Clinical trial NCT02240238
Conditions: Solid Tumors
Sponsor: NanoCarrier Co., Ltd.
Start date: 2014-05-01; Completion date: 2019-05-06
Enrollment: 119 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In the dose escalation phase (Part 1), this study will determine the dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and recommended Phase 2 (RPII) dose of NC 6004 in combination with gemcitabine.

In the expansion phase of the study (Part 2), study will evaluate the activity, safety, and tolerability at the RPII dose identified in Part 1 in patients with squamous NSCLC, biliary tract, and bladder cancer.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: NC-6004 intervention 2: Gemcitabine
Intervention descriptions: intervention 1: NC-6004 - given at escalating doses of 60, 75, 90, 105, 120, 135, 150, 165, or 180 mg/m2 according to observations of dose-limiting toxicity. intervention 2: Gemcitabine 1250 mg/m2 will be administered as a 30 minute intravenous infusion on Day 1 after the completion of the NC 6004 infusion and on Day 8 of each cycle.

Protocol documents:
Prot_000.pdf: 
NanoCarrier 
NC-6004-004A 
NC-6004 
NCT02240238 
 
CLINICAL STUDY PROTOCOL 
IND: 118108 
A Phase 1b/2 Dose Escalation and Expansion Trial of NC-6004 
(Nanoparticle Cisplatin) plus Gemcitabine in Patients with Advanced Solid 
Tumors or Squamous Non-Small Cell Lung, Biliary Tract, and Bladder 
Cancer 
NC-6004-004A 
 
Sponsor: 
NanoCarrier Co, Ltd 
144-15 Chuo Gaiku, 226-39 Wakashiba Kashiwa 
Chiba, 277-0871, Japan 
Sponsor Contact: 
Director of International Clinical Development 
NanoCarrier Co, Ltd 
Telephone: +81-3-3241-0551 
Medical Monitor: 
Medical Director, Pharmacovigilance 
PPD, Inc. 
929 North Front Street 
Wilmington, North Carolina, 28401-3331, USA 
Telephone: 800-201-8725 
Current Version 
and Date of 
Protocol: 
Amendment 4, Version 5.0: 13 March 2017 
Previous Dates 
and Versions: 
Original, Version 1.2: 17 October 2013 (US only) 
Amendment 1, Version 2.0: 31 December 2014 (US only) 
Amendment 2, Version 3.0: 07 July 2015 (US only) 
Amendment 3, Version 4.0: 31 July 2016 (US only) 
Amendment 3, Version 4.1: 31 August 2016 (EU only) 
Amendment 3, Version 4.2: 12 December 2016 (US and EU; 
harmonizes versions 4.0 and 4.1) 


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CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by NanoCarrier Co, 
Ltd. The concepts and information contained in this document or generated during the study 
are considered proprietary and may not be disclosed in whole or in part without the 
expressed, written consent of NanoCarrier Co, Ltd. 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R1): Good Clinical Practice. 


NanoCarrier 
NC-6004-004A 
Protocol Approval - Sponsor Signatory 
NC-6004 
Protocol 
Study Title 
 A Phase lb/2 Dose Escalation and Expansion Trial of NC-6004 
(Nanoparticle Cisplatin) plus Gemcitabine in Patients with Advanced 
Solid Tumors or Squamous Non-Small Cell Lung, Biliary Tract, and 
Bladder Cancer 
Protocol Number 
NC-6004-004A 
Protocol Date 
Protocol Version Final 5.0 incorporating 
Amendment 4 -13  March 2017 
Protocol accepted and approved by: 
    azuhiro Takahashi 
144-15 Chuo Gaiku, 226-39 Wakashiba Kashiwa 
Chiba, 277-0871, Japan
Sign 
Date 


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Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 1b/2 Dose 
Escalation and Expansion Trial of NC-6004 (Nanoparticle Cisplatin) plus Gemcitabine in 
Patients with Advanced Solid Tumors or Squamous Non-Small Cell Lung, Biliary Tract, and 
Bladder Cancer” and the accompanying investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 5.0, dated 13 March 2017, the International 
Council for Harmonisation harmonised tripartite guideline E6(R1): Good Clinical Practice 
and all applicable government regulations. I will not make changes to the protocol before 
consulting with NanoCarrier Co, Ltd. or implement protocol changes without independent 
ethics committee approval except to eliminate an immediate risk to patients. I agree to 
administer study treatment only to patients under my personal supervision or the supervision 
of a subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Patient identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from NanoCarrier Co, Ltd. 
Signature of Principal Investigator 
Date 
Printed Name of Principal Investigator 


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Table of Contents 
Table of Contents ...................................................................................................................... 5 
List of Tables ........................................................................................................................... 10 
Protocol Synopsis .................................................................................................................... 11 
List of Abbreviations ............................................................................................................... 26 
1 
Introduction ......................................................................................................................29 
2 
Study Objectives ..............................................................................................................32 
2.1 
Primary Objectives ................................................................................................. 32 
2.2 
Secondary Objectives ............................................................................................. 32 
2.3 
Exploratory Objectives ........................................................................................... 32 
3 
Investigational Plan ..........................................................................................................33 
3.1 
Study Design .......................................................................................................... 33 
3.1.1 
Rationale of Study Design ........................................................................ 42 
4 
Patient Selection and Withdrawal Criteria .......................................................................44 
4.1 
Selection of Study Population ................................................................................ 44 
4.1.1 
Inclusion Criteria ....................................................................................... 44 
4.1.2 
Exclusion Criteria ..................................................................................... 47 
4.2 
Withdrawal of Patients From the Study ................................................................. 49 
4.2.1 
Reasons for Withdrawal/Discontinuation .................................................. 49 
4.2.2 
Handling of Withdrawals .......................................................................... 50 
4.2.3 
Replacements ............................................................................................ 50 
5 
Study Treatments .............................................................................................................51 
5.1 
Method of Assigning Patients to Treatment Groups .............................................. 51 
5.2 
Prophylactic Treatments ......................................................................................... 51 
5.3 
Treatments Administered ........................................................................................ 52 
5.4 
Dose Delays and Modifications .............................................................................. 54 
5.4.1 
NC-6004 Dose Delay and Modification ................................................... 54 
5.4.2 
Gemcitabine Dose Delay and Modification .............................................. 55 
5.5 
Identity of Investigational Product ......................................................................... 56 


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5.5.1 
NC-6004 Drug Product ............................................................................ 56 
5.5.2 
Gemcitabine Drug Product ....................................................................... 57 
5.6 
Management of Clinical Supplies ......................................................................... 57 
5.6.1 
Study Drug Packaging and Storage .......................................................... 57 
5.6.2 
Test Article Accountability ....................................................................... 57 
5.7 
Overdose Management .......................................................................................... 57 
5.7.1 
Treatment of Overdose ............................................................................. 58 
5.8 
Prophylaxis and Management of Hypersensitivity Reactions ............................... 58 
5.9 
Treatment Compliance .......................................................................................... 59 
5.10 Prior, Concomitant, and Subsequent Therapy ....................................................... 59 
5.11 Prohibited Medications .......................................................................................... 60 
6 
Study Assessments and Procedures ................................................................................. 61 
6.1 
Efficacy Assessments ............................................................................................ 61 
6.1.1 
Disease Response Definitions .................................................................. 61 
6.1.2 
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire-Core 30 ..................................................................... 62 
6.1.3 
MD Anderson Symptom Inventory .......................................................... 63 
6.2 
Pharmacokinetic and Pharmacodynamic Assessments ......................................... 64 
6.3 
Safety and Tolerability Assessments ..................................................................... 65 
6.3.1 
Dose-Limiting Toxicities and Dose Escalation Scheme .......................... 65 
6.3.1.1 
Definition of Dose-Limiting Toxicities .................................. 65 
6.3.1.2 
Dose Escalation Scheme ........................................................ 66 
6.3.1.2.1 Safety Monitoring in Part 2 ................................. 68 
6.3.2 
Adverse Events ........................................................................................ 69 
6.3.2.1 
Definitions of Adverse Events ............................................... 69 
6.3.2.2 
Eliciting and Documenting Adverse Events .......................... 69 
6.3.2.3 
Reporting Adverse Events ...................................................... 70 
6.3.2.4 
Assessment of Severity .......................................................... 71 
6.3.2.5 
Assessment of Causality ........................................................ 71 
6.3.2.6 
Follow-up of Patients Reporting Adverse Events .................. 72 
6.3.2.7 
Management Guidelines for NC-6004-Related Liver 
Dysfunction ............................................................................ 72 
6.3.3 
Assessment of Nausea and Vomiting ....................................................... 73 


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6.3.4 
Pregnancy .................................................................................................. 74 
6.3.5 
Clinical Laboratory Analyses .................................................................... 74 
6.3.5.1 
Hematology and Coagulation ................................................. 75 
6.3.5.2 
Biochemistry ...........................................................................75 
6.3.5.3 
Urinalysis ................................................................................75 
6.3.6 
Electrocardiograms .................................................................................... 75 
6.3.7 
Physical Examination ................................................................................ 76 
6.3.8 
Vital Sign Measurements .......................................................................... 76 
6.3.9 
Eastern Cooperative Oncology Group Performance Status ...................... 77 
6.3.10 Audiometry ............................................................................................... 77 
7 
Statistical and Analytical Plan .........................................................................................78 
7.1 
Safety Endpoints .................................................................................................... 78 
7.2 
Exploratory Endpoints ............................................................................................ 78 
7.3 
Sample Size Calculations ....................................................................................... 78 
7.4 
Analysis Sets .......................................................................................................... 79 
7.5 
Description of Subgroups to be Analyzed .............................................................. 80 
7.6 
Statistical Analysis Methodology ........................................................................... 80 
7.6.1 
Efficacy Analysis ...................................................................................... 80 
7.6.1.1 
Progression–Free Survival ......................................................80 
7.6.1.2 
Overall Survival ......................................................................81 
7.6.1.3 
Duration of Response ..............................................................81 
7.6.1.4 
Disease Control Rate ...............................................................81 
7.6.1.5 
Overall Response Rate ............................................................82 
7.6.1.6 
Quality of Life Analyses .........................................................82 
7.6.1.7 
Symptoms Assessment Analyses ............................................82 
7.6.2 
Safety Analyses ......................................................................................... 83 
7.6.2.1 
Analyses of Adverse Events ....................................................83 
7.6.2.2 
Severity of Nausea and Incidence of Vomiting ......................83 
7.6.2.3 
Clinical Laboratory Results ....................................................84 
7.6.2.4 
Additional Safety Assessments ...............................................84 
7.6.3 
Pharmacokinetic and Pharmacodynamic Analyses ................................... 84 
7.6.4 
Study Drug Exposure ................................................................................ 85 
7.7 
Data Quality Assurance .......................................................................................... 85 
7.7.1 
Data Management ..................................................................................... 86 


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8 
Ethics .............................................................................................................................. 87 
8.1 
Independent Ethics Committee or Institutional Review Board ............................. 87 
8.2 
Ethical Conduct of the Study ................................................................................ 87 
8.3 
Patient Information and Consent ........................................................................... 87 
9 
Investigator’s Obligations ............................................................................................... 89 
9.1 
Confidentiality ....................................................................................................... 89 
9.2 
Financial Disclosure and Obligations .................................................................... 89 
9.3 
Investigator Documentation .................................................................................. 90 
9.4 
Study Conduct ....................................................................................................... 90 
9.5 
Adherence to Protocol ........................................................................................... 90 
9.6 
Adverse Events and Study Report Requirements .................................................. 91 
9.7 
Investigator’s Final Report .................................................................................... 91 
9.8 
Records Retention ................................................................................................. 91 
9.9 
Publications ........................................................................................................... 91 
10 
Study Management ......................................................................................................... 92 
10.1 Monitoring ............................................................................................................. 92 
10.1.1 Monitoring of the Study ........................................................................... 92 
10.1.2 Inspection of Records............................................................................... 92 
10.2 Management of Protocol Amendments and Deviations ........................................ 92 
10.2.1 Modification of the Protocol .................................................................... 92 
10.2.2 Protocol Violations and Deviations .......................................................... 93 
10.3 Study Termination ................................................................................................. 93 
10.4 Final Report ........................................................................................................... 93 
11 
Reference List ................................................................................................................. 95 
12 
Appendices ...................................................................................................................... 97 
12.1 Appendix: Schedule of Events .............................................................................. 98 
12.2 Appendix: European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire Core 30 ............................................................................. 101 
12.3 Appendix: MD Anderson Symptom Inventory–Lung Cancer ............................ 103 
12.4 Appendix: Protocol Amendment ......................................................................... 105 


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12.4.1 Protocol Amendment 1–Protocol Version 2.0, Incorporating Amendment 
1, Dated 31 December 2014 ................................................................... 105 
12.4.1.1 
Overview of Changes ........................................................... 105 
12.4.1.2 
Changes to the Protocol Text ............................................... 108 
12.4.2 Protocol Amendment 2–Protocol Version 3.0, Incorporating Amendment 
2, Dated 07 July 2015 ............................................................................ 125 
12.4.2.1 
Assessment of Risk Associated With Amendment 2 ........... 125 
12.4.2.2 
Overview of Changes ........................................................... 126 
12.4.2.3 
Changes to the Protocol Text ............................................... 130 
12.4.3 Protocol Amendment 3–Protocol Version 4.0, Incorporating 
Amendment 3, Dated 31 July 2016 ........................................................ 156 
12.4.3.1 
Assessment of Risk Associated With Amendment 3, 
Version 4.0 ........................................................................... 156 
12.4.3.2 
Overview of Changes ........................................................... 156 
12.4.3.3 
Changes to the Protocol Text ............................................... 162 
12.4.4 Protocol Amendment 3–Protocol Version 4.1, Incorporating Amendment 
3, Dated 31 August 2016 ........................................................................ 181 
12.4.4.1 
Overview of Changes ........................................................... 181 
12.4.4.2 
Changes to the Protocol Text ............................................... 182 
12.4.5 Protocol Amendment 3-Protocol Version 4.2, Incorporating 
Amendment 3-Version 4.0 (US only, dated 31 July 2016) .................... 188 
12.4.5.1 
Risk Assessment for Amendment 3, Version 4.2 ................. 188 
12.4.5.2 
Overview of Changes ........................................................... 188 
12.4.5.3 
Changes to the Protocol Text ............................................... 192 
12.4.6 Protocol Amendment 3-Protocol Version 4.2, Incorporating 
Amendment 3-Version 4.1 (EU only, dated 31 August 2016) ................ 204 
12.4.6.1 
Risk Assessment for Amendment 3, Version 4.2 ................. 204 
12.4.6.2 
Overview of Changes ........................................................... 204 
12.4.6.3 
Changes to the Protocol Text ............................................... 211 
12.4.7 Protocol Amendment 4-Protocol Version 5.0, Incorporating Amendment 
3- Version 4.2 (dated 12 December 2016) .............................................. 236 
12.4.7.1 
Risk Assessment for Amendment 4, Version 5.0 ................. 236 
12.4.7.2 
Overview of Changes ........................................................... 236 
12.4.7.3 
Changes to the Protocol Text ............................................... 237 


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List of Tables 
Table 3-1 
Dose Levels of NC-6004 ................................................................................. 34 
Table 5-1 
Dose Level Cohorts ......................................................................................... 53 
Table 12-1 
Schedule of Events .......................................................................................... 98 


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Protocol Synopsis 
 
Protocol Number: 
NC-6004-004A 
Title: 
A Phase 1b/2 Dose Escalation and Expansion Trial of NC-6004 
(Nanoparticle Cisplatin) plus Gemcitabine in Patients with 
Advanced Solid Tumors or Squamous Non-Small Cell Lung, 
Biliary Tract, and Bladder Cancer 
Sponsor: 
NanoCarrier Co, Ltd 
Study Phase: 
1b/2 
Study Sites: 
At least 20 sites in the United States and Europe 
Indication: 
Part 1: Advanced solid tumors 
Part 2: First-line metastatic squamous non-small cell lung cancer 
(NSCLC); first-line metastatic or locally advanced 
cholangiocarcinoma, gallbladder cancer, or ampullary cancer 
(biliary tract cancer); and first-line metastatic or locally advanced 
transitional cell carcinoma (TCC) of the urinary tract (bladder 
cancer) 
Rationale: 
NC-6004 is a polymeric micelle containing cisplatin as an active 
moiety. The nanoparticle provides sustained release of the 
cisplatin and utilizes the enhanced permeability retention-effect to 
target the release of platinum to tumors. Synergistic effects of 
cisplatin and gemcitabine have been evaluated extensively in 
various types of tumor cell lines, including NSCLC cell lines, and 
nonclinical studies have demonstrated that, in tumors in which 
the combination of cisplatin and gemcitabine exhibit synergistic 
effects, the combined effects of NC-6004 and gemcitabine also 
are synergistic. This study will establish a maximum-tolerated 
dose (MTD) and recommended Phase 2 (RPII) dose of NC-6004 
in combination with gemcitabine and evaluate the initial activity 
and tolerability profile. 
Objectives: 
The primary objectives of this study are: 
• In the dose-escalation phase of the study (Part 1), to 
determine the dose-limiting toxicities (DLTs), MTD, and RPII 
dose of NC-6004 in combination with gemcitabine; 
• In the expansion phase of the study (Part 2), to evaluate the 
activity of NC-6004 in combination with gemcitabine in 
patients with first-line Stage IV squamous NSCLC, first-line 
advanced or metastatic biliary tract cancer, and first-line 
metastatic or locally advanced bladder cancer compared with 
historical control as measured by local 


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investigator/radiologist-assessed progression-free survival 
(PFS), according to Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1. 
The secondary objectives of this study are: 
• To evaluate overall response rate (ORR), disease control rate 
(DCR = complete response + partial response + stable 
disease), duration of response (DOR), PFS, overall survival 
(OS) 
• To evaluate therapy-related adverse events (AEs) 
• To evaluate the safety and tolerability of NC-6004 when 
combined with gemcitabine 
• To evaluate quality of life using the European Organisation 
for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30) 
• To evaluate acute and delayed symptoms using the MD 
Anderson Symptom Inventory (MDASI) and a nausea and 
vomiting patient diary 
The exploratory objective of this study is: 
• To assess the pharmacokinetic and pharmacodynamic effects 
of NC-6004. 
Patient Population: 
Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled 
in this study: 
1. Provide signed written informed consent prior to the initiation 
of any study-specific procedures. 
2. (Part 1 only) Have a histologically or cytologically confirmed 
diagnosis of advanced solid tumor that has relapsed or is 
refractory to standard curative or palliative therapy or has a 
contraindication to standard therapy. 
(Part 2 only) Cohort 1: Have histologically or cytologically 
confirmed diagnosis of Stage IV squamous NSCLC and have 
not received prior chemotherapy or immunotherapy for 
metastatic disease and are not known to be PD-L1 positive 
(known high PD-L1 expression defined as Tumor Proportion 
Score [TPS] greater than or equal to 50%). Patients with 
known sensitizing mutation in the epidermal growth factor 
receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) 
fusion oncogene must have received at least 1 and up to 


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2 targeted therapies prior to enrollment. 
• A patient with stable, treated brain metastases is eligible, 
provided that there is no evidence of progression after 
treatment and the patient does not require corticosteroids, 
or, if the patient requires corticosteroids, has been 
receiving a stable dose of corticosteroids for at least 
14 days prior to assignment to treatment. 
• Patients whose tumors are known to harbor an exon 19 
deletion or exon 21 L858R EGFR mutation must have had 
intolerance or have progressed on at least 1 and up to 
2 EGFR tyrosine kinase inhibitors. 
• Patients whose tumors are known to harbor an ALK 
translocation must have had intolerance or have 
progressed on at least 1 and up to 2 ALK inhibitors. 
(Part 2 only) Cohort 2: Have histologically or cytologically 
confirmed diagnosis of nonresectable, recurrent, or metastatic 
biliary tract carcinoma (intrahepatic or extrahepatic 
cholangiocarcinoma, gallbladder cancer, or ampullary 
carcinoma) and have not received prior systemic anticancer 
therapy for advanced or metastatic disease. 
(Part 2 only) Cohort 3: Have histologically or cytologically 
confirmed diagnosis of metastatic or locally advanced TCC of 
the urinary tract (bladder, urethra, ureter, renal pelvis) 
(T3b-T4 N0 M0, Tany N1-N3 M0, or Tany Nany M1) and are 
not candidates for surgery. 
• Patients must not have received prior treatment with 
systemic anticancer therapy for metastatic or locally 
advanced urinary tract cancer. 
• Certain mixed histologies that are predominantly (>50%) 
TCC are eligible: squamous, adenocarcinoma, and 
undifferentiated. Mixed undifferentiated histology 
requires immunohistochemistry consistent with a TCC 
origin. Predominantly squamous or neuroendocrine 
tumors are excluded. 
3. Have measurable disease per RECIST version 1.1. 
4. Are males or females aged ≥18 years. 
5. Have an Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) of 0 to 1, with the exception of 
patients in Part 2 (Cohort 3, unfit bladder cancer patients) who 


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may have an ECOG PS of 2. 
6. Have adequate bone marrow reserve defined as: 
• 
Absolute neutrophil count of at least 1.5 × 109/L, 
• 
Platelet count of at least 100 × 109/L, and 
•  Hemoglobin level of at least 10 g/dL (transfusion is 
allowed to achieve hemoglobin level of at least 10 g/dL). 
7. Have adequate liver function defined as: 
•  Total serum bilirubin <1.5 × upper limit of normal (ULN) 
and 
• 
Baseline alanine transaminase and aspartate transaminase 
<2.0 × ULN or, in patients with documented hepatic 
metastasis <5.0 × ULN and 
• 
Serum albumin ≥3.5 g/dL 
8. Prothrombin time within normal limits 
9. In Part 1 and in Part 2 in Cohorts 1 and 2: have adequate renal 
function defined as a creatinine clearance (CrCl) 
≥50 mL/minute (calculated according to the formula of 
Cockcroft and Gault 1976) or serum creatinine <1.5 mg/dL. In 
Part 2, patients in Cohort 3 (bladder cancer) must have a CrCl 
of ≥30 mL/min. 
•  Bladder cancer patients in Cohort 3 of Part 2 will be 
stratified by ≥30 to <60 mL/min and/or ECOG PS 2 and 
≥60 mL/min and ECOG PS 0 to 1. If 2 of 6 patients (or 
≥33% at any point during the study) in the ≥30 to 
<60 mL/min group have a worsening of CrCl (ie, 50% 
reduction from baseline for 2 consecutive assessments, at 
least 1 week apart), then enrollment of patients with CrCl 
<60 mL/min will stop in the bladder cancer cohort. 
10. Have a negative pregnancy test result at screening (for 
females of childbearing potential; not applicable to patients 
who are unable to become pregnant, including those with 
bilateral oophorectomy and/or hysterectomy or 
postmenopausal [no menses for the previous 12 months]). The 
test must be performed within 1 week before Day 1 of 
treatment. 
11. Male patients must agree to use a condom during treatment 
and for 90 days after dosing. Male patients must agree not to 
donate sperm for 90 days after dosing. 


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12. For women of childbearing potential*: are willing to follow 
1 of the following effective methods of birth control from the 
time of study entry to 6 months after the last day of treatment: 
•  Combined (estrogen- and progestogen-containing) 
hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, or transdermal) 
•  Progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, or implantable) 
• 
Intrauterine devices 
• 
Intrauterine hormone-releasing system 
•  Vasectomized partner who has received medical 
assessment of surgical success 
• 
Bilateral tubal occlusion 
• 
True sexual abstinence** 
*Patients not of childbearing potential include those who are 
surgically sterile or postmenopausal (no menses for the 
previous 12 months). For women not currently taking 
contraceptive methods at screening, low user-dependency 
contraceptive methods (eg, implantable progestogen-only 
hormonal contraception, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, 
vasectomized partner) are recommended. 
**The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the patient. 
13. Have reasonably recovered from preceding major surgery as 
judged by the investigator or have had no major surgery 
within 4 weeks prior to Day 1 treatment. 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded 
from the study: 
1. Have received prior platinum therapy in the past 3 months 
(Part 1) or 6 months in the adjuvant or neoadjuvant setting 
(Part 2). 
2. Have received prior cisplatin and gemcitabine concomitantly 
within the last 6 months or are refractory to cisplatin and 
gemcitabine. 
3. Are unable to receive platinum-based therapy due to previous 


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toxicity. 
4. Have unresolved toxicity from prior radiation, chemotherapy, 
or other targeted treatment, including investigational 
treatment, with the exception of alopecia and ≤Grade 1 
peripheral neuropathy according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events 
NCI CTCAE version 4.03. Clinical judgment by the 
investigator is allowed to determine if Grade 1 fatigue at 
screening is residual toxicity from prior treatment or is a 
symptom of the patient’s general condition or disease. The 
investigator and Medical Monitor will discuss the eligibility 
of patients with baseline toxicity. 
5. Have evidence suggesting pulmonary fibrosis or interstitial 
pneumonia. 
6. Have a history of thrombocytopenia with complications 
including hemorrhage or bleeding of ≥Grade 2 per NCI 
CTCAE version 4.03 that required medical intervention or 
have any hemolytic condition or coagulation disorder that 
would make participation unsafe in the opinion of the 
investigator. 
7. Have known hypersensitivity to platinum compounds or 
gemcitabine. 
8. Have uncontrolled diabetes or have hypertension requiring 
more than 3 medications for control of hypertension. 
9. Have known active hepatitis B (defined as a known positive 
hepatitis B surface antigen [HBsAg] result) or hepatitis C 
(defined by a known positive hepatitis C antibody result and 
known quantitative HCV RNA results greater than the lower 
limits of detection of the assay). 
10. Are pregnant or breast-feeding. 
11. Have signs or symptoms of organ failure, major chronic 
illnesses other than cancer, or any concomitant medical or 
social condition that, in the opinion of the investigator, make 
it undesirable for the patient to participate in the study or that 
could jeopardize compliance with the protocol. 


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12. Have pre-existing alcoholic liver injury or significant liver 
disease. 
13. Are regularly consuming alcohol within 6 months of 
Screening defined as an average weekly intake of >21 units 
(or an average daily intake of >3 units) for males or >14 units 
(or an average daily intake >2 units) for females. One unit is 
equivalent to 8 g of alcohol: a half-pint (approximately 
240 mL) of beer, 1 glass (125 mL) of wine, or 1 measure 
(25 mL) of spirits. 
14. Have experienced any of the following within the 6-month 
period prior to screening: angina pectoris, coronary artery 
disease, cerebrovascular accident, transient ischemic attack, 
cardiac failure with known ejection fraction less than 40%, or 
cardiac arrhythmia requiring medical therapy. 
15. Are unwilling or unable to comply with study procedures or 
are planning to take a vacation for 7 or more consecutive days 
during the treatment phase of the study without prior consent 
from the Medical Monitor. 
Study Design: 
This study will consist of 2 parts; Part 1 is a Phase 1b, continual 
reassessment method dose-escalation trial, and Part 2 is a Phase 2, 
adaptive, open-label, expansion trial evaluating activity, safety, 
and tolerability at the RPII dose identified in Part 1. 
In Part 1, patients will receive intravenous infusion of NC-6004 at 
escalating doses on Day 1 in combination with gemcitabine at the 
fixed dose of 1250 mg/m2 on Days 1 and 8 of a 21-day cycle. The 
dose-escalation part of the trial will begin with a single-patient 
run-in phase. In the run-in phase, 1 patient will be enrolled 
sequentially at the following dose levels: 60, 75, 90, 105, 120, 
135, 150, 165, and 180 mg/m2 until a DLT is observed or until a 
patient is treated at 180 mg/m2 for 1 cycle without a DLT. During 
the single-subject run-in phase, after enrollment of the initial 
patient at 60 mg/m2, the first patient in each cohort will not be 
enrolled until the patient at the immediately lower cohort has 
completed at least 1 full cycle. A Bayesian 
continual-reassessment method per Neuenschwander et al 2008 
(N-CRM) model will be used for dose escalation. The N-CRM 
will model the starting dose for the remainder of the escalation 
using the run-in data. For the remainder of Part 1 of the study, 
4 patients will be enrolled as a cohort at each dose level predicted 


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by the N-CRM model. If no DLT is observed in the single-subject 
run-in phase at 180 mg/m2, the single-subject run-in phase will 
end and the next cohort will enroll 4 patients at 180 mg/m2. 
On Day 1 of each cycle, patients will receive NC-6004 over 
1 hour (+10-minute window) followed by an infusion of 
gemcitabine 1250 mg/m2 over 30 minutes. All patients will 
receive gemcitabine 1250 mg/m2 alone on Day 8 of each cycle. In 
Part 1, patients will continue to receive treatment until they 
experience disease progression, experience unacceptable toxicity 
(UT), or withdraw voluntarily. If the investigator and the patient 
request continuation of NC-6004 administration until progressive 
disease or until the drug is no longer tolerated (whichever occurs 
first), the sponsor may agree to supply the drug after discussion of 
the request with the investigator. 
In subsequent cohorts, the NC-6004 dose will be increased in 
15 mg/m2 increments based on the toxicity profile of the previous 
cohort. The dose-toxicity relationship will be re-evaluated at the 
completion of the first treatment cycle in each cohort until the 
MTD is identified. At any time, in the absence of an MTD from 
the N-CRM model, NanoCarrier can recommend a RPII dose less 
than or equal to the maximum administered dose based on 
efficacy, full safety, and/or pharmacokinetic (PK) data. 
Part 2 of the study (Phase 2 portion) will begin after the RPII dose 
of NC-6004 is identified for use in combination with gemcitabine. 
All patients will receive NC-6004 at the RPII dose (135 mg/m2, 
established in Part 1) in combination with gemcitabine 
1250 mg/m2 by the same regimen as in Part 1. 
Three cohorts of patients are eligible (Cohort 1: first-line 
metastatic squamous NSCLC; Cohort 2: first-line metastatic or 
locally advanced cholangiocarcinoma, gallbladder cancer, or 
ampullary cancer (biliary tract cancer); and Cohort 3: first-line 
metastatic or locally advanced TCC of the urinary tract (bladder 
cancer). Bladder cancer patients in Cohort 3 of Part 2 will be 
stratified by ≥30 to <60 mL/min and/or ECOG PS 2 (unfit) and 
≥60 mL/min and ECOG 0 to 1 (fit). If 2 of 6 patients (or ≥33% at 
any point during the study) in the ≥30 to <60 mL/min group have 
a worsening of CrCl (ie, 50% reduction from baseline for 
2 consecutive assessments, at least 1 week apart), then enrollment 
of patients with CrCl <60 mL/min will stop in the bladder cancer 
cohort. 
Part 2 will enroll up to 50 patients each in Cohorts 1 and 2, and 


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up to 60 patients (ie, 30 unfit and 30 fit patients) in Cohort 3, for a 
total of up to 160 patients in Part 2.The primary endpoint (PFS) 
will be continuously updated and compared with the historical 
PFS from Phase 3 pivotal cisplatin and gemcitabine trials within 
each cohort. The PFS hazard model will be updated as PFS data 
accrue. A hazard ratio (HR) for PFS for each cohort versus 
historical control will be obtained. 
 
 
Cohort 
Biliary 
Bladder 
(CrCl: 
≥60 
mL/min 
and 
ECOG PS 
0-1; fit) 
Bladder 
(CrCl: 
≥30 to 
<60 
mL/min 
and/or 
ECOG 
PS 2; 
unfit) 
Squamous 
NSCLC 
Historical 
Median 
Duration of 
PFS 
8.8 months 7.6 
months 
5.8 
months 
5 months 
Historical 
PFS 
Weekly 
Hazard 
0.01795 
0.020755 
0.02711 
0.031377 
Abbreviations: CrCl, creatinine clearance; ECOG, Eastern Cooperative 
Oncology Group; NSCLC, non-small cell lung cancer; PS, performance status. 
 
Once 10 PFS events have been observed, interim analyses will be 
performed every 6 weeks. At each interim and at the final 
analysis, there are 3 possible outcomes for each cohort. 
• Futility – 10 PFS events have been observed in each 
cohort and at least 1 of the following conditions is true: 
• 
Probability (Promising HR*) <0.4 
• 
Probability (Phase 3 Success*) <0.4 
• Success – 25 PFS events have been observed in each 
50-patient cohort and 15 PFS events in each 30-patient 
bladder cancer cohort and: 


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• 
Probability (Phase 3 Success*) >0.8 
• 
Inconclusive – neither futility nor success. 
*Phase 3 success is defined as success in a Phase 3 clinical trial 
with 381 events - enough to provide 80% power to detect an HR 
of 0.75. A promising HR is defined as one less than 0.85. 
*Futility can only be declared for a cohort after 10 PFS events 
have been observed in that cohort. Success can only be declared 
for a cohort after 25 or 15 PFS events have been observed in that 
50-patient cohort (Cohort 1 and 2) or 30-patient bladder cancer 
cohort (Cohort 3, fit and unfit), respectively. Accrual will stop for 
any cohort identified as futile or successful at interim. The 
conclusion of this Phase 2 trial will be that a Phase 3 trial with 
381 events should be conducted for each cohort that is a success. 
If any indication is declared a success, the combination of 
NC-6004 and gemcitabine advances to a Phase 3 randomized, 
controlled trial with sample size sufficient to observe 381 events. 
After completion of 6 cycles of treatment (Cohorts 1 and 3) or 
8 cycles of treatment (Cohort 2), patients will have an 
End-of-Treatment visit, will be followed with scans every 
9 weeks until disease progression, and will be contacted for 
survival every 12 weeks by telephone. 
Patients who discontinue treatment and have not progressed will 
have an End-of-Treatment visit, will be followed with scans every 
9 weeks until disease progression, and will be contacted for 
survival every 12 weeks by telephone. Patients who discontinue 
treatment due to disease progression will have an 
End-of-Treatment visit and be contacted for survival every 
12 weeks by phone. 
Estimated Study 
Duration: 
Part 1 of the study will include a screening period (up to 28 days); 
as many cycles until progressive disease or until the drug is no 
longer tolerated (whichever occurs first); tumor assessments for 
response and disease progression with scans every 6 weeks; and 
telephone calls for survival every 12 weeks. The cycles are 
21 days in duration. 
Part 2 of the study will include a screening period (up to 28 days); 
6 treatment cycles (Cohorts 1 and 3) or 8 treatment cycles 
(Cohort 2) that are 21 days in duration; tumor assessments for 
response and disease progression with scans every 6 weeks; and 
telephone calls for survival every 12 weeks. 
Patients will receive study treatment until any of the following 


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occur: 
• Progressive disease is observed (Part 1) or completion of 
6 cycles of treatment (Part 2; Cohorts 1 and 3) or 8 cycles of 
treatment (Part 2; Cohort 2) 
• Unacceptable toxicity experienced 
• Grade 4 liver enzyme elevation 
• Withdrawal of consent 
• Major protocol violation 
• Required treatment delay >14 days (except in case of potential 
patient benefit, then the duration of the delay is to be 
approved by the sponsor) 
• Symptoms or an intercurrent illness not consistent with the 
protocol requirements or that justifies withdrawal 
• For Cohort 3 only, unfit bladder cancer patient (≥30 to 
<60 mL/min CrCl at screening) has a worsening of CrCl (ie, 
50% reduction from baseline for 2 consecutive assessments, at 
least 1 week apart) 
• Lost to follow-up 
• Other (eg, pregnancy, development of contraindications of use 
of the study drug) 
• The investigator or sponsor determines it is in the best interest 
of the patient to discontinue the patient’s participation in the 
study. 
Efficacy Assessments: 
Disease response assessment will occur every 6 weeks until 
disease progression and will include radiological assessments per 
RECIST version 1.1 for ORR, DCR, PFS, DOR, and OS. Patients 
who have obtained a response (partial response or complete 
response) will have a confirmatory scan at a minimum of 4 weeks 
following the initial scan. Data will be collected continuously for 
OS while patients are receiving study drug. After the 
discontinuation or completion of treatment, patients without 
disease progression will be followed for progression with scans 
every 9 weeks and for survival (by telephone contact) every 
12 weeks. 
Quality of life will be assessed before treatment on Day 1 and 
Day 8 of each cycle and at the End-of-Treatment visit using the 
EORTC QLQ-C30. 
Symptoms will be assessed before treatment on Day 1 and Day 8 


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of each cycle and at the End-of-Treatment visit using the core MD 
Anderson Symptom Inventory or the MDASI-lung cancer (Part 1 
only). 
Pharmacokinetic or 
Pharmacodynamic 
Assessments: 
The concentration-versus-time profile of micellar platinum in 
plasma and of total platinum in plasma and plasma ultrafiltrate 
(ie, free platinum) will be determined in Part 1 and in Part 2. 
Part 1 Pharmacokinetic Time Points 
Pharmacokinetic plasma and plasma ultrafiltrate samples will be 
collected at the following times in Part 1: 
• Before the start of the NC-6004 infusion on Day 1 of Cycles 1 
through 6 
• At the end of NC-6004 infusion in Cycles 1, 3, and 5 
• After the start of NC-6004 infusion at Hours 3, 6, 12, 24 (Day 
2), 48 (Day 3), 96 (Day 5), 168 (Day 8, prior to gemcitabine 
infusion), and 336 (Day 15) in Cycles 1, 3, and 5 
• At End-of-Treatment visit 
Part 2 Pharmacokinetic Time Points 
Pharmacokinetic plasma and plasma ultrafiltrate will be collected 
at the following times in Part 2 for up to 6 cycles: 
• Before the start of the NC-6004 infusion on Day 1 
• At the end of NC-6004 infusion 
• Before gemcitabine infusion on Day 8 
• At End-of-Treatment visit 
Safety Assessments: 
Adverse events will be evaluated at each visit during every cycle 
and graded according to the NCI CTCAE version 4.03 dated 
June 14, 2010 (only abnormal laboratory results deemed to be 
clinically significant will be recorded as AEs or SAEs). 
Hematology and coagulation and biochemistry tests will be 
performed at screening and on Days 1, 8, and 15 of each cycle 
(before any study drug infusions), and at the End-of-Treatment 
visit. Urinalyses will be performed at screening and at the 
End-of-Treatment visit. A 12-lead electrocardiogram will be 
performed at screening, before and at various time points after 
NC-6004 infusions in selected cycles, before and after 
gemcitabine infusions in selected cycles, and at the 
End-of-Treatment visit. Physical examinations will be performed 
and vital signs will be measured at screening, before the start of 
treatment on Day 1 of each cycle (or can be completed on 


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Day -1), and at the End-of-Treatment visit. Additionally, on Day 1 
of Cycle 1, vital signs will be measured before the start of the 
NC-6004 infusion, every 20 minutes during the infusion, at the 
completion of the infusion, and 1 hour after the completion of the 
infusion. Starting in Cycle 2, vital signs will be measured before 
the NC-6004 infusion and at the completion of the NC-6004 
infusion on Day 1 of each cycle. Vital signs will be measured 
before and after gemcitabine infusion on Day 8 of each cycle. 
Audiometry will be performed at screening and only as clinically 
indicated before treatment on Day 1 of each cycle and as 
clinically indicated at the End-of-Treatment visit. 
Nausea severity and vomiting incidence will be assessed and 
recorded using a patient diary. 
Definition of DLT 
A DLT (monitored in Part 1 only) is defined as the following 
treatment-related AEs or laboratory abnormalities, graded 
according to NCI CTCAE version 4.03: 
• Grade 3 or 4 febrile neutropenia or neutropenic infection 
• Grade 4 neutropenia of duration longer than 7 days and 
unresponsive to growth factor support per institutional 
guidelines or American Society of Clinical Oncology 
guidelines 
• Grade 4 thrombocytopenia 
• Grade 3 thrombocytopenia with clinically significant bleeding 
or Grade 3 thrombocytopenia requiring a platelet transfusion 
• Grade 4 life-threatening anemia 
• Grade 3 or Grade 4 nonhematological toxicity (excluding 
alopecia and Grade 3 nausea, vomiting, diarrhea, and 
electrolyte imbalances lasting less than 48 hours or with 
suboptimal prophylactic and suboptimal curative treatment) 
• Grade 3 nausea, vomiting, diarrhea, or electrolyte imbalances 
lasting greater than 48 hours despite optimal prophylactic and 
curative treatment 
• Grade 4 vomiting, diarrhea, or electrolyte imbalances 
(life-threatening consequences) of any duration despite 
optimal prophylactic and curative treatment 
• ≥Grade 3 hypersensitivity reaction 
• Dosing delay >14 days due to toxicity 
Study Drug, Dosage, 
NC-6004 is provided in vials of 5 mL containing the equivalent of 


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and Route of 
Administration: 
50 mg cisplatin. After the administration of premedications, 
NC-6004 should be mixed with 500 mL of 5% dextrose solution. 
Saline must not be used for any dilution of NC-6004 before 
infusion because cisplatin is released easily from the micelle in 
the chloride-rich environment. Saline must not be used for 
flushing infusion lines immediately before or immediately 
after NC-6004 administration. 
In each part of the study, NC-6004 will be administered as a 
1-hour (+10-minute window) intravenous infusion on Day 1 of 
each cycle. The potential dosage levels of NC-6004 in this study 
include 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210, 225, 
and 240 mg/m2. A full safety review of all AEs for all cycles as 
well as an optional PK analysis will be conducted by the 
investigators, the Medical Monitor, and NanoCarrier before 
increasing the NC-6004 dose beyond 240 mg/m2. Gemcitabine 
1250 mg/m2 will be administered as a 30-minute intravenous 
infusion on Day 1 after the completion of the NC-6004 infusion. 
Gemcitabine 1250 mg/m2 will also be administered as a 
30-minute intravenous infusion on Day 8. The duration of each 
cycle will be 21 days. 
Dose Escalation 
Design: 
A Bayesian continual reassessment method per Neuenschwander 
et al 2008 (N-CRM) model is used for dose escalation and 
determination of MTD. The initial NC-6004 dose for evaluation 
will be 60 mg/m2. Sequential doses selected for evaluation are 75, 
90, 105, 120, 135, 150, 165, 180, 195, 210, 225, and 240 mg/m2. 
The dose-escalation part of the trial will begin with a 
single-patient run-in phase. In the run-in, 1 patient will be 
enrolled sequentially at each dose level until a DLT is observed. 
Dose escalation in the run-in phase will only occur after a patient 
at a given dose level has experienced a DLT or has completed the 
first cycle. The N-CRM will model the starting dose for the 
remainder of the escalation using the run-in data. For the 
remainder of the escalation, 4 patients will be enrolled as a cohort 
at each dose level predicted by the N-CRM model. For the 
remainder of Part 1 of the study, dose escalation will only occur 
after all patients in a cohort have either experienced a DLT or 
completed the first cycle. If no DLT is observed in the 
single-subject run-in phase at 180 mg/m2, the single-subject 
run-in phase will end and the next cohort will enroll 4 patients at 
180 mg/m2. 
Sample Size: 
Up to 49 patients with solid tumors will be enrolled in Part 1 of 
the study. Simulations were performed assuming scenarios with 


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different dose-toxicity relationships. The associated mean sample 
size in these scenarios ranged from 17.22 patients to 
25.79 patients. 
Part 2 is a 3-cohort study with an overall sample size of up to 
160 patients with no more than 50 patients each in Cohorts 1 and 
2 and no more than 60 patients in Cohort 3 (30 unfit and 30 fit 
bladder cancer patients). The total sample size will depend on the 
results of interim futility and superiority analyses. In order to 
evaluate the overall sample size, simulations were performed 
assuming scenarios with different HRs for PFS for each cohort 
compared with historical control and different sample sizes for a 
subsequent Phase 3 clinical trial. The associated mean sample 
size for this trial in these scenarios ranged from 92.7 to 
116.8 patients. 
Patients who receive study drug will not be replaced. 
Statistical Methods: 
Ninety-five percent confidence intervals may be calculated for 
selected safety and exploratory variables. Dose escalation will be 
based on the N-CRM model and the incidence of DLTs. Adverse 
events and serious AEs will be tabulated by system organ class 
and preferred term. Laboratory test results after the first dose will 
be summarized with regard to shifts from baseline values and the 
grade per NCI CTCAE version 4.03. Overall survival, PFS, and 
DOR will be summarized using Kaplan-Meier methods. The 
ORR and DCR will be summarized and 95% confidence intervals 
for both will be created. 
In Part 2, the following posterior probabilities will be derived 
using a Bayesian model updated every 6 weeks after 10 PFS have 
occurred within a cohort: 
• Probability (Promising HR) 
• Probability (Phase 3 Success) 
If any cohort at interim or final analyses has a probability 
(success in a Phase 3 trial with 381 PFS events) >0.8, that 
indication will be declared a success, and the combination of 
NC-6004 and gemcitabine advances to a Phase 3 randomized, 
controlled trial with a sample size sufficient to observe 381 PFS 
events. 
Date of Protocol: 
13 March 2017 


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List of Abbreviations 
 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
AI 
accumulation index 
ALK 
anaplastic lymphoma kinase 
ASCO 
American Society of Clinical Oncology 
AUC0-τ 
area under the concentration-time curve from time zero to the end of the 
dosing interval 
AUClast 
area under the concentration-time curve from time zero to the last 
quantifiable concentration 
AUC0-∞ 
area under the concentration-time curve from time zero to infinity 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
CL 
clearance 
Cmax 
maximum concentration 
CR 
complete response 
CRA 
clinical research associate 
CrCl 
creatinine clearance 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EMA 
European Medicines Agency 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire-Core 30 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 


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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
HR 
hazard ratio 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
λz 
terminal elimination phase rate constant 
MDSAI 
MD Anderson Symptom Inventory 
MDSAI-LC 
MD Anderson Symptom Inventory module specific for lung cancer 
MRT 
mean residence time 
MTD 
maximum-tolerated dose 
NCI 
National Cancer Institute 
N-CRM 
Bayesian continual reassessment method design per Neuenschwander et 
al 2008 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
OS 
overall survival 
PEG-pGlu 
polyethylene glycol-polyglutamate copolymer, also written as α- 
(methoxy-ω-aminopropyl, polyethylene glycol)-block-poly(sodium 
L-glutamate) copolymer 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PS 
performance status 
QoL 
quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RPII 
recommended Phase 2 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
T½ 
terminal half-life 
TCC 
transitional cell carcinoma 
TEAE 
treatment-emergent adverse event 


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Abbreviation 
Definition 
Tmax 
time to maximum concentration 
ULN 
upper limit of normal 
UT 
unacceptable toxicity 
VHP 
Voluntary Harmonisation Procedure 
Vss 
volume of distribution at steady-state 
Vz 
volume of distribution 


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1 Introduction 
Platinum compounds are well established agents in the treatment of cancer (Kelland and 
Sharp 1999). The leading platinum compounds in cancer chemotherapy are cisplatin, 
carboplatin, and oxaliplatin. They share a number of common structural chemical 
characteristics; however, they exhibit marked interanalogue differences in pharmacokinetics, 
adverse effect profiles, and optimal therapeutic indication. 
Cisplatin has been widely used for the treatment of cancer including lung cancer (both small 
cell and non-small cell lung cancer [NSCLC]), head and neck cancer, germ-cell tumors 
(testicular, ovarian, and extragonadal germ cell tumor), ovarian cancer, testicular tumor, 
bladder cancer, renal pelvis/ureter tumor, prostate cancer, esophageal cancer, cervical cancer, 
neuroblastoma, stomach cancer, osteosarcoma, and pleura malignant mesothelioma in 
monotherapy and including malignant bone tumor, endometrial cancer (adjuvant 
chemotherapy and chemotherapy for metastasis/recurrence), recurrent/refractory malignant 
lymphoma, and pediatric malignant solid tumor (rhabdomyosarcoma, neuroblastoma, 
hepatoblastoma and other primary malignant liver tumor, and medulloblastoma) in 
combination therapy. The mechanism of action of cisplatin is the inhibition of DNA synthesis 
induced by the platinum-DNA adduct formed by cross-linking between cisplatin and specific 
base sequences. This cross-linking inhibits DNA replication and transcription and activates 
signal transduction pathways leading to apoptosis and cell death (Pinto and Lippard 1985). 
As described above, cisplatin-based regimens represent the mainstay of treatment in a 
number of indications; however, its use is associated with irreversible ototoxicity and renal 
toxicity, which necessitates the use of pre-hydration regimens using mannitol and excludes 
its use in patients with less than normal renal function. Continuous administration of cisplatin 
is associated with neurotoxicity, myelotoxicity, and gastrointestinal toxicity, including nausea 
and vomiting. Decreased appetite, alopecia, and general disorder such as fatigue, which are 
common toxicological features of platinum compounds affecting patient’s quality of life 
(QoL), are also associated with cisplatin therapy (Hartmann and Lipp 2003). 
Nonclinical studies have indicated that NC-6004 (1) is preferentially distributed to tumors, 
(2) demonstrates significantly lower toxicity compared to cisplatin at an equivalent dose, and 
(3) has increased antitumor activity (Uchino et al 2005). Preferential tumor accumulation of 
polymer micelles with an average diameter of 30 nm can be explained by the mechanism of 


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the enhanced permeability and retention effect, characterized by marked vascular 
hyperpermeability to the circulating macromolecular carrier (>40 kilodalton) and impaired 
lymphatic drainage in the tumor (Matsumura and Maeda 1986). Furthermore, polymer 
micelles successfully avoid glomerular filtration (threshold diameter of 8 nm), and the 
hydrophilic outer shell composed of polyethylene glycol greatly extends the circulation time 
of micelles by preventing the micelles from being captured by the reticuloendothelial system, 
enhancing the specific tumor accumulation. These micelles progressively break down in the 
presence of chloride to release cisplatin and the copolymer. The cytotoxic activity of 
NC-6004 is considered to be exerted by the formation of cellular DNA adducts with released 
cisplatin. The slow release of cisplatin from NC-6004 achieves a long-period systemic 
exposure to cisplatin, leading to its continuous antitumor effect with a toxicity profile similar 
to that of cisplatin. 
Results of in vitro cytotoxicity studies of NC-6004 in combination with gemcitabine, showed 
a synergistic effect in MOR/CPR cisplatin-refractory lung adenocarcinoma, MDA-MB-231 
breast adenocarcinoma, LS174T colon adenocarcinoma, and BxPC-3 pancreas 
adenocarcinoma cells; and an additive effect was observed in K562 chronic myelogenous 
leukemia, HT1376 bladder carcinoma, HepG2 hepatocellular carcinoma, and NCI-N87 
gastric carcinoma cells. In in vivo studies of NC-6004 in combination with gemcitabine, 
significant antitumor effects were observed in MDA-MB-231, MOR/CPR, BxPC-3, and 
PC-3 prostate cancer xenograft models. 
 
The results of a Phase 1 study of NC-6004 as monotherapy in patients with solid tumors 
(Study NC-6004-001) suggested that NC-6004 monotherapy has potential activity for the 
treatment of solid tumors. The pharmacokinetic (PK) analysis indicated prolonged circulation 
of NC-6004 in the blood and delayed and sustained release of the potentially active platinum 
species, cisplatin, after the administration of NC-6004 (Plummer et al 2011). 
In the first part of the Phase 1/2 study performed in Asia in patients with pancreatic cancer 
(Study NC-6004-002), NC-6004 and gemcitabine combination therapy exhibited an 
improved efficacy profile with prolonged administration period compared to that in 
Study NC-6004-001. Although, this is partly due to the aggressive prophylactic regimen for 
hypersensitivity reactions, NC-6004 is well tolerated even in combination with gemcitabine, 
and further clinical results are anticipated. 


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Based on these results, it is concluded that further clinical study should proceed aiming at the 
development of a new micelle formulation of cisplatin for out-patient-based therapy without 
serious toxicity. 
This study will determine the maximum tolerated dose (MTD) and recommended Phase 2 
(RPII) dose of NC-6004 in combination with gemcitabine and evaluate the activity, safety, 
and tolerability of NC-6004 in combination with gemcitabine in patients with advanced solid 
tumors and first-line metastatic squamous NSCLC; first-line metastatic or locally advanced 
cholangiocarcinoma, gallbladder cancer, or ampullary cancer (biliary tract cancer); and 
first-line metastatic or locally advanced transitional cell carcinoma (TCC) of the urinary tract 
(bladder cancer). The study will also evaluate the overall response rate (ORR), disease 
control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall 
survival (OS), QoL, and therapy-related adverse events (AEs). In addition, the study will 
assess the PK and pharmacodynamic effects of NC-6004. 


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2 Study Objectives 
2.1 
Primary Objectives 
The primary objectives of this study are: 
 
• In the dose-escalation phase of the study (Part 1), to determine the dose-limiting toxicities 
(DLTs), MTD, and RPII dose of NC-6004 in combination with gemcitabine; 
• In the expansion phase of the study (Part 2), to evaluate the activity of NC-6004 in 
combination with gemcitabine in patients with first-line Stage IV squamous NSCLC, 
first-line advanced or metastatic biliary tract cancer, and first-line metastatic or locally 
advanced bladder cancer compared with historical control as measured by local 
investigator/radiologist-assessed progression-free survival (PFS), according to Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 
 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
 
• To evaluate ORR, DCR (DCR = complete response [CR] + partial response [PR] + stable 
disease [SD]), DOR, PFS, and OS 
• To evaluate therapy-related AEs 
• To evaluate the safety and tolerability of NC-6004 when combined with gemcitabine 
• To evaluate QoL using the European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) 
• To evaluate acute and delayed symptoms using the MD Anderson Symptom Inventory 
(MDASI) and a nausea and vomiting patient diary 
 
2.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
 
• To assess the PK and pharmacodynamic effects of NC-6004 


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3 Investigational Plan 
3.1 
Study Design 
This study will consist of 2 parts; Part 1 is a Phase 1b, continual reassessment method 
dose-escalation trial in patients with any advanced solid tumor, and Part 2 is a Phase 2, 
adaptive, open-label, expansion trial in patients with squamous NSCLC, biliary tract, and 
bladder cancer evaluating activity, safety, and tolerability at the RPII dose identified in Part 1. 
 
In Part 1, patients will receive intravenous infusion of NC-6004 and gemcitabine in 3-week 
treatment cycles. NC-6004 will be administered on Day 1 of each cycle and gemcitabine 
1250 mg/m2 will be administered on Day 1 of each cycle (after the administration of 
NC-6004) and on Day 8 of each cycle. Patients will be treated until disease progression. If 
the investigator and the patient request continuation of NC-6004 administration until 
progressive disease or until the drug is no longer tolerated (whichever occurs first), the 
sponsor may agree to supply the drug after discussion of the request with the investigator. 
A Bayesian continual-reassessment method per Neuenschwander et al 2008 (N-CRM) model 
will be used for dose escalation and determination of MTD (as described in Section 6.3.1.2). 
The initial NC-6004 dose for evaluation will be 60 mg/m2. Sequential doses selected for 
evaluation are listed in Table 3-1. 


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Table 3-1 
Dose Levels of NC-6004 
 
Dose Level Name 
NC-6004 Dose Level (mg/m2) 
1 
60 
2 
75 
3 
90 
4 
105 
5 
120 
6 
135 
7 
150 
8 
165 
9 
180a 
10 
195 
11 
210 
12 
225 
13 
240b 
a 
If no DLT is observed in the single-subject run-in phase at 180 mg/m2, the single-subject run-in phase will 
end and the next cohort will enroll 4 patients at 180 mg/m2. 
b 
A formal review by the safety committee will take place to decide if the dose can be increased beyond 
240 mg/m2. 
 
Part 1 will begin with a single-patient run-in phase. In the run-in phase, 1 patient will be 
enrolled sequentially at each dose level of NC-6004 until a DLT is observed. Dose escalation 
in the run-in phase will only occur after a patient at a given dose level has experienced a DLT 
or has completed the first cycle. The N-CRM will model the starting dose for the remainder 
of Part 1 using the run-in data. For the remainder of Part 1, 4 patients will be enrolled as a 
cohort at each dose level as predicted by the N-CRM model. The N-CRM model may enroll 
the next cohort at the previous dose level, the current dose level, or the next dose level. The 
N-CRM model will only be updated after all patients in a cohort have either experienced a 
DLT or completed the first cycle. If no DLT is observed in the single-subject run-in phase at 
180 mg/m2, the single-subject run-in phase will end and the next cohort will enroll 4 patients 
at 180 mg/m2. 
Once the MTD (or RPII dose) of NC-6004 is identified, dose escalation within Part 1 will 
cease. Patients in Part 1 who were not assigned to the NC-6004 dose identified as the RPII 
dose will continue treatment cycles at their assigned dose level. 


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Part 2 of the study (Phase 2 portion) will begin after the RPII dose of NC-6004 is identified 
for use in combination with gemcitabine. All patients will receive NC-6004 at the RPII dose 
(135 mg/m2, established in Part 1) in combination with gemcitabine 1250 mg/m2 by the same 
regimen as in Part 1. Cohort 3 will stratify patients by creatinine clearance (CrCl) to assess 
study drug in patients with reduced kidney function (ie, CrCl of ≥30 to <60 mL/min [unfit] 
and ≥60 mL/min [fit]) in a controlled manner and with the stipulation that enrollment will 
stop if 2 of 6 patients in the ≥30 to <60 mL/min group have a worsening of CrCl (ie, 50% 
reduction from baseline for 2 consecutive assessments, at least 1 week apart). 
Three cohorts of patients are eligible (Cohort 1: first-line metastatic squamous NSCLC; 
Cohort 2: first-line metastatic or locally advanced cholangiocarcinoma, gallbladder cancer, or 
ampullary cancer [biliary tract cancer]; and Cohort 3: first-line metastatic or locally advanced 
TCC of the urinary tract [bladder cancer]). Part 2 will enroll up to 50 patients each in 
Cohorts 1 and 2 and up to 60 patients (ie, 30 unfit and 30 fit bladder cancer patients) in 
Cohort 3, for a total of up to 160 patients in Part 2. The primary endpoint (PFS) will be 
continuously updated and compared with the historical PFS from Phase 3 pivotal cisplatin 
and gemcitabine trials within each cohort. The PFS hazard model will be updated as PFS data 
accrue. A hazard ratio (HR) for PFS for each cohort versus historical control will be obtained. 
 
Cohort 
Biliary 
Bladder 
(CrCl: ≥60 
mL/min and 
ECOG 
PS 0-1; fit) 
Bladder 
(CrCl: ≥30 
to 
<60 mL/min 
and/or 
ECOG PS 2; 
unfit) 
Squamous 
NSCLC 
Historical 
Median 
Duration of 
PFS 
8.8 months 
7.6 months 
5.8 months 
5 months 
Historical 
PFS Weekly 
Hazard 
0.01795 
0.020755 
0.02711 
0.031377 
Abbreviations: CrCl: creatinine clearance; ECOG, Eastern Cooperative Oncology Group; 
NSCLC, non-small cell lung cancer; PS, performance status. 
 
Once 10 PFS events have been observed, interim analyses will be performed every 6 weeks. 
At each interim and at the final analysis, there are 3 possible outcomes for each cohort. 


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• Futility – 10 PFS events have been observed in each cohort and at least 1 of the 
following conditions is true: 
• 
Probability (Promising HR*) <0.4 
• 
Probability (Phase 3 Success*) <0.4 
 
• Success – 25 PFS events have been observed in each 50-patient cohort and 15 PFS 
events in each 30-patient bladder cancer cohort and: 
• 
Probability (Phase 3 Success*) >0.8 
• 
Inconclusive – neither futility nor success. 
*Phase 3 success is defined as success in a Phase 3 clinical trial with 381 events - enough to 
provide 80% power to detect an HR of 0.75. A promising HR is defined as one less than 0.85. 
*Futility can only be declared for a cohort after 10 PFS events have been observed in that 
cohort. Success can only be declared for a cohort after 25 or 15 PFS events have been 
observed in that 50-patient cohort (Cohort 1 and 2) or 30-patient bladder cancer cohort 
(Cohort 3, fit and unfit), respectively. Accrual will stop for any cohort identified as futile or 
successful at interim. The conclusion of this Phase 2 trial will be that a Phase 3 trial with 
381 events should be conducted for each cohort that is a success. 
If any indication is declared a success, the combination of NC-6004 and gemcitabine 
advances to a Phase 3 randomized, controlled trial with sample size sufficient to observe 
381 events. 
In Part 1, patients will continue to receive treatment until they experience disease progression. 
The maximum number of cycles a patient undergoes is at the discretion of the investigator 
and depends on response as described in the American Society of Clinical Oncology (ASCO) 
guidelines (Azzoli et al 2011). Patients who complete 4 or more cycles will be considered as 
having completed the treatment. Subject to sponsor approval, individual patients will be 
treated until progressive disease. If the investigator and the patient request continuation of 
NC-6004 administration until progressive disease or until the drug is no longer tolerated 
(whichever occurs first), the sponsor may agree to supply the drug after discussion of the 
request with the investigator. In Part 2, patients will continue to receive treatment for up to 
6 cycles (Cohorts 1 and 3) or 8 cycles (Cohort 2). 


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After progressive disease is observed (Part 1) or the completion of 6 cycles (Part 2; Cohorts 1 
and 3) or 8 cycles (Part 2; Cohort 2), patients will have an End-of-Treatment visit, will be 
followed with scans every 9 weeks until disease progression, and will be contacted for 
survival every 12 weeks by telephone. Patients who discontinue treatment and have not 
progressed will have an End-of-Treatment visit, will be followed with scans every 9 weeks 
until disease progression, and will be contacted for survival every 12 weeks by telephone. 
Patients who discontinue treatment due to disease progression will have an End-of-Treatment 
visit and be contacted for survival every 12 weeks by phone. 
Disease assessment will be performed using RECIST version 1.1 (Eisenhauer et al 2009) and 
the same imaging method used at screening should be used for all subsequent assessments. 
Screening Period (Day -28 to -1) 
 
The following procedures will be performed during the screening period within 28 days prior 
to the first study treatment: 
• Signed informed consent can be obtained within 28 days of dosing and prior to 
performing any study evaluations. 
• Disease assessment will be evaluated with a baseline scan (see Section 6.1.1 for imaging 
methods) and should be performed within the 28 days before the start of study treatment. 
Screening Period (Day -14 to -1) 
The following procedures will be performed during the screening period within 14 days prior 
to the first study treatment: 
• Assessment of eligibility criteria 
• Patient demography 
• Medical history (to include a complete history of all surgeries and significant diagnoses) 
• Complete history of all cancer treatment (including surgery, radiation therapy, 
chemotherapy, etc.) 
• Physical examination 
• Height and weight 


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• Vital sign measurements 
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 
• Audiometry 
• Urinalysis 
• Cardiac risk factors (history of angina pectoris, coronary artery disease or 
cerebrovascular accident, transient ischemic attack, cardiac failure with known ejection 
fraction less than 40%, or cardiac arrhythmia requiring medical therapy) 
• Concomitant medication use (including prescription or over-the-counter medication, 
herbal or naturopathic products) within the past 30 days 
Screening Period (Day -7 to -1) 
 
The following procedures will be performed during the screening period within 7 days prior 
to the first study treatment: 
• Pregnancy test (serum or urine, only for women of childbearing potential) 
• Hematology and coagulation 
• Biochemistry 
• 12-lead electrocardiogram (ECG) 
• Safety assessments scheduled for Day 1 (physical examination, ECOG PS, and review of 
AEs and concomitant medication use) can be completed on Day –1 (not to be conducted 
in place of screening assessments) 
Day 1 of Cycle 
 
The following procedures will be performed on Day 1 prior to NC-6004 infusion in each 
treatment cycles unless otherwise specified: 
• Pregnancy test (serum or urine) on Day 1 of each cycle (at Cycle 1, serum or urine; test is 
not required on Day 1 of Cycle 1 if pregnancy test at screening was performed using 
serum) 
• Physical examination (if not performed on Day –1) 


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• Height, weight, and calculation of body surface area using the Mosteller formula 
(Mosteller 1987) 
• Vital sign measurements (For additional vital sign assessments following dosing, refer to 
Section 6.3.8.) 
• ECOG PS (if not performed on Day –1) 
• Disease assessment will be evaluated beginning in Cycle 3 and continuing through the 
remainder of the treatment cycles every 6 (±1) weeks (ie, every other cycle), and at the 
End-of-Treatment visit or until disease progression 
• Audiometry (only as clinically indicated) 
• Hematology and coagulation 
• Biochemistry 
• EORTC QLQ-C30 
• Part 1 only: Core MDASI or MDASI module specific for lung cancer (MDASI-LC) 
(Section 6.1.3) 
o MDASI-LC will only be performed by patients with NSCLC in Part 1 and 
will not be performed in Part 2 
• Nausea and vomiting patient diary completion (completed in all cycles in Part 1 and only 
for 2 cycles in Part 2 of the study) 
• 12-lead ECG (For additional ECGs following NC-6004 dosing, refer to Section 6.3.6.) 
• PK blood sample collection (For additional PK samples following dosing, refer to 
Section 6.2) 
• Adverse events (if not performed on Day –1) 
• Concomitant medication use (if not performed on Day –1) 
• Prophylactic administrations 


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Day 8 of Each Cycle 
 
The following procedures will be performed on Day 8 prior to gemcitabine infusion in each 
treatment cycle: 
• Vital signs 
• Hematology and coagulation 
• Biochemistry 
• EORTC QLQ-C30 
• Part 1 only: Core MDASI or MDASI-LC 
o MDASI-LC will only be performed by patients with NSCLC in Part 1 and 
will not be performed in Part 2 
• Nausea and vomiting patient diary completion (completed in all cycles in Part 1 and only 
for 2 cycles in Part 2 of the study) 
• 12-lead ECG (at Cycle 1 only, for additional ECGs following gemcitabine dosing refer to 
Section 6.3.6) 
• PK blood sample collection 
• Adverse events 
• Concomitant medication use 
Day 15 of Each Cycle (Part 1: required; Part 2: if clinically indicated) 
 
The following procedures will be performed on Day 15 in each treatment cycle: 
 
• Hematology and coagulation 
• Biochemistry 
• Nausea and vomiting patient diary completion (completed in all cycles in Part 1 and is 
not collected at Day 15 in Part 2 of the study) 
• PK blood sample collection (Cycles 1, 3, and 5 of Part 1 only) 


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• Adverse events 
• Concomitant medication use 
End-of-Treatment Visit 
 
The following procedures will be performed within 28 days after treatment discontinuation: 
 
• Pregnancy test (serum or urine) 
• Physical examination 
• Vital sign measurements 
• ECOG PS 
• Disease assessment if scan has not previously shown disease progression 
• Audiometry (only as clinically indicated) 
• Hematology and coagulation 
• Biochemistry 
• Urinalysis 
• EORTC QLQ-C30 
• Part 1 only: Core MDASI or MDASI-LC 
• 12-lead ECG 
• PK blood sample collection 
• Adverse events (All AEs will be followed until it meets criteria outlined in 
Section 6.3.2.6.) 
• Concomitant medication use 
Follow-Up 
 
Patients who complete treatment or discontinue treatment without disease progression will 
continue to be followed until disease progression with scans every 9 weeks. Following 


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disease progression, patients will be contacted by telephone every 12 (±1) weeks to collect 
the following data: 
• Survival 
• Adverse events (All AEs will be followed until resolution, Section 6.3.2.6) 
• New treatments (targeted therapy or chemotherapy used after study disease progression 
and treatment completion) 
 
3.1.1 Rationale of Study Design 
NC-6004 is a polymeric micelle containing cisplatin as an active moiety. The nanoparticle 
provides sustained release of the cisplatin and utilizes the enhanced permeability-retention 
effect to target the release of platinum to tumors. Synergistic effects of cisplatin and 
gemcitabine have been evaluated extensively in various types of tumor cell lines, including 
NSCLC cell lines, and nonclinical studies have demonstrated that, in tumors in which the 
combination of cisplatin and gemcitabine exhibit synergistic effects, the combined effects of 
NC-6004 and gemcitabine are synergistic. 
This study will determine the DLTs, MTD, and RPII of NC-6004 in combination with 
gemcitabine in patients with advanced solid tumors and first-line Stage IV squamous NSCLC, 
first-line advanced or metastatic biliary tract cancer, and first-line metastatic or locally 
advanced bladder cancer for use in future efficacy studies. The initial dose level in this study 
was selected as 60 mg/m2 based on the dose escalation and extension trial 
(Study NC-6004-002) where NC-6004 and gemcitabine were administered to Asian patients 
with pancreatic cancer. In Study NC-6004-002, the MTD and recommended dose of 
NC-6004 were determined to be 120 mg/m2 and 90 mg/m2, respectively, and the gemcitabine 
dose was 1000 mg/m2 × 2, one week apart, every 3 weeks for pancreatic cancer, whereas in 
the current study in the United States the gemcitabine dose is 1250 mg/m2 × 2, one week 
apart, every 3 weeks. Based upon these differences, as well as consideration of the 
differences in demographics between an Asian and a United States population, it is 
determined that the starting dose of NC-6004 in the current study should be one-half of the 
MTD and two-thirds the recommended dose determined in Study NC-6004-002. 
Dose escalation of subsequent cohorts will be performed at 15 mg/m2 increments to more 
precisely identify the actual MTD than has been performed in previous clinical trials. Dose 


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escalation in this study will follow an N-CRM which models the relationship between 
toxicities and dose level. This methodology allocates the fewest number of patients to doses 
with unacceptable toxicities and, based on our modeling, is better at identifying the correct 
MTD compared to a traditional 3 + 3 trial design. At any time, in the absence of an MTD 
from the N-CRM model, NanoCarrier can recommend a RPII dose less than or equal to the 
maximum administered dose based on efficacy, full safety, and/or PK data. 
The study will evaluate the safety and tolerability of NC-6004 in combination with 
gemcitabine in these patients by assessment of therapy-related AEs (particularly DLTs). 
These events are commonly associated with cisplatin therapy and the intent of this design is 
to assess the frequency of these events using nanoparticle technology in comparison to 
historical data of cisplatin therapy. The study will also evaluate tolerability by assessing the 
severity of nausea and incidence of vomiting, commonly associated with cisplatin therapy, 
using a patient diary designed specifically for this purpose. 
The study will also evaluate the activity of NC-6004 in combination with gemcitabine in 
terms of ORR, DCR, DOR, PFS, and OS. These are standard parameters for evaluating 
cancer chemotherapies. 
The EORTC QLQ-C30 will be used to evaluate QoL. The EORTC QLQ-C30 is a QoL 
questionnaire specific for cancer patients. It has been translated and validated into 
81 languages and has been used in more than 3000 studies worldwide. 
 
The MDASI is a multisymptom patient-reported outcome measure for clinical and research 
use. In Part 1 only, the MDASI will be used to evaluate symptoms related to QoL during 
treatment. The MDASI’s 13 core symptom items include those found to have the highest 
frequency and/or severity in patients with various cancers and treatment types. The MDASI 
has several advantages over other symptom-assessment scales in that it applies broadly 
across cancer types and treatments, is easy for patients to complete, includes items related to 
symptom interference with daily life, and it is easily translated into other languages. The 
MDASI-LC questionnaire is designed specifically for patients with lung cancer and will be 
used by patients with NSCLC in Part 1 of this study. 
This clinical trial will also assess the pharmacokinetics of NC-6004 in terms of micellar 
platinum and total platinum to determine the pharmacodynamic relationships for both of 
these forms of circulating platinum. 


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4 Patient Selection and Withdrawal Criteria 
4.1 
Selection of Study Population 
Approximately 209 patients (up to 49 patients in Part 1 and up to 160 patients in Part 2) will 
be enrolled in at least 20 sites in the United States and Europe. Patients will be assigned to a 
study treatment only if they meet all of the inclusion criteria and none of the exclusion 
criteria. 
 
4.1.1 Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in this study: 
 
1. Provide signed written informed consent prior to the initiation of any study-specific 
procedures. 
2. (Part 1 only) Have a histologically or cytologically confirmed diagnosis of advanced 
solid tumor that has relapsed or is refractory to standard curative or palliative therapy or 
has a contraindication to standard therapy. 
 
(Part 2 only) Cohort 1: Have histologically or cytologically confirmed diagnosis of 
Stage IV squamous NSCLC and have not received prior chemotherapy or immunotherapy 
for metastatic disease and are not known to be PD-L1 positive (known high PD-L1 
expression defined as Tumor Proportion Score [TPS] greater than or equal to 50%). 
Patients with known sensitizing mutation in the epidermal growth factor receptor (EGFR) 
gene or anaplastic lymphoma kinase (ALK) fusion oncogene must have received at least 
1 and up to 2 targeted therapies prior to enrollment. 
• 
A patient with stable, treated brain metastases is eligible, provided that 
there is no evidence of progression after treatment and the patient does not 
require corticosteroids, or, if the patient requires corticosteroid, has been 
receiving a stable dose of corticosteroids for at least 14 days prior to 
assignment to treatment. 
• 
Patients whose tumors are known to harbor an exon 19 deletion or 
exon 21 L858R EGFR mutation must have had intolerance or have 
progressed on at least 1 and up to 2 EGFR tyrosine kinase inhibitors. 


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• 
Patients whose tumors are known to harbor an ALK translocation must 
have had intolerance or have progressed on at least 1 and up to 2 ALK 
inhibitors. 
 
(Part 2 only) Cohort 2: Have histologically or cytologically confirmed diagnosis of 
nonresectable, recurrent, or metastatic biliary tract carcinoma (intrahepatic or 
extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary carcinoma) and have 
not received prior systemic anticancer therapy for advanced or metastatic disease. 
(Part 2 only) Cohort 3: Have histologically or cytologically confirmed diagnosis of 
metastatic or locally advanced TCC of the urinary tract (bladder, urethra, ureter, renal 
pelvis) (T3b-T4 N0 M0, Tany N1-N3 M0, or Tany Nany M1) and are not candidates for 
surgery. 
• 
Patients must not have received prior treatment with systemic anticancer 
therapy for metastatic or locally advanced urinary tract cancer. 
• 
Certain mixed histologies that are predominantly (>50%) TCC are eligible: 
squamous, adenocarcinoma, and undifferentiated. Mixed undifferentiated 
histology requires immunohistochemistry consistent with a TCC origin. 
Predominantly squamous or neuroendocrine tumors are excluded. 
 
3. Have measurable disease per RECIST version 1.1. 
 
4. Are males or females aged ≥18 years. 
 
5. Have an ECOG PS of 0 to 1, with the exception of patients in Part 2 (Cohort 3, unfit 
bladder cancer patients) who may have an ECOG PS of 2. 
6. Have adequate bone marrow reserve defined as: 
• 
Absolute neutrophil count of at least 1.5 × 109/L, 
• 
Platelet count of at least 100 × 109/L, and 
• 
Hemoglobin level of 10 g/dL (transfusion is allowed to achieve hemoglobin 
level of at least 10 g/dL). 


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7. Have adequate liver function defined as: 
• 
Total serum bilirubin <1.5 × upper limit of normal (ULN) and 
• 
Baseline alanine transaminase, and aspartate transaminase <2.0 × ULN or, 
in patients with documented hepatic metastasis <5.0 × ULN and 
• 
Serum albumin ≥3.5 g/dL 
 
8. Prothrombin time within normal limits 
 
9. In Part 1 and in Part 2 in Cohorts 1 and 2: have adequate renal function defined as a CrCl 
≥50 mL/min (calculated according to the formula of Cockcroft and Gault 1976) or serum 
creatinine <1.5 mg/dL. In Part 2, patients in Cohort 3 (bladder cancer) must have a CrCl 
of ≥30 mL/min. 
• 
Bladder cancer patients in Cohort 3 of Part 2 will be stratified by ≥30 to 
<60 mL/min and/or ECOG PS 2 and ≥60 mL/min and ECOG PS 0 to 1. If 
2 of 6 patients (or ≥33% at any point during the study) in the ≥30 to 
<60 mL/min group have a worsening of CrCl (ie, 50% reduction from 
baseline for 2 consecutive assessments, at least 1 week apart), then 
enrollment of patients with CrCl <60 mL/min will stop in the bladder 
cancer cohort. 
 
10. Have a negative pregnancy test result at screening (for females of childbearing potential; 
not applicable to patients who are unable to become pregnant, including those with 
bilateral oophorectomy and/or hysterectomy or postmenopausal [no menses for the 
previous 12 months]). The test must be performed within 1 week before Day 1 of 
treatment. 
11. Male patients must agree to use a condom during treatment and for 90 days after dosing. 
Male patients must agree not to donate sperm for 90 days after dosing. 
12. For women of childbearing potential*: are willing to follow 1 of the following effective 
methods of birth control from the time of study entry to 6 months after the last day of 
treatment: 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, or transdermal) 


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• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, or implantable) 
• 
Intrauterine devices 
 
• 
Intrauterine hormone-releasing system 
 
• 
Vasectomized partner who has received medical assessment of surgical success 
 
• 
Bilateral tubal occlusion 
 
• 
True sexual abstinence** 
 
*Patients not of childbearing potential include those who are surgically sterile or 
postmenopausal (no menses for the previous 12 months). For women not currently 
taking contraceptive methods at screening, low user-dependency contraceptive 
methods (eg, implantable progestogen-only hormonal contraception, intrauterine 
device, intrauterine hormone-releasing system, bilateral tubal occlusion, 
vasectomized partner) are recommended. 
**The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
 
13. Have reasonably recovered from preceding major surgery as judged by the investigator or 
have had no major surgery within 4 weeks prior to Day 1 treatment. 
4.1.2 Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
 
1. Have received prior platinum therapy in the past 3 months (Part 1) or 6 months in the 
adjuvant or neoadjuvant setting (Part 2). 
2. Have received prior cisplatin and gemcitabine concomitantly within the last 6 months or 
are refractory to cisplatin and gemcitabine. 
3. Are unable to receive platinum-based therapy due to previous toxicity. 


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4. Have unresolved toxicity from prior radiation, chemotherapy, or other targeted treatment, 
including investigational treatment, with the exception of alopecia and ≤Grade 1 
peripheral neuropathy according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.03 (National Cancer Institute 2010). 
Clinical judgment by the investigator is allowed to determine if Grade 1 fatigue at 
screening is residual toxicity from prior treatment or is a symptom of the patient’s general 
condition or disease. The investigator and Medical Monitor will discuss the eligibility of 
patients with baseline toxicity 
5. Have evidence suggesting pulmonary fibrosis or interstitial pneumonia. 
 
6. Have a history of thrombocytopenia with complications including hemorrhage or 
bleeding of ≥Grade 2 according to the NCI CTCAE version 4.03 that required medical 
intervention or have any hemolytic condition or coagulation disorders that would make 
participation unsafe in the opinion of the investigator. 
7. Have known hypersensitivity to platinum compounds or gemcitabine. 
 
8. Have uncontrolled diabetes or have hypertension requiring more than 3 medications for 
control of hypertension. 
9. Have known active hepatitis B (defined as a known positive hepatitis B surface antigen 
[HBsAg] result) or hepatitis C (defined by a known positive hepatitis C antibody result or 
known quantitative HCV RNA results greater than the lower limits of detection of the 
assay). 
10. Are pregnant or breast-feeding. 
 
11. Have signs or symptoms of organ failure, major chronic illnesses other than cancer, or 
any concomitant medical or social conditions that, in the opinion of the investigator, 
make it undesirable for the patient to participate in the study or that could jeopardize 
compliance with the protocol. 
12. Have pre-existing alcoholic liver injury or significant liver disease. 
 
13. Are regularly consuming alcohol within 6 months of Screening defined as an average 
weekly intake of >21 units (or an average daily intake of >3 units) for males or >14 units 
(or an average daily intake >2 units) for females. One unit is equivalent to 8 g of alcohol: 


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a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine, or 1 measure 
(25 mL) of spirits. 
14. Have experienced any of the following within the 6-month period prior to screening: 
angina pectoris, coronary artery disease or cerebrovascular accident, transient ischemic 
attack, cardiac failure with known ejection fraction less than 40%, or cardiac arrhythmia 
requiring medical therapy. 
15. Are unwilling or unable to comply with study procedures or are planning to take a 
vacation for 7 or more consecutive days during the treatment phase of the study without 
prior consent from the Medical Monitor. 
4.2 
Withdrawal of Patients From the Study 
The duration of the study for each patient is defined as the time from the date of signed 
written informed consent through the End-of-Treatment visit or until death. 
 
4.2.1 Reasons for Withdrawal/Discontinuation 
Patients may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or others at the study site. Every effort should be 
made to keep patients in the study. The reasons for patients not completing the study will be 
recorded. A patient may be withdrawn from the study for any of the following reasons: 
• Disease progression 
• Unacceptable toxicity experienced 
• Grade 4 liver enzyme elevation 
• Withdrawal of consent 
• Major protocol violation 
• Required treatment delay >14 days (except in case of potential patient benefit, which 
must be approved by the sponsor) 
• Symptoms or an intercurrent illness not consistent with the protocol requirements or that 
justifies withdrawal 


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• For Cohort 3 only, unfit bladder cancer patient (≥30 to <60 mL/min CrCl at screening) 
has a worsening of CrCl (ie, 50% reduction from baseline for 2 consecutive assessments, 
at least 1 week apart) 
• Lost to follow-up 
• Other (eg, pregnancy, development of contraindications of use of the study drug) 
• The investigator or sponsor determines it is in the best interest of the patient to 
discontinue the patient’s participation in the study. 
The investigator also will withdraw a patient if NanoCarrier terminates the study. Upon 
occurrence of a serious or intolerable AE, the investigator will confer with the sponsor. If a 
patient is discontinued because of an AE, then the event will be followed until it is resolved. 
 
4.2.2 Handling of Withdrawals 
Patients who discontinue study treatment or active participation in the study will no longer 
receive the study drug. When a patient withdraws from the study, the reason(s) for 
withdrawal shall be recorded by the investigator on the relevant page of the electronic case 
report form (eCRF). Whenever possible, all patients who discontinue study treatment or 
withdraw from the study prematurely will undergo all end-of-treatment assessments. Patients 
who fail to return for final assessments will be contacted by the site. Following a minimum 
of 2 documented unsuccessful telephone calls, a registered letter will be sent to the patient in 
a final attempt to ensure protocol compliance. 
It is vital to obtain follow-up data on any patient withdrawn because of an AE or serious AE 
(SAE). In every case, efforts must be made to undertake protocol-specified, safety, follow-up 
procedures. 
 
4.2.3 Replacements 
Patients in Part 1 who discontinue treatment without DLT before completion of the first cycle 
will be replaced. No other patients will be replaced. 


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5 Study Treatments 
5.1 
Method of Assigning Patients to Treatment Groups 
This is an open-label study that will be conducted in 2 parts. In both parts, NC-6004 will be 
administered as a 1-hour (+10-minute window) intravenous infusion on Day 1 of each cycle. 
Gemcitabine 1250 mg/m2 will be administered as a 30-minute intravenous infusion on Day 1 
of each cycle (after the administration of NC-6004) and on Day 8 of each cycle. The duration 
of each cycle will be 21 days. 
In Part 1, patients will be assigned to receive gemcitabine 1250 mg/m2 in combination with 
NC-6004 at doses of 60, 75, 90, 105, 120, 135, 150, 165, or 180 mg/m2 by the N-CRM model 
(as described in Section 6.3.1.2). 
In Part 2, all patients will receive the RPII dose (135 mg/m2) of NC-6004 identified in Part 1. 
Bladder cancer patients in Cohort 3 of Part 2 will be stratified by ≥30 to <60 mL/min and/or 
ECOG PS 2 (unfit) and ≥60 mL/min and ECOG PS 0 to 1 (fit). If 2 of 6 patients (or ≥33% at 
any point during the study) in the ≥30 to <60 mL/min group have a worsening of CrCl (ie, 
50% reduction from baseline for 2 consecutive assessments, at least 1 week apart), then 
enrollment of patients with CrCl <60 mL/min will stop in the bladder cancer cohort. 
 
5.2 
Prophylactic Treatments 
All patients will receive the following medications before administration of NC-6004 on 
Day 1 of each cycle: 
• Patients will be instructed to take 20 mg of dexamethasone orally at 12 hours and 6 hours 
before the start of NC-6004 infusion on Day 1 of each cycle. When necessary, 12 and 
6 hours before the first infusion may be defined as “immediately before sleeping” and 
“immediately after waking up.” 
• Patients will be given 50 mg of diphenhydramine hydrochloride intravenously 30 minutes 
before the start of the NC-6004 infusion on Day 1 of each cycle. 
• Patients will be given 50 mg of ranitidine intravenously or 20 mg famotidine 
intravenously 30 minutes before the start of NC-6004 infusion on Day 1 of each cycle. 


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• Pre-hydration will be administered over 1 to 3 hours, as outlined by institutional 
standards. A minimum of 1 L of 0.9% sodium chloride solution will be infused 
intravenously over 1 to 3 hours prior to NC-6004 administration, and a minimum of 
500 mL of 0.9% sodium chloride solution will be infused over 2 hours following 
NC-6004 administration. The 0.9% sodium chloride is changeable to 0.45% sodium 
chloride at investigator discretion based on the patient’s condition. When gemcitabine 
only is infused, hydration is not required. 
• At all cycles, 8 mEq (1 g) of magnesium sulfate will be added to the 1-L 0.9% sodium 
chloride pre-hydration regimen for all patients. Once a patient’s magnesium level drops 
to <1.8 mg/dL or <lower limit of normal (Grade 1 hypomagnesemia), the investigator 
may treat as clinically warranted by supplementing with oral and/or intravenous 
magnesium. 
• For 2 days after administration of NC-6004, dexamethasone 4 mg (twice per day) will be 
taken orally by all patients. 
Prophylactic antiemetic medications may be administered according to standard treatment 
center protocols for cisplatin-based treatments. The use of prophylactic growth factor support 
medications is also allowed according to ASCO guidelines (Smith et al 2006) and is 
encouraged in patients who have experienced myelosuppression on treatment and/or in 
patients at high risk for experiencing febrile neutropenia. 
 
5.3 
Treatments Administered 
The duration of each treatment cycle will be 21 days in both parts of the study. NC-6004 will 
be administered on Day 1 of each cycle as a 1-hour (+10-minute window) intravenous 
infusion. Note: NC-6004 nanoparticles degrade in the presence of chloride ions. 
Therefore, it is imperative that saline is never used as either a diluent for NC-6004 or to 
flush cannulas immediately before or immediately after the NC-6004 infusion. 
Gemcitabine 1250 mg/m2 will be administered as a 30-minute intravenous infusion on Day 1 
after the completion of the NC-6004 infusion and on Day 8 of each cycle. 
In Part 1 of the study, patients will receive treatment until disease progression. In Part 2 of 
the study, patients will receive treatment for 6 cycles (Cohorts 1 and 3) or 8 cycles (Cohort 2). 
Antiemetic medications may be administered according to standard treatment center 
protocols. The use of growth factor support medications is also allowed according to ASCO 
guidelines (Smith et al 2006) and is encouraged in patients who have experienced 


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myelosuppression on treatment and/or in patients at high risk for experiencing febrile 
neutropenia. 
The dose level may escalate to 75, 90, 105, 120, 135, 150, 165, 180, 195, 210, 225, or 
240 mg/m2 according to observations of DLTs and the dose-level toxicity relationship 
(Section 6.3.1.2). A full safety review of all AEs for all cycles as well as an optional PK 
analysis will be conducted by the investigators, the Medical Monitor, and NanoCarrier before 
increasing the NC-6004 dose beyond 240 mg/m2. 
In Part 1, cohorts will receive one of the following treatments shown in Table 5-1 as 
identified by the N-CRM model (as described in Section 6.3.1.2). 
Table 5-1 
Dose Level Cohorts 
 
Dose Level 
Day 1 of Each Cycle 
Day 8 of Each Cycle 
60 mg/m2 
60 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
75 mg/m2 
75 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
90 mg/m2 
90 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
105 mg/m2 
105 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
120 mg/m2 
120 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
135 mg/m2 
135 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
150 mg/m2 
150 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
165 mg/m2 
165 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
180 mg/m2, a 
180 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
195 mg/m2 
195 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
210 mg/m2 
210 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
225 mg/m2 
225 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
240 mg/m2 
240 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
a 
If no DLT is observed in the single-subject run-in phase at 180 mg/m2, the single-subject run-in 
phase will end and the next cohort will enroll 4 patients at 180 mg/m2. 


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In Part 2, on Day 1 of each cycle, all patients will receive NC-6004 at the RPII dose 
(135 mg/m2) identified in Part 1 and 1250 mg/m2 gemcitabine. On Day 8 of each cycle, all 
patients in Part 2 of the study will receive 1250 mg/m2 gemcitabine. 
 
5.4 
Dose Delays and Modifications 
The doses for NC-6004 and gemcitabine will be calculated in milligrams per square meter 
(mg/m2) at screening and will not be changed in subsequent cycles unless the patient’s body 
weight has increased or decreased by ≥10% from the patient’s weight measurement at 
screening. Any change in a patient’s weight by ≥10% during the study will require a 
recalculation of the doses of all study drugs (Note: This threshold should not be confused 
with a change in the patient’s body surface area [BSA] [m2]). Weight will be measured before 
treatments on Day 1 of each cycle, with calculation of BSA before dosing on Day 1 of each 
cycle (using the Mosteller formula [Mosteller 1987]). 
Patients experiencing significant toxicities must be immediately and permanently withdrawn 
from treatment with NC-6004 and gemcitabine as follows: 
• Any patient who experiences a Grade 3 or 4 hypersensitivity reaction during any cycle of 
treatment 
• Any patient who experiences 2 protocol-defined DLTs during treatment 
• Any patient who experiences a recurrent Grade 3 or 4 toxicity (recurrence of the same 
AE) after a dose reduction 
• Any patient who requires a dosing delay >14 days at any time during treatment (except in 
case of potential patient benefit, which must be approved by the sponsor) 
• Any patient who experiences a Grade 4 liver enzyme elevation 
 
5.4.1 NC-6004 Dose Delay and Modification 
During any treatment cycle, investigators should suspend further dosing with NC-6004 for up 
to 14 days after the scheduled dose in the event of a protocol-defined DLT or any Grade 4 
hematologic toxicity or Grade 3 or 4 nonhematologic toxicity that is possibly, probably, or 
definitely related to NC-6004 (excluding alopecia and Grade 3 nausea, vomiting, diarrhea, 
and electrolyte imbalances lasting less than 48 hours or with suboptimal prophylactic and 


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suboptimal curative treatment). Any patient experiencing a Grade 3 liver enzyme elevation 
should have their next dose of NC-6004 suspended until improvement to Grade 1 or lower. 
At the discretion of the investigator, the dose may also be delayed for up to 14 days for any 
toxicity possibly or probably related to NC-6004 that does not meet DLT criteria. A delay of 
more than 14 days will require the patient to be removed from the study (except in case of 
potential patient benefit, which must be approved by the sponsor). The toxicity for which the 
dose was suspended must have improved to Grade 1 or lower prior to NC-6004 infusion. 
Following recovery to Grade 1 or lower, treatment may resume at the investigator’s 
discretion. Patients who resume treatment following a dose delay will have the dose of study 
drug reduced by 50% for the remainder of study treatment. If toxicities persist or recur to 
Grade 3 or 4 (recurrence of the same AE) after the dose reduction, study treatment will be 
terminated. 
 
5.4.2 Gemcitabine Dose Delay and Modification 
For gemcitabine, investigators should withhold (for up to 14 days of the scheduled dose) or 
reduce (by 50%) the gemcitabine dose in the event of any Grade 3 or 4 nonhematologic 
toxicity that is possibly, probably, or definitely related to gemcitabine (excluding alopecia, 
nausea, and vomiting) until it is resolved to Grade 1 or lower prior to gemcitabine infusion. 
Once resolved, the dose can be reinstated at the full-dose level. Any patient who experiences 
any unexplained dyspnea or other evidence of severe pulmonary toxicity, severe hepatic 
toxicity, hemolytic-uremic syndrome, or capillary leak syndrome during any cycle of 
treatment must immediately and permanently discontinue treatment with gemcitabine. 
For hematologic toxicities, the recommended dose reductions for gemcitabine are shown in 
the following table: 
 
Absolute Granulocyte Count 
(× 106/L) 
Platelet Count 
(× 106/L) 
% of Full Dose 
≥1000 
And 
≥100 000 
100 
500-999 
Or 
50 000-99 999 
75 
<500 
Or 
<50 000 
hold 


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5.5 
Identity of Investigational Product 
NanoCarrier will provide NC-6004 to PPD, Inc (PPD) and PPD will distribute adequate 
supplies of NC-6004 to the study sites. 
The following drug supplies will be used in the study: 
 
Product 
Supplied As: 
NC-6004 
5-mL solution of drug product in a vial (equivalent of 50 mg cisplatin) 
Gemcitabine 
200 mg vial for injection or 1 g vial for injection 
 
5.5.1 NC-6004 Drug Product 
NC-6004 stock solution defined as the drug substance is colorless or pale yellow, clear 
solution with no visible contaminants. The mean diameter of a micellar nanoparticle is 
approximately 30 nm. The number of cisplatin residues in a micellar nanoparticle is 
approximately 720. 
NC-6004 is a sterile formulation containing cisplatin-incorporated micellar nanoparticles, 
derived from the α-(methoxy-ω-aminopropyl, polyethylene glycol)-block-poly(sodium 
L-glutamate) copolymer, also written as polyethylene glycol-polyglutamate copolymer, 
(PEG-pGlu) and cisplatin. It is provided preformulated in amber vials containing 5 mL of 
NC-6004 formulation containing the equivalent of 50 mg cisplatin. 
Each vial of NC-6004 drug product contains 32.5 mg of platinum (corresponding to 50 mg of 
cisplatin), 250 mg of D-mannitol to adjust tonicity, and water for injection. 
Saline must not be used for any dilution of the NC-6004 or for flushing infusion lines 
immediately before or immediately after NC-6004 administration because cisplatin is 
released easily from the micelle in the chloride-rich environment. After the administration 
of premedications, NC-6004 should be mixed with 500 mL of 5% dextrose solution for 
intravenous infusion. If necessary, NC-6004 may be diluted in 5% dextrose prior to the 
preparation of final infusion 500 mL. 


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5.5.2 Gemcitabine Drug Product 
Gemzar® (gemcitabine for injection, USP), is available in sterile single-use vials individually 
packaged in a carton containing: 200 mg white to off-white, lyophilized powder in a 
10-mL size sterile single-use vial or 1 g white to off-white, lyophilized powder in a 
50-mL size sterile single-use vial. Vials of gemcitabine contain either 200 mg or 1 g of 
gemcitabine hydrochloride (expressed as free base) formulated with mannitol (200 mg or 1 g, 
respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized 
powder. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. 
 
5.6 
Management of Clinical Supplies 
5.6.1 Study Drug Packaging and Storage 
NC-6004 will be prepared in vials and shipped by PPD. 
 
All study drugs must be stored in a secure area (eg, a locked cabinet). NC-6004 should be 
protected from light and stored refrigerated (2° to 8°C). Unopened vials of gemcitabine are 
stable until the expiration date indicated on the package when stored at controlled room 
temperature 20° to 25°C that allows for excursions between 15° and 30°C. 
 
5.6.2 Test Article Accountability 
The investigator will maintain accurate records of receipt of all test articles that are centrally 
provided, including dates of receipt. In addition, accurate records will be kept regarding 
when and how much test article is dispensed and used by each patient in the study. Reasons 
for departure from the expected dispensing regimen must also be recorded. At the completion 
of the study, to satisfy regulatory requirements regarding drug accountability, all study drugs 
will be reconciled and retained or destroyed according to applicable regulations. 
 
5.7 
Overdose Management 
An overdose is any dose of study treatment given to a patient or taken by a patient that 
exceeds the dose described in the protocol. Any overdose, with or without associated AEs, 
must be promptly reported to the PPD Drug Safety Center. Overdoses without signs or 


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symptoms do not need to be recorded as AEs; in case of any AEs associated with the 
overdose, these should be reported on relevant AE or SAE sections in the eCRF. 
 
5.7.1 Treatment of Overdose 
There is no clinically proven antidote available for NC-6004. The expected manifestations of 
overdose are likely to be an exaggerated form of the adverse drug reactions anticipated with 
the administration of the drug. Therefore, patients should be carefully monitored for signs of 
immunosuppression. Symptomatic treatment and standard supportive care measures for the 
management of this toxicity should be applied. 
 
5.8 
Prophylaxis and Management of Hypersensitivity Reactions 
All patients must receive the following prophylactic treatment at each cycle to reduce the risk 
of hypersensitivity reactions: 
• Dexamethasone 20 mg taken orally at 12 and 6 hours before the infusion of NC-6004. 
When necessary, 12 and 6 hours before the infusion of NC-6004 may be defined as 
“immediately before sleeping” and “immediately after waking up.” 
• Diphenhydramine hydrochloride 50 mg and either ranitidine 50 mg or 20 mg famotidine 
will be administered intravenously 30 minutes before the infusion of NC-6004. 
• For 2 days after administration of NC-6004, dexamethasone 4 mg twice per day will be 
taken orally. 
If a Grade 1 or Grade 2 hypersensitivity occurs in a patient, the following medications should 
be administered for 48 hours after NC-6004 infusion: 
• Ranitidine 150 mg orally given 2 times per day or 40 mg famotidine orally given once 
per day 
• Diphenhydramine hydrochloride 50 mg orally given 3 times per day 
If a Grade 3 or higher hypersensitivity occurs, the patient should be discontinued from the 
study and must be treated immediately with hydrocortisone 20 mg administered 
intravenously and/or other appropriate medications. In these cases, patients must be carefully 
observed after the treatment. Additional therapy per institution standard of care should also 
be followed. 


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5.9 
Treatment Compliance 
Administration of the study treatments will be performed by the investigator or a qualified 
designee; therefore, compliance will be verified by the study drug administration information. 
 
5.10 
Prior, Concomitant, and Subsequent Therapy 
(Part 2 only) Cohort 1: For patients with Stage IV NSCLC, they may not have received prior 
chemotherapy or immunotherapy for metastatic disease. Patients with known sensitizing 
mutation in the EGFR gene or ALK fusion oncogene must have received at least 1 and up to 
2 targeted therapies prior to enrollment. If a patient with treated, stable brain metastases is 
otherwise eligible and requires corticosteroids, the patient must have been receiving a stable 
dose of corticosteroids for at least 14 days prior to assignment to treatment. Patients whose 
tumors are known to harbor an exon 19 deletion or exon 21 L858R EGFR mutation must 
have had intolerance or have progressed on at least 1 and up to 2 EGFR tyrosine kinase 
inhibitors. Patients whose tumors are known to harbor an ALK kinase translocation must 
have had intolerance or have progressed on at least 1 and up to 2 ALK inhibitors. Patients 
with eligible biliary tract carcinoma must not have received prior systemic anticancer therapy 
for advanced or metastatic disease. Patients with eligible TCC of the urinary tract must not 
have received prior treatment with systemic anticancer therapy for metastatic or locally 
advanced urinary tract cancer. 
All patients must receive prophylactic treatment at each cycle to reduce the risk of 
hypersensitivity reactions and nausea and/or vomiting (Section 5.8). 
The use of antiemetic medications according to the site’s standard of care is allowed. The use 
of prophylactic growth factor support medications is also allowed according to ASCO 
guidelines (Smith et al 2006) and is encouraged in patients who have experienced 
myelosuppression on treatment and/or in patients at high risk for experiencing febrile 
neutropenia. 
Use of all concomitant medications, including antiemetic medications and those required for 
administration before the infusion on Day 1 of each cycle, will be recorded in the patient’s 
eCRF. The minimum requirement is that drug name and the dates of administration are to be 
recorded. This will include all prescription drugs, herbal products, vitamins, minerals, and 


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over-the-counter medications. Any changes in concomitant medications will also be recorded 
in the patient’s eCRF. 
Any concomitant medication deemed necessary for the welfare of the patient during the 
study may be given at the discretion of the investigator. However, it is the responsibility of 
the investigator to ensure that details regarding the medication are recorded in full in the 
eCRF. 
 
5.11 
Prohibited Medications 
The following products should be avoided during study treatment with NC-6004 and for 
1 month following treatment due to known interactions with the released cisplatin. 
• Bacillus Calmette-Guerin 
• Clozapine 
• Natalizumab 
• Tacrolimus (Topical) 
• Tofacitinib 
• Live vaccines 
This list is not comprehensive and a physician or a pharmacist should evaluate other 
concomitant medications used during the trial. 


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6 Study Assessments and Procedures 
Before performing any study procedures, all potential patients will sign an informed consent 
form (ICF). Patients will have the opportunity to have any questions answered before signing 
the ICF. The investigator must address all questions raised by the patient. The investigator 
will also sign the ICF. 
The Schedule of Events is presented in Appendix 12.1. 
 
Disease assessment is to be performed within the 28 days prior to the start of study treatment. 
For patients with advanced solid tumors, disease assessment will be performed according to 
RECIST version 1.1. Patients who have obtained a response (PR or CR) will have a 
confirmatory scan at a minimum of 4 weeks following the initial scan. 
 
6.1 
Efficacy Assessments 
Efficacy assessments include disease response assessments, QoL assessments, and symptom 
changes assessments. Disease response assessments (Section 6.1.1) will occur every 6 weeks 
(±1 week), at the End-of-Treatment visit, and every 9 weeks after discontinuation or 
completion of treatment until disease progression. Quality of life will be assessed using the 
EORTC QLQ-C30 version 3 (Section 6.1.2) on Days 1 and 8 of each cycle and at the 
End-of-Treatment visit. Symptom changes will be assessed using the core MDASI (Part 1 
only) or MDASI-LC (only in patients with NSCLC in Part 1) (Section 6.1.3) on Days 1 and 8 
of each cycle and at the End-of-Treatment visit. A schedule of the efficacy assessments is 
provided in Appendix 12.1. 
 
6.1.1 Disease Response Definitions 
• ORR: Defined as percentage of patients with CR or PR assessed using RECIST 
version 1.1 
• DCR: Defined as the percentage of patients with CR, PR, or SD assessed using RECIST 
version 1.1 
• PFS: 
Defined as the time from the beginning of NC-6004 treatment until objective 
tumor progression or death assessed using RECIST version 1.1 
• OS: 
Defined as the time from the beginning of NC-6004 treatment until death or last 
contact 


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The rate of confirmed response and tumor growth control will be determined according to 
RECIST version 1.1 in solid tumor patients for patients evaluable for response using the 
following imaging methods: 
Timing 
 
Disease assessment will occur at Screening and every 6 weeks (±1 week) until disease 
progression. Patients who have obtained a response (PR or CR) will have a confirmatory 
scan at a minimum of 4 weeks following the initial scan. 
Anatomic Coverage 
 
Imaging should include a computed tomography scan of the chest, abdomen, and pelvis. In 
addition, areas of known predisposition for metastases (eg, the brain for NSCLC) and any 
areas identified by the clinician as probable sites of metastasis based on clinical evaluation 
should be included in imaging if clinically indicated. Other imaging may be performed at the 
investigator’s discretion as standard of care. 
Imaging Method 
 
The preferred method for imaging is computed tomography with IV contrast. If the patient is 
allergic to contrast media or has another medical contraindication, magnetic resonance 
imaging with contrast can be used at the clinician’s discretion. It is critical that the same 
method of imaging is used throughout the study for a given patient. 
Slice Thickness 
 
The preferred slice thickness is 5 mm. If a larger slice thickness is used (eg, 7 mm), the 
smallest tumor measurement that can be reported is twice the thickness of the slice. 
 
6.1.2 European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30 
The EORTC QLQ-C30 (version 3) is a questionnaire developed to assess the QoL of cancer 
patients (Appendix 12.2). It is a copyrighted instrument which has been translated and 
validated into 81 languages and is used in more than 3000 studies worldwide. The 
questionnaire for this study is supplemented by a disease-specific validated module for lung 


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cancer. The questionnaire will be administered by the site before study treatments on Days 1 
and 8 of each cycle and at the End-of-Treatment visit. 
 
6.1.3 MD Anderson Symptom Inventory 
The MDASI (Cleeland et al 2000) is a multisymptom patient-reported outcome measure for 
clinical and research use. The MDASI’s 13 core symptom items include those found to have 
the highest frequency and/or severity in patients with various cancers and treatment types. 
The MDASI has several advantages over other symptom-assessment scales in that it applies 
broadly across cancer types and treatments, is easy for patients to complete, includes items 
related to symptom interference with daily life, and it is easily translated into other languages. 
This study will use the core MDASI (Appendix 12.3) for all patients in Part 1 of the study 
except those patients with NSCLC. 
For patients with NSCLC in Part 1 only, a specific MDASI module designed for patients with 
lung cancer will be used, MDASI-LC (Appendix 12.3). The MDASI-LC is a site-specific 
module. Along with the core MDASI’s 13 symptom items and 6 interference items, the 
MDASI-LC also assesses 3 lung cancer-specific symptom items: coughing, constipation, and 
sore throat. 
The MDASI-LC module includes the following: 
 
• Purpose: To assess the severity of multiple lung cancer-related symptoms and the impact 
of these symptoms on daily functioning 
• Population: Patients with symptoms caused by lung cancer and its treatment 
• Assessment areas: Severity of multiple symptoms and the impact of symptoms on daily 
functioning during the last 24 hours 
• Time required: 5 minutes 
The core MDASI and the MDASI-LC will be administered as a self-report paper-and-pencil 
form given to the patient at the site before study treatments on Days 1 and 8 of each cycle in 
Part 1 only. 


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6.2 
Pharmacokinetic and Pharmacodynamic Assessments 
Pharmacokinetic samples will be collected and processed according to the instructions 
provided by the bioanalytical laboratory to the clinical sites. Pharmacokinetic samples will be 
analyzed according to the bioanalytical laboratory protocol. The concentration profiles of 
micellar platinum in plasma and total platinum in plasma and plasma ultrafiltrate (ie, free 
platinum) will be characterized. The concentration-versus-time profile will be determined in 
Part 1 and in Part 2. 
Pharmacokinetic plasma and plasma ultrafiltrate samples will be collected at the following 
times in Part 1: 
• Before the start of the NC-6004 infusion on Day 1 of Cycles 1 through 6 
• At the end of NC-6004 infusion in Cycles 1, 3, and 5 
• After the start of NC-6004 infusion at Hours 3, 6, 12, 24 (Day 2), 48 (Day 3), 96 (Day 5), 
168 (Day 8, prior to gemcitabine infusion), and 336 (Day 15) in Cycles 1, 3, and 5 
• At End-of-Treatment visit 
Pharmacokinetic plasma and plasma ultrafiltrate samples will be collected at the following 
times in Part 2 for up to 6 cycles: 
• Before the start of the NC-6004 infusion on Day 1 
• At the end of NC-6004 infusion 
• Before gemcitabine infusion on Day 8 
• At End-of-Treatment visit 
Additional PK blood sample collections may be performed, at the discretion of the 
investigator, during any visit where toxicity is observed. 
Pharmacokinetics blood sampling should occur within 10% of nominal time for Days 1 and 2, 
±4 hours of nominal time for all other time points, and should occur within 10 minutes after 
the 12-lead ECGs performance at time-matched visits (Section 6.3.6). All PK samples will be 
evaluable as long as the actual collection times are recorded. 


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Pharmacodynamics will be assessed based on Cmax (maximum concentration) values and 
nephrotoxicity as assessed by reports of AEs and from clinical laboratory data. 
 
6.3 
Safety and Tolerability Assessments 
Safety will be assessed using frequent collection of AE reports (Section 6.3.2) and clinical 
hematology and coagulation, biochemistry, and urinalysis test results (Section 6.3.5). 
Adverse events will be graded according to the NCI CTCAE version 4.03 (National Cancer 
Institute 2010). Additional safety assessments include, periodic 12-lead ECG recordings 
(Section 6.3.6), physical examination findings (Section 6.3.7), vital sign measurements 
(Section 6.3.8), ECOG PS (Section 6.3.9), and audiometry (Section 6.3.10). A schedule of the 
safety assessments is provided in Appendix 12.1. 
 
6.3.1 Dose-Limiting Toxicities and Dose Escalation Scheme 
6.3.1.1 Definition of Dose-Limiting Toxicities 
A DLT (monitored in Part 1 only) is defined as the following treatment-related AEs or 
laboratory abnormalities, graded according to the NCI CTCAE version 4.03: 
• Grade 3 or 4 febrile neutropenia or neutropenic infection 
• Grade 4 neutropenia of duration longer than 7 days and unresponsive to growth factor 
support per institutional guidelines or ASCO guidelines 
• Grade 4 thrombocytopenia 
• Grade 3 thrombocytopenia with clinically significant bleeding or Grade 3 
thrombocytopenia requiring a platelet transfusion 
• Grade 4 life-threatening anemia 
• Grade 3 or Grade 4 nonhematological toxicity (excluding alopecia and Grade 3 nausea, 
vomiting, diarrhea, and electrolyte imbalances lasting less than 48 hours or with 
suboptimal prophylactic and suboptimal curative treatment) 
• Grade 3 nausea, vomiting, diarrhea or electrolyte imbalances lasting greater than 48 hours 
despite optimal prophylactic and curative treatment 


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• Grade 4 vomiting, diarrhea, or electrolyte imbalances (life-threatening consequences) of 
any duration despite optimal prophylactic and curative treatment 
• ≥Grade 3 hypersensitivity reaction 
• Dosing delay >14 days due to toxicity 
 
6.3.1.2 Dose Escalation Scheme 
To determine the MTD of NC-6004, an adaptive approach using an N-CRM model based on 
the paper by Neuenschwander et al 2008 will be used. The standard dose selection in a 
Bayesian N-CRM model is based on point estimates for the probability of a DLT at each dose. 
The uncertainty of the probability estimate is ignored. When this uncertainty is high, the risk 
of overdosing can be unacceptably high. The N-CRM classifies the probability of a DLT into 
4 categories: 
• Under-dosing: p∈ (0, 0.20] 
• Targeted toxicity: p∈ (0.20, 0.33] 
• Excessive toxicity: p∈ (0.33, 0.60] 
• Unacceptable toxicity: p∈ (0.60, 1.00] 
The N-CRM is updated with the dose level and DLT status of each patient. Updates occur 
after each patient experiences a DLT or completes the first cycle in the single-patient run-in 
phase. In the remainder of Part 1, updates occur after all 4 patients enrolled in the most recent 
cohort either experience a DLT or complete the first cycle. Each time the N-CRM is updated, 
the posterior distribution of the probability of a DLT will be summarized for each dose for 
the 4 toxicity categories and the estimated dose-toxicity relationship curve is updated. The 
dose selection relies on maximizing the probability of targeted toxicity while controlling the 
probability of excessive or unacceptable toxicity to be no more than 25%. The interval 
between dose levels is prespecified (Table 3-1) and is not determined by the N-CRM 
algorithm. 
In the run-in phase, 1 patient will be enrolled sequentially at the following dose levels: 60, 75, 
90, 105, 120, 135, 150, 165, and 180 mg/m2 until a DLT is observed or until a patient is 
treated at 180 mg/m2 for 1 cycle without a DLT. During the run-in phase of Part 1, if no DLT 


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is observed at a dose level, the next patient will be enrolled at the next higher dose level. If a 
DLT is observed at the current dose level or if the current dose level of the run-in phase is 
180 mg/m2, the first cohort of 4 patients will be enrolled at the dose level with the greatest 
posterior probability of targeted toxicity that controls the posterior probability of excessive or 
unacceptable toxicity to be no more than 25%, given the run-in data. If no DLT is observed in 
the single-subject run-in phase at 180 mg/m2, the single-subject run-in phase will end and the 
next cohort will enroll 4 patients at 180 mg/m2. 
After each patient in each cohort of 4 patients either completes the first cycle or experiences 
a DLT, the next cohort of 4 patients will be enrolled at one of the following 3 dose levels, 
unless Part 1 of the trial is stopped: the next lower dose level, the current dose level, or the 
next higher dose level. When the current dose level is the lowest dose level, the next dose 
level is restricted to 2 levels: the current dose level and the next higher dose level. Similarly, 
when the current dose level is the highest dose level, the next dose level is restricted to the 
next lower dose level and the current dose level. Of the 2 or 3 possible next dose levels, the 
dose level with the greatest posterior probability of targeted toxicity that controls the 
posterior probability of excessive or unacceptable toxicity to be no more than 25%, given all 
of the data from Part 1 collected through the current cohort is selected for the next cohort. 
 
Part 1 of the trial will be stopped when: 
1. 10 cohorts are completed, or 
2. 2 cohorts are treated at the MTD, or 
3. No dose level controls the posterior probability of excessive or unacceptable toxicity to 
be no more than 25% 
The dose level with the greatest posterior probability of targeted toxicity that controls the 
posterior probability of excessive or unacceptable toxicity to be no more than 25% when 
Part 1 is stopped is identified as the MTD. 
It is important to note that Part 1 of the study will not be stopped during the single-patient 
run-in phase, even if the first patient enrolled experiences a DLT. At least 2 cohorts of 
4 patients each must be enrolled in order to stop Part 1. Finally, Part 1 will not be stopped for 
any reason other than 10 cohorts completing unless at least 2 DLTs are observed. It is 
therefore possible that more than 2 cohorts are dosed at a single dose level. 


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More conservative dose escalation, evaluation of intermediate doses, and expansion of an 
existing dose level are all permissible following discussions between the sponsor and the 
investigators, if such measures are needed for patient safety or for a better understanding of 
the dose–related toxicity, exposure, or pharmacodynamics of NC-6004. 
After determination of the MTD, patients who are in cohorts receiving a lower dose of 
NC-6004 will continue at the previously assigned dose. 
 
6.3.1.2.1 
Safety Monitoring in Part 2 
During Part 2 of the study, patients treated with NC-6004 at the RPII dose from Part 1 will be 
monitored for safety. Dose delay and modification rules for both NC-6004 and gemcitabine 
apply in Part 2 as in Part 1. 
In Part 2 (Cohort 3), if 2 of 6 patients (or ≥33% at any point during the study) in the ≥30 to 
<60 mL/min group have a worsening of CrCl (ie, 50% reduction from baseline for 
2 consecutive assessments, at least 1 week apart), then enrollment of patients with CrCl 
<60 mL/min will stop in the bladder cancer cohort. In addition, in Part 2 (Cohort 3), if an 
unfit bladder cancer patient (≥30 to <60 mL/min CrCl at screening) has a worsening of CrCl 
(ie, 50% reduction from baseline for 2 consecutive assessments, at least 1 week apart) he or 
she may be withdrawn from the study (Section 4.2.1). 
NC-6004-related Grade 3 or higher related AEs (excluding toxicities related to the underlying 
disease, alopecia and Grade 3 peripheral neuropathy) resulting in study drug withdrawal prior 
to cycle 4 will be considered UTs. 
The cumulative UT incidence rate is defined as the number of patients experiencing at least 
one UT divided by the number of patients treated in Part 2 through the current date. The 
cumulative UT incidence rate will be updated monthly. If at any time in Part 2 after a 
minimum of 10 patients have been treated the cumulative UT incidence rate exceeds 30%, 
enrollment will be stopped pending a formal safety review by the sponsor, PPD Medical 
Monitor, and the investigators, who will ultimately decide whether to stop the trial. 


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6.3.2 Adverse Events 
6.3.2.1 Definitions of Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or their clinical significance. 
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to study drug. Patients will be instructed to contact the 
investigator at any time after randomization if any symptoms develop. 
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to 
study drug or any event already present that worsens in either intensity or frequency after 
exposure to study drug. 
An SAE is defined as any event that results in death, is immediately life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, or is a congenital anomaly/birth defect. Hospitalization for 
elective procedures or for protocol compliance is not considered an SAE. Important medical 
events that may not result in death, be life threatening, or require hospitalization may be 
considered SAEs when, based upon appropriate medical judgment, they may jeopardize the 
patient or may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
 
6.3.2.2 Eliciting and Documenting Adverse Events 
Adverse events will be assessed from the time the patient signs the ICF until 30 days after the 
last dose of study drug. 
Serious AEs that occur more than 30 days after the last dose of study drug need not be 
reported unless the investigator considers them related to study drug. 
At every study visit, patients will be asked a standard nonleading question to elicit any 
medically related changes in their well-being. They also will be asked if they have been 


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hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and over-the-counter medications). 
In addition to patient observations, AEs will be documented from any data collected on the 
AE page of the eCRF (eg, laboratory values, physical examination findings, ECG changes) or 
identified from review of other documents (eg, patient diaries) that are relevant to patient 
safety. 
 
6.3.2.3 Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page of the eCRF. 
Information to be collected includes drug treatment, dose, event terminology, date of onset, 
NCI CTCAE version 4.03 assessment of severity and relationship to study drug, date of 
resolution of the event, seriousness, any required treatment or evaluations, and outcome. 
With the exception of disease progression, adverse events resulting from concurrent illnesses, 
reactions to concurrent illnesses, and reactions to concurrent medications also must be 
reported. All AEs will be followed to adequate resolution (Section 6.3.2.6). The NCI CTCAE 
version 4.03 will be used to grade all AEs. The CTCAE includes 5 grades (1-5), with Grade 5 
being death. 
Any AE that meets SAE criteria (Section 6.3.2.1) must be reported to PPD immediately (ie, 
within 24 hours after the time site personnel first learn about the event). The event is reported 
via the electronic data capture (EDC) system where site personnel complete as much of the 
respective AE page (eCRF) as they are able. 
If the EDC system is unavailable, the AE information must be recorded on the manual SAE 
report form and immediately (ie, within 24 hours of awareness) sent to PPD by one of the 
following methods (refer to the “SAE Guidelines” document for WorldReach toll-free access 
numbers if necessary): 
 
Pharmacovigilance Department 
United States SAE Hotline: 
+1 800-201-8725 
United States SAE Fax line: 
+1 888-488-9697 
Europe SAE Hotline: +44 1223 374 240 (to be used for questions concerning SAEs) 
Europe SAE Fax line: +44 1223 374 102 (to be used for reporting SAEs) 


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Once the EDC system becomes available again, the site needs to transfer all data to the 
respective eCRF page of the patient. 
 
6.3.2.4 Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the patient’s 
daily activities. The intensity of the AE graded on a scale of 1 to 5 as follows: 
 
1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADLa 
3: 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
4: 
Life-threatening consequences; urgent intervention indicated 
5: 
Death related to AE 
a Instrumental activities of daily living (ADL) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
b Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterized 
as intermittent do not require documentation of onset and duration of each episode. 
 
6.3.2.5 Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug (combination of 
NC-6004 and gemcitabine) is part of the documentation process, but it is not a factor in 
determining what is or is not reported in the study. If there is any doubt as to whether a 
clinical observation is an AE, the event should be reported. 


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The relationship or association of the test article in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
 
Unrelated: 
This relationship suggests that there is no association between the study drug 
and the reported event. 
Possible: 
This relationship suggests that treatment with the study drug caused or 
contributed to the AE, ie, the event follows a reasonable temporal sequence 
from the time of drug administration or follows a known response pattern to the 
study drug, but could also have been produced by other factors. 
Probable: 
This relationship suggests that a reasonable temporal sequence of the event 
with drug administration exists and, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions to the drug 
or class of drugs, or judgment based on the investigator’s clinical experience, 
the association of the event with the study drug seems likely. The event 
disappears or decreases on cessation or reduction of the dose of study drug. 
Definite: 
This relationship suggests that a definite causal relationship exists between drug 
administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do 
not appear to explain the event. The event reappears or worsens if the study 
drug is re-administered. 
 
6.3.2.6 Follow-up of Patients Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page of the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the patient is considered to be stable. 
 
6.3.2.7 Management Guidelines for NC-6004-Related Liver Dysfunction 
At the onset of Grade 4 liver enzyme elevation, NC-6004 must be immediately and 
permanently discontinued. Patients should be referred promptly to a 
hepatologist/gastroenterologist/specialist to be further evaluated. Patients with Grade 4 liver 
enzyme elevation should have a physical examination performed and should be assessed for 
signs of fever, rash and jaundice. Liver function tests including serum transaminases, alkaline 


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phosphatase, γ-glutamyl transpeptidase, and total bilirubin (including direct and indirect), 
albumin choline esterase, total cholesterol, as well as hematological tests including 
prothrombin time (PT), PT/international normalized ratio (INR) and eosinophil count should 
be performed. Other testing including a serological test may be performed at the 
hepatologist/gastroenterologist/specialist’s discretion. Patients should then be monitored on a 
bi-weekly basis (or more frequent if indicated by the 
hepatologist/gastroenterologist/specialist) until improvement to Grade 2 or below and clinical 
stability. Section 5.4.1 provides details for management of Grade 3 liver enzyme elevation. 
 
6.3.3 Assessment of Nausea and Vomiting 
Before dosing on Day 1 of Cycle 1, the patient will rate the worst severity of their nausea and 
the number of emetic episodes (vomiting or retching) occurring over the last 24 hours. 
For Parts 1 and 2, each patient will be given a nausea and vomiting patient diary to take 
home. This diary will be used to record the severity of nausea and incidence of emetic 
episodes over the previous 24 hours daily on Days 2 through 21. The first 7 days of the diary 
will be recorded verbatim in the eCRF. The patient will be given the diary and instructed on 
how and when to complete the diary before discharge from the site on Day 1 of each cycle. 
Part 1: The investigator will collect the nausea and vomiting patient diary from each patient 
on Day 8 and Day 15 for Cycle 1. For all subsequent cycles, the investigator will collect 
diaries on Day 1 (prior to dosing to capture the last 7 days of the previous cycle), Day 8, and 
Day 15. The investigator will record the worst severity of the patient’s nausea and the total 
number of emetic episodes occurring over the previous 7 days in the eCRF for Day 8, Day 15, 
and Day 21. 
Part 2: The investigator will collect the nausea and vomiting patient diary from each patient 
at the site on Day 8 for Cycle 1. For Cycle 2, the investigator will collect diaries on Day 1 
(prior to dosing to capture the last 7 days of the previous cycle) and Day 8. Note that nausea 
and vomiting patient diaries will not be collected past Cycle 2. The investigator will record 
the worst severity of the patient’s nausea and the total number of emetic episodes occurring 
over the previous 7 days in the eCRF for Day 8 and Day 21. 


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Nausea will be rated on the following scale of 0 to 3: 
 
0 None (no nausea) 
 
1 Loss of appetite with change in eating habits 
 
2 Less eating and drinking than normal but without much weight loss 
 
3 Not able to eat food or drink, or tube feedings are given, or hospitalization is required 
for treatment of nausea 
 
6.3.4 Pregnancy 
Pregnancy is not regarded as an adverse event unless there is a suspicion that an 
investigational product may have interfered with the effectiveness of a contraceptive 
medication. Any pregnancy that occurs during study participation must be reported using a 
clinical study pregnancy form. To ensure patient safety, each pregnancy must be reported to 
PPD as described for reported SAEs in Section 6.3.2.3 within 2 weeks of learning of its 
occurrence. The pregnancy must be followed-up to determine outcome (including 
spontaneous miscarriage, elective termination, normal birth, or congenital abnormality) and 
status of mother and child, even if the patient was discontinued from the study. Pregnancy 
complications and elective terminations for medical reasons should not be reported as an AE 
or SAE. Spontaneous miscarriages must be reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the investigator’s attention 
after the patient has completed the study and considered by the investigator as possibly 
related to the study treatment must be promptly reported to PPD (Section 6.3.2.3). 
 
6.3.5 Clinical Laboratory Analyses 
Samples for hematology and coagulation, biochemistry, and urinalysis will be collected at the 
time points specified in Appendix 12.1, Schedule of Events. All samples for clinical 
laboratory analyses will be collected according to standard procedures. 
Only abnormal laboratory test results (hematology and coagulation, biochemistry, or 
urinalysis) that are deemed clinically significant by the PI will be recorded as AEs or SAEs 
per the NCI CTCAE version 4.03. 


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6.3.5.1 Hematology and Coagulation 
Hematology will include hemoglobin, reticulocytes, red blood cell count, differential white 
blood cell count, and platelets. Coagulation will include prothrombin time and international 
normalized ratio. Hematology and coagulation tests will be performed during the screening 
period on Day -7 to -1, prior to dosing on Day 1 of Cycle 1 (if they were last performed more 
than 24 hours before the start of the study drug administration), weekly at each study visit 
prior to any treatments, and at the End-of-Treatment visit. 
 
6.3.5.2 Biochemistry 
Biochemistry will include alanine aminotransferase, aspartate aminotransferase, 
gamma-glutamyl transferase, alkaline phosphatase, total bilirubin, sodium, potassium, 
calcium, magnesium, urea, creatinine, CrCl (calculated using the Cockcroft and Gault 1976 
formula), total protein, albumin, and lactate dehydrogenase. Biochemistry tests will be 
performed during the screening period on Day -7 to -1, prior to dosing on Day 1 of Cycle 1 
(if they were last performed more than 24 hours before the start of the study drug 
administration), weekly at each study visit prior to any treatments, and at the 
End-of-Treatment visit. 
 
6.3.5.3 Urinalysis 
Urinalysis will be performed and will include: leukocyte esterase, nitrite, urobilinogen, 
protein, pH, blood, specific gravity, ketones, bilirubin, and glucose. Urinalysis will be 
performed during the screening period on Day -14 to -1 and at the End-of-Treatment visit. 
 
6.3.6 Electrocardiograms 
All 12-lead ECGs will be performed after the patient has adequately rested in the supine 
position. 
A 12-lead ECG will be performed during the screening period at Day -7 to -1. On Day 1 of 
Cycle 1, 12-lead ECGs will be performed before the start of the NC-6004 infusion, at 
completion of infusion (~1 hour after start of infusion), and at Hours 3 and 24 hours (Day 2) 
after start of infusion. On Day 8 of Cycle 1, 12-lead ECGs will be performed before the start 
of gemcitabine infusion, at the completion of gemcitabine infusion, and at 1 hour after 


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completion of gemcitabine infusion. Twelve-lead ECGs will also be performed on Day 1 of 
Cycles 2 through 6 before the start of the NC-6004 infusion and at the End-of-Treatment visit. 
All 12-lead ECGs should be performed within a ±30-minute window. 
Any assessments, including those that worsen from baseline, believed to be clinically 
significant in the medical and scientific judgment of the investigator are to be recorded as 
AEs or SAEs per the NCI CTCAE version 4.03. 
 
6.3.7 Physical Examination 
A complete physical examination will be performed during the screening period at Day -14 
to -1, before study treatments on Day –1 or Day 1 of each cycle, and at the End-of-Treatment 
visit. Height and weight will also be assessed at the time of the screening period physical 
examination and before treatments on Day 1 of each cycle. Calculation of BSA will be done 
before each dosing on Day 1 of each cycle (using the Mosteller formula [Mosteller 1987]. 
(Note: Dose will only be recalculated if there is a ≥10% increase or decrease in the patient’s 
weight from the patient’s weight measurement at screening. Any change in a patient’s weight 
by ≥10% during the study will require a recalculation of the doses of all study drugs. This 
threshold should not be confused with a change in the patient’s BSA [m2]). 
Any abnormal assessments, including those that worsen from baseline, are to be recorded as 
AEs or SAEs as per the NCI CTCAE version 4.03. 
 
6.3.8 Vital Sign Measurements 
Vital sign measurements will include arterial blood pressure, heart rate, respiratory rate, and 
temperature. Vital signs will be measured after the patient has adequately rested in the supine 
position. 
Vital signs will be measured during the screening period on Day -14 to -1. On Day 1 of 
Cycle 1, vital signs will be measured before the start of the NC-6004 infusion, every 
20 minutes during the infusion, at the completion of the infusion, and 1 hour after the 
completion of the NC-6004 infusion. Starting in Cycle 2, vital signs will be measured before 
the start of the NC-6004 infusion and at the completion of the NC-6004 infusion on Day 1 of 
each cycle. Vital signs will be measured before and after gemcitabine infusion on Day 8 of 
each cycle. Vital signs will also be measured at the End-of-Treatment visit. 


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Any abnormal assessments, including those that worsen from baseline, are to be recorded as 
AEs or SAEs as per the NCI CTCAE version 4.03. 
 
6.3.9 Eastern Cooperative Oncology Group Performance Status 
The patient’s PS will be assessed during the screening period on Day -14 to -1 and before 
dosing on Day –1 or Day 1 of each cycle using the ECOG PS grades (Oken et al 1982) 
below: 
0 
Fully active, able to carry on all predisease performance without restriction 
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, eg, light 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 
 
6.3.10 Audiometry 
Audiometry will be performed to assess for ototoxicity during the screening period at 
Day -14 to -1. On Day 1 of each cycle prior to study treatments and at the End-of-Treatment 
visit, audiometry will be performed only as clinically indicated. 
Any abnormal assessments, including those that worsen from baseline, are to be recorded as 
AEs or SAEs per the NCI CTCAE version 4.03. 


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7 Statistical and Analytical Plan 
7.1 
Safety Endpoints 
The safety endpoints for this study are the incidence and severity of AEs and laboratory 
abnormalities, according to the NCI CTCAE version 4.03, the occurrence of SAEs and 
treatment discontinuations due to AEs, and nausea severity and vomiting incidence obtained 
from the patient diary. 
 
7.2 
Exploratory Endpoints 
The exploratory endpoints of this study include exploratory safety endpoints of the 
occurrence of AEs and SAEs after 6 cycles of treatment and the following PK endpoints for 
micellar platinum in plasma and total platinum in plasma and plasma ultrafiltrate calculated 
for all patients using noncompartmental analysis: 
 
• Cmax (maximum concentration) 
• Tmax (time to maximum concentration) 
• AUClast (area under the concentration-time curve from time zero to the last quantifiable 
concentration) 
• AUC0-τ (area under the concentration-time curve from time zero to the end of the dosing 
interval) 
• AUC0-∞ (area under the concentration-time curve from time zero to infinity) 
• AI (accumulation index) 
• Vss (volume of distribution at steady-state) 
• MRT (mean residence time) 
• λz (terminal elimination phase rate constant) 
• T½ (terminal half-life) 
• CL (clearance) 
• Vz (volume of distribution) 
7.3 
Sample Size Calculations 
This is a Phase 1b/2 study with an overall sample size of up to 209 patients (up to 49 patients 
in Part 1 and up to 160 patients in Part 2). The total sample size will depend on the number of 


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cohorts required to establish an RPII dose and the number of patients with NSCLC enrolled 
at the RPII dose in Part 1. 
Simulations were performed assuming scenarios with different dose-toxicity relationships to 
evaluate the sample size for Part 1 (Phase 1b). The associated mean sample size in these 
scenarios ranged from 17.22 to 25.79 patients. 
Part 2 is a 3-cohort study with an overall sample size of up to 160 patients with no more than 
50 patients each in Cohorts 1 and 2 and no more than 60 patients in Cohort 3 (30 unfit and 
30 fit bladder cancer patients). The total sample size will depend on the results of interim 
futility and superiority analyses. In order to evaluate the overall sample size, simulations 
were performed assuming scenarios with different HRs for PFS for each cohort compared 
with historical control and different sample sizes for a subsequent Phase 3 clinical trial. The 
associated mean sample size for this trial in these scenarios ranged from 92.7 to 116.8 
patients. 
No formal efficacy analysis will be performed and no inference regarding efficacy will be 
drawn based on the response rate of the overall study. 
Patients who receive study drug will not be replaced. 
 
7.4 
Analysis Sets 
Four analysis sets will be used in this study: 
 
• The DLT-evaluable analysis set consists of all patients in Part 1 who either experience a 
DLT in the first cycle or complete the first cycle without a DLT. 
• The safety analysis set consists of all patients in Part 1 or Part 2 who receive study 
product. 
• The Full Analysis Set (FAS) consists of all patients treated at RPII dose in Part 1 or Part 2 
who receive study product. 
• The PK analysis set consists of all patients in the safety analysis set who have sufficient 
concentration data for PK analysis. 


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7.5 
Description of Subgroups to be Analyzed 
No subgroup analyses are planned. 
 
7.6 
Statistical Analysis Methodology 
Ninety-five percent confidence intervals may be calculated for selected safety and 
exploratory variables. Dose escalation will be based on N-CRM model and DLT incidence. 
Adverse events and SAEs will be tabulated by system organ class and preferred term. 
Laboratory test results after the first dose will be summarized with regard to shifts from 
baseline values and grade per NCI CTCAE version 4.03. Overall survival, PFS, and DOR 
will be summarized using Kaplan-Meier methods. Ninety-five percent confidence intervals 
for ORR and DCR will be constructed. All safety analyses will be performed on the safety 
analysis set. All efficacy analyses will be performed on the FAS. All summaries will present 
data by dose level, for patients with NSCLC dosed at the MTD, and overall. 
In Part 2, the following posterior probabilities will be derived using a Bayesian model 
updated every 6 weeks after 10 PFS have occurred within a cohort: 
• Probability (Promising HR) 
 
• Probability (Phase 3 Success) 
 
If any cohort at interim or final analyses has a probability (success in a Phase 3 trial with 
381 PFS events) >0.8, that indication will be declared a success, and the combination of 
NC-6004 and gemcitabine advances to a Phase 3 randomized, controlled trial with a sample 
size sufficient to observe 381 PFS events. 
 
7.6.1 Efficacy Analysis 
7.6.1.1 Progression–Free Survival 
Progression-free survival will be defined as the time from first dose of study product until the 
first date of either disease progression or death due to any cause and will be evaluated for 
each dose level and for all patients in the FAS. The date of disease progression will be 
defined as the earliest date of radiological disease progression as assessed by the investigator 
using RECIST version 1.1 or clinical disease progression. For patients who have not 


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progressed or died at the time of the analysis, censoring will be performed using the date of 
the last adequate disease assessment. In addition, patients with disease progression or death 
after an extended loss to follow-up will be censored at the date of the last adequate disease 
assessment prior to the extended loss to follow-up. Further details on censoring rules will be 
outlined in the statistical analysis plan (SAP). 
 
7.6.1.2 Overall Survival 
Overall survival will be defined as the time from first dose of study product until the date of 
death due to any cause and will be evaluated for each dose level and for all patients in the 
FAS. For patients who have not died at the time of the analysis, censoring will be performed 
using the date the patient was last known to be alive. Further details on censoring rules will 
be outlined in the SAP. 
 
7.6.1.3 Duration of Response 
Duration of response will be defined as the time from the earliest date of confirmed response 
until the first date of either disease progression or death due to any cause and will be 
evaluated for each dose level and for all patients in the FAS. The date of disease progression 
will be defined as the earliest date of radiological disease progression as assessed by the 
investigator using RECIST version 1.1, or clinical disease progression. For patients who have 
not progressed or died at the time of the analysis, censoring will be performed using the date 
of the last adequate disease assessment. In addition, patients with disease progression or 
death after an extended loss to follow-up will be censored at the date of the last adequate 
disease assessment prior to the extended loss to follow-up. Further details on censoring rules 
will be outlined in the SAP. 
 
7.6.1.4 Disease Control Rate 
Disease control rate is defined as the proportion of patients with best overall response of SD 
longer than 7 weeks, confirmed PR, or confirmed CR at the time each patient discontinues 
study treatment. 


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7.6.1.5 Overall Response Rate 
Overall response rate is defined as the proportion of patients with best overall response of 
confirmed PR or confirmed CR at the time each patient discontinues NC-6004 and 
gemcitabine. 
 
7.6.1.6 Quality of Life Analyses 
Quality of life will be assessed using the EORTC QLQ-C30. Analyses will be based on the 
FAS. 
Each of the 30 scores of the EORTC QLQ-C30, as well as the 5 functional scales (physical, 
role, emotional, cognitive, social), and 9 symptom scales (fatigue, nausea and vomiting, pain, 
dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) will be 
summarized by visit. Changes from baseline will be summarized by dose level, for all 
patients dosed at MTD (or RPII dose), and overall. 
The calculation of scores and methods to deal with missing data will be handled according to 
the respective questionnaires’ standard scoring guidelines. Full details of all the QoL analyses 
will be provided in the SAP. 
 
7.6.1.7 Symptoms Assessment Analyses 
The MDASI core 13 symptom items and 6 interference items plus the 3 lung cancer-specific 
symptom items (MDASI-LC) will be summarized by visit. Analyses will be based on the 
FAS. Changes from baseline will be summarized by dose level, for all patients with NSCLC 
dosed at MTD (or RPII dose), and overall. 
The calculation of scores and methods to deal with missing data will be handled according to 
the respective questionnaires’ standard scoring guidelines. Full details of all the QoL analyses 
will be provided in the SAP. 


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7.6.2 Safety Analyses 
7.6.2.1 Analyses of Adverse Events 
An AE will be considered to be a TEAE if it begins or worsens on or after first dose date and 
before last dose date + 28 days. The following summaries of TEAEs by system organ class 
and preferred term will be provided: 
• All TEAEs 
• All serious TEAEs 
• All treatment-related TEAEs 
• All treatment-related serious TEAEs 
• All TEAEs resulting in study drug discontinuation 
• All TEAEs by NCI CTCAE grade 
• All TEAEs by relationship to study drug 
 
 
The following summaries of TEAEs by preferred term will be provided: 
 
• TEAEs with at least 5% incidence in all patients 
• Treatment-related TEAEs with at least 5% incidence in all patients 
• TEAEs with at least 5% incidence in all patients with NSCLC dosed at the MTD or RPII 
dose 
• Treatment-related TEAEs with at least 5% incidence in all patients with NSCLC dosed at 
the MTD or RPII dose 
The incidence of deaths and the primary cause of death will be summarized. 
 
7.6.2.2 Severity of Nausea and Incidence of Vomiting 
The severity of nausea and incidence of vomiting as captured in the diary data will be 
summarized. 


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7.6.2.3 Clinical Laboratory Results 
Clinical hematology and coagulation, biochemistry, and urinalysis data will be summarized 
at each scheduled assessment. Numeric hematology and coagulation and biochemistry results 
will be summarized using change from baseline. All results will be summarized using shift 
from baseline. Shifts for laboratory results that are can be graded with NCI CTCAE version 
4.03 will be summarized by NCI CTCAE grade. Shifts for other numeric laboratory results 
will be by high/normal/low flag. Shifts for all other laboratory results will be by 
normal/abnormal flag. 
Summaries by visit will include data from scheduled assessments only, and all data will be 
reported according to the nominal visit date for which it was recorded (ie, no visit windows 
will be applied). Unscheduled data will be included in “worst case postbaseline” summaries 
which will capture a worst case across all scheduled and unscheduled visits after the first 
dose of study treatment. Further details will be provided in the SAP. 
Numeric clinical hematology and coagulation, biochemistry, and urinalysis results will be 
summarized using change from baseline. All results will be summarized using shift from 
baseline. 
 
7.6.2.4 Additional Safety Assessments 
The results of scheduled assessments of vital signs, ECOG PS, and 12-lead ECG will be 
summarized. Summaries by visit will include data from scheduled assessments only. All data 
will be reported according to the nominal visit date for which it was recorded (ie, no visit 
windows will be applied). Unscheduled data will be included in “worst case” summaries 
which will capture a worst case across all scheduled and unscheduled visits after the first 
dose of study treatment. All data will be listed. Further details will be provided in the SAP. 
7.6.3 Pharmacokinetic and Pharmacodynamic Analyses 
Noncompartmental analysis will be used to calculate the following PK parameters for total 
platinum in plasma and plasma ultrafiltrate: 
• Cmax 
• Tmax 
• AUClast 


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• AUC0-τ 
• AUC0-∞ 
• AI 
• Vss 
• MRT 
• λz 
• T½ 
• CL 
• Vz 
 
Data for PK parameters will be summarized in tables and individual data will be listed. 
 
7.6.4 Study Drug Exposure 
Study drug exposure will be summarized by dose level and overall for the safety analysis set. 
Duration of treatment and total number of cycles dosed will be summarized for 
combination therapy. Total dose received (mg) will be summarized for NC-6004 and 
gemcitabine separately. The number of patients dosed by cycle will also be summarized 
using frequency counts and percentages. 
Duration of treatment, in days, will be calculated as (date of last dose of study product – date 
of first dose of study product + 1). 
 
7.7 
Data Quality Assurance 
Steps to be taken to ensure the accuracy and reliability of data include the selection of a 
qualified investigator and appropriate study center, review of protocol procedures with the 
investigator and associated personnel before the study, and periodic monitoring visits by the 
clinical research associate (CRA). Written instructions will be provided for collection, 
preparation, and shipment of blood and plasma samples. 
The eCRFs will be provided to the clinical contact and the CRA will review them with site 
personnel. 
The CRA will review eCRFs for accuracy and completeness by remote monitoring, during 
on-site monitoring visits, and after transmission to the sponsor; any discrepancies will be 


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resolved with the investigator or designee, as appropriate. After entry of the data into the 
clinical study database they will be verified for accuracy. 
 
7.7.1 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the patients treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include laboratory reports, ECG strips, 
and patient diaries. 
Investigative site personnel will enter patient data into Medidata Rave. The analysis data sets 
will be a combination of these data and data from other sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable PPD standards 
and data cleaning procedures to ensure the integrity of the data (eg, removing errors and 
inconsistencies in the data). Adverse events will be coded using MedDRA version 16.0. 
Concomitant medications will be coded using WHO Drug Dictionary, version 01-Jun-2013. 
 
After database lock, each study site will receive a CDROM containing all of their site 
specific eCRF data as entered into Oracle Clinical Remote Data Capture for the study, 
including full discrepancy and audit history. Additionally, a CDROM copy of all of the study 
site’s data from the study will be created and sent to the sponsor for storage. PPD will 
maintain a duplicate CDROM copy for its records. In all cases, patient initials will not be 
collected or transmitted to the sponsor. 


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8 Ethics 
8.1 
Independent Ethics Committee or Institutional Review Board 
Federal regulations and the International Council for Harmonisation (ICH) guidelines require 
that approval be obtained from an institutional review board (IRB)/independent ethics 
committee (IEC) before participation of human patients in research studies. Before study 
onset, the protocol, informed consent, advertisements to be used for the recruitment of study 
patients, and any other written information regarding this study to be provided to the patient 
or the patient’s legal guardian must be approved by the IRB/IEC. Documentation of all 
IRB/IEC approvals and of the IRB/IEC compliance with ICH harmonised tripartite guideline 
E6(R1): Good Clinical Practice (GCP) will be maintained by the site and will be available for 
review by the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for obtaining continued review of the clinical research at 
intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The investigator must 
supply the sponsor or its designee with written documentation of continued review of the 
clinical research. 
 
8.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, and all applicable regulations. 
 
8.3 
Patient Information and Consent 
A written informed consent in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50 shall be obtained from each patient before entering the study or performing 
any unusual or nonroutine procedure that involves risk to the patient. An informed consent 
template may be provided by the sponsor to investigative sites. If any institution-specific 
modifications to study-related procedures are proposed or made by the site, the consent 
should be reviewed by the sponsor or its designee or both before IRB/IEC submission. Once 


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reviewed, the consent will be submitted by the investigator to his or her IRB/IEC for review 
and approval before the start of the study. If the ICF is revised during the course of the study, 
all active participating patients must sign the revised form. 
Before recruitment and enrollment, each prospective patient or his or her legal guardian will 
be given a full explanation of the study and be allowed to read the approved ICF. Once the 
investigator is assured that the patient/legal guardian understands the implications of 
participating in the study, the patient/legal guardian will be asked to give consent to 
participate in the study by signing the ICF. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the patient or legal guardian. 


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9 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC but will not result in protocol amendments. 
 
9.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the patient (or the patient’s legal guardian), except as necessary for monitoring 
and auditing by the sponsor, its designee, the Food and Drug Administration (FDA), or the 
IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
 
9.2 
Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 CFR 54. In addition, the investigator must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor PPD is financially responsible for 
further treatment of the patient’s disease. 


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9.3 
Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R1) 8.2 
and Title 21 of the CFR by providing the following essential documents, including but not 
limited to: 
• IRB/IEC approval. 
• Original investigator-signed investigator agreement page of the protocol. 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 1572. 
• Curriculum vitae for the investigator and each subinvestigator listed on Form FDA 1572 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under 21 CFR 54. In addition, the 
investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
• IRB/IEC-approved informed consent, samples of site advertisements for recruitment for 
this study, and any other written information regarding this study that is to be provided to 
the patient or legal guardian, 
 
9.4 
Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH 
E6(R1). The investigator will conduct all aspects of this study in accordance with all national, 
state, and local laws or regulations. Study information from this protocol will be posted on 
publicly available clinical trial registers before enrollment of patients begins. 
 
9.5 
Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R1) and all applicable guidelines and regulations. 


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9.6 
Adverse Events and Study Report Requirements 
By participating in this study the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in the protocol. In addition, the investigator agrees to 
submit annual reports to the study site IRB/IEC as appropriate. 
 
9.7 
Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/IEC with a summary of the 
study’s outcome and the sponsor and regulatory authority(ies) with any reports required. 
 
9.8 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
 
9.9 
Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The sponsor has final approval authority over all 
such issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 


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10 Study Management 
10.1 
Monitoring 
10.1.1 Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely. In doing so, the monitor will visit the investigator and study site at periodic intervals, 
in addition to maintaining necessary telephone and letter contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documentation, and discussion of the conduct of the study with the investigator and 
personnel. 
All aspects of the study will be carefully monitored by the sponsor or its designee for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
 
10.1.2 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the investigator agrees to allow the sponsor, representatives 
of the sponsor, or a regulatory agency access to all study records. 
The investigator should promptly notify the sponsor and PPD of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
 
10.2 
Management of Protocol Amendments and Deviations 
10.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the patient, must be reviewed and approved by the sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the investigator’s 
IRB/IEC for approval before patients can be enrolled into an amended protocol. 


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10.2.2 Protocol Violations and Deviations 
The investigator or designee must document and explain in the patient’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
patients without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review and approval, to the sponsor for agreement, 
and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
patient or investigator that results in a significant, additional risk to the patient. Significant 
deviations can include nonadherence to inclusion or exclusion criteria or nonadherence to 
FDA regulations or ICH GCP guidelines, and will lead to the patient being withdrawn from 
the study (Section 4.2). 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Principal investigators will be notified in writing by the monitor of 
deviations. The IRB/IEC should be notified of all protocol deviations in a timely manner. 
 
10.3 
Study Termination 
Although NanoCarrier has every intention of completing the study, NanoCarrier reserves the 
right to discontinue the study at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last patient completes the last visit to 
the study site (includes any End-of Treatment visit to the site and any visit to the site to 
obtain confirmatory scan of response). 
 
10.4 
Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 
the applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 


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reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
Upon completion of the clinical study report, the sponsor will provide the investigator with 
the full summary of the study results. The investigator is encouraged to share the summary 
results with the study patients, as appropriate. The study results will be posted on publicly 
available clinical trial registers. 


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11 Reference List 
Azzoli CG, Baker S, Temin S, et al. 2011 Focused Update of 2009 American Society Clinical 
Oncology clinical practice guideline update on chemotherapy for Stage IV non-small cell 
lung cancer. J Clin Oncol. 2011;29(28):3825-31. Full guideline published (2009) in J Clin 
Oncol. 2009;27(36):6251-66. 
Cleeland CS, Mendoza TR, Wang XS, et al. Assessing symptom distress in cancer: the M. D. 
Anderson Symptom Inventory. Cancer. 2000;89(7):1634-46. 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31–41. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. 
Hartmann JT, Lipp HP. Toxicity of platinum compounds. Expert Opin Pharmacother. 
2003;4(6):889-901. 
Kelland LR, Sharp SY. Platinum compounds in cancer therapy. Curr Opin Oncol, Endocrine, 
Metabolic Invest Drugs. 1999;1:380-5. 
Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer 
chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent 
smancs. Cancer Res. 1986;46:6387-92. 
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 
1987;317(17):1098. 
National Cancer Institute. Common terminology criteria for adverse events (CTCAE) Version 
4.0 (v4.03) 14 June 2010. Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Stat Med. 2008;27(13):2420-39. 


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Oken MM, Creech RH, Tormey, DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55 
Pinto AL, Lippard SJ. Binding of the antitumor drug cis-diamminedichloroplatinum(II) 
(Cisplatin) to DNA. Biochim Biophys Acta. 1985;780(3):167-80. 
Plummer R, Wilson RH, Calvert H, et al.) A phase I clinical study of cisplatin-incorporated 
polymeric micelles (NC-6004) in patients with solid tumours. Br J Cancer. 2011;104(4):593- 
8. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of 
white blood cell growth factors: An evidence-based clinical practice guideline. J Clin Oncol. 
2006;24(19):3187-205. 
Uchino H, Matsumura Y, Negishi T, et al. Cisplatin-incorporating polymeric micelles 
(NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats. Br J Cancer. 
2005;93(6):678-87. 


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12 Appendices 


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12.1 
Appendix: Schedule of Events 
Table 12-1 
Schedule of Events 
 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7 Onwarda 
End-of- 
Treatmentb 
Follow- 
upc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
2 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Informed consent 
X 
Eligibility criteria 
X 
Demography 
X 
Medical history 
X 
Pregnancy test 
(serum or urine) 
X 
Xe 
X 
X 
X 
X 
Physical 
examination 
Xf 
Xf 
X 
X 
X 
X 
Height, weight, and 
BSA calculationg 
Xg 
X 
X 
X 
X 
Vital signsh 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status 
(ECOG) 
Xf 
Xf 
X 
X 
X 
X 
Disease assessmenti 
X 
Xi 
Xi 
X 
X 
Audiometry 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Hematology and 
coagulation 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
EORTC QLQ-C30 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDASI or 
MDASI-LC l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Continued 


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Table 12-1 
Schedule of Events (Continued) 
 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7 Onwarda 
End-of- 
Treatmentb 
Follow- 
upc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
2 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Part 1: Nausea and 
vomiting patient 
diarym 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Part 2 Nausea and 
vomiting patient 
diarym 
X 
X 
X 
X 
Cardiac risk factors 
X 
12-lead ECGn 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic 
assessments 
(Part 1)o 
X 
Xo 
X 
X 
X 
X 
Xo 
Xo 
X 
Pharmacokinetic 
assessments 
(Part 2)p 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
Xf 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
Prophylactic 
administrations 
X 
X 
X 
X 
NC-6004 
administrationa 
X 
X 
X 
X 
Gemcitabine 
administration 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BSA, body surface area; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-C30, European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; MDASI, MD Anderson Symptom Inventory; RECIST, Response Evaluation Criteria in 
Solid Tumors; MDASI-LC, MDASI-lung cancer. 
a. 
In Part 1 of the study, patients will receive treatment until progressive disease. In Part 2 of the study, patients will receive treatment for 6 cycles (Cohorts 1 and 3) 
or 8 cycles (Cohort 2). 
b. 
End-of-treatment assessments will be performed within 28 days after treatment discontinuation. 


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c. 
After patient discontinuation or completion of treatment without disease progression, patients will be followed with scans every 9 weeks until disease progression. 
Patients will be called every 12 (±1) weeks to collect data on patient survival, new treatments, and adverse events. 
d. 
Day 15 visit is required in Part 1. In Part 2, Day 15 visit is only necessary if it is clinically indicated. 
e. 
Not required if screening pregnancy test was performed using serum. 
f. 
Safety assessments of physical examination, ECOG, review of adverse events, and concomitant medication use can be completed on Day -1 to allow for early 
morning dosing. These should not be conducted in place of screening assessments. 
g. 
From Day -14 to -1 at screening, only height and weight will be measured. On Day 1 of each cycle, weight will be measured before treatments and BSA will be 
calculated before each dose using the Mosteller formula (Mosteller 1987). (Note: Dose will only be recalculated if there is a ≥10% increase or decrease in the 
patient’s weight from the patient’s screening weight measurement. Any change in a patient’s weight by ≥10% during the study will require a recalculation of the 
doses of all study drugs. This threshold should not be confused with a change in the patient’s BSA [m2]). 
h. 
Vital signs will be performed after the patient has adequately rested in the supine position. On Day 1 of Cycle 1, vital signs will be measured before the start of the 
NC-6004 infusion, every 20 minutes during the infusion, at the completion of the infusion, and 1 hour after the completion of the NC-6004 infusion. Starting in 
Cycle 2, vital signs will be measured before the start of the NC-6004 infusion and at the completion of the NC-6004 infusion on Day 1 of each cycle. Vital signs 
will be measured before and after gemcitabine infusion on Day 8 of each cycle. Vital signs will also be measured at the End-of-Treatment visit. 
i. 
Disease assessment will be performed using RECIST version 1.1 and the same imaging method used at screening should be used for all subsequent assessments. 
Beginning in Cycle 3 and continuing through the remainder of the treatment cycles, disease will be assessed every 6 (±1) weeks (ie, every other cycle) and at the 
End-of-Treatment visit or until disease progression. Patients who have obtained a partial response or complete response will have a confirmatory scan at a 
minimum of 4 weeks following the initial scan. 
j. 
To be performed only as clinically indicated. 
k. 
Hematology and coagulation and biochemistry tests will be repeated prior to dosing on Day 1 of Cycle 1 if they were last performed more than 24 hours before 
the start of the study drug administration. 
l. 
Symptom changes will be assessed using the core MDASI (Part 1 only) or MDASI-LC (only in patients with NSCLC in Part 1). 
m. Part 1: The investigator will collect the nausea and vomiting patient diary from each patient on Day 8 and Day 15 for Cycle 1. For all subsequent cycles, the 
investigator will collect diaries on Day 1 (prior to dosing to capture the last 7 days of the previous cycle), Day 8, and Day 15. Part 2: The investigator will collect 
the nausea and vomiting patient diary from each patient at the site on Day 8 for Cycle 1. For Cycle 2, the investigator will collect diaries on Day 1 (prior to dosing 
to capture the last 7 days of the previous cycle) and Day 8. Note that nausea and vomiting patient diaries will not be collected past Cycle 2. For additional details, 
see Section 6.3.3. 
n. 
Twelve-lead ECGs will be performed after the patient has adequately rested in the supine position. A 12-lead ECG will be performed during the screening period 
at Day -7 to -1. On Day 1 of Cycle 1, 12-lead ECGs will be performed before the start of the NC-6004 infusion, at completion of infusion (~1 hour after start of 
infusion), and at Hours 3 and 24 (Day 2) after the start of infusion. On Day 8 of Cycle 1, 12-lead ECGs will be performed before the start of gemcitabine infusion, 
at the end of gemcitabine infusion, and at 1 hour after completion of gemcitabine infusion. Twelve-lead ECGs will be performed on Day 1 of Cycles 2 through 6 
before the start of the NC-6004 infusion, and at the End-of-Treatment visit. All 12-lead ECGs should be performed within a ±30-minute window. 
o. 
For Part 1, blood samples will be collected at the following times: before the start of the NC-6004 infusion on Day 1 of Cycles 1 through 6, at end of NC-6004 
infusion in Cycles 1, 3, and 5, after the start of NC-6004 infusion at Hours 3, 6, 12, 24 (Day 2), 48 (Day 3), 96 (Day 5), 168 (Day 8, prior to gemcitabine infusion), 
and 336 (Day 15) in Cycles 1, 3, and 5, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample collections may be performed, at the 
discretion of the investigator, during any visit where toxicity is observed. Blood samples will be collected within 10 minutes after the 12-lead ECGs performance. 
p. 
For Part 2 (up to 6 cycles), on the day of NC-6004 infusion for each cycle, blood samples will be collected before the start of the NC-6004 infusion, at the end of 
the NC-6004 infusion, before gemcitabine infusion on Day 8, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample collections may be 
performed, at the discretion of the investigator, during any visit where toxicity is observed. Blood samples will be collected within 10 minutes after the 12-lead 
ECGs performance. 


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12.2 
Appendix: European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire Core 30 
 
 


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12.3 
Appendix: MD Anderson Symptom Inventory–Lung Cancer 
Note: The core MDASI is the same as the MDASI-LC (shown below) with the exception that 
the core MDASI does not include questions 14, 15, and 16 of the MDASI-LC. 
 
 


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12.4 
Appendix: Protocol Amendments 
 
12.4.1 Protocol Amendment 1–Protocol Version 2.0, Incorporating 
Amendment 1, Dated 31 December 2014 
The following sections detail the changes made to the original protocol (Version 1.2) dated 
17 October 2013. The integrated protocol, Version 2.0, including Amendment 1, was issued 
on 31 December 2014. 
 
12.4.1.1 
Overview of Changes 
The overview of significant changes includes the following: 
 
Title Page – Sponsor; Protocol Approval – Sponsor Signatory 
 
The sponsor address was updated to the following: 
144-15 Chuo Gaiku, 226-39 Wakashiba Kashiwa 
Chiba, 277-0871, Japan 
Title Page – Sponsor Contact 
The sponsor contact telephone was updated to the following: 
+81-4-7197-7623 
Synopsis – Exclusion Criteria; Section 4.1.2 – Exclusion Criteria 
• Exclusion criterion #4 was updated to allow clinical judgment by the investigator to 
determine if Grade 1 fatigue at screening was residual toxicity from prior treatment or 
was a symptom of the patient’s general condition or disease. The investigator and 
Medical Monitor were to discuss the eligibility of patients with baseline toxicity. 
• Exclusion criterion #8 was updated to exclude patients who had hypertension requiring 
more than 3 medications for control of hypertension. 
• Exclusion criterion #11 was updated to exclude patients who experienced any of the of 
the listed cardiac conditions within the 6-month period prior to screening (angina pectoris, 
coronary artery disease, cerebrovascular accident, transient ischemic attack, cardiac 
failure with known ejection fraction less than 40%, or cardiac arrhythmia requiring 
medical therapy). Previously, any history was exclusionary regardless of how long ago it 
had occurred. 


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Synopsis - Study Design; Section 6.3.1.2 – Dose Escalation Scheme 
It was also added that in the run-in phase, 1 patient will be enrolled at the sequentially listed 
dose levels until either a DLT is observed or a patient is treated at 180 mg/m2 for 1 cycle 
without a DLT. 
Synopsis – Study Design; Synopsis – Study Drug, Dosage, and Route of Administration; 
Synopsis – Dose Escalation Design; Section 3.1 – Study Design; Table 3-1 - Dose Levels of 
NC-6004; Table 5-1 - Dose Level Cohorts; Section 6.2 - Pharmacokinetic and 
Pharmacodynamics Assessments; Section 6.3.1.2 – Dose Escalation Scheme 
The study design was updated to include that if no DLT was observed in the single-subject 
run-in phase at 180 mg/m2, the single-subject run-in phase would end and the next cohort 
would enroll 4 subjects at 180 mg/m2. 
Synopsis – Study Design; Synopsis – Estimated Study Duration; Section 3.1 - Study 
Design; Section 5.3 - Treatments Administered; Appendix 12.1 - Schedule of Events 
It was added that after completion of 4 to 6 cycles of treatment, individual patients could 
continue study drug, subject to sponsor approval, for an additional 4 to 6 cycles of treatment 
(up to a maximum of 10 total cycles) if they had clinical benefit, with monitoring the same as 
that in the treatment phase. 
Synopsis – Study Design; Section 3.1.1 – Rationale of Study Design 
It was added that at any time, in the absence of an MTD from the N-CRM model, 
NanoCarrier can recommend a recommended Phase 2 dose less than or equal to the 
maximum administered dose based on efficacy, safety, and/or PK data. 
Synopsis – Pharmacokinetic or Pharmacodynamic Assessments; 
Section 6.2 - Pharmacokinetic and Pharmacodynamic Assessments; 
Section 7.2 - Exploratory Endpoints; Section 7.6.3 – Pharmacokinetic and 
Pharmacodynamic Analyses; Appendix 12.1 - Schedule of Events 
Whole blood was removed from the PK assessments. Note: for the schedule of events table 
(footnotes “k” and “l”), “whole” was removed from “whole blood samples” to increase 
clarity. 
Synopsis – Safety Assessments; Section 6.3.8 – Vital Sign Measurements; 
Appendix 12.1 - Schedule of Events 
It was added that vital signs will be measured before NC-6004 infusion and at the completion 
of NC-6004 infusion in Cycles 2 through 6 (or up to 10). Previously, vital signs were only 
measured from Cycles 2 through 6. 


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Synopsis – Definition of a DLT; Section 6.3.1.1 - Definition of Dose-Limiting Toxicities 
The definition of 1 of the listed DLT criteria was expanded to include Grade 4 neutropenia of 
duration longer than 7 days and unresponsive to growth factor support per institutional 
guidelines or American Society of Clinical Oncology guidelines. 
Synopsis – Study Drug, Dosage, and Route of Administration; Synopsis – Dose Escalation 
Design; Table 3-1 - Dose Levels of NC-6004; Section 5.3 - Treatments Administered; 
Table 5-1 - Dose Level Cohorts 
The following potential dosage levels were added to the study: 195, 210, 225, and 240 mg/m2. 
Synopsis – Study Drug, Dosage, and Route of Administration; Table 3.1 – Dose Levels of 
NC-6004; Section 5.3 – Treatments Administered 
It was added that a full safety review of all AEs for all cycles as well as an optional PK 
analysis will be conducted by the investigators, the Medical Monitor, and NanoCarrier before 
increasing the NC-6004 dose beyond 240 mg/m2. 
Synopsis – Sample Size; Section 7.3 - Sample Size Calculation 
The description for sample size calculation was updated to provide further clarification. 
 
Section 3.1 - Study Design; Appendix 12.1 - Schedule of Events 
It was clarified in the study design that the patient’s signed informed consent can be obtained 
within 28 days of dosing and prior to performing any study evaluations. 
Synopsis – Safety Assessments; Section 3.1 - Study Design; Section 6.3.7 - Physical 
Examination; Section 6.3.9 – Eastern Cooperative Oncology Group Performance Status; 
Appendix 12.1 - Schedule of Events 
It was confirmed that safety assessments scheduled for Day 1 (physical examination, ECOG 
performance status, and review of AEs and concomitant medication use) can be completed on 
Day –1 to allow for early morning dosing. These should not be conducted in place of 
screening assessments. 
Section 5.2 – Prophylactic Treatment 
• Pre-hydration will be administered over 1 to 3 hours, as outlined by institutional 
standards. This change would increase the allowable window for the pre-hydration 
infusion time. 


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• The text for pre-hydration was updated to indicate that the 0.9% sodium chloride is 
changeable to 0.45% sodium chloride at investigator discretion based on the patient’s 
condition. 
• It was added that 8 mEq (1 g) of magnesium sulfate was to be added to the 
1-L 0.9% sodium chloride pre-hydration regimen for all patients at all cycles. Once a 
patient’s magnesium level dropped to <1.8 mg/dL or <lower limit of normal (Grade 1 
hypomagnesemia), the investigator could treat as clinically warranted by supplementing 
with oral and/or intravenous magnesium. 
Section 7.4 – Analysis Sets 
The definition of the Full Analysis Set was updated to include all patients treated at MTD in 
Part 1 or Part 2 who received study product. 
 
12.4.1.2 
Changes to the Protocol Text 
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. Additions to the protocol text are shown in bold and 
deletions are shown in strikethrough text. Minor or obvious editorial and grammatical 
corrections are not highlighted. 
Title Page – Sponsor 
 
Yaesu Yamagata Bldg, 3-2-2 Nihonbashi Chuo-ku, 
Tokyo 103-0027, Japan 
144-15 Chuo Gaiku, 226-39 Wakashiba Kashiwa 
Chiba, 277-0871, Japan 
 
Title Page – Sponsor Contact 
 
Telephone: +81-3-3548-02134-7197-7623 
 
Protocol Approval – Sponsor Signatory 
Yaesu Yamagata Bldg, 3-2-2 Nihonbashi Chuo-ku, 
Tokyo 103-0027, Japan 
144-15 Chuo Gaiku, 226-39 Wakashiba Kashiwa 
Chiba, 277-0871, Japan 


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Synopsis – Exclusion Criteria 
… 
 
4. Have unresolved toxicity from prior radiation, chemotherapy, or other targeted treatment, 
including investigational treatment, with the exception of alopecia and ≤Grade 1 
peripheral neuropathy according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events NCI CTCAE version 4.03. Clinical judgment by the 
investigator is allowed to determine if Grade 1 fatigue at screening is residual toxicity 
from prior treatment or is a symptom of the patient’s general condition or disease. 
The investigator and Medical Monitor will discuss the eligibility of patients with 
baseline toxicity. 
… 
 
8. Have uncontrolled diabetes or have hypertension requiring more than 23 medications for 
control of hypertension. 
… 
 
11. Have a history of experienced any of the following within the 6-month period prior to 
screening: angina pectoris, coronary artery disease or cerebrovascular accident, transient 
ischemic attack, cardiac failure with known ejection fraction less than 40%, or cardiac 
arrhythmia requiring medical therapy. 
 
Synopsis – Study Design 
 
… 
The dose-escalation part of the trial will begin with a single patient run-in phase. In the 
run-in phase, 1 patient will be enrolled sequentially at the following dose levels: 60, 75, 90, 
105, 120, 135, 150, 165, and 180 mg/m2 until a DLT is observed or until a patient is treated 
at 180 mg/m2 for 1 cycle without a DLT. During the single-subject run-in phase, after 
enrollment of the initial patient at 60 mg/m2, the first patient in each cohort will not be 
enrolled until the patient at the immediately lower cohort has completed at least 1 full cycle. 
A Bayesian continual-reassessment method per Neuenschwander et al 2008 (N-CRM) design 
will be used for dose escalation. The N-CRM will model the starting dose for the remainder 
of the escalation using the run-in data. For the remainder of Part 1 of the study, 4 patients will 


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be enrolled as a cohort at each dose level predicted by the N-CRM model. If no DLT is 
observed in the single-subject run-in phase at 180 mg/m2, the single-subject run-in 
phase will end and the next cohort will enroll 4 patients at 180 mg/m2. 
… 
 
Patients will continue to receive treatment until they experience disease progression, 
experience unacceptable toxicity (UT), withdraw voluntarily, or complete a maximum of 4 to 
6 10 total cycles of treatment (4 to 6 cycles followed by an additional 4 to 6 cycles, if they 
have clinical benefit), whichever occurs first. 
… 
 
At any time, in the absence of an MTD from the N-CRM model, NanoCarrier can 
recommend a recommended Phase 2 dose less than or equal to the maximum 
administered dose on efficacy, full safety, and/or pharmacokinetic (PK) data. 
… 
 
After completion of 4 to 6 cycles of treatment (or up to 10 cycles), patients will have an 
End-of-Treatment visit, will be followed with scans every 9 weeks until disease progression, 
and will be contacted for survival every 12 weeks by telephone. 
 
Synopsis – Estimated Study Duration 
 
The study will include a screening period (up to 28 days),; 4 to 6 treatment cycles, followed 
by an additional 4 to 6 cycles (up to a maximum of 10 total cycles) of treatment, that are 
21 days in duration,; tumor assessments for response and disease progression with scans 
every 6 weeks,; and telephone calls for survival every 12 weeks. 
Patients will receive study treatment until any of the following occur: 
 
• Disease progression or completion of 4 to 6 cycles of treatment (followed by an 
additional 4 to 6 cycles, up to a maximum of 10 total cycles if they have clinical 
benefit). 


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Synopsis – Pharmacokinetic or Pharmacodynamic Assessments 
 
The concentration-versus-time profile of micellar platinum in whole blood and plasma and of 
total platinum in plasma, whole blood, and plasma ultrafiltrate (ie, free platinum) will be 
determined in Part 1 and in Part 2. 
Part 1 Pharmacokinetic Time Points 
 
Pharmacokinetic plasma, whole blood, and plasma ultrafiltrate samples will be collected at 
the following times in Part 1: 
… 
 
Part 2 Pharmacokinetic Time Points 
 
Pharmacokinetic plasma, whole blood, and plasma ultrafiltrate will be collected at the 
following times in Part 2 for each cycle: 
 
Synopsis – Safety Assessments 
 
… 
 
Physical examinations will be performed and vital signs will be measured at Screening, 
before the start of treatment on Day 1 of each cycle (or can be completed on Day –1), and at 
the End-of Treatment visit. 
 
… 
 
In Cycles 2 through 6 (or up to 10), vital signs will be measured before before NC-6004 
infusion and at the completion of the NC-6004 infusion. 
 
Synopsis – Definition of DLT 
 
• Grade 4 neutropenia lasting > of duration longer than 7 days and unresponsive to 
growth factor support per institutional guidelines or American Society of 
Oncology guidelines. 


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Synopsis – Study Drug, Dosage, and Route of Administration 
 
The potential dosage levels of NC-6004 in this study include 60, 75, 90, 105, 120, 135, 150, 
165, and 180, 195, 210, 225, and 240 mg/m2. A full safety review of all AEs for all cycles 
as well as an optional PK analysis will be conducted by the investigators, the Medical 
Monitor, and NanoCarrier before increasing the NC-6004 dose beyond 240 mg/m2. 
Synopsis – Dose Escalation Design 
 
Sequential doses selected for evaluation are: 75, 90, 105, 120, 135, 150, 165, or 180, 195, 
210, 225, and 240 mg/m2. 
 
… 
 
If no DLT is observed in the single-subject run-in phase at 180 mg/m2, the single-subject 
run-in phase will end and the next cohort will enroll 4 patients at 180 mg/m2. 
Synopsis – Sample Size 
 
The design for Part 2 assumes p0 (the response rate for a poor drug) = 0.05, p1 (the response 
rate for a good drug) = 0.20, alpha = 0.05, and power = 80%. In the first stage of Part 2, 
testing will be performed on 10 patients, and if no patients respond at the second disease 
assessment the trial will be terminated. Any evidence of response, regardless of duration, will 
be counted as a response. If the trial continues into the second stage, a total of 36 patients 
will receive study drug. The 36 patients with NSCLC dosed at MTD will provide a 95% 
chance to detect at least 1 AE of interest with underlying 8% incidence rate. 
In order to provide a 95% chance to detect at least 1 AE of interest with underlying 
8% incidence rate among patients treated at MTD, additional patients with NSCLC 
will be enrolled at the MTD in Part 2 of the study. Patients will be enrolled in 2 stages 
until a total of 36 patients with NSCLC have been dosed at the MTD, including patients 
with NSCLC receiving the MTD level in Part 1. In the first stage of Part 2, ten patients 
treated at the MTD will be evaluated for response. If no patients respond, then the 
patients with NSCLC treated at a lower dose level than the MTD will be considered and 
a discussion of terminating the trial early will be triggered. Any evidence of response, 
regardless of duration, will be counted as a response. If at least 1 response is observed, 
the remaining 26 patients will be treated at the MTD. No formal efficacy analysis will 


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be performed and no inference regarding efficacy will be drawn based on the response 
rate of the overall study. 
Section 3.1 – Study Design 
 
Patients will be treated until disease progression or up to 610 cycles of therapy, whichever 
occurs first. After completion of 4 to 6 cycles of treatment, individual patients can 
continue study drug, subject to sponsor approval, for an additional 4 to 6 cycles of 
treatment (up to a maximum of 10 total cycles) if they have clinical benefit, with 
monitoring the same as that in the treatment phase. 
In both Part 1 and Part 2, patients will continue to receive treatment until they experience 
disease progression or for up to 610 treatment cycles, whichever occurs first. The maximum 
number of cycles a patient undergoes (4 to 6 cyclesup to 10 total cycles) is at the discretion 
of the investigator and depends on response as described in the ASCO guideline 
(Appendix 12.4) (Azzoli et al 2011). Patients who complete 4 or more cycles will be 
considered as having completed the treatment. Subject to sponsor approval, individual 
patients could continue study drug for an additional 4 to 6 cycles of treatment (up to a 
maximum of 10 total cycles) if they have clinical benefit, with monitoring the same as 
that in the treatment phase. 


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Section 3.1 – Study Design, Table 3-1 Dose Levels of NC-6004 
 
Table 3-1 
Dose Levels of NC-6004 
 
Dose Level Name 
NC-6004 Dose Level (mg/m2) 
1 
60 
2 
75 
3 
90 
4 
105 
5 
120 
6 
135 
7 
150 
8 
165 
9 
180a 
10 
195 
11 
210 
12 
225 
13 
240b 
a 
If no DLT is observed in the single-subject run-in phase at 180 mg/m2, the single-subject run-in phase 
will end and the next cohort will enroll 4 patients at 180 mg/m2. 
b 
A formal review by the safety committee will take place to decide if the dose can be increased beyond 
240 mg/m2. 
 
Section 3.1 – Study Design 
 
The N-CRM model will only be updated after all patients in a cohort have either experienced 
a DLT or completed the first cycle. If no DLT is observed in the single-subject run-in 
phase at 180 mg/m2, the single-subject run-in phase will end and the next cohort will 
enroll 4 patients at 180 mg/m2. 
… 
 
In both Part 1 and Part 2, patients will continue to receive treatment until they experience 
disease progression or for up to 610 treatment cycles, whichever occurs first. The maximum 
number of cycles a patient undergoes (4 to 6up to 10 total cycles) is at the discretion of the 
investigator and depends on response as described in the ASCO guideline (Appendix 12.4) 
(Azzoli et al 2011). Patients who complete 4 or more cycles will be considered as having 


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completed the treatment. Subject to sponsor approval, individual patients can continue 
study drug for an additional 4 to 6 cycles of treatment (up to a maximum of 10 total 
cycles) if they have clinical benefit, with monitoring the same as that in the treatment 
phase. 
After the completion of 4 to 6 cycles of treatment (or up to 10 cycles), patients will have an 
End-of-Treatment visit, will be followed with scans every 9 weeks until disease progression, 
and will be contaced for survival every 12 weeks by phone. 
… 
Screening Period (Day -28 to -1) 
The following procedures will be performed during the screening period within 28 days prior 
to the first study treatment : 
• Signed informed consent can be obtained within 28 days of dosing and prior to 
performing any study evaluations. 
Screening Period (Day -14 to -1) 
The following procedures will be performed during the screening period within 14 days prior 
to the first study treatment: 
• Signed informed consent obtained from the patient prior to performing any study 
evaluations 
… 
Screening Period (Day -7 to -1) 
… 
• Safety assessments scheduled for Day 1 (physical examination, ECOG performance 
status, and review of AEs and concomitant medication use) can be completed on 
Day-1 (not to be conducted in place of screening assessments). 
Day 1 of Cycle 
 
… 
 
• Physical examination (if not performed on Day –1) 
… 


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• ECOG performance status (if not performed on Day –1) 
… 
• Adverse events (if not performed on Day –1) 
• Concomitant medication use (if not performed on Day –1) 
 
Section 3.1.1 – Rationale of Study Design 
… 
 
At any time, in the absence of an MTD from the N-CRM model, NanoCarrier can 
recommend a recommended Phase 2 dose less than or equal to the maximum 
administered dose based on efficacy, full safety, and/or PK data. 
 
Section 4.1.2 – Exclusion Criteria 
 
4. Have unresolved toxicity from prior radiation, chemotherapy, or other targeted treatment, 
including investigational treatment, with the exception of alopecia and ≤Grade 1 
peripheral neuropathy according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.03 (National Cancer Institute 2010). 
Clinical judgment by the investigator is allowed to determine if Grade 1 fatigue at 
screening is residual toxicity from prior treatment or is a symptom of the patient’s 
general condition or disease. The investigator and Medical Monitor will discuss the 
eligibility of patients with baseline toxicity. 
… 
 
8. Have uncontrolled diabetes or have hypertension requiring more than 2 3 medications for 
control of hypertension. 
… 
 
11. Have a history of experienced any of the following within the 6-month period prior to 
screening: angina pectoris, coronary artery disease or cerebrovascular accident, transient 
ischemic attack, cardiac failure with known ejection fraction less than 40%, or cardiac 
arrhythmia requiring medical therapy. 


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Section 5.2 – Prophylactic Treatment 
… 
• Pre-hydration will be administered over 1 to 3 hours, as outlined by institutional 
standards. A minimum of 1 L of 0.9% sodium chloride solution will be infused 
intravenously over 21 to 3 hours prior to NC-6004 administration, and a minimum of 
500 mL of 0.9% sodium chloride solution will be infused over 2 hours following 
NC-6004 administration. The 0.9% sodium chloride is changeable to 0.45% sodium 
chloride at investigator discretion based on the patient’s condition. When 
gemcitabine only is infused, hydration is not required. 
• At all cycles, 8 mEq (1 g) of magnesium sulfate will be added to the 
1-L 0.9% sodium chloride pre-hydration regimen for all patients. Once a patient’s 
magnesium level drops to <1.8 mg/dL or <lower limit of normal (Grade 1 
hypomagnesemia), the investigator may treat as clinically warranted by 
supplementing with oral and/or intravenous magnesium. 
 
Section 5.3 - Treatments Administered 
 
… 
In each part of the study, patients will receive treatment for 4 to 6 cycles as directed in the 
ASCO guidelines (Appendix 12.4) or until disease progression, whichever occurs first. After 
the initial 4 to 6 cycles of treatment, individual patients can continue study drug, 
subject to sponsor approval, for an additional 4 to 6 cycles of treatment (up to a 
maximum of 10 total cycles) if they have clinical benefit, with monitoring the same as 
that in the treatment phase. Prophylactic antiemetic medications may be administered 
according to standard treatment center protocols. 
The dose level may escalate to 75, 90, 105, 120, 135, 150, 165, or 180, 195, 210, 225, or 
240 mg/m2 according to observations of DLTs and the dose-level toxicity relationship 
(Section 6.3.1.2). A full safety review of all AEs for all cycles as well as an optional PK 
analysis will be conducted by the investigators, the Medical Monitor, and NanoCarrier 
before increasing the NC-6004 dose beyond 240 mg/m2. 


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Section 5.3 - Treatments Administered, Table 5-1 Dose Level Cohorts 
 
… 
 
Dose Level 
Day 1 of Each Cycle 
Day 8 of Each Cycle 
60 mg/m2 
60 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
75 mg/m2 
75 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
90 mg/m2 
90 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
105 mg/m2 
105 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
120 mg/m2 
120 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
135 mg/m2 
135 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
150 mg/m2 
150 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
165 mg/m2 
165 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
180 mg/m2, a 
180 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
195 mg/m2 
195 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
210 mg/m2 
210 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
225 mg/m2 
225 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
240 mg/m2 
240 mg/m2 NC-6004; 
1250 mg/m2 gemcitabine 
1250 mg/m2 gemcitabine 
a 
If no DLT is observed in the single-subject run-in phase at 180 mg/m2, the 
single-subject run-in phase will end and the next cohort will enroll 4 patients at 
180 mg/m2. 


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Section 6.2 – Pharmacokinetic and Pharmacodynamic Assessments 
 
… 
Pharmacokinetic samples will be analyzed for concentrations of micellar platinum in whole 
blood and plasma and total platinum in plasma, whole blood, and plasma ultrafiltrate (ie, free 
platinum). The concentration versus time profile will be determined in Part 1 and in Part 2. 
Pharmacokinetic plasma, whole blood, and plasma ultrafiltrate samples will be collected at 
the following times in Part 1: 
… 
 
Pharmacokinetic plasma, whole blood, and plasma ultrafiltrate samples will be collected at 
the following times in Part 2 for each cycle: 
 
Section 6.3.1.1 – Definition of Dose-Limiting Toxicities 
 
… 
• Grade 4 neutropenia lasting > of duration longer than 7 days and unresponsive to 
growth factor support per institutional guidelines or ASCO guidelines 
Section 6.3.1.2 – Dose Escalation Scheme 
… 
In the run-in phase, 1 patient will be enrolled sequentially at the following dose levels: 
60, 75, 90, 105, 120, 135, 150, 165, and 180 mg/m2 until a DLT is observed or until a 
patient is treated at 180 mg/m2 for 1 cycle without a DLT. 
… 
 
If no DLT is observed in the single subject run-in phase at 180 mg/m2, the single-subject 
run-in phase will end and the next cohort will enroll 4 patients at 180 mg/m2. 


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Section 6.3.7 – Physical Examination 
A complete physical examination will be performed during the screening period at Day -14 
to -1, before study treatments on Day –1 or Day 1 of each cycle, and at the End-of-Treatment 
visit. 
Section 6.3.8 – Vital Sign Measurements 
… 
 
In Cycles 2 through 6 (or up to Cycle 10, if there is clinical benefit), vital signs will be 
measured before the start of the NC-6004 infusion and at the completion of the NC-6004 
infusion. 
Section 6.3.9 - Eastern Cooperative Oncology Group Performance Status 
The patient’s performance status will be assessed during the screening period on Day -14 
to -1 and before dosing on Day –1 or Day 1 of each cycle using the ECOG performance 
status grades (Oken et al 1982) below. 
Section 7.2 – Exploratory Endpoints 
The exploratory endpoints of this study include exploratory safety endpoints of the 
occurrence of AEs and SAEs after 4 to 6 cycles of treatment and the following PK endpoints 
for micellar platinum in whole blood and plasma and total platinum in plasma, whole blood, 
and plasma ultrafiltrate calculated for all patients using noncompartmental analysis: 
Section 7.3 – Sample Size Calculations 
… 
In Part 2 of the study, additional patients with NSCLC will be enrolled at the MTD until a 
total of 36 patients with NSCLC have been dosed at the MTD, including patients with 
NSCLC receiving the MTD dose level in Part 1. In order to provide a 95% chance to 
detect at least 1 AE of interest with an underlying 8% incidence rate among patients 
treated at MTD, additional patients with NSCLC will be enrolled at the MTD in Part 2 
of the study. Patients will be enrolled in 2 stages until a total of 36 patients with NSCLC 
have been dosed at the MTD, including patients with NSCLC receiving the MTD level 
in Part 1. In the first stage of Part 2, ten patients treated at the MTD will be evaluated 
for response. If no patients respond, then the patients with NSCLC treated at a lower 


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dose level than the MTD will be considered and a discussion of terminating the trial 
early will be triggered. Any evidence of response, regardless of duration, will be counted 
as a response. If at least 1 response if observed, the remaining 26 patients will be treated 
at the MTD. No formal efficacy analysis will be performed and no inference regarding 
efficacy will be drawn based on the response rate of the overall study. 
The design for Part 2 assumes p0 (the response rate for a poor drug) = 0.05, p1 (the response 
rate for a good drug) = 0.20, alpha = 0.05, and power = 80%. In the first stage of Part 2, 
testing will be performed on 10 patients. If no patients respond at the second disease 
assessment the trial will be terminated. Any evidence of response, regardless of duration, will 
be counted as a response. If the trial continues into the second stage, a total of 36 patients 
will receive study drug. 
Section 7.4 – Analysis Sets 
… 
• The Full Analysis Set (FAS) consists of all patients treated at MTD in Part 1 or Part 2 
who receive study product. 
Section 7.6.3 – Pharmacokinetic and Pharmacodynamic Analyses 
Noncompartmental analysis will be used to calculate the following PK parameters for total 
platinum in plasma, whole blood, and plasma ultrafiltrate: 


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12.1 Appendix: Schedule of Events 
 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycles 7-10a 
End-of- 
Treatmentab 
Follow- 
upbc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Informed consent 
X 
X 
Eligibility criteria 
X 
Demography 
X 
Medical history 
X 
Pregnancy test (serum or urine) 
X 
 
Xcd 
Physical examination 
Xe 
Xe 
X 
X 
X 
X 
Height, weight, and BSA calculation 
 
Xdf 
X 
X 
X 
X 
Vital signs 
X 
 
Xeg 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status (ECOG) 
Xe 
Xe 
X 
X 
X 
X 
Disease assessmentfh 
X 
 
Xfh 
Xh 
X 
X 
Audiometry 
X 
 
Xgi 
Xg 
 
Xgi 
Xi 
 
Xgi 
Hematology 
X 
 
Xhj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
 
Xhj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (dipstick) 
X 
X 
EORTC QLQ-C30 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDASI or MDASI-LC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nausea and vomiting patient diaryik 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac risk factors 
X 
12-lead ECGjl 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic assessments (Part 1)k 
X 
X 
X 
X 
X 
 
Xkm 
 
Xkm 
X 
Pharmacokinetic assessments (Part 2)ln 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
Xe 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prophylactic administrations 
X 
X 
X 
X 
NC-6004 administrationa 
X 
X 
X 
X 


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Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycles 7-10a 
End-of- 
Treatmentab 
Follow- 
upbc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Gemcitabine administration 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BSA, body surface area; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-C30, European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; MDASI, MD Anderson Symptom Inventory; RECIST, Response Evaluation 
Criteria in Solid Tumors; MDASI-LC, MDASI-lung cancer. 
a 
An optional extension of an additional 4 to 6 cycles of treatment (up to 10 cycles of treatment [including gemcitabine if the patient is tolerating 
NC-6004]) is allowed, with monitoring the same as that in the treatment phase of the protocol. 
ab End-of-treatment assessments will be performed within 28 days after treatment discontinuation. 
bc After patient discontinuation or completion of treatment without disease progression, patients will be followed with scans every 9 weeks until disease 
progression. Patients will be called every 12 (±1) weeks to collect data on patient survival, new treatments, and adverse events. 
cd  Not required if screening pregnancy test was performed using serum. 
e 
Safety assessments of physical examination, ECOG, review of AEs, and concomitant medication use can be completed on Day -1 to allow for early 
morning dosing. These should not be conducted in place of screening assessments. 
df  Height and weight only. 
eg On Day 1 of Cycle 1, vital signs will be measured before the start of the NC-6004 infusion, every 20 minutes during the infusion, at the completion of the 
infusion, and 1 hour after the completion of the NC-6004 infusion. In Cycles 2 through 610, vital signs will be measured before the start of the NC-6004 
infusion and at the completion of the NC-6004 infusion. Vital signs will be measured before and after gemcitabine infusion on Day 8 of each cycle. 
fh Disease assessment will be performed using RECIST version 1.1 and the same imaging method used at screening should be used for all subsequent 
assessments. Beginning in Cycle 3 and continuing through the remainder of the treatment cycles, disease will be assessed every 6 (±1) weeks (ie, every other 
cycle) and at the End-of-Treatment visit or until disease progression. Patients who have obtained a partial response or complete response will have a 
confirmatory scan at a minimum of 4 weeks following the initial scan. 
gi 
To be performed only as clinically indicated. 
hj Hematology or biochemistry tests will be repeated prior to dosing on Day 1 of Cycle 1 if they were last performed more than 24 hours before the start of the 
study drug administration. 
ik Diary issued on Day 1 of each cycle. Assessment is performed at the site before dosing on Days 1 and Day 8 as well as Day 15 (no dosing on Day 15) of 
each cycle. Patient completes diary at home on Days 2 through 8 and returns diary on Day 8. 
jl 
Twelve-lead ECGs will be performed after the patient has rested in the supine position for at least 5 minutes. On Day 1 of Cycle 1, 12-lead ECGs will be 
performed before the start of the NC-6004 infusion, at completion of infusion (~1 hour after start of infusion), and at Hours 3 and 24 (Day 2) after the start 
of infusion. On Day 8 of Cycle 1, 12-lead ECGs will be performed before the start of gemcitabine infusion, at the end of gemcitabine infusion, and at 1 hour 
after completion of gemcitabine infusion. Twelve-lead ECGs will be performed on Day 1 of Cycles 2 through 6 before the start of the NC-6004 infusion, and 
at the End-of-Treatment visit. 


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km For Part 1, whole blood samples will be collected at the following times: before the start of the NC-6004 infusion on Day 1 of Cycles 1 through 6, at end of 
NC-6004 infusion in Cycles 1, 3, and 5, after the start of NC-6004 infusion at Hours 3, 6, 12, 24 (Day 2), 48 (Day 3), 96 (Day 5), 168 and prior to 
gemcitabine infusion (Day 8), and 336 (Day 15) n in Cycles 1, 3, and 5, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample 
collections may be performed, at the discretion of the investigator, during any visit where toxicity is observed. 
ln For Part 2, on the day of NC-6004 infusion for each cycle, whole blood samples will be collected before the start of the NC-6004 infusion, at the end of the 
NC-6004 infusion, before gemcitabine infusion on Day 8, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample collections may be 
performed, at the discretion of the investigator, during any visit where toxicity is observed. 


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12.4.2 Protocol Amendment 2–Protocol Version 3.0, Incorporating 
Amendment 2, Dated 07 July 2015 
The following sections detail the changes made to Amendment 1 of the protocol 
(Version 2.0) dated 31 December 2014. The integrated protocol, Version 3.0, including 
Amendment 2, was issued on 07 July 2015. 
 
12.4.2.1 
Assessment of Risk Associated With Amendment 2 
The combination of gemcitabine and cisplatin has been used in chemo-naïve patients with 
bladder, biliary tract cancer, as well as NSCLC, and the toxicity profile was similar overall in 
the 3 diseases. Nonclinical data suggested that NC-6004 has the potential to be at least as 
active as cisplatin with less renal toxicity and neurotoxicity compared with cisplatin, and 
clinical data of the combination of gemcitabine and NC-6004 in recurrent NSCLC showed 
good activity with a manageable toxicity profile. Thus, the overall risk of this combination in 
chemo-naïve patients with bladder and biliary tract cancer would be similar to the known risk 
to NSCLC patients. 


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12.4.2.2 
Overview of Changes 
The overview of significant changes includes the following: 
 
Title Page – Title; Protocol Approval – Sponsor Signature – Study Title; Protocol 
Synopsis – Title 
The title was amended to capture the added indications. The previous title was “... in Patients 
with Advanced Solid Tumors or Non-Small Cell Lung Cancer” and the amended title is …“in 
Patients with Advanced Solid Tumors or Squamous Non-Small Cell Lung, Biliary Tract, and 
Bladder Cancer.” 
Title Page – Sponsor Contact; Protocol Approval – Sponsor Signatory – Protocol accepted 
and approved by 
Sponsor contact name was changed to Kazuhiro Takahashi, and his role and contact 
information were added as applicable. 
Title Page – Project Manager 
Project manager name and contact information were removed from the protocol. 
Protocol Synopsis – Indication; Section 1 – Introduction; Section 3.1.1 – Rationale of 
Study Design 
The indication for Part 2 was updated to first-line metastatic squamous NSCLC; first-line 
metastatic or locally advanced cholangiocarcinoma, gallbladder cancer, or ampullary cancer 
(biliary tract cancer); and first-line metastatic or locally advanced TCC of the urinary tract 
(bladder cancer). 
Protocol Synopsis – Rationale; Protocol Synopsis – Objectives; Protocol Synopsis – Study 
Design; Section 1 – Introduction; Section 2.1 – Primary Objectives; Section 3.1 – Study 
Design; Section 3.1.1 – Rationale of Study Design; Section 5.1 – Method of Assigning 
Patients to Treatment Groups; Section 5.3 – Treatments Administered; 
Section 6.3.1.2.1 - Safety Monitoring in Part 2; Section 7.3 – Sample Size Calculation; 
Section 7.4 – Analysis Sets; Section 7.6.1.6 – Quality of Life Analyses; 
Section 7.6.1.7 - Symptoms Assessment Analyses; Section 7.6.2.1 – Analyses of Adverse 
Events 
It was added that a recommended Phase 2 (RPII) dose would be established in the study in 
addition to the maximum-tolerated dose, which was previously stated. As applicable, the 
NC-6004 dose used in Phase 2 of the study was changed from the MTD to the RPII dose. 


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Protocol Synopsis – Objectives; Section 2.1 – Primary Objectives 
The second primary objective was amended to reflect the updated indications in Part 2 of 
first-line Stage IV squamous NSCLC, first-line advanced or metastatic biliary tract cancer, 
and first-line metastatic or locally advanced bladder cancer compared with historical control 
as measured by local investigator/radiologist-assessed PFS, according to RECIST version 1.1. 
Protocol Synopsis – Objectives; Section 2.2 – Secondary Objectives 
The DCR in the first secondary objective was defined as CR+PR+SD. A third secondary 
objective of “To evaluate the safety and tolerability of NC-6004 when combined with 
gemcitabine” was added. 
Protocol Synopsis – Patient Population, Inclusion Criteria; Section 4.1.1 – Inclusion 
Criteria 
Inclusion criterion 2 was updated to include new definitions for Part 2 cohorts. Cohort 1 will 
include Stage IV squamous NSCLC patients who did not receive prior chemotherapy for 
metastatic disease. It was added that patients with known sensitizing mutation in the EGFR 
gene or ALK fusion oncogene must have received at least 1 and up to 2 targeted therapies 
prior to enrollment. 
It was also clarified that for patients whose tumors are known to harbor an exon 19 deletion 
or an exon 21 L858R EGFR mutation that they must have had tolerance or have progressed 
on at least 1 and up to 2 EGFR tyrosine kinase inhibitors. 
It was also clarified that for patients whose tumors are known to harbor an ALK translocation 
that they must have had intolerance or have progressed on at least 1 and up to 2 ALK 
inhibitors. 
For Part 2, Cohort 2, patients had to have a histologically or cytologically confirmed 
diagnosis of nonresectable, recurrent, or metastatic biliary tract carcinoma (intrahepatic or 
extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary carcinoma) and have not 
received prior systemic anticancer therapy for advanced or metastatic disease. 
For Part 2, Cohort 3, patients had to have a histologically or cytologically confirmed 
diagnosis of metastatic or locally advanced TCC of the urinary tract (bladder, urethra, ureter, 
renal pelvis) (T3b-T4 N0 M0, Tany N1-N3 M0, or Tany Nany M1) and are not candidates for 
surgery. Patients must not have received prior treatment with systemic anticancer therapy for 
metastatic or locally advanced urinary tract cancer. In addition, certain mixed histologies that 
are predominantly (>50%) TCC are eligible: squamous, adenocarcinoma, and 
undifferentiated. Mixed undifferentiated histology requires immunohistochemistry consistent 
with a TCC origin. Predominantly squamous or neuroendocrine tumors are excluded. 


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Protocol Synopsis – Patient Population, Exclusion Criteria; Section 4.1.2 – Exclusion 
Criteria 
Exclusion criterion 1 was amended to exclude prior platinum therapy in the past 3 months for 
Part 1 of the study and in the past 6 months in the adjuvant or neoadjuvant setting for Part 2 
of the study. 
Protocol Synopsis – Study Design; Section 3.1 – Study Design 
Text was added to specify that the study design is adaptive. Dosing in Part 1 was amended 
such that patients will receive intravenous infusion of NC-6004 at escalating doses on Day 1 
in combination with gemcitabine at the fixed dose of 1250 mg/m2 on Days 1 and 8 of a 
21-day cycle. The duration of treatment for Part 1 was changed to until progressive disease or 
until the drug is no longer tolerated (whichever occurs first). The sponsor may agree to 
supply the drug after discussion of the request with the investigator. 
All patients in Part 2 will receive the RPII dose of NC-6004 in combination with gemcitabine 
1250 mg/m2 by the same regimen in Part 1. It was added that stage 2 will continue in each 
cohort after achieving the minimum threshold of clinical responses required and enroll up to 
50 patients in each cohort for a total of up to 150 patients in Part 2. The primary endpoint 
(PFS) will be continuously updated and compared with the historical PFS from Phase 3 
pivotal cisplatin and gemcitabine trials within each cohort. The PFS hazard model will be 
updated as PFS data accrue. A HR for PFS for each cohort versus historical control will be 
obtained. The historical median durations of PFS and PFS weekly hazard for each cohort 
were added. 
In addition, once 10 PFS events have been observed, interim analyses will be performed 
every 6 weeks. At each interim and at the final analysis, there are 3 possible outcomes for 
each cohort, which include futility, success, or inconclusive. Each out is defined. Phase 3 
success is defined as success in a Phase 3 clinical trail with 381 events – enough to provide 
80% power to detect an HR of 0.75. A promising HR is defined as one less than 0.85. Futility 
can only be declared for a cohort after 10 PFS events have been observed in that cohort. 
Success can only be declared for a cohort after 25 PFS events have been observed in that 
cohort. Accrual will stop for any cohort identified as futile or successful at interim. The 
conclusion of this Phase 2 trial will be that a Phase 3 trial with 381 events should be 
conducted for each cohort that is a success. 
Protocol Synopsis – Study Design; Protocol Synopsis – Sample Size; Section 3.1 – Study 
Design; Section 7.3 – Sample Size Calculations 
The Part 2 sample size was added to include up to 150 patients with no more than 50 patients 
per cohort. The method to determine the sample size was also added. 


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Protocol Synopsis – Study Design; Protocol Synopsis – Estimated Study Duration; 
Section 3.1 – Study Design; Table 12-1 Schedule of Events, footnote “a” 
The number of cycles of treatment in Part 2 was changed to 6 cycles (Cohorts 1 and 3) or 
8 cycles of treatment (Cohort 2). 
Protocol Synopsis – Efficacy Assessments; Section 3.1 – Study Design; 
Section 3.1.1 - Rationale of Study Design; Section 6.1 – Efficacy Assessments; 
Section 6.1.3 – MD Anderson Symptom Inventory; Table 12-1 Schedule of Events, 
footnote “l” 
It was clarified that MD Anderson Symptom Inventory-lung cancer (MDASI-LC) was to be 
conducted in Part 1 only. 
Protocol Synopsis – Pharmacokinetic or Pharmacodynamic Assessments; Section 6.2 – 
Pharmacokinetic and Pharmacodynamic Assessments; Table 12-1 Schedule of Events, 
footnote “p” 
For the Part 2 pharmacokinetic time points, it was added that plasma and ultrafiltrate will be 
collected for up to 6 cycles. 
Protocol Synopsis – Safety Assessments; Section 6.38 – Vital Sign Measurments; 
Table 12-1 Schedule of Events, footnote “h” 
It was clarified that vital signs will be measured before the NC-6004 infusion and at the 
completion of the NC-6004 infusion on Day 1 of each cycle starting in Cycle 2. 
Protocol Synopsis – Statistical Methods; Section 7.6 – Statistical Analysis Methodology 
Text was removed that stated that no statistical testing is planned for this study. The statistical 
methods for Part 2 were added and will include a Bayesian model updated every 6 weeks 
after 10 PFS have occurred within a cohort. 
Section 6.2 – Pharmacokinetic and Pharmacodynamic Assessments 
It was clarified that the concentration profiles of micellar platinum in plasma and total 
platinum in plasma and plasma ultrafiltrate will be characterized. 
Section 12.4 – Appendix: American Society of Clinical Oncology Guideline 
 
This appendix was removed. 
Section 12.4.2.1 – Assessment of Risk Associated With Amendment 2 
A assessment of the risk associated with Amendment 2 was added. 


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12.4.2.3 
Changes to the Protocol Text 
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. Additions to the protocol text are shown in bold and 
deletions are shown in strikethrough text. Minor or obvious editorial and grammatical 
corrections are not highlighted. 
Title Page – Title 
 
A Phase 1/b2 Dose Escalation and Expansion Trial of NC-6004 (Nanoparticle Cisplatin) plus 
Gemcitabine in Patients with Advanced Solid Tumors or Squamous Non-Small Cell Lung, 
Biliary Tract, and Bladder Cancer 
Title Page – Sponsor Contact 
 
Atsuhiro MasadaKazuhiro Takahashi 
Director of International Clinical Development 
NanoCarrier Co, Ltd 
Telephone: +81-4-7197-76233-3241-0551 
 
Title Page – Project Manager 
 
Project Manager: 
Cynthia Nelson 
Senior Project Manager, PPD Global Project Management 
PPD, Inc. 
Telephone: 317-473-1980 
 
Protocol Approval – Sponsor Signatory 
 
A Phase 1/b2 Dose Escalation and Expansion Trial of NC-6004 (Nanoparticle Cisplatin) plus 
Gemcitabine in Patients with Advanced Solid Tumors or Squamous Non-Small Cell Lung, 
Biliary Tract, and Bladder Cancer 
… 
 
Protocol accepted and approved by: 
 
Director of International Clinical Development 
Atsuhiro MasadaKazuhiro Takahashi 


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Protocol Synopsis – Title 
 
A Phase 1/b2 Dose Escalation and Expansion Trial of NC-6004 (Nanoparticle Cisplatin) plus 
Gemcitabine in Patients with Advanced Solid Tumors or Squamous Non-Small Cell Lung, 
Biliary Tract, and Bladder Cancer 
Protocol Synopsis – Study Sites 
 
Approximately 6 At least 20 sites in the United States 
 
Protocol Synopsis – Indication 
 
… 
 
Part 2: Relapsed non-small cell lung cancer (NSCLC) First-line metastatic squamous 
non-small cell lung cancer (NSCLC); first-line metastatic or locally advanced 
cholangiocarcinoma, gallbladder cancer, or ampullary cancer (biliary tract cancer); and 
first-line metastatic or locally advanced transitional cell carcinoma (TCC) of the 
urinary tract (bladder cancer) 
Protocol Synopsis – Rationale 
 
… 
 
This study will establish a maximum-tolerated dose (MTD) and recommended Phase 2 
(RPII) dose of NC-6004 in combination with gemcitabine and evaluate the initial activity 
and tolerability profile. 
Protocol Synopsis – Objectives 
 
The primary objectives of this study are: 
 
• In the dose-escalation phase of the study (Part 1), to determine the dose-limiting toxicities 
(DLTs), and MTD, and RPII dose of NC-6004 in combination with gemcitabine. 
• In the expansion phase of the study (Part 2), to evaluate the activity of NC-6004 in 
combination with gemcitabine in patients with first-line Stage IV squamous NSCLC, 
first-line advanced or metastatic biliary tract cancer, and first-line metastatic or 
locally advanced bladder cancer compared with historical control as measured by 


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local investigator/radiologist-assessed progression-free survival (PFS), according to 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1., safety, and 
tolerability of NC-6004 in combination with gemcitabine in patients with relapsed 
(second- or third line) squamous and nonsquamous Stage IIIB/IV NSCLC. 
The secondary objectives of this study are: 
 
• To evaluate overall response rate (ORR), disease control rate (DCR = complete response 
+ partial response + stable disease), duration of response (DOR), PFS, overall survival 
(OS) 
… 
 
• To evaluate the safety and tolerability of NC-6004 when combined with gemcitabine 
 
Protocol Synopsis – Patient Population: Inclusion Criteria 
 
… 
 
(Part 2 only) Cohort 1: Have histologically or cytologically confirmed diagnosis of 
Stage IIIB or IV squamous NSCLC and have not received 1 or 2 lines of prior 
chemotherapy or targeted therapy for Stage IIIB or IV NSCLC (second- or third-line). for 
metastatic disease. Patients with known sensitizing mutation in the epidermal growth 
factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) fusion oncogene 
must have received at least 1 and up to 2 targeted therapies prior to enrollment. 
… 
 
• Patients whose tumors are known to harbor an exon 19 deletion or exon 21 L858R EGFR 
mutation must have had intolerance or have progressed on or had intolerance to anat 
least 1 and up to 2 EGFR tyrosine kinase inhibitors. 
• Patients whose tumors are known to harbor an ALK translocation must have had 
intolerance or have progressed on or had intolerance to crizotinibat least 1 and up to 2 
ALK inhibitors. 
• 
(Part 2 only) Cohort 2: Have histologically or cytologically confirmed 
diagnosis of nonresectable, recurrent, or metastatic biliary tract carcinoma 


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(intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary 
carcinoma) and have not received prior systemic anticancer therapy for advanced or 
metastatic disease. 
• 
(Part 2 only) Cohort 3: Have histologically or cytologically confirmed 
diagnosis of metastatic or locally advanced TCC of the urinary tract (bladder, urethra, 
ureter, renal pelvis) (T3b-T4 N0 M0, Tany N1-N3 M0, or Tany Nany M1) and are not 
candidates for surgery. 
• Patients must not have received prior treatment with systemic anticancer therapy 
for metastatic or locally advanced urinary tract cancer. 
• Certain mixed histologies that are predominantly (>50%) TCC are eligible: 
squamous, adenocarcinoma, and undifferentiated. Mixed undifferentiated histology 
requires immunohistochemistry consistent with a TCC origin. Predominantly 
squamous or neuroendocrine tumors are excluded. 
Protocol Synopsis – Exclusion Criteria 
 
… 
 
1. Have received prior platinum therapy in the past 3 months (Part 1) or 6 months in the 
adjuvant or neoadjuvant setting (Part 2). 
Protocol Synopsis – Study Design 
 
This study will consist of 2 parts; Part 1 is a Phase 1b, continual reassessment method 
dose-escalation trial, and Part 2 is a Phase 2, adaptive, two-stage, open-label, expansion trial 
evaluating activity, safety, and tolerability at the MTDRPII dose identified in Part 1. 
In Part 1, patients will receive intravenous infusion of NC-6004 at escalating doses on 
Day 1 in combination with gemcitabine at the fixed dose of 1250 mg/m2 on Days 1 and 8 
of a 21-day cycle. Doses of NC-6004 and gemcitabine will be administered as intravenous 
infusions in 3-week cycles (ie, 21 days will separate administration of the combined doses of 
NC-6004 and gemcitabine on Day 1 of each cycle). 
… 


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In Part 1, patients will continue to receive treatment until they experience disease 
progression, experience unacceptable toxicity (UT), or withdraw voluntarily, or complete a 
maximum of 10 total cycles of treatment (4 to 6 cycles followed by an additional 4 to 
6  cycles, if they have clinical benefit), whichever occurs first. If the investigator and the 
patient request continuation of NC-6004 administration until progressive disease or 
until the drug is no longer tolerated (whichever occurs first), the sponsor may agree to 
supply the drug after discussion of the request with the investigator. 
… 
 
Part 2 of the study (Phase 2 portion) will begin after the MTD RPII dose of NC-6004 is 
identified for use in combination with gemcitabine. All patients and will be conducted only 
in patients with NSCLC. Part 2 will be conducted in two stages. In the first stage, 10 patients 
with NSCLC will receive NC-6004 at the MTD RPII dose in combination with gemcitabine 
1250 mg/m2 by the same regimen as in Part 1. 
Three cohorts of patients are eligible (Cohort 1: first-line metastatic squamous NSCLC; 
Cohort 2: first-line metastatic or locally advanced cholangiocarcinoma, gallbladder 
cancer, or ampullary cancer (biliary tract cancer); and Cohort 3: first-line metastatic 
or locally advanced TCC of the urinary tract (bladder cancer). Stage 2 will continue in 
each cohort after achieving the minimum threshold of clinical responses required and 
enroll up to 50 patients in each cohort for a total of up to 150 patients in Part 2. The 
primary endpoint (PFS) will be continuously updated and compared with the historical 
PFS from Phase 3 pivotal cisplatin and gemcitabine trials within each cohort. The PFS 
hazard model will be updated as PFS data accrue. A hazard ratio (HR) for PFS for 
each cohort versus historical control will be obtained. 
 
Cohort 
Biliary 
Bladder 
Squamous 
NSCLC 
Historical 
Median 
Duration of 
PFS 
8.8 months 
7.6 months 
5 months 
Historical 
PFS Weekly 
Hazard 
0.01795 
0.020755 
0.031377 


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Once 10 PFS events have been observed, interim analyses will be performed every 
6 weeks. At each interim and at the final analysis, there are 3 possible outcomes for each 
cohort. 
• Futility – 10 PFS events have been observed in each cohort and at least 1 of the 
following conditions is true: 
• 
Probability (Promising HR*) <0.4 
• 
Probability (Phase 3 Success*) <0.4 
 
• Success – 25 PFS events have been observed in each cohort and: 
• 
Probability (Phase 3 Success*) >0.8 
 
• Inconclusive – neither futility nor success. 
 
* Phase 3 success is defined as success in a Phase 3 clinical trial with 381 events - 
enough to provide 80% power to detect an HR of 0.75. A promising HR is defined as 
one less than 0.85. 
Futility can only be declared for a cohort after 10 PFS events have been observed in 
that cohort. Success can only be declared for a cohort after 25 PFS events have been 
observed in that cohort. Accrual will stop for any cohort identified as futile or 
successful at interim. The conclusion of this Phase 2 trial will be that a Phase 3 trial 
with 381 events should be conducted for each cohort that is a success. 
If any indication is declared a success, the combination of NC-6004 and gemcitabine 
advances to a Phase 3 randomized, controlled trial with sample size sufficient to observe 
381 events. 
If at least one patient in the first stage is a responder (defined as CR or PR per RECIST 1.1 
by the week 12 disease assessment) then 26 additional patients with NSCLC will be enrolled 
in the second stage of Part 2. 
After completion of 4 to 6 cycles of treatment (Cohorts 1 and 3) or 8 cycles of treatment 
(Cohort 2) (or up to 10 cycles), patients will have an End-of-Treatment visit, will be 
followed with scans every 9 weeks until disease progression, and will be contacted for 
survival every 12 weeks by telephone. 
… 


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Protocol Synopsis – Estimated Study Duration 
 
The Part 1 of the study will include a screening period (up to 28 days); as many cycles until 
progressive disease or until the drug is no longer tolerated (whichever occurs first); 
tumor assessments for response and disease progression with scans every 6 weeks; and 
telephone calls for survival every 12 weeks. The cycles are 21 days in duration. 
Part 2 of the study will include a screening period (up to 28 days); 4 to 6 treatment cycles 
(Cohorts 1 and 3) or 8 treatment cycles (Cohort 2), followed by an additional 4 to 6 cycles 
(up to a maximum of 10 total cycles) of treatment, that are 21 days in duration; tumor 
assessments for response and disease progression with scans every 6 weeks; and telephone 
calls for survival every 12 weeks. 
Patients will receive study treatment until any of the following occur: 
 
• Disease progression or completion of 4 to 6 cycles of treatment (followed by an 
additional 4 to 6 cycles, up to a maximum 10 total cycles, if they have clinical benefit) 
Progressive disease is observed (Part 1) or completion of 6 cycles of treatment 
(Part 2; Cohorts 1 and 3) or 8 cycles of treatment (Part 2; Cohort 2) 
… 
 
Protocol Synopsis – Efficacy Assessments 
 
… 
 
Symptoms will be assessed before treatment on Day 1 and Day 8 of each cycle and at the 
End of Treatment visit using the core MD Anderson Symptom Inventory (MDASI) or the 
MDASI lung cancer (Part 1 only) (MDASI-LC). 
Protocol Synopsis – Pharmacokinetic or Pharmacodynamic Assessments 
 
… 
 
Pharmacokinetic plasma and plasma ultrafiltrate will be collected at the following times in 
Part 2 for each cycle up to 6 cycles: 
… 


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Protocol Synopsis – Safety Assessments 
 
… 
 
Additionally, in on Day 1 of Cycle 1, vital signs will be measured before the start of the 
NC-6004 infusion, every 20 minutes during the infusion, at the completion of the infusion, 
and 1 hour after the completion of the infusion. In Cycles 2 through 6 (or up to 10) Starting 
in Cycle 2, vital signs will be measured before NC-6004 infusion and at the completion of 
the NC-6004 infusion on Day 1 of each cycle. 
… 
 
Protocol Synopsis – Sample Size 
 
… 
 
Part 2 of the study (Phase 2 portion) will begin after the MTD of NC-6004 is identified for 
use in combination with gemcitabine and will be conducted only in patients with NSCLC. 
Part 2 will be conducted in two stages. In the first stage, 10 patients with NSCLC will receive 
NC-6004 at the MTD in combination with gemcitabine 1250 mg/m2 by the same regimen as 
in Part 1. If at least one patient in the first stage is a responder (defined as CR or PR per 
RECIST 1.1 by the week 12 disease assessment) then 26 additional patients with NSCLC 
will be enrolled in the second stage of Part 2. 
In order to provide a 95% chance to detect at least 1 AE of interest with an underlying 8% 
incidence rate among patients treated at MTD, additional patients with NSCLC will be 
enrolled at the MTD in Part 2 of the study. Patients will be enrolled in 2 stages until a total of 
36 patients with NSCLC have been dosed at the MTD, including patients with NSCLC 
receiving the MTD level in Part 1. In the first stage of Part 2, ten patients treated at the MTD 
will be evaluated for response. If no patients respond, then the patients with NSCLC treated 
at a lower dose level than the MTD will be considered and a discussion of terminating the 
trial early will be triggered. Any evidence of response, regardless of duration, will be counted 
as a response. If at least 1 response is observed, the remaining 26 patients will be treated at 
the MTD. No formal efficacy analysis will be performed and no inference regarding efficacy 
will be drawn based on the response rate of the overall study. 
Part 2 is a 3-cohort study with an overall sample size of up to 150 patients with no more 
than 50 patients per cohort. The total sample size will depend on the results of interim 


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futility and superiority analyses. In order to evaluate the overall sample size, 
simulations were performed assuming scenarios with different HRs for PFS for each 
cohort compared with historical control and different sample sizes for a subsequent 
Phase 3 clinical trial. The associated mean sample size for this trial in these scenarios 
ranged from 136 to 146 patients. 
Patients who receive study drug will not be replaced. 
 
Protocol Synopsis – Statistical Methods 
 
No formal statistical testing is planned for this study. Ninety-five percent confidence 
intervals may be calculated for selected safety and exploratory variables. Dose escalation will 
be based on the N-CRM model and the incidence of DLTs. Adverse events and serious AEs 
will be tabulated by system organ class and preferred term. Laboratory test results after the 
first dose will be summarized with regard to shifts from baseline values and the grade per 
NCI CTCAE version 4.03. Overall survival, PFS, and DOR will be summarized using 
Kaplan-Meier methods. The ORR and DCR will be summarized and 95% confidence 
intervals for both will be created. 
In Part 2, the following posterior probabilities will be derived using a Bayesian model 
updated every 6 weeks after 10 PFS have occurred within a cohort: 
• 
Probability (Promising HR) 
 
• 
Probability (Phase 3 Success) 
 
If any cohort at interim or final analyses has a probability (success in a Phase 3 trial 
with 381 PFS events) >0.8, that indication will be declared a success, and the 
combination of NC-6004 and gemcitabine advances to a Phase 3 randomized, controlled 
trial with a sample size sufficient to observe 381 PFS events. 
Section 1 – Introduction 
 
… 
 
This study will determine the maximum tolerated dose (MTD) and recommended Phase 2 
(RPII) dose of NC-6004 in combination with gemcitabine and evaluate the activity, safety, 
and tolerability of NC-6004 in combination with gemcitabine in patients with advanced solid 


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tumors and first-line metastatic squamous NSCLC; first-line metastatic or locally 
advanced cholangiocarcinoma, gallbladder cancer, or ampullary cancer (biliary tract 
cancer); and first-line metastatic or locally advanced transitional cell carcinoma (TCC) 
of the urinary tract (bladder cancer) second- or third line squamous and nonsquamous 
Stage IIIB/IV NSCLC. 
… 
 
Section 2.1 – Primary Objectives 
 
The primary objectives of this study are: 
 
• In the dose-escalation phase of the study (Part 1), to determine the dose-limiting toxicities 
(DLTs) and, MTD, and RPII dose of NC-6004 in combination with gemcitabine; 
• In the expansion phase of the study (Part 2), to evaluate the activity, safety, and 
tolerability of NC-6004 in combination with gemcitabine in patients with relapsed 
(second- or third-line) squamous and nonsquamous Stage IIIB/ first-line Stage IV 
squamous NSCLC, first-line advanced or metastatic biliary tract cancer, and first 
line metastatic or locally advanced bladder cancer compared with historical control 
as measured by local investigator/radiologist-assessed progression-free survival 
(PFS), according to Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1. 
Section 2.1 – Primary Objectives 
 
The secondary objectives of this study are: 
 
• To evaluate ORR, DCR (DCR = complete response [CR] + partial response [PR] + 
stable disease [SD]), DOR, PFS, and OS 
• To evaluate therapy-related AEs 
• To evaluate the safety and tolerability of NC-6004 when combined with gemcitabine 
… 
 
Section 3.1 – Study Design 
 
This study will consist of 2 parts; Part 1 is a Phase 1b, continual reassessment method 
dose-escalation trial in patients with any advanced solid tumor, and Part 2 is a Phase 2, 
adaptive two-stage, open-label, expansion trial in patients with squamous NSCLC, biliary 


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tract, and bladder cancer evaluating activity, safety, and tolerability at the MTD RPII dose 
identified in Part 1. 
 
In Part 1, patients will receive intravenous infusion of NC-6004 and gemcitabine in 3-week 
treatment cycles. NC-6004 will be administered on Day 1 of each cycle and gemcitabine 
1250 mg/m2 will be administered on Day 1 of each cycle (after the administration of 
NC-6004) and on Day 8 of each cycle. Patients will be treated until disease progression or up 
to 10 cycles of therapy, whichever occurs first. If the investigator and the patient request 
continuation of NC-6004 administration until progressive disease or until the drug is no 
longer tolerated (whichever occurs first), the sponsor may agree to supply the drug 
after discussion of the request with the investigator. After completion of 4 to 6 cycles of 
treatment, individual patients can continue study drug, subject to sponsor approval, for an 
additional 4 to 6 cycles of treatment (up to a maximum of 10 total cycles) if they have 
clinical benefit, with monitoring the same as that in the treatment phase. 
… 
 
Once the MTD (or RPII dose) of NC-6004 is identified, dose escalation within Part 1 will 
cease. Patients in Part 1 who were not assigned to the NC-6004 dose identified as the MTD 
RPII dose will continue treatment cycles at their assigned dose level. 
Part 2 of the study (Phase 2 portion) will begin after the MTD RPII dose of NC-6004 is 
identified for use in combination with gemcitabine and will be conducted only in patients 
with NSCLC. Part 2 will be conducted in two stages. In the first stage, 10 patients with 
NSCLC All patients will receive NC-6004 at the MTD RPII dose in combination with 
gemcitabine 1250 mg/m2 by the same regimen as in Part 1. 
Three cohorts of patients are eligible (Cohort 1: first-line metastatic squamous NSCLC; 
Cohort 2: first-line metastatic or locally advanced cholangiocarcinoma, gallbladder 
cancer, or ampullary cancer (biliary tract cancer); and Cohort 3: first-line metastatic or 
locally advanced TCC of the urinary tract (bladder cancer). Stage 2 will continue in 
each cohort after achieving the minimum threshold of clinical responses required and 
enroll up to 50 patients in each cohort for a total of up to 150 patients in Part 2. The 
primary endpoint (PFS) will be continuously updated and compared with the historical 
PFS from Phase 3 pivotal cisplatin and gemcitabine trials within each cohort. The PFS 
hazard model will be updated as PFS data accrue. A hazard ratio (HR) for PFS for each 
cohort versus historical control will be obtained. 


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Cohort 
Biliary 
Bladder 
Squamous 
NSCLC 
Historical 
Median 
Duration of 
PFS 
8.8 months 
7.6 months 
5 months 
Historical 
PFS Weekly 
Hazard 
0.01795 
0.020755 
0.031377 
Once 10 PFS events have been observed, interim analyses will be performed every 
6 weeks. At each interim and at the final analysis, there are 3 possible outcomes for each 
cohort. 
 
• Futility – 10 PFS events have been observed in each cohort and at least 1 of the 
following conditions is true: 
• 
Probability (Promising HR*) <0.4 
• 
Probability (Phase 3 Success*) <0.4 
 
• Success – 25 PFS events have been observed in each cohort and: 
• 
Probability (Phase 3 Success*) >0.8 
 
• Inconclusive – neither futility nor success. 
 
* Phase 3 success is defined as success in a Phase 3 clinical trial with 381 events - 
enough to provide 80% power to detect an HR of 0.75. A promising HR is defined as 
one less than 0.85. 
*Futility can only be declared for a cohort after 10 PFS events have been observed in 
that cohort. Success can only be declared for a cohort after 25 PFS events have been 
observed in that cohort. Accrual will stop for any cohort identified as futile or successful 
at interim. The conclusion of this Phase 2 trial will be that a Phase 3 trial with 
381 events should be conducted for each cohort that is a success. 
 
If any indication is declared a success, the combination of NC-6004 and gemcitabine 
advances to a Phase 3 randomized, controlled trial with sample size sufficient to observe 
381 events. 


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If at least one patient in the first stage is a responder (defined as CR or PR per RECIST 1.1 
by the week 12 disease assessment) then 26 additional patients with NSCLC will be enrolled 
in the second stage of Part 2. Approximately 36 patients with NSCLC will be treated at the 
MTD, including any patients with NSCLC receiving the MTD in Part 1 and patients 
receiving the MTD in Part 2. Evaluation will include patients with NSCLC treated at the 
MTD in either part of the study. 
In both Part 1 and Part 2, patients will continue to receive treatment until they experience 
disease progression or for up to 10 treatment cycles, whichever occurs first. The maximum 
number of cycles a patient undergoes (up to 10 total cycles) is at the discretion of the 
investigator and depends on response as described in the American Society of Clinical 
Oncology (ASCO) guidelines (Appendix 12.4) (Azzoli et al 2011). Patients who complete 4 
or more cycles will be considered as having completed the treatment. Subject to sponsor 
approval, individual patients can continue study drug for an additional 4 to 6 cycles of 
treatment (up to a maximum of 10 total cycles) if they have clinical benefit, with monitoring 
the same as that in the treatment phase will be treated until progressive disease. If the 
investigator and the patient request continuation of NC-6004 administration until 
progressive disease or until the drug is no longer tolerated (whichever occurs first), the 
sponsor may agree to supply the drug after discussion of the request with the 
investigator. In Part 2, patients will continue to receive treatment for up to 6 cycles 
(Cohorts 1 and 3) or 8 cycles (Cohort 2). 
After the completion of 4 to 6 cycles of treatment (or up to 10 cycles) progressive disease is 
observed (Part 1) or the completion of 6 cycles (Part 2; Cohorts 1 and 3) or 8 cycles 
(Part 2; Cohort 2), patients will have an End-of-Treatment visit, will be followed with scans 
every 9 weeks until disease progression, and will be contacted for survival every 12 weeks by 
telephone. 
… 
 
Section 3.1 – Study Design – Day 1 of Cycle 
 
… 
 
• EORTC QLQ-C30 
• Core MDASI or MDASI module specific for lung cancer (MDASI-LC) (Section 6.1.3) 


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o MDASI-LC will only be performed by patients with NSCLC in Part 1 
and will not be performed in Part 2 
• Nausea and vomiting patient diary completion (completed in all cycles in Part 1 and 
only for 2 cycles in Part 2 of the study) 
… 
 
Section 3.1 – Study Design – Day 8 of Each Cycle 
 
… 
 
• EORTC QLQ-C30 
• Core MDASI or MDASI-LC 
o MDASI-LC will only be performed by patients with NSCLC in Part 1 
and will not be performed in Part 2 
• Nausea and vomiting patient diary completion (completed in all cycles in Part 1 and 
only for 2 cycles in Part 2 of the study) 
… 
 
Section 3.1 – Study Design – Day 15 of Each Cycle (Part 1: required; Part 2: if clinically 
indicated) 
… 
 
• Biochemistry 
• Nausea and vomiting patient diary completion (completed in all cycles in Part 1 and is 
not collected at Day 15 in Part 2 of the study) 
… 
 
Section 3.1 – Study Design – End-of-Treatment Visit 
 
… 
 
• EORTC QLQ-C30 
• Core MDASI or MDASI-LC (Part 1 only) 


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• 12-lead ECG 
… 
 
Section 3.1.1 – Rationale of Study Design 
 
… 
 
This study will determine the DLTs and, MTD, and RPII of NC-6004 in combination with 
gemcitabine in patients with advanced solid tumors and relapsed Stage IIIB/ first-line 
Stage IV squamous NSCLC, first-line advanced or metastatic biliary tract cancer, and 
first-line metastatic or locally advanced bladder cancer for use in future efficacy studies. 
… 
 
The MDASI-LC questionnaire is designed specifically for patients with lung cancer and will 
be used by patients with NSCLC in Part 1 of this study. 
… 
 
Section 4.1 – Selection of Study Population 
 
Approximately 199 85 patients (up to 49 patients in Part 1 and up to 36 150 patients in Part 
2) will be enrolled in at approximately 6 least 20 sites in the United States. Patients will be 
assigned to a study treatment only if they meet all of the inclusion criteria and none of the 
exclusion criteria. 
Section 4.1.1 – Inclusion Criteria 
 
2. (Part 1 only) Have a histologically or cytologically confirmed diagnosis of advanced 
solid tumor that has relapsed or is refractory to standard curative or palliative therapy or 
has a contraindication to standard therapy. 
 
(Part 2 only) Cohort 1: Have histologically or cytologically confirmed diagnosis of 
Stage IIIB or IV squamous NSCLC and have not received 1 or 2 lines of prior 
chemotherapy for metastatic disease. Patients with known sensitizing mutation in the 
epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase 
(ALK) fusion oncogene must have received at least 1 and up to 2 targeted therapies 


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prior to enrollment or targeted therapy for Stage IIIB or IV NSCLC (second- or third- 
line). 
• 
A patient with stable, treated brain metastases is eligible, provided that 
there is no evidence of progression after treatment and the patient does not 
require corticosteroids, or, if the patient requires corticosteroid, has been 
receiving a stable dose of corticosteroids for at least 14 days prior to 
assignment to treatment. 
• 
Patients whose tumors are known to harbor an exon 19 deletion or exon 21 
L858R epidermal growth factor receptor (EGFR) mutation must have had 
intolerance or have progressed on or had intolerance to an at least 1 and 
up to 2 EGFR tyrosine kinase inhibitors. 
• 
Patients whose tumors are known to harbor an anaplastic lymphoma kinase 
ALK translocation must have had intolerance or have progressed on or 
had intolerance to crizotinib at least 1 and up to 2 ALK inhibitors. 
 
(Part 2 only) Cohort 2: Have histologically or cytologically confirmed diagnosis of 
nonresectable, recurrent, or metastatic biliary tract carcinoma (intrahepatic or 
extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary carcinoma) and 
have not received prior systemic anticancer therapy for advanced or metastatic 
disease. 
(Part 2 only) Cohort 3: Have histologically or cytologically confirmed diagnosis of 
metastatic or locally advanced TCC of the urinary tract (bladder, urethra, ureter, 
renal pelvis) (T3b-T4 N0 M0, Tany N1-N3 M0, or Tany Nany M1) and are not 
candidates for surgery. 
• 
Patients must not have received prior treatment with systemic 
anticancer therapy for metastatic or locally advanced urinary tract 
cancer. 
• 
Certain mixed histologies that are predominantly (>50%) TCC are 
eligible: squamous, adenocarcinoma, and undifferentiated. Mixed 
undifferentiated histology requires immunohistochemistry consistent 


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with a TCC origin. Predominantly squamous or neuroendocrine 
tumors are excluded. 
Section 4.1.2 – Exclusion Criteria 
 
Patients meeting any of the following criteria will be excluded from the study: 
 
1. Have received prior platinum therapy in the past 3 months (Part 1) or 6 months in the 
adjuvant or neoadjuvant setting (Part 2). 
… 
Section 5.1 – Method of Assigning Patients to Treatment Groups 
 
… 
 
In Part 2, all patients will receive the MTD RPII dose of NC-6004 identified in Part 1 
 
Section 5.2 – Prophylactic Treatments 
 
… 
 
Prophylactic antiemetic medications may be administered according to standard treatment 
center protocols for cisplatin-based treatments. The use of prophylactic growth factor 
support medications is also allowed according to ASCO guidelines (Smith et al 2006) 
and is encouraged in patients who have experienced myelosuppression on treatment 
and/or in patients at high risk for experiencing febrile neutropenia. 
Section 5.3 – Treatments Administered 
 
… 
 
In each part Part 1 of the study, patients will receive treatment until disease progression. In 
Part 2 of the study, patients will receive treatment for 4 to 6 cycles (Cohorts 1 and 3) or 
8 cycles (Cohort 2) as directed in the ASCO guidelines (Appendix 12.4) or until disease 
progression, whichever occurs first. After the initial 4 to 6 cycles of treatment, individual 
patients can continue study drug, subject to sponsor approval, for an additional 4 to 6 cycles 
of treatment (up to a maximum of 10 total cycles) if they have clinical benefit, with 
monitoring the same as that in the treatment phase. Prophylactic Aantiemetic medications 


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may be administered according to standard treatment center protocols. The use of growth 
factor support medications is also allowed according to ASCO guidelines (Smith et al 
2006) and is encouraged in patients who have experienced myelosuppression on 
treatment and/or in patients at high risk for experiencing febrile neutropenia. 
… 
 
In Part 2, on Day 1 of each cycle, all patients will receive NC-6004 at the MTD RPII dose 
identified in Part 1 and 1250 mg/m2 gemcitabine. On Day 8 of each cycle, all patients in 
Part 2 of the study will receive 1250 mg/m2 gemcitabine. 
Section 5.10 – Prior, Concomitant, and Subsequent Therapy 
 
(Part 2 only) Cohort 1: For patients with Stage IV NSCLC, they may not have received 
prior chemotherapy for metastatic disease. Patients with known sensitizing mutation in 
the EGFR gene or ALK fusion oncogene must have received at least 1 and up to 2 
targeted therapies prior to enrollment. If a patient with treated, stable brain metastases 
is otherwise eligible and requires corticosteroids, the patient must have been receiving a 
stable dose of corticosteroids for at least 14 days prior to assignment to treatment. 
Patients whose tumors are known to harbor an exon 19 deletion or exon 21 L858R 
EGFR mutation must have had intolerance or have progressed on at least 1 and up to 2 
EGFR tyrosine kinase inhibitors. Patients whose tumors are known to harbor an ALK 
kinase translocation must have had intolerance or have progressed on at least 1 and up 
to 2 ALK inhibitors. Patients with eligible biliary tract carcinoma must not have 
received prior systemic anticancer therapy for advanced or metastatic disease. Patients 
with eligible TCC of the urinary tract must not have received prior treatment with 
systemic anticancer therapy for metastatic or locally advanced urinary tract cancer. 
Prior chemotherapy or targeted therapy for first- or second-line, Stage IIIB/IV NSCLC is 
allowed and required for entry in Part 2 of the trial. All patients must receive prophylactic 
treatment at each cycle to reduce the risk of hypersensitivity reactions and nausea and/or 
vomiting (Section 5.8). 
The use of antiemetic medications according to the site’s standard of care is allowed. The use 
of prophylactic growth factor support medications is also allowed according to ASCO 
guidelines (Smith et al 2006) and is encouraged in patients who have experienced 


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myelosuppression on treatment and/or in patients at high risk for experiencing febrile 
neutropenia. 
… 
 
Section 6.1 – Efficacy Assessments 
 
… 
 
Symptom changes will be assessed using the core MDASI or MDASI-LC (only in patients 
with NSCLC in Part 1) (Section 6.1.3) on Days 1 and 8 of each cycle and at the End-of- 
Treatment visit. 
… 
 
Section 6.1.3 – MD Anderson Symptom Inventory 
 
… 
 
For patients with NSCLC in Part 1 and Part 2 only, a specific MDASI module designed for 
patients with lung cancer will be used, MDASI-LC (Appendix 12.3). 
… 
 
The core MDASI and the MDASI-LC will be administered as a self-report paper-and-pencil 
form given to the patient at the site before study treatments on Days 1 and 8 of each cycle in 
Part 1 only (as described in Study Manual). 
Section 6.2 – Pharmacokinetic and Pharmacodynamic Assessments 
 
… 
 
Pharmacokinetic samples will be analyzed for according to the bioanalytical laboratory 
protocol. The concentrations profiles of micellar platinum in plasma and total platinum in 
plasma and plasma ultrafiltrate (ie, free platinum) will be characterized. 
… 
 
Pharmacokinetic plasma and plasma ultrafiltrate samples will be collected at the following 
times in Part 2 for up to 6 cycles: 


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… 
 
Section 6.3.1.2.1 – Safety Monitoring in Part 2 
 
During Part 2 of the study, patients treated with NC-6004 at the MTD RPII dose from Part 1 
will be monitored for safety. 
… 
 
Section 6.3.3 – Assessment of Nausea and Vomiting 
 
… 
 
The investigator will collect the diaries on Day 8, Day 15 (Part 1 only), and Day 22. 
 
… 
 
The patient must return the diary to the site on Day 8, Day 15 (Part 1 only), and Day 22 
(Day 1 of the next cycle) of each cycle. 
… 
 
Section 6.3.8 – Vital Sign Measurements 
 
… 
 
In Cycles 2 through 6 (or up to Cycle 10, if there is clinical benefit) Starting in Cycle 2, vital 
signs will be measured before the start of the NC-6004 infusion and at the completion of the 
NC-6004 infusion on Day 1 of each cycle. 
… 
 
Section 7.2 – Exploratory Endpoints 
 
The exploratory endpoints of this study include exploratory safety endpoints of the 
occurrence of AEs and SAEs after 4 to 6 cycles of treatment and the following PK endpoints 
for micellar platinum in plasma and total platinum in plasma and plasma ultrafiltrate 
calculated for all patients using noncompartmental analysis: 
… 


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Section 7.3 – Sample Size Calculations 
 
This is a Phase 1b/2 study with an overall sample size of up to 85 199 patients (up to 
49 patients in Part 1 and up to 36 150 patients in Part 2). The total sample size will depend on 
the number of cohorts required to establish an MTD RPII dose and the number of patients 
with NSCLC enrolled at the MTD RPII dose in Part 1. 
… 
 
Part 2 is a 3-cohort study with an overall sample size of up to 150 patients with no more 
than 50 patients per cohort. The total sample size will depend on the results of interim 
futility and superiority analyses. In order to evaluate the overall sample size, 
simulations were performed assuming scenarios with different HRs for PFS for each 
cohort compared with historical control and different sample sizes for a subsequent 
Phase 3 clinical trial. The associated mean sample size for this trial in these scenarios 
ranged from 136 to 146 patients. 
In Part 2 of the study, additional patients with NSCLC will be enrolled at the MTD until a 
total of 36 patients with NSCLC have been dosed at the MTD, including patients with 
NSCLC receiving the MTD dose level in Part 1. In order to provide a 95% chance to detect 
at least 1 AE of interest with an underlying 8% incidence rate among patients treated at MTD, 
additional patients with NSCLC will be enrolled at the MTD in Part 2 of the study. Patients 
will be enrolled in 2 stages until a total of 36 patients with NSCLC have been dosed at the 
MTD, including patients with NSCLC receiving the MTD level in Part 1. In the first stage of 
Part 2, ten patients treated at the MTD will be evaluated for response. If no patients respond, 
then the patients with NSCLC treated at a lower dose level than the MTD will be considered 
and a discussion of terminating the trial early will be triggered. Any evidence of response, 
regardless of duration, will be counted as a response. If at least 1 response if observed, the 
remaining 26 patients will be treated at the MTD. No formal efficacy analysis will be 
performed and no inference regarding efficacy will be drawn based on the response rate of 
the overall study. 
 
A total of 36 patients with NSCLC will be sufficient to identify toxicities of interest arising 
from treatment with NC-6004. Toxicities at the MTD with 36 patients enrolled (ie, those with 
an incidence of at least 8%), will be observed with a probability of at least 95.03% 
(1-[1-0.08]36), and common toxicities (ie, those with an incidence of at least 20%) will be 
observed with a probability of at least 99.97% (1-[1-0.2]36). 


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Patients who receive study drug will not be replaced. 
 
Patients in Part 1 who discontinue treatment without DLT prior to completing the first cycle 
will be replaced. 
Section 7.4 – Analysis Sets 
 
... 
 
• The Full Analysis Set (FAS) consists of all patients treated at MTD RPII dose in Part 1 
or Part 2 who receive study product. 
… 
 
Section 7.6 – Statistical Analysis Methodology 
 
No formal statistical testing is planned for this study. Ninety-five percent confidence 
intervals may be calculated for selected safety and exploratory variables. 
… 
 
All summaries will present data by dose level, for patients with NSCLC dosed at the MTD, 
and overall. 
In Part 2, the following posterior probabilities will be derived using a Bayesian model 
updated every 6 weeks after 10 PFS have occurred within a cohort: 
• Probability (Promising HR) 
 
• Probability (Phase 3 Success) 
 
If any cohort at interim or final analyses has a probability (success in a Phase 3 trial 
with 381 PFS events) >0.8, that indication will be declared a success, and the 
combination of NC-6004 and gemcitabine advances to a Phase 3 randomized, controlled 
trial with a sample size sufficient to observe 381 PFS events. 


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Section 7.6.1.6 – Quality of Life Analyses 
 
… 
 
Changes from baseline will be summarized by dose level, for all patients with NSCLC dosed 
at MTD (or RPII dose), and overall 
… 
 
Section 7.6.1.7 – Symptoms Assessment Analyses 
 
… 
 
Changes from baseline will be summarized by dose level, for all patients with NSCLC dosed 
at MTD (or RPII dose), and overall 
… 
 
Section 7.6.2.1 – Analyses of Adverse Events 
 
… 
 
• TEAEs with at least 5% incidence in all patients with NSCLC dosed at the MTD or RPII 
dose 
• Treatment-related TEAEs with at least 5% incidence in all patients with NSCLC dosed at 
the MTD or RPII dose 
… 
 
Section 11 – Reference List 
 
… 
 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the 
use of white blood cell growth factors: An evidence-based clinical practice guideline. J 
Clin Oncol. 2006;24(19):3187-205. 
Section 12.1 – Appendix: Schedule of Events 


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Table 12-1 
Schedule of Events 
 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7 Onward 
Cycles 7-10a 
End-of- 
Treatmentb 
Follow- 
upc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Informed consent 
X 
Eligibility criteria 
X 
Demography 
X 
Medical history 
X 
Pregnancy test (serum or urine) 
X 
 
Xde 
Physical examination 
 
Xef 
 
Xef 
X 
X 
X 
X 
Height, weight, and BSA 
calculation 
Xfg 
X 
X 
X 
X 
Vital signs 
X 
 
Xgh 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status (ECOG) 
 
Xef 
 
Xef 
X 
X 
X 
X 
Disease assessmenthi 
X 
 
Xhi 
 
Xhi 
X 
X 
Audiometry 
X 
 
Xij 
 
Xij 
 
Xij 
 
Xij 
 
Xij 
Hematology 
X 
 
Xjk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
 
Xjk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (dipstick) 
X 
X 
EORTC QLQ-C30 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDASI or MDASI-LCl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nausea and vomiting patient 
diarykm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Part 2 Nausea and vomiting 
patient diarym 
X 
X 
X 
X 
Cardiac risk factors 
X 
12-lead ECGln 
X 
X 
X 
X 
X 
X 


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Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7 Onward 
Cycles 7-10a 
End-of- 
Treatmentb 
Follow- 
upc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Pharmacokinetic assessments 
(Part 1)ko 
X 
X 
X 
X 
X 
Xmo 
Xmo 
X 
Pharmacokinetic assessments 
(Part 2) np 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
Xef 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
 
Xef 
 
Xef 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prophylactic administrations 
X 
X 
X 
X 
NC-6004 administrationa 
X 
X 
X 
X 
Gemcitabine administration 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BSA, body surface area; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-C30, European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; MDASI, MD Anderson Symptom Inventory; RECIST, Response Evaluation Criteria 
in Solid Tumors; MDASI-LC, MDASI-lung cancer. 
a. 
In Part 1 of the study, patients will receive treatment until progressive disease. In Part 2 of the study, patients will receive treatment for 6 cycles 
(Cohorts 1 and 3) or 8 cycles (Cohort 2). An optional extension of an additional 4 to 6 cycles of treatment (up to 10 cycles of treatment [including 
gemcitabine if the patient is tolerating NC-6004]) is allowed, with monitoring the same as that in the treatment phase of the protocol. 
b. End-of-treatment assessments will be performed within 28 days after treatment discontinuation. 
c. 
After patient discontinuation or completion of treatment without disease progression, patients will be followed with scans every 9 weeks until disease 
progression. Patients will be called every 12 (±1) weeks to collect data on patient survival, new treatments, and adverse events. 
d. Day 15 visit is required in Part 1. In Part 2, Day 15 visit is only necessary if it is clinically indicated. 
de. Not required if screening pregnancy test was performed using serum. 
ef. Safety assessments of physical examination, ECOG, review of AEs, and concomitant medication use can be completed on Day -1 to allow for early morning 
dosing. These should not be conducted in place of screening assessments. 
fg. Height and weight only. 
gh. On Day 1 of Cycle 1, vital signs will be measured before the start of the NC-6004 infusion, every 20 minutes during the infusion, at the completion of the 
infusion, and 1 hour after the completion of the NC-6004 infusion. Starting in Cycle 2 In Cycles 2 through 10, vital signs will be measured before the start 
of the NC-6004 infusion and at the completion of the NC-6004 infusion on Day 1 of each cycle. Vital signs will be measured before and after gemcitabine 
infusion on Day 8 of each cycle. 
hi. Disease assessment will be performed using RECIST version 1.1 and the same imaging method used at screening should be used for all subsequent 
assessments. Beginning in Cycle 3 and continuing through the remainder of the treatment cycles, disease will be assessed every 6 (±1) weeks (ie, every other 


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cycle) and at the End-of-Treatment visit or until disease progression. Patients who have obtained a partial response or complete response will have a 
confirmatory scan at a minimum of 4 weeks following the initial scan. 
ij.  To be performed only as clinically indicated. 
jk. Hematology or biochemistry tests will be repeated prior to dosing on Day 1 of Cycle 1 if they were last performed more than 24 hours before the start of the 
study drug administration. 
l. 
Symptom changes will be assessed using the core MDASI or MDASI-LC (only in patients with NSCLC in Part 1). 
km. Diary issued on Day 1 of each cycle. Assessment is performed at the site before dosing on Days 1 and Day 8 as well as Day 15 (Day 15 diary collected in 
Part 1 only; note: no dosing on Day 15) of each cycle. Patient completes diary at home on Days 2 through 8 and returns diary on Day 8. 
ln. Twelve-lead ECGs will be performed after the patient has rested in the supine position for at least 5 minutes. On Day 1 of Cycle 1, 12-lead ECGs will be 
performed before the start of the NC-6004 infusion, at completion of infusion (~1 hour after start of infusion), and at Hours 3 and 24 (Day 2) after the start of 
infusion. On Day 8 of Cycle 1, 12-lead ECGs will be performed before the start of gemcitabine infusion, at the end of gemcitabine infusion, and at 1 hour 
after completion of gemcitabine infusion. Twelve-lead ECGs will be performed on Day 1 of Cycles 2 through 6 before the start of the NC-6004 infusion, and 
at the End-of-Treatment visit. 
mo. For Part 1, blood samples will be collected at the following times: before the start of the NC-6004 infusion on Day 1 of Cycles 1 through 6, at end of NC- 
6004 infusion in Cycles 1, 3, and 5, after the start of NC-6004 infusion at Hours 3, 6, 12, 24 (Day 2), 48 (Day 3), 96 (Day 5), 168 and prior to gemcitabine 
infusion (Day 8), and 336 (Day 15) in Cycles 1, 3, and 5, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample collections may be 
performed, at the discretion of the investigator, during any visit where toxicity is observed. 
np. For Part 2 (up to 6 cycles), on the day of NC-6004 infusion for each cycle, blood samples will be collected before the start of the NC-6004 infusion, at the 
end of the NC-6004 infusion, before gemcitabine infusion on Day 8, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample collections 
may be performed, at the discretion of the investigator, during any visit where toxicity is observed. 


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Section 12.4 – Appendix: American Society of Clinical Oncology Guideline 
 
This appendix was removed. 
 
12.4.3 Protocol Amendment 3–Protocol Version 4.0, Incorporating 
Amendment 3, Dated 31 July 2016 
The following sections detail the changes made to Amendment 2 of the protocol (Version 3.0) 
dated 07 July 2015. The integrated protocol, Version 4.0, including Amendment 3, was issued 
on 31 July 2016. 
 
12.4.3.1 
Assessment of Risk Associated With Amendment 3, 
Version 4.0 
No patients treated with NC-6004 in Study NC-6004-004A at the MTD and gemcitabine with 
normal renal function (≥50 mL/min) experienced a clinically significant decrease in CrCl 
after initial study drug administration. Creatinine clearance values were stable with no 
decrease in all patients beyond the first cycle through up to 10 cycles. Therefore, patients 
with CrCl <60 mL/min are not expected to experience clinically meaningful decreases in 
renal function after treatment with NC-6004 and gemcitabine. However, increased renal 
function monitoring and protocol-mandated discontinuation will mitigate this risk. 
 
12.4.3.2 
Overview of Changes 
The overview of significant changes includes the following: 
 
Protocol Synopsis – Study Sites; Section 4.1 – Selection of Study Population 
 
The study site details were updated to at least 20 sites in the Unites States and Europe. 
 
Protocol Synopsis – Inclusion Criteria; Section 4.1.1 – Inclusion Criteria 
 
The inclusion criterion 5 was updated to the following: 
 
5. Have an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1, with the exception of 
patients in Part 2 (Cohort 3, unfit bladder cancer patients) who may have an ECOG PS of 2. 


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Protocol Synopsis – Inclusion Criteria; Protocol Synopsis – Study Design; Section 
3.1 - Study Design; Section 4.1.1 – Inclusion Criteria; Section 5.1 – Method of Assigning 
Patients to Treatment Groups; Section 6.3.1.2.1 - Safety Monitoring in Part 2 
The inclusion criterion 8 and study design were updated to reflect the following: 
 
8. In Part 1 and in Part 2 in Cohorts 1 and 2: have adequate renal function defined as a CrCl 
≥50 mL/minute (calculated according to the formula of Cockcroft and Gault 1976) or serum 
creatinine <1.5 mg/dL. In Part 2, patients in Cohort 3 (bladder cancer) must have a CrCl of 
≥30 mL/min. 
 
• Bladder cancer patients in Cohort 3 of Part 2 will be stratified by ≥30 to 
<60 mL/min and/or ECOG PS 2 and ≥60 mL/min and ECOG PS 0 to 1. If 2 of 
6 patients (or ≥33% at any point during the study) in the ≥30 to <60 mL/min 
group have a worsening of CrCl (ie, 50% reduction from baseline for 
2 consecutive assessments, at least 1 week apart), then enrollment of patients 
with CrCl <60 mL/min will stop in the bladder cancer cohort. 
Protocol Synopsis – Inclusion Criteria; Section 4.1.1 – Inclusion Criteria 
 
The inclusion criterion 9 was updated to the following: 
 
9. Have a negative pregnancy test result at screening (for females of childbearing potential; 
not applicable to patients who are unable to become pregnant, including those with bilateral 
oophorectomy and/or hysterectomy or postmenopausal [no menses for the previous 
12 months]). The test must be performed within 1 week before Day 1 of treatment. 
 
Protocol Synopsis – Inclusion Criteria; Section 4.1.1 – Inclusion Criteria 
 
The inclusion criterion 10 was added as follows: 
 
10. Male patients must agree to use a condom during treatment and for 90 days after dosing. 
Male patients must agree not to donate sperm for 90 days after dosing. 


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Protocol Synopsis – Inclusion Criteria; Section 4.1.1 – Inclusion Criteria 
 
The inclusion criterion 11 was updated to the following: 
 
11. For women of childbearing potential*: are willing to abstain from heterosexual activity or 
practice physical barrier contraception follow 1 of the following effective methods of birth 
control from the time of study entry to 6 months after the last day of treatment.: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, or transdermal) 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, or implantable) 
• Intrauterine devices 
• Intrauterine hormone-releasing system 
• Vasectomized partner who has received medical assessment of surgical success 
• Bilateral tubal occlusion 
• True sexual abstinence** 
*Patients not of childbearing potential include those who are surgically sterile or 
postmenopausal (no menses for the previous 12 months). For women not currently taking 
contraceptive methods at screening, low user dependency contraceptive methods (eg, 
implantable progestogen-only hormonal contraception, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, vasectomized partner) are recommended. 
**The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. 
Protocol Synopsis – Study Design; Section 3.1 – Study Design 
 
All references to “two-stage” and a minimum threshold of clinical responses in Part 2 were 
removed. 


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Protocol Synopsis – Study Design; Section 3.1 - Study Design; Section 5.1 - Method of 
Assigning Patients to Treatment Groups; Section 5.3 - Treatments Administered 
The RPII dose of 135 mg/m2 was added to the protocol. 
 
Protocol Synopsis – Study Design; Section 3.1 - Study Design 
 
The historical median duration of PFS and PFS weekly hazard were added for the unfit 
bladder cancer cohort. A successful outcome for unfit and fit bladder cancer patient cohorts 
with 30 planned patients was updated to 15 PFS events. 
Protocol Synopsis – Study Design; Protocol Synopsis – Sample Size; Section 3.1 - Study 
Design; Section 4.1 – Selection of Study Population; Section 7.3 - Sample Size 
Calculations 
The total sample size in Part 2 of the study was changed to 160 patients with no more than 
50 patients each in Cohorts 1 and 2 and no more than 60 patients in Cohort 3 (30 unfit and 
30 fit bladder cancer patients). The simulated mean sample sizes for this trial were updated to 
92.7 to 116.8 patients. 
 
Protocol Synopsis – Estimated Study Duration; Section 4.2.1 – Reasons for 
Withdrawal/Discontinuation 
A study treatment discontinuation rule was added as follows: 
 
• For Cohort 3 only, unfit bladder cancer patient (≥30 to <60 mL/min CrCl at 
screening) has a worsening of CrCl (ie, 50% reduction from baseline for 2 
consecutive assessments, at least 1 week apart) 
Protocol Synopsis – Definition of a DLT; Section 6.3.1.1 – Definition of Dose-Limiting 
Toxicities 
It was clarified that DLTs will only be monitored in Part 1 of the study. 


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Section 3.1 - Study Design; Section 12.1 - Appendix: Schedule of Events 
 
A serum or urine pregnancy test was added to Day 1 of each cycle and at the 
End-of-Treatment visit. 
Section 3.1 - Study Design; Section 12.1 - Appendix: Schedule of Events; 
Section 6.1.3 - MD Anderson Symptom Inventory 
It was clarified that the MDASI will only be performed in Part 1. 
 
Section 5.1 - Method of Assigning Patients to Treatment Groups; Section 5.3 - Treatments 
Administered 
A +10-minute window was added for the 1-hour administration of NC-6004 infusion. 
 
Section 5.4 - Dose Delays and Modifications; Section 5.4.1 – NC-6004 Dose Delays and 
Modifications 
Updated “Grade 3 or 4 toxicity” to “Grade 3 or 4 toxicity (recurrence of the same AE)” to 
more clearly define the recurrence of DLTs that could lead to study drug withdrawn. 
Section 3.1 - Study Design; Section 5.4 - Dose Delays and Modifications; Section 6.3.7 - 
Physical Examination; Section 11 - Reference List; Section 12.1 - Appendix: Schedule of 
Events, footnote g 
It was added that the doses of NC-6004 and gemcitabine will be calculated in milligrams per 
square meter (mg/m2) at screening and will not be changed in subsequent cycles unless the 
patient’s body weight increases or decreases by at least 10% from the patient’s screening 
weight measurement. This threshold should not be confused with a change in the patient’s 
body surface area (mg/m2). Any change in a patient’s weight by at least 10% during the study 
will require a recalculation of the doses of NC-6004 and gemcitabine. Weight will be 
measured before treatments on Day 1 of each cycle, with a calculation of body surface area 
before each dosing on Day 1 of each cycle (using the Mosteller formula [Mosteller 1987]). 
Section 5.5.2 - Gemcitabine Drug Product; Section 5.6.1 - Study Drug Packaging and 
Storage 


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The generic gemcitabine was added to the protocol to clarify that it is acceptable for generic 
gemcitabine to be administered in this study (as per the original intent of the Protocol Author) 
in place of Gemzar. 
Section 5.6.2 – Test Article Accountability 
 
It was clarified that the PI should maintain accurate records of receipt of all test articles that 
are centrally provided. 
Section 6.2 - Pharmacokinetic and Pharmacodynamic Assessments Section 
12.1 - Appendix: Schedule of Events 
 
A 10-minute window after ECG performance was added for the pharmacokinetic blood 
sampling. 
Section 6.3.2.5 - Assessment of Causality 
 
“Study drug” was updated to “study drug (NC-6004 and gemcitabine)” to indicate that the 
assessment of an AE’s relatedness was to the combination of NC-6004 and gemcitabine. 
Section 6.3.6 – Electrocardiograms; Section 12.1 - Appendix: Schedule of Events 
 
A ±10-minute window for performance of 12-lead ECGs was added. 
 
Section 6.3.6 – Electrocardiograms; Section 6.3.8 - Vital Sign Measurements 
Section 12.1 - Appendix: Schedule of Events, footnote n 
The text “rest for at least 5 minutes” was updated to “adequately rested” for the patient 
before ECGs and vital sign measurements. 
Section 10.2.2 - Protocol Violations and Deviations 
 
Text was updated to clarify that Part 2 of this study will not require sponsor approval prior to 
each patient being enrolled in the study. 
Section 12.1 - Appendix: Schedule of Events 
 
A column was added to the Schedule of Events Table (Table 12-1) to clearly show that ECGs 
will be also performed on Day 2 of Cycle 1. For completeness, PK assessments, AE 
monitoring, and concomitant medication review were also added to Day 2 of Cycle 1. 


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12.4.3.3 
Changes to the Protocol Text 
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. Additions to the protocol text are shown in bold and 
deletions are shown in strikethrough text. Minor or obvious editorial and grammatical 
corrections are not highlighted. 
Protocol Synopsis – Study Sites 
 
Study Sites: At least 20 sites in the United States and Europe. 
 
Protocol Synopsis –Inclusion Criteria 
 
… 
 
5. Have an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1, with the exception 
of patients in Part 2 (Cohort 3, unfit bladder cancer patients) who may have an ECOG 
PS of 2. 
… 
 
8. In Part 1 and in Part 2 in Cohorts 1 and 2: Hhave adequate renal function defined as a 
creatinine clearance (CrCl) ≥50 mL/minute (calculated according to the formula of 
Cockcroft and Gault 1976) or serum creatinine <1.5 mg/dL. In Part 2, patients in Cohort 3 
(bladder cancer) must have a CrCl of ≥30 mL/min. 
• Bladder cancer patients in Cohort 3 of Part 2 will be stratified by ≥30 to 
<60 mL/min and/or ECOG PS 2 and ≥60 mL/min and ECOG PS 0 to 1. If 
2 of 6 patients (or ≥33% at any point during the study) in the ≥30 to 
<60 mL/min group have a worsening of CrCl (ie, 50% reduction from 
baseline for 2 consecutive assessments, at least 1 week apart), then 
enrollment of patients with CrCl <60 mL/min will stop in the bladder 
cancer cohort. 
9. Have a negative pregnancy test result at screening (for females of childbearing potential; 
not applicable to patients who are unable to become pregnant, including those with bilateral 
oophorectomy and/or hysterectomy or postmenopausal [no menses for the previous 
12 months]). The test must be performed within 1 week before Day 1 of treatment. 


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10. Male patients must agree to use a condom during treatment and for 90 days after 
dosing. Male patients must agree not to donate sperm for 90 days after dosing. 
11. 
For women of childbearing potential*: Aare willing to abstain from heterosexual 
activity or practice physical barrier contraceptionfollow 1 of the following effective 
methods of birth control from the time of study entry to 6 months after the last day of 
treatment.: 
• Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
• Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable) 
• Intrauterine devices 
• Intrauterine hormone-releasing system 
• Vasectomized partner 
• Bilateral tubal occlusion 
• True sexual abstinence** 
*Patients not of childbearing potential include those who are surgically sterile or 
postmenopausal (no menses for the previous 12 months). For women not currently 
taking contraceptive methods at screening, low user dependency contraceptive methods 
(eg, implantable progestogen-only hormonal contraception, intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner) 
are recommended. 
**The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient. 
Protocol Synopsis – Study Design 
 
This study will consist of 2 parts; Part 1 is a Phase 1b, continual reassessment method 
dose-escalation trial, and Part 2 is a Phase 2, adaptive, two-stage, open-label, expansion trial 
evaluating activity, safety, and tolerability at the RPII dose identified in Part 1. 


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… 
 
Part 2 of the study (Phase 2 portion) will begin after the RPII dose of NC-6004 is identified 
for use in combination with gemcitabine. All patients will receive NC-6004 at the RPII dose 
(135 mg/m2, established in Part 1) in combination with gemcitabine 1250 mg/m2 by the 
same regimen as in Part 1. 
Three cohorts of patients are eligible (Cohort 1: first-line metastatic squamous NSCLC; 
Cohort 2: first-line metastatic or locally advanced cholangiocarcinoma, gallbladder cancer, or 
ampullary cancer (biliary tract cancer); and Cohort 3: first-line metastatic or locally advanced 
TCC of the urinary tract (bladder cancer). Bladder cancer patients in Cohort 3 of Part 2 
will be stratified by ≥30 to <60 mL/min and/or ECOG PS 2 (unfit) and ≥60 mL/min and 
ECOG PS 0 to 1 (fit). If 2 of 6 patients (or ≥33% at any point during the study) in the 
≥30 to <60 mL/min group have a worsening of CrCl (ie, 50% reduction from baseline 
for 2 consecutive assessments, at least 1 week apart), then enrollment of patients with 
CrCl <60 mL/min will stop in the bladder cancer cohort. 
StagePart 2 will continue in each cohort after achieving the minimum threshold of clinical 
responses required and enroll up to 50 patients each in Cohorts 1 and 2, and up to 60 
patients in Cohort 3, for a total of up to 150 160 patients in Part 2. 
… 
 
Cohort 
Biliary 
Bladder (CrCl: 
≥60 mL/min 
and ECOG PS 
0-1; fit) 
Bladder (CrCl: 
≥30 to <60 
mL/min and/or 
ECOG PS 2; 
unfit) 
Squamous 
NSCLC 
Historical 
Median 
Duration of PFS 
8.8 months 
7.6 months 
5.8 months 
5 months 
Historical PFS 
Weekly Hazard 
0.01795 
0.020755 
0.02711 
0.031377 
Abbreviations: CrCl, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; NSCLC, non- 
small cell lung cancer; PS, performance status. 
Once 10 PFS events have been observed, interim analyses will be performed every 6 weeks. 
At each interim and at the final analysis, there are 3 possible outcomes for each cohort. 


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• Futility – 10 PFS events have been observed in each cohort and at least 1 of the 
following conditions is true: 
• Probability (Promising HR*) <0.4 
 
• Probability (Phase 3 Success*) <0.4 
 
• Success – 25 PFS events have been observed in each 50-patient cohort and 15 PFS 
events in each 30-patient bladder cancer cohort and: 
• Probability (Phase 3 Success*) >0.8 
 
• Inconclusive – neither futility nor success. 
 
* Phase 3 success is defined as success in a Phase 3 clinical trial with 381 events - enough to 
provide 80% power to detect an HR of 0.75. A promising HR is defined as one less than 0.85. 
*Futility can only be declared for a cohort after 10 PFS events have been observed in that 
cohort. Success can only be declared for a cohort after 25 or 15 PFS events have been 
observed in that 50-patient cohort (Cohort 1 and 2) or 30-patient bladder cancer cohort 
(Cohort 3, fit and unfit), respectively. Accrual will stop for any cohort identified as futile or 
successful at interim. The conclusion of this Phase 2 trial will be that a Phase 3 trial with 381 
events should be conducted for each cohort that is a success. 
Protocol Synopsis – Estimated Study Duration 
 
… 
 
Patients will receive study treatment until any of the following occur: 
… 
 
• For Cohort 3 only, unfit bladder cancer patient (≥30 to <60 mL/min CrCl at 
screening) has a worsening of CrCl (ie, 50% reduction from baseline for 
2 consecutive assessments, at least 1 week apart) 


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Protocol Synopsis – Definition of DLT 
 
A DLT (monitored in Part 1 only) is defined as the following treatment-related AEs or 
laboratory abnormalities, graded according to NCI CTCAE version 4.03: 
Protocol Synopsis – Sample Size 
 
… 
 
Part 2 is a 3-cohort study with an overall sample size of up to 150160 patients with no more 
than 50 patients per cohort in Cohorts 1 and 2 and no more than 60 patients in Cohort 3 
(30 unfit and 30 fit bladder cancer patients). The total sample size will depend on the 
results of interim futility and superiority analyses. In order to evaluate the overall sample size, 
simulations were performed assuming scenarios with different HRs for PFS for each cohort 
compared with historical control and different sample sizes for a subsequent Phase 3 clinical 
trial. The associated mean sample size for this trial in these scenarios ranged from 136 92.7 
to 146 116.8 patients. 
 
Protocol Synopsis – Study Drug, Dosage, and Route of Administration 
 
… 
 
In each part of the study, NC-6004 will be administered as a 1 hour (+10-minute window) 
intravenous infusion on Day 1 of each cycle. 
 
Section 3.1 - Study Design 
 
This study will consist of 2 parts; Part 1 is a Phase 1b, continual reassessment method 
dose-escalation trial in patients with any advanced solid tumor, and Part 2 is a Phase 2, 
adaptive two-stage, open-label, expansion trial in patients with squamous NSCLC, biliary 
tract, and bladder cancer evaluating activity, safety, and tolerability at the RPII dose 
identified in Part 1. 
… 
Part 2 of the study (Phase 2 portion) will begin after the RPII dose of NC-6004 is identified 
for use in combination with gemcitabine. All patients will receive NC-6004 at the RPII dose 
(135 mg/m2, established in Part 1) in combination with gemcitabine 1250 mg/m2 by the 
same regimen as in Part 1. Cohort 3 will stratify patients by creatinine clearance (CrCl) 
to assess study drug in patients with reduced kidney function (ie, CrCl of <60 to 


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≥30 mL/min [unfit] and ≥60 mL/min [fit]) in a controlled manner and with the 
stipulation that enrollment will stop if 2 of 6 patients in the <30 to ≥60 mL/min group 
have a worsening of CrCl (ie, 50% reduction from baseline for 2 consecutive 
assessments, at least 1 week apart). 
Three cohorts of patients are eligible (Cohort 1: first-line metastatic squamous NSCLC; 
Cohort 2: first-line metastatic or locally advanced cholangiocarcinoma, gallbladder cancer, or 
ampullary cancer (biliary tract cancer); and Cohort 3: first-line metastatic or locally advanced 
TCC of the urinary tract (bladder cancer). Stage 2 will continue in each cohort after 
achieving the minimum threshold of clinical responses required and Part 2 will enroll up to 
50 patients each in Cohorts 1 and 2, and up to 60 patients in Cohort 3, for a total of up 
to 160 patients in Part 2. in each cohort for a total of up to 150 patients in Part 2. The 
primary endpoint (PFS) will be continuously updated and compared with the historical PFS 
from Phase 3 pivotal cisplatin and gemcitabine trials within each cohort. The PFS hazard 
model will be updated as PFS data accrue. A hazard ratio (HR) for PFS for each cohort 
versus historical control will be obtained. 
 
Cohort 
Biliary 
Bladder 
(CrCl: ≥60 
mL/min; fit) 
Bladder 
(CrCl: ≥30 to 
<60 mL/min; 
unfit) 
Squamous 
NSCLC 
Historical 
Median 
Duration of 
PFS 
8.8 months 
7.6 months 
5.8 months 
5 months 
Historical 
PFS Weekly 
Hazard 
0.01795 
0.020755 
0.02711 
0.031377 
Abbreviations: CrCl: creatinine clearance; ECOG, Eastern Cooperative Oncology Group; 
NSCLC, non-small cell lung cancer; PS, performance status. 
 
Once 10 PFS events have been observed, interim analyses will be performed every 6 weeks. 
At each interim and at the final analysis, there are 3 possible outcomes for each cohort. 


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• Futility – 10 PFS events have been observed in each cohort and at least 1 of the 
following conditions is true: 
• Probability (Promising HR*) <0.4 
 
• Probability (Phase 3 Success*) <0.4 
 
• Success – 25 PFS events have been observed in each 50-patient cohort and 15 PFS 
events in each 30-patient bladder cancer cohort and: 
• Probability (Phase 3 Success*) >0.8 
 
• Inconclusive – neither futility nor success. 
 
* Phase 3 success is defined as success in a Phase 3 clinical trial with 381 events - enough to 
provide 80% power to detect an HR of 0.75. A promising HR is defined as one less than 0.85. 
*Futility can only be declared for a cohort after 10 PFS events have been observed in that 
cohort. Success can only be declared for a cohort after 25 or 15 PFS events have been 
observed in that 50-patient or 30-patient bladder cancer cohort, respectively. Accrual will 
stop for any cohort identified as futile or successful at interim. The conclusion of this Phase 2 
trial will be that a Phase 3 trial with 381 events should be conducted for each cohort that is a 
success. 
… 
Day 1 of Cycle 
The following procedures will be performed on Day 1 prior to NC-6004 infusion in each 
treatment cycles unless otherwise specified: 
• Pregnancy test (serum or urine) on Day 1 of each cycle (at Cycle 1only, serum or 
urine; test is not required if pregnancy test at screening was performed using serum) 
• Physical examination (if not performed on Day –1) 
• Height, weight, and calculation of body surface area using the Mosteller formula 
(Mosteller 1987) 
… 


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• Part 1 only: Core MDASI or MDASI module specific for lung cancer (MDASI-LC) 
(Section 6.1.3) 
… 
Day 8 of Each Cycle 
… 
• Part 1 only: Core MDASI or MDASI-LC 
… 
End-of-Treatment Visit 
The following procedures will be performed within 28 days after treatment discontinuation: 
 
• Pregnancy test (serum or urine) 
… 
• Part 1 only: Core MDASI or MDASI-LC (Part 1 only) 
Section 3.1.1 –Rationale of Study Design 
… 
In Part 1 only, Tthe MDASI will be used to evaluate symptoms related to QoL during 
treatment. 
Section 4.1 –Selection of Study Population 
Approximately 209 199 patients (up to 49 patients in Part 1 and up to 160 150 patients in 
Part 2) will be enrolled in at least 20 sites in the United States and Europe. Patients will be 
assigned to a study treatment only if they meet all of the inclusion criteria and none of the 
exclusion criteria. 
Section 4.1.1 – Inclusion Criteria 
 
5. Have an ECOG PS of 0 to 1, with the exception of patients in Part 2 (Cohort 3, unfit 
bladder cancer patients) who may have an ECOG PS of 2. 


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… 
 
8. In Part 1 and in Part 2 in Cohorts 1 and 2: Hhave adequate renal function defined as a 
CrCl ≥50 mL/minute (calculated according to the formula of Cockcroft and Gault 1976) or 
serum creatinine <1.5 mg/dL. In Part 2, patients in Cohort 3 (bladder cancer) must have 
a CrCl of ≥30 mL/min. 
• Bladder cancer patients in Cohort 3 of Part 2 will be stratified by ≥30 to 
<60 mL/min and/or ECOG PS 2 and ≥60 mL/min and ECOG PS 0 to 1. If 
2 of 6 patients (or ≥33% at any point during the study) in the ≥30 to 
<60 mL/min group have a worsening of CrCl (ie, 50% reduction from 
baseline for 2 consecutive assessments, at least 1 week apart), then 
enrollment of patients with CrCl <60 mL/min will stop in the bladder 
cancer cohort. 
9. Have a negative pregnancy test result at screening (for females of childbearing potential; 
not applicable to patients who are unable to become pregnant, including those with bilateral 
oophorectomy and/or hysterectomy or postmenopausal [no menses for the previous 
12 months]). The test must be performed within 1 week before Day 1 of treatment. 
 
10. Male patients must agree to use a condom during treatment and for 90 days after 
dosing. Male patients must agree not to donate sperm for 90 days after dosing. 
11. 
For women of childbearing potential*: Aare willing to abstain from heterosexual 
activity or practice physical barrier contraceptionfollow 1 of the following effective 
methods of birth control from the time of study entry to 6 months after the last day of 
treatment.: 
• Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
• Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable) 
• Intrauterine devices 
• Intra-uterine hormone-releasing system 
• Vasectomized partner 


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• Bilateral tubal occlusion 
• True sexual abstinence**. 
*Patients not of childbearing potential include those who are surgically sterile or 
postmenopausal (no menses for the previous 12 months). For women not currently 
taking contraceptive methods at screening, low user dependency contraceptive methods 
(eg, implantable progestogen-only hormonal contraception, intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner) 
are recommended. 
**The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient. 
… 
 
Section 4.2.1 – Reasons for Withdrawal/Discontinuation 
 
… 
 
A patient may be withdrawn from the study for any of the following reasons: 
 
… 
 
• For Cohort 3 only, unfit bladder cancer patient (≥30 to <60 mL/min CrCl at 
screening) has a worsening of CrCl (ie, 50% reduction from baseline for 
2 consecutive assessments, at least 1 week apart) 
Section 5.1 - Method of Assigning Patients to Treatment Groups 
This is an open-label study that will be conducted in 2 parts. In both parts, NC-6004 will be 
administered as a 1-hour (+10-minute window) intravenous infusion on Day 1 of each cycle. 
Gemcitabine 1250 mg/m2 will be administered as a 30-minute intravenous infusion on Day 1 
of each cycle (after the administration of NC-6004) and on Day 8 of each cycle. The duration 
of each cycle will be 21 days. 
… 
 
In Part 2, all patients will receive the RPII dose (135 mg/m2) of NC-6004 identified in Part 1. 
Bladder cancer patients in Cohort 3 of Part 2 will be stratified by ≥30 to <60 mL/min 


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and/or ECOG PS 2 (unfit) and ≥60 mL/min and ECOG PS 0 to 1 (fit) . If 2 of 6 patients 
(or ≥33% at any point during the study) in the ≥30 to <60 mL/min group have a 
worsening of CrCl (ie, 50% reduction from baseline for 2 consecutive assessments, at 
least 1 week apart), then enrollment of patients with CrCl <60 mL/min will stop in the 
bladder cancer cohort. 
Section 5.3 - Treatments Administered 
The duration of each treatment cycle will be 21 days in both parts of the study. NC-6004 will 
be administered on Day 1 of each cycle as a 1-hour (+10-minute window) intravenous 
infusion. 
… 
 
In Part 2, on Day 1 of each cycle, all patients will receive NC-6004 at the RPII dose 
(135 mg/m2) identified in Part 1 and 1250 mg/m2 gemcitabine. On Day 8 of each cycle, all 
patients in Part 2 of the study will receive 1250 mg/m2 gemcitabine. 
Section 5.4 - Dose Delays and Modifications 
 
The doses for NC-6004 and gemcitabine will be calculated in milligrams per square 
meter (mg/m2) at screening, and will not be changed in subsequent cycles unless the 
patient’s body weight has increased or decreased by ≥10% from the patient’s weight 
measurement at screening. Any change in a patient’s weight by ≥10% during the study 
will require a recalculation of the doses of all study drugs (Note: This threshold should 
not be confused with a change of a patient’s body surface area [BSA] [mg/m2]). Weight 
will be measured before treatments on Day 1 of each cycle, with calculation of BSA 
before dosing on Day 1 of each cycle (using the Mosteller formula [Mosteller 1987]). 
Patients experiencing significant toxicities must be immediately and permanently withdrawn 
from treatment with NC-6004 and gemcitabine as follows: 


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• Any patient who experiences a Grade 3 or 4 hypersensitivity reaction during any 
cycle of treatment 
• Any patient who experiences 2 protocol-defined DLTs during treatment 
 
• Any patient who experiences a recurrent Grade 3 or 4 toxicity (recurrence of the 
same AE) after a dose reduction 
Section 5.4.1 – NC-6004 Dose Delays and Modifications 
 
… 
 
Following recovery to Grade 1 or lower, treatment may resume at the investigator’s 
discretion. Patients who resume treatment following a dose delay will have the dose of study 
drug reduced by 50% for the remainder of study treatment. If toxicities persist or recur to 
Grade 3 or 4 (recurrence of the same AE) after the dose reduction, study treatment will be 
terminated. 
Section 5.5.2 - Gemcitabine Drug Product 
 
Gemzar® (gemcitabine for injection, USP), is available in sterile single-use vials individually 
packaged in a carton containing: 200 mg white to off-white, lyophilized powder in a 
10-mL size sterile single-use vial or 1 g white to off-white, lyophilized powder in a 
50-mL size sterile single-use vial. Vials of gemcitabineGemzar contain either 200 mg or 1 g 
of gemcitabine hydrochloride (expressed as free base) formulated with mannitol (200 mg or 
1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile 
lyophilized powder. Hydrochloric acid and/or sodium hydroxide may have been added for 
pH adjustment. 
Section 5.6.1 - Study Drug Packaging and Storage 
 
All study drugs must be stored in a secure area (eg, a locked cabinet). NC-6004 should be 
protected from light and stored refrigerated (2° to 8°C). Unopened vials 
of Gemzar (gemcitabine) are stable until the expiration date indicated on the package when 
stored at controlled room temperature 20° to 25°C that allows for excursions between 15° 
and 30°C. 
Section 5.6.2 – Test Article Accountability 


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The investigator will maintain accurate records of receipt of all test articles that are 
centrally provided, including dates of receipt. 
Section 6.1 – Efficacy Assessments 
 
… 
 
Symptom changes will be assessed using the core MDASI (Part 1 only) or MDASI-LC (only 
in patients with NSCLC in Part 1) (Section 6.1.3) on Days 1 and 8 of each cycle and at the 
End-of-Treatment visit. 
… 
 
Section 6.2 - Pharmacokinetic and Pharmacodynamic Assessments 
 
… 
 
Pharmacokinetics blood sampling should occur within 10% of nominal time for Days 1 and 2 
and ±4 hours of nominal time for all other time points, and should occur within 10 minutes 
after the 12-lead ECGs performance at time-matched visits (Section 6.3.6). All PK 
samples will be evaluable as long as the actual collection times are recorded. 
Section 6.3.1.1 – Definition of Dose-Limiting Toxicities 
 
A DLT (monitored in Part 1 only) is defined as the following treatment-related AEs or 
laboratory abnormalities, graded according to the NCI CTCAE version 4.03: 
Section 6.3.1.2.1 - Safety Monitoring in Part 2 
 
During Part 2 of the study, patients treated with NC-6004 at the RPII dose from Part 1 will be 
monitored for safety. Dose delay and modification rules for both NC-6004 and gemcitabine 
apply in Part 2 as in Part 1. 
In Part 2 (Cohort 3) if 2 of 6 patients (or ≥33% at any point during the study) in the ≥30 
to <60 mL/min group have a worsening of CrCl (ie, 50% reduction from baseline for 2 
consecutive assessments, at least 1 week apart), then enrollment of patients with CrCl 
<60 mL/min will stop in the bladder cancer cohort. In addition, in Part 2 (Cohort 3), if 
an unfit bladder cancer patient (≥30 to <60 mL/min CrCl at screening) has a worsening 


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of CrCl (ie, 50% reduction from baseline for 2 consecutive assessments, at least 1 week 
apart) he or she may be withdrawn from the study (Section 4.2.1). 
Section 6.3.2.5 - Assessment of Causality 
 
The investigator’s assessment of an AE’s relationship to study drug (combination of 
NC-6004 and gemcitabine) is part of the documentation process, but it is not a factor in 
determining what is or is not reported in the study. If there is any doubt as to whether a 
clinical observation is an AE, the event should be reported. 
Section 6.3.6 – Electrocardiograms 
 
All 12-lead ECGs will be performed after the patient has adequately rested in the supine 
position for at least 5 minutes. 
On Day 1 of Cycle 1, 12-lead ECGs will be performed before the start of the NC-6004 
infusion, at completion of infusion (~1 hour after start of infusion), and at Hours 3 and 
24 hours (Day 2) after start of infusion. On Day 8 of Cycle 1, 12-lead ECGs will be 
performed before the start of gemcitabine infusion, at the completion of gemcitabine infusion, 
and at 1 hour after completion of gemcitabine infusion. Twelve-lead ECGs will also be 
performed on Day 1 of Cycles 2 through 6 before the start of the NC-6004 infusion and at the 
End-of-Treatment visit. All 12-lead ECGs should be performed within a ±10-minute 
window. 
Section 6.3.7 - Physical Examination 
 
A complete physical examination will be performed during the screening period at Day -14 
to -1, before study treatments on Day –1 or Day 1 of each cycle, and at the End-of-Treatment 
visit. Height and weight will also be assessed at the time of the screening period physical 
examination and before treatments on Day 1 of each cycle. with Calculation of BSA will be 
done before each dosing on Day 1 of each cycle (using the Mosteller formula 
[Mosteller 1987]. (Note: Dose will only be recalculated if there is a ≥10% increase or 
decrease in the patient’s weight from the patient’s weight measurement at screening. 
Any change in a patient’s weight by ≥10% during the study will require a recalculation 
of the doses of all study drugs. This threshold should not be confused with a change of a 
patient’s BSA [mg/m2]). 
Section 6.3.8 - Vital Sign Measurements 


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Vital sign measurements will include arterial blood pressure, heart rate, respiratory rate, and 
temperature. Vital signs will be measured after the patient has adequately rested in the 
supine position for at least 5 minutes. 
Section 7.3 - Sample Size Calculations 
 
This is a Phase 1b/2 study with an overall sample size of up to 199 209 patients (up to 49 
patients in Part 1 and up to 150160 patients in Part 2). The total sample size will depend on 
the number of cohorts required to establish an RPII dose and the number of patients with 
NSCLC enrolled at the RPII dose in Part 1. 
… 
 
Part 2 is a 3-cohort study with an overall sample size of up to 150 160 patients with no more 
than 50 patients per cohort in Cohorts 1 and 2 and no more than 60 patients in Cohort 3. 
The total sample size will depend on the results of interim futility and superiority analyses. In 
order to evaluate the overall sample size, simulations were performed assuming scenarios 
with different HRs for PFS for each cohort compared with historical control and different 
sample sizes for a subsequent Phase 3 clinical trial. The associated mean sample size for this 
trial in these scenarios ranged from 92.7136 to 116.8 146 patients. 
Section 10.2.2 - Protocol Violations and Deviations 
 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
patient or investigator that results in a significant, additional risk to the patient. Significant 
deviations can include nonadherence to inclusion or exclusion criteria, enrollment of the 
patient without prior sponsor approval, or nonadherence to FDA regulations or ICH GCP 
guidelines, and will lead to the patient being withdrawn from the study (Section 4.2). 
Section 11 - Reference List 
 
… 
 
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 
1987;317(17):1098. 


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Section 12.1 - Appendix: Schedule of Events 


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Table 12-1 
Schedule of Events 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7 Onwarda 
End-of- 
Treatmentb 
Follow-upc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
2 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Informed consent 
X 
Eligibility criteria 
X 
Demography 
X 
Medical history 
X 
Pregnancy test (serum or urine) 
X 
Xe 
X 
X 
X 
X 
Physical examination 
Xf 
Xf 
X 
X 
X 
X 
Height, weight, and BSA 
calculationg 
Xg 
X 
X 
X 
X 
Vital signsh 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status (ECOG) 
Xf 
Xf 
X 
X 
X 
X 
Disease assessmenti 
X 
Xi 
Xi 
X 
X 
Audiometry 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Hematology 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (dipstick) 
X 
X 
EORTC QLQ-C30 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDASI or MDASI-LCl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nausea and vomiting patient 
diarym 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Part 2 Nausea and vomiting patient 
diarym 
X 
X 
X 
X 
Cardiac risk factors 
X 
12-lead ECGn 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic assessments 
(Part 1)o 
X 
X 
X 
X 
X 
X 
Xo 
Xo 
X 
Pharmacokinetic assessments 
(Part 2)p 
X 
X 
X 
X 
X 
X 
X 


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Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7 Onwarda 
End-of- 
Treatmentb 
Follow-upc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
2 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Adverse events 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
Xf 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prophylactic administrations 
X 
X 
X 
X 
NC-6004 administrationa 
X 
X 
X 
X 
Gemcitabine administration 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: BSA, body surface area; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-C30, European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; MDASI, MD Anderson Symptom Inventory; RECIST, Response Evaluation Criteria 
in Solid Tumors; MDASI-LC, MDASI-lung cancer. 
 
 
a. 
In Part 1 of the study, patients will receive treatment until progressive disease. In Part 2 of the study, patients will receive treatment for 6 cycles (Cohorts 1 
and 3) or 8 cycles (Cohort 2). 
b. End-of-treatment assessments will be performed within 28 days after treatment discontinuation. 
c. 
After patient discontinuation or completion of treatment without disease progression, patients will be followed with scans every 9 weeks until disease 
progression. Patients will be called every 12 (±1) weeks to collect data on patient survival, new treatments, and adverse events. 
d. Day 15 visit is required in Part 1. In Part 2, Day 15 visit is only necessary if it is clinically indicated. 
e. 
Not required if screening pregnancy test was performed using serum. 
f. 
Safety assessments of physical examination, ECOG, review of AEs, and concomitant medication use can be completed on Day -1 to allow for early morning 
dosing. These should not be conducted in place of screening assessments. 
g. Height and weight only. From Day -14 to -1 at screening, only height and weight will be measured, On Day 1 of Cycle 1 through 7, weight will be 
measured before treatments and BSA will be calculated before each dose using the Mosteller formula (Mosteller 1987). (Note: Dose will only be 
recalculated if there is a ≥10% increase or decrease in the patient’s weight from the patient’s screening weight measurement. Any change in a 
patient’s weight by ≥10% during the study will require a recalculation of the doses of all study drugs. This threshold should not be confused with a 
change of a patient’s BSA [mg/m2]). 
h. On Day 1 of Cycle 1, vital signs will be measured before the start of the NC-6004 infusion, every 20 minutes during the infusion, at the completion of the 
infusion, and 1 hour after the completion of the NC-6004 infusion. Starting in Cycle 2, vital signs will be measured before the start of the NC-6004 infusion 
and at the completion of the NC-6004 infusion on Day 1 of each cycle. Vital signs will be measured before and after gemcitabine infusion on Day 8 of each 
cycle. 


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i. 
Disease assessment will be performed using RECIST version 1.1 and the same imaging method used at screening should be used for all subsequent 
assessments. Beginning in Cycle 3 and continuing through the remainder of the treatment cycles, disease will be assessed every 6 (±1) weeks (ie, every other 
cycle) and at the End-of-Treatment visit or until disease progression. Patients who have obtained a partial response or complete response will have a 
confirmatory scan at a minimum of 4 weeks following the initial scan. 
j. 
To be performed only as clinically indicated. 
k. Hematology or biochemistry tests will be repeated prior to dosing on Day 1 of Cycle 1 if they were last performed more than 24 hours before the start of the 
study drug administration. 
l. 
Symptom changes will be assessed using the core MDASI (Part 1 only) or MDASI-LC (only in patients with NSCLC in Part 1). 
m. Diary issued on Day 1 of each cycle. Assessment is performed at the site before dosing on Day 1 and Day 8 as well as Day 15 (Day 15 diary collected in Part 
1 only; note: no dosing on Day 15) of each cycle. Patient completes diary at home on Days 2 through 8 and returns diary on Day 8. 
n. Twelve-lead ECGs will be performed after the patient has adequately rested in the supine position for at least 5 minutes. On Day 1 of Cycle 1, 12-lead 
ECGs will be performed before the start of the NC-6004 infusion, at completion of infusion (~1 hour after start of infusion), and at Hours 3 and 24 (Day 2) 
after the start of infusion. On Day 8 of Cycle 1, 12-lead ECGs will be performed before the start of gemcitabine infusion, at the end of gemcitabine infusion, 
and at 1 hour after completion of gemcitabine infusion. Twelve-lead ECGs will be performed on Day 1 of Cycles 2 through 6 before the start of the NC-6004 
infusion, and at the End-of-Treatment visit. All 12-lead ECGs can be performed within a ±10-minute window. 
o. For Part 1, blood samples will be collected at the following times: before the start of the NC-6004 infusion on Day 1 of Cycles 1 through 6, at end of NC- 
6004 infusion in Cycles 1, 3, and 5, after the start of NC-6004 infusion at Hours 3, 6, 12, 24 (Day 2), 48 (Day 3), 96 (Day 5), 168 and prior to gemcitabine 
infusion (Day 8), and 336 (Day 15) in Cycles 1, 3, and 5, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample collections may be 
performed, at the discretion of the investigator, during any visit where toxicity is observed. Blood samples will be collected within 10 minutes after the 
12-lead ECGs performance. 
p. For Part 2 (up to 6 cycles), on the day of NC-6004 infusion for each cycle, blood samples will be collected before the start of the NC-6004 infusion, at the 
end of the NC-6004 infusion, before gemcitabine infusion on Day 8, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample collections 
may be performed, at the discretion of the investigator, during any visit where toxicity is observed. Blood samples will be collected within 10 minutes 
after the 12-lead ECGs performance. 


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12.4.4 Protocol Amendment 3–Protocol Version 4.1, Incorporating 
Amendment 3, Dated 31 August 2016 
The following sections detail the changes made to Amendment 2 of the protocol 
(Version 3.0) dated 07 July 2015. The integrated protocol, Version 4.1, including 
Amendment 3, was issued on 31 August 2016. 
 
12.4.4.1 
Overview of Changes 
The overview of significant changes includes the following: 
 
Inclusion criteria numbers 9, 10, 11 (Synopsis and Section 4.1.1) and the Schedule of Events 
(Table 12-1, Section 12.1) were amended per the recommendation by the Voluntary 
Harmonisation Procedure (VHP) on 25 July 2016. These changes were made to account for 
the toxic reproductive characteristics of cisplatin and gemcitabine, and to adequately define 
contraceptive measures that comply with the “Recommendations related to contraception and 
pregnancy testing in clinical trials” per the Clinical Trials Facilitation Group (CTFG). 
Inclusion criterion #9 added that a negative pregnancy test is not applicable for female 
patients who are postmenopausal (defined as no menses for the previous 12 months). 
Inclusion criterion #10 added the requirement that male patients must agree to use a condom 
during treatment and for 90 days after dosing. Male patients must agree not to donate sperm 
for 90 days after dosing. 
Inclusion criterion #11 added that women of childbearing potential should be willing to 
follow 1 of the following effective methods of birth control from the time of study entry to 
6 months after the last day of treatment: 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, or transdermal) 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, or implantable) 
• 
Intrauterine devices 
• 
Intrauterine  hormone-releasing system 
• 
Vasectomized partner who has received medical assessment of surgical success 
• 
Bilateral tubal occlusion 


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• 
True sexual abstinence 
 
In the Schedule of Events, pregnancy testing was added for Day 1 of Cycle 2, Cycles 3 
through 6, and Cycle 7 Onward, and at the End of Treatment. 
 
12.4.4.2 
Changes to the Protocol Text 
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. Additions to the protocol text are shown in bold and 
deletions are shown in strikethrough text. Minor or obvious editorial and grammatical 
corrections are not highlighted. 
Synopsis – Inclusion Criteria 
 
… 
 
9. Have a negative pregnancy test result at screening (for females of childbearing 
potential; not applicable to patients who are unable to become pregnant, including 
those with bilateral oophorectomy and/or hysterectomy). or postmenopausal [no 
menses for the previous 12 months]). The test must be performed within 1 week 
before Day 1 of treatment. 
10. Male patients must agree to use a condom during treatment and for 90 days 
after dosing. Male patients must agree not to donate sperm for 90 days after 
dosing. 
11. For women of childbearing potential*: are willing to abstain from heterosexual 
activity or practice physical barrier contraception follow 1 of the following effective 
methods of birth control from the time of study entry to 6 months after the last day 
of treatment: 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
• 
Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable) 
• 
Intrauterine devices 


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• 
Intrauterine hormone-releasing system 
 
• 
Vasectomized partner who has received medical assessment of surgical 
success 
• 
Bilateral tubal occlusion 
 
• 
True sexual abstinence** 
 
*Patients not of childbearing potential include those who are surgically sterile or 
postmenopausal (no menses for the previous 12 months). For women not 
currently taking contraceptive methods at screening, low user-dependency 
contraceptive methods (eg, implantable progestogen-only hormonal 
contraception, intrauterine device, intrauterine hormone-releasing system, 
bilateral tubal occlusion, vasectomized partner) are recommended. 
**The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Section 4.1.1 – Inclusion Criteria 
 
… 
 
9. Have a negative pregnancy test result at screening (for females of childbearing 
potential; not applicable to patients who are unable to become pregnant, including 
those with bilateral oophorectomy and/or hysterectomy). or postmenopausal [no 
menses for the previous 12 months]). The test must be performed within 1 week 
before Day 1 of treatment. 
10. Male patients must agree to use a condom during treatment and for 90 days 
after dosing. Male patients must agree not to donate sperm for 90 days after 
dosing. 
11. For women of childbearing potential*: are willing to abstain from heterosexual 
activity or practice physical barrier contraception follow 1 of the following effective 
methods of birth control from the time of study entry to 6 months after the last 
day of treatment: 


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• 
Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
• 
Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable) 
• 
Intrauterine devices 
 
• 
Intrauterine hormone-releasing system 
 
• 
Vasectomized partner who has received medical assessment of surgical 
success 
• 
Bilateral tubal occlusion 
 
• 
True sexual abstinence** 
 
*Patients not of childbearing potential include those who are surgically sterile or 
postmenopausal (no menses for the previous 12 months). For women not currently 
taking contraceptive methods at screening, low user-dependency contraceptive 
methods (eg, implantable progestogen-only hormonal contraception, intrauterine 
device, intrauterine hormone-releasing system, bilateral tubal occlusion, 
vasectomized partner) are recommended. 
**The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Table 12-1, Section 12.1 – Schedule of Events 


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Table 12-1 
Schedule of Events 
 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7 Onwarda 
End-of- 
Treatmentb 
Follow- 
upc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Informed consent 
X 
Eligibility criteria 
X 
Demography 
X 
Medical history 
X 
Pregnancy test (serum or urine) 
X 
Xe 
X 
X 
X 
X 
Physical examination 
Xf 
Xf 
X 
X 
X 
X 
Height, weight, and BSA 
calculation 
Xg 
X 
X 
X 
X 
Vital signs 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status (ECOG) 
Xf 
Xf 
X 
X 
X 
X 
Disease assessmenti 
X 
Xi 
Xi 
X 
X 
Audiometry 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Hematology 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (dipstick) 
X 
X 
EORTC QLQ-C30 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDASI or MDASI-LCl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nausea and vomiting patient 
diarym 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Part 2 Nausea and vomiting patient 
diarym 
X 
X 
X 
X 
Cardiac risk factors 
X 
12-lead ECGn 
X 
X 
X 
X 
X 
X 
Pharmacokinetic assessments 
(Part 1)o 
X 
X 
X 
X 
X 
Xo 
Xo 
X 
Pharmacokinetic assessments 
(Part 2)p 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7 Onwarda 
End-of- 
Treatmentb 
Follow- 
upc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Concomitant medication 
Xf 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prophylactic administrations 
X 
X 
X 
X 
NC-6004 administrationa 
X 
X 
X 
X 
Gemcitabine administration 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BSA, body surface area; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-C30, European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; MDASI, MD Anderson Symptom Inventory; RECIST, Response Evaluation Criteria 
in Solid Tumors; MDASI-LC, MDASI-lung cancer. 
a. 
In Part 1 of the study, patients will receive treatment until progressive disease. In Part 2 of the study, patients will receive treatment for 6 cycles (Cohorts 1 
and 3) or 8 cycles (Cohort 2). 
b. End-of-treatment assessments will be performed within 28 days after treatment discontinuation. 
c. 
After patient discontinuation or completion of treatment without disease progression, patients will be followed with scans every 9 weeks until disease 
progression. Patients will be called every 12 (±1) weeks to collect data on patient survival, new treatments, and adverse events. 
d. Day 15 visit is required in Part 1. In Part 2, Day 15 visit is only necessary if it is clinically indicated. 
e. 
Not required if screening pregnancy test was performed using serum. 
f. 
Safety assessments of physical examination, ECOG, review of AEs, and concomitant medication use can be completed on Day -1 to allow for early morning 
dosing. These should not be conducted in place of screening assessments. 
g. Height and weight only. 
h. On Day 1 of Cycle 1, vital signs will be measured before the start of the NC-6004 infusion, every 20 minutes during the infusion, at the completion of the 
infusion, and 1 hour after the completion of the NC-6004 infusion. Starting in Cycle 2, vital signs will be measured before the start of the NC-6004 infusion 
and at the completion of the NC-6004 infusion on Day 1 of each cycle. Vital signs will be measured before and after gemcitabine infusion on Day 8 of each 
cycle. 
i. 
Disease assessment will be performed using RECIST version 1.1 and the same imaging method used at screening should be used for all subsequent 
assessments. Beginning in Cycle 3 and continuing through the remainder of the treatment cycles, disease will be assessed every 6 (±1) weeks (ie, every other 
cycle) and at the End-of-Treatment visit or until disease progression. Patients who have obtained a partial response or complete response will have a 
confirmatory scan at a minimum of 4 weeks following the initial scan. 
j. 
To be performed only as clinically indicated. 
k. Hematology or biochemistry tests will be repeated prior to dosing on Day 1 of Cycle 1 if they were last performed more than 24 hours before the start of the 
study drug administration. 
l. 
Symptom changes will be assessed using the core MDASI or MDASI-LC (only in patients with NSCLC in Part 1). 
m. Diary issued on Day 1 of each cycle. Assessment is performed at the site before dosing on Day 1 and Day 8 as well as Day 15 (Day 15 diary collected in Part 
1 only; note: no dosing on Day 15) of each cycle. Patient completes diary at home on Days 2 through 8 and returns diary on Day 8. 


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n. Twelve-lead ECGs will be performed after the patient has rested in the supine position for at least 5 minutes. On Day 1 of Cycle 1, 12-lead ECGs will be 
performed before the start of the NC-6004 infusion, at completion of infusion (~1 hour after start of infusion), and at Hours 3 and 24 (Day 2) after the start 
of infusion. On Day 8 of Cycle 1, 12-lead ECGs will be performed before the start of gemcitabine infusion, at the end of gemcitabine infusion, and at 1 hour 
after completion of gemcitabine infusion. Twelve-lead ECGs will be performed on Day 1 of Cycles 2 through 6 before the start of the NC-6004 infusion, and 
at the End-of-Treatment visit. 
o. For Part 1, blood samples will be collected at the following times: before the start of the NC-6004 infusion on Day 1 of Cycles 1 through 6, at end of NC- 
6004 infusion in Cycles 1, 3, and 5, after the start of NC-6004 infusion at Hours 3, 6, 12, 24 (Day 2), 48 (Day 3), 96 (Day 5), 168 and prior to gemcitabine 
infusion (Day 8), and 336 (Day 15) in Cycles 1, 3, and 5, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample collections may be 
performed, at the discretion of the investigator, during any visit where toxicity is observed. 
p. For Part 2 (up to 6 cycles), on the day of NC-6004 infusion for each cycle, blood samples will be collected before the start of the NC-6004 infusion, at the 
end of the NC-6004 infusion, before gemcitabine infusion on Day 8, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample collections 
may be performed, at the discretion of the investigator, during any visit where toxicity is observed. 


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12.4.5 Protocol Amendment 3-Protocol Version 4.2, Incorporating 
Amendment 3-Version 4.0 (US only, dated 31 July 2016) 
The following sections detail the changes made to Protocol Amendment 3-Version 4.0 (US 
only, dated 31 July 2016). Version 4.0 was submitted to the FDA and not subsequently 
modified. 
Version 4.0 included European Medicines Agency (EMA) VHP-requested changes in 
addition to other changes not specifically requested by the VHP. Following submission of 
Version 4.0 to the VHP, the VHP requested a version of the protocol that only included the 
VHP-requested changes; therefore, Protocol Amendment 3-Version 4.1 (dated 
31 August 2016) was submitted to the VHP (EU only) to meet this request. 
 
Protocol Amendment 3-Version 4.2 (US and EU) harmonizes Versions 4.0 and 4.1 and was 
finalized on 12 December 2016. A separate summary of the changes made to Version 4.1 is 
included in Section 12.4.6. 
 
12.4.5.1 
Risk Assessment for Amendment 3, Version 4.2 
No anticipated increased patient risk has been introduced with the updates made during this 
protocol amendment. Based on new safety information received from an ongoing non-US, 
non-IND, Japanese trial with NC-6004 (Study NC-6004-007), additional exclusion criteria 
have been added to mitigate risk of liver toxicity in patients predisposed to liver injury. In 
addition, sites and investigators have been instructed to closely monitor ongoing NC-6004 
patients who are known to have pre-existing alcoholic liver injury and/or concurrent heavy 
alcohol consumption for newly emerging liver injury. 
 
12.4.5.2 
Overview of Changes 
The overview of significant changes includes the following: 
 
Title Page – Current Version and Date of Protocol; Title Page – Previous Dates and 
Versions 
The current and previous protocol amendment versions and applicable regions were updated 
to provide complete transparency and increased clarity. 


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Declaration of Investigator 
 
A declaration of investigator page, which includes a principal investigator signature line was 
added. 
Protocol Synopsis – Exclusion Criteria; Section 4.1.2 – Exclusion Criteria 
 
The exclusion criteria 11 and 12 were added to reflect the following: 
 
11. Have pre-existing alcoholic liver injury or significant liver disease. 
 
12. Are regularly consuming alcohol within 6 months of Screening defined as an average 
weekly intake of >21 units (or an average daily intake of >3 units) for males or >14 units (or 
an average daily intake >2 units) for females. One unit is equivalent to 8 g of alcohol: a 
half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine, or 1 measure (25 mL) of 
spirits. 
Protocol Synopsis – Study Design 
 
A +10-minute window was added to the 1-hour infusion of NC-6004 infusion. 
 
Protocol Synopsis – Study Design; Section 3.1 – Study Design 
 
It was clarified that all patients who discontinue treatment and have not progressed will have 
an End-of-Treatment visit, will be followed with scans every 9 weeks until disease 
progression, and will be contacted for survival every 12 weeks by telephone. 


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Protocol Synopsis – Safety Assessments; Section 6.3.5 – Clinical Laboratory Analyses 
 
It was specified that only abnormal laboratory results deemed to be clinically significant will 
be recorded as AEs or SAEs. 
Protocol Synopsis – Safety Assessments 
 
For internal consistency, it was added that audiometry will also be performed as clinically 
indicated at the End-of-Treatment visit. 
Section 3.1 - Study Design 
 
A cross-reference to the amendment-specified imaging methods was added. 
 
At the Follow-up visit, text was updated to specify that new treatments would be collected 
(Previous text stated medication history would be collected). 
Section 3.1 - Study Design 
 
Text was added to specify that pregnancy testing at Cycle 1, serum or urine; test is not 
required on Day 1 of Cycle 1 if pregnancy test at screening was performed using serum. 
Section 5.2 – Prophylactic Treatments; Section 5.8 – Prophylaxis and Management of 
Hypersensitivity Reactions 
It was added that 20 mg famotidine can be given intravenously as an option in place of 50 mg 
of ranitidine given intravenously. 
Section 5.8 – Prophylaxis and Management of Hypersensitivity Reactions 
 
If a Grade 1 or Grade 2 hypersensitivity occurs in a patient, it was added that 40 mg 
famotidine can be given orally once per day as an option in place of ranitidine 150 mg orally 
given 2 times per day. 
Section 6.1.1 – Disease Response Definitions 
 
Guidelines for imaging, including the timing, anatomic coverage, imaging method, and slice 
thickness were added. 


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Section 6.1.3 – MD Anderson Symptom Inventory 
 
Reference to the Study Manual was removed from the protocol. 
 
Section 6.3.2.3 – Reporting Adverse Events 
 
Text was added to clarifying the process for capturing events in the EDC system, and 
European SAE hotline and fax line numbers were added. 
Section 6.3.3 – Assessment of Nausea and Vomiting; Section 12.1 - Appendix: Schedule of 
Events, footnote m 
Text was added to specify the process for administering and capturing data in the nausea and 
vomiting patient diary. 
Section 6.3.5.3 – Urinalysis; Section 12.1 - Appendix: Schedule of Events 
 
Reference to a dipstick urinalysis was removed to allow flexibility in the type of urinalysis 
testing. 
Section 6.3.6 – Electrocardiograms; Section 6.3.8 - Vital Sign Measurements; 
Section 12.1 - Appendix: Schedule of Events, footnote h and n 
Text was also added to specify that ECGs will be performed during the screening period at 
Day –7 to –1 and that vital signs will also be measured at the End-of-Treatment visit. The 
ECG performance window was updated to a ±30-minute window. 
Section 12.1 - Appendix: Schedule of Events, footnote g 
 
Text was updated to specify that weight will be measured on Day 1 of each cycle. 


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12.4.5.3 
Changes to the Protocol Text 
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. Additions to the protocol text are shown in bold and 
deletions are shown in strikethrough text. Minor or obvious editorial and grammatical 
corrections are not highlighted. 
Protocol Synopsis – Exclusion Criteria 
 
… 
 
11. Have pre-existing alcoholic liver injury or significant liver disease. 
 
12. Are regularly consuming alcohol within 6 months of Screening defined as an 
average weekly intake of >21 units (or an average daily intake of >3 units) for males or 
>14 units (or an average daily intake >2 units) for females. One unit is equivalent to 8 g 
of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine, or 
1 measure (25 mL) of spirits. 
 
Protocol Synopsis – Study Design 
 
… 
 
On Day 1 of each cycle, patients will receive NC-6004 over 1 hour (+10-minute window) 
followed by an infusion of gemcitabine 1250 mg/m2 over 30 minutes. 
 
Protocol Synopsis – Study Design 
 
… 
 
Patients who discontinue treatment due to an AE and have not progressed will have an 
End-of-Treatment visit, will be followed with scans every 9 weeks until disease progression, 
and will be contacted for survival every 12 weeks by telephone. 


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Protocol Synopsis – Safety Assessments 
 
Adverse events will be evaluated at each visit during every cycle and graded according to 
NCI CTCAE version 4.03 dated June 14, 2010 (only abnormal laboratory results deemed 
to be clinically significant will be recorded as AEs or SAES) (NCI CTCAE version 4.03). 
… 
 
Audiometry will be performed at screening and only as clinically indicated before treatment 
on Day 1 of each cycle and as clinically indicated at the End-of-Treatment visit. 
Section 3.1 - Study Design 
 
… 
 
Patients who discontinue treatment due to an AE and have not progressed will have an 
End-of-Treatment visit, will be followed with scans every 9 weeks until disease progression, 
and will be contacted for survival every 12 weeks by telephone. 
… 
 
The following procedures will be performed during the screening period within 28 days prior 
to the first study treatment: 
• Signed informed consent can be obtained within 28 days of dosing and prior to 
performing any study evaluations. 
• Disease assessment will be evaluated with a baseline computed tomography scan (see 
Section 6.1.1 for imaging methods) and should be performed within the 28 days before 
the start of study treatment. 
… 
 
The following procedures will be performed on Day 1 prior to NC-6004 infusion in each 
treatment cycles unless otherwise specified: 
• Pregnancy test (serum or urine) on Day 1 of each cycle (at Cycle 1, serum or urine; test is 
not required on Day 1 of Cycle 1 if pregnancy test at screening was performed using 
serum) 
Follow-Up 


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Patients who complete treatment or discontinue treatment without disease progression will 
continue to be followed until disease progression with scans every 9 weeks. Following 
disease progression, patients will be contacted by telephone every 12 (±1) weeks to collect 
the following data: 
• Survival 
• Adverse events (All AEs will be followed until resolution, Section 6.3.2.6) 
• Medication historyNew treatments (targeted therapy or chemotherapy used after study 
disease progression and treatment completion) 
Section 4.1.2 – Exclusion Criteria 
 
… 
11. 
Have pre-existing alcoholic liver injury or significant liver disease. 
12. Are regularly consuming alcohol within 6 months of Screening defined as an 
average weekly intake of >21 units (or an average daily intake of >3 units) for males or 
>14 units (or an average daily intake >2 units) for females. One unit is equivalent to 8 g 
of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine, or 
1 measure (25 mL) of spirits. 
 
Section 5.2 – Prophylactic Treatments 
 
All patients will receive the following medications before administration of NC-6004 on 
Day 1 of each cycle: 
… 
 
• Patients will be given 50 mg of ranitidine intravenously or 20 mg famotidine 
intravenously 30 minutes before the start of NC-6004 infusion on Day 1 of each cycle. 
Section 5.8 – Prophylaxis and Management of Hypersensitivity Reactions 
 
All patients must receive the following prophylactic treatment at each cycle to reduce the risk 
of hypersensitivity reactions: 
… 


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• Diphenhydramine hydrochloride 50 mg and either ranitidine 50 mg or 20 
mg famotidine will be administered intravenously 30 minutes before the infusion of 
NC-6004. 
… 
 
If a Grade 1 or Grade 2 hypersensitivity occurs in a patient, the following medications should 
be administered for 48 hours after NC-6004 infusion: 
• Ranitidine 150 mg orally given 2 times per day or 40 mg famotidine orally given once 
per day 
Section 6.1.1 – Disease Response Definitions 
 
… 
The rate of confirmed response and tumor growth control will be determined according to 
RECIST version 1.1 in solid tumor patients for patients evaluable for response using the 
following imaging methods: 
Timing 
 
Disease assessment will occur at Screening and every 6 weeks (±1 week) until disease 
progression. Patients who have obtained a response (PR or CR) will have a 
confirmatory scan at a minimum of 4 weeks following the initial scan. 
Anatomic Coverage 
 
Imaging should include a computed tomography scan of the chest, abdomen, and pelvis. 
In addition, areas of known predisposition for metastases (eg, the brain for NSCLC) 
and any areas identified by the clinician as probable sites of metastasis based on clinical 
evaluation should be included in imaging if clinically indicated. Other imaging may be 
performed at the investigator’s discretion as standard of care. 
Imaging Method 
 
The preferred method for imaging is computed tomography with IV contrast. If the 
patient is allergic to contrast media or has another medical contraindication, magnetic 
resonance imaging with contrast can be used at the clinician’s discretion. It is critical 
that the same method of imaging is used throughout the study for a given patient. 


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Slice Thickness 
 
The preferred slice thickness is 5 mm. If a larger slice thickness is used (eg, 7 mm), the 
smallest tumor measurement that can be reported is twice the thickness of the slice. 
The ORR, DCR, and DOR will be determined immediately prior to the initiation of 
maintenance therapy. The OS and PFS will be determined at the end of the study for 
evaluable patients without censoring at the initiation of maintenance therapy. Patients who 
have obtained a response (PR or CR) will have a confirmatory scan at a minimum of 4 weeks 
following the initial scan. 


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Section 6.1.3 – MD Anderson Symptom Inventory 
 
… 
 
The core MDASI and the MDASI-LC will be administered as a self-report paper-and-pencil 
form given to the patient at the site before study treatments on Days 1 and 8 of each cycle in 
Part 1 only (as described in Study Manual). 
Section 6.3.2.3 – Reporting Adverse Events 
 
… 
 
Any AE that meets SAE criteria (Section 6.3.2.1) must be reported to PPD immediately (ie, 
within 24 hours after the time site personnel first learn about the event). The following 
contact information is to be used for SAE reportingThe event is reported via the electronic 
data capture (EDC) system where site personnel complete as much of the respective AE 
page (eCRF) as they are able. 
If the EDC system is unavailable, the AE information must be recorded on the manual 
SAE report form and immediately (ie, within 24 hours of awareness) sent to PPD by one 
of the following methods (refer to the “SAE Guidelines” document for WorldReach toll- 
free access numbers if necessary): 
Pharmacovigilance Department 
 
United States SAE Hotline: +1 800-201-8725 
 
United States SAE Fax line: +1 888-488-9697 
 
Europe SAE Hotline: 
+44 1223 374 240 (to be used for questions 
concerning SAEs) 
Europe SAE Fax line: 
+44 1223 374 102 (to be used for reporting SAEs) 
 
 
 
Once the EDC system becomes available again, the site needs to transfer all data to the 
respective eCRF page of the patient. 
Section 6.3.3 - Assessment of Nausea and Vomiting 


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… 
 
For Parts 1 and 2, eEach patient will be given a nausea and vomiting patient diary to take 
home. This diary will be used to record the severity of nausea and incidence of emetic 
episodes over the previous 24 hours daily on Days 2 through 21. The first 7 days of the 
diary will be recorded verbatim in the eCRF. The patient will be given the diary and 
instructed on how and when to complete the diary before discharge from the site on 
Day 1 of each cycle. 
Part 1: The investigator will collect the nausea and vomiting patient diary from each 
patient diaries on Day 8 and Day 15 for Cycle 1. For all subsequent cycles, the 
investigator will collect diaries on Day 1 (prior to dosing to capture the last 7 days of the 
previous cycle), Day 8, and Day 15 (Part 1 only), and Day 22. The first 7 days of the diary 
will be recorded verbatim in the eCRF. The investigator will record the worst severity of the 
patient’s nausea and the total number of emetic episodes occurring over the previous 7 days 
in the eCRF for Day 8 , Day 15, and Day 21. The patient will be given the diary and 
instructed on how and when to complete the diary before discharge from the site on Day 1 of 
each cycle. The patient must return the diary to the site on Day 8, Day 15 (Part 1 only), and 
Day 22 (Day 1 of the next cycle) of each cycle. 
Part 2: The investigator will collect the nausea and vomiting patient diary from each 
patient at the site on Day 8 for Cycle 1. For Cycle 2, the investigator will collect diaries 
on Day 1 (prior to dosing to capture the last 7 days of the previous cycle) and Day 8. 
Note that nausea and vomiting patient diaries will not be collected past Cycle 2. The 
investigator will record the worst severity of the patient’s nausea and the total number 
of emetic episodes occurring over the previous 7 days in the eCRF for Day 8 and Day 21. 
Section 6.3.5 – Clinical Laboratory Analyses 
 
… 
 
Any Only abnormal laboratory test results (hematology, biochemistry, or urinalysis) that are 
deemed clinically significant by the PI will are to be recorded as AEs or SAEs per the NCI 
CTCAE version 4.03. 
Section 6.3.5.3 – Urinalysis 


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Urinalysis will be performed using a dipstick test and will include: leukocyte esterase, nitrite, 
urobilinogen, protein, pH, blood, specific gravity, ketones, bilirubin, and glucose. 
Section 6.3.6 – Electrocardiograms 
 
… 
 
A 12-lead ECG will be performed during the screening period at Day -7 to -1. On Day 1 
of Cycle 1, 12-lead ECGs will be performed before the start of the NC-6004 infusion, at 
completion of infusion (~1 hour after start of infusion), and at Hours 3 and 24 hours (Day 2) 
after start of infusion. On Day 8 of Cycle 1, 12-lead ECGs will be performed before the start 
of gemcitabine infusion, at the completion of gemcitabine infusion, and at 1 hour after 
completion of gemcitabine infusion. Twelve-lead ECGs will also be performed on Day 1 of 
Cycles 2 through 6 before the start of the NC-6004 infusion and at the End-of-Treatment visit. 
All 12-lead ECGs should be performed within a ±310-minute window. 
Section 6.3.8 - Vital Sign Measurements 
 
… 
 
Vital signs will also be measured at the End-of-Treatment visit. 
 
Section 7.3 - Sample Size Calculations 
 
… 
 
Part 2 is a 3-cohort study with an overall sample size of up to 150 160 patients with no more 
than 50 patients in Cohorts 1 and 2 and no more than 60 patients in Cohort 3 (30 unfit and 
30 fit bladder cancer patients). 
Section 12.1 - Appendix: Schedule of Events 


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Table 12-1 
Schedule of Events 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7 Onwarda 
End-of- 
Treatmentb 
Follow-upc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
2 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Informed consent 
X 
Eligibility criteria 
X 
Demography 
X 
Medical history 
X 
Pregnancy test (serum or urine) 
X 
Xe 
X 
X 
X 
X 
Physical examination 
Xf 
Xf 
X 
X 
X 
X 
Height, weight, and BSA 
calculationg 
Xg 
X 
X 
X 
X 
Vital signsh 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status (ECOG) 
Xf 
Xf 
X 
X 
X 
X 
Disease assessmenti 
X 
Xi 
Xi 
X 
X 
Audiometry 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Hematology 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (dipstick) 
X 
X 
EORTC QLQ-C30 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDASI or MDASI-LCl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Part 1: Nausea and vomiting 
patient diarym 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Part 2 Nausea and vomiting patient 
diarym 
X 
X 
X 
X 
Cardiac risk factors 
X 
12-lead ECGn 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic assessments 
(Part 1)o 
X 
X 
X 
X 
X 
X 
Xo 
Xo 
X 
Pharmacokinetic assessments 
(Part 2)p 
X 
X 
X 
X 
X 
X 
X 


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Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7 Onwarda 
End-of- 
Treatmentb 
Follow-upc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
2 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Adverse events 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
Xf 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
Prophylactic administrations 
X 
X 
X 
X 
NC-6004 administrationa 
X 
X 
X 
X 
Gemcitabine administration 
X 
X 
X 
X 
X 
X 
X 
X 


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Abbreviations: BSA, body surface area; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-C30, European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; MDASI, MD Anderson Symptom Inventory; RECIST, Response Evaluation Criteria 
in Solid Tumors; MDASI-LC, MDASI-lung cancer. 
a. 
In Part 1 of the study, patients will receive treatment until progressive disease. In Part 2 of the study, patients will receive treatment for 6 cycles (Cohorts 1 
and 3) or 8 cycles (Cohort 2). 
b. End-of-treatment assessments will be performed within 28 days after treatment discontinuation. 
c. 
After patient discontinuation or completion of treatment without disease progression, patients will be followed with scans every 9 weeks until disease 
progression. Patients will be called every 12 (±1) weeks to collect data on patient survival, new treatments, and adverse events. 
d. Day 15 visit is required in Part 1. In Part 2, Day 15 visit is only necessary if it is clinically indicated. 
e. 
Not required if screening pregnancy test was performed using serum. 
f. 
Safety assessments of physical examination, ECOG, review of adverse events, and concomitant medication use can be completed on Day -1 to allow for 
early morning dosing. These should not be conducted in place of screening assessments. 
g. From Day -14 to -1 at screening, only height and weight will be measured. On Day 1 of Cycle 1 through 7 each cycle, weight will be measured before 
treatments and BSA will be calculated before each dose using the Mosteller formula (Mosteller 1987). (Note: Dose will only be recalculated if there is a 
≥10% increase or decrease in the patient’s weight from the patient’s screening weight measurement. Any change in a patient’s weight by ≥10% during the 
study will require a recalculation of the doses of all study drugs. This threshold should not be confused with a change in the patient’s BSA [m2]). 
h. On Day 1 of Cycle 1, vital signs will be measured before the start of the NC-6004 infusion, every 20 minutes during the infusion, at the completion of the 
infusion, and 1 hour after the completion of the NC-6004 infusion. Starting in Cycle 2, vital signs will be measured before the start of the NC-6004 infusion 
and at the completion of the NC-6004 infusion on Day 1 of each cycle. Vital signs will be measured before and after gemcitabine infusion on Day 8 of each 
cycle. Vital signs will also be measured at the End-of-Treatment visit. 
i. 
Disease assessment will be performed using RECIST version 1.1 and the same imaging method used at screening should be used for all subsequent 
assessments. Beginning in Cycle 3 and continuing through the remainder of the treatment cycles, disease will be assessed every 6 (±1) weeks (ie, every other 
cycle) and at the End of Treatment visit or until disease progression. Patients who have obtained a partial response or complete response will have a 
confirmatory scan at a minimum of 4 weeks following the initial scan. 
j. 
To be performed only as clinically indicated. 
k. Hematology orand biochemistry tests will be repeated prior to dosing on Day 1 of Cycle 1 if they were last performed more than 24 hours before the start of 
the study drug administration. 
l. 
Symptom changes will be assessed using the core MDASI (Part 1 only) or MDASI-LC (only in patients with NSCLC in Part 1). 


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m. Part 1: The investigator will collect the nausea and vomiting patient diary from each patient on Day 8 and Day 15 for Cycle 1. For all subsequent 
cycles, the investigator will collect diaries on Day 1 (prior to dosing to capture the last 7 days of the previous cycle), Day 8, and Day 15. Part 2: The 
investigator will collect the nausea and vomiting patient diary from each patient at the site on Day 8 for Cycle 1. For Cycle 2, the investigator will 
collect diaries on Day 1 (prior to dosing to capture the last 7 days of the previous cycle) and Day 8. Note that nausea and vomiting patient diaries 
will not be collected past Cycle 2. For additional details, see Section 6.3.3. Diary issued on Day 1 of each cycle. Assessment is performed at the site 
before dosing on Day 1 and Day 8 as well as Day 15 (Day 15 diary collected in Part 1 only; note: no dosing on Day 15) of each cycle. Patient completes 
diary at home on Days 2 through 8 and returns diary on Day 8. 
n. Twelve-lead ECGs will be performed after the patient has adequately rested in the supine position. A 12-lead ECG will be performed during the screening 
period at Day –7 to –1. On Day 1 of Cycle 1, 12-lead ECGs will be performed before the start of the NC-6004 infusion, at completion of infusion (~1 hour 
after start of infusion), and at Hours 3 and 24 (Day 2) after the start of infusion. On Day 8 of Cycle 1, 12-lead ECGs will be performed before the start of 
gemcitabine infusion, at the end of gemcitabine infusion, and at 1 hour after completion of gemcitabine infusion. Twelve-lead ECGs will be performed on 
Day 1 of Cycles 2 through 6 before the start of the NC-6004 infusion, and at the End-of Treatment visit. All 12-lead ECGs should be performed within a 
±301-minute window. 
o. For Part 1, blood samples will be collected at the following times: before the start of the NC-6004 infusion on Day 1 of Cycles 1 through 6, at end of 
NC-6004 infusion in Cycles 1, 3, and 5, after the start of NC-6004 infusion at Hours 3, 6, 12, 24 (Day 2), 48 (Day 3), 96 (Day 5), 168 and (Day 8, prior to 
gemcitabine infusion (Day 8), and 336 (Day 15) in Cycles 1, 3, and 5, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample 
collections may be performed, at the discretion of the investigator, during any visit where toxicity is observed. Blood samples will be collected within 
10 minutes after the 12-lead ECGs performance. 
p. For Part 2 (up to 6 cycles), on the day of NC-6004 infusion for each cycle, blood samples will be collected before the start of the NC-6004 infusion, at the 
end of the NC-6004 infusion, before gemcitabine infusion on Day 8, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample collections 
may be performed, at the discretion of the investigator, during any visit where toxicity is observed. Blood samples will be collected within 10 minutes after 
the 12-lead ECGs performance. 


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12.4.6 Protocol Amendment 3-Protocol Version 4.2, Incorporating 
Amendment 3-Version 4.1 (EU only, dated 31 August 2016) 
The following sections detail the changes made to Protocol Amendment 3-Version 4.1 (EU 
only, dated 31 August 2016). 
Protocol Amendment 3-Version 4.0 (US only, dated 31 July 2016) included EMA 
VHP-requested changes in addition to other changes not specifically requested by the VHP. 
Following submission of Version 4.0 to the VHP, the VHP requested a version of the protocol 
that only included the VHP-requested changes; therefore, Version 4.1 was submitted to the 
VHP to meet this request. Version 4.0 was submitted to the FDA and not subsequently 
modified. 
Protocol Amendment 3-Version 4.2 (US and EU) harmonizes Versions 4.0 and 4.1 and was 
finalized on 12 December 2016. A separate summary of the changes made to Version 4.0 is 
included in Section 12.4.5. 
 
12.4.6.1 
Risk Assessment for Amendment 3, Version 4.2 
Because the following sections detail the changes made to Protocol Amendment 
3-Version 4.1 (EU only, dated 31 August 2016), the risk associated with this amendment 
comprises both the risk described in Section 12.4.3.1 and the risk assessed in the following 
text and repeated in Section 12.4.5.1. 
No anticipated increased patient risk has been introduced with the updates made during this 
protocol amendment. Based on new safety information received from an ongoing non-US, 
non-IND, Japanese trial with NC-6004 (Study NC-6004-007), additional exclusion criteria 
have been added to mitigate risk of liver toxicity in patients predisposed to liver injury. In 
addition, sites and investigators have been instructed to closely monitor ongoing NC-6004 
patients who are known to have pre-existing alcoholic liver injury and/or concurrent heavy 
alcohol consumption, for newly emerging liver injury. 
 
12.4.6.2 
Overview of Changes 
The overview of significant changes includes the following: 


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Title Page – Current Version and Date of Protocol; Title Page – Previous Dates and 
Versions 
The current and previous protocol amendment versions and applicable regions were updated 
to provide complete transparency and increased clarity. 
Declaration of Investigator 
 
A declaration of investigator page, which includes a principal investigator signature line was 
added. 
Protocol Synopsis – Study Sites; Section 4.1 – Selection of Study Population 
 
The study site details were updated to at least 20 sites in the Unites States and Europe. 
 
Protocol Synopsis – Inclusion Criteria; Section 4.1.1 – Inclusion Criteria 
 
The inclusion criterion 5 was updated to the following: 
 
5. Have an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1, with the exception of 
patients in Part 2 (Cohort 3, unfit bladder cancer patients) who may have an ECOG PS 
of 2. 
Protocol Synopsis – Inclusion Criteria; Protocol Synopsis – Study Design; 
Section 3.1 - Study Design; Section 4.1.1 – Inclusion Criteria; Section 5.1 – Method of 
Assigning Patients to Treatment Groups; Section 6.3.1.2.1 - Safety Monitoring in Part 2 
The inclusion criterion 8 and study design were updated to reflect the following: 
 
8. In Part 1 and in Part 2 in Cohorts 1 and 2: have adequate renal function defined as a 
creatinine clearance (CrCl) ≥50 mL/minute (calculated according to the formula of Cockcroft 
and Gault 1976) or serum creatinine <1.5 mg/dL. In Part 2, patients in Cohort 3 (bladder 
cancer) must have a CrCl of ≥30 mL/min. 
• Bladder cancer patients in Cohort 3 of Part 2 will be stratified by ≥30 to 
<60 mL/min and/or ECOG PS 2 and ≥60 mL/min and ECOG PS 0 to 1. If 2 of 
6 patients (or ≥33% at any point during the study) in the ≥30 to <60 mL/min 
group have a worsening of CrCl (ie, 50% reduction from baseline for 


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2 consecutive assessments, at least 1 week apart), then enrollment of patients 
with CrCl <60 mL/min will stop in the bladder cancer cohort. 
Protocol Synopsis – Exclusion Criteria; Section 4.1.2 – Exclusion Criteria 
 
The exclusion criteria 11 and 12 were added to reflect the following: 
 
11. Have pre-existing alcoholic liver injury or significant liver disease. 
 
12. Are regularly consuming alcohol within 6 months of Screening defined as an average 
weekly intake of >21 units (or an average daily intake of >3 units) for males or >14 units (or 
an average daily intake >2 units) for females. One unit is equivalent to 8 g of alcohol: a 
half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine, or 1 measure (25 mL) of 
spirits. 
Protocol Synopsis – Study Design; Section 3.1 – Study Design 
 
All references to “two-stage” and a minimum threshold of clinical responses in Part 2 were 
removed. 
Protocol Synopsis – Study Design; Protocol Synopsis – Study Drug, Dosage, and Route of 
Administration; Section 5.1 - Method of Assigning Patients to Treatment Groups; 
Section 5.3 - Treatments Administered 
 
A +10-minute window was added to the 1-hour infusion of NC-6004. 
 
Protocol Synopsis – Study Design; Section 3.1 - Study Design; Section 5.1 - Method of 
Assigning Patients to Treatment Groups; Section 5.3 - Treatments Administered 
The RPII dose of 135 mg/m2 was added to the protocol. 
 
Protocol Synopsis – Study Design; Section 3.1 - Study Design 
 
The historical median duration of PFS and PFS weekly hazard were added for the unfit 
bladder cancer cohort. A successful outcome for unfit and fit bladder cancer patient cohorts 
with 30 planned patients was updated to 15 PFS events. 


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Protocol Synopsis – Study Design; Protocol Synopsis – Sample Size; Section 3.1 - Study 
Design; Section 4.1 – Selection of Study Population; Section 7.3 - Sample Size 
Calculations 
The total sample size in Part 2 of the study was changed to 160 patients with no more than 
50 patients each in Cohorts 1 and 2 and no more than 60 patients in Cohort 3 (30 unfit and 
30 fit bladder cancer patients). The simulated mean sample sizes for this trial were updated to 
92.7 to 116.8 patients. 
 
Protocol Synopsis – Study Design; Section 3.1 – Study Design 
 
It was clarified that all patients who discontinue treatment and have not progressed will have 
an End-of-Treatment visit, will be followed with scans every 9 weeks until disease 
progression, and will be contacted for survival every 12 weeks by telephone. 
Protocol Synopsis – Estimated Study Duration; Section 4.2.1 – Reasons for 
Withdrawal/Discontinuation 
A study treatment discontinuation rule was added as follows: 
 
• For Cohort 3 only, unfit bladder cancer patient (≥30 to <60 mL/min CrCl at 
screening) has a worsening of CrCl (ie, 50% reduction from baseline for 
2 consecutive assessments, at least 1 week apart) 
Protocol Synopsis – Safety Assessments; Section 6.3.5 – Clinical Laboratory Analyses 
 
It was specified that only abnormal laboratory results deemed to be clinically significant will 
be recorded as AEs or SAEs. 
Protocol Synopsis – Safety Assessments 
 
For internal consistency, it was added that audiometry will also be performed as clinically 
indicated at the End-of-Treatment visit. 
Protocol Synopsis – Definition of a DLT; Section 6.3.1.1 – Definition of Dose-Limiting 
Toxicities 
It was clarified that DLTs will only be monitored in Part 1 of the study. 


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Section 3.1 - Study Design; Section 3.1.1 – Rationale of Study Design; 
Section 6.1 - Efficacy Assessments; Section 12.1 - Appendix: Schedule of Events; 
 
It was clarified that the MDASI will only be performed in Part 1. 
 
Section 3.1 - Study Design 
 
A cross-reference to the amendment-specified imaging methods was added. 
 
At the Follow-up visit, text was updated to specify that new treatments would be collected 
(Previous text stated medication history would be collected). 
Section 3.1 - Study Design 
 
Text was added to specify that at Cycle 1, either serum or urine; test is not required on Day 1 
of Cycle 1 if pregnancy test at screening was performed using serum. 
Section 5.2 – Prophylactic Treatments; Section 5.8 – Prophylaxis and Management of 
Hypersensitivity Reactions 
It was added that 20 mg famotidine can be given intravenously as an option in place of 50 mg 
of ranitidine given intravenously. 
Section 5.8 – Prophylaxis and Management of Hypersensitivity Reactions 
 
If a Grade 1 or Grade 2 hypersensitivity occurs in a patient, it was added that 40 mg 
famotidine can be given orally once per day as an option in place of ranitidine 150 mg orally 
given 2 times per day. 
Section 3.1 - Study Design; Section 5.4 - Dose Delays and Modifications; 
Section 6.3.7 - Physical Examination; Section 11 - Reference List; Section 12.1 - Appendix: 
Schedule of Events, footnote g 
It was added that the doses of NC-6004 and gemcitabine will be calculated in milligrams per 
square meter (mg/m2) at screening and will not be changed in subsequent cycles unless the 
patient’s body weight increases or decreases by at least 10% from the patient’s screening 
weight measurement. This threshold should not be confused with a change in the patient’s 
body surface area (m2). Any change in a patient’s weight by at least 10% during the study 
will require a recalculation of the doses of NC-6004 and gemcitabine. Weight will be 


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measured before treatments on Day 1 of each cycle, with a calculation of body surface area 
before each dosing on Day 1 of each cycle (using the Mosteller formula [Mosteller 1987]). 
Section 5.4 - Dose Delays and Modifications; Section 5.4.1 – NC-6004 Dose Delays and 
Modifications 
Updated “Grade 3 or 4 toxicity” to “Grade 3 or 4 toxicity (recurrence of the same AE)” to 
more clearly define the recurrence of events that could lead to study drug withdrawal. 
Section 5.5.2 - Gemcitabine Drug Product; Section 5.6.1 - Study Drug Packaging and 
Storage 
The generic gemcitabine was added to the protocol to clarify that it is acceptable for generic 
gemcitabine to be administered in this study (as per the original intent of the protocol) in 
place of Gemzar. 
Section 5.6.2 – Test Article Accountability 
 
It was clarified that the PI should maintain accurate records of receipt of all test articles that 
are centrally provided. 
Section 6.1.1 – Disease Response Definitions 
 
Guidelines for imaging, including the timing, anatomic coverage, imaging method, and slice 
thickness were added. 
Section 6.1.3 – MD Anderson Symptom Inventory 
 
Reference to the Study Manual was removed from the protocol. 
 
Section 6.2 - Pharmacokinetic and Pharmacodynamic Assessments; 
Section 12.1 - Appendix: Schedule of Events, footnotes o and p 
A 10-minute window after ECG performance was added for the PK blood sampling. 
 
Section 6.3.2.3 – Reporting Adverse Events 
 
Text was added to clarifying the process for capturing events in the EDC system, and 
European SAE hotline and fax line numbers were added. 


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Section 6.3.2.5 - Assessment of Causality 
 
“Study drug” was updated to “study drug (NC-6004 and gemcitabine)” to indicate that the 
assessment of an AE’s relatedness was to the combination of NC-6004 and gemcitabine. 
Section 6.3.3 – Assessment of Nausea and Vomiting; Section 12.1 - Appendix: Schedule of 
Events, footnote m 
Text was added to specify the process for administering and capturing data in the nausea and 
vomiting patient diary. 
Section 6.3.5.3 – Urinalysis; Section 12.1 - Appendix: Schedule of Events 
 
Reference to a dipstick urinalysis was removed to allow flexibility in the type of urinalysis 
testing. 
Section 6.3.6 – Electrocardiograms; Section 6.3.8 - Vital Sign Measurements; 
Section 12.1 - Appendix: Schedule of Events, footnotes n and h 
The text “rest for at least 5 minutes” was updated to “adequately rested” for the patient 
before ECGs and vital sign measurements. Text was also added to specify that ECGs will be 
performed during the screening period at Day –7 to –1 and that vital signs will also be 
measured at the End-of-Treatment visit. 
Section 6.3.6 – Electrocardiograms; Section 12.1 - Appendix: Schedule of Events, 
footnote n 
A ±30-minute window for collection of 12-lead ECGs was added. 
 
Section 10.2.2 - Protocol Violations and Deviations 
 
Text was updated to clarify that Part 2 of this study will not require sponsor approval prior to 
each patient being enrolled in the study. 
Section 12.1 - Appendix: Schedule of Events 
 
A column was added to the Schedule of Events Table (Table 12-1) to clearly show that ECGs 
will be also performed on Day 2 of Cycle 1. For completeness, PK assessments, AE 
monitoring, and concomitant medication review were also added to Day 2 of Cycle 1. 


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12.4.6.3 
Changes to the Protocol Text 
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. Additions to the protocol text are shown in bold and 
deletions are shown in strikethrough text. Minor or obvious editorial and grammatical 
corrections are not highlighted. 
Protocol Synopsis – Study Sites 
 
Study Sites: At least 20 sites in the United States and Europe. 
 
Protocol Synopsis – Inclusion Criteria 
 
… 
 
5. Have an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1, with the exception 
of patients in Part 2 (Cohort 3, unfit bladder cancer patients) who may have an ECOG 
PS of 2. 
… 
 
8. In Part 1 and in Part 2 in Cohorts 1 and 2: Hhave adequate renal function defined as a 
creatinine clearance (CrCl) ≥50 mL/minute (calculated according to the formula of 
Cockcroft and Gault 1976) or serum creatinine <1.5 mg/dL. In Part 2, patients in Cohort 3 
(bladder cancer) must have a CrCl of ≥30 mL/min. 
• Bladder cancer patients in Cohort 3 of Part 2 will be stratified by ≥30 to 
<60 mL/min and/or ECOG PS 2 and ≥60 mL/min and ECOG PS 0 to 1. If 
2 of 6 patients (or ≥33% at any point during the study) in the ≥30 to 
<60 mL/min group have a worsening of CrCl (ie, 50% reduction from 
baseline for 2 consecutive assessments, at least 1 week apart), then 
enrollment of patients with CrCl <60 mL/min will stop in the bladder 
cancer cohort. 
Protocol Synopsis – Exclusion Criteria 
 
… 
 
11. Have pre-existing alcoholic liver injury or significant liver disease. 


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12. Are regularly consuming alcohol within 6 months of Screening defined as an 
average weekly intake of >21 units (or an average daily intake of >3 units) for males or 
>14 units (or an average daily intake >2 units) for females. One unit is equivalent to 8 g 
of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine, or 
1 measure (25 mL) of spirits. 
 
Protocol Synopsis – Study Design 
 
This study will consist of 2 parts; Part 1 is a Phase 1b, continual reassessment method 
dose-escalation trial, and Part 2 is a Phase 2, adaptive, two-stage, open-label, expansion trial 
evaluating activity, safety, and tolerability at the RPII dose identified in Part 1. 
… 
 
On Day 1 of each cycle, patients will receive NC-6004 over 1 hour (+10-minute window) 
followed by an infusion of gemcitabine 1250 mg/m2 over 30 minutes. 
 
… 
 
Part 2 of the study (Phase 2 portion) will begin after the RPII dose of NC-6004 is identified 
for use in combination with gemcitabine. All patients will receive NC-6004 at the RPII dose 
(135 mg/m2, established in Part 1) in combination with gemcitabine 1250 mg/m2 by the 
same regimen as in Part 1. 
Three cohorts of patients are eligible (Cohort 1: first-line metastatic squamous NSCLC; 
Cohort 2: first-line metastatic or locally advanced cholangiocarcinoma, gallbladder cancer, or 
ampullary cancer (biliary tract cancer); and Cohort 3: first-line metastatic or locally advanced 
TCC of the urinary tract (bladder cancer). Bladder cancer patients in Cohort 3 of Part 2 
will be stratified by ≥30 to <60 mL/min and/or ECOG PS 2 (unfit) and ≥60 mL/min and 
ECOG PS 0 to 1 (fit). If 2 of 6 patients (or ≥33% at any point during the study) in the 
≥30 to <60 mL/min group have a worsening of CrCl (ie, 50% reduction from baseline 
for 2 consecutive assessments, at least 1 week apart), then enrollment of patients with 
CrCl <60 mL/min will stop in the bladder cancer cohort. 
StagePart 2 will continue in each cohort after achieving the minimum threshold of clinical 
responses required and enroll up to 50 patients each in Cohorts 1 and 2, and up to 60 
patients in Cohort 3, for a total of up to 150 160 patients in Part 2. 


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… 
 
Cohort 
Biliary 
Bladder (CrCl: 
≥60 mL/min 
and ECOG PS 
0-1; fit) 
Bladder (CrCl: 
≥30 to 
<60 mL/min 
and/or ECOG 
PS 2; unfit) 
Squamous 
NSCLC 
Historical 
Median 
Duration of PFS 
8.8 months 
7.6 months 
5.8 months 
5 months 
Historical PFS 
Weekly Hazard 
0.01795 
0.020755 
0.02711 
0.031377 
Abbreviations: CrCl, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; NSCLC, 
non-small cell lung cancer; PS, performance status. 
Once 10 PFS events have been observed, interim analyses will be performed every 6 weeks. 
At each interim and at the final analysis, there are 3 possible outcomes for each cohort. 
• Futility – 10 PFS events have been observed in each cohort and at least 1 of the 
following conditions is true: 
• Probability (Promising HR*) <0.4 
 
• Probability (Phase 3 Success*) <0.4 
 
• Success – 25 PFS events have been observed in each 50-patient cohort and 15 PFS 
events in each 30-patient bladder cancer cohort and: 
• Probability (Phase 3 Success*) >0.8 
 
• Inconclusive – neither futility nor success. 
 
*Phase 3 success is defined as success in a Phase 3 clinical trial with 381 events - enough to 
provide 80% power to detect an HR of 0.75. A promising HR is defined as one less than 0.85. 
*Futility can only be declared for a cohort after 10 PFS events have been observed in that 
cohort. Success can only be declared for a cohort after 25 or 15 PFS events have been 
observed in that 50-patient cohort (Cohort 1 and 2) or 30-patient bladder cancer cohort 
(Cohort 3, fit and unfit), respectively. Accrual will stop for any cohort identified as futile or 


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successful at interim. The conclusion of this Phase 2 trial will be that a Phase 3 trial with 381 
events should be conducted for each cohort that is a success. 
… 
 
Patients who discontinue treatment due to an AE and have not progressed will have an 
End-of-Treatment visit, will be followed with scans every 9 weeks until disease progression, 
and will be contacted for survival every 12 weeks by telephone. 
Protocol Synopsis – Estimated Study Duration 
 
… 
 
Patients will receive study treatment until any of the following occur: 
… 
 
• For Cohort 3 only, unfit bladder cancer patient (≥30 to <60 mL/min CrCl at 
screening) has a worsening of CrCl (ie, 50% reduction from baseline for 
2 consecutive assessments, at least 1 week apart) 


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Protocol Synopsis – Safety Assessments 
 
Adverse events will be evaluated at each visit during every cycle and graded according to 
NCI CTCAE version 4.03 dated June 14, 2010 (only abnormal laboratory results deemed 
to be clinically significant will be recorded as AEs or SAES) (NCI CTCAE version 4.03). 
… 
 
Audiometry will be performed at screening and only as clinically indicated before treatment 
on Day 1 of each cycle and as clinically indicated at the End-of-Treatment visit. 
Protocol Synopsis – Definition of DLT 
 
A DLT (monitored in Part 1 only) is defined as the following treatment-related AEs or 
laboratory abnormalities, graded according to NCI CTCAE version 4.03: 
 
Protocol Synopsis – Study Drug, Dosage, and Route of Administration 
 
In each part of the study, NC-6004 will be administered as a 1-hour (+10-minute window) 
intravenous infusion on Day 1 of each cycle. 
 
Protocol Synopsis – Sample Size 
 
… 
 
Part 2 is a 3-cohort study with an overall sample size of up to 150160 patients with no more 
than 50 patients per cohort in Cohorts 1 and 2 and no more than 60 patients in Cohort 3 
(30 unfit and 30 fit bladder cancer patients). The total sample size will depend on the 
results of interim futility and superiority analyses. In order to evaluate the overall sample size, 
simulations were performed assuming scenarios with different HRs for PFS for each cohort 
compared with historical control and different sample sizes for a subsequent Phase 3 clinical 
trial. The associated mean sample size for this trial in these scenarios ranged from 136 92.7 
to 146 116.8 patients. 
 
Section 3.1 - Study Design 
 
This study will consist of 2 parts; Part 1 is a Phase 1b, continual reassessment method 
dose-escalation trial in patients with any advanced solid tumor, and Part 2 is a Phase 2, 
adaptive two-stage, open-label, expansion trial in patients with squamous NSCLC, biliary 


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tract, and bladder cancer evaluating activity, safety, and tolerability at the RPII dose 
identified in Part 1. 
… 
Part 2 of the study (Phase 2 portion) will begin after the RPII dose of NC-6004 is identified 
for use in combination with gemcitabine. All patients will receive NC-6004 at the RPII dose 
(135 mg/m2, established in Part 1) in combination with gemcitabine 1250 mg/m2 by the 
same regimen as in Part 1. Cohort 3 will stratify patients by creatinine clearance (CrCl) 
to assess study drug in patients with reduced kidney function (ie, CrCl of <60 to 
≥30 mL/min [unfit] and ≥60 mL/min [fit]) in a controlled manner and with the 
stipulation that enrollment will stop if 2 of 6 patients in the <30 to ≥60 mL/min group 
have a worsening of CrCl (ie, 50% reduction from baseline for 2 consecutive 
assessments, at least 1 week apart). 
Three cohorts of patients are eligible (Cohort 1: first-line metastatic squamous NSCLC; 
Cohort 2: first-line metastatic or locally advanced cholangiocarcinoma, gallbladder cancer, or 
ampullary cancer [(biliary tract cancer)]; and Cohort 3: first-line metastatic or locally 
advanced TCC of the urinary tract [(bladder cancer]). Stage 2 will continue in each cohort 
after achieving the minimum threshold of clinical responses required and Part 2 will enroll 
up to 50 patients each in Cohorts 1 and 2, and up to 60 patients in Cohort 3, for a total of 
up to 160 patients in Part 2. in each cohort for a total of up to 150 patients in Part 2. The 
primary endpoint (PFS) will be continuously updated and compared with the historical PFS 
from Phase 3 pivotal cisplatin and gemcitabine trials within each cohort. The PFS hazard 
model will be updated as PFS data accrue. A hazard ratio (HR) for PFS for each cohort 
versus historical control will be obtained. 


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Cohort 
Biliary 
Bladder 
(CrCl: ≥60 
mL/min; fit) 
Bladder 
(CrCl: ≥30 
to 
<60 mL/min; 
unfit) 
Squamous 
NSCLC 
Historical 
Median 
Duration of 
PFS 
8.8 months 
7.6 months 
5.8 months 
5 months 
Historical 
PFS Weekly 
Hazard 
0.01795 
0.020755 
0.02711 
0.031377 
 
Abbreviations: CrCl: creatinine clearance; ECOG, Eastern Cooperative Oncology Group; 
NSCLC, non-small cell lung cancer; PS, performance status. 
 
Once 10 PFS events have been observed, interim analyses will be performed every 6 weeks. 
At each interim and at the final analysis, there are 3 possible outcomes for each cohort. 
• Futility – 10 PFS events have been observed in each cohort and at least 1 of the 
following conditions is true: 
• Probability (Promising HR*) <0.4 
 
• Probability (Phase 3 Success*) <0.4 
 
• Success – 25 PFS events have been observed in each 50-patient cohort and 15 PFS 
events in each 30-patient bladder cancer cohort and: 
• Probability (Phase 3 Success*) >0.8 
 
• Inconclusive – neither futility nor success. 
 
* Phase 3 success is defined as success in a Phase 3 clinical trial with 381 events - enough to 
provide 80% power to detect an HR of 0.75. A promising HR is defined as one less than 0.85. 
*Futility can only be declared for a cohort after 10 PFS events have been observed in that 
cohort. Success can only be declared for a cohort after 25 or 15 PFS events have been 
observed in that 50-patient (Cohort 1 and 2) or 30-patient bladder cancer cohort 
(Cohort 3, fit and unfit), respectively. Accrual will stop for any cohort identified as futile or 


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successful at interim. The conclusion of this Phase 2 trial will be that a Phase 3 trial with 381 
events should be conducted for each cohort that is a success. 
… 
 
Patients who discontinue treatment due to an AE and have not progressed will have an 
End-of-Treatment visit, will be followed with scans every 9 weeks until disease progression, 
and will be contacted for survival every 12 weeks by telephone. 
… 
 
The following procedures will be performed during the screening period within 28 days prior 
to the first study treatment: 
• Signed informed consent can be obtained within 28 days of dosing and prior to 
performing any study evaluations. 
• Disease assessment will be evaluated with a baseline computed tomography scan (see 
Section 6.1.1 for imaging methods) and should be performed within the 28 days before 
the start of study treatment. 
… 
 
The following procedures will be performed on Day 1 prior to NC-6004 infusion in each 
treatment cycles unless otherwise specified: 
• Pregnancy test (serum or urine) on Day 1 of each cycle (at Cycle 1, serum or urine; test is 
not required on Day 1 of Cycle 1 if pregnancy test at screening was performed using 
serum) 
… 
 
• Height, weight, and calculation of body surface area using the Mosteller formula 
(Mosteller 1987) 
… 
• Part 1 only: Core MDASI or MDASI module specific for lung cancer (MDASI-LC) 
(Section 6.1.3) 
… 


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Day 8 of Each Cycle 
… 
• Part 1 only: Core MDASI or MDASI-LC 
… 
Follow-Up 
Patients who complete treatment or discontinue treatment without disease progression will 
continue to be followed until disease progression with scans every 9 weeks. Following 
disease progression, patients will be contacted by telephone every 12 (±1) weeks to collect 
the following data: 
• Survival 
• Adverse events (All AEs will be followed until resolution, Section 6.3.2.6) 
• Medication historyNew treatments (targeted therapy or chemotherapy used after study 
disease progression and treatment completion) 
• Section 3.1.1 –Rationale of Study Design 
• … 
• In Part 1 only, Tthe MDASI will be used to evaluate symptoms related to QoL during 
treatment. 
Section 4.1 –Selection of Study Population 
Approximately 209 199 patients (up to 49 patients in Part 1 and up to 160 150 patients in 
Part 2) will be enrolled in at least 20 sites in the United States and Europe. Patients will be 
assigned to a study treatment only if they meet all of the inclusion criteria and none of the 
exclusion criteria. 
Section 4.1.1 – Inclusion Criteria 
 
5. Have an ECOG PS of 0 to 1, with the exception of patients in Part 2 (Cohort 3, unfit 
bladder cancer patients) who may have an ECOG PS of 2. 
… 
 
8. In Part 1 and in Part 2 in Cohorts 1 and 2: Hhave adequate renal function defined as a 
CrCl ≥50 mL/minute (calculated according to the formula of Cockcroft and Gault 1976) or 


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serum creatinine <1.5 mg/dL. In Part 2, patients in Cohort 3 (bladder cancer) must have 
a CrCl of ≥30 mL/min. 
• Bladder cancer patients in Cohort 3 of Part 2 will be stratified by ≥30 to 
<60 mL/min and/or ECOG PS 2 and ≥60 mL/min and ECOG PS 0 to 1. If 
2 of 6 patients (or ≥33% at any point during the study) in the ≥30 to 
<60 mL/min group have a worsening of CrCl (ie, 50% reduction from 
baseline for 2 consecutive assessments, at least 1 week apart), then 
enrollment of patients with CrCl <60 mL/min will stop in the bladder 
cancer cohort. 
Section 4.1.2 – Exclusion Criteria 
… 
11. 
Have pre-existing alcoholic liver injury or significant liver disease. 
12. Are regularly consuming alcohol within 6 months of Screening defined as an 
average weekly intake of >21 units (or an average daily intake of >3 units) for males or 
>14 units (or an average daily intake >2 units) for females. One unit is equivalent to 8 g 
of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine, or 
1 measure (25 mL) of spirits. 
 
Section 4.2.1 – Reasons for Withdrawal/Discontinuation 
 
… 
 
A patient may be withdrawn from the study for any of the following reasons: 
 
… 
 
• For Cohort 3 only, unfit bladder cancer patient (≥30 to <60 mL/min CrCl at 
screening) has a worsening of CrCl (ie, 50% reduction from baseline for 
2 consecutive assessments, at least 1 week apart) 
Section 5.1 - Method of Assigning Patients to Treatment Groups 
This is an open-label study that will be conducted in 2 parts. In both parts, NC-6004 will be 
administered as a 1-hour (+10-minute window) intravenous infusion on Day 1 of each cycle. 
Gemcitabine 1250 mg/m2 will be administered as a 30-minute intravenous infusion on Day 1 


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of each cycle (after the administration of NC-6004) and on Day 8 of each cycle. The duration 
of each cycle will be 21 days. 
… 
 
In Part 2, all patients will receive the RPII dose (135 mg/m2) of NC-6004 identified in Part 1. 
Bladder cancer patients in Cohort 3 of Part 2 will be stratified by ≥30 to <60 mL/min 
and/or ECOG PS 2 (unfit) and ≥60 mL/min and ECOG PS 0 to 1 (fit). If 2 of 6 patients 
(or ≥33% at any point during the study) in the ≥30 to <60 mL/min group have a 
worsening of CrCl (ie, 50% reduction from baseline for 2 consecutive assessments, at 
least 1 week apart), then enrollment of patients with CrCl <60 mL/min will stop in the 
bladder cancer cohort. 
Section 5.2 – Prophylactic Treatments 
 
All patients will receive the following medications before administration of NC-6004 on 
Day 1 of each cycle: 
… 
 
• Patients will be given 50 mg of ranitidine intravenously or 20 mg famotidine 
intravenously 30 minutes before the start of NC-6004 infusion on Day 1 of each cycle. 
Section 5.3 - Treatments Administered 
The duration of each treatment cycle will be 21 days in both parts of the study. NC-6004 will 
be administered on Day 1 of each cycle as a 1-hour (+10-minute window) intravenous 
infusion. 
… 
 
In Part 2, on Day 1 of each cycle, all patients will receive NC-6004 at the RPII dose 
(135 mg/m2) identified in Part 1 and 1250 mg/m2 gemcitabine. On Day 8 of each cycle, all 
patients in Part 2 of the study will receive 1250 mg/m2 gemcitabine. 
Section 5.4 - Dose Delays and Modifications 
 
The doses for NC-6004 and gemcitabine will be calculated in milligrams per square 
meter (mg/m2) at screening, and will not be changed in subsequent cycles unless the 


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patient’s body weight has increased or decreased by ≥10% from the patient’s weight 
measurement at screening. Any change in a patient’s weight by ≥10% during the study 
will require a recalculation of the doses of all study drugs (Note: This threshold should 
not be confused with a change of a patient’s body surface area [BSA] [m2]). Weight will 
be measured before treatments on Day 1 of each cycle, with calculation of BSA before 
dosing on Day 1 of each cycle (using the Mosteller formula [Mosteller 1987]). 
Patients experiencing significant toxicities must be immediately and permanently withdrawn 
from treatment with NC-6004 and gemcitabine as follows: 


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• Any patient who experiences a Grade 3 or 4 hypersensitivity reaction during any 
cycle of treatment 
• Any patient who experiences 2 protocol-defined DLTs during treatment 
 
• Any patient who experiences a recurrent Grade 3 or 4 toxicity (recurrence of the 
same AE) after a dose reduction 
Section 5.4.1 – NC-6004 Dose Delays and Modifications 
 
… 
 
Following recovery to Grade 1 or lower, treatment may resume at the investigator’s 
discretion. Patients who resume treatment following a dose delay will have the dose of study 
drug reduced by 50% for the remainder of study treatment. If toxicities persist or recur to 
Grade 3 or 4 (recurrence of the same AE) after the dose reduction, study treatment will be 
terminated. 
Section 5.5.2 - Gemcitabine Drug Product 
 
Gemzar® (gemcitabine for injection, USP), is available in sterile single-use vials individually 
packaged in a carton containing: 200 mg white to off-white, lyophilized powder in a 
10-mL size sterile single-use vial or 1 g white to off-white, lyophilized powder in a 
50-mL size sterile single-use vial. Vials of gemcitabineGemzar contain either 200 mg or 1 g 
of gemcitabine hydrochloride (expressed as free base) formulated with mannitol (200 mg or 
1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile 
lyophilized powder. Hydrochloric acid and/or sodium hydroxide may have been added for 
pH adjustment. 
Section 5.6.1 - Study Drug Packaging and Storage 
 
All study drugs must be stored in a secure area (eg, a locked cabinet). NC-6004 should be 
protected from light and stored refrigerated (2° to 8°C). Unopened vials 
of Gemzar (gemcitabine) are stable until the expiration date indicated on the package when 
stored at controlled room temperature 20° to 25°C that allows for excursions between 15° 
and 30°C. 
Section 5.6.2 – Test Article Accountability 


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The investigator will maintain accurate records of receipt of all test articles that are 
centrally provided, including dates of receipt. 
Section 5.8 – Prophylaxis and Management of Hypersensitivity Reactions 
 
All patients must receive the following prophylactic treatment at each cycle to reduce the risk 
of hypersensitivity reactions: 
… 
 
• Diphenhydramine hydrochloride 50 mg and either ranitidine 50 mg or 
20 mg famotidine will be administered intravenously 30 minutes before the infusion of 
NC-6004. 
… 
 
If a Grade 1 or Grade 2 hypersensitivity occurs in a patient, the following medications should 
be administered for 48 hours after NC-6004 infusion: 
• Ranitidine 150 mg orally given 2 times per day or 20 mg famotidine given 
intravenously once per day 


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Section 6.1 – Efficacy Assessments 
 
… 
 
Symptom changes will be assessed using the core MDASI (Part 1 only) or MDASI-LC (only 
in patients with NSCLC in Part 1) (Section 6.1.3) on Days 1 and 8 of each cycle and at the 
End-of-Treatment visit. 
Section 6.1.1 – Disease Response Definitions 
 
… 
 
The rate of confirmed response and tumor growth control will be determined according to 
RECIST version 1.1 in solid tumor patients for patients evaluable for response using the 
following imaging methods: 
Timing 
 
Disease assessment will occur at Screening and every 6 weeks (±1 week) until disease 
progression. Patients who have obtained a response (PR or CR) will have a 
confirmatory scan at a minimum of 4 weeks following the initial scan. 
Anatomic Coverage 
 
Imaging should include a computed tomography scan of the chest, abdomen, and pelvis. 
In addition, areas of known predisposition for metastases (eg, the brain for NSCLC) 
and any areas identified by the clinician as probable sites of metastasis based on clinical 
evaluation should be included in imaging if clinically indicated. Other imaging may be 
performed at the investigator’s discretion as standard of care. 
Imaging Method 
 
The preferred method for imaging is computed tomography with IV contrast. If the 
patient is allergic to contrast media or has another medical contraindication, magnetic 
resonance imaging with contrast can be used at the clinician’s discretion. It is critical 
that the same method of imaging is used throughout the study for a given patient. 


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Slice Thickness 
 
The preferred slice thickness is 5 mm. If a larger slice thickness is used (eg, 7 mm), the 
smallest tumor measurement that can be reported is twice the thickness of the slice. 
The ORR, DCR, and DOR will be determined immediately prior to the initiation of 
maintenance therapy. The OS and PFS will be determined at the end of the study for 
evaluable patients without censoring at the initiation of maintenance therapy. Patients who 
have obtained a response (PR or CR) will have a confirmatory scan at a minimum of 4 weeks 
following the initial scan. 
Section 6.1.3 – MD Anderson Symptom Inventory 
 
… 
 
The core MDASI and the MDASI-LC will be administered as a self-report paper-and-pencil 
form given to the patient at the site before study treatments on Days 1 and 8 of each cycle in 
Part 1 only (as described in Study Manual). 
Section 6.2 - Pharmacokinetic and Pharmacodynamic Assessments 
 
… 
 
Pharmacokinetics blood sampling should occur within 10% of nominal time for Days 1 and 
2, and ±4 hours of nominal time for all other time points, and should occur within 10 
minutes after the 12-lead ECGs performance at time-matched visits (Section 6.3.6). All 
PK samples will be evaluable as long as the actual collection times are recorded. 
Section 6.3.1.1 – Definition of Dose-Limiting Toxicities 
 
A DLT (monitored in Part 1 only) is defined as the following treatment-related AEs or 
laboratory abnormalities, graded according to the NCI CTCAE version 4.03: 
Section 6.3.1.2.1 - Safety Monitoring in Part 2 
 
During Part 2 of the study, patients treated with NC-6004 at the RPII dose from Part 1 will be 
monitored for safety. Dose delay and modification rules for both NC-6004 and gemcitabine 
apply in Part 2 as in Part 1. 


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In Part 2 (Cohort 3), if 2 of 6 patients (or ≥33% at any point during the study) in the 
≥30 to <60 mL/min group have a worsening of CrCl (ie, 50% reduction from baseline 
for 2 consecutive assessments, at least 1 week apart), then enrollment of patients with 
CrCl <60 mL/min will stop in the bladder cancer cohort. In addition, in Part 2 
(Cohort 3), if an unfit bladder cancer patient (≥30 to <60 mL/min CrCl at screening) 
has a worsening of CrCl (ie, 50% reduction from baseline for 2 consecutive assessments, 
at least 1 week apart) he or she may be withdrawn from the study (Section 4.2.1). 
Section 6.3.2.3 – Reporting Adverse Events 
 
… 
 
Any AE that meets SAE criteria (Section 6.3.2.1) must be reported to PPD immediately (ie, 
within 24 hours after the time site personnel first learn about the event).The following 
contact information is to be used for SAE reporting; The event is reported via the 
electronic data capture (EDC) system where site personnel complete as much of the 
respective AE page (eCRF) as they are able. 
If the EDC system is unavailable, the AE information must be recorded on the manual 
SAE report form and immediately (ie, within 24 hours of awareness) sent to PPD by one 
of the following methods (refer to the “SAE Guidelines” document for WorldReach toll- 
free access numbers if necessary): 
Pharmacovigilance Department 
 
United States SAE Hotline: +1 800-201-8725 
 
United States SAE Fax line: +1 888-488-9697 
 
Europe SAE Hotline: 
+44 1223 374 240 (to be used for questions 
concerning SAEs) 
Europe SAE Fax line: 
+44 1223 374 102 (to be used for reporting SAEs) 
 
 
 
Once the EDC system becomes available again, the site needs to transfer all data to the 
respective eCRF page of the patient. 


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Section 6.3.2.5 - Assessment of Causality 
 
The investigator’s assessment of an AE’s relationship to study drug (combination of 
NC-6004 and gemcitabine) is part of the documentation process, but it is not a factor in 
determining what is or is not reported in the study. If there is any doubt as to whether a 
clinical observation is an AE, the event should be reported. 
Section 6.3.3 - Assessment of Nausea and Vomiting 
 
… 
 
For Parts 1 and 2, eEach patient will be given a nausea and vomiting patient diary to take 
home. This diary will be used to record the severity of nausea and incidence of emetic 
episodes over the previous 24 hours daily on Days 2 through 21. The first 7 days of the 
diary will be recorded verbatim in the eCRF. The patient will be given the diary and 
instructed on how and when to complete the diary before discharge from the site on 
Day 1 of each cycle. 
Part 1: The investigator will collect the nausea and vomiting patient diary from each 
patient diaries on Day 8 and Day 15 for Cycle 1. For all subsequent cycles, the 
investigator will collect diaries on Day 1 (prior to dosing to capture the last 7 days of the 
previous cycle), Day 8, and Day 15 (Part 1 only), and Day 22. The first 7 days of the diary 
will be recorded verbatim in the eCRF. The investigator will record the worst severity of the 
patient’s nausea and the total number of emetic episodes occurring over the previous 7 days 
in the eCRF for Day 8 , Day 15, and Day 21. The patient will be given the diary and 
instructed on how and when to complete the diary before discharge from the site on Day 1 of 
each cycle. The patient must return the diary to the site on Day 8, Day 15 (Part 1 only), and 
Day 22 (Day 1 of the next cycle) of each cycle. 
Part 2: The investigator will collect the nausea and vomiting patient diary from each 
patient at the site on Day 8 for Cycle 1. For Cycle 2, the investigator will collect diaries 
on Day 1 (prior to dosing to capture the last 7 days of the previous cycle) and Day 8. 
Note that nausea and vomiting patient diaries will not be collected past Cycle 2. The 
investigator will record the worst severity of the patient’s nausea and the total number 
of emetic episodes occurring over the previous 7 days in the eCRF for Day 8 and Day 21. 
Section 6.3.5 – Clinical Laboratory Analyses 


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… 
 
Any Only abnormal laboratory test results (hematology, biochemistry, or urinalysis) that are 
deemed clinically significant by the PI will are to be recorded as AEs or SAEs per the NCI 
CTCAE version 4.03. 
Section 6.3.5.3 – Urinalysis 
 
Urinalysis will be performed using a dipstick test and will include: leukocyte esterase, nitrite, 
urobilinogen, protein, pH, blood, specific gravity, ketones, bilirubin, and glucose. 
Section 6.3.6 – Electrocardiograms 
 
All 12-lead ECGs will be performed after the patient has adequately rested in the supine 
position for at least 5 minutes. 
A 12-lead ECG will be performed during the screening period at Day -7 to -1. On Day 1 
of Cycle 1, 12-lead ECGs will be performed before the start of the NC-6004 infusion, at 
completion of infusion (~1 hour after start of infusion), and at Hours 3 and 24 hours (Day 2) 
after start of infusion. On Day 8 of Cycle 1, 12-lead ECGs will be performed before the start 
of gemcitabine infusion, at the completion of gemcitabine infusion, and at 1 hour after 
completion of gemcitabine infusion. Twelve-lead ECGs will also be performed on Day 1 of 
Cycles 2 through 6 before the start of the NC-6004 infusion and at the End-of-Treatment visit. 
All 12-lead ECGs should be performed within a ±30-minute window. 
Section 6.3.7 - Physical Examination 
 
A complete physical examination will be performed during the screening period at Day -14 
to -1, before study treatments on Day –1 or Day 1 of each cycle, and at the End-of-Treatment 
visit. Height and weight will also be assessed at the time of the screening period physical 
examination and before treatments on Day 1 of each cycle. with Calculation of BSA will be 
done before each dosing on Day 1 of each cycle (using the Mosteller formula 
[Mosteller 1987]. (Note: Dose will only be recalculated if there is a ≥10% increase or 
decrease in the patient’s weight from the patient’s weight measurement at screening. 
Any change in a patient’s weight by ≥10% during the study will require a recalculation 
of the doses of all study drugs. This threshold should not be confused with a change of a 
patient’s BSA [m2]). 


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Section 6.3.8 - Vital Sign Measurements 
 
Vital sign measurements will include arterial blood pressure, heart rate, respiratory rate, and 
temperature. Vital signs will be measured after the patient has adequately rested in the 
supine position for at least 5 minutes. 
… 
 
Vital signs will also be measured at the End-of-Treatment visit. 
 
Section 7.3 - Sample Size Calculations 
 
This is a Phase 1b/2 study with an overall sample size of up to 199 209 patients (up to 
49 patients in Part 1 and up to 150160 patients in Part 2). The total sample size will depend 
on the number of cohorts required to establish an RPII dose and the number of patients with 
NSCLC enrolled at the RPII dose in Part 1. 
… 
 
Part 2 is a 3-cohort study with an overall sample size of up to 150 160 patients with no more 
than 50 patients per cohort each in Cohorts 1 and 2 and no more than 60 patients in 
Cohort 3 (30 unfit and 30 fit bladder cancer patients). The total sample size will depend 
on the results of interim futility and superiority analyses. In order to evaluate the overall 
sample size, simulations were performed assuming scenarios with different HRs for PFS for 
each cohort compared with historical control and different sample sizes for a subsequent 
Phase 3 clinical trial. The associated mean sample size for this trial in these scenarios ranged 
from 92.7136 to 116.8 146 patients. 
Section 10.2.2 - Protocol Violations and Deviations 
 
… 
 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
patient or investigator that results in a significant, additional risk to the patient. Significant 
deviations can include nonadherence to inclusion or exclusion criteria, enrollment of the 


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patient without prior sponsor approval, or nonadherence to FDA regulations or ICH GCP 
guidelines, and will lead to the patient being withdrawn from the study (Section 4.2). 
Section 11 - Reference List 
 
… 
 
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 
1987;317(17):1098. 
Section 12.1 - Appendix: Schedule of Events 


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Table 12-1 
Schedule of Events 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7 Onwarda 
End-of- 
Treatmentb 
Follow-upc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
2 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Informed consent 
X 
Eligibility criteria 
X 
Demography 
X 
Medical history 
X 
Pregnancy test (serum or urine) 
X 
Xe 
X 
X 
X 
X 
Physical examination 
Xf 
Xf 
X 
X 
X 
X 
Height, weight, and BSA 
calculationg 
Xg 
X 
X 
X 
X 
Vital signsh 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status (ECOG) 
Xf 
Xf 
X 
X 
X 
X 
Disease assessmenti 
X 
Xi 
Xi 
X 
X 
Audiometry 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Hematology 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (dipstick) 
X 
X 
EORTC QLQ-C30 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDASI or MDASI-LCl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Part 1: Nausea and vomiting 
patient diarym 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Part 2 Nausea and vomiting patient 
diarym 
X 
X 
X 
X 
Cardiac risk factors 
X 
12-lead ECGn 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic assessments 
(Part 1)o 
X 
X 
X 
X 
X 
X 
Xo 
Xo 
X 
Pharmacokinetic assessments 
(Part 2)p 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
Xf 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 


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Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7 Onwarda 
End-of- 
Treatmentb 
Follow-upc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
2 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Prophylactic administrations 
X 
X 
X 
X 
NC-6004 administrationa 
X 
X 
X 
X 
Gemcitabine administration 
X 
X 
X 
X 
X 
X 
X 
X 


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Abbreviations: BSA, body surface area; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-C30, European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; MDASI, MD Anderson Symptom Inventory; RECIST, Response Evaluation Criteria 
in Solid Tumors; MDASI-LC, MDASI-lung cancer. 
a. 
In Part 1 of the study, patients will receive treatment until progressive disease. In Part 2 of the study, patients will receive treatment for 6 cycles (Cohorts 1 
and 3) or 8 cycles (Cohort 2). 
b. End-of-treatment assessments will be performed within 28 days after treatment discontinuation. 
c. 
After patient discontinuation or completion of treatment without disease progression, patients will be followed with scans every 9 weeks until disease 
progression. Patients will be called every 12 (±1) weeks to collect data on patient survival, new treatments, and adverse events. 
d. Day 15 visit is required in Part 1. In Part 2, Day 15 visit is only necessary if it is clinically indicated. 
e. 
Not required if screening pregnancy test was performed using serum. 
f. 
Safety assessments of physical examination, ECOG, review of adverse events, and concomitant medication use can be completed on Day -1 to allow for 
early morning dosing. These should not be conducted in place of screening assessments. 
g. From Day -14 to -1 at screening, only height and weight will be measured. On Day 1 of each cycle, weight will be measured before treatments and 
BSA will be calculated before each dose using the Mosteller formula (Mosteller 1987). (Note: Dose will only be recalculated if there is a ≥10% 
increase or decrease in the patient’s weight from the patient’s screening weight measurement. Any change in a patient’s weight by ≥10% during the 
study will require a recalculation of the doses of all study drugs. This threshold should not be confused with a change in the patient’s BSA [m2]). 
g. Height and weight only. 
h. 
Vital signs will be measured after the patient has adequately rested in the supine position for at least 5 minutes. On Day 1 of Cycle 1, vital signs will be 
measured before the start of the NC-6004 infusion, every 20 minutes during the infusion, at the completion of the infusion, and 1 hour after the completion 
of the NC-6004 infusion. Starting in Cycle 2, vital signs will be measured before the start of the NC-6004 infusion and at the completion of the NC-6004 
infusion on Day 1 of each cycle. Vital signs will be measured before and after gemcitabine infusion on Day 8 of each cycle. Vital signs will also be 
measured at the End-of-Treatment visit. 
i. 
Disease assessment will be performed using RECIST version 1.1 and the same imaging method used at screening should be used for all subsequent 
assessments. Beginning in Cycle 3 and continuing through the remainder of the treatment cycles, disease will be assessed every 6 (±1) weeks (ie, every other 
cycle) and at the End of Treatment visit or until disease progression. Patients who have obtained a partial response or complete response will have a 
confirmatory scan at a minimum of 4 weeks following the initial scan. 
j. 
To be performed only as clinically indicated. 
k. 
Hematology and biochemistry tests will be repeated prior to dosing on Day 1 of Cycle 1 if they were last performed more than 24 hours before the start of 
the study drug administration. 
l. 
Symptom changes will be assessed using the core MDASI (Part 1 only) or MDASI-LC (only in patients with NSCLC in Part 1). 


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m. Part 1: The investigator will collect the nausea and vomiting patient diary from each patient on Day 8 and Day 15 for Cycle 1. For all subsequent 
cycles, the investigator will collect diaries on Day 1 (prior to dosing to capture the last 7 days of the previous cycle), Day 8, and Day 15. Part 2: The 
investigator will collect the nausea and vomiting patient diary from each patient at the site on Day 8 for Cycle 1. For Cycle 2, the investigator will 
collect diaries on Day 1 (prior to dosing to capture the last 7 days of the previous cycle) and Day 8. Note that nausea and vomiting patient diaries 
will not be collected past Cycle 2. For additional details, see Section 6.3.3. Diary issued on Day 1 of each cycle. Assessment is performed at the site 
before dosing on Day 1 and Day 8 as well as Day 15 (Day 15 diary collected in Part 1 only; note: no dosing on Day 15) of each cycle. Patient completes 
diary at home on Days 2 through 8 and returns diary on Day 8. 
n. 
Twelve-lead ECGs will be performed after the patient has adequately rested in the supine position for at least 5 minutes. A 12-lead ECG will be performed 
during the screening period at Day –7 to –1. On Day 1 of Cycle 1, 12-lead ECGs will be performed before the start of the NC-6004 infusion, at 
completion of infusion (~1 hour after start of infusion), and at Hours 3 and 24 (Day 2) after the start of infusion. On Day 8 of Cycle 1, 12-lead ECGs will be 
performed before the start of gemcitabine infusion, at the end of gemcitabine infusion, and at 1 hour after completion of gemcitabine infusion. Twelve-lead 
ECGs will be performed on Day 1 of Cycles 2 through 6 before the start of the NC-6004 infusion, and at the End-of Treatment visit. All 12-lead ECGs 
should be performed within a ±30-minute window. 
n.o. For Part 1, blood samples will be collected at the following times: before the start of the NC-6004 infusion on Day 1 of Cycles 1 through 6, at end of 
NC-6004 infusion in Cycles 1, 3, and 5, after the start of NC-6004 infusion at Hours 3, 6, 12, 24 (Day 2), 48 (Day 3), 96 (Day 5), 168 and (Day 8, prior to 
gemcitabine infusion (Day 8), and 336 (Day 15) in Cycles 1, 3, and 5, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample 
collections may be performed, at the discretion of the investigator, during any visit where toxicity is observed. Blood samples will be collected within 
10 minutes after the 12-lead ECGs performance. 
o.p. For Part 2 (up to 6 cycles), on the day of NC-6004 infusion for each cycle, blood samples will be collected before the start of the NC-6004 infusion, at the 
end of the NC-6004 infusion, before gemcitabine infusion on Day 8, and at the End-of-Treatment visit. Additional pharmacokinetic blood sample collections 
may be performed, at the discretion of the investigator, during any visit where toxicity is observed. Blood samples will be collected within 10 minutes 
after the 12-lead ECGs performance. 


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12.4.7 
Protocol Amendment 4-Protocol Version 5.0, Incorporating 
Amendment 3-Version 4.2 (dated 12 December 2016) 
The following sections detail the changes made to Protocol Amendment 3-Version 4.2 (dated 
12 December 2016). The integrated protocol, Version 5.0, including Amendment 4, was 
issued on 13 March 2017. 
 
12.4.7.1 
Risk Assessment for Amendment 4, Version 5.0 
No anticipated increased patient risk has been introduced with the updates made during this 
protocol amendment. Detailed management guidelines for NC-6004-related liver dysfunction 
have been added in Section 6.3.2.7. 
 
12.4.7.2 
Overview of Changes 
The overview of significant changes includes the following. (Note that minor word changes 
and copyedits are not identified). Global changes for Protocol Amendment 4, Version 5.0 
include the following changes resulting from FDA feedback on IND 118108: 
• Revised the entry criteria to require baseline alanine transaminase and aspartate 
transaminase <2.0 × ULN or, in patients with documented hepatic metastasis 
<5.0 × ULN and also serum albumin ≥3.5 g/dL, and prothrombin time within normal 
limits. 
• Revised the entry criteria (Part 2 only) Cohort 1 to require that patients histologically 
or cytologically confirmed diagnosis of Stage IV squamous NSCLC and have not 
received prior chemotherapy or immunotherapy for metastatic disease and are not 
known to be PD-L1 positive (known high PD-L1 expression defined as Tumor 
Proportion Score [TPS] greater than or equal to 50%). 
• Added a criterion to exclude patients with known active hepatitis B (defined as a 
known positive HBsAg result) or hepatitis C (defined by a known positive hepatitis C 
antibody result and known quantitative HCV RNA results greater than the lower 
limits of detection of the assay). 


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• Revised Section 5.4.1 NC-6004 Dose Delay and Modification to hold NC-6004 in the 
event of a Grade 3 liver enzyme elevation until return to Grade ≤1. NC-6004 to be 
immediately and permanently discontinued for Grade 4 liver enzyme elevation. 
• Revised the protocol to include a section with detailed management guidelines for 
NC-6004-related liver dysfunction. 
 
12.4.7.3 
Changes to the Protocol Text 
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. Additions to the protocol text are shown in bold and 
deletions are shown in strikethrough text. Minor or obvious editorial and grammatical 
corrections are not described. 
Protocol Synopsis – Inclusion Criteria 
 
Inclusion Criterion 2 (Cohort 1) was revised: 
 
2. 
(Part 2 only) Cohort 1: Have histologically or cytologically confirmed diagnosis of 
Stage IV squamous NSCLC and have not received prior chemotherapy or 
immunotherapy for metastatic disease and are not known to be PD-L1 positive 
(known high PD-L1 expression defined as Tumor Proportion Score [TPS] greater 
than or equal to 50%). Patients with known sensitizing mutation in the epidermal 
growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) fusion 
oncogene must have received at least 1 and up to 2 targeted therapies prior to 
enrollment. 
Inclusion Criterion 7 was revised: 
 
7. 
Have adequate liver function defined as: 
 
• Total serum bilirubin <1.5 × upper limit of normal (ULN) and 
 
• Baseline Aalanine transaminase, and aspartate transaminase <2.50 × ULN or, in 
patients with documented hepatic metastasis ≤ <5.0 × ULN and 
• Serum albumin ≥3.5 g/dL 


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Inclusion criterion 8 was added: 
 
8. Prothrombin time within normal limits 
 
Protocol Synopsis – Exclusion Criteria 
 
… 
 
Exclusion Criterion 9 was added: 
 
9. 
Have known active hepatitis B (defined as a known positive hepatitis B surface 
antigen [HBsAg] result) or hepatitis C (defined by a known positive hepatitis C 
antibody result and known quantitative HCV RNA results greater than the lower 
limits of detection of the assay). 
 
 
Protocol Synopsis – Estimated Study Duration 
 
… 
 
Part 2 of the study will include a screening period (up to 28 days); 6 treatment cycles 
(Cohorts 1 and 3) or 8 treatment cycles (Cohort 2) that are 21 days in duration; tumor 
assessments for response and disease progression with scans every 6 weeks; and telephone 
calls for survival every 12 weeks. 
Patients will receive study treatment until any of the following occur: 
… 
• Grade 4 liver enzyme elevation 
Protocol Synopsis – Safety Assessments 
 
… 
 
Hematology and coagulation and biochemistry tests will be performed at screening and on 
Days 1, 8, and 15 of each cycle (before any study drug infusions), and at the End of 
Treatment visit. Urinalyses will be performed at screening and at the End of Treatment visit. 
Section 3.1 – Study Design 
 
… 


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Screening Period (Day -7 to -1) 
 
The following procedures will be performed during the screening period within 7 days prior 
to the first study treatment: 
… 
 
• Hematology and coagulation 
… 
 
Day 1 of Cycle 
 
The following procedures will be performed on Day 1 prior to NC-6004 infusion in each 
treatment cycles unless otherwise specified: 
… 
 
• Hematology and coagulation 
Day 8 of Each Cycle 
The following procedures will be performed on Day 8 prior to gemcitabine infusion in each 
treatment cycle: 
… 
 
• Hematology and coagulation 
… 
 
Day 15 of Each Cycle (Part 1: required; Part 2: if clinically indicated) 
 
The following procedures will be performed on Day 15 in each treatment cycle: 
 
• Hematology and coagulation 
… 


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End-of-Treatment Visit 
 
The following procedures will be performed within 28 days after treatment discontinuation: 
 
… 
 
• Hematology and coagulation 
Section 4.1.1 – Inclusion Criteria 
 
Inclusion Criterion 2 (Cohort 1) was revised: 
 
2. 
(Part 2 only) Cohort 1: Have histologically or cytologically confirmed diagnosis of 
Stage IV squamous NSCLC and have not received prior chemotherapy or 
immunotherapy for metastatic disease and are not known to be PD-L1 positive 
(known high PD-L1 expression defined as Tumor Proportion Score [TPS] greater 
than or equal to 50%). Patients with known sensitizing mutation in the epidermal 
growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) fusion 
oncogene must have received at least 1 and up to 2 targeted therapies prior to 
enrollment. 
Inclusion Criterion 7 was revised: 
 
7. 
Have adequate liver function defined as: 
 
• Total serum bilirubin <1.5 × upper limit of normal (ULN) and 
 
• Baseline Aalanine transaminase, and aspartate transaminase <2.50 × ULN or, in 
patients with documented hepatic metastasis ≤ <5.0 × ULN and 
• Serum albumin ≥3.5 g/dL 
 
Inclusion criterion 8 was added: 
 
9. Prothrombin time within normal limits 


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Section 4.1.2 – Exclusion Criteria 
 
… 
 
Exclusion Criterion 9 was added: 
 
9. Have known active hepatitis B (defined as a known positive hepatitis B surface 
antigen [HBsAg] result) or hepatitis C (defined by a known positive hepatitis C 
antibody result and known quantitative HCV RNA results greater than the lower 
limits of detection of the assay). 
Section 4.2.1 – Reasons for Withdrawal/Discontinuation 
 
… 
 
A patient may be withdrawn from the study for any of the following reasons: 
 
• Disease progression 
 
• Unacceptable toxicity experienced 
 
• Grade 4 liver enzyme elevation 
 
• Withdrawal of consent 
 
• Major protocol violation 
 
• Required treatment delay >14 days (except in case of potential patient benefit, which 
must be approved by the sponsor) 
• Symptoms or an intercurrent illness not consistent with the protocol requirements or 
that justifies withdrawal 
• For Cohort 3 only, unfit bladder cancer patient (≥30 to <60 mL/min CrCl at 
screening) has a worsening of CrCl (ie, 50% reduction from baseline for 
2 consecutive assessments, at least 1 week apart) 
 
• Lost to follow-up 
 
• Other (eg, pregnancy, development of contraindications of use of the study drug) 


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• The investigator or sponsor determines it is in the best interest of the patient to 
discontinue the patient’s participation in the study. 
Section 5.4 - Dose Delays and Modifications 
 
… 
 
• Any patient who experiences a Grade 3 or 4 hypersensitivity reaction during any 
cycle of treatment. 
• Any patient who experiences 2 protocol-defined DLTs during treatment. 
 
• Any patient who experiences a recurrent Grade 3 or 4 toxicity (recurrence of the same 
AE) after a dose reduction. 
• Any patient who requires a dosing delay >14 days at any time during treatment 
(except in case of potential patient benefit, which must be approved by the sponsor). 
• Any patient who experiences a Grade 4 liver enzyme elevation. 
 
Section 5.4.1 – NC-6004 Dose Delay and Modification 
 
During any treatment cycle, investigators should suspend further dosing with NC-6004 for up 
to 14 days after the scheduled dose in the event of a protocol-defined DLT or any Grade 4 
hematologic toxicity or Grade 3 or 4 nonhematologic toxicity that is possibly, probably, or 
definitely related to NC-6004 (excluding alopecia and Grade 3 nausea, vomiting, diarrhea, 
and electrolyte imbalances lasting less than 48 hours or with suboptimal prophylactic and 
suboptimal curative treatment). Any patient experiencing a Grade 3 liver enzyme 
elevation should have their next dose of NC-6004 suspended until improvement to 
Grade 1 or lower. At the discretion of the investigator, the dose may also be delayed for up 
to 14 days for any toxicity possibly or probably related to NC-6004 that does not meet DLT 
criteria. A delay of more than 14 days will require the patient to be removed from the study 
(except in case of potential patient benefit, which must be approved by the sponsor). The 
toxicity for which the dose was suspended must have improved to Grade 1 or lower prior to 
NC-6004 infusion. 


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Section 5.10 – Prior, Concomitant, and Subsequent Therapy 
 
(Part 2 only) Cohort 1: For patients with Stage IV NSCLC, they may not have received prior 
chemotherapy or immunotherapy for metastatic disease. 
Section 6.3 – Safety and Tolerability Assessments 
 
Safety will be assessed using frequent collection of AE reports (Section 6.3.2) and clinical 
hematology and coagulation, biochemistry, and urinalysis test results (Section 6.3.5). 
Section 6.3.2.7 – Management Guidelines for NC 6004-Related Liver Dysfunction 
 
At the onset of Grade 4 liver enzyme elevation, NC-6004 must be immediately and 
permanently discontinued. Patients should be referred promptly to a 
hepatologist/gastroenterologist/specialist to be further evaluated. Patients with Grade 4 
liver enzyme elevation should have a physical examination performed and should be 
assessed for signs of fever, rash and jaundice. Liver function tests including serum 
transaminases, alkaline phosphatase, γ-glutamyl transpeptidase, and total bilirubin 
(including direct and indirect), albumin choline esterase, total cholesterol, as well as 
hematological tests including prothrombin time (PT), PT/international normalized ratio 
(INR) and eosinophil count should be performed. Other testing including a serological 
test may be performed at the hepatologist/gastroenterologist/specialist’s discretion. 
Patients should then be monitored on a bi-weekly basis (or more frequent if indicated 
by the hepatologist/gastroenterologist/specialist) until improvement to Grade 2 or below 
and clinical stability. Section 5.4.1 provides details for management of Grade 3 liver 
enzyme elevation. 
Section 6.3.5 – Clinical Laboratory Analyses 
 
Samples for hematology and coagulation, biochemistry, and urinalysis will be collected at 
the time points specified in Appendix 12.1, Schedule of Events. 
… 
 
Only abnormal laboratory test results (hematology and coagulation, biochemistry, or 
urinalysis) that are deemed clinically significant by the PI will be recorded as AEs or SAEs 
per the NCI CTCAE version 4.03. 


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Section 6.3.5.1 – Hematology and Coagulation 
 
Hematology will include hemoglobin, reticulocytes, red blood cell count, differential white 
blood cell count, and platelets, and. Coagulation will include prothrombin time and 
international normalized ratio. Hematology and coagulation tests will be performed during 
the screening period on Day -7 to -1, prior to dosing on Day 1 of Cycle 1 (if they were last 
performed more than 24 hours before the start of the study drug administration), weekly at 
each study visit prior to any treatments, and at the End-of-Treatment visit. 
Section 7.6.2.3 – Clinical Laboratory Results 
 
Clinical hematology and coagulation, biochemistry, and urinalysis data will be summarized 
at each scheduled assessment. Numeric hematology and coagulation and biochemistry 
results will be summarized using change from baseline. 
… 
 
Numeric clinical hematology and coagulation, biochemistry, and urinalysis results will be 
summarized using change from baseline. 


Page 245 
 
 
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Table 12-1 – Schedule of Events 
 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycle 7 Onwarda 
End-of- 
Treatmentb 
Follow- 
upc 
Day 
-28 
to -1 
Day 
-14 
to -1 
Day 
-7 
to -1 
Day 
1 
Day 
2 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
Day 
1 
Day 
8 
Day 
15d 
… 
Hematology and 
coagulation 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
… 
… 
 
k. 
Hematology and coagulation and biochemistry tests will be repeated prior to dosing on Day 1 of Cycle 1 if they were last performed more than 24 hours before the start 
of the study drug administration. 

SAP_001.pdf: 
PPD 
NC-6004 
NCT02240238 
NanoCarrier Co, Ltd 
NC-6004-004A 
A Phase 1b/2 Dose Escalation and Expansion Trial of NC-6004 (Nanoparticle Cisplatin) plus 
Gemcitabine in Patients with Advanced Solid Tumors or Squamous Non-Small Cell Lung, 
Biliary Tract, and Bladder Cancer 
03JAN2019 
Statistical Analysis Plan 
Version 2.0 
Prepared by 
PPD 
929 North Front Street 
Wilmington, NC 28401 
Issued by: 
Reviewed by: 
 
 
Xianyi Kong 
Associate Director, Biostatistics 
PPD 
Date 
Upon review of this document, including table, listing, and figure shells, the undersigned 
approves the statistical analysis plan. The analysis methods and data presentation are acceptable, 
and the table, listing, and figure production can begin. 
Confidential 
Page 3401 
Date 


NanoCarrier Co, Ltd 
NC-6004--004A 
Statistical Analysis Plan, Version 2.0 
Date Issued: 03JAN2019 
Approved by: _4fj"""- -t/4i._._Q;--=- --
Atsushi Osada 
Study Director, International Clinical Development 
NanoCarrier Co, Ltd 
Page 3402 


NanoCarrier Co, Ltd 
NC-6004-004A 
Statistical Analysis Plan, Version 2.0 
Date Issued: 03JAN2019 
Page 3403 
III 
 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................................................... V 
1. 
INTRODUCTION ............................................................................................................ 7 
2. 
OBJECTIVES ................................................................................................................... 7 
2.1. PRIMARY OBJECTIVES ........................................................................................................ 7 
2.2. SECONDARY OBJECTIVES ................................................................................................... 8 
2.3. EXPLORATORY OBJECTIVES ................................................................................................ 8 
3. 
INVESTIGATIONAL PLAN ........................................................................................... 8 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 8 
3.2. TREATMENTS ................................................................................................................... 13 
3.3. DOSE DELAY/MODIFICATIONS .......................................................................................... 13 
4. 
GENERAL STATISTICAL CONSIDERATIONS ...................................................... 14 
4.1. SAMPLE SIZE .................................................................................................................... 14 
4.2. ANALYSIS SET .................................................................................................................. 15 
4.3. DEFINITION OF BASELINE VALUES .................................................................................... 15 
4.4. BAYESIAN MODEL FOR ONGOING DATA ANALYSES .......................................................... 15 
5. 
PATIENT DISPOSITION AND PROTOCOL DEVIATIONS ................................... 16 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................... 17 
6.1. DEMOGRAPHICS ............................................................................................................... 17 
6.2. INCLUSION/EXCLUSION CRITERIA ..................................................................................... 17 
6.3. MEDICAL HISTORY ........................................................................................................... 17 
6.3.1. 
General Medical History .......................................................................................... 17 
6.3.2. 
Prior Treatments ....................................................................................................... 17 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 18 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 18 
7.2. STUDY TREATMENTS ........................................................................................................ 18 
8. 
EFFICACY ANALYSIS ................................................................................................ 19 
8.1. PRIMARY EFFICACY ENDPOINT ......................................................................................... 19 
8.1.1. 
Progression-Free Survival (PFS).............................................................................. 19 
8.1.2. 
Overall Survival (OS) ............................................................................................... 21 
8.1.3. 
Duration of Response (DOR) .................................................................................... 21 
8.1.4. 
Disease Control Rate (DCR) ..................................................................................... 22 
8.1.5. 
Overall Response Rate (ORR) ................................................................................... 23 
8.2. SECONDARY EFFICACY ENDPOINT .................................................................................... 24 
8.2.1. 
Quality of Life Analyses ............................................................................................ 24 
8.2.2. 
Symptoms Assessment Analyses ................................................................................ 25 
9. 
SAFETY ANALYSIS ..................................................................................................... 25 
9.1. ADVERSE EVENTS ............................................................................................................ 25 
9.2. CLINICAL LABORATORY EVALUATIONS ............................................................................ 26 


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9.3. VITAL SIGN MEASUREMENTS ........................................................................................... 27 
9.4. PHYSICAL EXAMINATION .................................................................................................. 27 
9.5. ELECTROCARDIOGRAM ..................................................................................................... 28 
9.6. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS (PS) .......... 28 
10. 
PHARMACOKINETIC ASSESSMENTS .................................................................... 29 
10.1 PLASMA CONCENTRATION ................................................................................................. 29 
10.2 PLASMA PHARMACOKINETIC PARAMETERS ........................................................................ 30 
11. 
INTERIM ANALYSIS ................................................................................................... 32 
12. 
REFERENCES ............................................................................................................... 32 
APPENDIX A: LIST OF TABLES .................................................................................................... 33 
APPENDIX B: LIST OF LISTINGS................................................................................................... 36 
APPENDIX C: LIST OF FIGURES ................................................................................................... 37 
APPENDIX D: IMPUTATION ALGORITHM FOR PARTIAL AND MISSING DATES ............................... 38 


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List of Abbreviations 
AE 
adverse event 
AI 
Accumulation Index 
ATC 
Anatomical Therapeutic Chemical 
AUC0-τ 
area under the concentration-time curve from time zero to 
the end of the dosing interval 
AUClast 
area under the concentration-time curve from time zero to 
the last quantifiable concentration 
AUC0-∞ 
area under the concentration-time curve from time zero to 
infinity 
CL 
clearance 
Cmax 
maximum concentration 
CR 
complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
 disease control rate 
DOR 
duration of response 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EORTC QLQ-C30 
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire-Core 30 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HEENT 
head, ears, eyes, nose, throat 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intent-to-treat 
λz 
terminal elimination phase rate constant 
MDSAI 
 MD Anderson Symptom Inventory 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
 mean residence time 
MTD 
Maximum tolerated dose 
N-CRM 
Bayesian continual reassessment method design per 
Neuenschwander et al 2008 
NCI 
National Cancer Institute 


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NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
Pharmacokinetic 
PP 
per protocol 
PPS 
per protocol set 
PR 
partial response 
PT 
preferred term 
Pt 
platinum 
PVG 
Pharmacovigilance 
QoL 
Quality of Life 
QTcB 
Corrected QT interval - Bazett’s formula 
QTcF 
Corrected QT interval - Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SOC 
system organ class 
T½ 
terminal half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum concentration 
Vss 
volume of distribution at steady-state 
Vz 
volume of distribution 
WHO 
World Health Organization 


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1. Introduction 
 
In general, the purpose of the Statistical Analysis Plan (SAP) is to provide a framework 
that addresses the protocol objectives in a statistically rigorous fashion, with minimized 
bias or analytical deficiencies. Specifically, this plan has the following purpose: to 
prospectively (a priori) outline the types of analyses and data presentations that will 
addresses the study objectives outlined in the protocol, and to explain in detail how the 
data will be handled and analyzed, adhering to commonly accepted standards and practices 
of biostatistical analysis in the pharmaceutical industry. This document details the planned 
statistical methodology for data collected in the study NC-6004-004A based on protocol 
amendment 4.0. 
Cisplatin has been widely used for the treatment of cancer including lung cancer (both 
small cell and non-small cell lung cancer [NSCLC]), head and neck cancer, germ-cell 
tumors and so on. However, its use is associated with irreversible ototoxicity and renal 
toxicity, which necessitates the use of pre-hydration regimens using mannitol and excludes 
its use in patients with less than normal renal function. Nonclinical studies have indicated 
that NC-6004 (1) is preferentially distributed to tumors, (2) demonstrates significantly 
lower toxicity compared to cisplatin at an equivalent dose, and (3) has increased antitumor 
activity. In in vivo studies of NC 6004 in combination with gemcitabine, significant 
antitumor effects were observed in MDA-MB-231, MOR/CPR, BxPC-3, and PC-3 prostate 
cancer xenograft models. The results of a Phase 1 study of NC-6004 as monotherapy in 
patients with solid tumors (Study NC 6004-001) suggested that NC-6004 monotherapy has 
potential activity for the treatment of solid tumors. In Study NC 6004-002, NC-6004 and 
gemcitabine combination therapy exhibited an improved efficacy profile with prolonged 
administration period compared to that in Study NC-6004-001 and further clinical results 
are anticipated. Based on these results, it is concluded that further clinical study should 
proceed aiming at the development of a new micelle formulation of cisplatin for 
out-patient-based therapy without serious toxicity. 
 
 
 
2. Objectives 
 
2.1. Primary Objectives 
 
The primary objectives of this study are: 


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• In the dose-escalation phase of the study (Part 1), to determine the dose-limiting 
toxicities (DLTs) , maximum tolerated dose (MTD), and Recommended Phase II 
(RPII) dose of NC-6004 in combination with gemcitabine; 
• In the expansion phase of the study (Part 2), to evaluate the activity of NC-6004 in 
combination with gemcitabine in patients with first-line Stage IV squamous NSCLC, 
first-line advanced or metastatic biliary tract cancer, and first-line metastatic or locally 
advanced bladder cancer compared with historical control as measured by local 
investigator/radiologist-assessed progression-free survival (PFS), according to 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 
2.2. Secondary Objectives 
 
The secondary objectives of this study are: 
 
• To evaluate overall response rate (ORR), disease control rate (DCR=complete response 
[CR] + partial response [PR] + stable disease [SD]), duration of response (DOR), 
progression-free survival (PFS), and overall survival (OS) 
• To evaluate therapy-related adverse events (AEs) 
 
• The evaluate the safety and tolerability of NC-6004 when combined with Gemcitabine 
 
• To evaluate Quality of Life (QoL) using the European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) 
• To evaluate acute and delayed symptoms using the MD Anderson Symptom Inventory 
(MDSAI) and a nausea and vomiting patient diary 
2.3. Exploratory Objectives 
 
The exploratory objectives of this study are: 
 
• To assess the Pharmacokinetic (PK) and pharmacodynamic effects of NC-6004 
3. Investigational Plan 
 
3.1. Overall Study Design and Plan 


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
 
 
This study will consist of 2 parts; Part 1 is a Phase 1b, continual reassessment method 
dose-escalation trial in patients with any advanced solid tumor, and Part 2 is a Phase 2, 
adaptive, open-label, expansion trial in patients with squamous NSCLC, biliary tract, and 
bladder cancer evaluating activity, safety, and tolerability at the RPII dose identified in 
Part 1. 
 
In Part 1, patients will receive NC-6004 and gemcitabine in 3-week treatment cycles. 
NC-6004 will be administered on Day 1 of each cycle and gemcitabine 1250 mg/m2 will be 
administered on Day 1 of each cycle (after the administration of NC-6004) and on Day 8 of 
each cycle. 
 
A Bayesian continual-reassessment method per Neuenschwander et al 2008 (N-CRM) 
model will be used for dose escalation and determination of MTD. N-CRM classifies the 
probability of a DLT (p) into four categories: 
• 
Under-dosing: p∈ (0, 0.20] 
 
• 
Targeted toxicity: p∈ (0.20, 0.33] 
 
• 
Excessive toxicity: p∈ (0.33, 0.60] 
 
• 
Unacceptable toxicity: p∈ (0.60, 1.00] 
 
After each cohort, the posterior distribution of pi will be summarized for each dose by the 
four toxicity categories and the estimated dose-toxicity relationship curve is updated. The 
dose selection relies on maximizing the probability of targeted toxicity while controlling 
the probability of excessive or unacceptable toxicity to be less than a threshold. The 25% 
target toxicity is chosen. 
A two-parameter logistic model is used to model the dose-response relationship. 
 
 pi 
 
 di  
ln 
1 − p  = lnα + β ln 
i  
 
, 
 dr  
 
where pi is the probability of toxicity at dose level i; 
di is the dose in mg at level i ; 
dr is the reference dose, which is defined as median dose in this study. 


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α is the logit of toxicity at the reference dose 
 
β is the parameter to determine the slope of the curve 
 
An uninformative prior is selected. The dose level with the posterior probability of toxicity 
closest to the target toxicity while controlling the probability of excessive or unacceptable 
toxicity at 25% will be identified as MTD. 
The initial NC-6004 dose for evaluation will be 60 mg/m2. Sequential doses selected for 
evaluation are listed in Table 3–1. 
Table 3–1 
Dose Levels of NC-6004 
 
Dose Level Name 
NC-6004 Dose Level (mg/m2) 
1 
60 
2 
75 
3 
90 
4 
105 
5 
120 
6 
135 
7 
150 
8 
165 
9 
180 
 
 
Part 1 will begin with a single-patient run-in phase. In the run-in phase, 1 patient will be 
enrolled sequentially at each dose level of NC-6004 until a DLT is observed. Dose 
escalation in the run-in phase will only occur after a patient at a given dose level has 
experienced a DLT or has completed the first cycle. The N-CRM will model the starting 
dose for the remainder of Part 1 using the run-in data. For the remainder of Part 1, 4 
patients will be enrolled as a cohort at each dose level as predicted by the N-CRM model. 
The N-CRM model may enroll the next cohort at the previous dose level, the current dose 
level, or the next dose level. The N-CRM model will only be updated after all patients in a 
cohort have either experienced a DLT or completed the first cycle. If no DLT is observed 
in the single-patient run-in phase at 180 mg/ m2, the single-patient run-in phase will end 
and the next cohort will enroll 4 patients at 180 mg/ m2. 


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Once the MTD (or RPII dose) of NC-6004 is identified, dose escalation within Part 1 will 
cease. Patients in Part 1 who were not assigned to the NC-6004 dose identified as the RPII 
dose will continue treatment cycles at their assigned dose level. Part 2 of the study (Phase 
2 portion) will begin after the RPII dose of NC-6004 is identified for use in combination 
with gemcitabine. All patients will receive NC-6004 at the RPII dose (135 mg/m2, 
established in Part 1) in combination with gemcitabine 1250 mg/m2 by the same regimen 
as in Part 1. 
Three cohorts of patients are eligible in Part 2 (Cohort 1: first-line metastatic squamous 
NSCLC; Cohort 2: first-line metastatic or locally advanced cholangiocarcinoma, 
gallbladder cancer, or ampullary cancer [biliary tract cancer]; and Cohort 3: first-line 
metastatic or locally advanced TCC of the urinary tract [bladder cancer]). Part 2 will enroll 
up to 50 patients each in Cohorts 1 and 2. Cohort 3 will stratify patients by creatinine 
clearance (CrCl) to asses study drug in patients with reduced kidney function (i.e., CrCl of 
≥30 to <60 mL/min and/or ECOG PS 2 [unfit] and ≥60 mL/min and ECOG PS 0 to 1 [fit]). 
Up to 60 patients will be enrolled in Cohort 3 (i.e., 30 unfit and 30 fit bladder cancer 
patients), so total 160 patients will be enrolled in Part 2. The patients in Cohort 3 of Part 2 
will be enrolled in a controlled manner and with the stipulation that enrollment will stop if 
2 of 6 patients (or ≥33% at any point during the study) in the ≥30 to <60 mL/min group 
have a worsening of CrCl (i.e., 50% reduction from baseline for 2 consecutive 
assessments, at least 1 week apart). 
 
The primary endpoint (PFS) will be continuously updated and compared with the historical 
PFS from Phase 3 pivotal cisplatin and gemcitabine trials within each cohort. The PFS 
hazard model will be updated as PFS data accrue. A hazard ratio (HR) for PFS for each 
cohort versus historical control will be obtained. 
 
Once 10 PFS events have been observed, interim analyses will be performed every 6 
weeks. At each interim and at the final analysis, there are 3 possible outcomes for each 
cohort. 
 
• Futility – 10 PFS events have been observed in each cohort and at least 1 of the 
following conditions is true: 
• 
Probability (Promising HR*) <0.4 
• 
Probability (Phase 3 Success*) <0.4 
 
• Success – 25 PFS events have been observed in each 50-patient cohort and 15 PFS 
events in each 30-patient bladder cancer cohort and: 


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• 
Probability (Phase 3 Success*) >0.8 
 
• 
Inconclusive– neither futility nor success 
 
*Phase 3 success is defined as success in a Phase 3 clinical trial with 381 events - enough 
to provide 80% power to detect an HR of 0.75. A promising HR is defined as one less than 
0.85. 
 
*Futility can only be declared for a cohort after 10 PFS events have been observed in that 
cohort. Success can only be declared for a cohort after 25 or 15 PFS events have been 
observed in that 50-patient cohort (Cohort 1 and 2) or 30-patient bladder cancer cohort 
(Cohort 3, fit and unfit), respectively. Accrual will stop for any cohort identified as futile 
or successful at interim. The conclusion of this Phase 2 trial will be that a Phase 3 trial with 
381 events should be conducted for each cohort that is a success. 
 
If any indication is declared a success, the combination of NC-6004 and gemcitabine 
advances to a Phase 3 randomized, controlled trial with sample size sufficient to observe 
381events. 
In Part 1, patients may continue to receive treatment until they experience disease 
progression. The maximum number of cycles a patient undergoes is at the discretion of the 
investigator and depends on response. Patients who complete 4 or more cycles will be 
considered as having completed the treatment. Subject to sponsor approval, individual 
patients will be treated until progressive disease. 
 
After progressive disease (Part 1) or treatment discontinuation due to disease progression 
(Part 2) is observed, patients will have an End-of-Treatment visit and be contacted for 
survival every 12 weeks by phone. After the completion of 6 cycles (Part 2: Cohorts 1 and 
3) or 8 cycles (Part 2: Cohort 2), patients will have an End-of-Treatment visit, will be 
followed with scans every 9 weeks until disease progression, and will be contacted for 
survival every 12 weeks by telephone. Patients who discontinue treatment and have not 
progressed will have an End-of-Treatment visit, will be followed with scans every 9 weeks 
until disease progression, and will be contacted for survival every 12 weeks by telephone. 
 
Disease assessment will be performed using RECIST version 1.1 and the same imaging 
method used at screening should be used for all subsequent assessments. 


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3.2. Treatments 
 
This is an open-label study that will be conducted in 2 parts. In both parts, NC-6004 will 
be administered as a 1-hour (+10-minute window) intravenous infusion on Day 1 of each 
cycle. Gemcitabine 1250 mg/m2 will be administered as a 30-minute intravenous infusion 
on Day 1 of each cycle (after the administration of NC-6004) and on Day 8 of each cycle. 
The duration of each cycle will be 21 days. 
In Part 1, patients will be assigned to receive gemcitabine 1250 mg/m2 in combination with 
NC-6004 at doses of 60, 75, 90, 105, 120, 135, 150, 165, or 180 mg/m2 by the N-CRM 
model on Day 1 of each cycle. In Part 2, on Day 1 of each cycle all patients will receive the 
RPII dose (135 mg/ m2) of NC-6004 identified in Part 1 and 1250 mg/m2 gemcitabine. On 
Day 8 of each cycle all patients in Part 1 and Part 2 of the study will receive 1250 mg/m2 
gemcitabine. 
3.3. Dose Delay/Modifications 
 
The doses for NC-6004 and gemcitabine will be calculated in milligrams per square meter 
(mg/ m2) at screening and will not be changed in subsequent cycles unless the patient’s 
body weight has increased or decreased by ≥10% from the patient’s weight measurement 
at screening. Any change in a patient’s weight by ≥10% during the study will require a 
recalculation of the doses of all study drugs (Note: This threshold should not be confused 
with a change in the patient’s body surface area [BSA] [m2]). Weight will be measured 
before treatments on Day 1 of each cycle, with calculation of BSA before dosing on Day 1 
of each cycle. 
 
Patients experiencing significant toxicities must be immediately and permanently 
withdrawn from treatment with NC-6004 and gemcitabine as follows: 
• Any patient who experiences a Grade 3 or 4 hypersensitivity reaction during any cycle 
of treatment 
• Any patient who experiences 2 protocol-defined DLTs during treatment 
 
• Any patient who experiences a recurrent Grade 3 or 4 toxicity after a dose reduction 
 
• Any patient who requires a dosing delay >14 days at any time during treatment (except 
in case of potential patient benefit, which must be approved by the sponsor) 


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• Any patient who experiences a Grade 4 liver enzyme elevation. 
 
Dose delay and modification for NC-6004 and gemcitabine are discussed in details under 
protocol section 5.4.1 and 5.4.2 respectively. 
4. General Statistical Considerations 
 
No formal statistical testing is planned for this study. Ninety-five percent confidence 
intervals may be calculated for selected safety and exploratory variables. Dose escalation 
will be based on N-CRM design and DLT incidence. Adverse events (AE) and SAEs 
(Serious Adverse Event) will be tabulated by system organ class and preferred term. 
Laboratory test results after the first dose will be summarized with regard to shifts from 
baseline values (Section 4.3) and grade per the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. Overall survival (OS), 
progression free survival (PFS), and duration of response (DOR) will be summarized using 
Kaplan-Meier methods. Ninety-five percent confidence intervals for overall response rate 
(ORR) and disease control rate (DCR) will be constructed. All safety analyses will be 
performed on the safety analysis set. All efficacy analyses will be performed on the full 
analysis set (FAS). All summaries will present data by dose level, for patients with 
NSCLC dosed at the MTD, and overall. 
4.1. Sample Size 
 
This is a Phase 1b/2 study with an overall sample size of up to 209 patients (up to 49 
patients in Part 1 and up to 160 patients in Part 2). The total sample size will depend on the 
number of cohorts required to establish an RPII dose and the number of patients with 
NSCLC enrolled at the RPII dose in Part 1. 
 
Simulations were performed assuming scenarios with different dose-toxicity relationships 
to evaluate the sample size for Part 1 (Phase 1b). The associated mean sample size in these 
scenarios ranged from 17.22 to 25.79 patients. 
 
Part 2 is a 3-cohort study with an overall sample size of up to 160 patients with no more 
than 50 patients each in Cohorts 1 and 2 and no more than 60 patients in Cohort 3 (30 unfit 
and 30 fit bladder cancer patients). The total sample size will depend on the results of 
interim futility and superiority analyses. In order to evaluate the overall sample size, 
simulations were performed assuming scenarios with different hazard ratios (HRs) for PFS 
for each cohort compared with historical control and different sample sizes for a 


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subsequent Phase 3 clinical trial. The associated mean sample size for this trial in these 
scenarios ranged from 92.7 to 116.8 patients. 
 
No formal efficacy analysis will be performed and no inference regarding efficacy will be 
drawn based on the response rate of the overall study. 
 
Patients in Part 1 who discontinue treatment without DLT before completion of the first 
cycle will be replaced. No other patients will be replaced. 
4.2. Analysis Set 
 
Four analysis sets will be used in this study: 
 
• The DLT-evaluable analysis set consists of all patients in Part 1 who either experiences 
a DLT in the first cycle or complete the first cycle without a DLT. 
• The safety analysis set consists of all patients in Part 1 or Part 2 who receive study 
product. 
• The Full Analysis Set (FAS) consists of all patients treated at RPII dose in Part 1 or 
Part 2 who receive study product. 
• The Per Protocol Set (PPS) consists of all patients treated at RPII dose in Part 1 or Part 
2 who receive study product without major protocol deviation that might impact the 
efficacy results. 
• The PK analysis set will consist of all patients in the safety analysis set who have 
sufficient concentration data for PK analysis. 
4.3. Definition of Baseline Values 
 
Unless otherwise specified, for each safety parameter, the baseline value is defined as the 
value collected at the time closest to, but prior to, the start of study drug administration. 
4.4. Bayesian Model for Ongoing Data Analyses 
Once 10 PFS events have been observed in each cohort, ongoing data analyses will be 
performed every 6 weeks using Bayesian models on observed PFS events. The hazard rate 
λc in historical control can be derived from median PFS time 5.5 months and therefore 
 


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The estimate of the log hazard ratio θd of the hazard rate at RPII dose group over that in the 
historical control arm is assumed to follow a normal distribution with hierarchal model: 
 
and 
 
 
The prior mean µ is assumed 0 and prior ν is assumed as 1 as noninformative distribution 
for the prior distribution of θ1 and the prior mean τµ and prior weight τn are assumed as 1 as 
noninformative distribution for the prior inverse Gama (IG) distribution of variance τ2 . 
The posterior probability of the hazard ratio will be evaluated using Markov Chain Monte 
Carlo (MCMC) with individual parameters updated based on the data available at the time 
of the update. 
 
These algorithms will be implemented in FACTS with time to event endpoints for interim 
and final analyses. 
 
At each interim and the final analysis, there are three possible outcomes: Futility, Success 
and Inconclusive. These outcomes will be determined based on posterior probability of 
promising HR and phase III success as mentioned above. For Promising HR, the posterior 
probability of HR < 0.85 will be derived given 10 PFS events observed. For Phase III 
success, the posterior probability of HR < 0.75 will be derived given 381 PFS events 
observed. 
 
 
5. Patient Disposition and Protocol Deviations 
 
Patient disposition will be summarized for all enrolled and will include the number and 
percentage of patients in the DLT-evaluable, Safety, FAS and PK analysis sets as well as 
those patients who have completed or discontinued as well as reasons for 
discontinuation/withdrawal. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the Institutional Review Board 
(IRB)/ Independent Ethics Committee (IEC) and agreed to by the investigator. A 
significant deviation occurs when there is nonadherence to the protocol by the patient or 
investigator that results in a significant, additional risk to the patient. Significant deviations 
can include nonadherence to inclusion or exclusion criteria, enrollment of the patient 
without prior sponsor approval, or nonadherence to Food and Drug Administration (FDA) 


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regulations or International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines, and will lead to the patient being withdrawn from the study. Protocol 
violations and deviations will be displayed in a listing for Phase I and II patients and 
summarized in a table for Phase II patients. 
6. Demographics and Baseline Characteristics 
 
6.1. Demographics 
 
Baseline demographics will be summarized for all patients in the safety population. 
Baseline demographic data to be evaluated will include age, sex, ethnicity, race, height and 
weight. Age will be calculated as the integer part of (Informed Consent Date - Birth Date + 
1)/365.25. Age will also be displayed in categories of 18-65 and > 65 years. Summary 
statistics will be presented for continuous variables age, height, and weight by cohort and 
overall. Categorical variables ethnicity, race, age category and gender will be summarized 
by cohort and overall. No inferential statistics will be generated. All demographic and 
baseline characteristic data will be listed for each patient in safety population. 
6.2. Inclusion/Exclusion Criteria 
 
All inclusion/exclusion information (inclusion and exclusion criteria are detailed in section 
4.1.1 and 4.1.2 of the protocol) on enrolled patients (patients who provide signed written 
informed consent) will be included in a by-patient listing. The listing will include whether 
all criteria were satisfied. For patients who did not satisfy the criteria, the criteria number 
will be listed with the deviation, along with whether an exception was obtained. Patient 
pregnancy test results will be included in a separate by-patient listing. 
6.3. Medical History 
 
6.3.1. General Medical History 
 
Medical history will be presented in a data listing for each patient for all Safety population. 
A summary table of medical history by body system code and preferred term will also be 
provided for all Safety population in phase II patients with at least one event under each 
body system code (SOC) and preferred term (PT) using version 18.0 or later of the 
Medical Dictionary for Regulatory Activities (MedDRA). 
6.3.2. Prior Treatments 


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Prior chemotherapy, prior radiation and prior surgery will be presented in separate listings. 
Number and percentage of patients with at least one prior chemotherapy, prior radiation, 
and surgical procedure will be summarized for phase II patients. Number of regimens and 
prior surgery types will also be summarized in the table. 
7. Treatments and Medications 
 
7.1. Prior and Concomitant Medications 
 
If a medication ended before the start of the treatment, this medication is categorized as 
prior medication; if a medication started between the first dose date and 28 days after the 
last dosing date, it will be categorized as concomitant medication; if the medication range 
brackets the treatment start date, it is categorized as both. All medications will be mapped 
to preferred terms according to the World Health Organization (WHO) drug dictionary, 
version 01-Jun-2016 or the latest version. The number and percentage of patients in the 
safety population of phase II patients taking prior and concomitant medications will be 
tabulated by Anatomical Therapeutic Chemical (ATC) classification system and WHO 
drug preferred term. At each level of summarization, a patient is counted only once if 
she/he reported one or more medication. Concomitant medications and procedures will be 
presented in separate by-patient listings. If the start or end date of concomitant medications 
is missing, it will be imputed as shown in Appendix D. 
7.2. Study Treatments 
 
In Part 1, patients will be assigned to receive gemcitabine 1250 mg/m2 in combination with 
NC-6004 at doses of 60, 75, 90, 105, 120, 135, 150, 165, or 180 mg/m2 by the N-CRM 
model. In Part 2, all patients will receive the RPII dose (135 mg/ m2) of NC-6004 
identified in Part 1. 
Table for exposure and compliance will be produced separately for NC6004 and 
gemcitabine. Duration of exposure in days, total number of infusions given, total dose 
received (mg/m2), relative dose intensity, and number of patients dosed by cycle will be 
summarized for all patients in the safety analysis set. The number of patients who had 
dose(s) interrupted or incomplete and their reasons will be summarized. Patient listing of 
study treatment compliance will be provided as relative dose intensity. 
Total actual dose received (mg) is calculated as sum of the actual dose (mg) received for 
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Total number of infusions given is defined as sum of number of the actual infusions 
given for each drug. 
Duration of exposure is defined as the total number of days a patient was exposed to the 
study drug. It will be calculated as (last dose date – first dose date + 1), where the first dose 
date is assumed to be cycle 1 day 1 for each drug. 
The exposure information will be summarized by treatment groups for each drug separately. 
 
Relative dose intensity = actual dose intensity/planned dose intensity where planned dose 
intensity = planned dose * number of infusions /duration of exposure (days), actual dose 
intensity = total actual dose received (mg)/duration of exposure (days). The number of 
infusions will be the planned number of infusion during the exposure period according to 
the treatment regimen for each drug. The compliance will be categorized into three groups: 
<80, 80-120 and >120 %. A patient will be classified as compliant if relative dose intensity 
falls between 80 and 120, and will be classified as not compliant otherwise. A table with 
compliance, compliance category and compliant or not will be generated by treatment 
groups for each drug. 
8. Efficacy Analysis 
 
Efficacy assessments include disease response assessments, QoL assessments, and 
symptom changes assessments. OS, PFS, DOR will be summarized using Kaplan-Meier 
methods in both summary tables and figures. Ninety five percent confidence intervals for 
ORR and DCR will be constructed and displayed in the summary tables. 
The assessment of QoL will be summarized based on FAS by visit, Changes from baseline 
for QoL will be summarized by dose level, for all phase I MTD patients and phase II 
patients by cohort. 
 
All efficacy analyses will be performed on the FAS phase II patients by cohort. All 
summaries will present data by phase II NSCLC, phase II biliary tract carcinoma patients, 
phase II bladder cancer patients, phase II bladder cancer patients with CrCl ≥60 mL/min 
and ECOG PS 0-1; fit and phase II bladder cancer patients with CrCl ≥30 to <60 mL/min 
and/or ECOG PS 2; unfit. 
8.1. Primary Efficacy Endpoint 
 
8.1.1. Progression-Free Survival (PFS) 


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Progression - free survival will be defined as the time from first dose of study product until 
the first date of either disease progression or death due to any cause and will be evaluated 
for each dose level and for all patients in the FAS. The date of disease progression will be 
defined as the earliest date of radiological disease progression as assessed by the 
investigator using RECIST version 1.1 or clinical disease progression. Duration of 
progression-free survival (PFS) in days is defined as the time between the date of first dose 
of study drug and the date of the first occurrence of one of the following events: 
 
• Radiological disease progression per RECIST 1.1 as assessed by the investigator 
 
• 
Clinical/Symptomatic disease progression as assessed by the investigator 
 
• Death due to any cause 
 
For patients who do not experience one of these events by the time of data cutoff, PFS will 
be right censored at the date of last adequate disease assessment. An adequate disease 
assessment is a scan where the overall assessment as defined by RECIST 1.1 is not missing 
and not unable to evaluate. For patients who do not experience disease progression and do 
not have any adequate post-baseline disease assessments, PFS will be right censored at 
Day 1. Patients who died or progressed after an extended lost-to-follow-up period will be 
censored at the date of the last adequate disease assessment prior to the extended loss to 
follow-up. PFS = Date of event/censoring - date of first dose + 1. The full censoring rules 
for PFS are included in Table 8-1 below. 
Table 8-1: Censoring Conventions for PFS 
 
Situation 
Date of Progression or Censoring 
Outcome 
Disease progression documented at or 
between scheduled visits within 14 
weeks of previous adequate 
assessment or the first dose date 
Date of scan or clinical assessment of 
progression 
Event 
Disease progression documented from 
an assessment after extended lost-to- 
follow-up (greater than 14 weeks 
from the previous adequate 
assessment or the first dose date) 
Latest of: 
 
Last adequate disease assessment 
prior to the extended lost-to-follow- 
up 
 
The first dose date 
Censored 
Death due to any cause within 14 
weeks of the previous adequate 
assessment or the first dose date 
Date of death 
Event 


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Death due to any cause after an 
extended lost-to-follow-up time 
(greater than 14 weeks from the 
previous adequate assessment or the 
first dose date) 
Latest of: 
 Last adequate disease assessment 
prior to the extended lost-to-follow-up 
 The first dose date 
Censored 
Treatment discontinuation for 
toxicity or other reasons without 
disease progression or prior to 
disease progression 
Latest of: 
 
Last adequate disease assessment 
 
The first dose date 
Censored 
No death and no disease progression 
after first dose date 
Latest of: 
 
Last adequate disease assessment 
 
The first dose date 
Censored 
Start a new line of anti-cancer 
treatment 
Latest of: 
 
Last adequate disease assessment 
 
The first dose date 
Censored 
 
Sensitivity analysis will be performed based on PPS and additional PFS table will be 
provided separately by cohort based on PPS. 
8.1.2. Overall Survival (OS) 
 
Overall survival (OS) will be defined as the time from first dose of study product until the 
date of death due to any cause and will be evaluated for each dose level and for all patients 
in the FAS. For patients who have not died at the time of the analysis, censoring will be 
performed using the date the patient was last known to be alive. Overall Survival = Date of 
death (or date of last known alive) - Date of first dose + 1. 
 
 
8.1.3. Duration of Response (DOR) 
 
Duration of Response (DOR) will be defined as the time between the date of the earliest 
date of confirmed response (CR or PR) and the date of the first occurrence of one of the 
following events: 
• Radiological disease progression per RECIST 1.1 as assessed by the investigator 
 
• 
Clinical/Symptomatic disease progression as assessed by the investigator 
 
• Death due to any cause 


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For patients who do not experience one of these events by the time of data cutoff, DOR 
will be right censored at the date of last adequate disease assessment. An adequate disease 
assessment is one with a result that is not missing and not unable to evaluate. For patients 
who do not experience disease progression and do not have any adequate post-baseline 
disease assessments, DOR will be right censored at Day 1. Patients with disease 
progression or death after an extended loss to follow-up will be censored at the date of the 
last adequate disease assessment prior to the extended loss to follow-up. DOR = Date of 
event/censoring - date of the earliest response + 1. The full censoring rules for DOR are 
included in Table 8-2 below. 
 
Table 8-2: Censoring Conventions for DOR 
Situation 
Date of Progression or Censoring 
Outcome 
Progression documented at or between 
scheduled visits (within 14 weeks of 
previous adequate assessment or from the 
first confirmed response date if there is no 
assessment after the response) 
Date of scan or clinical assessment of 
progression 
Event 
No Progression till last assessment 
Date of last adequate assessment 
Censored 
Treatment discontinuation for toxicity or 
other reasons before disease progression. 
Date of last adequate assessment 
Censored 
Death within 14 weeks of previous 
adequate assessment, or of the first 
confirmed response date if there is no 
assessment after the response 
Date of death 
Event 
Death or disease progression after an 
extended lost-to-follow-up time (greater 
than 14 weeks from previous adequate 
assessment or from the first confirmed 
response date if there is no assessment after 
the response) 
Date of last adequate assessment 
prior to extended lost-to-follow-up 
Censored 
 
 
8.1.4. Disease Control Rate (DCR) 
 
Disease control rate (DCR) is defined as the proportion of patients with best overall 
response of SD longer than 7 weeks, confirmed PR, or confirmed CR at the time each 
patient discontinues study treatment. 
DCR will be summarized by cohort, two-sided 95% CI will be presented by using the 
Exact (Clopper-Pearson) method. 


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8.1.5. Overall Response Rate (ORR) 
 
Overall response rate (ORR) is defined as the proportion of patients with best overall 
response of confirmed PR or confirmed CR at the time each patient discontinues NC-6004. 
The best overall response is the best overall response recorded from the start of the 
treatment until the end of study considering any requirement for confirmation. In general, 
the patient’s best response assignment will depend on the achievement of both 
measurement and confirmation criteria. Patients who have obtained a response (PR or CR) 
will have a confirmatory scan at a minimum of 4 weeks following initial scan. When stable 
disease (SD) is believed to be the best response, it must be at least 7 weeks first 
documented evidence of SD until disease progression. Otherwise, the patient’s best 
response depends on the subsequent assessment. The best overall response when 
confirmation of CR and PR is required is presented in table 8-2. 
ORR will be summarized by cohort. The two-sided 95% CI will be presented by using the 
Exact (Clopper-Pearson) method. Best overall response will also be summarized in this 
table. 
Table 8-3: Best overall response when confirmation of CR and PR required 
Overall 
response first 
time point 
Overall 
response 
subsequent 
time point 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
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, 


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otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
Source: Eisenhauer EA et al. 
 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease, and NE = not evaluable. 
a If a 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. Secondary Efficacy Endpoint 
8.2.1. Quality of Life Analyses 
 
Quality of Life (QoL) will be assessed using the EORTC QLQ-C30. Analyses will be 
based on the FAS. Each of the 30 scores of the EORTC QLQ-C30, as well as the 5 
functional scales (physical, role, emotional, cognitive, social), and 9 symptom scales 
(fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, 
diarrhea, financial difficulties) will be summarized by visit. Changes from baseline will be 
summarized for all phase I MTD patients, by cohort of phase II patients, and overall. 
 
The standard scoring procedures as suggested by the EORTC v3.0 will be followed. All of 
the scales and single item measures range in score from 0 to 100. A high scale score 
represents a high response level. For all scales, the Raw Score, RS, is the mean of the 
component items. Then the functional scales will be calculated as: 
Score = (1- (RS-1)/range) x100, 
and 
 
For symptom scales/items and global health status/QoL: 


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Score = ((RS-1) /range) x 100. 
 
where range is the difference between the maximum possible value of RS and the 
minimum possible value. 
The calculation of scores and methods to deal with missing data will be handled according 
to the respective questionnaires’ standard scoring guidelines. If at least half of the items 
from the scale have been answered, use all the items that were completed and apply the 
standard equations given above: ignore any items with missing values when making the 
calculations. If less than half of the items from the scale have been answered, set scale 
score to missing. For single-item measures, set score to missing. 
8.2.2. Symptoms Assessment Analyses 
 
The MD Anderson Symptom Inventory (MDASI) core 13 symptom items (pain, fatigue, 
nausea, disturbed sleep, emotional distress, shortness of breath, lack of appetite, 
drowsiness, dry month, sadness, vomiting, difficulty remembering, and numbness or 
tingling) and 6 interference items (general activity, mood, walking ability, normal work, 
relationship with other people, and enjoyment of life) plus the 3 lung cancer-specific 
symptom items (MDASI-LC: coughing, constipation and sore throat) will be listed by visit, 
by dose level for all phase I patients and by cohort of phase II patients. 
9. Safety Analysis 
 
Safety evaluations will be based on the incidence, severity, type of adverse events (AEs), 
clinically significant changes or abnormalities in the patient’s clinical laboratory results, 
vital signs, physical examination, electrocardiogram (ECG), and Eastern Cooperative 
Oncology Group (ECOG). All safety analyses will be conducted on the Safety analysis set. 
9.1. Adverse Events 
 
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to study treatment. A treatment-emergent AE (TEAE) 
is defined as any event not present before exposure to study drug or any event already 
present that worsens in either intensity or frequency after exposure to study drug. A serious 
adverse event (SAE) is defined as any event that results in death, is immediately life 
threatening, requires inpatient hospitalization or prolongation of existing hospitalization, 
results in persistent or significant disability/incapacity, or is a congenital anomaly/birth 
defect. AE terms recorded by the clinical site will be mapped to PT using version 18.0 or 


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later of the MedDRA. Toxicity grade will be defined according to the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
 
A related AE is an event where the investigator determined that the relationship to study 
drug was “Possible Related”, “Probable Related” or “Definite Related”. For summaries by 
relationship, adverse events with missing relationship are counted as “Possible Related”. 
For summaries by CTCAE grade, adverse events with missing CTCAE grade are counted 
as CTCAE grade 3 – Severe. If the AE start date is missing, it will be imputed as shown in 
Appendix D. 
The following summaries of AEs by system organ class (SOC) and preferred term (PT) 
will be provided: 
• All TEAEs 
 
• All serious TEAEs 
 
• All treatment-related TEAEs for phase II patients 
 
• All TEAEs resulting in study drug discontinuation 
 
• All TEAEs by NCI CTCAE grade 
 
Data listing will be provided for all AEs. The incidence of deaths and the primary cause of 
death will be displayed in a listing. The severity of nausea and incidence of vomiting as 
captured in the diary data will be listed. The DLTs are summarized in a table and listed for 
DLT-evaluable Analysis Set. 
9.2. Clinical Laboratory Evaluations 
 
Clinical hematology and coagulation, biochemistry, and urinalysis data will be displayed at 
each scheduled assessment. Hematology will include hemoglobin, reticulocytes, red blood 
cell count, differential white blood cell count, platelets, and International Normalized Ratio. 
Coagulation will include prothrombin time and international normalized ratio. 
Biochemistry will include alanine aminotransferase, aspartate aminotransferase, 
gamma-glutamyl transferase, alkaline phosphatase, total bilirubin, sodium, potassium, 
calcium, magnesium, urea, creatinine, creatinine clearance, total protein, albumin, and 
lactate dehydrogenase. Urinalysis will be performed and will include: leukocyte esterase, 
nitrite, urobilinogen, protein, pH, blood, specific gravity, ketones, bilirubin, and glucose. 


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Numeric hematology and coagulation and biochemistry results will be summarized using 
actual result and change from baseline for Phase II patients. All results will be summarized 
using shift from baseline. Shifts for all laboratory results will be by normal/abnormal flag. 
Summaries by visit will include data from scheduled assessments only, and all data will be 
reported according to the nominal visit date for which it was recorded (i.e., no visit 
windows will be applied). Unscheduled data will be included in “Worst Case Post- 
baseline” summaries which will capture a worst case across all scheduled and unscheduled 
visits after the first dose of study treatment. 
Numeric clinical hematology and coagulation, biochemistry, and urinalysis results will be 
summarized using change from baseline for Phase II patients. All results will be 
summarized using shift from baseline and be displayed in separate data listings. 
9.3. Vital Sign Measurements 
 
Vital sign measurements will include arterial blood pressure, heart rate, respiratory rate, 
and temperature. Vital signs will be measured during the screening period on Day -14 to -1, 
On Day 1 and day 8 of each Cycle and End-of-Treatment. On day 1 of Cycle 1, vital signs 
will be measured before the start of the NC 6004 infusion, every 20 minutes during the 
infusion, at the completion of the infusion, and 1 hour after the completion of the NC-6004 
infusion. Starting in Cycles 2, vital signs will be measured before the start of the NC 6004 
infusion and at the completion of the NC-6004 infusion on Day 1 of each cycle. Vital signs 
will be measured before and after gemcitabine infusion on Day 8 of each cycle. 
The results of all time points will be displayed in a listing. A summary table of 
measurement values and changes from baseline by visit for phase II patients will be 
provided and unscheduled visits will be included in the “Worst Case”. 
9.4. Physical Examination 
 
A complete physical examination will be performed during the screening period at Day -14 
to -1, before study treatments on Day-1 or Day 1 of each cycle, and at the End-of- 
Treatment visit. Height and weight will also be assessed at the time of the screening period 
physical examination and before treatments on Day 1 of each cycle. Calculation of body 
surface area (BSA) will be done before each dosing on Day 1 of each cycle. (Note: Dose 
will only be recalculated if there is a ≥10% increase or decrease in the patient’s weight 
from the patient’s weight measurement at screening. Any change in a patient’s weight by 
≥10% during the study will require a recalculation of the doses of all study drugs. This 


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3 Ventricular Rate 
 
 
threshold should not be confused with a change in the patient’s BSA [m2]). All 
measurements will be displayed in a listing. 
9.5. Electrocardiogram 
 
A 12-lead ECGs will be performed during the screening period at Day -7 to -1. On Day 1 
of Cycle 1, 12-lead ECGs will be performed before the start of the NC-6004 infusion, at 
completion of infusion (~1 hour after start of infusion), and at Hours 3 and 24 hours (Day 
2) after start of infusion. On Day 8 of Cycle 1, 12-lead ECGs will be performed before the 
start of gemcitabine infusion, at the completion of gemcitabine infusion, and at 1 hour after 
completion of gemcitabine infusion. Starting in Cycles 2, twelve-lead ECGs will also be 
performed on Day 1 of each cycle before the start of the NC-6004 infusion and at the End- 
of-Treatment visit. All 12-lead ECGs should be performed within a ±30-minute window. 
 
All measurements including ventricular rate, QT interval, QTcB (Corrected QT interval - 
Bazett’s formula), QTcF (Corrected QT interval - Fridericia’s formula), and the overall 
interpretation will be displayed in a data listing. The QTcB and QTcF are calculated based 
on the formula below: 
QTcB = 
QT 
QTcF = 
QT 
 
Summary of actual value and change from baseline will be presented in a summary table 
for phase II patients. Overall interpretation is assessed as normal, abnormal; not clinically 
significant, clinically significant. A shift table from baseline to current visit will be 
presented for overall interpretation. The categories of QTcB and QTcF (≤450 msec, >450- 
480 msec, >480-500 msec, >500 msec) and the categories of change from baseline for 
QTcB and QTcF (≥30 msec and ≥60 msec) will be summarized by visit and cohort. 
9.6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 
 
The patient’s performance status will be assessed during the screening period on Day -14 
to -1 and before dosing on Day- 1 or day 1 of each cycle using the ECOG PS grades 
below: 
 
0 Fully active, able to carry on all predisease 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 


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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 
 
All measurements will be displayed in a data listing. A shift table from baseline to current 
ECOG status will be presented. 
10. Pharmacokinetic Assessments 
 
10.1 Plasma Concentration 
The concentration-versus-time profile of total and free platinum in plasma will be 
determined in Part 1 and in Part 2. 
 
Part 1 Pharmacokinetic Time Points 
 
• Before the start of the NC-6004 infusion on Day 1 of Cycles 1 through 6 
 
• At the end of NC-6004 infusion in Cycles, 1, 3, and 5 
 
• After the start of NC-6004 infusion at Hours 3, 6, 12, 24 (Day 2), 48 (Day 3), 96 
(Day 5), 168 (Day 8, prior to gemcitabine infusion), and 336 (Day 15) in Cycles 1, 
3, and 5 
 
• 
At End-of-Treatment visit 
 
Part 2 Pharmacokinetic Time Points 
 
Plasma will be collected at the following times in Part 2 for up to 6 cycles: 
 
• Before the start of the NC-6004 infusion on Day 1 
 
• At the end of NC-6004 infusion 
 
• Before gemcitabine infusion on Day 8 


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• 
At End-of-Treatment visit 
 
Actual sampling times, rather than scheduled sampling times, will be used in the 
computation of PK parameters. However, for ease of presentation, scheduled sampling 
times will be used to present results in summary tables. 
Individual plasma concentration and time deviation data will be presented in a listing. The 
plasma concentration data will be summarized over time by cohort and cycle using 
descriptive statistics: n, mean, standard deviation, coefficient of variation (CV), minimum, 
median, and maximum. All BLQ values will be set to zero for the summary statistics. The 
individual and mean plasma concentration versus time profiles will be presented in figures 
on both linear and semi-logarithmic scales. For ease of presentation, individual and mean 
plasma concentration versus time profiles will be presented with scheduled times. 
10.2 Plasma Pharmacokinetic Parameters 
Individual plasma concentration versus actual time data will be used to estimate the PK 
parameters of total and free Pt in plasma by standard noncompartmental methods using 
WinNonlin (Phoenix) Version 6.4 or higher for each individual. For the calculation of PK 
parameters all plasma concentrations that are BLQ before the first measurable 
concentration will be set to zero. The BLQ values that are between measurable 
concentrations will be set to missing. The BLQ values occur at the end of the profile (after 
the last quantifiable concentration) will be set to missing. 
The following PK parameters will be derived for total and free Pt in plasma for Part 1 for 
Cycle 1, Cycle 3, and Cycle 5: 
 
Parameter 
Description 
AUC0-t 
Area under the concentration versus time curve from time 0 to the last 
quantifiable concentration (Clast); calculated using the linear-up/ log-down 
trapezoidal rule 
AUC0-τ 
Area under the plasma concentration-time curve (AUC) from time 0 to the 
end of the dosing interval, calculated by the linear-up/ log-down trapezoidal 
rule 
AUC0-∞ 
Area under the plasma concentration-time curve from time 0 
extrapolated to infinity, calculated as AUC0-∞ = AUC0-t + Clast/ λz, 
where Clast is the last quantifiable plasma drug concentration. A 
%AUC, extrapolated <20% are required in order to retain AUC0-∞. 


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Parameter 
Description 
AI 
Accumulation index calculated as AUC0-τ in Cycle 3 or in Cycle 5 / 
AUC0-τ in Cycle 1. 
CL 
Total body clearance calculated as Dose/AUC0-inf. 
Cmax 
Maximum observed plasma concentration. 
MRTinf 
Mean residence time extrapolated to infinite time calculated as 
[(AUMC0-∞ / AUC0-∞) – TI/2], where TI represents the infusion time 
(infusion duration). 
Tmax 
Time to achieve maximum observed plasma concentration. 
λz 
The first-order terminal elimination rate constant, calculated using 
linear regression on the terminal portion of the ln-concentration versus 
time curve. At least 3 time points (excluding Tmax) and r2 >0.90 are 
required to calculate and retain Kel and its associated parameters (t1/2 
and AUC0-inf). 
T1/2 
Plasma terminal elimination half-life, calculated as t1/2= ln(2)/ λz. 
Vss 
Steady state volume of distribution calculated as: MRTinf x CL 
Vz 
Volume of distribution based upon the terminal phase calculated as: 
Dose / (λz × AUC0-inf) 
 
 
The individual PK parameters will be presented in the data listings for the PK analysis set. 
The PK parameters will be summarized by treatment using descriptive statistics: n, mean, 
SD, CV, median, minimum and maximum. Descriptive statistics will include geometric 
means, for AUC, Cmax, CL, Vss and Vz. 
Cmax, AUC0-t and AUC0-∞ (Y-axis) for total and free Pt in plasma will each be plotted 
against all available doses (X-axis) for dose proportionality evaluation to assess dose 
proportionality. 


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11. Interim Analysis 
 
Once 10 PFS events have been observed in each cohort, interim analyses will be performed 
every 6 weeks. At each interim and at the final analysis, there are 3 possible outcomes for 
each cohort (refer to Section 3.1 for details). 
 
Futility can only be declared for a cohort after 10 PFS events have been observed in that 
cohort. Success can only be declared for a cohort after 25 or 15 PFS events have been 
observed in that 50-patient cohort (Cohort 1 and 2) or 30-patient bladder cancer cohort 
(Cohort 3, fit and unfit), respectively. Accrual will stop for any cohort identified as futile 
or successful at interim. The conclusion of this Phase 2 trial will be that a Phase 3 trial with 
381 events should be conducted for each cohort that is a success. 
 
If any indication is declared a success, the combination of NC-6004 and gemcitabine 
advances to a Phase 3 randomized, controlled trial with sample size sufficient to observe 
381events. 
12. References 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45(2):228-47. 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Stat Med. 2008; 27(13):2420-39. 


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Appendix A: List of Tables 
 
Number 
Title 
Table 14.1.1.1 
Disposition of Phase I Patients Enrolled Population 
Table 14.1.1.2 
Disposition of Phase II Patients Enrolled Population 
Table 14.1.2 
Protocol Deviations of Phase II Patients Safety Analysis Set 
Table 14.1.3.1 
Demographics of Phase I Patients Safety Analysis Set 
Table 14.1.3.2 
Demographics of Phase II Patients Safety Analysis Set 
Table 14.1.4 
Medical History of Phase II Patients Safety Analysis Set 
Table 14.1.5 
Prior Cancer Therapy of Phase II Patients Safety Analysis Set 
Table 14.1.6 
Concomitant Medications of Phase II Patients Safety Analysis Set 
Table 14.1.7.1 
Drug Exposure of Phase I Patients Safety Analysis Set 
Table 14.1.7.2 
Drug Exposure of Phase II Patients Safety Analysis Set 
Table 14.1.8.1 
Drug Compliance of Phase I Patients Safety Analysis Set 
Table 14.1.8.2 
Drug Compliance of Phase II Patients Safety Analysis Set 
Table 14.1.9 
Summary of Total Platinum Concentrations (unit) in Plasma PK Analysis Set 
Table 14.1.10 
Summary of Free Platinum Concentrations (unit) in Plasma PK Analysis Set 
Table 14.1.11 
Summary of Pharmacokinetic Parameters of Total Platinum in Plasma PK 
Analysis Set 
Table 14.1.12 
Summary of Pharmacokinetic Parameters of Free Platinum in Plasma PK 
Analysis Set 
Table 14.1.13 
Statistical Analysis of Dose Proportionality of Cmax and AUC of Total and 
Free Platinum PK Analysis Set 
Table 14.2.1.1.1 
Summary of Duration of Progression-Free Survival Phase II NSCLC Patients 
Full Analysis Set 
Table 14.2.1.1.2 
Summary of Duration of Progression-Free Survival Phase II NSCLC Patients 
Per Protocol Set 
Table 14.2.1.2.1 
Summary of Duration of Progression-Free Survival Phase II Biliary Patients 
Full Analysis Set 
Table 14.2.1.2.2 
Summary of Duration of Progression-Free Survival Phase II Biliary Patients 
Per Protocol Set 
Table 14.2.1.3.1 
Summary of Duration of Progression-Free Survival Phase II Bladder Patients 
Full Analysis Set 
Table 14.2.1.3.2 
Summary of Duration of Progression-Free Survival Phase II Bladder Patients 
Per Protocol Set 
Table 14.2.2.1 
Summary of Duration of Overall Survival Phase II NSCLC Patients Full 
Analysis Set 
Table 14.2.2.2 
Summary of Duration of Overall Survival Phase II Biliary Patients Full 
Analysis Set 
Table 14.2.2.3 
Summary of Duration of Overall Survival Phase II Bladder Patients Full 
Analysis Set 
Table 14.2.3.1 
Summary of Duration of Response Phase II NSCLC Patients Full Analysis Set 


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Number 
Title 
Table 14.2.3.2 
Summary of Duration of Response Phase II Biliary Patients Full Analysis Set 
Table 14.2.3.3 
Summary of Duration of Response Phase II Bladder Patients Full Analysis 
Set 
Table 14.2.4.1 
Overall Response Rate and Disease Control Rate Phase II NSCLC Patients 
Full Analysis Set 
Table 14.2.4.2 
Overall Response Rate and Disease Control Rate Phase II Biliary Patients Full 
Analysis Set 
Table 14.2.4.3 
Overall Response Rate and Disease Control Rate Phase II Bladder Patients 
Full Analysis Set 
Table 14.2.5.1 
Actual Values and Change from Baseline in Quality of Life Phase II Patients 
Full Analysis Set 
Table 14.2.5.2 
Actual Values and Change from Baseline in Quality of Life Phase I MTD 
Patients Full Analysis Set 
Table 14.3.1.1.1 
Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term of Phase I Patients Safety Analysis Set 
Table 14.3.1.1.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term of Phase II Patients Safety Analysis Set 
Table 14.3.1.2.1 
Serious Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term of Phase I Patients Safety Analysis Set 
Table 14.3.1.2.2 
Serious Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term of Phase II Patients Safety Analysis Set 
Table 14.3.1.3 
Related Treatment-Emergent Adverse Events of Phase II Patients Safety 
Analysis Set 
Table 14.3.1.4.1 
Treatment-Emergent Adverse Events Resulting in Study Drug Discontinuation 
of Phase I Patients Safety Analysis Set 
Table 14.3.1.4.2 
Treatment-Emergent Adverse Events Resulting in Study Drug Discontinuation 
of Phase II Patients Safety Analysis Set 
Table 14.3.1.5.1 
Treatment-Emergent Adverse Events by NCI CTCAE Grade of Phase I 
Patients Safety Analysis Set 
Table 14.3.1.5.2 
Treatment-Emergent Adverse Events by NCI CTCAE Grade of Phase II 
Patients Safety Analysis Set 
Table 14.3.1.6.1 
Treatment-Emergent Adverse Events by Preferred Term in Descending Order 
of Frequency with at least 5% Incidence in All Patients of Phase I Patients 
Safety Analysis Set 
Table 14.3.1.6.2 
Treatment-Emergent Adverse Events by Preferred Term in Descending Order 
of Frequency with at least 5% Incidence in All Patients of Phase II Patients 
Safety Analysis Set 
Table 14.3.1.7 
Dose Limiting Toxicities DLT-evaluable Analysis Set 
Table 14.3.2.1 
Actual Values and Change from Baseline in Serum Chemistry of Phase II 
Patients Safety Analysis Set 
Table 14.3.2.2.1 
Shift from Baseline in Serum Chemistry by Normal/Abnormal Flag of Phase I 
Patients Safety Analysis Set 
Table 14.3.2.2.2 
Shift from Baseline in Serum Chemistry by Normal/Abnormal Flag of Phase 
II Patients Safety Analysis Set 
Table 14.3.3.1 
Actual Values and Change from Baseline in Hematology of Phase II Patients 


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Number 
Title 
Safety Analysis Set 
Table 14.3.3.2.1 
Shift from Baseline in Hematology by Normal/Abnormal Flag of Phase I 
Patients Safety Analysis Set 
Table 14.3.3.2.2 
Shift from Baseline in Hematology by Normal/Abnormal Flag of Phase II 
Patients Safety Analysis Set 
Table 14.3.4.1 
Actual Values and Change from Baseline in Coagulation and Treatment 
Group of Phase II Patients Safety Analysis Set 
Table 14.3.4.2.1 
Shift from Baseline in Coagulation on Normal Range by Parameter and 
Treatment Group of Phase I Patients Safety Analysis Set 
Table 14.3.4.2.2 
Shift from Baseline in Coagulation on Normal Range by Parameter and 
Treatment Group of Phase II Patients Safety Analysis Set 
Table 14.3.5.1 
Actual Values and Change from Baseline in Urinalysis of Phase II Patients 
Safety Analysis Set 
Table 14.3.5.2.1 
Shift from Baseline in Urinalysis by Normal/Abnormal Flag of Phase I 
Patients Safety Analysis Set 
Table 14.3.5.2.2 
Shift from Baseline in Urinalysis by Normal/Abnormal Flag of Phase II 
Patients Safety Analysis Set 
Table 14.3.6 
Actual Values and Change from Baseline in Vital Signs of Phase II Patients 
Safety Analysis Set 
Table 14.3.7.1 
Actual Values and Change from Baseline in Electrocardiogram Results of 
Phase II Patients Safety Analysis Set 
Table 14.3.7.2.1 
Shift from Baseline in Electrocardiogram Interpretation by Normal/Abnormal 
Flag of Phase I Patients Safety Analysis Set 
Table 14.3.7.2.2 
Shift from Baseline in Electrocardiogram Interpretation by Normal/Abnormal 
Flag of Phase II Patients Safety Analysis Set 
Table 14.3.7.3.1 
Summary of Categories of Actual Values and Change from Baseline for QTcB 
and QTcF of Phase I Patients Safety Analysis Set 
Table 14.3.7.3.2 
Summary of Categories of Actual Values and Change from Baseline for QTcB 
and QTcF of Phase II Patients Safety Analysis Set 
Table 14.3.8.1 
Shift from Baseline in ECOG Score of Phase I Patients Safety Analysis Set 
Table 14.3.8.2 
Shift from Baseline in ECOG Score of Phase II Patients Safety Analysis Set 


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Appendix B: List of Listings 
 
Number 
Title 
Listing 16.2.1.1 
Disposition Safety Analysis Set 
Listing 16.2.1.2 
Inclusion and Exclusion Criteria All Patients 
Listing 16.2.1.3 
Demographics Safety Analysis Set 
Listing 16.2.1.4 
Protocol Deviations by Study and Treatment Safety Analysis Set 
Listing 16.2.1.5 
General Medical History Safety Analysis Set 
Listing 16.2.1.6 
Prior Chemotherapy Safety Analysis Set 
Listing 16.2.1.7 
Prior Radiation Safety Analysis Set 
Listing 16.2.1.8 
Prior Surgery Safety Analysis Set 
Listing 16.2.1.9A 
Concomitant Medications Safety Analysis Set 
Listing 16.2.1.9B 
Concomitant Procedures Safety Analysis Set 
Listing 16.2.1.10 
Study Drug Dosing: Administration and Compliance Safety Analysis Set 
Listing 16.2.2.1 
Tumor Response Full Analysis Set 
Listing 16.2.2.2 
Duration of Progression-free Survival Full Analysis Set 
Listing 16.2.2.3 
Duration of Overall Survival Full Analysis Set 
Listing 16.2.2.4 
Duration of Response Full Analysis Set 
Listing 16.2.2.5 
Concentrations of Total Platinum in Plasma PK Analysis Set 
Listing 16.2.2.6 
Concentrations of Free Platinum in Plasma PK Analysis Set 
Listing 16.2.2.7 
Pharmacokinetic Parameters of Total Platinum in Plasma PK Analysis Set 
Listing 16.2.2.8 
Pharmacokinetic Parameters of Free Platinum in Plasma PK Analysis Set 
Listing 16.2.3.1 
Adverse Events Safety Analysis Set 
Listing 16.2.3.2 
Dose Limiting Toxicities DLT-evaluable Analysis Set 
Listing 16.2.3.3 
Deaths Safety Analysis Set 
Listing 16.2.4.1 
Laboratory Results: Serum Chemistry Safety Analysis Set 
Listing 16.2.4.2 
Laboratory Results: Hematology Safety Analysis Set 
Listing 16.2.4.3 
Laboratory Results: Coagulation by Treatment Groups Enrolled Population 
Listing 16.2.4.4 
Laboratory Results: Urinalysis Safety Analysis Set 
Listing 16.2.5 
Pregnancy Test Results Safety Analysis Set 
Listing 16.2.6 
Vital Signs, Height, and Weight Safety Analysis Set 
Listing 16.2.7 
Physical Exam Safety Analysis Set 
Listing 16.2.8 
Electrocardiogram Results Safety Analysis Set 
Listing 16.2.9.1 
Eastern Cooperative Oncology Group (ECOG) Performance Test Safety 
Analysis Set 
Listing 16.2.9.2 
EORTC QLQ C30 Safety Analysis Set 
Listing 16.2.9.3 
MD Anderson Symptom Inventory – Lung Cancer Safety Analysis Set 
Listing 16.2.9.4 
Nausea and Vomiting Diary Safety Analysis Set 


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Appendix C: List of Figures 
 
Number 
Title 
Figure 14.1.1.1 
Kaplan-Meier Plot of Progression-Free Survival among NSCLC Patients Full 
Analysis Set 
Figure 14.1.1.2 
Kaplan-Meier Plot of Progression-Free Survival among Biliary Patients Full 
Analysis Set 
Figure 14.1.1.3 
Kaplan-Meier Plot of Progression-Free Survival among Bladder Patients Full 
Analysis Set 
Figure 14.1.2.1 
Kaplan-Meier Plot of Overall Survival among NSCLC Patients Full Analysis Set 
Figure 14.1.2.2 
Kaplan-Meier Plot of Overall Survival among Biliary Patients Full Analysis Set 
Figure 14.1.2.3 
Kaplan-Meier Plot of Overall Survival among Bladder Patients Full Analysis 
Set 
Figure 14.1.3.1 
Kaplan-Meier Plot of Duration of Response among NSCLC Patients Full 
Analysis Set 
Figure 14.1.3.2 
Kaplan-Meier Plot of Duration of Response among Biliary Patients Full Analysis 
Set 
Figure 14.1.3.3 
Kaplan-Meier Plot of Duration of Response among Bladder Patients Full 
Analysis Set 
Figure 14.2.1 
Mean (± SD) Concentrations of Total Platinum in Plasma versus Time PK 
Analysis Set 
Figure 14.2.2 
Mean (± SD) Concentrations of Free Platinum in Plasma versus Time PK 
Analysis Set 
Figure 14.2.3 
Individual Total Platinum Concentrations in Plasma PK Analysis Set 
Figure 14.2.4 
Individual Free Platinum Concentrations in Plasma PK Analysis Set 
Figure 14.2.5 
Geometric Mean Cmax of Total Platinum in Plasma versus Dose of NC-6004 PK 
Analysis Set 
Figure 14.2.6 
Geometric Mean Cmax of Free Platinum in Plasma versus Dose of NC-6004 PK 
Analysis Set 
Figure 14.2.7 
Geometric Mean AUC0-tau of Total Platinum in Plasma versus Dose of NC- 
6004 PK Analysis Set 
Figure 14.2.8 
Geometric Mean AUC0-tau of Free Platinum in Plasma versus Dose of NC-6004 
PK Analysis Set 
Figure 14.2.9 
Geometric Mean AUC0-inf of Total Platinum in Plasma versus Dose of NC- 
6004 PK Analysis Set 
Figure 14.2.10 
Geometric Mean AUC0-inf of Free Platinum in Plasma versus Dose of NC-6004 
PK Analysis Set 


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Appendix D: Imputation Algorithm for Partial and Missing Dates 
Adverse Event 
• If onset date is completely missing, then onset date is set to date of first dose. 
• If (year is present and month and day are missing) or (year and day are present and 
month is missing): 
o If year = year of first dose, then set onset month and day to month and day 
of first dose 
o If year < year of first dose, then set onset month and day to December 31st. 
o If year > year of first dose, then set onset month and day to January 1st. 
• If month and year are present and day is missing: 
o If year=year of first dose and 
 If month = month of first dose then set day to day of first dose date 
 If month < month of first dose then set day to last day of month 
 If month > month of first dose then set day to 1st day of month 
o If year < year of first dose then set day to last day of month 
o If year > year of first dose then set day to 1st day of month 
• For all other cases, set onset date to date of first dose 
Concomitant Medications 
• If start date is completely missing then start date will not be imputed. 
• If (year is present and month and day are missing) or (year and day are present and 
month is missing) then set start month and start day to January 1. 
• If start year and start month are present and start day is missing then set start day to 
1st day of month. 
• If end date is completely missing then end date will not be imputed. 
• If (year is present and month and day are missing) or (year and day are present and 
month is missing) then set end month and end day to December 31. 
• If end year and end month are present and end day is missing then set end day to 
last day of the month.