Clinical trial NCT02915744
Conditions: Metastasis Breast Cancer
Keywords: Breast Cancer Brain Metastases (BCBM) Carcinoma
Sponsor: Nektar Therapeutics
Start date: 2016-11-01; Completion date: 2020-07-01
Enrollment: 178 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label, randomized, active comparator, multicenter, international Phase 3 study of NKTR-102 versus TPC in patients with metastatic breast cancer who have stable brain metastases and have been previously treated with an anthracycline, a taxane, and capecitabine in either the adjuvant or metastatic setting (prior anthracycline may be omitted if medically appropriate or contraindicated for the patient).

Detailed description:
This is an open-label, randomized, active comparator, multicenter, international Phase 3 study of NKTR-102 versus TPC in patients with metastatic breast cancer who have stable brain metastases and have been previously treated with an anthracycline, a taxane, and capecitabine in either the adjuvant or metastatic setting (prior anthracycline may be omitted if medically appropriate or contraindicated for the patient).

In Group A, NKTR-102 will be administered at a dose level of 145 mg/m2 on a q21d schedule as a 90-minute intravenous (IV) infusion on Day 1 of each treatment cycle. In Group B, TPC will be administered per standard of care. Patients randomized to TPC will receive single-agent IV chemotherapy, limited to choice of one of the following 7 agents: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel.

This study will randomize approximately 220 patients using a 1:1 randomization ratio and stratification based on geographic region, tumor receptor status, and Eastern Cooperative Oncology Group (ECOG) status. At Screening, the Investigator must determine which TPC will be offered to the patient.

Data will be collected on subsequent anticancer therapies in both treatment groups from the time patients come off the study treatment until the time of primary data analysis for Overall Survival (OS).

An independent data monitoring committee (DMC) will assess interim safety and efficacy data and determine final number of death events needed to provide 80% conditional power based on the zone adaptive design.

Arms: arm 1: In Group A, NKTR-102 will be administered at a dose level of 145 mg/m2 on a q21d schedule as a 90-minute intravenous (IV) infusion on Day 1 of each treatment cycle. arm 2: In Group B, TPC will be administered per standard of care. Patients randomized to TPC will receive single-agent IV chemotherapy, limited to choice of one of the following 7 agents: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel.
Interventions: intervention 1: NKTR-102 intervention 2: Eribulin intervention 3: Ixabepilone intervention 4: Vinorelbine intervention 5: Gemcitabine intervention 6: Paclitaxel intervention 7: Docetaxel intervention 8: Nab-paclitaxel
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None intervention 8: None

Protocol documents:
Prot_000.pdf: 


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INVESTIGATOR SIGNATURE PAGE 
Nektar Therapeutics 
TITLE: 
An Open-label, Multicenter, Extension Study of NKTR-102 in Subjects 
Previously Enrolled in NKTR-102 Studies  
PROTOCOL NUMBER: 
11-PIR-09 
PHASE OF STUDY: 
2 
PROTOCOL AMENDMENT 
3.0 DATE: 
14 January 2016 
STUDY SPONSOR: 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158  USA 
 
PRINCIPAL INVESTIGATOR COMMITMENT: 
I, the undersigned Principal Investigator, submit this statement of commitment as evidence that I 
understand my responsibilities pursuant to Federal Regulations (21 CFR § 312.60 through § 
312.70, 21 CFR § 11, 50, 54, 56) and ICH E6 Good Clinical Practice guidelines, as well as with 
any and all applicable federal, state and/or local laws and regulations, and agree to conduct the 
study in accordance with the protocol referenced herein. 
 




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1.0 
STUDY SYNOPSIS 
Name of Sponsor:  
Nektar Therapeutics 
Name of Finished Product: 
NKTR-102 for Injection 
Name of Active Ingredient: 
NKTR-102 (etirinotecan pegol) 
Title of Study: 
An Open-label, Multicenter, Extension Study of NKTR-102 in Subjects 
Previously Enrolled in NKTR-102 Studies 
Study Period: 
The estimated study duration is approximately 5 years.  The duration of 
treatment in this study is estimated to be approximately 2 years.  Subjects may 
continue to receive repeated cycles of study drug treatment until progression of 
disease, unacceptable toxicity, death, withdrawal by subject, Investigator 
decision, lost to follow-up, or study is terminated by the Sponsor. 
Phase of Development: 
Phase 2 
Indication: 
Solid tumors  
Objectives: 
Primary Objective: 
• To provide access to NKTR-102 to subjects who previously received 
NKTR-102 in a clinical trial and are without signs of disease progression 
since receiving NKTR-102.   
Secondary Objectives: 
• To evaluate the safety of continued exposure to NKTR-102. 
• To observe disease status and survival status in subjects receiving 
NKTR-102. 
• To evaluate the efficacy of NKTR-102 in subjects with advanced or 
metastatic solid tumors.   
Endpoints: 
• Incidence and duration of toxicities, with severity grading according to 
National Cancer Institute - Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) version 4.0.   
• Tumor response per Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 
Number of Study Sites: 
Up to 100 study sites may participate in this study.   
Countries: 
Multi-national 
Number of Subjects (planned):  
Up to 150 subjects may be enrolled in this study. 
Study Design: 
This is a multicenter, open-label, Phase 2 study of NKTR-102 in subjects with 
solid tumors who received NKTR-102 in a prior Nektar-sponsored clinical 
study.  Following completion of NKTR-102 treatment on a prior NKTR-102 
clinical study, subjects will be assessed for eligibility.  The Sponsor must assess 
eligibility criteria prior to enrollment of all subjects.   
Eligible subjects will continue treatment with NKTR-102 at a dose of 
145 mg/m2 or less in a q21d schedule.  Subjects who previously received a dose 
of NKTR-102 at <145 mg/m2 will continue at the lower dose in this study.  
Subjects who underwent dose reduction of NKTR-102 due to observed toxicity 
prior to participation in the Extension study (Protocol 11-PIR-09) will not be 


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re-escalated to the previous dose level upon resolution of the toxicity.  Dose 
escalation for NKTR-102 is not permitted. 
Disease assessments for tumor response and progression will be performed as 
per local standard of care until disease progression.  Minimal disease evaluation 
data (best response and date of progression) will be collected within this 
protocol.  Tumor measurements are not required; only an overall assessment of 
response or progression by the Investigator is required.  Subjects may continue 
to receive repeated cycles of NKTR-102 on this protocol as long as there is 
evidence of disease control in the judgment of the Investigator or until there is 
unacceptable toxicity, death, withdrawal of consent by the subject, Investigator 
decision, subject non-compliance, lost to follow-up, or study is terminated by 
the Sponsor.  After discontinuation of NKTR-102, all subjects, except those 
who withdraw consent from further study follow-up, are to be followed for 
disease status (as applicable), subsequent anti-cancer therapy, survival status, 
and resolution of toxicity attributable to study drug (with contact by phone, 
through a clinic visit, or through review of medical records approximately every 
12 weeks (±4 weeks)).   
Concomitant Medications: 
Permitted Treatments: 
• Palliative and supportive care for disease-related symptoms. 
• Standard therapies for concurrent medical conditions, including antiemetic 
prophylaxis and early interventional antidiarrheal therapy. 
• Diarrhea is an expected toxicity of NKTR-102.  All subjects must receive 
optimal antidiarrheal therapy immediately after the FIRST episode of 
diarrhea or loose stool regardless of severity. 
• Premedication with antihistamine and/or corticosteroid is allowed in 
subsequent cycles following occurrence of a self-limiting 
allergic/hypersensitivity reaction to a prior infusion of NKTR-102. 
Prohibited Treatments:  
• Any concurrent chemotherapy (other than NKTR-102), radiotherapy (with 
the exception of palliative radiation), biological therapy, hormonal agents 
used for the treatment of cancer, immunotherapy, or other systemic therapy 
for cancer; megestrol acetate for appetite stimulation may be used. 
• Other investigational agents within 28 days prior to Day 1 of Cycle 1 or 
during the study. 
• Investigators must monitor subjects for use of potent cytochrome P450 3A4 
(CYP3A4) inducers or inhibitors, as they may induce or inhibit irinotecan or 
SN38 metabolism.   Some of these agents are over-the-counter medications 
(e.g., St John’s Wort); subjects must provide a complete list of all 
concomitant medications as part of the screening process.   
Inclusion Criteria:  
Subjects must meet the following criteria to be eligible for enrollment:   
1) Subject or subject’s legal representative must provide written informed 
consent 
2) Subject is able and willing to comply with the study visit schedule and 
procedures 


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3) Subjects must have received prior treatment with NKTR-102 in a 
Nektar-sponsored study  
4) Subjects must be without signs of disease progression since receiving 
NKTR-102  
5) Women of childbearing potential must have a negative serum pregnancy 
test at screening and a negative urine pregnancy test at the predose visit of 
each cycle 
6) Women of childbearing potential and men who agree to use adequate 
contraception during study participation (at least two methods of 
contraception, one of which includes a barrier method [male condom] by 
the male partner or abstinence) or a male who has undergone a vasectomy 
greater than 6 months prior to Cycle 1 Day 1.  Appropriate contraception 
must be used for at least 8 months after the last dose of the study drug on 
this extension study 
7) Subjects must meet requirements with respect to hematopoietic function 
(hemoglobin > 8.0 g/dL or 80 g/L; absolute neutrophil count (ANC) 
> 1.5 X 109/L; platelets > 75 X 109/L).   
8) Subjects must be able to receive the first dose of NKTR-102 in the 
extension study within 8 weeks after receiving their last dose of NKTR-102
Exclusion Criteria: 
Subjects who meet any of the following criteria are ineligible for enrollment: 
1) Subjects who have received intervening anti-cancer therapy (between their 
last dose of NKTR-102 and administration of the first dose of NKTR-102 
in this extension study) 
2) Subjects with 2 dose reductions of NKTR-102 and have a toxicity that 
requires another dose reduction 
3) Female subjects who are pregnant or lactating, who plan to get pregnant, or 
who have a positive pregnancy test at screening or during participation in 
this study 
Test Product, dose and mode of 
administration:  
NKTR-102 will be administered as an intravenous (IV) infusion over 
approximately 90 minutes (± 15 minutes) on Day 1 of each 21-day treatment 
cycle.  The dose of NKTR-102 will be 145 mg/m2 or less.  Subjects who 
received a dose of NKTR-102 at <145 mg/m2 will continue at the lower dose in 
this study.  Subjects who underwent 2 dose reductions of NKTR-102 due to 
observed toxicity prior to participation in the Extension study will not be 
re-escalated to the previous dose level upon resolution of the toxicity.  Dose 
escalation for NKTR-102 is not permitted. 
Duration of Treatment:  
Subjects will continue to receive study drug treatment until progression of 
disease, unacceptable toxicity, death, withdrawal by the subject, Principal 
Investigator decision, lost to follow-up, or study is terminated by the Sponsor.   
Reference Therapy, dose and 
mode of administration, batch 
number (if applicable):  
Not applicable 


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Disease Evaluation (per 
Standard of Care): 
Tumor assessments will be performed according to local standard of care until 
disease progression.   
Statistical Methods: 
The primary objective will be measured by capturing AEs and SAEs using the 
data capture tools provided for this study.  
The primary endpoint of this study is to assess the incidence and duration of 
toxicities, with severity grading according to NCI-CTCAE v. 4.0.  
The incidence and duration of AEs will be tabulated by MedDRA preferred 
term, system organ class, severity grading by NCI-CTCAE v. 4.0 criteria and 
relationship to study drug.  The maximum intensity and frequency of AEs will 
be summarized by treatment (dose level). 
Tumor response will be summarized by histological tumor type and tabulated 
using by-subject listings based on disease assessments from this protocol.   
NKTR-102 Dose Modification: 
NKTR-102 dose modifications are provided in Section 6.7.   
Safety Monitoring: 
Clinical examinations including physical examinations and vital signs.  Local 
laboratory assessments including bone marrow, liver, and renal functions will 
be performed before each cycle of NKTR-102.  Other laboratory assessments 
can be performed at the investigator’s discretion. 
 


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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE......................................................................................2 
PRINCIPAL INVESTIGATOR COMMITMENT: ...................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
1.0 
STUDY SYNOPSIS ...........................................................................................................4 
TABLE OF CONTENTS ..............................................................................................................8 
LIST OF TABLES .......................................................................................................................11 
LIST OF FIGURES .....................................................................................................................11 
LIST OF APPENDICES .............................................................................................................11 
LIST OF ABBREVIATIONS .....................................................................................................12 
2.0 
INTRODUCTION............................................................................................................14 
2.1 
NKTR-102 .............................................................................................................14 
2.1.1 
Description of Nonclinical Studies .......................................................14 
2.1.2 
Clinical Experience with NKTR-102 ....................................................14 
2.1.2.1 
Phase 1 Study 06-IN-IR001 (Single-Agent NKTR-102) ...............14 
2.1.2.2 
Phase 2 studies ...............................................................................15 
2.1.2.3 
Clinical Pharmacokinetics of NKTR-102 ......................................16 
2.1.2.4 
NKTR-102 Safety Profile ..............................................................17 
2.1.2.5 
Study Drug Discontinuation due to Adverse Events and 
Physician Decision in Phase 3 BEACON (11-PIR-11) Study .......18 
2.2 
Study Rationale ......................................................................................................20 
3.0 
STUDY OBJECTIVES ....................................................................................................21 
3.1 
Primary Objective ..................................................................................................21 
3.2 
Secondary Objectives .............................................................................................21 
4.0 
STUDY DESIGN ..............................................................................................................22 
4.1 
Study Endpoint.......................................................................................................22 
4.1.1 
Endpoints ..............................................................................................22 
4.2 
Study Design ..........................................................................................................22 
4.2.1 
Administrative Structure .......................................................................24 
4.3 
Blinding..................................................................................................................24 
4.4 
Method of Assigning Subjects to Treatment Groups .............................................24 
4.5 
Drug Accountability and Reconciliation ...............................................................24 
5.0 
SELECTION OF STUDY POPULATION ...................................................................25 


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5.1 
Inclusion Criteria ...................................................................................................25 
5.2 
Exclusion Criteria ..................................................................................................25 
5.3 
Early Withdrawal/Discontinuation from Study .....................................................26 
5.3.1 
Withdrawal Procedures .........................................................................27 
6.0 
INVESTIGATIONAL PRODUCT(S)/STUDY MEDICATIONS ...............................28 
6.1 
Description and Formulation .................................................................................28 
6.2 
Packaging and Labeling .........................................................................................28 
6.3 
Reconstitution and Handling..................................................................................28 
6.4 
Treatment Assignment ...........................................................................................29 
6.5 
Dosage and Administration....................................................................................29 
6.6 
Duration of Treatment............................................................................................30 
6.7 
Dose Modifications and Delays .............................................................................30 
6.8 
Antidiarrheal Therapy ............................................................................................37 
6.9 
Antiemetic Therapy ...............................................................................................38 
6.10 
Use of Growth Factor Support and Transfusions ..................................................38 
6.11 
Prior and Concomitant Medications ......................................................................39 
6.11.1 
Permitted Treatments ............................................................................39 
6.11.2 
Prohibited Concomitant Medications ....................................................39 
6.11.3 
Adequate Forms of Birth Control .........................................................40 
7.0 
EVALUATIONS BY VISIT ............................................................................................41 
7.1 
Screening................................................................................................................41 
7.2 
Treatment Days ......................................................................................................42 
7.3 
End-of-Treatment Visit ..........................................................................................42 
7.4 
Quarterly Follow-up...............................................................................................43 
8.0 
STUDY OR STUDY SITE TERMINATION ................................................................44 
9.0 
ASSESSMENT OF SAFETY OR ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS .......................................................................................................45 
9.1 
Adverse Event Definition and Assessment ............................................................45 
9.2 
Monitoring Adverse Events ...................................................................................45 
9.3 
Grading of Adverse Events ....................................................................................46 
9.4 
Causality Relationship of Adverse Events .............................................................47 
9.5 
Adverse Event Reporting and Follow-up ..............................................................48 
9.6 
Serious Adverse Event Definition .........................................................................48 


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9.7 
Serious Adverse Event Reporting ..........................................................................49 
9.8 
Serious Adverse Event Follow-up .........................................................................50 
9.9 
Expedited Reporting of SAEs ................................................................................50 
9.10 
Ongoing Safety Monitoring ...................................................................................51 
10.0 
EFFICACY EVALUATIONS.........................................................................................52 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................53 
11.1 
Changes to the Protocol .........................................................................................53 
11.2 
Monitoring .............................................................................................................53 
12.0 
STATISTICAL CONSIDERATIONS ...........................................................................54 
12.1 
Analysis Populations ..............................................................................................54 
12.2 
Endpoints and Planned Analyses ...........................................................................54 
13.0 
ETHICS ............................................................................................................................55 
13.1 
IRB/IEC Approval .................................................................................................55 
13.2 
Written Informed Consent .....................................................................................55 
14.0 
DATA HANDLING AND RECORD KEEPING ..........................................................56 
14.1 
Case Report Forms and Source Documents...........................................................56 
14.1.1 
Study Records .......................................................................................56 
14.1.2 
Case Report Forms ................................................................................56 
14.2 
Retention of Essential Documents .........................................................................56 
14.3 
Confidentiality .......................................................................................................56 
15.0 
PUBLICATION POLICY ...............................................................................................58 
16.0 
REFERENCES .................................................................................................................59 
17.0 
APPENDICES ..................................................................................................................60 
  


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LIST OF TABLES 
Table 1: 
Treatment Emergent Adverse Events with a Frequency > 20%, Study 
11-PIR-11 (BEACON, N=425) .......................................................................18 
Table 2: 
Summary of TEAEs Leading to Study Drug Discontinuation by Preferred 
Term (> 1 Patient in NKTR-102 or TPC Treatment arm) (Safety 
Population) .......................................................................................................19 
Table 3: 
Nomenclature ...................................................................................................28 
Table 4: 
NKTR-102 Dose Modifications .......................................................................32 
  
LIST OF FIGURES 
Figure 1: 
Study Schematic...............................................................................................23 
  
LIST OF APPENDICES 
Appendix 1: 
Schedule of Assessments .................................................................................61 
Appendix 2: 
Cytochrome P450 3A Inhibitors and Inducers.................................................63 
  


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LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition/Explanation 
AE 
adverse event 
ALT  
alanine aminotransferase  
AST  
aspartate aminotransferase 
AUC 
area under the curve 
BSA 
body surface area 
Cmax 
maximum concentration 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CPT-11 
20-(S)-camptothecin 
CRC 
colorectal cancer 
CRF 
Case Report Form 
CT 
computed tomography 
CYP3A4 
cytochrome P450 3A4 
D5W 
dextrose for injection, 5 w/w% 
ECG 
electrocardiogram 
EMEA 
European Medicines Agency 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
intravenous 
Kg 
kilogram 
μg 
microgram 
MBC 
metastatic breast cancer  
m2 
meters squared 
mg 
milligram 
mL 
milliliter 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 


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Abbreviation or Term 
Definition/Explanation 
MTD 
maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
OTC 
over-the-counter 
PEG 
polyethylene glycol 
PK 
pharmacokinetic 
q14d 
once every 14 days 
q21d 
once every 21 days 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended phase 2 dose 
SAE 
Serious Adverse Event 
SN38 
7-ethyl-10-hydroxy-camptothecin 
SUSAR 
suspected unexpected serious adverse reactions 
t½ 
terminal elimination phase half-life 
TNBC 
triple negative breast cancer  
TPC 
treatment of physician’s choice 
ULN 
upper limit of normal 
UGT1A1 
uridine diphosphate-glucoronosynl transferase 1A1 
US 
United States 
USP 
United States Pharmacopeia 
w×3 q4week 
weekly for 3 weeks every 4 weeks 
WBC 
White Blood Cell 
 


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2.0 
INTRODUCTION 
2.1 
NKTR-102 
NKTR-102 (etirinotecan pegol) is a long acting topoisomerase I inhibitor polymer conjugate that 
was engineered by attaching irinotecan molecules to a polyethylene glycol (PEG) polymer using 
a biodegradable linker.  Irinotecan is released from NKTR-102 following administration and 
further metabolized to the active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN38), which 
causes deoxyribonucleic acid (DNA) damage through the inhibition of topoisomerase 1.   
The goal in designing NKTR-102 was to attenuate or eliminate some of the limiting side effects 
of irinotecan while improving efficacy by modifying the distribution of the agent within the 
body.  The size and structure of NKTR-102 results in a marked alteration of the pharmacokinetic 
(PK) profile of SN38 derived from NKTR-102 compared with that following irinotecan:  the 
maximum plasma concentration (Cmax) is reduced 5- to 10-fold, and the apparent elimination 
half-life (t½) of SN38 is increased from 2 days to approximately 40 days.  This altered profile 
leads to the prolonged exposure of the tumor to active drug.  In addition, the large NKTR-102 
molecule does not freely pass out of intact vasculature, possibly accounting for relatively higher 
concentrations of the compound and the active metabolites in tumor tissues in in vivo animal 
models, where the local vasculature may be relatively more permeable.  A single dose of 
145 mg/m2 NKTR-102, the dose used in the Phase 3 metastatic breast cancer (MBC) clinical 
study (BEACON trial), results in approximately the same plasma exposure (area under the 
plasma concentration-time curve [AUC]) to SN38 as a 350 mg/m2 dose of irinotecan, but 
exposure is protracted, resulting in continuous exposure between dosing cycles and a lower Cmax.  
NKTR-102 is therefore being developed as a new chemotherapeutic agent that may improve 
tolerability and patient outcome.   
2.1.1 
Description of Nonclinical Studies 
Nonclinical experience is summarized in the Investigator’s Brochure (IB). 
2.1.2 
Clinical Experience with NKTR-102 
2.1.2.1 
Phase 1 Study 06-IN-IR001 (Single-Agent NKTR-102) 
The NKTR-102 Phase 1 study, 06-IN-IR001, was open to patients with advanced solid tumors 
whose tumors had failed prior treatments or those for which no standard treatments were 
available.  The study evaluated three treatment schedules:  weekly for 3 weeks every 4 weeks 
(wx3 q4week), once every 14 days (q14d) and once every 21 days (q21d).  In all schedules, 
NKTR-102 was given as an intravenous (IV) infusion over 90 minutes.   


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For each schedule, the objectives were:   
• To establish the maximum tolerated dose (MTD)/Recommended Phase 2 dose (RP2D),  
• To characterize the safety and PK profile in subjects with refractory solid tumors, 
• To evaluate subjects for any evidence of anti-tumor activity.   
This study has been completed and final data are detailed in the IB. 
2.1.2.2 
Phase 2 studies 
A Phase 2 study (Protocol 08-PIR-05) of NKTR-102 in patients with metastatic breast cancer 
(MBC) evaluating 2 treatment schedules (145 mg/m2 q14d and q21d; n = 70 patients with 
35 patients per treatment schedule) showed significant antitumor activity.  The study showed the 
following activity in the 2 treatment schedules combined:   
• ORR by RECIST version 1.0 in the intent-to-treat population was 29%, with 2 complete 
responses (3%) and 18 partial responses (26%).   
• ORR was maintained in patients with advanced or high-risk disease (ORR equal to 33% in 
patients who had received prior anthracycline, taxane, capecitabine; ORR in patients with 
triple negative breast cancer (TNBC) was 33%).   
• Median progression free survival (PFS) and overall survival (OS) were 4.7 months and 
10.3 months, respectively.   
The q21d schedule resulted in less Grade 3 or higher toxicity (68.6% for the q14d and 54.3% for 
the q21d schedule), fewer serious adverse events (SAEs) (51.4% for q14d schedule and 42.9% 
for q21d schedule), and slightly fewer patients discontinuing the study drug, but not necessarily 
exiting the study, due to an adverse event (22.9% for q14d schedule and 20.0% for q21d 
schedule).  Two possible drug-related fatalities (acute renal failure and septic shock) occurred in 
patients treated with the q14d schedule and none occurred in patients treated with the q21d 
schedule.  There were no observations of Grade 4 diarrhea in the q21d schedule.   
Based on these findings, the 145 mg/m2 q21d regimen was selected for continued investigation 
in the Phase 3 study in patients with MBC.  See the IB for additional information on the Phase 3 
study in patients with MBC.   
A Phase 2 study (Protocol 08-PIR-04) of NKTR-102 in patients with platinum resistant ovarian 
cancer (disease progressing within 6 months following last dose of platinum) evaluated 
2 treatment schedules (145 mg/m2 q14d and q21d; n = 71; 36 and 35 patients per treatment 


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schedule).  Preliminary data indicated that NKTR-102 produced a RECIST version 1.0 ORR 
(confirmed and unconfirmed) of 27% and 22% in the q14d and q21d schedules, respectively.  
The Gynecologic Cancer InterGroup response (confirmed and unconfirmed) was 47% in q14d 
and 41% in the q21d schedule (Vergote et. al., 2010).  In those patients whose disease had 
progressed following both platinum (within 6 months) and liposomal doxorubicin (n = 33), ORR 
equaled 21%, median PFS equaled 5.5 months and OS equaled 14.0 months in combined q14d 
and q21d schedules (Garcia et. al., 2011).  Common related grade 3/4 toxicities (q14d/q21d 
schedules) were diarrhea (22%/11%), dehydration (14%/6%), hypokalemia (14%/6%), fatigue 
(6%/11%), nausea (14%/3%), and neutropenia (8%/9%) (Vergote et. al., 2010).  Two 
treatment-related deaths were observed; one patient died due to pre-renal azotemia (q14d 
schedule) and one patient died due to neutropenic sepsis (q21d schedule).  The q21d schedule, 
overall, had a better toxicity profile, supporting further development using the q21d schedule.   
A randomized Phase 2 study (Protocol 08-PIR-03) comparing single-agent NKTR-102 to 
single-agent irinotecan in 2nd-line KRAS-mutant metastatic colorectal cancer (CRC) patients was 
completed.  The final Clinical Study Report is not yet available.   
Combination studies have been completed (Protocol 07-PIR-02 with cetuximab and Protocol 
09-PIR-07 with 5-FU/leucovorin).  See the IB for additional information on these clinical 
studies.   
2.1.2.3 
Clinical Pharmacokinetics of NKTR-102 
Clinical PK profiles are consistent with preclinical PK profiles with NKTR-102 infusions 
demonstrating greater and sustained exposure to SN38 than had been reported for irinotecan 
infusions.  Additionally, proportional increases in the area under the concentration-time curve 
(AUC) and maximum concentration (Cmax) were observed for NKTR-102, irinotecan, and SN38.   
The apparent elimination t½ for SN38 after NKTR-102 administration is approximately 40 days, 
whereas after irinotecan administration, the SN38 t½ has been reported as 29 to 47 hours (
Kehrer et al., 2000).  This greatly increased SN38 t½ results in plasma SN38 concentrations that 
are significantly more sustained between doses than are possible with irinotecan.  Cumulative 
SN38 exposures, as indicated by AUC values, were 0.6 - 4.4 fold higher (mean 1.6, standard 
deviation 0.8) than those predicted for irinotecan (Xie et al., 2002) when administered at 
equivalent doses and schedules.   
Interpatient variability in SN38 clearance and volume of distribution is similar to that reported 
for SN38 following irinotecan administration.   


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There has been no obvious correlation of toxicity or SN38 PK parameters with age, race, gender, 
past or present smoking status, uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) 
status, or baseline liver or renal function.  Further exploratory analyses are ongoing.   
2.1.2.4 
NKTR-102 Safety Profile 
As of May 2015, 871 patients across all NKTR-102 clinical studies (completed and ongoing; 
single agent and combination therapy) have received at least one dose of NKTR-102.  See the 
current version of the IB for additional safety information.   
Observations across all studies (including safety data from ongoing studies) have been generally 
consistent with regard to the overall safety profile of NKTR-102.  Gastrointestinal toxicity, 
especially diarrhea, is the most common and clinically significant toxicity.  Other frequently 
observed AEs include nausea, vomiting, fatigue, decreased appetite, abdominal pain, 
constipation, and dehydration.   
Diarrhea and dehydration secondary to diarrhea were the most common serious adverse events 
(SAEs) across all studies evaluating NKTR-102, occurring at frequencies of 9.5% and 4.1%, 
respectively.  Prolonged severe diarrhea with dehydration leading to pre-renal azotemia and 
subsequent acute renal insufficiency has been fatal in 4 patients (1 patient in each of the Phase 2 
studies in metastatic colorectal, ovarian, and breast cancers and 1 patient in the Phase 3 
BEACON study).  Early onset cholinergic-mediated diarrhea has been observed with NKTR-
102. Late-onset, severe diarrhea can occur and may be life-threatening if treatment is delayed.  
The median time to onset of Grade 3 diarrhea for NKTR-102 in the Phase 3 BEACON study was 
43 days (range 3 to 488 days).  Early, proactive, and aggressive intervention with anti-diarrheal 
therapy, IV hydration, and maintenance of electrolyte balance had a significant favorable effect 
on the clinical course of events, preventing volume depletion and the development of renal 
failure.   
Myelosuppression, especially neutropenia, can occur in patients receiving NKTR-102; however, 
data from clinical studies evaluating NKTR-102 suggest a lower frequency and severity of 
neutropenia with NKTR-102 than with irinotecan.  NKTR-102 administered at a dose level of 
145 mg/m2 in a q21d schedule in the Phase 3 BEACON study resulted in an overall neutropenia 
incidence of 21.4%; about one-third of these (7.5%) was ≥ Grade 3 neutropenia.  The onset of 
neutropenia in the concomitant setting of severe diarrhea and dehydration with fever and 
infection must be carefully monitored and proactively treated as it can potentially lead to 
neutropenic sepsis, which may be fatal.   


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Safety results from the Phase 3 BEACON study show a generally manageable safety profile for 
NKTR-102. Common toxicities (related and unrelated) with a frequency > 20% are listed by 
grade in Table 1.   
Table 1: 
Treatment Emergent Adverse Events with a Frequency > 20%, Study 
11-PIR-11 (BEACON, N=425) 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Total 
Diarrhea 
41.6% 
14.8% 
9.6% 
- 
- 
66.1% 
Nausea 
36.9% 
19.5% 
3.5% 
- 
- 
60.0% 
Vomiting 
26.4% 
11.5% 
2.8% 
- 
- 
40.7% 
Fatigue 
14.6% 
15.3% 
4.5% 
- 
- 
34.4% 
Decreased appetite 
19.5% 
10.1% 
1.2% 
- 
- 
30.8% 
Constipation 
20.0% 
6.1% 
0.2% 
- 
- 
26.4% 
Headache 
15.8% 
5.4% 
1.2% 
- 
- 
22.4% 
Asthenia 
9.6% 
10.1% 
1.9% 
- 
- 
21.6% 
Abdominal pain 
11.5% 
8.7% 
1.2% 
 
 
21.4% 
Neutropenia 
2.1% 
11.8% 
5.4% 
2.1% 
- 
21.4% 
 
2.1.2.5 
Study Drug Discontinuation due to Adverse Events and Physician Decision in 
Phase 3 BEACON (11-PIR-11) Study 
A summary of the most common TEAEs leading to study drug discontinuation (> 1 patient in the 
NKTR-102 treatment arm) is presented in Table 2.  There was a higher overall incidence of 
TEAEs leading to discontinuation in the NKTR-102 treatment arm (11.1%) compared with TPC 
(6.7%), and there was a higher incidence of diarrhea leading to discontinuation in the NKTR-102 
treatment arm (3.1%) compared with the TPC treatment arm (0%).  The incidence of neuropathy 
leading to discontinuation was higher in the TPC treatment arm (2.2%) compared with the 
NKTR-102 treatment arm (0.2%).   
Strict protocol-mandated diarrhea management guidelines were implemented in the BEACON 
study, including requirements for removal of patients from the study due to diarrhea.  Guidelines 
were created based on the safety experience obtained in the prior phase 2 program where 
Grade ≥3 diarrhea occurred at a rate of approximately 20% (see IB for details).  Dose reductions 
were required to prevent the possibility of accumulation of active drug upon repeated dosing; 
occurrence of Grade ≥ 2 diarrhea was controlled by temporary discontinuation of NKTR-102.  
The BEACON protocol mandated discontinuation after the third occurrence of Grade ≥ 2 
diarrhea.  Because the incidence of Grade ≥ 3 diarrhea is less than 10% with the implementation 
of diarrhea management guidelines, and given that the median time to resolution for all Grades 


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of diarrhea was 1.5 days, any subsequent studies will not require treatment discontinuation after 
3 episodes of Grade ≥ 2 diarrhea.   
Also of importance, a greater proportion of patients were removed from NKTR-102 (2.8%) for 
neutropenia compared to TPC (0.2%), despite the lower rate of Grade ≥3 neutropenia with 
NKTR-102 (9.6%) compared with that of TPC (30.6%).  The median time to onset of Grade ≥ 3 
neutropenia was 120 days on NKTR-102 compared with 16 days on TPC.  The significance of 
the difference in time to onset is that the clinical decision to discontinue treatment due to 
neutropenia likely occurs at a much later time point for patients on NKTR-102, when there may 
be less clinical benefit to continue; this situation is quite different from an appropriate response 
to the occurrence of early neutropenia (ie, with TPC), where dose delay is more common.   
Table 2: 
Summary of TEAEs Leading to Study Drug Discontinuation by Preferred 
Term (> 1 Patient in NKTR-102 or TPC Treatment arm) (Safety 
Population) 
Preferred Terma 
NKTR-102 
(N = 425) 
TPC 
(N = 406) 
Total Number of TEAEs Leading to Study Drug Discontinuation b 
47 
27 
Number of Patients With at Least One TEAE Leading to Study Drug 
Discontinuation 
47 (11.1%) 
27 (6.7%) 
Diarrhea 
13 (3.1%) 
0 
Neutropeniac 
12 (2.8%) 
1 (0.2%) 
Pleural effusion 
2 (0.5%) 
2 (0.5%) 
Vomiting 
2 (0.5%) 
0 
Neuropathyd 
1 (0.2%) 
9 (2.2%) 
Dyspnea 
0 
2 (0.5%) 
Fatigue 
0 
2 (0.5%) 
Abbreviations: TEAE = treatment-emergent adverse event; TPC = treatment of physician’s choice 
a 
MedDRA v. 14.1 
b 
The total number of TEAEs counts all TEAEs for patients. A patient is counted only once within each summary 
level. The adverse event that was reported as the primary reason for study drug discontinuation is summarized. 
c 
Neutropenia includes neutropenia, neutrophil count decreased, febrile neutropenia and neutropenic sepsis. 
d 
Neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, paresthesia, neurotoxicity, 
neuralgia, peripheral motor neuropathy, polyneuropathy.  
 


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A higher proportion of patients was withdrawn from treatment due to physician decision in the 
TPC arm (57/423; 13.5%) compared with the NKTR-102 arm (28/429; 6.5%).  Typical reasons 
for clinical progression included symptoms of underlying disease such as increasing dyspnea, 
general deterioration, and reduced performance status.  In the presence of clinical evidence 
suggesting progression, benefit/risk assessment may lead to discontinuation of treatments with 
less tolerable safety profiles (eg, TPC).   
The nature, scope, and severity of the safety findings to date with NKTR-102 are clinically 
manageable and consistent with findings common to treatments for patients with MBC.   
2.2 
Study Rationale  
This study is designed to allow an extension period of NKTR-102 therapy for subjects who 
previously received NKTR-102 during a clinical study and are without signs of disease 
progression since receiving NKTR-102.   
The estimated study duration is approximately 5 years.  The duration of treatment in this study is 
estimated to be approximately 2 years.  Subjects may continue to receive repeated cycles of 
study drug treatment until progression of disease, unacceptable toxicity, death, withdrawal by 
subject, Investigator decision, lost to follow-up, or study is terminated by the Sponsor.  Since this 
trial may involve the longest exposure to NKTR-102 to date, it will allow for the collection of 
safety data, particularly serious adverse events (SAEs) that may appear only after long-term 
exposure to NKTR-102.   


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3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
• To provide access to NKTR-102 to subjects who previously received NKTR-102 in a clinical 
trial and are without signs of disease progression since receiving NKTR-102.   
3.2 
Secondary Objectives 
• To evaluate the safety of continued exposure to NKTR-102.   
• To observe disease status and survival status in subjects receiving NKTR-102.   
• To evaluate the efficacy of NKTR-102 in subjects with advanced or metastatic solid tumors.   


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4.0 
STUDY DESIGN 
4.1 
Study Endpoint 
4.1.1 
Endpoints 
• Incidence and duration of toxicities, with severity grading according to NCI-CTCAE v 4.0.   
• Tumor response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.   
4.2 
Study Design 
This is a multicenter, open-label, Phase 2 study of NKTR-102 in subjects with solid tumors who 
received NKTR-102 in a prior Nektar-sponsored clinical study.  Following completion of 
NKTR-102 treatment on a prior NKTR-102 clinical study, subjects will be assessed for 
eligibility.  The Sponsor must assess eligibility criteria prior to enrollment of all subjects.   
Eligible subjects will continue treatment with NKTR-102 at a dose of 145 mg/m2 or less in a 
q21d schedule as outlined in Section 6.5.  Subjects who previously received a dose of 
NKTR-102 at <145 mg/m2 will continue at the lower dose in this study.  Subjects who 
underwent dose reduction of NKTR-102 due to observed toxicity prior to participation in the 
Extension study (Protocol 11-PIR-09) will not be re-escalated to the previous dose level upon 
resolution of the toxicity.  Dose escalation for NKTR-102 is not permitted.   
NKTR-102 will be administered as an IV infusion over approximately 90 minutes (± 15 minutes) 
on Day 1 of each 21-day treatment cycle.  Disease assessments for tumor response and 
progression will be performed as per local standard of care until disease progression.  Minimal 
disease evaluation data (best response and date of progression) will be collected within this 
protocol.  Tumor measurements are not required; only an overall assessment of response or 
progression by the Investigator is required.  Subjects may continue to receive repeated cycles of 
NKTR-102 on this protocol as long as there is evidence of disease control in the judgment of the 
Investigator or until there is unacceptable toxicity, death, withdrawal of consent by the subject, 
Investigator decision, subject non-compliance, lost to follow-up or study is terminated by the 
Sponsor.  After discontinuation of NKTR-102, all subjects, except those who withdraw consent 
from further study follow-up, are to be followed for disease status (as applicable), subsequent 
anti-cancer therapy, survival status, and resolution of toxicity attributable to study drug (with 
contact by phone, through a clinic visit, or through review of medical records approximately 
every 12 weeks (± 4 weeks).   
A schematic of the study design is presented in Figure 1.   




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4.2.1 
Administrative Structure 
Protocol 11-PIR-09 is sponsored by Nektar Therapeutics and will be administered and monitored 
by Nektar or designee.  Monitoring will occur at each site on a periodic basis at Nektar’s 
discretion.  Monitors will perform verification of source documentation for study subjects.  Site 
Investigators will provide confirmation to Nektar that the eligibility criteria have been met for 
each subject.  Nektar will then inform the study site that the subject can be offered entry into the 
Extension study (Protocol 11-PIR-09).   
4.3 
Blinding 
This is an open-label study.   
4.4 
Method of Assigning Subjects to Treatment Groups 
There will be no randomization or subject stratification.  Subjects will retain their subject 
identification number from their original study.  Treatment with NKTR-102 will occur as 
described in Section 6.5.   
4.5 
Drug Accountability and Reconciliation 
NKTR-102 for Injection will be stored as per instructions provided in the pharmacy manual in a 
secured site with restricted access.   
Study drug accountability will be recorded by the site pharmacist or designee and verified by the 
Sponsor’s designee at the Sponsor’s discretion.  The pharmacist or designee will:   
• Maintain records of product delivery, lot number, inventory, and destruction or return  
• Maintain temperature monitoring 
• Maintain up-to-date accountability of NKTR-102 for Injection in the drug accountability log  
• Document the use of NKTR-102 for Injection by each subject 
• Return or destroy unused NKTR-102 for Injection as per Sponsor’s instructions 


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5.0 
SELECTION OF STUDY POPULATION 
Before any protocol mandated procedure is initiated, each subject or subject’s legal 
representative will sign and date an IRB or IEC-approved informed consent form (ICF).   
5.1 
Inclusion Criteria  
Each subject must meet the following criteria to be eligible for enrollment.   
1. Subject or subject’s legal representative must provide written informed consent.   
2. Subject is able and willing to comply with the study visit schedule and procedures.   
3. Subjects must have received prior treatment with NKTR-102 in a Nektar-sponsored 
study.   
4. Subjects must be without signs of disease progression since receiving NKTR-102.   
5. Women of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test at the predose visit of each cycle.   
6. Women of childbearing potential and men who agree to use adequate contraception 
during study participation (at least two methods of contraception, one of which includes a 
barrier method [male condom] by the male partner or abstinence) or a male who has 
undergone a vasectomy greater than 6 months prior to Cycle 1 Day 1.  Appropriate 
contraception must be used for at least 8 months after the last dose of the study drug on 
this extension study.   
7. Subjects must meet requirements with respect to hematopoietic function (hemoglobin 
> 8.0 g/dL or 80 g/L; absolute neutrophil count (ANC) > 1.5 X 109/L; platelets 
> 75 X 109/L).   
8. Subjects must be able to receive the first dose of NKTR-102 in the extension study within 
8 weeks after receiving their last dose of NKTR-102.   
5.2 
Exclusion Criteria 
Subjects who meet any of the following criteria are ineligible for enrollment.   
1. Subjects who have received intervening anti-cancer therapy (between their last dose of 
NKTR-102 and administration of the first dose of NKTR-102 in this extension study).   


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2. Subjects with 2 dose reductions of NKTR-102 and have a toxicity that requires another 
dose reduction.   
3. Female subjects who are pregnant or lactating, who plan to get pregnant, or who have a 
positive pregnancy test at screening or during participation in this study.   
5.3 
Early Withdrawal/Discontinuation from Study 
Subjects may choose to discontinue/withdraw from study drug treatment or the study at any time, 
for any reason, and without prejudice to further treatment.  A subject who withdraws consent 
from study participation will be asked to state the level of withdrawal:   
1. Withdrawal from treatment only; and/or 
2. Withdrawal from contact during the post-treatment period (for off-study data, such as 
subsequent anti-cancer therapy or survival).   
In the event of withdrawal of consent, the study staff and/or Investigator must make every effort 
to ascertain the level of consent withdrawn.  An objective of this study is to assess survival 
status, so site personnel must ascertain if subjects will permit continued follow-up if consent is 
withdrawn.  The type of consent withdrawal must be noted in source documents and CRF.   
Subjects may stop NKTR-102 treatment or be withdrawn from the study for any of the following 
reasons, but will be followed for safety until resolution or permanent sequelae of all toxicities 
attributable to NKTR-102 (see Section 9.5):   
• Progression of disease 
• Adverse Event (unacceptable toxicity) 
• Death 
• Non-compliance of the subject with protocol-mandated procedures 
• Withdrawal of consent by subject 
• Physician (Investigator) Decision 
• Lost to Follow-Up 
• Study is terminated by the Sponsor 


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5.3.1 
Withdrawal Procedures 
In the event of a subject’s withdrawal from treatment, the Investigator will promptly notify 
Nektar Therapeutics and will make every effort to complete the End-of-Treatment assessments 
and ascertain if subjects will permit continued follow-up (i.e., for survival status, subsequent 
anti-cancer therapy, and disease status).  Before a subject is considered “Lost to follow-up”, 
study personnel must attempt to contact the subject at least twice by phone and once by mail 
with documented receipt.  Study personnel may use public records to check for mortality for any 
subjects considered “Lost to follow-up” or who have withdrawn consent from the study, if 
permitted by applicable laws or regulations.   


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6.0 
INVESTIGATIONAL PRODUCT(S)/STUDY MEDICATIONS 
6.1 
Description and Formulation 
The drug substance NKTR-102 is a polymeric conjugate prodrug of irinotecan with 3 essential 
components:  a relatively large polymer, a biodegradable linker, and an active agent.  In 
NKTR-102, irinotecan is attached to PEG via a releasable linker that is hydrolyzed in vivo to 
deliver irinotecan, which is further metabolized to the active metabolite, SN38.  Table 3 
provides the nomenclature information for drug substance NKTR-102.   
Table 3: 
Nomenclature 
Compound Number/Name: 
NKTR-102 (etirinotecan pegol) 
Sponsor: 
Nektar Therapeutics 
Chemical classification: 
Topoisomerase 1 Inhibitor 
 
The investigational drug product NKTR-102 for Injection is formulated as a sterile lyophilized 
powder of NKTR-102 in lactate buffer at pH 3.5, intended for dilution with commercially 
available 5% Dextrose Injection (w/w%; D5W) or 0.9% Sodium Chloride for Injection before IV 
infusion.  The pH of the formulation is in the range of 3.2 to 4.2, and NKTR-102 for Injection 
storage condition is 2°C - 8°C, with a shelf-life of 48 months.   
Both 5% Dextrose Injection and 0.9% Sodium Chloride for Injection will be locally sourced at 
each clinical study site.   
6.2 
Packaging and Labeling 
NKTR-102 (drug substance) is light sensitive.  The lyophilized drug product NKTR-102 for 
Injection will be supplied in 25 mL Type 1 amber colored glass vials packaged in cartons of 
10 vials per carton.  Each vial contains lyophilized NKTR-102 equivalent to 100 mg of 
irinotecan.   
Each vial and carton will be labeled to comply with local regulations.   
6.3 
Reconstitution and Handling 
NKTR-102 for Injection must be reconstituted with D5W or 0.9% Sodium Chloride for Injection 
to a final concentration range of 0.2 to 1.6 mg/mL.  The reconstituted drug may be stored under 
ambient lighting conditions at room temperature (15 to 30°C) for up to 6 hours prior to start of 
infusion.  Other drugs must not be added to the infusion solution.   


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NKTR-102 for Injection must be administered as an IV infusion over approximately 90 minutes 
(± 15 minutes).  Premedications are not required to be administered prior to the initial infusion in 
this study, but may be used for an individual subject, as needed.  If a subject has reported 
symptoms (such as nausea and/or vomiting) in the original study, prophylactic use of 
anti-emetics may be attempted.   
The instructions for reconstitution and administration of NKTR-102 for Injection are described 
in detail in the Pharmacy Binder.   
6.4 
Treatment Assignment 
This is an open-label trial.  There will be no subject randomization or stratification.  Subjects will 
retain the subject identification numbers assigned in the original protocol.   
6.5 
Dosage and Administration 
Body surface area (BSA) will be determined before the start of each cycle, based on baseline 
height and most recent weight.  Body surface area may be calculated based on institutional 
guidelines.  NKTR-102 will be administered as an IV infusion over 90 minutes (± 15 minutes).  
The recommended dose and schedule of NKTR-102 is 145 mg/m2 q21d, with BSA capped at 2.4 
m2.  Subjects who were previously receiving the 145 mg/m2 dose will continue to receive this 
dose in this extension study in a q21d schedule.   
Subjects originally enrolled in a clinical study in which a lower-than-recommended dose was 
administered (e.g., Protocol 12-102-13 in subjects with impaired liver function) or was being 
administered after a dose reduction will continue to receive that same dose in a q21d schedule in 
this study.  For Protocol 12-102-13 subjects with hepatic dysfunction, as defined in that study, 
will continue in this extension study (Protocol 11-PIR-09) to receive the originally assigned dose 
from the 12-102-13 study in a q21d schedule.   
Subjects originally enrolled in a clinical study in which a higher-than-recommended dose was 
being administered (e.g., Protocol 12-102-12 to explore the effects of NKTR-102 on cardiac 
function) will receive the recommended dose of NKTR-102 of 145 mg/m2 in a q21d schedule in 
this extension study (Protocol 11-PIR-09).   
Subjects who underwent dose reduction of NKTR-102 due to observed toxicity prior to 
participation in the Extension study [Protocol 11-PIR-09] will not be re-escalated to the previous 
dose level upon resolution of the toxicity.   
Dose escalation for NKTR-102 is not permitted.   


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Refer to the Pharmacy Binder for further information.   
6.6 
Duration of Treatment 
The estimated study duration is approximately 5 years.  The duration of treatment in this study is 
estimated to be approximately 2 years.  Subjects may continue to receive repeated cycles of 
study drug treatment until progression of disease, unacceptable toxicity, death, withdrawal by 
subject, Investigator decision, lost to follow-up, or study is terminated by the Sponsor.   
6.7 
Dose Modifications and Delays 
All adverse events (AEs) will be assessed according to the NCI-CTCAE version 4.0.  In the 
event of multiple toxicities, dose delays and modifications should occur in accordance with the 
worst toxicity observed.   
Specific dose modifications for NKTR-102 will be made for diarrhea, dehydration, 
hematological, and other non-hematological toxicities.  Dose delays may be permitted between 
cycles.   
Prior to initiation of subsequent NKTR-102 cycles, subjects must meet requirements with respect 
to hematopoietic function (hemoglobin > 8.0 g/dL or 80 g/L; ANC > 1.5 X 109/L; platelets 
> 75 X 109/L).  Diarrhea must be fully resolved to NCI-CTCAE Grade 0 (a return to normal 
bowel movement habits) for at least 7 days without supportive antidiarrheal measures prior to 
retreatment.  Any treatment-related non-hematologic toxicities must have resolved to baseline or 
Grade 1.   
If the subject fails to meet the criteria for re-treatment, treatment may be delayed, followed by an 
additional evaluation to determine feasibility of retreatment.  Initiation of subsequent doses may 
be delayed for a maximum of 28 days to allow recovery from any toxicity to permit retreatment.  
Subjects whose treatment delays are ≥ 14 days but ≤ 28 days due to a drug-related toxicity must 
initiate their next treatment cycle with a dose reduction.  Subjects who require > 28 days delay 
due to unresolved toxicity must be withdrawn from treatment, unless, in the Investigator’s 
opinion, continuing in the study is of benefit for the subject.  In this case, the continuation of 
treatment must be discussed with the Medical Monitor and the reason for continuation must be 
approved and documented.   
Subjects from Protocol 12-102-13 with impaired liver function who are entering the extension 
study will receive the same dose as that received in the 12-102-13 study.  Investigators may 
choose to reduce the dose of NKTR-102 for either drug-related or non-drug related Grade 3 or 
higher liver dysfunction only after approval from Nektar Medical Monitor.   


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Supportive care may be implemented in order to treat diarrhea, nausea, vomiting, anorexia, 
myelosuppression, and/or other AEs.  Dose delays may be implemented to permit recovery if a 
subject is demonstrating clinical benefit, but with repeated Grade 2 toxicities that would 
otherwise mandate withdrawal.   
Dose reductions may also be implemented for subjects who experience recurrent or specific 
severe toxicities (see Table 4).  NKTR-102 doses for an individual subject may be reduced by 
25 mg/m2 based on conditions listed in Table 4.  Subjects should be discontinued from the study 
treatment if toxicity would indicate more than 2 dose reductions.  Dose re-escalation for 
NKTR-102 is not permitted.   
• For subjects entering this study at a starting dose of 145 mg/m2:  dose reductions to 
120 mg/m2, then to 95 mg/m2 may occur based on conditions listed in Table 4.   
• For subjects (i.e., from Protocol 12-102-13) entering this study at a starting dose of 
120 mg/m2:  dose reductions to 95 mg/m2, then to 70 mg/m2 may occur based on conditions 
listed in Table 4.   
• For subjects (i.e., from Protocol 12-102-13) entering this study at a starting dose of 
95 mg/m2:  dose reduction to 70 mg/m2 may occur based on conditions listed in Table 4.   
• For subjects (i.e., from Protocol 12-102-13) entering this study at a starting dose of 
50 mg/m2:  dose reduction should be approved by Medical Monitor.   
• Table 4 provides instructions regarding dose modification.   
• DURING A CYCLE:  Table 4/Column 2 describes the recommended guidelines for 
management and supportive care during a cycle of therapy.   
• INITIATION OF A SUBSEQUENT CYCLE:  Table 4/Column 3 describes the 
recommended dose modifications for Day 1 in subsequent cycles of therapy.  All dose 
modifications in a new cycle should be based on the worst toxicity observed in the previous 
cycle and the dose reduction will be relative to the Day 1 dose of the previous cycle.   


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Table 4: 
NKTR-102 Dose Modifications 
Toxicity NCI CTCAE Grade 
During a Cycle 
 
Dose Modifications for Day 1 of New 
Cycle 
 
Neutropenia / Febrile Neutropenia 
Grade 1  
(ANC <1500/mm3) 
 
Maintain dose level.  
Grade 2  
(ANC ≥1000/mm3, <1500/mm3) 
Consider growth factor support in 
accordance with local guidelines. 
If present on a treatment day, hold therapy 
until toxicity resolves to ANC≥1500/mm3.  
• ↓ 1 dose level after 1st occurrence 
(provided screening ANC > 2000/mm3); 
do not reduce dose for Grade 2 
neutropenia if screening ANC was ≥ 1500 
and < 2000/mm3. Consider prophylactic 
growth factor therapy. 
• ↓ 1 dose level after 2nd occurrence. 
Consider prophylactic growth factor 
therapy. 
Provided that adequate supportive care has 
been given to the patient, and the investigator 
believes it is in the best interest of the 
patient, retreatment may be attempted for a 
3rd episode of Grade 2 ANC. 
Grade 3 
(ANC ≥500/mm3, <1000/mm3) 
Consider growth factor support in 
accordance with local guidelines. 
If present on a treatment day, hold therapy 
until toxicity resolves to ANC ≥ 1500/mm3.  
• ↓ 1 dose level after 1st occurrence. Use 
prophylactic growth factor therapy. 
• ↓ 1 dose level after 2nd occurrence. Use 
prophylactic growth factor therapy. 
Provided that adequate supportive care has 
been given to the patient, and the investigator 
believes it is in the best interest of the 
patient, retreatment may be attempted for a 
3rd episode of Grade 3 ANC. 
Grade 4 
(ANC <500/mm3) 
Consider growth factor support in 
accordance with local guidelines. 
Consider use of antibiotic (oral 
fluoroquinolones) even in the 
absence of fever or diarrhea. 
If present on a treatment day, hold therapy 
until toxicity resolves to ANC ≥ 1500/mm3.  
• ↓ 1 dose level after 1st occurrence. Use 
prophylactic growth factor therapy. 
• ↓ 1 dose level after 2nd occurrence. Use 
prophylactic growth factor therapy. 
Discontinue NKTR-102 after 3rd occurrence.


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Toxicity NCI CTCAE Grade 
During a Cycle 
 
Dose Modifications for Day 1 of New 
Cycle 
 
Febrile Neutropenia 
Grade 3 or 4 
(ANC <1000/mm3 with a single 
temperature of ≥ 38.3°C (101°F) 
or a sustained temperature of 
≥ 38°C (100.4°F) for more than 
one hour 
Treat as appropriate (eg, growth 
factor support; antibiotics); 
consider hospital admission. 
Patients should be hospitalized for 
IV antibiotic therapy if sepsis is 
suspected. 
Retreatment must be delayed until the 
toxicity is Grade ≤ 1. 
• ↓ 1 dose level after 1st occurrence. Use 
prophylactic growth factor therapy. 
• ↓ 1 dose level after 2nd occurrence. Use 
prophylactic growth factor therapy. 
Discontinue NKTR-102 after 3rd occurrence.
Thrombocytopenia 
Grade 1 or 2 
 
Maintain dose level. 
Grade 3  
(Platelets ≥ 25, <50K) 
Consider platelet transfusion if 
active bleeding.  
Following platelet transfusion, 
retreatment must be delayed for 7 
days and patient must meet 
retreatment criteria prior to 
dosing. 
If present on a treatment day, hold therapy 
until toxicity resolves to platelets ≥ 50K.  
• ↓ 1 dose level after 1st occurrence. 
• ↓ 1 dose level after 2nd occurrence. 
Provided that adequate supportive care has 
been given to the patient, and the investigator 
believes it is in the best interest of the 
patient, retreatment may be attempted for a 
3rd episode of Grade 3 thrombocytopenia. 
Grade 4 
(Platelets < 25K) 
Consider platelet transfusion if 
platelets <10K or with active 
bleeding.   
Following platelet transfusion, 
retreatment must be delayed for 7 
days and patient must meet 
retreatment criteria prior to 
dosing. 
If present on a treatment day, hold therapy 
until toxicity resolves to platelets ≥ 50K.  
• ↓ 1 dose level after 1st occurrence. 
• ↓ 1 dose level after 2nd occurrence. 
Discontinue NKTR-102 after 3rd occurrence.
Anemia 
Grade 1 or 2 
 
Maintain dose level 
Grade 3 
Hgb <8 
Provide erythropoietin-stimulating 
agents or transfusion as 
appropriate. 
 
If present on a treatment day, hold therapy 
until toxicity resolves to Hgb >8 
• ↓ 1 dose level after 1st occurrence. 
• ↓ 1 dose level after 2nd occurrence. 
Provided that adequate supportive care has 
been given to the patient, and the investigator 
believes it is in the best interest of the 
patient, retreatment may be attempted for a 
3rd episode of Grade 3 anemia 


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Toxicity NCI CTCAE Grade 
During a Cycle 
 
Dose Modifications for Day 1 of New 
Cycle 
 
Grade 4 
Hgb<6.5 
Consider erythropoietin-
stimulating agents or transfusion 
as appropriate. 
• If present on a treatment day, hold therapy 
until toxicity resolves to Hgb >8 
• ↓ 1 dose level after 1st occurrence. 
• ↓ 1 dose level after 2nd occurrence. 
Discontinue NKTR-102 after 3rd occurrence 
Diarrhea 
Any Grade 
Institute supportive care upon first 
loose stool. (Unless 
contraindicated, use loperamide). 
Monitor bowel function; if 
diarrhea continues with 1st 
supportive care agent, consider 
switching to a 2nd agent or add a 
2nd agent (unless contraindicated, 
use diphenoxylate/atropine). 
Monitor for dehydration, 
electrolyte abnormalities; correct 
if present. Administer antibiotic 
therapy (oral fluoroquinolones) if 
the patient develops ileus, fevers, 
or Grade 3/4 neutropenia. Patients 
should be hospitalized for IV 
antibiotic therapy if there is 
evidence of colitis or ileus even in 
the absence of neutropenia or 
fever. If diarrhea is worsening, 
octreotide may be attempted.  
Monitor bowel function for 
continued need for supportive 
care. Stop supportive care after the 
patient is 48 hr without diarrhea.  
Confirm with the patient that diarrhea is no 
longer present for > 7 days without having 
received supportive care prior to retreatment. 
Treatment may be delayed up to 28 days; 
after this, contact Medical Monitor.  
 
Grade 1 
 
Maintain dose level; consider prophylactic 
anti-diarrheal supportive care  
Grade 2 
 
• ↓ 1 dose level after 1st occurrence; use 
prophylactic anti-diarrheal supportive care 
• ↓ 1 dose level after > 2nd occurrence; use 
prophylactic anti-diarrheal supportive care 
Provided that adequate supportive care has 
been given to the patient, retreatment may be 
attempted for a 3rd episode of Grade 2 
diarrhea (re-instruct the patient on supportive 
care).  


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Toxicity NCI CTCAE Grade 
During a Cycle 
 
Dose Modifications for Day 1 of New 
Cycle 
 
Grade 3/4 
 
• 
↓ 2 dose levels after 1st occurrence; use 
prophylactic anti-diarrheal supportive 
care  
Provided that adequate supportive care has 
been given to the patient, retreatment may be 
attempted for a 2nd episode of Grade 3 
diarrhea (re-instruct the patient on supportive 
care).  
Dehydration 
Grade 1: Increased oral fluids 
indicated; dry mucous 
membranes; diminished skin 
turgor 
Consider anti-emetic or anti-
diarrheal supportive care 
Maintain dose level; consider prophylactic 
anti-diarrheal or anti-emetic supportive care  
Grade 2: IV fluids indicated <24 
hours 
Use anti-emetic and/or anti-
diarrheal supportive care 
Maintain dose level or ↓ 1 dose level after 1st 
occurrence; use prophylactic anti-emetic or 
anti-diarrheal supportive care. 
• 
↓ 1 dose level after > 2nd occurrence; use 
prophylactic anti-emetic or anti-
diarrheal supportive care. 
Provided that adequate supportive care has 
been given to the patient, retreatment may be 
attempted for a 3rd episode of Grade 2 
dehydration (re-instruct the patient on 
supportive care). 
Grade 3: IV fluids or 
hospitalization 
Indicated;  Grade 4: Life-
threatening 
consequences; urgent 
intervention indicated 
Use anti-emetics, anti-diarrheal 
supportive care, and/or IV fluids 
as appropriate. 
Consider hospital admission. 
Treatment must be delayed until the toxicity 
recovered to baseline or Grade < 1. 
• 
↓ 2 dose levels after 1st occurrence; use 
prophylactic anti-emetic or anti-
diarrheal supportive care. 
Provided that adequate supportive care has 
been given to the patient, retreatment may be 
attempted for a 2nd episode of Grade 3 
dehydration (re-instruct the patient on 
supportive care). 
NKTR-102 must be discontinued for a 2nd 
episode of Grade 4 dehydration. 
Nausea/Vomiting/Abdominal Pain 
Grade 1/2 
Consider anti-emetic supportive 
care. 
Maintain dose level; consider prophylactic 
anti-emetic supportive care. 


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Toxicity NCI CTCAE Grade 
During a Cycle 
 
Dose Modifications for Day 1 of New 
Cycle 
 
Grade 3 
Use anti-emetic supportive care. 
Consider administration of IV 
fluids. 
Treatment must be delayed until the toxicity 
recovered to baseline or Grade < 1 
• ↓ 1 dose level after 1st occurrence; use 
prophylactic anti-emetic supportive care 
• ↓ 1 dose level after 2nd occurrence; use 
prophylactic anti-emetic supportive care. 
Provided that adequate supportive care has 
been given to the patient, retreatment may be 
attempted for a 3rd episode of Grade 3 
nausea/vomiting/abdominal pain  
Grade 4 
Use anti-emetic supportive care 
and IV fluids. 
Treatment must be delayed until the toxicity 
recovered to baseline or Grade < 1 
2 dose levels after 1st occurrence; use 
prophylactic anti-emetic supportive care 
Discontinue NKTR-102 after 2nd occurrence 
Other drug-related non-hematologic toxicities (except fatigue/asthenia and alopecia) 
Grade 1/2 
Consider supportive care as 
appropriate 
Maintain dose level (for Grade 2 toxicity, the 
Investigator may use discretion to ↓ 1 dose 
level after 1st occurrence depending on the 
nature of the toxicity). If recurrent Grade 2 
toxicity Investigator may choose to ↓ 1 dose 
level; continue supportive care. 
Grade 3 
Use supportive care as indicated 
Treatment must be delayed until the toxicity 
has resolved or returned to baseline  
↓ 1 dose level after 1st occurrence; 
supportive care as appropriate  
↓ 1 dose level after 2nd occurrence 
Provided that adequate supportive care has 
been given to the patient, retreatment may be 
attempted for a 3rd episode of Grade 3 other 
drug-related non-hematological toxicities 
(except fatigue, asthenia) 
Grade 4 
Use supportive care as indicated.  
Consider hospital admission. 
Treatment must be delayed until the toxicity 
recovered to baseline or Grade < 1 
↓ 2 dose levels after 1st occurrence. 
Discontinue NKTR-102 after 2nd occurrence 
 


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6.8 
Antidiarrheal Therapy 
Subjects may experience diarrhea following administration of NKTR-102.   
To date, early-onset diarrhea (occurring during or shortly after infusion of study drug) has rarely 
been seen with NKTR-102 administration.  It is usually transient and only infrequently severe.  It 
may be accompanied by symptoms of rhinitis, increased salivation, miosis, lacrimation, 
diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping.  Early 
diarrhea and other cholinergic symptoms may be prevented or ameliorated by administration of 
atropine (0.25 to 1 mg subcutaneous or IV), however, routine prophylactic use of atropine is not 
recommended.   
Late onset diarrhea (occurring more than 24 hours after the infusion) can be life-threatening, 
because it may be prolonged and may lead to dehydration, hypotension, and renal failure. In the 
BEACON study, 9.6% of patients reported Grade 3 diarrhea.  Among those patients, the median 
time to onset of Grade 2 or higher diarrhea was 40 days, and the median onset for Grade 3 
diarrhea was 43 days.  In addition, the median time to resolution of Grade 2 or higher diarrhea 
was 3.5 days and the median time to resolution of Grade 3 diarrhea was 6 days.  There were no 
incidents of Grade 4 diarrhea.   
It should be noted in the patient’s medical record whether the subject is currently receiving anti-
diarrhea supportive care and the date of the last episode of diarrhea/loose stool.   
Diarrhea must be treated promptly with anti-diarrheal therapy; loperamide is recommended.  
Each subject must be instructed to immediately begin taking anti-diarrheal therapy at the very 
first episode of poorly formed or loose stools or the earliest onset of bowel movements that are 
more frequent than normally expected for the subject.  Subjects with diarrhea must be carefully 
monitored, should be given adequate fluid and electrolyte replacement if they become 
dehydrated, and antibiotic support if they develop ileus, fever, or severe neutropenia.   
• Prophylactic antidiarrheal medications must not be used as they can confound the evaluation 
of recovery to Grade 0 (a return to normal bowel movement habits) and monitoring of 
diarrhea AEs in subjects receiving NKTR-102.   
• Each subject will be instructed to start taking anti-diarrheal therapy (i.e., loperamide) for 
diarrhea at the first episode of poorly formed or loose stools or the earliest onset of bowel 
movements more frequent than normally expected for the subject.   


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o One dosage regimen for loperamide used in clinical trials consisted of the following 
(Note: This dosage regimen exceeds the usual dosage recommendations for 
loperamide.):  4 mg at the first onset of diarrhea and then 2 mg every 2 hours until 
the subject is diarrhea-free for at least 12 hours.  Loperamide is not recommended 
to be used for more than 48 consecutive hours at these doses, because of the risk of 
paralytic ileus.  During the night, the subject may take 4 mg of loperamide every 4 
hours.   
• The use of drugs with stimulant laxative properties should be avoided because of the 
potential for exacerbation of diarrhea.   
• Subjects will be instructed to report the following:  diarrhea for the first time during the 
infusion of NKTR-102; black or bloody stools; symptoms of dehydration such as 
lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or 
vomiting; inability to get diarrhea under control within 24 hours; or fever or evidence of 
infection.   
An Institutional Review Board (IRB)-approved subject instruction sheet on the management of 
diarrhea will be provided to all the subjects.   
6.9 
Antiemetic Therapy 
If a subject experiences nausea and/or vomiting, the subject may be given prophylactic 
antiemetics treatment prior to the next dose of NKTR-102.  The subject must be carefully 
monitored throughout the study period, and given adequate fluid and electrolyte replacement to 
prevent dehydration and electrolyte imbalance.   
6.10 
Use of Growth Factor Support and Transfusions 
Upon NKTR-102 administration, subjects may experience neutropenia.  Subjects who do not 
meet retreatment criteria for ANC should return to clinic within 3-7 days for reassessment.  If the 
subject continues not to meet retreatment criteria for ANC, she should return to clinic at weekly 
intervals for reassessment.  Subjects must demonstrate an ANC > 1.5 X 109/L prior to 
retreatment with NKTR-102.   
Prophylactic use of growth factor support is not permitted, however use of growth factor support 
in a setting of neutropenia is permitted.  Use of growth factor support must follow American 
Society Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO) guidelines 
or standard of care at the local institution.  For example, if a subject required growth factor 
support during a previous cycle, a subject may be administered prophylactic growth factor 
support during a subsequent cycle at the investigator’s discretion.   


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Subjects may receive transfusions (platelets or blood products) at the Investigator’s discretion.   
6.11 
Prior and Concomitant Medications 
Throughout the study, Investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care.   
All medications (both prescription and over-the-counter [OTC] medications), vitamin and 
mineral supplements, and/or herbs taken by the subject from Screening through the 
End-of-Treatment visit will be documented on the concomitant medication eCRF.  Throughout 
the study, Investigators may prescribe any concomitant medications or treatments deemed 
necessary to provide adequate supportive care.  All concomitant medications administered to 
study subjects will be recorded in the eCRF.   
6.11.1 
Permitted Treatments 
• Palliative and supportive care for disease-related symptoms.   
• Standard therapies for concurrent medical conditions, including antiemetic prophylaxis (see 
Section 6.9) and early interventional antidiarrheal therapy (see Section 6.8).   
• Diarrhea is an expected toxicity of NKTR-102.  All subjects must receive optimal 
antidiarrheal therapy immediately after the FIRST episode of diarrhea or loose stool 
regardless of severity.   
• Premedication with antihistamine and/or corticosteroid is allowed in subsequent cycles 
following occurrence of a self-limiting allergic/hypersensitivity reaction to a prior infusion of 
NKTR-102.   
6.11.2 
Prohibited Concomitant Medications 
The treatments listed below are prohibited while on study.  For treatments prohibited on study, 
alternative medical intervention should be considered; if a prohibited treatment is required, study 
drug treatment should be discontinued.   
• Any concurrent chemotherapy (other than NKTR-102), radiotherapy (with the exception of 
palliative radiation), biological therapy, hormonal agents used for the treatment of cancer, 
immunotherapy, or other systemic therapy for cancer; megestrol acetate for appetite 
stimulation may be used; 
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• Investigators must monitor subjects for use of potent cytochrome P450 3A4 (CYP3A4) 
inducers or inhibitors, as they may induce or inhibit irinotecan or SN38 metabolism.  Some 
of these agents are OTC medications (e.g., St John’s Wort); subjects must provide a complete 
list of all concomitant medications as part of the screening process.  See Appendix 2 for a 
list of agents known to induce and inhibit CYP3A4.   
6.11.3 
Adequate Forms of Birth Control 
Over the course of the study, women of childbearing potential (WCBP) and men must agree to 
use adequate contraception during study participation (at least two methods of contraception, one 
of which includes a barrier method [male condom] by the male partner or abstinence) or a male 
who has undergone a vasectomy greater than 6 months prior to Cycle 1 Day 1.  Women of 
childbearing potential are women who are not 2 years postmenopausal or are not surgically 
sterile.   
Protections against pregnancy should be continued for at least 8 months after the last dose of 
NKTR-102.   


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7.0 
EVALUATIONS BY VISIT 
A summary of study assessments and procedures are shown in the Schedule of Assessments (
Appendix 1).  Laboratory evaluations prior to treatment in this study will be done at local 
laboratories.  Each laboratory must be certified and must be listed on the Statement of 
Investigator Form FDA 1572.   
7.1 
Screening 
The following procedures will be performed for all potential subjects at a screening visit 
conducted within 28 days prior to Cycle 1 Day 1.  Any procedures, as applicable, that were 
completed as part of the end-of-study visit for the original protocol may be used and do not need 
to be repeated if they were performed within 7 days of Cycle 1 Day 1 of this extension study.  
The maximum delay between treatment with the last dose of NKTR-102 and treatment with 
NKTR-102 in this study is 8 weeks.   
• Informed consent by subject or subject’s legal representative 
• Medication history (including previous chemotherapy, radiation, treatment with biologics, 
OTC drugs, herbs and St. John’s Wort)  
• Demographics including birth date, race/ethnicity, and gender at birth 
• Complete physical examination, including height and body weight and vital signs (pulse, 
temperature, and blood pressure) 
• ECOG performance status 
• Serum pregnancy test (WCBP only) 
• Disease assessment  with computed tomography (CT), magnetic resonance imaging (MRI) 
scanning, or digital photography, unless subject had disease assessment within 8 weeks prior 
to treatment in the Extension study 
• Hematology and serum chemistry:  minimally required are hemoglobin, ANC, platelets, and 
creatinine.  Complete blood count (CBC) and other laboratory tests will be obtained at the 
discretion of the Investigator.   
• Assessment of AEs (see Section 9.2 for details on AE collection from the time of the original 
protocol to the start of the Extension study) 


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7.2 
Treatment Days 
For all cycles, safety assessments are required before each treatment cycle.  All results must be 
available before dosing.  For all cycles, Day 1 assessments may be performed up to 5 days before 
Day 1.  The following procedures will be performed prior to each dose:   
• Symptom-directed physical examination, including body weight 
• ECOG performance status 
• Vital signs (pulse, temperature, blood pressure) 
• Hematology and serum chemistry:  minimally required are hemoglobin, ANC, platelets, and 
creatinine.  Complete blood count and other laboratory tests will be obtained at the discretion 
of the Investigator.   
• Body surface area 
• Urine pregnancy test (only for WCBP) 
• Assessment of concomitant medications 
• Assessment of AEs 
• Diarrhea must be fully resolved to NCI-CTCAE Grade 0 (a return to normal bowel 
movement habits) for at least 7 days without supportive antidiarrheal measures prior to 
treatment.  Any treatment-related non-hematologic toxicities must have resolved to baseline 
or Grade 1 
• NKTR-102 for Injection administration 
NOTE:  Disease assessment (tumor response and progression assessments) should be performed 
as per local standard of care.  Best response and date of progression will be collected in this 
protocol.  Other procedures and evaluations may be performed as clinically indicated and as 
determined by the investigator.   
All safety laboratory evaluations will be performed at a local laboratory.  Each laboratory must 
be certified and must be listed on the Statement of Investigator Form FDA 1572.   
7.3 
End-of-Treatment Visit 
The End-of-Treatment visit is to occur 30 days (± 7 days) after last dose of study drug.   


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The following procedures will be performed for all subjects at the end of the subject’s treatment:  
• Complete physical examination, including body weight 
• ECOG performance status 
• Vital signs (pulse, temperature, blood pressure) 
• Urine pregnancy test (only for WCBP) 
• Assessment of concomitant medications 
• Assessment of AEs 
7.4 
Quarterly Follow-up 
Approximately every 12 weeks (±4 weeks) following the End-of-Treatment visit, subjects will 
have their medical records reviewed and may be contacted to assess disease status, survival 
status, receipt of subsequent anti-cancer therapy, and resolution of all toxicity attributable to 
study drug.  Disease status during follow-up will only be assessed if the subject has not 
demonstrated disease progression since receiving NKTR-102.  Quarterly follow-up will continue 
until death, withdrawal of consent by subject, physician decision, lost to follow-up, or the study 
is terminated by the Sponsor.   


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8.0 
STUDY OR STUDY SITE TERMINATION 
If the Sponsor, Investigator, Medical Monitor, study monitor, or appropriate regulatory officials 
discover conditions arising during the study that indicate that the study should be halted or that 
the study center should be terminated, this action may be taken after appropriate consultation.  
Nektar Therapeutics has the right to terminate this study at any time for any reason.  Conditions 
that may warrant termination of the study include, but are not limited to, the following:   
• The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in the 
study 
• A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the study drug 
A study or study site may also warrant termination under the following conditions: 
• Failure of the Investigator to comply with pertinent regulations of appropriate regulatory 
authorities 
• Recording of inaccurate or incomplete data 
• Submission of knowingly false information from the research facility to the Sponsor, Study 
Monitor, or appropriate Regulatory Authority 
• Insufficient adherence to protocol requirements 
• General Good Clinical Practice (GCP) noncompliance as determined by the Sponsor 
In the event that the clinical development of the investigational product is discontinued, 
Nektar Therapeutics shall immediately inform all study Investigators/institutions and Regulatory 
Authorities.  Study termination and follow up will be performed in compliance with the 
conditions set forth in the ICH sixth efficacy publication (E6) on GCP and local regulatory 
requirements.   


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9.0 
ASSESSMENT OF SAFETY OR ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS 
In this section, the term study drug refers to NKTR-102 for Injection.   
9.1 
Adverse Event Definition and Assessment 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An AE can therefore be any unfavorable and 
unintended sign, symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.  An AE can also arise from any use 
of the drug and from any route of administration, formulation, or dose.  This definition includes 
intercurrent illnesses or injuries, and exacerbation of preexisting conditions as well as events 
attributed to protocol-mandated procedures.  Clinical laboratory abnormalities will only be 
reported as AEs if they are deemed clinically significant by the Investigator and/or are associated 
with signs and symptoms, require treatment, or require follow-up.   
An unexpected AE is one of a type not consistent in nature or severity with information in the 
current IB.   
An AE does not include: 
• A medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, or transfusion); 
an AE is the underlying condition that leads to the procedure 
• Pre-existing diseases or conditions present or detected before start of study drug 
administration and which do not worsen or increase in severity or frequency after the 
administration of study drug 
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery for a condition that has not worsened on study, social and/or convenience 
admissions to grant families a respite in caring for a subject) 
9.2 
Monitoring Adverse Events 
All AEs will be assessed by the Investigator and recorded in the appropriate case report form 
(CRF), including but not limited to, the date of onset and resolution, seriousness, severity, 
relationship to study drug, outcome, and action taken with study drug.  Adverse events will be 
reported starting immediately after the subject or subject’s legal representative has provided 
written informed consent through the End-of-Treatment visit (30 ± 7 days from the last dose of 
study drug in the extension study).   


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After providing informed consent for the extension study, if the subject is continuing in the 
original protocol and therefore will not have received the first dose of study drug in the extension 
study (Protocol 11-PIR-09), any AEs that occur will be collected under the original protocol.  
For subjects who have ended the original protocol and have provided informed consent for the 
extension study (Protocol 11-PIR-09), AEs will be collected under the extension study (Protocol 
11-PIR-09).   
Adverse events that were considered related to study drug in the original protocol and were 
ongoing when the subject ended the original protocol will be captured as a new AE in the 
extension study (Protocol 11-PIR-09) marked as continuing.  Unrelated AEs that were ongoing at 
the end of the original protocol may also be captured as new AEs in the extension study 
(Protocol 11-PIR-09) marked as continuing.   
For each AE, the following data elements will be recorded on the CRFs: 
• Verbatim description of event  
• NCI-CTCAE v. 4.0 grade for AE severity (refer to Section 9.3) 
• Start and stop date of AE 
• Relationship/causality attribution to study drug 
• Whether or not the administration of study drug was reduced, interrupted, delayed, or 
permanently discontinued due to the AE 
• Whether or not the event was considered as an SAE 
• Treatment provided for the AE (pharmacologic or non-pharmacologic) 
• Outcome of the AE 
9.3 
Grading of Adverse Events 
The severity of an event and the seriousness are not to be considered synonymous.  The severity 
is grading the intensity of an event.  The seriousness of event is based on the subject/event 
outcome or action criteria.  All AEs will be assessed for severity using the NCI-CTCAE 
version 4.0.  If a particular AE is not listed in the NCI-CTCAE, the following criteria will be 
used to assess severity by the Investigator:   
o grade 1 = Mild (asymptomatic or mild symptoms or clinical or diagnostic 
observations only, intervention not indicated) 


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o grade 2 = Moderate (minimal, or local or non-invasive intervention indicated or 
limiting age-appropriate instrumental activities of daily living [ADL]) 
o grade 3 = Severe (medically significant but not immediately life-threatening or 
hospitalization or prolongation of hospitalization indicated or disabling, limiting self 
care ADL) 
o grade 4 = Life threatening or disabling (life threatening consequences, urgent 
intervention indicated) 
o grade 5 = Death (related to AE) 
Adverse events will be reported using the maximal severity grade experienced for that 
continuing instance of the AE.  Please refer to the CRF Completion Guidelines for detailed 
reporting instructions.   
9.4 
Causality Relationship of Adverse Events 
The relationship of each AE to the study drug will be evaluated by the Investigator using the 
following definitions:   
• Not related:  The AE is clearly not related to the study drug(s).  The AE can be explained to 
be likely related to other factors such as concomitant medications or the subject’s clinical 
state.   
• Unlikely related:  The AE is doubtfully related to study drug(s).  The current knowledge or 
information about the AE indicates that a relationship to the study drug is unlikely.   
• Possibly related:  The AE may be related to the study drug(s).  A plausible temporal 
sequence exists between the time of administration of the study drug and the development of 
the AE and it follows a known response pattern to the study drug.  The reaction may have 
been produced by the subject’s clinical state or other concomitant therapies or interventions.   
• Definitely related:  The AE is clearly related to the study drug(s).  A plausible temporal 
sequence exists between the time of administration of the study drug and the development of 
the AE and it follows a known response pattern to the study drug.  The AE cannot be 
reasonably explained by the known characteristics of the subject’s clinical state or other 
concomitant therapies or interventions administered to the subject.   
The causality criteria of definitely related and possibly related will be considered related to the 
study drug as applicable for regulatory reporting requirements.   


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9.5 
Adverse Event Reporting and Follow-up 
All AEs will be followed until resolution or until 30 ± 7 days after last dose of study drug 
administration, whichever is earlier, except related AEs which will be followed until they 
stabilize or resolve; until the Investigator assesses the event as chronic or stable; start of new 
cancer therapy; subject lost to follow-up or subject death, whichever is earlier.  If an unrelated 
AE has not completely resolved up to 30 ± 7 days after last dose of study drug, the final outcome 
of these ongoing AEs will be captured as “Not Recovered/Not Resolved” or 
“Recovering/Resolving”, whichever is applicable.   
Any new AEs occurring more than 30 ± 7 days after last dose of study drug will be captured only 
if serious and assessed by the Investigator as related (possibly/definitely related) to study drug 
(i.e. a related SAE).  For specific instructions on identifying and reporting SAEs, see Sections 
9.6 and 9.7 below.   
This study will use the MedDRA for coding all AEs.   
9.6 
Serious Adverse Event Definition 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death 
• Is life threatening, i.e., in the opinion of the investigator, the AE places the subject at 
immediate risk of death from the event as it occurred; it does not include a reaction that, had 
it occurred in a more severe form, might have caused death.   
• Requires inpatient hospitalization or prolongation of an existing hospitalization that occurs 
during the course of a subject’s participation in a clinical study, except for those due to the 
following:   
o A surgery or procedure that was planned before the subject entered the study and 
which is part of the planned study procedure 
o Nonmedical reasons, in the absence of an AE 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 


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• Is an important medical event that, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
other outcomes listed above 
An unexpected SAE is any SAE in which the nature, frequency or severity is not consistent with 
that indicated in the IB.   
Death is an outcome of an AE, and not an AE in itself.  All deaths regardless of causality must be 
reported.  An efficacy failure is not considered an SAE.  “Life-threatening” means that the 
subject was at immediate risk of death from the event as it occurred.  This does not include an 
event that might have led to death, if it had occurred with greater severity.  “Inpatient 
hospitalization” means the subject has been admitted to a hospital for medical reasons for any 
length of time.  The Investigator should attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms.   
9.7 
Serious Adverse Event Reporting 
All SAEs with an onset within 30 days after the subject’s last dose of study drug, whether or not 
considered related to study drug treatment, will be reported to Nektar Therapeutics Drug Safety 
or its designee within 24 hours of when the site becomes aware of the event.  In addition, SAEs 
that are assessed by the Investigator as related to NKTR-102 and occurring > 30 days after last 
dose of study treatment will also be reported to Nektar Therapeutics Drug Safety or its designee 
within 24 hours of when the site becomes aware of the event.   
   
The Investigator must complete the SAE Report Form, assess the causality relationship to the 
study treatment as applicable, and send the completed SAE form by fax to Nektar Therapeutics 
Drug Safety or designee.   
A follow-up report and any additional records (such as hospital records, consultant reports, and 
autopsy findings) will be faxed to Nektar Therapeutics Drug Safety or designee as soon as these 
documents become available or promptly upon request.   
Any medication or other therapeutic measures used to treat the event will be recorded.   
All SAEs will be followed as described in Section 9.8 below.   


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Pregnancy, although reportable, is not considered an AE/SAE unless a male subject’s female 
partner experienced signs or symptoms of pregnancy complications.  Females who become 
pregnant will be followed every trimester until the outcome of the pregnancy is known.  
Pregnancy follow-up should describe the outcome of the pregnancy, including any voluntary or 
spontaneous termination, details of the birth, and the presence or absence of any congenital 
abnormalities or birth defects in the offspring.   
Reporting of SAEs to the IRB/IEC will be done in accordance with the standard operating 
procedures and policies of the IRB/IEC.  Adequate documentation must be provided to Nektar 
Therapeutics, showing that the IRB/IEC was properly notified.  Serious adverse events will be 
reported by Nektar Therapeutics or designee to the regulatory authorities, per local regulations.   
9.8 
Serious Adverse Event Follow-up 
All SAEs will be followed until the end of study or resolution, unless related to study drug and 
continuing or reported after the end of the study, in which the related SAE will be followed until 
any of the following occur (whichever comes first):   
• The event resolves. 
• The event has stabilized. 
• The event returns to baseline, if a baseline value is available. 
• It is unlikely that any additional information can be obtained (e.g., subject or health care 
practitioner refuses to provide additional information; lost to follow-up after demonstration 
of due diligence with follow-up efforts).   
• Further follow-up is not warranted based upon the medical judgment of the investigator.   
• Death 
All ongoing and new SAEs with a start date within 30 days of last dose of study drug and 
assessed as “Unrelated” to study drug will be followed until resolution or until 30 ± 7 days after 
last dose of study drug administration, whichever is earlier.   
9.9 
Expedited Reporting of SAEs 
A SUSAR is a SAE that is considered “unexpected” and assessed as related to the study drug by 
the Investigator or the Sponsor.  All SAEs deemed related to the study drug and not expected 
based on the most current IB are subject to expedited reporting by the Sponsor to the applicable 
Regulatory Authorities.  Therefore, the investigator or study site personnel must report all SAEs 


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to Nektar Therapeutics Drug Safety or its designee within 24 hours of first becoming aware of 
the event.   
Fatal or life-threatening SUSARs will be reported by the Sponsor to the Regulatory Authorities 
as soon as possible, but no later than 7 calendar days after Sponsor or Sponsor’s designee has 
first knowledge of the minimum criteria for expedited reporting.  Non-fatal or non-life-
threatening SUSARs will be reported to the Regulatory Authorities, IRBs/IECs, and 
Investigators as soon as possible, but no later than 15 calendar days after Sponsor or Sponsor’s 
designee has first knowledge of the SUSAR.   
Reporting of SUSARs to all applicable Regulatory Authorities will be done by Nektar 
Therapeutics Drug Safety or designee as per local country and regional regulations.   
Notification of SUSARs to the central IRBs will be done by Nektar Therapeutics Clinical 
Operations or designee in accordance with the SOPs and policies of the IRBs.  Reporting to local 
IRBs will be done by the applicable study site personnel as per their institutional guidelines.  
Adequate documentation must be provided to Nektar Therapeutics Clinical Operations or 
designee, showing that the local IRB was properly notified.   
9.10 
Ongoing Safety Monitoring 
Subject safety will be assessed throughout the study by a Safety Review Committee consisting of 
at minimum the Medical Monitor, Sponsor Clinical Lead and Sponsor Pharmacovigilance Lead 
or designee by review of SAEs.   


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10.0 
EFFICACY EVALUATIONS 
Due to the nature of this study, no specific schedule or type of tumor measurements/assessments 
are dictated within the protocol.  These will be conducted as per the local standard of care until 
disease progression.  Data on best response and disease progression (per physician assessment) 
will be collected according to RECIST criteria version 1.1 (Eisenhauer et. al., 2009).  
Radiographs that document response, stable disease, or progression should be performed 
according to routine patterns of care and (preferably original) copies should be maintained by the 
Investigator for review by the Sponsor, if requested.   
Approximately every 12 weeks (±4 weeks) following the End-of-Treatment visit, subjects will 
have their medical records reviewed and may be contacted to assess disease status, survival 
status, receipt of subsequent anti-cancer therapy, and resolution of all toxicity attributable to 
study drug.  Disease status during follow-up will only be assessed if the subject has not 
demonstrated disease progression since receiving NKTR-102.  Quarterly follow-up will continue 
until death, withdrawal of consent by subject, physician decision, lost to follow-up, or the study 
is terminated by the Sponsor.   


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11.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
Nektar Therapeutics shall implement and maintain quality control and quality assurance 
procedures with written standard operating procedures to ensure that the study is conducted and 
data are generated, documented, and reported in compliance with the protocol, GCP, and 
applicable regulatory requirements.   
All protocol deviations and the reasons for such deviations are to be documented in the source 
documents and reported to Nektar Therapeutics.   
11.1 
Changes to the Protocol 
The Investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IRB/IEC, except when necessary to eliminate 
immediate hazards to the subject.  Any deviation may result in the subject having to be 
withdrawn from the study and rendering that subject non-evaluable.   
11.2 
Monitoring 
In accordance with 21 CFR § 312.56, ICH GCP and local regulations, the clinical monitor will 
periodically inspect all study documents, research facilities, and clinical laboratory facilities 
associated with this study at mutually convenient times during and after completion of the study.  
As required by 21 CFR § 312 Subpart D, ICH GCP and local regulations:  Responsibilities of 
Sponsors and Investigators, the monitoring visits provide the Sponsor with the opportunity to 
evaluate the progress of the study; verify the accuracy and completeness of submitted data; 
ensure that all protocol requirements, applicable FDA, ICH GCP and local regulations, and 
Investigator’s obligations are being fulfilled; and resolve any inconsistencies in the study 
records.  This includes inspection of all documents and records that are required to be maintained 
by the Investigator, including but not limited to medical records (office, clinic, or hospital) for 
the subjects in this trial.  The names and identities of all research subjects will be kept in strict 
confidence and will not appear in the CRFs or other records provided to or retained by the 
Sponsor.  The IND regulations also require the Investigator to allow authorized representatives 
of the FDA and European Union Regulatory Authorities to inspect and make copies of the same 
records.  The names and identities of the subjects need not be divulged to the Sponsor; however, 
the records must nevertheless be inspected.  This can be accomplished by blacking out the 
subject’s name and replacing the name with the subject’s study identification number.  If these 
requirements are in conflict with local regulatory restrictions or institutional requirements, the 
Investigator must inform the Sponsor of these restrictions prior to initiation of the study.   


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12.0 
STATISTICAL CONSIDERATIONS 
12.1 
Analysis Populations 
Safety Population:  The safety population consists of all subjects who receive NKTR-102 for 
Injection.  Unless otherwise stated, all safety analyses will be based on this population.   
12.2 
Endpoints and Planned Analyses 
The primary endpoint of this study is assessment of safety for subjects receiving continued 
NKTR-102 therapy.   
The MedDRA medical dictionary will be used to map the AE/SAE verbatim terms to specific 
system organ classes and preferred terms.  The incidence and duration of AEs will be tabulated 
by MedDRA preferred term, system organ class, severity and relationship to study drug.  The 
maximum intensity and frequency of AEs will be summarized by treatment (dose level).  
By-subject listings will be provided.  No formal statistical testing is planned for AE or other 
safety and tolerability data.   
Tumor response will be summarized by histological tumor type and tabulated using by-subject 
listings based on disease assessments from this protocol.   
Other data will be tabulated using by-subject listings.   


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13.0 
ETHICS 
This study will be conducted according to the provisions of the Declaration of Helsinki 
(October 2008) and in accordance with FDA regulations (21 CFR § 11, 50, 54, 56, and 312), 
with the ICH guidelines on GCP (ICH E6), as well as with any and all applicable federal, state 
and/or local laws and regulations.   
13.1 
IRB/IEC Approval 
Prior to enrollment of subjects into the study, as required by Federal regulations (21 CFR § 56), 
ICH E6 GCP and local regulations, the protocol and informed consent form will be reviewed and 
approved by an appropriate IRB or IEC.  By signing the Statement of Investigator Form FDA 
1572, the Investigator assures that all aspects of the institutional review will be conducted in 
accordance with current federal regulations.  A letter documenting the IRB or IEC approval with 
the names and titles of the IRB or IEC members must be received by the Sponsor prior to the 
initiation of the study.  Amendments to the protocol will be subject to the same requirements as 
the original version of the protocol.   
The Investigator, the Sponsor or designee will submit a progress report at least once yearly to the 
IRB or IEC and Regulatory Authorities.  The frequency of these reports will depend on local 
regulations.  As soon as possible after completion or termination of the study, the Investigator 
will submit a final report to the IRB or IEC and to the Sponsor.  The results should be reported 
per the IRB or IEC’s local requirements.   
The Investigator, the Sponsor or designee is required to notify the IRB or IEC of SAEs, or any 
other information that may affect the safe use of the study drug during the course of the trial, per 
the IRB or IEC’s local requirements.   
13.2 
Written Informed Consent 
Written informed consent must be obtained from each subject or subject’s legal representative 
before entering the study.  Subjects/legal representatives will be informed of the nature of the 
study, and the ICF must be presented to each subject/subject’s legal representative in the 
language in which the subject/subject’s legal representative is fluent.  By signing the Statement 
of Investigator Form FDA 1572, the Investigator ensures that informed consent will be obtained 
from each subject/legal representative prior to any protocol-specific procedures, and that 
informed consent will be obtained and documented in accordance with current state and federal 
regulations.  Signed and dated ICFs will be retained by the Investigator with the study records.  
Each subject/legal representative will be given a copy of the signed and dated consent form.   


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14.0 
DATA HANDLING AND RECORD KEEPING 
14.1 
Case Report Forms and Source Documents 
14.1.1 
Study Records 
During the study, the Investigator will maintain adequate records for the study, including 
medical records, records detailing the progress of the study for each subject, laboratory reports, 
CRFs, signed informed consent forms, drug disposition records, correspondence with the IRB or 
IEC and regulatory agencies AE reports, and information regarding subject discontinuation and 
completion of the study.   
14.1.2 
Case Report Forms 
Case report forms will be used in this study.  These forms are used to transmit the information 
collected in the performance of this study to the Sponsor or Sponsor’s designee and Regulatory 
Authorities.  Case Report Forms must be completed in English.  The Investigator must review 
the CRFs for completeness and accuracy and must approve the appropriate CRF as indicated.  
Furthermore, the Investigator retains full responsibility for the adequacy and accuracy of all data 
entered on the CRFs.   
14.2 
Retention of Essential Documents 
All records and documents pertaining to the study including, but not limited to, those outlined 
above (see Section 14.1.1) will be maintained by the Investigator for a period of at least 2 years 
after FDA/European Medicines Agency (EMEA) approval of the drug or at least 2 years after 
withdrawal of the IND under which this study was conducted, whichever is longer.  In countries 
outside the US, as a minimum, records must be kept for the period of time required by the US 
FDA, and should also comply with the local country regulatory requirements, if longer retention 
times are required than in the US.  In order to avoid any possible errors, the Investigator will 
contact the Sponsor before transferring or destroying any study records.  The Investigator will 
also promptly notify the Sponsor in the event of accidental loss or destruction of any study 
records.   
14.3 
Confidentiality 
Attention is drawn to the regulations promulgated by the ICH E6 GCP guidelines, local 
confidentiality requirements and the FDA under the Freedom of Information Act providing, in 
part, that information furnished to clinical Investigators and IRBs/IECs will be kept confidential 
by the FDA/EMEA and local regulatory agencies only if maintained in confidence by the clinical 
Investigator and IRB/IEC.  The Sponsor will comply with the applicable regulations that ensure 


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the security and privacy of the individually identifiable health information of the study subjects 
is maintained and the rights of the subjects are protected.  By signing this protocol, the 
Investigator affirms to the Sponsor that the Investigator will maintain, in confidence, information 
furnished to him/her by the Sponsor and will divulge such information to the IRB/IEC under an 
appropriate understanding of confidentiality with such board.   


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15.0 
PUBLICATION POLICY 
All data are the property of the Sponsor.  However, it is intended that the results of the study will 
be published and/or presented at scientific meetings.  Any formal presentation or publication of 
data from this trial will be considered as a joint publication by the Investigator(s) and appropriate 
Sponsor personnel.  Authorship will be determined by mutual agreement.   
The Sponsor must receive copies of any intended communication in advance of publication (at 
least 14 days for an abstract or oral presentation and 30 days for a journal submission).  The 
Sponsor will review the communications for accuracy (thus avoiding potential discrepancies 
with submissions to health authorities), verify that confidential information is not being 
inadvertently divulged and provide any relevant supplementary information.   
The Investigator may be required to sign the clinical study report if it is to be used in a 
registration submission to the health authorities of some countries.   


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16.0 
REFERENCES 
1. 
Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in solid 
tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. 
2. 
Garcia AA, Vergote IB, Micha JP et al.  The role of NKTR-102 in women with platinum 
resistant/refractory ovarian cancer and failure on pegylated liposomal doxorubicin (PLD).  
ASCO Annual Meeting Proceedings.  J Clin Oncol.  2011; 29 (suppl; abstr 5047). 
3. 
Kehrer DF, Yamamoto W, Verweij J, de Jonge MJ, de Bruijn P, Sparreboom A. Factors 
involved in prolongation of the terminal disposition phase of SN-38: clinical and 
experimental studies. Clin Cancer Res 2000;6: 3451-3458. 
4. 
Vergote IB, Micha JP, Pippitt, Jr CH, et al.  Phase II study of NKTR-102 in women with 
platinum-resistant/refractory ovarian cancer.  ASCO Annual Meeting Proceedings.  J Clin 
Oncol.  2010; 28 (suppl; abstr 5013). 
5. 
Xie R, Mathijssen RH, Sparreboom A, et al. Clinical pharmacokinetics of irinotecan and 
its metabolites in relation with diarrhea.  Clin Pharmacol Ther. 2002;72(3):265-75. 


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17.0 
APPENDICES 
Appendix 1: Schedule of Assessments 
Appendix 2: Cytochrome 3A4 Inhibitors 
 


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APPENDIX 1: 
SCHEDULE OF ASSESSMENTS 
Study Procedures 
Screening 
 
Days  
-28 to -l 
All 
Cyclesa 
End of 
Treatme
ntc 
Quarterly 
Follow-up
 
Day lb 
Informed Consent 
X 
 
a 
Cycle length is 21 days.   
b 
Any procedures that were completed as part of the end-of-study visit for the original 
protocol that match those procedures required during Screening may be used and do not 
need to be repeated if they were performed within 7 days of Cycle 1 Day 1 of this 
extension study.  For all subsequent cycles, Day 1 assessments may be performed up to 5 
days before Day 1.  For all cycles, safety assessments are required before each treatment 
cycle.  All results must be available before dosing.   
c 
End-of-treatment visit to occur 30 ± 7 days after last dose of NKTR-102.   
d 
There will be a complete physical exam with height and weight during Screening, 
symptom-directed physical exams with weight during treatment, and a complete physical 
exam with weight at the End-of-Treatment.  Vital signs include pulse, temperature, and 
blood pressure.  ECOG performance status will be assessed as part of the physical exam.  
e 
Radiological exams or digital photography required during Screening unless subjects had 
disease assessment within 8 weeks prior to Cycle 1 Day 1 dosing.  Disease assessments 
will occur during the study as per local standard of care (e.g., approximately every 6-12 
weeks).  CT or MRI scanning is acceptable for radiologic exams.   
f 
If Grade 3 or 4 neutropenia is observed, more frequent CBC with differentials are 
recommended until Grade 1 or less.   
g 
Minimally required: hemoglobin, ANC, platelets, and creatinine.  Other tests obtained 
according to the Investigator’s discretion.   
h 
Body surface area (BSA) will be determined before the start of each cycle, based on 
baseline height and most recent weight.  Body surface area may be calculated based on 
institutional guidelines.   
Eligibility Criteria 
X 
 
Physical Examination, 
Vital Signsd 
X 
X 
X 
 
ECOG Performance 
Statusd 
X 
X 
X 
 
Serum Pregnancy Test (for 
WCBP) 
X 
 
 
 
Urine Pregnancy Test (for 
WCBP) 
 
X 
X 
 
Disease Assessment per 
standard of care e 
X 
[X] 
 
 
CBCf, g 
X 
X 
Serum Chemistryg 
X 
X 
Body Surface Area (BSA)h 
 
X 
 
NKTR-102 Infusioni 
 
X 
Concomitant Medicationsj 
X 
X 
X 
Adverse Events 
X 
X 
X 
Survival Follow-upk 
 
 
 
X 


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APPENDIX 1: 
SCHEDULE OF ASSESSMENTS 
Study Procedures 
Screening 
 
Days  
-28 to -l 
All 
Cyclesa 
End of 
Treatme
ntc 
Quarterly 
Follow-up
 
Day lb 
 
 
 
 
 
i 
NKTR-102 dosing administration for Cycle 2+ may occur within ±4 days of the 
scheduled date. 
j 
All concomitant medications, including over-the-counter medications, herbal therapies, 
dietary supplements, and St. John’s Wort.   
k 
Approximately every 12 weeks (±4 weeks) following the End-of-Treatment visit, subjects 
will be contacted or have their medical records reviewed to assess disease status, survival 
status, receipt of subsequent anti-cancer therapy, and resolution of all toxicity attributable 
to study drug.  Disease status during follow-up will only be assessed if the subject has not 
demonstrated disease progression since receiving NKTR-102.  Quarterly follow-up will 
continue until death, withdrawal of consent by subject, physician decision, lost to follow-
up, or the study is terminated by the Sponsor. 
 
 
 
 
 


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APPENDIX 2: 
CYTOCHROME P450 3A INHIBITORS AND INDUCERS 
Strong CYP3A Inhibitors 
 
Boceprevir, clarithromycin, conivaptan, grapefruit juicea, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, mibefradilb, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
voriconazole 
Moderate CYP3A Inhibitors 
Amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir/ritonavir, 
diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juicea, 
imatinib, verapamil 
Weak CYP3A Inhibitors 
 
Alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, 
cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgoc, 
goldensealc, isoniazid, nilotinib, ranitidine, ranolazine, 
tipranavir/ritonavir, zileuton 
Strong CYP3A Inducers 
Avasimibed, carbamazepine, phenytoin, rifampin, St. John’s Worte 
Moderate CYP3A Inducers 
Bosentan, efavirenz, etravirine, modafinil, nafcillin, phenobarbital 
Please note the following:  This is not an exhaustive list and is based on Food and Drug Administration (FDA) 
Guidance for Industry (Draft):  Drug Interaction Studies - Study Design, Data Analysis, Implications for Dosing, 
and Labeling Recommendations, February 2012 (FDA Guidance for Industry, 2012) and Scripture C and Figg W, 
2006.  For the most current information, see the following links: 
http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm08
0499.htm and http://medicine.iupui.edu/clinpharm/ddis/table.aspx. 
a 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent.  Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength).  
b 
Withdrawn from the United States market because of safety reasons. 
c 
Herbal product. 
d 
Not a marketed drug. 
e 
The effect of St. John’s Wort varies widely and is preparation-dependent. 
  

SAP_001.pdf: