A Phase 1 Extension Study to Determine the Safety of UC-961 (Cirmtuzumab) at the Recommended Phase 2 Dose for Retreatment of Patients With Chronic Lymphocytic Leukemia Treated Previously With UC-961
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukemia
Sponsor: University of California, San Diego

UC-961 (Cirmtuzumab) 
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Activated: 
 
Version Date: 
03/30/2017 
Closed: 
 
 
 
 
 
 
 
 
 
 
A Phase 1 extension study to determine the safety of UC-961 (Cirmtuzumab) at the 
recommended phase 2 dose for retreatment of patients with Chronic Lymphocytic Leukemia 
treated previously with UC-961. 
 
 
 
PRINCIPAL INVESTIGATORS 
 
 
Catriona Jamieson, MD/PhD  
Hematology/Oncology 
3855 Health Sciences Drive, #0987 
La Jolla, CA 92093-0987 
Phone: 858-534-7128 
Fax: 858-822-5399 
e-mail: cjamieson@ucsd.edu 
 
Michael Choi, MD (co-PI) 
Hematology/Oncology 
3855 Health Sciences Drive, #0820 
La Jolla, CA 92093-0820 
Phone: (858) 534-1765 
Fax: (858) 534-5620 
E-mail:  mychoi@ucsd.edu 
 
 
 
 
 
Protocol Number: 
 
HRPP #150851 
 
Investigational Product: 
UC-961 (Cirmtuzumab) 
 
IND Number:  
 
117975 
 
IND Holder:  
 
Thomas Kipps, MD/PhD  
 
NCT Number:  
 
02860676 
 
 
 
 

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LIST OF INVESTIGATORS 
 
 
PRINCIPAL INVESTIGATORS 
 
Catriona Jamieson, MD/PhD  
Hematology/Oncology 
3855 Health Sciences Drive, #0987 
La Jolla, CA 92093-0987 
Phone: 858-534-7128 
Fax: 858-822-5399 
e-mail: cjamieson@ucsd.edu 
 
 
Michael Choi, MD (co-PI) 
Hematology/Oncology 
3855 Health Sciences Drive, #0820 
La Jolla, CA 92093-0820 
Phone: (858) 534-1765 
Fax: (858) 534-5620 
E-mail:  mychoi@ucsd.edu  
 
 
 
STUDY STATISTICIANS 
Karen Messer, PhD 
Biostatistics 
3855 Health Sciences Drive, #0901 
La Jolla, CA 92093-0901 
Phone: 858-822-4334 
e-mail: kmesser@ucsd.edu 
 
Hongying Li, PhD 
Biostatistics 
3855 Health Sciences Drive, #0901 
La Jolla, CA 92093-0901 
Phone: 858-822-4818 
Email: hol031@ucsd.edu 
 
 
 
CO-INVESTIGATOR(S) 
Januario Castro, MD 
Hematology/Oncology 
3855 Health Sciences Drive, #0960 
La Jolla, CA 92093-0960 
Phone: 858-822-6386 
Fax: 
858-822-6844 
e-mail: jecastro@ucsd.edu 
 
Thomas Kipps, MD/PhD 
Hematology/Oncology 
3855 Health Sciences Drive, #0820 
La Jolla, CA 92093-0820 
Phone: 858-534-5400 
Fax: 
858-534-5620 
e-mail: tkipps@ucsd.edu 
 
 
 
 
 
 
 

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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 (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
LIST OF INVESTIGATORS .................................................................................................................................................... 2 
PROTOCOL SYNOPSIS ......................................................................................................................................................... 6 
SCHEMA .................................................................................................................................................................................... 10 
1.0 
BACKGROUND ........................................................................................................................................................... 10 
1.1 
INTRODUCTION/RATIONALE FOR DEVELOPMENT .............................................................................................................. 10 
1.2 
UC-961 DEVELOPMENT AND PRECLINICAL ACTIVITY IN CLL MODELS ..................................................................... 11 
1.3 
INITIAL CLINICAL TRIAL RESULTS ........................................................................................................................................... 13 
1.4 
RATIONALE FOR DOSE SELECTION ........................................................................................................................................ 14 
1.5 
OVERVIEW OF PROPOSED STUDY.......................................................................................................................................... 15 
2.0 
STUDY OBJECTIVES ................................................................................................................................................ 16 
2.1 
PRIMARY OBJECTIVE:....................................................................................................................................................................... 16 
2.2 
SECONDARY OBJECTIVES: ................................................................................................................................................................ 16 
2.3 
EXPLORATORY OBJECTIVES: ........................................................................................................................................................... 16 
3.0 
PATIENT ELIGIBILITY .............................................................................................................................................. 17 
3.1 
INCLUSION CRITERIA ................................................................................................................................................................... 17 
3.2 
EXCLUSION CRITERIA .................................................................................................................................................................. 17 
4.0 
INVESTIGATIONAL TREATMENT PLAN .......................................................................................................... 18 
4.1 
DOSE ASSIGNMENT...................................................................................................................................................................... 18 
4.2 
DOSE LIMITING TOXICITY ........................................................................................................................................................... 19 
4.3 
RECOMMENDED PRE-MEDICATIONS AND CONCOMITANT MEDICATIONS ................................................................ 19 
4.4 
UC-961 INFUSION PLAN ............................................................................................................................................................. 19 
4.5 
CRITERIA FOR DOSING ................................................................................................................................................................ 20 
4.6 
DOSE MODIFICATIONS AND DOSING DELAYS .................................................................................................................... 20 
4.7 
PERMITTED CONCOMITANT THERAPY .................................................................................................................................... 22 
4.8 
PROHIBITED CONCOMITANT THERAPY .................................................................................................................................. 22 
4.9 
DURATION OF THERAPY ............................................................................................................................................................. 23 
4.10 
DURATION OF FOLLOW UP ..................................................................................................................................................... 23 
4.11 
CRITERIA FOR REMOVAL FROM STUDY ............................................................................................................................. 23 
5.0 
STUDY PROCEDURES ............................................................................................................................................ 23 
5.1 
SCREENING/BASELINE PROCEDURES .................................................................................................................................. 23 
5.2 
UC-961 EXTENSION COURSE 1: ............................................................................................................................................ 24 
5.3 
DAY 169 +/- 7 DAYS: RESPONSE ASSESSMENT:.............................................................................................................. 25 
5.4 
UC-961 EXTENSION COURSE 2: ............................................................................................................................................ 25 
5.5 
LONG TERM FOLLOW-UP ................................................................................................................................................................. 26 
5.6 
PHARMACOKINETIC (PK) STUDIES......................................................................................................................................... 26 
5.7 
CORRELATIVE STUDIES .............................................................................................................................................................. 27 
6.0 
SCHEDULE OF EVENTS ......................................................................................................................................... 29 
7.0 
MEASUREMENT OF EFFECT................................................................................................................................ 31 
7.1 
SAFETY/TOLERABILITY ................................................................................................................................................................ 31 
7.2 
RESPONSE CRITERIA FOR PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA ................................................. 32 
8.0 
ADVERSE EVENTS.................................................................................................................................................... 33 
8.1 
ADVERSE EVENT MONITORING ............................................................................................................................................... 34 
8.2 
SEVERITY ......................................................................................................................................................................................... 34 
8.3 
SERIOUSNESS ................................................................................................................................................................................ 34 

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8.4 
RELATIONSHIP................................................................................................................................................................................ 35 
8.5 
PRIOR EXPERIENCE...................................................................................................................................................................... 35 
8.6 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS .................................................................................................... 35 
9.0 
AGENT INFORMATION ............................................................................................................................................ 36 
9.1 
UC-961 (CIRMTUZUMAB) .......................................................................................................................................................... 36 
10.0 
STATISTICAL CONSIDERATIONS ................................................................................................................... 37 
11.0 
STUDY MANAGEMENT ......................................................................................................................................... 38 
11.1 
CONFLICT OF INTEREST ........................................................................................................................................................... 38 
11.2 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT .......................................................................... 38 
11.3 
SUBJECT DATA PROTECTION ................................................................................................................................................ 38 
11.4 
DATA AND SAFETY MONITORING ......................................................................................................................................... 38 
11.5 
RECORD RETENTION ................................................................................................................................................................ 39 
11.6 
OBLIGATIONS OF INVESTIGATORS ....................................................................................................................................... 39 
12.0 
REFERENCES ........................................................................................................................................................... 40 
13.0 
APPENDICES ............................................................................................................................................................ 41 
APPENDIX A. PERFORMANCE STATUS .............................................................................................................................................. 41 
 
 
 

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PROTOCOL SYNOPSIS 
 
INVESTIGATIONAL 
AGENT 
UC-961 
TITLE 
A Phase 1B Extension Study to Determine the Safety, Pharmacokinetics 
and Pharmacodynamics of UC-961 (Cirmtuzumab) at the recommended 
phase 2 dose for patients with Chronic Lymphocytic Leukemia Previously 
Treated with Cirmtuzumab (UC-961). 
PROTOCOL NUMBER 
 
PHASE OF 
DEVELOPMENT 
Phase IB 
STUDY OBJECTIVES 
Primary Objective:  
1. To determine the safety and tolerability of UC-961 when 
administered for an extended duration. 
Secondary Objectives: 
2. To determine the clinical activity of biweekly doses of UC-961, 
including overall response rate (2008 iwCLL guidelines) and 
progression free and overall survival (new clinical endpoint from the 
initial phase 1 trial). 
3. To assess the SD, PR, and MRD- rates 
 
Exploratory Objectives:  
1. To assess the mechanism of action through immunophenotypic 
(FACS, ELISA), nanoproteomic ROR1 signaling pathway analysis  
and pharmacodynamic studies including ROR1+ cancer stem cell 
cycle and self-renewal assays. 
STUDY ENDPOINTS 
Primary Endpoint 
Safety and tolerability with extended dosing of UC-961 based on ongoing 
evaluation of AEs during treatment and 3 month follow up 
Secondary Endpoints 
1. Overall response rate by IWCLL criteria following 6 months of biweekly 
dosing of UC-961 (Hallek et al., 2008) 
2. Progression free and overall survival (progression determined by IWCLL 
working group criteria) 
3. SD, PR, and MRD- rates, as well as individual components of response 
(reduction in leukemia count, reduction in adenopathy and splenomegaly, 
and improvement in BM function), as determined by IWCLL working group 
criteria. 
Exploratory Endpoints 
1. ROR1 receptor density on circulating bulk tumor cells and stem cells 
2. Circulating  UC-961 levels in peripheral blood 
3. Level of circulating antibodies against UC-961 
4. Assay of ROR1 signaling via nanoproteomics (CB1000) 
5. Assay of cytokine signaling and other CLL signaling pathways via  
qPCR array. 
6. Assay of associated proteins including phosphorylated AKT versus 
total AKT ratio by western blot 
7. Assay of ROR1+ cancer stem cell inhibition by stromal co-culture 
FUCCI2BL cell cycle, survival and self-renewal analysis  
STUDY DESIGN 
This is an open-label extension study to determine the safety and efficacy. 

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NUMBER OF PATIENTS 
Patients enrolled in the initial phase 1 trial in CLL are eligible for enrollment 
in this extension trial.  We anticipate that 33 patients will be enrolled, 
however, up to 75 patients may be eligible to be enrolled should the initial 
phase 1 trial require expansion to 6 patients for each dosing cohort.  
INCLUSION CRITERIA 
1. Ability to understand and the willingness to sign a written informed 
consent. 
2. Clinical and phenotypic verification of B cell CLL and measurable 
disease. Immunophenotyping of the leukemic cells (blood or marrow) 
must demonstrate a monoclonal (or light chain positive) B cell 
population with immunophenotype consistent with CLL (e.g., co-
expressing CD19 and CD5). 
3. Recovered from toxic effects attributed to UC-961 to grade 1 levels, or 
baseline. 
4. Must have measurable disease, including one of the following: 
absolute lymphocyte count greater than 5000/uL, lymphadenopathy 
greater than 1.5 cm in longest dimension, splenomegaly (palpable at 
least 1 cm below the costal margin or radiographically enlarged), bone 
marrow biopsy with residual CLL cells, or resultant bone marrow 
dysfunction (platelet count < 100k /uL, hemoglobin < 10 g/dL). 
5. Women of childbearing potential (not postmenopausal for at least one 
year or not surgically incapable of bearing children) must agree not to 
become pregnant for the duration of the study. Both men and women 
must agree to use a barrier method of contraception for the duration of 
the study and until 10 weeks after the final dose of UC-961 (expected 
to be greater than 5 half-lives from pre-clinical data). 
6. Subjects must have an ECOG performance status of 0-2.  
7. Adequate hematologic function: 
 
 
Platelet count  50,000/µL unless due to heavily infiltrated 
bone marrow (> 80% CLL cell infiltrate);  AND 
 
Hemoglobin  8.0 g/dL (may be supported by erythropoietin); 
AND 
 
Absolute neutrophil count > 1000 /uL unless due to heavily 
infiltrated bone marrow (> 80% CLL cell infiltrate). 
8. Adequate renal function: 
 
Serum creatinine <1.5 times upper limit of normal; OR 
 
Calculated Creatinine clearance (CrCl) ≥ 40 mL/min (based 
upon the Cockcroft-Gault Equation [CrCl = (140-age) * actual 
wt (in kg) * (0.85 if female) / (72 * Cr)]. 
9. Adequate hepatic function: 
 
Total bilirubin ≤ 2.5 times upper limit of normal; AND 
 
ALT ≤ 2.5 times upper limit of normal. 
10. Adequate coagulation tests: 
 
Prothrombin time international normalized ratio (INR) ≤ 2; AND 
 
Partial thromboplastin time ≤ 1.66 times upper limit of normal. 
EXCLUSON CRITERIA 
1. Pregnant or breast-feeding women will not be entered on this study 
due to risks of fetal and teratogenic adverse events as seen in 
animal/human studies. IgG may cross the placental barrier and cause 
fetal B- and T-lymphocyte depletion. Therefore, women of childbearing 
age must obtain a pregnancy test, and pregnant or breast feeding 
females are excluded.  

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2. May have had intervening therapy since completion of initial UC-961 
dosing, but excluding the following: 
a. Within 14 days, or 5 half-lives (if known), whichever is 
shorter, of UC-961 restart: small molecule kinase inhibitor 
(eg: ibrutinib, idelalisib, AVL-292, IPI-145);  
b. Within 28 days of UC-961 restart: chemotherapy (e.g., 
purine analogues, alkylating agents), corticosteroids, 
radiation therapy, or participation in any other 
investigational drug treatment (besides UC-961);  
c. Within 56 days UC-961 restart: previous UC-961 dosing; 
d. Within 8 weeks of UC-961 restart: monoclonal antibody 
therapy directed against CLL (eg. rituximab, ofatumumab, 
obinutuzumab, alemtuzumab). 
3. Current infection requiring parenteral antibiotics.  
4. Active infection with HIV, HBV, or HCV.  
5. Concurrent malignancy or prior malignancy within the previous 3 years 
(other than completely resected carcinoma in situ, prostate cancer, or 
localized non-melanoma skin cancer).  
6. Known central nervous system (CNS) involvement by malignancy. 
7. Untreated autoimmunity such as autoimmune hemolytic anemia, or 
immune thrombocytopenia.  
8. Uncompensated hypothyroidism (defined as TSH greater than 2x 
upper limit of normal not treated with replacement hormone).  
9. Presence of more than 55% pro-lymphocytes in peripheral blood. 
Patients with Richter’s transformation are not excluded. 
10. Insufficient recovery from surgical-related trauma or wound healing. 
11. Impaired cardiac function including any of the following: 
 
Myocardial infarction within 6 months of starting study drug; 
 
A past medical history of clinically significant ECG abnormalities, 
eg: QTc 481 ms or greater. 
 
Other clinically significant heart disease (e.g. uncontrolled 
congestive heart failure, uncontrolled hypertension, history of labile 
hypertension, or history of poor compliance with an 
antihypertensive regimen) 
12. Patients who in the opinion of the investigator may be unable to 
comply with the safety monitoring requirements of the study. 
DURATION OF 
INVESTIGATIONAL 
AGENT 
ADMINISTRATION AND 
STUDY 
PARTICIPATION  
Duration of UC-961 administration is until disease progression, treatment 
intolerance, or lack of clinical benefit. Patients may remain on the clinical 
trial protocol until one of the following: 
 
Clinical or radiographic progressive disease (See Section 12). 
 
Adverse Events requiring removal from study (See Section 13). 
 
Refusal of further protocol therapy by patient/parent/guardian 
 
Non-compliance that in the opinion of the investigator does not 
allow for ongoing participation. 
 
Physician determines it is in the patient’s best interest to 
discontinue participation in the clinical trial. 
 
Completion of all clinical trial procedures. 
 

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Participation in the study and long-term follow-up will continue until one of 
the following: 
 
Death. 
 
Loss to follow-up. 
 
Withdrawal of consent for any further data submission. 
 
Progression requiring initiation of subsequent therapy. 
STUDY DRUG 
ADMINISTRATION 
UC-961 is administered by intravenous infusion on day 1, 15, 29, 43, 57, 
85, 113, and 141, after which responses will be assessed.  
Patients with an objective response (meeting working group criteria for 
partial response or complete response) will continue at the same dose and 
schema. Patients with stable disease or progressive disease are eligible to 
increase the dose of UC-961 for another 6-month course. 
CRITERIA TO 
EVALUATE SAFETY 
Safety will be determined by Principal Investigator, and will be assessed 
according to the NCI Common Terminology Criteria for Adverse Events 
version 4.03 (NCI CTCAE v4.03) for non-hematologic toxicity and modified 
iwCLL criteria for hematologic toxicity.    
CRITERIA TO 
EVALUATE EFFICACY 
Overall response rate is the percentage of patients meeting criteria for 
partial response, nodular partial response, or complete response based on 
iwCLL criteria. Progression free survival is according to iwCLL definition.  
 
 

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SCHEMA 
 
 
 
 
1.0 
BACKGROUND 
1.1 
Introduction/Rationale for Development 
Chronic Lymphocytic Leukemia (CLL) is the most prevalent hematologic cancer in the western 
hemisphere (Gribben and O'Brien, 2011). At this time, it is considered incurable. Treatment 
regimens that combine chemotherapy and immunotherapy (eg: Fludarabine + Cyclophosphamide 
+ Rituximab) have produced high response rates and have been associated with an improved 
overall survival (Hallek et al., 2010). However, patients inevitably relapse and there is no standard 
of care therapy in the relapsed or refractory setting. Moreover, many patients cannot tolerate 
chemoimmunotherapy regimens in the relapsed/refractory setting due to age, comorbidities, or 
compromised bone marrow function (Brown, 2011). Obinutuzumab (GA-101) in combination with 
chlorambucil was approved by the FDA in November 2013 based on efficacy as front-line therapy 
for patients older than 65.  However, responses were not durable with this treatment either (ASH 
2013, abstract 6). Oral agents that inhibit B-cell receptor associated tyrosine kinases, including 
Ibrutinib (which has been FDA approved for mantle cell lymphoma and CLL) may be approved 
for CLL by the FDA as well. However, it does not appear that these agents are capable of 
consistently inducing complete remissions, eradicating minimal residual disease (Byrd et al., 
2013) or a dormant malignant stem cell population. Thus, development, testing, and optimization 
of novel therapeutic strategies are required to provide more tractable clinical responses. 
 
ROR1 (receptor tyrosine kinase-like orphan receptor 1) is a transmembrane protein that is 
expressed on the surface of CLL cells, from nearly all patients with CLL (94% based on flow 
Completed UC-961 Phase 1 Clinical Trial 
(UC-961 q 14 days x 4 doses) 
Screen for eligibility for UC-961 Extension Trial
✓Tolerated UC-961 without dose limiting toxicity and 
recovered from toxic effects to grade 1 or baseline.
✓If intervening CLL therapy, maintains measurable 
disease.
Response assessment (labs, imaging, bone marrow 
biopsy)
UC-961 q 14 days x 4 doses, then q 28 days x 4 doses 
(dose based on ongoing phase 1 trial) 
Repeat UC-961 course (dose increase if PD or SD)

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cytometry analysis of the CLL research consortium) (Fukuda et al., 2008). It shares homology 
with other receptor tyrosine kinases, and is believed to participate in Wnt signaling, based on 
homology to the Wnt receptor, Frizzled. However, its precise function is unknown, and although 
the protein has a putative kinase domain, it may be a pseudo-kinase serving as a cofactor for 
other signaling proteins, leading to phosphorylation of Akt.  
 
Importantly, 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 are typically observed 
in the marrow of pediatric patients or patients recovering from myeloablative therapy, but are 
found in minute levels (<1% of mononuclear cells) in the marrow of healthy adults (Broome et al., 
2011). 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 second trimester fetal liver 
stage, and is not on marrow stem cells or normal adult tissues (Fukuda et al., 2008, Hudecek et 
al., 2010, Masiakowski and Carroll, 1992, Matsuda et al., 2001, Zhang et al., 2012). As such, it 
represents an ideal target for immunotherapy, due to a potential lack of cross-reactivity with 
normal adult tissues, reduced immunosuppression based on lack of targeting or normal myeloid 
or lymphoid cells. 
 
UC-961 (Cirmtuzumab) is a fully humanized monoclonal antibody designed to bind the 
extracellular immunoglobulin-like domain of ROR1 with high-affinity. Initial preclinical studies 
(described below) show that it is an ideal potential therapy due to the following features: 
 
High affinity for cell-surface ROR1 
 
Activity against cancer cells that express ROR1, which include cancer-stem 
cells, with a mechanism of cell death that appears to be due to inhibition of 
Wnt5a/ROR1 mediated Akt signaling and non-canonical Wnt signaling, 
both important pathways for the survival of CLL cells (Fukuda et al., 2008, 
Cui et al., 2013, Widhopf et al., 2014). 
 
Lack of cross reactivity with normal adult tissues  
 
Reduced immunosuppressive potential based on lack of targeting most 
normal lymphoid or myeloid cells  
 
Low immunogenic potential due to substantial humanization of the mAb 
framework 
 
Based on this biological rationale and the preclinical activity, an open label, phase I clinical trial is 
ongoing and will determine safety and efficacy of UC-961 for the treatment of patients with 
relapsed or refractory CLL. This phase I trial uses a 3+3 phase 1 dose escalation design, and a 
relatively short treatment duration of 2 months to evaluate for immediate adverse effects. See 
Section 1.3 for details. 
 
The study proposed herein will allow patients who wish to continue UC-961 therapy to receive 
continued UC-961 at the biologically active dose or recommended phase 2 dose (RP2D). It will 
also allow patients that were initially treated at doses below the RP2D to increase their dose of 
UC-961. It will also allow for improved data regarding long-term safety and safety with prolonged 
dosing of UC-961 at the R2PD. 
1.2 
UC-961 Development and preclinical activity in CLL models 
UC-961 is the result of testing and optimization of anti-human ROR1 monoclonal antibodies 
initially generated by classical hybridoma and phase display technologies. Initially, mice were 
inoculated with DNA, protein, adenoviral constructs of ROR1, cytokines, and immune stimulatory 
agents to generate anti-human ROR1 antibodies. These initial murine anti-ROR1 monoclonal 

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antibodies (designated 1-1-4A5 and 3-D10) have been tested using in vivo and in vitro test 
systems.  When tested in an immune deficient murine model, 3-D10 consistently demonstrated 
potent activity against human CLL patient samples. At this time, the 3-D10 mAb has been tested 
against human primary CLL cells in hundreds of mice and has consistently eliminated the human 
cells in a dose dependent manner. Mouse models have included immune-deficient mice with CLL 
cell xenografts, as well as immune competent transgenic models that spontaneously generate 
leukemic cells expressing the human ROR1 protein. In these models, the 3-D10 mAb, but not 
control IgG or 1-4A5, was able to inhibit the development and expansion of the ROR1 positive 
leukemic B cells in the blood and spleen of recipient animals. A dose of 10mg/kg was used. 
 
To improve binding affinity, chimeric truncated ROR1 screening proteins were then used to pan 
for high affinity anti-human ROR1 mAbs generated through the use of a proprietary enhanced 
phage library (Alere, Inc., San Diego, CA). High affinity antibodies that bind to the same epitope 
as 3-D10 and more importantly exhibit the same anti-leukemic activity of this prototypical mAb 
were identified. After cell line and animal testing and kinetic binding analysis, we chose a single 
antibody designated UC-99961 (UC-m961) for advancement in pre-clinical development.  
 
UC-m961 was humanized by BioAtla, Inc. (San Diego, CA), who employed a proprietary 
recombinant framework grafting technology to generate humanized antibodies that retain the 
biologic activities of the parent mAb. Over 20 different light and heavy chain humanized variant 
ROR1 targeting mAbs were screened.  
 
After conducting head-to-head analyses of several candidate humanized anti-ROR1 mAb, a final 
humanized mAb construct, designated UC-h961, was selected. This humanized mAb is 
essentially humanized except for a few amino acids adjacent to the CDR borders and framework 
4, which for the most part are tucked under CDR3 in an immune protected site. UC-h961 will 
hereafter be referred to as UC-961 or Cirmtuzumab. 
 
1.2.1 Pre-Clinical Pharmacology and Toxicology 
To 
support 
the 
UC-961 
phase 
I 
clinical 
trial, 
a 
comprehensive 
single-species 
pharmacology/toxicology study was conducted in rats.  In this study, groups of animals (15 of 
each sex) received UC-961 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 UC-961 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.   
 
1.2.2 Pre-Clinical Pharmacokinetics and Metabolism 

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Comprehensive pharmacokinetic studies were conducted in both immune deficient mice and in 
Wistar rats. Immune deficient mice (Rag2g-/-) were injected i.v. (1 mg/mouse), blood was drawn 
at different time points (left panel) and levels in plasma were measured by ELISA. One- 
compartment PK description of average data reveals that t1/2 = 11.4 days V= 1.18 mL (47 mL/kg) 
and CL = 0.072 mL/day (0.12 mL/hr/kg).  For studies in rats, cohorts of animals received 200, 60 
and 20 mg/kg of UC-961 mAb and were screened at 14, 28, 42 and 56 days after treatment. The 
results (right panel) indicate that the UC-961 was removed from the rats with an apparent half-life 
of 7 days irrespective of the initial dose of administered mAb.  
 
1.3 
Initial Clinical Trial Results 
 
The phase 1 trial of cirmtuzumab (UC-961) initiated in August 2014. Eligible patients have 
relapsed or refractory CLL or SLL, not amenable to approved treatment options. As April 2016, 
18 patients have received doses of UC-961 as part of the ongoing phase 1 clinical trial. Doses 
are administered every 14 days for a total of 4 doses with an intrapatient dose escalation scheme 
in place through cohort 4. Per the protocol design, any grade 2 adverse events (unless definitely 
not due to UC-961), triggered a cessation of intrapatient dose escalation, and conversion of the 
protocol to a standard 3+3 design starting at the dose at which the AE occurred. 
 
Cohort 1: 3 patients received 2 doses of 15 mcg/kg and 2 doses of 30 mcg/kg. 1 patient in the 
first cohort had progressive disease and stopped after only 1 infusion of UC-961.  
 
Cohort 2: 3 patients received 2 doses of 60mcg/kg and 2 doses of 240mcg/kg.  
 
Cohort 3: 3 patients received 2 doses of 500mcg/kg and 2 doses of 1mg/kg.  
 
Cohort 4: 2 patients received 2 doses of 2mg/kg and 2 doses of 4mg/kg. 1 patient in this cohort 
had progressive disease and stopped after only 1 infusion of UC-961 2mg/kg and therefore 
required replacement. The subsequent patient in this cohort received 2 doses of 2mg/kg and then 
had a grade 2 urinary tract infection associated with grade 2 neutropenia, thrombocytopenia, and 
confusion. These events were assessed to be unlikely related to UC-961. However, they triggered 
halting of intrapatient dose escalation. This patient received 1 additional dose of 2mg/kg and then 
elected to discontinue with stable disease to pursue other treatment options. Because 3 patients 
had received at least 28 days of UC-961 2mg/kg without dose limiting toxicity, the 2mg/kg dose 
level was determined to be safe. An additional patient was then enrolled in this cohort and 
received 4 doses of 4mg/kg to complete the 4mg/kg dose level (including the 2 patients that had 
been observed for 28 days at that dose earlier in the cohort). 
 

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Cohort 5: As of 4/8/16, 1 patient received 4 doses of 8 mg/kg. 2 patients are currently receiving 8 
mg/kg, and will pass the DLT observation period in April 2016. 
 
Cirmtuzumab was well tolerated with the majority of adverse events being grade 1 in severity. 
One patient had a grade 2 urinary tract infection associated with grade 2 neutropenia, 
thrombocytopenia, and confusion; these were assessed to be unlikely related to cirmtuzumab. All 
AEs, regardless of attribution, are listed in table 4. The most common AEs were anemia (6 pts), 
thrombocytopenia (5 pts), neutropenia (4 pts), restlessness (4 pts), bloating (3 pts), nausea (3 
pts), and diarrhea (3 pts). All hematologic AEs are attributed to underlying disease, and not to 
cirmtuzumab. 
 
 
  
AE summary that were probably, possibly, or unlikely due to UC-961, as of 4/1/16.  
 
 
Gr1 
Gr2 
Anemia 
6 
 
Thrombocytopenia 
4 
1 
Neutropenia 
3 
1 
Restlessness 
4 
 
Nausea 
3 
 
Bloating 
3 
 
Diarrhea 
3 
 
Lipase Increased 
1 
1 
Bilirubin increased 
2 
 
Dizziness 
2 
 
Flushing 
2 
 
Vomiting 
2 
 
Amylase Increased 
 
1 
Confusion 
 
1 
ALT increased 
1 
 
AST increased 
1 
 
Atrial fibrillation 
1 
 
Constipation 
1 
 
Cough 
1 
 
Creatinine increased 
1 
 
Dry mouth 
1 
 
Fatigue 
1 
 
Fecal incontinence 
1 
 
Headache 
1 
 
Hoarseness 
1 
 
Hot flashes 
1 
 
Hyperkalemia 
1 
 
Hypokalemia 
1 
 
Hypernatremia 
1 
 
Insomnia 
1 
 
Urinary frequency 
1 
 
 
1.4 
Rationale for Dose Selection 
 
Each extension course consists of 8 infusions. A patient may repeat the course, and therefore 
receive a total of 16 infusions on the extension study. Each individual patient will receive the same 

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dosage of UC-961 for each of the 8 infusions of each course. The dosage of UC-961 may be 
increased for the 2nd set of 8 infusions (if a higher dose has been shown to be safe on the phase 
1 trial AND there is Progressive Disease or Stable Disease after the first course of extension. 
 
The dose administered on this extension study will be the highest safe dose, or once established, 
the biologically active dose or the recommended phase 2 dose from the phase 1 trial.  To date, 
the 8 mg/kg dose level has been completed and determined to be safe. Therefore, patients on 
this extension study will begin at the 8 mg/kg dose level. Should subsequent dose levels be 
determined to be safe in the Phase 1 trial, the dose utilized in this trial may increase for 
subsequent patients. 
 
Planned dose levels (starting dose is the highest safe dose administered to a patient in the phase 
1 trial): 
Potential 
Dose Level 
Dose 
-1 
4 mg/kg 
1 (start) 
8 mg/kg 
2 
16 mg/kg (or max 2000 mg dose) 
3 
20 mg/kg (or max 2000 mg dose) 
 
1.5 
Overview of Proposed Study 
UC-961 will be examined for safety and tolerability in patients who enrolled and completed UC-
961 infusions on the phase 1 first-in-man clinical trial without dose limiting toxicity at doses at or 
below the RP2D, and receive retreatment with UC-961 at the established biologically active 
dose or MTD. The primary endpoint of this phase I trial will be assessment of adverse events 
during continued treatment. In addition there will be assessment of clinical activity according to 
iwCLL working group criteria and progression free survival.  Additionally, pharmacokinetic 
parameters will be assessed and blood samples will be collected for correlative analysis.  
 
 

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2.0 
STUDY OBJECTIVES AND ENDPOINTS: 
 
2.1 
Primary Objective:  
2.1.1 To determine the safety and tolerability of UC-961 when administered for an 
extended duration. 
2.2 
Secondary Objectives: 
2.2.1 To determine the clinical activity of biweekly doses of UC-961, including overall 
response rate (2008 iwCLL guidelines) and progression free and overall survival 
(new clinical endpoint from the initial phase 1 trial). 
2.2.2 To assess the SD, PR, and MRD- rates 
 
2.3 
Exploratory Objectives:  
2.3.1 To assess the mechanism of action through immunophenotypic (FACS, ELISA), 
nanoproteomic ROR1 signaling pathway analysis  and pharmacodynamic studies 
including ROR1+ cancer stem cell cycle and self-renewal assays. 
 
2.4 
Primary Endpoint 
2.4.1 
Safety and tolerability with extended dosing of UC-961 based on ongoing evaluation of 
AEs during treatment and 3 month follow up 
2.5 
Secondary Endpoints 
2.5.1 
Overall response rate by IWCLL criteria following 6 months of biweekly dosing of UC-961 
(Hallek et al., 2008) 
2.5.2 
Progression free and overall survival (progression determined by IWCLL working group 
criteria) 
2.5.3 
SD, PR, and MRD- rates, as well as individual components of response (reduction in leukemia 
count, reduction in adenopathy and splenomegaly, and improvement in BM function), as 
determined by IWCLL working group criteria. 
2.6 
Exploratory Endpoints 
2.6.1 
ROR1 receptor density on circulating bulk tumor cells and stem cells 
2.6.2 
Circulating  UC-961 levels in peripheral blood 
2.6.3 
Level of circulating antibodies against UC-961 
2.6.4 
Assay of ROR1 signaling via nanoproteomics (CB1000) 
2.6.5 
Assay of cytokine signaling and other CLL signaling pathways via  qPCR array. 
2.6.6 
Assay of associated proteins including phosphorylated AKT versus total AKT ratio by 
western blot 
2.6.7 
Assay of ROR1+ cancer stem cell inhibition by stromal co-culture FUCCI2BL cell cycle, 

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survival and self-renewal analysis 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study. 
1. Ability to understand and the willingness to sign a written informed consent. 
2. Clinical 
and 
phenotypic 
verification 
of 
B 
cell 
CLL 
and 
measurable 
disease. 
Immunophenotyping of the leukemic cells (blood or marrow) must demonstrate a monoclonal 
(or light chain positive) B cell population with immunophenotype consistent with CLL (e.g., co-
expressing CD19 and CD5). 
3. Recovered from toxic effects attributed to UC-961 to grade 1 levels, or baseline. 
4. Must have measurable disease, including one of the following: absolute lymphocyte count 
greater than 5000/uL, lymphadenopathy greater than 1.5cm in longest dimension, 
splenomegaly (palpable at least 1 cm below the costal margin or radiographically enlarged), 
bone marrow biopsy with residual CLL cells, or resultant bone marrow dysfunction (platelet 
count < 100k /uL, hemoglobin < 10 g/dL). 
5. Women of childbearing potential (not postmenopausal for at least one year or not surgically 
incapable of bearing children) must agree not to become pregnant for the duration of the 
study. Both men and women must agree to use a barrier method of contraception for the 
duration of the study and until 10 weeks after the final dose of UC-961 (expected to be greater 
than 5 half-lives from pre-clinical data). 
6. Subjects must have an ECOG performance status of 0-2.  
7. Adequate hematologic function:  
 
Platelet count  50,000/µL unless due to heavily infiltrated bone marrow (> 80% CLL cell 
infiltrate); AND 
 
Hemoglobin  8.0 g/dL (may be supported by erythropoietin); AND 
 
Absolute neutrophil count > 1000 /uL unless due to heavily infiltrated bone marrow (> 
80% CLL cell infiltrate). 
8. Adequate renal function: 
 
Serum creatinine <1.5 times upper limit of normal; OR 
 
Calculated Creatinine clearance (CrCl) ≥ 40 mL/min (based upon the Cockcroft-Gault 
Equation [CrCl = (140-age) * actual wt (in kg) * (0.85 if female) / (72 * Cr)]. 
9. Adequate hepatic function: 
 
Total bilirubin ≤ 2.5 times upper limit of normal; AND 
 
ALT ≤ 2.5 times upper limit of normal. 
10. Adequate coagulation tests: 
 
Prothrombin time international normalized ratio (INR) ≤ 2; AND 
 
Partial thromboplastin time ≤ 1.66 times upper limit of normal. 
3.2 
Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study participation. 
1. Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and 
teratogenic adverse events as seen in animal/human studies. IgG may cross the placental 
barrier and cause fetal B- and T-lymphocyte depletion. Therefore, women of child-bearing age 
must obtain a pregnancy test, and pregnant or breast feeding females are excluded.  

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2. May have had intervening therapy since completion of initial UC-961 dosing, but excluding 
the following: 
a. Within 7 days of UC-961 restart, or 5 half-lives (if known), whichever is shorter: 
small molecular tyrosine kinase inhibitor (eg: ibrutinib, idelalisib, AVL-292, IPI-
145);  
b. Within 28 days of UC-961 restart: chemotherapy (e.g., purine analogues, alkylating 
agents), corticosteroids, radiation therapy, or participation in any other 
investigational drug treatment (besides UC-961)  
c. Within 56 days UC-961 restart: previous UC-961 dosing 
d. Within 56 days of UC-961 restart: monoclonal antibody therapy directed against 
CLL (eg. rituximab, ofatumumab, obinutuzumab, alemtuzumab). 
3. Current infection requiring parenteral antibiotics.  
4. Active infection with HIV, HBV, or HCV.  
5. Concurrent malignancy or prior malignancy within the previous 3 years (other than completely 
resected carcinoma in situ, prostate cancer, or localized non-melanoma skin cancer).  
6. Known central nervous system (CNS) involvement by malignancy. 
7. Untreated 
autoimmunity 
such 
as 
autoimmune 
hemolytic 
anemia, 
or 
immune 
thrombocytopenia.  
8. Uncompensated hypothyroidism (defined as TSH greater than 2x upper limit of normal not 
treated with replacement hormone).  
9. Presence of more than 55% pro-lymphocytes in peripheral blood. Patients with Richter’s 
transformation are not excluded. 
10. Insufficient recovery from surgical-related trauma or wound healing. 
11. Impaired cardiac function including any of the following: 
 
Myocardial infarction within 6 months of starting study drug; 
 
A past medical history of clinically significant ECG abnormalities. 
 
Other clinically significant heart disease (e.g. uncontrolled congestive heart failure, 
uncontrolled hypertension, history of labile hypertension, or history of poor compliance 
with an antihypertensive regimen) 
12. Patients who in the opinion of the investigator may be unable to comply with the safety 
monitoring requirements of the study. 
 
4.0 
INVESTIGATIONAL TREATMENT PLAN 
4.1 
Dose Assignment 
The dose of UC-961 is currently undergoing evaluation in a phase 1 study.  
 
During the extension treatments, patients will be assigned to receive the highest safe dose from 
an ongoing phase 1 study, or the established maximum tolerated dose/ recommended phase 2 
dose (which may increase as the phase 1 trial accrues additional patients). Patients will receive 
the same dose of UC-961 for 1 course, which consists of 8 doses (every 14 days for 4 doses, 
then every 28 days for 4 doses). As of April 2016, the highest safe dose is 8 mg/kg. 
 
Following 1 course, patients will be assessed for response, and then are eligible to receive a 
second course. Patients with a complete response or partial response will continue at the same 

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dose. Patients with stable disease or progressive disease will receive a higher dose of UC-961, if 
a higher safe dose has been established in the concurrent CLL Phase 1 trial by that time. 
4.2 
Dose Limiting Toxicity 
Dose-Limiting Toxicity (DLT) is defined as any of the following adverse events that are 
considered by the investigator to be possibly, probably, or definitely related to the study agent 
UC-961 within the 28 days of the start investigational treatment: 
 
CTCAE Grade 3 or higher non-hematologic toxicity, except for: Grade 3 infections lasting 
< 7 days that have resolved, or one occurrence of Grade 3 infusion reaction; or 
 
Grade 4 or higher hematologic toxicity (by modified iwCLL criteria); or 
 
Any AE requiring a dose delay of greater than 28 days; 
 
 
4.3 
Recommended Pre-Medications and Concomitant Medications 
 
1. Antibiotics: per investigator discretion. 
 
2. Tumor lysis syndrome prophylaxis: allopurinol or other uric acid lower agent per 
investigator discretion. 
 
3. Infusion reaction prophylaxis:  
 
 
Acetaminophen 325-1000 mg PO prior to UC-961 administration, or per 
investigator discretion. 
 
Benadryl 50 mg IV or PO, or other antihistamine per investigator discretion, prior 
to UC-961 administration.  
 
Optional: Hydrocortisone 100 mg IV bolus (or infusion over 30 +/-10 minutes) or 
other equivalent corticosteroid, prior to UC-961 infusion. 
 
4.4 
UC-961 infusion plan 
 
Initial Infusion (Cycle 1, Day 1, or if longer than 56 day since prior UC-961 infusion) 
1. Test Dose: Infuse 8 mg/hour for 10 minutes, then stop infusion (or sooner if not 
tolerated prior to 10 minutes). 10 minutes (+/-5 minutes) following completion of test 
dose, monitor for any signs or symptoms of infusion reaction, including: hypotension 
(greater than 30 mm Hg drop in systolic blood pressure from baseline); fever 
(temperature greater than 101.3 degrees Fahrenheit); rigors. Management / 
supportive measures for these events is per institutional standards. 
2. In the absence of any of vital sign instability or signs/symptoms of infusion reaction, or 
after normalization of them, begin infusion: 
 
Initiate infusion at 25 mg/hr x 30 min (+/- 5 minutes) 
 
Check vital signs every 30 minutes (+/- 5 minutes).  
 
If vitals signs are stable (SBP is within 20 mm Hg of baseline, HR > 60 or < 120 
beats per minute or within 20% of baseline, and temperature <101.3 F) and without 
sign/symptoms of infusional toxicity, the rate of infusion is doubled every 30 
minutes (+/- 5 minutes) to a maximum of 800 mg/hr for remainder of infusion. 

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 
If a patient is unable to tolerate faster rate, continue infusion at the best tolerated 
rate until infusion is completed. Monitor for acute infusion-related reactions during 
and for 30 minutes (+/- 5 minutes) after infusion completed. 
 
Hold infusion and immediately notify MD if any of the following occur: hypotension 
(greater than 30 mm Hg drop in systolic blood pressure from baseline); fever 
(temperature greater than 101.3 degrees Fahrenheit); rigors. Management / 
supportive measures for these events is per institutional standards. Infusion of UC-
961 is resumed at half the previous rate once vital signs and symptoms have 
returned to baseline. 
 
Subsequent Infusions   
1. Test dose is not required. 
2. Initiate infusion at rate of 50 mg/hr (or at highest previously tolerated rate if it is lower 
than 50 mg/hr). Remainder of infusion, vital sign monitoring, and management of 
infusion reaction as above.  
 
4.5 
Criteria for dosing 
Doses are administered on day 1, 15, 29, 43, 57, 85, 113, and 141 (+/-3 days) if the patient is 
without ongoing Grade 3 non-hematologic or Grade 4 hematologic toxicities attributable to UC-
961.  
 
4.6 
Dose Modifications and Dosing Delays 
Each patient will be assessed for the development of toxicity according to the NCI Common 
Toxicity Criteria for Adverse Events (CTCAE), version 4.03 for non-hematologic toxicity or 
modified iwCLL criteria (section 7.1.2) for hematologic toxicity. Patients experiencing a DLT as 
defined in section 4.2 will be discontinued from study treatment. Otherwise, dose adjustments 
should be made according to the system showing the greatest degree of toxicity, as per 4.6.1, 
unless the adverse event is definitely unrelated to the study drug. Dose levels are listed in section 
1.4. 
 
4.6.1 Dose Modification Guidelines 
Toxicity – NCI CTCAE Grade  
(Hematologic- 
modified 
iwCLL) 
Occurrence 
Dose Modification 
Autoimmune anemia or autoimmune thrombocytopenia 
Grade ≥ 2 
any 
Withhold study treatment until resolved to 
Grade ≤ 1. 
 
Resume study treatment at same dose level. 
Tumor Lysis Syndrome 
Grade ≥ 3 
1st 
Withhold study treatment until clinical and 
laboratory signs resolved to baseline. 
 
Resume study treatment at same dose level. 
 
Repeat 
Discontinue therapy 
Confusion / Delirium 

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Grade ≥ 2 
1st 
Withhold study treatment until resolved to 
Grade ≤ 1. 
 
Resume study treatment at the next lower 
dose level. 
Repeat 
Discontinue therapy 
Pneumonitis 
Grade ≥ 2 
1st 
Withhold study treatment until resolved to 
Grade ≤ 1. 
 
Resume study treatment at the next lower 
dose level. 
Repeat 
Discontinue therapy 
Acute kidney injury 
Grade ≥ 2 (serum creatinine > 
2 x baseline) 
1st 
Withhold study treatment until resolved to 
Grade ≤ 1. 
 
Resume study treatment at the next lower 
dose level. 
Repeat 
Discontinue therapy 
Other Non-hematologic 
Grade ≥ 3 
1st 
Withhold study treatment until resolved to 
Grade ≤ 2. 
 
Resume study treatment at the next lower 
dose level. 
Repeat 
Discontinue therapy. 
Hematologic* 
ANC <500/mm3; 
Hemoglobin < 6.5 gm/dL; 
Platelet count ≥75% decrease 
from baseline (and/or platelet 
count ≤ 25,000/mm3) 
1st 
Withhold study treatment until resolved to 
ANC 
≥500/mm3 
and 
platelet 
count 
≥25,000/mm3.  
Resume study treatment at same dose. 
2nd 
Withhold study treatment until resolved to 
ANC 
≥500/mm3 
and 
platelet 
count 
≥25,000/mm3.  
Resume study treatment at the next lower 
dose level. 
3rd 
Permanently discontinue study treatment. 
*Dose adjustments or dose holds for hematologic toxicity will apply even if the baseline values 
are lower than these thresholds due to heavily infiltrated marrow. In those cases, growth factors 
and/or blood product transfusion may be administered prior to continuing with UC-961. 
Notes:  
1. If any of the above is noted, the patient will be re-assessed within 7 days by the treating 
physician or investigator. Isolated laboratory abnormalities may be re-evaluated by 
laboratory draw only, or based on physician or investigator discretion. 
2. UC-961 infusions can be delayed for a maximum of 28 days; if not restarted in that time-
span, study treatment will be permanently discontinued. 

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3. If dose is decreased for Grade 3 or 4 toxicity, dose re-escalation is not planned. 
4. For invasive procedures, not including biopsies or venous catheter placement: withhold 
study treatment for 1 week prior to procedure, and at least 1 week following surgery until 
satisfactory wound healing has been achieved. 
 
4.6.2 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. 
 
When resolved, resume study treatment at same 
dose level. Infusion rate adjustment per 4.4. 
Grade 3 
 
1st 
Institute supportive measures. 
 
When resolved, resume study treatment at the same 
dose level. Infusion rate adjustment per 4.4. 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. 
 
4.7 
Permitted concomitant therapy 
 
Supportive Care 
Appropriate antibiotics, anti-emetics, fluids, electrolytes and general supportive care are to be used 
as necessary. 
 
Blood Products and Growth Factors 
Blood products or myeloid growth factors can be administered for grade 4 toxicities (DLT), per 
investigator discretion for patient safety. The Principal Investigator (C. Jamieson, MD PhD or M. 
Choi, MD) should be called before growth factors are initiated. Erythropoietin or thrombopoietin 
mimetics are not to be used, unless continuation of a therapy that started ≥ 1 day prior to Cycle 
1, Day 1. 
 
4.8 
Prohibited concomitant therapy 
 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. Corticosteroids 
administration, even if for treatment of conditions other than CLL, at doses greater than 

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prednisone 20 mg daily (or equivalent dose of other steroids) are prohibited for greater than 14 
days. If these treatments are administered the patient will be removed from study. 
 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
4.9 
Duration of Therapy 
The investigational agent UC-961 will be administered until:  
a) 
Clinical or radiographic progressive disease. 
b) 
Unacceptable toxicities. 
c) 
Refusal of further protocol therapy by patient. 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Completion of therapy. 
f) 
Physician determines it is in the patient’s best interest to discontinue study agent. 
 
 
Clinical Study Stopping Rules: Enrollment will be held pending review and approval by the UC 
San Diego Moores Cancer Center Data Safety Monitoring Board (DSMB) in the event of either of 
the following:  
 
Death, or 
 
2 or more non-hematologic Grade 4 events at least possibly attributable to the study drug.  
4.10 
Duration of Follow Up 
Patients removed from study treatment for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. Patients will be followed after removal from study 
treatment every 28 days (+/-7 days) for 8 visits, then every 56 days (+/- 7 days) until death, lost 
to follow-up, withdrawal of consent, or initiation of subsequent therapy for disease progression 
(see Section 5 for assessments).  
 
4.11 
Criteria for Removal from Study 
Patients can be taken off the study at any time at their own request, or they may be withdrawn at 
the discretion of the investigator for safety, behavioral or administrative reasons. The reason(s) 
for discontinuation will be documented and may include: 
a) 
Death. 
b) 
Loss to follow-up. 
c) 
Withdrawal of consent for any further data submission. 
d) 
Disease progression requiring initiation of subsequent therapy. 
 
 
5.0 
STUDY PROCEDURES 
 
5.1 
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 

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determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
All screening procedures must be performed within 30 days prior to Cycle 1 Day 1 of the study 
unless otherwise stated. The screening procedures include: 
5.1.1 Complete history and physical examination including vital signs (blood pressure, 
heart rate, temperature, weight) and organ measurements (i.e., lymph nodes, 
spleen, liver).  
5.1.2 Current medications will be recorded in the subject's medical record but not 
captured in case report forms. 
5.1.3 12 lead ECG. ECG is required on screening. Subsequent ECG will be performed 
during the study as clinically indicated.  
5.1.4 Laboratory examinations: hematology (CBC w/differential), comprehensive 
metabolic panel (Na+, Cl-, K+, CO2, BUN, Creatinine, Glucose, Ca2+, total 
protein, albumin, total bilirubin, SGPT, SGOT, alkaline phosphatase), 
phosphorous, magnesium, uric acid, LDH, amylase, lipase.  
5.1.5 Coagulation parameters: PT/PTT.  
5.1.6 If female of child-bearing potential: serum pregnancy test within 14 days of Cycle 
1 Day 1. 
5.1.7 Subjects will have bone marrow aspirate and biopsy with samples sent for 
differential, morphology, and flow cytometry for MRD within 90 days prior to Cycle 
1 Day 1, so long as there has been no intervening CLL therapy.  
5.1.8 Disease staging to include CT, MRI, and/or PET scan as clinically indicated 
(typically including chest, abdomen, pelvis to measure non-palpable lymph nodes) 
within the last 60 days prior to Cycle 1 Day 1 if there has been no intervening CLL 
treatment.  Any appropriate radiological and radioisotope examinations should be 
performed as clinically indicated.  
5.1.9 Research Tests:  peripheral blood and serum collection for one or more of the 
following (i) Leukemia cell immunophenotype, (ii) T and B cell immune response, 
(iii) plasma cytokine levels. (see Correlative Studies Section 5.9). 
5.2 
UC-961 Extension Course 1:  
UC-961 doses are administered on Days 1, 15, 29, 43, 57, 85, 113, and 141; all +/- 3 days). The 
following are to be completed on the day of each infusion.  
5.2.1 Complete history and physical examination including vital signs (blood pressure, 
heart rate, temperature, weight) and organ measurements (i.e., lymph nodes, 
spleen, liver). 
5.2.2 Current medications will be recorded in the subject's medical record but not 
captured in case report forms. 
5.2.3 Adverse events assessment and grading per patient reporting. 
5.2.4 Standard 
laboratory 
examinations: 
hematology 
(CBC 
w/differential), 
comprehensive metabolic panel (Na+, Cl-, K+, CO2, BUN, Creatinine, Glucose, 
Ca2+, total protein, albumin, total bilirubin, SGPT, SGOT, alkaline phosphatase), 
phosphorous, magnesium, uric acid, LDH. Also: amylase; lipase. 

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5.2.5 Collection of PK samples. 
5.2.6 Collection of correlative lab samples. 
5.2.7 If criteria met for start of cycle (section 4.5), proceed with pre-medications (section 
4.3) and UC-961 infusion (dose per section 4.1; infusion procedure per section 4.4)  
5.2.8 Post-infusion monitoring: patients will be observed for at least 1 hour following the 
infusion of UC-961, with continued measurement of blood pressure, pulse, 
temperature every 30 minutes (+/- 10 minutes).  
5.2.9 Peripheral blood draw 1 hour after the end of the infusion (+/- 10 minutes), 
including comprehensive metabolic panel (CMP), phosphorous, uric acid, LDH.  
 
5.3 
Day 169 +/- 7 days: Response Assessment: 
Not all activities are required on the same day. 
5.3.1 Complete history and physical examination including vital signs (blood pressure, 
heart rate, temperature, weight) and organ measurements (i.e., lymph nodes, 
spleen, liver). 
5.3.2 Adverse events grading and reporting. 
5.3.3 Standard 
laboratory 
examinations: 
hematology 
(CBC 
w/differential), 
comprehensive metabolic panel (Na+, Cl-, K+, CO2, BUN, Creatinine, Glucose, 
Ca2+, total protein, albumin, total bilirubin, SGPT, SGOT, alkaline phosphatase), 
phosphorous, magnesium, uric acid, LDH. Also: amylase; lipase. 
5.3.4 Collection of correlative lab samples.  
5.3.5 Flow cytometry of peripheral blood for T-cell subtypes and CLL MRD. 
5.3.6 CT scan or MRI or PET of chest, abdomen, and pelvis.  
5.3.7 Bone marrow biopsy if clinically indicated to evaluate complete response / minimal 
residual disease. 
 
5.4 
UC-961 Extension Course 2:  
UC-961 doses are again administered every 14 days for the first 4 doses, then every 28 
days for 4 doses (Days 197, 211, 225, 239, 253, 281, 309, 337; all +/- 3 days). 
5.4.1 Complete history and physical examination including vital signs (blood pressure, 
heart rate, temperature, weight) and organ measurements (i.e., lymph nodes, 
spleen, liver). 
5.4.2 Current medications will be recorded in the subject's medical record but not 
captured in case report forms. 
5.4.3 Adverse events assessment and grading per patient reporting. 
5.4.4 Standard 
laboratory 
examinations: 
hematology 
(CBC 
w/differential), 
comprehensive metabolic panel (Na+, Cl-, K+, CO2, BUN, Creatinine, Glucose, 
Ca2+, total protein, albumin, total bilirubin, SGPT, SGOT, alkaline phosphatase), 
phosphorous, magnesium, uric acid, LDH. Also: amylase; lipase. 
5.4.5 Collection of PK samples. 

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5.4.6 Collection of correlative lab samples. 
5.4.7 If criteria met for start of cycle (section 4.5), proceed with pre-medications (section 
4.3) and UC-961 infusion (section 4.4)  
5.4.8 Post-infusion monitoring: patients will be observed for at least 1 hour following the 
infusion of UC-961, with continued measurement of blood pressure, pulse, 
temperature every 30 minutes (+/- 10 minutes).  
5.4.9 Peripheral blood draw 1 hour after the end of the infusion (+/- 10 minutes), 
including comprehensive metabolic panel (CMP), phosphorous, uric acid, LDH.  
 
5.5 
Long term follow-up 
 
Every 28 days (+/- 7 days) for 8 visits then every 56 days (+/- 7 days), until discontinuation of trial 
participation: 
5.5.1 Complete history and physical examination including vital signs (blood pressure, 
heart rate, temperature, weight) and organ measurements (i.e., lymph nodes, 
spleen, liver). 
5.5.2 Adverse events grading and reporting. 
5.5.3 Standard 
laboratory 
examinations: 
hematology 
(CBC 
w/differential), 
comprehensive metabolic panel (Na+, Cl-, K+, CO2, BUN, Creatinine, Glucose, 
Ca2+, total protein, albumin, total bilirubin, SGPT, SGOT, alkaline phosphatase), 
phosphorous, magnesium, uric acid, LDH.  
5.5.4 Collection of correlative lab samples. 
 
5.6 
Pharmacokinetic (PK) Studies 
Serum samples will be banked for analysis. HPLC–based assay used in antibody production will 
also be utilized for serum antibody levels. Limited PK studies are planned, with collection of serum 
prior to and 1 hour after each dose of UC-961. 
 
Sample Collection and Handling Instructions 
Blood samples (up to 10 ml) will be collected in heparinized tubes at a site distant from the infusion 
for pharmacokinetic evaluation. Samples cannot be drawn from the 2nd lumen of a multi-lumen 
catheter through which drug is being administered. The exact time that the sample is drawn along 
with the exact time that the drug is administered should be recorded. 
 
Sample Processing: Plasma will be isolated in the translational laboratory (Kipps) and stored at 
minus 20 degrees. 
 
Sample Labeling 
Each tube must be labeled with the patient’s de-identified study number, and the date and time 
the sample was drawn.  Data should be recorded on the Pharmacokinetic Study Form, which 
must accompany the sample(s). 
 
Sample Shipping Instructions 

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Samples may be shipped to third-party vendor for PK analysis. Samples will be shipped as per 
assay manufacturer recommendations. 
 
5.7 
Correlative Studies 
Studies will be performed in the Kipps laboratory, to correlate with PK and clinical responses. 
Samples will be taken at baseline/screening, during treatment and after treatment. However, not 
all assays will be performed for all time points for all patients, based on sample availability and 
leukemic cell number. Specimens will be banked in the CLL research consortium tissue repository 
(see below). 
 
Assays from patient serum may include:  
 
Measurement of cytokine levels (IL2, IL12, and TNFα) and Wnt5a levels. 
 
Assessment for anti-UC-961 antibody production.  
 
Isolation of leukemic cells by Ficoll-hypaque separation and assessment, which may include: 
 
UC-961 antibody binding, ROR1 expression and receptor occupancy 
 
ZAP-70, CD38, and Immunoglobulin heavy chain variable region (IgVH) mutation in CLL cells  
 
Assessment of down-stream signaling by multiplex qPCR 
 
Measurement of Akt and phospho-Akt levels prior to and after therapy. 
 
Expression of co-stimulatory molecules (CD80 and CD86), apoptosis related receptors (CD95 
and DR5), and expression of genes and proteins related to apoptosis, from pre-treated and 
post-treated samples. 
 
5.7.1 Sample Collection Guidelines 
Sampling Schedule  
Blood sample for correlative studies will be collected at the following time points: 
 
Screening  
 
Day 1 of each cycle, pre-treatment and 1 hour after each UC-961 infusion 
 
End of Treatment visit 
 
Response assessment 
 
Long-Term Follow-up visits 
 
Sample Collection and Handling Instructions 
Blood samples (approximately 15-20 ml) will be collected in anticoagulated (ACD) tubes at a site 
distant from the infusion for pharmacokinetic evaluation. Samples cannot be drawn from the 2nd 
lumen of a multi-lumen catheter through which drug is being administered. The exact time that 
the sample is drawn along with the exact time that the drug is administered should be recorded. 
 
Sample Processing 
Samples will be processed in the translational lab of Dr. Thomas Kipps, with separation of plasma, 
followed by isolation of mononuclear cells or neutrophils by Ficoll or Percoll differential 
centrifugation, respectively. 
 
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). 
 

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5.7.2 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 used up. 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. 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 
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 
 

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6.0 
Schedule of Events 
 
Treatment Cycle 
Screening 
Extension 
Course 1 
Response 
Assessment 1 
Extension 
Course 2 
Response 
Assessment 2 
Long-Term 
Follow-up 
Visit Day 
 
1, 15, 29, 43, 
57, 85, 113, 
141 
169 6 
197, 211, 225, 
239, 253, 281, 
309, 337 7 
365 6 
Q28d x8, 
then q56d 
Visit window 
≤ 30 days prior to 
visit 2 
±3d 
±7d 
±3d 
±7d 
±7d 
Informed Consent 
X 
 
 
 
 
 
Eligibility Checklist 
X 
 
 
 
 
 
History and Symptoms 
X 
X 
X 
X 
X 
X 
VS/Ht and Wt  
X 
X 
X 
X 
X 
X 
Comprehensive PE 
X 
X 
X 
X 
X 
X 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
X 
CBC and differential 
X 
X 
X 
X 
X 
X 
Blood chemistry panel1 
X 
X  
X 
X  
X 
X 
ECG 
X 
 
 
 
 
 
Adverse Events Screen 
 
X 
X 
X 
X 
X 
Concomitant Medication 
 
X 
X 
X 
X 
X 
UC-961 Administration 
 
X 
 
X 
 
 
CT scan Chest/ 
Abdomen/ Pelvis 2 
within 60 days of 
C1D1 
 
X 
 
X 
 
Bone marrow aspirate 
and biopsy 3 
within 90 days of 
C1D1 
 
X 
 
X 
 
Cytogenetics/FISH from 
bone marrow or 
peripheral blood 4 
X 
 
X 
 
X 
 
Serum hCG for female 
of child bearing potential  
within 14 days of 
C1D1 
 
 
 
 
 
Quantitative T-cell 
subsets 
X 
 
X 
 
X 
 

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Treatment Cycle 
Screening 
Extension 
Course 1 
Response 
Assessment 1 
Extension 
Course 2 
Response 
Assessment 2 
Long-Term 
Follow-up 
Visit Day 
 
1, 15, 29, 43, 
57, 85, 113, 
141 
169 6 
197, 211, 225, 
239, 253, 281, 
309, 337 7 
365 6 
Q28d x8, 
then q56d 
Visit window 
≤ 30 days prior to 
visit 2 
±3d 
±7d 
±3d 
±7d 
±7d 
PT/aPTT 
X 
 
 
 
 
 
Collection of 
Pharmacokinetic and 
Pharmacodynamic 
Samples 5 
X 
X 
PD only 
X 
PD only 
PD only 
 
1. Chemistry panel to include: comprehensive metabolic panel (Na+, Cl-, K+, CO2, BUN, Creatinine, Glucose, Ca2+, total protein, 
albumin, total bilirubin, SGPT, SGOT, alkaline phosphatase), phosphorous, magnesium, uric acid, LDH, amylase, and lipase.  
NOTE: amylase and lipase are not measured in long-term follow-up unless clinically indicated. 
2. Or MRI or PET scan.   
3. In the case of a CR, an additional bone marrow will be taken two months after patient first achieves CR 
4. Chromosome analysis and FISH Panel to include 11q, 12p, 13q, 17p analysis. 
5. Blood samples are collected for PK and/or PD analysis (refer to section 5.8 and 5.9) 
6. May be done earlier if progressive disease is suspected. 
7. Or 28 days after Response Assessment 1. 
 

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7.0 
Measurement of Effect 
7.1 
Safety/tolerability 
7.1.1 Common Terminology Criteria for Adverse Events (CTCAE) 
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 
(http://ctep.cancer.gov/reporting/ctc.html) for reporting of non-hematologic 
adverse events. 
7.1.2 International Working group for Chronic Lymphocytic Leukemia 
(IWCLL) criteria for hematologic toxicity 
As is the case with virtually all of the hematological malignancies, an 
evaluation of the hematological toxicity in patients with CLL must consider 
the high frequency of marrow involvement and consequent medullar 
compromise at the initiation of therapy. A substantial proportion of patients 
will have hematological parameters within the range of Grade 2 – 4 
hematological toxicity before therapy is given; therefore, a modified 
schema will be used to monitor hematological toxicity in patients with CLL. 
The modified hematological toxicity schema is displayed: 
 
Modified Grading Scale for Hematological Toxicity in CLL Studies 
Grade1 
Decrease 
in 
platelets 
(nadir) from pretreatment 
value (%)2 
ANC/µl (nadir)3 
Hemoglobin4 
0 (not AE) 10%, or above lower limit 
of normal for institution. 
≥ 1800, or above 
lower limit of normal 
for institution. 
Baseline or higher, or 
above lower limit of 
normal for institution. 
1 
11-24% 
≥ 1500 and < 1800 
> 10.0 g/dL and below 
baseline  
2 
25-49% 
≥ 1000 and < 1500 
< 10.0 – 8.0 g/dL and 
less than baseline 
3 
50-74% 
≥ 500 and < 1000 
< 8.0 – 6.5 g/dL and 
less than baseline 
4 
≥75% or ≤ 25,000/mm3 2 
< 500 
< 6.5 g/dL and less 
than baseline 
*This schema concurs with the CTEP CTCAE 4.03, except for the platelet values are 
taken from the iwCLL-WG guidelines working group criteria and hemoglobin toxicity 
modified from CTCAE only to account for low baseline values in CLL patients. No 
hematologic toxicity will be registered unless hemoglobin falls below baseline level. 
1 Grades: 1, mild; 2, moderate; 3, severe; 4, life threatening; 5, fatal. Death occurring as 
a result of toxicity at any level of decrease from pretreatment will be recorded as a Grade 
5. 
2 Treatment will be held for platelet count ≤ 25,000/mm3, even if it does not meet grade 
4 criteria based on percent decrease. See section 4.6.1 for dose hold/adjustment 
guidelines.  
3 If baseline ANC is <1,500/μL, neutrophil toxicity cannot be evaluated. In that case, if 

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the neutrophil count is less than 500/μL, it is still recommended to hold therapy until 
ANC is greater than 500/μL.  
4 If baseline Hemoglobin is < 10.0, hemoglobin toxicity cannot be evaluated. In that 
case, if the hemoglobin is less than 6.5, it is still recommended to hold therapy until Hgb 
is greater than 6.5. 
 
7.2 
Response Criteria for Patients with Chronic Lymphocytic Leukemia 
Criteria for response will utilize the IWCLL Guidelines for response, which includes clinical, 
hematological, and bone marrow features as outlined below (Hallek et al., 2008). 
 
Minimal Residual Disease negative: less than 0.01% CLL cell involvement by 4-color 
flow cytometry of bone marrow aspirate (less than 1 in 10,000 events) and meeting all 
other criteria for complete response. 
 
Complete response: Requires all of the following for a period of at least two months from 
completion of therapy:  
 
Absence of significant lymphadenopathy (e.g. >1.5cm in diameter) on physical 
exam; 
 
No hepatomegaly or splenomegaly on physical exam; 
 
Absence of constitutional symptoms; 
 
Blood counts corresponding to the following values: Lymphocytes < 4,000/uL, 
polymorphonuclear leukocytes >1500/μL, platelets >100,000/μL, hemoglobin 
>11.0 g/dL (untransfused) 
 
Bone marrow aspirate and biopsy must be normocellular for age with <30% of 
nucleated cells being lymphocytes. Lymphoid nodules must be absent. If the 
marrow is hypocellular, a repeat determination should be performed in one month. 
 
The marrow should be analyzed by flow cytometry and/or immunohistochemistry 
to demonstrate that the marrow is free of clonal B- CLL cells. 
 
A CT scan or MRI documenting absence of significant lymphadenopathy should 
be performed if previously abnormal. 
 
Patients who fulfill the criteria for CR with the exception of a persistent cytopenia 
that is believed to be treatment related will be considered CR with incomplete bone 
marrow recovery (CRi). Additionally, patients who fulfill the criteria of CR with 
exception of having bone marrow lymphoid nodules will be considered a nodular 
PR. 
 
Partial response: Requires at least 2 of the following criteria from group A, and at least 
one of the criteria from group B, and for a period of at least 2 months: 
Group A: 
 
≥50% decrease in peripheral absolute lymphocyte count from pretreatment value, 
or less than 4,000/uL. 
 
≥50% reduction in lymphadenopathy by examination or scan, or less than 1.5cm 
in size. 
 
≥50% reduction in splenomegaly (cm below costal margin) by examination or scan 
 
≥50% reduction hepatomegaly (total liver span) by examination or scan 
 
≥50% reduction in marrow infiltrate or B-lymphoid nodules 
Group B: 

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 
Polymorphonuclear leukocytes ≥1,500/μL or 50% improvement from pre-treatment 
value; 
 
Platelets >100,000/μL or 50% improvement from pre-treatment value; 
 
Hemoglobin >11.0 g/dl (un-transfused) or 50% improvement from pre-treatment 
value. 
 
Progressive Disease: Characterized by any one of the following events:  
 
≥50% increase in the products of at least two lymph nodes on two consecutive 
determinations two weeks apart (at least one lymph node must be ≥2 cm); 
appearance of new palpable lymph nodes. 
 
≥50% increase in the size of the liver and/or spleen as determined by 
measurement below the respective costal margin; appearance of palpable 
hepatomegaly or splenomegaly, which was not previously present. 
 
An increase in the number of blood lymphocytes by 50% or more with at least 5000 
B lymphocytes per microliter. 
 
Transformation to a more aggressive histology (i.e., Richter’s syndrome or 
prolymphocytic leukemia with ≥56% prolymphocytes). 
 
During therapy, patients not fulfilling the above criteria for progressive disease but 
demonstrating a decrease in hemoglobin >2 gm/dL, decrease >50% in platelet or 
granulocyte count will not be rated as progressive disease because these may 
occur as both a consequence of therapy. A bone marrow biopsy in such settings 
is strongly encouraged. Furthermore, during therapy, patients with progressive 
lymphocytosis but not any other findings of hemoglobin, platelet count, lymph node 
size, or spleen size meeting criteria for progressive disease will not be rated as 
progressive disease as agents that target the akt pathway have been 
demonstrated to induce a redistributive lymphocytosis as part of the mechanism 
of action (Byrd et al., 2013). 
 
After treatment, The progression of any cytopenia (unrelated to autoimmune 
cytopenia), as documented by a decrease of Hgb levels by more than 20 g/L (2 
g/dL) or to less than 100 g/L (10 g/dL), or by a decrease of platelet counts by more 
than 50% or to less than 100 × 109/L (100 000/μL), which occurs at least 3 months 
after treatment, defines disease progression, if the marrow biopsy demonstrates 
an infiltrate of clonal CLL cells. 
 
Stable Disease: Patients who do not fulfill the criteria for complete or partial response as 
defined above but do not exhibit progressive disease will be considered as having stable 
disease. 
7.2.1 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment until objective tumor progression or death. 
 
 
8.0 
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 an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an 

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experimental intervention, whether or not related to the intervention.  
8.1 
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) 
 
All patients experiencing an adverse event, regardless of its relationship to study drug, will 
be monitored until:  
 
the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline;  
 
any abnormal laboratory values have returned to baseline;  
 
there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 
death. 
8.2 
Severity 
All non-hematologic adverse events will be graded according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The CTCAE v4.03 is 
available at http://ctep.cancer.gov/reporting/ctc.html. All hematologic adverse events will 
be graded according to the modified iwCLL criteria. 
 
If no 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. 
8.3 
Seriousness 
A “serious” adverse event is defined in regulatory terminology as any untoward medical 

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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 for ≥ 24 hours. 
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. 
8.4 
Relationship 
Attribution categories for adverse events in relationship to protocol therapy are as follows: 
Definite – The AE is clearly related to the study treatment. 
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. 
8.5 
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 toxicities listed in the agent information section of this protocol. 
8.6 
Reporting Requirements for Adverse Events 
8.6.1 Expedited Reporting 
 
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.  
 
The UCSD Human Research Protections Program (HRPP) 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: 

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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. 
 
The FDA should be notified within 7 calendar days of any unexpected 
fatal or life-threatening adverse event with possible relationship to 
study drug, and 15 calendar days of any adverse event that is 
considered: 1) serious, 2) unexpected, and 3) at least possibly related 
to study participation. 
8.6.2 Routine Reporting Requirements 
 
The UCSD HRPP will 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.  
 
The FDA will be notified of all non-serious adverse events annually at 
the time of the annual report. 
 
 
9.0 
AGENT INFORMATION 
9.1 
UC-961 (Cirmtuzumab) 
Please refer to Investigator’s Brochure for more comprehensive information. 
 
Structure: Monoclonal antibody 
 
Supplied by: UC-961 will be produced at Pacific GMP (San Diego, CA) in compliance with 
cGMP standards. 
 
Formulation 
The agent is supplied as a liquid formulation at a concentration of 40 mg/ml protein, with 
7.2 to 7.8 mL/vial. Each ml of the formulation contains 40 mg UC-961, 14.7 mg sodium 
citrate, 10 mg trehalose, 216 µg Polysorbate 80, 15 µg sodium EDTA and adjusted to pH 
5.2 ± 0.2. 
 

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UC-961 will be 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 
UC-961 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 the following 
final concentrations: 
 
100 µg/mL for doses 15 µg/kg to 240 µg/kg 
 
500 µg/mL for doses 500 µg/kg to 2 mg/kg 
 
1 mg/mL dose 4 mg/kg 
 
2 mg/mL for dose 8 mg/kg 
 
4 mg/mL for doses 16mg/kg and 20 mg/kg  
 
Administration 
The drug will be administered by intravenous infusion with infusion rate according to 
section 4.4. 
  
 
 
 
Toxicities and tolerability 
No toxicities have been yet identified in the ongoing first-in-man study. The agent has 
been well tolerated. There is no off-target binding identified in initial preclinical assays. 
Infusion reaction, fluid retention, tumor lysis syndrome, 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 UC-961, have 
demonstrated binding to pancreatic islet cells and adipose tissue (Hudecek et al., 2010). 
Glucose levels and body weight will therefore be monitored. 
 
10.0 
STATISTICAL CONSIDERATIONS 
The primary aim of the study is to determine the safety of UC-961 therapy given at the 
currently used, biologically active dose, or RP2D for an extended duration. 
 
Safety will be assessed through summaries of adverse events, clinical laboratory 
abnormalities, and changes in physical exam and vital signs. All subjects who receive a 
single dose of study medication will be considered evaluable for safety.   
 
Adverse events will be listed, documenting the course, outcome, severity, and relationship 
to the study treatment. Incidence rates of AEs and the proportion of subjects prematurely 
withdrawn from the study due to AEs will be shown. 
 
The primary endpoint of this study is the rate of dose-limiting toxicity (DLT).  
 
SECONDARY ANALYSIS 
Secondary Endpoints are overall response rate by IWCLL criteria following 6 months of 
biweekly dosing of UC-961 (Hallek et al., 2008) ; Progression free and overall survival 
(progression determined by IWCLL working group criteria); and    SD, PR, and MRD- 
rates, as well as individual components of response (reduction in leukemia count, 
reduction in adenopathy and splenomegaly, and improvement in BM function), as 
determined by IWCLL working group criteria.   

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These secondary endpoints will be summarized by dose cohort, clinical characteristics 
and overall using percentages, means and median survival estimates as 
appropriate.  Data will also be presented graphically with Kaplan Meier plots, box plots, 
and bar charts.  All statistics will be presented with 95% confidence intervals.  The 
analysis will be descriptive; thus no correction for multiple analyses will be made and no 
formal tests of hypothesis will be done. 
 
 
 
11.0 
STUDY MANAGEMENT 
11.1 
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. 
11.2 
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. 
11.3 
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. 
11.4 
Data and Safety Monitoring 
In addition to adverse event monitoring and clinical oversight by the principal investigator 
and co-investigators, quality assurance of the study will be performed by the clinical trials 
office internal monitor.  

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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 after every 6 months, or sooner 
if required for clinical study stopping rules (Section 4.9), 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 date of first and most recent 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.  
 
11.5 
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. 
11.6 
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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12.0 
REFERENCES 
 
1.  
Hallek M, Cheson BD, Catovsky D et al. Guidelines for the diagnosis and treatment 
of chronic lymphocytic leukemia: a report from the International Workshop on 
Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working 
Group 1996 guidelines. Blood. 2008;111 (12):5446-5456. 
2. 
Gribben JG, O'Brien S. Update on therapy of chronic lymphocytic leukemia. J Clin 
Oncol. 2011;29 (5):544-550. 
3. 
Hallek M, Fischer K, Fingerle-Rowson G et al. Addition of rituximab to fludarabine 
and cyclophosphamide in patients with chronic lymphocytic leukaemia: a 
randomised, open-label, phase 3 trial. Lancet. 2010;376 (9747):1164-1174. 
4. 
Brown JR. The treatment of relapsed refractory chronic lymphocytic leukemia. 
Hematology Am Soc Hematol Educ Program. 2011;2011 (110-118. 
5. 
Byrd JC, Furman RR, Coutre SE et al. Targeting BTK with Ibrutinib in Relapsed 
Chronic Lymphocytic Leukemia. N Engl J Med. 2013 
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. 
Broome HE, Rassenti LZ, Wang HY et al. ROR1 is expressed on hematogones 
(non-neoplastic human B-lymphocyte precursors) and a minority of precursor-B 
acute lymphoblastic leukemia. Leuk Res. 2011;35 (10):1390-1394. 
8. 
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. 
9. 
Masiakowski P, Carroll RD. A novel family of cell surface receptors with tyrosine 
kinase-like domain. J Biol Chem. 1992;267 (36):26181-26190. 
10. Matsuda T, Nomi M, Ikeya M et al. Expression of the receptor tyrosine kinase 
genes, Ror1 and Ror2, during mouse development. Mech Dev. 2001;105 (1-
2):153-156. 
11. Zhang S, Chen L, Wang-Rodriguez J et al. The onco-embryonic antigen ROR1 is 
expressed by a variety of human cancers. Am J Pathol. 2012;181 (6):1903-1910. 
12. Cui B, Zhang S, Chen L et al. Targeting ROR1 inhibits epithelial-mesenchymal 
transition and metastasis. Cancer Res. 2013;73 (12):3649-3660. 
13. Widhopf GFn, 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. 
 
 
 

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13.0 
APPENDICES 
Appendix A. Performance Status 
 
PERFORMANCE STATUS CRITERIA 
ECOG Performance Status  
 
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
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 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead