Clinical trial NCT02380677
Conditions: Advanced Solid Tumor Malignancy
Sponsor: NewLink Genetics Corporation
Start date: 2015-04-01; Completion date: 2017-10-04
Enrollment: 42 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
A Phase 1/2a, open-label, dose-escalation study with enrollment in Phase 1 to continue until determination of the Maximum Tolerated Dose (MTD) /Recommended Phase 2a Dose (RP2D), and then enrollment into Phase 2a expansion cohorts will be initiated.

Detailed description:
Phase 1 is an open-label, dose-escalation protocol. It is anticipated that up to 36 patients will be enrolled in Phase 1. All patients will be assigned to treatment with CRLX301 as the single agent.

For the first 2 cohorts a 1+5 study design will be utilized. A single patient will be enrolled sequentially into cohort 1 and cohort 2. If either patient in cohort 1 or 2 experiences a dose limiting toxicity (DLT) during Cycle 1, then the cohort will be expanded to enroll additional patients up to a total of 6.

As of cohort 3 and for all subsequent cohorts, a 3+3 dose escalation schema will be utilized.

MTD/RP2D will be determined at the dose level when \<2 of 6 patients experience a DLT in a cohort.

The Phase 2a part of the study will be an open-label expansion cohort study. An additional 24 patients with advanced, histologically confirmed solid tumor malignancies will be enrolled. All patients will be assigned to treatment at the MTD/RP2D with CRLX301 as the single agent.

All patients will be followed for safety, tumor response, and progression free survival (PFS) all per RECIST version 1.1 guidelines. Patients will remain on study treatment until they experience progression of disease, unacceptable toxicity, or other specified reason for discontinuation.

Arms: arm 1: CRLX301 7.5 mg/m2 IV given every 3 weeks arm 2: CRLX301 15 mg/m2 IV given every 3 weeks arm 3: CRLX301 30 mg/m2 IV given every 3 weeks arm 4: CRLX301 60 mg/m2 IV given every 3 weeks arm 5: CRLX301 75 mg/m2 IV given every 3 weeks arm 6: CRLX301 90 mg/m2 IV given every 3 weeks arm 7: CRLX301 25 mg/m2 IV given weekly arm 8: CRLX301 35 mg/m2 IV given weekly arm 9: CRLX301 45 mg/m2 IV given weekly arm 10: CRLX301 54 mg/m2 IV given weekly arm 11: CRLX301 54 mg/m2 given weekly for 3 weeks with 1 week off arm 12: CRLX301 75mg/m2 IV given every 3 weeks
Interventions: intervention 1: CRLX301
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc. 
Protocol No.: CRLX301-101
Page 1 of 133
AMENDMENT 9   DATE: 16DEC2016
CONFIDENTIAL
PROTOCOL NUMBER:
CRLX301-101
TITLE:
Phase 1/2a Dose-Escalation Study of CRLX301 in 
Patients with Advanced Solid Tumor Malignancies
STUDY PHASE:
Phase 1 and Phase 2a
INVESTIGATIONAL 
PRODUCT:
CRLX301
SPONSOR:
CERULEAN PHARMA AUSTRALIA PTY LTD
c/o Baker & McKenzie
Level 27, AMP Centre
50 Bridge Street 
Sydney, New South Wales, 2000
Australia
www.ceruleanrx.com
CERULEAN PHARMA INC (parent company)
35 Gatehouse Drive
Waltham, MA USA 02451
STUDY DIRECTOR:
SAFETY MEDICAL 
MONITOR:
Adrian Senderowicz, MD
Senior VP and Chief Medical Officer, Cerulean 
Pharma Inc.
David Kingston, MD
Novotech, Sydney, Australia
PROTOCOL REVISION:
VERSION DATE:
AMENDMENT 9
16-December-2016
CONFIDENTIAL NOT FOR DISTRIBUTION 
(see confidentiality statement page 3) 
Adrian Senderowicz, MD
David Kingston, MD
35 Gatehouse Drive
Waltham, MA USA 02451
c/o Baker & McKenzie
Level 27, AMP Centre
50 Bridge Street 
Sydney, New South Wales, 2000
Australia
www.ceruleanrx.com


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Protocol No.: CRLX301-101
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AMENDMENT 9   DATE: 16DEC2016
CONFIDENTIAL
SPONSOR PROTOCOL SIGNATURE PAGE 
This Amendment 9 of the protocol number CRLX301-101 has been prepared and reviewed by 
the Sponsor for distribution to designated clinical sites, associated Ethics Committees / 
Institutional Review Boards, designated contractors, regulatory agencies, and with permission by 
the Sponsor. This version of the protocol and shall supersede the previous version of the 
specified protocol. 
Sponsor Signature 
Date 
Adrian Senderowicz, MD
Senior VP and Chief Medical Officer Cerulean Pharma Inc. 
22-Dec-16
Adrian Senderowicz, MD
AMENDMENT 


Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc. 
Protocol No.: CRLX301-101 
Page 3 of 133 
 
AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
CONFIDENTIALITY STATEMENT 
This document contains confidential information that is proprietary to Cerulean Pharma 
Australia PTY LTD and Cerulean Pharma Inc. (Cerulean).  You may only disclose the contents 
to study personnel under your supervision who need to know the contents for the purpose of 
conducting a clinical study, in addition to your Ethics Committee (EC) or Institutional Review 
Board (IRB) or other Committees for evaluation of the investigational drug as appropriate under 
the following condition: the contents of this document must remain confidential and may not be 
disclosed to any other person or entity without prior written permission from Cerulean.  This will 
not apply to disclosure that is required by governmental regulations or laws; however, you must 
promptly notify Cerulean of any such disclosure.  Any supplemental information that may be 
added or appended to this document is also confidential and proprietary to Cerulean and must be 
treated in the same manner.  
 
INVESTIGATOR ACKNOWLEDGEMENT 
I have received and read the Investigator’s Brochure for CRLX301 and this protocol number 
CRLX301-101, including all appendices, and agree to make all reasonable efforts to adhere to 
the protocol. I agree to conduct the study in compliance with all applicable Health Authority 
regulations (including 21 CFR Parts 312, 50 and 54), ICH Good Clinical Practice (GCP), and 
any locally applicable regulations.  I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol. 
I agree that, prior to the commencement of this study, I must obtain all required Institutional 
approvals including Independent Ethics Committee/ Institutional Review Board associated with 
the clinical facility where the study will be conducted for this protocol and the informed consent 
document.   
I will provide all study personnel under my supervision with copies of this protocol, the 
CRLX301 Investigator’s Brochure, and access to all study-related information provided by the 
Sponsor and designated CRA.  I will discuss this study-related information with my staff to 
ensure that they are fully informed about the investigational product and the protocol. 
I agree to provide all patients with a signed and dated copy of the informed consent document, as 
required by FDA regulations and ICH GCP. I further agree to report to Cerulean any adverse 
events in accordance with the terms of this protocol, as per the applicable regulations from US 
FDA regulation 21 CFR 312.64 and from TGA in Australia where applicable. 
 
 
 
 
 
 
 
 
Principal Investigator Printed Name 
 
Site Number 
 
 
 
 
 
 
 
Principal Investigator Signature 
 
Date 


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Protocol No.: CRLX301-101 
Page 4 of 133 
 
AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
SAFETY REPORTING AND CONTACT IN CASE OF EMERGENCY 
CONTACT PAGE VERSION DATED: 16 December 2016 (Version 7) 
Reporting Serious Adverse Event 
Any death or serious adverse event (SAE)* occurring in a patient while receiving study drug 
(investigational medicinal product) or within 30 days of receiving study drug, even though the 
event may not appear to be study-drug related, must be promptly reported (within 24 hours) to 
the 24-Hour Emergency and SAE Submission Line.  Ensure that the event is identified on the 
reporting form as “serious” (see definitions below). 
 
SAE IMMEDIATE NOTIFICATION METHODS 
24-Hour Emergency and 
SAE Submission Line 
SAE REPORT FORM 
SUBMISSION email or 
fax 
Submit paper SAE Form to email: 
CRLX301-101_Safety@novotech-cro.com 
 
OR 
fax: 02 8569 1498 (if within Australia) 
fax: 011 61 2 8569 1498 (if within USA) 
 
 
Contact for Urgent Medical or Eligibility Questions   
For urgent medical study questions or patient eligibility questions, contact by telephone or email 
the Study Safety Medical Monitor and/or the alternative contacts.  Responses will be provided 
within 24 hours.   
 
EMERGENCY CONTACT INFORMATION 
Role in Study 
Contact Name 
Email Address / Telephone  
Study Designated  
Safety Medical Monitor 
All Sites/Regions 
 
David Kingston, MD 
Email: David.kingston@novotech-
cro.com 
Phone: +61 2 8569 1472 
Cell: +61 408 444814  
Study Designated  
Project Manager 
See Investigator Site File 
See Investigator Site File 
Cerulean Sponsor Study 
Medical Director  
(Also safety contact back-up 
for US sites) 
Adrian Senderowicz, MD  Email: 
ASenderowicz@ceruleanrx.com 
Phone: +1 781-209-6433 
Cell:    +1 617-335-8960 
Cerulean Sponsor Study 
Back-up Medical Director  
 
Jian Li, MD 
Email: JLi@ceruleanrx.com 
Phone: +1 781-209-6448 
Cell: +1 617-909-7038 
 
CRLX301-101_Safety@novotech-cro.com
fax: 02 8569 1498 (if within Australia)
fax: 011 61 2 8569 1498 (if within USA)
David Kingston, MD
Adrian Senderowicz, MD
Email: David.kingston@novotech-
cro.com
Phone: +61 2 8569 1472
Cell: +61 408 444814
Email:
ASenderowicz@ceruleanrx.com
Phone: +1 781-209-6433
Cell: +1 617-335-8960
Email: JLi@ceruleanrx.com
Phone: +1 781-209-6448
Cell: +1 617-909-7038
Jian Li, MD


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Protocol No.: CRLX301-101 
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AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
DEFINITIONS FOR SAFETY REPORTING 
 
SERIOUS ADVERSE EVENT CRITERIA* 
A serious adverse event is any untoward medical occurrence that at any dose results in any of 
the following outcomes, regardless of relationship to study drug (see Section 8.4: Recording  
Adverse Events):  
x Death  
x Life-threatening 
x Inpatient hospitalization or prolongation of existing hospitalization  
x A persistent or significant disability/incapacity 
x A congenital anomaly/birth defect 
An important medical event that may jeopardize the patient and may require medical or 
surgical intervention to prevent any of the outcomes listed above should be reported 
following the SAE procedures. 
 
SERIOUS UNEXPECTED SUSPECTED ADVERSE REACTIONS CRITERIA**  
An unexpected adverse reaction is any untoward and unintended responses to an 
investigational product related to any dose administered, of which the nature, or severity, is 
not consistent with the available applicable product information.  
All suspected adverse reactions which occur during the study and that are both unexpected 
and serious (SUSARs) must be submitted to the Study Safety Medical Monitor via the 
expedited reporting procedures above.  
 
 
 


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AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Name of sponsor/company: CERULEAN PHARMA AUSTRALIA PTY LTD / 
CERULEAN PHARMA INC (parent company) 
Name of investigational product:  CRLX301 
Title of study: Phase 1/2a Dose-Escalation Study of CRLX301 in Patients with Advanced 
Solid Tumor Malignancies 
Study Number:  CRLX301-101 
Number of study center(s): approximately 7 
Study duration: approximately 3 years   
x Date first patient enrolled: December 
2014 
x Estimated date last patient completed: 
January 2018 
Phase of development:  
Phase 1 includes: Schedule 1 (Q3W) and 
Schedule 2 (QW, no break or QW, 3 week on/1 
week off, depending on enrollment cohort) dose 
escalation to establish maximally tolerated dose 
(MTD) / Recommended Phase 2 dose (RP2D) 
Phase 2a includes: Q3W and QW Stage 1 
MTD/RP2D expansion and Stage 2 expansion 
Objectives: 
Study objectives are as follows:  
Primary Study Objectives 
 Phase 1: 
x To determine MTD / RP2D of CRLX301 when administered by intravenous (IV) 
infusion on Schedule 1 (Q3W: Dosing Day 1 of a 21-day cycle) or Schedule 2 (QW: 
weekly dosing, no break or QW, 3 week on/1 week off dosing) in patients with 
advanced solid tumor malignancies 
  Phase 2a: 
x To further establish the safety and tolerability of the CRLX301 MTD / RP2D  
Secondary Study Objectives 
x To evaluate the pharmacokinetic (PK) profile of CRLX301 (both the total drug and 
released docetaxel) in plasma for both dosing schedules 
x To explore preliminary signs of efficacy of CRLX301 
 
 


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AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
Name of sponsor/company: CERULEAN PHARMA AUSTRALIA PTY LTD / 
CERULEAN PHARMA INC (parent company) 
Name of investigational product:  CRLX301 
Exploratory Study Objectives 
x To evaluate the pharmacodynamic activity of CRLX301 in the blood and tumor biopsy 
specimens when available from patients  
x To explore possible correlations between clinical response and/or toxicities with 
biomarkers  
x To explore the PK profile of CRLX301 (both the total drug and released docetaxel) in 
urine for both dosing schedules 
x To explore potential factors affecting potential inter- and intra-patient PK variability 
and the preliminary relationship between response and the exposure to total and 
unconjugated docetaxel in plasma and urine 
Methodology:  
Phase 1: Schedule 1 (Q3W) is an, open-label, 1+5 followed by classic 3+3 dose-escalation 
study with enrollment to continue until determination of the MTD/RP2D. Schedule 2 (QW, no 
break or QW, 3 week on/1 week off, depending on enrollment cohort*) is an open-label 3+3 
dose escalation study with enrollment to continue until determination of the MTD /RP2D.  
x For Schedule 1 only, patients were accrued in a step-wise manner into two initial 
cohorts of only 1 patient each. Since the patient in the first cohort of 7.5 mg/m2 did not 
experience a dose limiting toxicity (DLT) in Cycle 1, the protocol allowed proceeding 
to the next cohort level of 15 mg/m2. Starting at cohort 3 for Schedule 1 at 30 mg/m2, a 
minimum of 3 patients will be enrolled in all subsequent cohorts.  
x For Schedule 2, a minimum of 3 patients will be enrolled for all planned cohorts. If a 
patient in any Phase 1 escalation cohort experiences a DLT during the first 3 weeks for 
either schedule, then the cohort will be expanded to sequentially enroll additional 
patients up to a total of 6 who complete 3 weeks of treatment as per assigned Schedule.  
x A DLT is a treatment-emergent adverse event (TEAE) attributed to be at least possibly 
related to the investigational product in the first 3 weeks post-initiation of study drug 
infusion in either schedule and that meets the criteria for DLT as defined in the 
protocol. Enrollment in a Phase 1 dose cohort will be halted immediately when ≥2 
patients within the same cohort experience a DLT during the first 3 weeks. The study 
Safety Review Committee (SRC) will review, at a minimum, the safety data at the end 
of Cycle 1 (3 weeks) for Schedule 1, or Week 3 for Schedule 2, for all cohorts to 
confirm DLTs and to determine if dose escalation should occur and at what dose level. 


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Protocol No.: CRLX301-101 
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AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
Name of sponsor/company: CERULEAN PHARMA AUSTRALIA PTY LTD / 
CERULEAN PHARMA INC (parent company) 
Name of investigational product:  CRLX301 
The MTD is defined as the highest dose level at which fewer than 2 out of 6 patients 
experiences a DLT during Cycle 1 or the first 3 weeks. 
*NOTE: As of Amendment 9, for patients still receiving treatment in Schedule 2 Cohort 3 
(45mg/m2), and for patients enrolled in Schedule 2 Cohort 4 (54mg/m2), dosing will be on a 
once weekly, 3 week on/1 week off schedule. The dosing schedule for additional Schedule 2 
cohorts will be determined by the SRC. A single MTD/RP2D will be determined for Schedule 
2. See Section 1.8.3:Rationale for Evaluation of QW, 3 week on/1 week off for Schedule 2. 
Phase 2a: Stage 1 of Phase 2a will initiate when either dosing schedule determines the 
MTD/RP2D. For Stage 1, up to 16 patients will be enrolled into an expansion cohort for each 
dosing schedule at RP2D to further explore the safety and PK profile of CRLX301. Stage 2 of 
Phase 2a will initiate when Stage 1 expansion is complete for both dosing schedules. For 
Stage 2, the preferred dosing schedule (i.e., either Schedule 1 or 2) will be used for enrollment 
into additional RP2D expansion cohort of up to 36 patients.  
Number of patients enrolled: Up to 134 
Phase 1: Up to 66 evaluable patients are anticipated to be enrolled in the Phase 1 dose 
escalation cohorts (up to 36 patients in Schedule 1 (Q3W); up to 30 patients in Schedule 2 
(QW, no break or QW, 3 week on/1 week off)). The exact number of patients is dependent on 
the actual patients per cohort and number of cohorts investigated in each dosing schedule.  
Patients who do not complete a minimum of 3 weeks of treatment and do not experience a 
DLT will be replaced. 
Phase 2a: Up to 68 patients will be enrolled in Phase 2a RP2D expansion cohort(s) (up to 32 
patients for Stage 1 and up to 36 patients for Stage 2). 
Diagnosis and main criteria for inclusion: 
Patients must meet the following criteria for inclusion: 
1. Male or female adult patients ≥18 years of age 
2. Diagnosis of histologically or cytologically confirmed, advanced solid tumor 
malignancy: 
a. For Phase 1: that is refractory to standard therapy and/or for whom no further 
standard therapy is available, especially for those for whom taxane 
chemotherapy may be a reasonable therapeutic choice, in the opinion of the 
Investigator.  
b. For Phase 2a: advanced/metastatic tumors considered responsive to taxanes 
c. For prostate cancer patients in Phase 2a: that is castration resistant prostate 


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AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
Name of sponsor/company: CERULEAN PHARMA AUSTRALIA PTY LTD / 
CERULEAN PHARMA INC (parent company) 
Name of investigational product:  CRLX301 
cancer (CRPC*) and has not been previously treated with taxanes (taxane-
naïve [unless approved by Sponsor]) but has been treated with abiraterone 
and/or enzalutamide. *NOTE: CRPC is defined as: 
i. Castration: Undergone surgical castration, or medical castration with 
testosterone < 50ng/dL 
ii. Resistant: Disease progression while castrate with radiographic 
progression defined by Prostate Cancer Working Group 2 (PCWG2) 
criteria, OR disease progression defined as rise in PSA in subjects with 
baseline PSA of at least 2 ng/mL, OR disease progression as per 
RECIST1.1. 
3. For patients enrolled in Phase 2a only: at least one measurable target lesion as defined 
by RECIST 1.1 criteria for solid tumors, except for patients with advanced prostate 
cancer (in which case as per the PCWG2 criteria). Tumors within a previously 
irradiated field should be designated as “non-target” unless progression is documented 
or a biopsy is obtained to confirm persistence at least 90 days following completion of 
radiation therapy. 
4. If Patient has received: 
a. approved chemotherapy or small molecule targeted therapy; it has been ≥2 
weeks since last dose before CRLX301 first dose (hereafter referred to as "first 
dose") 
b. investigational therapy; it has been ≥30 days before first dose 
c. local palliative radiation; it has been ≥14 days prior to first dose  
d. radiation or invasive surgery requiring general anesthesia; it has been ≥30 days 
prior to first dose 
e. chemotherapy with nitrosoureas or mitomycin C; it has been ≥45 days before 
first dose 
5. ECOG Performance Status of 0 or 1 
6. Life expectancy in opinion of Investigator of >12 weeks 


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AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
7. Patients with acceptable pre-study hematology and biochemistry labs ≤3 days prior to 
first dose defined as: 
a. absolute neutrophil count (ANC) ≥1500 cells/μL (1.5 x10^9/L), without 
growth factor support 
b. platelet count ≥100,000 cells/μL (100 x10^9/L), without growth factor support 
c. hemoglobin ≥10 g/dL (100 g/L) for males, and ≥9 g/dL (90 g/L) for females 
d. total bilirubin within normal limits (WNL) 
e. AST/ALT ≤1.5 x upper limit of normal (ULN) 
f. serum creatinine ≤1.5 ULN or 24-hour clearance ≥40 mL/min 
g. PT/PTT ≤1.2 x ULN 
8. Contraception requirements: 
a. Women of child-bearing potential, defined as women physiologically capable 
of becoming pregnant, must use highly effective methods of contraception 
during study treatment and for 30 days after the last dose of study treatment. 
Highly effective methods of contraception include:  
i. Total abstinence (when this is the preferred and usual lifestyle of the 
subject). Withdrawal and periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) are not acceptable methods of 
contraception. 
ii. Female sterilization (defined as having had surgical bilateral 
oophorectomy with or without hysterectomy), total hysterectomy, or 
tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment. 
iii. Male sterilization for at least 6 months prior to screening. The 
vasectomized male partner should be the sole partner for that subject. 
iv. Use of oral, injected or implanted hormonal methods of contraception or 
placement of an intrauterine device (IUD) or intrauterine system (IUS), 
or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception. In case of use of oral contraception women 
should have been stable on the same pill for a minimum of 3 months 
before taking study treatment.  
b. Male subjects must use condoms during the study treatment period and for 120 
days following the last dose of study drug. 
9. Negative urine pregnancy test ≤3 days prior to first dose (women of childbearing 
potential only) 


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CONFIDENTIAL 
Name of sponsor/company: CERULEAN PHARMA AUSTRALIA PTY LTD / 
CERULEAN PHARMA INC (parent company) 
Name of investigational product:  CRLX301 
10. Ability to understand and willingness to sign a written informed consent form 
11. Able to comply with study visit schedule and assessments 
Patients will be excluded for the following:  
1. Uncontrolled grade 2 or greater toxicity except alopecia related to any prior 
treatment (i.e. chemotherapy, targeted therapy, radiation or surgery) within 7 days 
prior to C1D1 unless approved by the Medical Monitor 
2. Prolongation of QT/QTc interval (QTc interval >450 msec. for males and >470 
msec. for females) using the Fredericia method of QTc analysis. If single reading is 
above these minimum ranges, then repeat test in triplicate and evaluate eligibility 
based on average value 
3. Women who are pregnant or nursing 
4. Any known HIV infection or AIDS or any concurrent infection requiring IV 
antibiotics 
5. Any chronic or concurrent acute liver disease, including viral hepatitis 
6. Primary brain malignant tumors 
7. Known metastases to the brain: 
a. CNS confirmed by CT requiring treatment or radiation therapy, or that have 
b.  not been confirmed stable on imaging for ≥30 days prior to first dose 
8. Uncontrolled hypertension >150 (systolic) and >100 (diastolic) mmHg 
9. Concurrent participation in any other investigational study, unless non-
interventional study and approved by Sponsor 
10. Concurrent treatment with the following medication, unless approved by Sponsor: 
a. Anticoagulant 
b. Tubulin binding agents (e.g. colchicine) 
c. Strong CYP3A4 inhibitors (Appendix C) 
11. History of stroke, deep venous thrombosis (DVT), transient ischemic attack (TIA), 
or myocardial infarction, within 6 months prior to first dose 


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CONFIDENTIAL 
Name of sponsor/company: CERULEAN PHARMA AUSTRALIA PTY LTD / 
CERULEAN PHARMA INC (parent company) 
Name of investigational product:  CRLX301 
12. History of other cancer type, except for cutaneous basal cell or squamous cell 
carcinoma, or cervical in situ or very low/low risk prostate cancer within the last 2 
years prior to first dose 
13. Uncontrolled concurrent disease or illness including but not limited to: 
a. symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia 
b. unstable or untreated cardiac conditions or ejection fraction of <50% as 
determined by echocardiogram (ECHO) or multiple gated acquisition scan 
(MUGA); NOTE: ECHO or MUGA required at screening only in subjects 
with known history of cardiac insufficiency and symptomatic within 3 
months prior to screening.  
c. diabetes mellitus 
d. coagulation disorder 
e. psychiatric illness that would limit compliance with study requirements, as 
determined by the Investigator  
14. History of severe hypersensitivity reaction to taxanes 
15. For Phase 2a Stage 2: treatment with a taxane within 6 months of first dose; NOTE: 
advanced prostate cancer patients must be taxane-naïve 
16. Peripheral neuropathy defined as one or more of the following unless approved by 
the Sponsor: 
a.  Active peripheral neuropathy within 30 days prior to first dose defined as: 
i. Motor neuropathy of any grade (e.g., distal extremity weakness, loss 
of deep tendon reflex) 
ii. ≥Grade 2 neurosensory symptoms (e.g., pain, numbness, paresthesia, 
dysesthesia, etc.) 
b. History of ≥ Grade 3 neurologic reactions to prior chemotherapy; in 
particular, any neurological reactions that required a dose reduction or 
discontinuation from prior taxane therapy. 
17. Other severe, acute, or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study 
drug administration or that may interfere with the interpretation of study results and, 


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AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
Name of sponsor/company: CERULEAN PHARMA AUSTRALIA PTY LTD / 
CERULEAN PHARMA INC (parent company) 
Name of investigational product:  CRLX301 
in the judgment of the investigator, would make the patient inappropriate for the 
study. 
Investigational product, dosage and mode of administration: CRLX301 patients will 
receive an intravenous infusion of CRLX301 on either Dosing Schedule 1: Day 1 of a 21-day 
cycle (Q3W) or Dosing Schedule 2: weekly dosing (QW, no break or QW, 3 week on/1 week 
off dosing, depending on enrollment Cohort), and will continue the treatment schedule until 
progression of disease or unacceptable toxicity (see Section 6.1: Reasons for Discontinuation 
from Treatment). In Phase 1, the initial dose per patient will be determined by their enrollment 
Cohort and assigned dosing schedule according to the protocol dosing scheme. Phase 2a 
patients will all be dosed at the MTD/RP2D for either dosing schedule in Stage 1 and at the 
preferred dosing schedule at RP2D for Stage 2.  
Duration of Treatment:  Patients will remain on study treatment until they experience 
progression of disease (unless there is evidence of clinical benefit and the investigator believes 
it is in the patient’s best interest to continue the study drug treatment), unacceptable toxicity, 
or other specified reason for discontinuation (Section 6.1: Reasons for Discontinuation from 
Treatment).  
Reference therapy, dosage and mode of administration: 
All patients will receive CRLX301 via an intravenous infusion over approximately 120 
minutes. 
Criteria for evaluation: 
Dose Limiting Toxicities: A DLT is defined as any AE possibly, probably, or definitely 
related to CRLX301 that meets the per protocol criteria for DLT (see Section 3.1.3: Definition 
of Dose-Limiting Toxicity) and occurs at any point during Cycle 1 or the first 3 weeks post-
initiation of study drug infusion. The event must be assessed by the Investigator and Safety 
Medical Monitor and/or Study Director, and be determined to be unrelated to disease 
progression, intercurrent illness, or concomitant medications. All DLTs will be graded 
according to the current version of the National Cancer Institute’s (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE 4.03).  
Safety: Safety variables will include AEs, clinical laboratory parameters, vital signs, and ECG 
parameters.  For each safety parameter, the last assessment made before the first dose of the 
investigational product for each period will be used as the baseline for all analyses of that 
safety parameter.  
 


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CONFIDENTIAL 
Name of sponsor/company: CERULEAN PHARMA AUSTRALIA PTY LTD / 
CERULEAN PHARMA INC (parent company) 
Name of investigational product:  CRLX301 
Pharmacokinetic evaluation:  
Schedule 1 (Q3W): 
Plasma and urine samples for (PK) evaluation will be collected from Phase 1 and Phase 2a 
Stage 1 patients during Cycle 1 and from available patients in Cycle 3 and Cycle 6 as per the 
schedule defined in Section 5.13: Pharmacokinetic Sample Collection.  
If Schedule 1 is selected for Phase 2a Stage 2 expansion, patients will have plasma samples 
collected using the same schedule defined in Phase 1 until up to 10 patients have undergone 
PK collection at RP2D during both Cycle 1 and a repeat dose in either Cycle 3 and/or Cycle 6. 
Schedule 2 (QW, no break or QW, 3 week on/1 week off): 
Plasma and urine samples for PK evaluation will be collected from Phase 1 and Phase 2a 
Stage 1 patients during Week 1 and from available patients in Weeks 2 through 8 as per the 
schedule defined in Section 5.13: Pharmacokinetic Sample Collection.  
If Schedule 2 is selected for Phase 2a Stage 2 expansion, patients will have plasma samples 
collected using the same schedule defined in Phase 1 until up to 10 patients have undergone 
PK collection at RP2D during both Week 1 and a repeat dose during Week 4 or Week 7 if the 
QW, no break dosing schedule is selected or during both Week 1 and a repeat dose during 
Week 3 or Week 7 if the QW, 3 week on/1 week off dosing schedule is selected. 
Disease status: Disease status will be evaluated at screening and every 8-9 weeks for both 
dosing schedules while on study treatment (until disease progression) by CT scan, or by 
alternative methodologies consistent with tumor type and reviewed by Medical Monitor. See 
Follow Up for required tumor evaluations in patients who discontinue from study treatment 
for reasons other than progression. 
Tumor marker disease evaluation: Tumor marker data to evaluate disease status are 
collected only if appropriate for tumor-type and if feasible per Investigator discretion.   
Efficacy: Tumor response evaluations will be performed by either following RECIST 
guidelines, version 1.1 or alternative methodologies consistent with tumor type (e.g., PCWG2 
criteria for prostate cancer).  Tumor assessments by imaging methodology should be 
completed every 9 weeks for Schedule 1 and for QW, no break cohorts in Schedule 2. As of 
Amendment 9, tumor assessments by imaging methodology should be completed every 8 
weeks for QW, 3 week on/1 week off cohorts in Schedule 2. At investigator discretion, 
imaging should be repeated 3-4 weeks after a partial or complete response is observed. PSA 
assessment for Phase 2a prostate cancer patients should be done every 3-4 weeks. See Follow 
Up for required tumor evaluations in patients who discontinue from study treatment for 
reasons other than progression. 


Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc. 
Protocol No.: CRLX301-101 
Page 15 of 133  
AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
Name of sponsor/company: CERULEAN PHARMA AUSTRALIA PTY LTD / 
CERULEAN PHARMA INC (parent company) 
Name of investigational product:  CRLX301 
Additional blood collection for biomarker research:  Additional blood samples will be 
collected from all Phase 2a patients for additional biomarker research. Additionally, remaining 
plasma from PK samples from all patients who agree will be used for additional research for 
the same purposes. 
Additional blood collection for pharmacodynamic research:  In Phase 2a Stage 1 only, 
blood samples will be collected for isolation of circulating tumor cells (CTCs) and for 
mononuclear phagocytic system (MPS) function testing. CTC isolation will explore the utility 
of comparing the integrity of microtubule skeleton in CTCs from pre- and post-treatment 
patient samples as a potential read-out of CRLX301 PD activity. MPS function test will 
explore potential drug clearance in addition to renal and hepatic clearance of the study drug.    
Optional tumor tissue collection for research: Archived tumor tissue and pre- and post-dose 
tumor biopsy will be collected, as available, from all patients who consent to these optional 
collections. The tissue will be used for additional research to include exploration of markers 
for efficacy (e.g. proliferation, apoptosis, and cell cycle) and CRLX301 localization; it may 
also include genetic testing related to the cancer diagnosis for research purposes only, no other 
genetic testing will be performed.  
Discontinuation: Eligible patients who are enrolled into the study will be discontinued from 
study treatment if any of the following occur: 
x Documented radiographic or clinical progression of disease unless there is 
evidence of clinical benefit and the investigator believes it is in the patient’s 
best interest to continue the treatment despite disease progression 
x Grade 4 hypersensitivity/infusion related reaction (may also be discontinued 
for Grade 3; see Table 7) 
x AE with clinically unacceptable toxicities (unless there is evidence of sustained 
therapeutic benefit and the investigator believes it is in the patient’s best 
interest to continue the treatment despite the toxicity) including: 
o unresolved related AE ≥Grade 2 that causes a delay of >21 days to 
initiation of next dose of CRLX301 (both dosing schedules) 
o bilirubin >1.2 ULN, or AST and/or ALT >1.5 × ULN concomitant with 
alkaline phosphatase >2.5 × ULN; if either of these are unresolved for 
>21 days from planned next dose 
o any other clinically unacceptable toxicity (in agreement with the study 
Medical Monitor) 
x Withdrawal of consent 


Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc. 
Protocol No.: CRLX301-101 
Page 16 of 133  
AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
Name of sponsor/company: CERULEAN PHARMA AUSTRALIA PTY LTD / 
CERULEAN PHARMA INC (parent company) 
Name of investigational product:  CRLX301 
x Subject non-compliance with study schedule 
x Protocol violation (including lack of compliance or excessive deviations with 
study schedule) in agreement with the Sponsor/Medical Monitor and/or Study 
Director 
x Lost to follow-up (after repeated attempts for >30 days have been made to 
contact the patient including letters sent by registered mail) 
x Request for discontinuation by a regulatory agency (i.e. FDA) 
x Investigator decision (in consultation with the Safety Medical Monitor and/or 
Medical Director and the patient) if there are changes in the patient’s medical 
condition and/or intercurrent illness that render the patient unacceptable for 
further treatment. The reason for removal must be documented in the eCRF. 
Follow-up: Once study treatment is discontinued, all patients who are alive and not lost to 
follow-up are to be closely followed for evidence of delayed effects of study drug for 30 days 
from the last dose of study drug.  
For patients who are discontinued from study treatment for reasons other than disease 
progression, they will continue to have tumor evaluation with methodologies consistent with 
tumor type until another anti-cancer treatment is started, progression of disease, death, loss to 
follow up or withdrawal of consent, whichever comes first. Therefore, continued evaluations 
may be possible for some patients after the 30-day post dose visit. 
Statistical Methods 
Phase 1: 
The primary endpoint is the frequency of DLTs for each dosing schedule as a function of 
CRLX301 dose. 
Phase 2a: 
The primary endpoints are: 
x Safety and tolerability, evaluated by the following parameters: 
o Type, frequency and severity of AE(s) 
o Laboratory parameters (hematology and chemistry, especially those 
associated with bone marrow and hepatic function) 
o Vital signs 
o Physical examination 
o 12-lead ECG 
The secondary endpoints are: 


Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc. 
Protocol No.: CRLX301-101 
Page 17 of 133  
AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
Name of sponsor/company: CERULEAN PHARMA AUSTRALIA PTY LTD / 
CERULEAN PHARMA INC (parent company) 
Name of investigational product:  CRLX301 
x PK parameters in plasma: area under the concentration versus time curve (AUC), 
maximum concentration (Cmax), half-life (t1/2), volume of distribution (Vd), clearance 
(CL) for both total and released docetaxel after single dose and multiple doses when 
available for each dosing schedule. 
x  Efficacy measures: best overall response, duration of overall response, duration of 
stable disease, objective response rate, disease control rate, and progression free 
survival as per RECIST version 1.1 or methodologies consistent with specific tumor 
type  
Patients who receive any amount of study drug, including those who withdraw prematurely 
from the study, will be included within four analysis populations as specified below:  
Safety Population: The Safety Population will consist of all patients who receive any amount 
of investigational product. 
Pharmacokinetic Analysis Population: The PK Analysis Population will consist of all patients 
who receive at least part of 1 dose of CRLX301, have at least 1 PK sample collected on Cycle 
1 Day 1 or Week 1 Day 1 of the study, and have evaluable PK parameters. 
MTD and/or RP2D Population: The MTD and/or RP2D population will include all patients 
treated at the MTD and/or RP2D for each dosing schedule from both Phase 1 and Phase 2a of 
the study.  
MTD and/or RP2D Efficacy Evaluable Populations: The MTD and/or RP2D evaluable 
population will include all patients treated at the MTD/RP2D for each dosing schedule who 
have had tumor assessment at baseline and undergone at least 1 follow-up tumor assessment 
via imaging or methodologies consistent with specific tumor type. 
 
Schedules 1 and 2 will be analyzed separately. As appropriate analysis for each cohort in 
Phase 1 and for each of the MTD expansion cohorts will be reported separately. For Schedule 
2, a single MTD/RP2D will be determined, but other analyses will be reported separately for 
QW, no break cohorts and QW, 3 week on/1 week off cohorts. 
Descriptive statistics including, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented as appropriate for all cohorts treated.  PK parameters for 
individual patients will be calculated, summary (mean +/- SD, min, max, geometric mean and 
geometric coefficient of variation) of PK parameters for each dose cohort and cycle will be 
calculated and statistical analyses will be computed to evaluate differences between dose 
cohorts and cycles. Tumor response rates will be summarized with their 95% Pearson-Clopper 
confidence intervals. Time to event endpoints will be analyzed by survival analysis methods.   


Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc. 
Protocol No.: CRLX301-101 
Page 18 of 133  
AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
Name of sponsor/company: CERULEAN PHARMA AUSTRALIA PTY LTD / 
CERULEAN PHARMA INC (parent company) 
Name of investigational product:  CRLX301 
No formal sample size calculation is proposed as this study is not powered to demonstrate 
statistical significance. 
A detailed description of analysis methods will be prepared by the Sponsor designated study 
biostatistician in the study Statistical Analysis Plan. 


Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc.
Protocol No.: CRLX301-101 
Page 19 of 133  
AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
SCHEDULE OF PROCEDURES – SCHEDULE 1 (Q3W / DAY 1 DOSING OF A 21-DAY CYCLE) 
Procedures 
Pre-
Study 
Cycle 1, 3, 61 
Cycle 2, 4, 5, 71  
through discontinuation  
 EOS 
Follow 
Up28 
Study Day 
–30 to 
0 
1 
2 
3 
8 
15 
222 
1 
8 
15 
222 
30d 
(+10d) 
post last 
dose 
(if applies) 
Every 8-9 
weeks post 
last tumor 
evaluation 
Pre-dose 0-6 h 
24 h 
48 h 
168 h 
336 h 
504 h 
0 h 
168 h 
336 h 
504 h 
Informed Consent / HIPPA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
 
X 
X 
X 
X 
X 
X2 
X 
X 
X 
X 
 
ECOG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical examination3 
X 
X 
 
 
 
 
 
X 
X2 
 
 
X 
X 
 
Height, weight and BSA4 
X 
X4 
 
 
 
 
 
 
X4 
 
 
 
 
 
Vital signs5 
X 
X5 
X5 
 
 
X 
 
X 
X2,5 
X 
 
X 
X 
 
ECHO or MUGA (perform if needed)6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
X7 
X7 
 
 
 
 
 
X8 
 
 
 
X 
 
CT brain scan (pre-screen if needed) 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology10, 11 
X 
X10 
 
 
 
X 
X 
X 
X2, 11 
X11 
X11 
X11 
X 
 
Chemistry10, 11 
X 
X10 
 
 
 
X 
X 
X 
X2, 11 
X11 
X11 
X11 
X 
 
Coagulation10  
X 
X12 
Prior to post-dose biopsy as applicable (only from patients who undergo) 
 
 
Urinalysis with microscopy10, 11 
X 
X10 
 
 
 
X 
 
X 
X2, 11 
X11 
 
X11 
X 
 
Pregnancy test13 
X13 
X13 
 
 
 
 
 
 
 
 
 
 
X13 
 
PK blood: Ph 1; Ph 2a Stg 1 & subset Stg 2 only14 
 
X 
X 
X 
X 
X 
X15 
X 
 
 
 
 
 
 
PK urine :Ph 1 and Ph 2a Stg 1 only16 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
Blood sample for biomarker: Ph 2a only17 
 
X17 
 
X17 
 
 
 
 
 
 
 
 
X 
 
CTC: Ph 2a Stg 1 only18 
 
X18 
X18 
X18 
 
X18 
 
 
X18 
X18 
 
 
X 
 
MPS function: Ph 2a Stg 1 only19 
 
X19 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor measurement and staging 
X20 
 
 
 
 
 
X20 
 
 
 
X20 
 
X21 
X28 
PSA for prostate patients only in Phase 2a22 
X22 
 
 
 
 
 
 
X22 
 
 
 
X22 
X22 
X28 
Tumor biopsy23 
X 
Collect post-dose biopsy any time after 3rd dose completed (C3D1) if applicable 
 
 
Tumor marker Data24 
X24 
Collected based on tumor type and institution guidelines/Standard of Care 
 
Premedication25 
X25 
X25 
 
 
 
 
X25 
 
X25 
 
X25 
 
 
 
CRLX301 infusion26 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Assessment for adverse events 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 


Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc.
Protocol No.: CRLX301-101 
Page 20 of 133  
AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
Archived Tumor Tissue27 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Clinic visit window rules: For C1 and C2 no visit windows. For C3 through C7 allowable window for Day 1 visit only is ±1 day; for C4 and C5 allowable 
window for D8 and D15 clinic visits is ±1 day;  as of C7D8 and for all subsequent visits, allowable window is ±2 days. 
2. D22 is the equivalent of pre-dose D1 in the subsequent cycle. 
3. Complete PE of body systems must be performed by the Investigator during pre-study and EOS (includes weight).  Limited PE is performed pre-dose on 
C1D1 and at the end of each cycle (D22).  
4. Height required at pre-study only; repeat weight measurement C1D1 to calculate BSA not necessary if pre-study assessment was ≤3 days prior to C1D1. 
Record weight measurement at each subsequent cycle pre-dose and recalculate BSA only if body weight changes by more than 10% and change is attributed 
to dry weight. 
5. Refer to Section 5.7 for vital sign collection time points. Collect VS C1D1 pre-dose, during infusion at 30 min and 60 min, and end of infusion; post infusion 
at +60 min, +3 hr, and +6 hr (-1 hr); VS for all subsequent cycles D1 at pre-dose, +60 min. post-infusion, D8, D22, and EOS visit. Temperature (T) only at 
pre-dose, +6 hr (-1 hr) post infusion and at EOS visit.  As of Cycle 7 collect vital signs pre-dose and at EOS day of visit only. 
6. ECHO or MUGA performed pre-study only for patients with a known history of cardiac insufficiency and symptomatic in the last 3 months, and only if prior 
ECHO or MUGA not available within 30 days of first dose. 
7. ECG required pre-dose and at +1hr (+30min) after end of infusion. 
8. ECG required in C2 only pre-dose and at +1hr (+30min) after end of infusion.  
9. CT brain scan required to confirm known brain metastases have been stable for ≥ 30 days prior to C1D1. If a patient is asymptomatic at pre-study with no 
history of brain metastases, additional brain scanning for eligibility is not required. 
10. Chemistry, hematology, urinalysis and coagulation panels are referenced in Section 5.11. Assessment do not need to be repeated on C1D1 if assessment was 
≤3 days prior to C1D1. As of Cycle 2 it is permissible to perform pre-dose hematology, chemistry and urinalysis within 24 hours of dosing. 
11. As of Cycle 8 perform hematology, chemistry, urinalysis at the beginning of the cycle only on Day 1 pre-dose. The Day 8 (all three assessments) and Day 15 
(hematology and chemistry only) time points are only performed in Cycles 1-7. 
12. Coagulation within 3 days of first dose only for C1. Not performed in C3 or C6; also performed prior to post-dose biopsy in patients who consent to biopsy 
13. Pregnancy test is performed only at pre-study, prior to C1D1 dosing if needed and at EOS: repeat urine pregnancy test on C1D1 not necessary if pre-study 
assessment was ≤3 days prior to C1D1. Test should be repeated as needed for women of child-bearing potential if suspicion of pregnancy. Positive urine 
pregnancy tests should be confirmed with a serum pregnancy test. 
14. For Phase 1, Phase 2a Stage 1 and for up to 10 patients in Phase 2a Stage 2 plasma PK will be collected in C1, C3 and C6: On D1 pre-dose; after initiation of 
infusion at 30 min (during infusion) and 60 min (during infusion); at end of infusion; and after end of infusion at +30 min, +60 min, +3 hr, and +6 hr (-1 hr). 
Collect on D2; D3; D8, and D15 (C1 only). Collect pre-dose on D1 in C2, C4 & C7. Refer to Section 5.13 for complete details on PK time points and 
allowable windows. 
15. D15 plasma PK collection in C1 only.  
16. For Phase 1 and for Phase 2a Stage 1 urine PK will be collected on D1 in C1, C3 and C6. Collect a 15 mL spot urine sample pre-dose; then collect all urine 
from start of infusion (0 h) through 6 h post-infusion. On D8 collect a15 mL spot urine sample.  


Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc. 
Protocol No.: CRLX301-101 
Page 21 of 133  
AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
17. Blood sample for biomarkers in Phase 2a Stage 1 and Stage 2 only. Collect only in C1 and C3: D1 pre-dose and D2. 
18. CTCs in Phase 2a Stage 1 only. Collect only in C1: D1 pre-dose, 4hrs (-1hr) after end of infusion, 24hrs (+/- 4hrs) after end of infusion (D2) and on D8; and 
in C2: D1 pre-dose, 4hrs (-1hr) after end of infusion and on D8. 
19. MPS function in Phase 2a Stage 1 only. Collect pre-dose in Cycles 1 and 3 only. 
20. Perform the tumor measurement at the end of every third cycle or every 9 weeks (Cycle 3, 6, 9, etc.) within a week prior to D22 (as of D15 +6 days) until the 
patient discontinues study drug treatment due to disease progression. If a complete or partial response per RECIST1.1 criteria or with methodologies 
consistent with tumor type is reported, then repeat evaluation 3-4 weeks later for confirmation, at discretion of investigator. If stable response per 
RECIST1.1 criteria or with methodologies consistent with tumor type is reported, then continue repeat evaluation at end of every third cycle (every 9 
weeks). See Section 5.15.3 for alternative methodologies. Patients in Phase 1 with non-measurable disease will require Investigator and Medical Monitor 
review to determine proper disease staging, if any is required. Bone scans will also be required at each tumor evaluation for CRPC patients enrolled into 
Phase 2a. 
21. Tumor measurement and staging not required at EOS if previous evaluation was less than 22 days prior.  
22. For prostate cancer patients in Phase 2a only: collect PSA pre-study; pre-dose at the start of every cycle starting at Cycle 2; at EOS only if it has been > 14 
days since the last PSA measurement; and during Follow-Up if applicable at the same time tumor evaluation is performed 
23. Collect tumor biopsy only if accessible and feasible to collect and with consent of patient; collect pre-study prior to first dose. Collect post-dose any time 
after 3rd dose completed (C3D1). 
24. Tumor marker data will be collected per Institution guidelines only if appropriate for evaluation of disease for the specific tumor-type and if feasible; repeat 
as per standard of care. 
25. During screening, patients will be provided with Day (-1) oral premedication. Patients will be instructed on when (the night prior to the first CRLX301 
infusion) and how to take these medications by the study staff. On D15 of each cycle, oral premedication will be provided to each patient for the subsequent 
cycle. Refer to Section 5.10.2 for complete details on premedication. NOTE: Site staff will call each patient within 72 hours prior to D(-1) to remind patient 
to take premedication. 
26. NOTE: Prior to initiation of CRLX301 infusion, site will confirm whether patient took premedication regimen the prior evening (D(-1)). If patient did not 
take premedication, CRLX301 infusion will be initiated at discretion of investigator. Each CRLX301 infusion should start as slow as possible with no more 
than 15mL infused over the first 15 minutes. Provided the patient does not experience any infusion related symptoms during these 15 minutes, the rate of 
infusion can be gradually increased to complete the infusion in approximately 120 minutes (inclusive of 50mL flush). Refer to the Pharmacy Manual and 
Section 5.10.3.1 for complete administration instructions. 
NOTE: If hypersensitivity event occurs, collect blood sample for tryptase evaluation within 3 hours of event. If patient is to be retreated collect blood 
sample for tryptase prior to each subsequent infusion. See Table on Clinical Laboratory Test Parameters and Timing 
27. Archived tumor tissue confirmed if available and patient has consented. Preparation of slides and shipment to central lab will not be triggered until sponsor 
advises sites in writing. 
28. Patients who are discontinued from study treatment for reasons other than disease progression will continue to have tumor evaluation by RECIST1.1 or with 
methodologies consistent with tumor type every 8-9 weeks per investigator discretion until another anti-cancer treatment is started, progression of disease, 
death, loss to follow up or withdrawal of consent, whichever comes first. Therefore, continued scans may be possible for some patients after the EOS.  
Prostate cancer patients in Phase 2a only will also have PSA collected at the same time tumor evaluation is repeated. 
 


Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc. 
Protocol No.: CRLX301-101 
Page 22 of 133  
AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
SCHEDULE OF PROCEDURES – SCHEDULE 2 (QW: WEEKLY DOSING, NO BREAK / DAY 1 OF EACH 
WEEK) 
Procedures 
Pre-
Study 
Week of Treatment 
Treatment post W71 
 
Follow Up27 
(if applies) 
Every 8-9 
weeks post 
last tumor 
evaluation 
Study Week 
1, 4, 71  
2, 3, 5, 61 
QW 
Q2W 
Q3W 
EOS 
Day of Week 
D1 
D2 
D1 
D11 
D11 
D11 
30 (+10) 
days 
post last 
dose 
Time point 
-30 to 
0 day 
Pre-
dose 
0 - 
+6h 
24h 
Pre-dose 
0 - 
+6h 
e.g. W8, 
W11, etc. 
e.g. W9, 
W12, etc. 
e.g. W10, 
W13, etc. 
Informed Consent / HIPPA 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
ECOG 
X 
 
 
 
 
 
 
 
 
X  
 
Physical examination  
X2 
X3 
 
 
 
 
 
 
X3 
X2 
 
Height, weight & BSA4  
X 
X 
 
 
X 
 
X 
X 
X 
 
 
Vital signs5  
X 
X5 
X5, 
 
X5 
X5 
X6 
X6 
X6 
X5 
 
ECHO or MUGA (perform if needed)7 
X 
 
 
 
 
 
 
 
 
 
 
ECG  
X 
X 
X8 
 
 
 
 
 
 
X 
 
CT brain scan (pre-screen if needed)9 
X 
 
 
 
 
 
 
 
 
 
 
Hematology10  
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
Chemistry10 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
Coagulation10 
X 
X11 
Perform coagulation prior to post-dose biopsy as applicable (after third dose) 
 
 
Urinalysis w/ microscopy10 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
Pregnancy test12 
X12 
X12 
 
 
 
 
 
 
 
X12 
 
PK blood: Ph 1, Ph 2a Stg 1 & subset Stg 2 only13 
 
X 
X13 
X 
X13 
 
 
 
 
 
 
PK urine: Ph1 & Ph2a Stg 1 only 
 
X14 
X14 
 
X15 
 
X15 
 
 
 
 
Blood sample for biomarker –Ph2a only16 
 
X16 
 
X16 
  
 
 
 
 
X 
 
CTC – Ph2a Stg 1 only17 
 
X17 
X17 
X17 
X17 
X17 
 
 
 
X 
 
MPS function – Ph2a Stg 1 only 
 
X18 
 
 
 
 
 
 
 
 
 
Tumor measurement and staging 19 
X 
 
 
 
 
 
 
X 
 
X20 
X27 
PSA for prostate patients only in Phase 2a21 
X21 
X21 
 
 
X21 
 
 
 
X21 
X21 
X27 
Tumor biopsy22 
X 
Collect post-dose biopsy if applicable any time after the third (W3) dose is completed 
 
 
Tumor marker Data23 
X 
Collect data as available based on tumor type and institution guidelines/ Standard of Care 
 
Archived Tumor Tissue24 
X 
 
 
 
 
 
 
 
 
 
 
Premedication25 
 X25 
X25 
 
 
X25 
 
X25 
X25 
X25 
 
 
CRLX301 infusion26 
 
 
X 
 
 
X 
X 
X 
X 
 
 


Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc. 
Protocol No.: CRLX301-101 
Page 23 of 133  
AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
Procedures 
Pre-
Study 
Week of Treatment 
Treatment post W71 
 
Follow Up27 
(if applies) 
Every 8-9 
weeks post 
last tumor 
evaluation 
Study Week 
1, 4, 71  
2, 3, 5, 61 
QW 
Q2W 
Q3W 
EOS 
Day of Week 
D1 
D2 
D1 
D11 
D11 
D11 
30 (+10) 
days 
post last 
dose 
Time point 
-30 to 
0 day 
Pre-
dose 
0 - 
+6h 
24h 
Pre-dose 
0 - 
+6h 
e.g. W8, 
W11, etc. 
e.g. W9, 
W12, etc. 
e.g. W10, 
W13, etc. 
Assessment for AEs 
 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: BSA = body surface area, CT = computerized tomography, D = Day, Dx = Day ‘x’, ECG = electrocardiogram, EOS = End of Study, hr(s) = 
hour(s), min=minutes, PE = physical examination, PK = Pharmacokinetic, T = temperature, VS = vital sign(s), W = week(s) 
1. Clinic visit window rules: For W1 through W8 no visit windows. As of W9 allowable window for dosing is +/- 1d. 
2. Complete PE must be performed by the Investigator during pre-study and EOS (includes weight). 
3. Limited PE is performed pre-dose on W1 and pre-dose every 3 weeks (W4, W7, etc.). 
4. Height required at pre-study only; not necessary to repeat weight on D1W1 if per-study was ≤3 days prior to W1D1. Record weight measurement at each 
week pre-dose and recalculate BSA only if body weight changes by more than 10% and change is attributed to dry weight. 
5. Refer to Section 5.7 for vital sign collection time points. In W1, W4 and W7: D1 pre-dose, during infusion at 30 min and 60 min; end of infusion; post 
infusion at +60 min, +3 hr and +6 hr (-1 hr). In W2-3 and W5-6: D1 pre-dose and at end of infusion. VS for all subsequent weeks D1 at pre-dose, and EOS 
visit. Temperature (T) is recorded: W1, W4, W7 pre-dose and 6hrs (-1 hr) after end of infusion; W2, W3, W5 & W6 record temperature pre-dose and at end 
of infusion; all subsequent weeks record T pre-dose; and EOS.  
6. As of W8 and for EOS, collect vital signs and temperature pre-dose only (day of visit for EOS). 
7. ECHO or MUGA performed pre-study only for patients with a known history of cardiac insufficiency and symptomatic in the last 3 months, and only if prior 
ECHO or MUGA not available within 30 days of first dose. 
8. ECG required +1hr (+30min) after end of infusion. 
9. CT brain scan required to confirm if brain metastases have been stable for ≥ 30 days prior to W1D1. If a patient is asymptomatic at pre-study with no history 
of brain metastases, additional brain scanning for eligibility is not required. 
10. Chemistry, hematology, urinalysis and coagulation panels are referenced in Section 5.11. It is not necessary to repeat W1D1 assessment if pre-study 
assessment was ≤3 days prior to W1D1. All safety labs must be performed pre-dose for clinic days while on study treatment. As of W2: permissible to 
perform D1 chemistry, hematology and urinalysis within 24 hours of dosing. 
11. Coagulation within 3 days of first dose only in W1.  Not needed for other weeks unless post-dose biopsy performed. 
12. Pregnancy test is performed only at pre-study, prior to W1D1 dosing if needed and at EOS: repeat pregnancy test on W1D1 not necessary if pre-study test 
was ≤3 days prior to W1D1. Test should be repeated as needed for women of child-bearing potential if suspicion of pregnancy. Positive urine pregnancy 
tests should be confirmed with a serum pregnancy test. 
13. For Phase 1, Phase 2a Stage 1 and for up to 10 patients in Phase 2a Stage 2, plasma PK will be collected on the dosing day in weeks 1, 4 & 7: On D1 pre-
dose; after initiation of infusion at 30 min (during infusion) and 60 min (during infusion); at end of infusion; and after end of infusion at +30 min, +60 min, 
+3 hr and +6 hr (-1 hr). Also collect on D2. In Weeks 2, 3, 5 & 6 a pre-dose sample will be collected Refer to Section 5.13 for complete details on PK time 
points. 


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CONFIDENTIAL 
14. For Phase 1 and for Phase 2a Stage 1 urine PK will be collected on the dosing day in weeks 1, 4 & 7.  Collect a 15 mL spot urine pre-dose; then collect all 
urine from start of infusion (0 h) through 6 h post-infusion. 
15. Collect 15 ml spot urine for PK during week 2, 5, and 8 only pre-dose. 
16. Blood sample for biomarker in Phase 2a Stage 1 and Stage 2 only. During treatment collect only W1 and W4: D1 pre-dose and D2. 
17. Blood for CTC in Phase 2a Stage 1 only. Collect blood for CTC only at Week 1 pre-dose, 4hrs (-1hr) after end of infusion, 24hrs (+/-4hrs) after end of 
infusion (Day 2); Week 2 pre-dose; Week 4 pre-dose and 4hrs (-1hr) after end of infusion; and Week 5 pre-dose. 
18. Collect blood for MPS function test in phase 2a Stage 1 pre-dose only in Week 1 and 4. 
19. Perform the tumor measurement every 9 weeks (+6 days) (W9, W18, etc) until the patient discontinues study drug treatment due to disease progression. If a 
complete or partial response per RECIST 1.1 criteria or with methodologies consistent with tumor type is reported, then repeat evaluation 3-4 weeks later for 
confirmation at discretion of investigator. If stable response per RECIST criteria or with methodologies consistent with tumor type is reported, then continue 
repeat evaluation every 9 weeks. See Section 5.15.3 for alternative methodologies. In Phase 1, patients with non-measurable disease will require Investigator 
and Medical Monitor review to determine proper disease staging, if any is required. Bone scans will be required at each tumor evaluation for CRPC patients 
enrolled into Phase 2a. 
20. EOS tumor measurement and staging is not required if previous evaluation was less than 22 days prior.  
21. For prostate cancer patients only in Phase 2a: collect PSA pre-study; pre-dose at the start of every third week starting at Week 4 (e.g. W4, W7, W10, etc.); at 
EOS only if it has been > 14 days since the last PSA measurement; and during Follow-Up if applicable at the same time tumor evaluation is performed. 
22. Collect tumor biopsy only if accessible and feasible to collect and with consent of patient; collect biopsy pre-study prior to first dose. Collect post-dose 
biopsy any time after the third dose is completed. 
23. Tumor marker data will be collected per Institution guidelines only if appropriate for evaluation of disease for the specific tumor-type and if feasible; repeat 
as per standard of care. 
24. Archived tumor tissue confirmed if available and patient has consented. Preparation of slides and shipment to central lab will not be triggered until Sponsor 
advises sites in writing. 
25. During screening, patients will be provided with Day(-1) oral premedication. Patients will be instructed on when (prior to the first CRLX301 infusion) and 
how to take these medications by the study staff. On D1 or D2 (as applicable of given week), oral premedication will be provided to each patient for the 
subsequent week’s dosing event. Refer to Section 5.10.2 for complete details on premedication. NOTE: Site staff will call each patient within 72 hours prior 
to D(-1) to remind patient to take premedication. 
26. NOTE: Prior to initiation of CRLX301 infusion, site will confirm that patient ingested premedication regimen the prior evening (D(-1)). If patient did not 
take premedication, CRLX301 infusion will be initiated at discretion of investigator. Each CRLX301 infusion should start as slow as possible with no more 
than 15mL infused over the first 15 minutes. Provided the patient does not experience any infusion related symptoms during these 15 minutes, the rate of 
infusion can be gradually increased to complete the infusion in approximately 120 minutes, inclusive of the 50mL flush. Refer to the Pharmacy Manual and 
Section 5.10.3.1 for complete administration instructions. 
NOTE: If hypersensitivity event occurs, collect blood sample for tryptase evaluation within 3 hours of event. If patient to be retreated, collect blood 
sample for tryptase prior to each subsequent infusion. See Table on Clinical Laboratory Test Parameters and Timing. 


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27. Patients who are discontinued from study treatment for reasons other than disease progression will continue to have tumor evaluation by RECIST 1.1 or with 
methodologies consistent with tumor type until another anti-cancer treatment is started, progression of disease, death, loss to follow up or withdrawal of 
consent, whichever comes first.  Prostate cancer patients in Phase 2a only will also have PSA collected at the same time tumor evaluation is repeated.  
 
 
 
 
 
 
SCHEDULE OF PROCEDURES – SCHEDULE 2 (QW, 3 WEEK ON/1 WEEK OFF) 
Procedures 
Pre-
Study 
Week of Treatment (Week 1 to Week 8) 
Treatment post W81 
 
Study Week 
1, 3, 71  
2, 5, 61 
4,81 
3 week on/1 week off 
Q4W 
EOS 
Follow Up27 
(if applies) 
Every 8-9 weeks 
post last tumor 
evaluation 
Day of Week 
D1 
D2 
D1 
D1 
D11 
D11 
30 (+10) days 
post last dose 
Time point 
-30 to 
0 day 
Pre-
dose 
0 - 
+6h 
24h 
Pre-dose 
0 - 
+6h 
 
e.g. W9, W10, W11, 
W13, W14, W15, etc. 
e.g. W9, 
W13, etc. 
Informed Consent / HIPPA 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
ECOG 
X2 
 
 
 
 
 
 
 
 
X  
 
Physical examination  
X2 
X3 
 
 
X3 
 
 
 
X 
X2 
 
Height, weight & BSA4  
X 
X 
 
 
X 
 
 
X 
 
 
 
Vital signs5  
X 
X5 
X5, 
 
X5 
X5 
X5 
X6 
 
X6 
 
ECHO or MUGA (perform if needed)7 
X 
 
 
 
 
 
 
 
 
 
 
ECG  
X 
X 
X8 
 
 
 
 
 
 
X 
 
CT brain scan (pre-screen if needed)9 
X 
 
 
 
 
 
 
 
 
 
 
Hematology10  
X 
X 
 
 
X 
 
X 
X 
 
X 
 
Chemistry10 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
Coagulation10 
X 
X11 
Perform coagulation prior to post-dose biopsy as applicable (after third dose) 
 
 
Urinalysis w/ microscopy10 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
Pregnancy test12 
X12 
X12 
 
 
 
 
 
 
 
X12 
 
PK blood: Ph 1, Ph 2a Stg 1 & subset Stg 2 only13 
 
X 
X13 
X 
X13 
 
 
 
 
 
 
PK urine: Ph1 & Ph2a Stg 1 only 
 
X14 
X14 
 
X15 
 
 
 
 
 
 
Blood sample for biomarker –Ph2a only16 
 
X16 
 
X16 
  
 
 
 
 
X 
 


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CONFIDENTIAL 
Procedures 
Pre-
Study 
Week of Treatment (Week 1 to Week 8) 
Treatment post W81 
 
Study Week 
1, 3, 71  
2, 5, 61 
4,81 
3 week on/1 week off 
Q4W 
EOS 
Follow Up27 
(if applies) 
Every 8-9 weeks 
post last tumor 
evaluation 
Day of Week 
D1 
D2 
D1 
D1 
D11 
D11 
30 (+10) days 
post last dose 
Time point 
-30 to 
0 day 
Pre-
dose 
0 - 
+6h 
24h 
Pre-dose 
0 - 
+6h 
 
e.g. W9, W10, W11, 
W13, W14, W15, etc. 
e.g. W9, 
W13, etc. 
CTC – Ph2a Stg 1 only17 
 
X17 
X17 
X17 
X17 
 
 
 
 
X 
 
MPS function – Ph2a Stg 1 only 
 
X18 
 
 
 
 
 
 
 
 
 
Tumor measurement and staging 19 
X 
 
 
 
 
 
 
 
X19 
X20 
X27 
PSA for prostate patients only in Phase 2a21 
X21 
 
 
 
X21 
 
 
 
X 
X21 
X27 
Tumor biopsy22 
X 
Collect post-dose biopsy if applicable any time after the third (W3) dose is completed 
 
 
Tumor marker Data23 
X 
Collect data as available based on tumor type and institution guidelines/ Standard of Care 
 
Archived Tumor Tissue24 
X 
 
 
 
 
 
 
 
 
 
 
Premedication25 
 X25 
X25 
 
 
X25 
 
 
X25 
 
 
 
CRLX301 infusion26 
 
 
X 
 
 
X 
 
X 
 
 
 
Assessment for AEs 
 
X 
X 
X 
X 
X 
 
X 
 
Abbreviations: BSA = body surface area, CT = computerized tomography, D = Day, Dx = Day ‘x’, ECG = electrocardiogram, EOS = End of Study, hr(s) = 
hour(s), min=minutes, PE = physical examination, PK = Pharmacokinetic, T = temperature, VS = vital sign(s), W = week(s) 
1. Clinic visit window rules: For W1 through W8 no visit windows. There is no dosing on W4 and W8, but clinic visit required. As of W9 allowable window 
for dosing is +/- 1d. Clinic visits not required on non-dosing weeks as of W9. 
2. Complete PE and ECOG must be performed by the Investigator during pre-study and EOS (includes weight). 
3. Limited PE is performed pre-dose on W1 and pre-dose every 4 weeks (W5, W9, etc.). 
4. Height required at pre-study only; not necessary to repeat weight on D1W1 if per-study was ≤3 days prior to W1D1. Record weight measurement at each 
week pre-dose and recalculate BSA only if body weight changes by more than 10% and change is attributed to dry weight. 
5. Refer to Section 5.7 for vital sign collection time points. In W1, W3 and W7: D1 pre-dose, during infusion at 30 min and 60 min; end of infusion; post 
infusion at +60 min, +3 hr and +6 hr (-1 hr). In W2, W5 and W6: D1 pre-dose and at end of infusion. In W4 and W8: at clinic visit. Temperature (T) is 
recorded: W1, W3, W7 pre-dose and 6hrs (-1 hr) after end of infusion; W2, W5 & W6 record temperature pre-dose and at end of infusion; W4 and W8 
record temperature at clinic visit.  
6. For dosing weeks starting with W9 and for EOS, collect vital signs and temperature pre-dose only (day of visit for EOS). 
7. ECHO or MUGA performed pre-study only for patients with a known history of cardiac insufficiency and symptomatic in the last 3 months, and only if prior 
ECHO or MUGA not available within 30 days of first dose. 
8. ECG required +1hr (+30min) after end of infusion. 
9. CT brain scan required to confirm if brain metastases have been stable for ≥ 30 days prior to W1D1. If a patient is asymptomatic at pre-study with no history 
of brain metastases, additional brain scanning for eligibility is not required. 


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10. Chemistry, hematology, urinalysis and coagulation panels are referenced in Section 5.11. It is not necessary to repeat W1D1 assessment if pre-study 
assessment was ≤3 days prior to W1D1. All safety labs must be performed pre-dose for clinic days while on study treatment. As of W2: permissible to 
perform D1 chemistry, hematology and urinalysis within 24 hours of dosing. 
11. Coagulation within 3 days of first dose only in W1.  Not needed for other weeks unless post-dose biopsy performed. 
12. Pregnancy test is performed only at pre-study, prior to W1D1 dosing if needed and at EOS: repeat pregnancy test on W1D1 not necessary if pre-study test 
was ≤3 days prior to W1D1. Test should be repeated as needed for women of child-bearing potential if suspicion of pregnancy. Positive urine pregnancy 
tests should be confirmed with a serum pregnancy test. 
13. For Phase 1, Phase 2a Stage 1 and for up to 10 patients in Phase 2a Stage 2, plasma PK will be collected on the dosing day in weeks 1, 3 & 7: On D1 pre-
dose; after initiation of infusion at 30 min (during infusion) and 60 min (during infusion); at end of infusion; and after end of infusion at +30 min, +60 min, 
+3 hr, +6 hr (-1 hr), and +24 hr (D2). In addition, pre-dose plasma samples (trough samples) will be collected on Weeks 2, 5 & 6.  Refer to Section 5.13 for 
complete details on PK time points. 
14. For Phase 1 and for Phase 2a Stage 1 urine PK will be collected on the dosing day in weeks 1, 3 & 7.  Collect a 15 mL spot urine pre-dose; then collect all 
urine from start of infusion (0 h) through 6 h post-infusion. 
15. Collect 15 ml spot urine for PK during week 2, 5, and 6 only pre-dose. 
16. Blood sample for biomarker in Phase 2a Stage 1 and Stage 2 only. During treatment collect only W1 and W3: D1 pre-dose and D2. 
17. Blood for CTC in Phase 2a Stage 1 only. Collect blood for CTC only at Week 1 pre-dose, 4hrs (-1hr) after end of infusion, 24hrs (+/-4hrs) after end of 
infusion (Day 2); Week 2 pre-dose; Week 3 pre-dose and 4hrs (-1hr) after end of infusion; and Week 5 pre-dose. 
18. Collect blood for MPS function test in phase 2a Stage 1 pre-dose only in Week 1 and 3. 
19. Perform the tumor measurement every 8 weeks (+6 days), starting at Week 9 (e.g. W9, W17, etc.), until the patient discontinues study drug treatment due to 
disease progression. If a complete or partial response per RECIST 1.1 criteria or with methodologies consistent with tumor type is reported, then repeat 
evaluation 3-4 weeks later for confirmation at discretion of investigator. If stable response per RECIST criteria or with methodologies consistent with tumor 
type is reported, then continue repeat evaluation every 8 weeks. See Section 5.15.3 for alternative methodologies. In Phase 1, patients with non-measurable 
disease will require Investigator and Medical Monitor review to determine proper disease staging, if any is required. Bone scans will be required at each 
tumor evaluation for CRPC patients enrolled into Phase 2a. 
20. EOS tumor measurement and staging is not required if previous evaluation was less than 22 days prior.  
21. For prostate cancer patients only in Phase 2a: collect PSA pre-study; pre-dose at the start of every fourth week starting at Week 5 (e.g. W5, W9, W13, etc.); 
at EOS only if it has been > 14 days since the last PSA measurement; and during Follow-Up if applicable at the same time tumor evaluation is performed. 
22. Collect tumor biopsy only if accessible and feasible to collect and with consent of patient; collect biopsy pre-study prior to first dose. Collect post-dose 
biopsy any time after the third dose is completed. 
23. Tumor marker data will be collected per Institution guidelines only if appropriate for evaluation of disease for the specific tumor-type and if feasible; repeat 
as per standard of care. 
24. Archived tumor tissue confirmed if available and patient has consented. Preparation of slides and shipment to central lab will not be triggered until Sponsor 
advises sites in writing. 
25. During screening, patients will be provided with Day (-1) oral premedication. Patients will be instructed on when (prior to the first CRLX301 infusion) and 
how to take these medications by the study staff. On D1 or D2 (as applicable of given week), oral premedication will be provided to each patient for the 


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Protocol No.: CRLX301-101 
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CONFIDENTIAL 
subsequent week’s dosing event. Refer to Section 5.10.2 for complete details on premedication. NOTE: Site staff will call each patient within 72 hours prior 
to D(-1) to remind patient to take premedication. 
26. NOTE: Prior to initiation of CRLX301 infusion, site will confirm that patient ingested premedication regimen the prior evening (D(-1)). If patient did not 
take premedication, CRLX301 infusion will be initiated at discretion of investigator. Each CRLX301 infusion should start as slow as possible with no more 
than 15mL infused over the first 15 minutes. Provided the patient does not experience any infusion related symptoms during these 15 minutes, the rate of 
infusion can be gradually increased to complete the infusion in approximately 120 minutes, inclusive of the 50mL flush. Refer to the Pharmacy Manual and 
Section 5.10.3.1 for complete administration instructions. 
NOTE: If hypersensitivity event occurs, collect blood sample for tryptase evaluation within 3 hours of event. If patient to be retreated, collect blood 
sample for tryptase prior to each subsequent infusion. See Table on Clinical Laboratory Test Parameters and Timing. 
27. Patients who are discontinued from study treatment for reasons other than disease progression will continue to have tumor evaluation by RECIST 1.1 or with 
methodologies consistent with tumor type until another anti-cancer treatment is started, progression of disease, death, loss to follow up or withdrawal of 
consent, whichever comes first.  Prostate cancer patients in Phase 2a only will also have PSA collected at the same time tumor evaluation is repeated.  
 
 


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Protocol No.: CRLX301-101 
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CONFIDENTIAL 
TABLE OF CONTENTS 
SPONSOR PROTOCOL SIGNATURE PAGE .............................................................................. 2 
CONFIDENTIALITY STATEMENT ............................................................................................. 3 
INVESTIGATOR ACKNOWLEDGEMENT ................................................................................. 3 
SAFETY REPORTING AND CONTACT IN CASE OF EMERGENCY ..................................... 4 
PROTOCOL SYNOPSIS ................................................................................................................. 6 
SCHEDULE OF PROCEDURES – SCHEDULE 1 (Q3W / DAY 1 DOSING OF A 21-DAY 
CYCLE) ............................................................................................................................ 19 
SCHEDULE OF PROCEDURES – SCHEDULE 2 (QW: WEEKLY DOSING, NO BREAK / DAY 1 
OF EACH WEEK) ............................................................................................................ 22 
SCHEDULE OF PROCEDURES – SCHEDULE 2 (QW, 3 WEEK ON/1 WEEK OFF) ............ 25 
TABLE OF CONTENTS ............................................................................................................... 29 
TABLE OF TABLES .................................................................................................................... 33 
TABLE OF FIGURES ................................................................................................................... 34 
LIST OF ABBREVIATIONS AND SPECIAL TERMS ............................................................... 34 
1. 
INTRODUCTION ............................................................................................................ 37 
1.1 
Unmet Clinical Need ........................................................................................... 37 
1.2 
Docetaxel ............................................................................................................. 37 
1.3 
CRLX301 and Nanoparticle Delivery of Docetaxel ............................................ 38 
1.4 
Non-Clinical Pharmacokinetics, Pharmacology, Pharmacodynamics and Toxicology 
with CRLX301 ..................................................................................................... 39 
1.4.1 
Summary of non-GLP Studies ................................................................ 39 
1.4.2 
Summary of Pharmacokinetics in GLP Studies ...................................... 40 
1.4.3 
Summary of Pharmacology, Pharmacodynamics and Toxicology in GLP 
Studies ..................................................................................................... 40 
1.5 
Clinical Experience with CRLX301 for the Treatment of Advanced Solid Tumor41 
1.6 
Study Rationale .................................................................................................... 43 
1.7 
Rationale for Q3W Dosing and the Starting Dose Phase 1 Based on Clinical 
Experience with Docetaxel .................................................................................. 44 
1.8 
Rationale for Weekly Dosing (Schedule 2) and the Starting Dose Based on Clinical 
Experience with CRLX301 .................................................................................. 45 
1.8.1 
Rationale for Weekly Dosing ................................................................. 45 
1.8.2 
Rationale for Starting Dose for Schedule 2 during Phase 1 (QW, no break)
 ................................................................................................................ 46 
1.8.3 
Rationale for Evaluation of QW, 3 week on/1 week off for Schedule 2 47 
2. 
STUDY OBJECTIVES ..................................................................................................... 48 
2.1 
Primary Objectives .............................................................................................. 48 


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2.2 
Secondary Objectives .......................................................................................... 48 
2.3 
Exploratory Objectives ........................................................................................ 48 
3. 
INVESTIGATIONAL PLAN ........................................................................................... 49 
3.1 
Phase 1 Dose Escalation Study Design ................................................................ 49 
3.1.1 
Study Design Summary .......................................................................... 49 
3.1.2 
Definition of Maximum Tolerated Dose and Recommended Phase 2a Dose
 ................................................................................................................ 50 
3.1.3 
Definition of Dose-Limiting Toxicity ..................................................... 50 
3.1.4 
Treatment Schedule ................................................................................ 51 
3.1.5 
Phase 1 Dosing Cohorts .......................................................................... 52 
3.1.5.1 
Cohort Expansion for DLT ..................................................... 52 
3.1.5.2 
Cohort Dose Escalation Scheme............................................. 53 
3.1.6 
Study Safety Review Committee ............................................................ 55 
3.1.7 
Dose Reductions ..................................................................................... 56 
3.1.7.1 
Dose De-escalation ................................................................. 56 
3.2 
Phase 2a Expansion Study Design ....................................................................... 56 
3.2.1 
Phase 2a Stage 1 Expansion .................................................................... 57 
3.2.2 
Phase 2a Stage 2 Expansion .................................................................... 57 
4. 
STUDY POPULATION ................................................................................................... 58 
4.1 
Inclusion Criteria ................................................................................................. 58 
4.2 
Exclusion Criteria ................................................................................................ 60 
4.3 
Number of Patients .............................................................................................. 61 
4.4 
Replacement of Patients ....................................................................................... 62 
5. 
STUDY PROCEDURES .................................................................................................. 63 
5.1 
Informed Consent and HIPAA ............................................................................. 63 
5.2 
Eligibility, Study Enrollment, and Patient Number Assignment ......................... 63 
5.3 
Current Cancer Diagnosis, Prior Therapies, and Responses ................................ 64 
5.4 
Other Medical History ......................................................................................... 64 
5.5 
Concomitant Medications and Therapies ............................................................. 64 
5.5.1 
Concomitant Medications ....................................................................... 64 
5.5.1.1 
Concomitant Procedures ......................................................... 65 
5.5.2 
Concurrent Cancer Symptom Management ............................................ 65 
5.5.3 
Prohibited Concurrent Medications or Therapies ................................... 65 
5.6 
Physical Examination and BSA ........................................................................... 66 
5.7 
Vital Signs............................................................................................................ 66 
5.8 
Electrocardiogram ................................................................................................ 70 
5.9 
Echocardiogram (ECHO) or Multi Gated Acquisition Scan (MUGA) ................ 70 
5.10 
Study Treatment and Dose Assignment ............................................................... 70 
5.10.1 Cohort and Dose Assignment Phase 1: ................................................... 70 
5.10.2 Premedication Prior to CRLX301 Treatment for Both Schedules .......... 70 
5.10.3 CRLX301 Administration, Management of Infusion Related Reactions and 
Treatment Compliance ............................................................................ 72 
5.10.3.1 CRLX301 Administration ...................................................... 72 
5.10.3.2 Management of Infusion Related Reactions ........................... 73 
5.10.3.3 Treatment Compliance ........................................................... 75 
5.10.4 Dose Delay or Reductions or Treatment Discontinuation for Toxicity .. 75 
5.10.4.1 CRLX301 Treatment Modifications for Hematologic Toxicity76 


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5.10.4.2 CRLX301 Treatment Modifications for Non-Hematologic Toxicity
 ................................................................................................ 79 
5.11 
Clinical Laboratory Tests ..................................................................................... 82 
5.12 
Abnormal Results ................................................................................................ 85 
5.13 
Pharmacokinetic Sample Collection .................................................................... 86 
5.13.1 Patients with PK Collection .................................................................... 86 
5.13.2 PK Sample Collection Times .................................................................. 87 
5.14 
Estimated Total Blood Volume Collected ........................................................... 90 
5.15 
Evaluation of Target Tumors ............................................................................... 92 
5.15.1 CT Scans ................................................................................................. 92 
5.15.2 Bone Scans .............................................................................................. 93 
5.15.3 Alternative Evaluation Methods ............................................................. 93 
5.16 
Tumor Marker Data ............................................................................................. 94 
5.17 
Pharmacodynamic (PD) Sample: Pre- and Post-Dose Biopsy ............................. 94 
5.18 
Blood Sample Collection for Additional Biomarker Research ............................ 94 
5.19 
Archived Tumor Tissue ....................................................................................... 95 
5.20 
Circulating Tumor Cells (CTCs) ......................................................................... 95 
5.21 
Mononuclear Phagocyte System (MPS) Function ............................................... 95 
5.22 
End-of-Study Visit ............................................................................................... 96 
5.23 
Follow Up (as applicable) .................................................................................... 97 
6. 
DISCONTINUATION FROM TREATMENT AND STUDY WITHDRAWAL ........... 98 
6.1 
Reasons for Discontinuation from Treatment ...................................................... 98 
6.2 
Survival Status ..................................................................................................... 99 
7. 
STUDY DRUG AND PHARMACY INSTRUCTIONS ................................................ 100 
7.1 
Study Drug ......................................................................................................... 100 
7.2 
Study Drug Dose Calculation and Administration ............................................ 100 
7.2.1 
Body surface Area Calculation ............................................................. 100 
7.2.2 
CRLX301 Dose Reconstitution ............................................................ 100 
7.2.3 
CRLX301 Administration ..................................................................... 101 
7.3 
Study Drug Accountability ................................................................................ 101 
8. 
ADVERSE EVENTS ...................................................................................................... 102 
8.1 
Definition of Adverse Events and Adverse Reactions ....................................... 102 
8.2 
Evaluation of Adverse Events ............................................................................ 102 
8.2.1 
Serious Adverse Events (SAE) and Suspected Unexpected Serious Adverse 
Reactions (SUSAR) .............................................................................. 102 
8.2.2 
Unexpected Suspected Adverse Reaction ............................................. 103 
8.2.3 
Other Adverse Events of Special Interest ............................................. 104 
8.2.4 
Non-Serious Adverse Events ................................................................ 104 
8.2.5 
Laboratory Adverse Events .................................................................. 104 
8.2.6 
Severity of Adverse Events ................................................................... 105 
8.2.7 
Relationship to Study Drug ................................................................... 105 
8.3 
Expedited Reporting of SAEs, Patient Death and Unexpected AE ................... 107 
8.3.1 
Time-Frame for Reporting .................................................................... 107 
8.3.2 
Information to be Submitted for Reportable Event ............................... 107 
8.4 
Recording Adverse Events ................................................................................. 108 
8.5 
Exposure to Study Drug during Pregnancy ....................................................... 109 
8.6 
End-of-Study Post-treatment Safety Follow-up ................................................. 109 


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9. 
EVALUATION OF ANTI-TUMOR ACTIVITY .......................................................... 110 
9.1 
Measurable Disease and Target Lesions ............................................................ 110 
9.1.1 
Measurable Disease .............................................................................. 110 
9.1.2 
Target Lesions....................................................................................... 111 
9.2 
Response Evaluation of Target Lesions ............................................................. 111 
9.3 
Evaluation of Best Overall Response and Disease Control Rate ....................... 111 
9.4 
Progression-Free Survival .................................................................................. 112 
10. 
STATISTICAL METHODS ........................................................................................... 113 
10.1 
Patient Populations ............................................................................................ 113 
10.1.1 Safety Population .................................................................................. 113 
10.1.2 Pharmacokinetic Analysis Population .................................................. 113 
10.1.3 MTD and/or RP2D Population ............................................................. 113 
10.1.4 MTD and/or RP2D Efficacy Evaluable Populations ............................ 113 
10.2 
Endpoints ........................................................................................................... 113 
10.2.1 Phase 1 .................................................................................................. 113 
10.2.2 Phase 2a ................................................................................................ 113 
10.3 
Patient Disposition ............................................................................................. 114 
10.4 
Demographics and Other Baseline Characteristics ............................................ 114 
10.5 
Protocol Deviations ............................................................................................ 114 
10.6 
Extent of Exposure and Treatment Compliance ................................................ 114 
10.7 
Efficacy Analyses .............................................................................................. 115 
10.8 
Pharmacokinetic Analyses ................................................................................. 115 
10.9 
Safety Analyses .................................................................................................. 116 
10.9.1 Adverse Events ..................................................................................... 116 
10.9.2 Clinical Laboratory Parameters ............................................................ 116 
10.9.3 ECOG ................................................................................................... 117 
10.9.4 Vital Signs ............................................................................................ 117 
10.9.5 Electrocardiograms ............................................................................... 117 
10.9.6 Physical Examination ........................................................................... 117 
10.9.7 Weight and Height ................................................................................ 117 
10.9.8 Prior and Concomitant Medication ....................................................... 117 
10.10 Biomarker and Pharmacodynamic Exploratory Analyses ................................. 118 
10.11 Interim Analysis ................................................................................................. 118 
10.12 Missing data ....................................................................................................... 118 
11. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ...... 119 
12. 
ETHICAL CONSIDERATIONS .................................................................................... 120 
12.1 
Independent Ethics Committee / Institutional Review Board ............................ 120 
12.2 
Patient Information and Consent ....................................................................... 120 
13. 
STUDY MANAGEMENT AND INVESTIGATOR OBLIGATIONS .......................... 122 
13.1 
Principal Investigator and Clinical Sites ............................................................ 122 
13.2 
Study Safety Review Committee ....................................................................... 122 
13.3 
Data Monitoring ................................................................................................. 122 
13.4 
Data Recording and Documentation .................................................................. 123 
13.5 
Retention and Review of Records ...................................................................... 123 
13.6 
Patient Confidentiality ....................................................................................... 124 
14. 
STUDY SPONSORSHIP................................................................................................ 125 


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14.1 
Study Audits and Inspections ............................................................................ 125 
14.2 
Study Termination ............................................................................................. 125 
14.3 
Reporting and Publication.................................................................................. 125 
REFERENCES ............................................................................................................................ 126 
APPENDICES ............................................................................................................................. 129 
APPENDIX A .............................................................................................................................. 129 
APPENDIX B .............................................................................................................................. 130 
APPENDIX C .............................................................................................................................. 131 
 
 
TABLE OF TABLES 
Table 1: Schedule 1 Q3W Provisional Phase 1 Dose Escalation Scheme .................................... 54 
Table 2: Schedule 2 QW Provisional Phase 1 Dose Escalation Scheme ...................................... 54 
Table 3: Schedule 1 (Q3W) Vital Sign Assessment ..................................................................... 67 
Table 4: Schedule 2 (QW, no break) Vital Sign Assessment ....................................................... 68 
Table 5: Schedule 2 (QW, 3 week on/1 week off) Vital Sign Assessment .................................. 69 
Table 6: Premedication Schedule for Q3W and QW Schedules................................................... 71 
Table 7: Management of Infusion Related Hypersensitivity Reactions ....................................... 73 
Table 8: Schedule 1 (Q3W): CRLX301 Dose Delay or Reduction for Hematologic Toxicity .... 78 
Table 9: Schedule 1 (Q3W) CRLX301 Dose Delay or Reduction for Non-Hematologic Toxicity
....................................................................................................................................................... 80 
Table 10: Schedule 2 (QW, no break or QW, 3 week on/1 week off) CRLX301 Dose Delay or 
Reduction for Non-Hematologic Toxicity .................................................................................... 81 
Table 11: Schedule 1 (Q3W) Clinical Laboratory Test Parameters and Timing .......................... 83 
Table 12: Schedule 2 (QW, no break) Clinical Laboratory Test Parameters and Timing ............ 84 
Table 13: Schedule 2 (QW, 3 week on/1 week off) Clinical Laboratory Test Parameters and 
Timing ........................................................................................................................................... 85 
Table 14: Schedule 1 (Q3W) Blood PK Sample Collection Times (Phase 1 and subset of patients 
in Phase 2a) ................................................................................................................................... 87 
Table 15: Schedule 1 (Q3W) Urine PK Sample Collection Times (Phase 1, Phase 2a Stage 1, and 
subset of patients in Phase 2a Stage 2 only) ................................................................................. 88 
Table 16: Schedule 2 (QW, no break) Blood PK Sample Collection Times (Phase 1 and subset of 
patients in Phase 2a)...................................................................................................................... 88 
Table 17: Schedule 2 (QW, no break) Urine PK Sample Collection Times (Phase 1 and Phase 2a 
Stage 1 Only) ................................................................................................................................ 89 
Table 18: Schedule 2 (QW, 3 week on/1 week off) Blood PK Sample Collection Times (Phase 1 
and subset of patients in Phase 2a) ............................................................................................... 89 
Table 19: Schedule 2 (QW, 3 week on/1 week off) Urine PK Sample Collection Times (Phase 1 
and Phase 2a Stage 1 Only) .......................................................................................................... 90 
Table 20: Schedule 1 (Q3W) Estimated Blood Volume ............................................................... 91 
Table 21: Schedule 2 (QW, no break) Estimated Blood Volume ................................................. 91 
Table 22: Schedule 2 (QW, 3 week on/1 week off) Estimated Blood Volume ............................ 92 


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TABLE OF FIGURES 
Figure 1: Study Schematic ............................................................................................................ 50 
 
 
LIST OF ABBREVIATIONS AND SPECIAL TERMS 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
AIDS 
Acquired immune deficiency syndrome 
AST 
Aspartate aminotransferase 
ALT 
Alanine aminotransferase 
ALP                Alkaline phosphatase   
ANC 
Absolute neutrophil count 
AUC 
Area under the plasma concentration versus time curve 
BP 
Blood pressure 
BSA 
Body surface area 
C 
Cycle 
°C 
Degrees Celsius 
C1D1 
Cycle 1 Day 1 
CxDx 
Cycle “x” Day “x” 
CFR 
Code of Federal Regulations 
Cmax 
Maximum concentration observed 
CNS 
Central nervous system 
CRA 
Clinical Research Associate  
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CTCs 
Circulating tumor cells 
D or d 
Day/(s) 
dL 
Deciliter 
DLT 
Dose limiting toxicity 
DVT 
Deep venous thrombosis 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EPR 
Enhanced permeability and retention 
EOS 
End-of-Study 


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FDA 
Food and Drug Administration 
g 
Gram 
h 
Hour(s) 
hr(s) 
Hour(s) 
HSR 
Hypersensitivity (Infusion) Reaction 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation  
IEC 
Independent ethics committee 
IND 
Investigational new drug (application) 
IUD 
Intrauterine device 
IRB 
Institutional review board 
IV 
Intravenous(ly) 
kg 
Kilogram 
L 
Liter 
LDH 
Lactate dehydrogenase 
m 
meter 
mg 
milligram 
mg/m2 
milligrams per meter squared 
min 
Minute 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
millimeter of mercury  
MPS 
Mononuclear phagocyte system 
msec 
millisecond 
μL 
microliter 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
nm 
Nanometer 
NSCLC 
Non-small cell lung cancer 
PD 
Pharmacodynamic 
PE 
Physical Examination 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PCS 
Potentially clinically significant 
PCWG2 
Prostate Cancer Working Group 2 


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PR interval 
Duration of time from P wave (atrial depolarization) to the beginning of 
the QRS complex (ventricular depolarization) in the heart’s electrical 
cycle 
PSA 
Prostate-specific antigen 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PV 
Pharmacovigilance 
Q3W 
Dosing every 3 weeks 
QT 
Time interval between the start of the Q wave and the end of the T wave in 
the heart's electrical cycle 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)⅓) 
QW 
Weekly Dosing 
RBC 
Red blood cell 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended Phase 2 dose 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
Standard of Care 
SRC 
Safety Review Committee 
SUSAR 
Serious unexpected suspected adverse reaction 
T 
Temperature 
T1/2 
Elimination half-life 
TEAE 
Treatment-emergent adverse event 
TGA 
Therapeutic Goods Administration 
TIA 
Transient ischemic attack 
ULN 
Upper limit of normal 
US/USA 
United States 
VS 
Vital Signs 
WBC 
White Blood Cell 


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1. 
INTRODUCTION 
1.1 
Unmet Clinical Need 
According to the International Agency for Research on Cancer, there were 12.7 
million new cancer cases and 7.6 million cancer deaths in 2008, and the global 
cancer burden is expected to nearly double to 21.4 million cases and 13.15 million 
deaths by 2030.1   The most common cancer worldwide is lung cancer 
contributing nearly 13% of the total number of new cases diagnosed among men 
and women, while among women only breast cancer leads at nearly 23%. The 
highest cancer rate for men and women together diagnosed in 2008 is Denmark, 
followed by Ireland and then Australia with the US having the seventh highest.2  
In Australia an estimated 124,910 new cases of cancer will be diagnosed this year, 
with that number set to rise to 150,000 by 2020. In 2011, more than 43,700 people 
are estimated to have died from cancer making it a leading cause of death and 
accounting for about 3 in 10 deaths in Australia. The most 5 common cancers in 
Australia (excluding non-melanoma skin cancer) are prostate, colorectal, breast, 
melanoma and lung cancer and account for over 60% of all cancers.2  
In the United States, cancer will become the leading cause of death in 16 years, 
surpassing heart disease, according to a new report from the American Society of 
Clinical Oncology. The number of new cancer cases is expected to increase nearly 
45% by 2030, from 1.6 million cases to 2.3 million cases annually. Although 
there is a declining rate of deaths due to cancer and improvements in the 5-year 
survival rates, the overall incidence of cancer remains stable in women and with 
slight decline in men.3   The need to continue to identify cancer therapies 
including use of advanced technologies, to improve survival and control of 
disease remains high as cancer continues to be a major health issue in the United 
States and other countries.   
1.2 
Docetaxel 
The active pharmaceutical ingredient of CRLX301 is docetaxel which is a 
member of the taxane family derived from the European yew tree, Taxus 
baccata.4  Taxanes disrupt the microtubular network required for mitotic and 
interphase cellular functions. Docetaxel is a strong inhibitor of microtubule 
disassembly leading to interference with cell division and cell death by apoptosis.5  
By virtue of its strong inhibition of microtubule disassembly, docetaxel is active 
against a variety of cancers and has been approved to treat several human solid 
tumor malignancies including androgen-independent prostate cancer, non-small 
cell lung cancer (NSCLC), and locally advanced or metastatic breast cancer.6,7 It’s 
marketed under the trade name of Taxotere® (hereafter referred to as commercial 
docetaxel). Unfortunately, the therapeutic response to docetaxel is associated with 
dose-limiting side effects such as myelosuppression, neutropenia, anemia and 
fluid retention.8,9  In addition, the poor aqueous solubility of docetaxel requires 
the incorporation of polysorbate 80 and ethanol in the clinical formulation leading 
to increased toxicities such as hypersensitivity.10 


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1.3 
CRLX301 and Nanoparticle Delivery of Docetaxel 
CRLX301 is a docetaxel-containing nanoparticle that in preclinical animal models 
demonstrates improvements in efficacy with decreased toxicity over the parent 
drug docetaxel.  The polymeric nanoparticle is comprised of docetaxel conjugated 
to a linear cyclodextrin-PEG copolymer that self-assembles into nanoparticles of 
approximately 10-30 nm in size.  The nanoparticle is designed to have size and 
surface properties that favor increased plasma half-life as well as enhanced drug 
deposition and retention in tumors.  Nanoparticle entry into tumors is thought to 
be primarily via extravasation through disorganized leaky vasculature commonly 
found in tumors.  According to the literature, the enhanced permeability and 
retention (EPR) effect of the leaky vasculature allows the entry of particles of 
<200 nm and the poor lymphatic drainage of many tumors results in increased 
residence time of the nanoparticle drug.11 As a result, preclinical studies have 
demonstrated that CRLX301 exhibits extended plasma stability with prolonged 
circulation time, avoids rapid clearance, and accumulates in tumor tissue possibly 
through the EPR effect. 
Nanoparticle delivery of chemotherapeutic drugs is an active area of research 
holding promise for ameliorating problems of solubility and tolerability while 
improving pharmacokinetics and pharmacodynamics of the active drug.12,13,14  
Furthermore, by improving accumulation and distribution patterns of previously 
toxic drugs, nanoparticles offer the potential for improved combination 
therapy.15,16  Preclinical pharmacokinetic studies in mouse tumor models with 
CRLX301 have demonstrated that nanoparticle delivery of docetaxel results in 
high levels of active drug in the tumor. The majority of CRLX301 in the 
circulation is present as conjugated drug where it is inactive.  Upon tumor uptake, 
the majority of the docetaxel is released as active free drug. Conjugated docetaxel 
remains in the tumor tissue for extended periods of time during which there is a 
sustained release of free docetaxel at the target site resulting in enhanced tumor 
cell death over administration of docetaxel control. The combination of increased 
nanoparticle tumor localization and sustained docetaxel drug release results in an 
up to 10-fold increase in drug accumulation in mouse tumors for at least 72 hours 
post nanoparticle administration when compared to a docetaxel control. 
The same nanoparticle CDP (cyclodextrin-PEG copolymer) backbone that 
constitutes CRLX301 is also the CDP backbone used for CRLX101, a first-in-
class nanoparticle drug conjugate containing the payload of 20(S) camptothecin.  
This drug is currently being evaluated in clinical trials.17,18,19,20   
CRLX301 is a docetaxel-containing nanoparticle that in preclinical animal models 
demonstrates improvements in efficacy with decreased toxicity over the parent 
drug docetaxel.  The polymeric nanoparticle is comprised of docetaxel conjugated
to a linear cyclodextrin-PEG copolymer that self-f assembles into nanoparticles of 
approximately 10-30 nm in size.  The nanoparticle is designed to have size and 
surface properties that favor increased plasma half-f life as well as enhanced drug 
deposition and retention in tumors.  Nanoparticle entry into tumors is thought to 
be primarily via extravasation through disorganized leaky vasculature commonly 
found in tumors.  According to the literature, the enhanced permeability and 
retention (EPR) effect of the leaky vasculature allows the entry of particles of 
<200 nm and the poor lymphatic drainage of many tumors results in increased 
11
residence time of the nanoparticle drug.1 As a result, preclinical studies have
demonstrated that CRLX301 exhibits extended plasma stability with prolonged 
circulation time, avoids rapid clearance, and accumulates in tumor tissue possibly 
through the EPR effect.
Nanoparticle delivery of chemotherapeutic drugs is an active area of research 
holding promise for ameliorating problems of solubility and tolerability while 
12,13,14
improving pharmacokinetics and pharmacodynamics of the active drug.1
Furthermore, by improving accumulation and distribution patterns of previously 
toxic drugs, nanoparticles offer the potential for improved combination 
15,16
therapy.1
Preclinical pharmacokinetic studies in mouse tumor models with
CRLX301 have demonstrated that nanoparticle delivery of docetaxel results in 
high levels of active drug in the tumor. The majority of CRLX301 in the 
circulation is present as conjugated drug where it is inactive.  Upon tumor uptake,
the majority of the docetaxel is released as active free drug. Conjugated docetaxel 
remains in the tumor tissue for extended periods of time during which there is a 
sustained release of free docetaxel at the target site resulting in enhanced tumor 
cell death over administration of docetaxel control. The combination of increased 
nanoparticle tumor localization and sustained docetaxel drug release results in an 
up to 10-fold increase in drug accumulation in mouse tumors for at least 72 hours
post nanoparticle administration when compared to a docetaxel control.
The same nanoparticle CDP (cyclodextrin-PEG copolymer) backbone that
constitutes CRLX301 is also the CDP backbone used for CRLX101, a first-in-
class nanoparticle drug conjugate containing the payload of 20(S) camptothecin. 
17,18,19,20
This drug is currently being evaluated in clinical trials.1


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Preclinical studies of CRLX301 have demonstrated the ability to enhance tumor 
uptake of docetaxel compared to administration of the docetaxel control alone 
leading to a significant improvement in anti-tumor activity of CRLX301 
compared to delivery of docetaxel control alone in several xenograft models 
representing various tumor types including prostate, lung, melanoma and ovarian 
cancers.  In summary, CRLX301is a promising novel nanoparticle therapy for a 
variety of human cancers and has the potential to transform docetaxel into a more 
efficacious and less toxic therapeutic agent. 
1.4 
Non-Clinical Pharmacokinetics, Pharmacology, Pharmacodynamics and 
Toxicology with CRLX301 
1.4.1 
Summary of non-GLP Studies 
In rodent studies, intravenous (IV) administration of docetaxel results in a 
relatively short half-life in the blood, while IV administration of CRLX301 leads 
to prolonged levels of drug in circulation.  While the majority of drug is contained 
within the nanoparticles in circulation, nanoparticles are able to enter tumor and 
release free drug in the tumor. Mouse pharmacokinetic studies have demonstrated 
sustained levels of drug in tumor.  CRLX301 delivered at the same dose as 
docetaxel results in up to10-fold higher levels of free drug in the tumor.    
The anti-tumor activity of CRLX301 has also been studied in rodent xenograft 
models including triple negative breast carcinoma, prostate, multi-drug resistant 
ovarian cancer, squamous non-small cell lung carcinoma (NSCLC), adeno- 
NSCLC and in a syngeneic melanoma model. In all of the models, CRLX301 was 
either superior or comparable to docetaxel in either median survival, delay of 
tumor progression and/or complete response rate. The improved PK and 
biodistribution properties of CRLX301 translated into significant tumor growth 
delay and survival improvement in multiple xenograft models. See Investigator’s 
Brochure for more details. 
Preclinical studies of CRLX301 have demonstrated the ability to enhance tumor 
uptake of docetaxel compared to administration of the docetaxel control alone 
leading to a significant improvement in anti-tumor activity of CRLX301 
compared to delivery of docetaxel control alone in several xenograft models
representing various tumor types including prostate, lung, melanoma and ovarian 
cancers.  In summary, CRLX301is a promising novel nanoparticle therapy for a 
variety of human cancers and has the potential to transform docetaxel into a more 
efficacious and less toxic therapeutic agent.
In rodent studies, intravenous (IV) administration of docetaxel results in a
relatively short half-f life in the blood, while IV administration of CRLX301 leads
to prolonged levels of drug in circulation.  While the majority of drug is contained 
within the nanoparticles in circulation, nanoparticles are able to enter tumor and 
release free drug in the tumor. Mouse pharmacokinetic studies have demonstrated 
sustained levels of drug in tumor.  CRLX301 delivered at the same dose as
docetaxel results in up to10-fold higher levels of free drug in the tumor. 
The anti-tumor activity of CRLX301 has also been studied in rodent xenograft 
models including triple negative breast carcinoma, prostate, multi-drug resistant 
ovarian cancer, squamous non-small cell lung carcinoma (NSCLC), adeno-
NSCLC and in a syngeneic melanoma model. In all of the models, CRLX301 was 
either superior or comparable to docetaxel in either median survival, delay of 
tumor progression and/or complete response rate. The improved PK and 
biodistribution properties of CRLX301 translated into significant tumor growth 
delay and survival improvement in multiple xenograft models. See Investigator’s
Brochure for more details.


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1.4.2 
Summary of Pharmacokinetics in GLP Studies 
In a dog GLP repeat dose study of CRLX301 at dose levels of 0.25, 0.75 and 1.75 
mg/kg once every 3 weeks for 3 treatments. Blood was collected at the following 
time points post injection: 0, 5, 30 minutes; 1, 4, 8 hours, and 1, 2, 4, 8 and 22 
days and plasma samples were analyzed for levels of released and conjugated 
docetaxel. T1/2 values of released docetaxel ranged from 2.22 to 3.47 hours for the 
0.75 and 1.75 mg/kg groups. Total docetaxel T1/2 ranged from 3.87 to 6.14 hours. 
Released and total docetaxel exposure (area under the plasma concentration time 
curve (AUC) and Cmax) were generally dose proportional between 0.25 and 1.75 
mg/kg of the administered CRLX301. There was no notable change in released 
and total docetaxel exposure following repeated CRLX301 dosing with individual 
AUC accumulation ratios ranging from 0.71 to 1.25 for released docetaxel and 
from 0.95 to 1.23 for total docetaxel. There was no notable sex-related difference 
in released and total docetaxel exposure and conjugated drug was measurable out 
to 48 hours. Released docetaxel-to-total docetaxel AUC values ranged from 0.559 
to 1.07% indicating most of the docetaxel existed in the bound state.  
Details of the pharmacokinetic data for the dog and rat studies are available in the 
CRLX301 Investigator’s Brochure. 
1.4.3 
Summary of Pharmacology, Pharmacodynamics and Toxicology in GLP 
Studies 
In repeat dose GLP and non-GLP toxicology studies in dogs and rats, CRLX301 
administration resulted in a dose dependent reduction in reticulocytes, platelets 
and white blood cells by 2 days post dose with recovery by 21 days post dose, 
consistent with the known effects of docetaxel on hematological indices. There 
were no observed adverse effects of CRLX301 on ECG parameters and 
respiratory function up to 1.75 mg/kg/dose in the dog, or on neurologic 
assessment up to 10 mg/kg/dose in the rat. Decreases in food consumption in rats 
and dogs and decreases in body weight and/or body weight gain in rats reflected 
the known effects of docetaxel on the gastrointestinal system (mucosal 
degeneration of duodenum, jejunum, and necrosis of stomach). Decreased size 
and weight of testes was reported in both rat and dog studies and correlated with 
histopathologic evidence of degeneration of seminiferous tubules. Decreased size 
of epididymides was correlated with atrophy and single cell necrosis in both 
species.  Decreased spleen and thymus weights in the rat were correlated with 
lymphoid depletion in these organs. Both species had decreased bone marrow 
hematopoiesis reflecting the effects of docetaxel on rapidly dividing cells. In rats, 
other target organ effects included neuroaxonal degeneration of sciatic nerve, 
increased mitosis in Harderian, lacrimal, pituitary glands and in esophagus, eye, 
and liver, atrophy of mammary gland in males, and lymphoid depletion of 
mandibular and mesenteric lymph nodes. In both dogs and rats, there was 
evidence of single cell necrosis of stomach, tongue, esophagus, and also 
decreased prostate organ weight. In dogs there was histopathological evidence of 
atrophy of prostate, and in addition dogs exhibited increased mitoses in acinar 
cells in the pancreas. Increased hyperplasia and pigmentation of the skin was also 
In a dog GLP repeat dose study of CRLX301 at dose levels of 0.25, 0.75 and 1.75 
mg/kg once every 3 weeks for 3 treatments. Blood was collected at the following 
time points post injection: 0, 5, 30 minutes; 1, 4, 8 hours, and 1, 2, 4, 8 and 22
days and plasma samples were analyzed for levels of released and conjugated 
docetaxel. T1/2 values of released docetaxel ranged from 2.22 to 3.47 hours for the
/2
0.75 and 1.75 mg/kg groups. Total docetaxel T1/2 ranged from 3.87 to 6.14 hours. 
/2
Released and total docetaxel exposure (area under the plasma concentration time 
curve (AUC) and Cmax) were generally dose proportional between 0.25 and 1.75 
mg/kg of the administered CRLX301. There was no notable change in released 
and total docetaxel exposure following repeated CRLX301 dosing with individual
AUC accumulation ratios ranging from 0.71 to 1.25 for released docetaxel and
from 0.95 to 1.23 for total docetaxel. There was no notable sex-related difference 
in released and total docetaxel exposure and conjugated drug was measurable out 
to 48 hours. Released docetaxel-to-total docetaxel AUC values ranged from 0.559 
to 1.07% indicating most of the docetaxel existed in the bound state.
Details of the pharmacokinetic data for the dog and rat studies are available in the 
CRLX301 Investigator’s Brochure.
In repeat dose GLP and non-GLP toxicology studies in dogs and rats, CRLX301
administration resulted in a dose dependent reduction in reticulocytes, platelets 
and white blood cells by 2 days post dose with recovery by 21 days post dose,
consistent with the known effects of docetaxel on hematological indices. There 
were no observed adverse effects of CRLX301 on ECG parameters and 
respiratory function up to 1.75 mg/kg/dose in the dog, or on neurologic 
assessment up to 10 mg/kg/dose in the rat. Decreases in food consumption in rats 
and dogs and decreases in body weight and/or body weight gain in rats reflected 
the known effects of docetaxel on the gastrointestinal system (mucosal 
degeneration of duodenum, jejunum, and necrosis of stomach). Decreased size
and weight of testes was reported in both rat and dog studies and correlated with 
histopathologic evidence of degeneration of seminiferous tubules. Decreased size 
of epididymides was correlated with atrophy and single cell necrosis in both 
species.  Decreased spleen and thymus weights in the rat were correlated with
lymphoid depletion in these organs. Both species had decreased bone marrow 
hematopoiesis reflecting the effects of docetaxel on rapidly dividing cells. In rats, 
other target organ effects included neuroaxonal degeneration of sciatic nerve, 
increased mitosis in Harderian, lacrimal, pituitary glands and in esophagus, eye,
and liver, atrophy of mammary gland in males, and lymphoid depletion of 
mandibular and mesenteric lymph nodes. In both dogs and rats, there was
evidence of single cell necrosis of stomach, tongue, esophagus, and also
decreased prostate organ weight. In dogs there was histopathological evidence of 
atrophy of prostate, and in addition dogs exhibited increased mitoses in acinar 
cells in the pancreas. Increased hyperplasia and pigmentation of the skin was also 


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AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
observed in the dogs and skin hyperpigmentation but not hyperplasia was still 
present at 1 month recovery.   
A dose response (with respect to either incidence or severity) was found for all of 
the observed effects in both species.   
The majority of the observed toxicity effects of CRLX301 in dogs and rats are 
consistent with published toxicology studies with commercial docetaxel.  Most 
importantly, no new or unusual effects were observed with the CDP (cyclodextrin 
based polymer) delivery of docetaxel.  Recovery was noted for all effects except 
for skin (dogs), testis and sciatic nerve degeneration – this is also reported for 
commercial docetaxel i.e. the nerve and testis effects do not recover by 1 month 
post treatment.  The maximally tolerated dose (MTD) for docetaxel when 
delivered by CRLX301 was approximately 20% higher compared to toxicological 
effects for commercial docetaxel in the literature. 
Additional information is reported in the CRLX301 Investigator’s Brochure. 
1.5 
Clinical Experience with CRLX301 for the Treatment of Advanced Solid 
Tumor 
As of 26 March 2016, 20 patients have been treated with single agent CRLX301 
in Schedule 1 (Q3W) IV in this first-in-human study. Doses tested include 7.5 
mg/m2 (n=1), 15 mg/m2 (n=1), 30 mg/m2 (n=3), 60 mg/m2 (n=3), 75 mg/m2 (n=6) 
and 90 mg/m2 (n=6). All patients were evaluable for dose limiting toxicities 
(DLTs) and MTDs. Safety data from one additional patient treated on Schedule 2 
Cohort 1 (CRLX301 IV weekly [QW, no break] 25mg/m2) are included in the 
summary of the most common treatment-related AEs (TRAEs) in the paragraph 
below. See Section 1.8.3:Rationale for Evaluation of QW, 3 week on/1 week off 
for Schedule 2 for preliminary safety information from additional subjects 
enrolled in Schedule 2 after the 26 March 2016 data cut-off for the 17 August 
2016 CRLX301 Investigator’s IB. 
The most common TRAEs (all grades) experienced by the 21 subjects treated as 
of 26 March 2016 were (% of subjects): fatigue (76%), infusion-related reaction 
(38%); and decreased appetite, nausea and dysgeusia, each in 33% of subjects. 
The majority of these events were of mild to moderate severity. TRAEs ≥ Grade 3 
were reported for 9 (45%) subjects overall; all subjects were on Schedule 1 
(Q3W). The most common treatment-related events ≥ Grade 3 were infusion-
related reaction and neutropenia, each reported for 3 (14 %) subjects. 
observed in the dogs and skin hyperpigmentation but not hyperplasia was still
present at 1 month recovery. 
A dose response (with respect to either incidence or severity) was found for all of 
the observed effects in both species. 
The majority of the observed toxicity effects of CRLX301 in dogs and rats are 
consistent with published toxicology studies with commercial docetaxel.  Most
importantly, no new or unusual effects were observed with the CDP (cyclodextrin 
based polymer) delivery of docetaxel.  Recovery was noted for all effects except
for skin (dogs), testis and sciatic nerve degeneration – this is also reported for 
commercial docetaxel i.e. the nerve and testis effects do not recover by 1 month
f
post treatment.  The maximally tolerated dose (MTD) for docetaxel when 
delivered by CRLX301 was approximately 20% higher compared to toxicological 
effects for commercial docetaxel in the literature.
Additional information is reported in the CRLX301 Investigator’s Brochure.


Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc. 
Protocol No.: CRLX301-101 
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CONFIDENTIAL 
Two DLTs were observed during cycle 1 at the 90mg/m2 dose level in 2 subjects 
(1 DLT each) treated on Schedule 1 (Q3W CRLX301). One subject experienced 
reversible grade 3 elevations in transaminases concomitant with grade 2 bilirubin 
(<3 days duration), and 1 subject experienced grade 4 febrile neutropenia (<3 
days duration).  Per protocol, 90mg/m2 exceeded the MTD, and 75mg/m2 was 
declared as the MTD and selected as the RP2D for CRLX301 when administered 
Q3W (Schedule 1). Common side effects related to docetaxel, such as fluid 
retention, were not observed. No new toxicities have been observed that have not 
been reported for docetaxel.  
All 21 patients enrolled received pre-medication with dexamethasone 20 mg IV 
and one dose each of an anti-histamine and a histamine 2 receptor (H2) antagonist 
(IV or orally) within 30-90 minutes prior to CRLX301 administration. A total of 8 
(38%) patients enrolled in Schedule 1 have experienced hypersensitivity infusion 
reactions (HSRs). Within the cohorts which initiated treatment at a dose <90 
mg/m2, the HSRs were either mild (grade 1; n=1) or moderate (grade 2; n=4), 
with one exception of a Grade 3 event occurring at 75mg/m2.  Within the 90 
mg/m2 cohort, 1 patient experienced a Grade 2 HSR, 1 patient experienced a 
Grade 3 HSR and 1 patient experienced a Grade 4 HSR (the latter event, 
described in detail in the Investigator’s Brochure, did not occur until the dose had 
been reduced to 75mg/m2). Most HSRs occurred at cycle 1 or cycle 2 and within 
the first 15 minutes of administration, similar to docetaxel. Four of the 8 patients 
were re-challenged with study drug at a slower infusion rate and/or with an 
increased premedication regimen; these patients either did not have recurrence of 
HSR or experienced additional episodes of mild to moderate HSR that were 
manageable. Two other patients had their first episode of HSR in later cycles and 
were not re-challenged due to study discontinuation as a result of progressive 
disease. The 2 subjects experiencing ≥ Grade 3 HSRs at the 90 mg/m2 dose level 
were discontinued from study treatment and followed up per protocol.  
Secondary to these HSR events, protocol CRLX301-101 was amended 
(Amendment 7) to incorporate changes in the required premedication regimen 
prior to administration of CRLX301, and to prolong the duration of each 
CRLX301 infusion. 
A total of 7 serious adverse reactions considered at least possibly related to 
CRLX301 were reported for 6 subjects. These included the 2 DLTs described 
above, 3 cases involving infusion-related reactions (HSR), and 1 case involving a 
peripheral sensory neuropathy and peripheral motor neuropathy in a subject with 
multiple confounding factors (including a history of diabetes, gout and 
cardiovascular disease, and concomitant chronic colchicine and dexamethasone at 
the time of participation in CRLX301-101). Please see the latest version of the 
CRLX301 Investigator's Brochure for details on this case and other toxicities 
reported. 


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CONFIDENTIAL 
In terms of anti-tumor activity of study drug as of 26 March 2016, of 13 subjects 
evaluable for efficacy, stable disease lasting ≥ 3 cycles was observed in 6 patients 
with 2 patients experiencing prolonged stable disease (7 and 17 cycles). A patient 
with B-RAF mutant adenocarcinoma of unknown primary who was resistant to a 
prior B-RAF inhibitor had tumor shrinkage per RECIST and partial metabolic 
response per FDG-PET.   
Dose level 75 mg/m2 Q3W is the standard dose and dosing schedule of 
commercial docetaxel given to patients in multiple indications.22 Given the 
preliminary safety events and anti-tumor activity (tumor shrinkage in 1 patient) 
observed at 75 mg/m2 of CRLX301 treatment, the study continues with expansion 
of 75 mg/m2 Q3W cohort to further explore the safety, tolerability, and 
preliminary anti-tumor activity of CRLX301 at the dose that is equivalent to 
standard dose of commercial docetaxel. 
PK studies of CRLX301 were performed after administration of CRLX301 at 7.5, 
15, 30, 60, 75 and 90 mg/m2 IV x 1 over 1 h every 21 days.  Plasma PK studies of 
total and released docetaxel were performed on cycles 1, 3 and 6.  The PK (as 
measured by Cmax and AUC) of total docetaxel was linear from 7.5 to 90 mg/m2; 
whereas, the PK of released docetaxel was more variable.  There was no 
accumulation of total or released docetaxel from cycle 1 to 6. At the equivalent 
dose of 75 mg/m2, the plasma AUC of total docetaxel after CRLX301 is ~100-
fold greater than for commercial docetaxel. In addition after administration of 
CRLX301 at 75 mg/m2, the plasma AUC of released docetaxel is similar to 
commercial docetaxel; however, most of the measured AUC after CRLX301 is 
associated with exposure from 24-168 h, suggesting slow release in plasma. The 
Cmax of released docetaxel in plasma after CRLX301 was 21-fold lower than for 
commercial docetaxel, which might be associated with a decrease in toxicity with 
CRLX301. Refer to the IB for details about clinical PK 
1.6 
Study Rationale 
The development of CRLX301 is focused on the utility of nanoparticles to 
increase the extended plasma stability of docetaxel with slower clearance and 
prolonged circulation time, to provide effective delivery of docetaxel into tumors 
for prolonged periods, enhancing anti-tumor activity while potentially reducing 
the toxicity observed with traditional taxanes. The development program is 
focused on the demonstration of clinical activity and improved safety of docetaxel 
when administered in this nanoparticle formulation. 
Studies in animals have demonstrated the ability to maintain CRLX301 for 
prolonged periods while sustaining low released docetaxel concentrations in the 
blood optimizing the cell-cycle specific activity associated with continuous low 
drug exposure.  These specific characteristics have demonstrated, in vivo, the 
intended improvement in anti-tumor activity of CRLX301 compared to delivery 
of docetaxel alone. 


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This study protocol would allow the first-in-human dosing of CRLX301 in 
patients with advanced solid tumor malignancies to evaluate the safety and to 
establish the MTD and/or RP2D of CRLX301 in an optimal dosing schedule. The 
dosing, safety and clinical outcomes data reported from the Phase 1 and Phase 2a 
treated patients may support the future planning of clinical trials to evaluate 
efficacy endpoints for development of CRLX301.  
1.7 
Rationale for Q3W Dosing and the Starting Dose Phase 1 Based on Clinical 
Experience with Docetaxel 
Since a once every-three-week dose (Q3W) schedule is used as the standard 
dosing schedule for commercial docetaxel and the pre-clinical PK study showed 
that half-life of CRLX301 is longer than commercial docetaxel, Cerulean decided 
to evaluate a dosing schedule which is not more frequent than Q3W in this first-
in-human study. Therefore, Q3W dosing schedule was chosen as the initial dosing 
schedule of CRLX301 in this Phase 1 study.   
The recommended starting dose for Schedule 1 Q3W dosing in humans was based 
on the results of the CRLX301 nonclinical repeat dose toxicity studies in dogs, the 
more sensitive species, would be 5.8 mg/m2/dose. However, Cerulean medical 
advisors and clinical trial investigators considered it to be unethical to expose 
patients to a starting dose of less than 10% of the approved dose of docetaxel (75 
mg/m2), an active chemotherapy agent, and that this ratio for starting dose should 
not exceed 50%.  
The toxicological effects of CRLX301 reported in dogs (the more sensitive 
species) are all consistent with docetaxel findings, and are shown to be reversible 
within 3 weeks, with the exception of the testicular and skin effects at the HNSTD 
(1.75 mg/kg or 35 mg/m2). Furthermore, there were no observed adverse effects 
on ECG or respiratory parameters up to 1.75 mg/kg (35 mg/m2) in dogs, or 
adverse effects on neurologic function up to 10 mg/kg (60 mg/m2) in rats.  These 
evidences offer the opportunity for an actual starting dose to be potentially higher 
than the calculated starting dose at 5.8 mg/m2 per dose.  
A recent study reported that the mean ratio of MTD to starting dose and total 
number of required dose levels in clinical Phase 1 studies was significantly 
greater for nanoparticles compared to small molecules when using the usual 
method to determine clinical Phase 1starting dose from preclinical dog study 
results.23 The CRLX301 preclinical results along with the report finding clinical 
Phase 1 studies of nanoparticles start at lower dose levels relative to the clinical 
MTD support using a higher starting dose in a clinical Phase 1 study of docetaxel 
in a nanoparticle.  Accordingly, the starting dose employed in this initial Phase 1 
evaluation of CRLX301 for Schedule 1 was 10% of the approved dose of 
docetaxel (75 mg/m2). This dose is equivalent to 7.5 mg/m2.  


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CONFIDENTIAL 
1.8 
Rationale for Weekly Dosing (Schedule 2) and the Starting Dose Based on 
Clinical Experience with CRLX301 
1.8.1 
Rationale for Weekly Dosing 
As per Section 1.5: Clinical Experience with CRLX301 for the Treatment of 
Advanced Solid Tumor, no DLT was observed for Q3W dosing in the 6 patients 
treated at dose level 75 mg/m2 which is equivalent to the standard dose of 
commercial docetaxel. At dose levels below 75 mg/m2, CRLX301 was well 
tolerated with minimal toxicity. One exception is the patient receiving chronic use 
of colchicine in the 60 mg/m2 cohort who developed Grade 3 neuropathy (see 
Section 1.5: Clinical Experience with CRLX301 for the Treatment of Advanced 
Solid Tumor and the CRLX301 Investigator’s Brochure for additional details). 
Myelosuppression effect was minimally observed at 30 and 60 mg/m2 dose levels 
while stable disease was observed with 2 patients in each cohort. Based on this 
level of clinical activity and low observed toxicity to date, there is room to 
explore in parallel a more frequent (weekly) dosing schedule. 
PK studies of CRLX301 were performed after administration of CRLX301 at 7.5, 
15, 30, 60 and 75 mg/m2 IV x 1 over 1 h every 21 days.  Plasma PK studies of 
total and released docetaxel were performed on cycles 1, 3 and 6.  After 
CRLX301 infusion, elimination half-lie and total docetaxel in plasma was 
approximately 5 -8 hours and the T1/2 of released docetaxel was approximately 42 
– 121 hours. However, the long estimate of T½ of released docetaxel is related to 
a consistent release of docetaxel from CRLX301 rather than a slower elimination 
of released docetaxel.  The ability to administer CRLX301 on a weekly schedule 
is further supported by the measured concentration versus time profiles of 
CRLX301 at 30, 60 and 75 mg/m2 IV every 21 days.  In that study there was no 
detectable exposure of total docetaxel on day 8 of cycles 1, 3 or 6.  This supports 
the ability to explore weekly dosing. 
There's mounting evidence that higher frequency of treatment with chemotherapy 
agents at lower doses may be more optimal than therapy at higher doses 
administered less frequently.  This is supported by the emerging data from 
evaluation of metronomic chemotherapy.24 A study of weekly paclitaxel in the 
adjuvant treatment of breast cancer compared toxic effects of paclitaxel and 
docetaxel between Q3W and QW schedule and demonstrated that there were 
significantly less adverse events resulted from weekly dosing of docetaxel as 
opposed to Q3W dosing.25 Paclitaxel is currently given to patients with once 
weekly dosing schedule as a common practice. With the NDC technology 
platform, the preclinical study showed that weekly dosing of CRLX301 in mice 
could lead to  up to 10-fold increase in drug accumulation in mouse tumors for at 
least 72 hours post nanoparticle administration when compared to a docetaxel 
control, thus it’s hypothesized that more frequently dosing of CRLX301 would 
lead to more cumulative delivery of NDC conjugated form of docetaxel to tumor 
while potentially associating with less toxicities resulted from released form of 
docetaxel. 


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CONFIDENTIAL 
Therefore, the protocol is amended to add Schedule 2 with weekly CRLX301 
dosing. Schedule 2 dose escalation will initiate in parallel with the Schedule 1 
Q3W dose escalation.  
Once enrolled and assigned to either Schedule 1 or Schedule 2 dosing schedule, 
patients will not be allowed to switch dosing schedules during treatment.  
1.8.2 
Rationale for Starting Dose for Schedule 2 during Phase 1 (QW, no break)  
To better calculate the initial starting dose for the QW, no break schedule, we 
have performed two separate PK simulations from the ongoing Q3W schedule.  
Each model was performed to simulate the concentration versus time profiles of 
total and released docetaxel in plasma after administration of CRLX301 at 20, 25, 
30 and 40 mg/m2 administered IV x1 per week for nine consecutive weeks. The 
AUC versus time profiles of total and released docetaxel were estimated for the 
1st, 4th and 7th dose.  These doses are the proposed doses that would be evaluated 
in the phase 1 clinical trial of CRLX301 on the weekly dosing schedule. The PK 
simulations suggest that administration of CRLX301 at 20 to 40 mg/m2 IV x 1 
weekly for 9 weeks will not result in accumulation of total or released docetaxel 
in plasma. The estimated total docetaxel AUCs after the 1st, 4th, and 7th doses of 
CRLX301 at 20 and 40 mg/m2 are approximately 22% and 45% of the AUCs 
achieved after administration of CRLX301 at 75 mg/m2 Q3W. In addition, the 
estimated released docetaxel AUCs after the 1st, 4th, and 7th doses of CRLX301 
at 20 and 40 mg/m2 are approximately 32% and 65% of the AUCs achieved after 
administration of CRLX301 at 75 mg/m2 Q3W. The PK simulation further 
supports weekly dosing schedule as well as a starting dose in the range of 20 to 40 
mg/m2. 
The planned starting dose for Schedule 2 weekly dosing Phase 1 dose escalation 
is 25 mg/m2. This represents 1/3 of the dosing intensity of the MTD/RP2D 
following Q3W dosing.  
Also for Schedule 1, dose level 30 mg/m2 demonstrated to be well tolerated with 
minimal toxicity: 1 patient was on study for 3 cycles; 1 patient was on study for 7 
cycles and 1 patient was on study for 10 cycles. Multi-dose PK data (up to 6 doses 
in 2 patients) at 30 mg/m2 showed no detectable level of either total nor released 
docetaxel after the CRLX301 infusion by Day 8 in each treatment cycle. 
Therefore, 25 mg/m2 is deemed a safe starting dose for Schedule 2, a weekly 
dosing schedule.  


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1.8.3 
Rationale for Evaluation of QW, 3 week on/1 week off for Schedule 2 
As of 11 November 2016, a total of 12 patients have been enrolled into Schedule 
2 of CRLX301-101 (see Table 2). A review of safety data from Cohort 3 
(45mg/m2 QW) revealed new events of neuropathy in 3 patients after at least 3 
weeks of treatment with CRLX301. The first subject developed Grade 1 
peripheral neuropathy at week 6, which worsened to Grade 2 at week 9, leading to 
dose interruption. A second patient developed Grade 2 peripheral neuropathy at 
week 9, also leading to dose interruption, and a third patient developed Grade 1 
intermittent peripheral sensory neuropathy at week 4. This latter patient also 
reported Grade 2 bilateral episcleritis, which led to dose interruption. 
Based on these data, CRLX301 dosing has been revised from QW, no break to 
QW, 3 week on/1 week off for any patient enrolled into Schedule 2 Cohort 3 and 
continuing on treatment as of 11 November 2016. This change in dosing 
frequency will also apply to all patients enrolled into Schedule 2 Cohort 4 (54 
mg/m2). The dosing schedule for cohorts beyond Cohort 4 will be determined by 
the Safety Review Committee (SRC). 
 


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CONFIDENTIAL 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
x Phase 1: To determine the maximum tolerated dose (MTD) / recommended 
Phase 2 dose (RP2D) of CRLX301when administered by IV infusion on 
Schedule 1 (Dosing Day 1 of a 21-day cycle) or Schedule 2 (QW: weekly 
dosing, no break or QW, 3 week on/1 week off dosing) in patients with 
advanced solid tumor malignancies 
x Phase 2a: To further establish the safety and tolerability of the CRLX301 
MTD / RP2D 
2.2 
Secondary Objectives 
x To evaluate the pharmacokinetic (PK) profile of CRLX301 (both the total 
drug and released docetaxel) in plasma for both dosing schedules 
x To explore preliminary signals of efficacy for CRLX301 
2.3 
Exploratory Objectives 
x To evaluate the pharmacodynamic activity of CRLX301 in blood and tumor 
biopsy specimens when available from patients 
x To explore possible correlations between clinical response, toxicities and 
biomarkers  
x To explore the PK profile of CRLX301 (both the total drug and released 
docetaxel) in urine for both dosing schedules  
x To explore potential factors affecting potential inter- and intra-patient PK 
variability and the preliminary relationship between response and the 
exposure to total and unconjugated docetaxel in plasma and urine. 


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CONFIDENTIAL 
3. 
INVESTIGATIONAL PLAN 
3.1 
Phase 1 Dose Escalation Study Design 
3.1.1 
Study Design Summary 
Phase 1 of the study is an open-label, dose-escalation study examining two 
separate dosing schedules. Schedule 1 (Q3W dosing schedule) was initiated first 
and Amendment 6 incorporates Schedule 2 (QW, no break dosing schedule). As 
of Amendment 9, for patients still receiving treatment in Schedule 2 Cohort 3 
(45mg/m2), and for patients enrolled in Schedule 2 Cohort 4 (54mg/m2), dosing 
will be on a once weekly, 3 week on/1 week off schedule. The dosing schedule 
for additional Schedule 2 cohorts will be determined by the SRC. A single 
MTD/RP2D will be determined for Schedule 2. See Section 1.8.3: Rationale for 
Evaluation of QW, 3 week on/1 week off for Schedule 2. 
For Q3W dosing the first 2 cohorts utilized a 1+5 study design.  A single patient 
was enrolled sequentially into cohort 1 and cohort 2. If either patient in cohort 1 
or 2 had experienced a dose limiting toxicity (DLT) during Cycle 1, then the 
cohort would have been expanded to enroll additional patients up to a total of 6.  
Furthermore, if the initial patient in cohort 1 experienced a DLT in Cycle 1, then 
enrollment would have reverted to a 3+3 design for cohort 2.  
 
As of planned cohort 3 for Q3W dosing and for all cohorts in QW dosing, a 3+3 
dose escalation schema will be utilized.26  Initially a minimum of 3 patients will 
be accrued into each cohort. It is permissible to enroll more than 3 patients 
initially to further explore the safety or PK profile of a particular dose level.  If 
any 1 of the initial enrolled patients in a cohort experiences a DLT during Cycle 1 
or the first 3 weeks, then the cohort will be expanded to enroll additional patients 
up to a total of 6.  
Subsequent cohorts will enroll a minimum of 3 patients with dose escalation until 
≥2 patients in a cohort experience DLT(s) during Cycle 1 or the first 3 weeks.  A 
DLT is defined as any adverse event (AE) possibly, probably, or definitely related 
to CRLX301 that results in an unacceptable toxicity (per criteria specified) and 
occurs at any point during Cycle 1 or the first 3 weeks post-initiation of study 
drug infusion.  
Additionally, the Safety Review Committee (SRC) is responsible to determine 
whether or not there is a defined wait period between any or all patients into a 
new cohort.  See Section 3.1.6: Study Safety Review Committee for details. 
Enrollment in a particular dose cohort will be halted immediately when ≥2 
patients within the cohort experience a DLT during Cycle 1 or the first 3 weeks. 
At this point, dose de-escalation will occur until <2 of 6 patients experience a 
DLT in a cohort. Then dose escalation with an additional cohort assigned to a 
mid-way dose level may be required to determine MTD and/or RP2D.   


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Phase 1 enrollment into both dosing schedules may run in parallel.  Enrollment 
will be managed through close communication with participating clinical sites so 
that Investigators are aware of available patient slots in each of the dosing 
schedules. 
 
Figure 1: Study Schematic 
 
 
 
3.1.2 
Definition of Maximum Tolerated Dose and Recommended Phase 2a Dose 
The MTD is defined as the highest dose level at which fewer than 2 of 6 patients 
in a Phase 1 dose escalation cohort experiences a DLT during the first three weeks 
of treatment. This is the dose level for which the incidence of DLT is <33%.23 
The RP2D is defined as the dose which will be assigned in Phase 2a as advised by 
the SRC based on AEs, anti-tumor activity of CRLX301 and available PK and PD 
data.  The RP2D may be the same as the MTD dose level or it may be lower.  The 
RP2D may not exceed the MTD.  
3.1.3 
Definition of Dose-Limiting Toxicity 
A DLT is defined as any AE possibly, probably, or definitely related to CRLX301 
that results in an unacceptable toxicity (per criteria below) and occurs at any point 
during the first 3 weeks of treatment post-initiation of study drug infusion. The 
event must be assessed by the Investigator and study Medical Monitor, and be 
determined to be unrelated to disease progression, intercurrent illness, or 
concomitant medications.  All DLTs will be graded according to the current 
version of the Common Terminology Criteria for Adverse Events (CTCAE 
Version 4.03) (Appendix B).  


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Note that for any hematologic grade 3 or 4 events repeat lab values should be 
obtained every 48 - 72 hours or as clinically indicated to evaluate for DLT criteria 
and resolution. 
DLTs may include but are not limited to the following:  
x Grade 4 neutropenia >7 days  
x Grade 3 or 4 neutropenia with fever (≥38.5ºC)  
x Grade 4 thrombocytopenia, or ≥ Grade 3 thrombocytopenia in the 
presence of bleeding 
x AST/ALT elevation of 5-10x ULN lasting > 24 hours  
x Any single instance of AST or ALT elevation >10x ULN 
x Any single instance of total bilirubin elevation > 3 x ULN 
x Any single instance of AST/ALT elevation >3x ULN accompanied by 
bilirubin elevation >2x ULN that is not thought to be due to progressive 
disease 
x Grade 3 nausea, vomiting, or diarrhea for >72 hours despite standard of 
care treatment 
x Grade 4 nausea, diarrhea or vomiting of any duration 
x Any non-hematological toxicity ≥Grade 3 of any duration, excluding 
those above and the following: 
o Grade 3 fatigue lasting <7 days 
o Grade 3 anorexia 
o Grade 3 dehydration as a result of nausea and vomiting 
o Grade 3 constipation 
o Grade 3-4 hypersensitivity/infusion reaction 
o Grade 3 electrolyte disturbance resolving to ≤ Grade 1 or baseline 
within 7 days (supplementation allowed) 
x Any ≥ Grade 2 peripheral neuropathy > 14 days  
x Any unresolved related AE that results in >21day delay to initiate the patient’s 
second dose, excluding alopecia 
x Any other ≥Grade 2 toxicity of any duration that in the opinion of the 
Investigator and upon review with the Medical Monitor is determined to be a 
clinically unacceptable risk. 
3.1.4 
Treatment Schedule 
Eligible patients will receive an intravenous infusion of CRLX301 on: 
x Schedule 1 (Q3W): Day 1 of a 21-day cycle 


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x Schedule 2 (QW): Day 1 of every week, no break or QW, 3 week on/1 
week off * (depending on enrollment cohort) 
and continue treatment as per assigned Schedule until progression of disease 
(unless the Investigator and sponsor agree it is acceptable for the patient to 
continue treatment) or other specified reason for study discontinuation (see 
Section 6.1: Reasons for Discontinuation from Treatment).   
*For Schedule 2 (QW, 3 week on/1 week off), CRLX301 will be dosed weekly 
for the first 3 weeks of each 4-week period (e.g., week 1, week 2, week 3). No 
CRLX301 will be administered on week 4.  
3.1.5 
Phase 1 Dosing Cohorts 
Schedule 1 
Sequentially enrolled cohorts will receive increasing doses of CRLX301 in Cycle 
1 until ≥2 patients experience DLTs.  Eligible patients will be assigned to the 
currently open cohorts and assigned to the specified dose of CRLX301 per Table 
1: Schedule 1 Q3W Provisional Phase 1 Dose Escalation Scheme.  After halting 
dose escalation due to DLTs, dose de-escalation will occur until <2 patients out of 
6 experiences a DLT in a cohort.  
For determination of the MTD, an additional cohort may be enrolled and assigned 
to the dose level midway between the dose level at which <2 patients out of 6 
experiences DLTs and the dose level at which ≥2 patients out of 6 experiences 
DLT. 
The Schedule 1 Cohort 1 starting dose level was 7.5 mg/m2; see Section 1.7: 
Rationale for Q3W Dosing and the Starting Dose Phase 1 Based on Clinical 
Experience with Docetaxel. The initial dose level was increased by 2 times to 15 
mg/m2 dose-level; thereafter, the dose level increments will be an additional 15 
mg/m2.   
Schedule 2 
The Schedule 2 Cohort 1 starting dose level is 25 mg/m2, see Section 1.7: 
Rationale for Weekly Dosing (Schedule 2) and the Starting Dose Based on 
Clinical Experience with CRLX301.  
3.1.5.1 
Cohort Expansion for DLT 
If at any time during the first three weeks of treatment on either Schedule a 
patient experiences a DLT, then additional patients will be enrolled up to a total 
of 6 treated at the same dose level. Upon expansion, the SRC will decide if 
enrollment between each additional patient will require a defined wait period or if 
additional patients may enroll as soon as eligible.  If at any time during the first 
three weeks of treatment a second patient experiences a DLT then enrollment in 
that cohort will be halted immediately. 


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If none of the additional patients enrolled in the same cohort experiences a DLT 
in the first three weeks of treatment (i.e., <2 out of 6 patients in the cohort), then 
dose escalation may occur with enrollment of new patients at the next dose level 
per the Dose Escalation Scheme.  
3.1.5.2 
Cohort Dose Escalation Scheme 
Before a decision is made to increase the dose a minimum of 1 patient (Schedule 
1 Cohort 1 and 2 only) and a minimum of 3 patients (all subsequent Cohorts for 
Schedule 1 and for Schedule 2) must have been treated with the assigned dose of 
CRLX301 and have completed three weeks of treatment.  For Schedule 1 this 
includes the Day 22 safety evaluation (21 days post-infusion) and for Schedule 2 
this includes pre-dose or day of visit evaluations for Week 4.  The SRC will 
review emerging safety data from the current cohort and data from on-going 
patients in previous cohorts before proceeding to enrollment in the subsequent 
cohort.  Each dosing schedule will be reviewed independently.  
Cohort dose escalation will follow the Dose Escalation Scheme tables (Table 1 
and Table 2).   
x If in Cohort 1, there are 2 patients who experience a DLT during the first 
three weeks of treatment, dose escalation will not occur.  Subsequent 
cohorts may be dosed at a lower dose and/or at a less frequent schedule to 
be determined by the Sponsor, Medical Monitor, and Investigators and 
implemented per protocol amendment. 
x If in Cohort 1 there is no more than 1 patient who experiences a DLT 
during the first three weeks of treatment, then dose escalation will occur.  
x Similarly, for subsequent Cohort dose levels, if no more than 1 of up to 6 
patients in the cohort experiences a DLT during the first three weeks of 
treatment, then dose escalation will occur with enrollment of new patients 
at the next dose level per the Dose Escalation Scheme.  
Intermediate dose level cohorts are allowed as recommended by the SRC instead 
of escalating to the next planned dose cohort. 
In the absence of DLT if the SRC or sponsor wants to further define the safety, 
efficacy, PK or PD profile of CRLX301 at a particular dose level, additional 
patients may be enrolled at the same, intermediate or lower dose levels following 
consultation between the investigator and sponsor. 
Additionally, and for Schedule 1 only, based upon review of AEs and available 
PK data by SRC at the end-of cohort-review-meeting for the 30 mg/m2 cohort, 
100% dose escalation from 30 mg/m2 to as high as 60 mg/m2 (80% of the 
approved dose of docetaxel) for the next cohort was allowed if recommended by 
the SRC. No other planned cohorts may be skipped during Schedule 1 Phase 1 
dose escalation. 


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For Schedule 2 only, based upon review of AEs and available PK data by SRC at 
the end-of cohort-review-meeting it is allowable to skip a proposed dose level in 
order to minimize the number of patients treated at sub-optimal dose levels. 
However, dose increment to the next higher dose level shall not exceed 40% at 
dose levels below 50 mg/m2 and will not exceed 20% at dose levels at or above 
50 mg/m2. 
 
Table 1: Schedule 1 Q3W Provisional Phase 1 Dose Escalation Scheme 
Cohort 
Dose Level 
Number of Patients 
initially plus 
additional 
expansion if DLTs 
Actual 
Enrollment 
as of 
Amendment 7 
1 
7.5 mg/m2 
1 to 6 
1 
2 
15 mg/m2 
1 to 6 
1 
3* 
30* mg/m2 
3 to 6 
3 
4* 
45* mg/m2 
3 to 6 
0* 
5 
60 mg/m2 
3 to 6 
3 
6 
75 mg/m2 
3 to 6 
6 
7 
90 mg/m2 
3 to 6 
6 
8 
105 mg/m2 
3 to 6 
Cohorts will 
not be open as 
MTD/RP2D 
selected as 
75mg/m2 
9 
120 mg/m2 
3 to 6 
10 
plus additional 
cohorts 
135 mg/m2  
Increase dose levels by  
15 mg/m2 for additional cohorts  
(i.e. 150 mg/m2, etc.) 
3 to 6 
*SRC is allowed to dose escalate from 30 mg/m2 to as high as 60 mg/m2.  No other 
planned dose level cohorts may be skipped during Phase 1. 
 
 
Table 2: Schedule 2 QW Provisional Phase 1 Dose Escalation Scheme 
Cohort 
Proposed Dose Level* 
Number of 
Patients 
initially plus 
additional 
expansion if 
DLTs 
-1 
20 mg/m2 
Only if starting dose level not tolerated 
3 to 6 
 
1 
25 mg/m2 
2 
35 mg/m2 
3** 
45 mg/m2 
4** 
54 mg/m2 


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Additional 
cohorts** 
Increase dose levels by 5 mg/m2 or 
otherwise recommended by SRC 
based on available safety and PK data 
(dose increment to the next higher 
dose level will not exceed 20%)  
*SRC is allowed to dose escalate by as much as 40% (total over 3 weeks) for doses below 
50mg/m2 and by 20% (total over 3 weeks) for dose levels above 50mg/m2 
** As of Amendment 9, for patients still receiving treatment in Schedule 2 Cohort 3, and 
for patients enrolled in Schedule 2 Cohort 4, dosing will be on a weekly, 3 week on/1 
week off schedule. The dosing schedule for additional Schedule 2 cohorts will be 
determined by the SRC 
 
The final dose and schedule for cohorts beyond Cohort 4 will be selected by the 
SRC based upon review of AEs and available PK data from both dosing 
schedules.  
3.1.6 
Study Safety Review Committee 
Members: The Investigators, Sponsor representative, Sponsor designated Medical 
Monitor and Sponsor designated PK expert will comprise the Study Safety 
Review Committee (SRC).  
Phase 1 Meetings: This committee will discuss all DLTs, AEs, PK parameters if 
available, and other relevant data on regular teleconferences, no less frequently 
than after completion of enrollment and treatment in a cohort prior to dose 
escalation. 
Phase 1 Decision-making role: The SRC is designated to make decisions for the 
Study for each dosing schedule regarding: 
x confirmation of DLTs 
x confirmation to proceed with enrollment in a new cohort with dose 
escalation 
x confirmation of next dose level 
x determine if any type of enrollment wait period will be imposed between 
patients in the next cohort or during expansion (based on emerging safety 
data) 
x recommend if dose schedule modifications are needed according to the 
clinical and PK data available 
x determination of the MTD and/or RP2D. 
In the event the SRC is not in agreement, then the Sponsor Chief Medical Officer 
will make the final decision after consultation with additional medical advisors. 


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3.1.7 
Dose Reductions 
Patients experiencing a DLT in first 3 weeks will have the study drug interrupted 
and will be followed until recovery from their DLT to grade ≤1 or baseline. After 
that, if the investigator (along with the Sponsor) concludes that it is in the 
patient’s best interest to resume study treatment, the patient may continue in the 
study at a lower dose level. 
Patients who do not experience a DLT but are dosed in the same cohort where ≥2 
patients experienced DLTs, will be dose de-escalated to the next lower already 
studied dose level at the next scheduled treatment, as per the Dose Escalation 
Scheme.  
3.1.7.1 
Dose De-escalation 
If during later treatment beyond the DLT period, a patient experiences an 
unacceptable toxicity (defined as a toxicity that meets the same criteria of DLT 
for the first 3 weeks), the patient may continue in the next treatment cycle but 
must have a dose reduction to the next lower dose level as per the Dose 
Modification Scheme.  
A maximum of 2 dose de-escalations will be permitted per patient. Patients 
who require >2 dose reductions will be discontinued from treatment and will be 
followed up per protocol.  
3.2 
Phase 2a Expansion Study Design 
Phase 2a will be an open-label RP2D expansion study. Treatment guidelines for 
the RP2D expansion cohorts will be the same as those for the Phase 1 dose 
expansion cohorts.  
Patients will be followed for safety, tumor response, and progression free survival 
(PFS) while on the study per RECIST version 1.1 guidelines or with 
methodologies consistent with tumor type.  Patients will remain on study 
treatment until they experience progression of disease unless the Investigator feels 
the patient would benefit from continued treatment, unacceptable toxicity, or 
other specified reason for discontinuation (see Section 6.1: Reasons for 
Discontinuation from Treatment).  


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3.2.1 
Phase 2a Stage 1 Expansion 
Once either of the dosing schedules confirms MTD from Phase 1 and the sponsor 
confirms that all required pharmacodynamic assays are ready, Phase 2a Stage 1 
will initiate. This will be an expansion of up to 16 patients for each dose schedule 
at the RP2D. Up to 5 specific tumor types will be selected and only patients with 
the select tumor types may enroll into Phase 2a Stage 1. At the time of 
Amendment 8, taxane naïve (unless approved by Sponsor) castration resistant 
prostate cancer (CRPC) has been selected as one of the indications for Ph2a Stage 
1. Enrollment cap will be contingent upon enrolling at least 6 patients of the same 
indication (e.g. CRPC who are taxane naïve) and observation rates of anti-tumor 
activity. All sites will be notified of the select tumor type(s) in advance of 
initiating Stage 1. Due to shipping and processing requirements for CTCs and 
MPS function (both of which require freshly collected whole blood samples) only 
US sites will enroll patients in Stage 1.  
3.2.2 
Phase 2a Stage 2 Expansion 
Once both dosing schedules complete Phase 2a Stage 1 an optimal dosing 
schedule will be selected based on available safety and efficacy signals, PK and 
available PD data from both schedules. Further refinement of the RP2D may also 
be explored. Phase 2a Stage 2 expansion will enroll up to 36 additional patients 
using one selected dosing schedule and RP2D. Up to 5 specific tumor types only 
will be allowed to enroll into Phase 2a Stage 2. Sites in both Australia and US 
will enroll into Stage 2. All sites will be notified of the select tumor types in 
advance of initiating Stage 2. 
 


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4. 
STUDY POPULATION 
4.1 
Inclusion Criteria 
Patients must meet the following criteria for inclusion: 
1. Male or female adult patient ≥18 years of age  
2. Diagnosis of histologically or cytologically confirmed, advanced solid tumor 
malignancy: 
a. For Phase 1: that is refractory to standard therapy and/or for whom no 
further standard therapy is available, especially for those which taxane 
chemotherapy may be a reasonable therapeutic choice, in the opinion of 
the Investigator 
b. For Phase 2a: advanced/metastatic tumors considered responsive to 
taxanes 
c. For prostate cancer patients in Phase 2a: that is castration resistant prostate 
cancer (CRPC*) and has not been previously treated with taxanes (taxane-
naïve [unless approved by Sponsor]) but has been treated with abiraterone 
and/or enzalutamide.   *NOTE: CRPC is defined as: 
i. Castration: Undergone surgical castration, or medical castration with 
testosterone < 50ng/dL 
ii. Resistant: Disease progression while castrate with radiographic 
progression defined by Prostate Cancer Working Group 2 (PCWG2) 
criteria, OR disease progression defined as rise in PSA with baseline 
PSA of at least 2 ng/mL, OR disease progression as per RECIST 1.1. 
3. For patients enrolled in Phase 2a only at least one measurable target lesion as 
defined by RECIST 1.1 criteria for solid tumors, except for patients with 
advanced prostate cancer (as per the PCWG2 criteria). Tumors within a 
previously irradiated field should be designated as “non-target” unless 
progression is documented or a biopsy is obtained to confirm persistence at 
least 90 days following completion of radiation therapy. 
4. If Patient has received:  
a. approved chemotherapy or small molecule targeted therapy; it has 
been ≥2 weeks since last dose before CRLX301 first dose 
b. investigational therapy; it has been ≥30 days before first dose 
c. local palliative radiation; it has been ≥14 days prior to first dose 
d. radiation or invasive surgery requiring general anesthesia; it has been  
≥30 days before first dose 
e. chemotherapy with nitrosoureas or mitomycin C; it has been ≥45 days 
before first dose 
5. ECOG Performance Status of 0 or 1 


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6. Life expectancy in opinion of Investigator of greater than 12 weeks  
7. Patients with acceptable pre-study hematology and biochemistry labs ≤3 days 
prior to first dose defined as: 
a. absolute neutrophil count (ANC) ≥1500 cells/μL (1.5 x10^9/L), 
without growth factor support 
b. platelet count ≥100,000 cells/μL, without growth factor support 
c. hemoglobin ≥10 g/dL (100 g/L) for males, and ≥9 g/dL (90 g/L) for 
females 
d. total bilirubin within normal limits 
e. AST/ALT ≤1.5 x ULN 
f. creatinine 24-hour clearance ≥40 mL/min (measured or calculated) 
g. PT/PTT ≤1.2 x ULN 
8. 
Contraception requirements: 
a. Women of child-bearing potential, defined as women physiologically 
capable of becoming pregnant, must use highly effective methods of 
contraception during study treatment and for 30 days after the last dose 
of study treatment. Highly effective methods of contraception include:  
i. Total abstinence (when this is the preferred and usual lifestyle of the 
subject). Withdrawal and periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) are not 
acceptable methods of contraception. 
ii. Female sterilization (defined as having had surgical bilateral 
oophorectomy with or without hysterectomy), total hysterectomy, 
or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level 
assessment. 
iii. Male sterilization for at least 6 months prior to screening. The 
vasectomized male partner should be the sole partner for that 
subject. 
iv. Use of oral, injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or 
intrauterine system (IUS), or other forms of hormonal contraception 
that have comparable efficacy (failure rate <1%), for example 
hormone vaginal ring or transdermal hormone contraception. In case 
of use of oral contraception women should have been stable on the 
same pill for a minimum of 3 months before taking study treatment.  
b. Male subjects must use condoms during the study treatment period and 
for 120 days following the last dose of study drug. 
 


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9. Negative urine pregnancy test ≤3 days prior to first dose (women of 
childbearing potential only) 
10. Ability to understand and willingness to sign a written informed consent form 
11. Able to comply with study visit schedule and assessments. 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will not be eligible to participate 
in the study: 
1. Uncontrolled grade 2 or greater toxicity except alopecia related to any prior 
treatment (i.e. chemotherapy, targeted therapy, radiation or surgery) within 7 
days prior to C1D1 unless approved by the Medical Monitor 
2. Prolongation of QT/QTc interval (QTc interval >450 msec. for males and 
>470 msec. for females) using the Fredericia method of QTc analysis. If 
single reading is above these minimum ranges, then repeat test in triplicate 
and evaluate eligibility based on average value 
3. Women who are pregnant or nursing 
4. Any known HIV infection or AIDS or any concurrent infection requiring IV 
antibiotics 
5. Any chronic or concurrent acute liver disease, including viral hepatitis 
6. Primary brain malignant tumors 
7. Known metastases to the brain / CNS confirmed by CT requiring treatment or 
radiation therapy, or that have not been confirmed stable on imaging for ≥ 30 
days prior to first dose 
8. Uncontrolled hypertension >150 (systolic) and >100 (diastolic) mmHg 
9. Concurrent participation in any other investigational study, unless non-
interventional study and approved by Sponsor 
10. Concurrent treatment with the following medication, unless approved by 
Sponsor:  
a. Anticoagulant 
b. Tubulin binding agents (e.g. colchicine) 
c. Strong CYP3A4 inhibitors (see Appendix C) 
11. History of stroke, deep venous thrombosis (DVT), transient ischemic attack 
(TIA), or myocardial infarction, within 6 months prior to first dose 
12. History of other cancer type, except for cutaneous basal cell or squamous cell 
carcinoma, or cervical in situ or very low/low risk prostate cancer within the 
last 2 years prior to first dose 
13. Uncontrolled concurrent disease or illness including but not limited to: 


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a. symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia 
b. unstable or untreated cardiac conditions or ejection fraction of <50% 
as determined by echocardiogram (ECHO) or multiple gated 
acquisition scan (MUGA); NOTE: ECHO or MUGA required at 
screening only in subjects with known history of cardiac insufficiency 
and symptomatic in 3 months prior to screening. 
c. diabetes mellitus 
d. coagulation disorder 
e. psychiatric illness that would limit compliance with study 
requirements, as determined by the Investigator  
14. History of severe hypersensitivity reaction to taxanes 
15. For Phase 2a Stage 2: treatment with a taxane within 6 months of first dose; 
NOTE: advanced prostate cancer patients must be taxane-naïve. 
16. Peripheral neuropathy defined as one or more of the following unless 
approved by the Sponsor: 
a.  Active peripheral neuropathy within 30 days prior to first dose 
defined as: 
i. Motor neuropathy of any grade (e.g., distal extremity weakness, 
loss of deep tendon reflex) 
ii. ≥Grade 2 neurosensory symptoms (e.g., pain, numbness, 
paresthesia, dysesthesia, etc.) 
b. History of ≥ Grade 3 neurologic reactions to prior chemotherapy; in 
particular, any neurological reactions that required a dose reduction or 
discontinuation from prior taxane therapy. 
17. Other severe, acute, or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
study drug administration or that may interfere with the interpretation of study 
results and, in the judgment of the investigator, would make the patient 
inappropriate for the study. 
4.3 
Number of Patients 
Phase 1: Up to 66 patients may be enrolled in the Phase 1 dose escalation cohorts.  
Up to 36 patients may be enrolled for Schedule 1 (Q3W) and up to 30 patients 
may be enrolled for Schedule 2 (QW, no break or QW, 3 week on/1 week off). 
The exact number of patients is dependent on the actual number of patients per 
cohort and total cohorts investigated in both dosing schedules based on toxicities 
experienced. 


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Phase 2a: Up to an additional 68 patients with advanced, histologically confirmed 
solid tumor malignancies will be enrolled in the Phase 2a expansion cohorts 
inclusive of Stage 1 (up to 32 patients) and Stage 2 (up to 36 patients). Enrollment 
will be limited to up to 5 specific tumor types. 
4.4 
Replacement of Patients 
Phase 1:  Patients enrolled in the Phase 1 dose escalation cohorts who discontinue 
prior to completion of 3 weeks on treatment for any reason other than a DLT are 
deemed not evaluable for MTD and will be replaced. 
Phase 2a: Patients enrolled in both Stages of the Phase 2a RP2D expansion cohort 
who discontinue from the study for any reason at any time will not be replaced. 


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5. 
STUDY PROCEDURES 
See Schedule of Procedures. 
5.1 
Informed Consent and HIPAA 
Written informed consent, and HIPAA authorization (United States only) to use 
or disclose protected health information, must be obtained from a prospective 
patient before any study-specific procedures are performed for that individual.  
Standard of care assessments performed before informed consent is obtained may 
be utilized to screen for study eligibility.  Patients will read the Informed Consent 
Form (ICF), and the HIPAA authorization (as applicable), after being given an 
explanation of the study.  Before signing the ICF and HIPAA authorization form, 
patients will have an opportunity to discuss the contents of the ICF and HIPAA 
form with study center staff.  Patients will be made aware that they may withdraw 
from the study at any time.  Patients who agree to participate in the study will sign 
the most recently approved ICF and the HIPAA authorization form and will be 
provided with a copy of the fully executed documents.  The original, executed 
ICF and HIPAA will be maintained in the respective patient’s clinical study file. . 
Refer to Section 12: Ethical Considerations 
Once screening procedures have begun, patients will be provided with Day(-1) 
premedication along with instructions to be followed once eligibility is confirmed.  
NOTE: Research staff will call each patient within 72 hours prior to Day(-1) to 
remind the patient to take premedication. 
 
5.2 
Eligibility, Study Enrollment, and Patient Number Assignment 
Patients will be assigned screening numbers consecutively by the Investigator or 
designee at the time the patient signs the ICF. For all patients screened, the 
Investigator or designee will record the eligibility criteria assessment in the 
medical record.  A screening and enrollment log will capture screening number, 
date of enrollment or determination as ineligible, and the assigned subject 
enrollment number, if enrolled. 
Enrollment for this study is defined as any patient that has received at least one 
dose of CRLX301.   
Each eligible, enrolled patient in the study will be uniquely identified by a patient 
identification number.   Patients will be assigned a study number by the Sponsor 
only after screening eligibility is confirmed (repeat assessments being performed 
within 3 days of first dose may still be pending).  Once assigned, a patient 
identification number will not be reused.   
See the Investigator Site File for Enrollment forms and complete enrollment 
instructions. The Sponsor and Medical Monitor may review eligibility and have 
final determination regarding whether a patient is eligible as appropriate. 


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NOTE: The following information in Sections 5.3 through 5.21 is to be recorded on the 
eCRF for enrolled patients only. 
5.3 
Current Cancer Diagnosis, Prior Therapies, and Responses 
Record cancer history including but not limited to:  
x current cancer diagnosis 
x date of diagnosis 
x disease stage at time of diagnosis 
x disease stage at pre-Study 
Record all anti-cancer therapy received including but not limited to: 
x names of drugs 
x description of surgery 
x anatomic sites for radiation 
x start and stop dates 
x dosing 
x best response to each treatment 
5.4 
Other Medical History 
Record medical history including but not limited, to: 
Demographics: date of birth, gender, race, and ethnic origin 
Clinically significant prior diagnoses, prior surgeries, and concurrent 
medical conditions or illnesses noting current severity  
Allergies and known hypersensitivity reactions to any medications 
Any other cancer history (not current cancer), including prior therapies 
received, outcome of those therapies, and progression-free interval on 
those therapies 
5.5 
Concomitant Medications and Therapies 
5.5.1 
Concomitant Medications 
Record concomitant medications including: 
Medications administered to the patient within 30 days prior to the 
planned first dose of study drug.  Include name of medication, indication, 
dose if available, route and frequency of administration, and start dates 
and stop dates if applicable. 
Concomitant medications taken by the patient during the study period 
including all medications, supplements, and blood products from first dose 
through 30 days post the last dose of study drug. 


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5.5.1.1 
Concomitant Procedures 
Any other non-cancer related medical or surgical procedure received by the 
patient during the study period. Information to be recorded includes: the name 
of the medication or procedure, indication, dose and frequency if applicable, 
and duration of treatment.  
5.5.2 
Concurrent Cancer Symptom Management 
Palliative and supportive care for disease-related symptoms and pain management 
should be continued or initiated as clinically indicated during the study with the 
following exceptions: 
x Patients may not be treated with erythropoietin, darbepoetin (Aranesp®), or 
other erythrocyte-, neutrophil- or platelet-stimulating agents during the first 
three weeks of therapy. However, they may be used in subsequent 
cycles/weeks of treatment per investigator discretion or institutional standard 
guidelines. 
x Patients requiring palliative radiation therapy must be pre-approved by the 
Sponsor and study Medical Monitor. 
5.5.3 
Prohibited Concurrent Medications or Therapies 
Patients are prohibited from: 
x Receiving any other cancer treatment during the study period.  This 
includes but is not limited to:  
o 
any approved antineoplastic or biologic therapies 
o 
radiation therapy 
o 
surgical procedures 
o 
investigational chemotherapy or biologic therapy 
x Erythropoietin, darbopoietin or other erythrocyte, neutrophil-, or platelet-
stimulating agents during the first three weeks of treatment  
o 
These may be used in subsequent cycles/weeks as per investigator 
discretion or institutional standard guidelines. Please refer to 
Section 5.10.4.1: CRLX301 Treatment Modifications for 
Hematologic Toxicity for additional information.  
x Strong CYP3A inhibitors during the study period unless sponsor approval 
is obtained in writing prior to enrolling the patient or initiating treatment 
(Appendix C) 
x Other tubulin binding agents during the study period (e.g. colchicine) 


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5.6 
Physical Examination and BSA 
Patients will undergo a complete physical examination, which will be completed 
by the investigator who is a professionally trained physician or health professional 
listed on Form FDA 1572 and licensed to perform physical examinations, pre-
study and at the End-of-Study visit.  Complete physical examination will include 
the major body systems, including skin, height (pre-Study only), weight, and 
ECOG Performance Status (Appendix A).   
In addition, a limited physical examination will occur every three weeks (end of 
each cycle for Schedule 1 or pre-dose every 3 weeks for Schedule 2 – QW, no 
break) or every four weeks (pre-dose every 4 weeks for Schedule 2 – QW, 3 week 
on/1 week off).  Limited physical examinations will include general appearance, 
heart, lungs, abdomen, and any symptom directed examination of body/system 
organ(s).  Symptom directed exams will require the patient to report on any 
signs/symptoms that they may have and, based on the patient’s report, the 
Investigator will conduct physical examinations of relevant body/system organ(s). 
Height and weight will be used to calculate Body Surface Area (BSA). BSA will 
be calculated for the first dosing day and recalculated only if body weight changes 
by more than 10% and the change is attributed to dry weight. (Section 7.2.1: Body 
surface Area Calculation.) 
5.7 
Vital Signs 
Vital signs measurement includes diastolic and systolic blood pressure (BP), heart 
rate (HR), and respiratory rate (RR).  These will be assessed by study center staff 
as per the time points in the Schedule of Procedures and/or Table 3 and Table 4. 
BP and HR will be measured with patients in the sitting or supine position 
(patients must be sitting or supine for at least 5 minutes), using the same arm 
throughout the study, and before any corresponding blood sample is collected.  
All vital sign assessments will be recorded on the eCRF, including any additional 
assessments completed for evaluation of potential infusion reactions or possible 
AEs. 
 
 


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Table 3: Schedule 1 (Q3W) Vital Sign Assessment 
Study Day  
Timing 
Window 
Cycle 1 
Day 1 
Prior to start of CRLX301 IV infusion 
*Including Temperature 
none 
 
30 min after initiation of CRLX301 infusion 
±5 min 
 
60 min into infusion   
±5 min 
 
 End of infusion 
±5 min 
 
60 min (1 hour) after completion of CRLX301 
infusion 
±5 min 
 
180 min (3 hours) after completion of CRLX301 
infusion 
±10 min 
 
360 min (6 hours) after completion of CRLX301 
infusion 
*Including Temperature 
-1 hr 
All other 
cycles 
Day 1 
Prior to start of CRLX301 IV infusion 
* Including Temperature 
none 
60 min/1 hour after completion of CRLX301 
infusion 
±5 min 
All cycles 
Day 8 
7 days after completion 
N/A: day of 
visit 
All cycles 
Day 22 
21 days after completion and prior to initiation 
of CRLX301 for subsequent treatment cycle 
On day of 
visit, pre-dose 
EOS 
Day of Visit 
* Including Temperature 
N/A: day of 
visit 
*Temperature collection required per protocol. 
 
 


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Table 4: Schedule 2 (QW, no break) Vital Sign Assessment 
Study Day  
Timing 
Window 
Week 1, 4 
& 7 
Day 1 
Prior to start of CRLX301 IV infusion 
*Including Temperature 
none 
30 min after initiation of CRLX301 infusion 
±5 min 
60 min after initiation of CRLX301 infusion 
±5 min 
End of infusion 
±5 min 
60 min (1 hour) after completion of CRLX301 
infusion 
±5 min 
180 min (3 hours) after completion of CRLX301 
infusion 
±10 min 
360 min (6 hours) after completion of CRLX301 
infusion 
*Including Temperature 
-1 hr 
Week 2, 3, 
5, 6 
Day 1 
Prior to start of CRLX301 IV infusion 
* Including Temperature 
none 
End of CRLX301 infusion 
* Including Temperature 
±5 min 
Week 8 & 
subsequent 
weeks 
Day 1 
Prior to start of CRLX301 IV infusion 
* Including Temperature 
none 
EOS 
Day of Visit 
* Including Temperature 
N/A: day of 
visit 
* Temperature collection required per protocol. 
 
 
 
 
 
 
 
 


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Table 5: Schedule 2 (QW, 3 week on/1 week off) Vital Sign Assessment 
Study Day  
Timing 
Window 
Week 1, 3 
& 7 
Day 1 
Prior to start of CRLX301 IV infusion 
*Including Temperature 
none 
30 min after initiation of CRLX301 infusion 
±5 min 
60 min after initiation of CRLX301 infusion 
±5 min 
End of infusion 
±5 min 
60 min (1 hour) after completion of CRLX301 
infusion 
±5 min 
180 min (3 hours) after completion of CRLX301 
infusion 
±10 min 
360 min (6 hours) after completion of CRLX301 
infusion 
*Including Temperature 
-1 hr 
Week 2, 5 
& 6 
Day 1 
Prior to start of CRLX301 IV infusion 
* Including Temperature 
none 
End of CRLX301 infusion 
* Including Temperature 
±5 min 
Week 4 & 
8 
Day of Visit 
* Including Temperature 
N/A: day of 
visit 
Week 9 & 
subsequent  
dosing 
weeks 
Day 1 
Prior to start of CRLX301 IV infusion 
* Including Temperature 
none 
EOS 
Day of Visit 
* Including Temperature 
N/A: day of 
visit 
 
Every effort should be made to perform vital signs at the specified time points.  
When vital sign collection timing coincides with blood PK collection timing, 
collection of the PK on time point is the preferred priority if clinically feasible.  
However, vital signs collected outside of the allowable window, or after a 
coinciding plasma PK sample be logged as a minor protocol deviation with 
explanation. 


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5.8 
 Electrocardiogram 
Standard 12-lead ECG will be performed for safety as per the time points in the 
Schedule of Procedures.  The paper speed will be a standard 25 mm/second; the 
ECG tracing will be kept at the study center.  Measurements will be recorded for 
the following parameters in lead II or lead III: heart rate, PR interval, QRS 
duration, QT interval, and QTc (using the Fredericia method of QTc analysis). If 
any reading is abnormal, then the ECG will be repeated in triplicate and the 
average value of the 3 readings will be reported. 
ECGs will be clinically interpreted by the Investigator or designee and patient 
eligibility determined per QTc interval. Once enrolled, all ECGs should be 
interpreted prior to the patient leaving the clinic. 
Repeat ECG as clinically indicated if there are changes in cardiac medical 
condition or if the patient has reported concomitant medications with documented 
cardiac toxicities since the pre-study ECG.   
5.9 
Echocardiogram (ECHO) or Multi Gated Acquisition Scan (MUGA) 
ECHO or MUGA is required during pre-study for patients with known cardiac 
disease who are symptomatic within 3 months of planned first dose. Confirm 
sufficient cardiac function if testing has not already been performed within 30 
days of first dose. If a patient is asymptomatic at pre-study with no history of 
impairment of cardiac function, this procedure for eligibility is not required.  
5.10 
Study Treatment and Dose Assignment 
5.10.1 Cohort and Dose Assignment 
Phase 1:  
Patient dosing schedule, cohort and corresponding dose level assignment will be 
provided in writing from the Sponsor to the Investigator when the patient’s study 
identification number is assigned.   
Phase 2a: 
All patients will be assigned to the CRLX301 dose level that is determined to be 
the RP2D. Patient dosing schedule will be provided in writing from the Sponsor 
to the Investigator when the patient’s study identification number is assigned. The 
same treatment guidelines and assessments will apply as those specified in Phase 
1. 
5.10.2 Premedication Prior to CRLX301 Treatment for Both Schedules 
As a precaution to minimize the risk and/or severity of infusion-related 
hypersensitivity reactions, all patients will be provided premedication to allow for 
dosing the night prior (Day (-1), and also on day of CRLX301 infusion. 


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Once screening procedures have begun, patients will be provided with Day (-1) 
premedication along with instructions to be followed once eligibility is confirmed.  
NOTE: Research staff will call each patient within 72 hours prior to Day (-1) to 
remind the patient to take premedication. 
Prior to initiation of the CRLX301 infusion on day of dosing, sites should confirm 
that patient ingested premedication regimen the prior evening (Day (-1)). If 
patient did not take the premedication, the CRLX301 infusion will be initiated at 
discretion of the investigator. On day of dosing, premedication will be 
administered 30-90 minutes prior to the CRLX301 infusion.  
 
Table 6: Premedication Schedule for Q3W and QW Schedules  
Class 
Preferred 
Medication 
Dose 
Route 
Night Prior to CRLX301 Infusion Day (-1) 
corticosteroid 
 dexamethasone 
8 mg 
 oral 
antihistamine 
 diphenhydramine 
50 mg 
 oral 
H2 antagonist 
 ranitidine 
50 mg 
 oral 
30-90 minutes Prior to CRLX301 Infusion 
corticosteroid 
 dexamethasone 
8 mg 
 IV 
antihistamine 
 diphenhydramine 
50 mg 
 IV 
H2 antagonist 
 ranitidine 
50 mg 
IV 
OPTIONAL: 
Antiemetic 
with a 5-HT3 
receptor 
 dolasetron 
100 mg 
IV 
ondansetron 
8-24 mg 
IV 
SOC 
SOC 
oral 
 
 
If the subject has not experienced any infusion related reaction after the first three 
infusions of CRLX301, the dose of dexamethasone (both the night before and on 
day of CRLX301 dosing) may be tapered to 4mg for subsequent CRLX301 
infusions. If the subject continues to tolerate the subsequent three infusions of 
CRLX301, without experiencing any infusion related reaction, all “night prior” 
premedication may be stopped at the investigator's discretion. On the day of 
CRLX301 dosing, premedication are to continue throughout the study.  
 


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The example medications, route of administration, and dose indicated should be 
the medication-of-choice if clinically feasible. Note: It is particularly important to 
administer the premedication on the day of CRLX301 dosing via IV to achieve 
the quickest onset and maximum bioavailability of these medications to 
effectively prevent hypersensitivity/infusion reaction. The oral route is not 
recommended, especially for patients who have gastrointestinal tract (GI) tumor 
involvement, GI disease history and/or active GI symptoms (e.g., nausea, 
vomiting, diarrhea) that may negatively impact the absorption of the medications. 
If not clinically feasible or not site standard practice, the Investigator should 
discuss appropriate options with the medical monitor prior to Cycle 1 Day 1 
dosing for each patient. A prospective approval from the Medical Monitor or 
sponsor Medical Director may be provided in writing to acknowledge alternate 
route or alternate medication. All premedication will be recorded on the eCRF as 
concomitant medications with the name of the medication, dose, time 
administered, and the indication reported as “CRLX301 premedication”. 
 
Please refer to Section 5.10.4.2: CRLX301 Treatment Modifications for Non-
Hematologic Toxicity for management of any hypersensitivity reactions to 
CRLX301.  
5.10.3 CRLX301 Administration, Management of Infusion Related Reactions and 
Treatment Compliance 
5.10.3.1 CRLX301 Administration 
Each CRLX301 infusion should start as slow as possible with no more than 15mL 
infused over the first 15 minutes. Provided the subject does not experience any 
infusion related symptoms during these 15 minutes, the rate of infusion can then 
be gradually increased to complete the infusion in approximately 120 minutes, 
inclusive of 50mL flush. 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 CRLX301 infusion and for 
all subsequent infusions, at the discretion of the investigator. If the Day (-1) 
premedications have been stopped and the patient has tolerated at least 3 infusions 
without Day (-1) premedications, the CRLX301 infusion rate may be increased 
(while maintaining the rule of no more than 15mL in first 15 minutes) to complete 
infusion in no less than 60 minutes, at discretion of investigator. 
 
 
 


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5.10.3.2 Management of Infusion Related Reactions 
Table 7: Management of Infusion Related Hypersensitivity Reactions 
NCI CTCAE Grade 
Treatment 
Retreatment Rules 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
 
Collect data on tryptase as soon as 
possible (within 3 hours from onset 
of event) 
 
Retreatment may be 
considered. The 
investigator may consult 
an allergist to assess if 
potential desensitization 
needs to be done prior to 
retreatment. 
 
At investigator's 
discretion, infusion rate 
may be slower for all 
subsequent dosing. The 
use of premedication may 
be increased as indicated. 
Tryptase should be 
repeated prior to each 
subsequent infusion. 
 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
Immediately interrupt infusion 
and provide appropriate medical 
therapy as indicated. Collect data on 
tryptase as soon as possible (within 
3 hours from onset of event) 
 
 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator.  
If symptoms resolve within a few 
hours, at Investigator’s discretion, 
study drug may be resumed and 
administered at a slower rate (i.e. 2x 
slower rate). The rate may be 
slowly increased to complete 
administration of full dose. 
 
OR 
 
Hold dose administration on the day 
of the hypersensitivity event, and 
resume treatment at next scheduled 
day at same dose level. 
 
 
 
Retreatment may be 
considered. The 
investigator may consult 
an allergist to assess if 
potential desensitization 
needs to be done prior to 
retreatment. 
 
Infusion rate should be 
initiated at a slower (i.e. 
2x slower rate) for 
subsequent dosing. The 
use of premedication may 
be increased as indicated. 
Tryptase should be 
repeated prior to each 
subsequent infusion. 
 


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NCI CTCAE Grade 
Treatment 
Retreatment Rules 
Grade 3 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
 
Immediately Stop Infusion and 
provide appropriate medical 
therapy. 
 
Collect data on tryptase as soon as 
possible (within 3 hours from onset 
of event). 
 
 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
Review with study 
Medical Monitor to 
determine whether to 
discontinue from study 
treatment. Confirm that 
rate of administration was 
appropriate and premeds 
were given as suggested. 
 
Retreatment is allowed 
only for subjects with 
clinical benefit from 
study drug and only after 
successful 
desensitization. 
 
Infusion rate should be 
initiated at a slower (i.e. 
2x slower rate) for all 
subsequent dosing. The 
use of premedication may 
be increased as indicated.  
Tryptase should be 
repeated prior to each 
subsequent infusion. 
 
Grade 4 
Life-threatening; pressor or 
ventilatory support 
indicated 
Immediately Stop Infusion and 
provide appropriate medical therapy 
as indicated. 
 
Collect data on tryptase as soon as 
possible (within 3 hours from onset 
of event) 
 
 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
Retreatment not allowed. 
Subject to be permanently 
discontinued from study 
treatment and followed 
up per protocol. 
 
Please also note the following: 
x Appropriate resuscitation equipment should be available in the room and 
a physician readily available during the period of drug administration. 


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x A blood sample for tryptase should be drawn within 3 hours of onset of 
any infusion related reaction. Further, if a subject is to be re-treated, 
repeat blood sample for tryptase prior to each subsequent infusion. 
x For any ≤Grade 2 reaction, CRLX301 infusion may also be halted for 
the day, and the subject may return at the next scheduled visit for the 
next dose either as per study-specific CRLX301 administration 
procedures or per an Institutional desensitization protocol. For any 
subject that has experienced infusion related reaction while on study, all 
subsequent doses may be administered at a slower rate.  
5.10.3.3 Treatment Compliance 
All patients must meet hematology, bilirubin, AST, ALT and alkaline 
phosphatase eligibility criteria prior to receiving the first dose of CRLX301.  
Required hematology and chemistry lab results must be obtained within 3 days of 
the first dose date and within 24 hours of subsequent doses. 
Patients will receive all doses under the direct supervision of the Investigator and 
designated study personnel.  The intravenous infusion start time, stop time, 
volume infused, calculated dose and actual dose will be recorded.   
5.10.4 Dose Delay or Reductions or Treatment Discontinuation for Toxicity  
Modification and/or delay of treatment with CRLX301 will be based upon 
determination of hematologic and/or non-hematologic toxicities. Patients will 
continue to receive the same dose level of CRLX301 in Schedule 1 and in 
Schedule 2 as they were assigned at study entry unless a dose modification is 
required to manage AEs. In order to maintain dose-intensity and cumulative dose-
delivery on this study, reasonable efforts will be made to minimize dose reduction 
and treatment delays as specified below. Any patient whose treatment is delayed 
must be evaluated at least weekly until adequate hematologic and non-
hematologic parameters have recovered. All AEs and laboratory findings should 
be reviewed prior to dosing to determine whether any treatment modifications are 
required. The investigator should carefully assess all treatment-associated 
toxicities and, whenever possible, determine if they can reasonably be attributed 
to study drug.  
Dose delays for up to 21 days from the planned initiation of the next dose are 
permitted. Any dose delay of >21 days from planned date of next dose may result 
in withdrawal of the patient from further treatment upon review and discussion 
with Medical Monitor.  
Subsequent dosing days: 
For subsequent dosing days after the first dose, if a patient experiences ongoing 
Grade ≥2 related AE in Schedule 1 (Q3W) or Grade >2 related AE in Schedule 2 
(QW, no break or QW, 3 week on/1 week off), this will require a dose delay; if 


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the AE resolves to adequate hematologic and non-hematologic parameters in ≤21 
days, this may require dose reduction.  Refer to the information below for both 
hematologic and non-hematologic toxicity management. 
It is also up to Investigator discretion to delay or reduce the dose for any Grade 1 
AE. 
If the AE does not resolve to adequate hematologic and non-hematologic 
parameters, and results in >21 day delay to initiation of the next dose Day 1, then 
the patient is withdrawn from further study treatment.   
A maximum of 2 dose reductions will be permitted per patient.  If a patient 
experiences repeat toxicities after 2 dose reductions, then subsequent treatment 
with CRLX301 will be halted and the patient will be withdrawn from the study. 
Patients who do not experience a DLT but are dosed in the same cohort where ≥2 
patients experienced DLTs, will be dose de-escalated to the next lower dose level 
at the next planned dosing date, as per the Dose Escalation Scheme.  This does 
not constitute 1 of the 2 permitted dose reductions for toxicity described above. 
Similarly, a change in dosing schedule from QW, no break to QW, 3 week on/1 
week off dosing will not constitute 1 of the 2 permitted dose reductions.  
 
Review all proposed dosing changes with the Medical Monitor and record on the 
eCRF. 
5.10.4.1 CRLX301 Treatment Modifications for Hematologic Toxicity  
For both schedules: 
Treatment decisions will be based on the absolute neutrophil count (ANC) (rather 
than the total white cell count (WBC) and the platelet count. 
Refer to Section 5.5.3: Prohibited Concurrent Medications or Therapies 
The use of hematopoietic cytokines and protective reagents are restricted to after 
first 3 weeks and as noted below: 
Patients will NOT receive prophylactic growth factors [filgrastim (G-CSF), 
sargramostim (GM-CSF), pegfilgrastim (Neulasta)] unless they experience 
recurrent neutropenic complications despite the treatment modifications specified 
below. 
Patients will NOT receive prophylactic thrombopoietic agents. 


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Patients may receive erythropoietin (EPO), iron supplements, and/or transfusions 
as clinically indicated for management of anemia. Treating physicians should be 
aware of prescribing information for the erythropoiesis stimulating agents 
(including Aranesp, Epogen, and Procrit) which note that there is a potential risk 
of shortening the time to tumor progression or disease-free survival, and that these 
agents are administered only to avoid red blood cell transfusions. They do not 
alleviate fatigue or increase energy. They should not be used in patients with 
uncontrolled hypertension. They can cause an increased incidence of thrombotic 
events in cancer patients on chemotherapy. The updated package inserts should be 
consulted.  
 
 


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Table 8: Schedule 1 (Q3W): CRLX301 Dose Delay or Reduction for Hematologic 
Toxicity 
Absolute Neutrophil 
Count on Cycle 1  
Day 22 or  
Subsequent Cycles  
 
Platelet Count on 
Cycle 1 Day 22 or 
Subsequent Cycles 
CRLX301  
Dose for Next Cycle1  
Grade 2 
<1500 and ≥1000 
cells/μL  
And 
≥100,000 cells/μL  
Hold dose until neutrophil count is 
≥1500 cells/μL (Grade 1), then give 
full dose.  
Grade 3 
≥500 and <1000 
cells/μL  
And 
Grade 1 
≥75,000 cells/μL  
Hold dose until neutrophil count is 
≥1500 cells/μL.  If event duration is 
>7 days, consult Medical Monitor 
to confirm need for dose reduction 
by 1 dose level.  If event duration 
≤7 days, then resume dosing at full 
dose. If associated with fever, then 
reduce dose  
Grade 3 
≥500 and <1000 
cells/μL 
 
And 
Grade 2 
≥50,000 and  
< 75,000 cells/μL  
Hold dose until neutrophil count is 
≥1500 cells/μL and platelet count is 
≥75,000 cells/μL. If event duration 
>7 days, consult Medical monitor to 
confirm need for dose reduction by 
1 dose level. If event duration ≤7 
days, then resume dosing at full 
dose. If associated with fever, then 
reduce dose 
Grade 4 
<500 cells/μL  
Or 
Grade 3 
>25,000 and  
<50,000 cells/μL  
Hold dose until neutrophil count  is 
≥1500 cells/μL and platelet count is 
≥75,000 cells/μL  
If duration > 7 days, then consult 
Medical Monitor to consider dose 
reduction by 1 dose level.  
Any Grade or none at all 
And 
Grade 4 
< 25,000 cells/μL 
Study treatment to be discontinued 
1 In cases of dose delay if cytopenia persists for >21 days from planned initiation of next cycle, then patient 
is withdrawn from study treatment. 
 
Schedule 2 (QW, no break or QW, 3 week on/1 week off): CRLX301 Dose Delay or 
Reduction for Hematologic Toxicity:  
x CRLX301 will not be given unless ANC is ≥1000/mm³ and the platelet count is 
≥75,000/mm³. 
x If CRLX301 treatment is held, missed doses will not be made up.  
x During the first 3 weeks of treatment, GCSF use is not allowed. If the CRLX301 
dose is held due to insufficient ANC and/or platelet counts, then monitor counts 
weekly until they are adequate for treatment. Restart dosing at the same dose level 


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if delay is < 2 weeks. If the dosing delay is ≥2 weeks, contact the Medical 
Monitor to discuss the appropriate dose to be given to the subject. 
x After the first 3 weeks of treatment, if the CRLX301 dose is held due to 
insufficient ANC and/or platelet counts, monitor counts at least weekly until they 
are adequate for treatment. In the event where counts not recovered to adequate 
count within 7 days, GCSF should be instituted. If counts recover adequately 
within the next 7 days, then CRLX301 will be administered in the same dose used 
prior to the hold. However, if subjects do not recover within 7 days after GCSF 
support, subjects might restart dosing at a reduced dose level after the ANC 
and/or platelet recovers to adequate counts with GCSG support or be taken off 
study if dosing delay is more than 3 weeks. 
x Therapy will be delayed for a maximum of 3 weeks until the required ANC 
(despite GCSF support) and platelet count values are achieved. Subjects who fail 
to recover adequate counts despite of GCSF support with a three-week delay will 
be removed from study therapy. 
5.10.4.2 CRLX301 Treatment Modifications for Non-Hematologic Toxicity 
For both schedules: 
x Patients with nausea, emesis, diarrhea, constipation, dehydration, electrolyte 
disturbance should receive appropriate medical management without dose 
modification. However, patients with persistent (> 72 hours) ≥Grade 3 
toxicity—in spite of optimal medical management require a reduction of 1 
dose-level and delay in subsequent therapy until recovered to Grade 1. 
x If a Grade 3 recovered to adequate hematologic and non-hematologic 
parameters by the planned next dosing day and this is the first episode of such 
event, dose reduction is not required. It is up to the investigator’s discretion to 
reduce the dose or not. 
x There will be no required dose modifications for alopecia, fatigue or 
hypersensitivity reaction. 
 
 
 
 
 


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Table 9: Schedule 1 (Q3W) CRLX301 Dose Delay or Reduction for Non-
Hematologic Toxicity  
Non-Hematologic Event 
CRITERIA  
 
CRLX301 Dose for Next Cycle 
There will be no dose modifications for alopecia or fatigue.  
During cycle, onset of Grade 
2 event that is now recovered 
to <Grade 1 by the scheduled 
dosing day; and no dose 
adjustment during previous 
cycle 
Full dose 
Grade 2 toxicity resulting 
dose delay 
Hold dose until recovery to ≤Grade 1 and consult 
with Medical Monitor, may or may require dose 
reduction. 
 
If dose delay >21 days, withdraw from the study 
≥ Grade 2 peripheral 
neuropathy: 
Hold dose until recovery to ≤Grade 1, and require 
dose reduction by 1 level.  
If dose delay >3 weeks, then withdraw from study. 
During week onset of Grade 3 
event that is now recovered to 
<Grade 1 by the scheduled 
dosing day; and no dose 
adjustment during previous 
cycle 
For the first episode of Grade 3 toxicity, full dose. 
 
If the same Grade 3 toxicity in previous cycle, then 
requires dose reduction. 
(exception: fatigue, alopecia, hypersensitivity 
reaction) 
Grade 3 toxicity resulting in 
dose delay 
 
Hold dose until recovery to ≤Grade 1 and requires 
dose reduction 
Exceptions: fatigue, alopecia, dehydration as a result 
of nausea and vomiting;  constipation; electrolyte 
disturbance resolving to ≤ Grade 1 or baseline within 
7 days (supplementation allowed) 
During cycle if bilirubin >1.2 
x ULN, or AST and/or ALT 
>1.5 × ULN concomitant with 
alkaline phosphatase >2.5 × 
ULN 
Hold dose, and if either of these are unresolved >21 
days from planned initiation of next cycle, then 
withdraw from study treatment 
Grade 4 event 
Withdraw from study treatment 
 
 
 


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Table 10: Schedule 2 (QW, no break or QW, 3 week on/1 week off) CRLX301 Dose 
Delay or Reduction for Non-Hematologic Toxicity 
Grade of Event 
Intervention 
Nausea & Vomiting (unresponsive to adequate medical management) 
≤Grade 2 
No change in dose. Investigator’s discretion whether to hold dose or 
administer dose per schedule if Grade 2 persists, may discuss with 
study Medical Monitor. 
Grade 3 or 4 
Hold until resolved to <Grade 2, 
Resume at same dose level if resolved to ≤Grade 1 within 2 weeks. 
Resume at one dose level lower if resolved to ≤Grade 2 within 3 
weeks 
If not resolved with 3 weeks, then review with study Medical 
Monitor to determine whether to discontinue study treatment or 
follow for resolution and consider dose modification to reduced dose 
level. 
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 Medical Monitor to determine whether to 
discontinue from study drug treatment. Confirm that rate of 
administration was appropriate and premeds were given as suggested. 
Peripheral neuropathy 
≥Grade 2 
peripheral 
neuropathy 
Hold dose until recovery to ≤Grade 1, and require dose reduction by 1 
level.  
Liver functional test abnormality 
If Bilirubin >1.2 x 
ULN, or 
AST and/or ALT 
>1.5 × ULN 
concomitant with 
alkaline 
phosphatase >2.5 × 
ULN 
Hold dose, and if either of these are unresolved for >21 days from 
planned next dose date, then withdraw from study treatment 
Other CTCAEs other than those above (unresponsive to adequate medical 
management) 
≤Grade 2 
No change in dose. Review with study Medical Monitor whether to 
hold dose or administer dose per schedule 
Grade 3 or 4 
Hold until resolved to < Grade 1, 
Resume at one dose level lower, if resolved within 3 weeks 
If not resolved within 3 weeks, then review with study Medical 
Monitor to determine whether to discontinue study treatment or 
follow for resolution and consider dose modification to reduced dose 
level. 


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5.11 
Clinical Laboratory Tests 
Blood and urine samples for safety assessments will be collected and analyzed by each 
site’s institutional or local laboratory’s standard procedures. The following Table 11: 
Schedule 1 (Q3W) Clinical Laboratory Test Parameters and Timing, Table 12: Schedule 
2 (QW, no break) Clinical Laboratory Test Parameters and Timing and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 13: Schedule 2 (QW, 3 week on/1 week off) Clinical Laboratory Test Parameters 
and Timing detail the clinical laboratory tests to be performed according to the Schedule 
of Procedures.  
 
 
 


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Table 11: Schedule 1 (Q3W) Clinical Laboratory Test Parameters and Timing   
Lab Test 
Parameters5 
Timing 
Chemistry 
Sodium, potassium, calcium, chloride, 
glucose, blood urea nitrogen (BUN2) or 
urea, creatinine, total protein, alkaline 
phosphatase, albumin, total bilirubin, direct 
and indirect bilirubin (NOTE: recording of 
indirect bilirubin is optional), aspartate 
aminotransferase (AST), alanine 
aminotransferase (ALT), lactate 
dehydrogenase (LDH), inorganic 
phosphorus, uric acid, cholesterol, 
triglyceride levels, and tryptase4 
x Pre-study3  
x Cycle 1: Day 1 (pre-
dose)3 
x Cycles 1 – 7: Day 8, 
15 and 22 
x As of Cycle 8 and 
subsequent cycles: 
Day 1 pre-dose only 
x EOS 
Hematology Absolute and differential white blood cell 
count, red blood cell count, hemoglobin 
level, hematocrit level, platelet count, and 
reticulocyte count  
Coagulation 
Prothrombin time (PT), partial 
thromboplastin time (PTT), and 
international normalized ratio (INR) 
x Pre-study3 
x Cycle 1: Day 1 (pre-
dose)3  
x Prior to post-dose 
biopsy (as applicable) 
Urinalysis 
Specific gravity, pH, protein, glucose, 
ketones, bilirubin, microscopy (red blood 
cells/high-power field, white blood 
cells/high-power field, and casts/low-power 
field), and blood 
x Pre-study3 
x Cycle 1: Day 1 (pre-
dose)3 
x Cycles 1 – 7: Day 1 
(or Day 22) and 8 
x As of Cycle 8 and 
subsequent cycles: 
Day 1 pre-dose only 
x EOS 
Pregnancy 
test1 
Urine pregnancy test or Serum β-hCG as 
confirmation of positive urine test 
 
x Pre-study3 
x Cycle 1: Day 1 (pre-
dose)3  
x EOS 
1. Only for women of childbearing potential 
2. Urea acceptable if BUN is not standard 
3. Repeat if >3 days prior to C1D1 
4. Tryptase only required in subjects who experience an infusion related reaction 
5. Contact the Medical Monitor to discuss if any parameter results require >24 hrs. for turn-
around 
 


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Table 12: Schedule 2 (QW, no break) Clinical Laboratory Test Parameters and 
Timing 
Lab Test 
Parameters 
Timing 
Chemistry & 
Hematology 
See Table 9 
x Pre-study 
x Week 1: Day 1 (pre-dose)1 
x Week 2 & subsequent weeks: Day 1 pre-dose 
x EOS 
Coagulation 
x Pre-study 
x Week 1: Day 1 (pre-dose)1 
x Prior to post-dose biopsy (as applicable) 
Urinalysis 
x Pre-study 
x Week 1 Day 1 (pre-dose)1 
x Week 2 & subsequent weeks: Day 1 pre-dose 
x EOS 
Pregnancy 
test2 
x Pre-study 
x Week 1 Day 1 (pre-dose)1 
x EOS 
1 Repeat only if >3 days prior to W1D1 
2 Only for women of childbearing potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 13: Schedule 2 (QW, 3 week on/1 week off) Clinical Laboratory Test 
Parameters and Timing 
Lab Test 
Parameters 
Timing 
Chemistry & 
Hematology 
See Table 9 
x Pre-study 
x Week 1: Day 1 (pre-dose)1 
x Week 2 & subsequent dosing weeks: Day 1 
pre-dose 
x Week 4 and Week 8 visits 
x EOS 
Coagulation 
x Pre-study 
x Week 1: Day 1 (pre-dose)1 
x Prior to post-dose biopsy (as applicable) 
Urinalysis 
x Pre-study 
x Week 1 Day 1 (pre-dose)1 
x Week 2 & subsequent weeks: Day 1 pre-dose 
x Week 4 and Week 8 visits 
x EOS 
Pregnancy 
test2 
x Pre-study 
x Week 1 Day 1 (pre-dose)1 
x EOS 
1 Repeat only if >3 days prior to W1D1 
2 Only for women of childbearing potential 
 
Additional blood and urine safety samples should be collected if clinically 
indicated. 
All blood and urine samples for safety analyses will be analyzed by each center’s 
local laboratory.  Samples will be collected, processed, and stored according to 
the institutional instructions provided by the clinical laboratory. All reference 
ranges will be provided to the Sponsor for all lab parameters measured. 
The Investigator will assess and document the clinical significance of any values 
outside the reference ranges provided by the clinical laboratory and grade 
according to the CTCAE Version 4.03. 
5.12 
Abnormal Results 
The clinical significance of any abnormal findings found in the physical 
examination, clinical laboratory evaluations, vital sign assessments, and ECGs 
must be evaluated and documented by the Investigator. Onset of new abnormal 
findings not recorded in the medical history or worsening of baseline symptoms 
or concurrent medical conditions will be recorded on the eCRF as AEs (see 
Section 8: Adverse Events).   


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Abnormal findings that are considered not clinically significant by the 
Investigator may be reviewed by the Medical Monitor. 
5.13 
Pharmacokinetic Sample Collection 
5.13.1 Patients with PK Collection 
Phase 1:   
All patients enrolled in Phase 1 dosing cohorts will have blood and urine samples 
collected for PK analysis.  
All supplies for PK sample collection and handling will be provided as well as a 
study-specific PK Manual prepared by the Sponsor designated PK laboratory. 
Samples from each patient will be batched, stored as per instructions, and shipped 
after collection. Shipments will be triggered by the Sponsor to meet the needs of 
data review for of the end of cohort meetings.  Details for collection, processing, 
storage, handling and shipment will be specified in the PK Manual. 
Phase 2a:  
All patients enrolled in Stage 1 expansion will have blood and urine samples 
collected for PK analysis.  
Only a subset of patients enrolled in Stage 2 expansion will have blood samples 
for PK collected. The number of patients undergoing blood collection for PK will 
be based on the samples obtained from Stage 1 and whether or not the same 
dosing schedule and dose level will be examined in Stage 2.  
If Schedule 1 is selected for Stage 2, PK samples will be collected until it is 
confirmed that at least 10 patients have completed serial PK sampling at both 
Cycle 1 and at least 1 repeat dose (Cycle 3 or 6).  
If Schedule 2 is selected for Stage 2, PK samples will be collected until it is 
confirmed that at least 10 patients have completed serial PK sampling at both first 
dose and at least one additional serial sampling day.  
No urine samples will be collected from patients enrolled in Phase 2a Stage 2.  
For all patients in the study, an unscheduled single plasma PK sample should be 
collected if they present in the clinic with any SAE that is possibly related to 
infusion of CRLX301, provided the visit does not already have a PK collection 
scheduled.  
Also, based on emerging data in the clinic and available PK data, the sponsor may 
remove collection of one or some blood PK sample time points without issuing a 
protocol amendment.  The sites and patients would be alerted in writing. 


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5.13.2 PK Sample Collection Times  
The required blood and urine sample collections for PK analysis are specified in 
the Tables below for each dosing schedule. Sample collection date and time, the 
time of the start and end of the CRLX301 IV infusion and the total volume of 
urine collected must be recorded on the eCRF and sample collection forms.   
Every effort should be made to collect plasma PK samples at the specified time 
points.  PK samples collected outside of the allowable window will be logged as a 
minor protocol deviation. 
Table 14: Schedule 1 (Q3W) Blood PK Sample Collection Times (Phase 1 and subset 
of patients in Phase 2a) 
Cycle 1, 
3 & 6 
Timing 
Window 
Day 1 
Prior to start of CRLX301 IV infusion (pre-dose) 
None 
 
During infusion of CRLX301: 
30 min after initiation of infusion  
±5 min 
 
During infusion of CRLX301: 
60 min after initiation of infusion  
±5 min 
 
End of infusion (immediately after turning off infusion 
pump) 
±5 min 
 
After infusion of CRLX301: 
30 min after completion of infusion 
±5 min 
 
60 min after completion of infusion 
±5 min 
 
180 min (3 hours) after completion of infusion 
±30 min 
 
360 min (6 hours) after completion of infusion 
-1 hr 
Day 2 
Approximately 24 hours after completion of infusion 
±4 hrs. 
Day 3 
2 days after completion of infusion (48 hours after 
completion of infusion) 
N/A: day of visit 
Day 8 
7 days after completion of infusion (168 hours after 
completion of infusion) 
N/A: day of visit 
Day 15 
14 days after completion of infusion (336 hours after 
completion of infusion)  
Cycle 1 only 
N/A: day of visit 
Day 22 
(i.e., D1 
of cycle 
2, 4, 7) 
21 days after completion of infusion (504 hours after 
completion of infusion) 
day of visit / 
must be pre-dose 
if continuing 
treatment 
A single PK sample may be collected, as able, if patient experiences a CRLX301 
related SAE 


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Table 15: Schedule 1 (Q3W) Urine PK Sample Collection Times (Phase 1, Phase 2a 
Stage 1, and subset of patients in Phase 2a Stage 2 only)    
Cycle 1, 
3 & 6 
Timing 
Day 1 
Spot Urine collection (>15 mL) pre-dose, prior to CRLX301 infusion 
 
Collect all urine from start of CRLX301 infusion (0 min.) to 6 hours (-1 hr) 
after completion of infusion or to time of discharge if earlier. 
Note: record the total volume of urine collected and the start and stop time 
for the collection of urine.  
Day 8 
Spot Urine collection (>15 mL), 7 days after completion of infusion 
 
Table 16: Schedule 2 (QW, no break) Blood PK Sample Collection Times (Phase 1 
and subset of patients in Phase 2a)   
Timing 
Window 
Week 1, 4 & 7 
Day 1 
Prior to start of CRLX301 IV infusion (pre-dose) 
None 
 
During infusion of CRLX301: 
30 min after initiation of infusion  
±5 min 
 
During infusion of CRLX301: 
60 min after initiation of infusion   
±5 min 
 
End of infusion (immediately after turning off infusion 
pump) 
±5 min 
 
After infusion of CRLX301: 
30 min after completion of infusion 
±5 min 
 
60 min after completion of infusion 
±5 min 
 
180 min (3 hours) after completion of infusion 
±30 min 
 
360 min (6 hours) after completion of infusion 
-1 hr 
Day 2 
Approximately 24 hours after completion of infusion 
±4 hrs. 
Week 2, 3, 5, 6 
Day 1 
Prior to start of CRLX301 IV infusion (pre-dose) 
None 
A single PK sample should be collected, as able, if patient experiences a CRLX301 
related SAE. 
 
 
 


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Table 17: Schedule 2 (QW, no break) Urine PK Sample Collection Times (Phase 1 
and Phase 2a Stage 1 Only)    
 
Timing 
Week 1, 4 
and 7 
Day 1 
Spot Urine collection (>15 mL) pre-dose, prior to CRLX301 infusion 
Collect all urine from start of CRLX301 infusion (0 min.) to 6 hours (-1 
h) after completion of infusion or to time of discharge if earlier. 
Note: record the total volume of urine collected and the start and stop 
time for the collection of urine.  
Week 2, 5 
and 8 
Day 1 
Spot Urine collection (>15 mL), pre-dose 
 
Table 18: Schedule 2 (QW, 3 week on/1 week off) Blood PK Sample Collection 
Times (Phase 1 and subset of patients in Phase 2a)   
Timing 
Window 
Week 1, 3 & 7 
Day 1 
Prior to start of  CRLX301 IV infusion (pre-dose) 
None 
 
During infusion of CRLX301: 
30 min after initiation of infusion  
±5 min 
 
During infusion of CRLX301: 
60 min after initiation of infusion   
±5 min 
 
End of  infusion (immediately after turning off infusion 
pump) 
±5 min 
 
After infusion of CRLX301: 
30 min after completion of infusion 
±5 min 
 
60 min after completion of infusion 
±5 min 
 
180 min (3 hours) after completion of infusion 
±30 min 
 
360 min (6 hours) after completion of infusion 
-1 hr 
Day 2 
Approximately 24 hours after completion of infusion 
±4 hrs. 
Week 2, 5 & 6 
Day 1 
Prior to start of CRLX301 IV infusion (pre-dose) 
None 
A single PK sample should be collected, as able, if patient experiences a CRLX301 
related SAE. 


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Table 19: Schedule 2 (QW, 3 week on/1 week off) Urine PK Sample Collection 
Times (Phase 1 and Phase 2a Stage 1 Only)    
 
Timing 
Week 1, 3 
& 7 
Day 1 
Spot Urine collection (>15 mL) pre-dose, prior to CRLX301 infusion 
Collect all urine from start of CRLX301 infusion (0 min.) to 6 hours (-1 
h) after completion of infusion or to time of discharge if earlier. 
Note: record the total volume of urine collected and the start and stop 
time for the collection of urine.  
Week 2, 5 
& 6 
Day 1 
Spot Urine collection (>15 mL), pre-dose 
 
Detailed instructions for collection and shipment of PK samples will be provided 
in the study designated PK Laboratory Manual.  Supplies for collection of blood 
and urine samples, labels, and shipping materials will be provided to the clinical 
site. 
5.14 
Estimated Total Blood Volume Collected  
The Tables below show an estimate of the most blood volume to be collected if a 
patient underwent pre-study activities, completed 7 cycles (Schedule 1), 21 weeks 
(Schedule 2 - QW, no break) or 20 weeks (Schedule 2 – QW, 3 week on/1 week 
off) of treatment, the EOS visit and Follow-Up, if applicable.  Actual blood 
volume collected is dependent upon what phase /stage of the study the patient is 
enrolled, whether they undergo additional coagulation testing for post-dose 
biopsy, whether pregnancy serum collection is required and if additional safety 
labs need to be repeated, etc. 
 
 
 
 
 
 
 


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Table 20: Schedule 1 (Q3W) Estimated Blood Volume 
Assessment 
Blood volume 
per time point 
(mL) 
Pre-
study 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
EOS 
Follo
w-Up 
Hematology/ 
Chemistry 
15 
15 
45 
45 
45 
45 
45 
45 
45 
15 
 
Pregnancy 
serum test 
(if applicable) 
5 
5 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
5 
 
Coagulation 
5 
5 
5 -before post-dose biopsy (if applicable) 
-- 
 
PK - plasma 
6 
-- 
72 
6 
66 
6 
-- 
66 
6 
-- 
 
CTC 
10 
-- 
40 
30 
-- 
-- 
-- 
-- 
-- 
10 
 
MPS 
10 
-- 
10 
 
10 
-- 
-- 
 
-- 
-- 
 
Biomarker 
10 
-- 
20 
-- 
20 
-- 
-- 
-- 
-- 
10 
 
PSA* 
1 
1 
 
1 
1 
1 
1 
1 
1 
1 
1** 
*Phase 2a prostate cancer patients only   
**PSA amount collected in follow-up varies; depends on length of participation in follow-up 
 
Table 21: Schedule 2 (QW, no break) Estimated Blood Volume 
Assessment 
Blood 
volume 
per time 
point (mL) 
Pre-
study 
Weeks 
EOS 
Foll
ow-
Up 
1-3 
4-6 
7-9 
10-12 
13-15 
16-18 
19-21 
Hematology/ 
Chemistry 
15 
15 
45 
45 
45 
45 
45 
45 
45 
15 
 
Pregnancy 
serum test 
(if applicable) 
5 
5 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
5 
 
Coagulation 
5 
5 
5 -before post-dose biopsy if applicable 
 
 
PK - plasma 
6 
-- 
66 
66 
54 
-- 
-- 
-- 
-- 
-- 
 
CTC 
10 
-- 
40 
30 
-- 
-- 
-- 
-- 
-- 
10 
 
MPS 
10 
-- 
10 
10 
 
-- 
-- 
-- 
-- 
-- 
 
Biomarker 
10 
-- 
20 
20 
-- 
-- 
-- 
-- 
-- 
10 
 
PSA* 
1 
1 
 
1 
1 
1 
1 
1 
1 
1 
1** 
*Phase 2a prostate cancer patients only   
**PSA amount collected in follow-up varies; depends on length of participation in follow-up 
 
 
 
 


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Table 22: Schedule 2 (QW, 3 week on/1 week off) Estimated Blood Volume 
Assessment 
Blood 
volume 
per time 
point (mL) 
Pre-
study 
Weeks 
EOS 
Follow
-Up 
1-4 
5-8 
9-12 
13-16 
17-20 
Hematology/ 
Chemistry 
15 
15 
60 
60 
45 
45 
45 
15 
 
Pregnancy 
serum test 
(if applicable) 
5 
5 
-- 
-- 
-- 
-- 
-- 
5 
 
Coagulation 
5 
5 
5 -before post-dose biopsy if 
applicable 
-- 
 
PK - plasma 
6 
-- 
114 
66 
-- 
-- 
-- 
-- 
 
CTC 
10 
-- 
60 
10 
-- 
-- 
-- 
10 
 
MPS 
10 
-- 
20 
-- 
-- 
-- 
-- 
-- 
 
Biomarker 
10 
-- 
40 
-- 
-- 
-- 
-- 
10 
 
PSA* 
1 
1 
-- 
1 
1 
1 
1 
1 
1** 
*Phase 2a prostate cancer patients only   
**PSA amount collected in follow-up varies; depends on length of participation in follow-up 
 
5.15 
Evaluation of Target Tumors 
5.15.1 CT Scans 
For patients undergoing tumor evaluation via RECIST v.1.1, CT scans for tumor 
measurement will be recorded following RECIST v.1.1 guidelines. CT scans are 
to be collected pre-study, and then repeated every 8-9 weeks until the patient 
discontinues study drug treatment due to disease progression: 
Schedule 1: First evaluation during Cycle 3 Day 15 (+6 days) and perform within 
1 weeks prior to Day 22 of Cycle 6, Cycle 9 etc.  
Schedule 2 (QW, no break): First evaluation during Week 9 (post-dose) and 
complete before Week 10 dose, then during Week 18 (post-dose), Week 27 (post-
dose), etc. 
Schedule 2 (QW, 3 week on/1 week off): First evaluation complete before Week 9 
dose, then prior to Week 17 dose, prior to Week 25 dose, etc. 
Repeat CT Scans for tumor measurement at End-of-Study visit if prior CT scan 
and tumor evaluation is >3 weeks.  
If a complete or partial response per RECIST v.1.1 criteria is reported, then repeat 
CT scan approximately 3 - 4 weeks later for confirmation, per Investigator 
discretion. 
If stable response per RECIST v.1.1 criteria is reported, then continue repeat CT 
scan 8-9 weeks later for confirmation, per Investigator discretion. 


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Patients who are discontinued from study treatment for reasons other than disease 
progression will continue to have tumor evaluation by RECIST1.1 until another 
anti-cancer treatment is started, progression of disease, death, loss to follow up or 
withdrawal of consent, whichever comes first. Therefore, continued evaluations 
may be possible for some patients after the End-of-Study visit. 
5.15.2 Bone Scans 
Bone scans for tumor measurement will also be required and recorded for any 
CRPC patient enrolled into Phase 2a following PCWG2 criteria (see Section 
5.15.3: Alternative Evaluation Methods). Bone scans are to be collected pre-
study, and then repeated every 8-9 weeks until the patient discontinues study drug 
treatment due to disease progression: 
Schedule 1: First evaluation during Cycle 3 Day 15 (+6 days) and perform within 
1 weeks prior to Day 22 of Cycle 6, Cycle 9 etc.  
Schedule 2 (QW, no break): First evaluation during Week 9 (post-dose) and 
complete before Week 10 dose, then during Week 18 (post-dose), Week 27 (post-
dose), etc. 
Schedule 2 (QW, 3 week on/1 week off): First evaluation complete before Week 9 
dose, then prior to Week 17 dose, prior to Week 25 dose, etc. 
 
Repeat bone scans for tumor measurement at End-of-Study visit if prior bone scan 
and tumor evaluation is >3 weeks.  
5.15.3 Alternative Evaluation Methods 
If an alternative tumor evaluation methodology consistent with the tumor type is 
preferred, the Investigator will review this with the Medical Monitor when the 
patient enters the study, and plan to use the same methodology during the entire 
study period. The same schedule for evaluations will apply as for CT Scans. 
For Phase 2a prostate cancer patients, the alternative tumor evaluation method 
will be the PCWG2 criteria (see reference #33).  PSA in prostate patients will be 
collected pre-study, every three to four weeks as per the Schedule of Procedures 
and at the EOS visit only if it has been >21 days since the last PSA measurement.  
 
Patients who are discontinued from study treatment for reasons other than disease 
progression will continue to have tumor evaluation by the selected alternative 
evaluation method until another anti-cancer treatment is started, progression of 
disease, death, loss to follow up or withdrawal of consent, whichever comes first. 
Therefore, continued evaluations may be possible for some patients after the EOS 
visit. 
 


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5.16 
Tumor Marker Data 
Tumor marker data is collected only if appropriate for tumor-type and if already 
being performed as part of the patients Standard of Care. This includes treatment 
response markers (e.g. CA-125 for ovarian cancer, CA19-9 for pancreatic cancer, 
etc.) and tumor genotype markers (e.g. BRAF mutation status for melanoma, 
KRAS mutation status for colon cancer, EGFR status for lung cancer, etc.) The 
data should be entered into the eCRF. If tumor marker data is available prior to 
the first dose of CRLX301 (baseline) then additional data should be entered into 
the eCRF as available.  
5.17 
Pharmacodynamic (PD) Sample: Pre- and Post-Dose Biopsy 
Additional pharmacodynamic evaluations may be conducted by the Sponsor if 
tumor biopsies are obtained pre- and post- CRLX301 infusion.  The tissue will be 
used for additional research to include evaluation of markers for efficacy (e.g. 
proliferation, apoptosis, and cell cycle) and CRLX301 localization; it may also 
include genetic testing related to the cancer diagnosis for research purposes only, 
no other genetic testing on tumor tissue will be performed.  Individual patient 
results of any disease related genetic testing will not be provided to the 
Investigators or patients. 
Tumor biopsy is optional and is only required if accessible and feasible to collect 
and with consent of the patient. Collect a tissue sample pre-study prior to the first 
dose. Collect the post-dose biopsy as defined in the Schedule of Procedures 
Detailed instructions on tissue preparation and shipping will be provided to the 
site separately.  
5.18 
Blood Sample Collection for Additional Biomarker Research 
For Phase 2a only additional blood samples will be collected for additional 
exploratory research. Blood will be separated into peripheral blood mononuclear 
cells (PBMCs) and plasma. 
Pre- and post-study treatment blood samples will be used for analysis of genomic 
DNA for genetic alterations pertinent to the subject’s cancer diagnosis. A targeted 
panel of genes will be processed using next generation sequencing (NGS) to allow 
germline and tumor-specific mutations, amplifications and translocations (among 
other alterations) to be identified with high sensitivity and specificity. Plasma 
collected at progression will be used to determine whether new mutations may 
identify a potential marker for disease progression during treatment. 
 
A total of 6 mL of blood will be collected at each time point as per the Schedule 
of Procedures for each dosing schedule. 
For both schedules a total of 60 mL of blood will be collected during the study as 
per the time points detailed in each Schedule of Procedures.  


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The samples will be shipped to a central laboratory. Detailed instructions on 
collection, processing, and shipping of samples will be provided to the sites prior 
to enrollment into Phase 2a.  
5.19 
Archived Tumor Tissue 
Collection of archived tumor tissue is optional. For all patients who consent, up to 
12 slides from previously archived tumor tissue may be collected. Availability of 
archived tissue is not required in order to participate in the study. The site will be 
instructed to indicate during the pre-study visit if archived tissue is available, 
when the tissue was collected, and that the patient has consented to use of the 
tissue. Additional exploratory research may include evaluation of markers for 
efficacy (e.g. proliferation, apoptosis, and cell cycle) and CRLX301 localization; 
it may also include genetic testing related to the patient’s cancer diagnosis for 
research purposes only, no other genetic testing will be performed. Individual 
patient results of any disease related genetic testing will not be provided to the 
Investigators or patients.  
The trigger for preparation and shipment of slides will be a request in writing 
from the sponsor. The written request must occur prior to each site’s completion 
of the study. Detailed instructions on collection, preparation of slides, and 
shipping of samples will be provided to the sites at a future date.  
5.20 
Circulating Tumor Cells (CTCs) 
Whole blood will be collected for CTC analysis from patients enrolled in Phase 
2a Stage 1 expansion only. The samples will be used to explore 
pharmacodynamic effects of CRLX301 on tumor cells.27, 28 Fresh whole blood 
samples will be shipped to a central vendor. The samples must be shipped on the 
same day of collection in order to be analyzed within 24 hours.  Refer to the 
Schedule of Procedures for each dosing schedule for collection time points.  
Detailed instructions will be provided in the study binder prior to initiation of 
Phase 2a Stage 1.  
5.21 
Mononuclear Phagocyte System (MPS) Function 
Whole blood will be collected for MPS function analysis from patients enrolled in 
Phase 2a Stage 1 expansion only. The samples will be used to explore whether or 
not MPS plays a role in the clearance of CRLX301.29, 30, 31 Fresh whole blood 
samples will be shipped to a central vendor. The samples must be shipped on the 
same day of collection in order to be analyzed within 24 hours.  Refer to the 
Schedule of Procedures for each dosing schedule for collection time points.  
Detailed instructions will be provided in the study binder prior to initiation of 
Phase 2a Stage 1. 


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5.22 
End-of-Study Visit  
All dosed patients will have an End-of-Study (EOS) Visit 30 days (+10d) post last 
dose of study drug or at the time of early withdrawal if the patient cannot feasibly 
or is unwilling to return for the visit at the later date. 
If a patient discontinues from study drug and receives an investigational treatment 
or anti-cancer therapy prior to the 30 days post last dose of CRLX301 End-of-
Study visit, such treatment must be recorded on the eCRF.  Every attempt should 
be made to complete the End-of-Study visit 30 days post the last dose of 
CRLX301 prior to initiating other cancer treatment. AEs that occur after the 
initiation of new cancer treatment will not be collected.  
Patients will be followed for AEs and SAEs including clinically significant 
abnormal laboratory values.  In addition, any dosed patients who discontinue from 
the study due to an AE deemed to be related to study drug must be followed to 
report the final outcome of the AE as resolved, or symptoms returned to baseline 
or determined to be due to a chronic condition, or death.    
Discontinued patients who fail to return for an End-of-Study Visit within the 
designated time period must be requested in writing to return.  A copy of the letter 
will be kept by the study center with the source documentation.   
The reason for discontinuation from the study will be recorded on the End-of-
Study page of the Case Report Form (eCRF).   
The following procedures will be performed at the End-of-Study Visit: 
x Physical examination  
x ECOG performance status 
x Assess AEs and vital signs  
x Assess concomitant medication use  
x Collect blood and urine samples for hematology, chemistry and 
urinalysis, and pregnancy test if applicable  
x 12-lead ECG 
x Collect blood for biomarker (Phase 2a only) 
x Collect blood for CTC (Phase 2a Stage 1 only) 
x Collect PSA for CRPC patients only if prior PSA measurement is >14 
days 
x Repeat CT Scans (or alternative method consistent with tumor type) for 
tumor measurement if prior evaluation is > 21 days; and complete tumor 
response assessment 
x Collect blood for PSA for Phase 2a prostate cancer patients if prior 
evaluation is >21 days 


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x Record current patient contact as well as an alternate contact person. 
 
5.23 
Follow Up (as applicable) 
Patients who are discontinued from study treatment for reasons other than disease 
progression will continue to have tumor evaluation by RECIST1.1 or by 
alternative response evaluation for specific tumor type every 8-9 weeks or per 
Investigator discretion until another anti-cancer treatment is started, progression 
of disease, death, loss to follow up or withdrawal of consent, whichever comes 
first. Therefore, continued tumor evaluations may be possible for some patients 
after the EOS Visit.  
PSA will also be collected for CRPC patients only on Phase 2a.  PSA during 
follow-up will be done on the same scheduling as tumor evaluation. 
 


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6. 
DISCONTINUATION FROM TREATMENT AND STUDY WITHDRAWAL 
6.1 
Reasons for Discontinuation from Treatment 
Eligible patients who are enrolled into the study will be discontinued from study 
treatment if any of the following occur: 
x Documented radiographic or clinical progression of disease unless there is 
evidence of clinical benefit from the study drug and the investigator 
believes it is in the patient’s best interest to continue the treatment despite 
disease progression 
x Grade 4 hypersensitivity/infusion related reaction (may also be 
discontinued for Grade 3; see Table 7) 
x AE with clinically unacceptable toxicities (unless there is evidence of 
sustained therapeutic benefit and the investigator believes it is in the 
patient’s best interest to continue the treatment despite the toxicity) 
including: 
o unresolved related AE >Grade 2 that causes a delay of >21 days 
from planned initiation of next dose of CRLX301 
o repeat toxicities after 2 dose reductions 
o bilirubin >1.2 ULN, or AST and/or ALT >1.5 × ULN concomitant 
with alkaline phosphatase >2.5 × ULN; if either of these are 
unresolved for >21 days from planned next dose date 
o any other clinically unacceptable toxicity (in agreement with the 
Sponsor/Medical Monitor) 
x Withdrawal of consent 
x Subject non-compliance with study schedule 
x Protocol violation, (including lack of compliance or excessive deviations 
with study schedule) in agreement with the Sponsor/Medical Monitor 
and/or Study Director  
x Lost to follow-up (after repeated efforts for >30 days have been made to 
contact the patient including letters sent by registered mail) 
x Request for discontinuation by a regulatory agency (i.e. FDA) 
x Investigator decision (in consultation with the Safety Medical Monitor 
and/or Medical Director and the patient) if there are changes in the 
patient’s medical condition and/or intercurrent illness that render the 
patient unacceptable for further treatment. The reason for removal must be 
documented in the eCRF. 


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6.2 
Survival Status 
Last known survival status will be recorded on the eCRF at the End-of-Study 
Visit or post Follow-Up period as applicable. If a patient dies during the study, the 
cause of death and date will be recorded on the eCRF and every effort should be 
made to collect written documentation such as a death certificate.   


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7. 
STUDY DRUG AND PHARMACY INSTRUCTIONS 
7.1 
Study Drug  
CRLX301 is a conjugate of docetaxel and a linear cyclodextrin-based polymer 
(CDP).  The active drug unconjugated from the polymer is docetaxel. CRLX301 
contains a taxane antineoplastic agent, which can cause fetal harm; therefore, 
women of childbearing potential must agree to use of adequate form(s) of 
contraception. 
The Sponsor will provide the study center with drug supplies. CRLX301 will be 
supplied in a single form: 20 ml single-use vials containing 25 mg of docetaxel 
equivalents (approximately 125 mg of polymer-drug conjugate). The formulation 
contains mannitol as a bulking agent.  The drug is supplied in clear glass vials and 
appears as a white to off-white solid and transparent solution when reconstituted. 
CRLX301 for injection is stored at refrigerated conditions (2° - 8°C) and should 
only be accessible to authorized individuals.   
Refer to the CRLX301 Investigator’s Brochure for details on CRLX301-101 drug 
product and the CRLX301-101 Pharmacy Manual for details on storage, stability, 
reconstitution, preparation, handling, administration and accountability. 
7.2 
Study Drug Dose Calculation and Administration  
7.2.1 
Body surface Area Calculation 
Body surface area (BSA) calculations will be performed according to institutional 
practices. Every attempt should be made to follow the updated ASCO clinical 
practice guidelines including the guideline for dosing obese patients.32 
BSA is calculated according to the following method or alternate method as per 
the institutional practices: 
BSA (m²) = 0.20247 × height (m)0.725 × weight (kg)0.425 
A change in body weight of >10% will require recalculation of BSA if the change 
is attributed to dry weight. 
 
Refer to the Pharmacy Manual for detailed dose calculation instructions.  
7.2.2 
CRLX301 Dose Reconstitution 
After reconstitution the total amount of CRLX301 to be injected into the IV bag 
of normal saline is determined from the assigned patient treatment cohort dose 
level as mg/m2.  
Refer to the CRLX301-101 Pharmacy Manual for detailed reconstitution 
instructions. 
CRLX301 is a conjugate of docetaxel and a linear cyclodextrin-based polymer 
(CDP).  The active drug unconjugated from the polymer is docetaxel. CRLX301 
contains a taxane antineoplastic agent, which can cause fetal harm; therefore, 
women of childbearing potential must agree to use of adequate form(s) of 
contraception.
The Sponsor will provide the study center with drug supplies. CRLX301 will be 
supplied in a single form: 20 ml single-use vials containing 25 mg of docetaxel 
equivalents (approximately 125 mg of polymer-drug conjugate). The formulation
contains mannitol as a bulking agent.  The drug is supplied in clear glass vials and
appears as a white to off-f white solid and transparent solution when reconstituted.
CRLX301 for injection is stored at refrigerated conditions (2° - 8°C) and should 
only be accessible to authorized individuals. 
Refer to the CRLX301 Investigator’s Brochure for details on CRLX301-101 drug 
product and the CRLX301-101 Pharmacy Manual for details on storage, stability, 
reconstitution, preparation, handling, administration and accountability.
After reconstitution the total amount of CRLX301 to be injected into the IV bag 
of normal saline is determined from the assigned patient treatment cohort dose 
/m2. 
level as mg/m
Refer to the CRLX301-101 Pharmacy Manual for detailed reconstitution 
instructions.


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7.2.3 
CRLX301 Administration 
Allowable exceptions for administering the CRLX301 infusion at a slower rate 
include Investigator discretion for patients who have history of infusion related 
reactions to other drug treatment(s) or who have environmental allergies (e.g., 
food, pollen).  
7.3 
Study Drug Accountability 
The PI or appropriately trained designee will maintain an accurate record of the 
receipt of the investigational products shipped by the Sponsor’s contracted drug 
distribution center, including the date and quantity received.  In addition, an 
accurate drug disposition record will be kept that specifies the amount 
administered to each patient and the date of administration.  This inventory record 
must be available for inspection at any time, and copies of this record will be 
provided to the Sponsor at the conclusion of the study.  Also at the completion of 
the study, the PI (or appropriately trained designee) will provide the Sponsor with 
a complete record of investigational product accountability. 
Empty or partially used vials of study drug will be destroyed at the study center 
per study center procedures and documentation of destruction will be reviewed by 
the Sponsor designated Study Monitor. 
All unused study drug must be accounted for by the site and verified by the 
Sponsor designated Study Monitor prior to destruction at the study center or 
returned to the appropriate depot.  Determination of destruction or return will be 
provided by the Sponsor.  


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8. 
ADVERSE EVENTS 
8.1 
Definition of Adverse Events and Adverse Reactions 
An AE is defined as any unfavorable and unintended sign (e.g., an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
drug, experienced by a patient during the clinical study or the specified safety 
follow-up period, regardless of relationship to study drug. 
An adverse reaction is any adverse event caused by a drug. 
A suspected adverse reaction is any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  
8.2 
Evaluation of Adverse Events 
The investigator will determine the seriousness, severity (intensity), and causality 
of an AE to the use of the study drug based on the definitions described below. 
8.2.1 
Serious Adverse Events (SAE) and Suspected Unexpected Serious Adverse 
Reactions (SUSAR) 
An SAE is any untoward medical occurrence that at any dose results in any of the 
following outcomes, regardless of relationship to study drug. 
Notify Sponsor via the study designated SAE Submission Line email or fax 
within 24 hours per instructions in the Investigator Site File; and document events 
on eCRF. 
Death: All deaths, regardless of cause or relationship, must be reported for 
patients on study and for deaths occurring within 30 days of last study drug dose.  
Note: Death is an outcome of an AE, and not an AE in itself. Reports of death due 
to disease progression or progressive disease must be associated with a diagnosis 
caused by progression of disease, e.g., respiratory failure. The event(s) that caused 
death (e.g., illness, accident) is the SAE. Death due to progressive disease will not 
be considered an SAE. Death due to any other cause(s) must also be reported as 
an outcome of the reportable SAE.  
Life-threatening adverse drug event: This includes any adverse drug event that 
places the patient, in the view of the investigator, at immediate risk of death from 
the reaction as it occurred (i.e., this does not include a reaction that had it 
occurred in a more severe form, might have caused death).  


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Inpatient hospitalization or prolongation of existing hospitalization: “In-
patient hospitalization” means the patient has been formally admitted to a hospital 
for medical reasons, for any length of time. This may or may not be overnight. It 
does not include presentation to and care within an emergency department. 
Complications that occur during hospitalizations are AEs. If a complication 
prolongs hospitalization, it is a SAE.  
Persistent or significant disability/ incapacity: A disability is defined as any 
substantial disruption of a person’s ability to conduct normal life functions.  
Congenital anomaly/birth defect: Includes spontaneous miscarriage, Structural 
or functional anomalies, including metabolic disorders, which are present at the 
time of birth.  
Important medical event: An event that may not result in death, be life-
threatening, or require hospitalization may be considered a serious adverse drug 
event when, based upon appropriate medical judgment, it may jeopardize the 
patient and may require medical or surgical intervention to prevent any of the 
outcomes listed in this definition or meets the criteria for a SUSAR.  
Serious unexpected serious adverse reaction (SUSAR) is any adverse event for 
which there is a reasonable possibility that the study drug caused the adverse 
event of which the specificity or severity is not consistent with those noted in the 
current protocol and/or IB, and meets one of the above criteria for serious. This 
refers to any AE that has not been previously observed, (e.g., included in the IB), 
rather than from the perspective of such an event not being anticipated from the 
pharmacological properties of the product. 
Notify sponsor via the study designated SAE Submission Line email or fax by the 
next business day. 
8.2.2 
Unexpected Suspected Adverse Reaction 
An unexpected suspected adverse reaction is any adverse event for which there is 
a reasonable possibility that the study drug caused the adverse event, the 
specificity or severity of which is not consistent with those noted in the current 
protocol and/or Investigator’s Brochure. This refers to any AE that has not been 
previously observed, rather than from the perspective of such an event not being 
anticipated from the pharmacological properties of the product. Unexpected 
suspected adverse reaction(s) which are not serious are submitted to the Sponsor 
on the Serious Adverse Event /Adverse Event of Special Interest form and noted 
as not serious.  
Notify sponsor or sponsor representative via the study designated SAE 
Submission Line email or fax the next business day; document on eCRF. 


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8.2.3 
Other Adverse Events of Special Interest 
For all patients, the following adverse events are categorized as Adverse Events 
of Special Interest (AESI) 
x infusion-related hypersensitivity reaction(s) of any Grade 
x >Grade 2 non-infective cystitis 
x >Grade 2 bilirubin, ALT, or AST elevation 
x ≥Grade 3 fluid retention (in the form of edema, pleural effusion, or weight 
gain)  
Notify sponsor or sponsor representative within 3 business days of any non-
serious AESIs by documenting on the eCRF. 
8.2.4 
Non-Serious Adverse Events  
All other AEs, not fulfilling the previous definitions, are classified as non-serious. 
Document non-serious AEs on the Adverse Event page of the case report form 
(eCRF). 
8.2.5 
Laboratory Adverse Events  
All laboratory results must be filed in the patient’s medical record and monitored. 
The Investigator or designee must review laboratory results in a timely manner 
demonstrated by signature / date and assignment of clinical significance 
assessment. Non-clinically-significant laboratory abnormalities, i.e., minor 
deviations from the normal range, are expected and it is likely that no medical 
intervention will be required. Abnormal laboratory results should not be 
considered AEs unless they are associated with a diagnosis.  
Any grade laboratory abnormality that is considered to be clinically significant by 
the Investigator will be recorded on the AE eCRF. An abnormal test result will be 
considered an AE if:  
It is not associated with an already reported AE, diagnosis, or pre-existing 
condition;  
There is a change in concomitant medication or intervention is needed, in 
direct response to a Grade 3 or 4 laboratory result;  
Investigator considers the laboratory result to be clinically significant.  
All such laboratory abnormalities should be repeated and reassessed for 
“seriousness” by the Investigator or designee as soon as possible. If a result meets 
the regulatory definition of “serious”, it should be reported as an SAE following 
regulatory and protocol requirements. Repeat laboratory tests should be 
performed regularly to monitor patient status.  


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8.2.6 
Severity of Adverse Events  
The severity of each AE will be graded by the Investigator according to the NCI-
CTCAE Version 4.03.  
For AEs not listed in the NCI-CTCAE, the following similar grading system 
should be used: 
Grade 1 Mild AE 
Grade 2 Moderate AE 
Grade 3 Severe AE 
Grade 4 Life-threatening or disabling AE 
Grade 5 Death related to AE 
Severity, which is a description of the intensity of manifestation of the AE, is 
distinct from seriousness, which implies a patient outcome or AE-required 
treatment measure associated with a threat to life or functionality.  An AE 
assessed as Grade 4 based on the NCI-CTCAE grades may or may not be assessed 
as serious based on the seriousness criteria. 
The severity rating must be recorded on the appropriate AE reporting page of the 
patient’s CRF. 
8.2.7 
Relationship to Study Drug  
The Investigator will attempt to assess the relationship of the event and record it 
as unrelated, unlikely-related, possibly related, probably related, and definitely 
related. 
Unrelated: This category applies to those AEs which, after careful medical 
consideration, are clearly felt to be due to extraneous causes (disease, 
environment, etc.) that are unrelated to the administration of study drug.  
Unlikely-related:  This category applies to those AEs which, after careful 
medical consideration, are felt unlikely to be related to the administration of the 
study drug. The relationship of an AE to the study drug can be considered 
unlikely if (must have first 2 criteria below):  
x It does not follow a reasonable temporal sequence from administration of 
the drug 
x It could readily have been a result of the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to 
the patient 
x It does not follow a known response pattern to the suspected drug 
x It does not reappear or worsen when the drug is re-administered 


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Possibly related: This category applies to AEs which, after careful medical 
consideration, are considered not likely to be related, but the possibility cannot be 
ruled out with certainty. The relationship of an AE to the study drug can be 
considered possible if (must have first 2):  
x It follows a reasonable temporal sequence from administration of the study 
drug; 
x It could readily have been a result of the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to 
the patient; 
x It follows a known response pattern to the suspected study drug. 
Probably related: This category applies to AEs which, after careful medical 
consideration, are felt with a high degree of certainty to be related to the 
administration of the study drug. The relationship of an AE to the study drug can 
be considered probable if (must have first 3 criteria below):  
x It follows a reasonable temporal sequence from administration of the drug; 
x It could not be reasonably explained by the known characteristics of the 
patient’s clinical state, environmental or toxic factors or other modes of 
therapy administered to the patient; 
x It disappears or decreases upon cessation of drug, dose delay, or dose 
reduction; 
x It follows a known response pattern to the suspected drug. 
Related: This category applies to AEs, which, after careful medical 
consideration, are felt to be related to the administration of the study drug. The 
relationship of an AE to the study drug can be considered related if (must have 
first 3 criteria below):  
x It follows a reasonable temporal sequence from administration of the drug 
or drug levels have been established in body fluids or tissues; 
x It could not be reasonably explained by the known characteristics of the 
patient’s clinical state, environmental or toxic factors or other modes of 
therapy administered to the patient; 
x It disappears or decreases upon cessation of drug, dose delay, or dose 
reduction and appears upon re-challenge; 
x It follows a known response pattern to the suspected drug. 


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8.3 
Expedited Reporting of SAEs, Patient Death and Unexpected AE 
8.3.1 
Time-Frame for Reporting  
Any SAE, unexpected (and severe) AE experienced by the patient from time of 
informed consent through 30 days after receiving the last dose of study drug, 
regardless of relationship to study drug, or any death that occurs more than 30 
days after the last dose of study drug, and is believed to be study drug-related, 
must be promptly reported within 24 hours of the Investigator becoming 
aware of the event to the study designated SAE Submission Line email or fax. 
AEs that do not meet the definition for severe or unexpected should be collected 
from the time of first dose through 30 days after the last dose of study drug. 
If a non-serious AE is reported from time of informed consent up to the first dose 
it should be recorded in medical history. 
8.3.2 
Information to be Submitted for Reportable Event 
At the time of the initial contact(s), the Investigator must report to the Medical 
Monitor information for completion of an expedited Safety Report. The Sponsor 
representative will require all of the following information about the patient and 
the event:  
x Patient identification code, gender, and age or date of birth 
x Height, weight, or body surface area (where required for dose calculation) 
x Underlying diagnosis and extent of disease 
x Lot number and expiration date of study drug  
x Dose, route, frequency, and duration of study drug administered 
x Date of study drug administration 
x Description of event, including date of onset and duration 
x Date of death (if applicable) 
x Intervention(s) required 
x Concomitant therapy (including regimen[s] and indication) 
x Pertinent laboratory data/diagnostic study (including dates) 
x Pertinent medical history 
x Study drug status (dose interrupted, discontinued) 
x Did event abate after interruption of study drug administration (if 
applicable) 
x Did event recur after study drug was reintroduced (if applicable) 


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In addition to the above information, the sponsor will require the investigator’s 
assessment of the following:  
x Severity of the AE 
x Relationship of the AE to study treatment 
x Outcome of the AE 
Study center staff must transmit an SAE report form to the Sponsor within 
24 hours of knowledge of the event, even if an initial report is made by telephone, 
as well as any relevant Pregnancy Report forms.  Refer to the Investigator Site 
File for copies of the forms and instructions for reporting to the Sponsor.  
SAE Report Forms and Pregnancy Report Forms should be submitted to the 
study designated SAE submission email or fax. 
Supplemental information should be submitted as soon as available. 
8.4 
Recording Adverse Events 
All AEs and SAEs will be recorded, evaluated, and documented by the 
Investigator on source documents and on designated eCRF pages. 
Patients are to be questioned regarding any AEs or SAEs at every scheduled and 
non-scheduled visit.  Patients will be asked to volunteer information through 
open-ended questioning.  AEs will also be identified by physical examination and 
review of laboratory results. The Investigator or designee will record all pertinent 
information on the appropriate AE reporting page of the patient’s eCRF whether 
or not they are considered causally related to the investigational product. 
The Investigator should attempt to establish a diagnosis of the AE based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should 
be documented as the AE verbatim term rather than individual signs/symptoms.  
For every AE, the Investigator must document the following: 
x Diagnosis or description of event 
x Onset date 
x Assessment of the severity 
x Assessment causal relationship to the investigational product 
x Assessment of seriousness of the event (i.e. whether it is an SAE) 
x Method of treatment taken for the AE 
x Action taken related to study drug include the following: dose 
interruption, dose delay, dose reduction, or study drug discontinuation 


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x Outcome of event and end date; all SAEs must be followed until 
resolution, patient death or until the SAE is deemed stable or irreversible 
x Phase 1 during Cycle 1 only: any event which meets the criteria as a DLT 
will be noted as such on the eCRF 
8.5 
Exposure to Study Drug during Pregnancy 
The Investigator must report any pregnancy (including the pregnancy of a male 
patient’s partner), even if no AE has occurred, on a Pregnancy Report Form 
within 24 hours of the Investigator becoming aware of the pregnancy. See the 
Investigator Site File for a copy of the form and instructions on how to submit this 
information to the Sponsor.  
Female patients who become pregnant while on the study will be immediately 
discontinued from study treatment, and complete the End-of-Study visit at 30 
days post-last dose follow-up period, reporting all AEs including any related to 
the pregnancy. In addition, the Investigator will make every attempt to confirm 
the outcome of the pregnancy and report this on a follow-up Pregnancy Report 
form.    
8.6 
End-of-Study Post-treatment Safety Follow-up  
In this study, the post-treatment safety follow-up period is defined as 30 days after 
the last dose of CRLX301.  All AEs occurring during the study period from the 
time of the first dose to the last day of the 30-day post-treatment follow-up period 
will be reported. All patients should be instructed to report AEs or SAEs 
occurring during the 30-day post-treatment safety follow-up period. 
If a patient discontinues from study drug and is planning to receive an 
investigational treatment or anti-cancer therapy prior to the 30 days post last dose 
of CRLX301 every attempt should be made to complete the End-of-Study visit 
prior to initiating other cancer treatment.  AEs that occur after the initiation of 
new cancer treatment will not be collected. 
Unresolved study drug related (see Section 8.2.7: Relationship to Study Drug for 
definition) AEs and SAEs at the time of treatment discontinuation or new study 
drug-related AEs and SAEs that occur during the 30 day post last dose follow-up 
period will be followed until they have, in opinion of the Investigator, resolved to 
baseline, stabilized, or are deemed to be irreversible.   


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9. 
EVALUATION OF ANTI-TUMOR ACTIVITY 
Tumor response evaluations will be performed by following RECIST guidelines, version 
1.1 or by alternate methodology consistent for tumor type. A patient will be considered 
evaluable for efficacy if the patient received at least 1 dose of study drug and had either: 
x a pre-study CT scan and at least 1 follow-up CT scan assessment during the study 
period. CT scan assessments should be completed every 8 - 9 weeks if possible; 
and, whenever feasible a CT scan should be repeated 4 weeks after a partial or 
complete response is observed. 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. 
x a pre-study alternative response evaluation consistent with tumor type and at least 
one follow-up alternative response evaluation during the study period. 
NOTE: the rest of this section describes evaluation of anti-tumor activity via 
RECIST1.1. If an alternative response evaluation is used, please refer to the appropriate 
criteria. For example, for prostate cancer, see reference #33 for the PCWG2 criteria. 
9.1 
Measurable Disease and Target Lesions  
9.1.1 
Measurable Disease  
Measurable lesions are defined as those that can be accurately measured in at least 
1 dimension (longest diameter to be recorded) as >20 mm by chest x-ray or as 
>10 mm with CT scan, MRI, or calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of 
centimeters).  
Tumor lesions that are situated in a previously irradiated area may or may not be 
considered measurable.  
To be considered pathologically enlarged and measurable, a malignant 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.  
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.  


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9.1.2 
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, and lend themselves to reproducible repeated measurements. It 
may be that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which case the next largest lesion that can be reproducibly 
measured should be selected. The sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions should 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 included. The baseline sum diameters will be used 
as a reference to further characterize any objective tumor regression in the 
measurable dimension of the disease.  
9.2 
Response Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have a reduction in short axis to 
<10 mm.  
Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions, using the baseline sum diameters as a reference.  
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on the study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. (Note: the appearance of 1 or more new lesions is also considered 
progression).  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient 
increase to qualify for PD, taking as a reference the smallest sum diameters while 
on the study.  
9.3 
Evaluation of Best Overall Response and Disease Control Rate 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking the smallest measurements 
recorded since the treatment started as a reference for progressive disease).  
The duration of overall response is measured from the time the measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented.  


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Duration of stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking the smallest measurements recorded since 
the treatment started, including the baseline measurements, as a reference. 
 
The objective response rate is the proportion of all patients with PR or CR, from 
the start of treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the start of 
treatment).  
 
The disease control rate is the proportion of all patients with SD for 8-9 weeks, or 
PR, or CR, from the start of treatment until disease progression/recurrence (taking 
as reference for progressive disease the smallest measurements recorded since the 
start of treatment).   
9.4 
Progression-Free Survival  
Progression-free survival (PFS) is defined as the duration of time from the start of 
treatment to the time of progression or death, whichever occurs first while on the 
study. 


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10. 
STATISTICAL METHODS 
A detailed description of analysis methods will be prepared by the Sponsor designated 
study biostatistician in the study Statistical Analysis Plan. 
Schedules 1 and 2 will be analyzed separately. As appropriate analysis for each cohort in 
Phase 1 and for each of the MTD expansion cohorts will be reported separately. For 
Schedule 2, a single MTD/RP2D will be determined, but other analyses will be reported 
separately for QW, no break cohorts and QW, 3 week on/1 week off cohorts. 
10.1 
Patient Populations 
10.1.1 Safety Population 
The Safety Population will consist of all patients who receive any amount of 
investigational product. 
10.1.2 Pharmacokinetic Analysis Population 
The PK Analysis Population will consist of all patients who receive at least part of 
1 dose of CRLX301, have at least 1 PK sample collected on Cycle 1 Day 1 or 
Week 1 Day 1 of the study, and have evaluable PK parameters.  
10.1.3 MTD and/or RP2D Population 
The MTD and/or RP2D population will include all patients treated at the MTD 
and/or RP2D for each dosing schedule from both Phase 1 and Phase 2a of the 
study.  
10.1.4 MTD and/or RP2D Efficacy Evaluable Populations 
The MTD and/or RP2D evaluable population will include all patients treated at 
the MTD/RP2D for each dosing schedule who have had tumor assessment at 
baseline and undergone at least 1 follow-up tumor assessment via imaging or 
methodologies consistent with specific tumor type.  
10.2 
Endpoints 
10.2.1 Phase 1 
The primary endpoint is the frequency of dose limiting toxicities as a function of 
CRLX301 dose. 
10.2.2 Phase 2a 
The primary endpoint is safety and tolerability, evaluated by the following parameters: 
x Type, frequency and severity of adverse event(s) 
x Laboratory parameters (hematology and chemistry, especially those associated 
with bone marrow and hepatic function) 
x Vital signs 


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x Physical examination 
x 12-lead ECG 
 
The secondary endpoints are: 
x PK parameters in plasma: area under the concentration versus time curve (AUC), 
maximum concentration (Cmax), half-life (t1/2), volume of distribution (Vd), 
clearance (CL) for both total and released docetaxel after single dose and multiple 
doses when available for each dosing schedule. 
x Efficacy measures: best overall response, duration of overall response, duration of 
stable disease, objective response rate, disease control rate, and progression free 
survival as per RECIST, version 1.1 or alternative response evaluation criteria for 
specific tumor types 
10.3 
Patient Disposition 
All enrolled patients will be listed with the cohort treatment assignment, last 
cycle/week and date, date of the End-of-Study Visit, reason for discontinuation. 
Eligibility data will be listed for each patient. 
10.4 
Demographics and Other Baseline Characteristics 
Demographic parameters (e.g., age, race, ethnicity, sex) and other baseline 
characteristics will be summarized by cohort group for the Safety Population.  
Descriptive statistics (n, mean, median, SD, minimum, and maximum) will be 
presented for continuous variables.  Frequency distributions (counts and 
percentages) will be presented for categorical variables. 
Medical history and pregnancy test data will be listed for all patients. 
10.5 
Protocol Deviations 
Individual listings for protocol deviations will be presented for each subject.  
Protocol deviations will be summarized using the Safety Analysis Population. 
10.6 
Extent of Exposure and Treatment Compliance 
Exposure of the Safety Population to the investigational product during the study 
period will be summarized for treatment duration, calculated as the number of 
days from the date of the first dose of investigational product taken to the date of 
the last dose taken, inclusive.  Descriptive statistics (n, mean, median, SD, 
minimum, and maximum) will be presented. 
The intravenous infusion start time, stop time, and volume infused will be 
recorded.  Treatment compliance will not be calculated. 


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10.7 
Efficacy Analyses 
Exploratory analyses of efficacy will be undertaken by evaluating the RECIST 
findings or by alternative response evaluations for specific tumor types. All 
RECIST findings for target lesions or specific tumor type response evaluations 
will be listed. In addition, the following parameters will be determined: 
x Best overall response 
x Duration of overall response 
x Duration of stable disease 
x Objective response rate  
x Disease control rate 
x Progression free survival   
 
For the analysis of best overall response, objective response rate and disease control 
rate, summary tables presenting the number and proportion of responders and non-
responders, together with the two-sided 95% Pearson-Clopper confidence intervals 
for response rates will be produced.   
The analysis of time to event endpoints, such as duration of overall response, 
duration of stable disease, and progression free survival, will be based on the 
survival function, which is the probability to stay event-free beyond a certain point 
in time. The survival function will be estimated by the Kaplan-Meier method. The 
survival function will be summarized for 25th percentile, median, and 75th percentile 
and their 95% confidence intervals. The plot of Kaplan-Meier estimates of survival 
functions will be presented.  
 
10.8 
Pharmacokinetic Analyses 
Plasma samples will be collected from all patients in Phase 1 and a subset of 
patients in Phase 2a to evaluate the PK of total and unconjugated docetaxel in 
plasma. PK parameters will be calculated using noncompartmental analysis with 
the software program WinNonlin (version 15.3 or higher).  Actual sampling times 
will be used to calculate PK parameters in this study.  The plasma PK parameters 
will include area under the concentration versus time curve (AUC), maximum 
concentration (Cmax), half-life (t1/2), volume of distribution (Vd), clearance (CL) 
for both total and unconjugated. Urine samples will be collected from patients in 
Phase 1 to evaluate the urinary excretion of total and unconjugated docetaxel. PK 
parameters in urine will include the maximum concentration (Cmax), amount of 
drug in the urine, % of drug eliminated in the urine.  
For PK data the arithmetic mean, standard deviation (SD), median, minimum, 
maximum, coefficient of variation (CV%), geometric mean and geometric 
coefficient of variation (geo CV%) values will be presented. Details of the PK 
analyses will be provided in the Statistical Analysis Plan (SAP). 


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10.9 
Safety Analyses 
The safety analysis will be performed based on the Safety Population as specified 
in the SAP.  Safety variables will include AEs, clinical laboratory parameters, 
vital signs, and ECG parameters.  For each safety parameter, the last assessment 
made before the first dose of the investigational product for each period will be 
used as the baseline for all analyses of that safety parameter. 
10.9.1 Adverse Events 
An AE (classified by preferred term) that occurs during the treatment period will 
be considered a TEAE if it was not present before the first dose of investigational 
product or if it was present before the first dose of investigational product but 
increased in severity during the treatment period.  If more than 1 AE is reported 
before the first dose of study drug and is coded to the same preferred term, the AE 
with the greatest severity will be used as the benchmark for comparison with the 
AEs that were also coded to that preferred term and that occurred during the 
period.  An AE that occurs more than 30 days after the last dose of investigational 
product will not be counted as a TEAE, unless recommended by the Safety 
Medical Monitor or Investigator. 
The number and percentage of patients reporting TEAEs by cohort will be 
tabulated by system organ class and preferred term; by system organ class, 
preferred term, and severity; and by system organ class, preferred term, and 
relationship to the investigational product.  If more than 1 AE is coded to the 
same preferred term for the same patient, the patient will be counted only once for 
that preferred term using the most severe and most related occurrence for the 
summarization by severity and by relationship to the investigational product. 
Listings will be presented for patients with SAEs and patients with AEs leading to 
discontinuation.  A listing of all AEs by patient will also be presented. 
10.9.2 Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values and changes from the baseline 
values will be presented by cohort for each clinical laboratory parameter. 
The number and percentage of patients who have post-baseline potentially 
clinically significant (PCS) clinical laboratory values will be tabulated by cohort.  
The criteria for PCS laboratory values will be detailed in the SAP.  The 
percentages will be calculated relative to the number of patients who have 
available non-PCS baseline values and at least 1 post-baseline assessment.  The 
numerator will be the total number of patients with available non-PCS baseline 
values and at least 1 post-baseline PCS value.  A supportive listing of patients 
with post-baseline PCS values will be provided, including the patient number and 
baseline and post-baseline values by cohort for the Safety Population. 
Urinalysis and Coagulation results will be listed by patient. 


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10.9.3 ECOG 
Descriptive statistics for ECOG performance at baseline (pre-study) and changes 
from pre-study to End-of-Study will be presented by cohort.   
10.9.4 Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic BP, pulse rate, weight, 
respiration rate, and temperature) at baseline (pre-study) and changes from pre-
study to End-of-Study will be presented by cohort.  Descriptive statistics for 
interim vital signs (systolic and diastolic BP, pulse rate) during the PK profiling 
period (time between first dose of investigational product and the End-of-Study) 
at baseline (pre-dose) and changes from baseline at post-dose will be presented by 
cohort. 
Vital sign values will be considered to be PCS if they meet both the observed 
value criteria and the change from baseline value criteria that will be detailed in 
the SAP. The incidence of PCS values will be presented. The percentages will be 
calculated relative to the number of patients who have baseline values and at least 
1 post-baseline assessment.  The numerator will be the total number of patients 
with at least 1 PCS post-baseline value. For the Safety Population, a supportive 
listing of patients with PCS post-baseline values will be provided, including the 
patient number and baseline and post-baseline values, by cohort for pre-Study and 
End-of-Study assessments and by treatment for assessments during the PK 
profiling period. 
10.9.5 Electrocardiograms 
Descriptive statistics for ECG parameters (HR, PR interval, QRS duration, 
QT interval, and QTc) will be reported. 
10.9.6 Physical Examination 
Individual data listings for physical examination results will be presented for each 
subject. 
10.9.7 Weight and Height 
Weight, height, BMI and BSA will be listed and summarized by cohort. 
10.9.8 Prior and Concomitant Medication 
Prior medication will be defined as any medication taken within 14 days prior to 
the first dose of the study drug and stopped prior to the first dose of study drug.   
Concomitant medication will be defined as any medication taken during the study 
between the date of the first dose of study drug and the date of the End-of-Study 
Visit.  Any medications started after the End-of-Study Visit will not be considered 
concomitant medications. 


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Individual data listings will be presented for each subject, with separate listings 
for prior medications and concomitant medications.  In addition, concomitant 
medications will be summarized by Anatomical Therapeutic Chemical (ATC) 
classes and PT using frequency counts and percentages.  For the summaries of 
concomitant medications, subjects who take the same medication (in terms of PT) 
more than once will be counted only once for that medication. 
10.10 Biomarker and Pharmacodynamic Exploratory Analyses 
Descriptive statistics will be provided depending on the available data from 
evaluation of biomarker samples, available tumor biopsies and archived tissue 
samples for presence of study drug in the samples. 
Analyses and parameters will be detailed in the SAP. 
10.11 Interim Analysis 
No interim analysis is planned for this study. 
10.12 Missing data 
Missing data will not be imputed for this study. 
 


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11. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
If any amendments to this protocol are necessary, the Sponsor will propose them in 
writing to the Investigator.  Any amendments proposed by the Investigator will be 
reviewed and approved by the Sponsor prior to submission for IRB review and 
implementation.  No protocol amendment may be implemented (with the exceptions 
noted below) before it has been submitted to the Regulatory Agency and approved by the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC).  In addition the 
Investigator signature page must be signed and submitted to the Sponsor. 
If the protocol is amended to eliminate or reduce the risk to patients, the amendment may 
be implemented before IRB/IEC review and approval.  However, the IRB/IEC must be 
informed in writing of such an amendment, and approval must be obtained within 
reasonable time limits. 
Protocol waivers will be allowed only in extremely rare circumstances where patient 
benefit is established and there is complete agreement between the Investigator and the 
Sponsor. 
Protocol deviations brought to the attention of the Sponsor after their occurrence will 
only be recognized and assessed for ethical, medical, scientific, and regulatory 
implications and for impact on the patient’s participation in the study, and will be 
documented.  Such deviations cannot be waived. 
Protocol violations (which are deviations that have a major impact on the patient’s rights, 
safety, or well-being or the integrity and authenticity of the study data) can never be 
waived. 


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12. 
ETHICAL CONSIDERATIONS 
This study will be performed in accordance with the protocol, the Declaration of 
Helsinki, the International Conference on Harmonization (ICH) Harmonized Tripartite 
Guideline for GCP, and all applicable local regulatory requirements.  The study will be 
conducted in full compliance with Therapeutic Goods Administration (TGA)/ United 
States Food and Drug Administration(FDA) guidelines for GCP and in accordance with 
the ethical principles that have their origins in the Declaration of Helsinki and 21 CFR 
§312.120. 
12.1 
Independent Ethics Committee / Institutional Review Board  
It is the responsibility of the Investigator to obtain the approval of the IEC / IRB 
before the start of the study. A copy of the approval letter will be supplied to the 
Sponsor, along with a roster of IEC / IRB members.  During the course of the 
study, the Investigator or designee will provide timely and accurate reports to the 
IEC / IRB on the progress of the study at appropriate intervals (not to exceed 
1 year) and at the completion of the study.  Investigator or designee will notify the 
IEC / IRB of serious AEs (SAEs) or other important safety findings.  The study 
protocol, informed consent form (ICF), information sheet advertisements (if any), 
and amendments (if any) will be approved by the IRB at each study center in 
conformance CFR, Title 21, Part 56.  
12.2 
Patient Information and Consent 
Before the start of any study-related procedures are undertaken, the Investigator 
or designee must obtain written, informed consent from each patient  in 
accordance with US federal regulations (21 CFR §50) and the ICH document 
“Guidance for Industry – E6 Good Clinical Practice: Consolidated Guidance”.  
Informed consent will be obtained by discussing with the patient the purpose of 
the study, the risks and benefits, the study procedures, and any other information 
relevant to the patient. 
The Investigator or designee must explain to the patient that for purposes of 
evaluating the study results, that patient’s private health information obtained 
during the study may be shared with the Sponsor, regulatory agencies, and IECs / 
IRBs, before enrolling that patient into the study.  It is the US Investigator’s (or 
designee’s) responsibility to obtain permission to use private health information 
per the Health Information Portability and Accountability Act (HIPAA) from each 
patient, or if appropriate, the patient’s legal representative. 
The patient or his/her legal representative will document his/her informed consent 
by signing the current version of the written, IRB-approved ICF.  The person who 
conducted the informed consent discussion with the patient and/or patient’s legal 
representative (if applicable) must also sign the ICF. The patient is given a fully 
executed copy of the ICF bearing all appropriate signatures, and the original must 
be maintained in the clinical master files at the site. 


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The Investigator, or designee, is responsible for the content of the ICF, but the 
original and any updated versions must be approved by the Sponsor prior to 
submission to the IRB/IEC.  The ICF should also include any additional 
information required by local laws relating to institutional review.  All active 
patients participating on the protocol must be re-consented each time the ICF is 
updated and re-approved by the IRB/IEC. 


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13. 
STUDY MANAGEMENT AND INVESTIGATOR OBLIGATIONS 
13.1 
Principal Investigator and Clinical Sites 
The Principal Investigator (PI) at each study center (clinical site) will be responsible for 
ensuring that the investigation is conducted according to the signed Investigator’s 
statement, the protocol, and ICH GCP guidelines. 
The Principal Investigator at each clinical site will be responsible for the management of 
the study, which will include but not be limited to oversight of other designated study 
Investigators and study staff conducting any activities related to the study, maintenance 
of the study file and patient records, correspondence with the IRB, and completion of the 
electronic case report forms (eCRFs). 
13.2 
Study Safety Review Committee 
Members: The Investigators, Sponsor representative, Sponsor designated Medical 
Monitor and Sponsor designated PK expert will comprise the Study Safety Review 
Committee (SRC).  
A description of this committee’s role is defined in Section 3.1.6: Study Safety Review 
Committee. 
13.3 
Data Monitoring 
Before the first patient is dosed in the study, a Sponsor representative will meet with the 
Investigator and clinical site study staff to review the procedures for conducting the study 
and to train the staff on recording the data on the eCRFs using the electronic data 
capture (EDC) system.  The Sponsor representative will periodically monitor the progress 
of the study by conducting on-site visits.  The Sponsor representative will also be able to 
review query statuses remotely, which may warrant more frequent communication with 
the Investigators and clinical site study staff.   
The Investigator will make available to the Sponsor representative the source documents, 
the signed consent forms, all other study-related documents, and the computer that 
accesses the eCRFs.  The Investigator or designee will be responsible for reviewing 
eCRFs, resolving data queries generated by the Sponsor via the system, providing 
missing or corrected data, approving all changes to the data, and endorsing the patient 
data within the EDC system.  This approval method will include applying an electronic 
signature, a uniquely assigned username and a password that together will represent a 
traditional handwritten signature. 


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13.4 
Data Recording and Documentation 
Data collection will involve the use of the Sponsor EDC system, to which only 
authorized personnel will have access.  In addition to periodic monitoring 
occurring within the system by Sponsor personnel, programmatic edit checks will 
be used to review the data for completeness, logic, and adherence to study 
protocol.  As a result of this monitoring and these checks, queries may be issued 
electronically to the clinical study center and answered electronically by that 
study center.  The identifying information (assigned username, date, and time) for 
both the originator of the query (if created during the monitoring process) and the 
originator of the data change (if applicable), as well as the Investigator’s approval 
of all changes performed on his or her patients’ data, will be collected. 
All data collected in the context of this study will be stored and evaluated 
according to regulatory requirements and applicable guidance for electronic 
records.  Data will be stored and evaluated in such a way as to guarantee patient 
confidentiality in accordance with the legal stipulations applying to 
confidentiality of data.  Study records (e.g., copies of eCRFs, regulatory 
documents, etc.) will be retained at the study center, along with adequate source 
documentation, according to FDA and ICH requirements.  All study records must 
be available for inspection by the Sponsor, its authorized representatives, and 
FDA officials. 
13.5 
Retention and Review of Records 
The PI must maintain the documentation relating to this study.  If the Sponsor, the 
FDA, or another regulatory authority wishes to review any documentation relating 
to the study, the PI must permit access to such records. 
The PI must retain a copy of all records that support the CRFs for this study (e.g., 
ICFs, clinical laboratory reports, source documents, investigational product 
dispensing records) for a period of at least 15 years after study completion unless 
local regulations or study center policies require a longer retention period or 
otherwise notified in writing by the Sponsor.  
If the PI retires, relocates, or for other reasons withdraws from the responsibility 
of keeping the study records, custody must be transferred to a suitable alternate 
custodian employee of the study center or to a suitably qualified and responsible 
third party.  The Sponsor must be notified in writing of the name and address of 
the new custodian before such transfer is made.  
No study records shall be destroyed without notifying and giving the Sponsor the 
opportunity to arrange long-term storage for such study records or to authorize in 
writing the destruction of records after the required retention period. 


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13.6 
Patient Confidentiality 
All patient records will only be identifiable by a unique patient identification 
number.  Patients’ names or identifying information other than the data as 
specified for the eCRF collection are not to be transmitted to the Sponsor. The PI 
will keep a master patient list on which the patient number and full name, address, 
and telephone number of each patient are listed. 
 


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14. 
STUDY SPONSORSHIP 
The Sponsor for this study is: 
 
CERULEAN PHARMA AUSTRALIA PTY LTD 
c/o Baker & McKenzie 
Level 27, AMP Centre 
50 Bridge Street  
Sydney, New South Wales, 2000 
Australia  
www.ceruleanrx.com 
 
Cerulean Pharma Inc. (parent company) 
35 Gatehouse Drive 
Waltham MA USA 02451 
Main: 781-996-4300 
 
The Sponsor Medical Director and contact person is: 
Adrian Senderowicz, MD 
CMO, SVP 
Cerulean Pharma  
Email: ASenderowicz@ceruleanrx.com 
 
The Sponsor Back-up Medical Director and contact person is: 
 
Jian Li, MD 
Cerulean Pharma 
Email: JLi@ceruleanrx.com 
 
14.1 
Study Audits and Inspections 
The study may be evaluated by the Sponsor and/or designees and government 
inspectors who must be allowed access to eCRFs, source documents, and other 
study files. Sponsor audit reports will be kept confidential. The Investigator 
should promptly notify Sponsor of any audits scheduled by any regulatory 
authorities, and promptly forward copies of audit reports. 
14.2 
Study Termination 
The Sponsor reserves the right to terminate the study in its entirety or at a specific 
study center at any time. 
14.3 
Reporting and Publication 
All data generated in this study will be the property of the Sponsor.  An integrated 
clinical and statistical report will be prepared at the completion of the study. 
c/o Baker & McKenzie
Level 27, AMP Centre
50 Bridge Street 
Sydney, New South Wales, 2000
Australia 
www.ceruleanrx.com
35 Gatehouse Drive
Waltham MA USA 02451
Main: 781-996-4300
Adrian Senderowicz, MD
CMO, SVP
Cerulean Pharma 
Email: ASenderowicz@ceruleanrx.com
Jian Li, MD
Cerulean Pharma
Email: JLi@ceruleanrx.com


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Publication of the results by the Investigators will be subject to the signed 
contractual agreement between the PI and the Sponsor. 
 
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APPENDICES 
APPENDIX A   
ECOG Performance Status 
Level 
ECOG* 
0 
Normal activity 
1 
Symptoms but ambulatory 
2 
In bed <50% of time 
3 
In bed >50 % of time 
4 
100 % bedridden 
5 
Dead 
 
* As published in American Journal of Clinical Oncology: 
Oken M, Creech RH, Tormey DC, Horton J, Davis TE, McFadden E, Carbone PP. Toxicity and 
response criteria of the eastern cooperative oncology group.  Am J Clin Oncol. (CCT) 1982; 
5:649-655. 
 
Credit to Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair 
 


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Protocol No.: CRLX301-101 
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AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
APPENDIX B   
National Cancer Institute’s Common Terminology Criteria for Adverse Events 
NCI-CTCAE Version 4.03 
 
 
NCI Common Terminology Criteria for Adverse Events (CTCAE) v.4 data files and related 
documents can be accessed at: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
The quick reference document for version 4.03 can be accessed at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 
 


Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc. 
Protocol No.: CRLX301-101 
Page 131 of 133  
AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
APPENDIX C   
CYP3A Inhibitors 
 
http://www.straighthealthcare.com/cytochrome-p450-3a4.html 
 
x 
CYP3A STRONG INHIBITORS 
o Boceprevir (Victrelis®) [7,9] 
o Clarithromycin (Biaxin®) [1,9] 
o Cobicistat (part of Stribild®) [7] 
o Conivaptan (Vaprisol®)  [9] 
o Fluvoxamine (Luvox®) - likely a strong inhibitor [7] 
o Grapefruit Juice (in large amounts, > 1 liter a day, and in high concentrations) [9] 
o Indinavir (Crixivan®) [1,9] 
o Itraconazole (Sporanox®) [1,9] 
o Ketoconazole (Nizoral®) [1,9] 
o Lopinavir and Ritonavir (Kaletra®) [9] 
o Nefazodone (Serzone®) [1,9] 
o Nelfinavir (Viracept®) [1,9] 
o Posaconazole (Noxafil®) [9] 
o Quinupristin (Synercid®) [7] 
o Ritonavir (Norvir®, Viekira Pak™) [7, 9] 
o Saquinavir (Invirase®) [9]  
o Telaprevir (Incivek®) [7,9]   
o Telithromycin (Ketek®) [1,9] 
o Voriconazole (Vfend®) [7,9] 
 
x 
CYP3A MODERATE INHIBITORS 
o Aprepitant (Emend®) [9] 
o Atazanavir (Reyataz®) [7,9] 
o Ciprofloxacin (Cipro®) [9] 
o Darunavir (Prezista®) [9] 
o Diltiazem (Cardizem®, Cartia®, etc) [5,9] 
o Dronedarone (Multaq®) [7] 
o Erythromycin (E.E.S.®, Ery-Tab®, etc) [9] 
o Fluconazole (Diflucan®) [9] 
o Fosamprenavir (Lexiva®) 
o Grapefruit Juice (in lower concentrations and smaller amounts) [9] 
o Imatinib (Gleevec®) [9] 
o Verapamil (Calan®, Covera-HS®, Verelan®, etc) [9] 
 
x 
CYP3A WEAK INHIBITORS 


Cerulean Pharma Australia Pty Ltd / Cerulean Pharma Inc. 
Protocol No.: CRLX301-101 
Page 132 of 133  
AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
o Alprazolam (Xanax®) [9] 
o Amiodarone (Cordarone®) [9] 
o Amlodipine (Norvasc®) [9] 
o Atorvastatin (Lipitor®) [6,9] 
o Bicalutamide (Casodex®) [9] 
o Cilostazol (Pletal®) [9] 
o Cimetidine (Tagamet®) [9] 
o Cyclosporine (Neoral®,etc) [9] 
o Dihydroergotamine (DHE-45®, Migranal®) [5,7] 
o Ergotamine (Cafergot®) [5,7] 
o Fluoxetine (Prozac®) [9] 
o Ginkgo (supplement) [9] 
o Goldenseal (Hydrastis canadensis, root) [9] 
o Imipramine (Tofranil®) [11] 
o Isoniazid [9] 
o Nilotinib (Tasigna®) [9] 
o Oral contraceptives [9] 
o Ranitidine (Zantac®) [9] 
o Ranolazine (Ranexa®) [9] 
o Tipranavir (Aptivus®) [9] 
o Zileuton (Zyflo®) [9] 
 
x 
CYP3A INHIBITORS (CLASS UNCERTAIN) 
o Azithromycin (Zithromax®) [5] 
o Bromocriptine (Cycloset®, Parlodel®) [7] 
o Chloramphenicol [2] 
o Delavirdine (Rescriptor®) [7] 
o Desipramine (Norpramin ®) [5] 
o Danazol [5] 
o Felodipine (Plendil®) [5] 
o Iloperidone (Fanapt®) - in vitro studies only [7] 
o Linagliptin (Tradjenta®) [7] 
o Nicardipine (Cardene®) [5] 
o Nifedipine (Adalat®, Procardia®, etc) [7] 
o Quinidine [5] 
o Simeprevir (Olysio®) - intestinal CYP3A4 inhibitor [7] 
o Zafirlukast (Accolate®) (in vitro data only) [7] 
x 
1 - Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine 
(2007). http://medicine.iupui.edu/clinpharm/ddis/table.aspx. Accessed [2011]. 
x 
2 - SuperCYP website 
x 
3 - PMID 9884161 
x 
4 - PMID 12011477 


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Protocol No.: CRLX301-101 
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AMENDMENT 9   DATE: 16DEC2016 
CONFIDENTIAL 
x 
5 - PMID 18043468 - big 3a chart 
x 
6 - PMID 21182938 
x 
7 - Manufacturer's Package Insert (for drug labeled) 
x 
8 - PMID 19074530 
x 
9 - FDA drug development and drug interactions  
x 
10 - PMID 15557548 
x 
11 - PMID 17471183 
x 
12 - PMID 18505790 
 

SAP_001.pdf: 
Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
STATISTICAL ANALYSIS PLAN
PHASE 1/2A DOSE-ESCALATION STUDY OF CRLX301 IN PATIENTS WITH ADVANCED
SOLID TUMOR MALIGNANCIES
Protocol No.: CRLX301-101
Product Code: CRLX301
PREPARED FOR:
NewLink Genetics Corporation
2503 South Loop Drive, Suite 5100
Ames, IA 50010

PREPARED BY:
Novotech (Australia) Pty Ltd
Level 3, 235 Pyrmont Street
Pyrmont, NSW, 2009
Australia
DATE OF ISSUE:
22 June 2017
VERSION/STATUS:
Final Version 1.0
VERSION DATE:
22 June 2017
AUTHOR:
Stephan Mynhardt
p
2503 South Loop Drive, Suite 5100
Ames, IA 50010
p
(
)
y
Level 3, 235 Pyrmont Street
Pyrmont, NSW, 2009
,
y
Australia
y
,




Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
Table of contents 
List of Abbreviations ....................................................................................................... 5
1. Introduction ................................................................................................................ 6
2. Project Overview ........................................................................................................ 6
2.1. Description of the Study Design ..................................................................................... 6
2.1.1. Phase 1 Dose Escalation Study............................................................................................... 6
2.1.2. Phase 2a Expansion Study ..................................................................................................... 8
2.2. Objectives ....................................................................................................................... 9
2.2.1. Primary Objective .................................................................................................................. 9
2.2.2. Secondary Objectives ............................................................................................................. 9
2.2.3. Exploratory Objectives ........................................................................................................... 9
2.3. Sample Size ..................................................................................................................... 9
2.4. Assignment of Subjects to Treatment Groups ............................................................... 9
3. Statistical Considerations ......................................................................................... 10
3.1.General Considerations ................................................................................................. 10
3.2.Key Definitions............................................................................................................... 11
3.3.Handling of Data Following Protocol Amendment 9 ..................................................... 11
3.4.Hypothesis Testing ........................................................................................................ 11
3.5.Multiple Comparisons and Multiplicity Adjustments. ................................................... 12
3.6.Handling of Missing Data............................................................................................... 12
3.7.Coding of Events and Medications ................................................................................ 12
3.8.Treatment Group and Visit Display Conventions .......................................................... 12
4. Analysis Populations ................................................................................................ 13
4.1. Population Descriptions ............................................................................................... 13
4.1.1. Safety Analysis Population ................................................................................................... 13
4.1.2. Pharmacokinetic Analysis Population .................................................................................. 13
4.1.3. MTD and/or RP2D Population ............................................................................................. 13
4.1.4. MTD and/or RP2D Efficacy Evaluable Population ................................................................ 13
5. Patient Disposition and Analysis Populations .......................................................... 13
5.1. Patient Disposition ....................................................................................................... 13
5.2. Analysis Populations ..................................................................................................... 13
6. Protocol Deviations .................................................................................................. 14
7. Demographic and Baseline Information .................................................................. 14
7.1. Demographics and Baseline Data ................................................................................. 14
7.2. Oncology History .......................................................................................................... 14
7.3. Medical History ............................................................................................................. 14
7.4. Prior Anti-Neoplastic Treatment .................................................................................. 14
7.5. Echocardiogram (ECHO) and Multiple Gated Acquisition (MUGA) Scan Results ......... 14
7.6. Head Computed Tomography (CT)/ Magnetic Resonance Imaging (MRI) Scan Results14


Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
7.7. Pregnancy Test Results ................................................................................................. 15
7.8. Patient Eligibility ........................................................................................................... 15
7.9. Assignment to Treatment ............................................................................................. 15
8. Study Drug Administration and Extent of Exposure ................................................. 15
9. Efficacy ..................................................................................................................... 15
9.1. Best Overall Response .................................................................................................. 15
9.1.1. Biostatistical Methods ......................................................................................................... 16
9.2. Other Efficacy Data ....................................................................................................... 16
10. Safety ..................................................................................................................... 16
10.1. Adverse Events ........................................................................................................... 16
10.1.1. Biostatistical Methods ....................................................................................................... 16
10.2. Safety Laboratory Assessments .................................................................................. 18
10.2.1. Biostatistical Methods ....................................................................................................... 19
10.3. Vital Signs Measurements .......................................................................................... 20
10.3.1. Biostatistical Methods ....................................................................................................... 20
10.4. Echocardiogram (ECG) Measurements ...................................................................... 21
10.4.1. Biostatistical Methods ....................................................................................................... 21
10.5. Eastern Cooperative Oncology Group (ECOG) Performance Status .......................... 22
10.5.1. Biostatistical Methods ....................................................................................................... 22
10.6. Concomitant Medications .......................................................................................... 22
10.6.1. Biostatistical Methods ....................................................................................................... 22
11. Pharmacokinetic Concentrations ........................................................................... 23
12. Changes to the Planned Analysis ........................................................................... 23
13. Interim and Final Analysis ...................................................................................... 23
13.1. Interim Analyses ......................................................................................................... 23
13.2. Final Analysis (End of Study) ....................................................................................... 23
14. Software ................................................................................................................. 23
15. Tables ..................................................................................................................... 24
16. Listings ................................................................................................................... 25



Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
List of Abbreviations
Abbreviation
Description
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase 
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CRPS
Castration Resistant Prostate Cancer 
CSR
Clinical Study Report
CT
Computed Tomography 
CTCS
Circulating Tumor Cells 
DBP
Diastolic Blood Pressure
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram 
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group 
ECRF
Electronic Case Report Form
ICH GCP
International Conference on Harmonization of Good Clinical Practice Guidelines 
INR
International Normalized Ratio
IV
Intravenous
LDH
Lactate Dehydrogenase 
MEDDRA
Medical Dictionary for Regulatory Activities
MPS
Mononuclear Phagocyte System
MRI
Magnetic Resonance Imaging 
MTD
Maximum Tolerated Dose
MUGA
Multiple Gated Acquisition 
PD
Pharmacodynamic
PK
Pharmacokinetic
PSA
Prostate-Specific Antigen 
PT
Preferred Term
PT
Prothrombin Time 
PTT
Partial Thromboplastin Time 
QW
Weekly Dosing
Q3W
Dosing Every 3 Weeks
RBC
Red Blood Cells
RECIST
Response Evaluation Criteria In Solid Tumors
RP2D
Recommended Phase 2 Dose 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Standard Deviation
S.I.
International System of Units
SOC
System Organ Class
SOP
Standard Operating Procedure
SRC
Safety Review Committee
TEAE
Treatment Emergent Adverse Event
WBC
White Blood Cells
WHO-DD
World Health Organization Drug Dictionary


Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
1.Introduction
The following Statistical Analysis Plan (SAP) provides the outline for the statistical analysis
of the data from the CRLX301-101 study (protocol amendment version 9 dated 16
December 2016).
The study was prematurely terminated, therefore all the analyses that were planned in the
protocol will not be performed. The purpose of this SAP is to describe the analyses that
will be included in the abbreviated clinical study report (CSR).
2.Project Overview
2.1.Description of the Study Design
This is a phase 1/2a, open-label, dose-escalation study of CRLX301 in patients with advanced
solid tumor malignancies that will be conducted in two phases.
Up to 134 patients will be enrolled into the study: Up to 66 patients into Phase 1 and up to 68
patients into Phase 2a. The exact number of patients will depend on the actual number of
cohorts that are enrolled, and the actual number of patients enrolled into each cohort.
The following schematic provides and overview of the study design.
Study Schematic
2.1.1.Phase 1 Dose Escalation Study
Phase 1 of the study is an open-label, dose-escalation study examining two separate dosing
schedules to determine the maximum tolerated dose (MTD)/recommended Phase 2 dose
(RP2D) of CRLX301 when administered by intravenous (IV) infusion.
The MTD is defined as the highest dose level at which fewer than two of six patients in a Phase
1 dose escalation cohort experiences a dose limiting toxicity (DLT) during the first three weeks
of treatment. A DLT is defined as any adverse event (AE) that is possibly, probably, or related
to CRLX301 that results in an unacceptable toxicity (refer to Section 3.1.3 of the Protocol) and
occurs at any point during the first three weeks of treatment post-initiation of the study drug
infusion.
The RP2D is defined as the dose which will be assigned in Phase 2a as advised by the Safety
Review Committee (SRC) based on adverse events (AEs), anti-tumor activity of CRLX301 and
available pharmacokinetic (PK) and pharmacodynamic (PD) data.  The RP2D may be the same
as the MTD dose level or it may be lower. The RP2D may not exceed the MTD.


Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
Schedule 1 (dosing every three weeks [Q3W] dosing schedule) was initiated first and
Amendment 6 incorporated Schedule 2 (weekly dosing [QW], no break dosing schedule).
Amendment 9 altered Schedule 2 to a once weekly, three week on/one week off schedule for
Cohorts 3 and 4, with the dosing schedule for additional cohorts to be determined by the SRC.
Schedule 1 is an open-label, 1+5 (Cohorts 1 and 2) followed by classic 3+3 (all remaining
cohorts) dose-escalation design and Schedule 2 will follow the classical 3+3 design for all
cohorts.
Patients will be sequentially enrolled into cohorts and study assessment will
performed in accordance with the Schedule of Procedures (refer to the Protocol). Cohorts will
continue enrolling until the planned number of patients are enrolled, or until the DLT criteria are
met, in which case the cohort will be expanded to the maximum planned number of patients.
Patients will remain on study treatment until they experience progression of disease (unless
there is evidence of clinical benefit and the investigator believes it is in the patient’s best interest
to continue the study drug treatment), unacceptable toxicity, or any other specified reason for
discontinuation (refer to Section 6.1 of the Protocol).
The following tables give an overview of the planned dose levels and patient numbers for the
two schedules.
Table 1: Schedule 1 Q3W Provisional Dose Escalation Scheme
Cohort
Dose Level
Number of Patients 
initially plus additional 
expansion if DLTs
Actual Enrollment as 
of Amendment 7
1
7.5 mg/m2
1 to 6
1
2
15 mg/m2
1 to 6
1
3*
30* mg/m2
3 to 6
3
4*
45* mg/m2
3 to 6
0*
5
60 mg/m2
3 to 6
3
6
75 mg/m2
3 to 6
6
7
90 mg/m2
3 to 6
6
8
105 mg/m2
3 to 6
Cohorts will not be 
open as MTD/RP2D 
selected as 75mg/m2
9
120 mg/m2
3 to 6
10 and 
Additional 
Cohorts
135 mg/m2 Increase dose 
levels by 15 mg/m2 for 
additional cohorts (i.e. 
150 mg/m2, etc.)
3 to 6
*SRC is allowed to dose escalate from 30 mg/m2 to as high as 60 mg/m2.  No other planned dose level cohorts may
be skipped during Phase 1.


Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
Table 2: Schedule 2 QW Provisional Dose Escalation Scheme
Cohort
Proposed Dose Level*
Number of Patients initially plus 
additional expansion if DLTs
-1
20 mg/m2
Only if starting dose level not 
tolerated
3 to 6
1
25 mg/m2
3 to 6
2
35 mg/m2
3 to 6
3**
45 mg/m2
3 to 6
4**
54 mg/m2
3 to 6
Additional Cohorts**
Increase dose levels by 5 mg/m2
or otherwise recommended by 
SRC based on available safety 
and PK data (dose increment to 
the next higher dose level will 
not exceed 20%)
3 to 6
*SRC is allowed to dose escalate by as much as 40% (total over 3 weeks) for doses below 50mg/m2 and by 20%
(total over 3 weeks) for dose levels above 50mg/m2.
** As of Amendment 9, for patients still receiving treatment in Schedule 2 Cohort 3, and for patients enrolled in
Schedule 2 Cohort 4, dosing will be on a weekly, 3 week on/1 week off schedule. The dosing schedule for additional
Schedule 2 cohorts will be determined by the SRC.
2.1.2.Phase 2a Expansion Study
Phase 2a will be an open-label RP2D expansion study.
Up to an additional 68 patients with advanced, histologically confirmed solid tumor
malignancies will be enrolled in the Phase 2a expansion cohorts inclusive of Stage 1 (up to 32
patients) and Stage 2 (up to 36 patients). Enrollment will be limited to up to five specific tumor
types.
Patients will be followed for safety, tumor response, and progression free survival while on the
study per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines or
with methodologies consistent with the specific tumor type. Treatment guidelines for the RP2D
expansion cohorts will be the same as those for the Phase 1 dose expansion cohorts.
Phase 2a Stage 1 Expansion
Once either of the dosing schedules confirms the MTD from Phase 1 and the sponsor confirms
that all required pharmacodynamic assays are ready, Phase 2a Stage 1 will initiate. This will
be an expansion of up to 16 patients for each dose schedule at the RP2D. Up to five specific
tumor types will be selected and only patients with the selected tumor types may enroll into
Phase 2a Stage 1. At the time of Amendment 8, taxane naïve (unless approved by Sponsor)
castration resistant prostate cancer (CRPC) has been selected as one of the indications for
Ph2a Stage 1. Enrollment cap will be contingent upon enrolling at least six patients of the
same indication (e.g. CRPC who are taxane naïve) and observation rates of anti-tumor activity.
All sites will be notified of the select tumor type(s) in advance of initiating Stage 1. Due to
shipping and processing requirements for circulating tumor cells (CTCs) and mononuclear
phagocyte system (MPS) function (both of which require freshly collected whole blood
samples) only US sites will enroll patients in Stage 1.
Phase 2a Stage 2 Expansion
Once both dosing schedules complete Phase 2a Stage 1, an optimal dosing schedule will be
selected based on available safety and efficacy signals, PK and available PD data from both


Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
schedules.
Further refinement of the RP2D may also be explored.
Phase 2a Stage 2
expansion will enroll up to 36 additional patients using one selected dosing schedule and
RP2D. Up to five specific tumor types only will be allowed to enroll into Phase 2a Stage 2.
Sites in both Australia and US will enroll into Stage 2. All sites will be notified of the select
tumor types in advance of initiating Stage 2.
2.2.Objectives
2.2.1.Primary Objective
The primary objective for Phase 1 is to determine the MTD/RP2D of CRLX301 when
administered by IV infusion on Schedule 1 (Dosing Day 1 of a 21-day cycle) or Schedule 2
(QW: weekly dosing, no break or QW, 3 week on/1 week off dosing) in patients with
advanced solid tumor malignancies.
The primary objective for Phase 2a is to further establish the safety and tolerability of the
CRLX301 MTD / RP2D.
2.2.2.Secondary Objectives
The secondary objectives of the study are:
x
To evaluate the PK profile of CRLX301 (both the total drug and released
docetaxel) in plasma for both dosing schedules
x
To explore preliminary signals of efficacy for CRLX301
2.2.3.Exploratory Objectives
The exploratory objectives of the trial are:
x
To evaluate the pharmacodynamic activity of CRLX301 in blood and tumor biopsy
specimens when available from patients
x
To explore possible correlations between clinical response, toxicities and biomarkers
x
To explore the PK profile of CRLX301 (both the total drug and released docetaxel) in
urine for both dosing schedules
x
To explore potential factors affecting potential inter- and intra-patient PK variability
and the preliminary relationship between response and the exposure to total and
unconjugated docetaxel in plasma and urine.
2.3.Sample Size
No formal sample size calculations were performed.
In total, up to 134 patients (Phase 1: 66 patients and Phase 2a: 68 patients) were planned
to be enrolled into the study. The exact number of patients will depend on the actual number
of cohorts that are enrolled, and the actual number of patients enrolled into each cohort.
2.4.Assignment of Subjects to Treatment Groups
This is an open-label, non-randomised study and no attempts will be made to mask the
treatment that patients will receive.  Patients will be enrolled sequentially and will be aware of
the cohort into which they are enrolled.
For Phase 1, the patient dosing schedule, cohort and corresponding dose level assignment will
be provided in writing from the Sponsor to the Investigator when the patient’s study
identification number is assigned. Protocol Amendment 9 (11th of November 2016), altered the
dosing frequency of Schedule 2, but data for all patients that were ongoing or yet to be enrolled


Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
when the amendment became effective will be analysed based on the specific dosing schedule
that the patient was enrolled to at the start of the study.
For Phase 2a, all patients will be assigned to the CRLX301 dose level that is determined to be
the RP2D (75 mg/m2 is the confirmed MTD). The patient dosing schedule will be provided in
writing from the Sponsor to the Investigator when the patient’s study identification number is
assigned.
3.Statistical Considerations
Data will be handled and processed per the sponsor representative’s (Novotech) Standard
Operating Procedures (SOPs), which are written based on the principles of Good Clinical
Practice (GCP).
3.1.General Considerations
All data collected during the study (data originating from the electronic case report forms
[eCRFs] or electronic transfers [i.e., safety laboratory, PK concentrations, etc.]) will be
presented in the data listings.
Event-based listings will be sorted by study phase,
schedule/cohort, subject number and event identifier (i.e., AE number).  Assessment-based
listings will be sorted by study phase, schedule/cohort, subject number, parameter name
(alphabetically unless specifically stated otherwise), visit and time point (if applicable).
All summary tables will present the results by study phase, schedule/dose level and overall
schedule, as applicable.
Unless otherwise stated, the following methods will be applied:
x
Continuous variables:
Descriptive statistics will include the number of non-missing
values (n), arithmetic mean, standard deviation (SD), median, minimum and maximum
values.
The minimum and maximum values will be displayed to the same decimal precision as
the source data, the arithmetic mean and median values will be displayed to one more
decimal than the source data, and the SD values will be displayed to two more decimals
than the source data for the specific variable.
The appropriate precision for derived variables will be determined based on the
precision of the data on which the derivations are based, and statistics will be presented
in accordance with the abovementioned rules.
x
Categorical variables:  Descriptive statistics will include counts and percentages per
category. The denominator in all percentage calculations will be the number of patients
in the relevant analysis population with non-missing data, unless specifically stated
otherwise.
Two-sided 95% Clopper-Pearson confidence intervals (CIs) will be
presented where appropriate.
Percentages and CIs will be rounded to one decimal place. Percentages will not be
displayed for zero counts.
x
Repeat/unscheduled assessments:
Only values collected at scheduled study
visits/time points will be presented in summary tables. If a repeat assessment was
performed, the result from the original assessment will be presented as the result at the
specific visit/time point. All collected data will be included in the data listings.
x
Assessment windows: All assessments will be included in the data listings and no visit
windows will be applied to exclude assessments that were performed outside of the
protocol specified procedure windows.
x
Result display convention:  Results will be centre-aligned in all summary tables and
listings. Subject identifiers, visit and parameter labels may be left-aligned if required.


Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
x
Date and time display conventions: The following display conventions will be applied
in all outputs where dates and/or times are displayed:
R
Date only: YYYY-MM-DD
R
Date and time: YYYY-MM-DD/HH:MM
If only partial information is available, unknown components of the date or time will be
presented as ‘NK’ (not known), i.e., ‘2016-NK-NK’. Times will be reported in military time.
3.2.Key Definitions
The following definitions will be used:
x
Baseline:  The baseline value is defined as the last available valid, non-missing
observation for each patient prior to first study drug infusion. Repeat and unscheduled
assessments will be included in the derivation of the baseline values.
x
Change from Baseline: The change from baseline value is defined as the difference
between the result collected/derived at a post-baseline visit/time point and the baseline
value.
The change from baseline value at each post-baseline visit/time point will be calculated
for all continuous parameters using the following formula:
Change from Baseline Value = Result at Visit/Time Point – Baseline Value
The change from baseline value will only be calculated if the specific post-baseline
visit/time point result and the baseline value for the parameter are both available, and
will be treated as missing otherwise.  In the data listings, the change values will be set
to ‘N/A’ (not applicable) for pre-baseline assessments.
x
Study day: The study day of an event is defined as the relative day of the event starting
with the date of the first study drug infusion (reference date) as Day 1 (there will be no
Day 0).
The study day of events occurring before the first study drug infusion will be calculated
as:
Study Day = (Date of Event - Date of First Study Drug Infusion)
For events occurring on or after Day 1, study day will be calculated as:
Study Day = (Date of Event - Date of First Study Drug Infusion) + 1
Study days will only be calculated for events with complete dates, and will be
undefined for events that are ‘Ongoing’ at the end of the study.
Relative days compared to an alternative reference point will be calculated similarly,
but the alternative starting reference start date will be used instead of the date of the
first study drug infusion.
3.3.Handling of Data Following Protocol Amendment 9
Protocol Amendment 9 resulted in the introduction of a new QW dosing schedule that became
effective on the 11th of November 2016. All data for patients that were already enrolled at the
time of the amendment (Cohorts 3 and 4) will be analysed under the dosing schedule that the
patients were originally enrolled to. Patients who were enrolled after the amendment became
effective will be analysed under the new QW dosing schedule.
3.4.Hypothesis Testing
No formal hypothesis testing will be performed and only descriptive summaries will be
presented.


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3.5.Multiple Comparisons and Multiplicity Adjustments.
Not applicable for this study.
3.6.Handling of Missing Data
All data will be analysed as collected and missing values will not be imputed or replaced.
3.7.Coding of Events and Medications
Adverse event verbatim terms will be coded using the Medical Dictionary for Regulatory
Activities (MedDRA) Version 20.0.  Terms will be coded to the full MedDRA hierarchy, but the
system organ class (SOC) and preferred terms (PT) will be of primary interest for the analysis.
Prior and concomitant medications will be coded using the World Health Organization Drug
Dictionary (WHO-DD, SEP-2016). Medications will be mapped to the full WHO-DD Anatomical
Therapeutic Chemical (ATC) class hierarchy, but the ATC Level 3 terms and PTs will be of
primary interest in this analysis.
3.8.Treatment Group and Visit Display Conventions
The following treatment labels will be used in all outputs in the order presented below:
x
Phase 1 Schedule 1:
o
Q3W CRLX301 7.5 mg/m2
o
Q3W CRLX301 15 mg/m2
o
Q3W CRLX301 30 mg/m2
o
Q3W CRLX301 60 mg/m2
o
Q3W CRLX301 75 mg/m2
o
Q3W CRLX301 90 mg/m2
o
Q3W CRLX301 All Patients
x
Phase 1 Schedule 2:
o
QW CRLX301 25 mg/m2
o
QW CRLX301 35 mg/m2
o
QW CRLX301 45 mg/m2
o
QW CRLX301 54 mg/m2
o
QW (3 Weeks On/1 Week Off) CRLX301 45 mg/m2
o
QW (3 Weeks On/1 Week Off) CRLX301 54 mg/m2
o
QW CRLX301 All Patients
x
Phase 2a:
o
Q3W CRLX301 75 mg/m2
o
QW (3 Weeks On/1 Week Off) CRLX301 75 mg/m2
Visit labels will be used as reported in the clinical database.


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4.Analysis Populations
The protocol defines four analysis populations but due to the premature termination of the study
all data displays will be based on the Safety Population.
Data for Screen Failures will not be presented in any of the summary tables or data listings.
4.1.Population Descriptions
4.1.1.Safety Analysis Population
The Safety Population will consist of all patients who received any amount of investigational
product.
Patients will be analysed based on the actual treatment received.
4.1.2.Pharmacokinetic Analysis Population
The PK Analysis Population will consist of all patients who received at least part of one dose
of CRLX301, have at least one PK sample collected on Cycle 1 Day 1 or Week 1 Day 1 of the
study, and have evaluable PK parameters.
4.1.3.MTD and/or RP2D Population
The MTD and/or RP2D population will include all patients treated at the MTD and/or RP2D for
each dosing schedule from both Phase 1 and Phase 2a of the study.
4.1.4.MTD and/or RP2D Efficacy Evaluable Population
The MTD and/or RP2D evaluable population will include all patients treated at the MTD/RP2D
for each dosing schedule, who have had tumor assessment at baseline and undergone at least
one follow-up tumor assessment via imaging or methodologies consistent with specific tumor
type.
5.Patient Disposition and Analysis Populations
5.1.Patient Disposition
Patient disposition will be summarised using counts and percentages and will be based on the
safety population. The number and percentage of enrolled patients, patients withdrawing from
the study treatment as well as the primary reason for treatment termination will be presented.
All disposition information collected on the Treatment Termination eCRF page will be listed
together with the date that the patient provided informed consent (from the Add Patient eCRF
page) and the dates and times of the first and last study drug infusions (from the Treatment(s)
eCRF pages).
All follow-up status information collected on the Follow-up Status eCRF page will be listed
together with the date of the last study drug infusion.
A listing will be produced for patients that died during or after study participation. The listing
will include the date and cause of death (as reported on the Treatment Termination or Follow-
up Status eCRF pages), the dates of the first and last study drug infusions as well as the relative
study day of death compared to the first and last study drug infusions (refer to Section 3.2). In
addition, as separate listing will be produced for patients that died within 30 days of their last
study drug infusion.
5.2.Analysis Populations
The number of patients included in of each of the defined analysis populations will be
summarised using counts and percentages and will be based on the safety population.


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In addition, the inclusion/exclusion of each patient into/from each of the defined analysis
populations will be listed.
6.Protocol Deviations
All reported protocol deviations/violations will be listed.
7.Demographic and Baseline Information
Demographic and other baseline characteristics information collected during the screening
period will be analysed based on the safety population.
Continuous variables will be summarised as described in Section 3.1 and categorical variables
will be summarised using counts and percentages. Endpoints will be summarised by study
phase, dosing schedule (where applicable) and dose level, and for all patients overall within
the dosing schedules.
7.1.Demographics and Baseline Data
Demographic and baseline characteristics data, including age, gender, ethnicity, race, height
(cm), weight (kg), body mass index (BMI) (kg/m2), body surface area (BSA) (m2), childbearing
potential (Yes/No) and the Eastern Cooperative Oncology Group (ECOG) status at baseline
will be summarised. The summary table will also include the primary site of the disease at
study entry.
Body mass index (kg/m2) will be calculated as:
BMI (kg/m2) = Weight (kg) / (Height (cm) * 100)2
Demography and baseline body measurement data (as collected on the Add Patient and Vital
Signs eCRF pages or derived) will be listed in a single listing.
The remaining baseline
characteristics will be listed in the Baseline Patient Characteristics listing.
7.2.Oncology History
All information collected on the Oncology History eCRF page will be listed.
7.3.Medical History
All information collected on the Medical History eCRF page will be listed.
7.4.Prior Anti-Neoplastic Treatment
All information collected on the Prior Anti-Neoplastic Surgery, Prior Anti-Neoplastic Therapy
Medication and Prior Anti-Neoplastic Radiotherapy eCRF pages will be listed.  Separate listings
will be created for each type of treatment.
7.5.Echocardiogram (ECHO) and Multiple Gated Acquisition (MUGA) Scan Results
All information collected on the MUGAECHO eCRF page will be listed.
7.6.Head Computed Tomography (CT)/ Magnetic Resonance Imaging (MRI) Scan
Results
All information related to the head CT or MRI scan collected on the Pre-Study ECOG SCAN
eCRF page will be listed.


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7.7.Pregnancy Test Results
All information related to childbearing potential and pregnancy test results collected on the LAB
TEST eCRF pages will be listed. This listing will include all pregnancy test results collected
during the study.
7.8.Patient Eligibility
All information collected on the Inclusion Exclusion Criteria eCRF page will be listed.
7.9.Assignment to Treatment
All information collected on the Randomization eCRF page will be listed. The date of informed
consent and the date and time of the first study drug infusion will also be included on the listing.
8.Study Drug Administration and Extent of Exposure
Study drug administration and exposure outputs will be based on the safety population.
The total number of treatment cycles/weeks will be calculated as the number of cycles/weeks
during which a patient received any part of a study drug infusion.
The total dose of study drug administered (mg) will be calculated as the sum of the total doses
of study drug administered at each treatment visit during the study.
The duration of exposure (days) will be calculated as the difference between the date of the
first and last study drug infusions + 1 day.
The total number of treatment cycles/weeks will be summarize using counts and percentages.
The total dose of study drug administered and duration of exposure values will be summarized
as continuous variables as described in Section 3.1,
All study drug administration information collected on the Treatment(s) eCRF page will be
listed.
Exposure information (number of treatment cycles, total dose administered and the
duration of exposure) will be listed separately.
9.Efficacy
The planned exploratory analyses of efficacy are based on the evaluation of the Response
Evaluation Criteria in Solid Tumors (RECIST) v1.1 findings or by alternative response
evaluations for specific tumor types. Tumor measurement and evaluations were performed at
the time points specified in the Schedule of Procedures (refer to the Protocol). Results were
reported on the Tumor Measurement and Staging eCRF page.
In addition, bone scan,
prostate-specific antigen (PSA) (as appropriate for the specific disease) and tumor marker data
were collected.
The full planned efficacy analyses will however not be performed for the abbreviated CSR and
this SAP will only focus on the analysis of the best overall response rates.
The efficacy analysis will be based on the safety population.
9.1.Best Overall Response
The best overall response is the best response (based on the RECIST v1.1 guidelines)
recorded from the start of the treatment until disease progression/recurrence (taking the
smallest measurements recorded since the treatment started as a reference for progressive
disease).


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9.1.1.Biostatistical Methods
The best overall response will be summarized by counts and percentages. In addition, two-
sided 95% Clopper-Pearson CIs will be presented for the response rates within each RECIST
response category.
Tumor measurement data (including the RECIST evaluations) will be listed separately for target
and non-target tumors and new lesion data. A separate listing will be produced for the overall
tumor response at each evaluation, and the best overall response will be flagged.
9.2.Other Efficacy Data
Bone scan and PSA (Tumor assessment using PCWG2 eCRF) and tumor marker (Tumor
Markers eCRF) data will be listed separately (if data is available in the clinical database).
10.Safety
Statistical methods for the safety analyses will be descriptive in nature and no formal statistical
comparisons will be made. Endpoints will be summarised by study phase, dosing schedule
(where applicable) and dose level, and for all patients overall within the dosing schedules per
the methods described in Section 3.1.
Safety variables will include AEs, clinical laboratory parameters, vital signs, electrocardiogram
(ECG) parameters, and the use of concomitant medications.
Safety endpoints will be analysed based on the safety population.
10.1.Adverse Events
An AE is defined as any unfavorable and unintended sign (e.g., an abnormal laboratory finding),
symptom, or disease temporally associated with the use of a drug, experienced by a patient
during the clinical study or the specified safety follow-up period, regardless of relationship to
study drug.  Pre-existing conditions are not seen as AEs unless the condition worsens during
the trial.
Treatment-emergent adverse events (TEAEs) are defined as AEs that commenced on or after
the first study drug infusion. Events that started more than 30 days after the last study drug
infusion will not be considered to be treatment-emergent.
Serious AEs (SAEs) are defined as AEs where the events are reported as ‘Serious’ (with a
corresponding reason(s) indicating why the event is deemed to be serious).
Severe AEs are defined as AEs where the event severity rating is reported as ‘Severe’, ‘Life-
Threatening or Disabling’ or ‘Death’.
Treatment-related AEs are defined as AEs where the relationship to study drug is reported as
‘Possibly Related’, ‘Probably Related’, ‘Related’ or is missing.
Adverse events leading to the premature discontinuation of study medication are defined as
AEs the action taken was reported as ‘Study medication permanently discontinued’ on the
Adverse Events eCRF page.
A DLT is defined as any AE possibly, probably, or definitely related to CRLX301 that meets the
per protocol criteria for DLT (see Section 3.1.3 of the Protocol) and occurs at any point during
Cycle 1 or the first 3 weeks post initiation of study drug infusion.
10.1.1.Biostatistical Methods
Adverse events will be summarised by study phase, dosing schedule/cohort.
All tables will present the number of patients who experienced an AE (count and percentage)
and the actual number of AEs (counts only), within each specific category.
Patients who
experienced multiple AEs will only be counted once in each relevant category (SOC and PT),


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but all events will be included in the event counts. System organ class terms will be sorted
alphabetically, and PTs will be sorted alphabetically within SOCs. In addition to the summaries
by the coded terms, the number of patients who experienced at least one TEAE during specific
phase will be presented.
Tables will only include TEAEs.
The overall summary of TEAEs table will present the total number of patients who experienced
a TEAE and the total number of TEAEs within each of the following categories:
x
At least one TEAE
x
At least one serious TEAE
x
At least one DLT
x
At least one severe TEAE
x
At least one treatment-related TEAE
x
At least one TEAE leading to the premature discontinuation of study medication.
The summary of TEAEs table will include the number of patients who experienced at least one
TEAE and the corresponding number of events, and furthermore summarize the TEAE data by
SOC and preferred term within SOCs.
The summary of SAEs table will include the number of patients who experienced at least one
SAE and the corresponding number of SAEs, and furthermore summarize the SAE data by
SOC and preferred term within SOCs.
The summary of DLTs table will include the number of patients who experienced at least one
DLT and the corresponding number of DLTs, and furthermore summarize the DLT data by SOC
and preferred term within SOCs.
The summary of Grade 3/4 (severity rating) treatment-related TEAEs table will include the
number of patients who experienced at least one treatment-related severe or life-threatening
or disabling TEAE and the corresponding number of TEAEs, and furthermore summarize the
TEAE data by SOC and preferred term within SOCs.
The summary of TEAEs by worst severity tables will include the number of patients who
experienced at least one TEAE, the number of patients who experienced at least one TEAE
within each severity rating (‘Mild’, ‘Moderate’, ‘Severe’, ‘Life-threatening or Disabling’, ‘Death’)
and the corresponding number of events within each rating. In addition, the TEAE data will be
summarized by SOC, preferred term within SOC, and the severity rating within SOC/PT.
Patients who experienced multiple AEs under a specific PT will only be counted once under
the worst reported severity rating, but all events under the rating will be included in the event
counts.
System organ class terms will be sorted alphabetically, PTs will be sorted
alphabetically within SOCs and severity ratings will be sorted in increasing order of severity
within SOC/PT.
The summary of treatment-related TEAEs by worst severity rating tables will be similar to the
corresponding TEAE tables, but will be based on the subset of patients who experienced
treatment-related TEAEs.
The summary of TEAEs by strongest relationship to study drug (causality) tables will include
the number of patients who experienced at least one TEAE, the number of patients who
experienced at least one TEAE within each relationship category (‘Unrelated’, ‘Unlikely’
‘Possibly’, ‘Probably’, ‘Related’) and the corresponding number of events within each category.
In addition, the TEAE data will be summarized by SOC, preferred term within SOC, and
relationship category within SOC/PT. Patients who experienced multiple AEs under a specific
PT will only be counted once under the strongest reported relationship category, but all events
under the category will be included in the event counts.
System organ class terms will be


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sorted alphabetically, PTs will be sorted alphabetically within SOCs and relationship categories
will be sorted in increasing order of causality within SOC/PT.
The summary of treatment-related TEAEs by strongest relationship to study drug tables will be
similar to the corresponding TEAE tables, but will be based on the subset of patients who
experienced treatment-related TEAEs.
All information that was collected on the Adverse Events eCRF as well as the coded MedDRA
terms will be included in the listings. Furthermore, the relative event start and stop days (refer
to Section 3.1) will be presented where complete event start and stop dates are available.
In addition, DLTs, SAEs, AEs that lead to premature discontinuation of study medication and
AEs of Special Interest will be listed separately.
10.2.Safety Laboratory Assessments
Blood and urine samples will be collected at the time points specified in the Schedule of
Procedures (refer to the Protocol) to conduct hematology, chemistry, coagulation and urinalysis
(including microscopy) analyses.
The following tests will be performed within each of the specified test panels:
x
Hematology:  White blood cell (WBC) count (with automated differential for absolute
neutrophils, lymphocytes, monocytes, eosinophils, and basophils), red blood cell (RBC)
count, haemoglobin, haematocrit, platelet count, and reticulocyte count.
x
Chemistry: Sodium, potassium, calcium, chloride, glucose, blood urea nitrogen (BUN)
or urea, creatinine, total protein, alkaline phosphatase, albumin, total bilirubin, direct
and indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase
(ALT), lactate dehydrogenase (LDH), inorganic phosphorus, uric acid, cholesterol,
triglyceride levels, and tryptase (only required if patient experience an infusion related
reaction).
x
Coagulation:  Prothrombin
time
(PT),
partial
thromboplastin
time
(PTT),
and
international normalized ratio (INR).
x
Urinalysis:  Specific gravity, pH, protein, glucose, ketones, bilirubin, microscopy (red
blood cells/high-power field, white blood cells/high-power field, and casts/low-power
field), and blood.
The results for each laboratory parameter within the hematology, chemistry and coagulation
test panels will be reported on the respective eCRF pages.  The results will include the actual
measurement/concentration, the unit of measure (if applicable), the lower and upper limits of
the normal range for each specific test (if applicable), as well as a flag indicating whether the
result is clinically significant or not (‘Yes’/’No’).
The urinalysis test results (‘Negative’, ‘Positive’) are reported on the Urinalysis eCRF page.
For specific gravity and pH only, the results will include the actual measurement/concentration,
the unit of measure (if applicable), the lower and upper limits of the normal range for each test
(if applicable), as well as a flag indicating whether the result is clinically significant or not
(‘Yes’/’No’).


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10.2.1.Biostatistical Methods
All laboratory data collected at scheduled and unscheduled visits will be included in the listings,
but only results collected as scheduled visits will be included in the summary tables.
Results for individual parameters may be reported in different units depending on the analyzing
laboratory.
If required, the results (and the corresponding normal range cut-off values) for
individual parameters may be converted to S.I. units to summarize the data.
For the all parameters where a unit value has been reported, the parameter names that will be
used in the outputs will comprise of the test name and the unit of measure, for example,
‘Albumin (g/L)’. For the urinalysis parameters, the parameter name will be the reported test
name only. Parameters will be sorted alphabetically within tables and listings.
For all parameters where a normal range limit value was reported, the normal range will be
derived based on the available lower and upper limit values and any reported mathematical
symbols. If both a lower and upper limit value is available, the normal range will be presented
as ‘(Lower, Upper)’.
If only one of the limit values exist, ‘N/A’ will be used to replace the
‘missing’ limit value (for example, ‘(N/A, Upper)’), unless a direction has been specified, in
which case the normal range will be displayed as ‘(< or > Limit)’.
The reported results for each parameter with a defined normal range will be classified (‘Low’,
‘Normal’, ‘High’) in relation to the defined normal range limits. If a result is equal to the normal
range cut-off value, the result will be considered ‘Normal’.
The change from baseline values at each post-baseline visit will be calculated for all
parameters with continuous results (except for specific gravity and pH).
The decimal precision to which the summaries for each parameter will presented will be based
on the maximum number of decimals to which the reported result or the normal range limits
are presented to in the raw data. The results and normal ranges will be displayed to the same
decimal precision in the listings.
If a result for a parameter that is normally considered continuous is reported as a range (i.e.,
the result for basophils is reported as ‘<0.01’ for a single time point), the result may be
converted to a numeric value that is smaller than the reported result to contribute to the
derivations and the summary statistics.
Any conversion rules that are applied will be
highlighted in the footnotes of the affected tables and listings. The original reported result value
will however be included in the listing.
The summary of hematology, chemistry and coagulation results tables will present summary
statistics for each laboratory parameter within the specific test panel.  For each parameter,
summaries will be presented for the baseline and each scheduled post-baseline visit.  In
addition, summaries will be presented for the change from baseline values at each scheduled
post-baseline visit.
The summary of urinalysis table will present counts and percentages for the reported results
at baseline and each post-baseline visit within each test parameter.  Result categories will be
order alphabetically, or in ascending order.
The summary of hematology, chemistry and coagulation result classifications tables will
present summaries (counts and percentages) for the baseline and each scheduled post-
baseline visit for each of the defined categories (‘Low’, ‘Normal’, ‘High’) within each parameter
with a defined normal range, within the specific test panel.
The listings of haematology, chemistry and coagulation results will include all the information
(fields) that was collected on the respective eCRF pages including the derived results
classifications. In addition, the observations that were used as the baseline records (values)
for each parameter will be flagged, and the change from baseline values at each post-baseline
visit will be presented.


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The listing of urinalysis data will include all the information (fields) that was collected on the
Urinalysis eCRF page.
In addition, the observation that was used as the baseline record
(value) for each parameter will be flagged.
Separate listing that include only the subset of patients that had at least one abnormal result
will also be created for each test panel.
For the abnormal hematology, chemistry and
coagulation results listings, all the results for every parameter where at least one ‘Low’ or ‘High’
classification was observed will be included. For the abnormal urinalysis results listing, all the
results for every parameter where at least one result was reported as ‘Positive’ (or ‘Low’ or
‘High’ for specific gravity and pH) will be included.
10.3.Vital Signs Measurements
The following vital signs measurements were taken at the time points specified in the Schedule
of Procedures (refer to the Protocol):
x
Heart Rate (beats/min)
x
Systolic blood pressure (SBP) (mmHg)
x
Diastolic blood pressure (DBP) (mmHg)
x
Respiratory rate (breaths/min)
x
Temperature (C)
x
Height (cm)
x
Weight (kg)
x
BSA (m2)
x
BMI (kg/m2)
The results for each parameter were reported on the Vital Signs eCRF page.
10.3.1.Biostatistical Methods
All vital signs data collected at scheduled and unscheduled visits will be included in the listings,
but only results collected as scheduled visits will be included in the summary tables.
The parameter names that will be used in the outputs will comprise of the test name and the
unit of measure, for example, ‘Systolic Blood Pressure (mmHg)’.  Parameters will be sorted in
the order that the measurements were collected in on the Vital Signs eCRF page within the
tables and listings.
The change from baseline to the pre-dose assessment at each post-baseline visit will be
calculated for all parameters. In addition, the change from the pre-infusion value to each post-
infusion time point (i.e., 30 minutes after infusion) will be calculated for heart rate, SBP, DBP,
and respiratory rate where vital signs were collected during and after the infusion period.
The decimal precision to which the summaries for each parameter will presented will be based
on the maximum number of decimals to which the results were reported on the eCRF.
The summary of vital signs measurements table will present summary statistics for the results
at the baseline and each scheduled post-baseline visit for each of the parameters (excluding
height, weight, BSA and BMI). In addition, summaries will be presented for the change from
baseline values at each scheduled post-baseline visit.
The summary of vital signs measurements collected during the infusion period table will present
summary statistics for the results at the pre-infusion and each scheduled post-infusion time
point for each of the parameters (excluding temperature, height, weight, BSA and BMI), at each
visit. In addition, summaries will be presented for the change from the pre-infusion values at
each scheduled post-infusion time points at the specific visit.


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The summary of body measurements table will present summary statistics for the results at the
baseline and each scheduled post-baseline visit for height, weight, BSA and BMI. In addition,
summaries will be presented for the change from baseline values at each scheduled post-
baseline visit.
The listings of vital signs measurements and body measurements will include all the information
(fields) that was collected on the Vital Signs eCRF page. In addition, the observations that
were used as the baseline record (value) for each parameter will be flagged, and the change
from baseline values at each post-baseline visit will be presented.
The listing of vital signs measurements collected during the infusion period will include all the
information (fields) that was collected on the Vital Signs eCRF page. In addition, the change
from the pre-infusion values at each post-baseline visit will be presented.
10.4.Echocardiogram (ECG) Measurements
The following echocardiogram (ECG) measurements were taken at the time points specified in
the Schedule of Procedures (refer to the Protocol):
x
Heart Rate (beats/min)
x
PR Interval (msec)
x
QRS Duration (msec)
x
QT Interval (msec)
x
QTcF (msec)
x
ECG Result (overall interpretation)
The results for each parameter were reported on the ECG eCRF page.
10.4.1.Biostatistical Methods
All ECG data collected at scheduled and unscheduled visits will be included in the listings, but
only results collected as scheduled visits will be included in the summary tables.
The parameter names that will be used in the outputs will comprise of the test name and the
unit of measure (where applicable), for example, ‘Heart Rate (mmHg)’.  Parameters will be
sorted in the order that the measurements were collected in on the ECG eCRF page within the
tables and listings.
The decimal precision to which the summaries for each parameter will presented will be based
on the maximum number of decimals to which the results were reported on the eCRF.
The summary of ECG measurements table will present summary statistics for the results at the
baseline and each scheduled post-baseline visit/time point for each of the parameters
(excluding the overall interpretation). In addition, summaries will be presented for the change
from baseline values at each scheduled post-baseline visit/time point.
The summary of overall ECG interpretation results table will present counts and percentages
for the reported results at baseline and each post-baseline visit/time point. Result categories
will be order as ‘Normal’, ‘Abnormal NCS’ and ‘Abnormal CS’.
The listing of ECG measurements will include all the information (fields) that was collected on
the ECG eCRF page apart from the overall interpretation results. In addition, the observations
that were used as the baseline record (value) for each parameter will be flagged, and the
change from baseline values at each post-baseline visit/time point will be presented.
The listing of overall ECG interpretation results will include all the information (fields) that was
collected on the ECG eCRF page. In addition, the observations that were used as the baseline
record (value) will be flagged.


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10.5.Eastern Cooperative Oncology Group (ECOG) Performance Status
The ECOG performance status was assessed at the time points specified in the Schedule of
Procedures (refer to the Protocol) and the findings were reported on the ECOG SCAN eCRF
page.
10.5.1.Biostatistical Methods
All ECOG data collected at scheduled and unscheduled visits will be included in the listings,
but only results collected as scheduled visits will be included in the summary tables.
The summary of ECOG performance status table will present counts and percentages for the
reported results at baseline and each post-baseline visit.
The listing ECOG performance status results will include all the information (fields) that was
collected on the ECOG SCAN eCRF page. In addition, the observations that were used as the
baseline record (value) will be flagged.
10.6.Concomitant Medications
Prior medications are defined as any medication where the use was stopped prior to the first
application of study drug.
Concomitant medications are defined as any medication (other than the study drug) that was
used at least once after the first infusion of study drug. Medications that were stopped on the
same date as the first study drug infusion will be analysed as concomitant medications. If a
clear determination cannot be made (partial medication end dates) the medication will be
classified as concomitant. Medications that were started after the End of Study visit will not be
considered to be concomitant medications in the summary table.
Premedications are defined as medications that are administered as a precaution to minimize
the risk and/or severity of infusion-related hypersensitivity reactions. Premedications will be
medications where the indication was specified as ‘Premedication’ on the Concomitant
Medication eCRF page.
10.6.1.Biostatistical Methods
Concomitant mediations will be summarised by ATC Level 3 terms and by PT within the ATC
ter.
Within each category, the number of patients who used the medication (count and
percentage) will be presented. Patient who used the same medication on multiple occasions
will only be counted once in the specific category (ATC or PT).
Anatomical Therapeutic
Chemical terms will be sorted alphabetically, and PTs will be sorted alphabetically within ATC
term. In addition to the summaries by the coded terms, the number of patients who used at
least one concomitant medication during the study will be presented.
All information that was collected on the Concomitant Medication eCRF as well as the coded
WHO-DD terms will be included in the listings.  Furthermore, the relative medication start and
stop days (refer to Section 3.1) will be present where complete medication start and stop dates
are available.
Prior medications (history of medication use) will be listed as part of the baseline
characteristics. Concomitant medications and pre-medications will be listed separately.


Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
11.Pharmacokinetic Concentrations
The derivation of PK parameters and a formal PK analysis does not fall within the scope of this
SAP.
All information collected on the PK and Biomarker Samples eCRF page will be listed.  If
available, the actual concentration results from the PK laboratory will be included in the listings.
Separate listings will be produced for blood and urine PK data.
12.Changes to the Planned Analysis
Due to the early termination of the study and the decision that only an abbreviated CSR will be
produced, the efficacy and PK analyses proposed in the study protocol will not be performed.
13.Interim and Final Analysis
13.1.Interim Analyses
No interim analyses are planned for the study.
13.2.Final Analysis (End of Study)
The final analysis will be conducted after all patients have completed the study, the clinical
database has been locked, and the analysis populations have been approved.
The final analysis will be based on the final version of the SAP.  Any deviations from the planned
analysis will be documented in the CSR.
14.Software
The following software will be used to perform the statistical analyses:
x
SAS® Version 9.4 or higher (SAS Institute, Cary, North Carolina, USA)



Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
15.Tables
No.
Title
Analysis 
Populations
Table 14.1.1
Patient Enrollment and Disposition
Safety
Table 14.1.2
Demographics
Safety
Table 14.2.1
Best Overall Tumor Response
Safety
Table 14.3.0
Study Drug Exposure
Safety
Table 14.3.1.1
Overall Summary of Treatment-Emergent Adverse Events
Safety
Table 14.3.1.2.1
Incidence of Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term
Safety
Table 14.3.1.2.2
Incidence of Serious Adverse Events by System Organ 
Class and Preferred Term
Safety
Table 14.3.1.2.3
Incidence Dose Limiting Toxicities by System Organ Class 
and Preferred Term
Safety
Table 14.3.1.3
Incidence of Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term and Worst Severity 
Rating 
Safety
Table 14.3.1.4
Incidence of Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term and Strongest 
Relationship to Study Drug
Safety
Table 14.3.1.5.1
Incidence of Treatment-Related Treatment-Emergent 
Adverse Events by System Organ Class and Preferred 
Term
Safety
Table 14.3.1.5.2
Incidence of Treatment-Related Serious Adverse Events by 
System Organ Class and Preferred Term
Safety
Table 14.3.1.6
Incidence of Treatment-Related Treatment-Emergent
CTCAE Grade 3/4 Adverse Events by Treatment, Preferred 
Term
Safety
Table 14.3.2.1.1
Hematology Results (Summary of Actual and Change from 
Baseline Values)
Safety
Table 14.3.2.1.2
Hematology Result Classifications
Safety
Table 14.3.2.2.1
Chemistry Results (Summary of Actual and Change from 
Baseline Values)
Safety
Table 14.3.2.2.2
Chemistry Result Classifications
Safety
Table 14.3.2.3.1
Coagulation Results (Summary of Actual and Change from 
Baseline Values)
Safety
Table 14.3.2.3.2
Coagulation Result Classifications
Safety
Table 14.3.2.4
Urinalysis Results
Safety
Table 14.3.3.1
Vital Signs Measurements (Summary of Actual and Change 
from Baseline Values)
Safety
Table 14.3.3.2
Vital Signs Measurements During Infusion Period 
(Summary of Actual and Change from Pre-Infusion Values)
Safety
Table 14.3.3.1
Body Measurements (Summary of Actual and Change from 
Baseline Values)
Safety
Table 14.3.4.1
12-Lead Electrocardiogram (ECG) Measurements 
(Summary of Actual and Change from Baseline Values)
Safety
Table 14.3.4.2
12-Lead Electrocardiogram (ECG) Overall Interpretation
Safety
Table 14.3.5
Eastern Cooperative Oncology Group (ECOG) 
Performance Status
Safety
Table 14.3.6
Concomitant Medications by Anatomical Therapeutic 
Chemical Class and Preferred Term
Safety


Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
16.Listings
No.
Title
Analysis 
Populations
Listing 14.3.2.1
Deaths
Safety
Listing 14.3.2.2
Serious Adverse Events
Safety
Listing 14.3.2.3
Adverse Events Leading to Permanently Discontinuation 
of Study Medication 
Safety
Listing 14.3.2.4
Dose-Limiting Toxicities
Safety
Listing 14.3.2.5
Deaths within 30 Days of Last Study Drug Infusion
Safety
Listing 16.1.7
Assignment to Treatment
Safety
Listing 16.2.1.1
Analysis Populations
Safety
Listing 16.2.1.2
Patient Disposition
Safety
Listing 16.2.1.3
Follow-Up Status
Safety
Listing 16.2.2
Protocol Deviations
Safety
Listing 16.2.4.1
Demographics and Baseline Data
Safety
Listing 16.2.4.2
Baseline Patient Characteristics
Safety
Listing 16.2.4.3
Oncology History
Safety
Listing 16.2.4.4
Medical History
Safety
Listing 16.2.4.5
Prior Anti-Neoplastic Surgery
Safety
Listing 16.2.4.6
Prior Anti-Neoplastic Therapy Medications
Safety
Listing 16.2.4.7
Prior Anti-Neoplastic Radiotherapy
Safety
Listing 16.2.4.8
Prior Medications
Safety
Listing 16.2.4.9
Echocardiogram (ECHO) and Multiple Gated Acquisition 
(MUGA) Scan Results
Safety
Listing 16.2.4.10
Head Computed Tomography (CT)/ Magnetic 
Resonance Imaging (MRI) Scan Results
Safety
Listing 16.2.4.11
Pregnancy Test Results
Safety
Listing 16.2.4.12
Patient Eligibility
Safety
Listing 16.2.5.1
Premedications
Safety
Listing 16.2.5.2
Study Drug Infusions
Safety
Listing 16.2.5.3
Study Drug Exposure
Safety
Listing 16.2.5.4
Blood Pharmacokinetic CRLX301 Concentrations
Safety
Listing 16.2.5.5
Urine Pharmacokinetic CRLX301 Concentrations
Safety
Listing 16.2.6.1.1
Target Tumor Assessments
Safety
Listing 16.2.6.1.2
Non-Target Tumor Assessments
Safety
Listing 16.2.6.1.3
New Lesion Assessments
Safety
Listing 16.2.6.2
Overall Tumor Response
Safety
Listing 16.2.6.3
Bone Scan Results
Safety
Listing 16.2.6.4
Prostate-Specific Antigen (PSA) Results
Safety
Listing 16.2.6.5
Tumor Markers
Safety
Listing 16.2.7.1
Adverse Events
Safety
Listing 16.2.7.2
Adverse Events of Special Interest
Safety
Listing 16.2.8.1
Hematology Results
Safety
Listing 16.2.8.2
Abnormal Hematology Results
Safety
Listing 16.2.8.3
Chemistry Results
Safety
Listing 16.2.8.4
Abnormal Chemistry Results
Safety
Listing 16.2.8.5
Coagulation Results
Safety
Listing 16.2.8.6
Abnormal Coagulation Results
Safety
Listing 16.2.8.7
Dipstick Urinalysis Results
Safety
Listing 16.2.8.8
Abnormal Dipstick Urinalysis Results
Safety
Listing 16.2.8.9
Urine Microscopy Results
Safety
Listing 16.2.9.1.1
Vital Signs Measurements
Safety


Protocol Number: CRLX301-101
22 June 2017
Document status: Final SAP Version 1.0
No.
Title
Analysis 
Populations
Listing 16.2.9.1.2
Vital Signs Measurements During Infusion Period
Safety
Listing 16.2.9.1.3
Body Measurements
Safety
Listing 16.2.9.2.1
12-Lead Electrocardiogram (ECG) Measurements
Safety
Listing 16.2.9.2.2
12-Lead Electrocardiogram (ECG) Overall Interpretation
Safety
Listing 16.2.9.3
Eastern Cooperative Oncology Group (ECOG) 
Performance Status
Safety
Listing 16.2.10
Concomitant Medications
Safety