to urinate at night (nocturia)
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


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•
Decreased urine flow or incomplete emptying of bladder (urinary retention)
•
Infusion related reaction (symptoms, such as skin rash or red areas on the skin (hives) 
that are intensely itchy (urticarial), fast heart rate, low blood pressure, coughing or 
breathing difficulties, are related to the drug administration and may range from 
symptomatic discomfort to fatal events)
•
Shortness of breath (dyspnea)
•
Urinary tract infection
•
Increased ALT (a liver enzyme) in the blood
•
Dehydration
•
Hemoglobin Decreased
•
Pain in the extremities (arms and legs)
•
Abdominal pain 
•
Increased AST (a liver enzyme) in the blood
•
Weakness (asthenia)
•
Blood creatinine increased
•
Chills
•
Dizziness
•
Increased need to urinate (micturition urgency)
•
Abdominal distension
•
Increased blood alkaline phosphate increased
•
Bone pain
•
Cough
•
Indigestion (Dyspepsia)
•
Flatulence
•
High levels of sugar in the blood, if sugar in the blood is too high, it may require 
hospitalization or treatment (hyperglycemia)
•
Abnormally susceptible or sensitive physiologically to a specific agent (as a drug or 
antigen) (hypersensitivity)
•
Low potassium level in the blood (hypokalemia)
•
Difficulty sleeping or falling asleep (insomnia)
•
Lymphocyte count decreased
•
Muscle discomfort or pain (myalgia)
•
Urinary frequency (pollakiuria)
•
Rash
•
Puncture or hole in the last part of the small bowel (ileal perforation)
•
Pinpoint, round spots that appear on the skin as a result of bleeding (petechiae)
•
Infection in one or both of the lungs, symptoms vary from mild to severe, such as high 
fever, shaking chills, a cough with phlegm that does not improve or get worse, shortness 
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


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of breath, chest pain when breathing or coughing (pneumonia)
RISKS FROM OLAPARIB
VERY COMMON, MAY BE SERIOUS (In 100 people receiving olaparib, 10 or more 
people may be affected) 
•
Low red blood cell count (anemia) which may cause you to feel tired, weak, or have 
shortness of breath. In some instance, this decrease in red blood cell count may be 
serious and require blood transfusions (when you are given new blood or blood products 
from a donor).
•
A decrease in white blood cells (specific type called neutrophils) with or without fever. 
In some cases, this decrease can be serious and lead to infection requiring antibiotic 
treatment and possibly hospitalization (neutropenia)
•
A decrease in white blood cells in blood (leukopenia) which may be serious in rare cases
•
Loss of appetite
•
Dizziness
•
Headache
•
Altered taste (dysgeusia)
•
Cough
•
Shortness of breath
•
Nausea or vomiting which may be serious in some cases (feeling sick or actually being 
sick). If required, you will be offered medication to control these symptoms.
•
Diarrhea, which is frequent, loose water stools, which can cause dehydration and may 
require hospitalization and treatment with intravenous fluids. Although rare, severe and 
prolonged diarrhea can be life-threatening.
•
Constipation
•
Heartburn (dyspepsia)
•
Fatigue (including feeling weak)
COMMON, MAY BE SERIOUS (In 100 people receiving olaparib, more than 1 but less 
than 10 people may be affected) 
•
A reduction in platelets (blood cells that help the blood to clot), which can lead to 
bleeding requiring platelet transfusions (thrombocytopenia)
•
Lymphocyte (type of white blood cell that is part of the immune system) count decrease 
which may lead to an infection
•
Inflamed and sore mouth (stomatitis)
•
Upper abdominal pain 
•
Rash
•
Blood creatinine increase (creatinine is a measure that tells us how well your kidneys are 
working). This may mean that your kidneys are not working well.
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


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•
A blood clot that starts in a vein (venous thromboembolism). These clots can also 
develop in deep veins in the arm, lower leg, thigh or pelvis and can in serious cases travel 
to the lungs.  
UNCOMMON, MAY BE SERIOUS (In 1,000 people receiving olaparib, more than 1 but 
less than 10 people may be affected)
•
Irreversible abnormal blood counts and bone marrow damage, which may lead to 
leukemia (myelodysplasia).
•
Undesirable reactions produced by the normal immune system (hypersensitivity)
•
Swelling that occurs just beneath the surface of the skin (angioedema)
•
Skin irritation or inflammation (dermatitis)
•
Increased red blood cell size and volume (mean cell volume increased)
•
Cancer of the blood and bone marrow (the soft inner part of certain bones, where new 
blood cells are made), also called acute myeloid leukemia 
•
Embolism (blockage of an artery, typically by a clot of blood)
•
Pulmonary embolism (blockage in one of the arteries in your lungs)
•
Inflammation of the lung tissue (pneumonitis), which may cause new or worsening 
symptoms of shortness of breath. This may be serious or life threatening.
RARE, MAY BE SERIOUS (In 10,000 people receiving olaparib, more than 1 but less 
than 10 may be affected)
•
Flat, firm, hot, red, and painful lumps that usually appear on the shins (erythema 
nodosum)
•
Red blood cells that are larger than normal (anemia macrocytic)
•
Decrease in the amount of red blood cells (hematocrit decrease)
RISKS YOU MIGHT EXPERIENCE OTHER THAN THE DRUG SIDE EFFECTS 
Biopsy Risks
Risks associated with the biopsies, which are pain and bleeding at the biopsy site. Sometimes a 
CT scan may be needed to identify the right tumor to biopsy. 
Radiation Risks
During your participation in this research study, you will be exposed to radiation from up to 3 
CT guided biopsies and 9 CT scans.  The amount of radiation exposure you will receive from 
these procedures is equal to approximately up to 12.3 rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
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IRB EFFECTIVE DATE: 10/15/2024


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The CTs that you get in this study will expose you to roughly the same amount of radiation as up 
to 41 years’ worth of background radiation. Being exposed to too much radiation can cause 
harmful side effects such as an increase in the risk of cancer.  The risk depends on how much 
radiation you are exposed to. Please be aware that about 40 out of 100 people (40%) will get 
cancer during their lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting 
cancer from the radiation exposure in this study is 1.2 out of 100 (1.2%) and of getting a fatal 
cancer is 0.6 out of 100 (0.6%).
You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time.
Risks from CT scans
There is a chance of developing an allergic reaction from the contrast material, which may cause 
symptoms ranging from mild itching or a rash to severe difficulty breathing, shock or rarely, 
death.  The contrast material may also cause kidney problems.  The study doctors will do a blood 
test prior to the test to confirm that it is safe you to receive the contrast.
You may also feel discomfort when the contrast material is injected. You may feel warm, 
flushed, get a metallic taste in your mouth or, rarely, may make you vomit or feel sick to your 
stomach.  
Blood Draw Risks
Risks associated with blood draw, which include pain and bruising, lightheadedness, and 
rarely, fainting. Up to 15 tablespoons of blood may be drawn at any visit, with no more than 
55 tablespoons in an 8-week period.
Hair Collection Risks
Pain associated with hair collection.
Echocardiogram Risks
Other than mild discomfort during the test, there are no known risks to an echocardiogram.
Electrocardiogram Risks
Other than having some minor skin irritation from the electrodes, there are no known risks 
related to the EKG.
Privacy Risks Associated with Genetic Testing
It may be possible that genetic information from you could be used by law enforcement agencies 
or other entities to identify you or your blood relatives.
Psychological or Social Risks Associated with Return of Incidental or Secondary Findings
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might 
create a need to make challenging decisions about how to respond. 
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


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Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them. 
Protections against misuse of genetic information 
This study involves genetic testing on samples.  Some genetic information can help predict 
future health problems of you and your family and this information might be of interest to your 
employers or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law 
that prohibits plans and health insurers from requesting genetic information or using genetic 
information. It also prohibits employment discrimination based on your health information. 
However, GINA does not address discrimination by companies that sell life insurance, disability 
insurance, or long-term care insurance. GINA also does not protect you against discrimination 
based on an already-diagnosed condition or disease that has a genetic component.
Conscious Sedation Risks
The common side effects of conscious sedation include drowsiness, delayed reflexes, 
hypotension, headache, and nausea. These are generally mild and last no more than a few hours.
INCIDENTAL FINDINGS
Your tissue (tumor and normal tissue) and blood that is collected will be used to look for 
specific changes in the DNA in tumors that could be used to develop new ways of diagnosing 
and treating cancer. DNA (also called deoxyribonucleic acid) are the molecules inside cells that 
carry genetic information and pass it from one generation of cells to the next – like an 
instruction manual. Normal tissue contains the DNA (instructions) that you were born with, 
DNA in tumor cells has changed – or mutated – and we think that change in the DNA is what 
causes tumors to form and to grow.
In order to determine which parts of the DNA have mutated, we will compare the DNA in your 
tumor cells to DNA from your normal cells. We will then analyze all of the results from similar 
tumors to see if there are any changes in the DNA that are common to a particular type of 
tumor. In order to examine the tumor and normal tissue we may use several different 
techniques depending on the type of tissue we collect. These could include growing cell lines 
(cells which keep dividing and growing in the laboratory, sometimes for years allowing us to 
continually study those cells), growing your tissue for a short time in culture in the laboratory 
and growing your tumor tissue in mouse models and looking in great detail at the parts of the 
genes that produce specific proteins. When we are examining these pieces of your DNA, it is 
possible that we could identify possible changes in other parts of your DNA that are not related 
to this research. These are known as “incidental medical findings”. These include:
•
Changes in genes that are related to diseases other than cancer
•
Changes in genes that are not known to cause any disease. These are known as normal 
variations.
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


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•
Changes in genes that are new and of uncertain clinical importance. This means that we do 
not know if they could cause or contribute to a disease or if they are normal variations.
Some of your samples may be tested in a laboratory that is certified to perform genetic testing. If 
this happens, we will offer to share the results for these tests.
Some of the analyses will be performed in our laboratory and will be for research purposes only; 
they are not nearly as sensitive as the tests that are performed in a laboratory that is certified to 
perform genetic testing. Changes that we observe unrelated to our research may or may not be 
valid. Therefore, we do not plan to inform you of the results of testing on your tissue and blood 
that is performed in our research lab. However, in the unlikely event that we discover a finding 
that could be clinically relevant, we will contact you to ask if you would like to provide another 
sample to be tested at a certified lab and meet with a credentialed genetics healthcare provider 
for genetics education and counseling (either in clinic or via phone conference). The genetics 
healthcare provider will explain to you the nature of the result, implications for you and your 
family members, the need to confirm the results with an outside certified laboratory, the time 
frame for analysis, and implications of results including risks, benefits, and limitations.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study?
The aim of this study is to see if this experimental combination treatment will cause your 
tumors to shrink. We do not know if you will receive personal, medical benefit from taking 
part in this study. These potential benefits could include shrinking of your tumor or lessening 
of your symptoms, such as pain, that are caused by the cancer. The knowledge gained from this 
study may help others in the future who have cancer.
ALTERNATIVE APPROACHES OR TREATMENTS
What other choices do I have if I do not take part in this study?
Instead of being in this study, you have these options:
•
Getting treatment or care for your cancer without being in a study
•
Getting treatment with another FDA approved drug for your type of cancer
•
Taking part in another study
•
Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat the 
cancer directly. Instead, it tries to improve how you feel. Comfort care tries to keep you as 
active and comfortable as possible.
Please talk to your doctor about these and other options.
STOPPING THERAPY
Your doctor may decide to stop your therapy for the following reasons:
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•
if he/she believes that it is in your best interest
•
if your disease comes back during treatment
•
if you have side effects from the treatment that your doctor thinks are too severe
•
if you become pregnant
•
if new information shows that another treatment would be better for you
•
if you are permanently no longer able to provide consent
 In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part 
in the study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the pharmaceutical 
companies providing the drug or designated representatives. If you withdraw your consent and 
leave the trial, any samples of yours that have been obtained for the study and stored at the
NCI can be destroyed upon request. However, any samples and data generated from the 
samples that have already been distributed to other researchers or placed in the research 
databases cannot be recalled and destroyed.
CONFLICT OF INTEREST (COI)
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for 
conflicts of interest. This process is detailed in a COI Guide.  You may ask your research team 
for a copy of the COI Guide or for more information. Members of the research team who do not 
work for NIH are expected to follow these guidelines but they do not need to report their 
personal finances to the NIH.
The National Institutes of Health and the research team for this study are using EP0057 
provided by Ellipses and Olaparib developed by AstraZeneca through a joint study with your 
researchers and the company. The company also provides financial support for this study.
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying 
human samples. They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved. Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses. These specimens and data will be stripped of identifiers such as name, 
address or account number, so that it may be used for future research on any topic and shared 
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 09/26/2024
Page 17 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
broadly for research purposes. Your specimens and data will be used for research purposes only 
and will not benefit you. It is also possible that the stored specimens and data may never be 
used. Results of research done on your specimens and data will not be available to you or your 
doctor. It might help people who have cancer and other diseases in the future.
If you do not want your stored specimens and data used for future research, please contact us 
in writing and let us know that you do not want us to use your specimens and/or data. Then 
any specimens that have not already been used or shared will be destroyed and your data will 
not be used for future research. However, it may not be possible to withdraw or delete 
materials or data once they have been shared with other researchers.
Genomic Data Sharing
As part of this research study, we will put your genomic data in a large database for broad 
sharing with the research community. These databases are commonly called data repositories. 
The information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.  If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether 
these researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that  researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may 
be paid directly by the NIH and some may be reimbursed after you have paid.  Someone will 
work with you to provide more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
•
If some tests and procedures are performed outside the NIH Clinical Center, you may 
have to pay for these costs if they are not covered by your insurance company.
•
Medicines that are not part of the study treatment will not be provided or paid for by the 
NIH Clinical Center.
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 09/26/2024
Page 18 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
•
Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include:
•
The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.
•
National Institutes of Health Intramural Institutional Review Board
•
The study Sponsor (Center for Cancer Research, NCI) or their agent(s) or their agent(s) 
•
Qualified representatives from Ellipses, the pharmaceutical company who produces 
EP0057 and Astra Zeneca, the pharmaceutical company who produces olaparib.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section 
of this document on sharing of specimens and data, and as further outlined in the following 
sections.
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 09/26/2024
Page 19 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or 
your involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self 
or others including, for example, child abuse and neglect, and by signing below you consent to 
those disclosures. Other permissions for release may be made by signing NIH forms, such as the 
Notice and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
Act allows release of information from your medical record without your permission, for 
example, if it is requested by Congress. Information may also be released for certain research 
purposes with due consideration and protection, to those engaged by the agency for research 
purposes, to certain federal and state agencies, for HIV partner notification, for infectious disease 
or abuse or neglect reporting, to tumor registries, for quality assessment and medical audits, or 
when the NIH is involved in a lawsuit.  However, NIH will only release information from your 
medical record if it is permitted by both the Certificate of Confidentiality and the Privacy Act.
RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Anish 
Thomas,  anish.thomas@nih.gov, 240-760-7343.  You may also call the NIH Clinical Center 
Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, 
if you have a research-related complaint or concern. 
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 09/26/2024
Page 20 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either:
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Signature of Witness
Print Name of Witness
Date
NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not also serve 
as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 16C0107
IRB EFFECTIVE DATE: 10/15/2024