Clinical trial NCT03088878
Conditions: B-cell Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Mantle Cell Lymphoma Marginal Zone Lymphoma
Keywords: Chronic lymphocytic leukemia Small lymphocytic lymphoma Mantle cell lymphoma Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) Bruton Tyrosine Kinase (BTK) Ibrutinib Marginal zone lymphoma
Sponsor: Oncternal Therapeutics, Inc
Start date: 2018-01-03; Completion date: 2024-09-25
Enrollment: 95 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is Phase 1b/2 study to investigate the safety and effectiveness of the investigational drug, cirmtuzumab, when given in combination with ibrutinib in patients with B-cell lymphoid malignancies. Cirmtuzumab is a monoclonal antibody that attaches to a protein (called ROR 1) that is found on hematologic tumor cells. ROR1 has been shown to play a role in cell signaling that cause leukemia and lymphoma cells to grow and survive. ROR1 is rarely found on healthy cells.

Detailed description:
This is a Phase 1b/2 study to investigate the safety and effectiveness of the investigational drug, cirmtuzumab (INN:zilovertamab), when given in combination with ibrutinib in patients with B-cell lymphoid malignancies. The Phase 1b will be conducted in two parts (Part 1 and Part 2). Part 1 is a dose-finding evaluation of the sequential administration of cirmtuzumab monotherapy followed by cirmtuzumab and ibrutinib combination therapy in chronic lymphocytic leukemia /small lymphocytic leukemia (CLL/SLL), previously treated mantle cell lymphoma (MCL) subjects that are BTKI naiive or have received a prior Bruton tyrosine kinase (BTK) inhibitor therapy, unless they demonstrated primary or acquired resistance to BTKi. Up to 48 subjects will be enrolled in Part 1 to determine the recommended dosing regimen (RDR). In Part 2, up to 60 subjects (CLL/SLL, MCL and MZL (marginal zone lymphoma) will be enrolled to further evaluate the safety and pharmacology of the cirmtuzumab and ibrutinib combination given at the RDR determined in Part 1 of the study. MZL subjects that have been previously treated and have relapsed after or progressed during at least one prior anti-CD20 -based therapy will be evaluated. In the Phase 2 (Part 3) portion of the study, approximately 30 subjects with CLL/SLL who may have received minimal prior BTK inhibitor therapy will be randomized to either Arm 1 (cirmtuzumab and ibrutinib) at the RDR or Arm 2 (ibrutinib alone) to evaluate the clinical activity and safety of the two arms.

Arms: arm 1: Cirmtuzumab followed by Cirmtuzumab plus ibrutinib arm 2: Cirmtuzumab plus ibrutinib arm 3: Cirmtuzumab plus ibrutinib arm 4: Ibrutinib only
Interventions: intervention 1: Cirmtuzumab (2-16 kg/mg) plus Ibrutinib intervention 2: Cirmtuzumab (300mg) plus Ibrutinib intervention 3: Cirmtuzumab (600 mg) plus ibrutinib intervention 4: Cirmtuzumab (RDR) plus ibrutinib intervention 5: Cirmtuzumab plus ibrutinib intervention 6: Ibrutinib alone
Intervention descriptions: intervention 1: Participants will receive escalating doses of cirmtuzumab (2-16 mg/kg) administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter, plus ibrutinib (420 or 560 mg) orally once daily, starting at week 4. intervention 2: Participants will receive cirmtuzumab (300 mg) administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter, plus ibrutinib (420 mg) orally once daily. intervention 3: Participants will receive cirmtuzumab (600 mg) administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter, plus ibrutinib (420 mg) orally once daily. intervention 4: Participants will receive cirmtuzumab (600 mg) administered IV every 2 weeks for 3 administrations and then every 4 weeks thereafter, plus ibrutinib (420 or 560 mg) orally once daily intervention 5: Arm A: Participants will receive cirmtuzumab (600 mg) administered IV every 2 weeks for 3 administrations and then every 4 weeks thereafter, plus ibrutinib (420 mg) orally once daily. intervention 6: Arm B: Participants will receive ibrutinib (420 mg) orally once daily

Protocol documents:
Prot_SAP_002.pdf: 
Investigational Product: Cirmtuzumab (UC-961) 
 
Study Protocol:  CIRM-0001 
Oncternal Therapeutics, Inc. 
CONFIDENTIAL 
Page 1 of 115  
Version 7 (15 April 2022) 
 
 
 
 
CLINICAL STUDY PROTOCOL 
Protocol Title 
A Phase 1b-2 Study of the ROR1-Targeting Monoclonal 
Antibody, Cirmtuzumab (UC-961), and the Bruton Tyrosine 
Kinase Inhibitor, Ibrutinib, in Patients with B-Cell Lymphoid 
Malignancies 
Investigational Product 
Cirmtuzumab (UC-961) (INN: zilovertamab) 
Protocol Number 
CIRM-0001 (Oncternal Therapeutics, Inc) 
Developmental Phase 
Phase 1b-2 (Clinical Safety and Efficacy)  
US IND Number 
133131 
Sponsor Name and Address 
Oncternal Therapeutics, Inc 
12230 El Camino Real, Ste 230 
San Diego, CA 92130 
Protocol Versions (Dates) 
 
Version 1 (31 January 2017) 
Version 2 (22 March 2017) 
Version 3 (19 April 2017) 
Version 4 (27 April 2018) 
Version 5 (19 July 2019) 
Version 6 (05 February 2021) 
Version 6.1 (15 March 2021) 
Version 7.0 (15 April 2022) 
 
 
 
Confidentiality Statement 
This document contains confidential information belonging to the study sponsors. Except as may be 
otherwise permitted in writing, by accepting or reviewing these materials, it is agreed that this 
information should not be disclosed to others (except if required by applicable law or regulation) and 
should not be used for unauthorized purposes.  
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Investigational Product: Cirmtuzumab (UC-961) 
 
Study Protocol:  CIRM-0001 
Oncternal Therapeutics, Inc. 
CONFIDENTIAL 
Page 2 of 115  
Version 7 (15 April 2022) 
 
ONCTERNAL PROJECT PERSONNEL 
 
Oncternal Therapeutics, Inc 
Chief Medical Officer 
Salim Yazji, MD 
San Diego, CA, USA 
Telephone: +1(858) 434-1113 x223 
Email: CIRM-0001@oncternal.com 
 
 
Oncternal Therapeutics, Inc 
Clinical Operations  
Angela Pietrofeso  
San Diego, CA, USA 
Telephone: +1 (858) 434-1113 x210 
E-mail: CIRM-0001@oncternal.com  
 
 
ONCTERNAL SIGNATURE 
 
 
 
Salim Yazji, MD 
Chief Medical Officer 
 
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Investigational Product: Cirmtuzumab (UC-961) 
 
Study Protocol:  CIRM-0001 
Oncternal Therapeutics, Inc. 
CONFIDENTIAL 
Page 3 of 115  
Version 7 (15 April 2022) 
 
INVESTIGATOR’S SIGNATURE PAGE 
 
Investigator: 
 
 
 
 
Study Number: 
CIRM-0001 
Product Name(s): 
Cirmtuzumab (UC-961) (INN: zilovertamab) 
Study Title: 
A Phase 1b-2 Study of the ROR1-Targeting Monoclonal Antibody, 
Cirmtuzumab (UC-961), and the Bruton Tyrosine Kinase Inhibitor, 
Ibrutinib, in Patients with B-Cell Lymphoid Malignancies 
Document Date: 
15 April 2022 
 
As Principal Investigator, I agree: 
 
• To keep all documentation supplied to me or developed by me concerning this study, and 
that has not been previously published, in the strictest confidence. This documentation 
includes, but is not limited to, the Investigator’s Brochure and Case Report Forms (CRFs) 
• That the study will not commence without prior written approval of a properly 
constituted Institutional Review Board. No changes will be made to the study Protocol 
without prior written approval of Oncternal Therapeutics, Inc. and the Institutional 
Review Board, except where necessary to eliminate an immediate hazard to patients 
• To implement and conduct the study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations 
• To accurately transfer all required data from each patient’s source document to the CRFs. 
The original CRFs will be submitted to the Sponsor in a timely manner at the completion 
of the trial, or as otherwise specified by the Sponsor 
• To keep a complete and accurate accounting during and at the completion of the trial of 
all procedures performed with the drug provided by the Sponsor 
• To allow authorized representatives of Oncternal Therapeutics, Inc. or regulatory 
authority representatives to conduct on-site visits to review, audit and copy trial 
documents. I will personally meet with these representatives at mutually convenient times 
to answer any trial-related questions 
• To provide the Sponsor with an investigator’s summary within 90 days of completion of 
the final trial visit for the last patient enrolled, or as designated by Sponsor 
• To maintain all information supplied by the Sponsor in confidence and, when this 
information is submitted to an Institutional Review Board (IRB), Ethical Review 
Committee, or another group, it will be submitted with a designation that the material is 
confidential. 
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Investigational Product: Cirmtuzumab (UC-961) 
 
Study Protocol:  CIRM-0001 
Oncternal Therapeutics, Inc. 
CONFIDENTIAL 
Page 4 of 115  
Version 7 (15 April 2022) 
 
This protocol was designed and will be conducted, recorded, and reported in compliance with the 
principles of Good Clinical Practice (GCP) guidelines. These guidelines are stated in United 
States federal regulations as well as “Guidance for Good Clinical Practice,” International 
Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals 
for Human Use. 
 
I have read this protocol in its entirety, including the preceding statements, and I agree to comply 
with all aspects of this trial. 
 
 
 
 
 
Investigator Printed Name 
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
Institution Name 
 
 
 
 
 
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Investigational Product: Cirmtuzumab (UC-961) 
 
Study Protocol:  CIRM-0001 
Oncternal Therapeutics, Inc. 
CONFIDENTIAL 
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TABLE OF CONTENTS 
ONCTERNAL PROJECT PERSONNEL .......................................................................................2 
INVESTIGATOR’S SIGNATURE PAGE......................................................................................3 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF IN-TEXT TABLES ........................................................................................................10 
LIST OF IN-TEXT FIGURES.......................................................................................................10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................11 
STATEMENT OF COMPLIANCE ...............................................................................................14 
1. 
PROTOCOL SUMMARY ...................................................................................................15 
1.1. 
Synopsis ...........................................................................................................................15 
1.2. 
Schema ............................................................................................................................18 
1.3. 
Schedule of Activities ......................................................................................................18 
2. 
INTRODUCTION ................................................................................................................19 
2.1. 
Lymphoid Cancers ...........................................................................................................19 
2.2. 
Inhibition of Bruton Tyrosine Kinase in Lymphoid Cancers ..........................................19 
2.3. 
Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) ...........................................20 
2.4. 
Cirmtuzumab ...................................................................................................................22 
2.4.1. 
Discovery ....................................................................................................................22 
2.4.2. 
Chemistry ....................................................................................................................23 
2.4.3. 
Clinical Experience with Cirmtuzumab ......................................................................23 
2.4.4. 
Combination Studies of Cirmtuzumab and Ibrutinib..................................................23 
2.5. 
Conclusions/Study Rationale ...........................................................................................24 
3. 
OBJECTIVES AND ENDPOINTS .....................................................................................26 
3.1. 
Primary Objectives ..........................................................................................................26 
3.2. 
Secondary Objectives ......................................................................................................26 
3.3. 
Primary Study Endpoints .................................................................................................26 
3.4. 
Secondary Study Endpoints .............................................................................................26 
3.4.1. 
Antitumor Activity and Survival ................................................................................26 
3.4.2. 
Safety Profile ..............................................................................................................27 
3.4.3. 
Pharmacokinetics ........................................................................................................27 
3.4.4. 
Pharmacodynamics/Exploratory Biomarkers .............................................................27 
3.4.5. 
Immunogenicity ..........................................................................................................28 
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4. 
STUDY DESIGN .................................................................................................................29 
4.1. 
Part 1 – Dose-Finding (Cirmtuzumab → Cirmtuzumab + Ibrutinib) ..............................29 
4.2. 
Part 2 – Cohort Expansion (Cirmtuzumab + Ibrutinib) ...................................................30 
4.3. 
Part 3 – Efficacy Evaluation (Cirmtuzumab + Ibrutinib versus Ibrutinib) ......................30 
4.4. 
Rationale for Study Design .............................................................................................31 
4.5. 
Rationale for Study Drug Doses ......................................................................................32 
5. 
STUDY POPULATION: RECRUITMENT AND SELECTION OF STUDY 
PATIENTS ...........................................................................................................................33 
5.1. 
Planned Number of Patients ............................................................................................33 
5.1.1. 
Part 1 (Cirmtuzumab → Cirmtuzumab + Ibrutinib) ...................................................33 
5.1.2. 
Part 2 (Cirmtuzumab + Ibrutinib) ...............................................................................33 
5.1.3. 
Part 3 (Cirmtuzumab + Ibrutinib versus Ibrutinib) .....................................................33 
5.2. 
Enrollment of Study Patients ...........................................................................................33 
5.3. 
Patient Selection Criteria .................................................................................................33 
5.3.1. 
Inclusion Criteria ........................................................................................................34 
5.3.2. 
Exclusion Criteria .......................................................................................................36 
6. 
STUDY INTERVENTION ..................................................................................................38 
6.1. 
Cirmtuzumab ...................................................................................................................38 
6.1.1. 
Known Potential Risks: Cirmtuzumab (zilovertamab) ...............................................38 
6.1.2. 
Known potential benefits: Cirmtuzumab (zilovertamab) ...........................................38 
6.1.3. 
Description ..................................................................................................................38 
6.1.4. 
Source .........................................................................................................................39 
6.1.5. 
Packaging and Labelling .............................................................................................39 
6.1.6. 
Shipping, Storage, and Stability .................................................................................39 
6.1.7. 
Cirmtuzumab Administration .....................................................................................39 
6.2. 
Ibrutinib ...........................................................................................................................41 
6.2.1. 
Known potential risks: Ibrutinib .................................................................................41 
6.2.2. 
Description ..................................................................................................................42 
6.2.3. 
Source .........................................................................................................................42 
6.2.4. 
Packaging and Labelling .............................................................................................42 
6.2.5. 
Shipping, Storage, and Stability .................................................................................42 
6.2.6. 
Dispensing ..................................................................................................................42 
6.2.7. 
Return and Compliance Assessment ..........................................................................42 
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Oncternal Therapeutics, Inc. 
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6.2.8. 
Ibrutinib Administration .............................................................................................43 
6.3. 
Dose Modifications .........................................................................................................44 
6.3.1. 
Dose adjustments for Cirmtuzumab ...........................................................................44 
6.3.2. 
Treatment interruptions for Cirmtuzumab ..................................................................44 
6.3.3. 
Dose modifications for Ibrutinib ................................................................................45 
6.4. 
Concomitant Therapy ......................................................................................................46 
6.4.1. 
Cirmtuzumab Infusion-Reaction Prophylaxis ............................................................46 
6.4.2. 
Tumor Lysis Syndrome (TLS) Prophylaxis ...............................................................47 
6.4.3. 
TLS Management .......................................................................................................47 
6.4.4. 
Anticancer Therapies Other than the Study Drugs .....................................................47 
6.4.5. 
Anticoagulants ............................................................................................................48 
6.4.6. 
Drugs with Potential for Drug-Drug Interactions with Ibrutinib ................................48 
6.4.7. 
Drugs Known to Prolong the QT Interval ..................................................................49 
6.4.8. 
Procedures/Surgery .....................................................................................................49 
6.5. 
Study Restrictions ............................................................................................................49 
6.5.1. 
Breast Feeding ............................................................................................................49 
6.5.2. 
Contraception ..............................................................................................................49 
6.5.3. 
Diet .............................................................................................................................50 
7. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................51 
7.1. 
Duration of Study Drug Administration and Study Participation ...................................51 
7.2. 
Patient Replacement ........................................................................................................52 
7.3. 
Study Discontinuation .....................................................................................................52 
8. 
STUDY ASSESSMENTS AND PROCEDURES ...............................................................53 
8.1. 
Study Activities ...............................................................................................................53 
8.2. 
Schedule of Activities – Part 1 MCL and CLL/SLL (Cirmtuzumab → 
Cirmtuzumab + Ibrutinib) ................................................................................................54 
8.3. 
Schedule of Activities – Part 2 MCL, MZL and CLL/SLL (Cirmtuzumab + 
Ibrutinib) ..........................................................................................................................57 
8.4. 
Schedule of Activities – Part 3 CLL/SLL (Cirmtuzumab + Ibrutinib versus 
Ibrutinib) ..........................................................................................................................60 
8.5. 
Efficacy Assessments ......................................................................................................63 
8.5.1. 
Overview .....................................................................................................................63 
8.5.2. 
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma ............................63 
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8.5.3. 
Lymphoma ..................................................................................................................64 
8.6. 
Safety Assessments .........................................................................................................65 
8.6.1. 
Definitions ..................................................................................................................65 
8.6.2. 
Grading of the Severity of an Adverse Event .............................................................67 
8.6.3. 
Describing Adverse Event Relationship to Study Drug .............................................68 
8.6.4. 
Adverse Event Reporting Period ................................................................................69 
8.6.5. 
Adverse Event Reporting Requirements ....................................................................69 
8.6.6. 
Pregnancy and Reporting ............................................................................................70 
8.6.7. 
Sponsor Reporting Requirements ...............................................................................71 
9. 
STATISTICAL CONSIDERATIONS .................................................................................72 
9.1. 
Analysis Plan ...................................................................................................................72 
9.1.1. 
Pharmacokinetics ........................................................................................................72 
9.1.2. 
Pharmacodynamics .....................................................................................................72 
9.1.3. 
Efficacy Analyses .......................................................................................................72 
9.1.4. 
Other Analyses ............................................................................................................72 
9.2. 
Timing of Analyses .........................................................................................................73 
9.2.1. 
Interim Analyses .........................................................................................................73 
9.2.2. 
Final Analyses ............................................................................................................74 
9.3. 
Basis for the Planned Sample Sizes .................................................................................74 
9.3.1. 
Part 1 (Cirmtuzumab → Cirmtuzumab + Ibrutinib) and 
Part 2 (Cirmtuzumab + Ibrutinib) ...............................................................................74 
9.3.2. 
Part 3 (Cirmtuzumab + Ibrutinib versus Ibrutinib) .....................................................74 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ...........................................................................................................75 
10.1. 
Study Conduct .................................................................................................................75 
10.2. 
Study Committees ...........................................................................................................75 
10.3. 
Protocol Compliance .......................................................................................................75 
10.4. 
Institutional Review Board (IRB) ...................................................................................75 
10.5. 
Informed Consent ............................................................................................................76 
10.6. 
Confidentiality .................................................................................................................76 
10.7. 
Sample Shipping, Storage, and Retention .......................................................................77 
10.8. 
Study Files and Retention of Records and Biological Samples ......................................77 
10.9. 
Modifications of the Protocol ..........................................................................................78 
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10.10. 
Case Report Forms ..........................................................................................................78 
10.11. 
Study Drug Accountability ..............................................................................................79 
10.12. 
Monitoring .......................................................................................................................80 
10.13. 
Inspections .......................................................................................................................80 
10.14. 
Data Management ............................................................................................................80 
10.15. 
Communications with Regulatory Authorities ................................................................80 
10.16. 
Public Notification of Study Conduct .............................................................................81 
10.17. 
Study Reporting and Publication .....................................................................................81 
11. 
BIBLIOGRAPHY ................................................................................................................83 
12. 
APPENDICES ......................................................................................................................97 
12.1. 
ECOG Performance Status ..............................................................................................98 
12.2. 
Cockcroft-Gault Method for Estimating Creatinine Clearance .......................................99 
12.3. 
Potent Inhibitors and Inducers of CYP3A4 ...................................................................100 
12.4. 
RAI Staging System for CLL/SLL ................................................................................101 
12.5. 
Efficacy Assessments – CLL/SLL ................................................................................101 
12.5.1. 
Identification and Measurement of Tumor Lesions and Organomegaly ..................101 
12.5.2. 
Definitions of Tumor Response and Progression .....................................................103 
12.6. 
Efficacy Assessment – Lymphoma ...............................................................................107 
12.6.1. 
Identification and Follow-up of Tumor Lesions and Organomegaly .......................108 
12.6.2. 
Definitions of Tumor Response and Progression .....................................................110 
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LIST OF IN-TEXT TABLES 
Table 1: 
Dose Adjustments for Ibrutinib ..................................................................................46 
Table 2: 
Grading of Adverse Event Severity ............................................................................68 
Table 3: 
Relationship of Study Drug to Adverse Event ...........................................................69 
Table 4: 
Contact Information for Reporting Serious Adverse Events or Pregnancies .............70 
Table 5: 
Summary of Response Criteria for CLL/SLL Patients ............................................104 
Table 6: 
Summary of Response Criteria for MCL and MZL Patients ...................................114 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Part 1 – Dose-Finding (Cirmtuzumab → Cirmtuzumab + Ibrutinib) .........................18 
Figure 2: 
Part 2 – Cohort Expansion (Cirmtuzumab + Ibrutinib) ..............................................18 
Figure 3: 
Part 3 – Efficacy Evaluation (Cirmtuzumab + Ibrutinib versus Ibrutinib) .................18 
Figure 4. 
Structure of ROR1 ......................................................................................................21 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALC 
absolute lymphocyte count 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AV 
Atrioventricular 
Bcl2 
B-cell lymphoma 2 (protein) 
BTK 
Bruton tyrosine kinase 
BUN 
blood urea nitrogen 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
CHO 
Chinese hamster ovary (cells) 
CI 
confidence interval 
CK 
creatine kinase 
Cl 
clearance  
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum concentration 
CMR 
complete metabolic response 
CR 
complete response 
CRi 
complete response with incomplete blood count recovery 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 (enzyme) 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
Electrocardiogram, electrocardiographic 
eClCR 
estimated creatinine clearance 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMT 
epithelial-mesenchymal transition 
EU 
European Union 
FDA 
Food and Drug Administration 
FDAMA 
Food and Drug Modernization Act of 1997 
FDG 
Fluorodeoxyglucose 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GTPase 
guanosine-triphosphate-hydrolyzing enzyme 
GVHD 
graft-versus-host disease 
HBc 
hepatitis B core (antibody) 
HBsAg 
hepatitis B surface antigen 
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Abbreviation 
Definition 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
Ig 
Immunoglobulin 
IL 
Interleukin 
IND 
investigational new drug application 
INN 
International Nonproprietary Name 
IRB 
institutional review board 
IV 
intravenous, intravenously 
LD or LDi 
longest dimension 
LDH 
lactate dehydrogenase 
LLQ 
lower limit of quantitation 
LPD 
longest perpendicular dimension 
LVD 
longest vertical dimension 
MCL 
mantle cell lymphoma 
MFI 
mean fluorescent intensity 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MZL 
marginal zone lymphoma 
Na-EDTA 
sodium-ethylenediaminetetraacetic acid 
NCI 
National Cancer Institute 
NE 
Nonevaluable 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer (cells) 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PPD 
product of the perpendicular diameters 
PR 
partial response 
PR-L 
partial response with lymphocytosis 
PT 
prothrombin time 
Q4 
once every 
QD 
once per day 
QTc 
cardiac QT interval corrected for heart rate 
Rac1 
Ras-related C3 botulinum toxin substrate 
RDR 
recommended dosing regimen 
RhoA 
Ras homolog gene family member A 
RNA 
ribonucleic acid 
ROR1 
receptor tyrosine kinase-like orphan receptor 1 
R/R 
Relapsed or Refractory 
SAE 
serious adverse event 
SD 
stable disease 
SDi 
shortest dimension 
siRNA 
small interfering ribonucleic acid 
SLL 
small lymphocytic lymphoma 
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Abbreviation 
Definition 
SPD 
sum of the products of the diameters 
SRC 
safety review committee 
SUSAR 
suspected, unexpected, serious adverse reaction 
t1/2 
elimination half-life 
TEAE 
treatment-emergent adverse event 
TLS 
tumor lysis syndrome 
Tmax 
time of maximum concentration 
TNT 
time to next treatment 
TTR 
time to response 
TTF 
time to treatment failure 
UC-961 
alternate name for cirmtuzumab 
UCSD 
University of California, San Diego 
ULN 
upper limit of normal 
Vd 
volume of distribution 
βHCG 
beta human chorionic gonadotropin 
λz 
terminal elimination rate constant 
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STATEMENT OF COMPLIANCE  
The study will be performed in accordance with the principles as set forth under the requirements 
of 21 Code of Federal Regulations (CFR) 50 and the ICH E6 GCP guideline.  
The investigator will ensure that this study is conducted in accordance with 21 CFR parts 50 and 
54 and ICH guidelines. For studies conducted under a US IND, the investigator will ensure 
adherence to the basic principles of GCP as outlined in 21 CFR 312, subpart D, “Responsibilities 
of Sponsors and Investigators,” 21 CFR, Part 50, 1998, and 21 CFR, Part 56, 1998. This study is 
also subject to and will be conducted in accordance with 21 CFR, Part 320, 1993, “Retention of 
Bioavailability and Bioequivalence Testing Samples.” 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Investigational Product 
Cirmtuzumab (UC-961) (INN: Zilovertamab) 
Coadministered Drug 
Ibrutinib 
Study Title 
A Phase 1b-2 Study of the ROR1-Targeting Monoclonal Antibody, 
Cirmtuzumab (UC-961), and the Bruton Tyrosine Kinase Inhibitor, Ibrutinib, 
in Patients with B-Cell Lymphoid Malignancies 
Protocol Number 
CIRM-0001 (Oncternal Therapeutics, Inc) 
Study Background 
Among the agents approved for the therapy of chronic lymphocytic 
leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma 
(MCL) or marginal zone lymphoma (MZL) is the Bruton tyrosine kinase 
(BTK) inhibitor, ibrutinib, which has provided durable tumor regressions in 
the majority of patients with these disorders. However, the proportion of 
patients experiencing complete response (CR) to ibrutinib monotherapy is 
low (<7% in CLL/SLL, ~15% in MCL and ~3% for MZL) and resistance to 
ibrutinib eventually develops in many patients. Collectively, these data 
support development of a new agent with a complementary mechanism of 
action that can safely combine with ibrutinib to enhance disease clearance 
and circumvent disease resistance.  
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a cell surface 
protein that mediates signals from its ligand, the secreted glycoprotein, 
Wnt5a. Consistent with its role in influencing the fate of stem cells during 
embryogenesis, ROR1 expression is observed on invasive malignancies that 
revert to an embryonic transcriptional program, but is not observed on normal 
adult tissues, offering a favorable selectivity profile as a therapeutic target. 
ROR1 is expressed on the malignant cells in >90% of patients with CLL/SLL 
and >95% of patients with MCL and is also expressed on MZL [Barna 2011]. 
Oncternal Therapeutics, Inc. (Oncternal), in collaboration with The 
University of California, San Diego (UCSD) is developing the therapeutic 
monoclonal antibody, cirmtuzumab, for selective targeting of hematological 
and other cancers with high ROR1 expression. Cirmtuzumab is a humanized 
immunoglobulin (Ig) G1 monoclonal that shows high-affinity binding to 
ROR1. Cirmtuzumab is synergistic when tested together with ibrutinib, 
inhibiting the growth of CLL and MCL cells in vitro, and combination 
therapy was associated with substantially greater reductions in splenomegaly 
and leukemia-cell infiltration in splenic tissue in a murine CLL model than 
either single agent given alone.  
Clinical evaluation of cirmtuzumab has comprised a Phase 1a, sequential 
dose-escalation study in patients with CLL/SLL. Cirmtuzumab was very well 
tolerated over a dose range of 0.015 to 20 mg/kg. Adverse events (AEs) were 
largely attributable to patients’ cancers or comorbidities and were primarily 
Grade 1 or 2 in intensity. No DLTs were observed, no serious adverse events 
(SAEs) occurred, and no maximum tolerated dose (MTD) was identified 
within the tested dose range. Pharmacodynamic data indicted decreases in 
ROR1-mediated signaling as manifest by decreased Rac1 and RhoA 
expression in circulating CLL cells. Individual signs of disease control over 
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the 8-week drug administration period were observed, including reductions in 
circulating CLL cell numbers, lymphadenopathy, splenomegaly, and/or bone 
marrow infiltration. Many patients had persistent post-therapy disease 
stabilization.  
Collectively, these data provide context for the clinical development of the 
combination of cirmtuzumab and ibrutinib as therapy of CLL/SLL, MCL and 
MZL. It is hypothesized that coadministration of these 2 drugs will result in a 
higher proportion of patients achieving CR and experiencing longer 
progression-free survival (PFS). Given the exceptional clinical safety of both 
drugs, the combination is expected to be well tolerated. Accordingly, this 
clinical protocol will further characterize the safety, pharmacology, and 
activity of cirmtuzumab alone and when co-administered with ibrutinib in 
patients with recurrent or treatment-refractory CLL/SLL, MCL or MZL.  
 
Study Design 
This clinical trial is a Phase 1b-2 study of the safety, pharmacokinetics, 
pharmacodynamics, immunogenicity, and antitumor activity of the 
combination of cirmtuzumab and ibrutinib. The study will be conducted in 
3 parts. 
 Part 1 Dose-Finding 
Cirmtuzumab →  
Cirmtuzumab + 
Ibrutinib 
Part 1 comprises a Phase 1b, open-label, sequential allocation, dose-finding 
evaluation of the sequential administration of cirmtuzumab monotherapy 
followed by cirmtuzumab + ibrutinib combination therapy in patients with 
CLL/SLL or MCL. 
  
At the conclusion of Part 1 of the study, a recommended dosing regimen 
(RDR) of cirmtuzumab will be selected based primarily on safety, 
pharmacokinetic, and pharmacodynamic findings. 
 Part 2  
Cohort Expansion 
Cirmtuzumab + 
Ibrutinib 
Part 2 comprises a Phase 2 expansion and open-label evaluation of the 
concurrent administration of cirmtuzumab and ibrutinib based on the RDR 
derived from Part 1. Up to 18 evaluable patients with CLL/SLL will be 
enrolled. Up to 20 evaluable patients with MCL and up to 10 patients with 
relapsed/refractory (R/R) MZL will be enrolled into Part 2; a clinical review 
will then be performed to determine if additional patients are required to 
assess safety, efficacy, and exploratory biomarkers for further development. 
 Part 3  
Efficacy Evaluation 
Cirmtuzumab + 
Ibrutinib versus 
Ibrutinib 
Part 3 comprises a Phase 2 open-label, randomized, controlled, 2-arm, 
parallel-group evaluation of the clinical activity and safety of cirmtuzumab + 
ibrutinib versus ibrutinib alone. Patients with CLL/SLL will be randomized 
2:1 to one of the following 2 regimens: 
• Arm A: cirmtuzumab + ibrutinib 
• Arm B: ibrutinib alone 
Approximately 30 patients will be enrolled and randomized into Part 3.  
  
 
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Study Objectives 
 
 Primary Objectives 
• Part 1 (cirmtuzumab → cirmtuzumab + ibrutinib): To determine the RDR 
of cirmtuzumab when given alone and in combination with ibrutinib in 
patients with CLL/SLL or MCL 
  
• Part 2 (cirmtuzumab + ibrutinib): To further characterize the safety, 
pharmacology, and clinical responses of cirmtuzumab + ibrutinib when 
administered using the RDR in patients with CLL/SLL, MCL, or MZL 
  
• Part 3 (cirmtuzumab + ibrutinib versus ibrutinib): To further evaluate the 
CR rate associated with cirmtuzumab + ibrutinib when administered using 
the RDR in patients with CLL/SLL 
 
 Secondary Objectives 
• To determine the drug administration, safety, and supportive care profiles 
of cirmtuzumab and the combination of cirmtuzumab + ibrutinib 
  
• To evaluate the pharmacokinetic profile of cirmtuzumab alone and in 
combination with ibrutinib 
  
• To assess the effects of cirmtuzumab and cirmtuzumab + ibrutinib on 
exploratory biomarkers/pharmacodynamic markers relating to drug 
mechanism, immune profile, and disease manifestations 
  
• To characterize the immunogenicity of cirmtuzumab 
  
• To characterize the antitumor activity of cirmtuzumab monotherapy and 
cirmtuzumab + ibrutinib combination therapy 
 
Selection and Enrollment of Study Patients 
Planned Number of 
Patients 
Part 1 (Cirmtuzumab → Cirmtuzumab + Ibrutinib) 
If 6 patients (3 patients with CLL/SLL and 3 patients with MCL) are enrolled 
at all 4 planned dose levels, 24 patients will be enrolled. If 2 additional dose 
levels are explored in 6 patients/dose level (3 patients with CLL/SLL and 3 
patients with MCL), as many as 12 additional patients could be enrolled, 
bringing the potential sample size to 36 patients. To allow for the possibility 
that some patients may not be fully evaluable, up to 48 patients may be 
enrolled. 
 
Part 2 (Cirmtuzumab + Ibrutinib) 
 
It is planned that the RDR will be evaluated in up to 18 patients with 
CLL/SLL. To allow for the possibility that some patients may not be fully 
evaluable, up to 30 patients may be enrolled. The RDR will be the same for 
CLL/SLL, MCL and MZL. Up to 20 evaluable patients with MCL and up to 
10 patients with R/R MZL will be enrolled into Part 2; a clinical review will 
then be performed to determine if additional evaluable patients are required 
to assess safety, efficacy, and exploratory biomarkers for further 
development. This review could lead to a further adjustment and increase in 
enrollment. 
 
Part 3 (Cirmtuzumab + Ibrutinib vs Ibrutinib Alone) 
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Approximately 30 patients will be enrolled and randomized 2:1 into Part 3 
(~20 patients will receive cirmtuzumab + ibrutinib and ~10 patients will 
receive ibrutinib alone). 
Target Populations 
The target population comprises adult patients with adequate performance 
status and organ function who have CLL/SLL, MCL or  MZL and are 
appropriate candidates for ibrutinib treatment.  
 
1.2. 
Schema 
Figure 1: Part 1 – Dose-Finding (Cirmtuzumab → Cirmtuzumab + Ibrutinib) 
 
Patients exhibiting a PR or CR may be eligible to continue combination treatment beyond Week 52 as part of an 
extended therapy program. 
 
Figure 2: Part 2 – Cohort Expansion (Cirmtuzumab + Ibrutinib)  
 
 
 
Patients exhibiting a PR or CR may be eligible to continue combination treatment beyond Week 52 as part of an 
extended therapy program. 
 
Figure 3: Part 3 – Efficacy Evaluation (Cirmtuzumab + Ibrutinib versus Ibrutinib)  
 
Patients exhibiting a PR or CR may be eligible to continue combination treatment beyond Week 52 as part of an 
extended therapy program. 
1.3. 
Schedule of Activities 
Tabular schedules of study activities are presented in Section 8.2 (Part 1), Section 8.3 (Part 2), 
and Section 8.4 (Part 3). 
 
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2. 
INTRODUCTION 
2.1. 
Lymphoid Cancers 
B-cell lymphoid malignancies arise from the accumulation of monoclonal, neoplastic B 
lymphocytes in lymph nodes and often in organs such as blood, bone marrow, spleen, and liver. 
Among the variants of B-cell lymphoid cancers are chronic lymphocytic leukemia/small 
lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), and marginal zone 
lymphoma (MZL). These disorders are characterized by disabling constitutional symptoms; 
lymphadenopathy and organomegaly that can induce life-threatening organ dysfunction; and 
myelosuppression and immunocompromise that can result in susceptibility to infection and 
bleeding [Zhang 2014b; Hallek 2015; Vose 2015; Cheah 2016]. Front-line use of multiagent 
chemoimmunotherapy is commonly successful in suppressing disease manifestations for 
prolonged periods [NCCN 2016a; NCCN 2016b]. However, these diseases are incurable, and 
patients require further therapy to maintain disease control.  
2.2. 
Inhibition of Bruton Tyrosine Kinase in Lymphoid Cancers 
Among the agents approved for the therapy of patients with relapsed or refractory CLL/SLL, 
MCL or MZL is the Bruton tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765, 
Imbruvica™). Bruton tyrosine kinase (BTK) is a non-receptor enzyme in the TEC kinase family 
that is expressed among cells of hematopoietic origin, including B cells, myeloid cells, mast 
cells, and platelets, where it regulates multiple cellular processes including proliferation, 
differentiation, apoptosis, and cell migration [Khan 2001; Mohamed 2009; Bradshaw 2010]. 
Functional null mutations of BTK in humans cause the inherited disease, X-linked 
agammaglobulinemia, which is characterized by a lack of mature peripheral B cells 
[Vihinen 2000; Ponader 2014]. Conversely, BTK activation is implicated in the pathogenesis of 
several B-cell malignancies [Herman 2011; Buggy 2012; Herman 2014, Kil 2013; Woyach 
2014a]. In addition, BTK-dependent activation of mast cells and other immunocytes in 
peritumoral inflammatory stroma has been shown to sustain the complex microenvironment 
needed for tumor maintenance and growth [Ponader 2012; de Rooij 2012]. 
Based on this pharmacology, ibrutinib was developed by Pharmacyclics, Inc (now a subsidiary 
of AbbVie, Inc) and Janssen, Inc as an orally delivered, small-molecule, irreversible inhibitor of 
BTK for the treatment of B-cell malignancies. Studies in patients with heavily pretreated 
CLL/SLL have demonstrated that chronic ibrutinib therapy can provide lasting antitumor activity 
for the majority of patients [Advani 2013; Byrd 2013; Byrd 2014; Farooqui 2015; O’Brien 2016; 
Winqvist 2016]. Similarly, in patients with substantial prior therapy for MCL and MZL, chronic 
ibrutinib monotherapy has offered tumor regressions and durable tumor control [Wang 2013; 
Dreyling 2016; Maruyama 2016; Noy 2017].  
Ibrutinib has been generally well tolerated. For patients with lymphoid cancers receiving 
ibrutinib, clinical adverse events (AEs) (of any causality) have included: atrial fibrillation or 
atrial flutter; bleeding (primarily bruising and petechiae); infections; neutropenia, 
thrombocytopenia, or anemia; diarrhea, and rash. Such events have generally been infrequent 
and typically have been Grade 1 or 2 in intensity [Pharmacyclics 2020 and Ibrutinib Investigator 
Brochure 2021]. Across the tested ibrutinib dose range (through 1400 mg/day), no acute dose-
limiting toxicities (DLTs) were identified and the recommended Phase 2 doses (420 mg/day for 
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CLL/SLL and 560 mg/day for MCL and MZL) were established based on pharmacodynamic 
outcomes rather than safety limitations [Advani 2013]. The drug has also proved safe when 
administered as oral continuous monotherapy for periods of several years [Byrd 2015a; Wang 
2015]. Rates of discontinuations due to adverse events have consistently been <10% across 
studies in CLL/SLL, MCL and MZL although they may approach ~20% in clinical practice 
[Mato 2016]. Further, ibrutinib has been readily combined with therapeutic monoclonal 
antibodies and cytotoxic agents used to treat CLL/SLL, MCL and MZL; because of a lack of 
overlapping toxicities with such drugs, it has been possible to administer both ibrutinib and the 
other agents at the full recommended dose levels [Burger 2014; Younes 2014; Brown 2015; 
Maddocks 2015a; Chanan-Khan 2016; Wang 2016]. Whether given alone or in combination, 
instances of tumor lysis syndrome (TLS) at the initiation of ibrutinib have been rare [Howard 
2016]. Based on its efficacy and safety in patients with previously treated disease, ibrutinib has 
been approved for the therapy of previously untreated and previously treated CLL/SLL and for 
the therapy of previously treated MCL and MZL in the United States (US), the European Union 
(EU), and elsewhere [de Claro 2015; Pharmacyclics 2020].  
While ibrutinib offers tumor regressions in the substantial majority of patients, the proportion of 
patients with CLL/SLL experiencing a complete response (CR) to ibrutinib monotherapy is 
consistently <5% within the first year of therapy [Byrd 2013; Byrd 2014; Farooqui 2015; 
Burger 2015; O’Brien 2016] and rises to only 7% after several years of treatment [Byrd 2015a]. 
In previously treated MCL, rates of CR have ranged from 12.5% to 23%, even with long-term 
therapy [Wang 2013; Dreyling 2016; Maruyama 2016; Wang 2015]. In relapsed/refractory MZL 
treated with prior rituximab or rituximab-based chemoimmunotherapy, rate of CR to ibrutinib 
monotherapy was 3.2% and ORR was 46% after 19.4 months of follow-up [Pharmacyclics 
2020]. ORR rates increased to 58% after a median follow-up of 33.1 months [Noy 2020]. 
Progression-free survival (PFS) has been very long in most patients with CLL/SLL and has 
averaged 13 to 14.6 months in those with MCL [Wang 2015; Dreyling 2016]. For MZL, median 
PFS was 14.2 and 15.7 months, after a median follow-up of 19.4 and 33.1 months, respectively 
[Noy 2017; Noy 2020]. However, resistance to ibrutinib eventually develops in many patients 
with CLL and most patients with MCL [Chiron 2014; Furman 2014; Cheng 2015; Liu 2015; 
Burger 2016; Hamasy 2016]. Among those becoming resistant to ibrutinib, an aggressive natural 
history is common [Cheah 2015; Jain 2015; Maddocks 2015b; Stephens 2015; Martin 2016]. 
Collectively, these data support development of a new agent that targets a complementary 
mechanism of action and can safely be combined with ibrutinib to enhance disease clearance and 
circumvent disease resistance.  
2.3. 
Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) 
ROR1 is a type 1 transmembrane protein that shares homology to other receptor tyrosine kinases 
and shows high evolutionary conservation [Masiakowski 1992; Forrester 1999; Yoda 2003; 
Katoh 2005]. As shown in Figure 4, the extracellular portion contains immunoglobulin-like 
sequences, a cysteine-rich domain homologous to Frizzled receptors for various Wnt ligands, and 
a kringle domain. The cytoplasmic portion contains a tyrosine kinase-like domain followed by 
serine/threonine- and proline-rich motifs.  
 
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Figure 4. Structure of ROR1 
 
Abbreviations: Ig=immunoglobulin, m/h ROR=mouse/human receptor tyrosine kinase-like orphan receptor 1, 
ser=serine, thr=threonine 
Based on studies in rodents, ROR1 is an embryonic factor that is physiologically expressed 
during early embryogenesis and plays a critical role in neural, skeletal, and vascular 
organogenesis [Oishi 1999; Al-Shawi 2001; Matsuda 2001; Lyashenko 2010]. Functional studies 
in primary embryonic cells suggest that binding of the secreted glycoprotein ligand, Wnt5a, 
results in heterodimerization of ROR1 with ROR2 (the other member of the ROR family) and 
can stimulate neuronal synapse formation [Paganoni 2010]. During fetal development, the 
expression of ROR1 decreases [Masiakowski 1992; Al-Shawi 2001; Paganoni 2010]. With the 
exception of rare B-lymphocyte precursors known as hematogones (the non-neoplastic 
counterpart to precursor-B acute lymphoblastic leukemia (ALL) [Broome 2011], normal adult 
tissues lack surface expression of the ROR1 protein [Fukuda 2008; Hudecek 2010; Zhang 2012b; 
Liu 2015b]. 
However, consistent with a role as an onco-embryonic factor, high levels of ROR1 protein 
expression have been found in multiple cancers, including both hematological malignancies 
[Daneshmanesh 2008; Baskar 2008; Hudecek 2010; Barna 2011; Uhrmacher 2011; 
Daneshmanesh 2013; Kotašková 2016] and solid tumors [Zhang 2012b; Liu 2015b]. Among 
lymphoid cancers, these studies indicate near universal expression of ROR1 expression in 
CLL/SLL and MCL and document evidence of ROR1 expression in some patients with ALL 
[Bicocca 2012], marginal zone lymphoma (MZL), and diffuse large B-cell lymphoma (DLBCL) 
[Barna 2011]. ROR1 expression and activation appears to be correlated with features of tumor 
aggressiveness in models of CLL, breast cancer, lung cancer, gastric cancer, and melanoma 
[Li 2010; Daneshmanesh 2012; Zhang 2012a; Daneshmanesh 2013; Gentile 2011; 
Yamaguchi 2012; Hojjat-Farsangi 2013a; Hojjat-Farsangi 2013b; O’Connell 2013; Ida 2016; 
Janovska 2016]. Elevated levels of ROR1 expression in patients and cell lines are associated 
with genes involved in epithelial-mesenchymal transition (EMT) [Cui 2013]. In patients with 
CLL, high levels of ROR1 expression are associated with shorter treatment-free survival and 
overall survival (OS) [Cui 2016]. Similarly, in patients with ovarian cancer, high ROR1 
expression is associated with poor clinical outcomes [Zhang 2014a].  
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The potential functional significance of ROR1 signaling has been evaluated. In a gene therapy 
experiment in which 6 patients with CLL received infusion of adenovirus-CD145-transduced 
autologous CLL cells, it was noted that 3 of the patients made endogenous IgG that was reactive 
with ROR1 [Fukuda 2008]. In vitro studies indicated Wnt5a binding to ROR1 enhanced the 
survival of CLL cells in vitro, an effect that could be neutralized by sera from the 
anti-ROR1-positive patients. These results were supported by clinical data indicating that 
spontaneously developing anti-ROR1 immune responses in patients with CLL were associated 
with a better prognosis [Hojjat-Farsangi 2015]. In a mouse model, animals engineered to produce 
CLL-like B cells that were positive for ROR1 showed high transcriptome expression of 
subnetworks implicated in embryonic and tumor-cell proliferation, and relatively low levels of 
transcripts involved in cell-cell adhesion or cell death [Widhopf 2014]. These cells were also 
actively proliferating (as indicated by Ki-67-positivity) and showed relatively little spontaneous 
apoptosis.  
Treatment of these mice with an anti-ROR1 monoclonal antibody (D10) resulted in ROR1 
down-modulation, reduced down-stream signaling, and impaired engraftment of leukemia cells 
[Widhopf 2014]. Similarly, silencing of ROR1 with small interfering ribonucleic acid (siRNA) 
was observed to enhance apoptosis of human CLL cells [Choudhury 2010]. In nonclinical 
models of breast cancer, treatment with anti-ROR1 antibodies or siRNA reduced tumor growth 
and metastatic potential [Zhang 2012a; Cui 2013]. Likewise, treatment of melanoma with 
anti-ROR1 monoclonal antibodies resulted in apoptosis in ROR1-positive but not 
ROR1-negative cell lines [Hojjat-Farsangi 2013a]. 
Collectively, the accumulating data regarding its role in cancer and lack of expression in normal 
tissues indicate that ROR1 represents an attractive therapeutic target for cancer intervention. 
2.4. 
Cirmtuzumab 
2.4.1. 
Discovery 
Given its tumor-specific expression and potential functional significance in oncogenesis, 
investigators at the University of California, San Diego (UCSD) initiated a drug discovery 
program to generate monoclonal antibodies for the treatment of ROR1-expressing hematological 
and solid tumors. Oncternal Inc (Oncternal) was formed to further develop the technology. 
At UCSD, hybridomas were screened for production of monoclonal antibodies mimicking the 
activity of anti-ROR1 autoantibodies observed in patients vaccinated against transfected 
autologous leukemia cells [Fukuda 2008] and were tested in vivo using the TCL1 x ROR1 CLL 
mouse model [Widhopf 2014]. One murine monoclonal antibody, D10, was identified that could 
inhibit ROR1-mediated signaling and engraftment of ROR1+ leukemia cells in this model. When 
tested in an immune-deficient murine xenograft, the D10 antibody consistently demonstrated 
potent, dose-dependent activity against human CLL patient samples. Mapping the epitope bound 
by the D10 antibody allowed generation of monoclonal antibodies with substantially higher 
affinity for ROR1. Humanization of the variable regions allowed identification of an antibody 
that maintained high binding affinity while minimizing the potential for immunogenicity. This 
clinical development candidate was designated UC-961 or cirmtuzumab [Choi 2015]. 
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2.4.2. 
Chemistry 
Cirmtuzumab is a recombinant humanized IgG1κ monoclonal antibody with specificity for an 
epitope in the Ig-like region of the extracellular domain of human ROR1 (see Figure 4 above). 
The antibody has 1,320 amino acids and a molecular weight of ~148 kilodaltons including N-
linked glycosylation. The antibody is humanized except for amino acids adjacent to the borders 
of the complementarity-determining region and one of the framework regions, both of which are 
immune protected sites.  
The protein is produced in Chinese hamster ovary (CHO) cells and is purified by a process that 
includes viral inactivation and removal steps. No animal sources are used in the production of the 
drug substance and culture media are serum-free and protein-free.  
2.4.3. 
Clinical Experience with Cirmtuzumab 
Clinical evaluation of cirmtuzumab has comprised a Phase 1a, sequential, dose-escalation study 
[Choi 2017]. Patients enrolled to the study have been adult men and women with relapsed or 
refractory CLL/SLL requiring treatment, Eastern Cooperative Group (ECOG) performance status 
≤2, and adequate organ function. Study patients have received a total of 4 IV infusions of 
cirmtuzumab monotherapy, each to be administered every 2 weeks. Dose escalation has been 
performed with a 3+3 design with intrapatient dose escalation permitted in early dosing cohorts. 
Infusions have been given over 1.5 to 4 hours. The safety, pharmacokinetics, pharmaco-
dynamics, and clinical effects of cirmtuzumab have been assessed. 
In summary, the Phase 1a results with cirmtuzumab administration at dose levels of 0.015 to 
20 mg/kg show the drug to be very well tolerated, with no obvious drug-related toxicity 
(including no DLTs, no Grade 4 AEs, no SAEs and no discontinuations due to AEs). 
Pharmacokinetic and pharmacodynamic data indicate systemic drug exposure and provide 
preliminary clinical evidence of expected drug mechanism. Details are provided in the 
Investigator Brochure. 
2.4.4. 
Combination Studies of Cirmtuzumab and Ibrutinib 
Given that ibrutinib now represents a standard-of-drug in the therapy of CLL/SLL and MCL, 
studies were performed to evaluate the therapeutic potential of combining cirmtuzumab with 
ibrutinib in nonclinical models of these diseases [Yu 2017; Yu 2018].  
To evaluate the in vitro effects of ibrutinib on the ROR1 pathway, circulating mononuclear cells 
from patients who were taking ibrutinib at the standard dose of 420 mg once per day (QD) were 
evaluated [Yu 2017] or fresh CLL cells were incubated with ibrutinib in culture. The cells were 
examined for Wnt5a-induced Rac1 activation with or without ibrutinib and/or cirmtuzumab. The 
data showed that cirmtuzumab, but not ibrutinib, could inhibit Wnt5a-induced Rac1 activation in 
CLL cells and that ibrutinib did not block the capacity of cirmtuzumab to inhibit Wnt5a-induced 
Rac1 activation. To assess the combined effects of cirmtuzumab and ibrutinib on CLL 
proliferation, leukemic cells were co-cultured with HeLa cells expressing CD154 and 
recombinant interleukin (IL)-4 and IL-10 [Yu 2017]. Treatment of the CLL cells with 
cirmtuzumab, but not ibrutinib, could block Wnt5a-enhanced proliferation. A cell-cycle analysis 
found that Wnt5a stimulation significantly enhanced the fraction of leukemia cells in S/G2/M 
and that the proportion of cells in S/G2/M could be decreased by cirmtuzumab but not ibrutinib. 
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Collectively, these data demonstrate that cirmtuzumab can block ROR1-mediated leukemia-cell 
proliferation that is not affected by ibrutinib. 
In vivo studies of the combination of cirmtuzumab and ibrutinib in several nonclinical models of 
CLL/SLL were performed [Yu 2017]. To assess the activity of cirmtuzumab and/or ibrutinib in 
xenografts derived from patients with CLL, leukemic cells from such patients were transferred 
into the peritoneal cavities of immunodeficient Rag2−/−γc−/− mice. Following treatment with a 
single dose of cirmtuzumab or 7 days of ibrutinib administration, the percentages and total 
numbers of CLL cells in peritoneal lavage were significantly lower than in control mice. 
Coadministration of the 2 drugs resulted in an even greater antitumor effect than either drug 
administered alone. Similar combination effects were observed when ROR1 × TCL1 leukemia 
cell engraftment was evaluate in immunodeficient Rag2−/−γc−/− mice or in immunocompetent 
human-ROR1 transgenic (ROR1-Tg) mice. Treatment with either single agent resulted in 
reductions in spleen size, and a lower mean proportion and number of leukemia cells in the 
spleen. However, treatment with both agents led to significantly greater antitumor effects than 
were observed with either monotherapy.  
To determine the influence of the ROR1 signaling pathway in MCL, primary cells from patients 
with the disease were evaluated for evidence of ROR1 expression [Yu 2018]. All of the tested 
patient samples showed intense surface staining for ROR1; the median (±SD) values for mean 
fluorescence intensity relative to control (ΔMFI) were higher in patients with MCL (N=8, 
87.5±18.5) than in sample patients with CLL (N=167, 38.5±18.5), and substantially higher than 
those in normal lymphocytes (<1). It was also notable that immunoassay evaluation of plasma 
samples from patients with MCL all showed high Wnt5a concentrations, further supporting the 
potential importance of the Wnt5a-ROR1 pathway in the pathogenesis of MCL. 
As had be done with CLL cells, primary lymphoma cells from patients with MCL were 
examined for Wnt5a-induced, ROR1-dependent activation of the Rho-GTPase, Rac1 [Yu 2018]. 
As noted in CLL cells, Wnt5a induced activation of primary MCL cells in a ROR1-dependent 
fashion. Cirmtuzumab, but not ibrutinib, could inhibit the capacity of Wnt5a to induce Rac1 
activation. To evaluate cirmtuzumab effects on lymphoma proliferation, MCL cells were co-
cultured with HeLa cells expressing CD154, and recombinant IL-4 and IL-10 [Yu 2018]. The 
addition of exogenous Wnt5a to these co-cultures significantly enhanced the proportion of 
dividing MCL cells. Cell-cycle analysis showed that Wnt5a stimulation significantly increased 
the fraction of MCL cells in S/G2/M. The capacity of Wnt5a to enhance the proportion of 
primary MCL cells in S/G2/M could be inhibited by treatment with cirmtuzumab, but not with 
ibrutinib, as noted previously for CLL cells. 
These data demonstrate the functional importance of ROR1 signaling in both CLL and MCL and 
the ability of cirmtuzumab to inhibit ROR1-mediated oncogenic activity in these disorders with a 
mechanism that complements BTK inhibition by ibrutinib.  
2.5. 
Conclusions/Study Rationale 
The conduct of this Phase 1b-2 study of the combination of cirmtuzumab and ibrutinib for 
patients with CLL/SLL, MCL and R/R MZL is founded on a current understanding of the natural 
history and current therapies for patients with lymphoid malignancies; knowledge of the 
importance of ROR1 and BTK cellular pathways in the pathophysiology of these diseases; and 
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nonclinical and clinical information regarding the efficacy and safety of the 2 study drugs. 
The collective data support the following conclusions:  
• Relapsed or refractory CLL/SLL, MCL and MZL represent serious, disabling, and 
life-threatening disorders. Existing BTK inhibitor therapy demonstrates activity but only 
infrequently induces complete tumor regression and loses effectiveness over time. 
The development of cirmtuzumab with ibrutinib offers a potential method for enhancing 
antitumor immunotherapeutic activity, overcoming disease resistance, and improving both 
short- and long-term outcomes for patients with CLL/SLL, MCL and MZL. 
• Clinical evaluation of cirmtuzumab in combination with ibrutinib in patients with B-cell 
lymphoid cancers has sound scientific rationale founded on the known efficacy of BTK 
inhibition in lymphoid cancers, the frequent expression and oncogenic potential of ROR1 in 
these malignancies, and the results of nonclinical pharmacology studies that demonstrate the 
therapeutic potential of the combination of cirmtuzumab and ibrutinib in lymphoid cancers.  
• Advancing the development of cirmtuzumab together with ibrutinib in this study is well 
supported by nonclinical evaluations of cirmtuzumab pharmacology, pharmacokinetics, and 
toxicology; by Phase 1a safety, pharmacokinetic, and pharmacodynamic data obtained in 
patients with CLL/SLL receiving cirmtuzumab; and by extensive prior clinical experience 
with ibrutinib therapy. This collective information provides a basis for patient enrollment 
criteria; starting dose selection and dose escalation; administration of an appropriate dosing 
regimen; and for safety, pharmacodynamic, pharmacokinetic, and efficacy monitoring within 
this study. 
• Given the seriousness of previously treated, progressive CLL/SLL, MCL and MZL and the 
aggregate potential benefits considered in the context of potential risks, clinical development 
of cirmtuzumab with ibrutinib in patients with hematological cancers is justified. 
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3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Primary Objectives 
• Part 1 (cirmtuzumab → cirmtuzumab + ibrutinib): To determine the RDR of 
cirmtuzumab when given alone and in combination with ibrutinib in patients with 
CLL/SLL or MCL 
• Part 2 (cirmtuzumab + ibrutinib): To further characterize the safety, pharmacology, and 
clinical responses of cirmtuzumab + ibrutinib when administered using the RDR in 
patients with CLL/SLL MCL or R/R MZL 
• Part 3 (cirmtuzumab + ibrutinib versus ibrutinib): To further evaluate the CR rate 
associated with cirmtuzumab + ibrutinib when administered using the RDR in patients 
with CLL/SLL  
3.2. 
Secondary Objectives 
• To determine the drug administration, safety, and supportive care profiles of 
cirmtuzumab and the combination of cirmtuzumab + ibrutinib 
• To evaluate the pharmacokinetic profile of cirmtuzumab alone and in combination with 
ibrutinib 
• To assess the effects of cirmtuzumab and cirmtuzumab + ibrutinib on exploratory 
biomarkers/pharmacodynamic markers relating to drug mechanism, immune profile, and 
disease manifestations 
• To characterize the immunogenicity of cirmtuzumab 
• To characterize the antitumor activity of cirmtuzumab monotherapy and cirmtuzumab + 
ibrutinib combination therapy 
3.3. 
Primary Study Endpoints 
• Part 1 (cirmtuzumab → cirmtuzumab + ibrutinib): RDR within the tested dose range 
• Part 2 (cirmtuzumab + ibrutinib): RDR with the cirmtuzumab + ibrutinib combination 
• Part 3 (cirmtuzumab + ibrutinib versus ibrutinib): CR rate, defined as the proportion of 
patients achieving a CR per pre-established CLL/SLL response criteria 
3.4. 
Secondary Study Endpoints 
3.4.1. 
Antitumor Activity and Survival 
Efficacy will be evaluated using consolidated response criteria for CLL/SLL [Hallek 2018; 
Cheson 2012; Hallek 2008] and for lymphoma [Cheson 2014; Cheson 2007]. Efficacy will be 
evaluated as described in Section 8.5, Appendix 12.5, and Appendix 12.6. Efficacy endpoints 
will include: 
• Overall response (OR), defined as achievement of complete response (CR), complete 
response with incomplete blood count recovery (CRi), partial response (PR), or partial 
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response with lymphocytosis (PR-L) for those with CLL/SLL; and the achievement of a 
CR or PR for those with MCL or MZL 
• Complete response (CR), defined as achievement of CR or CRi for those with CLL/SLL; 
and the achievement of a CR for those with MCL or MZL  
• Percent change in tumor dimensions, defined as the best (most negative) percent change 
from baseline in the sum of the products of the diameters (SPD) of index lesions 
• Time to response (TTR), defined as the interval from the start of study therapy to the first 
documentation of an objective response 
• Duration of response (DOR), defined as the interval from the first documentation of 
objective response to the earlier of the first documentation of disease progression or death 
from any cause 
• Progression-free survival (PFS), defined as the interval from the start of study therapy to 
the earlier of the first documentation of disease progression or death from any cause 
• Time to progression (TTP), defined as the time from the start of study therapy until 
objective tumor progression; TTP does not include deaths  
• Time to treatment failure (TTF), defined as the interval from start of study therapy to the 
earliest of the first documentation of disease progression, the permanent cessation of 
study drug due to an AE, or death from any cause 
• Time to next treatment (TNT), defined as the interval from start of study therapy to the 
start of a new regimen for CLL/SLL ,MCL or MZL due to study treatment failure 
• Overall survival (OS), defined as the interval from the start of study therapy to death 
from any cause 
3.4.2. 
Safety Profile 
• Type, frequency, severity, timing of onset, duration, and relationship to study drugs of 
any treatment-emergent adverse events (TEAEs); laboratory abnormalities; vital sign 
abnormalities; adverse electrocardiogram (ECG) findings; SAEs; or AEs leading to 
interruption, modification, or discontinuation of study treatment 
3.4.3. 
Pharmacokinetics 
• Cirmtuzumab serum concentrations (as measured using a validated immunoassay) 
• Derived pharmacokinetic parameters (including area under the serum concentration-time 
curve [AUC], maximum concentration [Cmax], time of maximum concentration [Tmax], 
volume of distribution [Vd], terminal elimination half-life [t1/2], terminal elimination rate 
constant [λz], and clearance [Cl]) (as determined using noncompartmental methods) 
3.4.4. 
Pharmacodynamics/Exploratory Biomarkers 
• Evaluate pre- and post-regimen blood and bone marrow as well as any available 
CLL/SLL, MCL or MZL tumor biopsy samples for exploratory biomarkers that might be 
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predictive of tumor response and downstream effects of cirmtuzumab. Tests may include 
an examination of tumor receptor expression, gene activation, and blood cytokine levels. 
• Changes in ROR1 cell surface expression and receptor occupancy  
• Changes in ALC in peripheral blood (as assessed by standard cell counting methods) 
• Changes in cancer stem cell parameters 
• Changes in plasma concentrations of cytokines 
3.4.5. 
Immunogenicity 
Changes in titers and neutralizing capacity of circulating cirmtuzumab-reactive antibodies (as 
assessed using immunoassay methods) 
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4. 
STUDY DESIGN 
This clinical trial is a Phase 1b-2 study of the safety, pharmacokinetics, pharmacodynamics, 
immunogenicity, and antitumor activity of the combination of cirmtuzumab and ibrutinib. The 
study will be conducted in 3 parts (see schema, Section 1.2). 
4.1. 
Part 1 – Dose-Finding (Cirmtuzumab → Cirmtuzumab + Ibrutinib) 
Part 1 comprises a Phase 1b, open-label, sequential allocation, dose-finding evaluation of the 
sequential administration of cirmtuzumab monotherapy followed by cirmtuzumab + ibrutinib 
combination therapy in patients with CLL/SLL or MCL. Patients will be administered study 
therapy as follows:  
• Cirmtuzumab given by IV infusion every 2 weeks for 5 administrations (Weeks 0, 2, 4, 6, 
8) and then every 4 weeks thereafter (Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) 
at a dose of either 2, 4, 8, or 16 mg/kg. After establishment of safety at these dose levels, 
fixed doses of 300 and 600 mg IV per dose will be examined in patients with CLL/SLL. 
• Ibrutinib self-administered orally, QD, continuously starting in Week 4 at a dose of either 
420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with 
MCL).  
Allocation to cirmtuzumab dose within each disease type (CLL/SLL or MCL) will be performed 
such that each successive patient with that disease is assigned to 2, 4, 8, and then 16 mg/kg in a 
sequence that is repeated 3 times, resulting in enrollment of 3 patients with CLL/SLL and 
3 patients with MCL across each of the 4 dose levels. The fixed dose level cohorts will then be 
examined separately using a standard 3+3 design. 
Patients exhibiting a PR or CR may continue combination treatment beyond Week 52 until 
disease progression or unacceptable toxicity as part of an extended therapy program.  Patients 
who remain in a PR or CR at the end of the 2 year treatment period, may be eligible for Long-
term Therapy and continue to receive cirmtuzumab and ibrutinib until they experience disease 
progression, unacceptable toxicity, or the study ends. Sites should discuss these cases with the 
sponsor in advance for approval. 
For CLL/SLL patients, long-term follow-up consisting of patient contact every 6 months and 
collection of disease, treatment, and vital status data, will continue following the End of 
Treatment visit for up to 5 years. For MCL patients, long-term follow-up will occur every 3 
months and include collection of disease, treatment, and vital status data for up to 5 years. 
Imaging reports may be requested by the sponsor for CLL/SLL or MCL patients in long-term 
follow-up. These data will be used to determine progression free survival (PFS), time to 
progression (TTP), and time to next treatment. Once a patient in long-term follow-up has 
progressed and received an alternate treatment for their disease, only vital status will be 
collected. 
At the conclusion of Part 1 of the study, a recommended dosing regimen (RDR) of cirmtuzumab 
will be selected based primarily on safety, pharmacokinetic, and pharmacodynamic findings. 
This portion of the study has been completed and a 600 mg fixed dose of cirmtuzumab was 
determined to be the RDR for both CLL/SLL and MCL. [Choi 2019a, Choi 2019b].  
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4.2. 
Part 2 – Cohort Expansion (Cirmtuzumab + Ibrutinib) 
Part 2 comprises a Phase 2 expansion, open-label evaluation of the concurrent administration of 
cirmtuzumab and ibrutinib based on the RDR derived from Part 1. Up to 18 evaluable patients 
with CLL/SLL will be enrolled. Up to 20 evaluable patients with MCL and up to 10 patients with 
MZL will be enrolled into Part 2; a clinical review will then be performed to determine if 
additional evaluable patients are required to complete any safety, efficacy, or biomarker 
analyses. This review could lead to a further adjustment or increase in enrollment.  
Patients will be administered study therapy as follows:  
• Cirmtuzumab given by IV infusion every 2 weeks for 3 administrations (Weeks 0, 2, 4) 
and then every 4 weeks thereafter (Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 
52) using the RDR of cirmtuzumab (600 mg fixed dose IV). 
• Ibrutinib self-administered orally QD, continuously starting concurrently with 
cirmtuzumab in Week 0 at a dose of either 420 mg/day (for patients with CLL/SLL) or at 
a dose of 560 mg/day (for patients with MCL or MZL). 
Patients exhibiting a PR or CR may continue combination treatment beyond Week 52 until 
disease progression or unacceptable toxicity as part of an extended therapy program.  Patients 
who remain in a PR or CR at the end of the 2 year treatment period, may be eligible for Long-
term Therapy and continue to receive cirmtuzumab and ibrutinib until they experience disease 
progression, unacceptable toxicity, or the study ends. Sites should discuss these cases with the 
sponsor in advance for approval. 
For CLL/SLL patients, long-term follow-up consisting of patient contact every 6 months and 
collection of disease, treatment, and vital status data, will continue following the End of 
Treatment visit for up to 5 years. For MCL and MZL patients, long-term follow-up will occur 
every 3 months and include collection of disease, treatment, and vital status data for up to 5 
years. Imaging reports may be requested by the sponsor for CLL/SLL, MCL or MZL patients in 
long-term follow-up. These data will be used to determine progression free survival (PFS), time 
to progression (TTP), and time to next treatment. Once a patient in long-term follow-up has 
progressed and received an alternate treatment for their disease, only vital status will be 
collected. 
4.3. 
Part 3 – Efficacy Evaluation (Cirmtuzumab + Ibrutinib versus 
Ibrutinib) 
Part 3 comprises a Phase 2 open-label, randomized, controlled, 2-arm, parallel-group evaluation 
of the clinical activity and safety of cirmtuzumab + ibrutinib versus ibrutinib alone. Patients with 
CLL/SLL will be randomized 2:1 to one of the following 2 regimens in blocks of 6 patients 
using a pre-generated randomization list: 
o Arm A: cirmtuzumab + ibrutinib 
o Arm B: ibrutinib alone 
Approximately 30 patients will be enrolled and randomized into Part 3. 
Patients exhibiting a PR or CR may continue treatment beyond Week 52 until disease 
progression or unacceptable toxicity as part of an extended therapy program. Patients who 
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remain in a PR or CR at the end of the 2 year treatment period, may be eligible for Long-term 
Therapy and continue to receive cirmtuzumab and ibrutinib until they experience disease 
progression, unacceptable toxicity, or the study ends. Sites should discuss these cases with the 
sponsor in advance for approval. 
For CLL/SLL patients, long-term follow-up consisting of patient contact every 6 months and 
collection of disease, treatment, and vital status data, will continue following the End of 
Treatment visit for up to 5 years. Imaging reports may be requested by the sponsor for CLL/SLL 
patients in long-term follow-up. These data will be used to determine progression free survival 
(PFS), time to progression (TTP), and time to next treatment. Once a patient in long-term follow-
up has progressed and received an alternate treatment for their disease, only vital status will be 
collected. 
4.4. 
Rationale for Study Design 
The study has been designed to provide critical dosing, safety, pharmacokinetic, 
pharmacodynamic, and early efficacy data in support of future clinical development of 
cirmtuzumab and cirmtuzumab + ibrutinib.  
In Part 1 of the study, the intrapatient comparison of sequential administration of cirmtuzumab 
monotherapy followed by cirmtuzumab + ibrutinib combination therapy generates a rigorous 
evaluation of the pharmacology of cirmtuzumab at fixed repeated doses with and without 
ibrutinib. Such an evaluation is important for cirmtuzumab given knowledge that ibrutinib can 
increase pharmacokinetic exposure to therapeutic monoclonal antibodies (eg, rituximab) that 
have tumor cells as a major mediator of drug clearance [Cramer 2016]. The intent is to obtain 
critical information regarding pharmacokinetic and pharmacodynamic dose-response and dose-
exposure relationships and any potential drug-drug interaction to support selection of a RDR for 
use in Parts 2 and 3 of this study and in other trials of both single-agent and combination 
cirmtuzumab-based therapy. Introduction of ibrutinib within 4 weeks of starting the study 
ensures that study patients transition rapidly to established therapy for their CLL/SLL, MCL or 
MZL.  
The planned rotating, sequential dose-assignment process in Part 1 of the trial provides an 
efficient and impartial method of assigning dose levels while offering safety and simplicity 
advantages over conventional ascending-dose or randomized designs. A standard ascending-dose 
design is not warranted given the substantial safety and lack of DLTs for either cirmtuzumab and 
ibrutinib within the tested dose range, the lack of overlapping toxicities between the agents, and 
historical knowledge that ibrutinib can be combined with multiple types of intensive 
chemoimmunotherapy without the need for modification of either the ibrutinib or 
chemoimmunotherapy doses [Burger 2014; Younes 2014; Brown 2015; Maddocks 2015a; 
Chanan-Khan 2016; Wang 2016]. Randomized dose allocation is not necessary because it would 
introduce complexity that would be disproportionate to the modest size and exploratory goals of 
Part 1 of the trial. 
Part 2 of the study provides a confirmatory characterization of the safety and pharmacology of 
the cirmtuzumab + ibrutinib combination when administered using the provisional RDR defined 
from Part 1 of the trial. Interpatient comparisons between cohorts receiving cirmtuzumab alone 
during the first 2 infusions in Part 1 and cohorts receiving ibrutinib together with cirmtuzumab 
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during the first 2 infusions in Part 2 will strengthen an understanding of the pharmacological 
consequences of adding ibrutinib to cirmtuzumab. 
Part 3 of the trial offers a Phase 2 assessment of cirmtuzumab + ibrutinib activity that will be 
important as a basis for Phase 3 planning. The randomized, add-on design in Part 3 is customary 
in the comparative evaluation of new therapies for cancer; such a design documents the 
incremental benefit and safety of the investigational therapy (cirmtuzumab) in the context of a 
controlled clinical trial while ensuring that all participants receive potentially active treatment 
(ibrutinib). Randomization is an accepted means to reduce bias and allows for the highest 
standard of evidence in documenting a treatment effect. Use of a 2:1 allocation enlarges the 
clinical experience with the investigational cirmtuzumab + ibrutinib combination. 
  
Involvement of a coordinating SRC is considered appropriate to ensure safety and general study 
conduct oversight of this exploratory, open-label Phase 1b-2 trial; each study center may follow 
local standard operating procedures relating to institutional review of safety data at that study 
center.  
4.5. 
Rationale for Study Drug Doses 
The cirmtuzumab starting dose levels to be evaluated in this study were selected based on data 
from a Phase 1a study showing that cirmtuzumab was very well tolerated in the range of 0.015 to 
20 mg/kg and that dose levels of ≥2 mg/kg have the potential to induce pharmacodynamic 
inhibition of ROR1-mediated signaling [Choi 2017]. The specific doses (2, 4, 8, and 16 mg/kg) 
to be evaluated in the current clinical trial were selected with the intent of defining the shape of 
the dose-response and exposure-response profiles and to determine the minimal dose associated 
with maximal continuous ROR1 inhibition. The planned schedule of cirmtuzumab administration 
(2 infusions at 2-week intervals followed by subsequent infusions at 4-week intervals) builds on 
pharmacokinetics findings with the every-2-week schedule used in the Phase 1a study; the 
schedule in the current trial is intended to achieve early ROR1 inhibition with maintenance of 
target coverage during chronic therapy. The initial 90-minute cirmtuzumab infusion time 
considered the lack of infusion toxicities observed in the Phase 1a cirmtuzumab experience and 
safety information developed with the therapeutic monoclonal antibody, rituximab, showing the 
feasibility of this approach [Dakhil 2014, Genentech 2016]. Guidelines for the administration of 
cirmtuzumab are detailed in the Pharmacy manual. In general, the first infusion will be given 
over 90 minutes. If no adverse reactions are observed, the infusion time may be shortened with 
each subsequent administration as tolerated, following the guidelines in the Pharmacy Manual. 
The doses and schedule of ibrutinib (420 mg QD for patients with CLL/SLL and 560 mg QD for 
patients with MCL or MZL) and the dose modification provisions for ibrutinib are consistent 
with those recommended in product labeling [Pharmacyclics 2020]. 
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5. 
STUDY POPULATION: RECRUITMENT AND SELECTION OF 
STUDY PATIENTS 
5.1. 
Planned Number of Patients 
5.1.1. 
Part 1 (Cirmtuzumab → Cirmtuzumab + Ibrutinib) 
If 6 patients (3 patients with CLL/SLL and 3 patients with MCL) are enrolled at all 4 planned 
dose levels, 24 patients will be enrolled. If 2 additional dose levels are explored in 
6 patients/dose level (3 patients with CLL/SLL and 3 patients with MCL), as many as 
12 additional patients could be enrolled, bringing the potential sample size to 36 patients. To 
allow for the possibility that some patients may not be fully evaluable, up to 48 patients may be 
enrolled. 
5.1.2. 
Part 2 (Cirmtuzumab + Ibrutinib) 
The RDR derived from Part 1 will be evaluated in up to 18 patients with CLL/SLL. Up to 20 
evaluable patients with MCL and up to 10 evaluable patients with MZLwill be enrolled into Part 
2; a clinical review will then be performed to determine if additional evaluable patients are 
required. This review could lead to a further adjustment and an increase in enrollment.  
5.1.3. 
Part 3 (Cirmtuzumab + Ibrutinib versus Ibrutinib) 
Approximately 30 patients will be enrolled and randomized 2:1 into Part 3 (~20 patients will 
receive cirmtuzumab + ibrutinib and ~10 patients will receive ibrutinib alone). 
5.2. 
Enrollment of Study Patients  
Inclusion and exclusion criteria will be reviewed for each potential patient by qualified study 
center personnel. If the consented study candidate is considered eligible for study participation, 
the study center will transmit an enrollment request to Oncternal (or designee). 
Oncternal (or designee) will acknowledge receipt of the enrollment request and will assign the 
study part, the cirmtuzumab dose (Part 1), and the appropriate ibrutinib dose (for CLL/SLL, 
MCL or MZL). Once the study center has received this information, the patient can begin 
treatment.  
Study candidates who fail screening will be noted on a screening and enrollment log maintained 
by site staff. Their data will not be entered into the EDC system (eCRF). 
5.3. 
Patient Selection Criteria 
This clinical trial can fulfill its objectives only if appropriate participants are enrolled. The 
protocol-specified eligibility criteria are designed to select patients for whom study participation 
is considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a study candidate. Eligibility 
criteria may not be waived by the investigator and conformance to the eligibility criteria will be 
reviewed in the case of a GCP or a regulatory authority audit. Any questions regarding a study 
candidate’s eligibility should be discussed with the medical monitor before enrollment. 
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5.3.1. 
Inclusion Criteria 
Study candidates must meet all of the following inclusion criteria to be eligible for participation 
in this study: 
1. Men and women of age ≥18 years. 
2. ECOG performance status of 0, 1, or 2 (see Appendix 12.1). 
3. Histological diagnosis of CLL/SLL, MCL or MZL (including splenic,nodal and extranodal 
subtypes) as documented in medical records (pathology reports and slides or blocks should 
be available for review or additional testing).  
4. MCL has been previously treated and has relapsed after or progressed during prior therapy. 
CLL/SLL may have been previously treated or are treatment naïve but now require therapy. 
MZL has been previously treated and has relapsed after or progressed during at least one 
prior anti-CD20 -based therapy 
5. A medically appropriate candidate for ibrutinib treatment (based on the judgement of the 
clinical investigator). 
6. Patients who have received prior BTK inhibitor therapy are eligible, unless they 
demonstrated primary or acquired resistance to a BTK inhibitor or experienced a serious or 
severe adverse event attributed to BTK inhibitor therapy. 
7. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid 
malignancy (defined as the presence of ≥1 non-biopsied, non-irradiated lesion that measures 
>1.5 cm in the longest dimension [LD] and ≥1.0 cm in the longest perpendicular dimension 
[LPD] as assessed by computed tomography [CT] or magnetic resonance imaging [MRI]). 
8. Current medical need for therapy due to disease-related symptoms, lymphadenopathy, 
organomegaly, extranodal organ involvement, or progressive disease. 
9. Completion of all previous therapy (including any Bcl-2 or PI3K inhibitor therapy, surgery, 
radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of 
cancer ≥1 week (or ≥3 half-lives of the previous drug) before the start of study therapy.  
10. All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 before the start of 
study therapy (with the exceptions of alopecia, or neurotoxicity [Grade 1 or 2 permitted], or 
selected laboratory parameters [Grade 1 or Grade 2 permitted with exceptions as noted 
below]). 
11. Adequate bone marrow function: 
a. Absolute neutrophil count (ANC) ≥1.0 × 109/L. 
b. Platelet count ≥50 × 109/L. 
c. Hemoglobin ≥8.0 g/dL maintained for ≥1 week from any prior transfusion. 
Note: Grade ≥3 neutropenia, thrombocytopenia, or anemia is permitted if the abnormality is 
related to bone marrow involvement with hematological malignancy (as documented by bone 
marrow biopsy/aspirate obtained since the last prior therapy). 
12. Adequate hepatic profile: 
a. Serum alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN). 
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b. Serum aspartate aminotransferase (AST) ≤3 × ULN. 
c. Serum bilirubin ≤1.5 × ULN unless elevated due to Gilbert syndrome. 
13. Adequate renal function: 
a. Estimated creatinine clearance (eClCR) >30 mL/minute (with eClCR to be calculated by 
the Cockcroft-Gault formula [see Appendix 12.2]), or 
b. Measured creatinine clearance >30 mL/minute (as assessed with a 24-hour urine 
collection). 
14. Adequate coagulation profile: 
a. Prothrombin time (PT) ≤1.5 × ULN. 
b. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN. 
15. Negative viral serology: 
a. Negative human immunodeficiency virus (HIV) antibody. 
b. Negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core (HBc) 
antibody or undetectable hepatitis B (HBV) deoxyribonucleic acid (DNA) by quantitative 
polymerase chain reaction (PCR) testing. 
c. Negative hepatitis C virus (HCV) antibody or negative HCV RNA by quantitative PCR.  
16. For female patients of childbearing potential, a negative urine or serum pregnancy test prior 
to the start of study therapy. 
17. For female patients of childbearing potential, willingness to use a highly effective method of 
contraception from the start of the screening period until ≥3 months after the last dose of 
cirmtuzumab and ≥1 month after the last dose of ibrutinib, whichever is later. Note: A female 
patient is considered to be of childbearing potential unless she has had a hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian 
failure (with serum estradiol and follicle-stimulating hormone [FSH] levels within the 
institutional laboratory postmenopausal range and a negative serum or urine beta human 
chorionic gonadotropin [βHCG]); or is menopausal (age ≥50 years with amenorrhea for 
≥6 months).  
18. For male patients who can father a child and are having intercourse with females of 
childbearing potential who are not using adequate contraception, willingness to use an 
effective method of contraception from the start of study therapy until ≥3 months after the 
last dose of cirmtuzumab and ≥3 months after the last dose of ibrutinib, whichever is later 
and to refrain from sperm donation from the start of study therapy until ≥3 months after 
administration of the final dose of either of the study drugs. Note: A male patient is 
considered able to father a child unless he has had a bilateral vasectomy with documented 
aspermia or a bilateral orchiectomy. 
19. In the judgment of the investigator, participation in the protocol offers an acceptable benefit-
to-risk ratio when considering current disease status, medical condition, and the potential 
benefits and risks of alternative treatments for the patient’s cancer. 
20. Willingness and ability of the patient to comply with scheduled visits, drug administration 
plan, protocol-specified laboratory tests, other study procedures, and study restrictions. 
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21. Evidence of a personally signed informed consent indicating that the patient is aware of the 
neoplastic nature of the disease and has been informed of the procedures to be followed, the 
experimental nature of the therapy, alternatives, potential risks and discomforts, potential 
benefits, and other pertinent aspects of study participation. 
5.3.2. 
Exclusion Criteria 
Study candidates who meet any of the following criteria will not be eligible for participation in 
this study: 
1. Known histological transformation to an aggressive lymphoma (ie, Richter transformation). 
Note: Biopsy documentation of the absence or presence of transformation is not required. 
2. Known central nervous system malignancy. Note: Central nervous system imaging is only 
required in patients with suspected central nervous system malignancy. 
3. Presence of another cancer with disease manifestations or therapy that could adversely affect 
patient safety or longevity, create the potential for drug-drug interactions, or compromise the 
interpretation of study results. 
4. Significant cardiovascular disease (eg, myocardial infarction, arterial thromboembolism, 
cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina 
requiring therapy; symptomatic peripheral vascular disease; New York Heart Association 
Class 3 or 4 congestive heart failure; or uncontrolled Grade ≥3 hypertension (diastolic blood 
pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg) despite antihypertensive 
therapy.  
5. Significant screening ECG abnormalities, including unstable cardiac arrhythmia requiring 
medication, atrial fibrillation/flutter, left bundle branch block, 2nd-degree atrioventricular 
(AV) block type II, 3rd-degree AV block, or Grade ≥2 bradycardia.  
6. Gastrointestinal disease (eg, gastric or intestinal bypass surgery, pancreatic enzyme 
insufficiency, malabsorption syndrome, symptomatic inflammatory bowel disease, chronic 
diarrheal illness, bowel obstruction) that might interfere with drug absorption or with 
interpretation of gastrointestinal AEs. 
7. Contraindication for ibrutinib use because of a bleeding diathesis. 
8. Evidence of an ongoing systemic bacterial, fungal, or viral infection (including upper 
respiratory tract infections) at the time of start of study therapy. Note: Patients with localized 
fungal infections of skin or nails are not precluded from participation. 
9. In patients with prior hematopoietic progenitor cell transplantation, evidence of ongoing 
graft-versus-host disease (GVHD). 
10. Pregnancy or breastfeeding.  
11. Major surgery within 4 weeks before the start of study therapy. 
12. Prior solid organ transplantation. 
13. Prior anti-ROR1 therapy within 12 weeks prior to the start of study therapy. 
14. Use of a moderate or strong inhibitor or inducer of cytochrome P450 (CYP) 3A4 within 
7 days prior to the expected start of ibrutinib therapy (see Appendix 12.3). 
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15. Concurrent participation in another therapeutic or imaging clinical trial. 
16. Any illness, medical condition, organ system dysfunction, or social situation, including 
mental illness or substance abuse, deemed by the investigator to be likely to interfere with a 
patient’s ability to provide informed consent, adversely affect the patient’s ability to 
cooperate and participate in the study, or compromise the interpretation of study results. 
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6. 
STUDY INTERVENTION 
6.1. 
Cirmtuzumab 
6.1.1. 
Known Potential Risks: Cirmtuzumab (zilovertamab) 
 The safety profile (N = 31) of cirmtuzumab in combination with ibrutinib in subjects with MCL 
was recently presented (Lee, 2021). The overall safety profile of cirmtuzumab plus ibrutinib was 
similar to the known safety profile of ibrutinib alone, with no dose reductions and no SAEs 
attributed to cirtuzumab. Most TEAEs were Grades 1 and 2. Few subjects had a Grade 3 or 
above AE.  
6.1.2. 
Known Potential Benefits: Cirmtuzumab (zilovertamab)  
The efficacy data from 26 evaluable subjects with MCL enrolled in Study CIRM-0001 is 
summarized in Section 3.1 of the Cirmtuzumab Investigator Brochure, and was presented at 
ASH 2021 (Lee, 2021). The ORR of 80.8%, CR rate of 34.6%, and median PFS of 35.9 months 
(95% CI: 16.5 to 35.9 months) for evaluable subjects with MCL in Study CIRM-0001 compare 
favorably to the reported ORR of 66%, CR rate of 20%, and PFS of 12.8 months (95% CI: 8.5 to 
16.6 months) for 370 subjects with MCL in a merged analysis of 3 studies of single agent 
ibrutinib (Rule, 2017). 
The interim safety results from Study CIRM-0001 suggest that myelosuppression associated with 
ibrutinib monotherapy, especially neutropenia, may occur less frequently when ibrutinib is 
administered in combination with cirmtuzumab therapy. TEAEs related to myelosuppression 
appeared to be slightly lower than expected for ibrutinib treatment, so quantitative analysis of 
complete blood count data for MCL was undertaken. Grade 3 or greater neutrophil decrease and 
platelets decreased of 9.7%, respectively, for cirmtuzumab plus ibrutinib appear to be 
qualitatively lower than the 29% Grade 3 or greater neutrophils decreased and 17% platelets 
decreased reported for the ibrutinib MCL registration study (Ibrutinib Investigator Brochure 
2021). This could be related to the observation that residual tumor cells during ibrutinib 
treatment express ROR1, which is activated by its ligand Wnt5a, leading to cross-activation of 
inflammatory pathways including JAK/stat and secretion of inflammatory chemokines and 
cytokines including IL6 and IFN gamma. Cirmtuzumab has been shown to inhibit this 
inflammatory activity (Chen, 2019). These Grade 3 and above hematologic toxicities associated 
with monotherapy BTK inhibitor therapy may have contributed to dose reductions, delays, or 
treatment discontinuation that may be associated with monotherapy BTK inhibitor therapy 
administration, potentially reducing optimal dosing and efficacy. 
6.1.3. 
Description 
Cirmtuzumab is manufactured under current Good Manufacturing Practices (cGMP) and is 
supplied in vials nominally containing 300 mg of drug substance (40 mg/mL) in 7.5 mL of 
formulation buffer containing the excipients sodium citrate, trehalose, polysorbate 80, and 
sodium-ethylenediaminetetraacetic acid (Na-EDTA). The drug product appears as a clear to 
slightly opalescent, colorless to slightly yellow liquid and essentially free of visible particulates. 
The solution has a target pH of 5.2. The drug product is for IV administration. A pharmacy 
manual outlining the preparation of the cirmtuzumab infusion bag will be provided to the site 
personnel. 
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6.1.4. 
Source 
Cirmtuzumab will be provided by Oncternal. 
6.1.5. 
Packaging and Labelling 
Cirmtuzumab drug product is filled into sterile 10-ml Type I, clear, borosilicate glass vials with 
butyl siliconized rubber stoppers and aluminum seals. 
Labels for cirmtuzumab vials meet all applicable requirements of the FDA, Annex 13 of cGMP 
(Manufacture of Investigational Medicinal Products, July 2003), and/or other local regulations, 
as applicable. 
6.1.6. 
Shipping, Storage, and Stability 
During shipping and storage, vials should remain refrigerated at temperatures of 2 to 8°C [35.6 
to 46.4°F]). 
After dilution and prior to use, cirmtuzumab should be maintained at 2 to 8°C [35.6 to 46.4°F]) 
and is stable for at least 24 hours after dilution. However, cirmtuzumab contains no antimicrobial 
preservative and so should be administered as soon as possible after preparation. 
6.1.7. 
Cirmtuzumab Administration 
Cirmtuzumab will be given by IV infusion at dose levels and intervals as specified in Sections 
4.1-4.3. Intrapatient dose escalation to dose levels above the dose level assigned to a patient will 
not be permitted. 
A qualified person (eg, nurse or physician with experience in monitoring the administration of 
therapeutic agents used in patients with cancer) will be responsible for infusing cirmtuzumab. 
The initial cirmtuzumab infusion will be administered over a planned infusion time of 
~90 minutes, with 20% of the total dose to be administered in the first ~30 minutes and the 
remaining 80% of the total protein dose to be administered in the subsequent ~60 minutes. For 
patients who prove able to tolerate infusions without infusion-related toxicity, the infusion time 
may be shortened with each subsequent administration as tolerated following the guidelines in 
the Pharmacy Manual. Infusion times may be extended as necessary to accommodate individual 
patient tolerance of treatment. 
6.1.7.1. 
Transient Lymphocytosis 
An asymptomatic lymphocytosis has been observed in patients with CLL/SLL treated with 
cirmtuzumab [see Cirmtuzumab Investigator Brochure; Choi 2017]. This effect may represent a 
positive pharmacodynamic effect of cirmtuzumab to redistribute malignant cells from sanctuary 
sites in lymph nodes and spleen and should not be considered a drug-related AE or sign of 
disease progression unless other evidence of disease progression is also present. 
6.1.7.2. 
Cirmtuzumab Infusion Reactions 
Cirmtuzumab administration has been well-tolerated and only rare Grade 1 or 2 infusion 
reactions have been reported in 3 patients (considered at least possibly related in 2 patients, 
unrelated in 1 patient) [see Cirmtuzumab Investigator Brochure]. However, other monoclonal 
antibodies used in the treatment of CLL/SLL, MCL or MZL (eg, rituximab, ofatumumab, 
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obinutuzumab) can cause severe infusion reactions with manifestations that may include 
dyspnea, bronchospasm, laryngeal edema, pulmonary edema, acute respiratory distress 
syndrome, tachycardia, hypertension, hypotension, syncope, dizziness, cardiac 
ischemia/infarction, pyrexia, headache, chills, back pain, rigors, nausea, vomiting, abdominal 
pain, diarrhea, flushing, rash, urticaria, and angioedema. While infusion reactions are not 
expected with cirmtuzumab, the following guidelines for managing infusion reactions are 
provided as a precaution: 
• If a Grade 1-2 infusion reaction occurs, the infusion may be temporarily slowed or 
interrupted and then can be restarted at half of the previous rate when the patient’s 
condition has stabilized. After resuming the infusion, the infusion rate may be increased 
consistent with patient tolerance.  
• If an infusion reaction Grade ≥3 occurs, the infusion must be interrupted. Medical 
management (eg, oxygen, epinephrine, bronchodilators, corticosteroids) may be instituted 
as needed. After the severity of the reaction has decreased to Grade ≤2 the investigator 
may restart the infusion at a rate no higher than the initial rate for this cirmtuzumab dose. 
After resuming the infusion, the infusion rate may be increased consistent with patient 
tolerance. 
6.1.7.3. 
Overdose Precautions 
An overdose is defined as a dose taken (accidentally or intentionally) exceeding the overdose 
limit. In the case of a discrepancy in drug accountability, an overdose will be established only 
when it is clear that the patient has received an excess dose, or the investigator has reason to 
suspect that the patient has received an excess dose.  
There is no experience with overdose of cirmtuzumab. For this protocol, an overdose of 
cirmtuzumab is defined as administration of a dose that is ≥2-fold higher than that prescribed for 
the patient or exceeds 20 mg/kg (whichever is smaller).  
In a patient who experiences an overdose that is discovered during drug infusion, the 
cirmtuzumab infusion may be interrupted or modified, as appropriate. Depending upon the 
degree of an overdose, it may be necessary to delay administration of subsequent cirmtuzumab 
infusions. Observation for any symptomatic side effects may be instituted, and safety laboratory 
parameters may be followed closely (consistent with the protocol or more frequently, as needed). 
Appropriate supportive management to mitigate adverse effects may be initiated, as needed.  
The medical monitor should be contacted if a study drug overdose occurs. The occurrence of an 
overdose does not preclude further protocol therapy if the patient appears to be safely benefiting 
from treatment and the circumstances that led to the initial overdose are unlikely to recur. 
6.1.7.4. 
Inadvertent Exposure Precautions 
As noted in the cirmtuzumab investigator brochure, cirmtuzumab is not expected to be acutely 
toxic, irritating, or genotoxic at levels that are likely to result from inadvertent exposure. 
Personnel handling the drug should use reasonable precautions to avoid eye contact, skin contact, 
inhalation, ingestion, or injection of cirmtuzumab.  
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6.2. 
Ibrutinib 
6.2.1. 
Known potential risks: Ibrutinib 
In the Ibrutinib Investigator Brochure 2021, guidance regarding the following AEs associated 
with ibrutinib administration in patients with B-cell malignancies are conveyed: 
• Hemorrhage: Fatal bleeding events have occurred in patients who received ibrutinib. 
Use of either anticoagulant or antiplatelet agents concomitantly with ibrutinib 
increases the risk of major hemorrhage. 
• Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have 
occurred with ibrutinib therapy. Consider prophylaxis according to standard of care in 
patients who are at increased risk for opportunistic infections. 
• Cytopenias: In 645 patients with B-cell malignancies who received ibrutinib as a 
single agent, Grade 3 or 4 neutropenia occurred in 23% of patients, Grade 3 or 4 
thrombocytopenia in 8% and Grade 3 or 4 anemia in 3%, based on laboratory 
measurements. Monitor complete blood counts monthly. 
• Cardiac Arrhythmias and Cardiac Failure: Fatal and serious cardiac arrhythmias and 
cardiac failure have occurred with ibrutinib. At baseline and then periodically, 
monitor patients clinically for cardiac arrhythmias and cardiac failure. Obtain an 
electrocardiogram (ECG) for subjects who develop arrhythmic symptoms (e.g., 
palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. 
• Hypertension: Hypertension occurred in 19% of 1,476 patients who received ibrutinib 
in clinical trials. Monitor blood pressure in subjects treated with ibrutinib and initiate 
or adjust antihypertensive medication throughout treatment with ibrutinib as 
appropriate. 
• Second Primary Malignancies: Other malignancies (10%), including non-skin 
carcinomas (4%), occurred among the 1,476 patients who received ibrutinib in 
clinical trials. 
• Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) has been infrequently reported 
with ibrutinib. Assess the baseline risk (e.g., high tumor burden) and take appropriate 
precautions. Monitor patients closely and treat as appropriate. 
• Embryo-Fetal Toxicity: Based on findings in animals, ibrutinib can cause fetal harm 
when administered to a pregnant woman. Advise females of reproductive potential to 
use effective contraception during treatment with ibrutinib and for 4 weeks after the 
last dose. 
Ibrutinib is primarily metabolized by CYP3A4, so some patients treated with moderate or strong 
CYP3A4 inhibitors or inducers are not eligible for ibrutinib therapy unless these drugs are 
discontinued > 7 days before the first dose of ibrutinib (See Section 6.4.6 for more details and 
Appendix 12.3 for list of potent inhibitors and inducers of CYP3A4). 
Lymphocytosis has been observed after the administration of ibrutinib, and patients with MCL 
who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, 
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lethargy, gait instability, and headache. However, some of these cases were in the setting of 
disease progression (Ibrutinib Investigator Brochure 2021). 
Serious (Grade ≥ 3) hematologic effects (neutropenia, anemia, thrombocytopenia), pneumonia, 
and lymphocytosis are associated with the use of all approved BTK inhibitor therapies for the 
treatment of subjects with MCL, including ibrutinib. 
6.2.2. 
Description 
Ibrutinib is manufactured and formulated under cGMP. The drug product for investigational use 
is supplied as gray opaque Size 0, gelatin capsules that contain 140 mg ibrutinib as the active 
ingredient. Inactive compendial ingredients include: croscarmellose sodium, magnesium stearate, 
microcrystalline cellulose, and sodium lauryl sulfate. The capsule shell contains gelatin, titanium 
dioxide and black iron oxide.  
Further information regarding Imbruvica® (ibrutinib) as supplied for commercial use can be 
obtained in product labelling [Pharmacyclics 2020 and Ibrutinib Investigator Brochure 2021]. In 
addition, a pharmacy manual will be provided to site personnel with additional information. 
6.2.3. 
Source 
It is intended that sufficient investigational ibrutinib for a planned duration of study treatment in 
each patient will be supplied by the drug manufacturer (Pharmacyclics, LLC) and distributed by 
Oncternal.  
6.2.4. 
Packaging and Labelling 
Ibrutinib capsules are supplied in high-density polyethylene (HDPE) bottles, each of which is 
closed with an induction seal and a child-resistant, plastic screw cap. Each bottle contains either 
92 or 120 capsules per bottle (as indicated on the label). 
6.2.5. 
Shipping, Storage, and Stability 
Bottles of ibrutinib should be stored at 15 to 25°C (59 to 77°F). Excursions are permitted to 30°C 
(86°F). It is recommended that the capsules be retained in the original package until ingestion. 
Stability information will be provided to study center personnel. 
6.2.6. 
Dispensing  
For the investigational product, a pharmacist or other qualified staff member will dispense 
bottles containing ibrutinib capsules. Sufficient bottles will be dispensed to the patient to provide 
an adequate drug supply (with a modest overage) until the patient’s next planned clinic visit.  
For ibrutinib doses that are taken in the study center, patients will take the dose from the drug 
dispensed to them for that specific dispensing interval. All other ibrutinib doses will be taken at 
home. 
6.2.7. 
Return and Compliance Assessment 
At the completion of each dispensing interval, empty, partially used, or full bottles of ibrutinib 
should be retrieved from the patient. The quantities of unused ibrutinib and the date when these 
study supplies are returned by the patient should be recorded in the study drug accountability 
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records. Appropriate site personnel should confirm the number of capsules taken through an 
interview with the patient. Returned bottles of investigational product may be redispensed to the 
same patient but not to another patient. Returned capsules bottles may be destroyed according to 
the site’s standard operating procedures (see Section 10.11).  
Interruptions in treatment, for any reason, that result in missed doses of >7 days (sequential days 
or total days, for example 3 days and 4 days) during a 28 day period should be reported to the 
Sponsor as soon as possible.  
6.2.8. 
Ibrutinib Administration 
As described in Sections 4.1-4.3, ibrutinib will be started at a dose of 420 mg (for patients with 
CLL/SLL) or at a dose of 560 mg (for patients with MCL or MZL) on Day 28 (Study Part 1) or 
on Day 0 (Study Parts 2 and 3) with the first dose of ibrutinib administered ~30 minutes prior to 
the start of the cirmtuzumab infusion on that day. Thereafter, patient should self-administer 
ibrutinib at approximately the same time each day, ideally at ~24-hour intervals (eg, ~7 AM 
every day). While it is realized that variations in dosing schedule may occur in the outpatient 
setting, the prescribed regimen should be followed as closely as possible. 
At each dose administration, the required number of 140-mg capsules should be removed from 
the storage bottle and swallowed whole. Patients should be instructed not to bite or chew on the 
capsules. In case of breakage of the capsules in the oral cavity, additional water should be taken 
as a rinse. 
Ibrutinib may be given without regard to food, however ingestion of the drug following a meal 
may be desirable to enhance drug exposure [de Jong 2015; Marostica 2015]. 
Patients who have a delay in administration of a dose of ibrutinib of <12 hours should take the 
planned dose as soon as possible after the intended time of administration. For patients who have 
a delay in administration of ibrutinib of ≥12 hours, the dose should not be taken. The planned 
timing of subsequent ibrutinib dosing should not be altered.  
For patients who vomit shortly after taking ibrutinib, the vomited dose should not be replaced. 
The planned timing of subsequent ibrutinib dosing should not be altered. 
6.2.8.1. 
Overdose Precautions 
There are limited data on the effects of ibrutinib overdose. No MTD was reached in a Phase 1 
study in which patients received up to 12.5 mg/kg/day (1400 mg/day) [Advani 2013]. One 
healthy patient who received a dose of 1680 mg experienced reversible Grade 4 increases in 
serum ALT and AST [Pharmacyclics 2020, Ibrutinib Investigator Brochure 2021]. 
For this protocol, an overdose of ibrutinib is defined as administration of a daily dose ≥700 mg. 
In a patient who experiences an overdose, consideration should be given as to whether ibrutinib 
administration should be temporarily interrupted. If the overdose is recent and substantial, and if 
there are no medical contraindications, use of gastric lavage or induction of emesis may be 
considered. Observation for any symptomatic side effects may be instituted, and safety 
laboratory parameters may be followed closely (consistent with the protocol or more frequently, 
as needed). Appropriate supportive management should be instituted if needed to mitigate 
adverse effects. There is no specific antidote for ibrutinib. 
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The medical monitor should be contacted if a study drug overdose occurs. The occurrence of an 
overdose does not preclude further protocol therapy if the patient appears to be safely benefiting 
from treatment and the circumstances that led to the initial overdose are unlikely to recur. 
6.2.8.2. 
Inadvertent Exposure Precautions 
Based on available data, ibrutinib is not expected to be acutely toxic, irritating, or genotoxic at 
levels that are likely to result from inadvertent exposure. However, personnel handling the drug 
should use reasonable precautions to avoid eye contact, skin contact, inhalation, or ingestion of 
ibrutinib. Patients should be instructed to keep the drug secured such that it is out of the reach of 
children and is not inadvertently taken by others.  
6.3. 
Dose Modifications 
Recommendations for modifications of the dosing regimens for each of the study drugs are based 
on current knowledge regarding the safety profiles of these agents. Recommendations comprise 
only guidelines; variations from these recommendations may be warranted based on an 
investigator’s individual judgment in considering potential risks, benefits, and therapeutic 
alternatives available to each patient.  
6.3.1. 
Dose adjustments for Cirmtuzumab  
The Investigator is encouraged to discuss modifications in the dosing regimen with the Medical 
Monitor. For an AE that is attributed primarily to cirmtuzumab and requires a dose modification, 
the dose of cirmtuzumab should be reduced by 1 dose level to 300 mg per dose. Successive 
adjustments to progressively lower dose levels (ie, 150→100 mg fixed dose) can be made. If the 
patient cannot tolerate cirmtuzumab at a dose of 100 mg per dose, then the patient should be 
discontinued from cirmtuzumab therapy and from the study overall unless continued treatment is 
permitted by the medical monitor.  
After the cirmtuzumab or ibrutinib dose is reduced, the dose can be maintained at that dose level, 
even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates the 
drug at a reduced dose for ≥4 weeks, then the dose may be re-escalated to the next higher dose 
level at the discretion of the investigator (particularly if the AE comprised TLS or if further 
evaluation reveals that the AE that led to the dose reduction was primarily related to the 
underlying malignancy, an intercurrent illness, a comorbid condition, or a concomitant 
medication). Successive adjustments to progressively higher dose levels can be made at intervals 
of ≥4 weeks with the condition that the escalated dose level of either cirmtuzumab or ibrutinib 
cannot exceed the starting dose level for that patient.  
6.3.2. 
Treatment interruptions for Cirmtuzumab 
During the course of the study, treatment may be interrupted due to unforeseen causes including 
the COVID-19 pandemic. If the interruption was not due to a safety event and the PI and sponsor 
believe that the patient may safely continue therapy, the patient may be able to continue as long 
as the missed treatment interval is ≤ 60 days. If the patient's missed treatment interval is >60 
days and due to extenuating circumstances, the patient may only be allowed to continue after 
discussion with the sponsor and written approval.  
If a patient misses cirmtuzumab doses, treatment may resume following the guidelines below. 
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• Resuming therapy: If one dose of cirmtuzumab is missed AND the interval between last 
dose administered and planned next dose is <45 days: 
o Administer 1 dose as soon as possible 
o Continue with scheduled administrations after that 
• Reloading doses to reach optimal drug levels quickly: If one dose of cirmtuzumab is missed 
AND the interval between last dose administered and planned next dose is 45-60 days OR 
if two sequential doses of cirmtuzumab are missed: 
o Administer 1 dose as soon as possible 
o Administer a second dose 14 days later to ensure that cirmtuzumab serum 
concentrations are brought back to appropriate levels as fast as possible 
• If the missed treatment interval is >60 days, the reloading procedure will be determined 
by the sponsor based on the patient situation.  
Continue with scheduled doses after the patient has been reloaded. These guidelines may not cover 
all potential scenarios or circumstances. Please discuss with Oncternal all cases where such 
interruption in treatment is anticipated. Please refer to the Pharmacy manual for details. 
6.3.3. 
Dose modifications for Ibrutinib 
Recommendations for modifications of the dosing regimens for ibrutinib are based on current 
knowledge regarding its safety profile and in alignment with guidance in marketing authorization 
documents and the Ibrutinib Investigator Brochure 2021 for ibrutinib as a second-line or 
subsequent treatment of patients with CLL/SLL, MCL and MZL. 
6.3.3.1. 
Dosage modifications for Adverse Reactions 
Ibrutinib therapy should be interrupted for any Grade 3 or 4 non-hematological toxicities, 
Grade 3 or 4 neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the 
adverse reaction has improved to Grade 1 or baseline (recovery), ibrutinib may be reinitiated at 
the current dose. If the adverse reaction reoccurs (Table 1), the dose should be reduced by 
140 mg per day. Further dose reductions by 140 mg should be considered by the Investigator, as 
needed. If these adverse reactions persist or recur following two dose reductions, ibrutinib should 
be discontinued. 
 
 
 
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Table 1: Dose Adjustments for Ibrutinib  
Toxicity Occurrence 
Dose Modification for MCL and 
MZL After Recovery 
Starting Dose = 560 mg Dose 
Dose Modification for CLL 
After Recovery 
Starting Dose = 420 mg Dose 
First 
Restart at 560 mg daily 
Restart at 420 mg daily 
Second 
Restart at 420 mg daily 
Restart at 280 mg daily 
Third 
Restart at 280 mg daily 
Restart at 140 mg daily 
Fourth 
Discontinue ibrutinib 
Discontinue ibrutinib 
If the ibrutinib dose is reduced due to non-cardiac events, the dose can be maintained at that 
dose, even if there is minimal or no toxicity with the reduced dose. However, if the subject 
tolerates the drug at a reduced dose without toxicity for ≥ 8 weeks, then the dose may be re-
escalated to the next higher dose at the discretion of the Investigator (if the AE comprised TLS, 
as defined by Howard, 2011 or if further evaluation reveals that the AE that led to the dose 
reduction was primarily related to the underlying malignancy, an intercurrent illness, a comorbid 
condition, or a concomitant medication). Dose re-escalation to progressively higher doses can be 
made at intervals of ≥ 4 weeks if clinically indicated. For a change in ibrutinib dose, the 
appropriate study center personnel should dispense ibrutinib for the new dose and instruct the 
subject/caregiver about the change in dose. 
6.4. 
Concomitant Therapy 
If considered necessary for the patient’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The investigator’s 
decision to authorize the use of any drug other than study drug will take into account patient 
safety, the medical need, the potential for drug interactions, the possibility for masking 
symptoms of a more significant underlying event, and whether use of the drug will compromise 
the outcome or integrity of the study. 
Patients will be instructed about the importance of the need to inform the clinic staff of the use of 
any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during the 
study.  
6.4.1. 
Cirmtuzumab Infusion-Reaction Prophylaxis 
Based on the available experience, clinically significant infusion reactions are not expected in 
patients receiving cirmtuzumab. Thus, premedication for infusion-reaction prophylaxis should be 
avoided on Day 0 (and on Day 28 in Part 1 of the study) unless infusion reactions become a 
safety concern during the study.  
Patients who develop infusion-related toxicities may be premedicated before subsequent 
cirmtuzumab infusions with an antipyretic and an antihistamine to reduce the incidence and 
severity of infusion reactions, for example an oral or IV antipyretic (acetaminophen 650 to 
1,000 mg or equivalent) and an oral or IV antihistamine (cetirizine, 10 mg or equivalent) both 
given 30 to 60 minutes prior to each cirmtuzumab infusion. 
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6.4.2. 
Tumor Lysis Syndrome (TLS) Prophylaxis 
Based on the available experience in CLL/SLL, cirmtuzumab does not specifically pose a risk of 
TLS and ibrutinib monotherapy in patients with CLL/SLL, MCL or MZL is only rarely 
associated with TLS [Howard 2016]. However, patients who are at intermediate to high risk of 
TLS can be considered for medical prophylaxis of TLS depending upon physician judgement or 
if evidence of TLS is observed during the study. The general risk for TLS can be characterized 
according to the following criteria, considering established algorithms [Cairo 2010, 
MDACC 2016, Roberts 2016]: 
• Low-risk: Serum lactate dehydrogenase (LDH) ≤ULN, all measurable lymph nodes <5 
cm, and ALC <25 × 109/L. 
• Intermediate risk: Serum LDH >1 to ≤2 × ULN, ≥1 measurable lymph node with an LD 
of ≥5 but <10 cm, or ALC ≥25 × 109/L. 
• High risk: Serum LDH >2 × ULN, ≥1 measurable lymph node with a LD of ≥10 cm, or 
both ≥1 measurable lymph node with an LD of ≥5 but <10 cm and ALC ≥25 × 109/L. 
• An institutional TLS prophylaxis regimen may be used, or the following prophylaxis 
regimens may be considered: 
• Intermediate Risk of TLS: These patients may receive allopurinol, 100 to 300 mg orally 
daily starting ≥24 to 48 hours before the initial administration of ibrutinib; in addition, 
patients who develop hyperuricemia may receive rasburicase, 3 to 4.5 mg by IV infusion. 
• High Risk of TLS: These patients may receive allopurinol, 100 to 300 mg orally daily 
starting ≥24 to 48 hours before the initial administration of ibrutinib; in addition, high-
risk patients may receive rasburicase, 3 to 4.5 mg by IV infusion, administered 3 to 
4 hours prior to the first dose of ibrutinib. 
6.4.3. 
TLS Management 
Information regarding TLS prophylaxis is provided in Section 6.4.2. 
Patients who develop TLS may experience hyperkalemia, hypocalcemia, hyperuricemia, 
hyperphosphatemia, cardiac dysrhythmias, and acute renal failure; thus, close monitoring of 
electrolytes is important after initial therapy.  
Patients with TLS should receive IV hydration, rapid reversal of hyperkalemia, 
antihyperuricemic agents, and appropriate cardiac and renal support, including dialysis as 
indicated. Upon recovery to baseline functioning and as medically appropriate, such patients 
should continue with protocol therapy to maintain tumor control. 
6.4.4. 
Anticancer Therapies Other than the Study Drugs 
No systemic anticancer therapies (including chemotherapy, antibody therapy, hormonal therapy, 
immunotherapy, or other experimental therapies) for the patient’s cancer are permitted while the 
patient is receiving study treatment. Patients are not allowed to participate concurrently in any 
other therapeutic clinical or imaging study. 
The use of palliative radiotherapy should be minimized given the potential of such treatment to 
confuse assessments of cirmtuzumab + ibrutinib safety or therapeutic effect. However, in a 
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patient participating in Part 1 of the study, administration of limited-fraction radiotherapy is 
permitted after Week 8 to control local tumor-related symptoms if irradiation is unlikely to 
induce major organ toxicity or affect target lesions being followed for tumor response and 
progression. 
If required to maintain disease control, study drugs may be continued with caution during 
radiotherapy administration given that phototoxicity with cirmtuzumab is unlikely and has not 
been observed with ibrutinib in relevant in vitro studies. 
6.4.5. 
Anticoagulants 
Fatal bleeding events have occurred in patients treated with ibrutinib. Grade 3 or higher bleeding 
events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, 
and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any 
grade, including bruising and petechiae, occurred in approximately half of patients treated with 
ibrutinib [Pharmacyclics 2020, Ibrutinib Investigator Brochure 2021]. The mechanism for the 
bleeding events is not well understood, although ibrutinib may impair platelet function.  
Ibrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant 
therapies. Such agents should be administered with caution, and patients should be monitored for 
signs of bleeding. However, for patients who develop atrial fibrillation, it has been suggested that 
additional anticoagulation not be administered unless they are at substantial risk of 
thromboembolism based on the presence of comorbid conditions [Vrontikis 2016]. 
6.4.6. 
Drugs with Potential for Drug-Drug Interactions with Ibrutinib 
Ibrutinib is primarily metabolized by CYP3A4. In healthy subjects, coadministration of a strong 
CYP3A4 inhibitor, increased ibrutinib plasma exposure by >20-fold ibrutinib and 
coadministration of a strong CYP3A4 inducer decreased ibrutinib exposures by ≥10-fold 
[Pharmacyclics 2020, Ibrutinib Investigator Brochure 2021]. Based on these findings, protocol 
candidates who require therapy with the moderate or strong CYP3A4 inhibitors or inducers listed 
in Appendix 12.3 should not be enrolled into the study. If medically justified, protocol 
candidates may be enrolled if such inhibitors or inducers can be discontinued or alternative drugs 
that do not affect this enzyme can be substituted >7 days before the first dose of ibrutinib.  
During study participation, coadministration of ibrutinib with moderate or strong CYP3A4 
inhibitors or inducers listed in Appendix 12.3 should be avoided, if possible. However, a patient 
who develops a condition that may require use of such drugs is not required to discontinue 
ibrutinib if the patient is experiencing clinical benefit and other options for treating the patient’s 
cancer are limited. If medically appropriate, investigators may wish to use a therapeutic 
alternative that would not be expected to affect these enzymes. For patients who require 
temporary use of a drug that does affect these enzymes (eg, treatment with a systemic antifungal 
agent), ibrutinib therapy may be temporarily interrupted and then resumed after completion of 
the other drug. For patients who require initiation of chronic therapy with a moderate or strong 
inhibitor of CYP3A4, the dose of ibrutinib should be reduced to 140 mg QD and the patient 
should be monitored closely for signs of ibrutinib toxicity. 
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6.4.7. 
Drugs Known to Prolong the QT Interval 
To satisfy regulatory requirements, the clinical potential of cirmtuzumab to prolong the QT 
interval was assessed in CLL Parts 1 and 2 and MCL Part 1 of this study. Protocol candidates 
who were taking drugs at screening known to prolong the QT interval were not enrolled into 
those parts of the study. As of Amendment 6, MCL or MZL patients in Part 2, and for CLL/SLL 
patients in Part 3, the exclusion criteria restricting the enrollment of patients with QTc 
abnormalities or taking drugs known to prolong the QT interval is removed.  
6.4.8. 
Procedures/Surgery 
The extent to which cirmtuzumab may affect wound healing, enhance the risk of infection, or 
increase the risk of bleeding is unknown. Ibrutinib causes inhibition of platelet function (see 
Section 6.4.5). Considering parameters such as ANC, platelet count, and PT/aPTT, investigators 
may use clinical discretion in deciding whether to interrupt cirmtuzumab therapy before and after 
surgery or other invasive procedures. Depending upon the type of procedure or surgery and the 
risk of bleeding, investigators may wish to withhold ibrutinib for 3 to 7 days before and after 
surgery. 
6.5. 
Study Restrictions 
6.5.1. 
Breast Feeding 
There is no information regarding the presence of cirmtuzumab, ibrutinib, or ibrutinib 
metabolites in human milk. The effects of these drugs on the breastfed infant or on milk 
production are unknown. 
For these reasons, women who are nursing are not eligible to participate in this study. Lactating 
women who do participate in this clinical trial must discontinue nursing during protocol therapy 
and for ≥ 3 months after the last dose of cirmtuzumab and for ≥ 1 month after the last dose of 
ibrutinib, whichever is later. 
6.5.2. 
Contraception 
The effects, if any, of cirmtuzumab or ibrutinib on ovarian or testicular function are unknown. 
Sexually active females of childbearing potential must agree to use a highly effective method of 
contraception during heterosexual intercourse from the start of the screening period until ≥3 
months after the last dose of cirmtuzumab and ≥1 month after the last dose of ibrutinib, 
whichever is later.  
In the context of this protocol, a female patient is considered to be of childbearing potential 
unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 
institutional laboratory postmenopausal range and a negative serum or urine beta βHCG); or is 
menopausal (age ≥50 years with amenorrhea for ≥6 months).  
Sexually active male patients who can father a child and are having intercourse with females of 
childbearing potential who are not using adequate contraception must agree to use an effective 
method of contraception from the start of study therapy until ≥3 months after the last dose of 
cirmtuzumab and ≥3 months after the last dose of ibrutinib, whichever is later. Male patients 
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should also refrain from sperm donation from the start of study therapy until ≥3 months after 
administration of the final dose of either of the study drugs. 
In the context of this protocol, a male patient is considered able to father a child unless he has 
had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy. 
6.5.3. 
Diet 
Because ibrutinib is a sensitive substrate of CYP3A4, patients should be advised to avoid 
ingestion of grapefruit, grapefruit juice, or Seville oranges (which contains a potent CYP3A4 
inhibitor) and should not use St. John’s wort, which is a potent CYP3A4 inducer. No other 
specific dietary restrictions are required. 
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7. 
STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Duration of Study Drug Administration and Study Participation 
Patients exhibiting a PR or CR may continue combination treatment beyond Week 52 until 
disease progression or unacceptable toxicity as part of an extended therapy program.  
Patients who remain in a PR or CR at the end of the 2 year treatment period, may be eligible for 
Long-term Therapy and continue to receive cirmtuzumab and/or ibrutinib until disease 
progression, unacceptable toxicity, or the study ends. Sites should discuss these cases with the 
sponsor in advance for approval. 
For CLL/SLL patients, long-term follow-up consisting of patient contact every 3-6 months and 
collection of disease, treatment, and vital status data will continue following the End of 
Treatment visit for up to five years. For MCL or MZL patients, long-term follow-up will occur 
every 3 months and include collection of disease, treatment, and vital status data for up to five 
years. Imaging reports may be requested by the sponsor. These data will be used to establish 
PFS, TTP, and time to next treatment. Once a patient in long-term follow-up has progressed and 
received an alternate treatment for their disease, only vital status will be collected. 
For patients actively receiving study drug therapy, the occurrence of any of the following events 
requires treatment discontinuation: 
• Patients who withdraw from either ibrutinib or cirmtuzumab treatment will be withdrawn 
from the study. 
• Documented objective evidence of cancer progression while receiving combination study 
treatment 
• Intolerable toxicity despite appropriate supportive care and/or dose modification 
• The development of intercurrent illness or other substantial change in the patient’s 
condition or circumstances that would place the patient at unacceptable risk as 
determined by the study investigator in consultation with the medical monitor 
• Initiation of treatment for the patient’s cancer with an off-study therapeutic regimen 
• Pregnancy or breastfeeding 
• Substantial noncompliance with study drug administration, study procedures, or study 
requirements in circumstances that increase risk or substantially compromise the 
interpretation of study results 
• Discontinuation of the study by the study center, Oncternal, relevant regulatory agencies, 
or the IRB 
Patients in Part 1 who experience disease progression while receiving cirmtuzumab monotherapy 
should not be discontinued from study therapy solely for that reason; if otherwise medically 
appropriate, they should continue on study to receive combination cirmtuzumab + ibrutinib 
treatment. 
Unless they withdraw consent, patients will enter long-term follow-up. Patients who discontinue 
study therapy will be followed for acquisition of safety information through ≥30 days after the 
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last dose of study treatment, and for up to five years for further collection of information 
regarding subsequent anti-cancer therapies and vital status. 
7.2. 
Patient Replacement 
Patients who do not have the necessary baseline and on-study measurements to provide 
interpretable results for safety, pharmacodynamic, pharmacokinetics, or efficacy parameters may 
be replaced at the discretion of the sponsor. In general, this will mean that patients who do not 
complete study drug administration and protocol evaluation through Week 16 of therapy in 
Part 1 or through Week 12 of therapy in Parts 2 or 3 of the study will be considered for 
replacement. The replacement patient will be assigned to the same treatment cohort as the 
original patient. Accrual of additional patients to a treatment cohort may also be considered at 
the discretion of the SRC. A replacement patient or an additional patient may be accrued if there 
is agreement that treatment of such a patient is unlikely to constitute an unacceptable safety risk. 
7.3. 
Study Discontinuation 
Both the investigator and Oncternal reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures. The investigator will be 
responsible for notifying the relevant study center IRB. Oncternal will be responsible for 
notifying the appropriate regulatory authorities. In terminating the study, the investigator and 
Oncternal will assure that adequate consideration is given to the protection of the patients’ 
interests. As directed by Oncternal, all study materials must be collected and all eCRFs 
completed to the greatest extent possible.  
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Study Activities 
The specific study procedures and time of activities to be conducted for each patient enrolled in 
the study are presented in tabular form in Section 8.2 (Part 1), Section 8.3 (Part 2), and Section 
8.4 (Part 3) below. 
To provide necessary medical care to the patient while on study, additional types of clinical 
evaluations and laboratory studies or more frequent assessments may be performed if clinically 
indicated, even if not specified in the protocol. Physical examinations may be performed 
consistent with appropriate medical care for the patient, but physical examination data 
considered not clinically significant or an AE will not be routinely collected in the eCRF.  
To optimize scheduling convenience for the patient and for the study center staff, screening 
procedures may be performed over as many days as necessary provided that screening is 
completed within 28 days before initiation of treatment. For scheduled visits after Day 1, 
permitted visit windows are indicated in the table.  
For procedures to be performed at a specified time post-dose, the acceptable margin for actual 
time is the specified time ±15 minutes. If multiple procedures are to be done at the same time 
point, the preferred order is vital signs, blood sampling, and then ECG, with blood sampling 
(particularly for pharmacokinetics) occurring as close as possible to the specified time. 
Missed procedures or evaluations should be performed as close to the originally scheduled 
date/time as possible. Based on the investigator’s judgment, an exception can be made when 
rescheduling becomes medically unnecessary because it is too close in time to the next scheduled 
procedure or evaluation. In that case, the missed evaluation may be omitted. 
If necessary, remote/telemedicine visits and local laboratories are allowed to ensure continued 
safety monitoring.  
 
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8.2. 
Schedule of Activities – Part 1 MCL and CLL/SLL (Cirmtuzumab → Cirmtuzumab + Ibrutinib) 
Period 
Screen 
Treatment 
End of 
Tx  
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20+ 
22+ 
 
Safety 
FU 
Long-
term 
Week 
-4 
0 
0 
2 
4 
4 
6 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56+ 
64+ 
104 
Study Day 
Within 
28 Days 
0 
1 
14 
28 
29 
42 
56 
84 112 140 168 196 224 252 280 308 336 364 
Q 4 
weeks 
[bb] 
Q 12 
weeks 
[bb] 
728 
[bb] 
Within 
+30 
days 
To ≤5 
years 
Visit Window, days 
 
 
 
±2 
±2 
±2 
±2 
±2 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+7 
 
General Eligibility/Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed consent [b] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height [c] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/Vital signs [d] 
X 
X* 
X 
X* 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance status [e] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical history [f] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event (AE) assessment [g] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications [h] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG [i] 
X 
X* 
X 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Drug Administration/Dispensing/Return 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TLS prophylaxis [j] 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ibrutinib administration in the clinic [k] 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cirmtuzumab administration [l] 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispensing of ibrutinib [m] 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
Ibrutinib compliance check [m] 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory Assessments ## 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum virology [n] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry [o] 
X 
X(a) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology [p] 
X 
X(a) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis [q] 
X 
X(a) 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
Coagulation [r] 
X 
X(a) 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
Serum or urine pregnancy test [s] 
X 
X(a) 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
Serum for cirmtuzumab pharmacokinetics [t] 
 
X* 
X 
X* X*(k) X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Xt 
Xt 
 
Blood for ROR1 [u] 
 
X* 
X 
X* X*(k) X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
MCL ONLY: Blood for exploratory 
biomarkers[v] 
 
X 
X 
X 
X(k) 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Serum for cirmtuzumab-reactive antibodies 
[w] 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
Disease Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiology examination [x] 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
XX 
 
 
Blood and Bone marrow biopsy/aspirate [y] 
 
X 
 
 
 
 
 
 
 
------------ If required to document complete response ---------- 
 
 
 
Posttherapy Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Posttherapy safety assessment [z] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Long-term follow-up [aa] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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Footnotes – Part 1 
Note:  For procedures to be performed at a specified time postdose, the acceptable margin for actual time is the specified time ±15 minutes. If multiple procedures are to be 
done at the same time point, the preferred order is vital signs, blood sampling, and then ECG, with blood sampling occurring as close as possible to the specified time. 
## 
General safety lab assays will be done utilizing your CLIA approved local lab. Other required labs will utilize a central laboratory, so samples will need to be prepared and 
shipped according to the study lab manual. 
a. 
If obtained within 7 days prior to the start of therapy, urinalysis and serum pregnancy, serum chemistry, hematology, and coagulation studies collected during Screening need 
not be repeated on Day 0. 
b. 
Written informed consent will be obtained before any study procedures are performed that are not part of routine medical care. 
c. 
Height (in centimeters) will be obtained at Screening only.  
d. 
Weight (in kilograms) and vital signs (blood pressure, pulse, and temperature) will be assessed prior to the cirmtuzumab infusion, and at any time if no infusion that day.  
* -  on Days 0, 14, and 28 vital signs will also be assessed immediately after the end of the cirmtuzumab infusion. 
e. 
Performance status will be assessed using ECOG scale (see Appendix 12.1). 
f. 
Medical history to include recording of cancer history, previous therapy for cancer, clinically significant past and ongoing medical conditions, review of systems, and relevant 
social history and will be obtained at Screening only. 
g. 
Description of all AEs using concise medical terminology, including whether the AE is serious, the date of onset, the date of resolution, the severity based on the CTCAE, 
Version 4.03, a description of the potential relatedness to study drug or to a study procedure, the action taken, and the outcome (see Section 8.6). 
h. 
Concomitant medication assessments should include information regarding all prescription, nonprescription, illicit, and alternative medications.  
i. 
12-lead ECGs will be obtained with the patient resting in a supine position.  
* -  on Days 0 and 14 ECGs will also be assessed one hour after the end of the cirmtuzumab infusion. 
j. 
Based on the risk of TLS (low, intermediate, or high), patients at intermediate or high risk should be considered for TLS prophylaxis (see Section 6.4.2).  
k. 
The first dose of ibrutinib will be administered to the patient in the study center after collection of the predose blood samples and ~30 minutes prior to the start of the 
cirmtuzumab infusion (with recording of the date and actual clock time of the ibrutinib administration). 
l. 
Cirmtuzumab will be infused as indicated in Section 6.1.5, with recording of the date and actual clock time of the start and end of the infusion. Record any cirmtuzumab 
infusion reaction as an adverse event(s) in the eCRF, and record any supportive care provided. If infusion prophylaxis is required for subsequent infusions, see Section 6.4.1. 
m. A supply of ibrutinib will be dispensed to the patient with instructions for self-administration at home. At subsequent visits, empty, partially used, or full bottles of ibrutinib 
will be retrieved from the patient and drug compliance will be assessed.  
n. 
Virology evaluation to include serum HIV antibody, HBsAg antibody, HBc antibody, HCV antibody. Patients with a positive antibody evaluation for HBc or HCV should 
undergo evaluation for HBV DNA and for HCV RNA to determine if the antibody test may be falsely positive.  
o. 
Serum chemistry to include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, phosphorus, magnesium (screening only), total protein, albumin, 
ALT, AST, ALP, LDH, and total bilirubin. 
p. 
Hematology to include hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils; platelet count. 
q. 
Urinalysis to include specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase as assessed by dipstick, and microscopic 
urinalysis evaluating white blood cells, red blood cells, epithelial cells, bacteria, cast and crystals.  
r. 
Coagulation studies to include PT and aPTT. 
s. 
Serum or urine pregnancy testing will be performed in women of childbearing potential only. See Section 8.6.6 for reporting requirements in the event of a pregnancy. 
t. 
Serum for cirmtuzumab pharmacokinetics will be collected on the indicated days prior to the cirmtuzumab infusion, and at any time if no infusion that day.  
* -  on Days 0, 14 and 28 serum for cirmtuzumab pharmacokinetics will also be collected one hour after the end of the cirmtuzumab infusion. Serum for cirmtuzumab 
pharmacokinetics may also be collected with any unscheduled blood draw if indicated. Optional PK collection at select sites: on the day of the last infusion, 1 sample post 
infusion should be collected and, if possible, 1 additional sample every 28 days x4 (post last infusion). 
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Investigational Product: Cirmtuzumab (UC-961) 
 
Study Protocol:  CIRM-0001 
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CONFIDENTIAL 
Page 56 of 115 
Version 7 (15 April 2022) 
u. 
Blood for ROR1 cell surface expression and receptor occupancy will be collected on the indicated days prior to the cirmtuzumab infusion, and at any time if no infusion that 
day.  
* -  on Days 0, 14 and 28, blood for ROR1 cell surface expression and receptor occupancy will also be collected one hour after the end of the cirmtuzumab infusion.  
v. 
MCL Patients Only: Blood for exploratory biomarkers, such as cytokines and stem cell gene profile, will be collected on the indicated days prior to the cirmtuzumab infusion. 
On Day 28 the blood must be collected prior to ibrutinib administration. (The samples collected for each Part of the study will be described in the lab manual.) Tumor 
samples (unstained slides, tissue/cells or blocks) obtained pre-treatment or post-treatment, if available, may be requested for biomarker testing. 
w. Serum for cirmtuzumab-reactive antibodies will be collected on the indicated days prior to the cirmtuzumab infusion. 
x. 
Radiology examination to include contrast-enhanced CT or MRI imaging of neck, chest, abdomen, and pelvis and may include FDG-PET/CT for MCL. The same method of 
assessment (CT, MRI, FDG-PET/CT) and the same technique should be used, whenever possible, to characterize each identified and reported lesion at Screening and while 
on study. Evaluations may be performed within the 7 days prior to the indicated day. Baseline examination should be within 14 days of Day 0. For details see Section 8.5, 
Appendix 12.5, and Appendix 12.6. For patients having an End of Treatment visit and evaluations, if radiology imaging studies were last performed > 8 weeks before the End 
of Treatment visit, then they should be performed as part of this visit. For patients ending treatment due to radiographic confirmation of disease progression following 
cirmtuzumab + ibrutinib combined therapy, the End of Treatment visit should occur ≤4 weeks after the documentation of progression and the imaging studies do not need to 
be performed. 
y. 
A bone marrow aspirate, biopsy and peripheral blood sample should be obtained prior to Day 0 and before the cirmtuzumab infusion for exploratory biomarkers, with a 
biopsy for disease assessment if no biopsy results are available in the preceding 45 days. Subsequent bone marrow aspirate and biopsy plus peripheral blood sample, 
including samples for exploratory biomarkers, will only be obtained as needed to confirm a clinical/radiologic complete response. A blinded bone marrow sample may be 
sent for central review/confirmation.  
z. 
The End of Treatment visit will be performed after permanent cessation of study therapy. The Safety Follow-up visit will occur either 30 days after the last dose of study 
treatment or upon resolution/stabilization of any ongoing drug-related AEs and/or SAEs, whichever occurs later. AE/SAE follow-up may be obtained in person, by telephone, 
or by e-mail contact. 
aa. Long-term follow-up information will be obtained for up to 5 years in all surviving patients who permanently discontinue study therapy. Long term follow-up data should be 
obtained every 6 months for CLL patients. Long term follow-up data should be collected every 3 months for MCL patients. Data on the timing of disease progression and 
post-study cancer therapies (including ibrutinib) will be collected. Once a patient has progressed and received a subsequent cancer therapy, only vital status will be collected. 
Reports of imaging studies performed during long-term follow-up may be requested by the sponsor for review.  
bb. For patients continuing beyond Week 52, the combination treatment will continue at the same dose and schedule as year 1. Assessments will continue to be performed with 
visits and infusions every 4 weeks and scans and other additional assessments every 12 weeks, as indicated in the SOA.  
Abbreviations: AE=adverse event, ALP=alkaline phosphatase, ALT=alanine aminotransferase, aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, 
BUN=blood urea nitrogen, CLL/SLL=chronic lymphocytic leukemia/small lymphocytic lymphoma, CR=complete response, CT=computed tomography, DNA=deoxyribonucleic 
acid, ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, FDG=fluorodeoxyglucose, HBc antibody=anti-hepatitis B core antibody, HBsAg=hepatitis B surface 
antigen, HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human immunodeficiency virus, LDH=lactate dehydrogenase, MCL=mantle cell lymphoma, MRD=minimal 
residual disease, MRI=magnetic resonance imaging, OS=overall survival, PD=progressive disease, PET=positron emission tomography, PT=partial thromboplastin time, 
RNA=ribonucleic acid, ROR1= receptor tyrosine kinase-like orphan receptor 1, SAE=serious adverse event, TLS=tumor lysis syndrome, Tx=treatment. 
 
 
 
 
 
 
DocuSign Envelope ID: 79119608-04B8-451D-8A29-573F49B08D37


Investigational Product: Cirmtuzumab (UC-961) 
 
Study Protocol:  CIRM-0001 
Oncternal Therapeutics, Inc. 
CONFIDENTIAL 
Page 57 of 115 
Version 7 (15 April 2022) 
8.3. 
Schedule of Activities – Part 2 MCL, MZL and CLL/SLL (Cirmtuzumab + Ibrutinib) 
Period 
Screen 
Treatment 
End of 
Tx 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18+ 
19+ 
 
Safety 
FU 
Long-term 
Week 
-4 
0 
0 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56+ 
60+ 
104 
Study Day 
Within 
28 
Days 
0 
1 
14 28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 364 
Q 4  
weeks 
[bb] 
Q 12  
weeks 
[bb] 
 
728 
[bb] 
Within 
+30 
days 
To 
≤5 years 
Visit Window, days 
 
 
 
±2 ±2 
±2 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+7 
 
General Eligibility/Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed consent [b] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height [c] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/Vital signs [d] 
X 
X* 
X 
X* X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance status [e] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical history [f] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event (AE) assessment [g] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications [h] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG [i] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Drug Administration/Dispensing/Return 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TLS prophylaxis [j] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ibrutinib administration in the clinic [k] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cirmtuzumab administration [l] 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispensing of ibrutinib [m] 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xcc 
X 
X 
X 
 
 
 
Ibrutinib compliance check [m] 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory Assessments ## 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum virology [n] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry [o] 
X 
X(a) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology [p] 
X 
X(a) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis [q 
X 
X(a) 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Coagulation [r] 
X 
X(a) 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Serum or urine pregnancy test [s] 
X 
X(a) 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Serum for cirmtuzumab pharmacokinetics [t] 
 
X*(k) 
 
X 
X 
 
 
 
 
X* 
 
 
X 
 
 
X 
 
 
 
Xt 
Xt  
 
Blood for ROR1 [u] 
 
X(k) 
 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Blood for exploratory biomarkers [v] 
 
X(k) 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Serum for cirmtuzumab-reactive antibodies 
[w] 
 
X(k) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
Disease Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiology examination [x] 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
XX 
 
 
Blood and Bone marrow biopsy/aspirate [y] 
 
X 
 
 
 
 
------------ If required to document complete response ---------- 
 
 
 
Posttherapy Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Posttherapy safety assessment [z] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Long-term follow-up [aa] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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Investigational Product: Cirmtuzumab (UC-961) 
 
Study Protocol:  CIRM-0001 
Oncternal Therapeutics, Inc. 
CONFIDENTIAL 
Page 58 of 115 
Version 7 (15 April 2022) 
Footnotes – Part 2  
Note:  For procedures to be performed at a specified time postdose, the acceptable margin for actual time is the specified time ±15 minutes. If multiple procedures are to be 
done at the same time point, the preferred order is vital signs, blood sampling, and then ECG, with blood sampling occurring as close as possible to the specified time. 
## 
General safety lab assays will be done utilizing your CLIA approved local lab. Other required labs will utilize a central laboratory, so samples will need to be prepared and 
shipped according to the study lab manual. 
a. 
If obtained within 7 days prior to the start of therapy, urinalysis and serum pregnancy, serum chemistry, hematology, and coagulation studies collected during Screening 
need not be repeated on Day 0. 
b. 
Written informed consent will be obtained before any study procedures are performed that are not part of routine medical care. 
c. 
Height will be obtained once at Screening. 
d. 
Weight (in kilograms) and vital signs (blood pressure, pulse, and temperature) will be assessed prior to the cirmtuzumab infusion, and at any time if no infusion that day.  
* -  on Days 0, 14, and 28 vital signs will also be assessed immediately after the end of the cirmtuzumab infusion and on Day 0 only, vital signs should also be assessed one 
hour post infusion to ensure no delayed reaction occurs following the first infusion. 
e. 
Performance status will be assessed using ECOG scale (see Appendix 12.1) once on each designated day. 
f. 
Medical history to include recording of cancer history, previous therapy for cancer, clinically significant past and ongoing medical conditions, review of systems, and 
relevant social history and will be obtained at Screening only. 
g. 
Description of all AEs using concise medical terminology, including whether the AE is serious, the date of onset, the date of resolution, the severity based on the CTCAE, 
Version 4.03, a description of the potential relatedness to study drug or to a study procedure, the action taken, and the outcome (see Section 8.6). 
h. 
Concomitant medication assessments should include information regarding all prescription, nonprescription, illicit, and alternative medications .  
i. 
12-lead ECGs will be obtained with the patient resting in a supine position. If ECG abnormalities such as QT prolongation are observed compared to baseline following 
study treatment, the test result should be confirmed and ECG repeated at the Safety Follow-up visit (post the End of Treatment visit). 
j. 
Based on the risk of TLS (low, intermediate, or high), patients at intermediate or high risk should be considered for TLS prophylaxis (see Section 6.4.2).  
k. 
The first dose of ibrutinib will be administered to the patient in the study center after collection of the predose blood samples and ~30 minutes prior to the start of the 
cirmtuzumab infusion (with recording of the date and actual clock time of the ibrutinib administration).  
l. 
Cirmtuzumab will be infused as indicated in Section 6.1.5, with recording of the date and actual clock time of the start and end of the infusion. Record any cirmtuzumab 
infusion reaction as an adverse event(s) in the eCRF, and record any supportive care provided. If infusion prophylaxis is required for subsequent infusions, see Section 6.4.1. 
m. For patients receiving investigational ibrutinib, a supply of ibrutinib will be dispensed to the patient with instructions for self-administration at home. At subsequent visits, 
empty, partially used, or full bottles of ibrutinib will be retrieved from the patient and drug compliance will be assessed.  
n. 
Virology evaluation to include serum HIV antibody, HBsAg antibody, HBc antibody, HCV antibody. Patients with a positive antibody evaluation for HBc or HCV should 
undergo evaluation for HBV DNA and for HCV RNA to determine if the antibody test may be falsely positive.  
o. 
Serum chemistry to include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, phosphorus, magnesium (screening only), total protein, albumin, 
ALT, AST, ALP, LDH, and total bilirubin. 
p. 
Hematology to include hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils; platelet 
count. 
q. 
Urinalysis to include specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase as assessed by dipstick, and microscopic 
urinalysis evaluating white blood cells, red blood cells, epithelial cells, bacteria, cast and crystals.  
r. 
Coagulation studies to include PT and aPTT. 
s. 
Serum or urine pregnancy testing will be performed in women of childbearing potential only. See Section 8.6.6 for reporting requirements in the event of a pregnancy. 
DocuSign Envelope ID: 79119608-04B8-451D-8A29-573F49B08D37


Investigational Product: Cirmtuzumab (UC-961) 
 
Study Protocol:  CIRM-0001 
Oncternal Therapeutics, Inc. 
CONFIDENTIAL 
Page 59 of 115 
Version 7 (15 April 2022) 
t. 
Serum for cirmtuzumab pharmacokinetics will be collected on the indicated days prior to the cirmtuzumab infusion. 
* -  In addition, on Day 0 and Day 168 a sample should be drawn at the end of the cirmtuzumab infusion. Optional PK collection at select sites: on the day of the last 
infusion, 1 sample post infusion should be collected and, if possible, 1 additional sample every 28 days x4 (post last infusion). 
u. 
Blood for ROR1 cell surface expression and receptor occupancy will be collected on the indicated days prior to the cirmtuzumab infusion, and at any time if no infusion that 
day. Additional timepoints may be requested, should it be needed to complete the dataset.  
v. 
Blood for exploratory biomarkers will be collected on the indicated days prior to the cirmtuzumab infusion. Additional timepoints may be requested, should it be needed to 
complete the dataset. Tumor samples (unstained slides, tissue/cells or blocks) obtained pre-treatment or post-treatment, if available, may be requested for biomarker testing.  
w. Serum for cirmtuzumab-reactive antibodies will be collected on the indicated days prior to the cirmtuzumab infusion. 
x. 
Radiology examination to include contrast-enhanced CT (preferred) or MRI imaging of neck, chest, abdomen, and pelvis (for MCL and MZL FDG-PET/CT, is preferred). 
The same method of assessment (CT, MRI, FDG-PET/CT) and the same technique should be used, whenever possible, to characterize each identified and reported lesion at 
Screening and while on study. Evaluations may be performed within the 7 days prior to the indicated day. Baseline examination should be within 14 days of Day 0. For 
details see Section 8.5, Appendix 12.5, and Appendix 12.6. For patients having an End of Treatment visit and evaluations, if radiology imaging studies were last performed 
> 8 weeks before the End of Treatment visit, then they should be performed as part of this visit. For patients ending treatment due to radiographic confirmation of disease 
progression following cirmtuzumab + ibrutinib combined therapy, the End of Treatment visit should occur ≤4 weeks after the documentation of progression and the imaging 
studies do not need to be performed. 
y. 
A bone marrow aspirate, biopsy and peripheral blood sample should be obtained prior to Day 0 and before the cirmtuzumab infusion for exploratory biomarkers, with a 
biopsy for disease assessment if no biopsy results are available in the preceding 45 days. Subsequent bone marrow aspirate and biopsy plus peripheral blood sample, 
including samples for exploratory biomarkers, will only be obtained as needed to confirm a clinical/radiologic complete response. As the data for exploratory biomarkers 
develops, additional samples may be requested to better analyze and confirm the results of these tests. A blinded bone marrow sample may be sent for central 
review/confirmation.  
z. 
The End of Treatment visit will be performed after permanent cessation of study therapy. The Safety Follow-Up visit will occur the later of either 30 days after the last dose 
of study treatment or until resolution/stabilization of any ongoing drug-related AEs and/or SAEs. AE/SAE follow-up may be obtained in person, by telephone, or by e-mail 
contact. 
aa. Long-term follow-up information will be obtained for up to 5 years in all surviving patients who permanently discontinue study therapy. Long term follow-up data should be 
obtained every 6 months for CLL patients. Long term follow-up data should be collected every 3 months for MCL and MZL patients. Data on the timing of disease 
progression and post-study cancer therapies (including ibrutinib) will be collected. Once a patient has progressed and received a subsequent cancer therapy, only vital status 
will be collected. Reports of imaging studies performed during long-term follow-up may be requested by the sponsor for review.  
bb. For patients continuing beyond Week 52, the combination treatment will continue at the same dose and schedule as year 1. Assessments will continue to be performed with 
visits and infusions every 4 weeks and scans and other additional assessments every 12 weeks, as indicated in the SOA. 
cc. Ibrutinib can be dispensed if documented intention is for patient to extend and scans are planned or pending. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, BUN=blood urea 
nitrogen, CLL/SLL=chronic lymphocytic leukemia/small lymphocytic lymphoma, CR=complete response, CT=computed tomography, DNA=deoxyribonucleic acid, 
ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, FDG=fluorodeoxyglucose, HBc antibody=anti-hepatitis B core antibody, HBsAg=hepatitis B surface 
antigen, HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human immunodeficiency virus, LDH=lactate dehydrogenase, MCL=mantle cell lymphoma, MRD=minimal 
residual disease, MRI=magnetic resonance imaging,MZL= Marginal Zone Lymphoma, OS=overall survival, PD=progressive disease, PET=positron emission tomography, 
PT=partial thromboplastin time, RNA=ribonucleic acid, ROR1= receptor tyrosine kinase-like orphan receptor 1, SAE=serious adverse event, SOA=schedule of activities, 
TLS=tumor lysis syndrome, Tx=treatment. 
 
 
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Investigational Product: Cirmtuzumab (UC-961) 
 
Study Protocol:  CIRM-0001 
Oncternal Therapeutics, Inc. 
CONFIDENTIAL 
Page 60 of 115 
Version 7 (15 April 2022) 
8.4. 
Schedule of Activities – Part 3 CLL/SLL (Cirmtuzumab + Ibrutinib versus Ibrutinib) 
Period 
Screen 
Treatment 
End of 
Tx 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17+ 
18+ 
 
Safety 
FU 
Long-
term 
Week 
-4 
0 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56+ 
60+ 
104 
Study Day 
Within 
28 Days 
0 
14 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
364 
Q 4  
weeks 
[z] 
Q 12 
weeks 
[z] 
728 
[z] 
Within 
+30 days 
To ≤5 
years 
Visit Window, days 
 
 
±2 
±2 
±2 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+7 
 
General Eligibility/Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed consent [b] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height [c] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/Vital signs [d] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance status [e] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical history [f] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event (AE) assessment [g] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications [h] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG [i] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Drug Administration/Dispensing/Return 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TLS prophylaxis [j] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ibrutinib administration in the clinic [k] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cirmtuzumab administration (Arm A) [l] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispensing of ibrutinib [m] 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xaa 
X 
X 
X 
 
 
 
Ibrutinib compliance check [m] 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum virology [n] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry [o] 
X 
X(a) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology [p] 
X 
X(a) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis [q] 
X 
X(a) 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Coagulation [r] 
X 
X(a) 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Serum or urine pregnancy test [s] 
X 
X(a) 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Serum for cirmtuzumab-reactive antibodies 
and cytokines, and blood for exploratory 
biomarkers [t] 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Disease Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rai stage [u] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiology examination [v] 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
XV 
 
 
Bone marrow biopsy/aspirate [w] 
 
X 
 
 
 
------------ If required to document complete response ------- 
 
 
 
Posttherapy Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Posttherapy safety assessment [x] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Long-term follow-up [y] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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Footnotes – Part 3 
Note:  For procedures to be performed at a specified time postdose, the acceptable margin for actual time is the specified time ±15 minutes. If multiple procedures are to be 
done at the same time point, the preferred order is vital signs, blood sampling, and then ECG, with blood sampling occurring as close as possible to the specified time. 
a. 
If obtained within 7 days prior to the start of therapy, urinalysis and serum pregnancy, serum chemistry, hematology, and coagulation studies collected during Screening 
need not be repeated on Day 0. 
b. 
Written informed consent will be obtained before any study procedures are performed that are not part of routine medical care. 
c. 
Height will be measured once during Screening. 
d. 
Weight (in kilograms) and vital signs (blood pressure, pulse, temperature) will be assessed at Screening and on each subsequent study day prior to cirmtuzumab treatment, 
and at any time if no infusion that day. 
e. 
Performance status will be assessed using ECOG scale (see Appendix 12.1) once on each designated day. 
f. 
Medical history to include recording of cancer history, previous therapy for cancer, clinically significant past and ongoing medical conditions, review of systems, and 
relevant social history and will be obtained at Screening only. 
g. 
Description of all AEs using concise medical terminology, including whether the AE is serious, the date of onset, the date of resolution, the severity based on the CTCAE, 
Version 4.03, a description of the potential relatedness to study drug or to a study procedure, the action taken, and the outcome (see Section 8.6). 
h. 
Concomitant medication assessments should include information regarding all prescription, nonprescription, illicit, and alternative medications.  
i. 
12-lead ECGs will be obtained with the patient resting in a supine position. ECGs will be collected at Screening and at End of Treatment visits. If ECG abnormalities such 
as QT prolongation are observed compared to baseline following study treatment, the test result should be confirmed and ECG repeated at the Safety Follow-up visit (post 
the End of Treatment visit). 
j. 
Based on the risk of TLS (low, intermediate, or high), patients at intermediate or high risk should be considered for TLS prophylaxis (see Section 6.4.2).  
k. 
The first dose of ibrutinib will be administered to the patient in the study center ~30 minutes prior to the start of the cirmtuzumab infusion (with recording of the date and 
actual clock time of the ibrutinib administration). 
l. 
Cirmtuzumab will be infused as indicated in Section 6.1.5, with recording of the date and actual clock time of the start and end of the infusion. Record any cirmtuzumab 
infusion reaction as an adverse event(s) in the eCRF, and record any supportive care provided. If infusion prophylaxis is required for subsequent infusions, see Section 6.4.1. 
m. For patients receiving investigational ibrutinib, a supply of ibrutinib will be dispensed to the patient with instructions for self-administration at home. At subsequent visits, 
empty, partially used, or full bottles of ibrutinib will be retrieved from the patient and drug compliance will be assessed.  
n. 
Virology evaluation to include serum HIV antibody, HBsAg antibody, HBc antibody, HCV antibody. Patients with a positive antibody evaluation for HBc or HCV should 
undergo evaluation for HBV DNA and for HCV RNA to determine if the antibody test may be falsely positive.  
o. 
Serum chemistry to include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, phosphorus, magnesium (screening only), total protein, albumin, 
ALT, AST, ALP, LDH (screening only), and total bilirubin. 
p. 
Hematology to include hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils; platelet 
count. 
q. 
Urinalysis to include specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase as assessed by dipstick, and microscopic 
urinalysis evaluating white blood cells, red blood cells, epithelial cells, bacteria, cast and crystals.  
r. 
Coagulation studies to include PT and aPTT. 
s. 
Serum or urine pregnancy testing will be performed in women of childbearing potential only. See Section 8.6.6 for reporting requirements in the event of a pregnancy. 
t. 
Serum for cirmtuzumab-reactive antibodies and cytokines, and blood for exploratory biomarkers will be collected on the indicated days prior to the cirmtuzumab infusion. 
Tumor samples (unstained slides, tissue/cells or blocks) obtained pre-treatment or post-treatment, if available, may be requested for biomarker testing. 
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u. 
For patients with CLL/SLL, Rai stage will be calculated (see Appendix 12.4).  
v. 
Radiology examination to include contrast-enhanced CT (preferred) or MRI imaging of neck, chest, abdomen, and pelvis (and may include FDG-PET/CT, if relevant). The 
same method of assessment (CT, MRI, FDG-PET/CT) and the same technique should be used, whenever possible, to characterize each identified and reported lesion at 
Screening and while on study. Evaluations may be performed within the 7 days prior to the indicated day. Baseline examination should be within 14 days of Day 0. For 
details see Section 8.5, Appendix 12.5, and Appendix 12.6. For patients having an End of Treatment visit and evaluations, if radiology imaging studies were last performed 
> 8 weeks before the End of Treatment visit, then they should be performed as part of this visit. For patients ending treatment due to radiographic confirmation of disease 
progression following cirmtuzumab + ibrutinib combined therapy, the End of Treatment visit should occur ≤4 weeks after the documentation of progression and the imaging 
studies do not need to be performed. 
w. A bone marrow aspirate, biopsy and peripheral blood sample should be obtained prior to Day 0 and before the cirmtuzumab infusion for exploratory biomarkers, with a 
biopsy for disease assessment if no biopsy results are available in the preceding 45 days. Subsequent bone marrow aspirate and biopsy plus peripheral blood sample, 
including samples for exploratory biomarkers, will only be obtained as needed to confirm a clinical/radiologic complete response. A blinded bone marrow sample may be 
sent for central review/confirmation.  
x. 
The End of Treatment visit will be performed after permanent cessation of study therapy. The Safety Follow-up visit will occur either 30 days after the last dose of study 
treatment or upon resolution/stabilization of any ongoing drug-related AEs and/or SAEs, whichever occurs later. AE/SAE follow-up may be obtained in person, by 
telephone, or by e-mail contact. 
y. 
Long-term follow-up information will be obtained for up to 5 years in all surviving patients who permanently discontinue study therapy. Long term follow-up data should be 
obtained every 6 months. Data on the timing of disease progression and post-study cancer therapies (including ibrutinib) will be collected. Once a patient has progressed and 
received a subsequent cancer therapy, only vital status will be collected.  Reports of imaging studies performed during long-term follow-up may be requested by the sponsor 
for review.  
z. 
For CLL/SLL patients continuing beyond Week 52, they will continue with the assigned treatment at the same dose and the same assessments will be performed with visits 
and infusions every 4 weeks and scans and other additional assessments every 12 weeks. 
aa. Ibrutinib can be dispensed if documented intention is for patient to extend and scans are planned or pending. 
Abbreviations: AE=adverse event, ALP=alkaline phosphatase, ALT=alanine aminotransferase, aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, 
BUN=blood urea nitrogen, CLL/SLL=chronic lymphocytic leukemia/small lymphocytic lymphoma, CT=computed tomography, DNA=deoxyribonucleic acid, 
ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, FDG=fluorodeoxyglucose, HBc antibody=anti-hepatitis B core antibody, HBsAg=hepatitis B surface 
antigen, HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human immunodeficiency virus, LDH=lactate dehydrogenase, MCL=mantle cell lymphoma, MRD=minimal 
residual disease, MRI=magnetic resonance imaging, OS=overall survival, PD=progressive disease, PET=positron emission tomography, PT=partial thromboplastin time, 
RNA=ribonucleic acid, SAE=serious adverse event, TLS=tumor lysis syndrome 
 
 
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8.5. 
Efficacy Assessments 
8.5.1. 
Overview  
Tumor response and progression will be assessed using standard criteria appropriate for each 
hematological malignancy. During the course of the study, investigators will periodically 
determine general disease status based on radiographic and laboratory evaluations (supplemented 
by physical examination, as appropriate). Treatment decisions by the investigator in this study 
will be based, in part, on these assessments. The investigator assessment of tumor control 
endpoints will be used for the primary analyses in all Parts of the study.  
8.5.2. 
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 
8.5.2.1. 
Tumor Assessment Criteria 
The determination of CLL/SLL response and progression will be based on standardized criteria 
iwCLL [Hallek 2008], as recently updated [Hallek 2018; Cheson 2012]. A detailed description of 
response assessment for this study is presented in Appendix 12.5. 
8.5.2.2. 
Method of Assessment 
Imaging-based evaluation will be used in this study in all patients enrolled. CT scan is the 
preferred method for radiographic tumor assessment. MRI scanning may be used at the 
investigator’s discretion in patients for whom this may be a preferred alternative to CT scanning; 
however, if MRI is performed, a non-contrast CT of the chest should be performed. Contrast-
enhanced scanning is preferred, but iodine-containing or gadolinium contrast material may be 
omitted in patients for whom use of a contrast agent would be medically contraindicated. Chest 
x-ray, ultrasound, endoscopy, laparoscopy, PET, radionuclide scans, or tumor markers will not 
be considered for response assessment. 
For radiographic evaluations, the same method of assessment and the same technique (eg, scan 
type, scanner, patient position, dose of contrast, injection/scan interval) should be used, 
whenever possible, to characterize each identified and reported lesion at screening and during 
study treatment and follow-up. However, if a patient is imaged without contrast at screening, 
subsequent assessments should be performed with contrast, unless the patient cannot tolerate the 
contrast.  
All relevant radiographic and clinical information required to make each tumor status assessment 
must be made available for source verification and review. 
8.5.2.3. 
Timing of Assessments 
During screening, imaging-based and laboratory assessments should be performed within the 
specified screening period. On-study tumor assessments should be scheduled as indicated in 
Section 8. For patients having an End of Treatment visit and evaluations, if radiology imaging 
studies were last performed > 8 weeks before the End of Treatment visit, then they should be 
performed as part of this visit. For patients ending treatment due to radiographic confirmation of 
disease progression following cirmtuzumab + ibrutinib combined therapy, the End of Treatment 
visit should occur ≤4 weeks after the documentation of progression and the imaging studies do 
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not need to be performed. If a patient permanently discontinues study drug prior to objective 
documentation of CLL/SLL progression, investigators should attempt to obtain further follow-up 
at ~12-week intervals until CLL/SLL progression is documented or until the initiation of a new 
post-study therapy for the patient’s CLL/SLL.  
8.5.3. 
Lymphoma 
8.5.3.1. 
Tumor Assessment Criteria 
The determination of response and progression for MCL and MZL will be based on standardized 
criteria [Cheson 2007] as recently updated [Cheson 2014]. A detailed description of response 
assessment for this study is presented in Appendix 12.6. 
8.5.3.2. 
Method of Assessment 
Imaging-based evaluation will be used in this study as the primary basis of lymphoma 
assessment. Preferred methods for radiographic tumor assessment are diagnostic CT (with 
contrast enhancement) or PET/CT. If CT is performed, contrast-enhanced scanning is preferred, 
but contrast material may be omitted in patients for whom use of a contrast agent becomes 
medically contraindicated or if the CT is obtained in conjunction with PET scanning. If 
available, PET scan data will be considered in response and progression assessment; however, 
PET scanning will not be a required component of assessment in this study. As required by the 
protocol or as otherwise necessary, bone marrow aspirate/biopsy (eg, for confirmation of CR) or 
cytological/histological evaluation of lymph nodes, effusions, ascites, or other organ 
abnormalities) will be also be considered. Clinical palpation, chest x-ray, ultrasound, endoscopy, 
laparoscopy, radionuclide scan, or tumor markers will not be considered for response 
assessment. MRI scanning is not advised but may be used at the investigator’s discretion in 
patients for whom this becomes a necessary alternative to CT scanning.  
For radiographic assessments, the same method of assessment and the same technique (eg, scan 
type, scanner, patient position, dose of contrast, injection/scan interval) should be used, 
whenever possible, to characterize each identified and reported lesion at screening and during 
study treatment and follow-up. CT of the neck, chest, abdomen, and pelvis should be performed 
with cuts of ≤0.5 mm in slice thickness contiguously. If performed, whole-body FDG PET-CT 
scanning should be extended from the base of the skull to mid-thigh.  
All relevant radiographic and clinical information required to make each tumor status assessment 
must be made available for source verification and review.  
8.5.3.3. 
Timing of Assessments 
During screening, imaging-based and laboratory assessments should be performed within the 
specified screening period. On-study tumor assessments should be scheduled as indicated in 
Section 8. For patients having an End of Treatment visit and evaluations, if radiology imaging 
studies were last performed > 8 weeks before the End of Treatment visit, then they should be 
performed as part of this visit. For patients ending treatment due to radiographic confirmation of 
disease progression following cirmtuzumab + ibrutinib combined therapy, the End of Treatment 
visit should occur ≤4 weeks after the documentation of progression and the imaging studies do 
not need to be performed. If a patient permanently discontinues treatment prior to objective 
documentation of lymphoma progression, investigators should continue further follow-up of 
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tumor status with assessments at ~12-week intervals until disease progression is documented or 
until the initiation of a new post-study therapy for the patient’s lymphoma. 
8.6. 
Safety Assessments 
8.6.1. 
Definitions 
8.6.1.1. 
Adverse Event 
An AE can be any unfavorable and unintended sign or symptom, or disease temporally 
associated with the use of a study drug, whether or not related to the study drug. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
In this study, any of the following events will be considered an AE: 
• Any preexisting condition that increases in severity or changes in nature during or as 
a consequence of study drug administration. Worsening manifestations of the 
underlying cancer (eg, increase in pain, tumor flare reaction, TLS) may be considered 
AEs in this study but should be reported as disease progression.  
• Any injury or accident. If a medical condition is known to have caused the injury or 
accident (eg, a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) should be reported as 2 separate AEs.  
• Any abnormality in physiological testing or a physical examination finding that 
requires clinical intervention or further investigation (beyond ordering a repeat 
[confirmatory] test). 
• Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational 
abnormality (eg, ECG, X-ray) independent of the underlying medical condition that 
requires clinical intervention, results in further investigation (beyond ordering a 
repeat [confirmatory] test), or leads to investigational medicinal product interruption 
or discontinuation unless it is associated with an already reported clinical event. If the 
laboratory abnormality is part of a syndrome, the syndrome or diagnosis (eg, anemia) 
not the laboratory result (eg, decreased hemoglobin) should be recorded.  
• A complication related to pregnancy or termination of a pregnancy (see Section 8.6.6 
for additional information). 
• However, none of the following events is considered an AE: 
• Asymptomatic lymphocytosis 
• Cancer progression without worsening disease manifestations. In cases of SAEs, 
cancer progression may be reported if there is no alternative term that can be 
satisfactorily substituted. In such cases, the AE description should match the SAE 
description. 
• Laboratory abnormalities not requiring clinical intervention or further investigation. 
Such abnormalities will be captured as part of laboratory monitoring. 
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• A diagnostic, medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, 
transfusion). However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE. For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE 
and the resulting appendectomy should be recorded in the source documents.  
• A preexisting disease or condition or laboratory abnormality present or detected 
before the initial screening visit and that does not worsen. 
• An intervention not associated with an untoward medical occurrence (eg, 
hospitalization for elective surgery or for social and/or convenience reasons). 
• An overdose without clinical sequelae. 
8.6.1.2. 
Serious Adverse Event 
An SAE is defined as an untoward medical occurrence that results in any of the following 
outcomes: 
• Death (ie, all deaths occurring from the time of the first drug administration to within 
30 days after last study drug administration), including deaths due to cancer 
progression if no other event more satisfactorily explains the reason for death. Deaths 
that occur as a result of an AE that started during the study period should be reported. 
Death is not an SAE term; the reported AE should be the event that caused the death. 
Death is the outcome of this SAE. 
• Life-threatening situation (ie, with an immediate risk of death from the event as it 
occurred but not including an event that, had it occurred in a more serious form, might 
have caused death). 
• In-patient hospitalization or prolongation of existing hospitalization. Of note, an 
untoward medical occurrence that occurs during hospitalization is an AE but a 
complication that prolongs hospitalization is an SAE. Inpatient hospitalization 
comprises formal admission to a hospital for medical reasons, for any length of time, 
whether or not hospitalization extends overnight. However, hospital admissions for 
administration of the study drug or procedures required by the study protocol, 
diagnostic observations or procedures, logistical issues (eg, lengthy travel), or the 
convenience of the patient or clinical personnel are not considered serious.  
• Persistent or significant disability/incapacity. 
• Congenital anomaly/birth defect in the offspring of a patient who received the 
investigational medicinal product. 
• Other medically significant event. Such events may not be immediately life-
threatening or result in death or hospitalization, but based upon appropriate medical 
and scientific judgment, may jeopardize the patient or may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such events 
might include: 
o Allergic bronchospasm requiring intensive treatment in an emergency room or 
at home 
o New cancers or blood dyscrasias 
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o Convulsions that do not result in hospitalization 
o Development of drug dependency or drug abuse 
8.6.1.3. 
Unexpected Adverse Event 
An unexpected AE is defined as an event that has a nature, severity, or specificity that is not 
consistent with the applicable investigator brochure, or that is symptomatically and 
pathophysiologically related to a known toxicity but differs because of greater severity or 
specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue 
of greater severity) if the investigator brochure only referred to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the investigator brochure only listed cerebral vascular accidents. 
“Unexpected,” as used in this definition, refers to an adverse drug experience that has not been 
previously observed and reported rather than an experience that has not been anticipated based 
on the pharmacological properties of the study drug. 
8.6.1.4. 
Treatment-Emergent Adverse Event  
A TEAE is defined as an AE that occurs or worsens in the period from the first dose of study 
drug administration to 30 days after the final dose of study drug administration. 
8.6.1.5. 
Adverse Events of Special Interest 
The AEs of special interest in this protocol will be: 
• Grade ≥3 infusion reactions 
• TLS 
• Major hemorrhage (defined as any of hemorrhagic TEAEs of Grade ≥3, treatment-
emergent hemorrhagic SAEs of any grade, or treatment-emergent central nervous 
system hemorrhage of any grade). 
• Covid-19 infection (in addition, if the patient withdraws due to fear of contracting 
Covid-19 at the treatment site, due to travel, or other causes associated with trial, 
please note this as a reason for discontinuation.) 
In addition to description in listings and tables, these types of events will be characterized in 
narratives. 
8.6.2. 
Grading of the Severity of an Adverse Event 
The severity of AEs will be graded using the CTCAE, Version 4.03 [NCI 2010]. For each 
episode, the highest severity grade attained should be reported.  
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to 
describe the maximum intensity of the AE. For purposes of consistency with the CTCAE, these 
intensity grades are defined in Table 2. 
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Table 2: Grading of Adverse Event Severity 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Sign or symptom is present, but it is easily tolerated, is not expected to 
have a clinically significant effect on the patient’s overall health and 
well-being, does not interfere with the patient’s usual function, and is 
not likely to require medical attention. 
Grade 2 
Moderate 
Sign or symptom causes interference with usual activity or affects 
clinical status, and may require medical intervention. 
Grade 3 
Severe 
Sign or symptom is incapacitating or significantly affects clinical status 
and likely requires medical intervention and/or close follow-up. 
Grade 4 
Life-threatening 
Sign or symptom results in a potential threat to life. 
Grade 5 
Fatal 
Sign or symptom results in death. 
The distinction between the seriousness and the severity of an AE should be noted. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met one of 
the criteria for serious events (as listed in Section 8.6.1.2). 
8.6.3. 
Describing Adverse Event Relationship to Study Drug 
The investigator will evaluate the causal relationship of each AE to a study drug and record that 
relationship on the appropriate CRFs. Causality will be assessed considering whether the AE is 
reasonably related to the study drug or whether the AE is not reasonably related to the study drug 
considering the definitions in Table 3. 
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Table 3: Relationship of Study Drug to Adverse Event 
Relationship 
Description 
Definite 
A clinical event in which a relationship to the use of the study drug seems definite because 
of such factors as consistency with known effects of the drug; a clear temporal association 
with the use of the drug; lack of alternative explanations for the event; improvement upon 
withdrawal of the drug (de-challenge); and recurrence upon resumption of the drug 
(rechallenge).  
Probable 
A clinical event in which a relationship to the study drug seems probable because of such 
factors as consistency with known effects of the drug; a reasonable temporal association 
with the use of the drug; lack of alternative explanations for the event; and improvement 
upon withdrawal of the drug (de-challenge). 
Possible 
A clinical event with a reasonable temporal association with administration of the study 
drug, and that is not likely to be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking. 
Unlikely 
A clinical event with a temporal relationship to study drug administration that makes a 
causal relationship improbable and for which other factors suggesting an alternative etiology 
exist. Such factors might include a known relationship of the clinical event to a concomitant 
drug, past medical history of a similar event, the patient’s disease state, intercurrent illness, 
or environmental factors. 
Unrelated 
A clinical event in which a relationship to the study drug seems improbable because of 
factors such as inconsistency with known effects of the study drug; lack of a temporal 
association with study drug administration; lack of association of the event with study drug 
withdrawal or rechallenge; and/or presence of alternative explanations for the event. 
Alternative explanations might include a known relationship of the clinical event to a 
concomitant drug, past medical history of a similar event, the patient’s disease state, 
intercurrent illness, or environmental factors. 
8.6.4. 
Adverse Event Reporting Period 
The start of the AE reporting for a study patient will coincide with study day 0, upon the start of 
dosing. After the first administration of study drug, all AEs (serious and nonserious, related and 
unrelated) should be reported. Unless a patient withdraws consent for follow-up, each patient 
must be followed until the end of the AE reporting period at 30 days after the final cirmtuzumab 
administration or when any ongoing drug-related AEs and/or SAEs have resolved or become 
stable. The investigator should use appropriate judgment in ordering additional tests as necessary 
to monitor the resolution of events. The medical monitor or Oncternal may request that certain 
AEs be followed longer.  
Investigators are not obligated to actively seek information regarding the occurrence of new 
SAEs beginning after the 30-day post-cirmtuzumab period. However, if the investigator learns of 
such an SAE and that event is deemed relevant to the use of cirmtuzumab, he/she should 
promptly document and report the event. A longer reporting period applies in the case of 
pregnancy (see Section 8.6.6). 
8.6.5. 
Adverse Event Reporting Requirements 
Whether completing a paper SAE form or entering the SAE through the EDC system, SAEs must 
be reported to the sponsor or designee within 24 hours of first awareness.  
Investigators must also submit written safety reports as required by the IRB within timelines set 
by their IRBs. The study site should retain documentation of the submission of expedited safety 
reports to the IRB, and their receipt.  
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The following minimum information is required when reporting the SAE to the sponsor or 
designee: 
• Patient identification (ie, patient number, sex, age) 
• Description of the SAE (diagnosis preferred, symptoms, etc.) 
• Study drug and causal relationship of the SAE to the study drugs 
• Investigator name 
The original SAE form and any follow-up forms must be kept on file at the study site. An SAE is 
followed until it is considered resolved, it returns to baseline, is chronically ongoing, or 
explained otherwise by the principal investigator.  
Contact information for reporting an SAE to Oncternal (or designee) is provided in Table 4. 
Table 4: Contact Information for Reporting Serious Adverse Events or Pregnancies 
Function 
Contact Information 
Vigilare International 
E-mail: SAEONTX@vigilareintl.com 
8.6.6. 
Pregnancy and Reporting 
Each female patient should be instructed to inform the investigator immediately if she becomes 
pregnant at any time between the start of study screening until 30 days after the last 
administration of study drug.  
The investigator should counsel the patient regarding the possible effects of study drug exposure 
on the fetus and the need to inform the study center, the medical monitor, and Oncternal (or 
designee) of the outcome of the pregnancy. 
Neither the pregnancy itself nor an induced elective abortion to terminate the pregnancy without 
medical reasons is considered an AE; such occurrences should be reported on the appropriate 
pregnancy report forms. However, if the outcome of the pregnancy meets the criteria for 
classification as an SAE (ie, spontaneous abortion, induced abortion due to complications, 
stillbirth, neonatal death, or congenital anomaly [including that in an aborted fetus]), the 
investigator should follow the procedures for reporting SAEs (ie, report the event to Oncternal 
[or designee] and follow up by submission of the appropriate AE eCRFs (see Section 8.6.5). 
Information regarding any pregnancy in a study patient or the female partner of a male patient 
must be documented on a pregnancy report form and forwarded to Oncternal (or designee) 
within 24 hours of becoming aware of the pregnancy. Monitoring of the pregnancy in both 
female study patients and female partners of male study patients should continue until the 
conclusion of the pregnancy. For female partners of male study patients, such monitoring applies 
if they became pregnant in the period from the patient’s start of study drug until 30 days after the 
patient’s last dose of study drug. The outcome of the pregnancy should be reported on the 
pregnancy outcome report form within 5 days of the conclusion of the pregnancy. If the end of 
the pregnancy occurs after the study has been completed, the outcome should be reported to 
Oncternal (or designee). 
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Study Protocol:  CIRM-0001 
Oncternal Therapeutics, Inc. 
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Contact information for reporting a pregnancy to Oncternal (or designee) is provided in Table 4. 
8.6.7. 
Sponsor Reporting Requirements 
Each SAE or special situation report received from the investigator will be evaluated by 
Oncternal (or designee). Oncternal (or designee) will assess the seriousness of the event the 
expectedness of the event, and the relationship to participation in the study. Oncternal (or 
designee) will also indicate whether there is concurrence with the details of the report provided 
by the investigator.  
Oncternal (or designee) will provide information for reporting of suspected, unexpected, serious 
adverse reactions (SUSARs) to the FDA per US FDA CFR. SUSARS will be reported to within 
7 calendar days for life-threatening and fatal events, or 15 calendar days for all others. These 
timeframes begin with the first notification of the event from the reporting investigator to 
Oncternal (or designee), which represents the start of the regulatory clock (Day 0). . 
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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Analysis Plan 
Details of the statistical analyses will be fully described in a statistical analysis plan to be 
finalized prior to the analyses. 
9.1.1. 
Pharmacokinetics 
Pharmacokinetic parameters will be calculated using non-compartmental methods. Only serum 
concentrations greater than or equal to the validated lower limit of quantitation (LLQ) will be 
used in the pharmacokinetic analyses. Per-protocol times will be used to calculate mean serum 
concentrations for graphical displays. Actual blood sampling times will be used in all 
pharmacokinetic analyses.  
9.1.2. 
Pharmacodynamics 
For each pharmacodynamic variable, the value at each assessment will be described. Changes 
from baseline to each assessment and the most extreme changes from baseline during the study 
will be summarized using tabular and graphical methods. The data may also be described by 
baseline variables such as sex, age, weight, body-mass index, and disease type (CLL/SLL, MCL 
or MZL). 
As appropriate, changes in the pharmacodynamic parameters will be assessed using paired t-tests 
or analysis of covariance (ANCOVA) with baseline values as covariates; in these analyses, both 
changes from baseline to each subsequent time point and most extreme on study changes will be 
evaluated.  
9.1.3. 
Efficacy Analyses 
Tumor control will be documented at each assessment by response category (eg, CR, PR, PR-L, 
SD, PD, or NE), as defined for each response parameter, the SPDs, percentage change in the 
SPDs from the pre-cirmtuzumab and pre-ibrutinib baselines (Part 1), or pretreatment baseline 
(Parts 2 and 3); percentage change in the SPDs from the nadir, date that response is first 
documented, date that response is confirmed, and date of tumor progression. Evaluable patients 
for efficacy are those who have completed treatment and have had the planned 3 month post 
cirmtuzumab + ibrutinib combination therapy imaging studies or had documented or clinical PD 
following 28 days of therapy. These analyses will be further described in the Statistical Analysis 
Plan. 
9.1.4. 
Other Analyses 
Using appropriate regression techniques, possible relationships between patient characteristics 
(eg, sex, race, age, weight, tumor characteristics, dose) and outcome measures 
(eg, pharmacodynamic and pharmacokinetic parameters) may be assessed. Similarly, 
associations between outcome measures (eg, relationships between pharmacokinetic and 
pharmacodynamic parameters) may be evaluated. 
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9.2. 
Timing of Analyses 
9.2.1. 
Interim Analyses 
During Parts 1 and 2, conference calls among the members of the SRC will be conducted 
periodically to discuss study progress, exchange study information, and review safety events, 
determine whether additional dose levels should be evaluated, and discuss potential amendments 
to the protocol. It is expected that these discussions will be scheduled at intervals of ~4 weeks 
unless accrual to the study and decisions regarding study conduct or transitions between the 
dosing cohorts indicate the need for an alternate schedule of reviews. As needed for scientific or 
business reasons, Oncternal may collate and summarize available study results during conduct of 
the study. 
During Part 2 of the study, interim futility analyses are planned that will evaluate whether there 
is sufficient antitumor activity to warrant further development of the cirmtuzumab + ibrutinib 
combination in the selected disease types (CLL/SLL and MCL). The interim analysis will be 
performed when: ≥9 evaluable patients with either disease type from Part 1 and Part 2 of the 
study (eg, ≥6 from Part 1 and ≥3 from Part 2) have: a) received treatment using a dose of 
cirmtuzumab that is at or below the RDR for the combination, and, b) have ≥24 weeks of 
evaluable efficacy data on combination treatment.  
In patients with CLL/SLL, the target CR rate of interest with cirmtuzumab + ibrutinib is an 
increment of ≥25% over that expected with ibrutinib alone. Thus, for CLL/SLL a CR rate of 
≥30% is targeted with the combination based on knowledge of an anticipated CR rate of ≤5% 
with ibrutinib monotherapy [Byrd 2013; Byrd 2014; Farooqui 2015; Burger 2015, 
O’Brien 2016]. Futility will be tested using a 1-sided exact binomial CI upper bound of 90% 
considering all evaluable patients meeting the criteria (a and b) described above. Assuming the 
minimum futility sample for CLL/SLL, if 0/9 evaluable patients experience a CR, then a 
population CR rate of ≥30% can be ruled out with >90% certainty (1-sided exact binomial 90% 
CI upper bound=22.5%). The interim analysis of this study presented at ASCO 2020 showed that 
the CLL/SLL data did not satisfy the hypothesis that cirmtuzumab + ibrutinib would produce a 
CR rate 25% greater than that for ibrutinib alone [Lee 2020]. Therefore, the number of patients 
to be enrolled and randomized into Part 3 was reduced to include approximately 30 patients. 
For MCL, a CR rate of ≥50% is targeted with the combination based on knowledge of an 
anticipated CR rate of ≤23 to 27% with ibrutinib monotherapy [Wang 2013; Dreyling 2016, 
Maruyama 2016; Wang 2015, Rule 2019]. Pooled analyses of large single agent ibrutinib studies 
in MCL indicate an overall CR rate of 27% with a 23% CR rate in those previously receiving 2 
or more prior treatments [Rule 2019]. The interim analysis of this study presented at ASCO 2020 
[Lee 2020] indicates that a complete response rate of 58% was achieved in heavily pre-treated 
patients with MCL. Because of the promising clinical results from this interim analysis, the 
sample size of the MCL expansion study was increased.  
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9.2.2. 
Final Analyses 
9.2.2.1. 
Part 1 (Cirmtuzumab → Cirmtuzumab + Ibrutinib) and 
Part 2 (Cirmtuzumab + Ibrutinib)) 
Parts 1 and 2 of the study may be reported separately from Part 3. Final study reporting for these 
components of the study is expected to occur after all Part 1 and 2 patients have completed 
planned cirmtuzumab treatment and have been followed for ≥30 days thereafter. 
9.2.2.2. 
Part 3 (Cirmtuzumab + Ibrutinib versus Ibrutinib) 
Final study reporting for Part 3 of the study is expected to occur after all Part 3 patients have 
discontinued study treatment or ≥72 weeks after accrual of the final patient (whichever occurs 
earlier).  
9.3. 
Basis for the Planned Sample Sizes 
9.3.1. 
Part 1 (Cirmtuzumab → Cirmtuzumab + Ibrutinib) and 
Part 2 (Cirmtuzumab + Ibrutinib) 
Sample sizes for Part 1 and Part 2 of the study are not based on formal statistical hypotheses but 
on experience from similar types of Phase 1b dose-ranging studies and Phase 2 expansion 
cohorts of patients treated with the same regimen.  
9.3.2. 
Part 3 (Cirmtuzumab + Ibrutinib versus Ibrutinib) 
In patients with CLL/SLL receiving ibrutinib, rates of CR have been ≤5% [Byrd 2013; 
Byrd 2014; Farooqui 2015; Burger 2015, O’Brien 2016]. Based on these data, it is assumed that 
in Part 3 of this trial, the CR rate in patients with CLL/SLL receiving ibrutinib monotherapy will 
be ≤5%. A ≥25% absolute improvement in CR rate (to ≥30%) is targeted for patients with 
CLL/SLL treated with cirmtuzumab + ibrutinib, with testing of this hypothesis using Fisher’s 
exact test with a 1-sided significance level of ≤0.05. 
The interim analysis performed for ASCO 2020 showed that the CLL/SLL data did not satisfy 
the hypothesis that cirmtuzumab + ibrutinib would produce a CR rate 25% greater than that for 
ibrutinib alone [Lee 2020]. Therefore, the number of patients to be enrolled and randomized into 
Part 3 was reduced to include approximately 30 patients. 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Study Conduct 
Oncternal will serve as the regulatory sponsor for the study and will maintain the investigational 
new drug (IND) applications with the FDA. The current and future protocol amendments will be 
submitted to Oncternal’s IND (IND#133131) for cirmtuzumab and the trial design has been and 
will be subject to review by the FDA. 
Oncternal will serve as the operational coordinator for all aspects of the study and will oversee 
conduct of the study at participating study centers and through contract research organization 
(CROs). The CROs will perform activities relating to pharmacovigilance, site monitoring, data 
collection, data management and study reporting, sample handling, centralized performance of 
pharmacokinetic and pharmacodynamic assays, and centralized assessments of drug efficacy 
(Part 3 only). 
10.2. 
Study Committees 
During Parts 1, 2, and 3 of the study, assessments of safety and trial conduct will be performed 
by a safety review committee (SRC) comprising the investigators, the medical monitor, and the 
Oncternal study director. AEs and SAEs will be reviewed on an ongoing basis to identify any 
safety concerns. Conference calls among the members of the SRC will be conducted periodically 
to discuss study progress, exchange study information, and review safety events (in particular, 
SAEs and AEs leading to dose interruption, dose reduction, or therapy discontinuation), 
determine whether the dose range should be restricted or whether additional dose levels should 
be evaluated based on emerging safety data, and discuss potential amendments to the protocol.  
10.3. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.4. 
Institutional Review Board (IRB) 
This protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB. Approval from the IRB must be 
obtained before starting the study and should be documented in a letter from the IRB to the 
investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.  
Any modifications or amendments made to the protocol or informed consent document after 
receipt of the initial IRB approval must also be submitted to the IRB for approval before 
implementation. Only changes necessary to eliminate apparent immediate hazards to the patients 
may be initiated prior to IRB approval. In that event, the investigator must notify the IRB, the 
medical monitor, and Oncternal in writing within 5 working days after implementation. If a 
change to the protocol in any way increases the risk to the patient or changes the scope of the 
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study, then written documentation of IRB approval must be received by Oncternal before the 
amendment may take effect.  
10.5. 
Informed Consent 
The investigator, or designee (designee must be listed on the Study Personnel 
Responsibility/Signature Log), must explain to each patient the purpose and nature of the study, 
the study procedures, the possible adverse effects, and all other elements of consent as defined in 
21 CFR Part 50 and other applicable national and local regulations governing informed consent. 
Each patient must provide a signed and dated informed consent before enrollment into this study. 
Signed consent forms must remain in each patient’s study file and be available for verification by 
study monitors at any time. 
10.6. 
Confidentiality 
Every effort will be made to maintain the anonymity and confidentiality of all patients during 
this clinical study. However, because of the experimental nature of this study drug, the 
investigator agrees to allow the IRB, representatives of Oncternal and its designated agents, and 
authorized employees of appropriate regulatory agencies to inspect the facilities used in this 
study and, for purposes of verification, allow direct access to the study center records of all 
patients enrolled into this study. This includes providing by fax, email, or regular mail 
de-identified copies of clinical, laboratory, ECG, radiology, pathology, and/or other test results 
when requested by Oncternal. A statement to this effect will be included in the informed consent 
and a permission form authorizing the use of protected health information will also be included. 
In accordance with local and national patient privacy regulations, the investigator or designee 
must explain to each patient that in order to evaluate study results, the patient’s protected health 
information obtained during the study may be shared with IRBs, Oncternal and its designees, and 
regulatory agencies. It is the investigator’s or designee’s responsibility to obtain written 
permission to use protected health information from each patient. If a patient withdraws 
permission to use protected health information, it is the investigator’s responsibility to obtain the 
withdrawal request in writing from the patient and to ensure that no further data will be collected 
from the patient. Any data collected on the patient before withdrawal will be used in the analysis 
of study results. Oncternal will only use or disclose the patient’s protected health information as 
defined in the informed consent document. 
The investigator must assure that each patient’s anonymity will be strictly maintained, and that 
each patient’s identity is protected from unauthorized parties. Only patient initials, date of birth, 
and an identification code (but no patient names) should be recorded on any form or biological 
sample submitted to the IRB, to Oncternal or its designees (eg, laboratories), or to regulatory 
authorities. However, sufficient information must be retained at the study center to permit 
sample data and data in the database to be connected with the unique patient number assigned to 
each study participant. 
The investigator agrees that all information received from Oncternal, including but not limited to 
the study drug, the investigator brochure, this protocol, the eCRFs, and any other study 
information remain the sole and exclusive property of Oncternal during the conduct of the study 
and thereafter. This information is not to be disclosed to any third party (except employees or 
agents directly involved in the conduct of the study or as required by law) without prior written 
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Oncternal Therapeutics, Inc. 
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consent from Oncternal. The investigator further agrees to take all reasonable precautions to 
prevent the disclosure by any employee or agent of the study center to any third party or 
otherwise into the public domain. 
10.7. 
Sample Shipping, Storage, and Retention 
Routine clinical safety samples (for serum virology, serum pregnancy test, serum chemistry, 
hematology, and coagulation) will be analyzed at the CLIA certified clinical laboratory at the 
study center and will not be shipped.  
Other samples (serum for pharmacokinetics, blood, bone marrow, and plasma for 
pharmacodynamics, serum for immunogenicity, and blood and bone marrow for disease 
characterization, exploratory biomarkers, and MRD assessment) will be prepared following the 
instructions outlined in the clinical study laboratory manual.  
These samples will be shipped to Oncternal, UCSD or the contract analytical laboratories using a 
shipping service designated by Oncternal and as specified in the study laboratory manual. For the 
duration of the sample analysis campaign, samples will be stored at these contract laboratory 
facilities or sent for long-term storage at a storage facility designated by Oncternal.  
10.8. 
Study Files and Retention of Records and Biological Samples 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified by the IRB, representatives 
of Oncternal and its designated agents, and authorized employees of appropriate regulatory 
agencies. These documents should be classified into at least the following 2 categories: (1) 
investigator’s study file, and (2) patient clinical source documents.  
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, the 
IRB and governmental approval with correspondence, signed informed consent documents, drug 
accountability records, staff curriculum vitae and authorization forms (eg, Form FDA 1572), and 
other appropriate documents and correspondence pertaining to the conduct of the study.  
The required source data referenced in the monitoring plan for the study should include 
sequential notes containing at least the following information for each patient: 
• Patient identification (name, date of birth, gender) 
• Documentation that the patient meets eligibility criteria, eg, history, physical 
examination, and confirmation of diagnosis (to support inclusion and exclusion criteria) 
• Participation in trial (including trial number) 
• Trial discussed and date of informed consent 
• Dates of all visits 
• Documentation that protocol-specific procedures were performed 
• Results of efficacy parameters, as required by the protocol 
• Start and end date (including dose regimen) of study drug (including relevant drug 
dispensing information) 
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• Record of all AEs and other safety parameters (including start and end date, causality and 
intensity) 
• Concomitant medications (including start and end date and dose if relevant dose changes 
occur) 
• Date of trial completion and reason for discontinuation, if applicable 
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (ie, the United States, Europe, or 
Japan) and until there are no pending or contemplated marketing applications in an ICH region; 
or, if no application is filed or if the application is not approved for such indication, until 2 years 
after the investigation is discontinued and regulatory authorities have been notified or for 
15 years, whichever is longer. Investigators may be required to retain documents longer if 
required by applicable regulatory requirements, by local regulations, or by an agreement with 
Oncternal. The investigator must notify Oncternal and obtain written approval from Oncternal 
before destroying any clinical study records. The investigator will promptly notify Oncternal in 
the event of accidental loss or destruction of any study records. Oncternal will inform the 
investigator of the date that study records may be destroyed or returned to Oncternal. 
Oncternal must be notified in advance and must provide express written approval of any change 
in the maintenance of the foregoing documents if the investigator wishes to move study records 
to another location or assign responsibility for record retention to another party.  
If the investigator cannot guarantee this archiving requirement at the study center for any or all 
of the documents, special arrangements must be made between the investigator and Oncternal to 
store these in sealed containers outside of the study center so that they can be returned sealed to 
the investigator in case of a regulatory audit. When source documents are required for the 
continued care of the patient, appropriate copies should be made for storage outside of the study 
center. 
Any biological samples retained by the investigator that have not been collected by the CROs 
will be stored and maintained by the investigator until notification is received from Oncternal 
that the retained samples and records no longer need to be retained. The investigator must obtain 
written permission from Oncternal before disposing of any retained samples. The investigator 
should promptly notify Oncternal in the event of accidental loss or destruction of any study 
samples. With the permission of Oncternal, the retained samples may be transferred to an 
acceptable designee, such as another investigator, another institution, a contract laboratory, a 
contract storage site, or to Oncternal. 
10.9. 
Modifications of the Protocol  
Protocol modifications, except those intended to reduce immediate risk to study participants, will 
be made only by Oncternal. All protocol modifications must be submitted to the IRB in 
accordance with local requirements. Except as noted in Section 10.4, IRB approval must be 
obtained before changes can be implemented. 
10.10. Case Report Forms 
Authorized study center personnel will submit all required information into a central electronic 
case report form (eCRF) designed for this study and maintained by Oncternal’s CRO, according 
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to the completion guidelines that will be provided. An eCRF is required and must be completed 
for each enrolled patient, with all required study data accurately recorded such that the 
information matches the data contained in medical records (eg, physicians’ notes, nurses’ notes, 
study center charts, or other study-specific source documents). The investigator will ensure that 
the eCRFs are accurate, complete, legible, and completed in a timely fashion after each patient’s 
visit. If a patient withdraws from the study, the reason must be noted on the eCRF and thorough 
efforts should be made to clearly document outcome.  
The eCRFs for this study will exist within a web-based electronic data capture (EDC) system.  
10.11. Study Drug Accountability  
The disposition of all investigational cirmtuzumab and ibrutinib should be documented from the 
time of receipt at the study center through patient administration. An investigational drug 
accountability log must be maintained for drug accountability. It is acceptable to use a protocol-
specific form or a study center form that captures the relevant information. Within the drug 
accountability log, the responsible study center personnel must maintain accurate records of the 
receipt of all cirmtuzumab and ibrutinib shipped by Oncternal (or its designee), including, but 
not limited to, the date received, lot number, amount received, pertinent details about the 
condition of the study drug upon receipt based on visual inspection, and the disposition of the 
drug (eg, to storage). If a cirmtuzumab or ibrutinib drug shipment arrives damaged, or if there 
are any other complaints relating specifically to the drug, a product complaint should be emailed 
to the sponsor or the sponsor’s representative. Cirmtuzumab and ibrutinib accountability records 
must also be maintained that include the patient number to whom the study drug was 
administered and the date, quantity and lot number of the cirmtuzumab administered. 
Study personnel must ensure that cirmtuzumab and ibrutinib are kept in a secure locked area 
with access limited to authorized personnel. The study drugs must not be used outside the 
context of this protocol. Under no circumstances should the investigator or study center 
personnel supply cirmtuzumab or ibrutinib designated for this study to other investigators, 
patients, or clinics, or allow the study drugs to be used other than as directed by this protocol 
without the prior authorization from Oncternal.  
Depending upon the decision of Oncternal, remaining unused cirmtuzumab and ibrutinib 
supplies will be returned to Oncternal or its designee after the study is completed or will be 
discarded or destroyed at the study center. After investigational product accountability has been 
performed, cirmtuzumab and ibrutinib may be returned or destroyed on an ongoing basis during 
the study if appropriate. If the study drug is discarded or destroyed at the study center, standard 
institutional policy should be followed. At study initiation, the monitor will evaluate the study 
center’s standard operating procedure for study drug disposal/destruction in order to ensure that 
it complies with Oncternal requirements. At the end of the study, following final drug inventory 
reconciliation by the monitor, the study center will dispose of and/or destroy all unused study 
drug supplies, including empty containers, according to these procedures. If the study center 
cannot meet Oncternal requirements for disposal, arrangements will be made between the study 
center and Oncternal or its representative for destruction or return of unused study drug supplies. 
All study drug supplies and associated documentation will be periodically reviewed and verified 
by the study monitor over the course of the study. Study drug accountability records must be 
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readily available for inspection by the study monitor or other representatives of Oncternal or by 
regulatory authorities.  
10.12. Monitoring 
Representatives of Oncternal or its designee will monitor this study until completion at 
appropriate intervals. Clinical site monitoring is conducted to ensure that the rights and well-
being of trial participants are protected, that the reported trial data are accurate, complete and 
verifiable and the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), and within ICH guidelines and the CFR. 
In accordance with GCP, the study monitor must have direct access to the investigator’s source 
documentation in order to verify the data recorded in the eCRFs for consistency. Because of 
constraints caused by the COVID-19 pandemic, Oncternal has determined that remote and 
centralized monitoring of study data is acceptable. The investigator agrees to cooperate with the 
monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved. 
10.13. Inspections 
The source documents for this trial must be made available to appropriately qualified personnel 
from Oncternal or its representatives, to IRBs, and to regulatory authority or health authority 
inspectors as a part of their responsibility to protect human subjects in research. The investigator 
agrees to provide access to records, facilities, and personnel for the effective conduct of any 
inspection or audit to representatives of Oncternal and regulatory agencies. It is important that 
the investigator and relevant institutional personnel are available during monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process. If the investigator 
is notified of an inspection by a regulatory authority the investigator agrees to notify Oncternal 
immediately.  
10.14. Data Management 
The eCRFs for this study will exist within a web-based electronic data capture (EDC) system.  
During the data collection process, automated quality assurance programs will be used to identify 
missing data, out-of-range data, and other data inconsistencies. Requests for data clarification or 
correction will be forwarded to the investigative study center for resolution. 
Quality assurance and quality control systems will be implemented and maintained according to 
written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
electronic records and electronic signatures.  
10.15. Communications with Regulatory Authorities 
Oncternal (or its designee) will have responsibility for interactions with the FDA and any other 
relevant regulatory authorities. Oncternal will maintain their IND for the development of 
cirmtuzumab in support of the study in the US. In fulfilling these responsibilities, Oncternal (or a 
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designee) will collect and assemble all required regulatory documents (eg, Form FDA 1572, 
investigator financial disclosure forms, protocol and protocol amendments, investigator 
brochures, informed consent documents, annual reports) as required by regulation. Oncternal (or 
a designee) will assume primary responsibility for AE reporting to regulatory authorities (as 
described in Section 8.6.7). 
10.16. Public Notification of Study Conduct 
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and to 
ensure meeting the requirement of the International Committee of Medical Journal Editors 
(ICMJE) as a condition of consideration for publication of study results, Oncternal will register 
this protocol at the ClinicalTrials.gov website (or equivalent). Oncternal will appropriately 
update the information at the website relating to study design and conduct during the course of 
the study. In order to facilitate this process, investigators will need to supply Oncternal with 
appropriate contact information for study center personnel. 
10.17. Study Reporting and Publication 
Oncternal may make information obtained during this study available in order to further the 
scientific or business needs of the company or as required by law or regulation. In this regard, 
Oncternal may provide study information to private or public organizations (eg, business 
partners, collaborators, consultants, CROs, investors, other physicians who are conducting 
similar studies, funding organizations, regulatory authorities, or other government authorities). 
The results may also be used for papers, abstracts, posters or other material presented at 
scientific meetings or published in professional journals or as part of an academic thesis. 
Oncternal will prepare a clinical study report for submission to relevant regulatory agencies. 
Oncternal will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). An abbreviated report may be 
prepared in certain cases, as appropriate. 
Oncternal intends that the data from this study will be presented and published. Because the 
study will ultimately part of a multicenter clinical trial, data from all study centers will be pooled 
and analyzed for a primary publication of the study results. Oncternal will coordinate and 
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relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in 
a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia 
Group. Haematologica. 2016 Dec;101(12):1573-1580. PMID: 27198718.  
Woosley RL, Romero KA. QTdrugs List, 2015 Jul 3, AZCERT, Inc., Available at: 
www.Crediblemeds.org (accessed 27 Dec 2016). 
Woyach JA, Bojnik E, Ruppert AS, Stefanovski MR, Goettl VM, Smucker KA, Smith LL, 
Dubovsky JA, Towns WH, Macmurray J, Harrington BK, Davis ME, Gobessi S, Laurenti L, 
Chang BY, Buggy JJ, Efremov DG, Byrd JC, Johnson AJ. Bruton's tyrosine kinase (BTK) 
function is important to the development and expansion of chronic lymphocytic leukemia (CLL). 
Blood. 2014a Feb 20;123(8):1207-13. PMID: 24311722. 
Yamaguchi T, Yanagisawa K, Sugiyama R, Hosono Y, Shimada Y, Arima C, Kato S, Tomida S, 
Suzuki M, Osada H, Takahashi T. NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain 
EGFR survival signaling in lung adenocarcinoma. Cancer Cell. 2012 Mar 20;21(3):348-61. 
PMID: 22439932. 
Yoda A, Oishi I, Minami Y. Expression and function of the Ror-family receptor tyrosine kinases 
during development: lessons from genetic analyses of nematodes, mice, and humans. J Recept 
Signal Transduct Res. 2003 Feb;23(1):1-15. PMID: 12680586. 
Younes A, Thieblemont C, Morschhauser F, Flinn I, Friedberg JW, Amorim S, Hivert B, Westin 
J, Vermeulen J, Bandyopadhyay N, de Vries R, Balasubramanian S, Hellemans P, Smit JW, 
Fourneau N, Oki Y. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell 
non-Hodgkin lymphoma: a non-randomised, phase 1b study. Lancet Oncol. 2014 
Aug;15(9):1019-26. PMID: 25042202.  
Yu J, Chen L, Cui B, Wu C, Choi MY, Chen Y, Zhang L, Rassenti LZ, Widhopf GF, Kipps TJ. 
Cirmtuzumab inhibits Wnt5a-induced Rac1-activation in chronic lymphocytic leukemia treated 
with ibrutinib. Leukemia. 2017 Jun;31(6):1333-1339. PMID: 27904138. 
Yu J, Chen Y, Chen L, Zhang L, Rassenti L, Widhopf GF, Kipps, TJ.  Cirmtuzumab inhibits 
ibrutinib-resistant, Wnt5a-induced Racl activation and proliferation in mantle cell lymphoma. 
Oncotarget 2018; 9: 24731-24736. PMID: 29872501.  
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Yun S, Vincelette ND, Acharya U, Abraham I. Risk of atrial fibrillation and bleeding diathesis 
associated with ibrutinib treatment: a systematic review and pooled analysis of four randomized 
controlled trials. Clin Lymphoma Myeloma Leuk. 2016 Sep 19. [Epub ahead of print]. 
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Zhang H, Qiu J, Ye C, Yang D, Gao L, Su Y, Tang X, Xu N, Zhang D, Xiong L, Mao Y, Li F, 
Zhu J. ROR1 expression correlated with poor clinical outcome in human ovarian cancer. Sci 
Rep. 2014a Jul 24;4:5811. PMID: 25056203. 
Zhang S, Chen L, Cui B, Chuang HY, Yu J, Wang-Rodriguez J, Tang L, Chen G, Basak GW, 
Kipps TJ. ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell 
growth. PLoS One. 2012a;7(3):e31127. PMID: 22403610.  
Zhang S, Chen L, Wang-Rodriguez J, Zhang L, Cui B, Frankel W, Wu R, Kipps TJ. The onco-
embryonic antigen ROR1 is expressed by a variety of human cancers. Am J Pathol. 2012b 
Dec;181(6):1903-10. PMID: 23041612.  
Zhang S, Cui B, Lai H, Liu G, Ghia EM, Widhopf GF 2nd, Zhang Z, Wu CC, Chen L, Wu R, 
Schwab R, Carson DA, Kipps TJ. Ovarian cancer stem cells express ROR1, which can be 
targeted for anti-cancer-stem-cell therapy. Proc Natl Acad Sci U S A. 2014b Dec 
2;111(48):17266-71. PMID: 25411317.  
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12. 
APPENDICES 
 
12.1 
ECOG Performance Status 
12.2 
Cockcroft-Gault Method for Estimating Creatinine Clearance 
12.3 
Potent Inhibitors and Inducers of CYP3A4 
12.4 
RAI Staging System for CLL/SLL 
12.5 
Efficacy Assessments - CLL 
12.6 
Efficacy Assessment – Lymphoma 
 
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12.1. 
ECOG Performance Status 
Grade 
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, eg, light housework, 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 
Reference: [Oken 1982] 
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12.2. 
Cockcroft-Gault Method for Estimating Creatinine Clearance 
Formulas for calculating the estimated creatinine clearance (eClCR) are provided below. The 
formula appropriate to the units in which serum creatinine was measured and the patient’s sex 
should be used. 
Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance 
Serum  
Creatinine Units 
Sex 
Formula 
 
 
 
 
 
 
mg/dL 
Males 
eClCR 
[mL/min] 
= (140-patient age [years]) × patient weight [kilograms] × 1.0 
72 × patient serum creatinine [mg/dl] 
 
 
Females 
eClCR 
[mL/min] 
= (140-patient age [years]) × patient weight [kilograms] × 0.85 
72 × patient serum creatinine [mg/dl] 
 
 
µM/dL 
Males 
eClCR 
[mL/min] 
= (140-patient age [years]) × patient weight [kilograms] × 1.23 
Patient serum creatinine [µM/dL] 
 
 
Females 
eClCR 
[mL/min] 
= (140-patient age [years]) × patient weight [kilograms] × 1.04 
Patient serum creatinine [µM/dL] 
 
 
 
 
 
Abbreviation: eClCR=estimated creatinine clearance 
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12.3. 
Potent Inhibitors and Inducers of CYP3A4 
Effect on 
CYP3A  
Drug Class 
Medications 
Moderate to 
Strong CYP3A 
Inhibitors 
Antibiotics 
chloramphenicol, ciprofloxacin, clarithromycin, erythromycin, 
telithromycin 
Antiemetic 
aprepitant 
Antifungals 
ketoconazole, fluconazole, itraconazole, posaconazole, 
voriconazole 
Antiviral 
protease inhibitors 
amprenavir, atazanavir, boceprevir, cobicistat, darunavir, 
elvitegravir, fosamprenavir, indinavir, lopinavir, nelfinavir, 
ritonavir, saquinavir, telaprevir, tenofovir, tipranavir 
Calcium-channel blockers 
diltiazem, mibifradil, verapamil 
Foods/herbs 
grapefruit, grapefruit juice, Seville oranges 
Serotonin antagonist 
nefazodone 
Tyrosine kinase inhibitor 
imatinib 
Vasopressin antagonist 
conivaptan 
Moderate to 
Strong CYP3A 
Inducers 
 
Antibiotics 
nafcillin, rifampin 
Anticonvulsants 
carbamazepine, phenobarbital, phenytoin 
Antiviral reverse 
transcriptase inhibitors 
efavirenz, etravirine 
Endothelin receptor 
antagonist 
bosentan  
Foods/herbs 
St. John’s wort 
Wakefulness-promoting 
agent 
modafinil 
Reference: [FDA 2014] 
Abbreviation: CYP=cytochrome P450 enzyme 
 
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12.4. 
RAI Staging System for CLL/SLL 
Grade 
Disease Manifestations 
0 
• 
Absolute lymphocytosis (>15 × 109/L) 
• 
No lymphadenopathy, splenomegaly, hepatomegaly, anemia (hemoglobin <11 g/dL), or 
thrombocytopenia (platelet count <100 × 109/L) 
1 
• 
Lymphadenopathy with or without absolute lymphocytosis (>15 × 109/L) 
• 
No splenomegaly, hepatomegaly, anemia (hemoglobin <11 g/dL), or thrombocytopenia 
(platelet count <100 × 109/L) 
2 
• 
Absolute lymphocytosis (>15 × 109/L) 
• 
Splenomegaly and/or hepatomegaly with or without absolute lymphocytosis (>15 × 109/L) 
and/or lymphadenopathy 
• 
No anemia (hemoglobin <11 g/dL) or thrombocytopenia (platelet count <100 × 109/L) 
3 
• 
Absolute lymphocytosis (>15 × 109/L) 
• 
Anemia (hemoglobin <11 g/dL) with or without absolute lymphocytosis (>15 × 109/L), 
lymphadenopathy, splenomegaly, and/or hepatomegaly 
• 
No thrombocytopenia (platelet count <100 × 109/L) 
4 
• 
Thrombocytopenia (platelet count <100 × 109/L) with or without absolute lymphocytosis 
(>15 × 109/L), lymphadenopathy, splenomegaly, hepatomegaly, and/or anemia 
(hemoglobin <11 g/dL) 
Reference: [Rai 1975] 
 
12.5. 
Efficacy Assessments – CLL/SLL 
The determination of CLL/SLL response and progression will be based on standardized criteria 
[Hallek 2008], as recently updated [Hallek 2018; Cheson 2012].  
12.5.1. 
 Identification and Measurement of Tumor Lesions and Organomegaly 
12.5.1.1.   Index Lesions 
At screening, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should be 
located in disparate regions of the body. Only peripheral nodes need be selected as index lesions. 
However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed whenever 
these sites are involved. 
Index lesions will be measured and recorded at screening and at the stipulated intervals. The 
cross-sectional dimensions (the largest cross-sectional diameter, ie, the LD × LPD) will be 
recorded (in cm) for each index lesion. The product of the perpendicular diameters (PPD) (in 
cm2) for each index lesion and SPD (in cm2) for all index lesions will be calculated and recorded. 
The screening SPD will be used as references by which objective tumor response will be 
characterized during treatment. The nadir LD of individual lesions and the nadir SPD will be 
used as references by which CLL/SLL progression will be characterized. All LD and LPD 
diameters will be reported in centimeters and all PPDs and SPDs will be reported in centimeters 
squared. 
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
screening. A lymph node lesion is considered abnormal if it has a single diameter that is >1.5 cm 
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and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being ≥1.0 cm and the LPD also being ≥1.0 cm. 
Index lesions measuring >1.5 cm in the LD, regardless of the measurement of the LPD, will be 
prioritized during screening index lesion selection. 
At follow-up timepoints, the LDs for individual lesions and the SPD of all nodal index lesions 
will be considered. Because nodal index lesions that have one or both diameters >0 cm and 
<1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned for each 
diameter that meets these criteria and the resulting PPD will be used in SPD calculations. Based 
on this convention, a CR may be achieved even if an SPD value is >0 cm2, (ie, if all lymph nodes 
measure <1.0 cm2). 
A new node that measures ≥1.5 cm in any diameter will be considered progressive disease 
[Hallek 2018]. 
In cases in which a large lymph node mass has split into multiple components, only those 
elements that are >1.0 cm in ≥1 diameter will be considered abnormal and used in calculating the 
SPD. Progression of the lesion can only be based on the SPD of abnormal sub-components. 
Lesion sub-components that are considered normal but measurable will have the true PPDs 
calculated, with the result used only for calculating an accurate nadir. Similarly, lesion sub-
components that are visible but neither abnormal nor measurable will have the default PPD of 
1.0 cm2 (1.0 cm × 1.0 cm) stored only for the purposes of calculating the nadir SPD value. 
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally. 
12.5.1.2.   Spleen and Liver 
Both the spleen and liver will be assessed by CT/MRI scan at screening and at the stipulated 
intervals during treatment. The screening and nadir values for the longest vertical dimension 
(LVD) of each organ will be used as reference to further characterize the objective tumor 
response of the measurable dimensions of the CLL/SLL during treatment. All spleen and liver 
LVD measurements should be recorded in centimeters. 
By imaging, the spleen will be considered enlarged if it is >13 cm in LVD [Bezerra 2005; 
Asghar 2011], with the LVD being obtained by multiplying the number of sections on which the 
spleen is visualized by the thickness of the sections (eg, if the spleen is seen in 14 contiguous 
cross-sectional images with 0.5-cm thickness, the LVD is recorded as 7 cm).  
For patients with splenomegaly at screening or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement of 
the spleen (ie, the portion of the LVD that is >13 cm by imaging) at screening or nadir, not 
changes relative to the total splenic LVD.  
A 50% decrease from screening (minimum decrease of 2 cm) in the enlargement of the spleen in 
its LVD or to ≤13 cm by imaging is required for declaration of a splenomegaly response. 
Conversely, an increase in splenic enlargement by ≥50% (minimum increase of 2 cm) from nadir 
is required for declaration of splenic progression. Patients with a normal spleen LVD (ie, a LVD 
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of ≤12 cm by imaging) at nadir will only be considered to have progressed if the spleen attains a 
LVD of >14 cm by imaging. 
There is no firmly established international consensus of the size of a normal liver. For this 
study, an increase in the liver size of ≥50% of the extent enlargement of the liver below the 
costal margin defined by palpation, or the de novo appearance of hepatomegaly by imaging 
compared to baseline should be considered. However, given the impact of numerous medical 
conditions, liver size by physical examination or by CT scan is not a reliable measure of hepatic 
involvement by CLL and should only be counted if hepatomegaly is clearly attributable to 
lymphoid involvement [Hallek 2018]. 
A 50% decrease from screening (minimum decrease of 2 cm) in the enlargement of the liver in 
its LVD or to ≤18 cm by imaging is required for declaration of a hepatomegaly response. 
Conversely, an increase in liver enlargement by ≥50% (minimum increase of 2 cm) from nadir is 
required for declaration of hepatic progression.  
12.5.1.3.   Non-Index Lesions 
Any other measurable and abnormal nodal lesions not selected for quantitation as index lesions 
may be considered non-index lesions. In addition, non-measurable evidence of CLL/SLL such as 
nodal lesions with both diameters <1.0 cm, extranodal lesions, bone lesions, leptomeningeal 
disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal 
masses that are not confirmed and followed by imaging techniques, cystic lesions, previously 
irradiated lesions, and lesions with artifacts may be considered as non-index disease. 
The presence or absence of non-index disease should be recorded at screening and at the 
stipulated intervals during treatment. If present at screening, up to 6 non-index lesions should be 
recorded. The non-index disease at screening will be used as a general reference to further 
characterize regression or progression of CLL/SLL during assessments of the objective tumor 
response during treatment. Measurements are not required, and these lesions should be followed 
as “present” or “absent”. 
12.5.1.4.   Bone Marrow 
Bone marrow assessments will be based on morphologic evaluation of bone marrow biopsies. 
Immunohistochemistry may be used to assess response if the sample is indeterminate by 
morphology.  
12.5.2. 
  Definitions of Tumor Response and Progression  
Responses will be categorized as complete response (CR), complete response with incomplete 
blood count recovery (CRi), partial response (PR), partial response with lymphocytosis (PR-L), 
stable disease (SD), or progressive disease (PD). In addition, a response category of 
nonevaluable (NE) is provided for situations in which there is inadequate information to 
otherwise categorize response status. A summary of response criteria is provided in Table 5. 
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until PD/recurrence. The screening measurement will be 
taken as a reference for determinations of response. The nadir measurement will be taken as a 
reference for PD; this measurement constitutes the smallest measurement recorded, including the 
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screening measurement if this is the smallest measurement. Where imaging data are available, 
these data will supersede physical examination data in determining tumor status. 
Table 5: Summary of Response Criteria for CLL/SLL Patients 
Group 
Parameter 
CR 
PR 
PD 
SD 
A 
Lymph nodes  
None ≥1.5 cm 
Decrease ≥50% 
(from baseline)* 
Increase ≥50%  
from baseline or 
from response 
Change of  
‒49% to +49% 
Liver and/or spleen 
size† 
Spleen size <13 cm; 
liver size normal 
Decrease ≥50% 
(from baseline) 
Increase ≥50%  
from baseline or 
from response 
Change of  
‒49% to +49% 
Constitutional 
symptoms 
None 
Any 
Any 
Any 
Circulating 
lymphocyte count 
Normal 
Decrease ≥50% 
from baseline 
Increase ≥50%  
over baseline 
Change of  
‒49% to +49% 
B 
Platelet count  
≥100 × 109/L  
≥100 × 109/L or 
increase ≥50% 
over baseline  
Decrease of ≥50% 
from baseline 
secondary to CLL 
Change of  
‒49% to +49% 
Hemoglobin  
≥11.0 g/dL 
(untransfused and 
without 
erythropoietin) 
≥11 g/dL or 
increase ≥50% 
over baseline 
Decrease of ≥2 g/dL 
from baseline 
secondary to CLL 
Increase <11.0 
g/dL or <50% 
over baseline, or 
decrease <2 g/dL 
Marrow  
Normocellular, no 
CLL cells, no B-
lymphoid nodules  
Presence of CLL 
cells, or of B-
lymphoid nodules, 
or not done  
Increase of CLL cells 
by ≥50% on 
successive biopsies  
No change in 
marrow infiltrate 
Source: Hallek 2018 
*Sum of the products of 6 or fewer lymph nodes (as evaluated by CT scans and physical examination in clinical trials or by physical examination 
in general practice). 
†Spleen size is considered normal if <13 cm. There is no firmly established international consensus of the size of a normal liver; therefore, liver 
size should be evaluated by imaging and manual palpation in clinical trials and be recorded according to the definition used in a study protocol. 
CR, complete remission (all of the criteria have to be met); PD, progressive disease (at least 1 of the criteria of group A or group B has to be 
met); PR, partial remission (for a PR, at least 2 of the parameters of group A and 1 parameter of group B need to improve if previously abnormal; 
if only 1 parameter of both groups A and B is abnormal before therapy, only 1 needs to improve); SD, stable disease (all of the criteria have to be 
met; constitutional symptoms alone do not define PD). 
12.5.2.1.   Complete Response and Complete Response with Incomplete Blood Count 
Recovery 
To satisfy criteria for CR or CRi, all of the following conditions must be attained:  
• No evidence of new disease 
• ALC in peripheral blood of <4 x 109/L 
• Regression of all index nodal masses to normal size <1.5 cm in the LD 
• Normal spleen and liver size 
• Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease 
• Morphologically negative bone marrow defined as <30% of nucleated cells being 
lymphoid cells and no lymphoid nodules in a bone marrow sample that is normocellular 
for age 
• Peripheral blood meeting all of the following criteria: 
o 
ANC ≥1.5 x 109/L without need for exogenous growth factors (eg, G-CSF) 
o 
Platelet count ≥100 x 109/L without need for exogenous growth factors 
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o 
Hemoglobin ≥110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin) 
Note: Patients who fulfill all the criteria for a CR (including bone marrow criteria) but who 
have a persistent anemia, thrombocytopenia, or neutropenia or a hypocellular bone marrow 
that is related to prior or ongoing drug toxicity (and not to CLL/SLL) will be considered as a 
CRi.  
12.5.2.2.   Partial Response 
To satisfy criteria for a PR, all of the following conditions must be attained: 
• 
No evidence of new disease 
• 
A change in disease status meeting ≥2 of the following criteria, with 2 exceptions in which only 1 
criterion is needed: (1) Only lymphadenopathy is present at screening; or (2) only 
lymphadenopathy and lymphocytosis are present at screening; in these 2 cases, only 
lymphadenopathy must improve to the extent specified below:  
o Decrease in peripheral blood ALC by ≥50% from screening 
o A decrease by ≥50% from the screening in the SPD of the index nodal lesions 
o In a patient with enlargement of the spleen at screening, a splenomegaly response as 
defined in Section 12.5.1.2 
o In a patient with enlargement of the liver at screening, a hepatomegaly response as 
defined in Section 12.5.1.2 
o A decrease by ≥50% from screening in the CLL/SLL bone marrow infiltrate or in 
B-lymphoid nodules 
• No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD 
• Peripheral blood meeting ≥1 of the following criteria: 
o ANC ≥1.5 x 109/L or ≥50% increase over screening without need for exogenous 
growth factors (eg, G-CSF) 
o Platelet count ≥100 x 109/L or ≥50% increase over screening without need for 
exogenous growth factors 
o Hemoglobin ≥110 g/L (11.0 g/dL) or ≥50% increase over screening without red blood 
cell transfusions or need for exogenous growth factors (eg, erythropoietin)  
12.5.2.3.   Partial Response with Lymphocytosis 
To satisfy criteria for a PR-L, the following conditions must be attained: 
• No evidence of new disease 
• All criteria for PR achieved (per Section 12.5.2.2) except for the lack of a decrease in 
peripheral blood ALC by ≥50% from screening 
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12.5.2.4.  Stable Disease 
To satisfy criteria for SD, the following conditions must be attained: 
• No evidence of new disease 
• There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD 
12.5.2.5.   Progressive Disease 
The occurrence of any of the following events indicates PD:  
• Evidence of any new disease: 
o A new node that measures >1.5 cm in any diameter 
o New splenomegaly as defined in Section 12.5.1.2 
o New hepatomegaly as defined in Section 12.5.1.2 
o New non-index disease (eg, effusions, ascites, or other organ abnormalities related to 
CLL/SLL) 
Note: Isolated new effusions, ascites, or other organ abnormalities are not sufficient evidence 
alone of PD unless histologically confirmed. Thus, a declaration of PD should not be made if 
this is the only manifestation of apparently new disease. 
• Evidence of worsening of index lesions, spleen or liver, or non-index disease:  
o Increase from the nadir by ≥50% from the nadir in the SPD of index lesions 
o Increase from the nadir by ≥50% in the LD of an individual node or extranodal mass 
that now has an LD of >1.5 cm and an LPD of > 1.0 cm 
o Splenic progression as defined in Section 12.5.1.2 
o Hepatic progression as defined in Section 12.5.1.2 
 Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or 
other organ abnormalities related to CLL/SLL)  
 Transformation to a more aggressive histology (eg, Richter syndrome) as 
established by lymph node biopsy (with the date of the lymph node biopsy being 
considered the date of CLL/SLL progression if the patient has no earlier objective 
documentation of CLL/SLL progression)  
• Decrease in platelet count or hemoglobin that is attributable to CLL/SLL, is not 
attributable to an autoimmune phenomenon, and is confirmed by bone marrow biopsy 
showing an infiltrate of clonal CLL/SLL cells 
o The current platelet count is <100 x 109/L and there has been a decrease by >50% 
from the highest on-study platelet count  
o The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a decrease by 
>20 g/L (2 g/dL) from the highest on-study hemoglobin  
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Note: If there is uncertainty regarding whether there is true progression, the patient should 
continue study treatment and remain under close observation (eg, evaluated at 4-week 
intervals) pending confirmation of progression status. In particular, worsening of 
constitutional symptoms in the absence of objective evidence of worsening CLL/SLL will not 
be considered definitive disease progression; in such patients, both CLL/SLL-related and 
non-CLL/SLL-related causes for the constitutional symptoms should be considered. 
Worsening of disease during temporary interruption of study treatment (eg, for intercurrent 
illness) is not necessarily indicative of resistance to study treatment. In these instances, 
CT/MRI or other relevant evaluations should be considered in order to document whether 
definitive disease progression has occurred. If subsequent evaluations suggest that the patient 
has experienced persistent definitive CLL/SLL progression, then the date of progression 
should be the timepoint at which progression was first objectively documented. 
12.5.2.6.   Nonevaluable 
In a patient who does not have evidence of PD, the response status of NE will be assigned when 
there are no images or inadequate or missing images to visualize index, non-index or splenic 
disease.  
In addition, the following occurrence indicates a response status of NE:“Clinically significant” 
contemporaneous period of interruption of study drug administration or other event that in the 
opinion of the investigator suggests there is some uncertainty as to whether there is true 
progression. 
Note: When there is uncertainty of true progression, the response status of NE should not be 
used more than one time in succession. The prior and subsequent tumor assessments must not 
demonstrate PD for the NE assessment to stand. If the radiographic response is PD for the 
subsequent evaluation, even if there was an interruption to study drug administration or 
uncertainty remains about true progression, PD will be assessed (not NE) in both cases. The 
date of PD should be the date the progression was first suspected. These cases should be 
discussed in advance with the Sponsor. 
12.5.2.7.   Lymphocytosis during Therapy 
Lymphocytosis early in cirmtuzumab or ibrutinib therapy may not represent disease progression 
in patients who have persistent control of other CLL/SLL-related signs and symptoms 
[Cheson 2012]. In the absence of other objective evidence of disease progression, 
lymphocytosis alone will not preclude patients from meeting the criteria for PR if other criteria 
for PR are met and will not be considered evidence of PD if occurring in isolation. Patients 
with lymphocytosis should be continued on study drug until the occurrence of definitive disease 
progression (ie, disease progression that is manifest by worsening CLL/SLL-related signs other 
than lymphocytosis alone), or the occurrence of another reason to discontinue study therapy as 
described in Section 7.1.  
12.6. 
  Efficacy Assessment – Lymphoma 
The determination of response and progression for MCL and MZL will be based on standardized 
criteria [Cheson 2007] as recently updated [Cheson 2014]. A summary of updated response 
criteria is provided in Table 6. 
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12.6.1. 
  Identification and Follow-up of Tumor Lesions and Organomegaly 
12.6.1.1.   Index Lesions 
Up to 6 lesions (eg, lymph nodes, liver or spleen nodules, and/or other circumscribed extranodal 
masses) should be selected as index lesions that will be used to quantitate the status of the 
disease during study treatment. Ideally, the index lesions should be located in disparate regions 
of the body and include mediastinal, abdominal, and retroperitoneal areas of disease whenever 
these sites are involved. For patients with FDG-avid lymphomas undergoing PET, selection of 
FDG-avid lesions is preferred. The IWG criteria for reviewing PET scans were based on visual 
interpretation and intended for end-of-treatment evaluation, using mediastinal blood pool as the 
comparator. The current recommendation is to use the Deauville 5-point scale, both for clinical 
trials including interim analysis and for end-of-treatment assessment. 
Index lesions will be measured and recorded at screening and at the stipulated intervals during 
treatment. The largest cross-sectional dimensions (ie, the LDi × shortest dimension [SDi] will be 
recorded (in cm) for each index lesion. Using the LD and SDi, the product of the perpendicular 
diameters (PPD) for each index lesion will be calculated. The PPDs and the SPDs for all index 
lesions will be calculated and recorded. The screening and nadir PPDs of individual lesions and 
the screening and nadir SPDs will be used as references by which objective tumor response and 
progression will be characterized during treatment. All PPD and SPD measurements will be 
reported in centimeters squared. 
12.6.1.2.   Nodal Index Lesions 
A nodal mass may be selected as a nodal index lesion if it is measurable at screening. A lymph 
node lesion is considered measurable if it has 2 perpendicular diameters (LDi and SDi) that can 
be accurately measured in cross section. A measurable node must have an LDi greater than 1.5 
cm [Cheson 2014]. Nodal index lesions measuring >1.5 cm in the LD, regardless of the 
measurement of the LPD, will be prioritized during screening index lesion selection. 
At follow-up timepoints, the PPDs for individual nodal lesions and the SPD of all nodal index 
lesions will be considered. 
A new node that measures >1.5 cm in any diameter will be considered PD. Criteria for response 
assessments are detailed below and in Table 6 [Cheson 2014]. 
In cases in which a large lymph node mass has split into multiple components, the individual 
PPDs of the nodes will be summed together to represent the PPD of the split lesion; this PPD 
will be added to the sum of the PPDs of the remaining lesions to measure response. If subsequent 
growth of any or all of these discrete nodes occurs, the nadir of each individual node will be used 
to determine PD (as if each individual node was selected as a target lesion at baseline).  
If nodal lesions merge, the PPD of the current confluent mass will be compared with the sum of 
the PPDs of the individual nodes, with >50% increase in the PPD of the confluent mass 
compared with the sum of individual nodes necessary to indicate PD.  
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12.6.1.3.   Extranodal Index Lesions  
An extranodal mass may be selected as an index lesion if it is measurable at screening. It is 
considered measurable at screening if it has 2 perpendicular diameters that can be accurately 
measured in cross section with the LD being >1.0 cm. 
At follow-up timepoints, the PPD of each single extranodal index lesion and the SPD of all 
extranodal index lesions will be considered. Because extranodal index lesions that have one or 
both diameters <0.5 cm and >0 cm cannot be reliably measured, a default value of 0.5 cm will be 
assigned for each diameter that meets these criteria and the resulting PPD will be used in SPD 
calculations. If an extranodal lesion is no longer clearly visible, it will be considered resolved 
and its PPD will be defined as 0 cm2.  
If an extranodal lesion that had resolved (ie, had a PPD of 0 cm2) subsequently reappears and 
reaches >1.0 cm in LDi, the patient will be considered to have PD. Criteria for response 
assessments are detailed below and in Table 6 [Cheson 2014]. 
12.6.1.4.   Non-Index Lesions 
Any other measurable and abnormal nodal or extranodal lesions not selected for quantitation as 
index lesions may be considered non-index lesions. In addition, non-measurable evidence of 
lymphoma such as abnormal, non-measurable nodal lesions, extranodal lesions with both 
diameters <1.0 cm, bone lesions, leptomeningeal disease, ascites, pleural or pericardial effusions, 
lymphangitis of the skin or lung, abdominal masses that are not confirmed and followed by 
imaging techniques, cystic lesions, previously irradiated lesions, or lesions with artifacts may be 
considered as non-index disease.  
If present at screening, up to 10 non-index lesions should be recorded. Measurements are not 
required.  
Non-index disease will be used as a general reference to further characterize regression or 
progression of lymphoma during assessments of the objective tumor response during treatment. 
These lesions should be followed as “present” or “absent”. 
12.6.1.5.   Spleen  
Assessments of the sizes of the spleen will be performed. For patients with splenomegaly at 
screening or at the nadirs for assessments of the spleen, evaluations will consider only changes 
relative to the enlargement of the organ (ie, the portion of the LVD that is >13 cm by imaging for 
the spleen) at screening or nadir, not changes relative to the total splenic LVD. 
By imaging, the spleen will be considered enlarged if it is >13 cm in LVD [Cheson 2014]. In the 
setting of splenomegaly, the splenic length must increase by > 50% of the extent of its prior 
increase beyond the LVD normal of 13 cm (eg, a 15-cm spleen must increase to > 16 cm). If no 
prior splenomegaly, must increase by at least 2 cm from baseline. 
12.6.1.6.   Bone Marrow 
Bone marrow assessments will be based on morphologic evaluation of bone marrow biopsies. 
Immunohistochemistry or flow cytometry may be used to assess response if the sample is 
indeterminate by morphology. The recommendation for bone marrow response is that 
histologically normal bone marrows with a small (< 2%) clonal B-cell population detected by 
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flow cytometry should be considered normal, given that definitive clinical studies that 
demonstrate an inferior outcome are lacking [Cheson 2007]. (Note: Blinded independent review 
may be used to determine responses.) 
In a patient who has a screening bone marrow biopsy showing bone marrow lymphoma or does 
not have a screening bone marrow examination, declaration of an on-study CR requires bone 
marrow biopsy documentation of the absence of bone marrow lymphoma. In a patient who has a 
screening bone marrow biopsy showing no evidence of lymphoma, declaration of an on-study 
CR does not require bone marrow examination as long as other criteria for CR are met. Of note, 
in patients with an FDG-PET avid lymphoma, declaration of an on-study CR can be based on 
FDG-PET documentation of the absence of bone marrow involvement, even if a bone marrow 
biopsy is not available, or if by blinded, independent pathologic review a marrow is reported as 
normal or indeterminant. 
12.6.1.7.   Lymph Node Biopsy 
During study participation, a patient who has a lymph node biopsy indicating transformation to a 
more aggressive lymphoma (eg, DLBCL) will be considered to have PD even in the absence of 
other evidence of PD. If the patient has no earlier objective documentation of PD, the date of the 
lymph node biopsy will be considered the date of PD.  
12.6.2. 
  Definitions of Tumor Response and Progression 
Responses will be categorized as complete response (CR), partial response (PR), stable disease 
(SD), or progressive disease (PD). In addition, a response category of nonevaluable (NE) is 
provided for situations in which there is inadequate information to otherwise categorize response 
status.  
The best overall response will be determined. The best overall response is the best on-treatment 
response from screening recorded from the start of treatment until PD/recurrence. The screening 
measurement will be taken as a reference for determinations of response. The nadir measurement 
will be taken as a reference for PD; this measurement constitutes the smallest measurement 
recorded, including the screening measurement if this is the smallest measurement. For 
FDG-avid tumors, metabolic criteria for response by PET-CT will take precedence over 
anatomic criteria for response by contrast CT when assessing CR. 
12.6.2.1.   Complete Response 
To satisfy criteria for CR, all of the following conditions must be attained: 
• No evidence of new disease 
• Regression of all index nodal lesions to ≤1.5 cm in the LDi 
• Regression to ≤1.5 cm of all nodal non-index disease  
• Disappearance of all detectable extranodal index and non-index disease 
• Normal spleen size by imaging studies 
• If PET performed, no evidence of residual disease – ie, score of 1 (no uptake above 
background), 2 (uptake ≤mediastinum), or 3 (uptake > mediastinum but ≤liver) on the 
Deauville 5-point scale, with or without a residual mass [Cheson 2014]. [Note: In 
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Waldeyer’s ring or in extranodal sites (eg, gastrointestinal tract, liver, bone marrow), 
FDG uptake may be greater than in the mediastinum with complete metabolic response, 
but should be no higher than surrounding normal physiologic uptake (eg, with marrow 
activation as a result of chemotherapy or myeloid growth factors)]. 
• Negative for bone marrow involvement by PET for a PET-avid tumor or by 
morphological assessment of a unilateral core biopsy; if the bone marrow biopsy is 
indeterminate by morphology, it should be negative by immunohistochemistry or flow 
cytometry. Due to its greater accuracy, in this study priority is given to flow cytometry 
analyses when available. The recommendation for bone marrow response is that 
histologically normal or indeterminant bone marrows with a small (< 2%) clonal B-cell 
population detected by flow cytometry should be considered normal, given that definitive 
clinical studies that demonstrate an inferior outcome are lacking [Cheson 2007].  
• A complete metabolic response (CMR) based on PET-CT would be attained if a score of 
1, 2, or 3 with or without a residual mass on the Deauville 5-point scale is observed in 
lymph node or extralymphatic sites, no new lesions, and no evidence of FDG-avid 
disease in marrow. 
12.6.2.2.   Partial Response 
To satisfy criteria for PR, all of the following conditions must be attained: 
• No evidence of new disease 
• A ≥50% decrease from screening in the SPD of the index nodal and extranodal lesions  
o When a lesion is too small to measure on CT, assign 5 mm x 5 mm (0.25 cm2) as the 
default value 
o When no longer visible, 0 x 0 mm 
o For a node > 5 mm x 5 mm, but smaller than normal, use actual measurement for 
calculation 
• No increase from the nadir in the size of non-index disease 
• In a patient with enlargement of the spleen at screening, a splenomegaly response as 
defined in Section 12.6.1.5  
• If PET performed:  
o Typically, FDG-avid lymphoma: Score of 4  or 5 on the Deauville 5-point scale with 
reduced uptake compared with baseline and residual mass(es) of any size. 
o Variably FDG-avid lymphoma/FDG-avidity unknown: if no pretreatment PET scan 
or if the pretreatment PET scan was negative for lymphoma, CT criteria should be 
used in assessing the tumor during treatment. If the PET scan was positive before 
therapy, the on-treatment PET is positive in ≥1 previously involved site. 
 Bone Marrow: If PET performed, residual uptake should be higher than uptake in normal 
marrow but reduced compared with baseline (diffuse uptake compatible with reactive changes 
from chemotherapy allowed) [Cheson 2014]. 
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12.6.2.3.   Stable Disease 
To satisfy criteria for SD, all of the following conditions must be attained: 
• No evidence of new disease 
• Neither sufficient tumor shrinkage from screening to qualify for PR nor sufficient 
evidence of tumor growth to qualify for PD 
• If PET performed, the results show a score of 4 (uptake moderately >liver) or score of 5 
(uptake markedly >liver) on the Deauville 5-point scale with no significant change in 
uptake compared with screening or end of treatment [Cheson 2014]. 
12.6.2.4.   Progressive Disease 
The occurrence of any of the following events indicates progressive disease (PD): 
• Evidence of any new disease that was not present at screening: 
o A new node that measures >1.5 cm in any diameter 
o Reappearance of an extranodal lesion that had resolved (ie, had previously been 
assigned a PPD of 0 cm2) 
o A new extranodal lesion >1.0 cm. If < 1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to lymphoma. 
o New non-index disease (eg, effusions, ascites, or other organ abnormalities) of any 
size unequivocally attributable to lymphoma (usually requires PET, biopsy, 
cytology, or other non-radiologic confirmation to confirm disease attributable to 
lymphoma). Note: Isolated new effusions, ascites, or bone lesions are not sufficient 
evidence alone of PD unless histologically confirmed. In patients with no prior 
history of pulmonary lymphoma, new lung nodules identified by CT are usually 
benign. Thus, a declaration of PD should not be made if this is the only 
manifestation of an apparently new lesion. 
o New FDG-avid foci consistent with lymphoma rather than another etiology (eg, 
infection, inflammation). If there is uncertainty regarding the etiology of new 
lesions, biopsy or interval scan may be considered. 
o New or recurrent bone marrow involvement with lymphoma by PET or by bone 
marrow biopsy if prior PET or bone marrow biopsy performed as part of the study 
was negative for lymphoma. 
• Evidence of worsening of nodal or extranodal index lesions: 
o Increase from the nadir by ≥50% in the SPD of index lesions 
o Evidence of worsening of individual index lymph nodes or nodal masses with an 
increase from the nadir by ≥50% in the PPD for any individual node if the node now 
has an LDi of >1.5 cm, an increase by ≥50% from the nadir PPD, and an increase in 
LDi or SDi from the nadir by: 
 ≥0.5 cm for lesions measuring ≤2.0 cm (in LDi or SDi) or 
 ≥1.0 cm for lesions measuring >2.0 cm (in LDi or SDi) 
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o Unequivocal increase in the size of non-index disease 
o Unequivocal worsening in the size of the spleen as defined in Section 12.6.1.5  
• Transformation to a more aggressive NHL histology as established by lymph node biopsy 
• If PET performed, there is a score of 4 (uptake moderately >liver) or score of 5 (uptake 
markedly >liver) on the Deauville 5-point scale with an increase in uptake compared with 
the nadir in conjunction with an anatomic increase in lesion size consistent with PD. 
Note: Study patients undergoing PET for lymphoma assessment can experience transient 
disease flare on imaging before having subsequent therapy-induced tumor regression. 
Worsening of constitutional symptoms or performance status in the absence of objective 
evidence of worsening lymphoma (eg, due to infection) may not represent definitive disease 
progression. Further, transient worsening of disease during temporary interruptions of study 
therapy (eg, for drug-related toxicity or inter-current illness) may not indicate definitive 
progressive lymphoma. If there is uncertainty regarding whether there is true lymphoma 
progression and if medically appropriate, the patient may continue or resume study treatment 
and remain under close observation (eg, evaluated at 4-week intervals) while relevant 
radiographic, clinical, and/or laboratory assessments are performed to document whether 
tumor control can be maintained or whether disease progression has truly occurred. If 
subsequent evaluations suggest that the patient has experienced persistent definitive disease 
progression, then the date of progression will be the timepoint at which progression was first 
objectively documented.  
12.6.2.5.   Nonevaluable 
In a patient who does not have evidence of PD, the response status of NE will be assigned when 
there are no images or inadequate or missing images to visualize index, non-index, or splenic 
disease. 
In addition, the following occurrence indicates a response status of NE: “Clinically significant” 
contemporaneous period of interruption of study drug administration or other event that in the 
opinion of the investigator suggests there is some uncertainty as to whether there is true 
progression. 
Note: When there is uncertainty of true progression, the response status of NE should not be 
used more than one time in succession. The prior and subsequent tumor assessments must not 
demonstrate PD for the NE assessment to stand. If the radiographic response is PD for the 
subsequent evaluation, even if there was an interruption to study drug administration or 
uncertainty remains about true progression, PD will be assessed (not NE) in both cases. The 
date of PD should be the date the progression was first suspected. These cases should be 
discussed in advance with the Sponsor. 
 
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Table 6: Summary of Response Criteria for MCL and MZL Patients 
 
 
 
 
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Source: Cheson 2014 
 
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