Conditions: Stage IV Non-small Cell Lung Cancer (NSCLC) Recurrent Non-small Cell Lung Cancer (NSCLC) Extensive-stage Small Cell Lung Cancer (SCLC) Recurrent Small Cell Lung Cancer (SCLC) Tumors Metastatic to Brain Metastatic Breast Cancer (mBC)
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

Brief summary:
This phase 2 trial evaluates how well pegylated irinotecan (NKTR-102) works in treating patients with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or breast cancer (mBC) that has spread to the brain and does not respond to treatment. Pegylated irinotecan may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
Primary Objective:

For cohort A and Cohort C, to determine the central nervous system (CNS) disease control rate (number of patients with stable disease or partial response or complete response / total number of treated patients) at 12 weeks following treatment with etirinotecan pegol in patients with advanced non-small cell lung cancer (NSCLC) or with metastatic brain cancer (mBC) with refractory brain metastases

Secondary Objectives:

Cohorts A and C:

* To measure the overall disease control rate and response rate for patients receiving study therapy
* To measure the systemic (non-CNS) disease control rate and response rate for patients receiving study therapy
* To observe the progression free survival of the study population
* To observe the overall survival of the study population

Cohort B:

• To observe CNS and systemic disease control in small cell lung cancer (SCLC)

Cohorts A, B and C:

• To determine the safety profile of etirinotecan pegol

Arms:
arm 1: Patients with non-small cell lung carinoma (NSCLC) will receive pegylated irinotecan intravenously (IV) over 90 minutes every 21 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients with small cell lung carinoma (SCLC) will receive pegylated irinotecan intravenously (IV) over 90 minutes every 21 days in the absence of disease progression or unacceptable toxicity. arm 3: Patients with metastatic breast cancer (MBC) to brain will receive pegylated irinotecan intravenously (IV) over 90 minutes every 21 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Pegylated Irinotecan
Intervention descriptions: intervention 1: Administered intravenously (IV) at 145 mg/m² as monotherapy once every 21 days (1 cycle)

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
1 
 
A phase II study of etirinotecan pegol (NKTR-102) in patients with refractory brain 
metastases and advanced lung cancer or metastatic breast cancer (MBC)  
 
 
Version #4.0 / Version Date: February 19, 2016 
NCT02312622 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
 
Protocol Director (Lung Cancer)  
Joel W. Neal, MD, PhD 
Assistant Professor 
Department of Medicine 
Division of Oncology 
875 Blake Wilbur Dr. 
Stanford, CA 94305 
Phone 650-725-3081 
Fax 650-498-5800 
jwneal@stanford.edu 
 
Co-Protocol Director (Breast Cancer) 
Suleiman Massarweh, MD 
Associate Professor,  
Department of Medicine, Division of Oncology 
269 Campus Dr. 
 CCSR 4115 
Stanford, CA 94305 
Phone 650-724-8935 
Fax 4985800 
smass2@stanford.edu 
 
Key Co-Investigators (Additional Co-I’s may be listed on the IRB website) 
Heather Wakelee, MD 
Associate Professor 
Department of Medicine 
Division of Oncology 
875 Blake Wilbur Dr. 
Stanford, CA 94305 
Phone 650-723-9094 
Fax 650-724-3697 
hwakelee@stanford.edu 
 
Seema Nagpal, MD 
Clinical Assistant Professor 


A phase II study of etirinotecan pegol (NKTR-102)  in patients with advanced lung cancer and refractory brain 
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Protocol Version #4.0 
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Department of Neurology 
875 Blake Wilbur Drive CC2221 
Stanford, CA 94305 
Phone 650-725-8630 
Fax 650-498-4686 
snagpal@stanford.edu 
 
 
Lawrence D. Recht, MD 
Professor, Neurology and NeuroSurgery 
Department of Neurology 
875 Blake Wilbur Drive CC2221 
Stanford, CA 94305 
Phone 650-725-8630 
Fax 650-498-4686 
lrecht@stanford.edu 
 
Reena Thomas 
Clinical Assistant Professor 
Department of Neurology 
875 Blake Wilbur Drive CC2221 
Stanford, CA 94305 
Phone 650-725-8630 
Fax 650-498-4686 
reent@stanford.edu  
 
Biostatistician 
Alex McMillan, PhD 
Health Research and Policy 
Redwood Building T106A, 259 Campus Drive 
Stanford, CA 94305 
Phone 650-725-5352 
Fax 650-725-6951 
Alex.McMillan@stanford.edu 
 
Study Coordinators 
Sophie Bertrand 
Tel: 650-723-4467 
Fax: 650-498-4686 
sophieb@stanford.edu 
 
Cathy Recht, RN 
Tel: 650-723-6095 
ckrecht@stanford.edu 
 
Vani Jain 


A phase II study of etirinotecan pegol (NKTR-102)  in patients with advanced lung cancer and refractory brain 
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Tel: 650-723-1005 
vani@stanford.edu  
 
Funding Source / Manufacturer:  Nektar Therapeutics 
IND 76,182 
Manufacturer’s IND number 
IND 123519 
Sponsor-Investigator’s IND number  
IRB-30982 
IRB number 
 


A phase II study of etirinotecan pegol (NKTR-102)  in patients with advanced lung cancer and refractory brain 
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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................. 6 
SCHEMA ....................................................................................................................................... 8 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 9 
1 
OBJECTIVES ..................................................................................................................... 10 
1.1 
PRIMARY OBJECTIVE ..................................................................................................... 10 
1.2 
SECONDARY OBJECTIVES ............................................................................................... 10 
2 
BACKGROUND ................................................................................................................. 10 
2.1 
LUNG AND BREAST CANCERS ......................................................................................... 10 
2.2 
ETIRINOTECAN PEGOL .................................................................................................... 11 
2.3 
RATIONALE .................................................................................................................... 16 
2.4 
STUDY DESIGN .............................................................................................................. 16 
2.5 
CORRELATIVE STUDIES BACKGROUND .......................................................................... 17 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ...................... 18 
3.1 
INCLUSION CRITERIA ..................................................................................................... 19 
3.2 
EXCLUSION CRITERIA .................................................................................................... 20 
3.3 
INFORMED CONSENT PROCESS ....................................................................................... 21 
3.4         RANDOMIZATION PROCEDURES ..................................................................................... 21 
3.5 
STUDY TIMELINE ........................................................................................................... 22 
4. 
TREATMENT PLAN ......................................................................................................... 22 
4.1 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............... 22 
4.2 
CRITERIA FOR REMOVAL FROM STUDY .......................................................................... 23 
4.3 
ALTERNATIVES .............................................................................................................. 24 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ............... 25 
5.1 
 ETIRINOTECAN PEGOL ................................................................................................... 25 
5.2 
AVAILABILITY ............................................................................................................... 25 
5.3 
AGENT ORDERING ......................................................................................................... 26 
5.4 
AGENT ACCOUNTABILITY .............................................................................................. 26 
6. 
DOSE MODIFICATIONS ................................................................................................. 26 
6.1 
RE-TREATMENT CRITERIA ............................................................................................. 26 
6.2 
TREATMENT DELAY DUE TO TOXICITY .......................................................................... 27 
6.3  
DOSE MODIFICATIONS FOR TOXICITY ............................................................................ 27 
6.4  
ANTIDIARRHEAL THERAPY ............................................................................................ 31 
6.5  
ANTIEMETIC THERAPY ................................................................................................... 33 
6.6  
USE OF GROWTH FACTOR SUPPORT AND TRANSFUSIONS .............................................. 33 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES ........................................... 33 
7.1 
POTENTIAL ADVERSE EVENTS ....................................................................................... 33 
7.2 
ADVERSE EVENT REPORTING......................................................................................... 36 
8. 
CORRELATIVE/SPECIAL STUDIES ............................................................................ 37 
9. 
STUDY CALENDAR ......................................................................................................... 38 


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10. MEASUREMENTS ............................................................................................................ 39 
10.1  
PRIMARY AND SECONDARY OUTCOME MEASURES ......................................................... 40 
11. REGULATORY CONSIDERATIONS ............................................................................ 45 
11.1 
INSTITUTIONAL REVIEW OF PROTOCOL .......................................................................... 45 
11.2 
DATA AND SAFETY MONITORING PLAN ......................................................................... 45 
11.3 
DATA MANAGEMENT PLAN ........................................................................................... 45 
12. STATISTICAL CONSIDERATIONS .............................................................................. 46 
12.1 
STATISTICAL DESIGN ..................................................................................................... 46 
12.2 
INTERIM ANALYSES ........................................................................................................ 46 
12.3 
DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS ................................... 46 
12.4 
PRIMARY ANALYSIS ....................................................................................................... 46 
12.5 
SECONDARY ANALYSIS .................................................................................................. 47 
12.6  
SAMPLE SIZE .................................................................................................................. 47 
12.7 
CRITERIA FOR FUTURE STUDIES ..................................................................................... 48 
13. REFERENCES .................................................................................................................... 49 
APPENDICES ............................................................................................................................. 51 
APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST ............................................................. 51 


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PROTOCOL SYNOPSIS 
 
TITLE 
A phase II study of etirinotecan pegol 
(NKTR-102) in patients with advanced 
lung cancer or metastatic breast cancer 
(MBC) and refractory brain metastases 
STUDY PHASE 
II 
INDICATION 
Metastatic non-small cell lung cancer, or 
small cell lung cancer, or breast cancer 
with brain metastases progressing after at 
least one systemic therapy AND one CNS 
treatment OR not eligible for standard CNS 
treatment 
INVESTIGATIONAL PRODUCT OR 
PROCEDURE 
Etirinotecan pegol (NKTR-102) 
PRIMARY OBJECTIVE 
For cohort A, to determine the CNS disease 
control rate (number of patients with stable 
disease or partial response or complete 
response / total number of treated patients) 
at 12 weeks following treatment with 
etirinotecan pegol in patients with 
advanced NSCLC  with refractory brain 
metastases For cohort C, to determine the 
CNS disease control rate (number of 
patients with stable disease or partial 
response or complete response / total 
number of treated patients) at 12 weeks 
following treatment with etirinotecan pegol 
in patients with locally recurrent or MBC 
and refractory brain metastases 
SECONDARY OBJECTIVES 
Cohort A and Cohort C:  
• 
To measure the overall disease control 
rate and response rate for patients receiving 
study therapy 
• 
To measure the systemic (non-CNS) 
disease control rate and response rate for 
patients receiving study therapy 
• 
To observe the progression-free 
survival of the study population 
• 
To observe the overall survival of the 
study population 
 
Cohort B:  
 To observe CNS and systemic disease 
control in SCLC 
 


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Cohorts A ,B and C:  
• 
To determine the safety profile of 
etirinotecan pegol (NKTR-102) 
 
TREATMENT SUMMARY 
All patients will receive etirinotecan pegol 
(NKTR-102) 145 mg/m2 IV as 
monotherapy once every 21-day cycle.  
Response assessment of the CNS and 
systemic disease will be performed by MRI 
and/or CT scan at baseline and every 2 
cycles.  Patients will receive therapy until 
disease progression, unacceptable toxicity, 
withdrawal of consent, or investigator's 
decision. 
SAMPLE SIZE  
Cohort A: 12 NSCLC patients  
Cohort B:  3 SCLC patients 
Cohort C: 12 patients with MBC to the 
brain 
STATISTICAL CONSIDERATIONS 
This is a single-stage phase II design with 
CNS disease control rate at 12 weeks as the 
primary endpoint.  In cohort A, 12 patients 
with NSCLC will be enrolled. In Cohort C 
12 patients with MBC will be enrolled   In 
Cohort A or Cohort C, if 3 or more patients 
have controlled disease in either cohort 
(SD, PR, or CR) in the CNS at 12 weeks, 
we will be able to reject the null hypothesis 
that the disease control rate is not larger 
than 5%, assuming a one-sided significance 
level of 5%.  The sample size and cutoff 
provide 81% power with an effective alpha 
level of 2% (one-sided).  This calculation is 
based on binomial probabilities, assuming 
an alternative of 33% 
The study will also include an exploratory, 
observational group of up to 3 patients with 
SCLC (Cohort B). 


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SCHEMA 
  
 
 
 
 
12 patients with metastatic NSCLC (Cohort A) , 3 
patients with metastatic SCLC (Cohort B) and 12 
MBC (Cohort C) with brain metastases who had 
progressed on at least one line of systemic 
treatment AND (initial CNS treatment OR 
ineligibility for standard CNS treatment).  ECOG 
PS 0-2. 
Register 
Etirinotecan pegol 145 mg/m2 IV every 21-day 
cycle. 
 
Response assessment of the CNS and systemic 
disease will be performed by MRI and/or CT 
scan at baseline and every 2 cycles 
 
Continue until disease progression, 
unacceptable toxicity, withdrawal of consent, or 
investigator's decision 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Include additional abbreviations as needed.  Remove any unnecessary abbreviations. 
 
ADL 
Activities of daily living 
AE 
Adverse event 
BID 
Twice daily 
BSA 
Body surface area 
CBC 
Complete blood count 
CI 
Confidence interval 
CMAX 
Maximum concentration of drug 
CNS 
Central nervous system 
CRF 
Case report/Record form 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High-power field  
HTN 
Hypertensions 
IRB 
Institutional Review Board 
IV 
Intravenous 
LLN 
Lower limit of normal  
NSCLC 
Non-small cell lung cancer 
OS 
Overall survival  
PLT 
Platelet 
PD 
Progressive diseased 
PFS 
Progression free survival  
PR 
Partial response 
QD 
Once daily 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
TKI 
Tyrosine kinase inhibitor 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
WBC 
White blood cell 
WHO 
World Health Organization 
 


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1 
OBJECTIVES 
 
1.1 
Primary Objective  
For cohort A and Cohort C, to determine the CNS disease control rate (number of 
patients with stable disease or partial response or complete response / total number of 
treated patients) at 12 weeks following treatment with etirinotecan pegol in patients with 
advanced NSCLC or with  MBC  with refractory brain metastases 
 
1.2 
Secondary Objectives 
Cohorts A and C:  
• 
To measure the overall disease control rate and response rate for patients receiving study 
therapy 
• 
To measure the systemic (non-CNS) disease control rate and response rate for patients 
receiving study therapy 
• 
To observe the progression-free survival of the study population 
• 
To observe the overall survival of the study population 
 
Cohort B:  
 To observe CNS and systemic disease control in SCLC 
 
Cohorts A, B and C:  
• 
To determine the safety profile of etirinotecan pegol (NKTR-102) 
 
 
 
 
2 
BACKGROUND 
 
2.1 
Lung and breast cancers 
Lung cancer  
Lung cancer is the leading cause of cancer-related deaths in the United States, with estimated 
159,000 deaths in 2013(Siegel, Naishadham et al. 2013), and worldwide, with 1.3 million deaths 
per year.(Jemal, Bray et al. 2011) Lung cancer frequently metastasizes to the brain, resulting in 
an extremely poor prognosis with few effective therapies.(Sorensen, Hansen et al. 1988)   
         
In non-small cell lung cancer, newly diagnosed brain metastases are often treated with radiation 
therapy and/or surgery.  Concurrent chemoradiation for CNS disease is not supported by 
adequate evidence.  There is no standard of care treatment chemotherapy for relapsed or 
progressing CNS disease, though pemetrexed chemotherapy or erlotinib targeted therapy can 
work in selected patient groups for limited periods of time.  In a series of 39 patients with 
NSCLC and brain metastases who received pemetrexed as a second-line or further-line 
treatment, 15 patients (38%) had a partial response in the brain, and 12 patients (31%) had stable 
disease.(Bearz, Garassino et al. 2010) In a phase II study of erlotinib as second-line therapy in 48 
Chinese patients with NSCLC and asymptomatic brain metastases, response (PR or CR) was 
observed in 67% of patients with known EGFR mutations, 33% with wild-type tumors, and 68% 
with unknown EGFR mutation status.(Wu, Zhou et al. 2013) Of note, neither pemetrexed nor 


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erlotinib has been shown to have significant activity in squamous histology, thus further 
necessitating the need for a better agent that is potentially efficacious for brain metastases of all 
NSCLC histologies.  
 
In small cell lung cancer, several studies have suggested that brain metastases are as sensitive to 
chemotherapy, such as cisplatin and etoposide, as extracranial disease at least initially, with 
response rates ranging from 27% to 85% for previously untreated patients(Lee, Murphy et al. 
1989; Twelves, Souhami et al. 1990; Kristjansen, Soelberg Sorensen et al. 1993) and 22% to 
50% for previously treated patients.(Kristensen, Kristjansen et al. 1992; Groen, Smit et al. 1993; 
Postmus, Smit et al. 1995; Kaba, Kyritsis et al. 1997; Grossi, Scolaro et al. 2001; Korfel, Oehm 
et al. 2002) However, there is also evidence that the response rate for brain metastases is 
significant lower than that for systemic disease.(Seute, Leffers et al. 2006) While the addition of 
whole brain radiation can increase the response rate but does not necessarily improve overall 
survival,(Postmus, Haaxma-Reiche et al. 2000) the use of prophylactic cranial irradiation is 
indicated for patients with response to chemotherapy and can improve survival,(Slotman, Faivre-
Finn et al. 2007) suggesting that treatment of brain metastasis is important.  Finally, while 
topotecan is the only FDA approved therapy for the second line treatment of small cell lung 
cancer,(von Pawel, Schiller et al. 1999; von Pawel, Gatzemeier et al. 2001; O'Brien, Ciuleanu et 
al. 2006; Eckardt, von Pawel et al. 2007) many clinicians prefer the use of irinotecan instead 
with its favorable response and toxicity profile.  Therefore, etirinotecan pegol appears ideally 
suited for both the systemic and CNS treatment of SCLC that is resistant or refractory to 
platinum.  
 
 Metastatic breast cancer (MBC)  
 
Despite progressive improvements in disease control rates and improved survival in metastatic 
breast cancer, brain metastasis remains a devastating complication in the natural history of 
advanced disease progression and is invariably associated with worsened survival in advanced 
disease.(Sanna, Franceschelli et al. 2007)  Standard therapy includes surgical resection for oligo 
metastatic disease, whole brain radiation, and stereotactic surgery when feasible. In general, 
systemic chemotherapy has poor CSF penetration and the brain is considered sanctuary for 
metastatic disease.(Freilich, Seidman et al. 1995) With the limited current treatment options, new 
treatment approaches and novel therapeutic agents are needs to enrich our armamentarium in 
treatment of brain metastasis.  
 
While all subtypes of breast cancer can be complicated by the development of brain metastasis, 
triple negative and HER2-positive disease carry the highest risk of CNS involvement.(Sanna, 
Franceschelli et al. 2007) 
  
2.2 
Etirinotecan pegol 
NKTR-102 (etirinotecan pegol) is a polyethylene glycol (PEG) conjugate prodrug of irinotecan 
having topoisomerase I inhibitor antitumor activity.  Irinotecan is a topoisomerase I inhibitor 
approved worldwide for the treatment of colorectal cancer (CRC).  Irinotecan is indicated as a 
component of first-line therapy in combination with 5-fluorouracil (5-FU) and leucovorin for 
patients with metastatic carcinoma of the colon or rectum or as a single agent in patients whose 


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disease has recurred or progressed following initial fluorouracil-based therapy.  Irinotecan has a 
half-life (T½) of approximately 9 hours in humans and upon repeat dosing demonstrates the 
saw-tooth pharmacokinetic (PK) profile that typifies a short T½ for both irinotecan and its major 
active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN38), with a T½ of about 47 hours.  
NKTR-102 was specifically engineered to provide an extended release of irinotecan thereby 
providing a more continuous exposure to the active metabolite SN38.  By reducing peak 
concentration and markedly prolonging the T½ of SN38 to about 50 days, it is possible that 
anti-tumor activity can be enhanced while maintaining a favorable toxicity profile.  In addition, 
the large NKTR-102 molecule does not freely pass out of intact vasculature, which may account 
for relatively higher concentrations of the compound and the active metabolites in tumor tissues 
in in vivo models, where the local vasculature may be relatively more permeable.  
2.2.1  Preclinical data 
NKTR-102 doses are expressed as irinotecan equivalents throughout the entire protocol.  
 
Pharmacokinetic, pharmacologic, and toxicologic characteristics of NKTR-102 have been 
studied in mice, rats, and dogs.  Pharmacokinetic studies in mice, rats, and dogs showed that 
NKTR-102 disposition kinetics are dominated by the polymer moiety.  In all species examined, 
dosing of NKTR-102 resulted in sustained and greater exposure to the active metabolite SN38 
than dosing with irinotecan at equivalent doses and schedules.  Interspecies differences in the 
metabolism of NKTR-102 were observed.  Rodents achieved higher SN38 exposure than dogs, 
presumably because of more rapid and extensive cleavage of irinotecan due to higher level of 
esterases in rodents than in dogs.  
 
The anti-tumor activity of NKTR-102 was evaluated in mouse models of human colorectal 
(HT29), non-small cell lung (NCI H460), breast (MCF-7), ovarian (A2780), and gastric 
(NCI-N87) tumors.  NKTR-102 was active in all models, with dose-related increases in number 
of regressions and tumor growth delay.  Tumor growth delay was frequently the highest possible 
value, with evidence of sustained tumor growth suppression for 2 to 10 weeks after 
administration of the last dose.  In contrast, irinotecan resulted in little to no suppression of 
tumor growth.  In an HT29 colorectal tumor model, NKTR-102 was eliminated very slowly from 
the tumor (T½=17 days) and achieved higher and more sustained tumor exposures to its active 
metabolites compared with irinotecan.  The increased tumor exposure following NKTR-102 
correlated with superior and sustained suppression of tumor growth.  The relative benefit was 
sustained in combination studies comparing anti-tumor activity of NKTR-102 to irinotecan each 
given with other therapy.  These included NKTR-102 given with cetuximab in a mouse model of 
human DLD-1 colorectal tumor, with bevacizumab in a mouse model of human HT29 colorectal 
tumor, with 5-FU in a model of human HT29 colorectal tumor, and with Doxil® in a model of 
human A2780 ovarian tumor.  
 
Brain tumor exposure and anti-tumor activity of NKTR-102 was also evaluated in an 
experimental model of breast cancer brain metastases using brain-seeking MDA-MB-231Br 
breast cancer cells.  Preferential accumulation in brain tumor tissue over plasma was observed 
with NKTR-102, but not with irinotecan.  Vehicle- and irinotecan-treated animals showed a 


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median survival of 21 days, while 50% of NKTR-102-treated animals were still alive 61 days 
after treatment initiation, with a censored median survival of 51 days.  
 
The safety of NKTR-102 was evaluated in both single and repeat-dose toxicity studies in rats and 
dogs.  Toxicity studies included a comparator group of irinotecan-treated animals.  In all studies 
conducted, NKTR-102 was better tolerated than equivalent doses of irinotecan.  The maximum 
tolerated dose (MTD) of NKTR-102 in toxicology studies was 25 to 50% higher for NKTR-102 
than irinotecan based on irinotecan equivalent dosing.  Direct comparison of NKTR-102 with 
irinotecan at the same doses in a 4-weekly dose study in dogs showed substantially lower 
neutropenia and gastrointestinal (GI) effects with NKTR-102.  A 3-month toxicity study in the 
dog has demonstrated that a dose of 30 mg/kg of NKTR-102 (600 mg/m2), every two weeks, 
was tolerated without major overt toxicity; the no observed adverse effect level (NOAEL) was 
determined to be 6 mg/kg of NKTR-102; the MTD was determined to be ≥ 30 mg/kg of 
NKTR-102. 
 
2.2.2 Clinical pharmacokinetics 
The apparent elimination T½ for SN38 after NKTR-102 for Injection administration is 
approximately 50 days versus approximately 2 days after irinotecan dosing.  This greatly 
increased SN38 T½ from NKTR-102 results in plasma SN38 concentrations that are significantly 
more prolonged between doses than are possible with irinotecan.  After an initial dose of 
NKTR-102 at the recommended Phase 2 dose of 145 mg/m2, plasma SN38 AUC is 
approximately the same as with the 350 mg/m2 dose of irinotecan, but maximal concentrations 
are approximately 10-fold less.  Moreover, plasma SN38 concentrations are sustained throughout 
the q21d dosing interval, compared to lack of SN38 exposure for 70% of the q21d dosing 
interval after an irinotecan dose of 145 mg/m2.  Eighty percent of steady-state for SN38 
exposure is typically reached after 4 cycles of therapy on the q21d schedule.  Overall, 
NKTR-102 for Injection administration resulted in prolonged and controlled systemic exposure 
to SN38.  Pharmacokinetics of NKTR-102 and metabolites are predictable and do not require 
complex dosing adjustments. 
2.2.3  Clinical safety 
As of 18 October 2013, safety data from  786 patients across all clinical studies (completed and 
ongoing; single-agent and combination therapy) have been analyzed and included in the 
Investigator’s Brochure, version 10.  
Observations across all studies (including safety data from ongoing studies) have been generally 
consistent with regard to the overall safety profile of etirinotecan pegol.  Gastrointestinal 
toxicity, especially diarrhea, is the most common and clinically significant toxicity occurring 
with the use etirinotecan pegol.  Other frequently observed AEs have been nausea, vomiting, 
fatigue, and dehydration (secondary to diarrhea and/or vomiting).  
Diarrhea and dehydration were also the most common serious adverse events (SAEs) across all 
studies evaluating etirinotecan pegol.  The incidence of grade 3 diarrhea in the phase 2 study in 
patients with MBC at the recommended dose and schedule equaled 23%, with 11% grade 3 


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dehydration and 6% grade 3 vomiting (there was no grade 4 diarrhea, dehydration or vomiting).  
Prolonged severe diarrhea with associated dehydration leading to pre-renal azotemia/kidney 
failure has been fatal in three patients in the ongoing phase 2 studies in metastatic colorectal, 
ovarian, and breast cancers (one each of an ovarian cancer and breast cancer patient on the 
14-day schedule; one CRC patient on the 21-day schedule).  Early cholinergic toxicities 
(including diarrhea), commonly associated with irinotecan, has not been observed with the use of 
etirinotecan pegol in any of the completed or ongoing clinical studies.  Late-onset, severe 
diarrhea can occur: the median time-to-onset of grade 3 diarrhea for etirinotecan pegol for the 
q21d schedule is 93 days (range 8 to 107 days).  Early, proactive and aggressive intervention 
with anti-diarrheal therapy, IV hydration, and maintenance of electrolyte balance was observed 
to have a significant favorable effect on the clinical course of events, as this may prevent volume 
depletion, electrolyte imbalances and the development of kidney failure.  
Myelosuppression, especially neutropenia, can occur in patients receiving etirinotecan pegol; 
however, data from clinical studies evaluating etirinotecan pegol suggest a lower frequency and 
severity of neutropenia than for irinotecan.  Etirinotecan pegol administered at a dose level of 
145 mg/m² in a q21d schedule overall across all ongoing phase 2 studies showed an overall 
incidence of neutropenia of ≤ 20% (all NCI-CTCAE grades) with 11% reported as NCI-CTCAE 
grade 3/4.  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.  
2.2.4 Clinical Efficacy 
A Phase 1 clinical study of single-agent NKTR-102 is completed and was designed to evaluate 
the safety, tolerability, and PK of the different treatment schedules of NKTR-102 in patients with 
refractory solid tumors.  The MTD of NKTR-102 was 115 mg/m2 for the wx3 q4wk treatment 
schedule, and 145 mg/m2 for the q21d and q14d treatment schedules.  
 
Efficacy data observed in this completed Phase 1 study showed that NKTR-102 has an 
encouraging level of anti-tumor activity (11%) in a broad spectrum of tumors: eight confirmed 
PRs in patients with triple-negative breast cancer, non-small cell and small cell lung cancers, 
cervix, colorectal, pancreas, maxillary sinus, and bladder.  
 
A Phase 2a study is also completed and was designed to determine the tolerable dose, safety and 
efficacy of NKTR-102 in combination with cetuximab in patients with refractory solid tumors.  
When NKTR-102 for Injection was administered in combination with cetuximab, 100 mg/m2 at 
q21d was better tolerated than 125 mg/m2 at q21d.  
 
In addition a Phase 2 study of NKTR-102 in patients with MBC evaluating 2 treatment regimens 
(145 mg/m2 q14d and q21d; n = 70 patients; 35 patients per treatment regimen) showed 
significant antitumor activity when efficacy data were presented in The Lancet 
Oncology.(Awada, Garcia et al. 2013) The ORR by RECIST version 1.0 was 28.6% with 2 CRs 
and 18 PRs.  The median PFS was 4.7 months and OS was 10.3 months.  Clinical activity 


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appeared to be numerically superior in the 21d schedule, although the trial was not designed to 
compare the 2 treatment arms.  
 
Two Phase 2 clinical studies are evaluating NKTR-102 in colorectal and ovarian cancers.  The 
Phase 2 study in CRC patients is currently ongoing.  In the Phase 2 study of patients with ovarian 
cancer, efficacy data are presented in the Journal of Clinical Oncology.(Vergote, Garcia et al. 
2013) The ORR was 20% (20% for the once-every-14-day schedule and 19% for the 
once-every-21-day schedule).  Median PFS was 4.1 months for every 14 days and 5.3 months for 
every 21 days.  Median OS was 10.0 months for every 14 days and 11.7 months for every 21 
days.  Efficacy data from this study of patients with ovarian cancer are preliminary, since the 
data evaluation is currently ongoing.  See Section 5.3 of the Investigator's Brochure version 10 
for details on antitumor efficacy from Phase 1 and 2 trials investigating NKTR-102.  
 
The NKTR-102 Phase 3 clinical program (BEACON trial) began enrollment in December 2011 
and closed enrollment in August 2013.  This study compares NKTR-102 for Injection 145 
mg/m2 q21d to TPC in patients with locally recurrent or metastatic breast cancer who were 
previously treated with an anthracycline, a taxane, and capecitabine therapy. On 17 March 2015, 
Nektar Therapeutics announced results of the BEACON study, a trial comparing NKTR-102 to 
Treatment of Physician's Choice ("TPC", any of seven standard of care anticancer drugs) in 
women with advanced breast cancer.  In a topline analysis of 852 patients from the trial, NKTR-
102 provided a 2.1 month improvement in median overall survival (OS) over (12.4 months for 
patients receiving NKTR-102 compared to 10.3 months for patients receiving TPC).  The overall 
comparison of survival did not show a statistically significant result comparing the 
NKTR-102 group to the TPC group.  The incidence of severe toxicities was lower in the NKTR-
102 arm (48%) compared to the TPC arm (63%).  Common severe toxicities observed with 
NKTR-102 were diarrhea (9.6%), low white blood cell counts  (9.4%) which could lead to 
infection, low red blood cell counts (4.7%) which could lead to being tired and fatigue (4.5%). 
Common severe toxicities observed with TPC were low white blood cell counts 
(30.5%) which could lead to infection, low red blood cell counts 
(4.7%) which could lead to being tired, and feeling short of breath (4.4%). 
Severe nerve pain was seen in 3.7% of patients on TPC versus 0.5% of patients in the NKTR-
102 arm.. The full press release can be read on <http://www.nektar.com> www.nektar.com. 
 
This trial was also presented at ASCO 2015 with the abstract verbatim as follows. EP is the first 
long-acting topoisomerase 1 inhibitor providing sustained levels of SN38. In Phase II, EP 
demonstrated a 29% ORR following a median of 2 prior regimens for aBC. BEACON study 
(NCT01492101) randomized (1:1) pts with aBC and progressive disease following A,T and C to 
EP (145 mg/m2q3w over 90 minutes) or TPC (any of 7 cytotoxics). Methods: Eligible pts had 
any ER/HER2 and ECOG 0-1; stable brain metastases were allowed. 852 pts enrolled over 20 
months and reached target for events in Dec2014. The choice of TPC: eribulin 40%, vinorelbine 
23%, gemcitabine 18%, taxane 15%, ixabepilone 4%. Primary efficacy endpoint was overall 
survival (OS) by 2-sided log-rank test stratified by region, prior eribulin and receptor status; the 
study had 90% power to detect a target Hazard Ratio (HR) of 0.77. Circulating tumor cells 
(CTCs) were isolated in ~80% of pts and analyzed for target-specific pharmacodynamic 
biomarkers. This is the first presentation of these data. Results: EP provided a 2.1 month 
improvement in median OS over TPC (12.4 vs 10.3 months; HR 0.87, p = 0.08). In a pre-


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specified subgroup of 67 pts with brain metastases, EP showed an improvement of 5.2 months in 
median OS (10.0 vs 4.8 months; HR 0.51, p < 0.01); the proportion of pts with brain metastases 
alive at 12-mo survival was higher with EP (44.4% vs 19.4%). Similarly, in pts with liver 
metastases (n = 456) median OS improved with EP (10.9 vs 8.3 months; HR 0.73, p = 0.002). 
Grade (G) ≥ 3 AEs were lower with EP (48%) than TPC (63%). Common G ≥ 3 AE with EP: 
diarrhea (9.6%), neutropenia (9.6%), anemia (4.7%) and fatigue (4.5%); TPC: neutropenia 
(30.5%), anemia (4.7%) and dyspnea (4.4%). Severe neuropathy: 3.7% of pts (TPC) vs 0.5% 
(EP). Alopecia was less with EP (10% vs 23%). Data on efficacy in CTC biomarker defined sub-
groups (TOP1, TOP2) will be presented. Conclusions: EP provided a clinically meaningful 
benefit to pts with late-stage aBC, although this did not reach statistical significance. In pts with 
brain metastases, median OS doubled; improved survival was also seen in other pt subsets. 
Toxicity with EP was less than with TPC. Clinical trial information: NCT01492101.(Perez, 
Awada et al. 2015)  
 
For clinicaltrials.gov compliance 
Etirinotecan pegol is not approved by the FDA for this indication.  Stanford will hold the IND 
for use of etirinotecan pegol in advanced lung cancer and metastatic breast cancer patients with 
brain metastases.  
 
2.3 
Rationale 
 
Etirinotecan pegol is a topoisomerase I inhibitor that has demonstrated promising results in 
drug-resistant solid tumors, such as advanced and heavily pre-treated breast and ovarian 
cancers.(Awada, Garcia et al. 2013; Vergote, Garcia et al. 2013) The active metabolite of 
etirinotecan pegol is SN-38, a drug known to have activity in solid tumors.  Irinotecan, which is 
converted to SN-38, can only be given every 1-3 weeks based on its toxicity profile.  In that 
time, however, serum levels of irinotecan drop to undetectable.  The long-acting delivery 
mechanism of etirinotecan pegol, however, provides sustained levels of SN-38 throughout 
treatment cycles with an improved side effects profile. It is also believed that pegylation may 
allow more drug accumulation in tumors, including brain metastases, creating a higher local 
concentration of chemotherapy. This makes etirinotecan pegol an attractive agent for study in 
patients with advanced tumors with brain metastases.  
 
2.4 
Study Design 
The primary purpose of this protocol is to evaluate the efficacy of etirinotecan pegol as a 
treatment for advanced NSCLC and SCLC and locally recurrent or MBCwith brain metastases.  
We will evaluate a single group of 12 patients with NSCLC (Cohort A), 3 patients with SCLC 
(Cohort B) and 12 patients with metastatic breast cancer (Cohort C) in this single-arm, 
non-randomized study.  This trial is open; neither investigators nor patients will be blinded.  It 
will be powered based on an estimated minimal non-treatment disease control rate of 5%, type I 
error of 5%, and power of 81%.  We will consider achieving a 33% disease control rate a 
positive signal.  
 
Primary Endpoint: 


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 For cohort A and C, to determine the CNS disease control rate (number of patients 
with SD+PR+CR/total number of evaluable patients) at 12 weeks  
Secondary Endpoints:  
 
Cohort A and C:  
• 
To measure the overall disease control rate and response rate for patients receiving 
study therapy 
• 
To measure the systemic (non-CNS) disease control rate and response rate for 
patients receiving study therapy 
• 
To observe the progression-free survival of the study population 
• 
To observe the overall survival of the study population 
 
Cohort B:  
 To observe CNS and/or systemic disease control in  SCLC 
 
Cohorts A, B, and C:  
• 
To determine the safety profile of etirinotecan pegol (NKTR-102) 
 
 
We will recruit 12 eligible patients with NSCLC (Cohort A),  3 eligible patients with SCLC 
(Cohort B)  and 12 patients with MBC to the brain (Cohort C) who enroll on study and receive at 
least one dose of study therapy.  All patients will receive etirinotecan pegol on a 21-day dosing 
schedule (cycle).  Patients will not receive other concurrent chemotherapy.  Patients will be 
followed with a clinical exam every cycle and body CT and brain MRI every 2 cycles for the 
first 4 cycles, then consistently through the end of treatment.  Those who have not progressed 
will continue to receive etirinotecan pegol until disease progression, unacceptable toxicity, 
withdrawal of consent, or investigator's decision. 
 
We will monitor for toxicity as defined in the CTCAE version 4.  Adverse reactions attributed to 
etirinotecan pegol will follow dose delay and modifications outlined in section 6.1. 
 
The Stanford Cancer Center data safety monitoring board (DSMB) will be used to review the 
safety of etirinotecan pegol in the study and to assess interim efficacy data. 
 
2.5 
Correlative Studies Background 
 
DNA is continually shed into the circulation by primary or metastatic tumors, and can be 
isolated in the form of cell-free DNA (cfDNA).  Methods to quantitatively identify rare strands 
of DNA have become much more powerful following the development of next-generation 
sequencing (NGS), which uses massively parallel PCR-based methodologies to quantitatively 
measure the prevalence of a population of DNA molecules.  
 
At Stanford, our collaborator Max Diehn has developed a highly sensitive method to sequence 
tumor DNA in the peripheral blood, termed CAPP-Seq (CAncer Personalized Profiling by Deep 
Sequencing).  CAPP-Seq uses targeted hybrid capture to identify genomic “hotspot” alterations 
in a region totaling approximately 125 kB, a relatively small fraction of the entire genome.  


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Designed specifically to identify mutations in non-small cell lung cancer (NSCLC), 
CAPP-Seq can be applied to peripheral blood plasma as well as paraffin-embedded tumor tissue.  
By sequencing a 
limited portion of the 
entire genome at over 
5000-fold depth 
producing relatively 
even coverage of the 
targeted regions, 
CAPP-Seq identifies 
at 
least one mutation in 
>90% of NSCLC 
tumors and detects 
mutant allele 
frequencies down to 
0.025% with a 
negligible technical 
background 
(~0.007%), allowing 
accurate quantitation 
of 
circulating tumor 
DNA in early and 
advanced stage 
tumors.  (Figure 2) In 
contrast, a recently 
published similar 
technique has a allelic detection frequency of 2-5% to detect cancer specific mutations and small 
nucleotide variants (SNVs).(Newman, Bratman et al. 2014) 
 
Here we propose to apply CAPP-Seq to detect tumor signatures longitudinally over time 
in blood specimens from patients undergoing active treatment for NSCLC.  By interrogating 
hundreds of recurrently mutated genomic regions, CAPP-Seq can identify mutations in the vast 
majority of individual NSCLCs and can thus be directly applied to a broad patient population.  
We have deliberately optimized CAPP-Seq for use on plasma samples collected in routinely 
available EDTA-containing tubes, as opposed to more specialized tubes.  Finally, CAPP-Seq is 
economical at less than $300 per assay currently and will be covered by Stanford research funds, 
and per sample costs should drop further as sequencing costs continue to fall.  This will not be 
done for Cohort C 
 
 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
Refer to the Participant Eligibility Checklist in Appendix A.  
 
 
 
 
 
Figure 2: CAPP-Seq in NSCLC, which can identify 1 
individual mutations in most tumors, average peripheral blood 
cfDNA fragment length, and even coverage above 5000-depth 
of sequencing. 


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3.1 
Inclusion Criteria 
3.1.1 Patients must have histologically proven metastatic non-small cell lung cancer (Stage IV 
disease or recurrent metastatic disease, according to the 7th edition of the lung cancer 
TNM classification system) (for cohort A),  
 
-or-  
 
Histologically proven metastatic small cell lung cancer (extensive stage or recurrent 
metastatic disease) for cohort B.  (Patients with tumors having mixed small cell and 
non-small cell elements may be enrolled on cohort B.), 
-or-   
Females with histologically or cytologically confirmed carcinoma of the breast (either the 
primary or metastatic lesions) for whom single-agent cytotoxic chemotherapy is 
indicated.. 
 
3.1.2 Patients must have previously received at least one line of prior systemic chemotherapy 
or targeted treatment for metastatic disease OR have received prior adjuvant systemic 
chemotherapy within prior 6 months.  Patients with MBC must have received at least a taxane 
based regimen. Patients with EGFR and ALK mutations should have failed prior standard 
tyrosine kinase inhibitor (TKI) therapy.  Patients must have completed previous treatment 
(including other investigational therapy) in greater than or equal to the following times prior to 
initiation of study treatment: 
• 
Chemotherapy/targeted therapy administered in a daily or weekly schedule must be 
completed ≥ 2 weeks prior to study treatment;  
• 
Chemotherapy/targeted therapy administered in a 2-weekly schedule must be 
completed ≥ 3 weeks prior to study treatment;  
• 
Chemotherapy/targeted therapy administered in a 3-weekly or greater schedule must 
be completed ≥ 4 weeks prior to study treatment. 
 
3.1.3  Patients must have previously received at least one CNS-directed treatment (such as 
surgery or radiation) OR not be eligible for CNS stereotactic radiosurgery 
 
3.1.4 Patients must have measurable CNS disease, either previously untreated (not counting 
systemic therapy), or progressed following previous radiation treatment. Lesions that have 
progressed after prior radiosurgery should not be selected as measurable disease if they are 
suspected of being radionecrosis. The following measurement criteria are required (not counting 
tumor edema, as visualized by contrast enhanced MRI with slice thickness of 1.5 mm or smaller, 
unless prospective permission is obtained from the PI allowing absence of contrast or thicker 
slices):  
 At least one CNS tumor measuring 10 mm or greater in longest diameter, 
-OR-  
 At least one CNS tumor measuring 5-9 mm in longest diameter, plus one or two 
additional CNS tumors measuring 3 mm or greater in longest diameter, for which the sum 
of the longest diameters of these lesions is equal to or greater than 10 mm. Patient may 
have additional tumors as well. 
 
3.1.5 Patients must be at least 18 years of age. 
 


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3.1.6 Patients must have a life expectancy of 3 months or longer. 
 
3.1.7 Patients must have an ECOG performance status of 0, 1, or 2. 
 
3.1.8 Women of childbearing potential (less than 12 consecutive months since last regular 
menses, or surgically sterile) must have a negative serum β-hCG pregnancy test and must agree 
to use hormonal, IUD, or barrier birth control with spermicide to avoid pregnancy during the 
study.  Agreement to participate in this study via the informed consent will indicate subjects 
commitment to subject avoid pregnancy in self or a partner of childbearing potential for up to 
6 months after the last dose of study therapy.  
 
3.1.9 Adequate organ function as evidenced by: 
 
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without GCSF support within 7 
days 
 
b. Hemoglobin (Hgb) ≥ 9.0 g/dL (90 g/L) without blood transfusion within 7 days 
 
c. Platelet count ≥ 100 x 109/L without platelet transfusion within 7 days 
 
d. Bilirubin ≤ 1.5 x upper limit of normal (ULN), except for patients with 
documented history of Gilbert’s disease who may have direct bilirubin ≤ 1.5 x 
upper limit of normal (ULN)  
 
e. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 2.5 X 
ULN (for patients with liver metastases, ≤ 5 X ULN) 
 
g. Serum creatinine ≤ 1.5 X ULN; or calculated creatinine clearance ≥ 50 mL/min 
(using Cockcroft-Gault formula); or measured creatinine clearance ≥ 50 mL/min. 
 
3.1.10 Patients must be willing and able to comply with the protocol and provide written 
informed consent prior to study-specific screening procedures. 
 
3.2 
Exclusion Criteria 
3.2.1 Previous treatment with a camptothecin derivative (eg,, irinotecan, topotecan, and 
investigational agents including but not limited to exatecan, rubitecan, gimatecan, karenitecan, 
SN38 investigational agents, EZN-2208, SN-2310, and AR-67) is not allowed. 
 
3.2.2 Patients may not have a known history of leptomeningeal disease, as diagnosed by 
positive CSF cytology, unless prospective permission for enrollment is granted from the sponsor 
and the PI.  
 
3.2.3 Patients may not have had major surgery or radiotherapy (therapeutic and/or palliative) 
within 14 days prior to initiation of study treatment, including CNS-directed radiation therapy.  
Minor procedures, such as tumor biopsy, thoracentesis, or intraveneous catheter placement are 
allowed with no waiting period.  


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3.2.4 Patients may not have the following co-morbid disease or concurrent illness: 
 
a. Chronic or acute GI disorders resulting in diarrhea of any severity grade.  Patients may 
not use chronic anti-diarrheal supportive care (more than 3 days/week) to control diarrhea 
in the 28 days prior to first dose of investigational drug (exception: anti-diarrheal 
medications used to control symptoms from a medication that will be discontinued prior 
to study are allowed with a 7 day washout before study therapy, for example loperamide 
for erlotinib-associated diarrhea) 
 
b. Known cirrhosis, defined as Child-Pugh Class A or higher liver disease. 
 
c. Other malignancy undergoing active treatment. 
 
d. Any other severe/uncontrolled inter-current illness or significant co-morbid conditions 
that in the opinion of the investigator would impair study participation or cooperation. 
 
3.2.5 Patients may not have a known allergy or hypersensitivity to any of the components of 
the investigational therapy, including polyethylene glycol (PEG) or topoisomerase inhibitors. 
 
3.2.6 Patients may not be receiving the following medications at the time of first dose of 
investigational drug: 
 
 
 
a. pharmacotherapy for known hepatitis B or C, tuberculosis, or HIV.  
 
b. any of the following enzyme inducing anti-epileptic medications (EIAEDs): phenytoin, 
carbamazepine, oxcarbazepine, phenobarbital. 
 
c. other chemotherapy, hormonal therapy, immunotherapy, other investigational agents, 
or biologic agents for the treatment of cancer except for bisphosphonates or denosumab. 
 
3.2.7 Pregnant or nursing patients will be excluded from the study.  
 
3.2.8 Significant unresolved toxicities from previous anticancer therapy that have not resolved, 
or have not stabilized at a new baseline.   
 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants must 
sign the IRB approved informed consent prior to participation in any study specific procedure.  
The participant must receive a copy of the signed and dated consent document.  The original 
signed copy of the consent document must be retained in the medical record or research file.  
 
3.4       Randomization Procedures 
Patients in this study will not be randomized. 


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3.5 
Study Timeline 
Primary Completion: 
The study will reach primary completion 24 months from the time the study opens to accrual. 
 
Study Completion: 
The study will reach study completion 36 months from the time the study opens to accrual. 
 
4. 
TREATMENT PLAN 
Screening, study visits, and end of treatment visit will be conducted as outlined on the 
Study Calendar (Section 9). 
 
Study drug will be administered every cycle (21 days) using the dose in section 5.1, below.  
 
Post-treatment Follow-Up 
Unless a patient has specifically withdrawn consent to be followed for survival, he or she will be 
contacted by phone or clinic visit approximately every 12 weeks following the End of Treatment 
visit, or as directed by the Sponsor, to collect data regarding survival status.  In addition, unless 
consent was withdrawn for contact during survival follow-up period, patients will be asked about 
subsequent anti-cancer therapy and progression if not determined during study treatment.  
Follow-up will continue until death, withdrawal by patient, lost to follow up, or study 
termination by Sponsor. 
For any toxicity the investigator attributes to study drug, the investigator will assess the patient to 
determine whether the toxicity has resolved or worsened.  Interval of assessment must be based 
on the clinical significance of the toxicity; patients should be more frequently assessed for grade 
3 or higher toxicities.  Information on whether the toxicity has resolved or worsened must be 
entered into the eCRF. 
 
4.1 
General Concomitant Medication and Supportive Care Guidelines 
The treatments listed below are permitted while on study: 
 Bone agents such as bisphosphonates and denosumab for prevention of skeletal related 
events 
 Palliative and supportive care for disease-related symptoms 
 Limited exposure/duration radiation therapy to treat pain is permitted.  Radiation therapy 
use must be recorded in the eCRF. 
 Steroids for edema/symptom management will be considered palliative and supportive 
care and doses will be recorded in the eCRF. 
 Standard therapies for concurrent medical conditions, including antiemetic prophylaxis 
and early interventional antidiarrheal therapy. 
 Premedication with an antihistamine and/or a corticosteroid is allowed in subsequent 
cycles following occurrence of a self-limiting CTCAE v4.0 grade 1-2 
allergic/hypersensitivity reaction to a prior infusion. 


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 Nutritional supplements (including “nutriceuticals”) are permitted as long as the agent is 
not considered “investigational” in the country.  Their use should be recorded in the 
eCRF. 
 Palliative radiotherapy to the CNS or other body sites is permitted with permission from 
the overall study PI. Generally study treatment should not be given within 7 days before 
or after radiotherapy. 
 
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 treatment must be discontinued but the patient should continue to be followed for study 
outcomes. 
 Other investigational agents. 
 Any concurrent chemotherapy, hormonal therapy, immunotherapy, or other systemic 
therapy for cancer. 
 Investigators must monitor patients 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, eg, St John’s Wort.  Patients must provide a 
complete list of all concomitant medications as part of the screening process. 
 
For a list of these agents, see: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm#4 
 
4.2 
Criteria for Removal from Study 
Patients may choose to discontinue the trial at any time, for any reason, and without prejudice to 
further treatment.  A patient who withdraws consent from study participation will be asked to 
state the level of withdrawal: 
 
1. Withdrawal from treatment only; in this case follow up and survival data will continue as 
planned. 
 
2. Withdrawal from contact during the post-treatment period (allowing no collection of off-study 
data, such as subsequent anti-cancer therapy, progression if not determined during study 
treatment, and 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.  The type of consent withdrawal must be noted in 
source documents and eCRF. 
 
Patients will stop study drug therapy for any of the following reasons.  These patients will be 
followed up for efficacy outcomes until the end of the study.  They must be followed for safety 
until resolution or permanent sequelae of all toxicities attributable to the study drug: 
 Any unacceptable toxicity 
 The patient withdraws consent for treatment 


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 Investigator's decision, eg, clinical deterioration or not in the patient’s best interests to 
continue in the study 
 Pregnancy 
 The patient is lost to follow-up 
 Death 
 Consistent and significant non-compliance of the patient with protocol-mandated 
procedures 
 The study is terminated by the investigator or Nektar.  If the study is terminated by 
Nektar, patients who are receiving clinical benefit from their participation in this study 
(defined as SD or an objective response without unacceptable toxicity) will continue to 
receive etirinotecan pegol from Nektar. 
 
Patients may continue on study therapy with permission of the overall study PI in the following 
situations:  
 
 Patients with progression of disease as determined by the investigator should generally 
discontinue study therapy. However, if the patient is having clinical benefit (for example 
response or stable disease in the CNS or systemically, with mild progression in the other 
compartment) patients may be considered to continue on therapy post-progression. The 
patient should have permission from the overall study PI to receive post-progression 
therapy before the second post progression dose is given (i.e. they can receive one post 
progression dose without prospective permission)  
 
 For patients who require > 28 days delay (starting from the time the next dose was 
supposed to be administered), the post-study treatment period would begin, including 
follow-up for survival, unless, in the investigator’s opinion, continuing in the study is of 
benefit for the patient.  In this case, the reason of continuation must be documented and 
they should have permission from the overall study PI before resuming treatment 
 
If a patient withdraws from study treatment, the investigator must promptly notify the Stanford 
Medical Monitor and will make every effort to complete the End-of-Treatment visit.  Every 
effort must be made to ascertain if patients will permit follow-up for survival. 
 
Before a patient is considered “lost to follow-up”, study personnel must contact the patient at 
least twice by phone and once by mail with documented receipt.  Study personnel may use public 
records to check for mortality for any patients considered “lost to follow-up,” if permitted by 
applicable laws or regulations. 
 
4.3 
Alternatives 
Patients may withdraw from the study at any time without prejudice to their further care.  
Patients with progressing advanced lung cancer or MBC and brain metastases may be offered a 
variety of alternate treatment options.  They may also be offered palliative and supportive care 
services. 
 


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5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
5.1 
 Etirinotecan pegol   
The drug substance etirinotecan pegol (topoisomerase I inhibitor polymer conjugate) is a 
conjugate that was engineered by attaching a PEG polymer to irinotecan molecules that are 
released following in vivo cleavage of a biodegradable linker.  Table 5 provides the 
nomenclature information for etirinotecan pegol. 
 
Table 5: Nomenclature 
Compound Number/Name 
NKTR-102/etirinotecan pegol 
Manufacturer  
Nektar Therapeutics 
Chemical classification 
Topoisomerase 1 inhibitor 
 
The investigational drug product (NKTR-102 for Injection) is formulated as a sterile lyophilized 
powder of etirinotecan pegol in lactate buffer at pH 3.5, intended for dilution with commercially 
available 5% Dextrose Injection, USP (w/w%; D5W) or 0.9% Sodium Chloride for Injection, 
USP, before IV infusion.  The pH of the formulation is in the range of 3.2 to 4.2, and etirinotecan 
pegol for injection storage condition is 2°C - 8°C (with a shelf-life of at least 48 months). 
 
Etirinotecan pegol (drug substance) is light-sensitive.  The vial provides sufficient protection for 
the drug product.  The diluted drug product does not require light precautions.  The lyophilized 
drug product (NKTR-102 for Injection) will be supplied in 25 mL type 1 amber colored glass 
vials packaged in cartons.  Each vial contains lyophilized etirinotecan pegol equivalent to 100 
mg of irinotecan.  Each vial and carton will be labeled to comply with local guidelines. 
 
Body surface area (BSA) will be determined before the start of each cycle using the Mosteller 
formula, based on baseline height and most recent weight.   
 
Dose:  
Each patient’s etirinotecan pegol dose will be determined by multiplying most recent BSA 
times the starting dose of 145 mg/m2, with BSA capped at 2.4 m2. 
 
NKTR-102 for Injection will be administered as an IV infusion over 90 minutes (± 15 minutes).  
Pre-medications should not be administered prior to the initial infusion, but if a patient reports 
symptoms (such as nausea and/or vomiting), prophylactic use of anti-emetics may be attempted. 
 
Etirinotecan pegol will be initiated and maintained at a dose of 145 mg/m2 every 21 days unless 
dose delay or modifications are required per guidelines specified in the protocol until progression 
or unacceptable toxicity develops.   
 
5.2 
Availability 
Nektar Therapeutics will provide the study drug. 
 
An initial supply of NKTR-102 for Injection vials will be shipped refrigerated (2 to 8 degrees C) 
to the site pharmacy upon completion of the site activation process.  Re-supply will occur via 
manual shipment request to Nektar Drug Supply & Distribution.  Based on expanded stability 


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data, the temperature monitors used for etirinotecan pegol for Injection shipments have been 
programmed to alarm when the transit temperature falls outside -25°C to 25°C. 
 
5.3 
Agent Ordering 
Drug Supply & Distribution 
Nektar Therapeutics  
455 Mission Bay Blvd South 
San Francisco, CA 94158 
Phone: 415-482-5580 
 
Re-supply will occur via direct contact with the supplier, Nektar Therapeutics.  Upon individual 
patient enrollment, Nektar will supply up to 2 months of drug product for dosing for enrolled 
patients.  
 
5.4 
Agent Accountability 
NKTR-102 for Injection vials 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.  The pharmacist or designee will: 
 Maintain records of product delivery, inventory, destruction, and returns 
 Maintain temperature monitoring 
 Maintain up-to-date accountability of the study drug in the trial accountability log 
 Document the use or disposition of study product by each patient 
 Return or destroy unused study product as per Nektar’s instructions and approval 
 
6. 
DOSE MODIFICATIONS 
6.1 
Re-treatment Criteria  
Prior to initiation of subsequent cycles, patients must meet requirements with respect to 
hematopoietic function: 
 
Hgb ≥ 8.0 g/dL 
ANC ≥ 1.5 x 109/L 
platelets ≥ 75 x 109/L.  
 
Diarrhea must be fully resolved to CTCAE grade 0 for at least 7 days without supportive 
antidiarrheal measures prior to re-treatment.  
 
Any treatment-related non-hematologic toxicities must have resolved to baseline or CTCAE 
grade 1 except for non-clinically significant toxicities, such as electrolyte abnormalities in the 
absence of diarrhea.  
 
Supportive care may be implemented in order to ameliorate diarrhea, nausea, vomiting, anorexia, 
or myelosuppression.  
 


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Dose reductions may also be implemented for patients who experience recurrent or specific 
severe toxicities.  See table 6.1. 
 
6.2 
Treatment Delay due to Drug Related Toxicity 
All AEs will be assessed according to CTCAE version 4.0.  In the event of multiple toxicities, 
dose delays and modifications should occur in accordance with the worst toxicity observed.  If 
the patient fails to meet the criteria for re-treatment (section 6.1 above), treatment may be 
delayed, followed by an additional evaluation to determine feasibility of re-treatment.  Initiation 
of subsequent doses may be delayed for a maximum of 28 days to allow recovery from any 
toxicity to permit re-treatment (with the delay calculated from the scheduled date of the next 
infusion).  Patients whose treatment delays are ≥14 days but ≤28 days due to a drug-related 
toxicity should initiate their next treatment cycle with a dose reduction (see Sections 6.2 + 6.3).  
For example: if a patient receives therapy on March 1, the next cycle should be initiated on 
March 22); the patient would receive a dose reduction if the dose is delayed such that it occurs 
between April 5 - 18.  Patients who require > 28 days delay due to unresolved toxicity must be 
withdrawn from treatment (the post-study treatment period would begin, including follow-up for 
survival), unless, in the investigator’s opinion, continuing in the study is of benefit for the 
patient.  In this case, the reason of continuation must be documented. 
 
 
6.3  
Dose Modifications for Drug Related Toxicity 
Dose escalation for etirinotecan pegol is not permitted.  Patients who undergo dose reduction of 
etirinotecan pegol due to observed toxicity may not be re-escalated to the previous dose level 
upon resolution of the toxicity. 
 
Etirinotecan pegol dose modifications (reductions or delays) must be recorded for each patient in 
the appropriate section of the eCRF. 
 
Dose levels:  
Etirinotecan pegol doses for an individual patient may be reduced to:  
 
Dose level -1:    120 mg/m2 
 
Dose level -2:    95 mg/m2  
 
Only two dose reductions are permitted.  Patients will be off study if toxicity requires a dose 
reduction beyond the 2 dose reduction steps.  Dose reductions and holds should generally follow 
the recommendations below, but dose reduction or dose holds can be for lower grade or other 
toxicities, or dose reductions or holds can be omitted, at investigator discretion if believed to be 
in the best interest of the patient. 
 
 DURING A CYCLE: Table 6.1/Column 2 describes the recommended guidelines for 
management and supportive care during a cycle of therapy. 
 INITIATION OF A SUBSEQUENT CYCLE: Table 6.1/Column 3 describes the 
recommended dose modifications for Day 1 in subsequent cycles of therapy.  All dose 


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modifications in a new cycle should be based on the worst toxicity observed in the 
previous cycle and are relative to the Day 1 dose of the previous cycle. 
 
Table 6.1 
 
Toxicity 
NCI CTCAE 
Grade 
During a Cycle  
 
Dose Modifications for Day 1 of New 
Cycle  
Based on Worst Toxicity in Prior 
Cycle 
Thrombocytopenia / Anemia / Neutropenia / Febrile Neutropenia 
Grade 1 or 2  
 
- 
Maintain dose level 
Grade 3 
 
Platelets: consider platelet 
transfusion if active bleeding.  
ANC: consider growth factor 
support in accordance with local 
guidelines.  Hgb: 
erythropoietin-stimulating agents or 
transfusion as appropriate. 
If present on a treatment day, hold 
therapy for a week or until toxicity 
resolves to grade ≤ 1, with a 
maximum of 3 weeks. 
 1 dose level after 1st  occurrence 
 1 dose level after 2nd occurrence 
Discontinue patient after 3rd occurrence 
Grade  4 
(ANC < 500 x 
106/L or plt < 25 x 
109/L or Hgb < 6.5 
g/dL) 
Platelets: consider platelet 
transfusion if plt < 10 x 109/L or 
with active bleeding.   
ANC: consider growth factor 
support in accordance with local 
guidelines.  Antibiotic, eg, 
fluoroquinalones, should be 
considered even in the absence of 
fever or diarrhea. 
Hgb: consider 
erythropoietin-stimulating agents or 
transfusion as appropriate. 
If present on a treatment day, hold 
therapy for a week or until toxicity 
resolves to grade ≤ 1, with a 
maximum of 3 weeks. 
 1 dose level after 1st occurrence 
 1 dose level after 2nd occurrence 
Discontinue patient after 3rd occurrence 
Febrile neutropenia Patients should be hospitalized 
immediately for IV antibiotic 
therapy if they develop neutropenic 
fever or sepsis. 
 1 dose level after1st  occurrence 
 1 dose level after 2nd occurrence 
Discontinue patient after 3rd 
occurrence 


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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 
fluoroquinalones) if the patient 
develops ileus, fever or grade 3/4 
neutropenia.  Patients should be 
immediately hospitalized for IV 
antibiotics therapy if they have 
evidence of colitis or ileus even in 
the absence of neutropenia or fever.  
If worsening diarrhea, octreotide 
may be attempted.  
Monitor bowel function for 
continued need for supportive care.  
Stop supportive care after the 
patient is 48 hrs without diarrhea.  
Confirm with the patient that diarrhea 
is no longer present for > 7 days 
without having received supportive 
care prior to re-treatment.  
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 2nd occurrence; 
recommend prophylactic anti-diarrheal 
supportive care (see section 6.4) 
After 3rd occurrence; retreatment may 
be attempted provided that adequate 
supportive care has been given to the 
patient (re-instruct patient on the 
supportive care).  (See Section 6.4) 


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Grade 3 
 1 dose level after 1st occurrence; 
recommend prophylactic anti-diarrheal 
supportive care (see Section 6.4 
 1 dose level after 2nd occurrence; 
recommend prophylactic anti-diarrheal 
supportive care (see Section 6.4) 
After 3rd occurrence: retreatment may 
be attempted at 95 mg/m2 provided that 
adequate supportive care has been 
given to the patient (re-instruct patient 
on supportive care). 
Grade 4 
2 dose level after 1st occurrence; 
recommend prophylactic anti-diarrheal 
supportive care (see Section 6.4) 
Retreatment may be attempted after 2nd 
recurrence provided that adequate 
supportive care has been given to the 
patient (instruct the patient on 
supportive care) 
Dehydration 
Grade 1: Increased 
oral fluids 
indicated; dry 
mucous 
membranes; 
diminished skin 
turgor 
Grade 2: IV fluids 
indicated <24 hrs 
Consider anti-emetic or 
anti-diarrheal supportive care 
Maintain dose level; consider 
prophylactic anti-emetic or 
anti-diarrheal supportive care 
Grade 3: IV fluids 
or hospitalization 
Use anti-emetic supportive care 
 1 dose level after 1st occurrence; 
consider prophylactic anti-emetic or 
anti-diarrheal supportive care 
 1 dose level after 2nd occurrence 
Discontinue patient after 3rd occurrence 
Grade 4: 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Use anti-emetic supportive care and 
IV fluids.  Consider hospital 
admission. 
2 dose level after 1st occurrence; use 
prophylactic anti-emetic or 
anti-diarrheal supportive care 
Discontinue patient after 2nd 
occurrence 


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Nausea / Vomiting / Abdominal Pain 
Grade 1 or 2 
Consider anti-emetic supportive 
care. 
Maintain dose level; consider 
prophylactic anti-emetic supportive 
care 
Grade 3 or 4 
Use anti-emetic supportive care. 
Consider administration of IV 
fluids. 
 1 dose levelafter1st occurrence; use 
prophylactic anti-emetic supportive 
care 
 1 dose levelafter2nd occurrence 
Discontinue patient after 3rd occurrence 
Other drug-related non-hematologic toxicities (except fatigue/asthenia, alopecia, and non 
clinically significant electrolyte abnormalities) 
Grade 1 or 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).  
Grade 3 or 4 
Use supportive care as indicated 
 1 dose levelafter1st occurrence; 
supportive care as appropriate.  
 1 dose levelafter2nd occurrence 
Discontinue patient after 3rd occurrence 
 
6.4  
Antidiarrheal Therapy 
Patients receiving to NKTR-102 may experience diarrhea.  Diarrhea must be treated promptly 
with loperamide.  It is recommended that patients have loperamide from Cycle 1 Day 1 and 
throughout the study for their use at home.   
Patients with diarrhea must be carefully monitored, given adequate fluid and electrolyte 
replacement if they become dehydrated, and given antibiotic support if they develop ileus, fever, 
or severe neutropenia.   
Early onset diarrhea (occurring during or shortly after infusion of study drug) has occasionally 
been seen with NKTR-102 as a cholinergic manifestation.  It is usually transient and is only 
infrequently severe.  It may be accompanied by symptoms of blurred vision, blepharospasm, 
miosis, lacrimation, muscle twitching, and/or intestinal hyperperistalsis that can cause abdominal 
cramping.  If necessary, early diarrhea and other cholinergic symptoms may be ameliorated by 
administration of atropine (0.25 to 1 mg subcutaneous or IV).  However, few patients 
required atropine in the BEACON study, and the nature of the cholinergic toxicities usually does 
not warrant the prophylactic use of atropine.   
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 


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time to onset of Grade 2 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 diarrhea was 1.5 days and the 
median time to resolution of Grade 3 diarrhea was 6 days.  There were no incidents of Grade 4 
diarrhea.   
Patients must be assessed prior to dosing to ascertain whether they have had diarrhea since the 
last dose of NKTR-102, whether they are currently receiving anti-diarrheal supportive care, and 
what was the date of the last episode of diarrhea/loose stool.  A patient must be without 
symptoms of diarrhea and without anti-diarrheal supportive care for at least 7 days prior to the 
next dose of NKTR-102.   
Diarrhea Prophylaxis 
In the absence of constipation, the physician may recommend to initiate prophylactic use of 
loperamide starting with Cycle 2 to mitigate the risk for late onset diarrhea.  The recommended 
loperamide dosage regimen is 2 mg every 24 hours (q24h) starting after the Cycle 2 dose and 
continuing for 7 days.  The 7-day prophylactic regimen is repeated with each subsequent cycle 
starting after the dose until Cycle 6.  In the absence of constipation, the recommended 
loperamide regimen is 2 mg every 8 to 12 hours (q8-12h) starting after the Cycle 6 dose and 
continuing for 7 days.  The 7-day prophylactic regimen is repeated after the dose in each 
subsequent cycle.   
Diarrhea Treatment 
Each patient will be instructed to begin loperamide for diarrhea at the first episode of poorly-
formed or loose stool, or at the earliest onset of bowel movements that are more frequent than 
normally expected for the patient.   
The recommended dosage regimen for loperamide is 4 mg at the first onset of late diarrhea and 
then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours.  This dosage 
regimen exceeds the usual dosage recommendations for loperamide; it is not recommended to be 
used at this high dosage for more than 48 consecutive hours, due to the risk of paralytic 
ileus.  During the night, the patient may take 4 mg of loperamide every 4 hours.   
The use of drugs with laxative properties should be avoided due to the potential for exacerbation 
of diarrhea.  Patients should contact their physician to discuss any laxative use.   
Patients must be instructed to contact their physician or nurse if any of the following occur: 
diarrhea at any time during study drug treatment; 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 control diarrhea within 24 hours; fever or evidence of 
infection.   


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Investigators should contact the Medical Monitor to review diarrheal supportive care instructions 
for patients whose diarrhea has been documented to be due to a cause other than NKTR-102 (eg, 
positive stool test for C. difficile).   
 
6.5  
Antiemetic Therapy 
If a patient experiences nausea and/or vomiting, the patient may be given prophylactic antiemetic 
treatment prior to the next dose of etirinotecan pegol.  The patient must be carefully monitored 
throughout the study period and given adequate fluid and electrolyte replacement to prevent 
dehydration and electrolyte imbalance. 
 
6.6  
Use of Growth Factor Support and Transfusions 
Upon etirinotecan pegol administration, patients may experience neutropenia, though its severity 
appears to be less than seen with Camptosar® (irinotecan) administration.  It may be 
accompanied by gastrointestinal toxicities, such as diarrhea, vomiting, nausea, constipation and 
abdominal pain/cramping.  
 
Patients who do not meet retreatment criteria for ANC should return to clinic within 1-7 days for 
reassessment.  If the patient continues not to meet retreatment criteria for ANC, the patient 
should return to clinic at weekly intervals for reassessment.  Patients must demonstrate an ANC 
≥ 1.5 x 109/L prior to re-treatment with etirinotecan pegol. 
 
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), ESMO guidelines, or standard of care at Stanford.  
 
Patients may receive transfusions (platelets or blood products) at the investigator’s discretion.  A 
patient who has a re-treatment value of Hgb < 8.0 g/dL or platelets < 75 x 109/L may receive a 
transfusion; however, patients must meet retreatment criteria prior to retreatment. 
 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
Observations across all studies (including safety data from ongoing studies presented below as of 
18 October 2013, which are preliminary) have been generally consistent with regard to the safety 
profile of NKTR-102.  Gastrointestinal toxicity, especially diarrhea, continues to be the most 
common and clinically significant toxicity occurring with the use of NKTR-102.  Other 
frequently observed AEs include nausea, fatigue, vomiting, abdominal pain, decreased appetite, 
constipation, and dehydration.  Dehydration has usually been secondary to GI toxicities such as 
diarrhea and/or vomiting. 
 
Diarrhea and dehydration (secondary to diarrhea) were also the most common serious adverse 
events (SAEs) reported across all studies evaluating NKTR-102 (occurring at a frequency of 
9.4% and 4.1%, respectively).  Prolonged severe diarrhea with dehydration leading to pre-renal 
azotemia and subsequent acute renal insufficiency has been fatal in three patients in the ongoing 


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Phase 2 studies in metastatic colorectal, ovarian, and breast cancers (one patient in each study).  
Although early onset cholinergic diarrhea is reported with the use of irinotecan and patients can 
receive atropine as a premedication to prevent this, atropine as a premedication is not 
recommended prior to NKTR-102 for Injection administration, as this toxicity has been only 
rarely reported in patients who received NKTR-102. 
 
Severe diarrhea can occur without any evidence of significant GI toxicity observed in preceding 
courses of treatment with NKTR-102.  Exposure to SN38, the active metabolite of NKTR-102, is 
a function of dose, schedule, and each patient’s capacity to metabolize and eliminate NKTR-102 
and SN38.  Given the extended T½ of SN38 derived from NKTR-102 (approximately 50 days), 
late onset diarrhea may occur and can be life-threatening if treatment is delayed.  Early, 
proactive, and aggressive intervention with anti-diarrheal therapy, IV hydration, and 
maintenance of electrolyte balance is essential to prevent volume depletion, electrolyte 
imbalances, and the development of kidney failure. 
 
Myelosuppression, especially neutropenia, can occur in patients receiving NKTR-102.  
Neutropenia in the setting of dehydration and unresolving GI toxicities may lead to the 
development of life-threatening or fatal sepsis.  To date across all clinical studies, three patients 
have died within 30 days from last dose of NKTR-102 due to potentially drug-related 
neutropenic sepsis or complications of neutropenic sepsis, such as septic shock. 
 
Prior to retreatment, patients must meet minimal requirements with respect to hematopoietic 
function especially neutrophil count with an ANC of ≥ 1.5 X 109/L.  Please refer to each specific 
protocol for retreatment requirements for other hematological toxicities. 
 
Except for diarrhea (which must completely resolve prior to retreatment), all Grade 3 or higher 
toxicities must resolve to baseline or Grade 1 severity prior to retreatment.  Supportive care may 
be implemented in order to ameliorate diarrhea, nausea, vomiting, anorexia, or 
myelosuppression.  Dose reductions must also be implemented for patients who experience 
recurrent or specific severe toxicities as defined by the dose modification guidelines included in 
each protocol.  Refer to Section 6.6 for more detailed guidance regarding management of 
NKTR-102 related hematological toxicities especially neutropenia. 
Hypersensitivity or mild allergic reactions characterized by itching, swollen tongue, flushing, 
dizziness, muscle twitching, and/or temporary speech impairment have been observed in some 
patients.  In those patients who experienced muscle twitching, the majority of cases occurred on 
the day of infusion and were self-limited in nature.  In most cases, symptoms were mild in 
severity and management with antihistamines and/or steroids led to successful resolution of these 
events.  In many patients, NKTR-102 rechallenge has been successful in subsequent cycles of 
therapy following premedication with antihistamines and/or corticosteroids.  
 
7.1.1  Adverse Event Definition and Assessment 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, at any dose, not necessarily related to the treatment.  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 


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administration, formulation, or dose.  This definition includes intercurrent illnesses or injuries, 
and exacerbation of preexisting conditions.  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 intervention or treatment, or require follow-up. 
 
For patients receiving NKTR-102 for Injection, an unexpected AE is one of a type not consistent 
in nature or severity with information in the current Investigator’s Brochure for etirinotecan 
pegol. 
 
An AE does not include: 
 A medical or surgical procedure, eg, 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 medication 
administration and which do not worsen or increase in severity or frequency after the 
administration of study medication 
 Situations where an untoward medical occurrence has not occurred, eg, 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 patient 
 Overdose of either study medication or concomitant medication without any signs or 
symptoms unless the patient is hospitalized for observation 
 
7.1.2  Serious Adverse Event Definition 
An adverse event will be classified as an SAE if it meets one of the following criteria: 
Fatal: 
AE resulted in death. 
Life threatening: 
The AE’s placed the patient at immediate risk of death.  This 
classification does not apply to an AE that hypothetically might 
cause death if it were more severe. 
Hospitalization: 
AE that required or prolonged inpatient hospitalization.  
Hospitalizations for elective medical or surgical procedures or 
treatments planned before enrollment in the treatment plan or 
routine check-ups are not SAE's by this criterion.  Admission to a 
palliative unit or hospice care facility is not considered to be a 
hospitalization. 
Disabling/incapacitating 
AE resulted in substantial and permanent disruption of the patient’s 
ability to carry out normal life functions. 
Congenital anomaly or 
birth defect: 
An adverse outcome in a child or fetus of a patient exposed to the 
treatment regimen before conception or during pregnancy. 
Medically significant: 
The AE did not meet any of the above criteria, but could have 
jeopardized the patient and might have required medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
7.1.3  Adverse Event Attribution 


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The investigator will evaluate the relationship of each AE to study treatment using the following 
criteria: 
Fatal: 
AE resulted in death. 
Unrelated: 
Another cause of the AE is more plausible, a temporal sequence 
cannot be established with the onset of the AE and administration 
of the treatment, or a causal relationship is considered biologically 
implausible. 
Possibly Related: 
There is a clinically plausible time sequence between onset of the 
AE and administration of treatment, but the AE could also be 
attributed to concurrent or underlying disease, or the use of other 
drugs or procedures.  Possibly related should be used when 
treatment is one of several biologically plausible AE causes. 
Definitely Related: 
The AE is clearly related to use of the treatment. 
 
7.2 
Adverse Event Reporting 
Adverse events will be graded according to CTCAE v4.0.  Both Serious and Non-Serious 
Adverse Events will be clearly noted in source documentation and listed on study specific Case 
Report Forms (CRFs).  The Protocol Director or designee will assess each Adverse Event (AE) 
to determine whether it is unexpected according to the Investigator’s Brochure, and related to the 
investigation.  All Serious Adverse Events (SAEs) will be tracked until resolution, or until 30 
days after the last dose of the study treatment.  
 
SAEs CTCAE grade 3 and above, and all subsequent follow-up reports, will be reported to the 
Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study 
specific CRF regardless of the event’s relatedness to the investigation.  Following review by the 
DSMC, events meeting the IRB definition of "unanticipated problem" will be reported to the 
IRB using eProtocol within 10 working days of DSMC review, or within 5 working days for 
deaths or life-threatening experiences. 
 
It is the investigator's responsibility to report adverse events to the FDA promptly under the 
terms of the Protocol and in compliance with applicable law.  To insure that Nektar is aware of 
relevant safety data, reports of all “life-threatening adverse events and life-threatening suspected 
adverse reactions,” "serious adverse events and serious suspected adverse reactions” and 
“unexpected adverse events and unexpected suspected adverse reactions” (as such terms are 
defined in 21 CFR 312.32) (whether initial or follow-up) shall be faxed, within twenty-four (24) 
hours of first knowledge of the investigator, to the following (or to such other fax number of 
which Nektar shall notify Stanford and the investigator in writing), with a confirmation copy sent 
by overnight courier (such as Federal Express) to the address provided below (or to such other 
address of which Nektar shall notify Stanford and the investigator in writing):  
 
Nektar Global Medical Safety Surveillance  
Primary Fax: 855-482-7233 
Secondary Fax: 415-482-5410 
Email: pharmacovigilance@nektar.com 


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with a copy by express courier addressed to:  
 
Nektar Drug Safety  
Nektar Therapeutics  
455 Mission Bay Boulevard South  
San Francisco, California 94158  
Phone: 415-482-5718 
 
8. 
CORRELATIVE/SPECIAL STUDIES  
We will collect samples for correlative analysis of circulating free tumor DNA on individual 
patients in all cohorts as outlined above in the correlative studies background.  Up to three 
10-mL tubes containing sodium-EDTA will be drawn periodically as indicated in the study 
calendar, below.  
 
Within 2 hours of draw, they should be taken to the laboratory of Max Diehn by the study 
coordinator, or delegate, for centrifugation to separate blood cells from plasma, and freezing into 
aliquots at -80 degrees C 
 
They will be processed at the end of the study and the total amount of tumor-related circulating 
tumor DNA will be assessed as a potential surrogate for response to treatment.  
 
 


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9. 
STUDY CALENDAR 
 
Study procedures 
Screen-
ing a 
Cycl
e 1 a 
Mid- 
cycle 
for all 
cycles   
Cycle 
2 a 
Cycle 
3+ a 
Treatmen
t Discont-
inuation 
Visit a 
Every 3 
months 
until 
Patient 
Expires 
Day -21 
to -1 
Day 
1 
Day 
2-21 
Day 
22 
(week 
3) 
Day 43 
(week 
6) 
 
(+/- 14 
days) 
Administration of 
etirinotecan pegol 
(90-minute infusion) 
 
X 
 
X 
X 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Verify Eligibility 
Criteria 
X 
 
 
 
 
 
 
Medical History 
X 
X 
 
X 
X 
X 
 
Physical Exam 
X 
X 
 
X 
X 
X 
 
Weight/Height/BSA f 
X 
X 
 
X 
X 
X 
 
Vital Signs 
X 
X 
 
X 
X 
X 
 
Labs (CBC with 
differential and CMP) 
b 
X 
X 
 
X 
X 
X 
 
Serum Pregnancy 
Test c 
X 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
Coagulation Tests 
(PT, INR, PTT) 
X 
 
 
 
 
 
 
ECOG Performance 
Score 
X 
X 
 
X 
X 
X 
 
Brain MRI Scand 
X 
 
 
 
X 
 
 
Body CT Scand 
X 
 
 
 
 
X 
 
 
Assessment of AEs 
(contact by phone, 
secure device, or in 
person) 
 
 
X 
 
 
X 
 
Concomitant 
Medications 
X 
X 
 
X 
X 
X 
 
Correlative bloode   
 
X 
 
X 
X 
X 
 
Assessment of 
Survival 
 
 
 
 
 
 
X 


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a  Screening assessments must be within 21 days of registration, and study therapy should start 
within 3 days of patient registration.  On treatment visit window is -3/ +7 days.  Clinic visit and/or 
laboratory assessments may be done up to 72 hours before infusion treatment.  Off treatment visit 
should be approximately 30 days after final drug infusion (+/- 14 days), but may be conducted by 
telephone if infeasible for patient to come to clinic. If patient remains in active screening, informed 
consent does not need to be repeated if more than 21 days from day 1.  
b  Comprehensive metabolic panel (CMP): Albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT[AST], 
SGPT[ALT], sodium) 
c  Serum pregnancy test for women of childbearing potential. 
d  Brain MRI and body CT should be performed within 8 days prior to visit on week 6 and week 12 
on study, even if cycle therapy is delayed for toxicity.  Thereafter imaging ideally should be done 
every 6 weeks (2 cycles) prior to treatment visits, but interval of scans may be increased to every 
9- 12 weeks (3-4 cycles) at investigator discretion.  Brain MRI should include contrast (unless 
contraindicated) and slice thickness should be 1.5 mm or thinner (unless permission is given from 
PI).  Body CT should include a CT thorax with IV contrast (unless contraindicated) plus any other 
areas of known disease that are being measured.  CT thorax window is 28 days from day 1 but 
MRI is 21 days.  
e  Cohorts A and B only: Up to Three 10-mL purple top sodium-EDTA tubes pre-treatment (cycle 
1), cycle 2, cycle 3, cycle 5, then at imaging visits until disease progression. 
f  Height is only required at baseline 
 
10. 
MEASUREMENTS 
Primary Outcome Measure 
The primary outcome measure is CNS disease control rate at 12 weeks for cohort A 
 Title: CNS disease control rate (number of patients with SD+PR+CR/total number of 
evaluable patients) at 12 weeks assessed by modified response criteria (Section 10.1)  
 Time Frame: At 12 weeks 
 Safety Issue: No, this is not a safety endpoint 
 
Secondary Outcome Measures 
 
For cohort A and C: 
 Title: Overall disease control rate and  response rate for patients receiving study 
therapy 
 Time Frame: At 12 weeks 
 Safety Issue: No, this is not a safety endpoint 
 
 Title: Systemic (non-CNS) disease control rate and  response rate for patients 
receiving study therapy 
 Time Frame: At 12 weeks 
 Safety Issue: No, this is not a safety endpoint 
 
 Title: Progression-free survival of the study population 


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 Time Frame: From date of first dose of etirinotecan pegol to date of disease 
progression 
 Safety Issue: No, this is not a safety endpoint 
 
 Title: Overall survival of the study population  
 Time Frame: From date of pathologic diagnosis to date of death 
 Safety Issue: No, this is not a safety endpoint 
 
 
For cohort B: 
 Title: Observation of CNS and/or systemic disease control in SCLC 
 Time Frame: At 12 weeks 
 Safety Issue: No, this is not a safety endpoint. 
 
 
For cohorts A, B and C: 
 Title: Safety profile of etirinotecan pegol (NKTR-102) in patients with advanced lung 
cancer with refractory brain metastases 
 Time Frame: From date of first dose of etirinotecan pegol to date of death 
 Safety Issue: Yes, observational endpoint.  Drug has been tested in other cancer 
populations. 
 
 
10.1  Primary and Secondary Outcome measures 
10.1.1 Relevant Subset 
 
Cohorts A , B and C will be analyzed separately. 
  
10.1.2 Tumor Measurements and Response Criteria 
 
Anti-Tumor Effect 
 
Imaging will be obtained at baseline throughout treatment for both systemic disease and CNS 
disease.  
 
10.1.2.1 Measurement of Systemic Disease:  
 
Systemic tumor responses will be assessed by Response Evaluation Criteria in Solid Tumors 
Guideline (RECIST v1.1)(Eisenhauer, Therasse et al. 2009) For convenience, these criteria are 
outlined below.  
 
Measurable: 
 Tumor lesions: Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
o Body organ lesions: 10 mm by CT, MRI or PET scan (slice thickness no 
greater than 5 mm)  
o 10 mm caliper measurement by clinical exam (lesions which cannot be 


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accurately measured with calipers should be recorded as non-measurable) 
o 20 mm by chest X-ray 
 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT, 
MRI or PET scan (slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed.  
 
Non-measurable: 
 All other lesions, including small lesions (longest diameter < 10mm--except for 
pathological lymph nodes with ≥ 10 to < 15mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging 
 
Measurement of lesions:  
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start  
 
Method of assessment: 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  Imaging-based 
evaluation should always be done rather than clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam. 
 Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial and ≥ 10mm diameter as assessed using calipers (eg, skin nodules).  
For the case of skin lesions, documentation by color photography including a 
ruler to estimate the size of the lesion is suggested.  As noted above, when lesions 
can be evaluated by both clinical exam and imaging, imaging evaluation should 
be undertaken since it is more objective and may also be reviewed at the end of 
the study. 
 Chest X-ray: Chest CT is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, 
particularly in identifying new lesions.  However, lesions on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated lung.  
 CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment.  This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5mm or less.  
 Ultrasound: Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. 
 Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  
 Tumor markers: Tumor markers alone cannot be used to assess objective tumor 


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response.  If markers are initially above the upper normal limit, however, they 
must normalize for a patient to be considered in complete response.  
 Cytology, histology: These techniques can be used to differentiate between PR 
and CR in rare cases if required by protocol. 
 
Tumor Response Evaluation 
 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
 When more than one measurable lesion is present at baseline all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions and will be 
recorded and measured at baseline. 
 Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  
 A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters.  If 
lymph nodes are to be included in the sum, then as noted above, only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the 
disease. 
 
Systemic Response Criteria 
 
Complete Response (CR) requires ALL of the following:  
 Disappearance of all target and non-target lesions 
 All pathological lymph nodes, whether target or non-target, must have reduction in short 
axis to < 10 mm.  
 No new lesion 
 
Partial Response (PR) requires ALL of the following: 
 At least 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum of diameters. 
 No unequivocal progression of existing non-target lesions 
 No new lesion 
 
Progression of Disease (PD) requires ANY of the following: 
 At least 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. 
 Unequivocal progression of existing non-target lesions 
 Appearance of one or more new lesions 
 
Stable Disease (SD) requires ALL of the following: 
 Not CR 


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 Not PR 
 Not PD 
 
 
10.1.2.2 Measurement of CNS Disease:  
 
CNS tumor responses will be assessed by the specific criteria outlined below. 
 
 
Must be measured by MRI with contrast (unless contrast is contraindicated and lesions 
are clearly delineated) with a slice thickness of 1.5 mm or thinner (unless permission is given 
from the PI for another slice thickness to be acceptable – in general the size of the measurable 
lesion should be at least two times the slice thickness with 0 mm skip). 
 
 
 
Measurable disease will be defined as:  
 At least one CNS tumor measuring 10 mm or greater in longest diameter, 
-OR-  
 At least one CNS tumor measuring 5-9 mm in longest diameter, plus one or two 
additional CNS tumors measuring 3 mm or greater in longest diameter, for which 
the sum of the longest diameters of all lesions is equal to or greater than 10 mm.  
 
These lesions should be previously untreated (not counting systemic therapy), or progressed 
following previous radiation treatment.  Lesions that have progressed after prior radiation or 
radiosurgery should not be selected if they are suspected of being radionecrosis. 
 
 
Non-measurable disease will be defined as:  
 Brain lesions smaller than those above.  
 Edema, midline shift, or other secondary process 
 In general, tumor around a cyst or surgical cavity should be considered non-
measurable unless there is a nodular component at least 5 mm in longest diameter.  
 Lesions that cannot be reproducibly measured 
 Bony skull metastases 
 Dural metastases (these may be measurable as systemic disease) 
 Cystic-only lesions 
 Leptomeningeal disease 
 
Baseline documentation of Target and Non-Target Lesions in the CNS: 
 
For CNS target lesions, each lesion should be measured in mm. Lesions should be classified as 
measurable or non-measurable (as above) and up to 5 most reproducibly measurable lesions 
selected as target lesions. If lesions not previously treated with local therapies are present, these 
are preferred for selection as target lesions. A sum of the diameters for all target lesions will be 
calculated and reported as the baseline sum of longest diameters (sum LD). All other CNS 
lesions should be identified as non-target lesions and should also be recorded at baseline. They 
may be recorded as a group. Measurements are not required and these lesions should be followed 
as ‘present’, ‘absent’, or ‘unequivocal progression’. Documentation of how each lesion or group 
of lesions was previously treated is recommended (stereotactic radiosurgery (SRS), whole brain 


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radiotherapy (WBRT), surgical resection, etc) 
 
CNS Response Criteria: 
 
Evaluation of Target Lesions:  
Complete Response (CR) requires ALL of the following:  
 Disappearance of all CNS target lesions, sustained for at least 4 weeks 
 No new lesion 
 Patient must be off corticosteroids or on physiologic replacement doses only 
 Stable or improved clinically.  
 
Partial Response (PR) requires ALL of the following:  
 At least 30% decrease, compared with baseline, in the sum LD of CNStarget enhancing 
lesions, sustained for at least 4 weeks. Note that any lesion <10 mm in LD should be 
regarded as unchanged from baseline unless there is at least a 3 mm change in the 
measured LD. 
 No new lesion 
 Stable to decreased corticosteroid dose 
 Stable or improved clinically 
 
Progression of Disease (PD) requires ANY of the following: 
 At least 20% increase in the sum of the longest diameters of all target enhancing lesions 
(compared with baseline if no decrease) on stable or increasing doses of corticosteroids. 
Note that any lesion <10 mm in LD should be regarded as unchanged from baseline 
unless there is at least a 3 mm change in the measured LD. 
 A significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of 
corticosteroids compared with baseline scan or best response after initiation of therapy, 
not due to comorbid events 
 Appearance of one or more new lesions 
 Unequivocal progression of nonmeasurable/nontarget lesions 
 Definite clinical deterioration not attributable to other causes apart from the tumor, or to 
decrease in corticosteroid dose.  
 
Stable Disease (SD) requires ALL of the following:  
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum LD while on study 
Evaluation of Non-Target Lesions:  
Complete Response (CR) requires ALL of the following:  
 disappearance of all enhancing CNS non-target lesions 
 No new CNS lesions 
 
Non-CR/Non-PD:  
 Persistence of one or more non-target CNS lesion(s) No new lesion 
 
Progression of Disease (PD) requires ANY of the following: 


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 Unequivocal progression of existing enhancing non-target CNS lesions 
 Unequivocal progression of existing tumor-related non-enhancing (T2/FLAIR) CNS 
lesions 
 
Stable Disease (SD) requires ALL of the following:  
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum LD while on study 
 
 
 
10.1.3 Overall Response Criteria 
 
The least favorable response from the CNS and systemic measurements will be chosen as the 
overall response score if they are unequal (from favorable to unfavorable CR > PR > SD > PD), 
if one site is non-evaluable (NE) then the response score from the other site may be used rather 
than scoring overall response NE.  
 
Failure to return for evaluation as a result of deteriorating condition may be considered clinical 
overall progression. 
 
11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (eg, advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes 
made to the protocol will be submitted as a modification and will be approved by the IRB prior 
to implementation.  The Protocol Director will disseminate the protocol amendment information 
to all participating investigators. 
 
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study.  The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  This may include review of the 
following types of documents participating in the study: regulatory binders, case report forms, 
eligibility checklists, and source documents.  In addition, the DSMC will regularly review 
serious adverse events and protocol deviations associated with the research to ensure the 
protection of human subjects.  Results of the DSMC audit will be communicated to the IRB and 
the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
 
11.3 
Data Management Plan 
The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific Case 


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Report Forms (CRFs) will document treatment outcomes for data analysis.  Case report forms 
will be developed using the OnCore database system and will be maintained by study personnel.  
The database will be secured with passwords, only accessible to the research team. 
 
12. 
STATISTICAL CONSIDERATIONS 
12.1 
Statistical Design 
This is a single-stage phase II design with CNS disease control rate at 12 weeks as the primary 
endpoint.  For cohort A and C, 12 patients will be enrolled.  If 3 or more patients with either 
NSCLC or MBC have controlled disease (SD, PR, or CR) in the CNS at 12 weeks, we will be 
able to reject the null hypothesis that the disease control rate is not larger than 5%, assuming a 
one-sided significance level of 5%.  The sample size and cutoff provide 81% power with an 
effective alpha level of 2% (one-sided).  This calculation is based on binomial probabilities, 
assuming an alternative of 33%. 
 
For cohort B, up to 3 patients with SCLC will be enrolled.  They will be observed for CNS and 
systemic disease response as an exploratory group. 
 
12.1.1 Randomization 
There is no randomization for this single-arm phase II study. 
 
12.2 
Interim analyses 
There is no stopping rule and no interim analysis.  
 
12.3 
Descriptive Statistics and Exploratory Data Analysis 
Not applicable 
 
12.4 
Primary Analysis  
 
12.4.1 Analysis Population 
All participants will be included in data analysis in an intention-to-treat manner. 
The safety population: All patients who are randomized and receive at least one dose (or partial 
dose) of study drug etirinotecan pegol.  Safety analyses will be conducted based on this 
population. 
 
12.4.2. Analysis Plan 
The data will be analyzed at least 6 months following the achievement of the primary endpoint 
(CNS disease control) of the last patient enrolled into this study. 
 
Disease control rate is defined as the number of patients with CNS SD+PR+CR divided by the 
total number of evaluable patients.  The proportion, its 95% confidence interval using the Exact 
method, and p-value of rejection the null hypothesis (5%) will be summarized. 
 
Patient demographic and clinical characteristics will be described using the appropriate summary 


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statistics (proportions, means, ranges, etc.) 
 
12.5 
Secondary Analysis 
 
12.5.1 Analysis Population 
The outcomes will be measured on all enrolled patients  in an intention-to-treat manner.  
Additionally, we may evaluate selected outcomes on the subset of enrolled patients that receive 
any dose or partial dose of study treatment, and also the Efficacy Evaluable patients (those that 
receive at least 1 cycle of therapy and have relevant imaging performed at or subsequent to the 6 
week timepoint.) 
 
The safety population: All patients who are randomized and receive at least one dose (or partial 
dose) of study drug etirinotecan pegol.  Safety analyses will be conducted based on this 
population. 
 
12.5.2  Analysis Plan 
Time to event data (progression-free survival, overall survival) will be described using 
Kaplan-Meier estimates.  The PFS probability at 12 weeks will be estimated with an 80% power 
and 95% confidence intervals (80% in accord with the planned alpha level, 95% for 
comparability with other studies, confidence intervals based on the Grenwood formula for the 
variance of a survival probability).  
 
Toxicity will be tabulated by organ system and grade.   
 
12.6  Sample Size 
12.6.1 Accrual estimates  
 
We estimate that we will enroll 6 eligible and evaluable NSCLC patients, 6 eligible and 
evaluable patients with locally recurrent or MBC) and 1 or 2 SCLC patients per 12-month 
period, for a total of 12 NSCLC patients and 3 SCLC patients over 24 months.  In addition, there 
are few trials within northern California competing for accrual in the population of patients with 
advanced lung cancer or advanced breast cancer with brain metastases. 
 
12.6.2 Sample size justification 
The null hypothesis: etirinotecan pegol will have no effect on the disease control rate at 12 weeks 
for patients with advanced lung cancer with brain metastases. 
 
The alternate hypothesis: etirinotecan pegol will have a significant effect on the disease control 
rate at 12 weeks for patients with advanced lung cancer with brain metastases.  
 
This study has 81% power to reject a 5% disease control rate at 12 weeks with an effective alpha 
level of 2% (one-sided) if the true disease control rate is 33% or more.  
 
12.6.3 Effect size justification 
This is a single arm, non-randomized, phase II trial of etirinotecan pegol in patients with 
advanced lung cancer with brain metastases.  The disease control rate of 33% is estimated based 


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on prior studies involving etirinotecan pegol in other cancers.  The null hypothesis reflects the 
opinion that a disease control rate of 5% is not of clinical interest. 
 
12.7 
Criteria for future studies 
A statistically significant result as described above would be a minimal criterion.  An observed 
disease control rate of 33% would be very encouraging and would motivate proceeding to a 
larger, phase III trial. 
 


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A phase II study of etirinotecan pegol (NKTR-102)  in patients with advanced lung cancer and refractory brain 
metastases 
 
Protocol Version #4.0 
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APPENDICES 
APPENDIX A: Participant Eligibility Checklist  
The Participant Eligibility Checklist will be created directly from the eligibility section of the 
protocol to avoid discrepancies between the protocol sections, as is standard research practice at 
Stanford University.