A Phase I/Ib Open-Label, Multi-Center, Dose-Escalation Study to Investigate the Safety, Pharmacokinetics and Preliminary Efficacy of Intravenous NBF 006 in Patients With Non-Small Cell Lung, Pancreatic, or Colorectal Cancer Followed by a Dose Expansion Study in Patients With KRAS-Mutated Non-Small Cell Lung Cancer
Phase: PHASE1
Conditions: Non-Small Cell Lung Cancer, Pancreatic Cancer, Colorectal Cancer
Sponsor: Nitto BioPharma, Inc.

 
 
Nitto BioPharma Inc. 
 
Clinical Study Protocol 
 
NBF-006-001: A Phase I/Ib Open-Label, Multi-Center, Dose-Escalation Study to 
Investigate the Safety, Pharmacokinetics and Preliminary Efficacy of Intravenous 
NBF-006 in Patients with Non-Small Cell Lung, Pancreatic, or Colorectal Cancer 
Followed by a Dose Expansion Study in Patients with KRAS-Mutated Non-Small Cell 
Lung Cancer 
 
 
Investigational Product: NBF-006 
 
 
NCT03819387 
 
 
06 June 2022 
 
 
 
 
 
 

Nitto BioPharma, Inc. 
Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
Pancreatic, or Colorectal Cancer 
 
1155_CSP_A4 
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Amendment 4 – 06 June 2022 
Confidential – Entire Page 
 
 
A Phase I/Ib Open-Label, Multi-Center, Dose-Escalation Study to Investigate the 
Safety, Pharmacokinetics and Preliminary Efficacy of Intravenous NBF-006 in 
Patients with Non-Small Cell Lung, Pancreatic, or Colorectal Cancer Followed by a 
Dose Expansion Study in Patients with KRAS-Mutated Non-Small Cell Lung Cancer  
 
 
Protocol No.: 
NBF-006-001 
IND No.: 
139860 
 
 
Sponsor: 
Nitto BioPharma, Inc. 
10618 Science Center Drive 
San Diego, California, 92121 
(858) 255-3010 
 
 
Medical Monitor: 
Theradex Oncology 
4365 Route 1 South, Suite 101 
Princeton, New Jersey, 08540 
(609) 799-7580 
 
 
Protocol Version: 
Amendment 4 
 
Date: 
06 June 2022 
 
 
Replaces: 
 
Amendment 3, 08 February 2021 
 
 
CONFIDENTIAL 
 
This document contains strictly confidential information and cannot be disclosed or used, 
unless authorized in writing by Theradex Oncology and Nitto BioPharma, Inc. 

Nitto BioPharma, Inc. 
Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
Pancreatic, or Colorectal Cancer 
 
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INVESTIGATOR'S STATEMENT 
1. 
I have carefully read this protocol entitled “A Phase I/Ib Open-Label, Multi-Center, Dose-
Escalation Study to Investigate the Safety, Pharmacokinetics and Preliminary Efficacy of 
Intravenous NBF-006 in Patients with Non-Small Cell Lung, Pancreatic, or Colorectal 
Cancer Followed by a Dose Expansion Study in Patients with KRAS-Mutated Non-Small 
Cell Lung Cancer” and agree that it contains all the necessary information required to 
conduct the study. I agree to conduct this study as outlined in the protocol. 
2. 
I understand that this study will not be initiated without approval of the appropriate 
Institutional Review Committee/Independent Ethics Committee (IRB/IEC), and that all 
administrative requirements of the governing body of the Institution will be complied with 
fully. 
3. 
Informed written consent will be obtained from all participating patients in accordance with 
institutional guidelines, FDA requirements as specified in Title 21 CFR, Part 50, the European 
Union Directive 2001/20/EC and its associated Detailed Guidances, European Union Good 
Clinical Practice (GCP) Directive 2005/28/EC, the International Council for Harmonization 
(ICH) Guideline for GCP, Section 4.8, and the terms of the Declaration of Helsinki (2013). 
4. 
I will enroll patients who meet the protocol criteria for entry. 
5. 
I understand that my signature on each completed electronic Case Report Form (eCRF) 
indicates that I have carefully reviewed the complete set of eCRFs and accept full 
responsibility for the contents thereof. 
6. 
I understand that the information presented in this study protocol is confidential, and I 
hereby assure that no information based on the conduct of the study will be released 
without prior consent from the Sponsor unless this requirement is superseded by the 
Food and Drug Administration, a Competent Authority of the European Union or another 
Regulatory Authority. 
Amendment 4 – 06 June 2022 
Investigator:   
 
Name: 
 
 
Telephone: 
 
Address: 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
Date: 
 
 
Sponsor Representative: 
Signature: 
 
 
Date: 
 
 
 
Joachim Gullbo, MD PhD 
 
 
Medical Monitor, Theradex Oncology 
Sponsor Contact: 
Signature: 
 
 
Date:  
 
 
 
Sonya Zabludoff PhD 
 
 
Vice-President, Clinical Operations (GCP Clinical Director), Nitto BioPharma, Inc.  
 

Nitto BioPharma, Inc. 
Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
Pancreatic, or Colorectal Cancer 
 
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TABLE OF CONTENTS 
 
        Page No. 
INVESTIGATOR'S STATEMENT ................................................................................................. 2 
TABLE OF CONTENTS ............................................................................................................... 3 
CLINICAL STUDY SYNOPSIS ..................................................................................................... 7 
ABBREVIATIONS ..................................................................................................................... 16 
1.0 
GENERAL INFORMATION ......................................................................................... 18 
1.1 Protocol Number and Title of the Study ...................................................................... 18 
1.2 Sponsor ........................................................................................................................... 18 
1.3 Monitor ............................................................................................................................ 18 
1.4 Signature Authorization ................................................................................................ 18 
2.0 
BACKGROUND INFORMATION ................................................................................ 18 
2.1 Introduction .................................................................................................................... 18 
2.2 The Investigational Product .......................................................................................... 20 
2.3 Preclinical Studies .......................................................................................................... 21 
2.3.1 In Vitro Efficacy of NDT-05-1040 siRNA ........................................................... 21 
2.3.2 In Vivo Efficacy of NBF-005 LNPs containing NDT-05-1040 siRNA ............... 22 
2.3.3 In Vitro Evaluation of GSTP Knockdown in PBMCs by NBF-006 ................... 22 
2.3.4 Toxicology Evaluation of NBF-005 and NBF-006 LNPs containing NDT-05-
1040 siRNA ..................................................................................................................... 23 
2.4 Previous Clinical Studies ................................................................................................ 24 
2.5 Rationale for Starting Dose, Dose Range, and Dosing Schedule .............................. 25 
2.6 Potential Risks and Benefits .......................................................................................... 25 
2.7 Characteristics of a Well-Conducted Trial ................................................................... 26 
2.8 Patient Population ......................................................................................................... 27 
3.0 
TRIAL OBJECTIVES AND PURPOSE ........................................................................... 27 
4.0 
TRIAL DESIGN ............................................................................................................ 28 
4.1 Overview of Trial Design ................................................................................................ 28 
4.2 End of Study .................................................................................................................... 28 
4.3 Minimizing Bias .............................................................................................................. 28 
4.4 Drug Product .................................................................................................................. 29 
4.5 Duration of Therapy....................................................................................................... 29 
4.6 Trial Discontinuation ...................................................................................................... 29 
4.7 Drug Accountability/Disposition of Clinical Trial Supplies ......................................... 30 
4.8 Registration ..................................................................................................................... 30 
5.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................................ 30 
5.1 Inclusion Criteria ............................................................................................................ 30 
5.2 Exclusion Criteria ............................................................................................................ 31 

Nitto BioPharma, Inc. 
Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
Pancreatic, or Colorectal Cancer 
 
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5.3 Inclusion of Women, Minorities and Children ............................................................ 32 
5.4 Withdrawal Criteria ........................................................................................................ 32 
5.4.1 Withdrawn Subjects .......................................................................................... 32 
5.4.2 Replacement of Subjects .................................................................................. 32 
5.5 Noncompliance .............................................................................................................. 32 
6.0 
TREATMENT OF SUBJECTS ........................................................................................ 33 
6.1 Drug Preparation and Administration ......................................................................... 33 
6.1.1 Dose Escalation Scheme ................................................................................... 34 
6.1.2 Part B (Dose Expansion) ................................................................................... 35 
6.1.3 Dose-Limiting Toxicity (Part A) ......................................................................... 35 
6.1.4 Maximum Tolerated Dose (Part A) .................................................................. 36 
6.2 Dose Interruptions/Withholding for Infusion Reactions or Other Reasons ............ 36 
6.3 Concomitant Treatment ................................................................................................ 37 
6.4 Monitoring Subject Compliance ................................................................................... 37 
7.0 
STUDY EVALUATIONS ............................................................................................... 37 
7.1 Schedule of Study Evaluations ...................................................................................... 38 
7.2 Pre-treatment ................................................................................................................. 45 
7.3 During Treatment ........................................................................................................... 46 
7.3.1 Cycle 1 ................................................................................................................. 46 
7.3.2 Cycle 2 ................................................................................................................. 47 
7.3.3 Cycle 3 and Beyond ........................................................................................... 49 
7.4 End of Treatment (to be performed within 30 ± 3 days after last treatment) ........ 50 
7.5 30 Day Safety Follow up Visit (±3) ................................................................................. 50 
8.0 
STUDY ASSESSMENTS ............................................................................................... 51 
8.1 Safety Assessments ....................................................................................................... 51 
8.1.1 Safety Analysis ................................................................................................... 51 
8.1.2 Reporting of Adverse Events ............................................................................ 51 
8.2 Efficacy Assessments ..................................................................................................... 57 
8.2.1 Definitions .......................................................................................................... 57 
8.2.2 Guidelines for Evaluation of Measurable Disease ......................................... 60 
8.2.3 Response Criteria .............................................................................................. 61 
8.2.4 Confirmatory Measurement/Duration of Response ..................................... 65 
8.3 Pharmacokinetics ........................................................................................................... 66 
8.4 Anti-Drug Antibodies (ADAs) ......................................................................................... 67 
8.5 KRAS Genotyping ............................................................................................................ 67 
8.6 Immune Activation Biomarkers .................................................................................... 68 
8.7 Exploratory Biomarkers ................................................................................................ 69 
8.8 GSTP Knockdown ........................................................................................................... 69 
8.9 GSTT1 Genotyping.......................................................................................................... 69 
9.0 
STATISTICS ................................................................................................................. 69 
9.1 Analysis Populations ...................................................................................................... 69 

Nitto BioPharma, Inc. 
Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
Pancreatic, or Colorectal Cancer 
 
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9.2 Endpoints ........................................................................................................................ 70 
9.2.1 Primary ............................................................................................................... 70 
9.2.2 Secondary ........................................................................................................... 70 
9.3 Safety ............................................................................................................................... 70 
9.4 Efficacy ............................................................................................................................. 71 
9.4.1 Duration of Overall Response .......................................................................... 71 
9.4.2 Duration of Stable Disease ............................................................................... 71 
9.5 Exploratory/Other Studies ............................................................................................ 71 
9.6 Sample Size ..................................................................................................................... 71 
10.0 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ............................ 71 
10.1 Monitoring of the Study and Regulatory Compliance ................................................ 71 
10.2 Curricula Vitae and Financial Disclosure of Investigators ......................................... 72 
10.3 Protocol Modifications ................................................................................................... 72 
10.4 Publication Policy ........................................................................................................... 72 
11.0 
ETHICAL CONSIDERATIONS ..................................................................................... 72 
11.1 Informed Consent .......................................................................................................... 72 
11.2 Institutional Review Board/Independent Ethics Committee ..................................... 73 
11.3 Patient Privacy ................................................................................................................ 73 
12.0 
DATA HANDLING AND RECORD KEEPING .............................................................. 73 
12.1 Data to be Entered Directly in the Electronic Case Report Form.............................. 73 
12.2 Recording of Data .......................................................................................................... 73 
12.3 Study Records ................................................................................................................. 74 
13.0 
REFERENCES .............................................................................................................. 75 
APPENDIX I – ECOG Performance Status ............................................................................ 77 
APPENDIX II – Common Terminology Criteria for Adverse Events (CTCAE) v5.0 ............ 78 
APPENDIX III – Acceptable Contraceptive Methods .......................................................... 79 
 
List of In-text Tables 
Table 1: Part A NBF-006 Dose Levels ............................................................................................ 35 
Table 2: Part B NBF-006 Dose Levels ............................................................................................ 35 
Table 3: Study Calendar (Part A) ................................................................................................... 39 
Table 4: Study Calendar (Part B) ................................................................................................... 42 
Table 5: Dosing Modification and Toxicity Management Guidelines for Infusion-Related 
Reactions ......................................................................................................................................... 56 
Table 6: Time point response: Patients with target (+/- non-target) disease .......................... 63 
Table 7: Time point response: Patients with non-target disease only ..................................... 64 
Table 8: Best overall response when confirmation of CR and PR required ............................. 65 
 
List of In-text Figures 
Figure 1: Interactions Among Several Key Components Involved in the MAPK and PI3K 

Nitto BioPharma, Inc. 
Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
Pancreatic, or Colorectal Cancer 
 
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Pathways ......................................................................................................................................... 19 
Figure 2: Relative Gene Expression of GSTP in PBMCs by qRT-PCR. ........................................ 23 
Figure 3: Schematic Overview of the Trial ................................................................................... 28 
 

Nitto BioPharma, Inc. 
Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
Pancreatic, or Colorectal Cancer 
 
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CLINICAL STUDY SYNOPSIS 
Name of Sponsor:  
Nitto BioPharma, Inc. 
10618 Science Center Drive 
San Diego, California, 92121 
(858) 255-3010 
Name of Monitor: 
Theradex Oncology 
4365 Route 1 South, Suite 101 
Princeton, New Jersey, 08540 
(609) 799-7580 
Name of finished product: NBF-006 
Name of active ingredient: NDT-05-1040 
Title of the study: A Phase I/Ib Open-Label, Multi-Center, Dose-Escalation Study to Investigate the 
Safety, Pharmacokinetics, and Preliminary Efficacy of Intravenous NBF-006 in Patients with 
Non-Small Cell Lung, Pancreatic, or Colorectal Cancer Followed by a Dose Expansion Study in 
Patients with KRAS-Mutated Non-Small Cell Lung Cancer  
Protocol number: NBF-006-001 
Clinical phase: Phase I/Ib 
Objectives:   
Part A (Dose escalation) 
Primary: 
• 
To determine the safety profile, maximum tolerated dose (MTD), and recommended dose of 
NBF-006 for Part B in patients with advanced non-small cell lung cancer (NSCLC), pancreatic, 
or colorectal cancer for dose levels 1-4 (0.15, 0.3, 0.6, and 1.2 mg/kg) and in patients with 
Kirsten rat sarcoma (KRAS)-mutated NSCLC for dose level 5 (1.6 mg/kg). 
 
Secondary: 
• 
To evaluate preliminary efficacy of NBF-006 in patients with advanced NSCLC, pancreatic, or 
colorectal cancer for dose levels 1-4 (0.15, 0.3, 0.6, and 1.2 mg/kg) and in patients with 
KRAS-mutated NSCLC for dose level 5 (1.6 mg/kg).  
• 
To investigate the pharmacokinetics (PK) of NBF-006. 
 
Exploratory: 
• 
To evaluate correlation between biomarkers and clinical outcome. 
• 
To evaluate correlation between KRAS mutations and clinical outcome. 
 
Part B (Dose expansion) 
Primary:  
• 
To evaluate preliminary efficacy and safety profile of NBF-006 in patients with KRAS-mutated 
NSCLC. 
 
Secondary: 
• 
To investigate the PK of NBF-006. 
 
Exploratory: 
• 
To evaluate correlation between glutathione S-transferase pi (GSTP) messenger ribonucleic 
acid (mRNA) knockdown (KD) in surrogate tissue (peripheral blood mononuclear cells 
[PBMCs]), biomarkers, and clinical outcome. 

Nitto BioPharma, Inc. 
Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
Pancreatic, or Colorectal Cancer 
 
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Study Overview:   
This is an open-label, non-placebo-controlled study conducted in two parts: Part A (dose escalation) 
and Part B (dose expansion). In both parts, NBF-006 will be administered via intravenous (IV) 
infusion over approximately 70 minutes, once a week (QW) for 4 weeks followed by a 2-week rest 
period. The length of each cycle is 6 weeks.  
 
Part A (Dose escalation): 
Patients in Part A will have previously treated progressive or metastatic NSCLC, pancreatic, or 
colorectal cancer, with or without KRAS mutation. 
 
The first dose level (0.15 mg/kg) will be a single patient cohort. If any Grade 2 or greater 
drug-related event occurs during the first cycle of treatment, the cohort will be expanded up to 3 
patients. If a dose-limiting toxicity (DLT) occurs during the first cycle, the cohort will be expanded 
up to 6 patients before proceeding with dose escalation. 
 
Subsequent cohorts in the dose escalation phase will enroll patients following the standard 3+3 
design. If 1 out of 3 patients experience a DLT during the first cycle of treatment, the dose cohort 
will be expanded up to 6 patients. If no DLT is observed in the first 3 patients enrolled at the highest 
dose, this cohort will be expanded to 6 patients. If 2 or more out of 6 patients experience DLTs, the 
MTD has been exceeded, and dose escalation will cease. Up to 3 additional patients will be enrolled 
at a lower dose if only 3 patients were treated at that dose level, to confirm safety of that dose. 
MTD will be defined as a dose where 0 or 1 out of 6 patients have DLTs. To collect clinically 
important information in the target population, and prepare for Part B, the 6-patient cohort(s) 
must each include at least 3 patients with histologically or cytologically confirmed progressive or 
metastatic NSCLC, up to dose level 4 (1.2 mg/kg). In dose level 5 (1.6 mg/kg), only patients with 
previously-treated NSCLC with KRAS mutation will be included. Once safety has been confirmed in 
Part A at 1.6 mg/kg (i.e., 0-1 DLT in 6 patients), an additional 4 patients with KRAS-mutated NSCLC 
will be enrolled in Part B of the study at this dose level. Stratification for GSTT1-null genotype 
patients will not occur in Part A. 
 
Part A NBF-006 Dose Levels 
Dose level 
NBF-006 dose 
Number of patients 
1 
0.15 mg/kg 
1-6 
2 
0.3 mg/kg 
3-6 
3 
0.6 mg/kg 
3-6 
4 
1.2 mg/kg 
3-6 
5 
1.6 mg/kg 
3-6 
 
Part B (Dose expansion): 
Patients in Part B must have previously treated NSCLC with confirmed KRAS mutation. Two dose 
levels will be explored further in Part B: 0.6 mg/kg and 1.2 mg/kg. Twenty (20) patients will be 
enrolled in Part B, with 10 patients enrolled in each of the two cohorts. Both cohorts will be 
stratified for GSTT1-null genotype patients. Once dose level 5 (1.6 mg/kg) has been confirmed to 
be safe in Part A, an additional 4 patients will then be enrolled at 1.6 mg/kg, for a planned total of 
24 patients in Part B. The proportion of GSTT1-null patients treated at the highest dose level 
(1.6 mg/kg) will be balanced with the previous two expansion cohorts as much as possible by 

Nitto BioPharma, Inc. 
Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
Pancreatic, or Colorectal Cancer 
 
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applying stratification rules in Part B (depending on the distribution of patients enrolled in Part A, 
unstratified).  
Part B NBF-006 Dose Levels 
Dose level 
NBF-006 dose 
Number of patients 
3 
0.6 mg/kg 
10 
4 
1.2 mg/kg 
10 
5 
1.6 mg/kg 
4* 
*Dose level 5 pending confirmation of safety in Part A 
 
Visits and study examinations will be performed per the Study Calendar. In both Part A and Part B, 
patients will be monitored regularly with physical examinations and laboratory tests. Concomitant 
measures and adverse events (AEs) will be monitored throughout the study. AEs will be assessed 
per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0. Tumor measurement by Response Evaluation Criteria in Solid Tumors (RECIST) version 
1.1 will be conducted at baseline and after every second cycle in Part A dose levels 1-4, and at the 
end of every cycle for dose level 5 in Part A and all patients in Part B. A post-treatment safety visit 
will be conducted approximately 30 days following the last dose.  
Part A and B Schematic of Study Design 
 
Number of patients: Part A: Up to 20 patients anticipated 
 
 Part B: 20 or 24 patients (depending on outcome of 1.6 mg/kg dose level in 
Part A)   
Diagnosis and main criteria for inclusion:   
Inclusion Criteria: 
1. Part A: Patients with histologically or cytologically confirmed progressive or metastatic NSCLC, 
pancreatic, or colorectal cancer that have failed standard treatment and for which no other 
effective treatment is available or appropriate for the patient up to dose level 4. In dose level 5 
(1.6 mg/kg), patients with histologically or cytologically confirmed progressive or metastatic 
NSCLC with documented KRAS-mutant genotype, who have failed standard treatment and 
have no other effective treatment available or appropriate for the patient. 

Nitto BioPharma, Inc. 
Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
Pancreatic, or Colorectal Cancer 
 
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Part B: Patients with histologically or cytologically confirmed progressive or metastatic NSCLC 
with documented KRAS-mutant genotype, who have failed standard treatment and have no 
other effective treatment available or appropriate for the patient.  
2. Eastern Cooperative Oncology Group performance status of 0-2. 
3. Men and women  18 years of age. 
4. Patients must have recovered from all acute adverse effects (excluding alopecia) of prior 
therapies to baseline or  Grade 1 prior to study entry.  
5. Adequate bone marrow function, defined as an absolute neutrophil count (ANC)  1.5 x 109/L 
and a platelet count  100 x 109/L. 
6. Adequate renal function, defined as serum creatinine  1.5 x upper limit of normal (ULN) for 
the institution or calculated creatinine clearance [Cockcroft-Gault method] must be 
≥ 60 mL/min/1.73 m2. If serum creatinine is >1.5 x ULN, then creatinine clearance can be 
calculated from a 24-hour urine collection. 
7. Adequate hepatic function, defined as total bilirubin  1.5 mg/dL and alanine transaminase 
(ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN, or ≤ 5 x ULN if known liver metastases.  
8. Female patients of childbearing potential must have a negative serum or urine pregnancy test 
result at time of pre-treatment screening. 
9. Patients with reproductive potential must agree to use at least one form of highly effective 
contraception (APPENDIX III) prior to study entry and for up to 30 days beyond the last 
administration of study drug. 
10. Patients must be capable of providing informed consent and must be willing to provide written 
informed consent prior to the start of any study-specific procedures. 
11. All patients must have measurable tumor per RECIST 1.1. 
12. Agree to adhere to all study protocol requirements. 
 
Exclusion Criteria: 
1. Prior radiation therapy within 2 weeks; or prior chemotherapy or non-cytotoxic therapy within 
4 weeks or 5 drug half-lives, whichever is shorter (exception: 6 weeks for nitrosoureas or 
mitomycin C); or monoclonal antibodies within 4 weeks prior to the first dose of study 
treatment.  
2. Concurrent use of any other investigational agent. 
3. Known or clinically suspected central nervous system or leptomeningeal metastases, unless 
irradiated or treated a minimum of 4 weeks prior to first study treatment and stable without 
requirement of corticosteroids for > 1 week. 
4. Pregnant or breast feeding. A negative pregnancy test must be documented at baseline for 
women of childbearing potential. Patients may not breast-feed infants while on this study. 
5. Significant cardiovascular disease or condition, including: 
a. Congestive heart failure currently requiring therapy 
b. Need for antiarrhythmic medical therapy for ventricular arrhythmia 
c. Severe conduction disturbance 
d. Angina pectoris requiring therapy 
e. QTc interval > 450 msec (males) or > 470 msec (females) Fridericia’s correction.  
Note: QTc values up to 500 ms will be acceptable where patient’s medical history e.g., 
bundle branch block, is known to cause mild QTc prolongation and the condition is well 
controlled. 
f. 
History of congenital long QT syndrome or congenital short QT syndrome 
g. Uncontrolled hypertension (per the Investigator's discretion) 

Nitto BioPharma, Inc. 
Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
Pancreatic, or Colorectal Cancer 
 
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h. Class III or IV cardiovascular disease according to the New York Heart Association’s 
Functional Criteria 
i. 
Myocardial infarction within 6 months prior to first study drug administration 
6. Known history of human immunodeficiency virus or active infection with hepatitis B virus or 
hepatitis C virus.   
7. Known uncontrolled intercurrent illnesses, including uncontrolled viral influenza and 
COVID-19, systemic bacterial infections, and fungal infections. 
8. Psychiatric disorder or altered mental status that would preclude understanding of the 
informed consent process and/or completion of the necessary studies. 
9. Known allergic reactions to H1/H2 antagonists. 
 
Test product, dose and mode of administration:   
NBF-006 (10 mg of active ingredient per vial) will be reconstituted with 5.6 mL of the 60 mM sodium 
acetate diluent (provided by Sponsor) and then diluted with normal saline to 300 mL (or to 320 mL 
for the 1.6 mg/kg dose level) and administered to the patient via IV infusion.  
 
The infusion will be implemented as a stepwise infusion: 
(1) 0.5 mL/min for 10 minutes,  
(2) then 1.5 mL/min for 10 minutes, and 
(3) finally 6 mL/min for the remaining volume 
Total infusion duration of approximately 70 minutes (± 20 minutes). 
 
Doses ranging from 0.15 to 1.6 mg/kg will be evaluated. The drug will be administered weekly for 
4 weeks, followed by a 2-week rest period. The length of each cycle is 6 weeks.  
 
For detailed instructions on vial concentration, preparation and dispensing, please refer to the 
Pharmacy Manual. 
 
In the case of an infusion reaction, the infusion should be temporarily interrupted. If symptoms 
resolve, then resume and complete the stepwise infusion as outlined above. If the symptoms have 
not resolved by 15 minutes, wait until the symptoms have resolved before resuming the infusion 
or the patient should receive symptomatic treatment. Recommencing the infusion should only be 
attempted after reactions have resolved completely. If the infusion reaction does not resolve 
within one hour after administration of symptomatic treatment (e.g., acetaminophen and/or 
antihistamines) the dosing should not be resumed the same day. Rechallenge should be discussed 
with the Medical Monitor, and premedication must be given if the patient receives any further 
doses. 
Dose-limiting toxicity: 
AEs will be assessed per NCI CTCAE version 5.0. DLT is defined as any treatment related toxicity 
(i.e., not attributable to the underlying active disease or intercurrent illness) during the first 42 days 
(Cycle 1) of study treatment meeting any of the criteria below. Ongoing safety events beyond 
Cycle 1 will be reviewed across all cohorts during the study to help inform dose escalation 
decisions.  
 

Nitto BioPharma, Inc. 
Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
Pancreatic, or Colorectal Cancer 
 
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DLT includes: 
1. Treatment-related hematological toxicities as follows:  
• 
Grade 4 neutropenia.  
• 
Any grade neutropenic fever. 
• 
≥ Grade 3 thrombocytopenia lasting longer than 3 consecutive days. 
• 
≥ Grade 3 thrombocytopenia with bleeding. 
• 
Any other confirmed hematological toxicity ≥ Grade 4 (a repeat test may be required for 
confirmation of an isolated abnormality in the absence of clinical signs, symptoms or other 
abnormal investigations, i.e., a suspected spurious value).  
 
2. Treatment-related non-hematological toxicity ≥ Grade 3 including:  
• 
Electrolyte abnormalities that do not resolve within 48 hours of intervention (a repeat test 
may be required for confirmation of an isolated abnormality in the absence of clinical signs, 
symptoms or other abnormal investigations, i.e., a suspected spurious value). 
• 
≥ Grade 3 infusion-related reactions. 
• 
≥ Grade 3 cytokine release syndrome. 
• 
Any hepatic toxicity meeting Hy's Law criteria. 
• 
Grade 3 nausea/vomiting or diarrhea or other self-limited or medically controllable toxicities 
that last > 72 hours regardless of medical intervention. 
 
3. Any other treatment-related toxicity i.e., greater than at baseline, which is clinically significant 
and/or unacceptable, does not respond to supportive care and results in a disruption of the dosing 
schedule of more than 14 days.  
 
4. Any death not clearly due to the underlying disease or extraneous causes. 
 
DLT excludes:  
• 
Alopecia of any grade.  
Duration of treatment:   
Upon completion of Cycle 1, in the absence of disease progression or unacceptable toxicity, 
patients may continue to be treated with NBF-006 at the same dose and schedule until disease 
progression, death, withdrawal of consent, Investigator decision to remove patient, or intolerable 
toxicity, whichever occurs first. A patient may continue on study (even if one or more criterion 
meets Disease Progression per RECIST 1.1) at the Investigator’s discretion if deemed that the drug 
is well-tolerated and that the patient may continue to receive benefit from continuing treatment. 
Reference therapy, dose and mode of administration: Not applicable. 
Criteria for evaluation:   
Study assessments are summarized in the Study Calendar. All screening procedures will be 
performed within 28 days prior to the first dose, unless otherwise specified.  
 
Safety: All patients who have received any component of study treatment will be considered 
evaluable for safety. 
 
Safety will be assessed by means of physical examination, weight, vital signs, performance status, 
laboratory evaluations (hematology, biochemistry), electrocardiogram (ECG), pain assessment, and 

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recording of concurrent illness/therapy and AEs. NCI CTCAE version 5.0 will be used to grade all 
toxicities. All related AEs will be monitored until resolution. 
 
Patients will be monitored for safety and concomitant medications throughout the study. 
 
Efficacy: Response to treatment will be assessed according to RECIST 1.1. For Part A (dose levels 
1-4), the objective evaluation will be performed at baseline and at the end of every even numbered 
cycle. For Part A (dose level 5) and Part B, the objective evaluation will be performed at baseline 
and at the end of every cycle. A patient may continue on-study (even if one or more criterion meets 
Disease Progression per RECIST 1.1) at the Investigator’s discretion if deemed that the drug is well-
tolerated and that the patient may continue to receive benefit from continuing treatment. 
 
Pharmacokinetics:  
Plasma concentrations of NDT-05-1040 will be measured from blood samples collected at the 
following timepoints for Part A:  
• 
Cycle 1, Day 1:  
• 
Before start of infusion (SOI),  
• 
During the infusion: 20 m (±5m) after the start of the last infusion step 
implemented at 6 mL/min rate 
• 
End of Infusion (EOI); after EOI: 0.5 hr (5m), 2 hr (10m), 6 hr (15m), 24 hr (1hr), 
48 hr (2hr), 72 hr (3hr) 
• 
Cycle 1, Day 8: pre-dose 
• 
Cycle 1, Day 22:  
• 
Before SOI 
• 
During the infusion: 20 m (±5m) after the start of the last infusion step 
implemented at 6 mL/min rate 
• 
EOI; after EOI: 0.5 hr (5m), 2 hr (10m), 6 hr (15m), 24 hr (1hr), 48 hr (2hr), 
72 hr (3hr) 
• 
Cycle 2, Day 1: pre-dose 
 
Plasma concentrations of NDT-05-1040 will be measured from blood samples collected at the 
following timepoints for Part B. (Note: timepoints are the same as the Part A PK sample collection 
with the exception of the 48 and 72 hr timepoint collections, which will not be measured in Part B): 
• 
Cycle 1, Day 1:  
• 
Before SOI,  
• 
During the infusion: 20 m (±5m) after the start of the last infusion step 
implemented at 6 mL/min rate 
• 
EOI; after EOI: 0.5 hr (5m), 2 hr (10m), 6 hr (15m), 24 hr (1hr) 
• 
Cycle 1, Day 8: pre-dose 
• 
Cycle 1, Day 22:  
• 
Before SOI 
• 
During the infusion: 20 m (±5m) after the start of the last infusion step 
implemented at 6 mL/min rate 
• 
EOI; after EOI: 0.5 hr (5m), 2 hr (10m), 6 hr (15m), 24 hr (1hr) 
• 
Cycle 2, Day 1: pre-dose 
 
 

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Anti-drug antibody (ADA) assay: 
• 
Cycle 1, Day 1: pre-dose 
• 
Cycle 1, Day 15: pre-dose 
• 
Cycle 2, Cycle 4, Cycle 6, Cycle 8, etc. (i.e., every even numbered cycle), up to one year: Day 1 
pre-dose  
• 
Year 2 and beyond: every 6 months 
• 
End of treatment (EOT) 
• 
30-day safety follow-up visit 
 
KRAS genotyping: 
Depending upon availability and patient consent, we may request an archival tumor sample and/or 
results of a genomic tumor profile, but these are not required to confirm patient eligibility for dose 
levels 1-4 in Part A. 
 
Confirmation of KRAS mutation is a requirement for dose level 5 (1.6 mg/kg) in Part A and for all 
patients in Part B. Genomic tumor profile results from either core biopsies or liquid biopsies can 
be used (outlined in Section 8.5). Fresh biopsy (if needed) may be obtained only if it has minimal 
risk of complications for the patient. If such type of biopsy is needed but cannot feasibly be 
collected, the sponsor and Medical Monitor should be consulted. 
 
GSTT1 genotyping and stratification: 
In Part A dose level 5 (1.6 mg/kg) of the study, patients will not be stratified for the GSTT1-null 
genotype, but whole blood samples will still be collected during the screening visit and batch 
analyzed at a central lab. 
 
Patients enrolled in Part B of the study will be stratified for the GSTT1-null genotype. Analysis will 
be done at a central lab from blood samples collected during the screening visit.  
 
Immune activation markers (cytokines):  
Blood samples will be collected during Cycle 1 (Week 1) for all patients treated in Part A of the study 
for determination of cytokines (IFN-γ, IL-1β, IL-6, TNF-α): 
• 
Pre-dose 
• 
10 ± 3 minutes after SOI 
• 
60 ± 10 minutes after EOI 
• 
6 hr ± 15 minutes after EOI 
• 
24 hr ± 1 hr after EOI 
 
For Dose levels 3 (0.6 mg/kg) and 4 (1.2 mg/kg) did not result in immune activation in Part A and 
therefore, cytokine activity will not be monitored at those two dose levels in Part B. However, if a 
patient, during or after any infusion of NBF-006, develops IRR symptoms (e.g., backache, fever, 
nausea, headache, rash, rapid heartbeat, low blood pressure, or trouble breathing), best attempts 
should be made to collect cytokines as described for Part A with the exception of 10 ± 3 minutes 
after SOI, which should be collected as close as feasible to the IRR. If there is no meaningful 
cytokine induction in the 6-patient dose level 5 (1.6 mg/kg) during Part A, then cytokine testing will 
also not be needed in the remaining 4 patients in Part B at that same dose level (1.6 mg/kg).  

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Protocol No. NBF-006-001 
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Immune activation markers (complement): 
Blood samples will be collected during Cycle 1 (Week 1) for all patients in Part A and Part B of the 
study for determination of complement (CH50, Bb, C3a, C5a): 
• 
Pre-dose 
• 
10 ± 3 minutes after SOI 
• 
60 ± 10 minutes after EOI 
• 
6 hr ± 15 minutes after EOI 
• 
24 hr ± 1 hr after EOI  
 
Exploratory studies: 
PBMCs isolated from patient blood samples (at baseline) and/or tumor tissue (archival samples or 
those procured for routine medical care during the course of the study) may be retained for 
biomarker testing. Biomarkers may include (but are not limited to) GSTP or related proteins of the 
glutathione S-transferase (GST) family. 
 
GSTP mRNA KD: 
Blood samples will be collected at the following timepoints for evaluation of GSTP KD in the 
6 patients from Part A at 1.6 mg/kg dose level and from all patients in Part B of the study: 
• 
Cycle 1, Day 1: 
• 
Before SOI 
• 
After EOI: 6 hr (±15m), 24 hr (±1hr) 
• 
Cycle 1, Day 8: before SOI 
 
Patients who are willing to provide exploratory pre- and on-study biopsies will be sampled prior to 
the first dose and 24 hours after the fourth dose in Cycle 1, if clinically feasible. If possible, lesions 
selected as RECIST target lesions should not be biopsied. 
Statistical methods:   
All analyses will be descriptive. Categorical variables will be presented with numbers and, if 
meaningful, percentages. Continuous variables will be presented by n, mean, median, standard 
deviation and range (min and max) as appropriate. Presentations will be by each dose cohort. 
 
The Intent-to-Treat population will include all participants who were enrolled into the study, 
irrespective of whether study medication was administered or not.   
Safety Evaluable Population: All patients who received any component of study treatment. 
Efficacy Evaluable Population: Patients with measurable disease by RECIST 1.1 who had a baseline 
assessment and at least one post-baseline assessment. Responses must be confirmed at a second 
imaging evaluation that should be performed at 4 weeks but no later than 5 weeks for patients in 
dose levels 1-4 in Part A after the criteria for response are first met. Response will be confirmed at 
4 weeks or at the next scheduled scan at Week 6 of the following cycle for patients in dose level 5 
in Part A and all patients in Part B. If a confirmative scan is done after 4 weeks, the next scheduled 
scan may be omitted. Responders (partial response [PR] and complete response [CR]) with 
confirmatory imaging will be denoted as PR and CR, respectively. Those with only one evaluation 
documenting PR or CR will be denoted as partial response-unconfirmed (PR-UC) and complete 
response unconfirmed (CR-UC). The primary evaluation of efficacy will focus on PR and CR but 
analyses incorporating PR-UC and CR-UC will also be performed. 

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Protocol No. NBF-006-001 
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ABBREVIATIONS 
ADA 
anti-drug antibodies 
AE 
adverse event 
Akt 
protein kinase B 
ALT/SGPT 
alanine transaminase / serum glutamic-pyruvic transaminase 
ANC 
absolute neutrophil count 
API 
active pharmaceutical ingredient 
AST/SGOT 
aspartate transaminase / serum glutamic-oxaloacetic transaminase 
AUC 
area under the curve 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentration 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
dL 
deciliter 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOI 
end of infusion 
EOT 
end of treatment 
ERK 
extracellular signal-regulated kinase 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GDP 
guanosine diphosphate 
GLP 
Good Laboratory Practice 
GST 
glutathione S-transferase 
GSTP 
glutathione S-transferase pi 
GTP 
guanosine triphosphate 
HED 
human equivalent dose 
HNSTD 
highest non-severely toxic dose 
hr 
hour 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IFN-γ 
interferon-gamma 
IL 
interleukin 
IL-1ra 
interleukin-1 receptor antagonist 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IV 
intravenous 
JNK 
c-JUN N-terminal kinase 
KD 
knockdown 

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Protocol No. NBF-006-001 
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kg 
kilogram 
KRAS 
Kirsten rat sarcoma 
LD 
longest diameter 
LNP 
lipid nanoparticle 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
mitogen-activated extracellular signal-regulated kinase 
m 
minute 
mL 
milliliter 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
msec 
millisecond 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
NCI 
National Cancer Institute 
NE 
not evaluable 
nM 
nanomolar 
NSCLC 
non-small cell lung cancer 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PEG 
polyethylene glycol 
PEG-DSPE 
poly(ethylene glycol)–distearoylphosphatidylethanolamine 
PET 
positron emission tomography 
PI3K 
phosphatidylinositol-3-kinase 
PK 
pharmacokinetic 
PR 
partial response 
PTEN 
phosphatase and tensin homolog 
qRT-PCR 
quantitative reverse transcriptase polymerase chain reaction  
QT/QTc 
time between start of the Q wave and end of the T wave/corrected 
QW 
once a week 
RAF 
rapidly accelerated fibrosarcoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SD 
stable disease 
siRNA 
small interfering ribonucleic acid 
SOC 
standard of care 
SOI 
start of infusion 
TGI 
tumor growth inhibition 
TNF-α 
tumor necrosis factor-alpha 
UC 
unconfirmed 
ULN 
upper limit of normal 
US 
ultrasound 
 

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Protocol No. NBF-006-001 
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1.0 GENERAL INFORMATION 
1.1 
Protocol Number and Title of the Study 
Protocol No. NBF-006-001, “A Phase I/Ib Open-Label, Multi-Center, Dose-Escalation Study to 
Investigate the Safety, Pharmacokinetics and Preliminary Efficacy of Intravenous NBF-006 in 
Patients with Non-Small Cell Lung, Pancreatic, or Colorectal Cancer Followed by a Dose 
Expansion Study in Patients with KRAS-Mutated Non-Small Cell Lung Cancer”  
 
1.2 
Sponsor 
Nitto BioPharma, Inc. 
10618 Science Center Drive 
San Diego, California, 92121 
(858) 255-3010 
 
1.3 
Monitor 
Theradex Oncology 
4365 Route 1 South, Suite 101  
Princeton, New Jersey, 08540 
(609) 799-7580 
 
1.4 
Signature Authorization 
Theradex Oncology will act as the Sponsor Representative.  
 
2.0 
BACKGROUND INFORMATION 
2.1 
Introduction 
Mutations of genes encoding protein kinases in the mitogen-activated protein kinase (MAPK) 
(KRAS/RAF/MEK/ERK) and phosphatidylinositol-3-kinase (PI3K) (PI3K/Akt/mTOR) signal-
transduction pathways can alter the normal cellular kinase cascade regulatory function, 
resulting in the dysregulation of cellular proliferation, apoptosis, survival and cell migration 
common to tumor cell development and tumor progression (Figure 1). In the MAPK pathway, 
oncogenic Kirsten rat sarcoma (KRAS) drives the activation of the subsequent signaling 
proteins (RAF/MEK/ERK) and is known to be mutated frequently in pancreatic, colorectal, 
lung and gastric adenocarcinomas, as well as multiple myeloma and endometrioid 
carcinoma.1 The PI3K pathway is regulated by the phosphatase and tensin homolog (PTEN) 
tumor suppressor and activated by guanosine triphosphate-RAS (GTP-RAS). Mutations of 
PTEN and KRAS thus alter the control of this important signaling pathway and multiple 
effector components of the PI3K pathway are known to be frequently mutated or altered in 

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a large variety of cancers.2,3 
 
 
 
Figure 1: Interactions Among Several Key Components Involved in the MAPK and PI3K 
Pathways 
KRAS is a member of the GTPase family of proteins, which switches to active mode when 
bound to GTP and inactive mode when bound to guanosine diphosphate. In pathological 
condition, KRAS mutation results in KRAS-GTP driving oncogenesis. Activation of KRAS 
phosphorylates and activates downstream targets, such as MEK/ERK in the MAPK pathway 
and Akt/mTOR in the PI3K pathway. This activation results in increased growth and 
proliferation. 
 
With the central role of these two signaling pathways in cancer, the inhibition of KRAS and 
the signaling pathway effector proteins has been a major focus of cancer pharmaceutical 
research. The mutated KRAS oncoprotein itself has been difficult to target for inhibition due 
to difficulties in overcoming the impaired GTP hydrolysis of mutant KRAS, similarities of 
mutant and wild-type KRAS, and the availability of alternate mechanisms for required KRAS 
membrane association in the face of farnesyl transferase inhibition.1,4 As a result, while KRAS 
inhibition remains an ongoing research undertaking, therapies inhibiting specific 
downstream effector signaling proteins along both pathways comprise the majority of 
targeted agents currently available or in development.   
 
Nitto BioPharma, Inc. has targeted glutathione S-transferase pi (GSTP), one of a multigene 

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Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
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family of glutathione S-transferases (GST) isoenzymes that exist as mitochondrial, 
microsomal, or cytosolic enzymes involved in catalyzing thioether bonds between 
glutathione and electrophilic toxins and protecting cells from cellular oxidative stress.5 
Importantly, GSTP is also a significant protein in cancer cells and is implicated in the 
modulation of multiple signaling proteins in the RAS and PI3K pathways. GSTP has been 
detected at high levels in many tumors including ovarian, non-small cell lung, breast, colon, 
pancreas and lymphomas and has been associated with cancer disease progression as well 
as chemotherapy drug resistance.5,6 GSTs have been recognized for their ability to bind 
structurally to diverse non-substrate ligands. In this non-enzymatic role, GSTs function to 
sequester the kinase in a complex, thus preventing it from acting on downstream targets.  
 
GSTs are involved in detoxification of many potentially carcinogenic compounds. The 
homozygous deletions or null genotypes of GSTT1 (theta class) can be found in varying 
frequency in the normal population and may be associated with cancer incidence and drug 
effects. The frequency of GSTT1-null varies widely in different populations: approximately 
50-60% in Asians, 15% in White populations, 15-20% in Blacks or African Americans, and less 
than 10% in Hispanic populations.7   
 
GSTP has been implicated in regulation of cell signaling in response to intra- and extracellular 
stimuli in many pathways involving MAPKs. The result of this action is a regulation of 
pathways that control cell proliferation and apoptotic cell death. For example, GSTP was 
among the first isoenzymes found to inhibit c-JUN N-terminal kinase (JNK) through direct 
protein–protein interaction. JNK is a MAP kinase involved in stress response, apoptosis, 
inflammation, and cellular differentiation and proliferation. Thus, elevated expression of 
GSTP also has an anti-apoptotic role in tumor cells by interacting directly with MAPK/JNK 
through binding of the C-terminus of JNK.8  
 
2.2 
The Investigational Product 
The drug product, NBF-006 contains a novel active pharmaceutical ingredient (API), 
NDT-05-1040, a small interfering ribonucleic acid (siRNA) encapsulated within lipid 
nanoparticles (LNPs). The LNP is composed of 5 key lipids, designed to inhibit the expression 
of GSTP messenger ribonucleic acid (mRNA) and protein in tumors and lung tissue. Before 
use, NBF-006 is reconstituted with 60 mM Sodium Acetate Diluent (Acetate Diluent), which 
will also be provided by the sponsor.  
 
The significant technological achievement of this program is to provide effective extrahepatic 
delivery of siRNA. Historically, LNPs have tended to deliver cargo exclusively to the liver. 
NBF-006 was designed to distribute the siRNA cargo primarily to tumors and the lung. The 
current preclinical development of NBF-006 has been focused on KRAS-mutant non-small 
cell lung cancer (NSCLC) given the unmet medical need and the ability to deliver siRNA to 
lung tumors in preclinical models. 
 

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Protocol No. NBF-006-001 
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Importantly, NBF-006 delivery is also achieved in other organ locations and the pleiotropic 
effects of GSTP on the key pathways of many cancers indicate that the siRNA knockdown 
(KD) of GSTP protein expression may be effective for other cancer indications. Once the 
safety profile and preliminary anti-cancer activity of NBF-006 is established with this 
Phase I/Ib clinical trial, the efficacy of NBF-006 in additional malignancies may be explored. 
 
2.3 
Preclinical Studies 
Key preclinical findings are summarized below. Please refer to the current Investigator’s 
Brochure (IB) for details of these and other studies. 
 
2.3.1 In Vitro Efficacy of NDT-05-1040 siRNA 
As the RAS and PI3K signaling pathways play an important role in NSCLC, development and 
disease progression, preclinical characterization of the mechanism of action and 
anti-proliferative activity of GSTP-targeted siRNA NDT-05-1040 (the API) was established 
using KRAS mutant NSCLC cell lines for in vitro and in vivo experiments. 
 
In cell-based assays, NDT-05-1040 demonstrated dose-dependent downregulation of GSTP 
and high potency in multiple cell lines, including KRAS-mutant NSCLC cells, while not affecting 
the survival of normal cells. Maximum reduction (~90%) in GSTP mRNA was achieved 
24 hours post transfection and maintained for at least 5 days in A549 tumor cells. Maximum 
reduction was achieved with 10 nM NDT-05-1040, with minimal protein KD observed at 
0.016 nM NDT-05-1040. Potential off-target effects of the siRNA were only observed for the 
guide strand but at concentrations 100-fold higher than the half maximal inhibitory 
concentration levels required for potent KD of the target gene. 
 
Studies in cancer cell lines have shown an increase in sensitivity to GSTP KD in cell lines that 
are GSTT1-null and KRAS-mutant. Specifically, data from cell viability assays showed that 60% 
of the NSCLC cell lines screened were highly sensitive to NDT-05-1040. Furthermore, 38% of 
the NSCLC lines were GSTT1-null and within GSTT1-null cell lines, an increased sensitivity 
(72%) to NDT-05-1040 was observed. In addition, 67% of the KRAS-mutant NSCLC were 
sensitive to NDT-05-1040 treatment. Interestingly, of the KRAS-mutant cell lines, 44% with 
GSTT1 wild-type were sensitive to NDT-05-1040 as compared to 89% of GSTT1-null cell lines.   
 
GSTP KD by NDT-05-1040 impacted the RAS/MEK/ERK, Akt, mTOR pathways leading to 
increased apoptosis and decreased proliferation. NDT-05-1040 triggered cell death through 
caspase activation (i.e., caspase 3/7). Furthermore, cell cycle analysis suggested that 
NDT-05-1040 inhibited tumor cell growth by reducing the S-phase population and enhancing 
the sub-G1 cell population.  
 

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Protocol No. NBF-006-001 
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2.3.2 In Vivo Efficacy of NBF-005 LNPs containing NDT-05-1040 siRNA 
In vivo efficacy studies were performed using NBF-005 (an earlier formulation of the drug 
product that is identical to NBF-006, except for additional salt content) consisting of 
NDT-05-1040 siRNA encapsulated in an LNP. The LNP formulation serves as a protector to 
reduce the likelihood of the active siRNA component being metabolized by nucleases in 
blood and removed by other elimination systems, primarily through the renal excretion 
system. 
 
NBF-005 demonstrated potent dose-dependent tumor growth inhibition (TGI) in A549, H23, 
and H2009 xenograft models in mice. A once a week (QW) dosing schedule of 0.5 to 
4.0 mg/kg/week resulted in significant TGI, tumor stasis and tumor regression. Moreover, 
there were no significant differences on TGI between 8 consecutive weekly dosing 
(continuous) versus 8 doses broken up by a 4-week rest period in between (QW x 4 doses 
followed by 4-week rest period followed again by QW x 4 doses). 
 
To better mimic human NSCLC tumors, efficacy in two lung orthotopic models –– tail vein 
injection and surgically grafted –– was evaluated. In the bioluminescent (A549Luc) tail-vein 
injection orthotopic lung tumor model, the average luminescent signal response in the 
NBF-005 treated group was markedly lower than the vehicle control group (14.3 vs 69.6 
million photon/second, P < 0.05). Additionally, in the surgically implanted orthotopic lung 
tumor model, the survival of NBF-005 treated mice was significantly prolonged (P < 0.005) at 
a 4 mg/kg dose compared to the vehicle control group.  
 
2.3.3 In Vitro Evaluation of GSTP Knockdown in PBMCs by NBF-006 
In vitro studies were performed on healthy human peripheral blood mononuclear cell 
(PBMC) samples and were utilized for quantitative analysis of the mRNA level of GSTP using 
quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The purpose of this 
study was to examine the kinetic profile of GSTP mRNA in PBMCs after NBF-006 treatment. 
Timepoints and concentrations of NBF-006 were tested in vitro, which would best mimic the 
expected clinical exposure (based on pharmacokinetic [PK] data generated during the dose 
escalation phase of this study (NBF-006-001)). 
 
The rationale for selecting 50 nM and 500 nM concentrations for in vitro PBMC testing is 
based on a representative, sustained plasma concentration range of patients dosed at 0.6 
and 1.2 mg/kg, over the time frame of 6-72 hours, i.e., minimum to mean and median 
concentration levels, to reflect drug duration in blood circulation for the majority of patients.  
 
As seen in Figure 2, when treated with 500 nM NBF-006, GSTP KD started as early as 6 hours 
and lasted for at least 72 hours in PBMCs. At 500 nM, maximal KD of ~61% was observed at 
6 hours which decreased slightly at 48 and 72 hours. At the lower concentration (50 nM), the 
maximum KD was observed 6 hours post treatment and returned to baseline by 48 hours.  

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Protocol No. NBF-006-001 
A Phase I/Ib Study of NBF-006 in NSCLC,  
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Kinetic KD with NBF-006 using PBMC
0
25
50
75
100
125
% of GSTP expression
normalized by Mock (Mean  SEM)
6 hrs
24 hrs
48 hrs
72 hrs
nM
50
500
50
500
50
500
50
500
 
Figure 2: Relative Gene Expression of GSTP in PBMCs by qRT-PCR. 
PBMCs were transfected with 50 nM and 500 nM of NBF-006 (pretreated with 5 µg/mL phospholipase A2 for 24 hours which reduces 
polyethylene glycol from the LNP and allows for in vitro transfection). Following NBF-006 treatment, cells were lysed, total RNA 
isolated, and GSTP mRNA levels were measured by qRT-PCR. Target gene mRNA level was normalized to RPLPO gene. Values represent 
mean ± standard error with triplicates.  
 
Based on these results, timepoints for PBMC isolation from whole blood samples have been 
selected to be studied in this trial. A quantitative analysis of the mRNA GSTP levels with 
qRT-PCR in the PBMCs will allow for an assessment of target engagement, and therefore a 
pharmacodynamic correlation, in patients treated with NBF-006 in a surrogate tissue. 
 
2.3.4 Toxicology Evaluation of NBF-005 and NBF-006 LNPs containing NDT-05-1040 
siRNA 
NBF-005 and NBF-006 triggered minimal or no immune response (7 cytokine panel) in PBMC 
samples from 4 healthy human donors at concentrations which cover the projected 
maximum concentration (Cmax) of the first two dose levels (0.15 and 0.3 mg/kg) proposed in 
humans. No severe hemolytic activity was observed at doses up to 10 µM for either NBF-005 
or NBF-006, a dose that is 6-fold greater than the projected clinical Cmax at the highest 
planned dose of 1.2 mg/kg. No toll-like receptor response was stimulated at NBF-006 doses 
ranging from 0.0156 μM to 1 µM, which covers the projected Cmax of the first three dose levels 
(0.15, 0.3, and 0.6 mg/kg) proposed in humans.  
 
In dose range finding and Good Laboratory Practice (GLP) toxicology studies in monkeys, a 
mild and transient degree of activation of the classical and alternative complement pathways 
was evident from the small increases in Bb and C4a; however there was no increase in C5a. 
C5a is produced when activation of the classical or alternative pathways cascades into 
activation of the terminal pathway, leading to cleavage of C5 to C5a. C5a is a marker of 
terminal pathway activation and is the most powerful anaphylatoxin produced during 
complement activation. C5a has its own pro-inflammatory properties, and its accumulation 

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Protocol No. NBF-006-001 
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is generally associated with adverse effects in monkeys. Conversely, the absence of C5a 
accumulation may be considered an indication that increases in other split products may not 
have deleterious consequences. These results indicate that the generally small increases in 
Bb or C4a were not toxicologically significant. 
 
Minimal changes in hematologic and clinical chemistries were observed in mice and 
monkeys in repeat-dose GLP toxicology studies. A common microscopic finding was the 
presence of vacuolation of the tubular epithelial cells or transitional epithelium, and 
aggregation of vacuolated phagocytic cells, in several organs (kidney, lung, urinary bladder, 
spleen and lymph nodes). Vacuolation was dose-dependent and showed signs of reversibility 
following the recovery period. Since the vacuolated phagocytic cells were observed in both 
NBF-005 and NBF-005 Empty (LNP only) treated animals, vacuolation was considered related 
to uptake and clearance of the LNP component. One of the NBF-006 LNP components is 
poly(ethylene glycol)–distearoylphosphatidylethanolamine (PEG-DSPE). Polyethylene glycol 
(PEG)-containing vacuoles in cells have been observed with several licensed PEGylated drugs 
with no associated pathological changes or human toxicity. There is evidence PEG vesicles 
can resolve with time.9 A review published in 2015 showed that PEG-related histologic 
changes, characterized as cellular vacuolation in certain tissues and cell types, is a common 
finding in nonclinical toxicology studies of PEGylated drugs. These changes were not 
associated with pathologic effects such as tissue degeneration, necrosis, and cellular 
distortion or changes in study endpoints including hematology, clinical chemistry, urinalysis, 
or 
organ 
weight.10 
The 
body 
of 
evidence 
available 
for 
approved 
PEGylated 
biopharmaceuticals has not identified any clinically reported functional consequences for 
compounds where vacuolation was observed in toxicology studies.10 
 
Mice were the most sensitive species. Deaths were observed at the 40 mg/kg/week in both 
the GLP-repeat dose toxicology study and the non-GLP study at this dose. In the GLP-repeat 
dose toxicology study, 11 out of 126 mice treated with 40 mg/kg/week of NBF-005 and 2 out 
of 30 animals treated with 40 mg/kg/week of the reference item (empty liposomes) were 
found dead or euthanized. In the non-GLP study, only one animal died and this was 
considered an incidental event due to the lack of pathologic findings. The dose of 
20 mg/kg/week in mice was a non-toxic dose at which there were no deaths and no overt 
adverse findings. 
 
2.4 
Previous Clinical Studies 
There were no previous clinical studies with NBF-006. Dose levels 1-4 (0.15 mg/kg, 0.3 mg/kg, 
0.6 mg/kg, and 1.2 mg/kg) of Part A were evaluated for the first time in 14 patients with 
advanced NSCLC (n=4), colorectal cancer (n=5), or pancreatic cancer (n=5) in Part A of this 
study from March 2019. No treatment-related serious adverse events (SAEs), treatment-
related grade 3-4 adverse events (AEs), or dose-limiting toxicities (DLTs) have been observed 
in any patient treated at dose levels 1-4 in Part A of the study. One patient (dose level 2, 
0.3 mg/kg) experienced a mild infusion related reaction (grade 2) that was managed with 

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standard therapy, and the patient could continue treatment in the study. Other reported, 
possibly related, grade 2 events included diarrhea (1 patient, dose level 1, 0.15 mg/kg), and 
fatigue and vomiting (1 patient each, dose level 4, 1.2 mg/kg). No clinically meaningful 
immune activation (complement and cytokines) was observed at dose levels 1-4 (0.15 mg/kg, 
0.3 mg/kg, 0.6 mg/kg, and 1.2 mg/kg). 
 
2.5 
Rationale for Starting Dose, Dose Range, and Dosing Schedule 
While ribonucleic acid (RNA) therapeutics are not biologics, the starting dose in humans takes 
into account industry guidance and best practices that advise using the highest non-severely 
toxic dose (HNSTD) in the most sensitive species studied in the preclinical toxicology studies. 
The highest non-toxic dose was 20 mg/kg/week in the most sensitive species, mice. The 
human equivalent dose (HED) is a weekly dose of 1.6 mg/kg. Per the guidance, 1/6th the 
HNSTD11, which would be a weekly dose of 0.3 mg/kg, is an appropriate starting dose. We 
have taken additional safety precautions by lowering the starting dose further to 0.15 mg/kg 
(1/12th the HNSTD). Preclinical efficacy was observed in the dose range of 2-4 mg/kg with 
maximal efficacy demonstrated at 4 mg/kg in mice (0.3 mg/kg HED). 
 
Based on the toxicology data in the most sensitive species, mice, NBF-006 doses of 5 to 
20 mg/kg caused non-severely toxic effects; the HED of this range is 0.41 to 1.63 mg/kg, which 
overlaps with the range of human doses to be used in this trial. The highest dose, 1.6 mg/kg, 
in this trial does not exceed the HNSTD equivalent in mice. Based on the well-tolerated doses 
in Part A up to 1.2 mg/kg, Part A will be further escalated to the top of the projected non-
severely toxic dose range (1.6 mg/kg).  
 
Based on the observation of vacuolation in the repeat-dose GLP toxicology studies, a rest 
period of 2 weeks has been implemented for the initial patient trial to allow for clearance of 
the LNPs. Vacuolation was dose-dependent and showed signs of reversibility following the 
2-week recovery period. The rest period also reduces the burden on the patients. The dosing 
schedule (4 weekly doses + 2-week rest period) is well supported by the nonclinical xenograft 
and repeat-dose toxicology studies. 
 
2.6 
Potential Risks and Benefits 
As this is the first-in-man study of NBF-006, no human data regarding the safety or potential 
benefit of NBF-006 was available before the study started. Since the clinical study began, 
14 patients (IB v 4.0, 26MAR2021) have been treated at dose levels 1-4 (0.15 mg/kg, 0.3 
mg/kg, 0.6 mg/kg, and 1.2 mg/kg) without any signs of overt toxicity. No clinically meaningful 
immune activation (complement and cytokines) was observed at dose levels 1-4 (0.15 mg/kg, 
0.3 mg/kg, 0.6 mg/kg, and 1.2 mg/kg). 
 
Nucleic acids like the siRNA are rapidly degraded by nucleases when not protected by LNPs. 
Much of the potential toxicity of NBF-006 would result from the LNP components 

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themselves. Many clinical studies of LNP-formulated siRNAs have observed dose-dependent 
inflammatory cytokine elevations.12 Although many early phase trials of similar 
LNP-formulated siRNAs demonstrated a tolerable safety profile, immunogenicity (e.g., 
immune responses) could be a potential toxicity of this study treatment, especially at high 
doses or with frequent dosing of NBF-006.13 
 
Based on other clinical trials with LNP-encapsulated siRNAs, the following are possible risks 
of NBF-006: 
• 
Elevated cytokine levels or complement activation which could lead to inflammation. 
The symptoms would be flu-like symptoms, such as back pain, fever, nausea, 
headache, rash, rapid heartbeat, low blood pressure, temporary tightness in the 
chest, and trouble breathing. In severe cases, cytokine release syndrome could 
potentially develop. 
• 
Allergic reaction (rash, wheezing, shortness of breath, heart palpitations, swelling of 
the face, and lowered blood pressure) to the drug or one of the drug or LNP 
components. 
• 
In animals, NBF-006 administration led to increased vacuolation in tissues and cells. 
The appearance of vacuoles was not associated with any changes in organ function 
and went away over time.  
 
Please see the current IB for further details about the potential risks and benefits associated 
with this study. 
 
2.7 
Characteristics of a Well-Conducted Trial 
The following characteristics of an adequate and well-conducted trial will be implemented: 
 
1. 
The Investigators will be well qualified by scientific training and experience. 
 
2. 
Detailed electronic Case Report Forms (eCRFs) will be completed for every patient. 
 
3. 
Requirements for institutional ethics review as set forth by the appropriate 
Institutional Review Board/Independent Ethics Committee (IRB/IEC), Title 21 Code of 
Federal Regulations (CFR) Part 56, the European Union Directive 2001/20/EC and its 
associated Detailed Guidances, European Union Good Clinical Practice (GCP) Directive 
2005/28/EC, the International Council for Harmonization (ICH) Guideline for GCP, 
Sections 3 and 4, and the terms of the Declaration of Helsinki (2013), will be followed. 
 
4. 
Requirements for informed consent in accordance with institutional guidelines, Food 
and Drug Administration (FDA) requirements as specified in Title 21 CFR, Part 50, the 
European Union Directive 2001/20/EC and its associated Detailed Guidances, 

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European Union GCP Directive 2005/28/EC, the ICH Guideline for GCP, Section 4.8, 
and the terms of the Declaration of Helsinki (2013), will be followed. 
 
5. 
Safety data will be recorded and evaluated. 
 
6. 
Routine monitoring visits will be conducted by the Sponsor’s representative 
(Theradex Oncology) to ensure data accuracy, if allowed per local regulations. If on-
site monitoring visits are not possible due to local regulations, restrictions, and/or 
guidance, monitoring visits to ensure data accuracy will be conducted remotely. 
 
7. 
Drug accountability will be strictly maintained. 
 
8. 
This trial will be conducted according to GCP, the protocol and applicable regulatory 
requirements. The Safety Review Committee (consisting of Investigators, Theradex 
Oncology Medical Monitor, and Sponsor) will also review safety data periodically and 
make recommendations accordingly. 
 
2.8 
Patient Population 
This study will initially enroll adult male and female patients with progressive or metastatic 
NSCLC, pancreatic, or colorectal cancer that has failed standard treatment for which no other 
effective treatment is available or appropriate for the patient.  
 
For dose level 5 (1.6 mg/kg) in Part A and all patients in Part B (dose expansion), the patients 
must have KRAS-mutant NSCLC. 
 
3.0 
TRIAL OBJECTIVES AND PURPOSE 
Part A (Dose escalation) 
Primary: 
• 
To determine the safety profile, maximum tolerated dose (MTD), and recommended 
dose of NBF-006 for Part B in patients with advanced NSCLC, pancreatic, or colorectal 
cancer for dose levels 1-4 (0.15, 0.3, 0.6, and 1.2 mg/kg) and in patients with KRAS-
mutated NSCLC for dose level 5 (1.6 mg/kg). 
 
Secondary: 
• 
To evaluate preliminary efficacy of NBF-006 in patients with advanced NSCLC, pancreatic, 
or colorectal cancer for dose levels 1-4 (0.15, 0.3, 0.6, and 1.2 mg/kg) and in patients with 
KRAS-mutated NSCLC for dose level 5 (1.6 mg/kg). 
• 
To investigate the PK of NBF-006. 
 
Exploratory: 
• 
To evaluate correlation between biomarkers and clinical outcome. 

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• 
To evaluate correlation between KRAS-mutations and clinical outcome.  
 
Part B (Dose expansion) 
Primary:  
• 
To evaluate preliminary efficacy and safety profile of NBF-006 in patients with 
KRAS-mutated NSCLC. 
 
Secondary: 
• 
To investigate the PK of NBF-006. 
 
Exploratory: 
• 
To evaluate GSTP mRNA KD in surrogate tissue (PBMCs) and correlation between 
biomarkers and clinical outcome. 
 
4.0 
TRIAL DESIGN 
4.1 
Overview of Trial Design 
This is an open-label, non-controlled study conducted in two parts –– Part A (dose escalation) 
followed by Part B (dose expansion) (study schematic in Figure 3).    
 
 
Figure 3: Schematic Overview of the Trial 
 
4.2 
End of Study 
The end of the study is defined as the date of the last visit of the last patient undergoing the 
trial. 
 
4.3 
Minimizing Bias 
This is an open-label, non-placebo-controlled study. Randomization will not be used. Patients 
enrolled in Part B will be stratified for GSTT1-null genotype to ensure equal allocation to the 

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cohorts with different doses. Patients treated at the highest dose level in Part B will be 
balanced for GSTT1-null genotype to match the distribution of patients at the other 
(stratified) dose levels as much as possible. This will be determined based on the first 6 
patients treated at this dose in Part A (not stratified).   
 
4.4 
Drug Product  
NBF-006 is a sterile, injectable, parenteral product containing 10 mg of the active ingredient 
per vial. The vial is stored frozen at -20 °C ± 5 °C until use. 
 
NBF-006 is an LNP formulation that incorporates five (5) key lipid components (i.e., Lp-081, 
cholesterol, 
dioleoyl 
phosphatidylethanolamine, 
dioleoyl 
phosphatidylcholine, 
and 
PEG-DSPE) to encapsulate siRNA API (NDT-05-1040), forming the siRNA LNP complex for drug 
delivery. The API, NDT-05-1040 siRNA, is a synthetic, double-stranded RNA. NBF-006 is 
reconstituted for use with 60 mM Acetate Diluent. The Acetate Diluent is provided with the 
drug product. 
 
4.5 
Duration of Therapy 
Upon completion of Cycle 1, in the absence of disease progression or unacceptable toxicity, 
patients may continue to be treated with NBF-006 at the same dose and schedule until 
disease progression, death, withdrawal of consent, Investigator decision to remove patient, 
or intolerable toxicity, whichever occurs first. A patient may continue on study (even if one 
or more criterion meets Disease Progression per Response Evaluation Criteria in Solid 
Tumors [RECIST] 1.1) at the Investigator’s discretion if deemed that the drug is well-tolerated 
and that the patient may continue to receive benefit from continuing treatment. 
 
4.6 
Trial Discontinuation  
For reasonable cause, either the Investigator or the Sponsor may terminate this study 
prematurely. Written notification of the termination is required. Conditions that may warrant 
termination include, but are not limited to: 
 
• 
The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled 
in the study. 
• 
Failure of the Investigator to enter patients at an acceptable rate. 
• 
Insufficient adherence to protocol requirements (non-compliance). 
• 
Lack of evaluable and/or complete data. 
• 
Decision to modify the developmental plan of the drug. 
• 
A decision on the part of the Sponsor to suspend or discontinue development of the drug. 
 

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4.7 
Drug Accountability/Disposition of Clinical Trial Supplies 
Drug accountability records will be maintained for all clinical trial supplies. 
 
All unused clinical trial supplies will be destroyed per the institution’s standard operating 
procedure. Destruction of drug and trial supplies must be documented, and the 
documentation will be reviewed by/sent to the Sponsor or their Designee.  
 
4.8 
Registration 
Prior to registration and any study-specific evaluations being performed, all patients must 
have given written informed consent for the study and must have completed the pre-study 
evaluations (see Section 0). Patients must meet all of the eligibility requirements listed in 
Section 5.0. Patients will be registered on the study by using the Theradex Oncology 
Interactive Web Response System automated patient registration system (see the Study 
Operations Manual for specific instructions). 
 
5.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 Inclusion Criteria 
1. Part A: Patients with histologically or cytologically confirmed progressive or metastatic 
NSCLC, pancreatic, or colorectal cancer that have failed standard treatment and for which 
no other effective treatment is available for that patient up to dose level 4. In dose level 5 
(1.6 mg/kg), patients with histologically or cytologically confirmed progressive or 
metastatic NSCLC with documented KRAS-mutant genotype, who have failed standard 
treatment and have no other effective treatment available or appropriate for the patient. 
Part B: Patients with histologically or cytologically confirmed progressive or metastatic 
NSCLC with documented KRAS-mutant genotype, who have failed standard treatment 
and have no other effective treatment available or appropriate for the patient. 
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (APPENDIX I). 
3. Men and women  18 years of age. 
4. Patients must have recovered from all acute adverse effects (excluding alopecia) of prior 
therapies to baseline or  Grade 1 prior to study entry.  
5. Adequate bone marrow function, defined as an absolute neutrophil count 
(ANC)  1.5 x 109/L and a platelet count  100 x 109/L. 
6. Adequate renal function, defined as serum creatinine  1.5 x upper limit of normal (ULN) 
for the institution or calculated creatinine clearance [Cockcroft-Gault method] must be 
≥ 60 mL/min/1.73 m2. If serum creatinine is >1.5 x ULN, then creatinine clearance can be 
calculated from a 24-hour urine collection. 
7. Adequate hepatic function, defined as total bilirubin  1.5 mg/dL and alanine 
transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN, or ≤ 5 x ULN if known 
liver metastases.  

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8. Female patients of childbearing potential must have a negative serum or urine pregnancy 
test result at time of pre-treatment screening. 
9. Patients with reproductive potential must agree to use at least one form of highly 
effective contraception (APPENDIX III) prior to study entry and for up to 30 days beyond 
the last administration of study drug. 
10. Patients must be capable of providing informed consent and must be willing to provide 
written informed consent prior to the start of any study-specific procedures. 
11. All patients must have measurable tumor per RECIST 1.1. 
12. Agree to adhere to all study protocol requirements. 
 
5.2 Exclusion Criteria 
1. Prior radiation therapy within 2 weeks; or chemotherapy or non-cytotoxic therapy within 
4 weeks or 5 drug half-lives, whichever is shorter (exception: 6 weeks for nitrosoureas or 
mitomycin C); or monoclonal antibodies within 4 weeks prior to the first dose of study 
treatment. 
2. Concurrent use of any other investigational agent.  
3. Known or clinically suspected central nervous system (CNS) or leptomeningeal 
metastases, unless irradiated or treated a minimum of 4 weeks prior to first study 
treatment and stable without requirement of corticosteroids for > 1 week. 
4. Pregnant or breast feeding. A negative pregnancy test must be documented at baseline 
for women of childbearing potential. Patients may not breast-feed infants while on this 
study. 
5. Significant cardiovascular disease or condition, including: 
a. Congestive heart failure currently requiring therapy 
b. Need for antiarrhythmic medical therapy for ventricular arrhythmia 
c. Severe conduction disturbance 
d. Angina pectoris requiring therapy 
e. QTc interval > 450 msec (males) or > 470 msec (females) Fridericia’s correction 
Note: QTc values up to 500 ms will be acceptable where patient’s medical history e.g., bundle 
branch block, is known to cause mild QTc prolongation and the condition is well controlled. 
f. History of congenital long QT syndrome or congenital short QT syndrome 
g. Uncontrolled hypertension (per the Investigator’s discretion) 
h. Class III or IV cardiovascular disease according to the New York Heart Association’s 
Functional Criteria 
i. 
Myocardial infarction within 6 months prior to first study drug administration 
6. Known history of human immunodeficiency virus or active infection with hepatitis B virus 
or hepatitis C virus.   
7. Known uncontrolled intercurrent illnesses, including uncontrolled viral influenza and 
COVID-19, systemic bacterial infections, and fungal infections. 
8. Psychiatric disorder or altered mental status that would preclude understanding of the 
informed consent process and/or completion of the necessary studies. 
9. Known allergic reactions to H1/H2 antagonists. 

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5.3 
Inclusion of Women, Minorities and Children 
Both men and women and members of all races and ethnic groups are eligible for this study. 
Children are not eligible for this study because the safety and tolerability of the proposed 
dosing schedule has not been determined in adults. 
 
5.4 
Withdrawal Criteria 
Protocol therapy will be discontinued at any time if any of the following situations occur: 
 
1. Progressive disease (PD).  
2. The development of toxicity which, in the Investigator’s judgment, precludes further 
therapy.  
3. Patient refusal. 
4. Unacceptable AE(s). 
5. Lost to follow-up/noncompliance. 
6. Intercurrent illness that prevents further administration of treatment. 
7. At the discretion of the Investigator. 
8. Pregnancy. 
9. Study termination. 
 
Additionally, refer to the safety-related stopping rules in Section 8.1.2.11. 
 
5.4.1 Withdrawn Subjects  
When a patient is removed from the study, the Investigator will clearly document the reason 
in the medical record and complete the appropriate eCRF page describing the reason for 
discontinuation. In addition, every effort should be made to complete the appropriate 
assessments listed in Section 7.4. 
 
5.4.2 Replacement of Subjects 
Patients who discontinue due to toxicity (related to study drug) during Cycle 1, or who do not 
receive all doses due to toxicity in Cycle 1, will not be replaced. Patients who discontinue or 
who do not receive all doses for any reason other than toxicity will be replaced. Note, that 
all patients who enrolled in the study, regardless of their replacement, will be included in 
assessment of DLT per Section 6.1.3. 
 
5.5 
Noncompliance 
All instances of protocol deviations will be entered into Monitor Express and will be reviewed 
and signed off by the Investigator and Theradex Oncology.  
 

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6.0 
TREATMENT OF SUBJECTS 
6.1 
Drug Preparation and Administration 
NBF-006 is intended for intravenous (IV) infusion use and exposure to direct sunlight should 
be avoided. Before use, the drug product vial is reconstituted with 5.6 mL of Acetate Diluent 
to bring the total constituted volume to approximately 6.7 mL, yielding a drug concentration 
of approximately 1.5 mg/mL. The constituted suspension is diluted into sterile saline diluent 
to a total volume of 300 mL (or to a total volume of 320 mL for the 1.6 mg/kg dose level) in 
the clinic for IV infusion to patients. The admixture solution will achieve a final desired drug 
concentration within acceptable physiological pH and tonicity for IV administration to 
patients.  
 
NBF-006 infusion will be implemented as a stepwise infusion: 
(1) 0.5 mL/min for 10 minutes,  
(2) then 1.5 mL/min for 10 minutes, and 
(3) finally 6 mL/min for the remaining volume 
Total infusion duration of approximately 70 minutes (± 20 minutes). 
 
Doses ranging from 0.15 to 1.6 mg/kg will be evaluated. The drug is administered weekly for 
4 weeks followed by a 2-week rest period. The length of each cycle is 6 weeks. 
 
For detailed instructions on vial concentration, preparation, and dispensing, please refer to 
the Pharmacy Manual. 
 
The target infusion time is 70 minutes, but infusion rate will be adjusted as needed (e.g., due 
to infusion reaction). Premedication with H1/H2 antagonists should be considered if infusion 
reactions occur; refer to the management of infusion-related reactions (IRRs) outlined in 
Section 8.1.2.8. 
 
The reconstituted drug (NBF-006 in Acetate Diluent) is stable in the glass vial for 2 hours at 
ambient conditions. The reconstituted drug solution is further diluted to the appropriate 
dose concentration with saline into a DEHP-free IV bag; this IV infusion solution is stable for 
4 hours at ambient conditions. The drug product (lyophilized form, reconstituted solution, 
and IV infusion solution) should be kept out of direct sunlight. 
 
Both NBF-006 and the Acetate Diluent will be provided by the Sponsor. Ordering instructions 
will be provided. 
 

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6.1.1 Dose Escalation Scheme 
Part A (Dose escalation; Table 1): 
NBF-006 (300 mL, or 320 mL for the 1.6 mg/kg dose level) will be administered via IV infusion 
over 70 minutes, QW for 4 weeks followed by a 2-week rest period. The length of each cycle 
is 6 weeks. Patients in dose levels 1-4 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, and 1.2 mg/kg) of 
Part A, will have previously treated progressive or metastatic NSCLC, pancreatic, or colorectal 
cancer, regardless of KRAS mutation status. Patients in dose level 5 (1.6 mg/kg) of Part A 
must have previously treated progressive or metastatic NSCLC with confirmed KRAS 
mutation.  
 
The first dose level (0.15 mg/kg) will be a single patient cohort. If any Grade 2 or greater 
drug-related event occurs during the first cycle of treatment, the cohort will be expanded up 
to 3 patients. If a DLT occurs during the first cycle, the cohort will be expanded up to 
6 patients before proceeding with dose escalation. 
 
Subsequent cohorts in the dose escalation phase will enroll patients following the standard 
3+3 design. If 1 out of 3 patients experience a DLT during the first cycle of treatment, the 
dose cohort will be expanded up to 6 patients. If no DLT is observed in the first 3 patients 
enrolled at the highest dose, this cohort will be expanded to 6 patients. If 2 or more out of 
6 patients experience DLTs, the MTD has been exceeded, and dose escalation will cease. Up 
to 3 additional patients will be enrolled at a lower dose if only 3 patients were treated at that 
dose level, to confirm safety of that dose. MTD will be defined as a dose where 0 or 1 out of 
6 patients have DLTs. To collect clinically important information in the target population, and 
prepare for Part B, the 6-patient cohort(s) must each include at least 3 patients with 
histologically or cytologically confirmed progressive or metastatic NSCLC, up to dose level 4 
(1.2 mg/kg). In dose level 5 (1.6 mg/kg), only patients with previously-treated NSCLC with 
KRAS mutation will be included. Once safety has been confirmed in Part A at 1.6 mg/kg (i.e. 
0-1 DLT in 6 patients), an additional 4 patients with KRAS-mutated NSCLC will be enrolled in 
Part B of the study at this dose level. Stratification for GSTT1-null genotype patients will not 
occur in Part A, but whole blood samples will still be collected during the screening visit for 
Part A dose level 5 (1.6 mg/kg) and batch analyzed at a central lab. 
 
One dose de-escalation is permitted. 
 
 
 
 
 
 
 
 
 

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Table 1: Part A NBF-006 Dose Levels 
Dose level 
NBF-006 dose 
Number of patients 
1 
0.15 mg/kg 
1-6 
2 
0.3 mg/kg 
3-6 
3 
0.6 mg/kg 
3-6 
4 
1.2 mg/kg 
3-6 
5 
1.6 mg/kg 
3-6 
 
 
6.1.2 Part B (Dose Expansion) 
After MTD is confirmed in Part A for up to dose level 4 (1.2 mg/kg), enrollment in Part B may 
commence. Part B will enroll patients with previously treated progressive or metastatic 
NSCLC with confirmed KRAS mutation. 
 
The two dose levels that will be explored further in Part B are 0.6 mg/kg and 1.2 mg/kg. 
Twenty patients will be enrolled in Part B, with 10 patients enrolled in each of the two 
cohorts. Both cohorts will be stratified for GSTT1-null genotype patients to ensure equal 
allocation to the cohorts with different doses. Once dose level 5 (1.6 mg/kg) has been 
confirmed to be safe in Part A, an additional 4 patients will be enrolled at dose level 
1.6 mg/kg, for a planned total of 24 patients in Part B. This last dose level in Part B at 
1.6 mg/kg will also be stratified for GSTT1-null genotype patients to be balanced with the 
previous two expansion cohorts as much as possible. The final proportion of GSTT1-null 
patients treated at the highest dose level may depend on the first 6 patients treated in Part A 
(not stratified).  
 
 
Table 2: Part B NBF-006 Dose Levels 
Dose level 
NBF-006 dose 
Number of patients 
3 
0.6 mg/kg 
10 
4 
1.2 mg/kg 
10 
5 
1.6 mg/kg 
4* 
*Dose level 5 pending confirmation of safety in Part A 
 
NBF-006 will be administered by weekly infusion for 4 consecutive weeks of a 6-week cycle.   
 
6.1.3 Dose-Limiting Toxicity (Part A) 
AEs will be assessed per National Cancer Institute (NCI) Common Terminology Criteria 
(CTCAE) version 5.0. DLT is defined as any treatment related toxicity (i.e., not attributable to 
the underlying active disease, or intercurrent illness) during the first 42 days (Cycle 1) of 
study treatment meeting any of the criteria described below. Ongoing safety events beyond 

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Cycle 1 will be reviewed across all cohorts during the study to help inform dose escalation 
decisions. Note, that all patients who enrolled in the study, regardless of their replacement 
as per Section 5.4.2, will be included in assessment of DLT. 
DLT includes: 
1. Treatment-related hematological toxicities as follows:  
• 
Grade 4 neutropenia.  
• 
Any grade neutropenic fever. 
• 
≥ Grade 3 thrombocytopenia lasting longer than 3 consecutive days. 
• 
≥ Grade 3 thrombocytopenia with bleeding. 
• 
Any other confirmed hematological toxicity ≥ Grade 4 (a repeat test may be required 
for confirmation of an isolated abnormality in the absence of clinical signs, symptoms 
or other abnormal investigations, i.e., a suspected spurious value).  
 
2. Treatment-related non-hematological toxicity ≥ Grade 3 including:  
• 
Electrolyte abnormalities that do not resolve within 48 hours of intervention (a repeat 
test may be required for confirmation of an isolated abnormality in the absence of 
clinical signs, symptoms or other abnormal investigations, i.e., a suspected spurious 
value). 
• 
≥ Grade 3 IRRs. 
• 
≥ Grade 3 cytokine release syndrome. 
• 
Any hepatic toxicity meeting Hy’s Law criteria. 
• 
Grade 3 nausea/vomiting or diarrhea or other self-limited or medically controllable 
toxicities that last > 72 hours regardless of medical intervention. 
 
3. Any other treatment-related toxicity, i.e., greater than at baseline, which is clinically 
significant and/or unacceptable, does not respond to supportive care and results in a 
disruption of the dosing schedule of more than 14 days.  
 
4. Any death not clearly due to the underlying disease or extraneous causes. 
 
DLT excludes:  
• 
Alopecia of any grade.  
 
6.1.4 Maximum Tolerated Dose (Part A) 
The definition of MTD will be based upon review of safety data and DLTs corresponding to 
the first cycle of therapy in at least 6 evaluable patients. MTD will be defined as a dose where 
0 or 1 out of 6 patients have DLTs.  
 
6.2 
Dose Interruptions/Withholding for Infusion Reactions or Other Reasons 
Guidelines for management of IRRs, including circumstances for interrupting or 

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discontinuing dosing, are in Section 8.1.2.8. 
 
Study drug may be withheld from a patient based on the Investigator’s decision in the event 
of intercurrent illness, AEs, administrative reasons, or other reasons. If the patient‘s 
condition subsequently improves, or the situation that resulted in withholding study drug 
rectifies itself, the Investigator may resume dosing on the next practical dosing day.  
 
Do not “make up” for missed or skipped doses i.e. if Week 3 dose is missed, do not administer 
a dose during the rest period (Week 5 or 6). Patients who miss a dose during Cycle 1 may be 
replaced per Section 5.4.2. The interruption and/or missed dose(s) should be recorded. 
 
6.3 
Concomitant Treatment  
Patients must not receive any other concurrent anti-cancer therapy, including investigational 
agents (with exception of the Acetate Diluent), chemotherapy, immunotherapy, hormonal, 
or biologic therapies while on study treatment. Palliative radiotherapy is allowed as medically 
indicated after completion of the first treatment cycle, and after discussion with medical 
monitor. 
 
Supportive treatment may include anti-emetic, anti-diarrheal, anti-pyretic, anti-histamines, 
analgesics, antibiotics, and blood products. Treatment with denosumab or bisphosphonates, 
to prevent skeletal-related events in patients with bone metastases, is allowed throughout 
the trial. 
 
At the discretion of the treating physician, patients may receive anti-histamine prophylaxis 
according to the standard of care (SOC) in clinical practice. 
 
In case of IRRs, patients may be pretreated as needed with an H1 antagonist (e.g., 
diphenhydramine, hydroxyzine, or chlorpheniramine) and an H2 antagonist (e.g., 
famotidine) dosed in accordance with approved labelling or SOC. If premedication is 
administered parenterally, it should be given within 30 minutes of the start of infusion (SOI); 
if premedication is given orally, it should be given 60-90 minutes prior to SOI. 
 
6.4 
Monitoring Subject Compliance 
This study will be monitored by Nitto BioPharma, Inc. or its Contract Research Organization 
(Theradex Oncology) according to ICH E6 guidelines of GCP. The study site monitor will 
regularly visit the study sites to ensure that the study is conducted according to the protocol 
and GCP principles. 
 
7.0 
STUDY EVALUATIONS 
 

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7.1 
Schedule of Study Evaluations 
Study evaluations for Part A and Part B are summarized in Table 3 and Table 4, respectively, 
and described in Sections 0 through 7.5. 

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Table 3: Study Calendar (Part A) 
Part A  
Evaluations 
Pre-
treat-
menta 
Cycle 1 
Cycle 2 
Cycle 3 & beyond 
EOT 
30-day 
safety 
FU visit 
(±3) 
Wk 
1 
D1 
Wk 2 
D8 
±3 
Wk 3 
D15 
±3 
Wk 4 
D22 
±3 
Wk 5 
D29-35 
Wk 6 
D36-42 
Wk 1 
D1 
Wk 2 
D8  
±3 
Wk 3 
D15 
±3 
Wk 4 
D22 
±3 
Wk 5 
D29-35 
Wk 6 
D36-42 
Wk 1 
D1 
Wk 2 
Wk 3 
Wk 4 
Wk 
5 
Wk 
6 
Informed consent (incl. 
optional biopsy consent) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 Xb 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Weight 
X 
 Xb 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Vital signse 
X 
Xb 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
ECGf 
X 
Xb 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECOG performance status 
X 
Xb 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Tumor measurementg 
(tumor markers, if 
applicable) 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Hematologyh 
X 
Xb 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
Blood chemistryi 
X 
Xb 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
Urinalysis 
X 
Xb 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Blood sample for immune 
activation biomarkersj 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test  
Xk 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Blood sample for ADA 
assayc 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
PK blood sampling d 
 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
exploratory biomarkers 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for GSTP KDn 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of KRAS 
mutationl 
(dose levels 1-4 optional; 
dose level 5 mandatory) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GSTT1 genotypingp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional biopsyo 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NBF-006 administration m 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
 
Concomitant medications 
X 
<------------------------------------- throughout study -------------------------------------> 
X 
 

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Adverse events 
 
<------------------------------------- throughout study -------------------------------------> 
X 
X 
a: Screening assessments may be performed within 28 days of study to treatment initiation, unless specified. 
b: For Cycle 1 Day 1, these tests may be performed within 3 days prior to Cycle 1 Day 1. Physical exam and pre-treatment tests done within 3 days of Cycle 1 Day 1 do not need to be 
repeated for Wk1D1 unless clinically indicated. 
c:  ADA assay timepoints: 
• 
Cycle 1, Day 1: pre-dose 
• 
Cycle 1, Day 15: pre-dose 
• 
Cycle 2, Cycle 4, Cycle 6, Cycle 8, etc. (i.e., every even numbered cycle), up to one year: Day 1 pre-dose  
• 
Year 2 and beyond: every 6 months 
• 
EOT 
• 
30-day safety follow up visit 
d: PK timepoints:  
• 
Cycle 1, Day 1:  
• 
Before start of infusion (SOI),  
• 
During the infusion: 20 m (±5min) after the start of the last infusion step implemented at 6 mL/min rate 
• 
End of Infusion (EOI); after EOI: 0.5 hr (5min), 2 hr (10min), 6 hr (15min), 24 hr (1hr), 48 hr (2hr), 72 hr (3hr) 
• 
Cycle 1, Day 8: pre-dose 
• 
Cycle 1, Day 22:  
• 
Before SOI 
• 
During the infusion: 20 min (±5min) after the start of the last infusion step implemented at 6 mL/min rate 
• 
End of Infusion (EOI); after EOI: 0.5 hr (5min), 2 hr (10min), 6 hr (15min), 24 hr (1hr), 48 hr (2hr), 72 hr (3hr) 
• 
Cycle 2, Day 1: pre-dose 
e: Vital signs, including blood pressure, heart rate, respiration rate, and temperature. During Cycle 1: Before SOI, EOI; after EOI: 1hr (5min), 2hr (10min). Other days: only before SOI and 
EOI. 
f: 
Standard 12-lead ECG (in triplicate) while patient is in semi-recumbent position. Perform at screening, Cycle 1 First and fourth doses: within 15 minutes prior to SOI, then 15 min (±5min), 
30 min (±10min), 1 hr (±10min) (at EOI) 
g: Tumor measurement by RECIST version 1.1 and tumor markers will be collected at baseline and at the end of every even numbered cycle in Part A, dose levels 1-4 (0.15 mg/kg, 0.3 mg/kg, 
0.6 mg/kg, 1.2 mg/kg) and at the end of every cycle for dose level 5 (1.6 mg/kg), if applicable; the same method used at baseline for a patient should be used consistently for all 
evaluations throughout the study. To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat assessments that should be performed at 4 weeks 
but no later than 5 weeks for patients in dose levels 1-4 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, and 1.2 mg/kg) in Part A after the criteria for response are first met. Response will be 
confirmed at 4 weeks or at the next scheduled scan (at Week 6 of the following cycle) for patients in dose level 5 (1.6 mg/kg) in Part A. If a confirmative scan is done after 4 weeks, the 
next scheduled scan at Week 6 of the following cycle may be omitted. In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a 
minimum interval of 5 weeks. 
h: Hematology, including hemoglobin, white blood cell with differential, and platelet count. 
i: 
Blood chemistry, including sodium, potassium, blood urea nitrogen, glucose, SGOT/SGPT (ALT/AST), alkaline phosphatase, total protein, total bilirubin, albumin, creatinine, and calcium. 
j: 
Blood samples collected during Cycle 1 (Week 1) for all patients treated in Part A of the study for determination of complement (CH50, Bb, C3a, C5a) and cytokines (IFN-γ, IL-1β, IL-6, 
TNF-α): 
• 
Pre-dose 
• 
10 ± 3 minutes after SOI 
• 
60 ± 10 minutes after EOI 

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• 
6 hr ± 15 minutes after EOI 
• 
24 hr ± 1 hr after EOI 
k: Pregnancy test; for women of childbearing potential, a negative pregnancy test (urine or serum) must be done within 7 days prior to study treatment initiation and documented. 
l: 
Confirmation of KRAS mutation: optional for Part A dose levels 1-4 and mandatory for Part A dose level 5 (1.6 mg/kg). Obtain archive sample if available; otherwise, a fresh biopsy (low or 
minimal risk only) is required. If such type of biopsy is needed but cannot feasibly be collected, the Sponsor and Medical Monitor should be consulted. Genomic tumor profile report is 
acceptable in lieu of a biopsy. Note: if at any time during the trial a biopsy is performed as part of routine medical care, we may request a sample. 
m: NBF-006 is administered IV QC (minimum 4 days apart) preferably on a Monday or Tuesday (to accommodate the PK schedule) during Cycle 1. 
n:  GSTP KD time points collected in the 6 patients from Part A at dose level 5 (1.6 mg/kg): 
• 
Cycle 1, Day 1: 
• 
Before SOI 
• 
After EOI: 6 hr (±15min), 24 hr (±1hr) 
• 
Cycle 1, Day 8: before SOI 
o: Optional biopsy collected during screening and 24 (±3) hours after the 4th dose in cycle 1. Only for patients signing the optional biopsy consent, and when the biopsy can be safely 
obtained.  
p: In Part A of the study, patients will not be stratified for the GSTT1- null genotype, but whole blood samples will still be collected during the screening visit and batch-analyzed at a central 
laboratory. 
Note: Each patient must remain in clinic for a 6-hour safety observation period after each NBF-006 infusion, until the safety review committee has reviewed a 3-patient cohort and 
recommended a reduced observation time at that dose level.  Please see Section 8.1.2.8 for details. 
 
 
 
 
 
 
 
 

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Table 4: Study Calendar (Part B) 
Part B Evaluations 
Pre-
treat-
menta 
Cycle 1 
Cycle 2 
Cycle 3 & beyond 
EOT 
30-day 
safety 
FU visit 
(±3) 
Wk 1 
D1 
Wk 2 
D8 
±3 
Wk 3 
D15 
±3 
Wk 4 
D22 
±3 
Wk 5 
D29-35 
Wk 6 
D36-42 
Wk 1 
D1 
Wk 2 
D8  
±3 
Wk 3 
D15 
±3 
Wk 4 
D22 
±3 
Wk 5 
D29-35 
Wk 6 
D36-42 
Wk 1 
D1 
Wk 2 
Wk 3 
Wk 4 
Wk 
5 
Wk 
6 
Informed consent (incl. 
optional biopsy consent) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
Xb 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Weight 
X 
Xb 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Vital signse 
X 
Xb 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
ECGf 
X 
Xb 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECOG performance status 
X 
Xb 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Tumor measurementg 
(tumor markers, if 
applicable) 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Hematologyh 
X 
Xb 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
Blood chemistryi 
X 
Xb 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
Urinalysis 
X 
Xb 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Blood sample for immune 
activation biomarkers j 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test  
Xk 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Blood sample for ADA 
assay c 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
PK blood sampling d 
 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
exploratory biomarkers  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for GSTP 
KDn 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of KRAS 
mutation l 
(Part B mandatory) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GSTT1 genotypingp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional biopsyo 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NBF-006 administration m 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
 
Concomitant medications 
X 
<------------------------------------- throughout study -------------------------------------> 
X 
 
Adverse events 
 
<------------------------------------- throughout study -------------------------------------> 
X 
X 

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a:  Screening assessments may be performed within 28 days of study to treatment initiation, unless specified. 
b:  For Cycle 1 Day 1, these tests may be performed within 3 days prior to Cycle 1 Day 1. Physical exam and pre-treatment tests done within 3 days of Cycle 1 Day 1 do not need to be 
repeated for Wk1D1 unless clinically indicated. 
c:  ADA assay timepoints: 
• 
Cycle 1, Day 1: pre-dose 
• 
Cycle 1, Day 15: pre-dose 
• 
Cycle 2, Cycle 4, Cycle 6, Cycle 8, etc. (i.e., every even numbered cycle), up to one year: Day 1 pre-dose  
• 
Year 2 and beyond: every 6 months 
• 
EOTs 
• 
30-day safety follow up visit 
d:  PK timepoints:  
• 
Cycle 1, Day 1:  
• 
Before start of infusion (SOI),  
• 
During the infusion: 20 m (±5min) after the start of the last infusion step implemented at 6 mL/min rate 
• 
End of Infusion (EOI); after EOI: 0.5 hr (5min), 2 hr (10min), 6 hr (15min), 24 hr (1hr) 
• 
Cycle 1, Day 8: pre-dose 
• 
Cycle 1, Day 22:  
• 
Before SOI 
• 
During the infusion: 20 m (±5min) after the start of the last infusion step implemented at 6 mL/min rate 
• 
End of Infusion (EOI); after EOI: 0.5 hr (5min), 2 hr (10min), 6 hr (15min), 24 hr (1hr) 
• 
Cycle 2, Day 1: pre-dose 
e: Vital signs, including blood pressure, heart rate, respiration rate, and temperature. During Cycle 1: Before SOI, EOI; after EOI: 1hr (5min), 2hr (10min). Other days: only before SOI and 
EOI. 
f: 
Standard 12-lead ECG (in triplicate) while patient is in semi-recumbent position. Perform at screening, Cycle 1 First and fourth doses: within 15 minutes prior to SOI, then 15 min (±5min), 
30 min (±10min), 1 hr (±10min) (at EOI) 
g: Tumor measurement by RECIST version 1.1 and tumor markers will be measured at baseline and at the end every cycle, if applicable; the same method used at baseline for a patient 
should be used consistently for all evaluations throughout the study. To be assigned a status of PR or CR, changes in tumor measurements must be confirmed at 4 weeks or at the next 
scheduled scan (at Week 6 of the following cycle). If a confirmative scan is done after 4 weeks, the next scheduled scan at Week 6 of the following cycle may be omitted. In the case of SD, 
follow-up measurements must have met the SD criteria at least once after study entry at a minimum interval of 5 weeks. 
h: Hematology, including hemoglobin, white blood cell with differential, and platelet count. 
i: 
Blood chemistry, including sodium, potassium, blood urea nitrogen, glucose, SGOT/SGPT (ALT/AST), alkaline phosphatase, total protein, total bilirubin, albumin, creatinine, and calcium. 
j: 
Blood samples collected during Cycle 1 (Week 1) for all patients treated in Part B of the study for determination of complement (CH50, Bb, C3a, C5a): 
• 
Pre-dose 
• 
10 ± 3 minutes after SOI 
• 
60 ± 10 minutes after EOI 
• 
6 hr ± 15 minutes after EOI 
• 
24 hr ± 1 hr after EOI 
Dose levels 3 (0.6 mg/kg) and 4 (1.2 mg/kg) did not result in immune activation in Part A and therefore, cytokine activity will not be monitored at those two dose levels 
in Part B. However if a patient, during or after any infusion of NBF-006, develops IRR symptoms ( e.g. backache, fever, nausea, headache, rash, rapid heartbeat, low blood pressure, or 
trouble breathing), best attempts should be made to collect cytokines as described for Part A with the exception of 10 ± 3 minutes after SOI, which should be collected as close as feasible 

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to the IRR. If there is no meaningful cytokine induction in the 6-patient dose level 5 (1.6 mg/kg) during Part A, then cytokine testing will also not be needed in the remaining 4 patients at 
that same dose level (1.6 mg/kg), unless there are symptoms of IRR. However, complement samples will continue to be collected for all patients. 
k: Pregnancy test; for women of childbearing potential, a negative pregnancy test (urine or serum) must be done within 7 days prior to study treatment initiation and documented. 
l: 
Confirmation of KRAS mutation required for Part B. Obtain archive sample if available; otherwise, a fresh biopsy (low or minimal risk only) is required. If such type of biopsy is needed but 
cannot feasibly be collected, the sponsor and Medical Monitor should be consulted. Genomic tumor profile report is acceptable in lieu of a biopsy. Note: if at any time during the trial a 
biopsy is performed as part of routine medical care, we may request a sample. 
m: NBF-006 is administered IV QC (minimum 4 days apart) preferably on a Monday or Tuesday (to accommodate the PK schedule) during Cycle 1. 
n:  GSTP mRNA KD time points: 
• 
Cycle 1, Day 1: 
• 
Before SOI 
• 
After EOI: 6 hr (±15min), 24 hr (±1hr) 
• 
Cycle 1, Day 8: before SOI 
o:  Optional biopsy collected during screening and 24 (±3) hours after the 4th dose in cycle 1. Only for patients signing the optional biopsy consent, and when the biopsy can be safely 
obtained. 
p: In Part B of the study, patients will be stratified for the GSTT1- null genotype. Analysis will be done at a central lab from blood samples collected during the screening visit. Initial patients 
may be enrolled before the GSTT1 status is known. 
Note: Each patient must remain in clinic for a 6-hour safety observation period after the first dose, 2 hours after EOI for remaining doses in Cycle 1. The observation period may be further 
reduced to 30 minutes starting Cycle 2, after Medical Monitor and Investigator safety review. Please see Section 8.1.2.8 for details. 

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7.2 
Pre-treatment 
Within 28 days of study treatment initiation (Cycle 1 Day 1): 
• 
Sign informed consent including optional biopsy consent. 
• 
Medical history 
• 
Physical exam 
• 
Weight 
• 
Vital signs 
• 
ECOG performance status (APPENDIX I) 
• 
Hematology 
• 
Blood chemistry 
• 
Urinalysis 
 
• 
Electrocardiogram (ECG) (for this and all other timepoints, a standard 12-lead ECG is 
taken while patient is in a semi-recumbent position) 
• 
Confirmation of KRAS mutation: 
o Optional for Part A dose levels 1-4 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, and 
1.2 mg/kg). Depending upon availability and patient consent, we may request 
archival tumor sample and/or results of genomic tumor profile, but these are 
not required to confirm patient eligibility for Part A.  
o Requirement for Part A dose level 5 (1.6 mg/kg) and all patients in Part B. 
Genomic tumor profile results can be used. Otherwise, a tumor tissue sample 
(archival or fresh) can be tested locally for eligibility. Fresh biopsy (if needed) 
may be obtained only if it has minimal risk of complications for the patient. If 
such type of biopsy is needed but cannot feasibly be collected, the Sponsor 
and Medical Monitor should be consulted. 
o Liquid biopsy may also be used to confirm KRAS status. In the case that both 
a liquid and tumor biopsy is available, the following criteria will be used to 
evaluate eligibility: 
 
  
• 
Collect samples to be used for exploratory biomarkers to measure GST family 
members including GSTP.  
• 
GSTT1 samples will also be collected for both Parts A and B, but GSTT1 genotype will 
only be used for stratification in Part B. 
• 
Optional tumor biopsy. 
• 
Concomitant medications 
 
 
 
Tumor 
Wildtype 
Mutant 
Liquid 
Wildtype 
Fails Inclusion # 1 
Meets Inclusion # 1 
Mutant 
Meets Inclusion # 1 
Meets Inclusion # 1 

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Within 14 days of study treatment initiation (Cycle 1 Day 1): 
• 
Imaging for tumor measurements 
 
Within 7 days of study treatment initiation (Cycle 1 Day 1): 
• 
Pregnancy test 
 
7.3 
During Treatment 
Each patient must remain in clinic to be monitored for infusion related reactions after 
receiving a dose of NBF-006. A 6-hour safety observation period is required after completion 
of the first dose in both Part A and Part B. The observation period after subsequent doses 
may be reduced, as detailed in Section 8.1.2.8.    
 
After completion of at least 3 cycles of study treatment (i.e., after receiving ≥12 doses of NBF 
-006 over the course of 18 weeks), no more than one dose of NBF-006 may be omitted during 
a cycle for convenience reasons (to improve patient’s quality of life), at the investigator’s 
discretion after discussion with medical monitor. 
 
7.3.1 Cycle 1 
7.3.1.1 Week 1 (Day 1, first dose) 
• 
Physical Exam (may be done within 3 days prior) 
• 
Weight (may be done within 3 days prior) 
• 
Vital signs 
• 
ECG 
• 
ECOG (may be done within 3 days prior) 
• 
Hematology (may be done within 3 days prior) 
• 
Blood chemistry (may be done within 3 days prior) 
• 
Urinalysis (may be done within 3 days prior) 
• 
Immune activation biomarkers (pre- and post-dose; see Section 8.6) 
• 
Anti-drug antibody (ADA) assay sampling (pre-dose) 
• 
PK blood sampling (pre- and post-dose; see Section 8.3) 
• 
Blood sample for GSTP KD (pre- and post-dose, see Section 8.8) 
• 
NBF-006 administration 
• 
Concomitant medications 
• 
AEs 
 
7.3.1.2 Week 2 (Day 8 ± 3) 
• 
Vital signs 
• 
Hematology 
• 
Blood chemistry 

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• 
PK blood sampling (pre-dose) 
• 
Blood sample for GSTP KD (pre-dose) 
• 
NBF-006 administration 
• 
Concomitant medications 
• 
AEs 
 
7.3.1.3 Week 3 (Day 15 ± 3) 
• 
Vital signs 
• 
Hematology 
• 
Blood chemistry 
• 
ADA assay sampling (pre-dose) 
• 
NBF-006 administration 
• 
Concomitant medications 
• 
AEs 
 
7.3.1.4 Week 4 (Day 22 ± 3) 
• 
Vital signs 
• 
ECG 
• 
Hematology 
• 
Blood chemistry 
• 
PK blood sampling (pre- and post-dose) 
• 
NBF-006 administration 
• 
Concomitant medications 
• 
AEs 
• 
Optional biopsy 24 (±3) hours after completion of the 4th dose in cycle 1. 
 
7.3.1.5 Weeks 5 (Day 29-35) 
Rest 
 
7.3.1.6 Week 6 (Day 36-42) 
• 
Tumor measurement (use same method as baseline) performed at the end of every 
even cycle for Part A dose levels 1-4 and performed at the end of every cycle for Part A 
dose level 5 and all patients in Part B. 
 
7.3.2 Cycle 2 
7.3.2.1 Week 1 (Day 1 should occur within 3 days of Day 42 of previous cycle) 
• 
Physical Exam 
• 
Weight 

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Vital signs 
• 
ECOG 
• 
Hematology 
• 
Blood chemistry 
• 
Urinalysis 
• 
Pregnancy test 
• 
ADA assay sampling (pre-dose) 
• 
PK blood sampling (pre-dose) 
• 
NBF-006 administration 
• 
Concomitant medications 
• 
AEs 
 
7.3.2.2 Week 2 (Day 8 ± 3) 
• 
Vital signs 
• 
Hematology 
• 
Blood chemistry 
• 
NBF-006 administration 
• 
Concomitant medications 
• 
AEs 
 
7.3.2.3 Week 3 (Day 15 ± 3) 
• 
Vital signs 
• 
Hematology 
• 
Blood chemistry 
• 
NBF-006 administration 
• 
Concomitant medications 
• 
AEs 
 
7.3.2.4 Week 4 (Day 22 ± 3) 
• 
Vital signs 
• 
Hematology 
• 
Blood chemistry 
• 
NBF-006 administration 
• 
Concomitant medications 
• 
AEs 
 
7.3.2.5 Week 5 (Day 29-35) 
Rest 
 

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7.3.2.6 Week 6 (Day 36-42) 
• 
Tumor measurement (use same method as baseline) performed at the end of every 
even cycle for Part A dose levels 1-4 and performed at the end of every cycle for Part A 
dose level 5 and all patients in Part B. 
 
7.3.3 Cycle 3 and Beyond 
7.3.3.1 Week 1 (Day 1 should occur within 3 days of Day 42 of previous cycle) 
• 
Physical Exam 
• 
Weight 
• 
Vital signs 
• 
ECOG 
• 
Hematology 
• 
Blood chemistry 
• 
Urinalysis 
• 
Pregnancy test 
• 
ADA assay sampling pre-dose every even numbered cycle, e.g., Cycle 4, Cycle 6, 
Cycle 8, etc.) up to 1 year. Year 2 collection occurs every 6 months. 
• 
NBF-006 administration 
• 
Concomitant medications 
• 
AEs 
 
7.3.3.2 Week 2 (Day 8 ± 3) 
• 
NBF-006 administration 
• 
Concomitant medications 
• 
AEs 
• 
Perform safety exams (e.g., vital signs, hematology, blood chemistries) as clinically 
indicated 
 
7.3.3.3 Week 3 (Day 15 ± 3) 
• 
NBF-006 administration 
• 
Concomitant medications 
• 
AEs 
• 
Perform safety exams (e.g., vital signs, hematology, blood chemistries) as clinically 
indicated 
 
7.3.3.4 Week 4 (Day 22 ± 3) 
• 
NBF-006 administration 
• 
Concomitant medications 

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• 
AEs 
• 
Perform safety exams (e.g., vital signs, hematology, blood chemistries) as clinically 
indicated 
 
7.3.3.5 Week 5 (Day 29-35) 
Rest 
 
7.3.3.6 Week 6 (Day 36-42) 
• 
Tumor measurement (use same method as baseline) performed at the end of every 
even cycle for Part A dose levels 1-4 and performed at the end of every cycle for Part A 
dose level 5 and all patients in Part B. 
 
7.4 
End of Treatment (to be performed within 30 ± 3 days after last treatment) 
The following assessments will be performed for all patients who are terminating treatment 
due to any reason. The End of Treatment (EOT) visit should be performed immediately after 
the patient discontinues treatment and should be no later than 30 ± 3 days after the last 
dose.   
 
• 
Physical Exam 
• 
Weight 
• 
Vital signs 
• 
ECG 
• 
ECOG 
• 
Tumor measurement (use same method as baseline) 
• 
Hematology 
• 
Blood chemistry 
• 
Urinalysis 
• 
Pregnancy test 
• 
ADA assay sampling 
• 
Concomitant medications 
• 
AEs 
 
7.5 
30 Day Safety Follow up Visit (±3) 
• 
Physical Exam 
• 
Weight 
• 
ECOG 
• 
Hematology 
• 
Blood chemistry 
• 
Urinalysis 

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• 
ADA assay sampling 
• 
AEs 
 
If the EOT visit is performed 30 ± 3 days after the last dosing, the safety follow-up visit can 
be omitted.  
 
8.0 
STUDY ASSESSMENTS 
8.1 
Safety Assessments 
8.1.1 Safety Analysis 
Safety data will be tabulated for all patients and include vital signs, laboratory parameters, 
and AEs. 
 
8.1.2 Reporting of Adverse Events 
8.1.2.1 Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship 
with the treatment. An AE can be any unfavorable and unintended sign (including a 
laboratory finding), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.  
 
The AE reporting period starts on Cycle 1 Day 1; if an AE occurs before the first dose of study 
drug it will be considered a non-treatment emergent AE. At each evaluation, patients should 
be interviewed in a non-directed manner to elicit potential adverse reactions from the 
patient. The occurrence of an AE will be based on changes in the patient’s physical 
examination, laboratory results, and/or signs and symptoms. 
 
All AEs (except Grade 1 and 2 laboratory abnormalities that do not require an intervention), 
regardless of causal relationship, are to be recorded in the eCRF and source documentation. 
The Investigator must determine the intensity of any AEs according to the NCI CTCAE Version 
5.0 (APPENDIX II) and their causal relationship. Those AEs not covered by these criteria will 
be graded as follows:  
 
1. 
Mild: Discomfort noticed, but no disruption of normal daily activity. Prescription drug 
not ordinarily needed for relief of symptom but may be given because of personality 
of patient. 
 
2. 
Moderate: Discomfort sufficient to reduce or affect normal daily activity. Patient is 
able to continue in study; treatment for symptom may be needed. 

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3. 
Severe: Incapacitating, severe discomfort with inability to work or to perform normal 
daily activity. Severity may cause cessation of treatment with test drug; treatment for 
symptom may be given and/or patient hospitalized. 
 
4. 
Life-Threatening: Symptom(s) place the patient at immediate risk of death from the 
reaction as it occurred; it does not include a reaction that, had it occurred in a more 
serious from, might have caused death. 
 
5.  
Fatal: Event caused the death of the patient.  
 
AEs will be followed until resolution or stabilization while the patient remains on-study. Once 
the patient is removed from study, events thought to be related to the study medication will 
be followed until resolution or stabilization, unless, in the Investigator's opinion the event is 
unlikely to resolve due to the patient’s underlying disease, or until the patient starts a new 
treatment regimen or the patient is lost to follow-up. 
 
8.1.2.2 Attribution Definitions 
An AE is considered to be associated with the use of the Investigational Product if the 
attribution is determined as possible, probable or definite. Attribution of AEs will be recorded 
in the eCRF as: 
 
• 
Unrelated: The AE is clearly NOT related to the study treatment. 
• 
Unlikely: The AE is doubtfully related to the study treatment. 
• 
Possible: The AE may be related to the study treatment. 
• 
Probable: The AE is likely related to the study treatment. 
• 
Definite: The AE is clearly related to the study treatment. 
 
8.1.2.3 Definition of an Unexpected Adverse Event 
An unexpected AE is defined as any adverse drug experience, the specificity or severity of 
which is not consistent with the current IB; or, if an IB is not required or available, the 
specificity or severity of which is not consistent with the risk information described in this 
protocol or in the regulatory agency study authorization application.   
 
Unexpected, as used in this definition, refers to an adverse drug experience that has not 
been previously observed (e.g., included in the IB) rather than from the perspective of such 
experience not being anticipated from the pharmacological properties of the pharmaceutical 
product. 
 

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8.1.2.4 Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
 
1. 
Results in death, 
2. 
Is life-threatening (i.e., the patient was at risk of death at the time of the event. It does 
not refer to an event which hypothetically might have caused death if it was more 
severe), 
3. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
excluding that for pain management, disease staging/re-staging procedures, or 
catheter placement unless associated with other serious events, 
4. 
Results in persistent or significant disability/incapacity, or 
5. 
Is a congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based on appropriate 
medical judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
 
8.1.2.5 Reference Safety Information 
The Reference Safety Information (RSI), in the current, approved IB, is a list of expected 
Serious Adverse Reactions which are classified using Preferred Terms according to the 
Medical Dictionary for Regulatory Activities (MedDRA). The RSI section will be used for 
assessing the expectedness of the study medication. 
 
8.1.2.6 Pregnancy 
Any pregnancy detected during the study, or that occurs within 30 days after stopping study 
medication, must be reported immediately to the Investigator. Pregnancy, in and of itself, is 
not regarded as an AE, unless there is suspicion that study medication may have interfered 
with the effectiveness of a contraceptive medication. If the patient becomes pregnant while 
on-study, the study drug should be immediately discontinued. Pregnancy information about 
a female patient or a female partner of a male patient should be reported immediately from 
the time the Investigator first becomes aware of a pregnancy or its outcome. This will be 
performed by the Investigator completing a Pregnancy Form and emailing it or faxing it to 
the Theradex Oncology Safety Desk (see Section 8.1.2.7); contact the Theradex Oncology 
Safety Desk for the Pregnancy Form.  
 

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Any pregnancy complication, spontaneous abortion, elective termination of a pregnancy for 
medical reasons, outcome of stillbirth, congenital anomaly/birth defect, or SAE in the mother 
will be recorded as an SAE and will be reported as described in Section 8.1.2.7.  
 
8.1.2.7 Reporting of Serious Adverse Events 
AEs classified as serious require expeditious handling and reporting to Theradex Oncology 
to comply with regulatory requirements. 
 
For any SAE that occurs while a patient is on-study; within 30 days of the last study drug 
administration, regardless of any opinion as to the relationship of the SAE to the study drug; 
or if any SAE that the Investigator feels is related to the study drug occurs later than 30 days 
after the last study drug administration, the Theradex Oncology Safety Desk must be notified 
immediately (within 24 hours of becoming aware of the event) by email, fax or telephone. 
Notification by email is preferred. The email address, fax and telephone numbers listed 
below may be used during both business and non-business hours. During non-business 
hours a recorded message will provide the telephone caller with the contact information for 
the on-call monitor. 
 
All SAEs require that a Serious Adverse Event Report Form be completed and forwarded 
either via facsimile or as a PDF via email to Theradex Oncology at the fax number or email 
listed below within 24 hours of becoming aware of the event.  
 
SAEs will be reported to: 
Theradex Oncology Safety Desk 
 
 
 
 
Telephone: (609) 799-7580 
 
 
 
 
Fax: (609) 799-1567 
 
 
 
 
Email: SafetyDeskUS@Theradex.com 
 
8.1.2.8 Post-Infusion Observation Period 
Observe/monitor for any signs and symptoms of IRRs, such as back pain, fever and/or 
shaking chills, flushing and/or itching, alterations in heart rate and blood pressure, dyspnea 
or chest discomfort, skin rashes, or anaphylaxis (e.g., generalized urticaria, angioedema, 
wheezing, hypotension, tachycardia, etc.). 
 
During Part A of the study, each patient must remain in clinic for a minimum 6-hour safety 
observation period after each NBF-006 infusion until at least three patients at a specific dose 
level have been reviewed by the Safety Review Committee.  
 
Reductions in the observation period at a given dose level may be recommended by the 
Safety Review Committee (consisting of Investigators, Theradex Oncology Medical Monitor, 
and Sponsor) after at least three patients have received a full cycle of treatment (defined as 
at least four doses and 2-week drug holiday) at that dose level.  

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Recommendations by the Safety Review Committee for a reduced observation period will be 
contingent upon: 
 
• 
Absence of any significant safety concerns following a complete review of all clinical 
and laboratory data for all treated subjects at the given dose level and the preceding 
dose levels, 
• 
Absence of any late-onset (>2 hours post-dose) IRRs or IRR symptoms that continue 
beyond 2 hours post-dose, and lack of any severe or serious IRRs, 
• 
Review and consideration of cytokine and complement activation data at the given 
dose prior to making a recommendation to shorten the observation period.  
 
If the Safety Review Committee recommends a reduced observation period, the minimum 
observation period allowed will be 2 hours following EOI from Cycle 2 onward during Part A 
of the study. Further reductions in the observation period may be suggested by the safety 
review committee as additional data has accumulated.  
 
For Part B of the study, each patient must remain in clinic for a 6-hour safety observation 
period after the first dose, 2 hours after EOI for remaining doses in Cycle 1. The observation 
period may be further reduced to 30 minutes starting Cycle 2, after Medical Monitor and 
Investigator safety review. The observation period may be lengthened, if clinically indicated. 
 
8.1.2.9 Management of Infusion-Related Reactions 
The guidelines on dose modification and toxicity management for IRRs are outlined in 
Table 5. All toxicities are graded according to NCI CTCAE Version 5.0. 

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8.1.2.10 Safety Data Review 
The Medical Monitor will be responsible for ongoing safety data for the study. This will 
include a review of all AEs (serious and non-serious AEs) as they are reported by the study 
site.   
 
Safety data will be reviewed periodically by a Safety Review Committee consisting of 
Theradex Oncology Medical Monitor, Sponsor, and Investigator. Details are provided in the 
Safety Plan. They will make decisions on dose modifications, cohort dose escalation, 
Table 5: Dosing Modification and Toxicity Management Guidelines for 
Infusion-Related Reactions 
Severity 
Grade 
Dose Interruption or 
Modification 
Toxicity Management 
Grade 1 
The infusion should be 
temporarily interrupted 
and then resumed when 
symptoms are resolved.   
If symptoms have not resolved in 15 minutes: 
- 
Acetaminophen and/or antihistamines may be 
administered per institutional standard at the 
discretion of the investigator  
- 
Consider premedication prior to subsequent 
doses. 
- 
H1 antagonist (e.g., diphenhydramine, 
hydroxyzine, or chlorpheniramine) and an H2 
antagonist (e.g., famotidine) dosed in 
accordance with approved labelling or the SOC 
before the start of investigational treatment 
administration (if premedication is 
administered parenterally, it should be given 
within 30 minutes of SOI; if premedication is 
given orally, it should be given 60-90 minutes 
prior to SOI). 
 
If the infusion reaction does not resolve within one 
hour after administration of acetaminophen and/or 
antihistamines the dosing should not be resumed the 
same day. Rechallenge should be discussed with the 
Medical Monitor, and premedication must be given if 
the patient receives any further doses. 
Grade 2 
 
The infusion should be 
temporarily interrupted 
and then resumed when 
symptoms are resolved.   
Grade 3/4 
Permanently discontinue 
study drug/study regimen 
For Grade 3 or 4: 
Manage severe IRRs per institutional standards 
(e.g., IM epinephrine, followed by IV 
antihistamines, and IV glucocorticoid) 

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transition to dose expansion phase (Part B), and may recommend changes to the post-
infusion observation period. 
 
8.1.2.11 Safety-Related Stopping Rules 
If there is Grade 5 toxicity definitely, probably or possibly attributed to NBF-006 within 
30 days of the last NBF-006 dose, the study may be temporarily or permanently stopped, 
pending a review by the Sponsor, Medical Monitor, and Investigators. During that time, no 
drug can be administered to any patient, until a decision is made.  
 
8.2 
Efficacy Assessments 
Patients with measurable disease will be assessed at baseline and during the study by 
standard criteria. For the purpose of this study, patients should be reevaluated at the end of 
every even numbered cycle in Part A, dose levels 1-4 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 
1.2 mg/kg), and at the end of every cycle for dose level 5 (1.6 mg/kg) in Part A and for all dose 
levels tested in Part B patients. In the event objective response (partial response [PR] or 
complete response [CR]) is noted, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed at 4 weeks but no later than 5 weeks for 
patients in dose levels 1-4 in Part A after the criteria for response are first met. Response will 
be confirmed at 4 weeks or at the next scheduled scan (at Week 6 of the following cycle) for 
patients in dose level 5 in Part A and all patients in Part B. If a confirmative scan is done after 
4 weeks, the next scheduled scan (at Week 6 of the following cycle) may be omitted. For 
stable disease (SD), follow-up measurements must meet the SD criteria at least 5 weeks after 
study entry.  
 
8.2.1 Definitions 
Response and progression will be evaluated in this study using the international criteria 
(version 1.1) proposed by the RECIST Committee.14 Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST 1.1 criteria. Note: 
Lesions are either measurable or non-measurable using the criteria provided below. The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
 
8.2.1.1 Measurable Disease 
Measurable disease is defined by the presence of at least one measurable lesion. 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension [longest diameter (LD) in the plane of measurement to be recorded] with a 
minimum size of:  
• 
10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 
5 mm) 

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• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest x-ray 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be  15 mm in short axis when assessed by CT scan (CT scan slice thickness no 
greater than 5 mm). 
 
8.2.1.2 Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (LD < 10 mm or pathological 
lymph nodes with  10 to < 15 mm short axis) are considered non-measurable disease. 
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
abdominal masses/abdominal organomegaly identified by physical exam and not followed 
by CT or magnetic resonance imaging (MRI). 
 
Bone lesions, cystic lesions and lesions previously treated with local therapy must be 
considered as follows: 
 
Bone lesions: 
• 
Bone scan, positron emission tomography (PET) scan or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can 
be used to confirm the presence or disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques (i.e., CT or MRI) can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• 
Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable or non-measurable) since they are, by 
definition, simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered measurable 
lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
 

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Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  
 
8.2.1.3 Target Lesions 
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the LD) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. The baseline sum diameters will be used as reference by which to characterize 
the objective tumor response. 
 
8.2.1.4 Lymph Node Assessment 
For lymph nodes, measurements should be made of the short axis, which is defined as 
perpendicular to the LD of node assessed in the plane of measurement: 
• 
Target lesion if short axis  15 mm 
• 
Non-target lesion if short axis is  10 but < 15 mm 
• 
Normal if short axis < 10 mm 
For baseline, add the actual short axis measurement to the sum of LD of non-nodal lesions. 
 
8.2.1.5 Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements of these 
lesions are not required and these lesions should be followed as “present”, “absent”, or in 
rare cases “unequivocal progression”. In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the eCRF (e.g., ‘multiple enlarged pelvic 
lymph nodes’ or ‘multiple liver metastases’). 
 
8.2.1.6 Response Assessments After Palliative Radiotherapy 
Palliative radiotherapy is allowed as medically indicated after completion of the first 
treatment cycle, and after discussion with medical monitor. Lesions assigned as targets at 
baseline should preferably not be included in the radiotherapy field, as it would preclude 
further response assessment per RECIST. Following palliative radiotherapy of RECIST target 
lesions, the irradiated lesion(s) and overall response assessment should be NA/Not 
evaluated, but remaining target and non-target lesions should continue to be monitored (an 
individualized schedule for radiology assessment is acceptable). 

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8.2.2 Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been 
used to assess the antitumor effect of a treatment. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial and  10 mm diameter as assessed using calipers (e.g., skin nodules). In the case 
of skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is recommended. When lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may be 
reviewed at the end of the study. 
 
Chest x-ray. Chest CT is preferred over chest x-ray, particularly when progression is an 
important endpoint. Lesions on chest x-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice 
thickness > 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. Contrast enhancement should normally be used, unless the patient is allergic. MRI 
is acceptable in certain situations (e.g., at the Investigator's discretion for CNS metastases, 
or in cases with iodine contrast allergy). 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements. However, 
if the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can 
be used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the 
CT introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
 
Ultrasound (US). US should not be used to measure tumor lesions. US examinations cannot 
be reproduced in their entirety for independent review at a later date because they are 

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operator dependent. If new lesions are identified by US, confirmation by CT or MRI is advised. 
If there is concern about radiation exposure at CT, MRI may be used instead of CT. 
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation 
is not advised. However, such techniques can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following CR or surgical resection is an endpoint. 
 
Tumor markers. Tumor markers alone cannot be used to assess objective tumor response. 
If markers are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response.   
Cytology, Histology. These techniques can be used to differentiate between PR and CR in 
rare cases (e.g., residual lesions in tumor types such as germ cell tumors, where known 
residual benign tumors can remain).  
 
8.2.3 Response Criteria 
8.2.3.1 Evaluation of Target Lesions 
Complete Response (CR): 
 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to < 10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest). In addition to 
the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. The appearance of one 
or more new lesions is also considered progression.  
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. 
 
8.2.3.1.1 Assessment of Target Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline exam), 
even if the nodes regress to below 10 mm on study. In order to qualify for CR, each node 

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must achieve a short axis < 10 mm. For PR, SD, and PD, the actual short axis measurement 
of the nodes is to be included in the sum of target lesions. 
 
8.2.3.1.2 Target Lesions that Become “too small to measure” 
All lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g., 2 mm). 
If it is the opinion of the radiologist that the lesion has disappeared, the measurement should 
be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small 
to measure, a default value of 5 mm should be assigned.   
 
8.2.3.1.3 Lesions that Split or Coalesce on Treatment 
When non-nodal lesions fragment, the LD of the fragmented portions should be added 
together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, 
the vector of the LD should be the maximal LD for the ‘coalesced lesion’. 
 
8.2.3.2 Evaluation of Non-target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological 
in size (< 10 mm short axis). 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions. (The 
appearance of one or more new lesions is also considered 
progression.) To achieve ‘unequivocal progression’ on the 
basis of the non-target disease, there must be an overall level 
of substantial worsening in non-target disease such that, even 
in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation. 
 
8.2.3.3 New Lesions 
The finding of a new lesion should be unequivocal (i.e., not attributed to differences in 
scanning technique, change in imaging modality, or findings thought to represent something 
other than tumor, such as a ‘new’ healing bone lesion). A lesion identified on a follow-up 
study in an anatomical location that was not scanned at baseline is considered a new lesion 
and will indicate disease progression. If a new lesion is equivocal, continued therapy and 

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follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm this 
is definitely a new lesion, then progression should be declared using the date of the initial 
scan. 
 
8.2.3.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). The patient’s best overall response assignment will 
depend on findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the 
study, it may also require confirmatory measurement. Specifically, in non-randomized trials 
where response is the primary endpoint, confirmation of PR or CR is needed to deem either 
one the “best overall response”.   
 
It is assumed that at each protocol-specified time point, a response assessment occurs. Table 
6 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. When patients have non-measurable 
disease, Table 7 should be used. 
Table 6: Time point response: Patients with target (+/- non-target) disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR / non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response, PR=partial response, SD=stable disease 
PD=progressive disease, NE=not evaluable 
 

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Table 7: Time point response: Patients with non-target disease only 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR / non-PD 
No 
Non-CR / non-PD* 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR=complete response; PD=progressive disease; NE=not evaluable 
* Non-CR/non-PD is preferred over SD for non-target disease 
 
Best response determination for studies where confirmation of CR or PR is required: CR or 
PR may be claimed only if the criteria for each are confirmed by a repeat assessment at 
4 weeks but no more than 5 weeks later for patients in dose levels 1-4 in Part A (0.15 mg/kg, 
0.3 mg/kg, 0.6 mg/kg, 1.2 mg/kg), after the criteria for response are first met. Response will 
be confirmed after 4 weeks or at the next scheduled scan (at Week 6 of the following cycle) 
for patients in dose level 5 (1.6 mg/kg) in Part A and all patients in Part B. If a confirmative 
scan is done after 4 weeks, the next scheduled scan (at Week 6 of the following cycle) may 
be omitted. In this circumstance, the best overall response can be interpreted as in Table 8. 

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Table 8: Best overall response when confirmation of CR and PR required 
Overall 
response 
First time point 
Overall response 
Subsequent time 
point 
 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR* 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; NE=nonevaluable 
* If CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria 
relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response 
would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when subsequent 
scans suggest small lesions were likely still present and in fact the patient had PR, not CR, at the first time point. Under 
these circumstances, the original CR should be changed to PR and the best response is PR. 
 
8.2.4 Confirmatory Measurement/Duration of Response 
8.2.4.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed at 4 weeks but no later than 5 weeks for 
patients in dose levels 1-4 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.2 mg/kg) in Part A after the 
criteria for response are first met. Response will be confirmed after 4 weeks or at the next 
scheduled scan (at Week 6 of the following cycle) for patients in dose level 5 (1.6 mg/kg) in 
Part A and all patients in Part B. If a confirmative scan is done after 4 weeks, the next 
scheduled scan (at Week 6 of the following cycle) may be omitted. In the case of SD, follow-
up measurements must have met the SD criteria at least once after study entry at a minimum 
interval of 5 weeks.   
 

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8.2.4.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for PD the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented. 
 
8.2.4.3 Duration of Stable Disease 
SD is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started. 
 
8.3 
Pharmacokinetics 
Plasma concentrations of NDT-05-1040 will be measured from blood samples collected at 
the following timepoints for Part A:  
• 
Cycle 1, Day 1:  
• 
Before SOI,  
• 
During the infusion: 20 m ± 5 m after the start of the last infusion step 
implemented at 6 mL/min rate 
• 
EOI; after EOI: 0.5 hr (5m), 2 hr (10m), 6 hr (15m), 24 hr (1hr), 48 hr (2hr), 
72 hr (3hr) 
• 
Cycle 1, Day 8: pre-dose 
• 
Cycle 1, Day 22:  
• 
Before SOI 
• 
During the infusion: 20 m ± 5 m after the start of the last infusion step 
implemented at 6 mL/min rate 
• 
EOI; after EOI: 0.5 hr (5m), 2 hr (10m), 6 hr (15m), 24 hr (1hr), 48 hr (2hr), 
72 hr (3hr) 
• 
Cycle 2, Day 1: pre-dose 
 
Plasma concentrations of NDT-05-1040 will be measured from blood samples collected at 
the following timepoints for Part B. (Note: timepoints are the same as the Part A PK sample 
collection with the exception of the 48 and 72 hr timepoint collections, which will not be 
measured in Part B):  
• 
Cycle 1, Day 1:  
• 
Before SOI,  
• 
During the infusion: 20 m ± 5 m after the start of the last infusion step 
implemented at 6 mL/min rate 
• 
EOI; after EOI: 0.5 hr (5m), 2 hr (10m), 6 hr (15m), 24 hr (1hr) 

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• 
Cycle 1, Day 8: pre-dose 
• 
Cycle 1, Day 22:  
• 
Before SOI 
• 
During the infusion: 20 m ± 5 m after the start of the last infusion step 
implemented at 6 mL/min rate 
• 
EOI; after EOI: 0.5 hr (5m), 2 hr (10m), 6 hr (15m), 24 hr (1hr) 
• 
Cycle 2, Day 1: pre-dose 
 
8.4 
Anti-Drug Antibodies (ADAs) 
Blood samples will be collected at the following timepoints for possible evaluation for ADAs: 
• 
Cycle 1, Day 1: pre-dose 
• 
Cycle 1, Day 15: pre-dose 
• 
Cycle 2, Cycle 4, Cycle 6, Cycle 8, etc. (i.e., every even numbered cycle), up to one year: 
Day 1 pre-dose  
• 
Year 2 and beyond: every 6 months 
• 
EOT 
• 
30-Day Follow-up Visit after Last Dose 
 
8.5 
KRAS Genotyping 
Depending upon availability and patient consent, we may request archival tumor sample 
and/or results of genomic tumor profile, but these are not required to confirm patient 
eligibility for dose levels 1-4 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.2 mg/kg) in Part A.  
 
Confirmation of KRAS mutation is a requirement for dose level 5 (1.6 mg/kg) in Part A and 
for all patients in Part B. Genomic tumor profile results can be used. Otherwise, a tumor 
tissue sample (archival or fresh) can be tested locally for eligibility. Fresh biopsy (if needed) 
may be obtained only if it has minimal risk of complications for the patient. If such type of 
biopsy is needed but cannot feasibly be collected, the sponsor and Medical Monitor should 
be consulted. 

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Liquid biopsy may also be used to confirm KRAS status. In the case that both a liquid and 
tumor biopsy is available, the following criteria will be used to evaluate eligibility: 
 
 
 
 
 
 
8.6 
Immune Activation Biomarkers 
Cytokines:  
Blood samples will be collected during Cycle 1 (Week 1) for all patients in Part A of the study 
for determination of cytokines (IFN-γ, IL-1β, IL-6, TNF-α): 
 
• 
Pre-dose 
• 
10 ± 3 minutes after SOI 
• 
60 ± 10 minutes after EOI 
• 
6 hr ± 15 minutes after EOI 
• 
24 hr ± 1 hr after EOI 
 
Dose levels 3 (0.6 mg/kg) and 4 (1.2 mg/kg) did not result in immune activation in Part A and 
therefore, cytokine activity will not be monitored at those two dose levels in Part B. However, 
if a patient, during or after any infusion of NBF-006, develops IRR symptoms (e.g., backache, 
fever, nausea, headache, rash, rapid heartbeat, low blood pressure, or trouble breathing), 
best attempts should be made to collect cytokines as described for Part A with the exception 
of 10 ± 3 minutes after SOI, which should be collected as close as feasible to the IRR. 
 
If there is no meaningful cytokine induction in the 6-patient dose level 5 (1.6 mg/kg) during 
Part A, then cytokine testing will also not be needed in the remaining 4 patients in Part B at 
that same dose level (1.6 mg/kg), unless there are symptoms of IRR. 
 
Complement:  
Blood samples will be collected during Cycle 1 (Week 1) for all patients in Part A and Part B 
of the study for determination of complement (CH50, Bb, C3a, C5a): 
 
• 
Pre-dose 
• 
10 ± 3 minutes after SOI 
• 
60 ± 10 minutes after EOI 
• 
6 hr ± 15 minutes after EOI 
• 
24 hr ± 1 hour after EOI 
 
 
Tumor 
Wildtype 
Mutant 
Liquid 
Wildtype 
Fails Inclusion # 1 
Meets Inclusion # 1 
Mutant 
Meets Inclusion # 1 
Meets Inclusion # 1 

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8.7 
Exploratory Biomarkers 
Blood sample will be collected at baseline. PBMCs will be isolated from patient blood samples 
for exploratory studies. Tumor tissue (archival samples or those procured for routine 
medical care during the course of the study) may be retained from all patients in Parts A 
and B, for biomarker testing. Biomarkers may include (but are not limited to) GSTP or related 
proteins of the GST family. 
 
8.8 
GSTP Knockdown 
Blood samples will be collected at the following timepoints for evaluation of GSTP KD in the 
6 patients from Part A at 1.6 mg/kg dose level and from all patients in Part B of the study: 
• 
Cycle 1, Day 1: 
• 
Before SOI 
• 
After EOI: 6 hr (±15m), 24 hr (±1hr) 
• 
Cycle 1, Day 8: before SOI 
 
Patients who are willing to provide exploratory pre- and on-study biopsies will be sampled 
prior to the first dose and 24 hours after the 4th dose in cycle 1, if clinically feasible. If 
possible, lesions selected as RECIST target lesions should not be biopsied.  
 
8.9 
GSTT1 Genotyping 
In Part A dose level 5 (1.6 mg/kg) of the study, patients will not be stratified for the GSTT1- 
null genotype, but whole blood samples will still be collected during the screening visit and 
batch analyzed at a central lab.  
 
Patients in Part B of the study will be stratified across all cohorts for the GSTT1-null genotype 
to ensure that all dose levels receive even distribution of GSTT1-null patients. Analysis will 
be done at a central lab from blood samples collected during the screening visit.  
 
9.0 
STATISTICS 
Demographic data and disease-related characteristics will be summarized using descriptive 
statistics (count and percent, mean, median, standard deviation, minimum, maximum). All 
patient data, efficacy and safety data will be summarized. Results from Part A and Part B will 
be presented separately. 
 
9.1 
Analysis Populations 
The Intent-to-Treat population will include all participants who were enrolled (signed 
consent) into the study, irrespective of whether study medication was administered or not.   
 
Safety Evaluable Population: All patients who received any component of study treatment. 

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Efficacy Evaluable Population: Patients with measurable disease by RECIST 1.1 who had a 
baseline assessment and at least one post-baseline assessment. Responses must be 
confirmed at a second imaging evaluation that should be performed at 4 weeks but no later 
than 5 weeks for patients in dose levels 1-4 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.2 mg/kg) in 
Part A after response criteria are met. Response will be confirmed after 4 weeks or at the 
next scheduled scan (at Week 6 of the following cycle) for patients in dose level 5 (1.6 mg/kg) 
in Part A and all patients in Part B. If a confirmative scan is done after 4 weeks, the next 
scheduled scan (at Week 6 of the following cycle) may be omitted. Responders (PR and CR) 
with confirmatory imaging will be denoted as PR and CR. Those with only one evaluation 
documenting PR or CR will be denoted as partial response-unconfirmed (PR-UC) and 
complete response (CR-UC). The primary evaluation of efficacy will focus on PR and CR but 
analyses incorporating PR-UC and CR-UC will also be performed. 
 
9.2 
Endpoints 
9.2.1 Primary 
Part A: number of patients with DLTs and AEs. 
 
Part B: best overall response (CR, PR, SD) per RECIST 1.1 and safety (DLT, AEs), duration of 
overall response, duration of stable disease. 
 
9.2.2 Secondary  
Part A: best overall response (CR, PR, SD) per RECIST 1.1 and PK parameters (Cmax, clearance 
[CL], volume of distribution [Vss], terminal elimination half-life [T1/2], area under the curve 
[AUC]0-t) of siRNA, duration of overall response, duration of stable disease. 
 
Part B: PK parameters (Cmax, CL, Vss, T1/2, AUC0-t, AUC0-∞) of siRNA. 
 
9.3 
Safety 
Safety will be assessed by means of physical examination, weight, vital signs, performance 
status, laboratory evaluations (hematology, biochemistry), ECG, pain assessment and 
recording of concurrent illness/therapy and AEs. NCI CTCAE version 5.0 will be used to grade 
all toxicities. All related AEs will be monitored until resolution. Patients will be monitored for 
safety and concomitant medications throughout the study. 
 
Safety data will be summarized for the safety evaluable population. These data will include 
AEs and laboratory parameters. AE terms will be coded using the most current version of 
MedDRA®.   
 

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9.4 
Efficacy 
Response to treatment will be assessed according to RECIST 1.1. The objective evaluation will 
be performed at baseline and at the end of even numbered cycles for dose levels 1-4 in 
Part A and at baseline and at the end of every cycle for dose level 5 in Part A and all patients 
in Part B of the study. 
 
The efficacy endpoints include best overall response (BOR), disease control rate (DCR= rate 
of SD+PR+CR), duration of response (DOR), duration of CR, and duration of stable disease 
(SD). 
 
9.4.1 Duration of Overall Response 
DOR is measured from the time of CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented. Only patients with a 
confirmed CR or PR are included in the analysis. For a patient without evidence of PD, DOR 
will be censored. 
 
9.4.2 Duration of Stable Disease 
Stable Disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started. Duration of stable disease will be analyzed in a similar method as DOR. 
 
9.5 
Exploratory/Other Studies 
Separate reports will be generated for the analysis of ADAs, immune activation biomarkers, 
GSTP KD, and other biomarker activity.  
 
9.6 
Sample Size 
This is an exploratory trial and therefore no sample size calculations have been performed. 
The number of patients in Part A (up to 20) is based on the planned number of dose 
escalation cohorts required to identify the MTD. The planned number of patients in Part B is 
approximately 20-24. 
 
10.0 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
10.1 Monitoring of the Study and Regulatory Compliance 
The project manager, or designee, will make an initiation site visit to each institution to 
review the protocol and its requirements with the Investigator(s), inspect the drug storage 
area, fully inform the Investigator of his/her responsibilities and the procedures for assuring 
adequate and correct documentation. During the initiation site visit the eCRFs will be 

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reviewed. Other pertinent study materials will also be reviewed with the Investigator's 
research staff. During the course of the study, the monitor will make regular site visits in 
order to review protocol compliance, examine eCRFs and individual subject’s medical records 
and assure that the study is being conducted according to pertinent regulatory 
requirements. All eCRF entries will be verified with source documentation. The review of 
medical records will be done in a manner to assure that patient confidentiality is maintained.  
 
10.2 Curricula Vitae and Financial Disclosure of Investigators  
All Principal Investigators will be required to provide a current (within 2 years) signed and 
dated curriculum vitae, a completed FDA Form 1572 and a financial disclosure statement to 
Theradex Oncology. All Sub-Investigators will be required to provide a current curriculum 
vitae and a financial disclosure statement to Theradex Oncology. 
 
10.3 Protocol Modifications 
No modification of the protocol should be implemented without the prior written approval 
of the Sponsor or the Sponsor’s representative (Theradex Oncology). Any such changes 
which may affect a patient’s treatment or informed consent, especially those increasing 
potential risks, must receive prior approval by the IRB/IEC. The exception to this is where 
modifications are necessary to eliminate an immediate hazard to trial subjects, or when the 
change involves only logistical or administrative aspects of the trial (e.g., change in monitor, 
change in telephone number). Other administrative revisions which may impact the clinical 
portion of a study will be duly reported to the IRB/IEC by the Principal Investigator. 
 
10.4 Publication Policy 
The publication of the results of the study will be subject to the terms and conditions of the 
clinical trial agreement between the Sponsor and Investigators. Sponsor approval is required 
for publication of any data from this trial.  
 
11.0 ETHICAL CONSIDERATIONS 
11.1 Informed Consent 
The Investigator will obtain written informed consent from each patient, or their authorized 
representative, participating in the study. The form must be signed, witnessed and dated 
before any screening assessments are performed. The informed consent form will contain 
all the Essential Elements of Informed Consent set forth in 21 CFR, Part 50, the European 
Union Directive 2001/20/EC and its associated Detailed Guidances, European Union GCP 
Directive 2005/28/EC, the ICH Guideline for GCP, Section 4.8, and the terms of the 
Declaration of Helsinki (2013). Copies of the signed document should be given to the patient 
and filed in the Investigator's study file, as well as the patient’s medical record if in 
conformance with the institution’s Standard Operating Procedures.  

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11.2 Institutional Review Board/Independent Ethics Committee 
The study will not be initiated without approval of the appropriate IRB/IEC and compliance 
with all administrative requirements of the governing body of the institution. This protocol, 
consent procedures, and any amendments must be approved by the IRB/IEC in compliance 
with current regulations of the FDA and the European Union as applicable and in accordance 
with ICH/GCPs. A letter of approval will be sent to the Sponsor prior to initiation of the study 
and when any subsequent modifications are made. The IRB/IEC will be kept informed by the 
Investigator, Theradex Oncology or the Sponsor, as required by national regulations, as to 
the progress of the study as well as to any serious and unexpected AEs.  
 
11.3 Patient Privacy  
In order to maintain patient confidentiality, all eCRFs, study reports, and communications 
relating to the study will identify patients by initials and assigned patient numbers; patients 
should not be identified by name. In accordance with local, national or federal regulations, 
the Investigator will allow the Sponsor or designee personnel access to all pertinent medical 
records in order to verify the data gathered on the eCRFs and to audit the data collection 
process. Regulatory agencies such as the U.S. FDA may also request access to all study 
records, including source documentation for inspection. Clinical information will not be 
released without the written permission of the patient as outlined in the patient consent 
form. 
 
12.0 DATA HANDLING AND RECORD KEEPING 
12.1 Data to be Entered Directly in the Electronic Case Report Form 
The eCRF will be the source record. 
 
12.2 Recording of Data 
Data collected during the study will be entered in the patient’s eCRF by the investigational 
site staff. The staff will keep records of the patient’s visit in the files considered as source 
documents for the site, e.g., hospital chart, research chart. The Investigator will be 
responsible for the recording of all data on the eCRF and for submitting the data to the 
Sponsor or their designee in a timely manner. Should any value be significantly different 
from normal, the Investigator will comment in the appropriate sections provided in the eCRF. 
The Investigator will provide access to his/her original records to permit a representative 
from the Sponsor to verify the proper transcription of data.  
 

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12.3 Study Records 
U.S. Federal laws require that an Investigator maintain all study records for the indication 
under investigation for two years following the date a Product Licensing Application is 
approved or, if no application is to be filed or if the application is not approved for such 
indication, until two years after the investigation is discontinued and the FDA is notified. 
 
 

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13.0 REFERENCES 
 
1  
Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable Ras: 
mission possible? Nature reviews Drug discovery. 2014;13(11):828-851. 
2  
Castellano E, Downward J. RAS Interaction with PI3K: More Than Just Another 
Effector Pathway. Genes Cancer. 2011 Mar,2(3):261-274. 
3  
Mills SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R. Landscape of Phosphatidylinositol-
3-Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors. JAMA Oncol. 
2016;2(12):1565-1573. 
4  
Sunaga N, Shames DS, Girard L, et al. Knockdown of Oncogenic KRAS in Non-Small 
Cell Lung Cancers Suppresses Tumor Growth and Sensitizes Tumor Cells to Targeted 
Therapy. Mol Cancer Ther. 2011 Feb;10(2): 336–346. 
5  
E Laborde, Glutathione transferases as mediators of signaling pathways involved in 
cell proliferation and cell death, Cell Death and Differentiation. 2010 Sep;17(9),1373–
1380. 
6  
Tew KD, Manevish Y, Grek C, Xiong Y, Uys J, Townsend DM. The Role of Glutathione 
S-transferase P in signaling pathways and S-glutathionylation in Cancer, Free Radic 
Biol Med. 2011 Jul 15; 51(2): 299–313. 
7  
Thorn CF, Ji Y, Weinshilboum RM, Altman RB, Klein TE. PharmGKB summary: very 
important pharmacogene information for GSTT1. Pharmacogenet Genomics. 2012 
Aug;22(8):646-51. doi: 10.1097/FPC.0b013e3283527c02. PMID: 22643671; PMCID: 
PMC3395771. 
8  
Wang T, Arifoglu P, Ronai Z, Tew KD, Glutathione S-transferase P1–1 (GSTP1–1) 
Inhibits c-Jun N-terminal Kinase (JNK1) Signaling through Interaction with the C 
Terminus. J Biol Chem. 2001 Jun 15;276(24):20999-1003. 
9  
Webster R., Elliott V., Park B.K., Walker D., Hankin M., Taupin P. PEG and PEG 
conjugates toxicity: towards an understanding of the toxicity of PEG and its 
relevance to PEGylated biologicals. In: Veronese F.M. (eds) PEGylated Protein Drugs: 
Basic Science and Clinical Applications. Milestones in Drug Therapy. Birkhäuser 
Basel. 2009. 
10  
Ivens IA, Achanzar W, Baumann A, Brandu-Baiocco A, Cavagnaro J, Dempster M et al. 
PEGylated Biopharmaceuticals: Current Experience and Considerations for 
Nonclinical Development. Toxicologic Pathology, 43: 959-983, 2015. 
11  
Hansen AR, Cook N, Ricci MS, Razak A, Le Tourneau C, McKeever K et al. Choice of 
Starting Dose for Biopharmaceuticals in First-in-Human Phase I Cancer Clinical 
Trials. Oncologist. 2015 Jun;20(6):653-659. 
12  
Kumar V et al. Shielding of Lipid Nanoparticles for siRNA Delivery: Impact on 
Physicochemical Properties, Cytokine Induction, and Efficacy. Molecular Therapy - 
Nucleic Acids. 2014;3, e210. 
 

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Pancreatic, or Colorectal Cancer 
 
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13  
Zatsepin, Timofei S, Yuri V Kotelevtsev, and Victor Koteliansky. “Lipid Nanoparticles 
for Targeted siRNA Delivery – Going from Bench to Bedside.” International Journal of 
Nanomedicine 11 (2016): 3077–3086. PMC. Web. 21 July 2018. 
14 
Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.   

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APPENDIX I – ECOG Performance Status 
 
 
 
       Grade 
 
 
 
0 
 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
 
1 
 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
house work, office work. 
 
 
2 
 
Ambulatory and capable of all self-care but unable to carry out 
any work activities. Up and about more than 50% of waking 
hours. 
 
 
3 
 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
 
 
4 
 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
 
 
5 
 
Dead. 
 
 
 

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APPENDIX II – Common Terminology Criteria for Adverse Events (CTCAE) v5.0 
 
Available from the Cancer Therapy Evaluation Program website: 
https: //ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 

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APPENDIX III – Acceptable Contraceptive Methods 
 
● Male or female condom with or without spermicide 
● Cervical cap, diaphragm, or sponge with spermicide 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progesterone-containing) hormonal contraception b 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progesterone-only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomy  
Vasectomy is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the female of childbearing potential and the absence of 
sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies. 
a) Typical use failure rates are lower than perfect-use failure rates (i.e., when used 
consistently and correctly).  
b) If hormonal contraception efficacy is potentially decreased due to interaction with 
study treatment, condoms must be used in addition to the hormonal contraception 
during the treatment period and for at least 120 days, (corresponding to time needed to 

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eliminate study treatment plus 30 days for study treatments with genotoxic potential) 
after the last dose of the study treatment. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.