Conditions: Metastatic Castration Resistant Prostate Cancer Prostate Neoplasms
Keywords: Androgen Receptor Antagonist PSA Hormonal Therapy Nanoparticle Drug Antitumor
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 4
Healthy volunteers: no

Brief summary:
Background:

Some prostate cancer keeps growing even when testosterone in the body drops to very low levels. This is called castrate-resistant prostate cancer. One treatment is enzalutamide. This is a modern hormonal therapy. But it only works for a certain amount of time and then the cancer becomes resistant to it. Researchers want to see if adding the treatment CRLX101 (formerly IT-101) could make enzalutamide work again for people who have already had it.

Objective:

To test a new way of treating prostate cancer using CRLX101 plus enzalutamide in people with certain prostate cancer who already had enzalutamide treatment.

Eligibility:

Adults ages 18 years and older with metastatic, castration-resistant prostate cancer who have had enzalutamide treatment

Design:

Participants will be screened with a medical history and physical exam. They will have blood and urine tests. They will have a scan of the chest/abdomen/pelvis. They will have a bone scan.

Participants will get treatment in cycles. A cycle lasts 28 days. They will take enzalutamide by mouth once a day. They will get CRLX101 through an intravenous (IV) every 1 or 2 weeks.

Participants will repeat screening tests throughout the study.

Participants will have a follow-up visit 3-4 weeks after they stop taking the study drug. They will repeat most screening tests and have an electrocardiogram.

Detailed description:
Background:

* Enzalutamide is established as first-line hormonal therapy in participants with metastatic castration resistant prostate cancer (mCRPC). However, it is increasingly recognized that acquired resistance to therapy (e.g., androgen receptor (AR) overexpression, androgen receptor variant 7 (AR-V7) could limit the durability of response to therapy
* Upregulation of Hypoxia-inducible factor 1-alpha (HIF-1Alpha) in hypoxic tumor cells provides a mechanism of acquired resistance to current hormonal therapies and chemotherapies. Acquired resistance increases angiogenesis and metastasis, leading to disease progression
* Targeting the hypoxia driven tumor microenvironment (e.g., down-regulation of HIF-1Alpha) in addition to the androgen receptor (e.g., enzalutamide) has synergistic activity against prostate cancer cell line models (e.g., LNCaP, 22Rv1).
* CRLX101 is a nanoparticle drug conjugate composed of 20(S)-camptothecin (a potent and highly selective topoisomerase I inhibitor with anti-HIF-1Alpha properties) conjugated to a linear, cyclodextrin-polyethylene glycol-based polymer
* CRLX101 has been shown to be safe, tolerable, and efficacious in numerous Phase II clinical investigations in a variety of tumor subtypes.
* Preclinical and clinical studies have shown CRLX101 significantly down-regulates HIF-1alpha, impacting tumor-driven angiogenesis.
* The treatment combination of CRLX101 and enzalutamide provides a reasonable approach to re-sensitizing prostate cancer cells to hormonal therapy via synergistic antitumor activity and inhibition of acquired resistance

Objectives:

-Primary Objective: To evaluate the anti-tumor activity of CRLX101 at the recommended phase II dose (RP2D) in combination with enzalutamide with respect to treatment response, defined as greater than or equal to 50% PSA decline or stable disease on imaging following 5 months of treatment.

Eligibility:

* Patients must have progressive mCRPC per Prostate Cancer Working Group 3(PCWG3)
* Patients must be at least 18 years of age and able to give informed consent
* Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2
* Evaluable metastatic disease on bone scan or measurable disease on computed tomography (CT) Scan per PCWG3 and/or Response Evaluation Criteria in Solid Tumors (RECIST)
* Patients must have had disease progression while receiving prior enzalutamide treatment

Design:

* The study will be conducted using an optimal two stage Phase II design (8 participants, expandable to 21 participants total) aimed to determine the percentage of participants with a prostate-specific antigen (PSA) decline of greater than 50% or stable disease at 5 months.
* The first 3 to 6 participants enrolled on study will follow a lead-in dosing scheme to confirm the safety of the combination (CRLX101 12 mg/m(2) every 2 weeks for the first two cycles, followed by CRLX101 15 mg/m(2) every 2 weeks at the start of cycle 3, with enzalutamide 160 mg administered once daily starting on cycle 1 day 2) prior to initiation of the optimal two stage study design.
* For participants enrolled on study following the lead-in, the confirmed tolerable dose of CRLX101 will be administered via intravenous (IV) infusion every 2 weeks. Enzalutamide 160 mg will be administered orally once daily beginning on cycle 1 day 2.
* Blood and urine will be collected at multiple time points for pharmacokinetic (PK) and pharmacodynamic (PD0 analyses.
* Tumor assessments will be made using Technetium-99 (99Tc) bone scintigraphy and/or CT scan (chest, abdomen, and pelvis) at baseline, prior to Cycle 3 and every 3 cycles thereafter.
* The accrual ceiling for the study is set at 30 participants.

Arms:
arm 1: Combination treatment of increasing dose of CRLX101 (formerly IT-101) with enzalutamide arm 2: Tolerable dose of CRLX101 (formerly IT-101) in combination with enzalutamide (8 participants, expandable to 21 total participants)

Interventions: intervention 1: enzalutamide intervention 2: CRLX101
Intervention descriptions: intervention 1: enzalutamide is an androgen receptor (AR) antagonist that is standard care therapy for metastatic prostate cancer intervention 2: CRLX101 is a nanoparticle-drug conjugate (NDC) comprised of a linear cyclodextrin-polyethylene glycol-base polymer conjugated to multiple 2 (S)-camptothecin (CPT) molecules (Poly-CD-PEG-Camptothecin)

Protocol document:
Prot_SAP_000.pdf: 
1 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
Abbreviated Title: CRLX101 in mCRPC 
NIH Protocol #: 18C0096   
Version Date: 12/18/2020 
NCT Number: NCT03531827 
 
Title: A Single Arm Phase II Study Combining CRLX101, a Nanoparticle Camptothecin, with 
Enzalutamide in Patients with Progressive Metastatic Castration Resistant Prostate Cancer 
Following Prior Enzalutamide Treatment 
 
Principal Investigator: 
 
Ravi A. Madan, M.D.  
 
 
 
 
 
Genitourinary Malignancies Branch 
 
 
 
 
 
CCR/NCI/NIH 
 
 
 
 
 
10 Center Drive 
 
 
 
 
 
Building 10, Room 13N240B 
 
 
 
 
 
Bethesda, MD 20892 
 
 
 
 
 
Phone: (301) 480-7168 
 
 
 
 
 
Fax: (301) 480-5094 
 
 
 
 
 
Email: madanr@mail.nih.gov  
 
 
Investigational Agents:     
Drug Name: 
CRLX101 
IND Number: 
138099 
Sponsor: 
Center for Cancer Research 
Manufacturer: 
Ellipses Pharma 
 
Commercial Agents: Enzalutamide  
 


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Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
PRÉCIS  
Background: 
• Enzalutamide is established as first-line hormonal therapy in participants with metastatic 
castration resistant prostate cancer (mCRPC). However, it is increasingly recognized that 
acquired resistance to therapy (e.g. AR overexpression, AR-V7) could limit the durability 
of response to therapy 
• Upregulation of HIF-1α in hypoxic tumor cells provides a mechanism of acquired 
resistance to current hormonal therapies and chemotherapies. Acquired resistance 
increases angiogenesis and metastasis, leading to disease progression 
• Targeting the hypoxia driven tumor microenvironment (e.g. down-regulation of HIF-1α) 
in addition to the androgen receptor (e.g. enzalutamide) has synergistic activity against 
prostate cancer cell line models (e.g. LNCaP, 22Rv1). 
• CRLX101 is a nanoparticle drug conjugate composed of 20(S)-camptothecin (a potent 
and highly selective topoisomerase I inhibitor with anti-HIF-1α properties) conjugated to 
a linear, cyclodextrin-polyethylene glycol-based polymer 
• CRLX101 has been to shown to be safe, tolerable, and efficacious in numerous Phase II 
clinical investigations in a variety of tumor subtypes.  
• Preclinical and clinical studies have shown CRLX101 significantly down-regulates HIF-
1α, impacting tumor-driven angiogenesis. 
• The treatment combination of CRLX101 and enzalutamide provides a reasonable 
approach to re-sensitizing prostate cancer cells to hormonal therapy via synergistic 
antitumor activity and inhibition of acquired resistance  
Objectives: 
• Primary Objective: To evaluate the anti-tumor activity of CRLX101 at the recommended 
phase II dose (RP2D) in combination with enzalutamide with respect to treatment 
response, defined as ≥50% PSA decline or stable disease on imaging following 5 months 
of treatment. 
Eligibility: 
• Patients must have progressive mCRPC per Prostate Cancer Working Group 3 (PCWG3) 
• Patients must be at least 18 years of age and able to give informed consent 
• ECOG Performance Status ≤ 2 
• Evaluable metastatic disease on bone scan or measurable disease on CT Scan per 
PCWG3 and/ or RECIST 
• Patients must have had disease progression while receiving prior enzalutamide treatment 
Design: 


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Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
• The study will be conducted using an optimal two stage Phase II design (8 participants, 
expandable to 21 participants total) aimed to determine the percentage of participants 
with a PSA decline of greater than 50% or stable disease at 5 months. 
• The first 3 to 6 participants enrolled on study will follow a lead-in dosing scheme to 
confirm the safety of the combination (CRLX101 12 mg/m2 every 2 weeks for the first 
two cycles, followed by CRLX101 15 mg/m2 every 2 weeks at the start of cycle 3, with 
enzalutamide 160 mg administered once daily starting on cycle 1 day 2) prior to initiation 
of the optimal two stage study design.  
• For participants enrolled on study following the lead-in, the confirmed tolerable dose of 
CRLX101 will be administered via IV infusion every 2 weeks. Enzalutamide 160 mg will 
be administered orally once daily beginning on cycle 1 day 2. 
• Blood and urine will be collected at multiple time points for PK and PD analyses. 
• Tumor assessments will be made using 99Tc bone scintography and/or CT scan (chest, 
abdomen, and pelvis) at baseline, prior to Cycle 3 and every 3 cycles thereafter.  
• The accrual ceiling for the study is set at 30 participants.  


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Version Date: 12/18/2020 
TABLE OF CONTENTS  
PRÉCIS .......................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 4 
STATEMENT OF COMPLIANCE .............................................................................................. 10 
1. 
INTRODUCTION ................................................................................................................ 10 
1.1 
Study Objectives ............................................................................................................ 10 
1.1.1 
Primary Objective ................................................................................................... 10 
1.1.2 
Secondary Objectives .............................................................................................. 10 
1.1.3 
Exploratory Objectives ........................................................................................... 11 
1.2 
Background and rationale............................................................................................... 11 
1.2.1 
Overview ................................................................................................................. 11 
1.2.2 
Enzalutamide........................................................................................................... 12 
1.2.3 
AR, HIF-1α and Intratumoral Hypoxia ................................................................... 13 
1.2.4 
Camptothecin Derivatives Investigated in Prostate Cancer .................................... 15 
1.2.5 
CRLX101 ................................................................................................................ 16 
1.2.6 
Targeting DNA Damage in Prostate Cancer ........................................................... 25 
1.3 
Rationale ......................................................................................................................... 26 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 26 
2.1 
Eligibility Criteria .......................................................................................................... 26 
2.1.1 
Inclusion Criteria .................................................................................................... 26 
2.1.2 
Exclusion Criteria ................................................................................................... 28 
2.1.3 
Inclusion of Minorities and Women ....................................................................... 29 
2.1.4 
Recruitment Strategies ............................................................................................ 29 
2.2 
Screening Evaluation ...................................................................................................... 29 
2.3 
Participant Registration and status update Procedures ................................................... 30 
2.3.1 
Treatment Assignment Procedures ......................................................................... 30 
2.4 
Baseline Evaluation ........................................................................................................ 30 
2.4.1 
Clinical Evaluation .................................................................................................. 30 
2.4.2 
Laboratory studies ................................................................................................... 31 
3 
STUDY IMPLEMENTATION ............................................................................................ 31 
3.1 
Study Design .................................................................................................................. 31 
3.1.1 
Lead-In Component ................................................................................................ 32 


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3.1.2 
Dosing Schema following Lead-In Component ..................................................... 34 
3.2 
Drug Administration ...................................................................................................... 34 
3.2.1 
CRLX101 ................................................................................................................ 34 
3.2.2 
Enzalutamide........................................................................................................... 36 
3.3 
Dose Modifications ........................................................................................................ 36 
3.3.1 
General Rules for Dosing Delays/Dose Modifications and Management of 
Toxicities ................................................................................................................ 36 
3.3.2 
CRLX101 Dose Modification ................................................................................. 36 
3.3.3 
Enzalutamide Dose Modification ........................................................................... 42 
3.4 
Study Calendar ............................................................................................................... 43 
3.5 
Cost and Compensation .................................................................................................. 47 
3.5.1 
Costs ........................................................................................................................ 47 
3.5.2 
Compensation ......................................................................................................... 47 
3.5.3 
Reimbursement ....................................................................................................... 47 
3.6 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 47 
3.6.1 
Criteria for removal from protocol therapy ............................................................ 47 
3.6.2 
Off-Study Criteria ................................................................................................... 47 
3.6.3 
Lost to Follow-up .................................................................................................... 48 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 48 
4.1 
General Guidelines ......................................................................................................... 48 
4.1.1 
Seizure threshold lowering drugs ............................................................................ 49 
4.1.2 
Cytochrome P450 and P-glycoprotein .................................................................... 49 
4.2 
SUPPORTIVE CARE .................................................................................................... 49 
4.2.1 
Concomitant medications........................................................................................ 49 
4.2.2 
Palliative radiotherapy ............................................................................................ 50 
4.2.3 
Administration of other anti-cancer agents ............................................................. 50 
4.2.4 
Medications that may NOT be administered .......................................................... 50 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 50 
5.1 
Correlative Studies for Research/Pharmacokinetic Studies ........................................... 50 
5.1.1 
Pharmacokinetics .................................................................................................... 51 
5.2 
Figg Lab Samples ........................................................................................................... 55 
5.2.1 
Plasma and Urine PK Sample Collection ............................................................... 55 


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5.2.2 
Plasma Protein Measurement (VEGF).................................................................... 55 
5.2.3 
Circulating Tumor Cells (CTCs) and AR Analysis ................................................ 55 
5.2.4 
EPIC Sciences ......................................................................................................... 56 
5.2.5 
AR Analysis ............................................................................................................ 56 
5.3 
Whole blood- Multiplexed gene expression approach to profiling DNA damage 
response signatures – Trepel Lab .............................................................................................. 56 
5.4 
Sample Storage, Tracking and Disposition .................................................................... 57 
5.4.1 
Clinical Pharmacology Program (Figg Lab) ........................................................... 57 
5.4.2 
Molecular Targets Core (Dr. Cao’s Lab) ................................................................ 58 
5.4.3 
Trepel Lab ............................................................................................................... 58 
5.4.4 
Future Use/IRB Reporting/Protocol Completion/Sample Destruction ................... 59 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 59 
6.1 
Data Collection ............................................................................................................... 59 
6.2 
Data Sharing Plans ......................................................................................................... 60 
6.2.1 
Human Data Sharing Plan ....................................................................................... 60 
6.2.2 
Genomic Data Sharing Plan .................................................................................... 60 
6.3 
Response Criteria ........................................................................................................... 61 
6.3.1 
Disease Parameters ................................................................................................. 61 
6.3.2 
Methods for Evaluation of Measurable Disease ..................................................... 62 
6.3.3 
Response Criteria .................................................................................................... 64 
6.3.4 
Duration of Response .............................................................................................. 66 
6.3.5 
Overall Survival ...................................................................................................... 66 
6.3.6 
Response Review .................................................................................................... 66 
6.4 
Toxicity Criteria ............................................................................................................. 66 
7 
NIH REPORTING REQUIREMENTS/ DATA AND SAFETY MONITORING PLAN ... 67 
7.1 
Definitions ...................................................................................................................... 67 
7.2 
OHSRP Office of Compliance and Training/IRB Reporting ......................................... 67 
7.2.1 
Expedited Reporting ............................................................................................... 67 
7.2.2 
IRB Requirements for PI Reporting at Continuing Review ................................... 67 
7.3 
NCI Clinical Director Reporting .................................................................................... 67 
7.4 
NIH Required Data and Safety Monitoring Plan ........................................................... 67 
7.4.1 
Principal Investigator/Research Team .................................................................... 67 


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8 
SPONSOR SAFETY REPORTING ..................................................................................... 68 
8.1 
Definitions ...................................................................................................................... 68 
8.1.1 
Adverse Event ......................................................................................................... 68 
8.1.2 
Serious Adverse Event (SAE) ................................................................................. 68 
8.1.3 
Life Threatening...................................................................................................... 68 
8.2 
Assessment of Safety Events .......................................................................................... 69 
8.3 
Reporting of Serious Adverse Events ............................................................................ 69 
8.4 
Safety Reporting Criteria To The Pharmaceutical Collaborators .................................. 70 
8.4.1 
To be sent by OSRO Safety .................................................................................... 70 
8.4.2 
To Be Reported by the Research team .................................................................... 70 
8.5 
Reporting Pregnancy ...................................................................................................... 71 
8.5.1 
Paternal Exposure ................................................................................................... 71 
8.6 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .................. 71 
9 
CLINICAL MONITORING ................................................................................................. 71 
10 STATISTICAL CONSIDERATIONS .................................................................................. 72 
10.1 Statistical hypotheses ..................................................................................................... 72 
10.1.1 
Primary efficacy endpoints ..................................................................................... 72 
10.1.2 
Secondary Efficacy endpoints ................................................................................. 72 
10.2 Sample size determination ............................................................................................. 72 
10.3 Populations for analysis ................................................................................................. 73 
10.4 Statistical analyses.......................................................................................................... 73 
10.4.1 
General approach .................................................................................................... 73 
10.4.2 
Analysis of the primary endpoints .......................................................................... 73 
10.4.3 
Analysis of the secondary endpoints ....................................................................... 73 
10.4.4 
Safety Analyses ....................................................................................................... 74 
10.4.5 
Baseline Descriptive Statistics ................................................................................ 74 
10.4.6 
Planned interim analyses ......................................................................................... 74 
10.4.7 
Exploratory analyses ............................................................................................... 74 
11 COLLABORATIVE AGREEMENTS ................................................................................. 75 
11.1 Cooperative Research and Development Agreement (CRADA) ................................... 75 
11.1.1 
Ellipses Pharma ....................................................................................................... 75 
12 HUMAN SUBJECTS PROTECTIONS ............................................................................... 75 


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12.1 Rationale For Subject Selection ..................................................................................... 75 
12.2 Participation of Children ................................................................................................ 75 
12.3 Participation of Subjects Unable to Give Consent ......................................................... 75 
12.4 Please see section 12.6.1 for consent procedure.   Evaluation of Benefits and 
Risks/Discomforts ..................................................................................................................... 75 
12.5 Risks/Benefits Analysis.................................................................................................. 75 
12.5.1 
Risks related to Imaging ......................................................................................... 76 
12.5.2 
Risks from Radiation Exposure .............................................................................. 76 
12.6 Consent Process and Documentation ............................................................................. 76 
12.6.1 
Consent Process for Adults Who Lack Capacity to Consent to Research 
Participation ............................................................................................................ 77 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS ......................................... 77 
13.1 Study Discontinuation and Closure ................................................................................ 77 
13.2 Quality Assurance and Quality Control ......................................................................... 77 
13.3 Conflict of Interest Policy .............................................................................................. 78 
13.4 Confidentiality and Privacy ............................................................................................ 78 
14 PHARMACEUTICAL INFORMATION ............................................................................. 79 
14.1 CRLX101 (#138099)...................................................................................................... 79 
14.1.1 
Source ..................................................................................................................... 79 
14.1.2 
Toxicity ................................................................................................................... 79 
14.1.3 
Handling and Dispensing ........................................................................................ 79 
14.1.4 
Formulation and preparation ................................................................................... 79 
14.1.5 
Stability and Storage ............................................................................................... 80 
14.1.6 
Dosage and Administration procedures .................................................................. 80 
14.1.7 
Incompatibilities ..................................................................................................... 80 
14.1.8 
Premedication and Hydration ................................................................................. 80 
14.1.9 
Return and Retention of CRLX101 ........................................................................ 80 
14.2 Enzalutamide .................................................................................................................. 81 
14.2.1 
Source ..................................................................................................................... 81 
14.2.2 
Toxicity ................................................................................................................... 81 
14.2.3 
Formulation and Preparation ................................................................................... 82 
14.2.4 
Storage and Stability ............................................................................................... 82 


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14.2.5 
Dosage and Administration Procedures .................................................................. 82 
14.2.6 
Incompatibilities and Drug-Drug Interactions ........................................................ 82 
15 REFERENCES ..................................................................................................................... 83 
16 APPENDIX A-Performance Status Criteria ......................................................................... 89 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on 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. 
 
1. INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
1.1.1.1 To evaluate the anti-tumor activity of CRLX101 at the recommended phase II dose 
(RP2D) combined with enzalutamide with respect to treatment response, defined as 
≥50% PSA decline or stable disease on imaging following 5 months of treatment. 
1.1.2 Secondary Objectives 
1.1.2.1 To evaluate the duration of response as defined by a sustained >30% decline in PSA, 
overall survival, and changes in measurable disease as determined by Response 


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Evaluation Criteria in Solid Tumors (RECIST) and Prostate Cancer Working Group 3 
(PCWG3) for the treatment combination. 
1.1.2.2 To validate the recommended phase 2 dose (RP2D) of CRLX101 in combination with 
enzalutamide 
1.1.3 Exploratory Objectives  
1.1.3.1 To evaluate the pharmacokinetic profile of CRLX101 (both total drug and released 
camptothecin) and enzalutamide in plasma. 
1.1.3.2 To evaluate the underlying mechanism of camptothecin-induced cystitis. 
1.1.3.3 To evaluate the pharmacodynamic activity of CRLX101 and enzalutamide using 
surrogate biomarkers to measure acquired treatment resistance mediated by 
angiogenesis and androgen receptor signaling (e.g. VEGF, CTCs, AR-V7). 
1.1.3.4 To evaluate the activity of CRLX101 and enzalutamide with respect to the prevalence 
of circulating tumor cells with high genomic instability.  
1.1.3.5 To explore possible correlations between clinical response and biomarkers of DNA 
damage response (e.g.  DNA damage response panel). 
1.2 
BACKGROUND AND RATIONALE  
1.2.1 Overview 
Prostate cancer is the most common cancer diagnosis among males in the United States, with 
180,890 estimated new cases each year, 26,120 of these cases resulting in death(1). 
Advancement in disease detection as well as improvements in the treatment of castration 
resistant disease has greatly contributed to more favorable patient outcomes. Androgen 
deprivation therapy (ADT) has long been a mainstay of initial prostate cancer management, but 
the disease inevitably progresses and becomes resistant to androgen ablation. Uncontrolled tumor 
growth despite adequate castrate levels of androgens (serum testosterone <50 ng/mL) indicates 
the failure of ADT and the development of castrate resistant prostate cancer (CRPC)(2). 
Advanced CRPC carries significant morbidity and mortality, and necessitates a transition in 
treatment. Treatment options with the capability to manage CRPC were limited until the U.S. 
Food and Drug Administration (FDA) approval of docetaxel in 2004. Two pivotal phase III 
randomized trials, TAX 327 and SWOG 99-16, demonstrated an overall survival benefit (with 
prednisone or estramustine, respectively) compared to mitoxantrone and prednisone.(3, 4) As of 
result, docetaxel would remain the only approved treatment for CRPC for approximately one 
decade. 
Following the approval of a second line chemotherapeutic, cabazitaxel, in 2010,(5) CRPC 
pharmacologic management has progressed rapidly. Continued drug development led to the first 
therapeutic vaccine for asymptomatic disease and a radioactive therapeutic agent for metastatic 
bone disease (sipuleucel-T and radium-223 respectively).(6, 7) Improvements in anti-androgen 
therapy provided a significant overall survival benefit in patients with metastatic CRPC 
(mCRPC). Two agents with improved pharmacologic properties to down-regulate androgen 
signaling, abiraterone acetate and enzalutamide, were initially approved in the post-docetaxel 
patient population via the COU-AA-301 and AFFIRM trials respectively.(8, 9) Additional 


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Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
studies investigating first line therapy in patients with mCRPC (COU-AA-302 and PREVAIL) 
led to the approval of both abiraterone acetate and enzalutamide for primary disease 
management.(10, 11) Currently, abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, 
sipuleucel-T, and radium-223 are all FDA approved therapies for patients with CRPC.  
Current approaches to maximizing efficacy of currently approved therapies include optimal 
treatment sequencing and limiting acquired resistance. The latter approach can be accomplished 
via combining treatment modalities, often incorporating agents that target resistance pathways 
that lead to CRPC or pluripotent tumor cells of the microenvironment. This clinical study is 
focused on combining the currently accepted standard of care (androgen receptor blockade via 
enzalutamide) with an experimental agent shown to reduce the metabolic signaling of hypoxic 
tumor (HIF-1α down-regulation via CRLX101). Dual inhibition of the androgen receptor (AR) 
and hypoxia inducible factor-1α (HIF-1α) in heavily pre-treated patients with progressive 
mCRPC is proposed to counteract acquired resistance and re-sensitize prostate cancer tumor cells 
to treatment.  
1.2.2 Enzalutamide 
Enzalutamide is a current standard of care therapy for patients with metastatic castration resistant 
prostate cancer (mCRPC). Developed as a second-generation androgen receptor antagonist 
(ARA), enzalutamide has significantly improved target affinity over previous ARAs (e.g. 
nilutamide, bicalutamide, and flutamide).(12, 13) Enzalutamide exhibits stronger affinity to the 
androgen receptor than previous ARAs while also preventing nuclear translocation, DNA 
binding, and signaling to co-activators (12). Initially approved in docetaxel refractory patients, 
enzalutamide has since received U.S. FDA approval as first line therapy for patients with 
mCRPC. Further investigation of enzalutamide is ongoing, evaluating the use of the drug in 
potential combination regimens and at different stages of prostate cancer (e.g. enzalutamide in 
combination with PROSTVAC in patients with mCRPC, neoadjuvant enzalutamide and 
androgen deprivation in newly diagnosed prostate cancer).  
Following a Phase I/II study of enzalutamide that demonstrated safety and suggested efficacy in 
both chemotherapy naïve and chemotherapy treated patients with mCRPC(14), two phase III 
studies were initiated: AFFIRM and PREVAIL. The AFFIRM trial enrolled 1199 patients with 
progressive mCRPC on docetaxel, who were then randomized 2:1 to enzalutamide 160 mg/day 
(n=800) or placebo (n=399). The overall survival favored patients randomized to enzalutamide 
versus placebo, 18.4 months to 13.6 months respectively. This 4.8 month improvement in 
survival represented a 37% risk reduction in death (hazard ratio (HR) 0.63; 95% CI: 0.53 to 0.75; 
P<0.001), the largest relative and absolute improvement in overall survival in an appropriately 
powered phase III study in prostate cancer. Median time to progression (TTP) based on 
radiographic findings was 8.3 vs. 2.9 months (HR: 0.40; 95% CI 0.35 to 0.47; P<0.001). Modest 
increases in fatigue, hot flashes, diarrhea, musculoskeletal pain, and headaches were reported in 
the enzalutamide group, but this was possibly related to the substantially longer monitoring time 
for patients on the treatment compared to the placebo group. Therefore, there were minimal 
concerns about the side effect profile of enzalutamide compared to placebo.(9) The U.S. FDA 
approved enzalutamide for patients with chemotherapy-refractory mCRPC in August of 2012.  
The PREVAIL trial enrolled 1717 patients with chemotherapy naïve mCRPC. Patients were 
randomized 1:1 to enzalutamide 160 mg/day (n=872) or placebo (n=845), with co-primary 


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endpoints of radiographic progression free survival and overall survival. The overall survival 
favored patients in the enzalutamide arm, with a 29% decrease in the risk of death at time of 
follow-up (HR 0.71; 95% CI, 0.60 to 0.84; P<0.001)(11). Estimates of median overall survival 
were 32.4 months and 30.2 months for the enzalutamide and placebo arms respectively. At 12 
months, the rate of radiographic progression free survival was 65% and 14% for patients on 
enzalutamide and placebo respectively (HR 0.19; 95% CI, 0.15 to 0.23; P<0.001). Fatigue and 
hypertension were the most common clinically relevant adverse events associated with 
enzalutamide(11). The U.S. FDA approved enzalutamide for chemotherapy-naïve mCRPC 
patients in August of 2014. 
1.2.2.1 Acquired Resistance in mCRPC 
Disease progression following monotherapy with enzalutamide is inevitable. Response to 
therapy diminishes over time, primarily due to acquired resistance of prostate cancer cells. While 
several mechanisms of resistance have been reported in the literature, splice variants of the 
androgen receptor have received the most attention. Currently, androgen receptor splice variant 7 
(AR-V7) is a biomarker of enzalutamide resistance that is approaching clinical utility. 
Antonararkis et. al. demonstrated that the presence of AR-V7, a splice variant without a ligand 
binding domain, was up-regulated in patients following treatment with either abiraterone acetate 
or enzalutamide. Importantly, Antonararkis et al. also validated the use of reverse transcriptase 
polymerase chain reaction (RT-PCR) to accurately detect AR-V7 messenger RNA in circulating 
tumor cells (CTCs)(15). Other means of detecting AR splice variants (e.g. droplet digital PCR) 
have been developed and are currently in use in clinical trial settings. It is accepted that the 
enumeration of CTC plasma concentrations can provide information about disease progression 
(16). 
A recent cohort analysis of patients with CRPC prior to abiraterone or enzalutamide treatment 
reported 107 of 150 patients (71.3%) harbored AR pathway alterations, a majority of which were 
direct alterations affecting the AR through amplification and mutation. Common AR mutations 
(e.g. T878A, W742C, L702H) and varying levels of AR splice variants were present in these 
patients. Alterations in AR pathway members (NCOR1, NCOR2, FOXA1) and the AR regulated 
gene, ZBTB16, were also present. Excluding the alterations of the AR pathway, 65% of patients 
had tumors with actionable aberrations, including alterations of pathways associated with HIF-1α 
signaling (PI3K/Akt/mTOR,(17), Wnt/β-catenin(18)) and mechanisms of DNA repair(19). In a 
separate study, increased AR copy number was found in a higher proportion of patients who did 
not respond to abiraterone than patients who responded(20). 
1.2.3 AR, HIF-1α and Intratumoral Hypoxia 
Intratumoral hypoxia is a common feature of prostate cancers that are associated with poor 
prognosis (21). Prostate cancer tumor cells acquire the ability to adapt to hypoxic environments 
caused by androgen deprivation, enhancing transcriptional activity of the androgen receptor.(22, 
23) Hypoxia Inducible Factor (HIF)-1α mediates key hypoxia-associated genes involved in 
angiogenesis, metabolism, survival, immunity and invasion(24-26). Several studies suggested the 
cross-talk between the HIF-1α and AR pathways, with emphasis on a potential ternary complex 
(AR, HIF-1α, and β-catenin) responsible for AR target genes (27-31). Given HIF-1α and AR are 
key regulators of multiple cellular processes in prostate cancer, dual targeting of both axes 
represents an attractive therapeutic approach.  


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Several experiments were initiated in an androgen-dependent prostate cancer cell line, LNCaP, to 
evaluate the effect of combining enzalutamide with HIF-1α inhibition. LNCaP cells cultured in 
the presence of low concentration of DHT under hypoxic conditions (simulated using CoCl2) had 
increased transcription of AR-dependent genes (KLK3, FKBP5, TMPRSS2) and hypoxia-
dependent genes (VEGF, ENO1, LDHA). Under the same conditions, chetomin, a disrupter of an 
interaction of HIF-1α with its transcriptional co-activator, p300, in combination with 
enzalutamide resulted in a significant decrease of the mRNA transcripts of AR-dependent and 
hypoxia-dependent genes. The direct knockdown of HIF-1α expression (via HIF-1α siRNA) in 
combination with enzalutamide suppressed AR transcriptional activation and VEGF protein 
expression in LNCaP cells. Similar effects on AR transcriptional activity and VEGF expression 
were also shown in 22Rv1 cells, an androgen resistant prostate cancer cell line. Simultaneous 
treatment with HIF-1α siRNA synergistically enhances the inhibitory effect of enzalutamide on 
LNCaP cell viability through increased apoptosis. The treatment combination was also effective 
at reducing the growth rate of the enzalutamide-resistant 22Rv1 prostate cancer cell line, which 
suggests that HIF-1α inhibition can restore sensitivity to enzalutamide-resistant cells(32). 
 
Figure 1: Synergy of dual AR inhibition and HIF-1α knockdown in both enzalutamide sensitive and enzalutamide 
resistant prostate cancer cell lines. Under hypoxic conditions, combination treatment with enzalutamide and HIF-1α 
siRNA led to decreased cell proliferation in both LNCaP (A) and 22Rv1 (B) cells. Under normoxic and hypoxic 
conditions, the combination treatment significantly reduced the luciferase activity of Androgen Receptor Response 


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Element (ARE) in both LNCaP (C) and 22Rv1 (D) cell lines, demonstrating a down-regulation of AR transcriptional 
activity. Similarly, the treatment combination demonstrated a reduction of downstream VEGF protein concentration 
in LNCaP (E) and 22Rv1 (F) cells. 
Multiple drugs have been shown to down-regulate the activity of HIF-1α.(33, 34) Camptothecins 
were found to modulate HIF-1α expression through a Topoisomerase I (Top1) dependent 
mechanism(35). Topotecan was shown to inhibit HIF-1α protein accumulation independently of 
proteosomal degradation in a time and dose dependent fashion. The accumulation of HIF-1α 
mRNA was not affected rather a decrease of HIF-1α protein translation was observed following 
metronomic topotecan treatment of U251 cells. The presence of Top1 for the facilitation of RNA 
transcription is necessary for topotecan-induced inhibition of HIF-1α protein accumulation(36). 
Kummar et. al. evaluated topotecan’s effects on HIF-1α in a pilot trial assessing patients with 
advanced solid tumors over-expressing HIF-1α(37). Biopsies of 4 patients showed undetectable 
levels of HIF-1α following treatment with topotecan in addition to decreased levels of VEGF and 
GLUT-1 mRNA(37). Decreased tumor blood flow and permeability were observed by DCE-MRI 
in 7 of 10 patients after 1 cycle. One patient had a partial response accompanied by inhibition of 
HIF-1α in tumor and reduction in tumor blood flow on DCE-MRI. This trial demonstrated that 
topotecan could decrease HIF-1α expression in advanced solid tumors.  
1.2.4 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 re-ligation, 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).(38-40) The administration of CPT in LNCaP cells was shown to down-regulate 
expression of the AR and PSA.(41) Camptothecin was shown to suppress the expression of 
matrix-metalloproteinase-9 (MMP-9) and VEGF through inhibition of NF-κB activity in DU145 
cells.(42) 
Topotecan use in prostate cancer has been limited, in part, due to its low efficacy and high non-
target toxicity. In a phase II study, 15 men with metastatic, PSA-progressive disease after 
primary androgen deprivation were given irinotecan at a dose of 125 mg/m2 weekly for 4 weeks 
followed by two weeks of rest (6 week cycles). None of the 15 patients had a decline in PSA of 
greater than 50%, and eight patients had stable disease as a best response. Hematologic and 
gastrointestinal toxicities were common, with granulocytopenia and diarrhea occurring most 
frequently.(43) In another phase II study, 26 men with hormone resistant prostate cancer who 
failed one or two prior androgen ablative therapies were administered 21-day continuous 
intravenous infusion of topotecan at a dose of 0.5 mg/m2 every 28 days. Of the 24 evaluable 
patients, four patients had PSA decline of 50% from baseline, 5 patients had stable disease as the 
best response, and the median (overall) survival was 9 months. Eight of 24 patients experienced 
grade 4 hematologic toxicity.(44) The discovery of topotecan and CPT as small molecule 


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inhibitors of HIF-1α has renewed interest in this class of drugs with development of novel 
derivatives or finding alternative dosing schedules. Indeed recent studies have shown that 
metronomic dosing increases the efficacy of topotecan in models of human prostate cancer.(45)  
Treatment of hypoxic 22Rv1 cells with topotecan has been shown to knockdown HIF-1α protein 
concentration. Decreased nuclear translocation of the full length AR and AR-V7 splice variant 
was found to be associated with topotecan-mediated knockdown of HIF-1α. Furthermore, the 
decreased nuclear AR-V7 levels following topotecan treatment was associated with increased 
sensitivity to enzalutamide.(46) These findings support the hypothesis that camptothecin-
mediated knockdown of HIF-1α could modulate enzalutamide resistance. 
1.2.5 CRLX101 
CRLX101, formerly named IT-101, is a nanoparticle-drug conjugate (NDC) comprised of a 
linear cyclodextrin-polyethylene glycol-base polymer conjugated to multiple 20(S)-camptothecin 
(CPT) molecules (Poly-CD-PEG-Camptothecin) (CRLX101 Investigator’s Brochure). Upon 
reconstitution, CRLX101 self-assembles into nanoparticles 20 to 30 nm in diameter and releases 
CPT over prolonged periods of time in a pH dependent manner. The unique properties of this 
nanoparticle allow for prolonged circulation in the plasma compartment, decreased hepatic and 
renal clearance, decreased recognition via the mononuclear phagocyte system, and enhanced 
localization to the tumor.(47, 48)  
Utilizing the Enhance Permeability and Retention (EPR)(49) effect, CRLX101 is able to 
selectively penetrate tumor tissue due to abnormally “leaky vasculature” and remain within the 
tumor for a prolonged period of time. CRLX101 provides sustained release of CPT from the 
polymer in the tumor for prolonged periods of time while maintaining a slow rate of clearance of 
unconjugated CPT into the plasma compartment. Animal xenograft models indicate that 
CRLX101 accumulates in solid tumors and releases CPT over several days to give sustained 
inhibition of its target. CRLX101 thus is proposed to optimize the potential antitumor activity by 
prolonging exposure in tumor tissue, providing more consistent tumor exposure compared to 
metronomic topotecan therapy, and improving tolerability with low systemic exposure.  
Drug localization analyses have been conducted in tumor collected from subjects with HER-2 
negative gastric cancer who enrolled in a clinical trial investigating CRLX101 monotherapy. 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 
CRLX101 and CPT were 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. The 
images obtained of these tumor samples show bright and highly resolved CPT signal specific to 
tumor tissue following treatment with CRLX101, with rare events of CPT signal co-localized 
with anti-PEG signal (Figure 2). A decrease in Carbonic Anhydrase XI (CAXI, a downstream 
effector of HIF-1α) was shown in 6 patients with tumor biopsies obtained pre and post-treatment 
with CRLX101. A separate study collected pre- and post- treatment biopsies from 3 subjects 
with ovarian cancer receiving CRLX101 15 mg/m2 monotherapy, 2 of whom had biopsies of 
sufficient quality for analysis. The post treatment tumor tissue showed evidence that CRLX101 


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and CPT are still present 6 days after the first dose of CRLX101. Additionally, staining with an 
antibody against γ-H2AX (used to visualize double strand DNA breaks) suggested that DNA 
damage persists for at least 6 days after the first dose of CRLX101 (CRLX101 Investigator’s 
Brochure). 
 
 
 
 
Figure 2: Immunofluorescence visualization in gastric cancer tumor tissue and adjacent normal tissue after the first 
dose with CRLX101 in subjects on the Gastric Cancer Investigator-Sponsored Trial. Left: Healthy adjacent tissue – 
24 hour post-treatment; Right: Tumor - 24 hour post-treatment;  
The payload of CRLX101 is CPT, a very potent topoisomerase 1 (topo-1) inhibitor, is largely 
active during cell replication, it is expected to produce effects on rapidly dividing normal tissues 
such as bone marrow and gastrointestinal mucosa are anticipated. Possible toxicities include: 
neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, mucositis, anorexia, and 
cystitis. However, nanoparticle drug conjugate (NDC) technology mitigated significantly these 
adverse events leading to a better safety profile due to accumulation of CPT in tumor cells. 
Commonly reported toxicities in clinical trials with  CRLX101 are anemia, fatigue, cystitis, 
nausea, hematuria, neutropenia, diarrhea, vomiting, dysuria, constipation, thrombocytopenia, 
decreased appetite, and infusion-related reaction.  
 
1.2.5.1 CRLX101 and HIF-1α Inhibition 
The HIF-1α inhibitory properties of camptothecin have been assessed in several breast cancer 
models. A comparison of camptothecin (CPT) and topotecan (TPT) administration in SUM159 
cells, a breast cancer stem cell line, showed the cells were more resistant to the cytotoxic effects 
of TPT than CPT (IC50 values of 35.3 nM vs. 8.6 nM, respectively). CPT showed a more potent 


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effect of decreasing HIF-1α accumulation in response to hypoxia, with TPT requiring greater 
than a 1000-fold higher dose to decrease HIF-1α compared to CPT. The combination of 
CRLX101 with bevacizumab, a VEGF inhibitor, was assessed in NOD/SCID mice injected with 
SUM159 cells. Combination therapy resulted in decreased tumor diameter, with higher doses of 
CRLX101 in combination with bevacizumab exhibiting the greatest effect. In regions of hypoxic 
tumor, the addition of CRLX101 to bevacizumab resulted in significant down-regulation of HIF-
1α (Figure 3). CRLX101 alone had the most significant effect on tumor volume compared to the 
combination with bevacizumab.(50) In addition, CRLX101 has shown activity in PC3 cells in 
vitro.(40)  
 
 
Figure 3: Hypoxyprobe staining of low oxygen zones (green) and HIF-1α staining (red) of tumors from a 
bevacizumab-treated mouse and a CRLX101 + bevacizumab-treated mouse. Scale bars 200 μM.  
 
CRLX101 maintains or improves tumor perfusion and reduces tumor density. CEUS and PA 
imaging, used to measure blood flow volume and oxygen saturation respectively, of LM2-4 
tumor xenografts characterized the ability of CRLX101 to restore functional vasculature to dense 
tumor tissue, enabling enhanced delivery of a secondary agent in combination (Figure 4). 
Paradoxically, high doses of CRLX101 did not promote the formation of micrometastases. 
CRLX101 with and without bevacizumab were evaluated in a post-surgical metastatic breast 


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cancer model of advanced breast cancer (YFP-SCID mice orthotopically implanted with LM2-4 
cells, followed by primary tumor resection when 400-500 mm3). CRLX101 prevented the 
emergence of new metastases in mice with no apparent metastases at the start of treatment and 
caused the regression of metastases in mice with apparent metastases. High doses of CRLX101 
significantly extended the survival of mice with metastatic disease, showing no significant 
benefit with the addition of bevacizumab.(51) 
 
Figure 4: CEUS and PA imaging of primary LM2-4 tumors. (A) Representative CEUS images of one tumor from 
each therapy group overlaid with parametric color mapping to show areas of high (red), low (blue) or no perfusion 
(black). (B) Representative PA images of the same tumors overlaid with color mapping to indicate areas of high 
(red) and low tissue oxygenation (blue). 
CRLX101’s ability to down-regulate HIF-1α was also demonstrated in a preclinical mouse 
model of advanced ovarian cancer. Preliminary Phase II clinical data assessing CRLX101 
monotherapy in patients with advanced platinum-resistant ovarian cancer demonstrated benefit in 
patients with RECIST-evaluable disease. Three of 19 patients had tumor reductions greater than 
or equal to 30%.(52) 
1.2.5.2 CRLX101 Preclinical Toxicology 
Dose-limiting toxicities 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 (CRLX101 Investigator’s 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.  
1.2.5.3 CRLX101 Pharmacokinetics 
The plasma exposure (as assessed by AUCall  [period of 24 hours post end of infusion]) of the 
polymer-conjugated and unconjugated camptothecin increased in a dose-dependent manner (6 to 
15 mg/m2). Comparison of the polymer-conjugated to unconjugated CPT exposure showed a 


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~11-fold increase in exposure for conjugated CPT relative to unconjugated CPT. The mean 
clearance and volume of distribution values for the conjugated CPT over the dose range 
evaluated were dose independent and ranged from 0.0914 to 0.132 L/hr and 2.33 to 4.63 L 
respectively. The T1/2 values appeared to be dose dependent with individual subject T1/2 values 
ranging from 19.9 to 42.0 hours and 27.5 to 111 hours for the conjugated and unconjugated 
species respectively.  
The polymer-conjugated and unconjugated camptothecin is primarily cleared via renal excretion. 
In vitro pharmacologic evaluation of CRLX101 with S9 liver microsomal fractions indicated no 
metabolites nor induction of cytochrome P450 enzymes following incubation up to 120 minutes. 
Additional studies showed CRLX101 bound moderately to rat RBCs and did not significantly 
inhibit CYP450 enzymes. In clinical evaluation of urinary excretion during the first 48 hours, the 
majority of CPT excreted was in the polymer-conjugated (16.2% of the total CRLX101 dose) 
compared to the unconjugated form (4.4% of the total CRLX101 dose). The majority of 
polymer-conjugated CPT was excreted in the first 24 hours, with a noteworthy decline in the 24- 
to 48-hour collection. Urinary clearance of unconjugated CPT was notably higher than that for 
polymer-conjugated CPT over all observation periods. Urinary clearance of unconjugated CPT in 
the first 48 hours following administration was similar over all collection periods and was not 
correlated with dose or creatinine clearance.  
The majority of subjects receiving CRLX101 15 mg/m2 or 18 mg/m2 every 2 weeks (Q2W) 
schedule had measurable levels of unconjugated CPT in plasma at 14 days post CRLX101 
administration. The values represented less than 3.1% of the respective mean Cmax values for 
each dose level. The lower dose group (12 mg/m2) on a Q2W schedule did not have any 
measurable levels of unconjugated CPT in their plasma by 14 days post CRLX101 
administration. A dosing interval greater than one week is required to avoid a significant carry-
over of unconjugated plasma CPT from one dose to the next. No polymer-conjugated CPT was 
detectable in plasma at 14 days post administration of CRLX101 for all Q2W administration 
groups. The data suggests CRLX101 dosed at 15 mg/m2 maintains a consistent low concentration 
of CPT in tumor tissue for 14 days post administration.  
1.2.5.4 CRLX101 Clinical Development Overview 
The safety and efficacy information for CRLX101 contained herein is based on the data available 
as of June 29, 2020. 
As of March 12, 2020, there have been 6 clinical trials sponsored by Cerulean (prior to April 17, 
2017) and NewLink Genetics (after April 17, 2017): CRLX-001, CRLX-002, CRLX101-208, 
CRLX101-209, CRLX101-102, and CRLX101-OVAR0801. Overall, 286 subjects received at 
least 1 dose of CRLX101 at doses ranging from 6 to 18 mg/m2 in these 6 NewLink Genetics-
sponsored studies 
There have been 8 investigator-sponsored trials (ISTs) with CRLX101, and as of March 12, 
2020, 193 subjects received at least 1 dose of CRLX101 at starting doses ranging from 12 to 15 
mg/m2 in these ISTs. 
When tested in the every two week (Q2W) schedule, the MTD/RP2D of CRLX101 monotherapy 
was determined to be 15 mg/m2 IV. CRLX101 has generally well-tolerated, and has shown 


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preliminary anti-tumor activity in subjects with solid tumors such as ovarian cancer and renal 
cell carcinoma.  
1.2.5.5 Dosing Considerations for CRLX101 
1.2.5.5.1 CRLX101 Monotherapy  
Patients with advanced solid malignancies were enrolled to an open-label, single-arm dose 
escalation study (Study CRLX-001). CRLX101 was administered intravenously over 60 minutes 
initially weekly at 6, 12, and 18 mg/m2, and later every other week at 12, 15, and 18 mg/m2. The 
MTD was determined to be 15 mg/m2 Q2W, and an expansion Phase 2a study was completed. 
See Section 1.2.5.7.1 for Adverse Event Information. 
More intensive once weekly dosing was assessed in patients with advanced solid tumors (Arm 1 
of Study CRLX101-102). CRLX101 was given once weekly at either 12 mg/m2 (N=7) or 15 
mg/m2 (N=8) intravenously over 1-2 hours for 7 weeks. Plasma pharmacokinetic analysis was 
performed at weeks 1, 3, and 7, measuring total conjugated CPT AUC0-168h and unconjugated 
CPT AUC0-168h. In plasma, >90% of the total CPT remains as the conjugated form, and the 
plasma exposure for both unconjugated and conjugated CPT from week 1 to 7 with no evidence 
of significant drug accumulation. One Grade 3 adverse event was reported for a subject receiving 
the 12 mg/m2 dose, which was considered a dose limiting toxicity (febrile neutropenia). The 
MTD for Arm 1 (CRLX101 QW alone) in this study was determined to be 15 mg/m2 once 
weekly.(53)  
1.2.5.5.2 CRLX101 Combination Therapy 
A Phase II study with a lead-in Phase I dose escalation combined CRLX101 and bevacizumab in 
patients with metastatic renal cell carcinoma (mRCC). The dose escalation assessed a 12 mg/m2 
dose of CRLX101 (given every 2 weeks) in combination with the FDA approved dose of 
bevacizumab (10 mg/m2 given every 2 weeks) in dose level 1 (N=3) and the 15 mg/m2 dose of 
CRLX101 in combination with bevacizumab in dose level 2 (N=3). The 15 mg/m2 dose of 
CRLX101 was determined to be the recommended Phase II dose and 27 total patients were 
evaluated for safety on the study. Bevacizumab, a drug without significant overlapping toxicities, 
did not exhibit additive toxicity when used in combination with CRLX101. An observed increase 
in Grade 3/4 cystitis with CRLX101 and bevacizumab is likely attributed to the impaired healing 
of the bladder tissue following the accumulation of camptothecin (CRLX101 Investigator’s 
Brochure).(54) See Section 1.2.5.7.2 for more information on adverse events and Section 1.2.5.9 
for more information on camptothecin-induced cystitis. 
More intensive once weekly dosing of CRLX101 in combination with bevacizumab was assessed 
in patients with advanced solid tumors (Arm 2 of Study CRLX101-102). 7 subjects were treated 
with CRLX101 at the 12 mg/m2 dose intravenously once weekly, with one reported DLT (Grade 
3 cystitis). Eight subjects were treated with CRLX101 at the 15 mg/m2 dose, with 2 reported 
DLTs (both Grade 3/4 neutropenia). The first subject required a dosing delay of >2 weeks 
following the second week of dosing (meeting definition of DLT), whereas the second patient 
experienced febrile neutropenia 4 days following the Week 4 dose of CRLX101. The Safety 
Review Committee (SRC) deemed it reasonable to administer CRLX101 15 mg/m2 once weekly 
for three weeks with one week off in combination with bevacizumab Q2W, thus declaring this 
dosing schema the MTD for this combination. Once weekly intravenous CRLX101 at 12 mg/m2 


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in combination with bevacizumab Q2W was also considered an acceptable dose (CRLX101 
Investigator’s Brochure).(53)  
1.2.5.6 Efficacy of CRLX101 Therapy 
The following efficacy information includes data as of March 12, 2019 per CRLX101 
Investigator’s Brochure version 15. 
CRLX-001 – Phase 1/2a Study: Of 44 subjects with advanced solid tumors treated with 
CRLX101 at the MTD (15 mg/m2 IV Q2W), 28 (64%) subjects had a best overall response of 
stable disease (SD) per RECIST criteria. For a subset of subjects treated with NSCLC treated at 
the MTD, 16 patients (73%) subjects had SD. Stable disease was documented for 6 or more 
cycles of treatment with CRLX101 in 7 (16%) subjects treated at the MTD and in 4 (18%) 
subjects with NSCLC treated at the MTD. Median PFS for subjects treated with CRLX101 at the 
MTD and for those treated at the MTD in the NSCLC population (3.7 months and 4.4 months, 
respectively) was similar to the median PFS for these subjects on prior cancer therapy (4.0 
months and 4.5 months, respectively).  
CRLX-002 – Phase 2 NSCLC Study: The median OS (mOS) of patients treated with CRLX101 
(15 mg/m2 IV Q2W) + BSC was 6.3 months (95% CI: 4.70, 8.68). The mOS for the BSC alone 
arm, by comparison, was 11.9 months (95% CI: 6.74, not evaluable). More subjects in the 
CRLX101 + BSC arm were treated with surgery, XRT, and ≥2 lines of antineoplastic regimens 
compared with subjects in the BSC alone arm. Discontinuation due to symptomatic deterioration 
and withdrawal by subjects was reported at a higher frequency in the BSC alone arm. Thus, the 
survival estimate may be biased due to a much higher number of censored subjects (~50%) in the 
BSC arm. 
CRLX101-208 – Phase 2 mRCC Study: As of March 12, 2020, this study completed accrual, but 
the clinical study report has yet to be finalized. The primary endpoint was median progression-
free survival (mPFS) for the clear cell renal carcinoma population (n=102), with secondary 
endpoints including overall response rate, duration of response, and overall survival. mPFS was 
3.7 months for the CRLX101 (15 mg/m2 IV Q2W) + bevacizumab (10 mg/m2 IV Q2W) 
treatment group vs. 3.9 months for the standard of care arm (HR: 1.25; p=0.822). The 95% 
confidence interval for PFS for the combination treatment group was 2.0 months to 4.3 months 
vs. 2.2 months to 5.4 months for the standard of care arm. Objective response rate by 
independent radiological review for the combination treatment group was 5% (2/42) compared 
with 14% (6/43) for the standard of care group (p=0.836). 
CRLX101-209 – Phase 1b/2 Ovarian Cancer Study: A total of 30 patients received CRLX101 
(12 mg/m2 IV Q2W or 15 mg/m2 IV Q2W) + paclitaxel (80 mg/kg on Day 1, 8, and 15 of a 28-
day cycle). One of 30 subjects (3.3%) achieved a complete response, 7 of 30 subjects (23.3%) 
achieved a partial response and 16 of 30 subjects (53.3%) had stable disease. The median 
duration of response was 6.0 months. Of 19 subjects who had previously failed bevacizumab, 5 
subjects (26.3%) achieved a partial response. Note: Efficacy data reporting cut-off was March 
12, 2019.  
CRLX101-102 – Phase 1 Advanced Solid Tumor Study: A total of 14 patients with advanced 
solid tumors receiving CRLX101 (12 mg/m2 IV weekly or 15 mg/m2 IV weekly) ± bevacizumab 
(10 mg/m2 IV Q2W) were evaluable. Five subjects had PRs: one subject with SCLC receiving 


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CRLX101 15 mg/m2 monotherapy, one subject with rectal cancer receiving CRLX101 12 mg/m2 
+ bevacizumab, and one subject with RCC receiving CRLX101 12 mg/m2 + bevacizumab. Eight 
subjects had stable disease.  
1.2.5.7 Adverse Events with CRLX101 Therapy 
The safety information for CRLX101 is based on the data available as of March 12, 2020. 
(CRLX101 Investigator’s Brochure) Provided below is the summary of the overall safety 
assessment: 
• Across all studies, 479 subjects experienced a total of 309 serious adverse events (SAEs) 
during the reporting period.  
• During the reporting period, serious adverse reactions (SARs) have been reported in 13 
subjects in the CRLX101-209 study and 7 subjects in Study CRLX101-102. None of the 
subjects in Study CRLX101-208 or in the Investigator-sponsored trials experienced an 
SAR during the reporting period 
• A total of 20 deaths were reported during the reporting period, including 15 in Study 
CRLX101-208, 4 in Study CRLX101-209 and 1 in an Investigator-sponsored trial (NCI 
16-C-0107).  
1.2.5.7.1 CRLX101 Monotherapy/Dose Escalation Studies 
Study CRLX-001 (Phase 1/2a Solid Tumors): Thrombocytopenia, neutropenia, anemia, and 
leukopenia were dose limiting following weekly administration of CRLX101 18 mg/m2 via IV 
infusion. Thrombocytopenia and neutropenia were dose-limiting following treatment with 
CRLX101 18 mg/m2 every other week (Q2W), leading to the MTD of CRLX101 15 mg/m2 
administered IV Q2W. The majority of TEAEs were Grade 1 or 2. The commonly reported 
treatment-related TEAEs (>10% of subjects) were: fatigue (23 subjects, 37%), cystitis (17 
subjects, 27%); nausea (12 subjects, 19%); anemia (12 subjects, 19%); dysuria (11 subjects, 
18%); hematuria (11 subjects, 18%); neutropenia (9 subjects, 15%);diarrhea (7 subjects, 11%); 
and vomiting (6 subjects, 10%). Among the 44 subjects treated at the MTD, of whom 22 had 
NSCLC, the commonly reported treatment-related TEAEs were fatigue (15 subjects, 34%); 
cystitis (11 subjects, 25%); nausea (10 subjects, 23%); anemia (6 subjects, 14%); dysuria (6 
subjects, 14%); and neutropenia (5 subjects, 11%). Three subjects had serious infusion-related 
hypersensitivity, which were resolved without sequelae.  
Study CRLX101-102 (Phase 1 Solid Tumors): In patients receiving CRLX101 12 mg/m2 IV 
weekly, the following serious adverse events were observed: febrile neutropenia (1 subject, 
14.3%), thrombocytopenia (1 subject, 14.3%), and small intestinal obstruction (1 subject, 
14.3%). In patients receiving CRLX101 15 mg/m2 IV weekly, the following serious adverse 
events were observed: pericarditis (1 subject, 12.5%), pain (1 subject, 12.5%), cognitive disorder 
(1 subject, 12.5%), dyspnea (1 subject, 12.5%), and pulmonary edema (1 subject, 12.5%). 
Study CRLX-002 (Phase 2 NSCLC): A total of 97 subjects were treated with CRLX101 15 
mg/m2 IV Q2W + best supportive care (BSC).) At least 1 TEAE related to the study drug was 
reported for 53 subjects (55%) and at least one Grade ≥3 TEAE was reported for 18 subjects 
(19%). The commonly reported TEAEs regardless of grade (>88%) were: anemia (19 subjects, 
20%), nausea (10 subjects, 10%), and cystitis (8 subjects, 8%). The following Grade ≥3 TEAEs 


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were reported in more than one patient: neutropenia (2 subjects, 2%). One TEAE with a fatal 
outcome was reported for one subject (atrial flutter, suspected to be related to study drug). 
1.2.5.7.2 CRLX101 and Bevacizumab 
A total of 49 subjects were treated with CRLX101 and bevacizumab on 3 different schedules 
(CRLX101 12 mg/m2 QW and bevacizumab Q2W, N=7; 15 mg/m2 CRLX101 QW and 
bevacizumab Q2W, N=4; 15 mg/m2 CRLX101 Q2W and bevacizumab Q2W, N=55).  
For patients treated with CRLX101-208, at least 1 TEAE related to study treatment (CRLX101 
15 mg/m2 IV Q2W + bevacizumab 10 mg/m2 IV Q2W) was reported for 54 subjects (98.2%) and 
at least 1 Grade ≥3 TEAE was reported for 17 subjects (34.7%). The commonly reported TEAEs 
regardless of grade (>10%) were: fatigue (21 subjects, 38.2%), nausea (16 subjects, 29.1%), 
constipation (10 subjects, 18.2%), anemia (8 subjects, 14.5%), decreased appetite (7 subjects, 
12.7%), non-infective cystitis (7 subjects, 12.7%), diarrhea (6 subjects, 10.9%), headache (6 
subjects, 10.9%), epistaxis (6 subjects, 10.9%) and proteinuria (6 subjects, 10.9%). The 
following Grade ≥3 TEAEs were reported in more than one subject: fatigue (4 subjects, 7.3%), 
anemia (3 subjects, 5.5%), hypertension (3 subjects, 5.5%), vomiting (1 subject, 1.8%), and 
headache (1 subject, 1.8%). One TEAE with a fatal outcome was reported for one subject 
receiving CRLX101 15 mg/m2 IV Q2W and bevacizumab 10 mg/m2 IV Q2W (sudden death, 
suspected to be related to study drug) 
For patients treated on CRLX101-102, the following serious adverse events were reported in the 
CRLX101 12 mg/m2 IV weekly + bevacizumab 10 mg/m2 IV Q2W: vomiting (2 subjects, 
28.6%), nausea (1 subject, 14.3%), constipation (1 subject, 14.3%), chest pain (1 subject, 
14.3%), urinary tract infection (1 subject, 14.3%), tremor (1 subject, 14.3%), noninfective 
cystitis (1 subject, 14.3%), hematuria (1 subject, 14.3%), and renal failure (1 subject, 14.3%). No 
serious adverse events reported in the CRLX101 15 mg/m2 IV weekly + bevacizumab 10 mg/m2 
IV weekly treatment group.  
1.2.5.7.3 CRLX101 and Paclitaxel 
A total of 30 subjects were treated with CRLX101 and paclitaxel on 2 different dose cohorts: 
CRLX101 12 mg/m2 IV Q2W and paclitaxel 80 mg/kg IV QW (3 out of 4 weeks), N=3; 
CRLX101 15 mg/m2 IV Q2W and paclitaxel 80 mg/kg IV QW (3 out of 4 weeks), N=27). In the 
CRLX101 12 mg/m2 Q2W + paclitaxel group, there was a report of an attempted suicide (1 
subject, 33.3%). The following serious adverse events were reported in the CRLX101 15 mg/m2 
Q2W and paclitaxel group: small intestinal obstruction (2 subjects, 7.4%), infusion-related 
reaction (2 subjects, 7.4%), skin infections (2 subjects, 7.4%), uncoded respiratory disorders (2 
subjects, 7.4%), abdominal pain (1 subject, 3.7%), ascites (1 subject, 3.7%), infectious 
enterocolitis (1 subject, 3.7%), hyperglycemia (1 subject, 3.7%), and non-infective cystitis (1 
subject, 3.7%). There have been four deaths reported on this study: three subjects died of disease 
progression and the cause of death for one subject was not related to treatment or disease.  
1.2.5.8 Hypersensitivity Reactions 
Infusion related reactions (IR) have been observed in a small number of subjects treated with 
CRLX101. IRs are observed in other nanotechnologies and may occur in a higher incidence 
when CRLX101 is combined with weekly paclitaxel. Most IRs associated with CRLX101 are 
mild and moderate, reversible upon study drug interruption. In general, subjects restarted 


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Abbreviated Title: CRLX101 in mCRPC 
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CRLX101 infusion at a slower rate without recurrence. Mandatory premedication has been 
implemented in all CRLX101 protocols. In addition, it is recommended that the duration of 
CRLX101 infusion be prolonged from 1 hour to 2 hours for at least the first 4 infusions. In a few 
severe cases, a simple desensitization protocol allowed patients to continue therapy. 
1.2.5.9 Camptothecin-Induced Cystitis 
Cystitis is a common adverse event following CRLX101 administration. The proposed 
mechanism of toxicity involves the reclosing of the camptothecin lactone ring once the drug is 
cleared into the more acidic pH of the bladder. The closed lactone ring leads to reactivation of 
camptothecin, thus increasing the likelihood for off-target effect and subsequent toxicity in the 
bladder. The current management of the risk for cystitis involves dilution of the urine via 
increased hydration. Alkalinization of the urine is another proposed method of prophylaxis, 
which could be achieved via sodium bicarbonate administration. Although higher urine pH will 
limit the concentration of active camptothecin, it could lead to higher release of CPT from intact 
CRLX101 nanoparticles that are cleared renally. The use of sodium bicarbonate to circumvent 
high grade camptothecin-induced cystitis requires further investigation. 
In vitro experiments were conducted at varying pH levels in urine following a 72-hour 
incubation at 37°C to measure the release of CPT from the CRLX101 nanoparticle and the ratio 
of lactone to carboxylate of the unconjugated CPT. While increasing pH lead to an increased rate 
of CPT release, the ratio of CPT species favored the carboxylate form, especially at pH values of 
8 or greater (See Figure 5). Despite a higher concentration of total CPT, urine alkalinization led 
to a decrease in the active lactone form compared to lower urine pH values. 
 
Figure 5: Total concentration of free CPT released from CRLX101 at various pH values (left) and the percentage 
of carboxylate form graphed against percentage of lactone form at various pH values (right). 
Sodium Bicarbonate for Rapid Onset Urine Alkalinization 
In a prospective open-label trial, 9 healthy volunteers were given 4 grams of sodium bicarbonate 
orally 3 times daily for 24 hours. All participants had a urine pH of at least 7 after 10 hours and a 
urine pH of at least 8 at 20 hours. During the 24 hour follow-up, no adverse effects or abnormal 
blood results were documented.(55) 
1.2.6 Targeting DNA Damage in Prostate Cancer 
Alterations of DNA repair pathways have been shown to be a significant mechanism of 
resistance following the failure of androgen deprivation therapy.(19) A phase II trial in patients 


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with mCRPC previously treated with chemotherapy and abiraterone/enzalutamide examined the 
efficacy of administering olaparib and evaluated the correlation of clinical response with the 
genomic signature. Following assessment of DNA repair genes, 16 patients were identified to 
have homozygous deletions, deleterious mutations, or both (BRCA1/2, ATM, Fanconi’s anemia 
genes, CHEK2), with 14 of 16 patients responding to olaparib.(56) The characterization of DNA 
repair alterations in patients with progressive mCRPC before and after treatment with CRLX101, 
a topoisomerase I inhibitor, may provide useful information for future hypothesis generation 
and/or clinical investigation. 
Identification of CTCs with high genomic instability from their phenotypic features alone has 
been used to classify patients with resistance to taxanes and AR targeted therapies. An algorithm 
with a cut point for high genomic instability (an indication of homologous recombination 
deficiency [HRD+]) was found to maximize prognostication for standard of care drugs. The 
overall prevalence of CTCs with high phenotypic genomic instability in patients following AR 
targeted therapy was 27% (36 of 134 patients), and was associated with inferior OS times 
(HR=7.69, p<0.0001).(59) In a follow-up study using this alogorithm, the CTC HRD+ phenotype 
cell counts were shown to increase on average from baseline (9 to 24 HRD+ CTCs/patient) in 
patients receiving abiraterone alone. By comparison, patients receiving abiraterone and veliparib 
(a PARP inhibitor [PARPi]) were shown to have a decrease in CTC HRD+ phenotype cell counts 
on average (17 to 3 HRD+ CTCs/patient).(60) The serial assessment of CTCs using this 
algorithm could aid in characterizing the effect of CRLX101 and enzalutamide on acquired 
resistance attributable to genomic instability.  
1.3 
RATIONALE 
Acquired resistance to enzalutamide monotherapy limits the durability of response in both the 
first line and second line treatment setting.(61) Dual targeting of the AR and HIF-1α axis 
represents a novel therapeutic approach for CRPC treatment, with the inhibition of HIF-1α as a 
possible mechanism for overcoming enzalutamide resistance and potentiating anti-androgen/AR 
therapy.(32, 46) The treatment combination of enzalutamide and CRLX101, a HIF-1α inhibitor, 
is aimed to reduce cross-talk of both androgen receptor and HIF-1α signaling pathways, reverse 
enzalutamide resistance and increase time to progression. To test this concept, this pilot study 
will examine the efficacy of combination therapy to determine if further investigation is 
warranted.  
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have histologically or cytologically confirmed prostate cancer confirmed 
by either the Laboratory of Pathology at the NIH Clinical Center or Walter Reed 
National Military Medical Center at Bethesda prior to starting this study. If no 
pathological specimen is available, patients may enroll with a pathologist’s report 


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showing a histological diagnosis of prostate cancer and clinical course consistent with 
the disease.  
2.1.1.2 Patients must have progressive mCRPC. There must be radiographic evidence of 
disease progression or biochemically (rising PSA levels on successive measurements) 
recurring disease despite adequate testosterone suppression.  
2.1.1.3 Progression must be evidenced and documented by any of the following parameters: 
• PSA progression defined by a minimum of two rising PSA levels with an interval of 
≥1 week between each determination 
• Appearance of one or more new lesions consistent with prostate cancer on bone 
scan 
• New or growing lesions on CT scan 
2.1.1.4 Patients must have metastatic disease, per RECIST 1.1(62). See Section 6.3 for the 
evaluation of measurable disease.  
2.1.1.5 Patients must have received treatment with prior enzalutamide for two or more cycles 
and must have had evidence of disease progression while on enzalutamide.  
2.1.1.6 Patients who have received antiandrogens such as flutamide, bicalutamide, or 
nilutamide for >6 months immediately before enrollment on this study must be off 
treatment for 4 weeks (6 weeks for bicalutamide) and demonstrate a continued rise in 
PSA. Patients on antiandrogens for <6 months must be off medication for 2 weeks.  
2.1.1.7 Age >18 years. Because no dosing or adverse event data are currently available on the 
use of enzalutamide and CRLX101 in patients <18 years of age and prostate cancer is 
not common in children <18 years of age, children are excluded from this study. 
2.1.1.8 Patients must have adequate organ and marrow function as defined below:  
− leukocytes  
 
 
 
 
>3,000/mcL 
− absolute neutrophil count 
 
>1,500/mcL 
− platelets  
 
 
 
 
 
>100,000/mcL 
− total bilirubin 
 
 
 
 
within normal institutional limits; for 
patients with Gilbert’s syndrome, total bilirubin ≤3.0 mg/dL 
− hemoglobin   
 
 
 
 
≥9 g/dL 
− serum albumin  
 
 
 
≥ 2.8 g/dL  
− AST(SGOT)/ALT(SGPT)  
<2.5 X institutional upper limit of normal  
(<5 X institutional ULN for liver 
metastases) 
− creatinine 
 
 
 
 
 
within 1.5X normal institutional limits 
 
OR 
− creatinine clearance  
 
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal. 


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Abbreviated Title: CRLX101 in mCRPC 
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2.1.1.9 Patients must have castrate levels of testosterone (<50 ng/dL [1.74 nmol/L]). 
2.1.1.10 Patients must have undergone bilateral surgical castration or must continue on GnRH 
agonists/antagonists for the duration of the study. 
2.1.1.11 Patients on 5-alpha reductase inhibitors such as finasteride or dutasteride must stop 
medication at least 28 days prior to study entry. 
2.1.1.12 The effects of enzalutamide and CRLX101 on the developing human fetus are 
unknown.  For this reason and because androgen receptor antagonists and 
topoisomerase I inhibitors as well as other therapeutic agents used in this trial are 
known to be teratogenic, all study subjects must agree to use a condom during the study 
treatment period and for 120 days following the last dose of study drug.  Should a 
woman become pregnant or suspect she is pregnant while her partner is participating in 
this study, she should inform her treating physician immediately. 
2.1.1.13 ECOG performance status ≤2 (Karnofsky >60%, see APPENDIX A). 
2.1.1.14 Ability of subject to understand and the willingness to sign a written informed consent 
document. 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients who are receiving any other investigational agents. A minimum washout period 
of 28 days is required prior to the initiation of on study treatment, unless the patient is 
receiving immunotherapy, for which the minimum washout period will be 14 days. This 
is because Immune-related toxicities are distinct and unlikely to synergize with this 
protocol therapy, a shorter washout period is reasonable and customary in clinical trials. 
2.1.2.2 Patients who have been treated with prior secondary hormonal manipulations with 
proposed investigational rationale for having efficacy against AR-V7 splice variants. 
This includes but is not limited to EPI-002 and AZD5312. (Note: patients previously 
treated with abiraterone, orteronel (TAK-700), apalutamide (ARN-509), galeterone, or 
VT-464 will be eligible for this study. Patients who have received prior chemotherapy 
will also be eligible for this study). 
2.1.2.3 Patients with known brain metastases should be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events. 
2.1.2.4 Patients with a recent (within 1 year) history of seizure or any condition that, in the 
opinion of the investigator, significantly increases seizure risk. Also current or prior 
treatment with anti-epileptic medications for the treatment of seizures. Transient 
ischemic attack within 12 months prior to study enrollment will not be permitted. 
2.1.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to enzalutamide, CRLX101, or other agents used in study. 
2.1.2.6 Patients with a history within the last 3 years of another invasive malignancy (localized 
non-melanoma skin and bladder cancers are allowed). 
2.1.2.7 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 


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Abbreviated Title: CRLX101 in mCRPC 
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arrhythmia, uncontrolled hypertension (SBP>170/DBP>105), or psychiatric 
illness/social situations within 6 months that would limit compliance with study 
requirements. 
2.1.2.8 Patients who have received palliative radiotherapy within 2 weeks of study entry and 
have not recovered to Grade 1 or baseline from associated toxicities. Note: Patients may 
receive palliative radiation once enrolled on study, as per guidance outline in Section 
4.2.2.The subject 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. 
2.1.2.9 Patients who are unable to swallow tablets or have a gastrointestinal disease that could 
hinder the absorption of enzalutamide 
2.1.2.10 The use of any herbal products that may lower PSA levels (e.g. saw palmetto). 
2.1.2.11 Patients with microscopic hematuria (defined as >100 RBCs on urinalysis) or 
worsening urinary symptoms within 7 days prior to the initiation of study treatment. 
2.1.2.12 Known HIV-positive patients on antiretroviral therapy are ineligible because of 
potential pharmacokinetic interactions with study drugs. However, patients with long-
standing (>5 years) HIV on antiretroviral therapy >1 month (undetectable HIV viral 
load and CD4 count > 150 cells/µL) may be eligible if the Principal Investigator or 
designee determines no anticipated clinically significant drug-drug interactions.  
2.1.3 Inclusion of Minorities and Women 
Men of all races and ethnic groups are eligible for this trial. Women are excluded as prostate 
cancer does not exist in this population. 
2.1.4 Recruitment Strategies 
This study will be listed on available websites (e.g. www.clinicaltrials.gov) and on NIH social 
media forums. Additionally, participants will be recruited from the current patient population at 
NIH. 
2.2 
SCREENING EVALUATION 
Note: screening evaluation testing/procedures are conducted under the separate screening 
protocol, 01-C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural 
Research Program Clinical Protocols). 
 
The following tests may be obtained any time prior to enrollment:  
• Pathological confirmation of diagnosis and PSA expression in either the Laboratory of 
Pathology at NIH Clinical Center, Walter Reed National Military Medical Center at 
Bethesda. However, if no pathologic specimen is available, participants may enroll with a 
pathologist’s report showing a histologic diagnosis of prostate cancer and a clinical 
course consistent with the disease. 
The following parameters will be obtained within 30 days prior to enrollment (unless otherwise 
noted):  


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• Tc-99 whole body scintigraphy  
• CT of chest/abdomen /pelvis (MRI may be substituted at investigator’s discretion).  
• History and physical examination with ECOG and vital signs  
• Serum PSA  
• Complete blood count plus differential and platelet count  
• Hepatic and Acute Care panels  
• Testosterone level  
• Urinalysis  
• EKG 
2.3 
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 here. 
2.3.1 Treatment Assignment Procedures 
2.3.1.1 Cohorts 
Number 
Name 
Description 
1 
Lead-in Cohort 
First 3-6 participants with metastatic castration resistant prostate 
cancer receiving escalating doses of CRLX101 
2 
Combination Treatment 
Cohort  
Up to 21 participants with metastatic castration resistant prostate 
cancer receiving tolerable dose of CRLX101 
2.3.1.2 Arms 
Number 
Name 
Description 
1 
Lead-in safety  
Combination treatment of increasing dose of CRLX101  with 
enzalutamide  
2 
Efficacy  
Tolerable dose of CRLX101 in combination with enzalutamide (8 
participants, expandable to 21 total participants) 
2.3.1.3 Arm Assignment  
Participants in cohort 1 will be directly assigned to arm 1 based on enrollment time in the study. 
Participants in cohort 2 enrolled after the lead-in study will be directly assigned to arm 2. 
2.4 
BASELINE EVALUATION 
The following parameters will be obtained within 14 days prior to start of treatment (unless 
otherwise noted): 
2.4.1 Clinical Evaluation  
• History and physical examination  


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• ECOG performance status  
• Height, Weight  
• Baseline EKG 
2.4.2 Laboratory studies  
• Complete blood count plus differential and platelet count  
• Acute care panel  
• Hepatic panel  
• Mineral panel  
• LDH, CK, Uric Acid, Total Protein  
• Urinalysis within 7 days prior to treatment  
• Serum PSA  
• Activated partial thromboplastin time (APTT) and International normalized ratio (INR) 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is an open label single arm phase 2 study that will explore the potential benefit of CRLX101 
in combination with enzalutamide in participants with progressive mCRPC following prior 
enzalutamide treatment. Participants meeting eligibility criteria will be enrolled into a single 
cohort to receive standard of care enzalutamide at the FDA-approved dose (160 mg orally once 
daily) in combination with CRLX101 administered as a via IV infusion if given every 2 weeks as 
monotherapy). The duration of each cycle will be 28 days. Please note, participants taking 
Enzalutamide at the time of enrollment will not be required to stop. 
Blood and urine will be collected at multiple time points for PK, PD analyses as described in 
Section 5.1. For logistical purposes, participants may be admitted to the inpatient unit for 
frequent serial sample collections on select cycles.  
Toxicity will be graded according to CTCAE version 5.0. Participants will be treated until 
radiographic progression on scans using RECIST v1.1(62) and PCWG3(2, 63) criteria. 
The primary endpoint of this trial will be treatment response (defined as ≥50% PSA decline or 
stable disease at 5 months), with secondary endpoints including duration of response (defined as 
sustained >30% decline in PSA), overall response and changes in measurable disease using 
RECIST v1.1 and PCWG3 criteria.  


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3.1.1 Lead-In Component 
 
Figure 6: Lead-In Dosing Schema and DLT Assessment 
For the first 3 to 6 participants, there will be a lead-in period of two cycles to ensure the safety 
and tolerability of CRLX101 in combination with enzalutamide. CRLX101 will be started at a 
dose of 12 mg/m2, administered via IV infusion on Day 1. Enzalutamide will be administered 
orally at a dose of 160 mg once daily starting on Day 2 (C1D2) once the 24-hour 
pharmacokinetic sample timepoint has been collected (at least 24 hours after the end of the 
CRLX101 infusion). After the first dose on C1D2, Enzalutamide will be taken once daily for the 
full duration of the study. Participants will receive CRLX101 12 mg/m2 via IV infusion on Cycle 
1 Day 15 (C1D15), Cycle 2 Day 1 (C2D1), and Cycle 2 Day 15 (C2D15). On Cycle 3 Day 1 
(C3D1), and Cycle 3 Day 15 (C3D15), CRLX101 will be administered at the previously 
established MTD (15 mg/m2 administered via IV infusion). Participants will be assessed from 
Day 1 to Day 56 (C1D1 to C2D28) for dose limiting toxicities of the CRLX101 12 mg/m2 dose 
and from Day 57 to 84 (C3D1 to C3D28) for dose limiting toxicities of the CRLX101 15 mg/m2 
dose (Enzalutamide will be at approximate steady state concentration following Day 29 [C2D1]). 
Following the DLT assessment period (at the start of Cycle 4), each participant will continue to 
receive CRLX101 at the participant’s specific maximum tolerated dose via IV infusion every 2 
weeks (Days 1 and 15) for every subsequent cycle. 
For the purposes of this study, re-assessment of the CRLX101 RP2D will be determined based 
on DLTs deemed likely attributable to CRLX101. DLTs are outlined in Section 3.1.1.1 and the 
dose modification procedures of CRLX101 are outlined in 3.3.2. Adverse events deemed 
attributable to enzalutamide will not influence the on-trial treatment of subsequent participants 
and will be managed according to the dose modification protocol outlined in Section 3.3.3. Final 
determination of the drug attributable to an adverse event is at the discretion of the Principal 
Investigator or designee.  
If none of the three participants experience a dose limiting toxicity during the lead-in phase (Day 
1-84), subsequent participants enrolled on trial with receive CRLX101 at a dose of 15 mg/m2 via 
IV infusion every 2 weeks.  
If one of three participants experience intolerable toxicity during the lead-in phase, an additional 
3 participants will be enrolled with no adjustments to the lead-in dosing schema. If no further 
toxicity is observed (or a total of 1 in 6 participants experience dose-limiting toxicity), 


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Abbreviated Title: CRLX101 in mCRPC 
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subsequent participants enrolled on study will receive CRLX101 at a dose of 15 mg/m2 every 2 
weeks. If 2 of 6 participants experience a dose limiting toxicity, the dose at which the DLT 
occurred will determine further action:  
• If both participants experience a DLT attributable to CRLX101 at a dose of 15 mg/m2 or 
only one participant experiences a DLT at 12 mg/m2, subsequent participants will receive 
CRLX101 at 12 mg/m2 every 2 weeks. 
• If both participants experience a DLT attributable to CRLX101 at a dose of 12 mg/m2, 
participants will be given one dose of CRLX101 at 9 mg/m2.  
o If further toxicity is observed with the 9 mg/m2 dose, an amendment to modify 
dosing strategies will be considered. If necessary, the RP2D will be determined at 
the discretion of the Principal Investigator or designee after factoring in 
participant specific characteristics and the nature of the adverse event.  
Based on limited potential for overlapping toxicity and well-characterized pharmacokinetics for 
both enzalutamide and CRLX101, it is anticipated 3 participants will participate in the lead-in 
phase. An accrual ceiling of 6 participants for the lead-in phase will be used to account for 
possible dose adjustments based on DLTs.  
3.1.1.1 Dose Limiting Toxicity  
Dose-limiting toxicity (DLT) is defined as an adverse event that is related (possibly, probably, or 
definitely) to the administration of CRLX101. DLTs (toxicities occurring within the first 84 days 
of treatment after the first intravenous infusion of CRLX101) will be defined using the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
The following events will be considered DLTs if deemed drug-related: 
• Grade ≥3 neutropenia complicated by fever ≥38.5°C (i.e. febrile neutropenia and/or 
documented infection. 
• Grade 4 neutropenia that does not improve within 5 days * 
• Grade 4 thrombocytopenia that does not resolve within 5 days* or any grade 3-4 
thrombocytopenia complicated with hemorrhage; 
• Grade 4 anemia that does not resolve within 7 days despite optimal therapy (withholding 
study drug and red blood cell transfusion); 
• 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 lasts less than 72 hours whether treated with an optimal anti-emetic or anti-
diarrheal regimen or not; or alkaline phosphatase changes) 
• Failure to receive at least 75% of study drug doses during cycle 1 due to toxicity. 
• Laboratory results of 3xULN elevation of transaminases and concomitant 2xULN total 
bilirubin without an alternative etiology 
• Any toxicity resulting in greater than two weeks of dose delay. 


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*Note: In the event of a Grade 4 neutropenia or thrombocytopenia, a full blood count must be 
performed no more than 5 days after the onset of the event to determine if a DLT has occurred. 
The subject will be closely monitored until the resolution to Grade 3 or less. 
3.1.2 Dosing Schema following Lead-In Component 
 
Figure 7: Dosing schema following the lead-in component.  
Following the DLT assessment during the lead-in component and validation of the RP2D, 
participants enrolled thereafter will not participate in the lead-in period. Participants will receive 
CRLX101 at the RP2D established during the lead-in component via IV infusion on Cycle 1 Day 
1 (C1D1). Enzalutamide will be administered orally at a dose of 160 mg once daily beginning on 
Cycle 1 Day 2 (C1D2), at least 24 hours after the end of the infusion of CRLX101. After the first 
dose on C1D2, Enzalutamide will be taken once daily for the full duration of the study. 
Participants will receive CRLX101 at the established RP2D via IV infusion on C1D15 and on 
Days 1 and 15 of each subsequent cycle.  
Following establishment of the RP2D, enrollment on this study will continue until 8 participants 
are evaluable for the primary endpoint. If 3 or more participants achieve response, then 
additional participants will be enrolled until a total of 21 participants have been evaluated for the 
primary endpoint. The accrual ceiling is set for 30 participants, to account for participants that 
are inevaluable or participants that do not tolerate treatment in the lead-in phase. For more 
details, refer to Section 8. 
3.2 
DRUG ADMINISTRATION 
3.2.1 CRLX101 
CRLX101 will be diluted with 5% dextrose for injection (D5W) to a total volume of 500 mL and 
should be infused intravenously over 60-75 minutes (See 13.1). Nothing else should be added 
to the bag. 
The CRLX101 infusion should begin immediately after preparation and diluted CRLX101 
infusion solution not used within 6 hours should be destroyed following institutional practices. 


35 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
Hypersensitivity reaction (HSR) have been observed in a small number of subjects treated with 
CRLX101. Most HSR associated with CRLX101 are mild and moderate, reversible upon study 
drug interruption. In general, subjects restarted CRLX101 infusion at a slower infusion rate 
without recurrence. In addition to the mandatory premedication to prevent HSR, the duration of 
CRLX101 infusion must be prolonged from 1 hour to 2 hours (+/- 10 minutes) in participants 
who have experienced a previous infusion-related reaction. 
3.2.1.1 Hydration and Premedication Prior to CRLX101 Treatment  
Subjects will receive IV hydration infused approximately over two hours with up to 1,000 mL of 
0.9% sodium chloride solution before and after the administration of CRLX101 to reduce risk of 
cystitis adverse reaction. The administration rate and volume should follow standard site 
procedures and may be adjusted by the Principal Investigator or designee based on patient-
specific factors. Participants should be encouraged to adequately hydrate throughout the cycle, 
especially during the first 48 hours following the infusion of CRLX101. 
Subjects should be pre-medicated with the following drug classes 30-90 minutes prior to start of 
CRLX101 infusion to reduce likelihood of hypersensitivity adverse reactions: 
• a corticosteroid (dexamethasone 20 mg IV or PO) 
• an antihistamine (diphenhydramine 50 mg IV or PO) 
• an H2 antagonist (famotidine 20 mg IV or PO; 30-60 minutes prior to start of CRLX101) 
• an anti-emetic, (e.g., a 5-HT3 receptor antagonist)  
At the discretion of the Principal Investigator or designee, a 650 mg dose of Acetaminophen PO 
may also be given.  
The drug recommendations can be adjusted per local institutional guidelines with approval from 
the Principal Investigator  or designee.  
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 participant safety during the study (for example, if a participant experiences a 
hypersensitivity/infusion reaction related to study drug, the premedication regimen may be 
altered for subsequent cycle dosing based on the Principal Investigator or designee’s discretion). 
3.2.1.2 Sodium Bicarbonate Administration with CRLX101 Treatment 
Participants will undergo an experimental urine alkalinization protocol in addition to IV 
hydration on C2D15 (See Section 5.1.1.2). Participants will receive sodium bicarbonate orally 
pre- and post-CRLX101 infusion on C2D15. Details about recommended dosing are outlined 
below (Table 1) and in Section 5.1.1. All other doses of CRLX101 will be given with IV 
hydration as described above. At the discretion of the Principal Investigator or designee, the 
strength, frequency, and/or schedule of oral sodium bicarbonate dosing may be modified on a 
participant by participant basis.    
Table 1: Recommended Oral Alkalinization Pre- and Post-CRLX101 Infusion 
Timing 
Dose, route, and frequency 


36 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
Starting from 48 hours prior to 
CRLX101 infusion 
Take sodium bicarbonate by mouth, 650mg x2, 4 times a day 
(QID), for two days before CRLX101 infusion 
On the day of CRLX101 
infusion 
Take sodium bicarbonate by mouth, 650mg x2, 4 times a day 
(QID), for one day 
After CRLX101 infusion 
Take sodium bicarbonate by mouth, 650mg x2, 4 times a day 
(QID), for one day after CRLX101 infusion 
At the discretion of Principal Investigator or designee, participants who are prone, or likely, to 
develop cystitis may be recommended to receive either oral or intravenous sodium bicarbonate 
pre and/or post CRLX101 administration. 
3.2.2 Enzalutamide 
All participants will receive enzalutamide 160 mg orally, daily starting cycle 1 day 2 (C1D2). 
Enzalutamide may be administered with or without food. It is recommended that enzalutamide 
be administered daily in the evenings, however, daily administration time of enzalutamide is 
based on participant preference.  
3.3 
DOSE MODIFICATIONS 
3.3.1 General Rules for 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 participant has a dose reduction for toxicity, the dose will not be increased. 
• A maximum of two dose reductions are permitted 
• If either agent is discontinued due to toxicity, the participant 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. When 
logistically feasible, willing participants will remain on the study to have additional 
assessments.  
• For AEs that are unrelated to the study drugs, dose may be held for up to 28 days at the 
discretion of the Principal Investigator or designee. 
• 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.  
3.3.2 CRLX101 Dose Modification 
3.3.2.1 General Recommendations  
The lead-in dosing schema is designed to ensure against significant drug-drug interactions 
between CRLX101 and enzalutamide. If dose modifications are necessary, the general approach 
to dose modification is listed in Table 2. Such dose modifications should be followed according 
to the dose level in which the participant experiences an undesirable adverse event (See Section 


37 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
3.1.1 for Lead-in schema rules). Adverse events should be treated with the appropriate maximum 
intervention and dose reductions should be clearly documented in participant notes.  
Table 2: Guidelines for CRLX101 Dosing Reductions 
 
CRLX101 Dosage Schedule 
Initial Dosing 
First dose reduction 
Second dose reduction 
Dose Level 1 
12 mg/m2  
9 mg/m2  
6 mg/m2  
Dose Level 2 
15 mg/m2  
12 mg/m2  
9 mg/m2  
3.3.2.2 CRLX101-Related Hematologic Toxicities 
Table 3: Dose Modification and Management of Hematologic Adverse Events (CRLX101) 
Cycle 
Day 
Grade or 
count 
(cells/mm3) 
Dose Delay or Reduction for Hematological Toxicity  
(Phase 2 stage and after Cycle 1 of a new dose level in lead-in 
stage) 
Neutropenia 
1 or 15 
 
 
  
Grade 2 
(<1500)  
• For first neutropenic eventa, delay CRLX101 dose until ≤ Grade 
1, resume CRLX101 with no dose change  
• For second neutropenic eventa, delay CRLX101 until ≤ Grade 1, 
resume CRLX101 with no dose change, add G-CSFb support 
• For third neutropenic eventa, delay dose until ≤ Grade 1, resume 
CRLX101 with the dose reduced by one dose level, continue G-
CSFb support 
≥ Grade 3 
(<1000) 
• For first neutropenic eventa, delay CRLX101 dose until ≤ Grade 
1, resume CRLX101 with no dose change, add G-CSFb support 
• For second neutropenic eventa, delay CRLX101 until ≤ Grade 1, 
resume CRLX101 with dose reduced by one dose level, continue 
G-CSFb support 
• For third neutropenic eventa, delay dose until ≤ Grade 1, resume 
CRLX101 with the dose reduced by one further dose level, 
continue G-CSFb support 
Thrombocytopenia 
1 or 15 
<100,000 
• Delay CRLX101 dose until ≥ 100,000 


38 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
Cycle 
Day 
Grade or 
count 
(cells/mm3) 
Dose Delay or Reduction for Hematological Toxicity  
(Phase 2 stage and after Cycle 1 of a new dose level in lead-in 
stage) 
• Resume CRLX101 with no dose change 
Grade 2 
(<75,000) and 
Grade 3 
(<50,000) 
• Delay dose forCRLX101 until ≥ 100,000 
• Resume CRLX101 with no dose change (the dose may be 
reduced one dose level or kept at the same dose at the discretion 
of the Principal Investigator or designee) 
 
if grade 2 or grade 3 recurs,  
• Hold dose for CRLX101 until ≥ 100,000 
• Resume CRLX101 with dose reduced by one dose level  
Grade 4 
• Hold dose for CRLX101 until ≥ 100,000 
• Resume CRLX101 with dose reduced by one dose level  
• Do not make up missing dose 
Anemia 
1 or 15 
≥ Grade 3 
(<8g/dL) 
• Delay dose for CRLX101, and consider RBC transfusion(s) 
based on clinical criteria 
• After improved to ≤ Grade 2, resume CRLX101 with no dose 
change (the dose may be reduced one dose level or kept at the 
same dose at the discretion of the Principal Investigator or 
designee) 
• Consider EPO support per guidelines 
 
If Grade 3 recurs,  
• Delay dose for CRLX101, and consider RBC transfusion(s) 
based on clinical criteria 
• After improved to ≤ Grade 2, resume CRLX101 with dose 
reduced by one dose level 
• Consider EPO support per guidelines 


39 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
Cycle 
Day 
Grade or 
count 
(cells/mm3) 
Dose Delay or Reduction for Hematological Toxicity  
(Phase 2 stage and after Cycle 1 of a new dose level in lead-in 
stage) 
Grade 4 
• Delay dose for CRLX101, and consider RBC transfusion(s) 
based on clinical criteria 
• After improved to ≤ Grade 2, resume CRLX101 with dose 
reduced by one dose level 
• Consider EPO support per guidelines. 
a A neutropenic event is defined as ≥ Grade 2 neutropenia on D1 or ≥ Grade 3 neutropenia on 
Day 15 
b G-CSF (filgrastim or equivalent, pegfilgrastim is also permitted) should not start until at least 
24 hours after discontinuation of chemotherapy. Discontinue G-CSF once ANC is 
≥1000/mm³.  Wait at least 24 hours after G-CSF is discontinued before resuming 
chemotherapy. 
• Treatment may be delayed for a maximum of 28 days after holding the treatment for 
toxicities that develop and do not resolve as defined above (exemptions: lymphopenia, or 
leukopenia in the absence of grade 3 or higher neutropenia). 
• Bi-weekly blood counts will be obtained throughout the study. If any evaluation 
demonstrates grade ≥ 3 neutropenia or grade ≥ 2 thrombocytopenia, a repeat hematology 
assessment will be obtained 2-4 days later.  
• Management of prolonged hematological toxicities while on study treatment 
If a participant 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 x 109/L)  
• ≥3 week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia (Platelets < 50 x 109/L)  
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 could be considered (may be done at an outside facility). If any blood 
parameters remain clinically abnormal after 4 weeks further investigations could be considered 
including hematology evaluation. Bone marrow analysis and/or blood cytogenic analysis could 
be considered at this stage according to standard hematological practice.  


40 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
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. 
3.3.2.2.1 Neutropenia 
In the lead-in stage, subjects will not receive growth factors prior to C1D1 and prophylactic use 
of growth factors is prohibited during the first 3 cycles (Days 1-84) or until neutropenia is 
identified as a DLT (at discretion of the Principal Investigator or designee), whichever comes 
first. Growth factors can be used during a drug hold to assist the recovery and in subsequent 
cycles after a drug hold. Please note that G-CSF should not be used within at least 24 hours of 
the last dose of CRLX101 treatment.  
In the Phase 2 stage, subjects may receive growth factors prophylactically at the discretion of the 
Principal Investigator or designee.  
3.3.2.2.2 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 participant develops bleeding, platelet transfusions 
should be administered in accordance with the standard of practice, usually maintaining a platelet 
count above 50,000/mcL 
3.3.2.2.3 Anemia 
Symptomatic anemia should be treated with red blood cell transfusion and is recommended if the 
hemoglobin falls below 8 g/dL or the participant is symptomatic. Erythropoietin (EPO) may also 
be given per clinical guidelines. 
3.3.2.3 CRLX101-Related Non-Hematologic Adverse Events 
Table 4: Dose Modification and Management of Non-Hematologic Adverse Events (CRLX101) 
Observation 
Action 
Grade 1 or 2 AEs resolves 
promptly (within 48 hours) with 
supportive care 
Maintain dose level (DL) 
Any ≥ 3 non-hematologic* 
Hold study drug(s) causing the toxicity for up to 28 days 
until toxicity resolves to ≤ Grade 1. Treatment with 
CRLX101 may be restarted at one DL lower, as per the 
dose reduction guidelines. 
Lab abnormalities that can be readily corrected (e.g. 
electrolyte abnormalities) do not require a dose reduction 
unless by discretion of the PI or designee.  
Grade 3 or 4 non-hematologic AE 
related to drugs that does not 
Remove participant from CRLX101 therapy. 


41 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
Observation 
Action 
resolve to grade 1 or less within 
28 days despite maximum 
supportive care after treating 
participant at the lowest reduced 
DL 
Toxicities requiring more than 2 
dose reductions 
Remove participant from CRLX101 therapy. 
* 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 
3.3.2.4 Management of the hypersensitivity/infusion reactions 
Table 5: Dosing modification and management of hypersensitivity reactions (CRLX101) 
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 Principal Investigator or 
designee’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 the slower rate. 
Additionally, if an HSR occurs upon re-administration at the slower 
infusion rate, the participant will be removed from study. 
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 or designee to determine 
whether to discontinue from study drug treatment. Confirm that rate 
of administration was appropriate and pre-meds were given as 
suggested. 
If opting to resume CRLX101 infusion following Grade 1 or 2 HSR, administration of CRLX101 
should be over 120 minutes (+/- 10 minutes) (using the following infusion schedule) with 
additional pre-medications (dexamethasone 20 mg PO or IV, famotidine 20 mg IV or PO, 
acetaminophen 650 mg PO, ondansetron 16 mg PO or IV, and diphenhydramine 50 mg PO or 
IV). 


42 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
CRLX101 in 500 mL 5% dextrose IV infusion: 
• 15 mL/hr for 15 minutes, then increase to 
• 30 mL/hr for 15 minutes, then increase to 
• 60 mL/hr for 15 minutes, then increase to 
• 120 mL/hr for 15 minutes, then increase to 
• 240 mL/hr for 15 minutes, then increase to 
• 480 mL/hr for 15 minutes, then increase to 
• 528 mL/hr for 30 minutes to complete infusion 
Please note: a gradual increase in rate may be used in place of incremental rate increases. 
Infusion rates may also be adjusted at the discretion of the investigator. 
If a subject has a history of infusion related reactions to other drug treatments, or has many 
environmental allergies (e.g. food, pollen), the total infusion time may be slowed during the first 
CRLX101 infusion and for all subsequent infusions, at the discretion of the Principal Investigator 
or designee. 
3.3.3 Enzalutamide Dose Modification 
If a participant experiences a ≥ Grade 3 non-hematologic toxicity (except hypertension) 
attributable to enzalutamide, withhold dosing for up to 1 month or until symptoms improve to ≤ 
Grade 2, then resume at the same dose if clinically appropriate. If toxicity recurs and/or in the 
judgment of the investigator dose reduction is appropriate, lower dose levels (120 mg/DL-1 or 80 
mg/DL-2), may be considered. Enzalutamide may be discontinued if toxicity recurs and dose 
modification is no longer clinically appropriate.  
3.3.3.1 Enzalutamide Dose Delay 
Enzalutamide may be continued within 28 days if an appointment is missed due to scheduling or 
logistical issues (e.g. vacation, weather) during the treatment period. If more than 28 days have 
elapsed, participant will need to be seen to assess continuation of treatment procedure.


43 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
 
3.4 
STUDY CALENDAR 
On study assessment can be performed within ±7 days of the specified time, unless otherwise indicated. CRLX101 can be given 
within ±2 days of the specified time, unless otherwise indicated.  
Table 6: Study Calendar 
Procedure 
1Screening/ 
Baseline 
Cycle 1 
Cycle 2 
Subsequent Cycles 
2Disease  
Progression 
3End of 
Treatment 
4Long Term 
Follow-Up 
Day 1 
Day 2 
Day 15 
Day 1 
Day 15 
Day 1 
Day 
 15 
History and PE 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Score 
X 
 
 
 
 
 
 
 
 
 
 
5Pathologic Confirmation of Dx 
X 
 
 
 
 
 
 
 
 
 
 
6CBC/Diff 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
7Acute Care Panel w/ Mineral Panel, Hepatic 
Panel, LDH, CK, Uric Acid, Total Protein 
8X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
9Urinalysis 
10X 
X 
 
 
 
X 
 
 
 
 
 
Serum PSA 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Serum Testosterone 
X 
X 
 
 
X 
 
X 
 
X 
 
 
11EKG 
X 
X 
 
X 
X 
 
 
 
 
 
 
Tumor Assessment: CT scan (chest, abdomen 
& pelvis), 99Tc bone scintography 
X 
 
 
 
 
 
12X 
 
X 
 
 


44 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
Procedure 
1Screening/ 
Baseline 
Cycle 1 
Cycle 2 
Subsequent Cycles 
2Disease  
Progression 
3End of 
Treatment 
4Long Term 
Follow-Up 
Day 1 
Day 2 
Day 15 
Day 1 
Day 15 
Day 1 
Day 
 15 
CRLX101 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
Enzalutamide 
 
 
X 
 
 
 
 
 
 
 
 
13Plasma PK 
 
X 
 
 
 
X 
 
 
 
 
 
13Urine PK 
 
X 
 
 
 
X 
 
 
 
 
 
14VEGF Biomarker, CTC, and Whole Blood  
Collection 
 
X 
 
 
 
X 
15X 
 
X 
 
 
14NanoString Sample Collection 
 
X 
 
 
 
X 
 
 
X 
 
 
Adverse Events 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
16APTT, INR 
X 
 
 
 
 
 
 
 
 
 
 
Survival Phone Call 
 
 
 
 
 
 
 
 
 
 
X 
1Baseline procedures are performed within 2 weeks of initiation of study therapy. Screening labs may also be used as baseline/Day 1 
labs if performed within two weeks of study initiation.  Height and weight must be done within 14 days of the first study dose. 
2To be completed on the day disease progression is noted according to PCWG3 and/or RECIST criteria. May be completed within 30 
days or at end of treatment visit if logistically necessary and feasible. Subject may also be contacted by phone to assess adverse events 
if unwilling or unable to come to NIH.”  
3To be completed within 30 days after the last dose of study therapy, presuming logistically feasible. The study team may contact the 
participant by phone to assess adverse events if unwilling or unable to come to NIH.  


45 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
4After the end of treatment visit the participant will receive a phone call every 6 months to assess for survival until expiration.  
5Pathologic confirmation should be obtained at any point prior to enrollment. If no pathological specimen is available, participants 
may enroll with a pathologist’s report showing the histological diagnosis of prostate cancer and clinical course consistent with disease. 
Participant may begin therapy based on evidence of disease progression if pathologic confirmation is not available at the time of study 
enrollment.  
6Includes Neutrophils, Lymphs, Monos, Eos, Basos, WBC, RBC, Hemoglobin, Hematocrit, RBC Indices, MCV, RDW, Platelets, and 
RBC Indices. Results should be available prior to administration of study drugs. If absolute differentials are not available, percentage 
differentials are acceptable. 
7Acute Care Panel: Sodium (Na), Potassium (K), Chloride (Cl) Total CO2 (Bicarbonate), Creatinine, random Glucose, urea or blood urea 
nitrogen [BUN], eGFR; Hepatic Panel: Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin;  Mineral Panel: 
Albumin, Calcium, Magnesium, Phosphorous; Lactate Dehydrogenase (LDH); Creatine Kinase (CK);  Uric Acid; Total Protein; 
8Only the Acute Care and Hepatic panels are required at screening 
9Additional urinalysis will be performed as clinically indicated in the investigator’s judgment. 
10To be done within 7 days prior enrollment/treatment. 
11Must be completed within 14 days prior to the first study dose of CRLX10. Please note: EKGs are required within 60-180 minutes 
post-infusion on C1D1, C1D15 and C2D1 of CRLX101 for participants with any conduction abnormality on baseline ECG.  
12Tumor Assessments will be performed prior to or on C3D1, C6D1, C9D1, and every 3rd cycle thereafter until evidence of disease 
progression. Primary endpoint assessment will be conducted following tumor assessment on C6D1.  
13See Section 5.1.1 for complete details about PK biospecimen collection time points on C1D1 and C2D15. The exact time of the draw 
should be recorded.  
14Samples are to be collected prior to treatment on the specified days. For samples collected prior to dosing on C1D1, the sample may 
be collected during baseline assessment or any time following baseline assessment but prior dosing on C1D1. Following disease 
progression, samples should be collected within 30 days, if logistically feasible. 
15After sample collection on C2D15, samples will be collected prior to C6D1 and at disease progression for VEGF measurement, CTC 
analysis, and whole blood collection. 
16Coagulation [activated partial thromboplastin time (APTT) and international normalized ratio (INR)] will be performed at baseline 
and if clinically indicated unless the participant is receiving warfarin. Participants taking warfarin may participate in this study; 


46 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
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. 


47 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
 
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 performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not 
covered by insurance company.  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 study, effort must be made to have all subjects complete an end of 
treatment visit approximately 30 days after 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 Section 3.3 
• Toxicity related dose delay lasting longer than 28 days in which case participant will be 
removed from the drug causing the toxicity 
• Investigator discretion 
• Requirement for any drug deemed to cause an significant drug-drug interaction that could 
impact the study treatment (at discretion of the PI and/or Associate Investigator and as 
discussed in Section 4.1) 
3.6.2 Off-Study Criteria 
• Participant requests to be withdrawn from study 
• Death 
• PI decision to end the study 
• Participant lost to follow up  


48 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
• Investigator’s discretion  
 
3.6.3 Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to return for 3 consecutive 
scheduled visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the participant and reschedule the missed visit over the 
course of the 3 consecuteively miised visits and counsel the participant on the importance 
of maintaining the assigned visit schedule and ascertain if the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
4 
CONCOMITANT MEDICATIONS/MEASURES 
Participants will be on concomitant androgen suppression therapy with a GnRH agonist or 
GnRH antagonist (unless they have had a prior orchiectomy). Participants may also be on 
concomitant drugs to prevent bone loss, including bisphosphonates and denosumab.  
Other supportive care with blood components, antibiotics, analgesics, general medical therapy, 
etc., will be delivered as required. Use caution when co-administering medication which may 
lower the seizure threshold.  
4.1 
GENERAL GUIDELINES 
All medications (other than study drug) and significant non-drug therapies (including physical 
therapy and blood transfusions) taken within 28 days of starting study treatment through the 30  
day end of treatment visit should be reported on the CRF.  
While participants on protocol treatment, all medications required for the health of the 
participant are allowed with the following exceptions: 
• Concurrent chemotherapy or secondary hormonal treatment outside of the investigational 
treatment 
• Concurrent cancer immunotherapy (e.g. therapeutic cancer vaccines) 
• Concurrent anti-cancer radionuclides 
Concomitant use of herbal supplements should be discouraged and/or avoided.  


49 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
Palliative radiotherapy is allowed for pre-existing small areas of painful metastases (e.g. bone) 
that are uncontrolled with local or systemic analgesics as long as no evidence of disease 
progression is present and the metastatic site treated is not a target lesion. 
4.1.1 Seizure threshold lowering drugs 
• Use caution when co-administering medications which may lower the seizure threshold 
(e.g. atypical antipsychotic drugs, phenothiazines, bupropion, 
aminophylline/theophylline, tricyclic and tetracyclic antidepressants, lithium, pimozide, 
venlafaxine). 
4.1.2 Cytochrome P450 and P-glycoprotein 
• Co-administration of enzalutamide with strong or moderate CYP2C8 inducers (e.g., 
rifampin) may alter the plasma exposure of enzalutamide. Moderate CYP2C8 inducers 
maybe used concomitantly with enzalutamide at the Principal Investigator or designee’s 
discretion. If co-administration of enzalutamide with a strong CYP2C8 inhibitor cannot 
be avoided, reduce the dose of enzalutamide to 80 mg per day. 
• Co-administration of enzalutamide with strong CYP3A4 inducers (e.g., carbamazepine, 
phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma 
exposure of enzalutamide and should be avoided if possible. Selection of a concomitant 
medication with no or minimal CYP3A4 induction potential is recommended.  
• Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) 
and St. John’s Wort may also reduce the plasma exposure of enzalutamide and should be 
avoided if possible. 
• Concomitant use of enzalutamide with narrow therapeutic index drugs that are 
metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, 
warfarin) should be avoided, as enzalutamide may decrease their exposure. 
• Grapefruit, Seville oranges, and starfruit affect P450 and PgP activity. Concomitant use 
should be avoided.  
4.2 
SUPPORTIVE CARE 
Participant 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.  
The preferred anticoagulant therapy is subcutaneous heparin or low molecular weight heparin. A 
participant may continue warfarin (with increased INR monitoring) or other anticoagulant agents 
under close supervision and at the discretion of the Principal Investigator or designee. 
4.2.1 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. 


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4.2.2 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 Principal Investigator or designee does not feel that these 
are indicative of clinical disease progression during the study period.  
CRLX101 should be discontinued for a minimum of 3 days before the participant undergoes 
palliative radiation treatment. CRLX101 should be restarted at least 14 days but no more than 21 
days after palliative radiation, as long as any bone marrow toxicity has recovered ≤ Grade 1.  
Consistent with the PREVAIL trial which demonstrated improved survival in mCRPC and led to 
FDA approval in the chemotherapy-naïve subgroup, palliative radiation is allowed to be given in 
combination with enzalutamide.   
4.2.3 Administration of other anti-cancer agents 
Participants must not receive any other concurrent anti-cancer therapy, including investigational 
agents, while on study treatment. Participants may continue the use of bisphosphonates for bone 
disease provided the dose is stable before and during the study. 
4.2.4 Medications that may NOT be administered 
No other chemotherapy, immunotherapy, hormonal therapy (with the exception of LHRH 
agonists/antagonists that will be continued while on study) or other novel agent is to be permitted 
while the participant is receiving study medication. 
Live virus and bacterial vaccines should not be administered whilst the participant is receiving 
CRLX101 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.  
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
Pharmacokinetic analyses of camptothecin will assessed at two points during the study treatment. 
Plasma camptothecin concentrations will be measured before and after initiation of enzalutamide 
treatment to determine the impact of enzalutamide on CRLX101/camptothecin 
pharmacokinetics. Urine camptothecin concentrations will also be measured with and without the 
co-administration of sodium bicarbonate to assess the impact of urine alkalinization on the 
physicochemical characteristics of camptothecin accumulating in the bladder.  
Multiple pharmacodynamic biomarkers will be assessed prior to study treatment and at multiple 
time points following treatment. The inhibition of HIF-1α will be measured indirectly via the 
circulating plasma protein biomarker, VEGF, a prominent downstream target and marker of 
tumor angiogenesis. The presence of acquired resistance will be assessed via the enumeration of 
CTCs and the measurement of androgen receptor splice variation in CTCs. The presence of 
CTCs with high phenotypic genomic instability will also be measured before and after initiation 
of combination therapy. 


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Biomarkers of DNA damage will be measured using a novel NanoString platform aimed to 
measure gene expression of 192 gene markers. Evaluation of the response to a DNA damaging 
agent (camptothecin) may help generate hypotheses for future studies. 
Table 7: Correlative Studies Summary 
Sample  
Assay 
Time Points 
Type of Tube/ 
Sample  
(sample amount) 
Location of 
specimen 
analysis 
Plasma 
 
Pharmacokinetics 
Refer to PK sampling 
outlined in Section 5.1.1 
Refer to PK 
sampling outlined 
in Section 5.1.1 
Figg Lab 
Urine 
 
Pharmacokinetics 
Refer to PK sampling 
outlined in Section 5.1.1 
Refer to PK 
sampling outlined 
in Section 5.1.1 
Figg Lab 
Whole Blood 
Circulating 
Plasma Proteins 
(VEGF) 
Pre-treatment on C1D1, 
C2D15, C6D1, and at 
disease progression 
Purple top EDTA 
(one 6 mL each) 
Cao Lab 
 
Nanostring DNA 
damage response 
panel (192 genes) 
Pre-treatment on C1D1, 
C2D15, and at disease 
progression 
PAXgene RNA 
(one 2.5 mL each) 
Trepel Lab 
Circulating 
Tumor Cells 
(CTCs) and 
AR Analysis 
Enumeration 
Androgen 
Receptor (AR) 
Analysis 
Genomic 
Instability 
γ-H2AX 
Expression (if 
feasible) 
Pre-treatment on C1D1, 
C2D15, C6D1and at 
disease progression 
one 10 mL Streck 
Cell-Free DNA 
and  
one 2.5 mL 
PAXgene RNA  
EPIC 
Sciences 
and 
Figg Lab 
5.1.1 Pharmacokinetics 
Table 8: Plasma Pharmacokinetic Sample Collection with CRLX101 Infusion. Note: Samples are 
to be approximately drawn around these time points, with the collection times noted on the tubes.   
Sample 
Cycle 
Day 
PK Collection with CRLX101 Infusion 
1 
1 
1 Predose 


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Sample 
Cycle 
Day 
PK Collection with CRLX101 Infusion 
2 
1 
1 Mid-infusion (~30 minutes into infusion) 
3 
1 
1 End of Infusion (EOI) 
4 
1 
1 1 hr post EOI 
5 
1 
1 2 hr post EOI 
6 
1 
1 3 hr post EOI 
7 
1 
1 4 hr post EOI 
8 
1 
1 8 hr post EOI 
9 
1 
1 12 hr post EOI 
10 
1 
2 24 hr post EOI 
11 
2 
15 Predose 
12 
2 
15 Mid-infusion (~30 minutes into infusion) 
13 
2 
15 End of infusion (EOI) 
14 
2 
15 1 hr post EOI 
15 
2 
15 2 hr post EOI 
16 
2 
15 3 hr post EOI 
17 
2 
15 4 hr post EOI 
18 
2 
15 8 hr post EOI 
19 
2 
15 12 hr post EOI 
20 
2 
16 24 hr post EOI 
5.1.1.1 Plasma PK 
CRLX101 Pharmacokinetics 
To identify a drug-drug interaction between CRLX101, camptothecin, and enzalutamide on 
clinically-relevant doses, blood samples for the determination of camptothecin plasma 
concentrations will be obtained from each participant on cycle 1 day 1 prior to CRLX101 
administration, when CRLX101 will be administered alone. Blood will be collected into a 6 mL 


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sodium heparin tube (BD, Franklin Lakes, NJ) at the following time points: pre-infusion, mid-
infusion, immediately at end of infusion (EOI), then 1, 2, 3 4, 8, 12, and 24 hr post-EOI. After 
the 24 hour time point, the first dose of enzalutamide will be administered. 
On cycle 2 day 15 (C2D15), after being on the daily combination of CRLX101 and enzalutamide 
for at least 4 weeks to establish steady state, participants will have blood drawn at pre-infusion, 
mid-infusion, EOI, then 1, 2, 3, 4, 8, 12, and 24 hr post EOI. Comparisons of CRLX101 and 
camptothecin exposure between cycle 2 (with enzalutamide) and first-dose (alone) will 
determine the extent of a drug-drug interaction (if any) with enzalutamide.  
Note: PK samples should be drawn approximately around the specified time points, with the 
collection times noted on the tubes.  
Enzalutamide Pharmacokinetics 
Blood will be collected during the visit on C2D15 prior to the participant’s scheduled dose of 
enzalutamide and the infusion of CRLX101 to measure enzalutamide trough plasma 
concentrations. Blood will be collected into a 6 mL sodium heparin tube (BD, Franklin Lakes, 
NJ). Enzalutamide steady-state trough concentrations during cycle 2 dosing will be compared to 
relevant literature to determine the extent of a drug-drug interaction with CRLX101 and 
camptothecin.  
Bioanalytical Measurements and Assay Methodology 
Bioanalytical measurements of unconjugated camptothecin, conjugated camptothecin (measured 
indirectly), enzalutamide, and enzalutamide metabolites (e.g. N-desmethyl enzalutamide) will be 
conducted on an ultra HPLC-MSMS system using an assay developed and validated by the 
Clinical Pharmacology Program.  
The PK sampling will also be used to monitor camptothecin and enzalutamide exposure metrics 
in order to correlate to pharmacodynamic endpoints, clinical response, toxicity, and 
pharmacogenetic analyses. 
5.1.1.2 Urinary Clearance of CRLX101/camptothecin 
To identify a mechanism of camptothecin-induced cystitis on clinically relevant doses, urine 
samples for the determination of camptothecin species (e.g. closed lactone vs. open carboxylate 
form) and nanoparticle concentrations will be obtained from each participant on C1D1 and 
C2D15, with or without the administration of sodium bicarbonate to alkalinize urine 
accumulating in the bladder.  
Urine samples (dependent upon whether the participant needs to void) will be collected when 
feasible in willing participants at the discretion of the Principal Investigator from pre-infusion 
through 24 hours post-EOI. The nursing staff will be supplied with urine collection tubes for the 
duration of urine PK collection time frame. Each time the participant needs to void, the 
participant will be asked to notify the nurse, who will collect a urine sample, if feasible, and then 
record the date/time on each collection tube. Each collected sample will be kept separately and 
should be obtained using the “clean catch” method (total urinary excretion is not of importance). 
On C1D1, participants will receive IV fluids pre- and post-infusion following the currently 
established hydration protocol (HP) for CRLX101. On C2D15, participants will follow the 
hydration protocol with the additional administration of oral sodium bicarbonate (HP+SB). 


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Comparisons of CRLX101 and camptothecin urinary accumulation between the HP and HP+SB 
protocols will be used to help characterize an underlying mechanism of cystitis and determine a 
potential method of prophylaxis for participants at high risk for camptothecin-induced cystitis.  
Prior to C2D15, participants will be given instructions on how to administer sodium bicarbonate 
before their scheduled clinic appointment visit. Table 9 provides recommendations for the 
administration of oral sodium bicarbonate on C2D15. The oral sodium bicarbonate dosing 
schedule may be modified at the discretion of the Principal Investigator or designee. 
Table 9: Recommended Urine Alkalinization Procedure On C2D15 
Timing 
Dose, route, and frequency 
Starting from 48 hours prior to 
CRLX101 infusion 
Take sodium bicarbonate by mouth, 650mg x2, 4 times a day 
(QID), for two days before CRLX101 infusion 
 
On the day of CRLX101 
infusion 
Take sodium bicarbonate by mouth, 650mg x2, 4 times a day 
(QID), for one day 
*Within Two Hours Prior to 
CRLX101 Infusion 
If feasible, Obtain a Urine Sample for Analysis  
After CRLX101 infusion 
Take sodium bicarbonate by mouth, 650mg x2, 4 times a day 
(QID), for one day after CRLX101 infusion 
Note: Doses may be reduced based on age (e.g. over 60) or based on renal function at the discretion of 
the  Investigator. Dosing frequency, dose strength and dosing schedule may also be modified at the 
discretion of the Principal Investigator or designee. In the case of poor compliance to oral sodium 
bicarbonate administration for the experimental procedure, collection of urine samples will be done 
when feasible in willing participants, at the discretion of the principal investigator or designee 
Urine collection will not be a requirement in participants with incontinence, conditions 
preventing urine collection by standard techniques, or other conditions at the discretion of the 
Principal Investigator or designee. If a participant with incontinence is willing to participate, a 
sterile catheter inserted into the bladder will be placed on C1D1 and C2D15 to facilitate urine 
collection.  
Bioanalytical Measurements and Assay Methodology 
Bioanalytical measurements of CRLX101 and camptothecin accumulation and pH dependent 
properties of CRLX101 and camptothecin (e.g. ratio of closed lactone form vs. open carboxylate 
from, release of camptothecin from CRLX101) will be conducted on an HPLC-FLD system 
using an assay developed and validated by the Clinical Pharmacology Program.  
The urine sampling will also be used to monitor camptothecin exposure metrics specific to the 
bladder in order to correlate to toxicity and clinical response.  


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5.2 
FIGG LAB SAMPLES 
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred). 
For sample pickup, 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). 
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. 
5.2.1 Plasma and Urine PK Sample Collection 
All samples will be immediately placed on wet ice and refrigerated. The date and the exact time 
of each blood draw and urine samples should be recorded on the sample tube and the PK sheet 
provided. 
5.2.2 Plasma Protein Measurement (VEGF) 
VEGF protein expression has been shown to be reduced following the down-regulation of HIF-
1α in preclinical assessments in vitro. As a downstream target of HIF-1α and a biomarker of 
angiogenesis, VEGF will serve as a surrogate biomarker for the efficacy of CRLX101. One 6 mL 
EDTA plasma tube (BD Franklin Lakes, NJ) will be collected from each participant prior to drug 
administration on C1D1 (baseline), C2D15, C6D1, and at disease progression to measure VEGF 
for anti-angiogenic activity.  
The analyses will be performed with assays developed and validated in Dr. Liang Cao’s 
laboratory using electrochemiluminescence technology that provides ultra-high sensitivity and 
very large signal dynamic range. The VEGF assay utilized by Dr. Liang Cao’s laboratory has 
been used in previous studies evaluating anti-angiogenic therapies.(64) Purified protein standards 
will be used for generating standard curves for concentration determination.  
Immediately after collection, invert the blood tube 8-10 times. Place the tube on wet ice and then 
store at 4°C in the refrigerator. The date and exact time of each blood draw should be recorded 
on the tube.  Contact Dr. Figg’s lab for sample pick-up. 
5.2.3 Circulating Tumor Cells (CTCs) and AR Analysis 
Circulating tumor cells (CTCs), often prevalent in mCRPC, present a readily accessible ‘liquid 
biopsy’.   Methods to purify and analyze CTCs have been developed and widely utilized to help 
determine if biomarkers could be correlated with treatment response and/or disease progression. 
Of particular interest, the enumeration of CTCs and AR splice variant analyses have been shown 
to be potential clinical biomarkers of disease recurrence and treatment resistance.(65) The 
enumeration of CTCs with genomic instability has been shown to be a potential biomarker of 
treatment resistance and susceptibility to DNA damaging agents (e.g. camptothecin).(59, 60) 
Previously, the expression of γ-H2AX in biopsied tumor tissue has also been used to confirm the 
activity of CRLX101 (CRLX101 Investigator’s Brochure); this study will assess this biomarker 
in CTCs if feasible.  


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Peripheral blood will be collected prior to treatment on C1D1 (baseline), C2D15, C6D1, and at 
disease progression. Two tubes of blood will be collected: one 10 mL Streck Cell-Free DNA 
(brown-black top) tubes and one 2.5 mL PAXgene tube.  
5.2.4 EPIC Sciences  
The blood collected in one Streck Cell-Free DNA tube will be shipped via FedEx Priority 
Overnight to Epic Sciences. These samples will be sent in ambient shippers provided by Epic 
Sciences to keep samples at room temperature. CTC detection and analysis (e.g. enumeration, 
AR expression, phenotypic genomic instability) will be assessed using the Epic Sciences 
platform technology. If feasible, detection of AR-V7 in CTCs may also be examined using the 
Epic AR-V7 test. Additionally, the expression of γ-H2AX in CTCs may be examined if feasible. 
Samples will be shipped to the following address: 
Epic Sciences 
Attn: Joseph Schonhoft 
9381 Judicial Drive, Ste 200 
San Diego, CA 92121 
Phone: 858-263-0694   
Assuming this study treats at least 24 participants, at least 6 of these evaluable participants will 
have high phenotypic genomic instability CTCs at baseline as determined by the Epic Sciences 
algorithm. Differences in clinical response will be examined between participants who are 
positive for high phenotypic genomic instability CTCs in comparison to participants who are 
negative. 
5.2.5 AR Analysis 
Blood will be collected in a PAXgene tube (PreAnalytix; 2.5 mL peripheral blood per tube) per 
the manufacturer’s instructions. Briefly, immediately after blood collection, gently invert the 
PAXgene Blood RNA 8-10 times. Store the PAXgene Blood RNA Tube upright at room 
temperature (18-25°C).  Contact Figg Lab for PAXgene tube.  
The blood collected in the PAXgene tube will be retained in the Figg Laboratory. AR/ARV and 
AR-regulated gene (e.g., PSA) expression levels will be assayed from RNA isolated using 
PAXgene Blood RNA Kit according to the manufacturer’s instructions.  
5.3 
WHOLE BLOOD- MULTIPLEXED GENE EXPRESSION APPROACH TO PROFILING DNA DAMAGE 
RESPONSE SIGNATURES – TREPEL LAB 
Camptothecin induces DNA damage via topoisomerase I inhibition. DNA damage response 
transcriptional signatures will be evaluated by the Trepel Lab using the NanoString nCounter 
platform (NanoString Technologies, Seattle, WA). The 192 gene DNA Damage and Repair panel 
will be used in this study. Peripheral blood will be collected in a PAXgene tube (PreAnalytix; 2.5 
mL 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. Specimens for 
peripheral gene signature analysis will be collected prior to treatment on C1D1 (baseline), 
C2D15, and at disease progression to look for correlates of clinical response. Contact Figg Lab 
for PAXgene tubes.  


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5.4 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
All samples (except samples processed via the Trepel Lab [NanoString] and EPIC Sciences 
[CTCs]) will be sent to and stored in Dr. Figg’s Lab.  
Samples will be ordered in CRIS and tracked through Clinical Trial Data management system. 
Should a CRIS screen not be available, 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. 
5.4.1 Clinical Pharmacology Program (Figg Lab) 
Upon arrival in the Clinical Pharmacology Program, blood samples will be centrifuged and the 
plasma transferred into cryovials for storage at -80° C until the time of analysis. Urine samples 
will be aliquoted into cryovials, diluted with an equal volume of methanol and stored at -80°C 
until the time of analysis. In addition, samples will be barcoded.  
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix 
limited to defined Figg lab personnel, who are issued individual user accounts. Installation of 
Labmatrix is limited to computers specified by Dr. Figg. These computers all have a password 
restricted login screen.  
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to participants without Labmatrix access. The data recorded for each sample includes the 
participant ID, name, trial name/protocol number, time drawn, cycle time point, dose, material 
type, as well as box and freezer location. Participant demographics associated with the clinical 
center participant 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.). 
Barcoded 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 Labmatrix. 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. 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. 
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 participant 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 participant, if 


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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 participant demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to participant information such as race, 
age, dates of diagnosis and death, and histological information about the tumor, in order to 
correlate genotype with these variables. 
5.4.2 Molecular Targets Core (Dr. Cao’s Lab)  
Biospecimens will be collected and processed using validated SOPs that will ensure both 
specimen quality and participant confidentiality pursuant to informed consent provisions. To 
ensure participant confidentiality, only containers used for the initial specimen collections will 
be labeled with participant identifiers. Coded, linked  labels will be applied to all subsequent 
specimen containers. When specimens are processed and aliquoted, no participant information 
will be included on the new containers. Samples are labeled with printed consecutive numbers, 
frozen on dry ice, and stored in a -80°C freezer located at the NCI Research Facility. The freezer 
is locked and monitored 24/7 for temperature control. Samples will be tracked using a limited 
access Excel database.  
Access to the inventory system and associated documents will be restricted to appropriate 
personnel only. Requests to use specimens stored in the repository must be approved by the IRB. 
SOPs ensure that any changes in the informed consent made by a participant and relayed to the 
PI will be reflected in the inventory system to ensure that specimens are destroyed as 
appropriate. All laboratory personnel will be trained to adhere to SOPs and will be monitored for 
high-quality performance. The PI will record any loss or unanticipated destruction of samples as 
a deviation.  Reporting will be per the requirements of section 7.2. 
5.4.3 Trepel Lab 
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 includes 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 participant 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 
Trepel lab 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 participant ID, it is also electronically linked via Labmatrix to the sample ID. The Trepel 
lab will proceed with sample analysis and record data under the unique sample ID. 


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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 
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. 
5.4.4 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.  
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 7.2. If the subject 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.  
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system, C3D,  and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or contracted data manager will assist 
with the data management efforts. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant.  
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.  
Document AEs from the first study intervention, Study Day 1, through 30 days after the last dose 
of study therapy. Beyond 30 days after the last of study therapy, only adverse events which are 
serious and related to the study intervention need to be recorded.   
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  


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Abbreviated Title: CRLX101 in mCRPC 
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• 
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 
participant’s outcome. 
As the toxicity profile of Enzalutamide and CRLX101 is well defined and published, expected 
grade 1 clinical adverse events will not be recorded in the database.  
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: 
_X__Coded, linked data in an NIH-funded or approved public repository.   
_X_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
_X_ Coded, linked or identified data with approved outside collaborators under appropriate 
agreements. 
How and where will the data be shared?  
Data will be shared through: 
_X__ An NIH-funded or approved public repository.  Insert name or names:: ClinicalTrials.gov. 
_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 
The present protocol, which ascertains transcriptomic data from 192 genes, does not apply to the 
GDS policy. The GDS policy states that RNA sequencing data from 100-sample threshold need 
to be shared. This protocol will not meet the 100 sample threshold.  


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6.3 
RESPONSE CRITERIA 
Restaging bone scans and/or CT scan of chest, abdomen and pelvis will be obtained at prior to 
Cycle 3 and every 3 cycles thereafter.  
Progression will be evaluated in this study using the international criteria proposed by the 
Prostate Cancer Working Group 3 (PCWG3) guideline(2) and/or the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).(62) 
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.  
Changes in PSA and measurable lesions will be analyzed for efficacy according to PCWG3 
recommendations. The recommended PSA progressions criteria will not be applied to the study 
as the criteria are arbitrarily proposed and do not necessarily reflect overall disease status. PSA 
values will be captured at each visit and PSA declines and progression will be followed. PSA is 
not sufficient in the evaluation of disease progression in this participant population. This is 
consistent with the recent recommendations by the Prostate Cancer Clinical Trials Working 
Group 2. Progression will be determined by radiographic evidence as discussed below or by 
clinical symptoms (symptomatic clinical progression). 
6.3.1 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 
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. 


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‘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 participant, 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.  
6.3.2 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. 
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 


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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. 
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, 


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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. 
6.3.3 Response Criteria 
6.3.3.1 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 
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. 
6.3.3.2 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 
participant 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). 


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6.3.3.3 Metastatic Bone Lesions  
Disease progression is considered if a minimum of two new lesions is observed on bone scan. 
New lesions seen on first re-staging (at 3 months) may represent disease that was not detected on 
the baseline scan. In these circumstances, the first re-staging scan then will serve as the baseline 
comparison for future scans. Participant can be removed at first re-staging at the discretion of the 
investigator if the clinical scenario is most consistent with disease progression and not “flare” on 
bone scan. This is consistent with Prostate Cancer Working Group 3 recommendations.(63) 
6.3.3.4 Clinical Disease Progression 
• The need for chemotherapy or other change in therapy based on increased cancer related 
symptoms 
• Worsening ECOG PS to a PS of 3 or 4 based on cancer (not treatment) related symptoms 
• Clinical disease progression can also be determined based on the clinical discretion of the 
investigator 
6.3.3.5 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 participant's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
For Participants 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 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 


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Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
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: 
Participants 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 Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
6.3.4 Duration of Response 
The duration of  response is defined by time of sustained >30% decline in PSA from baseline. 
6.3.5 Overall Survival 
Overall Survival is defined as the duration of time from the start of treatment to the time of  
death.. 
6.3.6 Response Review 
Tumor measurements will be performed in consultation with the Center for Cancer Research 
Radiology and Imaging Sciences processing service.  
6.4 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
participant while on the study.  The descriptions and grading scales found in the revised NCI 
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 measured is not 
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Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
7 
NIH REPORTING REQUIREMENTS/ DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
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 here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem 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 here.   
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at 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 weekly regular basis when participants are being 
actively treated on the trial to discuss each participant. Decisions about dose level enrollment and 
dose escalation if applicable will be made based on the toxicity data from prior participants.  
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 participant 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 
research staff.  


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8 
SPONSOR 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 
• 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 participant 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 


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The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0. 
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. 
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. 
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. 
 
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. 
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/pages/viewpage.action?pageId=157942842  


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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. 
8.4 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
All events listed below must be reported in the defined timelines to OSROSafety@mail.nih.gov .  
8.4.1 To be sent by OSRO Safety 
8.4.1.1 Ellipses Pharma Reporting Requirements  - Expedited Reporting 
To ensure patient safety, 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 will  be 
reported by the Sponsor to Ellipses Pharma via their safety vendor, Simbec-Orion, within 1-2 
business days  of learning of its occurrence. The MedWatch 3500a form or equivalent will be 
used to report all SAEs.  
Any SAE experienced after this 30 day period should only be reported to Ellipses Pharma if the 
investigator suspects a causal relationship to the study drug. Recurrent episodes, complications, 
or progression of the initial SAE must be reported as follow-up to the original episode within 1-2 
business days  of the sponsor receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered separately as a new event. The investigator must 
assess and record the relationship of each SAE to each specific study drug (if there is more than 
one study drug). 
 
Ellipses safety vendor, Simbec-Orion: 
  
Email address: pharmacovigilance@simbecorion.com  
Fax no: +1 609 514 1000 
Back-up SAE fax: +1 609 452 7888 
8.4.1.2 Routine Reporting 
The Sponsor will also send the FDA annual report to Ellipses Pharma as agreed upon in the 
collaborative agreement. 
8.4.2 To Be Reported by the Research team 
8.4.2.1 Adverse Events of Special Interest (AESI) associated with CRLX101 
For all subjects, the following adverse events are categorized as Adverse Events of Special 
Interest (AESI) associated with CRLX101: 
• Infusion-related hypersensitivity reaction(s) of any grade 
• Any newly developed cystitis (including Grade 1) in subjects without cystitis at baseline 
Any occurrence of hypersensitivity/allergic reactions and/or cystitis a patient experiences 
associated with CRLX101 must be reported to Ellipses Pharma within 1-2 business days of 
learning of its occurrence using the OSRO  Serious Adverse Event Form.  
AESIs will be sent to Ellipses Pharma via their safety vendor, Simbec-Orion by email to: 
pharmacovigilance@simbecorion.com  
Or alternatively by fax to: +1 609 514 1000 or back-up fax: +1 609 452 7888 .  


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8.5 
REPORTING PREGNANCY 
8.5.1 Paternal Exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
120 days following the last dose of study drug. 
Pregnancy of the patient’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should if possible be followed up and documented.  
The outcome of any conception occurring from the date of the first dose until 120 days after the 
last dose of study drug should be followed up and documented. 
8.6 
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. 
9 
CLINICAL MONITORING  
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through 
independent verification of study data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.   


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10 STATISTICAL CONSIDERATIONS   
10.1 STATISTICAL HYPOTHESES 
10.1.1 Primary efficacy endpoints  
The primary efficacy endpoint is response to therapy as defined by a composite endpoint.  
The primary objective is to evaluate the anti-tumor activity of CRLX101 at the recommended 
phase II dose (RP2D) combined with enzalutamide with respect to treatment response, defined as 
≥50% PSA decline or stable disease on imaging following 5 months of treatment in participants 
with progressive mCRPC following enzalutamide treatment.    
10.1.2 Secondary Efficacy endpoints 
The secondary efficacy endpoints are duration of response, overall survival, and safety. 
The secondary objectives are to evaluate the duration of response as defined by a sustained 
>30% decline in PSA, overall survival, and changes in measurable disease as determined by 
Response Evaluation Criteria in Solid Tumors (RECIST) and Prostate Cancer Working Group 3 
(PCWG3) for the treatment combination; and to validate the recommended phase 2 dose (RP2D) 
of CRLX101 in combination with enzalutamide. 
10.2 SAMPLE SIZE DETERMINATION 
For the first 3 to 6 participants, there will be a lead-in period of two cycles to ensure the safety 
and tolerability of CRLX101 in combination with enzalutamide. CRLX101 will be started at a 
dose of 12 mg/m2, administered via IV infusion on Day 1. Based on limited potential for 
overlapping toxicity and well-characterized pharmacokinetics for both enzalutamide and 
CRLX101, it is anticipated 3 participants will participate in the lead-in phase. An accrual ceiling 
of 6 participants for the lead-in phase will be used to account for possible dose adjustments based 
on DLTs.  
Following the 3- to 6-participant lead-in cohort, this study will comprise a single arm cohort of 
participants with mCRPC eligible for treatment following prior disease progression while on 
enzalutamide therapy. Based on data derived from a retrospective cohort analysis, the estimated 
mPFS of participants with mCRPC who failed two prior therapies (all participants received 
docetaxel first line, followed by either cabazitaxel, enzalutamide, or abiraterone acetate) and 
were receiving third line of treatment (cabazitaxel, enzalutamide or abiraterone acetate) was 4 
months (n = 260 participant; IQR – 3 to 8 months). The ORR (defined as the percentage of 
participants with a PSA decline of ≥50%) of this participant population was 24%. The reported 
data for participants receiving a 4th line of treatment (n = 38 participants) showed a mPFS of 5 
months (IQR - 3 to 12 months) and an ORR of 16%. The most common therapy sequence of the 
third line treatment cohort was docetaxel followed by abiraterone acetate or enzalutamide then 
cabazitaxel (n = 110 participants), which demonstrated an ORR of 28% with a mPFS of 5 
months (IQR of 3 to 9 months).(66)  
The goal is to determine if the addition of CRLX101 with enzalutamide following prior 
enzalutamide failure could improve current response rates. Response to therapy will be assessed 
as a composite endpoint (biochemical response defined as 50% decline in PSA or clinical 
response defined as stable disease on bone scan after 5 months); attaining either of these 


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endpoints will be considered a success. To see at least minimal potential improvement beyond 
~35% of participants, the goal is to rule out a 25% cohort specific response (success) rate and 
target a 50% success rate.  
Following the three- to six-participant lead-in cohort, the trial will be conducted using an optimal 
two-stage phase II trial design to rule out an unacceptably low success rate of 25% (p0 = 0.25) in 
favor of an improved success rate of 50% (p1 = 0.50). With an alpha = 0.10 (probability of 
accepting a poor treatment = 0.10) and beta = 0.20 (probability of rejecting a good treatment = 
0.20), this trial will enroll 8 evaluable participants. If 0 to 2 of the 8 participants have success, no 
further clinical evaluation will be warranted for this combination treatment. If 3 or more of the 8 
evaluable participants have success, then accrual will continue until a total of 21 evaluable 
participants have been treated in the two-stage portion of the trial. If there are 3 to 7 participants 
with a success, this will be considered inadequate for further investigation while if there are 8 or 
more participants out of 21 with a success, then this will be considered worthy of further 
investigation for subsequent trials. Under the null hypothesis (25% success rate), the probability 
of early termination is 67.9% 
Participants who receive at least one dose of the study treatment will be evaluable for safety. 
Participants who receive at least one dose of CRLX101 and have a follow-up imaging study will 
be evaluable for efficacy in an overall study report but the participants in the two-stage portion of 
the trial will be the primary cohort for efficacy analysis.  The maximum number of evaluable 
participants enrolled in the lead-in component will be 6 participants (anticipation to enroll 3 
participants). With up to 6 participants explored in the lead-in portion, and up to 21 participants 
in the two-stage portion of the trial, up to 27 evaluable participants would need to be enrolled 
onto the trial. To allow for a small number of inevaluable participants, the accrual ceiling will be 
set at 30 participants.  
10.3 POPULATIONS FOR ANALYSIS 
Modified intention to treat: all participants who receive at least one dose of each of the two 
agents will be included in the statistical analyses performed. 
10.4 STATISTICAL ANALYSES 
10.4.1 General approach 
For participants in the primary efficacy cohort, the proportion of evaluable participants who 
experience a success will be reported along with a confidence interval. Safety will be evaluated 
by tabulating and describing the DLTs in the first 6 participants of the lead-in arm. 
10.4.2 Analysis of the primary endpoints 
The fraction of evaluable participants who experience a success as defined above will be 
determined and reported along with 80% and 95% two-sided confidence intervals. 
10.4.3 Analysis of the secondary endpoints 
Duration of response and overall survival will be estimated using a Kaplan-Meier curve based on 
all evaluable participants included in the two-stage cohort of the trial. The validation of the 
RP2D of CRLX101 in combination with enzalutamide will be done by evaluating the toxicity 


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and safety data obtained and the RP2D and confirming that the number of DLTs does not 1/6 in 
participants enrolled during the lead-in phase.    
10.4.4 Safety Analyses 
Safety of the agent will be assessed by determining the grade of adverse events noted in each 
participant, and reporting the fraction with grade 3 and grade 4 adverse events. Participants who 
receive at least one dose of the study treatments will be evaluable for safety.  Safety data will be 
presented in a summary. Results from the safety evaluation in the initial 3-6 participant safety 
cohort will be reported separately from safety data from participants included in the efficacy 
cohort. The safety data will consist of the reporting of all adverse events, and may also include 
reporting vital signs, physical examination data, and laboratory safety data. 
10.4.5 Baseline Descriptive Statistics 
Limited demographic and clinical characteristics of all participants will be reported. 
10.4.6  Planned interim analyses 
An evaluation of the safety data based on the initial 3-6 participant lead-in cohort will be 
performed prior to enrollment of participants in the efficacy cohort. As indicated in the sample 
size determination section, an interim evaluation of the number of participants who experienced 
a success in the first stage of the two-stage optimal design will be performed to ensure that 
enrollment to the second stage is warranted.   
10.4.7 Exploratory analyses 
The following are the intended exploratory objectives: 
• To evaluate the pharmacokinetic profile of CRLX101 (both total drug and released 
camptothecin) and enzalutamide in plasma;  
• To evaluate underlying mechanisms of camptothecin-induced cystitis; 
• To evaluate the pharmacodynamic activity of CRLX101 and enzalutamide using 
surrogate biomarkers to measure acquired treatment resistance mediated by angiogenesis 
and androgen receptor signaling (e.g. VEGF, CTCs, AR-V7);  
• To evaluate the activity of CRLX101 and enzalutamide with respect to the prevalence of 
circulating tumor cells with high genomic instability; 
• To explore possible correlations between clinical response and biomarkers of DNA 
damage response (e.g. PAR up-regulation, DNA damage response panel). 
Any exploratory evaluations which generate quantitative measures will be done using descriptive 
statistics including confidence intervals when appropriate. Any statistical tests performed for 
evaluation of exploratory objectives will be done without formal adjustment for multiple 
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11 COLLABORATIVE AGREEMENTS  
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
11.1.1 Ellipses Pharma  
The investigational study agent, CRLX101 is provided by the company, Ellipses Pharma  under 
MTA # 45025-18 executed 10/10/2018, under CRADA #  03089.   
12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
Subjects treated on this study will be individuals with metastatic castration resistant prostate 
cancer, which has recurred (or persisted) after appropriate treatment. Men of any race or ethnic 
group will be eligible for this study. Eligibility assessment will be based solely on the 
participant’s medical status. Women will not be eligible as the disease under study is not present 
in this population. Recruitment of participants onto this study will be through standard CCR 
mechanisms. No special recruitment efforts will be conducted.  
12.2 PARTICIPATION OF CHILDREN 
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have prostate cancer, and because of unknown toxicities of CRLX101 in combination 
with enzalutamide in the pediatric participant.  
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol. However,  re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 12.4), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. 
Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for 
evaluation to assess ongoing capacity of the subjects and to identify an LAR, as needed. 
12.4 PLEASE SEE SECTION 12.6.1 FOR CONSENT PROCEDURE.   EVALUATION OF BENEFITS AND 
RISKS/DISCOMFORTS 
The potential benefit to a participant that goes onto study is a reduction in the bulk of their tumor 
and improvement in their bony lesions, which may or may not have favorable impact on 
symptoms and/or survival. Potential risks include the possible occurrence of any of a range of 
side effects which are listed in the Consent Document. The procedure for protecting against or 
minimizing risks will be to medically evaluate participants on a regular basis.  
12.5 RISKS/BENEFITS ANALYSIS 
For participants with castration resistant prostate cancer, median survival is in the range of 12-18 
months. Enzalutamide has shown activity against prostate cancer in a clinical setting. CRLX101 
has demonstrated clinical activity to down-regulate HIF-1α in ovarian cancer and in vitro 


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assessments examining the down-regulation of HIF-1α in combination with enzalutamide have 
demonstrated a synergistic effect, decreasing angiogenesis and androgen receptor signaling in 
LNCaP cell models. Preclinical assessments (in vitro and in vivo) examining this treatment 
combination are currently ongoing. Although possible toxicities from the proposed therapy are 
serious, given the nature of the underlying disease, they are reasonable. Additionally, we do not 
anticipate toxicities significantly more severe than those observed with other approved agents. 
For these reasons, the risk/benefit ratio of this protocol is favorable; therefore, this protocol 
involves greater than minimal risk to all participants on study, but presents the potential for 
direct benefit to all individual subjects enrolled on study.  
NOTE:  This same risks/benefits analysis applies to all study populations included in this 
clinical study. 
12.5.1 Risks related to Imaging 
CT scans and TC-99 scas often use a contrast agent. There is a small risk of having a reaction to 
the contrast and most often include nausea, pain in the vein where the contrast is given, 
headache, metallic and/or bitter taste in the mouth and a warm, flushing feeling. Rarely, some 
people have more severe allergic reactions to the contrast which may include skin rashes, 
shortness of breath, wheezing or low blood pressure. 
12.5.2 Risks from Radiation Exposure 
The procedures for performing the CT scans (chest/abdomen/pelvis) and Tc-99 whole body 
scintography scans will follow clinical policies, no special procedures apply to these additional 
assessments for research purposes. In summary, subjects may receive additional radiation 
exposure in one year from up to four (4) CT scans of the chest, abdomen, and pelvis, and four (4) 
Tc-99 whole body scintography scans. Radiation exposure is associated with an increased risk of 
cancer. 
12.6 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided to the participant or consent designee(s) as 
applicable 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. If a prolonged period of time 
expires during the decision making process (several weeks, as an example), it may be necessary 
to reassess the participant for protocol eligibility. A signed informed consent document will be 
obtained prior to entry onto the study. 
Re-consent, when required, may take place in person or remotely (e.g., via telephone or other 
NIH approved remote platforms) 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 
maintained. Consenting investigators (and participant, when in person) will be located in a 
private area (e.g., clinic consult room). When re-consent is conducted remotely, the participant 
will be informed of the private nature of the discussion and will be encouraged to relocate to a 
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12.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation 
For participants addressed in section 12.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 12.6.  
 
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 
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 
Each 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 a 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 Conference 
on 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 
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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 NCI 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 
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 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 transmitted to and stored at the NCI. 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 clinical sites and by NCI research staff will be secured and password protected. 
At the end of the study, all study databases will be de-identified and archived at the NCI. 
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 
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14 PHARMACEUTICAL INFORMATION   
14.1 CRLX101 (#138099) 
CRLX101 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. 
CRLX101 nanoparticles are believed to be taken up by tumor cells followed by release of the 
active pharmaceutical ingredient 20(S)-camptothecin. 
14.1.1 Source  
The CRLX101 is provided by the company, Ellipses Pharma, the manufacturer of drug under a 
Collaborative Agreement [Cooperative Research and Development Agreement (CRADA)]. 
14.1.2 Toxicity  
Please see Section 1.2.5.  
14.1.3 Handling and Dispensing 
CRLX101 is a sterile injectable and must be handled under appropriate controls, conditions, and 
aseptic techniques to maintain product sterility. CRLX101, 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 participants.  
14.1.4 Formulation and preparation  
CRLX101 will be provided at no cost to the study participant. It is supplied as a lyophilized cake 
in: a 30 mL single-use vial containing 35 mg of CPT equivalents (approximately 350 mg of 
polymer drug conjugate). 
Vials of CRLX101 should be removed from the refrigerator and warmed to room temperature for 
approximately one hour prior to preparation. Concentrated CRLX101 solution is prepared by 
adding 14 mL of USP Sterile Water for Injection (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, homogeneous solution will take longer and may require up to 30 minutes. The 
CRLX101 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 


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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 CRLX101 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 CRLX101 
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 CRLX101 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 Stability and Storage  
CRLX101 vials should be stored at refrigerated conditions (2°-8°C) and should only be 
accessible to authorized individuals. CRLX101 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 CRLX101 (i.e., IV bag) should be used within 6 hours of reconstituting the drug 
product vials.  
14.1.6 Dosage and Administration procedures 
See Sections 3.2 and 3.3 for the dose levels of CRLX101 to be evaluated in this study. Each dose 
should be administered by IV infusion over 60-75 minutes on Day 1 and Day 15 of each cycle. 
See Section 13.1.4 for how to prepare each dose for administration.  
See Section 3.3.2.4 for management of any CLRX101 infusion related/hypersensitivity reactions.  
The second and subsequent dose of CRLX101 may be delayed if related AEs have not resolved 
to grade 1 or better. If a dose of CRLX101 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 28 days 
beyond which the participant will be taken off treatment.  
14.1.7 Incompatibilities   
No known incompatibilities at this time. 
14.1.8 Premedication and Hydration 
The premedication prior to CRLX101 treatment and pre and post hydration and additional 
prevention measurements to prevent hypersensitivity/infusion reaction have been described in 
Section 3.3.2.4. 
14.1.9 Return and Retention of CRLX101 
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 
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14.2 ENZALUTAMIDE 
Enzalutamide (XTANDI ©) is an androgen receptor inhibitor. The chemical name is 4-(3-[4-
cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl)-2-
fluoro-N-methylbenzamide. 
Please see FDA-approved package insert for Enzalutamide for complete agent information. 
14.2.1 Source 
Enzalutamide will be obtained from commercial sources and dispensed by the institutional 
pharmacy. 
14.2.2 Toxicity 
Seizures 
In the randomized clinical trial, 7 of 800 (0.9%) participants treated with enzalutamide 160 mg 
once daily experienced a seizure. No seizures occurred in participants treated with placebo. 
Seizures occurred from 31 to 603 days after initiation of enzalutamide. Participants experiencing 
seizure were permanently discontinued from therapy and all seizures resolved. There is no 
clinical trial experience re-administering enzalutamide to participants who experienced seizures. 
The safety of enzalutamide in participants with predisposing factors for seizure is not known 
because these participants were excluded from the trial. These exclusion criteria included a 
history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack 
within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous 
malformation or the use of concomitant medications that may lower the seizure threshold. 
Because of the risk of seizure associated with enzalutamide use, participants should be advised 
of the risk of engaging in any activity where sudden loss of consciousness could cause serious 
harm to themselves or others.  
Other adverse events 
The most common adverse drug reactions (≥5%) reported in participants receiving enzalutamide 
in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, 
peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular 
weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression, and cauda 
equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse 
reactions were reported among 47% of enzalutamide-treated participants and 53% of placebo-
treated participants. Discontinuations due to adverse events were reported for 16% of 
enzalutamide-treated participants and 18% of placebo-treated participants. The most common 
adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the 
enzalutamide-treated participants compared to none (0%) of the placebo-treated participants.  
Laboratory Abnormalities 
In the randomized clinical trial, Grade 1-4 neutropenia occurred in 15% of participants on 
enzalutamide (1% Grade 3-4) and in 6% of participants on placebo (no Grade 3-4). The 
incidence of Grade 1-4 thrombocytopenia was similar in both arms; 0.5% of participants on 
enzalutamide and 1% on placebo experienced Grade 3-4 thrombocytopenia. Grade 1-4 elevations 
in ALT occurred in 10% of participants on enzalutamide (0.3% Grade 3-4) and 18% of 


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participants on placebo (0.5% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of 
participants on enzalutamide and 2% of participants on placebo.  
Infections 
In the randomized clinical trial, 1.0% of participants treated with enzalutamide compared to 
0.3% of participants on placebo died from infections or sepsis. Infection-related serious adverse 
events were reported in approximately 6% of the participants on both treatment arms. 
Falls and Fall-reported Injuries 
In the randomized clinical trial, 1.6% of participants treated with enzalutamide were reported to 
have Grade 1 or 2 hallucinations compared to 0.3% of participants on placebo. Of the 
participants with hallucinations, the majority were on opioid-containing medications at the time 
of the event. Hallucinations were visual, tactile, or undefined. 
14.2.3 Formulation and Preparation 
Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water. 
XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule 
contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive 
ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated 
hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and 
black iron oxide. 
14.2.4 Storage and Stability 
Store enzalutamide capsules at 20°C to 25°C (68°F to 77°F) in a dry place and keep the 
container tightly closed. Excursions permitted from 15°C to 30°C (59°F to 86°F). 
The company providing the IND drug will also provide the expiration date for each lot allocated 
to this study. 
14.2.5 Dosage and Administration Procedures 
Enzalutamide 160 mg (four 40 mg capsules) administered orally once daily. Swallow capsules 
whole. Enzalutamide can be taken with or without food. 
14.2.6 Incompatibilities and Drug-Drug Interactions 
Drugs that Inhibit or Induce CYP2C8 
Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area 
under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl 
enzalutamide in healthy volunteers. Co-administration of enzalutamide with strong CYP2C8 
inhibitors should be avoided if possible. If co-administration of enzalutamide with a strong 
CYP2C8 inhibitor cannot be avoided, reduce the dose of enzalutamide. The effects of CYP2C8 
inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. 
Co-administration of enzalutamide with strong or moderate CYP2C8 inducers (e.g., rifampin) 
may alter the plasma exposure of enzalutamide and should be avoided if possible. Selection of a 
concomitant medication with no or minimal CYP2C8 induction potential is recommended.  
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Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of 
enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers. The effects of 
CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. 
Co-administration of enzalutamide with strong CYP3A4 inducers (e.g., carbamazepine, 
phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of 
enzalutamide and should be avoided if possible. Selection of a concomitant medication with no 
or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., 
bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the 
plasma exposure of enzalutamide and should be avoided if possible. 
Effect of Enzalutamide on Drug Metabolizing Enzymes 
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in 
humans. At steady state, enzalutamide reduced the plasma exposure to midazolam (CYP3A4 
substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate). Concomitant use of 
enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., 
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., proton 
pump inhibitors and clopidogrel) should be avoided as enzalutamide may decrease their 
exposure. If co-administration with warfarin cannot be avoided, conduct additional INR 
monitoring. 
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61. 
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Understanding and overcoming the mechanisms of primary and acquired resistance to 
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Onstenk W, de Klaver W, de Wit R, Lolkema M, Foekens J, Sleijfer S. The use of 
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66. 
Caffo O, De Giorgi U, Fratino L, Alesini D, Zagonel V, Facchini G, et al. Clinical 
Outcomes of Castration-resistant Prostate Cancer Treatments Administered as Third or Fourth 
Line Following Failure of Docetaxel and Other Second-line Treatment: Results of an Italian 
Multicentre Study. Eur Urol. 2015;68(1):147-53. 
 
 


89 
Abbreviated Title: CRLX101 in mCRPC 
Version Date: 12/18/2020 
16 APPENDIX A-PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor 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). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
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. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  Death 
not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/02/2021
Page 1 of 13
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Ravi A. Madan, M.D. 
STUDY TITLE: A Single Arm Phase II Study Combining CRLX101, a Nanoparticle 
Camptothecin, with Enzalutamide in Patients with Progressive Metastatic Castration Resistant 
Prostate Cancer Following Prior Enzalutamide Treatment
STUDY SITE: NIH Clinical Center
Cohort:  Standard 
Consent Version: 03/02/2021
 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:
Ravi Madan, M.D.
Tel: 301-480-7168
Email: madanr@mail.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 (such as blood transfusions). 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.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document. 
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?
You have been diagnosed with metastatic, castration-resistant prostate cancer.  There are several 
therapies available to treat your disease.  One of them is enzalutamide, a modern hormonal 
therapy, that is FDA approved to treat metastatic prostate cancer.  Unfortunately, enzalutamide 
only works for a period of time before the cancer becomes resistant to enzalutamide.  This study 
will evaluate if combination with a second treatment could make enzalutamide effective again in 
people who have already had enzalutamide.
IRB NUMBER: 18C0096
IRB APPROVAL DATE: 03/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/02/2021
Page 2 of 13
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
In this manner, this study will test a new way of potentially treating prostate cancer using an 
investigational drug called CRLX101 in combination with enzalutamide in people with 
progressive metastatic, castration-resistant prostate cancer following prior enzalutamide 
treatment.
CRLX101 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.  The study will test how safe it is to receive CRLX101 and how 
well it works in prostate cancer in combination with enzalutamide.  
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
Because you have been diagnosed with metastatic castration-resistant prostate cancer and have 
prior history of enzalutamide treatment, you are invited to take part in this clinical research. 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 30 subjects will be enrolled in this study.
DESCRIPTION OF RESEARCH STUDY
What will happen if you take part in this research study?  
Before you begin the study
Before beginning the study, you will need to have tests and/or procedures to help your doctor 
decide whether you can take part in the study.  This is called screening.  Most of the exams, tests, 
and procedures you will have are part of regular cancer care.  However, there are some extra tests 
that you will need to have if you take part in this study.  If you have had some of them recently, 
they may not need to be repeated.  
These tests include:

Review of your previously collected tissue or a laboratory report to confirm your 
diagnosis

History and physical evaluation including vital signs

Routine blood tests

Urine tests

CT scan of chest/abdomen/pelvis or MRI

Bone scan

Testosterone and prostate-specific antigen (PSA) levels 

Electrocardiogram (EKG)
During the study
Participants meeting eligibility criteria will be enrolled to receive standard dose of enzalutamide 
in combination with CRLX101.  The duration of each cycle will be 28 days.  Enzalutamide will 
be administered orally and will be taken once daily.  CRLX101 will be administered as IV infusion. 
IRB NUMBER: 18C0096
IRB APPROVAL DATE: 03/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/02/2021
Page 3 of 13
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The participants will be evaluated by a provider, with history, physical exams and standard blood 
tests and panels on day 1 and day 15 of each cycle. Serum PSA will be drawn on day 1 and day 15 
of each cycle, and testosterone levels will also be evaluated on day 1 of each cycle. Bone scans 
and CT scans will be done on the first day of every 3rd cycle (Cycle 3 Day 1, Cycle 6 Day 1, etc.) 
until evidence of disease progression present. Participants will have an EKG at baseline. If the 
baseline EKG is abnormal, it will be repeated again on C1D1, C1D15 and C2D1 1-3 hours after 
CRLX101 infusion is completed.
Additionally, throughout the study, participants will be encouraged to drink fluids before and after 
CRLX101 treatment during the cycle, with the administration of IV fluids. As part of a research 
test, we will collect your urine on day 1 of cycle 1 and day 15 of cycle 2. Participants will be asked 
to take sodium bicarbonate tablets starting from 48 hours before and through one day after the 
CRLX101 infusion on C2D15. This is being done to determine whether adding bicarbonate can 
reduce bladder inflammation that is sometimes caused by camptothecin. Urine collection is not 
required if you have incontinence or other conditions preventing urine collection by standard 
techniques. If you have incontinence and you are willing to participate, a sterile catheter inserted 
into your bladder will be placed on C1D1 and C2D15 to allow urine collection. Participants will 
need to stay in hospital up to 24-26 hours after end of infusion for research sample collection and 
urine collection, at the discretion of the Principal Investigator.  
We will first enroll 3 to 6 subjects to receive enzalutamide with a lower dose of CRLX101.  This 
is called lead-in period.  If no subjects develop intolerable side effects in the first two cycles, these 
same participants will continue with a higher dose of CRLX101.  For these participants, CRLX101 
will be administered every 2 weeks for each subsequent cycle.  
All other subjects enrolled after the lead-in period will receive enzalutamide with a higher dose of 
CRLX101.  CRLX101 will be administered every 2 weeks for each cycle.
You will continue to receive the study drugs (in repeated 28-day cycles) until you cancer worsens, 
you have unacceptable side effects, you decide to no longer take part in the study or your study 
doctor decides it is no longer suitable for you to continue. The study doctor will continue to follow-
up with you indefinitely.
Research Samples:
Research tests will be done on blood taken at various times during your participation in this study: 
prior to treatment dose on Cycle 1 Day 1, Cycle 2 Day 15 and Cycle 6 Day 1, and at the time that 
your disease gets worse.  The NIH has set a limit on the maximum amount of blood that can be 
taken for research. This limit is based on your age.  For adults, no more than 37 tablespoons can 
be taken over an 8-week period.  
Research tests will also be done on urine samples taken on Cycle 1 Day 1 and Cycle 2 Day 15.
When you are finished taking the drugs
We would like to see you again within 30 days after you have stopped taking the study drug in 
order to perform the following tests:

History and physical evaluation including vital signs
IRB NUMBER: 18C0096
IRB APPROVAL DATE: 03/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Standard blood tests including a complete blood count

CT scan of chest/abdomen/pelvis or MRI

Bone scan

EKG 
Additionally, you will be asked to come back 30 days after you have stopped taking the study drug 
for an end of treatment visit. These 2 visits can happen simultaneously or at 2 different times. After 
the end of treatment visit you will be contacted every 6 months via telephone to enquire about your 
disease status.
If you are unable to return to clinic for either of these visits you will be contacted by phone to 
assess toxicities. 
BIRTH CONTROL
Your study doctor will discuss the risks to unborn children for the drugs used in this study. The 
effects of the study drugs, if any, on unborn children are unknown. If your partner is capable of 
becoming pregnant and you wish to participate in this study, you must agree to use a condom 
during the study treatment period and for 120 days following the last dose of study drug. You must 
also agree not to donate sperm during the study and through 120 days following your last dose of 
study medication.
If your partner becomes pregnant or suspect she is pregnant while you are participating in this 
study, she should inform her treating physician immediately and you should inform your study 
doctor immediately. 
RISKS OR DISCOMFORTS OF PARTICIPATION
What side effects or risks can I expect from being in this study?
As with all treatments, there are several side effects or risks from the treatments provided in this 
study. However, doctors don’t know all the side effects that may happen with this combination of 
drugs, so it is important to report any changes that you notice, even if your study team does not 
ask specifically about them. Side effects may be mild or severe. Your study team will give you 
medicines to help lessen side effects. Many side effects go away with those medicines and others 
may go away soon after you stop treatment. In some cases, side effects can be serious, long-lasting, 
or may never go away. In very rare instances, they could cause death.
Possible side effects of CRLX101
The following risks and discomforts have been reported from previous and ongoing studies of 
CRLX101.
Very common (>10% of people 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)
IRB NUMBER: 18C0096
IRB APPROVAL DATE: 03/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Nausea

Inflammation of the bladder (cystitis)

Blood in the urine (hematuria)
Common (3-10% of people 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 people 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)

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 
IRB NUMBER: 18C0096
IRB APPROVAL DATE: 03/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/02/2021
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
breathing difficulties, are related to the drug administration and may range from 
symptomatic discomfort to fatal events)

Shortness of breath (dyspnoea)

Urinary tract infection

Increased ALT (a liver enzyme) in the blood

Dehydration

Haemoglobin 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 

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 (hypokalaemia)

Difficulty sleeping or falling asleep (insomnia)

Lymphocyte count decreased

Muscle discomfort or pain (myalgia) 

Urinary frequency (pollakiuria)
IRB NUMBER: 18C0096
IRB APPROVAL DATE: 03/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

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 
of breath, chest pain when breathing or coughing (pneumonia)
Possible side effects of enzalutamide
Likely:

Ankle swelling.

Fatigue

Headache

Hot flashes

Diarrhea 

Low blood counts

Back pain

Upper respiratory tract infection
Less Likely:

High blood pressure

Dizziness, anxiety

Dry skin

Blood in urine

Jaundice

Weakness of muscles
Rare but Serious:

Seizures

*Posterior reversible encephalopathy syndrome (PRES)
*There have been rare reports of posterior reversible encephalopathy syndrome (PRES), a rare, 
reversible condition involving the brain, in people treated with enzalutamide. If you have a seizure, 
worsening headache, confusion, blindness or other vision problems, please contact your doctor 
right away. Your doctor will stop enzalutamide if you develop PRES.  
IRB NUMBER: 18C0096
IRB APPROVAL DATE: 03/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Other Risks
Blood draws: There may be some side effects associated with the procedures for drawing blood in 
this study, but the person drawing your blood will attempt to minimize this discomfort.  Side effects 
include pain and bruising in the area where the needle is inserted, lightheadedness, and rarely, 
fainting. When large amounts of blood are collected, low red blood cell count (anemia) is a risk.
CT scan and PET contrast: Although rare, the intravenous (IV) contrast material involved in some 
CT and PET scans causes medical problems or allergic reactions in some people. Most reactions 
are mild and result in hives or itchiness. In rare instances, an allergic reaction can be serious and 
potentially life threatening. Make sure to tell your study doctor if you've ever had a prior reaction 
to contrast material during medical tests.
WHAT ARE THE RISKS OF RADIATION?
During your participation in this research study, you will be exposed to radiation from CT scans 
and bone scans. The amount of radiation exposure you will receive from these procedures is equal 
to approximately 6.0 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. 
The CT scan and bone scan that you get in this study will expose you to the roughly the same 
amount of radiation as 20 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 0.6 out of 100 (0.6%) and of getting a 
fatal cancer is 0.3 out of 100 (0.3%).
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
We do not know if you will receive personal, medical benefit from taking part in this study.  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

Taking part in another study
IRB NUMBER: 18C0096
IRB APPROVAL DATE: 03/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH 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:

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 new information shows that another treatment would be better for you
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.  You must notify your  study doctor and your 
regular doctor of your decision as soon as possible..
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 Ellipses Pharma 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 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review 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.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest. 
The National Institutes of Health and the research team for this study are using drugs developed 
by Ellipses Pharma  through a joint study with your researchers and the company.   The 
companies also provide 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 
IRB NUMBER: 18C0096
IRB APPROVAL DATE: 03/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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 they may be used for future research on any topic and shared 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.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
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. The amount and form 
of these payments are determined by the NCI Travel and Lodging Reimbursement Policy.   You 
will be given a summary of the policy which provides 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.

Once you have completed taking part in the study, medical care will no longer be provided 
by the NIH Clinical Center.
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IRB APPROVAL DATE: 03/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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:
1) The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.
2) National Institutes of Health Intramural Institutional Review Board
3) The study Sponsor (Center for Cancer Research) or their agent(s) 
4) Qualified representatives from Ellipses Pharma, the pharmaceutical company who 
produces CRLX101.
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
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: 18C0096
IRB APPROVAL DATE: 03/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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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.
POLICY REGARDING 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, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Ravi Madan, 
M.D., Email: madanr@mail.nih.gov, Telephone: 301-480-7168.  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: 18C0096
IRB APPROVAL DATE: 03/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/02/2021
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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
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
Witness:
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: 18C0096
IRB APPROVAL DATE: 03/02/2021