Clinical trial NCT02776917
Conditions: Breast Neoplasms
Keywords: metastatic breast cancer locally advanced, unresectable breast cancer HER2/NEU negative
Sponsor: Barbara Parker, MD
Start date: 2018-08-15; Completion date: 2024-02-26
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a pilot phase 1b study to investigate the safety and side effects of combining the ROR1-targeting monoclonal antibody, cirmtuzumab, with paclitaxel for patients with HER2 negative, metastatic breast cancer. Cirmtuzumab is a type of drug called a monoclonal antibody. This drug is designed to attach to a protein called receptor-tyrosine-kinase like orphan receptor 1 (ROR1) on the surface of breast cancer cells. Cirmtuzumab blocks the growth and survival of the breast cancer cells in laboratory tests. ROR1 is rarely expressed on healthy cells. Cirmtuzumab is considered experimental and is not approved by United States (U.S.) Food and Drug Administration (FDA).

Detailed description:
* This is a phase 1b, open-label, non-randomized, fixed dose study in patients with HER2 negative metastatic, or locally advanced, unresectable breast cancer.
* Cirmtuzumab and paclitaxel will be administered until disease progression or unacceptable toxicity. Cirmtuzumab or paclitaxel may be continued alone if the other drug is discontinued due to toxicity, as long as the subject is tolerating the drug and does not exhibit disease progression.
* Blood and tissue samples will be collected at pre-specified times to enable pharmacokinetic and correlative studies.
* Adverse events (AE) will be monitored throughout the trial. Reporting of AEs will be in accordance with CTCAE version 4.03.
* Assessment of tumor response will be performed by physical examination and/or by radiographic imaging and according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.
* Patients will be assessed at 28 days following the last dose of cirmtuzumab to assess tumor response and at 56 days following the last dose of cirmtuzumab to assess any adverse events and to document any concomitant cancer therapy.

Arms: arm 1: Cirmtuzumab 600 mg is administered intravenously on Days 1 and 15 of the first 28-day cycle, then on Day 1 of each subsequent 28-day cycle.

Paclitaxel 80 mg/m\^2 is administered weekly on Days 1, 8, 15, and 22 of each 28-day cycle.
Interventions: intervention 1: Cirmtuzumab + Paclitaxel
Intervention descriptions: intervention 1: Cirmtuzumab and paclitaxel may be administered until disease progression or unacceptable toxicity. Cirmtuzumab or paclitaxel may be continued alone if the other drug is discontinued due to toxicity.

Protocol documents:
Prot_000.pdf: 
Cirmtuzumab - metastatic breast cancer  
 
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Protocol Date 07/31/2020 
 
 
 
 
 
 
 
 
 
 
 
Protocol ID: 160178 
NCT02776917 
 
Study of Cirmtuzumab and Paclitaxel for Metastatic or Locally Advanced, 
Unresectable Breast Cancer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Date 07/31/2020 
 
 
 
 
 
A Phase 1b pilot clinical trial of Cirmtuzumab, an anti-ROR1 monoclonal antibody, in 
combination with paclitaxel (TAXOL) for the treatment of patients with metastatic, or 
locally advanced, unresectable breast cancer 
 
 
 
PRINCIPAL INVESTIGATORS 
Barbara Parker, M.D. 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
Phone: (858) 249-3248 
Fax: (858) 249-3250 
Email: baparker@ucsd.edu 
 
Rebecca Shatsky, M.D.  
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
Phone: (858) 249-3781 
Fax: (858) 249-3250 
Email: rshatsky@ucsd.edu 
 
 
 
 
Protocol Number: 
HRPP  #160178 
 
Study Agent:  
Cirmtuzumab (UC-961) 
 
IND Number:  
130537 
 
IND Holder:  
Barbara Parker, MD 
 
 
Protocol 
Date 
Original (v 1.0) 
18-May-2016 
Amendment 1 
01-Dec-2016 
Amendment 2 
16-Apr-2018 
Amendment 3 
30-Nov-2018 
Amendment 4 
07-Mar-2019 
Amendment 5 
Amendment 6 
27-Mar-2019 
05-May-2019 
Amendment 7 
Amendment 8 
14-Oct-2019 
31-July-2020 
 
 
 


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LIST OF INVESTIGATORS 
 
 
PRINCIPAL INVESTIGATORS  
 
Barbara Parker, M.D. 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
Phone: (858) 249-3248 
Fax: (858) 249-3250 
Email: baparker@ucsd.edu 
 
Rebecca Shatsky, M.D.  
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
Phone: (858) 249-3781 
Fax: (858) 249-3250 
Email: rshatsky@ucsd.edu 
 
BIOSTATISTICIANS 
 
Ruifeng Chen, MS 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive # 0901 
La Jolla, CA 92093 
Phone: (858) 822-4334 
Email: ruc075@ucsd.edu 
 
 
Karen Messer, PhD 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive # 0901 
La Jolla, CA 92093 
Phone: (858) 822-4334 
Email: kmesser@ucsd.edu 
 
 
 
CO-INVESTIGATORS 
 
Sarah Boles, M.D. 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
Phone: (858) 249-3249 
Fax: (858) 249-3250 
Email: sboles@ucsd.edu 
 
Teresa Helsten, M.D. 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
Phone: (858) 249-3249 
Fax: (858) 249-3250 
Email: thelsten@ucsd.edu 
 
 
Richard Schwab, M.D. 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0820 
La Jolla, CA 92093 
Phone: (858) 249-3781 
Fax: (858) 249-3250 
Email: rschwab@ucsd.edu 
 
 
 
 
 
 
 
 


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Protocol Date 07/31/2020 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator  
 
 
_____________________________ 
Printed Name 
 
 
_____________________________  
____________________ 
Signature 
 
 
 
 
Date 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
LIST OF INVESTIGATORS ............................................................................................. 3 
LIST OF ABBREVIATIONS ............................................................................................. 8 
STUDY SCHEMA .......................................................................................................... 10 
STUDY SUMMARY ....................................................................................................... 11 
1.0 
BACKGROUND AND RATIONALE ............................................................. 15 
1.1 
Disease Background ............................................................................................... 15 
1.2 
ROR1 and Cancer Stem Cells ................................................................................ 15 
1.3 
Cirmtuzumab and Paclitaxel .................................................................................... 16 
1.4 
Cirmtuzumab Pre-clinical Pharmacology and Toxicology ....................................... 17 
1.5 
Cirmtuzumab Clinical Experience - Phase 1 CLL Trial ........................................... 17 
1.6 
Rationale ................................................................................................................. 19 
2.0 
STUDY OBJECTIVES .................................................................................. 20 
2.1 
Primary Objectives .................................................................................................. 20 
2.2 
Secondary Objectives ............................................................................................. 20 
2.3 
Exploratory Objectives ............................................................................................ 20 
2.4 
Endpoints ................................................................................................................ 20 
3.0 
PATIENT ELIGIBILITY ................................................................................. 21 
3.1 
Inclusion Criteria ...................................................................................................... 21 
3.2 
Exclusion Criteria .................................................................................................... 22 
4.0 
TREATMENT PLAN ..................................................................................... 23 
4.1 
Study Drugs Dose Assignment ............................................................................... 23 
4.2 
Definition of Dose-Limiting Toxicity ......................................................................... 24 
4.3 
Dose Reduction and safety stopping rule ................................................................ 24 
4.4 
Pre-Medications ...................................................................................................... 25 
4.5 
Study Drugs Infusion ............................................................................................... 25 
4.5.1 
Cirmtuzumab infusion plan ...................................................................................... 25 
4.5.2 
Paclitaxel infusion .................................................................................................... 25 
4.6 
Permitted Concomitant Therapy .............................................................................. 25 
4.7 
Prohibited Concomitant Therapy ............................................................................. 26 
4.8 
Toxicities and Dosing Delays/Dose Modifications ................................................... 26 
4.8.1 
Dosage Modification Criteria and Guidelines for Management of Cirmtuzumab 
Related Toxicities .................................................................................................... 26 
4.8.2 
Dosage Modification Criteria and Guidelines for Management of Paclitaxel Related 
Toxicities ................................................................................................................. 29 
4.8.3 
Modifications for Infusion Reactions ........................................................................ 29 
4.9 
Duration of Study Treatment ................................................................................... 29 
4.10 
Duration of Follow Up .............................................................................................. 30 
4.11 
Discontinuation from Study Participation ................................................................. 30 
5.0 
STUDY PROCEDURES ............................................................................... 30 
5.1 
Definitions of Study Assessments ........................................................................... 31 
5.1.1 
Medical history and symptoms ................................................................................ 31 
5.1.2 
Demographics ......................................................................................................... 31 


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5.1.3 
Review subject eligibility criteria .............................................................................. 31 
5.1.4 
Concomitant medications ........................................................................................ 31 
5.1.5 
Physical exam ......................................................................................................... 31 
5.1.6 
Vital signs and height .............................................................................................. 31 
5.1.7 
Performance status ................................................................................................. 31 
5.1.8 
Adverse event assessment ..................................................................................... 31 
5.1.9 
CBC and differential ................................................................................................ 31 
5.1.10 CMP ........................................................................................................................ 32 
5.1.11 Coagulation ............................................................................................................. 32 
5.1.12 Blood draw for pharmacokinetic (PK) and correlative studies ................................. 32 
5.1.13 Pregnancy test (for females of child bearing potential) ........................................... 32 
5.1.14 Tumor assessment .................................................................................................. 32 
5.1.15 Tumor sample collection ......................................................................................... 32 
5.2 
Screening/Baseline Procedures .............................................................................. 32 
5.3 
Procedures During Treatment ................................................................................. 33 
5.4 
Follow-up Procedures (56 days (+/-7) after last dose of cirmtuzumab or paclitaxel)
 
36 
5.5 
Correlative Studies .................................................................................................. 36 
5.5.1 
Blood Sample Collection Guidelines for PK and Correlative Studies ...................... 36 
5.5.2 
Tumor and Malignant Ascites / Pleural Effusion Sample Collection Guidelines ...... 37 
5.5.3 
Specimen Banking .................................................................................................. 37 
5.5.4 
Assay methodologies .............................................................................................. 38 
5.6 
Patient Discontinuation ............................................................................................ 38 
6.0 
MEASUREMENT OF EFFECT ..................................................................... 38 
6.1 
Safety/tolerability ..................................................................................................... 38 
6.2 
Antitumor Effect- Solid Tumors ............................................................................... 39 
6.2.1 
Best Overall Response ............................................................................................ 39 
6.2.2 
Progression-Free Survival ....................................................................................... 39 
6.2.3 
Time to Progression ................................................................................................ 39 
7.0 
ADVERSE EVENTS ..................................................................................... 39 
7.1 
Adverse Event Monitoring ....................................................................................... 39 
7.2 
Severity ................................................................................................................... 40 
7.3 
Seriousness ............................................................................................................. 40 
7.4 
Relationship ............................................................................................................. 40 
7.5 
Prior experience ...................................................................................................... 41 
7.6 
Reporting Requirements for Adverse Events .......................................................... 41 
7.6.1 
Expedited Reporting ................................................................................................ 41 
7.6.2 
Routine Reporting Requirements ............................................................................ 41 
8.0 
AGENT INFORMATION ............................................................................... 42 
8.1 
Cirmtuzumab ........................................................................................................... 42 
8.1.1 
Return and Retention of Study Drug ....................................................................... 43 
8.2 
Paclitaxel ................................................................................................................. 43 
9.0 
STATISTICAL CONSIDERATIONS ............................................................. 44 
9.1 
Study Design/Study Endpoints ................................................................................ 44 
9.1.1 Study Stopping Rules ............................................................................................ 45 
9.2 
Sample Size and Accrual ........................................................................................ 46 
9.2.1 
Evaluable Subjects and Subject Replacement ........................................................ 46 


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9.3 
Data Analyses Plans ............................................................................................... 47 
9.3.1 
Primary Analyses .................................................................................................... 47 
9.3.2 
Secondary Analyses ................................................................................................ 47 
9.3.3 
Exploratory Analyses ............................................................................................... 47 
10.0 
STUDY MANAGEMENT .............................................................................. 47 
10.1 
Conflict of Interest ................................................................................................... 48 
10.2 
Institutional Review Board (IRB) Approval and Consent ......................................... 48 
10.3 
Subject Data Protection ........................................................................................... 48 
10.4 
Data and Safety Monitoring/Auditing ....................................................................... 48 
10.5 
Adherence to the Protocol ....................................................................................... 48 
10.6 
Amendments to the Protocol ................................................................................... 49 
10.7 
Record Retention .................................................................................................... 49 
10.8 
Obligations of Investigators ..................................................................................... 49 
11.0 
REFERENCES ............................................................................................. 50 
12.0 
APPENDICES .............................................................................................. 51 
Appendix A. Performance Status ............................................................................................ 51 
Appendix B. Response evaluation criteria in solid tumors (RECIST) ..................................... 52 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
BID 
Bis in die/ twice a day 
BUN 
Blood Urea Nitrogen 
CAP 
College of American Pathologists 
CBC 
Complete Blood Count 
CLL 
Chronic Lymphocytic Leukemia 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central Nervous System 
CR 
Complete Response 
CSC 
Cancer Stem Cells 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice  
HIV 
Human Immunodeficiency Virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HRPP 
Human Research Protections Program 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry  
IRB 
Institutional Review Board 
I.V. 
Intravenous 
LDH 
Lactate Dehydrogenase 
mAb 
Monoclonal Antibody 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PK 
Pharmacokinetic 
PDX 
Patient Derived Xenograft 
PET 
Positron Emission Tomography 
p.o. 
per os/by mouth/orally 


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PR 
Partial Response 
PT 
Prothrombin Time 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROR1 
Receptor-tyrosine-kinase-like Orphan Receptor 1 
RP2D 
Recommended phase II dose 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
ULN 
Upper Limit of Normal 
UPR 
Unanticipated Problems involving Risk to subjects or others 


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STUDY SCHEMA  
 
 
 
* Cirmtuzumab dose will be 600 mg. Patients will be enrolled in cohorts of 5. If two or more of the 5 patients in a cohort 
experience dose-limiting toxicity, then further patients will be enrolled at a 50% dose reduction (300 mg fixed dose level). 
 
 
Screening/ 
Baseline 
Cirmtuzumab IV*  Cycle 1: 600 mg  
(Days 1, 15)  
 
Cycles 2 and beyond:  
Every 28 days (Day 1) 
plus Paclitaxel 80 mg/m
2 IV weekly 
______________________________________ 
Treatment continues until disease progresson or 
unacceptable toxicity.  
Note: Cirmtuzumab or paclitaxel may be continued 
alone if the other drug is discontinued due to toxicity, as 
long as the subject is tolerating the continued drug and 
doesn’t exhibit disease progression. If continuing 
Cirmtuzumab alone then labs and AE assessments 
should be done within one day of treatment. If 
continuing paclitaxel alone then labs and AE 
assessments should be done within one day of planned 
weekly treatment. 
______________________________________ 
Tumor response assessments occur approximately 
every 2 cycles for 6 cycles and then may decrease to 
every 3 cycles while on treatment. 
Treatment Cycle = 28 days 
End of 
Treatment 
Phone contact 
for safety x 1 


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STUDY SUMMARY 
Title 
A phase 1b pilot clinical trial to determine the safety and tolerability of 
cirmtuzumab, an anti-ROR1 monoclonal antibody, in combination with 
paclitaxel for the treatment of patients with metastatic, or locally 
advanced, unresectable breast cancer. 
Short Title 
Cirmtuzumab treatment for metastatic breast cancer 
Protocol Number 
HRPP #160178 
Phase 
Phase 1b 
Methodology 
Single arm, open label 
Study Duration 
Subjects will continue study treatment until disease progression or 
unacceptable toxicity. Subjects will have a follow-up 56 days after study 
treatment discontinuation unless patient has started new anti-cancer 
therapy.  
Study Center 
Single center: UC San Diego 
Objectives 
Primary Objectives:   
1. To determine the safety of fixed dose cirmtuzumab during the first 4 
weeks when administered in combination with weekly, standard of 
care paclitaxel to patients with metastatic, or locally advanced, 
unresectable breast cancer. 
 
Secondary Objectives: 
1. To determine the safety and tolerability of cirmtuzumab in 
combination with paclitaxel by ongoing evaluation of adverse events 
(AE’s) during treatment and follow-up. 
2. To assess clinical activity by evaluating objective tumor response 
according to RECIST v1.1 and time to progression. 
3. To measure ROR1 density on tumor and on the putative cancer stem 
cell population, and to correlate these with response.  
 
Exploratory Objectives:  
1. To assess the mechanism of action through pharmacokinetic, safety 
and pharmacodynamic studies including: 
• 
Circulating cirmtuzumab levels in peripheral blood 
• 
Level of circulating antibodies against cirmtuzumab 
• 
As available, we will perform pharmacodynamic, biochemical 
and molecular studies on tissue samples of treated patients, 
depending on sample availability. 
2. To assess imaging correlation of optional PET/CT with standard 
cross-sectional imaging 
 
Number of Subjects 
Up to 30 patients will be consented with a goal of 15 evaluable patients 
who complete at least 4 weeks of combination therapy or experience 
DLT 
Diagnosis and Main 
Inclusion Criteria 
• 
Women or men with biopsy proven (most recent biopsy), Her2/neu 
negative, metastatic or locally advanced, unresectable breast cancer 
who have not received paclitaxel in the metastatic setting. 
• 
There is no limit to prior therapies received.  
• 
CNS metastases are allowed, as long as the metastases are 
asymptomatic, have been treated with radiation, and have been 
stable for > 6 weeks off steroids.  
• 
Patients must have no greater than grade 1 neuropathy 


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• 
ECOG ≤ 2.  
• 
Patients must have adequate hematologic, renal, hepatic and 
coagulation function.  
• 
No concurrent antibody therapy is allowed with the exception of 
denosumab for use in bone metastasis.  
Study Product(s), Dose, 
Route, Regimen 
Each treatment cycle is 28 days. 
Cirmtuzumab is administered by intravenous infusion every other week 
for two doses (i.e., Days 1 and 15 of Cycle 1) then every 28 days for 
subsequent cycles (i.e., Day 1 of each cycle). 
 
Paclitaxel 80 mg/m2 is administered weekly by intravenous infusion on 
Days 1, 8, 15, and 22 of each 28-day cycle. On Days when both 
paclitaxel and cirmtuzumab are administered, paclitaxel will be given at 
least 30 minutes following cirmtuzumab infusion. 
Duration of Administration 
Cirmtuzumab and paclitaxel are administered until the subject 
experiences disease progression or unacceptable toxicity.  
Cirmtuzumab or paclitaxel may be continued alone if the other drug is 
discontinued due to toxicity, as long as the subject is tolerating the drug 
and does not exhibit disease progression. 
Reference Therapy 
Paclitaxel 80 mg/m2 weekly. 


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SCHEDULE OF EVENTS 
Treatment Cycle 
Screening 
Cycle 1 
Cycle 2 and beyond (– 
(Combionation Therapy phase). 
Mono-
Therapy 
phase12 
End of 
Treatment 
Follow-up 
Visit Day 
 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
28 days after 
last dose of 
cirmtuzumab 
or paclitaxel 
(whichever is 
stopped last) 
14 
56 days after 
last dose of 
cirmtuzumab 
or paclitaxel 
(whichever is 
stopped last) 
15  
Visit window 
≤ 14 days 
±1d13 
±1d13 
±1d13 
±1d13 
±1d13 
±1d13 
±1d13 
±1d13 
+1d12,13 
±3d 
±7d 
Informed Consent 
≤ 30 days 
of C1D1 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Checklist 
X 
 
 
 
 
 
 
 
 
 
 
 
History and 
Symptoms 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Vital signs 
(Height: screening 
only) 
X 
X 
X 
X 
X 
X 
X12 
X12 
X12 
X12 
X 
 
Comprehensive 
PE 
X 
X 
 
X 
 
X1 
 
X1 
 
X 
X 
 
ECOG 
Performance 
Status 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
CMP2 
X 
X 
X 
X 
X 
X 
X12 
 X12 
 X12 
X12 
X 
 
CBC and 
differential3 
X 
X 
X 
X 
X 
X 
X12 
 X12 
 X12 
X12 
X 
 
INR or PT 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum hCG 
(female of child 
bearing potential) 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
Screen 
 
X 
X 
X 
X 
X 
 X12 
 X12 
 X12 
X12 
X14 
X15 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
 X12 
 X12 
 X12 
X 
X 
X4 
Cirmtuzumab 
administration 
 
X 
 
X 
 
X 
 
 
 
X12 
 
 
Paclitaxel 
administration 
 
X 
X 
X 
X 
X 
 X12 
 X12 
 X12 
X12 
 
 
Tumor assessment 
by physical exam5 
X 
X 
 
 
 
X 
 
 
 
X12 
X 
 
CT/MRI scan 
Chest/ Abdomen/ 
Pelvis (optional 
PET scan)6 
≤ 30 days 
of C1D1 
X6 
X7 
 
Bone Scan8 
≤ 30 days 
of C1D1 
X8 
 
 
 
Blood collection 
for 
pharmacokinetics 
and correlative 
studies9 
≤30 days 
of C1D1 
X 
X 
X 
X 
X 
 
 
 
X12 
X 
 
Tumor biopsy 
and/or fluid 
collection samples 
for correlative 
studies10, 11 
≤ 30 days 
of C1D1 
X10,11 
X 
 


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1. 
Comprehensive PE will not be performed at Day 15 for Cycles 2 and beyond. 
2. 
Comprehensive metabolic panel (CMP) to include: Na+, Cl-, K+, CO2, BUN, Creatinine, Glucose, Ca2+, total protein, albumin, total 
bilirubin, SGPT, SGOT, alkaline phosphatase. 
3. 
If grade 4 neutropenia is documented (ANC <500/mcl), obtain twice per week until resolved to grade 2. 
4. 
Record if patient is receiving concomitant medication for cancer treatment. 
5. 
For those patients whose disease can be evaluated by physical examination according to RECIST v1.1. 
6. 
CT (or MRI) should be should be performed within 7 days of Day 1 of Cycles 3, 5, and 7. Beyond Cycle 7, scans may be decreased to every 
3 cycles (i.e., within 7 days of Day 1 of Cycles 10, 13, etc.). Scans should be performed at the same frequency but within 7 days of Day 1 of 
the cycle.. Optional PET/CT imaging will be performed at the same time as CT (or MRI). 
7. 
Assess response at disease progression. 
8. 
Bone scans may be performed at baseline (recommended within 30 days of C1D1 if possible) and whenclinically indicated. Bone scans will 
not be used to determine progression of disease. 
9. 
Blood samples are collected for PK analysis and correlative studies according to Protocol Table 5-1. 
10. If the patient consents to biopsy, a core needle biopsy (3 samples) of tumor tissue should be performed or tumor cells should be collected 
from body fluid within 30 days prior to starting study treatment on Cycle 1 Day1.  If feasible, a new sample of tumor tissue may be obtained 
between Day 1 and Day 15 of Cycle 3 and at the time of progression. Patients can still participate in study whether or not biopsies are 
performed.  Biopsies will be obtained either using imaging-guided needle biopsy, skin biopsy, lymph node biopsy, or by recovering tumor 
cells from malignant ascites, pleural effusion,or other body fluid.  
11. In addition, samples from pleural and peritoneal fluid may be obtained from patients who have repeated pleural taps, pleural drainage, or 
peritoneal taps for palliation at other timepoints while the patient is on study or in follow-up per the protocol.  
12. If continuing Cirmtuzumab alone then labs and AE assessments should be done within one day of treatment (typically every four weeks). If 
continuing paclitaxel alone then labs and AE assessments should be done weekly within one day of treatment. 
13. The intent of the visit window is within 1 Day of each planned treatment; however, the visit window of +3d allows for an unanticipated 
delay in treatment. 
14. End of Treatment (EOT)  adverse event monitoring and visit will occur at 28 days +/- 3 days or at the initiation of new cancer therapy 
whichever occurs earlier. PK blood specimen may be drawn at 28 days or, if not feasible, at the start of new anti-cancer therapy.  
15. Followup Visit will occur 56 days +/- 7 days or at the initiation of new cancer therapy whichever occurs earlier. In the event that the start 
of a different anti-cancer therapy occurs earlier than 28 +/- 3 days, the End of Treatment visit and the Followup Visit will be the same visit. 
 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Breast cancer is the most commonly diagnosed cancer, and the second leading cause of 
cancer-related mortality in women. There are approximately 232,000 new cases of invasive 
breast cancer every year in the US, and an estimated 40,000 breast cancer deaths every year.1 
Despite recent advances, the projected 5 year overall survival for a female diagnosed with 
metastatic breast cancer is still only 25.9%.2 Also, although there are a variety of agents 
available for the treatment of metastatic breast cancer many of these agents are associated 
with significant toxicity and poor tolerability.  
 
In addition, highly proliferative hormone receptor positive (Luminal B) or triple negative 
metastatic breast cancer are aggressive subtypes of breast cancer with a poor overall 
prognoses. Currently, the only FDA approved targeted agent for triple negative breast cancer is 
olaparib for the small minority of patients who have BRCA1 or BRCA2 associated breast 
cancer. The backbone of treatment for endocrine-refractory or triple negative breast cancer is 
cytotoxic chemotherapy with significant toxicity and clinical benefit that last months not years. 
The success of agents like trastuzumab and second-generation HER2 targeted agents in 
breast cancer over the past 20 years has illustrated that the goal of treating breast cancer with 
less toxic, targeted therapies is very effective. However, for Her2-negative aggressive breast 
cancers, an unmet medical need exists for new breast cancer therapies that can target rapidly 
proliferating cancer cells and target cancer stem cells, with minimal damage to normal tissues. 
1.2 
 ROR1 and Cancer Stem Cells 
Promising translational research from the lab of Dr. Thomas Kipps and several others have 
recently demonstrated that the highly conserved transmembrane protein ROR1 (receptor 
tyrosine kinase-like orphan receptor 1) is expressed on many high-grade cancers including 
breast cancer. ROR1 is not expressed on the surface of normal adult tissues, with the possible 
exception of a rare subset of precursor B cells, called hematogones, which may be observed in 
the marrow of pediatric patients or patients recovering from myeloablative therapy.3 ROR1 plays 
a key role in fetal development, but based on exhaustive profiling studies in human 
hematopoietic stem cells, it is no longer detectable by the 2nd trimester fetal liver stage, and is 
not on marrow stem cells. Due to a potential lack of cross-reactivity with normal adult tissues it 
represents an ideal target for immunotherapy. 
 
Adult chronic lymphocytic leukemia (CLL) cells express ROR1, and patients immunized with 
CLL cells can make auto-antibodies against this protein.4-6 Some breast cancer cells also 
express ROR1. Several groups have discovered that high-level expression of ROR1 is 
associated with shorter progression-free survival after therapy and shorter median overall 
survival in some datasets. Expression of ROR1 may also be associated with more 
aggressive growth as well as with activation of PI3K, AKT, and cAMP-response-element-
binding protein (CREB). ROR1 may interact with EGFR, and play a pivotal role in 
epithelial-mesenchymal transition and metastasis.
7-9   
 
Zhang et. al recently demonstrated, both in vitro and in triple negative, patient-derived-xenograft 
(PDX) murine models that ROR1 expressed in breast cancer is associated with shorter 
progression-free survival after therapy and shorter overall median survival.7,8 Our recent studies 
have shown that some tumors that express ROR1 also express the putative cancer stem cell 


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(CSC) markers ALDH1, CD44 and CD24. In addition, in both cell culture and in murine models, 
these cells revealed aggressive growth patterns characteristic of CSC.10  
1.3 
Cirmtuzumab and Paclitaxel 
Cirmtuzumab (CLL Interacting Ror1 Molecule TUmor targeting Z(enotropic) hUmanized 
Monoclonal AntiBody) is a fully-humanized monoclonal antibody designed to bind the 
extracellular immunoglobulin-like domain of ROR1 with high-affinity.  
 
Initial preclinical studies show that cirmtuzumab is an ideal therapy due to the following 
features: 
• 
High affinity for cell-surface ROR1 
• 
Activity against cancer cells that express ROR1, which include cancer-stem cells. 
• 
Lack of cross reactivity with normal adult tissues 
• 
Reduced immunosuppressive potential with lack of targeting most normal 
lymphoid or myeloid cells 
• 
Low immunogenic potential due to substantial humanization of the antibody 
framework 
 
The anti-microtubule agent paclitaxel is well established as an effective therapy for metastatic 
breast cancer both in the first line and heavily pretreated population. Expected overall response 
rates for single agent paclitaxel are between 20-45%.11-14 When given weekly at a dose of 
80mg/m2, paclitaxel is both effective and generally well tolerated.15  
 
In this study we propose to combine the monoclonal antibody (mAb) cirmtuzumab with weekly 
paclitaxel. The rationale for this combination comes from recent pre-clinical data shown in 
Figure 1, which displays the activity of cirmtuzumab with and without paclitaxel (Taxol) in 
immune-deficient mice bearing tumors following engraftment with PDX5 cells. For this, tumor-
bearing mice received intravenous (i.v.) control IgG or 
cirmtuzumab (at 10 mg/kg) with and without paclitaxel 
(Taxol, at 13.4 mg/kg). The tumors grew significantly more 
slowly in cirmtuzumab or paclitaxel treated mice compared 
to control IgG treated mice. Moreover, the inhibitory effect 
of cirmtuzumab in combination with paclitaxel on the 
growth of PDX5 cells was greater than that of either 
cirmtuzumab or paclitaxel alone.8 Perhaps most 
importantly, when cells were harvested from tumors treated 
with both agents and implanted in fresh host animals, no 
tumors formed, suggesting that the tumor initiating stem 
cells had been eliminated. These data demonstrate that 
cirmtuzumab has activity against human breast cancer and 
that this effect is augmented when used in combination 
with paclitaxel.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.4 
Cirmtuzumab Pre-clinical Pharmacology and Toxicology 
To support the use of cirmtuzumab in clinical trials, a comprehensive single-species 
pharmacology/toxicology study was conducted in rats.  In this study, groups of animals (15 of 
each sex) received cirmtuzumab at doses of 40, 120 and 400 mg/kg given weekly for 5 doses 
over 28 days.  Three days following the final product administration, 20 animals (10 of each sex) 
in each dosing cohort were sacrificed and the remaining animals in the recovery phase 
sacrificed on day 56.  During the study, parameters measured included twice-daily clinical signs, 
food consumption, weekly body weights, ophthalmic examinations (pretreatment, after last dose 
and last week of drug-free period) urinalysis (prior to sacrifice) and clinical pathology indices 
including serum chemistries, hematology and coagulation studies (prior to sacrifice).  Safety 
pharmacology measurements including functional observation batteries were conducted weekly.  
Finally, full necropsy and a complete microscopic analysis was performed on all animals in all 
groups and a select panel of organs including the liver, spleen, heart, kidneys, brain and ovaries 
were weighed.   
 
In all dosing cohorts, the cirmtuzumab drug product was well tolerated by the treated rats. No 
adverse events were noted during the conduct of the study.  At terminal sacrifice, gross 
pathologic exams were normal and no untoward effects of product administration were noted. 
1.5 
Cirmtuzumab Clinical Experience - Phase 1 CLL Trial 
The single agent safety of cirmtuzumab was evaluated in a Phase 1, open label clinical trial that 
enrolled patients with relapsed/refractory chronic lymphocytic leukemia.  
 
Between September 2014 and September 2017, 26 patients enrolled and received 
Cirmtuzumab at doses between 15 mcg/kg and 20 mg/kg every 14 days for a maximum of four 
infusions. All patients had relapsed or refractory disease with objective signs of disease 
progression and an indication for therapy according to international working group criteria 
(Hallek et al., 2008). The majority of patients had at least one factor associated with poor 
prognosis, including unmutated immunoglobulin heavy-chain variable region gene (IGHV) or 
deletion of chromosome 17p (Del 17p). All patients were previously treated with anti-CD20 
monoclonal antibodies, and 27% and 23% previously received inhibitors of BCL-2 and B-cell 
receptor signaling (including ibrutinib), respectively. All patients had leukemic cells that 
expressed ROR1 (MFI range 11.6 to 113.9), with half of the patients having a mean 
fluorescence intensity (MFI) greater than 32, which was previously associated with a poor 
prognosis (Cui et al., 2016). 
 
Cirmtuzumab infusions were safe and well-tolerated. There were no infusion-related reactions, 
though all patients received pre-medications for the first infusion with corticosteroids, 
acetaminophen, and antihistamine. The maximum rate of infusion was 800 mg/hr. There was 
also no dose-limiting toxicities (DLT) and there were no serious adverse events up to a dose of 
20 mg/kg. The main recurrent laboratory abnormalities included anemia, thrombocytopenia, and 
neutropenia, which were primarily attributed to underlying CLL. There were two instances of 
grade 3 lipase elevation (greater than two-times the upper limit of normal). Neither was 
accompanied by abdominal pain or other symptoms of pancreatitis. Both resolved 
spontaneously without intervention, including one case resolving within the same day upon a 
repeat blood draw. There was one instance of grade 3 ALT elevation, which coincided with a 
patient having a gallstone. Table 1 lists all recurrent AEs, regardless of attribution. 
 


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Table 1: Adverse Events 
Adverse Events (AE) by Type, Incidence, and Intensity, % (Total N=26) 
AE (Regardless of Attribution) 
CTCAE (Ver 4.03) or iwCLL Grade 
Total 
1 
2 
3 
4 
 
Anemia 
58% 
19% 
8% 
 
85% 
Thrombocytopenia 
38% 
23% 
4% 
 
65% 
Neutropenia 
23% 
15% 
4% 
 
42% 
Upper Resp. Infection 
 
27% 
 
 
27% 
Fatigue 
23% 
4% 
 
 
27% 
Diarrhea 
27% 
 
 
 
27% 
Cough 
23% 
 
 
 
23% 
Cough 
23% 
  
  
  
23% 
Headache 
23% 
  
  
  
23% 
Dyspnea 
19% 
  
  
  
19% 
Lipase Increased 
4% 
4% 
8% 
  
16% 
Nausea 
16% 
  
  
  
16% 
Constipation 
16% 
  
  
  
16% 
Urinary Tract Infection 
  
12% 
  
  
12% 
Akathisia 
12% 
  
  
  
12% 
Dizziness 
12% 
  
  
  
12% 
Bloating 
12% 
  
  
  
12% 
Insomnia 
12% 
  
  
  
12% 
Urinary Frequency 
12% 
  
  
  
12% 
Creatinine Increased 
12% 
  
  
  
12% 
Hyperuricemia 
12% 
  
  
  
12% 
Skin Infection 
  
4% 
4% 
  
8% 
Amylase Increased 
  
4% 
4% 
  
8% 
ALT Increased 
4% 
  
4% 
  
8% 
Conjunctivitis 
4% 
4% 
  
  
8% 
Anorexia 
4% 
4% 
  
  
8% 
Maculopapular Rash 
4% 
4% 
 
  
8% 
Hypokalemia 
8% 
  
  
  
8% 
Vomiting 
8% 
  
  
  
8% 
Flushing 
8% 
  
  
  
8% 
Hyperkalemia 
8% 
  
  
  
8% 
Urinary Urgency 
8% 
  
  
  
8% 
Hyperhidrosis 
8% 
  
  
  
8% 
GERD 
8% 
  
  
  
8% 
 
 
Overall, no patient stopped treatment due to an adverse event. Five patients discontinued 
cirmtuzumab prior to completing the four planned infusions. One patient in the first cohort 
stopped due to progressive disease with worsening thrombocytopenia following 1 dose of 15 
mcg/kg. The other patients met criteria for stable disease at the time of discontinuation, but 
stopped to pursue other treatment options that became available to them (eg: approval of 
venetoclax by the US Food and Drug Administration in 2016). 
 
Pharmacokinetic studies performed using an ELISA assay generated for human IgG binding to 
immobilized ROR1 detected cirmtuzumab at levels above background, with peak concentrations 
that were highest in samples collected within 60 minutes of the completion of each infusion, and 
increased with each subsequent infusion of cirmtuzumab. Peak levels increased proportionally 


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with the dosage administered, with peak cirmtuzumab concentrations above 400 mcg/mL for 
patients who received doses of 20 mg/kg. There was evidence of in vivo antibody stability. 
Plasma collected approximately 3 months after the last infusion still had significant levels of 
cirmtuzumab (> 40 ug/ml). The half-life of cirmtuzumab is calculated to be 32.4 days, similar to 
other monoclonal antibodies.  
 
Pharmacodynamic studies confirmed sustained and dose-dependent target inhibition. Starting 
at doses of 2 mg/kg or higher, there was inhibition of leukemia-cell Rho-GTPase activation 
within 24 hours of the initial cirmtuzumab dose. Phosphorylation of HS-1 was also inhibited 
upon initiation of cirmtuzumab.  In keeping with plasma pharmacokinetics of cirmtuzumab, 
inhibition of leukemia-cell activation of pHS-1 was sustained four to six months after the final 
infusion of cirmtuzumab.   
 
Following Cirmtuzumab treatment, 16 of 20 evaluable patients, including 9 of 10 evaluable 
patients treated at dose levels of 2 mg/kg or greater, had stable disease, despite having 
progressive disease upon study entry. Patients that discontinued cirmtuzumab early without 
meeting criteria for progressive disease were considered not evaluable, although they met 
criteria for stable disease at the time of discontinuation. While 4 patients met criteria for 
progressive disease, three received cirmtuzumab doses of 240 mcg/kg or less and 1 patient 
received 20 mg/kg. Patients did not require subsequent therapy for prolonged periods. The 
median time to requiring next treatment due to progressive disease was 259 days, which is 
similar to the time at which cirmtuzumab plasma levels become undetectable. 
 
1.6 
Rationale 
Currently, the standard of care for patients with metastatic breast cancer is palliative anti-
estrogen therapy for patients with ER-positive or PR-positive and Her2-negative breast cancer 
until the patient becomes refractory, at which time serial monotherapy chemotherapy agents are 
administered, as long as performance status remains adequate.  For triple negative breast 
cancer patients, serial monotherapy chemotherapy, or combination chemotherapy regimens are 
administered depending upon how rapidly the disease is progressing.  For all patients with 
metastatic breast cancer approximately 75% die within 5 years (40,000 patients annually) due to 
refractory disease2; therefore, new therapeutic approaches are needed. Paclitaxel’s relatively 
low toxicity profile when given on a weekly basis makes it an ideal agent for combination drug 
studies like the one proposed. Based on the biological rationale behind cirmtuzumab and 
preclinical activity with paclitaxel, an open label, pilot phase Ib clinical trial is proposed to 
evaluate the safety of cirmtuzumab in combination with paclitaxel for the treatment of 
metastatic, or locally advanced, unresectable breast cancer. 
 
Given the observation of clinical benefit and inhibition of ROR1 signaling at cirmtuzumab dose 
levels of 2 mg/kg or higher in a majority of chronic lymphocytic leukemia patients, the prolonged 
time to progression after discontinuation of 4 doses of cirmtuzumab, and the half-life of 32.4 
days, the recommended fixed dose of 600 mg would translate to 8 mg/kg in an average woman 
and with dose reduction 4 mg/kg – dose levels above those for which disease stability were 
observed in a majority of chronic lymphocytic leukemia patients. Therefore 2 mg/kg is felt to be 
the minimum Biologically Active Dose, and is the lowest dose planned for evaluation in 
subsequent Cirmtuzumab trials. The 600 mg dose is therefore justified based on safety and 
biologic activity.  
 
 


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Standard imaging to assess therapeutic response to treatment for patients with metastatic 
breast cancer is by cross-sectional imaging of target lesions by CT or MRI. PET/CT imaging 
offers the potential to monitor for changes in the metabolic activity of metastatic foci.  Currently it 
is not certain whether this information will have any predictive value for assessing outcome.  As 
such, PET/CT cannot be used for tumor response assessment for investigational 
agents.   However, by providing the option of Fluoro-deoxy-glucose PET/CT imaging at baseline 
and at 8-week intervals to patients treated on protocol, we can collect such information and 
assess how it relates to outcome in order to generate hypotheses for future prospective trials. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
1. To determine the safety and tolerability during the first 4 weeks of fixed dose 
cirmtuzumab when administered in combination with weekly standard of care 
paclitaxel to patients with metastatic, or locally advanced, unresectable breast 
cancer. 
2.2 
Secondary Objectives   
1. To determine the safety and tolerability of cirmtuzumab in combination with paclitaxel 
by ongoing evaluation of adverse events (AE’s) during treatment and follow up.  
2. To assess clinical activity by evaluating objective tumor response and time to 
progression as defined by RECIST v1.1. 
3. To measure ROR1 receptor density on primary tumor or metastatic tumor specimen 
and on putative cancer stem cell population and to correlate this with anti-tumor 
activity. 
2.3 
Exploratory Objectives  
1. To assess the mechanism of action through pharmacokinetic and safety studies 
including 
• 
Circulating cirmtuzumab levels in peripheral blood  
• 
Level of circulating antibodies against cirmtuzumab  
• 
As available, we will perform pharmacodynamic, biochemical and molecular 
studies on tissue samples of treated patients, depending on sample availability. 
• 
Compare PET/CT imaging to standard cross-sectional imaging 
2.4 
Endpoints 
 
Primary Endpoint:  
• 
Safety as determined by the rate of dose-limiting toxicities during the first 4 
weeks of treatment at a fixed dose of cirmtuzumab in combination with paclitaxel 
by recording adverse events (description, CTCAE v 4.03 grade, seriousness) at 
least possibly related to cirmtuzumab or to cirmtuzumab with paclitaxel.  
 
Secondary Endpoints: 
• 
Safety and tolerability of the combination therapy since the start of any study 
treatment.  
• 
Objective tumor response rate, best tumor response rate, and time to 
progression as assessed by RECIST v1.1. 
• 
ROR1 expression levels and putative breast cancer stem cell markers in tumor 


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pre-treatment tumor specimen measured by immunohistochemistry or flow 
cytometry  
 
Exploratory Endpoints: 
• 
Plasma pharmacokinetics of cirmtuzumab. 
• 
Level of circulating antibody formation against cirmtuzumab. 
• 
As available, we will perform pharmacodynamic biochemical and molecular 
studies on tissue samples of treated patients, depending on sample availability. 
• 
Compare PET/CT imaging to standard cross-sectional imaging 
3.0 
PATIENT ELIGIBILITY 
The protocol-specified eligibility criteria are designed to select subjects for whom study 
participation is considered appropriate. All relevant medical and non-medical conditions should 
be taken into consideration when deciding whether this clinical trial is suitable as a potential 
study subject. Prior to treatment, the Principal Investigator and the treating physician must 
agree that participation in this clinical trial is in the best interest of patient. 
3.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study.  
 
1. Patient has the ability to understand and the willingness to sign a written informed consent. 
 
2. Patients must have biopsy-confirmed, metastatic or locally advanced surgically 
unresectable, Her2 negative breast cancer. Her2 status should reflect the most recent 
biopsy results. 
Note: HER2 negative breast cancer is defined according to the American Society of Clinical 
Oncology (ASCO)/College of American Pathologists (CAP) guidelines 2013 for HER2 testing 
performed in a CLIA-certified laboratory.16  
 
3. Patient should have ER/PR negative (<10% of cells staining for ER or PR) breast cancer or 
have ER/PR positive (≥10% of cells staining for ER or PR) breast cancer that has exhausted 
standard endocrine therapy and/or in the opinion of the treating oncologist, warrants 
cytotoxic chemotherapy. 
 
4. Patient must have measurable disease as defined by RECIST v1.1. Measurable lesions will 
be confirmed by radiographic imaging (CT or MRI). Patients with bone only disease will be 
eligible if disease is considered measurable and a soft tissue component is present and can 
be biopsied. 
 
5. Allowable types and amount of prior therapy: 
There is no limit to prior lines of therapy, but patients must not have received prior taxane 
chemotherapy in the metastatic setting. 
 
6. Patient must be ≥ 18 years of age. 
 
7. All genders, races and ethnic groups are eligible for this trial. 
 
8. Patients must have ECOG Performance Status ≤ 2. 
 
9. Patient has adequate organ function as defined below: 


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• 
Absolute Neutrophil Count 
≥ 1.0 x 109/L 
• 
Platelet count 
≥ 100,000 /μl 
• 
Hemoglobin 
≥ 8.0 g/dL  
• 
Total bilirubin 
≤ 1.5 x upper limit of normal 
• 
AST and ALT 
≤ 3 x upper limit of normal 
• 
Serum creatinine 
≤ 2 x upper limit of normal OR 
• 
Creatinine clearance 
> 40 ml/min/1.73 m2 
 
10. Women of child-bearing potential and male subjects who are sexually active with a woman 
of childbearing potential must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry, for the duration of study 
participation, and for at least 6 months following last infusion of cirmtuzumab. Should a 
woman become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. 
 
11. Women of childbearing potential must have a negative pregnancy test prior to initiating 
study drug dosing. 
 
12. Existing neuropathy must be no greater than Grade 1. 
 
13. No concurrent antibody therapy can be planned with the exception of denosumab for use in 
bone metastasis. 
 
14. CNS metastases are allowed as long as the metastases are asymptomatic, have been 
treated with radiation, and have been stable for > 6 weeks off steroids. 
 
3.2 
Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
 
1. Patient is currently receiving chemotherapy or has received another chemotherapy within 5 
half-lives, radiotherapy or immunotherapy within 2 weeks prior to study treatment initiation. 
 
2. Patient has known, untreated and/or symptomatic central nervous system (CNS) 
metastases and/or carcinomatous meningitis. 
 
3. Patient had disease that was refractory to paclitaxel in the neoadjuvant setting and/or 
developed metastatic breast cancer within 6 months of neoadjuvant or adjuvant taxane 
chemotherapy. 
 
4. Patient has had major surgery within 3 weeks prior to enrollment. 
 
5. Patient has severe and/or uncontrolled medical disease(s) (i.e., myocardial infarction within 
6 months of study, CKD stage IV or above, severe chronic pulmonary disease or active 
infection). 
 
6. The patient has known acute or chronic hepatitis B or C. 
 


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7. The patient has a history of allergic reactions attributed to compounds of similar chemical or 
biologic composition to paclitaxel. 
 
8. The patient has a history of another malignancy within 2 years prior to study entry, except 
curatively treated non-melanotic skin cancer, cervical carcinoma in situ or stage I colon 
cancer. 
 
9. Patient has a history of non-compliance or other medical illness that would preclude 
compliance with study procedures. 
 
10. Patient has a known diagnosis of human immunodeficiency virus (HIV) infection. 
 
11. Patient has severe cardiac insufficiency (NYHA III or IV) with uncontrolled and/or unstable 
cardiac or coronary artery disease 
 
12. Patient is pregnant or nursing. There is a potential for congenital abnormalities and for this 
regimen to harm nursing infants. 
 
 
4.0 
TREATMENT PLAN 
4.1 
Study Drugs Dose Assignment  
This is an open label, single institution, Phase Ib, study of fixed dose cirmtuzumab in 
combination with weekly paclitaxel in patients with metastatic, or locally advanced, unresectable 
breast cancer.  
 
During the treatment period, cirmtuzumab and paclitaxel will be administered by intravenous 
(IV) infusion on an outpatient basis. Treatment cycles are 28 days in length. Cirmtuzumab will 
be administered IV with acetaminophen and cetirizine pre-medication (see below infusion plan) 
on day 1 and 15 of cycle 1, and on day 1 of each subsequent cycle. Paclitaxel will be 
administered after cirmtuzumab with diphenhydramine, dexamethasone, famotidine and anti-
emetic medication as indicated on days 1, 8, 15 and 22 of each cycle per institutional standard 
and/or physician discretion. 
 
The dose of cirmtuzumab will be 600 mg fixed dose (the full contents of two vials). Paclitaxel will 
be given at a dose of 80 mg/m2.  
 
REGIMEN DESCRIPTION 
 
Agent 
 
Pre-medications 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Cirmtuzumab acetaminophen 650 mg 
p.o.;cetirizine 10 mg p.o. 
600mg  
 
IV prior to 
paclitaxel 
Cycle 1:  
Day 1, 15 
 
Cycles 2 
and beyond:  
Day 1 
 28 days 
 


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Paclitaxel 
Per physician discretion or 
institutional standard, may 
include dexamethasone* 10 
mg IV at least 30 minutes 
prior to paclitaxel; 
famotidine 20 mg IV; 
diphenhydramine 25 mg IV; 
and anti-emetic medication 
as indicated. 
80 mg/m2  
 
IV at least 30 
minutes after 
completion of 
cirmtuzumab  
Days 1,8,15, 
22 
*Note: additional dexamethasone may be given up to 24 hours prior to paclitaxel if indicated according to 
institutional practice. 
 
Replacement patients may be enrolled for the following: 
Patients who withdraw prior to completing 2 cycles of study treatment for a reason that is 
definitely unrelated to toxicity of cirmtuzumab (e.g., disease progression). Replacement patients 
will ensure enough safety data is obtained from patients having received 8 weeks of 
combination treatment in order for cirmtuzumab to potentially meet entry criteria as an agent for 
the I-SPY 2 clinical trial (NCT01042379). 
4.2 
Definition of Dose-Limiting Toxicity 
For the purposes of defining the recommended phase 2 dose (RP2D), dose-limiting toxicities 
are based on events occurring during the first 28 days of treatment. The recommended dose for 
further study will be equal to or less than the MTD and will take into account any cumulative or 
delayed toxicity. 
 
DLTs will be graded for severity based according to NCI Common Terminology Criteria for 
Adverse Events version 4.03 (NCI CTCAE v4.03).17  If two of the first 5 patients experience 
dose-limiting toxicity, then further patients will be enrolled at a 50% dose reduction or 300 mg 
flat dose level.  
 
Dose limiting toxicity is defined as a clinically significant adverse event that is considered by the 
investigator to be possibly, probably or definitely related to cirmtuzumab or the combination of 
cirmtuzumab with paclitaxel within 28 days of investigational treatment initiation: 
• 
Grade 4 hematologic toxicity lasting > 7 days. 
• 
Grade 3 thrombocytopenia lasting > 7 days or with bleeding requiring transfusion. 
• 
Grade 3 neutropenia (ANC <1000 per mm3) and documented infection or febrile 
neutropenia lasting > 7 days. 
• 
Grade 3 diarrhea that lasts longer than 48 hours (despite intensive loperamide therapy). 
• 
Grade 3 fatigue that lasts more than 1 week. 
• 
Rash associated with pain not relieved with analgesia or rash causing disfigurement. 
• 
Other Grade ≥ 3 non-hematologic toxicity 
 
Exceptions:  
• 
Grade 4 neutropenia lasting less than 8 days. 
• 
Grade 3 infusion reaction. 
4.3 
Dose Reduction and safety stopping rule 
Subjects will be enrolled in cohorts of five. If two or more of the first five patients experience 
dose-limiting toxicity (DLT) attributed to cirmtuzumab, then further patients will be enrolled at a 
50% dose reduction (300 mg flat dose level); if two or more of the next five patients experience 
dose-limiting toxicity attributed to cirmtuzumab, then the study will be stopped. If fewer than two 


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of the first five patients experience dose-limiting toxicity attributed to cirmtuzumab, but two or 
more of the next five patients experience dose-limiting toxicity again, then the last five patients 
will also undergo dose reduction and be treated at the 300 mg dose level. 
4.4 
Pre-Medications 
Patients will be pre-medicated with acetaminophen 650 mg p.o. and cetirizine 10 mg p.o. prior 
to cirmtuzumab infusion. Prior to paclitaxel infusion, patients be pre-medicated with 
dexamethasone 10 mg IV, diphenhydramine 25 mg IV, famotidine 20 mg IV, and an anti-emetic 
medication as indicated. Pre-medication may be changed according to institutional standards, 
patient allergies/intolerances, and/or physician discretion. Dexamethasone injection will be 
given at least 30 minutes prior to start of paclitaxel infusion. 
4.5 
Study Drugs Infusion  
4.5.1 Cirmtuzumab infusion plan 
 
• 
A qualified person (eg, nurse with experience in monitoring the administration of 
therapeutic agents used in patients with cancer) will be responsible for infusing 
cirmtuzumab.  
• 
Using an infusion pump, cirmtuzumab should be administered via a polyvinyl chloride 
(PVC) administration set and through a 0.2 μm in-line filter. The IV line should be flushed 
with 0.9% Sodium Chloride Injection, USP, before and after each dose.  
• 
The initial cirmtuzumab infusion will be administered over a planned infusion time of ~90 
minutes, with 20% of the total dose to be administered in the first ~30 minutes and the 
remaining 80% of the total protein dose to be administered in the subsequent ~60 
minutes. For subjects who prove able to tolerate infusions without infusion-related 
toxicity, subsequent infusions may be administered over a minimum time of ~30 minutes. 
Infusion times may be extended as necessary to accommodate individual subject 
tolerance of treatment.  
 
4.5.2 Paclitaxel infusion  
• 
If cirmtuzumab is given on that day, once cirmtuzumab infusion has completed, the IV line 
must be flushed and then pre-medication for paclitaxel can begin. 
• 
Patients must be pre-medicated with dexamethasone 10 mg IV at least 30 minutes prior to 
start of paclitaxel infusion. Patients might have received additional dexamethasone within 24 
hours priors to paclitaxel if indicated according to institutional practice. 
• 
Patients will also receive diphenhydramine 25 mg IV, famotidine 20 mg IV, and anti-emetic 
medication as indicated. 
• 
Paclitaxel 80 mg/m2 in 250cc D5W will be run over one hour (+/-10 minutes) or as tolerated 
according to institutional standards.  
4.6 
Permitted Concomitant Therapy 
• 
All concomitant medications and blood products, as well as interventions received by 
patients from the first dose of study drugs until the end of study visit should be recorded. 
 
• 
Palliative and supportive care for disease-related symptoms, including pain medications 
and antiemetics, are permitted. Hematopoietic white blood cell growth factors such as 
filgrastim are allowed, if clinically indicated, according to institutional standards. 


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• 
Patients may continue bone anti-resorptive agents if started prior to study treatment. 
4.7 
Prohibited Concomitant Therapy 
• 
Use of anti-neoplastic or anti-tumor agents not part of the study therapy, including 
chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer therapy, are 
not permitted while participating in this study.  
 
• 
Use of concurrent investigational agents is not permitted. 
4.8 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each patient 
will be assessed for the development of toxicity according to the NCI Common Toxicity Criteria 
for Adverse Events (CTCAE), version 4.03. Dose adjustments should be made according to the 
system showing the greatest degree of toxicity.  
 
Dose reduction or deferral of cirmtuzumab and/or paclitaxel administration for toxicity may take 
place at any time during the study. Dose reductions for paclitaxel will be made according to the 
product label and institutional standards. Patients requiring dose reductions of cirmtuzumab will 
be dose reduced according to.Table 4-1. 
 
Table 4-1. Cirmtuzumab dose reduction scheme 
Cirmtuzumab Dose-Reduction 
 Dose 
Dose Reduction 
 
600 mg 
300 mg 
  
Patients experiencing a DLT attributed to cirmtuzumab will have their dose lowered unless, in 
the interest of the patient, the treating investigator recommends study discontinuation. 
 
Patients who discontinue paclitaxel due to unacceptable toxicity attributed to paclitaxel may 
continue receiving cirmtuzumab in the absence of disease progression and cirmtuzumab-related 
unacceptable toxicity. 
 
Patients who discontinue cirmtuzumab due to unacceptable toxicity attributed to cirmtuzumab 
may continue receiving paclitaxel in the absence of disease progression and paclitaxel-related 
unacceptable toxicity. 
 
4.8.1 Dosage Modification Criteria and Guidelines for Management of Cirmtuzumab 
Related Toxicities 
NCI-CTCAE (v4.03) 
Grade 
Cirmtuzumab Dose 
Modification 
Guideline for Management 
Diarrhea 
Grade 1 
None 
Consider loperamide (4 mg 
at first onset, followed by 2 
mg q 2–4 hours until free of 
diarrhea for 12 hours) 


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NCI-CTCAE (v4.03) 
Grade 
Cirmtuzumab Dose 
Modification 
Guideline for Management 
Grade 2 
None 
(Dose reduction of cirmtuzumab 
is necessary if diarrhea persists 
over 48–72 hours despite 
optimal medical management) 
Loperamide (4 mg at first 
onset, followed by 2 mg q 2–
4 hours until diarrhea free for 
12 hours) 
Grade 3 
• 
Defer then dose reduce 
cirmtuzumab. Cirmtuzumab 
should not be re-escalated. 
• 
If diarrhea persists over 48 
hours despite optimal 
medical management 
during the first 28 days, 
discontinue study treatment. 
Defer cirmtuzumab and 
paclitaxel administration until 
resolution to Grade £1, and 
restart at reduced 
cirmtuzumab dose 
Grade 4 
Discontinue study treatment. 
 
Pulmonary Events (if possibly Interstitial Lung Disease)  
All Grades 
Temporarily defer cirmtuzumab 
and paclitaxel administration 
pending diagnostic evaluation.  
If the pulmonary adverse event 
is assessed as possibly, 
probably, or definitely related to 
cirmtuzumab, discontinue the 
patient from study treatment. 
Unexplained dyspnea, either 
new or progressive, should 
be aggressively evaluated.   
Rash 
Grade 1 and 2 
Tolerable rash 
None 
Any of the following: oral 
antibiotics (tetracycline, 
minocycline, doxycycline) 
topical clindamycin, 
diphenhydramine, topical or 
oral corticosteroids at 
discretion of investigator 
Grade 3 
Intolerable rash 
Consider deferral and/or dose 
reduction if unresponsive to 
symptomatic management.  
Re-escalation is allowed. 
Manage as described above 
Grade 4 
Discontinue study treatment. 
 
Hepatotoxicity 
AST/ALT Grade 3 
(>5.0 – 10.0 x ULN) 
Defer cirmtuzumab and 
paclitaxel then dose reduce 
cirmtuzumab; cirmtuzumab 
should not be re-escalated. 
Defer cirmtuzumab and 
paclitaxel until resolution to 
Grade £1, and restart at 
reduced dose 


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NCI-CTCAE (v4.03) 
Grade 
Cirmtuzumab Dose 
Modification 
Guideline for Management 
Bilirubin > 1.5 X ULN  
Defer cirmtuzumab and 
paclitaxel, unless patient has 
history of Gilbert’s syndrome in 
which case defer cirmtuzumab 
and paclitaxel if bilirubin >2.0 X 
ULN.Reduce dose of 
cirmtuzumab for all other 
patients.  
Defer cirmtuzumab and 
paclitaxel until resolution to 
< 1.25 X ULN and restart 
cirmtuzumab at reduced 
dose. If patient has history of 
Gilbert’s syndrome, defer 
cirmtuzumab and paclitaxel 
until resolution to <2.0 X 
ULN. 
Hematologic 
ANC <1000/mm3 
Grade 3; 
Hemoglobin < 8 
gm/dL Grade 3;  
 
Defer cirmtuzumab and 
paclitaxel administration until 
resolution to Grade £2 
(filgrastim may be used per 
investigator discretion), and 
restart at same dose.  
Defer cirmtuzumab and 
paclitaxel administration until 
resolution to Grade £2, and 
restart at same dose 
cirmtuzumab. If occurs a 
second time, cirmtuzumab 
will be reduced to reduced 
dose level. 
Platelet count < 
75,000/uL Grade 2 
Defer cirmtuzumab and 
paclitaxel administration until 
resolution to £ Grade 1 
(>75,000/uL); restart 
cirmtuzumab without dose 
modification 
Defer cirmtuzumab and 
paclitaxel administration until 
resolution to £ Grade 1, 
restart cirmtuzumab at full 
dose. 
When paclitaxel only is 
administered and platelet 
count is <75,000/uL, defer 
paclitaxel and resume the 
following week if platelet 
count is >75,000/uL 
Other Non-hematologic 
Grade ≥ 3 
First occurrence: Defer 
cirmtuzumab and paclitaxel 
then dose reduce cirmtuzumab; 
Re-escalation per discretion of 
Principal Investigator. 
 
Second occurrence: 
discontinue treatment. 
Defer cirmtuzumab and 
paclitaxel administration until 
resolution to Grade £1, and 
restart at reduced dose. Re-
escalation per discretion of 
Principal Investigator. 
Second occurrence: 
Discontinue treatment. 
Notes:  
1. If any of the above are noted, the patient will be re-assessed within 4 days by the 
treating physician or co-investigator. Isolated laboratory abnormalities may be re-
evaluated by laboratory draw only, or based on physician or investigator discretion. 
2. Cirmtuzumab infusions can be delayed for a maximum of 28 days; if not restarted in 
that time-span, cirmtuzumab study treatment will be permanently discontinued. 
3. If dose is decreased for Grade 3 or 4 toxicity, dose re-escalation is not planned 
except as noted above. 
4. For unanticipated invasive procedures, cirmtuzumab infusions can be delayed for a 
maximum of 28 days; if not restarted in that time-span, cirmtuzuamb study treatment 
will be permanently discontinued. 


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5. Doses of cirmtuzumab and paclitaxel will be deferred until improvement in toxicity is 
seen to allow patient to receive all treatment. Study procedures will be deferred and 
repeated the following week to allow patients to complete the full treatment regimen.  
6. If doses of cirmtuzumab are delayed by 8 days for issues other than toxicity due to 
study treatment, the same cirmtuzumab dose will be repeated 2 weeks after 
resumption of cirmtuzumab and then continued every 4 weeks. The purpose of the 
additional two-week “loading dose” is to optimize pharmacokinetic levels of 
cirmtuzumab. 
4.8.2 Dosage Modification Criteria and Guidelines for Management of Paclitaxel Related 
Toxicities  
Dose modification for paclitaxel will occur according to the product label and institutional 
standards.  
For Grade > 2 rash, allergy, or infusion reaction, ABRAXANE® for Injectable Suspension 
(paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 100 mg/m2 per 
week may be substituted for paclitaxel according to investigator discretion. Any premedications 
are at the discretion of the investigator. 
 
4.8.3 Modifications for Infusion Reactions 
Patients will be monitored for the presence of infusion-related reactions. Treatment for infusion-
related reactions will be managed according to the following guidelines: 
Infusion 
Reaction 
Occurrence Management Guidelines 
Grade ≤ 2 
any 
Institute supportive measures. 
 
See section 4.8.2 for option to switch to Abraxane per 
investigator discretion. 
 
When resolved, resume study treatment at same dose 
level.  
Grade 3 
 
1st 
Institute supportive measures. 
 
See section 4.8.2 for option to switch to Abraxane per 
investigator discretion. 
 
When resolved, resume study treatment at the same dose 
level. Pre-medications listed in protocol are mandatory for 
re-challenge. 
2nd 
Institute supportive measures. 
 
Permanently discontinue study treatment. 
Grade 4 
any 
Institute institutional procedures for adult medication 
reaction/anaphylactic response. 
Permanently discontinue study treatment. 
4.9 
Duration of Study Treatment 
In the absence of treatment delays due to adverse events, treatment with cirmtuzumab and 


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paclitaxel combination therapy may continue until one of the following, whichever occurs first: 
• 
Disease progression unless the patient is receiving clinical benefit based on physician 
judgement,  
• 
Inter-current illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from study treatment, OR 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
Note: During the study treatment period, if one treatment agent is discontinued due to 
unacceptable toxicity, the patient may continue receiving the other treatment agent in the 
absence of disease progression. The patient is considered on study treatment until both drugs 
are discontinued for toxicity or disease progression. If continuing Cirmtuzumab alone then labs 
and AE assessments should be done within one day of treatment. If continuing paclitaxel alone 
then labs and AE assessments should be done within one day of the planned weekly treatment. 
4.10 
Duration of Follow Up 
Patients will be contacted to document any adverse events 28 days (+/- 7 days) after the End of 
Treatment visit (56 days after the last dose of cirmtuzumab or paclitaxel treatment) or at the 
time of initiation of a different anti-cancer therapy, whichever occurs first. In the event that the 
start of a different anti-cancer therapy occurs earlier than 28 +/- 3 days, the End of Treatment 
visit and the Followup Visit will be the same visit. Patients removed from treatment for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event.  
4.11 
Discontinuation from Study Participation 
Patients may be removed from study participation for the following reasons: 
• 
The patient or legal representative withdraws consent for treatment. 
• 
The patient or legal representative withdraws consent (termination of treatment and 
follow-up). 
• 
The patient has documented disease progression. 
• 
The patient experiences clinically significant deterioration of their condition prior to 
treatment discontinuation. 
• 
The patient is non-compliant. 
• 
The patient is lost to follow-up. 
• 
The patient dies. 
• 
The investigator determines that it is not in the patient’s best interest to continue 
participation. 
• 
The patient becomes pregnant. 
• 
The patient develops a second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment which would interfere with 
the study 
 
5.0 
STUDY PROCEDURES 
Refer to the study Schedule of Events for procedures. 
 


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All patients will be closely monitored for safety and tolerability during all cycles of therapy, at 
study treatment completion/early study treatment discontinuation, and during the follow-up 
period. 
5.1 
Definitions of Study Assessments 
5.1.1 Medical history and symptoms 
Medical/Oncology history should include smoking history, surgeries, clinically significant 
diseases within the last 5 years, history of malignancy (date of first diagnosis, disease 
course, and prior therapies), and all medications per 5.1.4. 
5.1.2 Demographics 
Demographics consist of age, gender, race, and ethnicity. 
5.1.3 Review subject eligibility criteria 
Review of eligibility criteria as described in Section 3 to ensure subject qualification for 
study entry. 
5.1.4 Concomitant medications 
All concomitant therapy, including anesthetic agents, vitamins, homeopathic/herbal 
remedies, nutritional supplements, received by patients from five days prior to the first 
day of study treatment until 28 days after the last study dose (or until the start of a new 
treatment, whichever comes first) will be recorded in the patient’s medical record. If a 
reportable adverse event deemed related to study intervention (see Section 7) occurs 
within 28 days after last study dose and the patient has not started a new treatment, 
recording of concomitant medications related to the treatment of that adverse event 
should continue until resolution of the adverse event. 
5.1.5 Physical exam 
A complete physical examination should include the evaluation of general appearance; 
evaluation of head, eyes, ears, nose, and throat (HEENT); and cardiovascular, 
pulmonary, abdominal, musculoskeletal, skin, lymph nodes, neurological, and 
genitourinary systems. Subsequent exams may be targeted as appropriate. 
 
Changes from baseline abnormalities should be recorded at each subsequent physical 
examination. New or worsened abnormalities should be recorded as adverse events if 
clinically significant. 
5.1.6 Vital signs and height  
Vital signs should include temperature, pulse, and blood pressure and weight. Height will 
only be collected at screening.  
5.1.7 Performance status 
Performance status will be evaluated according the ECOG criteria listed in Appendix A. 
5.1.8 Adverse event assessment 
Baseline assessment of subject status for determining adverse events. See Section 7 for 
Adverse Event monitoring and reporting. 
5.1.9 CBC and differential 


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Complete Blood Count (CBC) including hemoglobin, hematocrit, platelet count, white 
blood cell count, and percentage or absolute differential count. 
5.1.10 CMP 
Serum chemistry panel includes comprehensive metabolic panel (sodium, potassium, 
chloride, bicarbonate, BUN, creatinine, glucose, calcium, total protein, albumin, AST, 
ALT, total bilirubin, and alkaline phosphatase).  
5.1.11 Coagulation 
Coagulation profile includes International Normalized Ratio (INR) or prothrombin time 
(PT). 
5.1.12 Blood draw for pharmacokinetic (PK) and correlative studies  
Blood samples (up to 20 ml) for pharmacokinetic evaluation will be collected in the 
appropriate tubes.  
See Section 5.5 for additional details. 
5.1.13 Pregnancy test (for females of child bearing potential) 
All women of childbearing potential will have a serum or urine pregnancy test at 
screening. 
5.1.14 Tumor assessment 
Assessment of radiographic response will occur according to the Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 from the National Cancer Institute listed in 
Appendix B. 
5.1.15 Tumor tissue or fluid sample collection 
Tumor tissue will be collected by an image-directed core needle biopsy that is not 
collected from a site close to vital structures. Tumor cells from malignant (peritoneal) 
ascites, pleural effusion, or other body fluid may also be collected. 
See Section 5.5 for additional details. 
5.2 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
The study population for this trial will consist of men and women with biopsy proven Her2 
negative, locally advanced, unresectable or metastatic breast cancer. Measurable lesions will 
be confirmed by radiological scans (CT or MRI). All patients who meet the inclusion and 
exclusion criteria, and the Principal Investigator and treating physician determines the trial to be 
in the best interest of patient, will be offered enrollment into this study. To confirm patient 
eligibility for study participation, the following assessments and procedures will be completed 
during the screening phase.  
 
All screening procedures must be performed within 14 days prior to registration unless 
otherwise stated. The screening procedures include: 
• 
Written informed consent (within 30 days prior to registration). 
• 
Review of inclusion and exclusion criteria. 


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• 
Complete medical/oncology history. 
• 
Documentation of concomitant medications. 
• 
Demographics. 
• 
Complete physical examination.  
• 
Vital signs and height. 
• 
ECOG performance status assessment. 
• 
CBC with differential, CMP, and INR or PT.  
Note: if blood samples are taken within 5 days of the first dose of study 
treatment, Cycle 1 Day 1 samples do not need to be re-collected. 
• 
Pregnancy test. 
• 
Documentation of tumor status per RECIST (tumor assessment within 30 days 
prior to Cycle 1 Day 1). 
• 
Tumor assessment by physical exam, for patients whose disease can be 
evaluated by physical exam. 
• 
Chest/abdomen/pelvis imaging with CT or MRI (within 30 days prior to Cycle 1 
Day 1). 
• 
Bone scan if clinically indicated (recommended within 30 days prior to Cycle 1 
Day 1 if possible).  
• 
Blood draw for correlative studies, and if patient consents, tumor biopsy (within 
30 days prior to Cycle 1 Day 1). 
• 
Optional PET/CT for correlation with cross-sectional imaging 
5.3 
Procedures During Treatment 
During the treatment period, a window of +/- 1 day will apply to all visits and assessments, 
unless otherwise specified. Not all procedures need to be completed on the same day provided 
they are completed within the specified window. Assessments scheduled on the day of study 
drug administration should be performed prior to study drug administration, unless otherwise 
noted. Cirmtuzumab and paclitaxel administration may be delayed due to unforeseen 
scheduling issues but should not be delayed more than 5 days.  
 
 
Cycle 1 Day 1 (+/- 1 day) 
• 
Physical exam, vital signs 
• 
History and symptoms 
• 
ECOG performance status 
• 
Blood collection for CBC, CMP and PK/correlative studies  
• 
Tumor assessment by physical exam, for patients whose disease can be 
evaluated by physical exam. 
• 
Cirmtuzumab and paclitaxel administration 
• 
Concomitant medication recording 
• 
Adverse events screening 
 
Cycle 1 Day 8 (+/- 1 day) 
• 
Vital signs 
• 
Blood collection for CBC,CMP and PK/correlative studies 
• 
Paclitaxel administration 
• 
Concomitant medication recording 
• 
Adverse events screening 
 


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Cycle 1 Day 15 (+/- 1 day) 
• 
Physical exam, vital signs 
• 
History and symptoms 
• 
Blood collection for CBC, CMP and PK/correlative studies 
• 
Cirmtuzumab and paclitaxel administration 
• 
Concomitant medications recording 
• 
Adverse events screening 
 
Cycle 1 Day 22 (+/- 1 day) 
• 
Vital signs 
• 
Blood collection for CBC, CMP and PK/correlative studies 
• 
Paclitaxel administration  
• 
Concomitant medication recording 
• 
Adverse events screening 
 
Cycles 2 and beyond (Combination Therapy phase) , Day 1 (+/- 1 day) 
• 
Physical exam, vital signs 
• 
History and symptoms 
• 
ECOG performance status 
• 
Blood collection for CBC, CMP and PK/correlative studiesTumor assessment by 
physical exam, for patients whose disease can be evaluated by physical exam. 
• 
Cirmtuzumab and paclitaxel administration 
• 
Concomitant medication recording 
• 
Adverse events screening 
 
Cycles 2 and beyond, Day 8 (+/- 1 day) 
• 
Vital signs 
• 
Blood collection for CBC and CMP 
• 
Paclitaxel administration  
• 
Concomitant medication recordingAdverse events screening 
 
Cycles 2 and beyond, Day 15 (+/- 1 day) 
• 
Vital signs  
• 
History and symptoms 
• 
Blood collection for CBC and CMP 
• 
Paclitaxel administration 
• 
 Concomitant medication recording 
• 
Adverse events screening 
(NOTE: Physical exam will not be performed at Day 15 for Cycles 7 and beyond.) 
 
Cycles 2 and beyond, Day 22 (+/- 1 day) 
• 
Vital signs 
• 
Blood collection for CBC and CMP 
• 
Paclitaxel administration  
• 
Concomitant medication recording 
• 
Adverse events screening 
 


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Assess Response [Within 7 days of Day 1 of Cycles 3, 5, and 7. Beyond Cycle 7, scans may be 
decreased to every 3 cycles (i.e., within 7 days of Day 1 of Cycles 10, 13, etc.)] 
• 
Chest/abdomen/pelvis imaging by CT or MRI 
• 
Bone scan if clinically indicated 
• 
Optional PET/CT scan  
Monotherapy phase Day 1 (+/- 1 day) 
• 
Physical exam, vital signs 
• 
History and symptoms 
• 
ECOG performance status 
• 
Blood collection for CBC, CMP and PK/correlative studies. Tumor assessment by 
physical exam, for patients whose disease can be evaluated by physical exam. 
• 
Cirmtuzumab and paclitaxel administration 
• 
Concomitant medication recording 
• 
Adverse events screening 
 
Monotherapy phase Day 8 (+/- 1 day) 
• 
Vital signs 
• 
Blood collection for CBC and CMP 
• 
Paclitaxel administration  
• 
Concomitant medication recording 
• 
Adverse events screening 
(NOTE: For patients taking Cirmtuzumab monotherapy there will be no Day 8 visit.) 
 
Monotherapy phase Day 15 (+/- 1 day) 
• 
Vital signs  
• 
History and symptoms 
• 
Blood collection for CBC and CMP 
• 
Paclitaxel administration 
• 
Concomitant medication recording 
• 
Adverse events screening 
(NOTE: Physical exam will not be performed at Day 15 during the monotherapy phase . 
For patients taking Cirmtuzumab monotherapy there will be no Day 15 visit.) 
 
Monotherapy phase Day 22 (+/- 1 day) 
• 
Vital signs 
• 
Blood collection for CBC and CMP 
• 
Paclitaxel administration  
• 
Concomitant medication recording 
Adverse events screening(NOTE: For patients taking Cirmtuzumab monotherapy there 
will be no Day 22 visit.) 
 
End of Treatment Visit (28 days (+/-1) after last dose of cirmtuzumab or paclitaxel) or at 
the time of initiation of a different anti-cancer therapy, whichever occurs earlier. 
PK/correlative studies blood sample may be drawn at 28 days or, if not feasible, at the 
start of new anti-cancer therapy if new therapy starts before 28 days 
• 
Physical exam, vital signs 
• 
ECOG performance status 
• 
Blood collection for CBC, CMP and PK/correlative studies 


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• 
Blood collection for correlative studies 
• 
Repeat tumor sample collection at the time of progression, if safe and patient 
consents. 
• 
Tumor assessment by physical exam, for patients whose disease can be 
evaluated by physical exam. 
• 
Concomitant medication recording 
• 
Adverse events screening 
5.4 
Follow-up Procedures (56 days (+/-7) after last dose of cirmtuzumab or paclitaxel) 
Patients will be contacted by telephone 28 days (+/- 7 days) after their End of Treatment Visit to 
determine if any serious or non-serious adverse events have occurred, and to document any 
concomitant cancer therapy. Follow up procedures will occur at 56 days +/- 7 days after last 
dose of cirmtuzumab or paclitaxel or at the time of starting different anti-cancer therapy, 
whichever occurs first. In the event that the start of a different anti-cancer therapy occurs earlier 
than 28 days, the End of Treatment visit and the Followup Visit will be the same visit. 
5.5 
Correlative Studies 
5.5.1 Blood Sample Collection Guidelines for PK and Correlative Studies 
Blood Sampling Schedule  
Serum samples for pharmacokinetic analyses and research will be collected as outlined in 
Table 5-1. 
 
Table 5-1. Blood PK and Correlative sampling schedule  
Cycle 
Day 
Time point 
1 
1 
• 
Prior to cirmtuzumab infusion  
• 
30 minutes (+/- 5 minutes) post completion of cirmtuzumab infusion 
• 
immediately post completion of paclitaxel infusion 
8 
• 
Prior to paclitaxel infusion 
 
15 
• 
Prior to cirmtuzumab infusion 
• 
30 minutes (+/- 5 minutes) post completion of cirmtuzumab infusion 
• 
immediately post completion of paclitaxel infusion 
 
22 
• 
Prior to paclitaxel infusion 
2 and beyond 
 
• 
Prior to any cirmtuzumab infusion 
End of Treatment 
and/or Progression 
visit  
28 (+/- 3) days after last dose of cirmtuzumab 
 
Blood Collection and Handling Instructions 
Blood will be collected using the appropriate tubes (up to 10ml). The exact time that the sample 
is drawn along with the exact time that the drug is administered should be recorded. 
 
Sample Processing 
Blood samples will be processed in the translational lab of Dr. Thomas Kipps. 


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Sample Labeling 
Each tube must be labeled with the patient’s study number and the date and time the sample was 
drawn.  Data should be recorded on the Correlative Study Form, which must accompany the 
sample(s). 
 
5.5.2 Tumor and Malignant Ascites / Pleural Effusion Sample Collection Guidelines 
When feasible, tumor samples will be collected by image-directed core needle biopsy, or by 
recovering tumor cells from malignant ascites, pleural effusion or body fluid at the following time 
points: 
• 
Within 30 days prior to Cycle 1 Day 1 
• 
Between Cycle 3, Day 1 and Day 15  
• 
At the time of progression 
 
In addition, samples from pleural or peritoneal fluid may be obtained from patients who have 
repeated pleural taps, pleural drainage, or peritoneal taps for palliation while receiving protocol 
therapy and who do not meet progressive disease criteria. These sample collections may occur 
at timepoints other than the three timepoints stated above and while the patient is on study or in 
follow-up per the protocol.  
If baseline biopsy not feasible, paraffin block material from the patient’s prior metastatic biopsy 
(or biopsies) and/or from the primary tumor at diagnosis may be obtained for ROR1 correlative 
studies as in Section 5.5.5. 
 
When biopsies are performed, at least three cores should be obtained. One core will be placed 
in formalin, and the other two cores will be placed in shipping material without fixation. These 
samples are to be sent to the Pathology Core at UCSD, 3855 Health Sciences Drive, #5314, at 
room temperature.  
5.5.3 Specimen Banking 
Patient samples collected for this study will be retained at the UCSD School of Medicine (Kipps 
Laboratory). Specimens will be stored indefinitely or until they are exhausted. If future use is 
denied or withdrawn by the patient, best efforts will be made to stop any additional studies and 
to destroy the specimens. Samples will be labeled with the subject’s de-identified study number 
and collection date. The link between study number and medical record number will be viewed 
over a password secured encrypted server-client.   
 
Drs. Parker and Shatsky, in collaboration with Dr. Kipps, will be responsible for reviewing and 
approving requests for research specimens from potential research collaborators outside of 
UCSD. Collaborators will be required to complete an agreement (a Material Transfer Agreement 
or recharge agreement) that states specimens will only be released for use in disclosed 
research.  Any data obtained from the use of clinical specimens will be the property of UCSD for 
publication and any licensing agreement will be strictly adhered to.   
 
The study research coordinator will review the subject's medical record for demographic and 
clinical information pertaining to the subject's general medical history, diagnosis, and outcomes 
of any treatments received.  Samples and data extracted from the subject's medical record will 
be coded with a de-identified study number, and the subject's name and identifying information 
will be removed.  A log that links the subject's name and identifiers to the study number will be 


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maintained in a secure database distinct from the secure database into which the subject's 
clinical information will be entered 
 
The specimens and their derivatives may have significant therapeutic or commercial value.  The 
Informed Consent form contains this information and informs the subject that there is the 
potential for financial gain by UCSD, the investigator or a collaborating researcher or entity.  
 
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available:   
• 
Diagnosis  
• 
Collection time in relation to study treatment 
• 
Clinical outcome – if available 
• 
Demographic data 
5.5.4 Assay methodologies  
1. Cirmtuzumab and anti-cirmtuzumab antibody levels in peripheral blood will be monitored.  
 
2. We will examine tumor cells for expression of ROR1 and other stem cell markers, such as 
ALDH and CD133 by immunohistochemistry or flow cytometry.  
 
3. Functional assays will be performed if enough tumor specimens are available. These 
include assays on the relative capacity of tumor cells to form spheroids or engraft immune 
deficient mice. 
 
5.6 
Patient Discontinuation 
Patients may discontinue study treatment at any time.  Any patient who discontinues treatment 
will be encouraged to return to the study center to undergo treatment discontinuation 
assessments.  The primary reason for discontinuation should be recorded.  Reasons for 
discontinuation of a patient by the investigator include, but are not limited to, the following:   
• 
Voluntary withdrawal from treatment (follow-up permitted) 
• 
Voluntary withdrawal of consent (termination of treatment and follow-up) 
• 
Documented disease progression  
• 
Clinically significant deterioration of the patient’s condition prior to treatment 
discontinuation 
• 
Patient noncompliance 
• 
Investigator determination that it is not in the patient’s best interest to continue 
participation 
• 
Pregnancy 
• 
Development of second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment which would interfere with the study 
• 
Lost to follow-up 
• 
Death 
 
6.0 
MEASUREMENT OF EFFECT 
6.1 
Safety/tolerability 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the CTCAE version 4.03 for reporting of adverse events.16 


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6.2 
Antitumor Effect- Solid Tumors 
Response and progression will be evaluated using Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 guidelines.18 
6.2.1 Best Overall Response 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for confirmation. 
6.2.2 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of study 
treatment until objective tumor progression or death. 
6.2.3 Time to Progression 
Time to progression is defined as the duration of time from start of study treatment until 
objective tumor progression. 
 
7.0 
ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention.  
 
Progression of the cancer under study or events, which are unequivocally due to disease 
progression should not be reported as an AE during the study (unless it is considered to be drug 
related by the investigator). 
7.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at 
scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of patient safety and care.  
 
As far as possible, each adverse event should be evaluated to determine: 
• 
duration (start and end dates) 
• 
severity (grade) 
• 
seriousness 
• 
relationship to study agent 
• 
action taken (i.e., none, study agent modification, medical intervention) 
• 
outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
Adverse events monitoring begins after initiation of study procedures and ends 30 days 
following the last administration of study treatment or start of new anti-cancer therapy, 
whichever occurs earlier. 
 
All patients experiencing an adverse event, regardless of its relationship to study drug or at least 
possibly related to the drug, will be monitored until:  


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• 
the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
• 
any clinically significant abnormal laboratory values have returned to baseline;  
• 
there is a satisfactory explanation other than the study drug for the changes 
observed; or 
• 
death. 
7.2 
Severity 
All adverse events will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.16 The CTCAE v4.03 is available at 
http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily activities 
or significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death. 
7.3 
Seriousness 
A “serious” adverse event is defined in regulatory terminology as any untoward medical 
occurrence that: 
1. Results in death. 
If death results from (progression of) the disease, the disease should be reported as 
event (SAE) itself. 
2. Is life-threatening. 
The patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
3. Requires in-patient hospitalization or prolongation of existing hospitalization.  
Note: Hospitalization (including hospitalization for an elective procedure) for a pre-
existing condition, which has not worsened does not constitute a serious adverse event. 
4. Results in persistent or significant disability or incapacity. 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent one of 
the outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; convulsions that may not result in hospitalization; development of drug 
abuse or drug dependency. 
7.4 
Relationship 
Attribution categories for adverse events in relationship to protocol therapy are as follows: 
Definite – The AE is clearly related to the study treatment. 


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Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.5 
Prior experience 
Expected events are those that have been previously identified as resulting from administration 
of the agent. An adverse event is considered unexpected, for expedited reporting purposes 
only, when either the type of event or the severity of the event is not listed in the current known 
adverse events listed in the agent clinical experience section of this protocol or the current 
Investigator’s Brochure. 
7.6 
Reporting Requirements for Adverse Events 
7.6.1 Expedited Reporting 
A. The Principal Investigator must be notified within 24 hours of learning of any serious 
adverse events, regardless of attribution, occurring during the study or within 30 days of the 
last administration of the study drug.  
B. The UCSD Human Research Protections Program (HRPP) and Moores Cancer Center 
Data and Safety Monitoring Board (DSMB) must be notified within 10 business days of 
“any unanticipated problems involving risk to subjects or others” (UPR). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), which in the 
opinion of the Principal Investigator was unanticipated, involved risk to subjects or 
others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved protocol that 
alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated sponsor 
safety report), interim result or other finding that indicates an unexpected change 
to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that cannot be 
resolved by the Principal Investigator. 
C. The FDA must be notified according to the following timelines: 
• 
Within 7 calendar days of any unexpected fatal or life-threatening adverse event with 
possible relationship to study drug, and  
• 
Within 15 calendar days of any event that is considered: 1) serious, 2) unexpected, and 
3) at least possibly related to study participation. 
7.6.2 Routine Reporting Requirements 
A. The UCSD HRPP must be notified of any adverse events that are not unanticipated 
problems involving risk to subjects or others (non-UPRs) at the time of the annual 
Continuing Review.  


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B. The FDA must be notified of all non-serious adverse events annually at the time of the annual 
report. 
 
8.0 
AGENT INFORMATION 
8.1 
Cirmtuzumab 
Please refer to Investigator’s Brochure for more comprehensive information. 
 
Other names for the drug: UC-961 
 
Structure: Monoclonal antibody 
 
Mechanism of action (or Product description):   
Cirmtuzumab is a fully-humanized monoclonal antibody designed to bind the extracellular 
immunoglobulin-like domain of ROR1 with high-affinity.  
 
Supplied by: Cirmtuzumab has been produced at Pacific GMP (San Diego, CA) and Oncternal 
Therapeutics, Inc. in compliance with cGMP standards. 
 
Formulation: 
Cirmtuzumab supplied by Pacific GMP is a liquid formulation with a concentration of 44 mg/ml 
protein, with 7.2 to 7.8 mL/vial. Each ml of the formulation contains 40 mg cirmtuzumab, 14.7 
mg sodium citrate, 10 mg trehalose, 216 µg Polysorbate 80, 15 µg sodium EDTA and adjusted 
to pH 5.2 ± 0.2. Each vial is considered to deliver approximately 300mg of cirmtuzumab. 
Cirmtuzumab manufactured by Oncternal Therapeutics, Inc. is supplied in vials nominally 
containing 300 mg of drug substance in 7.5 mL of diluent (40 mg/mL). Each milliliter of drug 
product contains: 14.7 mg of sodium citrate, 10 mg of trehalose, 216 μg of polysorbate 80, and 
15 μg of sodium EDTA. 
Cirmtuzumab is filled into 10ml clear borosilicate Type 1 glass vials with 20 mm grey butyl 
siliconized rubber stopper and 20 mm aluminum royal blue flip off seals. 
  
Storage: 
Cirmtuzumab is to be kept refrigerated (2-8°C) until use, in single use vials. 
 
Solution Preparation: 
To prepare the agent for administration, it will be dissolved in normal saline to a final 
concentration of 1 mg/mL. 
  
Administration: 
The drug will be administered by intravenous infusion per infusion plan outlined in Section 4.1. 
 
Side effects:  
Common adverse events associated with cirmtuzumab administration have not yet been 
determined. In the phase I trial of cirmtuzumab in CLL, no adverse events have been probably 
or definitely related to cirmtuzumab at doses between 15 μg/kg and 20 mg/kg.  
 
Potential risks are based on class effects of monoclonal antibody therapies, including infusional 
toxicity. Patients will receive premedication with antihistamine and acetaminophen, and infusion 


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rates increased based on vital sign and nursing monitoring every 15-20 minutes. Grade 1 or 
higher infusion reactions will prompt discontinuation of infusion until resolution of symptoms; 
grade 2 or higher reactions will be treated with additional corticosteroid or symptom-directed 
therapies. 
 
Toxicities: 
Toxicity associated with cirmtuzumab administration has not yet been determined. In the phase 
I trial of cirmtuzumab in CLL, no adverse events have been probably or definitely related to 
cirmtuzumab at doses between 15 μg/kg and 20 mg/kg. There was no off-target binding 
identified in initial preclinical assays. Infusion reaction, fluid retention, and immunogenicity are 
possible class effects of monoclonal antibody therapy. Depletion of precursor B cells and B cell 
lymphopenia are possible as well. Other ROR1 antibodies, distinct from cirmtuzumab have 
demonstrated binding to pancreatic islet cells and adipose tissue.19 Glucose levels and body 
weight will therefore be monitored. 
8.1.1 Return and Retention of Study Drug 
Remaining drug is to be destroyed, according to Moores Cancer Center Investigational Drug 
Services destruction policy. 
8.2 
Paclitaxel 
Please refer to the TAXOL product Label19 for more comprehensive information. 
 
Other names for the drug:  
TAXOL 
 
Structure:  
 
Mechanism of action (or Product description):   
Paclitaxel is an anti-microtubule agent that promotes assembly of microtubules from tubulin 
dimers and stabilizes microtubules by preventing depolymerization. This stability results in the 
inhibition of the normal dynamic reorganization of the microtubule network that is essential for 
vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or 
“bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during 
mitosis.  
 
Supplied by:  commercially supplied. 
 


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Formulation: 
Paclitaxel injection is a clear, colorless to slightly yellow viscous solution. It is supplied as a non-
aqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous 
infusion. Paclitaxel is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) 
multidose vials. Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of 
purified Cremophor® EL* (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, 
USP. 
 
Storage: 
Store the vials in original cartons between 20°–25° C (68°–77° F). Retain in the original package 
to protect from light. 
 
Solution Preparation:   
Paclitaxel will be prepared in accordance with UCSD institutional standard practice.  
  
Administration: Intravenous. 
 
Side effects:  
The most common side effects of paclitaxel include but are not limited to: 
• 
Neutropenia, leucopenia,  
• 
Thrombocytopenia and anemia resulting in red blood cell and platelet transfusions 
• 
Infection 
• 
Bleeding 
• 
Hypersensitivity reactions 
• 
Bradycardia 
• 
Hypotension 
• 
Peripheral neuropathy 
• 
Myalgias/arthralgias 
• 
Nausea and vomiting 
• 
Diarrhea 
• 
Mucositis 
• 
Alopecia 
• 
Hepatic toxicity 
• 
Injection site reactions 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design/Study Endpoints 
This is an open label, single institution, Phase Ib pilot study of the safety and tolerability of 
cirmtuzumab at fixed dose administered with paclitaxel in patients with metastatic, or locally 
advanced, unresectable breast cancer. Patients will be enrolled in cohorts of five.  Each cohort 
will be assessed for DLT’s prior to enrolling the next cohort.   
 
Patients will start with cirmtuzumab 600mg (2 cirmtuzumab vials) on Day 1 and Day 15 of Cycle 
1. If two or more of the first 5 patients experience dose-limiting toxicity, further patients will be 
enrolled at a 50% dose reduction, 300 mg flat dose level(1 cirmtuzumab vial).The DLT rate is 
expected to be low, but if there are two or more DLTs occurring in any cohort of 5 patients, the 
study team may request a DSMB review before proceeding to enroll next cohort 
 


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• 
 1): Five patients are initially enrolled into the 600 mg cirmtuzumab and 80 mg/m2 
paclitaxel cohort. If there are fewer than 2 DLTs observed out of these 5 patients, 
proceed to 2), otherwise, reduce the dose level of cirmtuzumab to 300 mg for further 
patients and proceed to 3).  
• 
2): The trial proceeds to enroll an additional five subjects. If there are fewer than 2 DLTs 
observed out of these 5 patients, proceed to 4), otherwise reduce the dose level of 
cirmtuzumab to 300 mg and proceed to 4)  
• 
3): The trial proceeds to enroll an additional 5 subjects. If there are 2 or more DLTs 
observed out of these 5 patients, the study would be stopped, otherwise proceed to 4). 
• 
4): The trial proceeds to enroll the last additional five subjects. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The primary endpoint is the rate of dose-limiting toxicities during the first 4 weeks of treatment, 
assessed to be related to cirmtuzumab, or to the combination of cirmtuzumab with paclitaxel.  
 
Secondary endpoints include: 
• 
Safety and tolerability of the combination therapy since the start of any study 
treatment.  
• 
Objective tumor response rate, best tumor response rate and time to progression 
as assessed by RECIST v1.1. 
• 
ROR1 expression levels and putative breast cancer stem cell markers in tumor 
specimen measured by immunohistochemistry. 
 
Exploratory endpoints include: 
• Plasma pharmacokinetics of cirmtuzumab. 
• Level of circulating antibody formation against cirmtuzumab.  
• As available, we will perform pharmacodynamic, biochemical and molecular 
studies on tissue samples of treated patients, depending on sample availability. 
• 
Comparison of PET/CT imaging to standard cross-sectional imaging using 
Spearman Rank Correlation. 
 
9.1.1 Study Stopping Rules 
The study will also be placed on hold if any of the following occur that are at least possibly 
Enroll 5 (600 mg)  
DLT < 2 
DLT >= 2 
Enroll 5 (600mg) 
Dose reduction and enroll 5 (300mg) 
DLT < 2 
DLT >= 2 
DLT < 2 
DLT >= 2 
Enroll 5 (300mg) 
Stop 
Enroll 5 (600mg) 
Enroll 5 (300mg) 


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attributable to cirmtuzumab or the combination of cirmtuzumab and paclitaxel: 
• 
Any death  
• 
2 or more non-hematological Grade 4 adverse events not resolving with standard 
therapy within 7 days. Grade 4 hematologic events will not stop the study, but do meet 
protocol-defined criteria for Dose Limiting Toxicity (with the exception of Grade 4 
neutropenia lasting less than 8 days). 
All events resulting in the stoppage of the clinical trial will be reported to the appropriate 
regulatory agencies.  The Principal Investigator will be required to report to the UCSD IRB and 
the DSMB chair. UCSD will be responsible for reporting serious adverse events to the FDA.  
 
9.1.1.1 Treatment-related DLT 
Protocol-defined criteria for Dose Limiting Toxicity will be monitored in every five patients to 
evaluate whether the study should be stopped early. Two or more DLT’s in the first five patients 
would lead to dose reduction. Two or more DLT’s in an additional five patients would lead to 
study termination.  The table below gives the probability of observing two or more DLT’S in each 
group of 5 patients, under assumed DLT rates of 10%, 20%, and 30%.  
 
Probability of 
DLT at 600 mg 
cirmtuzumab 
level 
Probability of 
DLT at 300 mg 
cirmtuzumab 
level 
Probability of 
early 
stopping 
(first 5 
patients) 
Probability of 
early 
stopping  
(middle 5 
patients) 
Probability of 
early 
stopping  
(last 5 
patients) 
Probability 
of early 
stopping 
(total) 
0.1 
0.05 
0 
0.002 
0.003 
0.005 
0.2 
0.1 
0 
0.021 
0.035 
0.056 
0.3 
0.15 
0 
0.078 
0.106 
0.184 
 
This computation assumes that the probability of a DLT drops by half when the dose is reduced. 
 
9.2 
Sample Size and Accrual 
The planned sample size is 15 evaluable patients defined as undergoing combination therapy 
for at least 2 cycles. Replacement patients will be enrolled, up to a maximum of 30 patients to 
achieve 15 evaluable patients. Currently, we estimate enrolling 1 patient per month.  Given the 
maximum number of study subjects is 30, the longest time period to complete enrollment would 
be approximately 30 months.  
9.2.1 Evaluable Subjects and Subject Replacement 
A subject will be considered evaluable for assessment of DLTs if the subject receives at least 2 
doses of cirmtuzumab and completes the safety follow-up through the DLT evaluation period of 
28 days, or the subject experiences a DLT at any time during the DLT evaluation period.  
 
The safety population will include all subjects who receive any treatment of cirmtuzumab. The 
safety population will be used to evaluate baseline characteristics as well as all descriptive 
endpoints for safety. 
 
The intent-to-treat efficacy population will include all subjects who receive at least one dose of 
cirmtuzumab. 
 
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cirmtuzumab treatment. These efficacy populations will be used to evaluate the efficacy related 
endpoints, such as the objective response rate. 
9.3 
Data Analyses Plans 
9.3.1 Primary Analyses 
The rate of DLTs or RP2D will be calculated along with its 95% confidence interval using the 
exact (Clopper-Pearson) method, appropriately adjusted for the 5+5+5 stopping rule. 
9.3.2 Secondary Analyses 
Safety will be assessed through summaries of adverse events. All subjects who receive at least 
one dose of study medication will be considered evaluable for safety.   
 
Adverse events from treatment beginning to six months after treatment completion, will be 
listed, documenting the dose level, course, outcome, severity, and relationship to the study 
treatment. AEs will be summarized by the event type, grade, relatedness, outcome, and organ 
system. Incidence rates of AEs and the proportion of subjects prematurely withdrawn from the 
study due to AEs will be reported. Specifically, the rates of infusion reactions, major infections 
and grade 3 or higher non-infection adverse events will be reported.  
 
Tumor response and time to progression will be assessed by RECIST v1.1. The objective tumor 
response rate (CR, PR) and best tumor response rate (stable disease, or better) will be reported 
with 95% confidence intervals. Median progression-free survival will be estimated using the 
Kaplan-Meier method. These analyses will be done by overall and dose cohorts. 
 
The expression levels of ROR1 and other cancer stem cell markers (ALDH, CD133) on the 
primary pre-treatment and after-treatment tumor specimens will be measured by 
immunohistochemistry. The changes for each patient will be tested by the Wilcoxon signed rank 
test. Fisher’s exact test will be used to test the association of the baseline levels with tumor 
responses. 
 
All statistical analyses will be at the 5% significance level using 2-sided tests. 
9.3.3 Exploratory Analyses 
Exploratory endpoints to be analyzed include the following mechanism of action studies, by dose 
cohort: 
1. Plasma pharmacokinetics of cirmtuzumab 
2. Level of circulating antibody formation against cirmtuzumab.  
3. As available, we will perform pharmacodynamic, biochemical and molecular studies 
on tissue samples of treated patients, depending on sample availability. 
4. Compare PET/CT imaging to standard cross-sectional imaging using Spearman 
Rank Correlation 
 
 
The serum concentrations of cirmtuzumab will be evaluated via descriptive summary statistics 
(N, mean, standard deviation, median, quartiles) and graphical measures (boxplots, time-course 
graphs, etc.). 
 
10.0 
STUDY MANAGEMENT 


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10.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed according to UCSD conflict of interest policy. 
10.2 
Institutional Review Board (IRB) Approval and Consent  
The IRB should approve the consent form and protocol prior to any study-related activities.  It is 
expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
10.3 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), subjects 
who have provided written informed consent must also sign a subject authorization to release 
medical information to the study Sponsor and allow a regulatory authority, or Institutional 
Review Board access to subject’s medical information relevant to the study. 
10.4 
Data and Safety Monitoring/Auditing 
In addition to adverse event monitoring and clinical oversight by the principal investigator and 
co-investigators, this study will also use the UCSD Moores Cancer Center Data Safety and 
Monitoring Board (DSMB) to provide oversight in the event that this treatment approach leads to 
unforeseen toxicities. Data from this study will be reported annually and will include: 
 
1) 
the protocol title, IRB protocol number, and the activation date of the study.  
2) 
the number of patients enrolled to date  
3) 
the dates of patient enrollment 
4) 
a summary of all adverse events regardless of grade and attribution   
5) 
a response evaluation for evaluable patients when available 
6) 
a summary of any recent literature that may affect the ethics of the study.  
10.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, investigators are required to conduct their 
research according to the plans reviewed and approved by the IRB.  


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10.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Study Chair. It should also be noted that when an amendment to the 
protocol substantially alters the study design or the potential risk to the patient, a revised 
consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the IRBs 
for approval prior to implementation. 
10.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient 
consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Government agency regulations and directives require that the study investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with a 
drug seeking regulatory approval and marketing, these documents shall be retained for at least 
two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region. In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
10.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to his/her 
original records to permit verification of proper entry of data. At the completion of the study, all 
case report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data. 
 
 


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11.0 
REFERENCES 
 
 
1. 
DeSantis CE, Fedewa SA, Goding Sauer A, Kramer JL, Smith RA, Jemal A. Breast cancer 
statistics, 2015: Convergence of incidence rates between black and white women. CA Cancer J 
Clin. 2015. 
2. 
Surveillance EaERSP. Percent of Cases & 5 year Suvival by Stage at Diagnosis: Female Breast 
Cancer. In: Institute NC, ed. Bethesda, Maryland2015. 
3. 
Widhopf GF, 2nd, Cui B, Ghia EM, et al. ROR1 can interact with TCL1 and enhance 
leukemogenesis in Emu-TCL1 transgenic mice. Proc Natl Acad Sci U S A. 2014;111(2):793-798. 
4. 
Baskar S, Kwong KY, Hofer T, et al. Unique cell surface expression of receptor tyrosine kinase 
ROR1 in human B-cell chronic lymphocytic leukemia. Clin Cancer Res. 2008;14(2):396-404. 
5. 
Daneshmanesh AH, Mikaelsson E, Jeddi-Tehrani M, et al. Ror1, a cell surface receptor tyrosine 
kinase is expressed in chronic lymphocytic leukemia and may serve as a putative target for 
therapy. Int J Cancer. 2008;123(5):1190-1195. 
6. 
Fukuda T, Chen L, Endo T, et al. Antisera induced by infusions of autologous Ad-CD154-
leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a. Proc Natl Acad 
Sci U S A. 2008;105(8):3047-3052. 
7. 
Zhang S, Chen L, Cui B, et al. ROR1 is expressed in human breast cancer and associated with 
enhanced tumor-cell growth. PLoS One. 2012;7(3):e31127. 
8. 
Zhang S. BCRF Progress Report. 2015. 
9. 
Cui B, Zhang S, Chen L, et al. Targeting ROR1 inhibits epithelial-mesenchymal transition and 
metastasis. Cancer Res. 2013;73(12):3649-3660. 
10. 
Zhang S, Cui B, Lai H, et al. Ovarian cancer stem cells express ROR1, which can be targeted for 
anti-cancer-stem-cell therapy. Proc Natl Acad Sci U S A. 2014;111(48):17266-17271. 
11. 
Schneider B, Wang, M, Radovich, M, Sledge, GW. Association of vascular endothelial growth 
factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a 
trial of pacliataxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 
2100. J Clin Oncol. 2008;26(28):4672-4678. 
12. 
Eniu A, Palmieri F, Perez E. Weekly administration of doctaxel and paclitaxel in metastatic or 
advanced breast cancer. The Oncologist. 2005;10(9):665-685. 
13. 
Perez E, Vogel C, Irwin D. Multicenter Phase II Trial of Weekly Paclitaxel in Women with 
Metastatic Breast Cancer. J Clin Oncol. 2001:4216-4223. 
14. 
Rugo H, Barry, William T, Moreno-Aspitia, Alvaro. Randomized Phase III Trial of Pacliatxel Once 
Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel Once Per Week or 
Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally Recurrent or Metastatic 
Breast Cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol. 2015;33(21):2361-2369. 
15. 
Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of weekly compared with 
every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 
overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final 
results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008;26(10):1642-1649. 
16. 
Wolff AC, Hammond MEH, Hicks DG, et al. Recommendations for Human Epidermal Growth 
Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of 
American Pathologists Clinical Practice Guideline Updae. J Clin Onc. 2013;31(31):3997-4014. 
17. 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. In: Services DoHaH, 
ed2010. 
18. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
19. 
Hudecek M, Schmitt TM, Baskar S, et al. The B-cell tumor-associated antigen ROR1 can be 
targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. Blood. 
2010;116(22):4532-4541. 
20. 
Paclitaxel INJECTION. In: Squibb BM, ed. Princeton, New Jersey. 2011. 
 
 


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12.0 
APPENDICES 
Appendix A. Performance Status 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% of 
waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair 
5 
Dead. 
 
 
 


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Appendix B. Response evaluation criteria in solid tumors (RECIST) 
Tumor assessments will be made according to the schedule of assessments. Response and 
progression will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 guidelines [Eisenhauer et al. 2009]. 
 
B1 
MEASURABILITY OF TUMOR AT BASELINE 
 
B1.1 
Definitions 
At baseline, tumor lesions will be categorized as follows: 
 
B1.1.1 Measurable 
Tumor lesions: must be accurately measured in at least one dimension (longest diameter in the 
plane of measurements is to be recorded) with a minimum size of: 
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 
20 mm by chest X-ray. 
 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph 
node must be >= 15 mm in short axis when assessed by CT scan. At baseline and in follow-up, 
only the short axis will be measured and followed. 
 
B1.1.2 Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodes 
with >= 10 to < 15 mm short axis) as well as truly non-measurable lesions include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques. 
 
B1.1.3 Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
 
Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• 
Blastic bone lesions are non-measurable.  
 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 


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Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
 
B1.2 
Specifications by methods of measurements 
 
B1.2.1 Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
 
B1.2.2 Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and 10mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
 


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Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in complete response. Because tumor markers are disease specific, instructions 
for their measurement should be incorporated into protocols on a disease specific basis.  
 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease. 
 
 
B2 
TUMOR RESPONSE EVALUATION 
 
B2.1 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this 
means in instances where patients have only one or two organ sites involved a maximum of two 
and four lesions respectively will be recorded).  
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected.  
 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
P15mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20mm· 30mm has a short axis of 
20mm and qualifies as a malignant, measurable node. In this example, 20mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis P10mm 
but <15 mm) should be considered non-target lesions. Nodes that have a short axis <10mm are 
considered non-pathological and should not be recorded or followed. 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 


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these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’ (more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
B2.2  Response criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
 
B2.2.1 Evaluation of target lesions 
Complete Response (CR):  
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm. 
 
Partial Response (PR):  
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one 
or more new lesions is also considered progression). 
 
Stable Disease (SD):  
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study.  
 
B2.2.2  Special notes on the assessment of target lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10mm on study. This means that when lymph 
nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if complete 
response criteria are met, since a normal lymph node is defined as having a short axis of 
<10mm. Case report forms or other data collection methods may therefore be designed to have 
target nodal lesions recorded in a separate section where, in order to qualify for CR, each node 
must achieve a short axis <10mm. For PR, SD and PD, the actual short axis measurement of 
the nodes is to be included in the sum of target lesions. 
 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measure and may report them as 
being ‘too small to measure’. When this occurs, it is important that a value be recorded on the 
case report form. If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0mm. If the lesion is believed to be present and is faintly 
seen but too small to measure, a default value of 5mm should be assigned (Note: It is less likely 
that this rule will be used for lymph nodes since they usually have a definable size when normal 
and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node 
is believed to be present and is faintly seen but too small to measure, a default value of 5mm 


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should be assigned in this circumstance as well). This default value is derived from the 5mm CT 
slice thickness (but should not be changed with varying CT slice thickness). The measurement 
of these lesions is potentially non-reproducible; therefore providing this default value will prevent 
false responses or progressions based upon measurement error. To reiterate, however, if the 
radiologist is able to provide an actual measure, that should be recorded, even if it is below 
5mm. 
 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
 
B2.2.3 Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
 
Complete Response (CR):  
Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in 
size (<10mm short axis). 
 
Non-CR/Non-PD:  
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions 
is also considered progression).  
 
B2.2.4  Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
 
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to quality for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be 
extremely rare. 
 
When the patient has only non-measurable disease. This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 


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required to declare PD for measurable disease: i.e. an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols 
as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the patient 
should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so, therefore the increase must be substantial.  
 
B2.2.5  New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly important 
when the patient’s baseline lesions show partial or complete response. For example, necrosis of 
a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not. 
 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline. 
 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow- up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-
existing site of disease on CT that is not progressing on the basis of the anatomic images, 
this is not PD. 
 
B2.3 
Evaluation of best overall response  
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the 


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findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. Furthermore, depending on the nature of the study and the protocol 
requirements, it may also require confirmatory measurement. Specifically, in non-randomized 
trials where response is the primary endpoint, confirmation of PR or CR is needed to deem 
either one the ‘best overall response’. This is described further below. 
 
B2.3.1 Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each time point for patients 
who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used. 
 
Table 1. Time point response: patients with target (+/- non-target) disease. 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Table 2. Time point response: patients with non-target disease only. 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
Inevaluable 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
B2.3.2 Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a patient had a baseline sum of 50mm with three measured lesions and at follow-up 


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only two lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
 
B2.3.3 Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
 
Best response determination in trials where confirmation of complete or partial response IS NOT 
required: Best response in these trials is defined as the best response across all time points (for 
example, a patient who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). When SD is believed to be best response, it 
must also meet the protocol specified minimum time from baseline. If the minimum time is not 
met when SD is otherwise the best time point response, the patient’s best response depends on 
the subsequent assessments. For example, a patient who has SD at first assessment, PD at 
second and does not meet minimum duration for SD, will have a best response of PD. The 
same patient lost to follow-up after the first SD assessment would be considered inevaluable. 
 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). In this 
circumstance, the best overall response can be interpreted as in Table 3. 
 
Table 3. Best overall response when confirmation of CR and PR required. 
Overall response 
 First time point 
Overall response 
Subsequent time 
point 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD OR PR 
CR 
SD 
SD provided minimum criteria for SD duration 
met, otherwise PD 
CR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise PD 
CR 
Inevaluable 
SD provided minimum criteria for SD duration 
met, otherwise inevaluable 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise PD 
PR 
Inevaluable 
SD provided minimum criteria for SD duration 
met, otherwise inevaluable 
Inevaluable 
Inevaluable 
Inevaluable 
 
B2.3.4 Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans. This measurement 
should be recorded even though the nodes are normal in order not to overstate progression 
should it be based on increase in size of the nodes. As noted earlier, this means that patients 
with CR may not have a total sum of ‘zero’ on the case report form (CRF). 
 


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In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression. For 
example, in most trials it is reasonable to consider a patient with time point responses of PR-
NE-PR as a confirmed response. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic 
deterioration’. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. The objective response status of such 
patients is to be determined by evaluation of target and non-target disease as shown in Tables 
1–3. 
 
Conditions that define ‘early progression, early death and inevaluability’ are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. 
 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If 
at the next scheduled assessment, progression is confirmed, the date of progression should be 
the earlier date when progression was suspected. 
 
B2.4  Confirmatory measurement/duration of response 
B2.4.1 Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, i.e. in 
randomized trials (phase II or III) or studies where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in studies 
which are not blinded. 
 
In the case of SD, measurements must have met the SD criteria at least once after study entry 
at a minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol. 
 
B2.4.2 Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease 


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is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). 
 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
 
B2.4.3 Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
 
The clinical relevance of the duration of stable disease varies in different studies and diseases. 
If the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular trial, the protocol should specify the minimal time interval required 
between two measurements for determination of stable disease. 
 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account 
many parameters including disease types and stages, treatment periodicity and standard 
practice. However, these limitations of the precision of the measured endpoint should be 
considered if comparisons between trials are to be made. 
 
 

SAP_001.pdf: 
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Statistical Plan 
 
Protocol ID: 160178 
NCT02776917 
 
Study of Cirmtuzumab and Paclitaxel for Metastatic or Locally Advanced, 
Unresectable Breast Cancer 
 
 
 


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Study of Cirmtuzumab and Paclitaxel for Metastatic or Locally Advanced, Unresectable 
Breast Cancer 
 
 
Purpose of Study  
 
The primary objective of this trial is to determine the safety and tolerability of a fixed dose of 
cirmtuzumab when administered in combination with weekly standard of care paclitaxel.  
 
Patient Population  
 
Subjects with biopsy-confirmed metastatic or locally advanced surgically unresectable, HER-2 
negative and ER/PR-negative or ER/PR-positive breast cancer where standard endocrine therapy 
has been exhausted and/or cytotoxic chemotherapy is warranted. 
 
Study Overview 
 
Up to 30 subjects were planned for inclusion in the study to obtain 15 subjects evaluable for dose-
limiting toxicities (DLTs). Evaluable subjects are defined as subjects who undergo combination 
therapy for at least two 28-day cycles of study treatment. At the May 24, 2022 data cut-off, 22 
subjects signed informed consent, 16 subjects received the investigational product, 6 subjects were 
screen failures, 1 subject dropped out of the study early. One subject, who was an early 
screenfailure, was re-consented and treated. 
 
Brief Description of Study Results  
Sixteen patients were evaluable for safety and 15 were evaluable for DLTs.  A median of 6 prior 
metastatic therapies (endocrine therapy + chemotherapy) had been received. No discontinuations 
due to cirmtuzumab toxicity and no DLTs were observed. Adverse events (AEs) were consistent 
with the known safety profile of paclitaxel. Of 16 patients, 6 (38%) had a partial response (PR) 
with one patient receiving total treatment duration of 52 weeks and 6/16 (38%) patients had 
stable disease as their best response. Pharmacokinetic (PK) data were consistent with a drug half-
life of approximately 30 days.  
The combination of cirmtuzumab and paclitaxel was safe and well-tolerated in heavily pre-
treated metastatic breast cancer patients. Further evaluation of ROR1 targeting in breast cancer 
with cirmtuzumab is warranted. Due to the small number of patients with baseline tumor tissue, 
the ability to correlate ROR1 staining with clinical outcomes is limited.   
 
Statistical analysis 
 
DLTs were defined as clinically significant adverse events considered by the investigator to be 
possibly, probably, or definitely related to cirmtuzumab or the combination of cirmtuzumab with 
paclitaxel within 28 days of investigational treatment initiation. DLTs included Grade 4 
hematologic toxicity lasting more than 7 days and nonhematologic toxicity of grade 3 or higher. 
Patients were enrolled in cohorts of five, and each cohort was assessed for DLTs prior to 


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enrollment of the next cohort. If two or more patients in the first cohort experienced DLT 
attributed to cirmtuzumab at full dose, then the next cohort would be enrolled at a 50% dose 
reduction (300 mg flat dose). If two or more patients in the second cohort experienced DLT 
attributed to cirmtuzumab at a 50% dose reduction, then the study would be stopped. If fewer 
than two patients in the first cohort experienced DLT attributed to cirmtuzumab at full dose, but 
two or more in the second cohort experienced DLT at full dose, then the third cohort would be 
treated with 50% dose-reduced cirmtuzumab. For adverse events other than DLTs attributed to 
study treatment, dose and schedule changes were specified in the protocol. The protocol also 
specified that for Grade > 2 rash, allergy, or infusion reaction, nab-paclitaxel may be substituted 
at investigator discretion. The intent-to-treat population includes all patients who started at least 
one dose of cirmtuzumab. Descriptive statistics are used to characterize demographics, safety, 
toxicities, and anti-tumor activity. Best tumor responses are shown in a waterfall plot, and a 
swimmer plot is used to show tumor responses for each patient while on study treatment. 
Confidence intervals of the median progression-free survival (PFS) time are estimated based on 
Kaplan–Meier estimates, with PFS defined as weeks from the first day of study treatment to first 
disease progression or death. The duration of partial response (PR) was defined as the time from 
the first PR assessment to the time of recurrence, progression, or death.