Clinical trial NCT01876446
Conditions: Recurrent Small Cell Lung Carcinoma
Sponsor: Roswell Park Cancer Institute
Start date: 2013-08-29; Completion date: 2020-02-24
Enrollment: 38 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well pegylated irinotecan NKTR 102 works in treating patients with small cell lung cancer that has returned after a period of improvement. Pegylated irinotecan NKTR 102 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the 18-week progression free survival (PFS) rate of relapsed small cell lung cancer (SCLC) patients treated with NKTR-102 (pegylated irinotecan NKTR 102).

SECONDARY OBJECTIVES:

I. To evaluate the objective response rate. II. To evaluate the duration of response. III. To evaluate the overall survival. IV. To evaluate the toxicity of NKTR-102 in this patient population.

TERTIARY OBJECTIVES:

I. To explore the correlation between UDP glucuronosyltransferase 1 family, polypeptide A cluster (UGTIA1) polymorphisms and NKTR-102 toxicities.

OUTLINE:

Patients receive pegylated irinotecan NKTR 102 intravenously (IV) over 90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.

Arms: arm 1: Patients receive pegylated irinotecan NKTR 102 IV over 90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Pegylated Irinotecan intervention 3: Pharmacological Study
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given IV intervention 3: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
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TITLE: A Phase II Study of Single Agent Topoisomerase-I Inhibitor Polymer Conjugate, 
Etirinotecan Pegol (NKTR-102), in Patients with Relapsed Small Cell Lung Cancer
Roswell Park Cancer Institute
Study Number:
I 225612
Initial Date:
March 8, 2013
Amendment 1:
June 18, 2013
Amendment 2:
December 12, 2013
Amendment 3:
January 29, 2014
Amendment 4:
April 25, 2014
Amendment 5:
September 8, 2014
Amendment 6:
February 23, 2015
Amendment 7:
February 4, 2016
Amendment 8:
Amendment 9:
September 23, 2016
January 27, 2017
IND Number/Holder:
IND 119186
Principal Investigator:
Hongbin Chen, MD, PhD
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, New York 14263
716-845-4578
Hongbin.Chen@RoswellPark.org
Industry/Other Supporter:
Nektar Therapeutics
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and 
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shall remain the exclusive property of the party(ies) mentioned above. The use of such 
confidential information must be restricted to the recipient for the agreed purpose and 
must not be disclosed, published, or otherwise communicated to any unauthorized persons, 
for any reason, in any form whatsoever without the prior written consent of the party(ies) 
above.
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Network Investigator Signature Page
Title: A Phase II Study of Single Agent Topoisomerase-I Inhibitor Polymer Conjugate, 
Etirinotecan Pegol (NKTR-102), in Patients with Relapsed Small Cell Lung Cancer
Protocol Approval and Investigator Agreement
I have read and familiarized myself with this protocol and agree to conduct the study as 
described according to Good Clinical Practices (GCP) and International Conference on 
Harmonisation (ICH) guidelines.
Principal Investigator’s Signature
Date
Principal Investigator’s Print
Address:
Phone:
Fax:
Email:
NOTE: Please see Appendix A for Network-specific instructions that will apply to your site.
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SYNOPSIS
Title / Phase
A Phase II Study of Single Agent Topoisomerase-I Inhibitor Polymer 
Conjugate, Etirinotecan Pegol (NKTR-102), in Patients with Relapsed Small 
Cell Lung Cancer
Roswell Park Cancer Institute 
Study Number
I 225612
Roswell Park Cancer Institute 
Investigator
Hongbin Chen, MD, PhD
Sponsor
Nektar Therapeutics
Study Drug
Etirinotecan Pegol (NKTR-102)
Objectives
Primary Objective:
•
To evaluate the 18-week progression free survival (PFS) rate of relapsed 
SCLC patients treated with NKTR-102.
Secondary Objectives:
•
To evaluate the objective response rate.
•
To evaluate the duration of response.
•
To evaluate the overall survival.
•
To evaluate the toxicity of NKTR-102 in this patient population.
Correlative Objective:
•
To explore the correlation between UGT1A1 polymorphisms and 
NKTR-102 toxicities.
Study Design
This is a single stage Phase II study of relapsed small cell lung cancer patients 
who have received only one prior systemic therapy regimen. There will be 
2 patient cohorts: those progressing on first-line therapy < 3 months after 
completion of treatment (Group A: chemo resistant) and those progressing on 
first-line therapy ≥ 3 months after completion of treatment (Group B: chemo 
sensitive). Etirinotecan pegol will be administered at 145 mg/m2 IV once 
every 3 weeks. Cycles will be repeated every 21 days (± 3 days) until disease 
progression. Patients who develop metastases in the central nervous system 
(CNS) as the only site of disease progression could receive therapeutic whole 
brain radiation therapy (WBRT), or gamma knife radiosurgery and after 
completion of WBRT continue on NKTR-102. Imaging studies are scheduled 
to be obtained after every other 21-day cycle.
Target Accrual and Study 
Duration
This study will accrue a total of 38 patients  over approximately 3 years 
(Group A; 20 patients, Group B; 18 patients). Patients will be on study for 
approximately 18 – 24 months.
Study Procedures
Adverse Events: From time of Cycle 1 Day 1 until 30 days after receiving 
last dose of study drug.
Hematology: ≤ 14 days prior to initiation of study drug, Cycle 1 (Day 1 and 
weekly), and prior to treatment on Day 1 of subsequent cycles, 30-Day 
Follow-Up.
Chemistry: ≤ 14 days prior to initiation of study drug, Cycle 1 (Day 1 and 
weekly), prior to treatment on Day 1 of subsequent cycles, 30-Day Follow-
Up.
Physical Examination (including vital signs, body weight, and height): 


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≤ 14 days prior to initiation of study drug, Cycle 1 (Day 1 and weekly), and 
prior to treatment on Day 1 of subsequent cycles, 30-Day Follow-Up.
Performance Status: ≤ 14 days prior to initiation of study drug, Cycle 1 
(Day 1 and weekly), and prior to treatment on Day 1 of subsequent cycles, 30-
Day Follow-Up.
12-Lead ECG: ≤ 14 days prior to initiation of study drug and prior to 
treatment on Day 1 of Cycle 2 and Cycle 3, if clinically indicated.
Statistical Analysis
Efficacy Assessments:
•
18-week PFS is defined as the proportion of patients whose disease has 
not progressed at 18 weeks after getting etirinotecan pegol.
•
Tumor response is defined as a complete response (CR) or partial 
response (PR) by RECIST 1.1 criteria, which will be evaluated by CT-
scan every other cycle.
•
OS is defined as the time from enrollment to death from any cause.
Safety Assessments:
•
The maximum grade for each type of adverse events (AEs) will be 
recorded for each patient based on NCI CTCAE version 4.0, and 
frequency tables will be reviewed to determine AE and toxicity 
(unrelated, unlikely, possible, probably, or definitely related to study 
treatment) patterns in each group.
•
A single-stage design will be used to assess the primary endpoint 
separately for each. Based on this, the primary endpoint of this trial will 
be the proportion of patients who are progression-free at 18 weeks.
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Study Schema 
Relapsed small cell lung cancer patients who 
received only one prior systemic regimen.
Group A (chemo-resistant)
Progressed on previous 
treatment < 3 months
Group B (chemo-sensitive)
Progressed on previous 
treatment ≥ 3 months
Etirinotecan pegol 145 mg/m
2 IV dose once every 
3 weeks (21-day cycle)
PR, SD, CR
Continue 
treatment until 
PD then event 
monitoring.
CNS-only PD
Non-CNS PD
WBRT then 
continue treatment 
until PD then event 
monitoring.
Come off study 
treatment then 
event monitoring.
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Subject Name:  (Network sites use subject initials):___________________________________
Medical Record No.: (Network sites use subject ID): _________________________________
Title: A Phase II Study of Single Agent Topoisomerase-I Inhibitor Polymer Conjugate, 
Etirinotecan Pegol (NKTR-102), in Patients with Relapsed Small Cell Lung Cancer
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “YES or “N/A” for patient enrollment.
Date
1.
Written informed consent granted prior to initiation of any study-specific 
screening procedures, given with the understanding that the patient has 
the right to withdraw from the study at any time, without prejudice.
2.
18 years of age or older.
3.
Histologic or cytologic diagnosis of SCLC. (Note: Patients with mixed 
histology are not eligible.)
4.
ECOG performance status of 0 or 1 (refer to Appendix B).
5.
Presence of measurable disease as defined by ≥ 1 lesion whose longest 
diameter can be accurately measured as ≥ 20 mm with conventional 
techniques or as ≥ 10 mm with spiral CT.
6.
Previously treated SCLC with only one prior treatment regimen 
[cyclophosphamide/doxorubicin/vincristine (CAV) alternating with 
etoposide/cisplatin (EP) is acceptable].
7.
Resolution of all acute toxic effects of prior chemotherapy, radiotherapy, 
hormonal therapy, or surgery to NCI-CTCAE version 4.0 Grade ≤ 1, 
except for diarrhea (which must be Grade 0 without supportive 
antidiarrheal medications) and alopecia (any grade).
8.
Adequate hematologic, liver, and renal function, defined as: 
•
Platelet count ≥ 100 × 109/L
•
Hgb ≥ 9 gm/dL
•
Absolute neutrophil count (ANC) ≥ 1500/μL
•
Serum creatinine ≤ 1.5 mg/dL or creatinine clearance > 45 mL/min. 
Use either measured or calculated with Cockcroft - Gault formula 
(Appendix C).
•
Serum total bilirubin ≤ 1.5 x ULN
•
Aspartate Transaminase (AST) and alanine transaminase 
(ALT) ≤ 3 x ULN or ≤ 5 x ULN if caused by liver metastasis
9.
Women of childbearing potential must have a negative pregnancy test 
performed within seven days prior to the start of study drug. Male and 
female subjects of child-bearing potential must agree to use double-
barrier contraceptive measures, or avoidance of intercourse during the 
study and for 6 months after last investigational drug dose received.
Study participant meets all entry criteria:
Yes
No
Investigator Signature: ___________________________________
Date: __________
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Subject Name: (Network sites use subject initials):_________________________________
Medical Record No.: (Network sites use subject ID): _______________________________
Title: A Phase II Study of Single Agent Topoisomerase-I Inhibitor Polymer Conjugate, 
Etirinotecan Pegol (NKTR-102), in Patients with Relapsed Small Cell Lung Cancer
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “NO” or “N/A” for patient enrollment.
Date
1.
Previous anti-cancer chemotherapy, immunotherapy or investigational 
agents < 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the 
first day of study defined treatment. Palliative radiation < 2 weeks, 
biological therapy within 2 weeks, hormonal therapy within 1 week prior 
to Day 1 Cycle 1.
2.
Prior treatment with a topoisomerase-I inhibitor (e.g., topotecan, 
irinotecan).
3.
Prior malignancy except for non-melanoma skin cancer and carcinoma in 
situ, unless diagnosed and definitively treated more than 5 years prior to 
enrollment.
4.
Substance abuses, medical, psychological or social conditions that may, in 
the opinion of the Investigator, interfere with the patient’s participation in 
the study or evaluation of the study results.
5.
Known human immunodeficiency virus (HIV) infection due to concerns of 
potential drug interaction with various antiretroviral agents.
6.
Pregnancy or breast-feeding.
7.
Concurrent administration or received CYP3A4 inducers or inhibitors 
within 2 weeks prior to the first day of study drug treatment. Lists 
including medications and substances known or with the potential to 
interact with CYP3A4 are provided in Section 7.3.7.
8.
Patients with chronic or acute GI disorders resulting in diarrhea of any 
severity grade; patients who are using chronic anti-diarrheal supportive 
care (more than 3 days/week) to control diarrhea in the 28 days prior to 
study entry.
9.
Major surgery < 4 weeks or minor surgery (e.g., talc pleurodesis, 
excisional biopsy, etc) < 2 weeks prior to the first day of study defined 
treatment.
10. Have central nervous system (CNS) metastases (unless the patient has 
completed successful local therapy for CNS metastases and has been off 
corticosteroids for at least 4 weeks before starting study therapy). Brain 
imaging is required in symptomatic patients to rule out brain metastases, 
but is not required in asymptomatic patients.
11. Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements.
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12. Unwilling or unable to follow protocol requirements.
Study participant meets all entry criteria:
Yes
No
Investigator Signature: ___________________________________
Date: ___________
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TABLE OF CONTENTS
1
Background .....................................................................................................................15
1.1
Study Drug: NKTR-102..................................................................................................16
1.2
Preclinical Studies...........................................................................................................18
1.3
Clinical Studies ...............................................................................................................19
1.3.1
Clinical Pharmacokinetics .......................................................................................19
1.3.2
Clinical Safety .........................................................................................................20
1.3.3
Clinical Efficacy ......................................................................................................21
1.4
Correlative Studies..........................................................................................................23
1.4.1
Pharmacogenetics ....................................................................................................23
1.5
Risks Associated with NKTR-102..................................................................................23
2
Rationale .........................................................................................................................24
3
Objectives........................................................................................................................25
3.1
Primary Objective ...........................................................................................................25
3.2
Secondary Objectives......................................................................................................25
3.3
Correlative Objective ......................................................................................................25
4
Methodology ...................................................................................................................25
4.1
Study Design...................................................................................................................25
4.2
Target Accrual and Study Duration ................................................................................25
5
Subject Selection.............................................................................................................26
5.1
Inclusion criteria .............................................................................................................26
5.2
Exclusion criteria ............................................................................................................27
5.3
Inclusion of Women and Minorities ...............................................................................27
5.4
Subject Withdrawal.........................................................................................................28
6
Investigational Product ...................................................................................................28
6.1
Active Substance and Source..........................................................................................28
6.2
Drug Shipment ................................................................................................................29
6.3
Reconstitution and Handling...........................................................................................29
6.4
Storage and Stability .......................................................................................................30
6.5
Handling and Disposal....................................................................................................30
7
Treatment Plan ................................................................................................................30
7.1
Dosage and Administration.............................................................................................30
7.2
Dose Modification Due to Toxicity ................................................................................31
7.2.1
Retreatment Criteria.................................................................................................31
7.2.2
Treatment Delay ......................................................................................................31
7.2.3
Dose Reductions ......................................................................................................31
7.3
Concomitant Medication and Supportive Care...............................................................35
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7.3.1
Anti-Emetic Therapy ...............................................................................................35
7.3.2
Anti-Diarrheal Therapy ...........................................................................................35
7.3.3
Platelet Transfusion .................................................................................................36
7.3.4
Growth Factor Use...................................................................................................36
7.3.5
Other Antineoplastic Therapy..................................................................................36
7.3.6
Bisphosphonates and Denosumab ...........................................................................36
7.3.7
Medications NOT ALLOWED During Study (P450 inhibitors/inducers) .............36
7.4
Duration of Treatment.....................................................................................................37
7.5
Treatment Discontinuation..............................................................................................37
7.6
Compliance .....................................................................................................................38
7.7
Subject Randomization and Registration........................................................................38
7.8
Baseline Evaluations.......................................................................................................38
7.9
Evaluations Performed on Cycle 1 Day 1.......................................................................39
7.10
Evaluations Performed Weekly for Cycle 1 ...................................................................40
7.11
Evaluations Performed Prior to Treatment on Day 1 of Subsequent Cycles ..................40
7.12
Evaluations Performed at 30 Day Follow-Up.................................................................41
7.13
Survival Follow-up .........................................................................................................41
7.14
Schedule of Procedures and Observations......................................................................41
7.15
Pharmacogenetics............................................................................................................43
7.15.1
Blood Sample Collection and Processing................................................................43
7.15.2
Sample Handling and Shipment ..............................................................................43
8
Efficacy Evaluations .......................................................................................................43
8.1
Objective Tumor Response.............................................................................................43
8.2
Target Lesions.................................................................................................................43
8.3
Non-Target Lesions.........................................................................................................44
8.4
Evaluation of Response...................................................................................................44
8.5
Confirmation Measurement ............................................................................................46
8.6
Guidelines for Evaluation of Measurable Disease..........................................................46
9
Safety Evaluation ............................................................................................................48
9.1
Adverse Events ...............................................................................................................48
9.1.1
Definition.................................................................................................................48
9.1.3
Reporting Adverse Events .......................................................................................50
9.2
Serious Adverse Events ..................................................................................................51
9.2.1
Definition.................................................................................................................51
9.2.2
Reporting Serious Adverse Events ..........................................................................51
9.3.1
Follow-Up for Serious Adverse Events...................................................................52
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9.4
Unanticipated Problems ..................................................................................................52
9.4.1
Definition.................................................................................................................52
9.4.2
Reporting Unanticipated Problems..........................................................................53
9.5
FDA Reporting................................................................................................................53
10
Data and Safety Monitoring............................................................................................54
11
Statistical Methodology ..................................................................................................54
11.1
Sample Size Determination and Analysis.......................................................................54
11.2
Randomization ................................................................................................................55
11.3
Demographics and Baseline Characteristics ...................................................................55
11.4
Efficacy Analysis ............................................................................................................55
11.5
Safety Analysis ...............................................................................................................56
11.6
Adverse Event.................................................................................................................56
12
Correlative Data Analysis ...............................................................................................56
12.1
Pharmacogenetic Analysis ..............................................................................................56
13
Ethical and Regulatory Standards...................................................................................57
13.1
Ethical Principles ............................................................................................................57
13.2
Informed Consent............................................................................................................57
14
Study Responsibilities.....................................................................................................58
14.1
Data Collection ...............................................................................................................58
14.2
Maintenance of Study Documents ..................................................................................58
15
Administrative Rules.......................................................................................................59
15.1
Revisions to the Protocol ................................................................................................59
15.2
Termination of the Study ................................................................................................59
15.3
Confidentiality ................................................................................................................59
16
Appendices......................................................................................................................60
17
References.......................................................................................................................65
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IN-TEXT TABLES
Table 1.
Topotecan and Irinotecan in Relapsed Small Cell Lung Cancer.................................16
Table 2.
Phase I Study of NKTR-102 .......................................................................................21
Table 3.
Dose Modifications Based on Toxicities.....................................................................31
Table 4.
Schedule of Procedures and Observations ..................................................................41
Table 5.
Time Point Response Criteria (+/- non-target disease) ...............................................45
Table 6.
Time Point Response Criteria (non-target disease only).............................................45
Table 7.
Guidelines for Routine Adverse Event Reporting for Phase II Studies (Regardless of 
Expectedness) ................................................................................................................................50
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IN-TEXT FIGURES
Figure 1.
Targeted Prodrug Enables Sustained Exposure and Continuous
Targeting to Tumors ....................................................................................................17
Figure 2.
Concentration and Time Curve of Irinotecan and SN38 After
Administration of NKTR-102......................................................................................18
Figure 3.
Proposed Metabolic Pathway for NKTR-102 .............................................................18
Figure 4.
Predicted Plasma SN38 Concentration-Time Profiles After Administration of 
145 mg/m2 NKTR-102 (solid line) or 350 mg/m2 Irinotecan (broken line)................20
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APPENDICES
Appendix A.
Instructions for Network Sites .............................................................................60
Appendix B.
ECOG Performance Status Scores.......................................................................63
Appendix C.
Cockcroft-Gault Calculation for Creatinine Clearance........................................64
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1
BACKGROUND
Small-cell lung cancer (SCLC) is one of the most aggressive and lethal cancers in humans. It 
accounts for 15% - 20% of lung cancer. The standard combination cytotoxic chemotherapy 
agents have shown antitumor activity with initial responses seen in 70%–90% for both limited-
stage disease (LD) and extensive-stage disease (ED) of SCLC.1-3 Fifty to 60% of patients with 
LD and 20% - 40% of patients with ED will achieve a clinical complete response (CR) to initial 
chemotherapy with or without thoracic radiotherapy. Long-term survival is low and most 
patients eventually develop progressive disease. Overall, the median survival time (MST) for LD 
and ED is 12 – 15 months and 8 – 10 months, respectively, with 5-year survival of 10% (LD) 
and 0% - 2% (ED).4,5 Even among patients who achieve CR, there is a high rate of relapse.6 In 
previous studies, 60% of LD patients achieved a CR.1,3 Seventy percent of these CR patients 
relapsed within 2 years. Although SCLC is very responsive to initial treatment, most patients 
relapse with relatively resistant disease. Moreover, among patients who relapse, prognosis 
remains poor with second-line therapy. Response to subsequent therapy is influenced by the 
progression-free interval from cessation of initial therapy. Patients who relapse within 3 months 
are considered to have refractory disease and typically have response rates to second-line therapy 
that are inferior to patients considered to have ‘sensitive’ disease, generally defined as those who 
relapse more than 3 months after therapy.7 The first generation topoisomerase-I inhibitors such 
as; topotecan and irinotecan are the second line treatment for relapsed SCLC with the response 
rate (RR) 13% - 47% and progression-free survival (PFS) 2.2 - 3.7 months compared with other 
single cytotoxic drugs or best supportive care (Table 1).6,8-12 Based on the high relapse rate after 
CR, leveling off of the therapeutic results, and poor long-term survival, it is clear that new active 
agents are needed in the treatment of relapsed SCLC.
The anti-tumor activity of topoisomerase-I inhibitor, irinotecan, has been demonstrated in 
multiple tumor types including SCLC13-18, non-small cell lung cancer (NSCLC)19-21, gastric 
adenocarcinoma22,23, colorectal cancer24,25 and ovarian cancer26-28. Immediately after dosing, 
however, standard topoisomerase-I inhibitors reach high peak concentrations and diffuse quickly 
throughout the body, penetrating and damaging healthy tissue, such as bone marrow, as well as 
tumor tissue. Subsequent rapid metabolism limits topoisomerase-I exposure in tumor cells, 
reducing the duration of their effect and resulting in a much lower tumor exposure to the active 
metabolite that may limit their efficacy. The usage of irinotecan is often hampered by its sub-
optimal toxicity profiles and pharmacokinetics. It has a half-life (t½) of approximately 9 hours in 
humans, and 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 (Figure 1). Additionally, there is no good second-line 
therapy available. Accordingly, due to the activity observed as front-line therapy and some 
activity of each of the single agents as second-line therapy, this study will investigate the 
efficacy of novel generation of topoisomerase-I inhibitor, NKTR-102, against relapsed or 
refractory small cell lung cancer. Because of the fact that second-line treatment is not curative 
and these patients have a limited survival, this study will explore NKTR-102 that would be less 
toxic than irinotecan and would be applicable in the community practice.
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Table 1.
Topotecan and Irinotecan in Relapsed Small Cell Lung Cancer
Phase
(N)
Primary 
endpoint
RR (%)
TTP/PFS
(months)
OS
(months)
Topotecan IV
vs
CAV 6
Phase III
(211)
ORR
26 vs 19
3.3 vs 3
6 both arms
Oral topotecan
vs
BSC 12
Phase III
(141)
OS
7
(topotecan arm)
4 of TTP 
(topotecan arm)
6 vs 3.5
Topotecan IV
vs
Oral Topotecan 8
Phase III
(309)
ORR
22 vs 18
3.7 vs 3
3.5 vs 3.3
Amrubicin
vs
Topotecan 9
Phase II
(60)
ORR
38 vs 13
53 vs 21 
(chemosensitive)
17 vs 0 (refratorry)
3.5 vs 2.2
NA
Amrubicin
vs
Topotecan 10
Phase II
(76)
ORR
44 vs 15
4.5 vs 3.3
9.2 vs 7.6
Irinotecan
(single arm) 11
Phase II
(16)
ORR
47
NA
6
*CAV; cyclophosphamide/doxorubicin/vincristine, BSC; best supportive care, NA; not available, ORR; overall 
response rate, OS; overall survival, PFS; progression-free survival, RR; response rate, TTP; time to progression.
1.1
Study Drug: NKTR-102
Etirinotecan pegol (NKTR-102) is a polyethylene glycol (PEG) conjugate of irinotecan. It is a 
unique and a next generation topoisomerase I-inhibitor designed for prolonged tumor cell 
exposure using the polymer conjugate technology platform which conjugates cytotoxic small 
molecules to a uniquely engineered macromolecular polymer core using specialized linkers 
which provide a continuous concentration of active drug in tumor cells with reduced peak 
concentrations and minimizing its toxicities (Figure 1).
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Figure 1.
Targeted Prodrug Enables Sustained Exposure andContinuous Targeting to 
Tumors
Unlike first generation topoisomerase-I inhibitors that exhibit a high initial peak concentration 
and short half-life, NKTR-102's unique pro-drug design results in a lowered initial peak 
concentration of active topoisomerase-I inhibitor in the blood (Figure 2). It provides 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. The large NKTR-102 molecule is inactive when administered. Over time, natural 
processes in the body continuously free active drug that then works to stop tumor cell division 
through inhibition of topoisomerase-I.
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Figure 2.
Concentration and Time Curve of Irinotecan and SN38 After Administration
of NKTR-102
The proposed biotransformation pathway of NKTR-102 is shown in Figure 3. After cleavage of 
irinotecan from the PEG moiety, this pathway is the same as that for irinotecan and SN38.
Figure 3.
Proposed Metabolic Pathway for NKTR-102
NKTR-102
Irinotecan
SN38
APC
NPC
SN38-G
Hydrolysis
UGT1A1
UGT1A9
Esterases
Abbreviations: 
UGT; 
uridine 
diphosphate 
glucuronosyltransferases, 
CYP; 
cytochrome 
P450, 
SN38; 
7-ethyl-10-hydroxycamptothecin, 
APC; 
7-ethyl-10-[4-N-(5-aminopentanoic 
acid)-1-piperidino]-carbonyloxycamptothecin, 
NPC; 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin.
1.2
Preclinical Studies
Pharmacokinetic, pharmacologic, and toxicologic characteristics of NKTR-102 have been 
studied in mice, rats, and dogs. Pharmacokinetic studies in mice, rats, and dogs showed slower 
plasma clearance (CL) as well as greater and sustained exposure to irinotecan and SN38 
following NKTR-102 dosing compared to irinotecan dosing. In mice and rats, the SN38 terminal 
t½ increased by approximately one order of magnitude, and SN38 total exposure, expressed in 
terms of area under the curve (AUC), increased by more than two orders of magnitude. 
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Prolonged exposure to irinotecan and SN38 was also observed in dogs, where SN38 t½ values 
increased by approximately one order of magnitude and SN38 AUC values increased 2- to 6-fold 
following NKTR-102 dosing, when compared to equivalent irinotecan dosing.
The anti-tumor activity of NKTR-102 was evaluated in several tumor xenograft studies, and 
included cell lines from human colorectal (HT29), non-small cell lung (NCI H460), breast 
(MCF-7), ovarian (A2780), and gastric (NCI-N87) tumors. Significantly longer tumor growth 
delays were seen with NKTR-102 compared to irinotecan in all tumor xenograft studies. 
NKTR-102 is hypothesized to be more efficacious than irinotecan due to greater and prolonged 
topoisomerase-I inhibition resulting from prolonged tumor cell exposure to both irinotecan and 
SN38. 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 or 
irinotecan given with cetuximab in a mouse model of human DLD-1 colorectal tumor, 
NKTR-102 or irinotecan given with bevacizumab in a mouse model of human HT29 colorectal 
tumor, and NKTR-102 or irinotecan given with 5-FU in a model of human HT29 colorectal 
tumor.
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.
1.3
Clinical Studies
1.3.1
Clinical Pharmacokinetics
The t½ for SN38 after NKTR-102 administration is approximately 50 days, whereas after 
irinotecan administration, the SN38 t½ has been reported as 10 to 47 hours.29 This greatly 
increased SN38 t½ results in plasma SN38 concentrations that are significantly more sustained 
between doses than are possible with irinotecan. Shown in Figure 4, a single 145 mg/m2 dose of 
NKTR-102 results in approximately the same SN38 plasma exposure (AUC) as a 350 mg/m2 
dose of irinotecan, but exposure is continuous throughout a 21-day cycle rather than intermittent 
(there is no measurable SN38 after approximately 1 week with irinotecan), and maximal 
concentrations are approximately 5- to 10-fold less for NKTR-102 versus irinotecan.30
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Figure 4.
Predicted Plasma SN38 Concentration-Time Profiles After Administration of 
145 mg/m2 NKTR-102 (solid line) or 350 mg/m2 Irinotecan (broken line)
0
3
6
9
12
0.1
1
10
Time (weeks)
Predicted SN38 Conc. (ng/mL)
Simulation of SN38 after irinotecan administration is based on Xie et al., 2002.30 Simulation of SN38 after 
NKTR-102 administration is based on 06-IN-IR001 derived population parameters for SN38.
Interpatient variability in SN38 clearance (CL) and volume of distribution (V) is similar to that 
reported for SN38 following irinotecan administration. There has been no obvious correlation of 
toxicity or SN38 PK parameters with age, race, gender, past or present smoking status, or 
baseline liver or renal function. Cumulative plasma SN38 AUC is not predictive of the 
occurrence of NCI-CTCAE Grade 2 or higher diarrhea. Further exploratory analyses, including 
assessment of toxicity based on uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) 
status, are ongoing.
1.3.2
Clinical Safety
As of July 2012, a total of 397 patients across all clinical studies (completed and ongoing; 
single-agent and combination therapy) have received at least 1 administration of NKTR-102. 
Safety data from 309 patients are included in the Investigator’s Brochure, version 8.0. 
Observations across all studies (including safety data from ongoing studies) have been generally 
consistent with regard to the overall safety profile of NKTR-102. Gastrointestinal toxicity, 
especially diarrhea, is the most common and clinically significant toxicity occurring with the use 
NKTR-102. 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 NKTR-102. The 
incidence of Grade 3 diarrhea in the Phase II study in patients with metastatic breast cancer 
(MBC) at the recommended dose and schedule equaled 23%, with 11% Grade 3 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 3 patients in the ongoing Phase II 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 NKTR-102 in any 
of the completed or ongoing clinical studies. Late-onset, severe diarrhea can occur: the median 
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time-to-onset of Grade 3 diarrhea for NKTR-102 for the q21d schedule is 93 days (range 8 days 
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 NKTR-102; however, data from clinical studies evaluating 
NKTR-102 suggest a lower frequency and severity of neutropenia than for irinotecan. 
NKTR-102 administered at a dose level of 145 mg/m² in a q21d schedule overall across all 
ongoing Phase II 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.
1.3.3
Clinical Efficacy
Nektar initiated its NKTR-102 clinical program with the Phase I Study 06-IN-IR001. 
Study 06-IN-IR001 evaluated three treatment schedules (wx3 q4wk, q21d, and q14d) in patients 
with refractory solid tumors. In all schedules, NKTR-102 was administered as an IV infusion 
over 90 minutes. NKTR-102 demonstrated anti-tumor activity in a broad spectrum of tumors 
(Table 2). Eight of the 76 patients enrolled in this study had a confirmed partial response (PR) 
by RECIST 1.0 (for an ORR of 11%). These responses were seen in lung cancers (SCLC and 
NSCLC), breast, bladder, cervix, maxillary sinus, pancreas, and colorectal cancers. Two 
unconfirmed responses were seen in colorectal cancer and ovarian cancer. These findings led to 
the initiation of a Phase II development program in colorectal cancer and in cancers not normally 
associated with use of irinotecan in the US, but for which preliminary evidence was seen of anti-
tumor activity associated with NKTR-102 (ovarian and breast). On the basis of the results of this 
study, the recommended Phase II dose was initially identified as 170 mg/m2 on either a q14d or 
q21d schedule. The dose was later revised to 145 mg/m2 q14d or q21d after additional safety 
data related to diarrhea were received from this Phase I study and from the ongoing Phase II 
studies.
Table 2.
Phase I Study of NKTR-102
Primary 
Tumor
Confirmed PR
Unconfirmed PR
SD ≥ 90 days
PR + SD
CRC 
17
1
1
5
7 (41%)
NSCLC 
15
1
-
3
4 (26%)
SCLC 
3
1
-
1
2 (66%)
Cervix 
5
1
-
-
1 (20%)
Pancreas 
5
1
-
-
1 (20%)
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Breast 
4
1 
1 (25%)
Head & Neck
3
1
-
-
1 (33%)
Bladder 
1
1
-
-
1 (100%)
Ovarian 
5
-
1
-
1 (20%)
*CRC; colorectal cancer, NSCLC; non-small cell lung cancer, PR; partial response, SCLC; small cell lung cancer, 
SD; stable disease.
A Phase II study (Protocol 08-PIR-05) of NKTR-102 in patients with MBC evaluating two 
treatment regimens (145 mg/m2 q14d and q21d; n = 70; 35 per treatment regimen) showed 
significant antitumor activity.31 The study showed the following activity in the two treatment 
regimens combined: The ORRs in the total population was 29%, including 2 complete 
responders and an additional 4 patients who had complete resolution of target lesions. The ORR 
was maintained in patients with advanced or high-risk disease (ORR equal to 31% in patients 
who had received prior anthracycline, taxane, capecitabine [ATC]; ORR in patients with triple 
negative breast cancer [TNBC] was 39%). As of May 2011, median progression free survival 
(PFS) and overall survival (OS) were 4.6 months and 10.3 months, respectively; the q21d 
schedule had longer PFS and OS than the q14d regimen (5.3 months versus 3.5 months, and 
13.1 months versus 8.8 months, respectively). Based on better tolerability, a trend towards 
improved OS and PFS, as well as the convenience of a less frequent dosing regimen, the q21d 
145 mg/mg2 treatment schedule of NKTR-102 was selected for the Phase III study.
A Phase II study (Protocol 08-PIR-04) of NKTR-102 in patients with platinum resistant ovarian 
cancer evaluated two treatment regimens (145 mg/m2 q14d and q21d; n = 71; 36 and 35 patients 
per treatment regimen). Overall, NKTR-102 produced a RECIST 1.0 ORR of 23% and 
Gynecologic Cancer InterGroup (GCIG) response of 38% in  	 
.32 In those 
patients whose disease had progressed following both platinum (within 6 months) and liposomal 
doxorubicin (n = 33), ORR equaled 21%, median PFS equaled 5.4 months and OS equaled 
13.9 months.33 Based on these data, enrollment to the q21d regimen continued for patients with 
platinum resistant disease whose disease has also progressed following pegylated liposomal 
doxorubicin. A randomized Phase II study (Protocol 08-PIR-03) comparing single-agent 
NKTR-102 to single-agent irinotecan in patients with 2nd-line metastatic colorectal cancer 
(whose malignancy is positive for a KRAS mutation) is ongoing.
The Phase IIa study of NKTR-102 in combination with cetuximab (Protocol 07-PIR-02) is 
completed and the Phase I study of NKTR-102 in combination with 5-fluorouracil/leucovorin 
(FULPIRI) (Protocol 09-PIR-07) is in progress. See the Investigator’s Brochure for additional 
information on these clinical trials.
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1.4
Correlative Studies
1.4.1
Pharmacogenetics
The genes that have been associated with irinotecan pharmacodynamic and pharmacokinetic 
pathways include those responsible for activation, inactivation and transport of the drug. These 
genes include ABCB1, ABCC2, ABCG2, BCHE, CES1, CES2, CYP3A4, CYP3A5, SLCO1B1, 
TOP1, UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9 and UGT1A10. As NKTR-102 is a conjugate of 
irinotecan, most of the irinotecan pathway genes may interact with it thus resulting in similar 
phenotypic effects. Hence, several genetic variants associated with the pathways may contribute 
to the clinical outcome of NKTR-102 therapy.
Some of the well-known genetic variants that have been associated with irinotecan clinical 
outcomes include the polymorphic repeat in UGT1A1 promoter region (UGT1A1*28, rs8175347; 
UGT1A1*93) and the ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCC2 (-24C > T, 1249G 
> A, 3972C > T), and ABCG2 (34G > A, 421C > A) polymorphisms. It is reported that nearly 
50% of the variations in neutropenia among individuals could be explained by a combination of 
genetic polymorphisms and non-genetic covariates, with gene combinations attributing to 28% of 
the variations, suggesting a polygenetic basis for neutropenia.32 UGT1A1*28 and *93 genotypes 
have been associated with toxicity; ABCC2 3972C > T with severe diarrhea in both Korean and 
European patients while SLCO1B1*5 allele is reported to be associated with increased risk of 
severe neutropenia in Asians, and the SLCO1B1*1b allele is suggested to be protective of 
neutropenia.32-35
This Phase II study (38 patient samples) will initially focus, in an exploratory manner, on the 
primary genes which will activate (CES1, CES2, CYP3A4, and CYP3A5) and inactivate 
(UGT1A1) NKTR-102. It is hypothesized that germline polymorphic variants in CES1, CES2, 
CYP3A4, CYP3A5 and UGT1A1 may affect toxicity as well as response to NKTR-102 therapy.
SNP Identification: We will generate tagSNPs from National Center for Biotechnology 
Information (NCBI), HapMap and/or the Genome Variation Server databases using the 
Caucasian SNP information for these 5 genes in addition to using SNPs previously reported in 
literature. These SNPs will be selected with sufficient frequency that its impact on the clinical 
outcome at a population level would be meaningful and have some degree of likelihood to alter 
the function of the gene in a biologically relevant manner. Fifty-three SNPs have been identified 
for genotyping.
Genotyping: The tagSNPs will be genotyped using the MassARRAY Compact system 
(Sequenom) at RPCI as previously described.36 Whenever possible, the published methods and 
primers will be used for polymorphic variants such as UGT1A1*28.
1.5
Risks Associated with NKTR-102
A majority of NKTR-102 related treatment-emergent adverse events (TEAEs) occurred in the 
system organ class (SOC) of GI disorders with diarrhea experienced most commonly by 85.5% 
of patients, followed closely by nausea (77.6%), fatigue (51.3%), and vomiting (48.7%). Other 
clinically significant NKTR-102-related TEAEs with an incidence rate > 10% included anorexia, 
dehydration, alopecia, electrolyte disturbances like hypokalemia and hypomagnesemia, 
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abdominal pain, anemia, and blurred vision, in decreasing order of frequency. Prolonged severe 
diarrhea with dehydration leading to pre-renal azotemia and subsequent acute renal insufficiency 
has been fatal in three patients in the ongoing Phase II studies in metastatic colorectal, ovarian, 
and breast cancers (one patient in each study). To date, early onset cholinergic diarrhea (as seen 
with irinotecan) has not been observed in any patient who received NKTR-102. 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.
Myelosupression, 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. Except for diarrhea 
(complete resolution of diarrhea to Grade 0 should be present for at least seven days without the 
need for anti-diarrheal medications and/or supportive care prior to retreatment with NKTR-102), 
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 myelosuppresion. 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.
Hypersensitivity or mild allergic reactions characterized by itching, flushing, dizziness, muscle 
twitching, and/or temporary speech impairment have been observed in some patients. 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.
2
RATIONALE
Small-cell lung cancer (SCLC) is one of the most aggressive and lethal cancers in humans. 
Although standard combination cytotoxic chemotherapy agents have shown antitumor activity 
with initial responses seen in 70% - 90% for both limited and extensive stages of SCLC, long-
term survival is low and most patients eventually develop progressive disease within the first 
2 years. Moreover, among patients who relapse, prognosis remains poor with second-line therapy 
(Table 1).
Etirinotecan pegol (NKTR-102) is a targeted, long-acting topoisomerase-I inhibitor designed to 
provide continuous exposure to SN38 (7-ethyl-10-hydroxycamptothecin), while reducing 
excessively high irinotecan and SN38 plasma concentrations associated with toxicities upon 
administration of irinotecan. Preclinical and clinical studies have shown that the half-life of 
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active drug generated from NKTR-102 is greatly extended to 50 days and that active drug 
remains in circulation throughout the entire chemotherapy cycle, providing sustained exposure to 
active metabolite of irinotecan (SN38). We propose to investigate the efficacy of NKTR-102 
against relapsed or refractory small cell lung cancer.
3
OBJECTIVES
3.1
Primary Objective
The primary objective of this study is to evaluate the 18-week progression free survival (PFS) 
rate of relapsed SCLC patients treated with NKTR-102.
3.2
Secondary Objectives
•
To evaluate the objective response rate.
•
To evaluate the duration of response.
•
To evaluate the overall survival.
•
To evaluate the toxicity of NKTR-102 in this patient population.
3.3
Correlative Objective
•
To explore the correlation between UGT1A1 polymorphisms and NKTR-102 toxicities.
4
METHODOLOGY
4.1
Study Design
This is a single stage Phase II study of relapsed small cell lung cancer patients who have 
received only one prior systemic therapy regimen. There will be 2 patient cohorts:  those 
progressing on first-line therapy < 3 months after completion of treatment (Group A: chemo 
resistant) and those progressing on first-line therapy ≥ 3 months after completion of treatment 
(Group B: chemo sensitive). Etirinotecan pegol will be administered at 145 mg/m2 IV once every 
3 weeks. Cycles will be repeated every 21 days (± 3 days) until disease progression. Patients who 
develop metastases in the central nervous system (CNS) as the only site of disease progression 
could receive therapeutic whole brain radiation therapy (WBRT), or gamma knife radiosurgery 
and after completion of WBRT continue on NKTR-102. Imaging studies are scheduled to be 
obtained after every other 21-day cycle.
4.2
Target Accrual and Study Duration
A maximum of 38 subjects (20 patients from Group A and 18 patients from Group B) at multiple 
sites, including RPCI will be enrolled. Accrual is expected to take up to 4 years. Patients will be 
on study for approximately 18 – 24 months.
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5
SUBJECT SELECTION
5.1
Inclusion criteria
Each prospective subject must meet ALL of the following inclusion criteria in order to be 
eligible for this study (except where noted):
1. Written informed consent granted prior to initiation of any study-specific screening 
procedures, given with the understanding that the patient has the right to withdraw from 
the study at any time, without prejudice.
2. 18 years of age or older.
3. Histologic or cytologic diagnosis of SCLC. (Note: Patients with mixed histology are not 
eligible.)
4. ECOG performance status of 0 or 1 (refer to Appendix B).
5. Presence of measurable disease as defined in with ≥ 1 lesion whose longest diameter can 
be accurately measured as ≥ 20 mm with conventional techniques or as ≥ 10 mm with 
spiral CT.
6. Previously 
treated 
SCLC 
with 
only 
one 
prior 
treatment 
regimen 
[cyclophosphamide/doxorubicin/vincristine (CAV) alternating with etoposide/cisplatin 
(EP) is acceptable].
7. Resolution of all acute toxic effects of prior chemotherapy, radiotherapy, hormonal 
therapy, or surgery to NCI-CTCAE version 4.0 Grade ≤1, except for diarrhea (which 
must be grade 0 without supportive antidiarrheal medications) and alopecia (any grade).
8. Adequate hematologic, liver, and renal function, defined as:
•
Platelet count ≥ 100 x 109/L
•
Hgb ≥ 9 gm/dL
•
Absolute neutrophil count (ANC) ≥ 1500/μL
•
Serum creatinine ≤ 1.5 mg/dL or creatinine clearance > 45 mL/min. Use either 
measured or calculated with Cockcroft -Gault formula (Appendix C)
•
Serum total bilirubin ≤ 1.5 x ULN
•
Aspartate Transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN or 
≤ 5 x ULN if caused by liver metastasis
9. Women of childbearing potential must have a negative pregnancy test performed within 
seven days prior to the start of study drug. Male and female subjects of child-bearing 
potential must agree to use double-barrier contraceptive measures, or avoidance of 
intercourse during the study and for 6 months after last investigational drug dose received
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5.2
Exclusion criteria
Potential subjects who meet ANY of the following exclusion criteria are not eligible for 
enrollment into this study:
1. Previous anti-cancer chemotherapy, immunotherapy or investigational agents < 4 weeks 
(6 weeks for nitrosoureas or mitomycin C) prior to the first day of study defined 
treatment. Palliative radiation < 2 weeks, biological therapy within 2 weeks, hormonal 
therapy within 1 week prior to Day 1 Cycle 1.
2. Prior treatment with a topoisomerase-I inhibitor (e.g., topotecan, irinotecan).
3. Prior malignancy except for non-melanoma skin cancer and carcinoma in situ, unless 
diagnosed and definitively treated more than 5 years prior to enrollment.
4. Substance abuses, medical, psychological or social conditions that may, in the opinion of 
the Investigator, interfere with the patient’s participation in the study or evaluation of the 
study results.
5. Known human immunodeficiency virus (HIV) infection due to concerns of potential drug 
interaction with various antiretroviral agents.
6. Pregnancy or breast-feeding.
7. Concurrent administration or received CYP3A4 inducers or inhibitors within 2 weeks 
prior to the first day of study drug treatment. Lists including medications and substances 
known or with the potential to interact with CYP3A4 are provided in Section 7.3.7.
8. Patients with chronic or acute GI disorders resulting in diarrhea of any severity grade; 
patients who are using chronic anti-diarrheal supportive care (more than 3 days/week) to 
control diarrhea in the 28 days prior to study entry.
9. Major surgery < 4 weeks or minor surgery (e.g. talc pleurodesis, excisional biopsy, etc) 
< 2 weeks prior to the first day of study defined treatment.
10. Have central nervous system (CNS) metastases (unless the patient has completed 
successful local therapy for CNS metastases and has been off corticosteroids for at least 
4 weeks before starting study therapy). Brain imaging is required in symptomatic patients 
to rule out brain metastases, but is not required in asymptomatic patients.
11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.
12. Unwilling or unable to follow protocol requirements.
5.3
Inclusion of Women and Minorities
This study will be available to all eligible subjects, regardless of race, gender, or ethnic origin. 
There is no information currently available regarding differential effects of this regimen in 
subsets defined by race, gender, or ethnicity, and there is no reason to expect such differences to 
exist. Therefore, although the planned analysis will, as always, look for differences in treatment 
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effect based on racial and gender groupings, the sample size is not increased in order to provide 
additional power for subset analyses.
5.4
Subject Withdrawal
It is the right and the duty of the investigator or co-investigator to stop treatment in any case in 
which emerging effects are of unacceptable risk to the individual subject. In addition, the 
investigator or co-investigator is to stop treatment of any subject with unmanageable factors that 
may interfere significantly with the trial procedures and/or the interpretation of results.
A subject must be discontinued from treatment for any of the following reasons:
•
The subject or legal representative (such as, a parent or legal guardian) withdraws 
consent.
•
Disease progression.
•
The development of unacceptable toxicity for which symptomatic treatment and/or dose 
reduction are not considered sufficient.
•
The development of an intercurrent condition precluding further administration of the 
treatment.
•
The investigator believes it is no longer in the best interest of the subject to receive 
treatment on the study.
•
Pregnancy of the subject.
•
Failure to comply with requirements of the study.
•
Administrative reasons (e.g., termination of the study by the Principal Investigator).
6
INVESTIGATIONAL PRODUCT
NKTR-102 will be provided by Nektar Therapeutics.
6.1
Active Substance and Source
The investigational drug product (NKTR-102 for Injection) is formulated as a sterile lyophilized 
powder of NKTR-102 in lactate buffer at pH 3.5, intended for dilution with commercially 
available 5% dextrose injection (w/w%; D5W) or 0.9% sodium chloride for injection before IV 
infusion. The pH of the formulation is in the range of 3.2 to 4.2, and NKTR-102 for Injection 
storage condition is 2°C to 8°C (with a shelf-life of 36 months).
NKTR-102 (drug substance) is light sensitive. The lyophilized drug product (NKTR-102 for 
Injection) will be supplied in 25 mL Type 1 amber colored glass vials packaged in cartons. Each 
carton will contain 10 vials of NKTR-102. Each vial contains lyophilized NKTR-102 equivalent 
to 100 mg of irinotecan. Each vial and carton will be labeled to comply with local regulations.
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6.2
Drug Shipment
NKTR-102 will be shipped to participating sites. Each site will document the date of receipt and 
condition of the shipment. Drug shipment records will be retained by the investigational 
pharmacist or designee.
6.3
Reconstitution and Handling
The NKTR-102 for injection vial is for single use only. Allow vial(s) to reach room temperature 
(approximately 30 minutes). 
Using pharmacy standard operating procedure, withdraw 20 mL of D5W from a 250 mL D5W 
infusion bag using sterile needle and syringe and inject into each vial of lyophilized study drug 
required for a given dose. The final concentration in the vial is now 5 mg/mL. Note: Normal 
Saline (0.9% w/w) may also be used as diluent for reconstitution. It is not necessary to 
remove overfill. 
Gently invert vial for 1-5 minutes until study drug has fully dissolved. Visually inspect vial 
contents for particulate matter and repeat inspection when study drug is withdrawn from vial into 
syringe. If any particulate matter is seen, return the syringe contents to the vial and invert several 
more times.
If the study drug does not fully dissolve and particulates or small matter is identified in the 
reconstituted NKTR-102, it is recommended that the reconstituted drug in question NOT be 
used. Please document in the investigational drug accountability log and prepare a new dose for 
the patient. Please also quarantine the drug in question and contact Nektar with the following 
additional information: 
i.
Details on how the NKTR-102 was reconstituted 
ii.
What diluents were used and in what volume(s)? 
iii.
How long was the drug product reconstituted for? 
Due to the high viscosity, the study drug solution in the syringe may contain trapped 
bubbles. This is normal. 
Inject the required volume of reconstituted study drug back into the 250 mL infusion bag. The 
final concentration of NKTR-102 in a 250 mL D5W or Normal Saline infusion bag must be 
within a range of 0. 2 to 1.6 mg/mL and 0.16 to 1.6 mg/mL respectively. 
Inspect the 250 mL infusion bag for particulates prior to infusion. If the particulates do not clear 
with gentle inversion, discard the bag, document in the investigational drug accountability log 
and inform Nektar.   
The reconstituted drug may be stored protected from direct ambient lighting at room temperature 
(15°C to 30°C) for up to 6 hours prior to start of infusion. Other drugs must not be added to the 
infusion solution.
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6.4
Storage and Stability
The Investigator or designate is responsible to store and dispense the investigational product and 
will ensure that study drug is securely maintained in a locked, limited-access facility, as specified 
by Nektar Therapeutics and in accordance with the applicable regulatory requirements.
Drug product NKTR-102 for injection and reconstituted infusion solution can be handled in 
normal room lighting, but should be protected from extensive exposure to light. It is not 
necessary to cover the IV bag and administration set with sheathing or aluminum foil. 
All study drug supplies must be kept in a locked limited access room within the carton they are 
packaged and refrigerated at 2ºC to 8ºC, as specified on the drug label.
6.5
Handling and Disposal
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by Nektar Therapeutics exercising accepted medical and 
pharmaceutical practices. Study drugs must be handled as cytotoxic agents and appropriate 
precautions taken per the institution’s environmentally safe handling procedures. All 
investigational drugs will be dispensed in accordance with the Investigator’s prescription or 
written order.
All products dispensed will be recorded on a product accountability record. Records of product 
lot numbers and dates received will be entered on a product accountability form. This record will 
be reviewed by the Sponsor’s staff or representative during periodic monitoring visits. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
Used vials (excess drug), expired product, and unused vials will be destroyed according to 
standard practices at the site after properly accounting for the dispensing. Partially used vials of 
study drug will not be re-used for other subjects.
7
TREATMENT PLAN
7.1
Dosage and Administration
NKTR-102 will be administered 145 mg/m2 IV dose over a 90-minute period once every 
3 weeks. Cycles will be repeated every 21 days (± 3 days). The patient’s actual weight at 
baseline (Day 1 of Cycle 1) will be used. It is not necessary to correct dosing based on ideal body 
weight. If the patient’s weight changes by > 10% during the course of the study, the body surface 
area and drug doses should be recalculated.
Treatment will be administered in an outpatient basis. Reported adverse events (AEs) and 
potential risks are described in Investigator’s Brochure. Appropriate dose modifications are 
described in Section 7.2. No other investigational or commercial drugs or therapies other that 
those described below may be administered with the intent to treat the subject.
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7.2
Dose Modification Due to Toxicity
All AEs should be assessed according to the NCI-CTCAE version 4.0. In the event of multiple 
toxicities, dose delays and modifications should occur in accordance with the worst toxicity 
observed. NKTR-102 dose modifications (reductions or delays) must be recorded for each 
patient in the appropriate section of the electronic case report form (eCRF).
7.2.1
Retreatment Criteria
To ensure safe use of NKTR-102, subjects must meet requirements with respect to hematopoietic 
function (Hgb ≥ 8.0 g/dL; ANC ≥ 1.5 x 109/L; platelets ≥ 75 x 109/L) prior to initiation of 
subsequent cycles. Diarrhea must be fully resolved to Grade 0 for at least 7 days without 
supportive antidiarrheal measures prior to retreatment. Any non-hematologic toxicities must 
have resolved to baseline or Grade 1 except for alopecia. Supportive care may be implemented in 
order to ameliorate diarrhea, nausea, vomiting, or myelosuppression. Dose reductions may also 
be implemented for subjects who experience recurrent or specific severe toxicities.
7.2.2
Treatment Delay
If the patient fails to meet the criteria for re-treatment, treatment may be delayed, followed by an 
additional evaluation to determine feasibility of retreatment. Initiation of subsequent doses may 
be delayed for a maximum of 28 days to allow recovery from any toxicity to permit retreatment. 
Subjects whose treatment delays are ≥ 14 days but ≤ 28 days due to a drug-related toxicity must 
initiate their next treatment cycle with a dose reduction. Subjects who require > 28 days delay 
due to unresolved toxicity must be withdrawn from treatment, unless, in the Investigator’s 
opinion, continuing in the study is of benefit for the patient. In this case, the reason of 
continuation must be documented.
7.2.3
Dose Reductions
NKTR-102 doses for an individual patient may be reduced 25 mg/m2 based on conditions listed 
in the Table 3 below. Only 2 dose reductions are permitted. Subjects should be discontinued 
from the study treatment if toxicity requires a dose reduction beyond the 2 dose reduction steps. 
Dose re-escalation for NKTR-102 is not permitted.
Table 3.
Dose Modifications Based on Toxicities
Toxicity
NCI CTCAE 
Grade
During a Cycle:
Recommended Guidelines for 
Management and Supportive Care
Day 1 of New Cycle:
Dose Modifications Based on Worst 
Toxicity in Prior Cycle
Thrombocytopenia / Anemia / Neutropenia / Febrile Neutropenia
Grade 1 or Grade 2
-
Maintain dose level
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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 Hgb ≥ 8 g/dL or 80 g/L; 
ANC ≥ 1.5 x 109/L; platelets 
≥ 75 x 109/L, with a maximum of 
28 days.
↓ 1 dose level after 1st occurrence.
↓ 1 dose level after 2nd occurrence.
Discontinue patient after 3rd occurrence.
Grade 4
Platelets: consider platelet transfusion if 
platelets < 20K or with active bleeding.
ANC: consider growth factor support in 
accordance with local guidelines. 
Antibiotic (Fluoroquinolones) should be 
initiated 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 Hgb > 8 g/dL or 80 g/L; 
ANC > 1.5 x 109/L; 
platelets > 75 x 109/L, with a maximum 
of 28 days.
↓ 1 dose level after 1st occurrence.
↓ 1 dose level after 2nd occurrence.
Discontinue patient after 3rd occurrence.
Febrile 
Neutropenia
Subjects should be hospitalized 
immediately for IV antibiotic therapy if 
they develop neutropenic fever or sepsis 
(e.g., growth factor support; antibiotics); 
consider hospital admission.
↓ 1 dose level after 1st 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 
fluoroquinolones) if the patient develops 
ileus, fevers or Grade 3/4 neutropenia. 
Subjects 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 of supportive care.
Stop supportive care after the patient is 
48 hour without diarrhea.
Confirm with the patient that diarrhea is no 
longer present for > 7 days without having 
received supportive care prior to 
retreatment.
Treatment may be delayed up to 28 days; 
after this, contact Medical Monitor.
Grade 1
If still present within 7 days prior to 
treatment hold therapy until diarrhea is 
no longer present for ≥ 7 days without 
having received supportive care.
Maintain dose level; consider prophylactic 
anti-diarrheal supportive care
Grade 2
If still present within 7 days prior to 
treatment hold therapy until diarrhea is 
no longer present for ≥ 7 days without 
having received supportive care.
↓ 1 dose level after 1st occurrence.
↓ 1 dose level after 2nd occurrence.
Discontinue patient after 3rd occurrence.
Grade 3/4
If still present within 7 days prior to 
treatment hold therapy until diarrhea is 
no longer present for ≥ 7 days without 
having received supportive care.
↓ 2 dose level after 1st occurrence.
Provided that adequate supportive care has 
been given to the patient, discontinue 
patient after 2nd occurrence. If the patient 
has not received adequate supportive care, 
retreatment may be attempted for a  2nd 
episode of Grade 3 diarrhea (re-instruct 
patient on supportive care).
Patients must be discontinued for a 2nd 
episode of Grade 4 diarrhea. 
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Dehydration
Grade 1 or Grade 2
Consider anti-emetic and/or anti-diarrheal 
therapy.
If Grade 2 present on a treatment day, 
hold therapy for a week or until toxicity 
resolves to baseline or Grade ≤ 1, with a 
maximum of 28 days.
Consider prophylactic anti-emetic 
therapy.
Maintain dose level.
Grade 3
Use anti-emetic and/or anti-diarrheal 
therapy.
If present on a treatment day, hold 
therapy for a week or until toxicity 
resolves to baseline or Grade ≤ 1, with a 
maximum of 28 days.
Consider prophylactic anti-emetic 
therapy.
↓ 1 dose level after 1st occurrence;
↓ 1 dose level after 2nd occurrence
Discontinue patient after 3rd occurrence
Grade 4
Use anti-emetic therapy and IV fluids.
Consider hospital admission.
If present on a treatment day, hold 
therapy for a week or until toxicity 
resolves to baseline or Grade ≤ 1, with a 
maximum of 28 days.
Use prophylactic anti-emetic therapy.
↓ 2 dose level after 1st occurrence.
Discontinue patient after 2nd occurrence.
Nausea / Vomiting / Abdominal Pain
Grade 1 or Grade 2
Consider anti-emetic therapy.
If Grade 2 present on a treatment day, 
hold therapy for a week or until toxicity 
resolves to baseline or Grade ≤ 1, with a 
maximum of 28 days.
Consider prophylactic anti-emetic 
therapy.
Maintain dose level.
Grade 3 or Grade 4
Use anti-emetic therapy.
Consider administration of IV fluids.
If present on a treatment day, hold 
therapy for a week or until toxicity 
resolves to baseline or Grade ≤ 1, with a 
maximum of 28 days.
After 1st occurrence use prophylactic 
anti-emetic therapy and maintain dose 
level
↓ 1 dose level after 2nd occurrence
Discontinue patient after 3rd occurrence
Other Drug-Related Non-Hematologic Toxicities (Except Fatigue/Asthenia and Alopecia)
Grade 1 or Grade 2
Consider supportive care as appropriate.
If Grade 2 present on a treatment day, 
hold therapy for a week or until toxicity 
resolves to baseline or Grade ≤ 1, with a 
maximum of 28 days.
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 Grade 4
Use supportive care as appropriate.
If present on a treatment day, hold 
therapy for a week or until toxicity 
resolves to baseline or Grade ≤ 1, with a 
maximum of 28 days.
↓ 1 dose level after 1st occurrence; 
supportive care as appropriate.
↓ 1 dose level after 2nd occurrence.
Discontinue patient after 3rd occurrence.
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7.3
Concomitant Medication and Supportive Care
7.3.1
Anti-Emetic Therapy
Prophylactic anti-emetics will be allowed according to standard practices.
Based on investigator discretion, an investigator may prescribe prophylactic antiemetics prior to 
the first dose of the study drugs. The patient must be carefully monitored throughout the study 
period, and given adequate fluid and electrolyte replacement to prevent dehydration and 
electrolyte imbalance. Dexamethasone, ondansetron, lorazepam or prochlorperazine can be given 
at the discretion of the treating physician.
7.3.2
Anti-Diarrheal Therapy
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 not 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.
Prophylactic antidiarrheal medications should not be used, as they can confound the evaluation 
of recovery to Grade 0 and monitoring of diarrhea associated with NKTR-102. Use of 
antidiarrheal medications for the treatment of diarrhea or loose stool is mandatory.
Guidelines for the treatment of diarrhea include:
1. Each patient must be instructed to immediately begin taking loperamide at the very first 
episode of poorly formed or loose stools or the earliest onset of bowel movements that 
are more frequent than normally expected for the patient.
2. One dosage regimen for loperamide used in clinical trials consisted of the following: 
4 mg at the first onset of diarrhea and then 2 mg every 2 hours until the patient is 
diarrhea-free for at least 12 hours. Loperamide is not recommended to be used for more 
than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the 
night, the patient may take 4 mg of loperamide every 4 hours.
3. The use of concomitant drugs with laxative properties should be avoided because of the 
potential for exacerbation of diarrhea. Patients must be advised to contact their physician 
to discuss any laxative use.
4. Patients must be instructed to contact their physician or nurse if any of the following 
occur: diarrhea for the first time during study drug treatment; black or bloody stools; 
symptoms of dehydration such as excessive thirst, dry lips and mouth, lightheadedness, 
dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; 
inability to get diarrhea under control within 24 hours; or fever or evidence of infection.
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5. Patients who are dehydrated must promptly receive adequate IV fluids, electrolytes to 
combat electrolyte imbalance if present and antibiotics in case of fever. Serial complete 
and differential blood counts must be done for early identification of the concomitant 
occurrence of neutropenia.
7.3.3
Platelet Transfusion
Patients may receive transfusions (platelets or blood products) at the Investigator’s discretion. If 
platelet count < 20,000/mm3, 1 unit single-donor apheresis platelet transfusion may be given. A 
post-transfusion platelet count should be collected at 15 minutes post-transfusion to demonstrate 
increment.
7.3.4
Growth Factor Use
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 the local institution. 
If a patient required growth factor support during a previous cycle, a patient may be administered 
prophylactic growth factor support during a subsequent cycle at the investigator’s discretion.
7.3.5
Other Antineoplastic Therapy
The administration of other antineoplastic therapy (e.g., chemotherapy, hormone therapy, 
immunotherapy, targeted therapy, monoclonal antibodies and radiation therapy) is not permitted. 
Patients requiring radiation therapy after the start of the study are considered as having 
progression of disease and must discontinue study treatment.
7.3.6
Bisphosphonates and Denosumab
Patients may continue or start Bisphosphonates and Denosumab if required during the study.
7.3.7
Medications NOT ALLOWED During Study (P450 inhibitors/inducers)
Because there is a potential for interaction of drug with other concomitantly administered drugs 
through the cytochrome P450 system, the electronic case report form (eCRF) must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies. The 
Investigator should be alerted if the subject is taking any agent known to affect or with the 
potential to affect selected CYP450 isoenzymes.
In vitro drug interaction studies of NKTR-102 with cytochrome P450 3A4 enzyme (CYP3A4) 
have not been done. However, drug interactions have been documented between CYP3A4 
enzymes and irinotecan and are listed in the Camptosar® USPI August 2010. Please refer to the 
Camptosar® package insert for further information.
St. John’s Wort: St. John’s Wort is an inducer of CYP3A4 enzymes. Exposure to the active 
metabolite SN-38 is reduced in patients receiving concomitant St. John’s Wort. St. John’s Wort 
should be discontinued at least 2 weeks prior to the first cycle of irinotecan, and St. John’s Wort 
is contraindicated during irinotecan therapy.
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Anticonvulsants: Exposure to irinotecan and its active metabolite SN-38 is substantially reduced 
in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing 
anticonvulsants phenytoin, phenobarbital or carbamazepine. The appropriate starting dose for 
patients taking these anticonvulsants has not been formally defined. The following drugs are also 
CYP3A4 inducers: rifampin, rifabutin. For patients requiring anticonvulsant treatment, 
consideration should be given to substituting non-enzyme inducing anticonvulsants at least 
2 weeks prior to initiation of NKTR-102 therapy. Dexamethasone does not appear to alter the 
pharmacokinetics of irinotecan.
Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 enzymes. Patients receiving 
concomitant ketoconazole have increased exposure to irinotecan and its active metabolite SN-38. 
Patients should discontinue ketoconazole at least 1 week prior to starting irinotecan therapy and 
ketoconazole is contraindicated during irinotecan therapy.
Neuromuscular blocking agents: Interaction between irinotecan and neuromuscular blocking 
agents cannot be ruled out. Irinotecan has anticholinesterase activity, which may prolong the 
neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-
depolarizing drugs may be antagonized.
Atazanavir sulfate: Coadministration of atazanavir sulfate, a CYP3A4 and UGT1A1 inhibitor 
has the potential to increase systemic exposure to SN-38, the active metabolite of irinotecan. 
The Principal Investigator should be contacted with any questions related to concomitant 
medications (from 4 weeks prior to the first dose of NKTR-102 through 4 weeks after the last 
dose of NKTR-102).
7.4
Duration of Treatment
Subjects may remain on study treatment in the absence of disease progression, unacceptable 
toxicity, and withdrawal from study or study termination. Patients who develop metastases in the 
central nervous system (CNS) as the only site of disease progression could receive therapeutic 
whole brain radiation therapy (WBRT), or gamma knife radiosurgery and after completion of 
WBRT continue on NKTR-102. Imaging studies are scheduled to be obtained after every other 
21-day cycle.
7.5
Treatment Discontinuation
Upon treatment discontinuation all end of treatment evaluations and tests will be conducted. All 
subjects who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, 
or until abnormal laboratory findings have returned to acceptable or pre-study limits. The final 
status of the AE will be reported in the subject’s medical records and the appropriate eCRF.
Reasons for treatment discontinuation should be classified as follows:
•
Death
•
Progressive disease
•
Treatment-related toxicity


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•
Toxicity unrelated to treatment
•
Noncompliance
•
Investigator judgment
o
The Investigator may withdraw a subject if, in his/her judgment, it is in the 
subject’s best interest to do so.
•
Subject voluntary withdrawal
o
A subject may withdraw from the study at any time, for any reason. If a subject 
discontinues treatment, an attempt should be made to obtain information 
regarding the reason for withdrawal.
Subjects who are unavailable for follow-up evaluations should be classified as lost to follow-up 
for 1 of the following reasons:
•
Lost to follow-up: For a subject to be considered lost to follow-up, the investigator must 
make 2 attempts to re-establish contact with the subject. The attempts to re-establish 
subject contact must be documented (e.g., certified letter).
•
Death: Date and cause of death will be recorded for those subjects who die within 
30 days after last dose of study drug (telephone contact is acceptable).
7.6
Compliance
On Day 1 of each treatment cycle, study-treatment administration will be documented on the 
eCRF. Any deviations from the protocol-specified study drug administration will be 
documented, including the date and reason for each dosing noncompliance.
7.7
Subject Randomization and Registration
This is a non-randomized study. Patients will be categorized into two groups depending on their 
prior response to treatment. Group A (chemoresistant group) includes patients progressing 
< 3 months after first-line therapy and Group B (chemosensitive group) includes patients 
progressing ≥ 3 months after first-line therapy.
7.8
Baseline Evaluations
The following will be performed ≤ 14 days prior to initiation study drug:
•
Informed consent: Must be completed prior to receiving any study-related procedures.
•
Medical history (Full history)
•
Physical examination, including vital signs, body weight, and height
•
ECOG performance status
•
Adverse events evaluation
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•
Tumor assessment by CT/PET or CT scan should be performed within 28 days prior to 
initiation of study drug
•
CT scan/MRI brain (brain imaging is required in symptomatic patients to rule out brain 
metastases, but not required in asymptomatic patients)
•
Pregnancy test (urine or serum) in females of childbearing potential. Must be done 
≤ 7 days prior to initiation of study drug.
•
Coagulation (INR, PTT)
•
Hematology (4 hour fasting) (i.e., complete blood count (CBC) with automated 
differentials or the physician discretion; WBC, RBC, HGB, HCT, platelet, MCV, MCH, 
MCHC, %neutrophils, absolute neutrophils, %lymphocytes, absolute lymphocytes, 
%monocytes, absolute monocytes, %eosinophils, absolute eosinophils, %basophils, 
absolute basophils, %Large Unspecified Cells (LUC), %lymphocyte total, absolute 
lymphocyte total, platelet confirmation, and differential confirmation)
•
Chemistry (4 hour fasting) (i.e., complete metabolic panel (CMP): chloride, CO2, 
potassium, sodium, BUN, glucose, calcium, creatinine, total protein, albumin, total 
bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol 
(Calc), anion gap
•
12-Lead ECG. The patient will be asked to lie down and rest for about 10 minutes before 
this procedure.
7.9
Evaluations Performed on Cycle 1 Day 1
•
Medical history (Updated from previous clinical visit)
•
Physical examination, including vital signs and body weight
•
ECOG performance status
•
Adverse events evaluation
•
Hematology (4 hour fasting) (i.e., complete blood count (CBC) with automated 
differentials or the physician discretion; WBC, RBC, HGB, HCT, platelet, MCV, MCH, 
MCHC, %neutrophils, absolute neutrophils, %lymphocytes, absolute lymphocytes, 
%monocytes, absolute monocytes, %eosinophils, absolute eosinophils, %basophils, 
absolute basophils, %Large Unspecified Cells (LUC), %lymphocyte total, absolute 
lymphocyte total, platelet confirmation, and differential confirmation)
•
Chemistry (4 hour fasting) (i.e., complete metabolic panel (CMP): chloride, CO2, 
potassium, sodium, BUN, glucose, calcium, creatinine, total protein, albumin, total 
bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol 
(Calc), anion gap
•
Pharmacogenetic blood sample
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7.10 Evaluations Performed Weekly for Cycle 1
•
Medical history (Updated from previous clinical visit)
•
Physical examination, including vital signs and body weight
•
ECOG performance status
•
Adverse events evaluation
•
Hematology (4 hour fasting) (i.e., complete blood count (CBC) with automated 
differentials or the physician discretion; WBC, RBC, HGB, HCT, platelet, MCV, MCH, 
MCHC, %neutrophils, absolute neutrophils, %lymphocytes, absolute lymphocytes, 
%monocytes, absolute monocytes, %eosinophils, absolute eosinophils, %basophils, 
absolute basophils, % Large Unspecified Cells (LUC), %lymphocyte total, absolute 
lymphocyte total, platelet confirmation, and differential confirmation)
•
Chemistry (4 hour fasting) (i.e., complete metabolic panel (CMP): chloride, CO2, 
potassium, sodium, BUN, glucose, calcium, creatinine, total protein, albumin, total 
bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol 
(Calc), anion gap
7.11 Evaluations Performed Prior to Treatment on Day 1 of Subsequent Cycles
•
Medical history (Updated from previous clinical visit)
•
Physical examination, including vital signs and body weight
•
ECOG performance status
•
Adverse events evaluation
•
Hematology (4 hour fasting) (i.e., complete blood count (CBC) with automated 
differentials or the physician discretion; WBC, RBC, HGB, HCT, platelet, MCV, MCH, 
MCHC, %neutrophils, absolute neutrophils, %lymphocytes, absolute lymphocytes, 
%monocytes, absolute monocytes, %eosinophils, absolute eosinophils, %basophils, 
absolute basophils, %Large Unspecified Cells (LUC), %lymphocyte total, absolute 
lymphocyte total, platelet confirmation, and differential confirmation)
•
Chemistry (4 hour fasting) (i.e., complete metabolic panel (CMP): chloride, CO2, 
potassium, sodium, BUN, glucose, calcium, creatinine, total protein, albumin, total 
bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol 
(Calc), anion gap
•
12-Lead ECG (prior to Cycle 2 and Cycle 3, if clinically indicated). The patient will be 
asked to lie down and rest for about 10 minutes before this procedure.
•
Radiological assessments (same method as baseline) to be performed every other cycle 
after completing Cycle 2. Confirmation of objective tumor responses should be 
performed consistent with RECIST 1.1.
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7.12 Evaluations Performed at 30 Day Follow-Up
•
Medical history (Updated from previous clinical visit)
•
Physical examination, including vital signs and body weight
•
ECOG performance status
•
Adverse events evaluation
•
Hematology (4 hour fasting) (i.e., complete blood count (CBC) with automated 
differentials or the physician discretion; WBC, RBC, HGB, HCT, platelet, MCV, MCH, 
MCHC, %neutrophils, absolute neutrophils, %lymphocytes, absolute lymphocytes, 
%monocytes, absolute monocytes, %eosinophils, absolute eosinophils, %basophils, 
absolute basophils, %Large Unspecified Cells (LUC), %lymphocyte total, absolute 
lymphocyte total, platelet confirmation, and differential confirmation)
•
Chemistry (4 hour fasting) (i.e., complete metabolic panel (CMP): chloride, CO2, 
potassium, sodium, BUN, glucose, calcium, creatinine, total protein, albumin, total 
bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol 
(Calc), anion gap
7.13 Survival Follow-up
•
Patients will also be followed for survival every 3 months following the 30 day follow-up 
visit. Survival follow-up assessments may be collected via telephone.
7.14 Schedule of Procedures and Observations
The schedule of procedures and observations for this study is summarized in Table 4 below.
Table 4.
Schedule of Procedures and Observations
Cycle 1
Tests and Procedures
Screening 
(≤ 14 Days 
Prior to 
Initiation of 
Study 
Drug)
Day 1
Weekly1
(± 2 days)
Prior to 
treatment 
on Day 1 of 
Subsequent 
Cycles 
(± 3 days) 
30 Day 
Follow-
Up
(± 7 days)
Survival 
Follow-
Up
Informed Consent
X
Medical History
X2
X3
X3
X3
X3
Physical Exam, (including 
vital signs, body weight, 
height)4
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
Adverse Event Evaluation
X
X5
X
X
X
Tumor Assessment
X6
X7
CT Scan/MRI Brain
X8
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Tests and Procedures
Screening 
(≤ 14 Days 
Prior to 
Initiation of 
Study 
Drug)
Cycle 1
Prior to 
treatment 
on Day 1 of 
Subsequent 
Cycles 
(± 3 days) 
30 Day 
Follow-
Up
(± 7 days)
Survival 
Follow-
Up
Day 1
Weekly1
(± 2 days)
Pregnancy Test (urine or 
serum)
X9
Coagulation (INR, PTT)
X
Hematology (4 hour fasting)10
X
X
X
X
X
Chemistry (4 hour fasting)11
X
X
X
X
X
Pharmacogenetic Blood 
Sample
X12
12-Lead ECG13
X
X14
Survival Follow-Up
X15
1
Patients will be evaluated weekly during Cycle 1 only. Complete physical examination is not mandatory but 
will be performed as needed at the discretion of the treating physician.
2
Full medical history.
3
Updated medical history from previous clinical visit.
4
Height collected at baseline only.
5
Reassess the patient for adverse events just prior to administration of the first dose of study drug on Day 1 
Cycle 1. (Reassess adverse events on Day 1 of subsequent cycles and modify dose if necessary according to the 
dose modification Table 3, if clinically indicated, for Grade 2 or higher adverse events).
6
Imaging studies such as chest x-ray, CT scans, PET-CT, and MRIs can be performed ≤ 28 days prior to 
initiation of study drug. Use same imaging throughout the study. Assessment by physical exam should be done 
≤ 14 days prior to initiation of study drug. If using PET-CT, use the CT portion to obtain measurements.
7
Tumor assessment must be performed at least every other cycle after completing Cycle 2. Tumor assessment 
may be performed ± 3 days  prior to treatment on Day 1 of subsequent cycles. Tumor assessment should be 
performed at any time during the treatment cycle that disease progression is clinically suspected so that patient 
can go off treatment and receive other therapy. If PET-CT was used at baseline, CT only may be used for 
subsequent cycles.
8
Brain imaging is required in symptomatic patients to rule out brain metastases, but is not required in 
asymptomatic patients.
9
Women of childbearing potential only. Must be done ≤ 7 days prior to initiation of study drug.
10
Hematology (i.e., complete blood count (CBC) with automated differentials or the physician discretion; WBC, 
RBC, HGB, HCT, platelet, MCV, MCH, MCHC, %neutrophils, absolute neutrophils, %lymphocytes, absolute 
lymphocytes, %monocytes, absolute monocytes, %eosinophils, absolute eosinophils, %basophils, absolute 
basophils, %Large Unspecified Cells (LUC), %lymphocyte total, absolute lymphocyte total, platelet 
confirmation, and differential confirmation).
11
Chemistry (i.e., complete metabolic panel (CMP): chloride, CO2, potassium, sodium, BUN, glucose, calcium, 
creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine 
ratio, osmol (Calc), anion gap).
12
Pharmacogenetic blood sample collection will be obtained at Day 1 of Cycle 1.
13 The patient will be asked to lie down and rest for about 10 minutes before this procedure.
14
Prior to Cycle 2 and Cycle 3, if clinically indicated.
15
Survival follow-up assessments may be collected via telephone.
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7.15 Pharmacogenetics
7.15.1 Blood Sample Collection and Processing
Peripheral blood will be collected from enrolled patients at C1 D1 into (1) 10 mL EDTA 
lavender top tube. Genomic DNA will be extracted from the blood samples, using the QIAamp 
DNA isolation kit from Qiagen (Valencia, CA) and following the manufacturer’s instructions.
7.15.2 Sample Handling and Shipment
Whole blood samples collected at RPCI will be sent on ice for processing the same day of 
collection.
Whole blood samples collected at participating sites will be frozen and stored at -70° until 
batched shipped monthly Monday - Thursday. Do not ship specimens on Fridays or on day 
before a holiday. Packaging should be clearly labelled as follows with e-mail notification:
Roswell Park Cancer Institute
Grace Cancer Drug Center (GCDC) Room 151
Attn: Mateusz Opyrchal – I 225612
Elm & Carlton Streets
Buffalo, New York 14263
716-845-4695
Mateusz.Opyrchal@RoswellPark.org
8
EFFICACY EVALUATIONS
8.1
Objective Tumor Response
All protocol-defined imaging studies must be performed at the investigative site or sponsor-
approved facility using protocol-defined parameters. 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. RECIST 1.1 will be used to assess objective tumor response.
8.2
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, will be identified as target lesions and recorded and 
measured at baseline. Target lesions will be selected on the basis of their size. Lesions with the 
longest diameter (short axis for lymph nodes) and are ≥ 10 mm (CT and MRI), ≥ 15 mm lymph 
nodes, > 20 mm CXR and are for accurate repetitive measurements (either by imaging 
techniques or clinically) will be chosen. A sum of the longest diameter (short axis for lymph 
nodes) of all target lesions will be calculated and reported as the baseline sum diameters. This 
will be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease.
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•
Complete Response (CR): Disappearance of all target lesions. Any lymph nodes must have 
a reduction in short axis to < 10 mm. Changes in tumor measurements must be confirmed by 
repeat studies performed no less than 6 weeks after the criteria for response are first met.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. Changes in tumor measurements must be 
confirmed by repeat studies performed no less than 6 weeks after the criteria for response are 
first met.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as references 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. The appearance of one or more new lesions is also 
considered progression.
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameter while on study. Subjects having 
a documented response with no confirmation of the response will be listed with stable 
disease.
8.3
Non-Target Lesions
All other small lesions (longest diameter < 10 mm or lymph nodes ≥ 10 mm to < 15 mm short 
axis) and non-measurable lesions (i.e., leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, blastic bone 
lesions, or abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by imaging) should be identified as non-target lesions and indicated as present in the 
source documents at baseline. The general location will also be documented on the images 
drawing a regularly-shaped Region of Interest. Measurements of the non-target lesions will not 
be performed, but the presence or absence of each should be noted throughout follow-up and 
evaluation.
•
Complete Response: Disappearance of all non-target lesions and normalization of tumor 
marker level, if applicable. All lymph nodes must be non-pathological in size (< 10 mm short 
axis).
•
Non-Complete Response/Non-Progressive Disease: Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the upper limits of normal.
•
Progressive Disease: Appearance of 1 or more new lesions or the unequivocal progression 
of existing non-target lesions. Although a clear progression of non-target lesions is 
exceptional, in such circumstances, the opinion of the treating physician should prevail and 
the progression status should be confirmed at a later time.
8.4
Evaluation of Response
Time point response assessments will be performed every other cycle (timed to coincide with the 
end of a cycle) with a confirmatory assessment (required for non-randomized trials) no less than 


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4 weeks after a PR or CR is deemed. To determine time point response, refer to Table 5 and 
Table 6.
Table 5.
Time Point Response Criteria (+/- non-target disease)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Table 6.
Time Point Response Criteria (non-target disease only)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD1
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
1
Non-CR/non-PD is preferred over SD for non-target disease since SD is used as endpoint for assessment of 
efficacy in trials so to assign this category when no lesions can be measured is not advised.
The best overall response is the best response recorded from the start of study treatment until 
progression or death or discontinuation for any reason (the end of treatment taking into account 
any requirement for confirmation). In general, the subject’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria and will be 
determined by combining the subject’s status of target lesions, non-target lesions, and new 
lesions.
•
Symptomatic Deterioration: Subjects with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time, 
and not related to study treatment or other medical conditions should be reported as 
progressive disease due to “symptomatic deterioration.” Every effort should be made to 
document objective progression even after discontinuation of treatment due to symptomatic 
deterioration. Symptomatic deterioration that may lead to discontinuation of treatment 
include, but is not limited to, symptoms such as:
o
Weight loss > 10% of body weight.
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o
Worsening of disease-related symptoms (e.g., worsening dyspnea, increasing 
pain/increasing requirement for narcotic analgesics).
o
Decline in performance status of > 1 level on ECOG scale.
8.5
Confirmation Measurement
The main goal of confirmation of objective response in clinical trials is to avoid overestimating 
the response rate observed. This aspect of response evaluation is particularly important in 
nonrandomized trials where response is the primary endpoint. In this setting, to be assigned a 
status of partial response or complete response, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed no less than 4 weeks after the criteria 
for response are first met. Longer intervals as determined by the study protocol may also be 
appropriate.
In the case of stable disease, measurements must have met the stable disease criteria at least once 
after study entry at a minimum interval (in general, not less than 6 – 8 weeks).
8.6
Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination 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 (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.
•
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.
•
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g., for body scans).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
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the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible.
•
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements. 
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time. Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed.
•
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances.
•
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation 
is not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint.
•
Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a subject to be considered in 
complete clinical response.
•
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
•
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG PET imaging can be identified according to the following algorithm:
•
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
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•
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
•
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. 
The use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease-specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity.
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
9
SAFETY EVALUATION
9.1
Adverse Events
9.1.1
Definition
 An adverse event or adverse experience (AE) is any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can 
be ANY unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product (attribution of ‘unrelated’, 
‘unlikely’, ‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
9.1.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
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9.1.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
9.1.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 x the upper limit of normal associated with 
cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event 
CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated serum potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
9.1.1.4 Preexisting Medical Conditions (Baseline Signs and Symptoms)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
9.1.2
Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP 
Version 4 
of 
the 
CTCAE 
is 
identified 
and 
located 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. AEs not covered by 
specific terminology listed should be reported with common medical terminology, and 
documented according to the grading scales provided in the CTCAE Version 4.
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The relationship of event to study drug will be documented by the Investigator as follows:
•
Unrelated: The event is clearly related to other factors such as the patient’s clinical state, 
other therapeutic interventions or concomitant drugs administered to the patient.
•
Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the patient’s clinical state, other therapeutic 
interventions, or concomitant drugs.
•
Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the patient’s 
clinical state, other therapeutic interventions or concomitant drugs.
•
Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot 
be reasonably explained by other factors such as the patient’s clinical state, therapeutic 
interventions or concomitant drugs.
•
Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the patient’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, improves 
upon stopping the drug, or reappears on re-exposure.
9.1.3
Reporting Adverse Events
Table 7.
Guidelines for Routine Adverse Event Reporting for Phase II Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
•
Routine AEs occurring between the start date of intervention until 30 days after the last 
intervention or until the event has resolved, the study patient is lost to follow-up, the start of 
a new treatment, or until the study investigator assesses the event(s) as stable or irreversible, 
will be reported. New information will be reported after it is received.
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9.2
Serious Adverse Events
9.2.1
Definition
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:
•
Death.
•
A life-threatening adverse event (experience). Any AE that places a patient or patient, in 
the view of the Investigator or sponsor, at immediate risk of death from the reaction as it 
occurred. It does NOT include an AE that, had it occurred in a more severe form, might 
have caused death.
•
Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).
•
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.
•
A congenital anomaly or birth defect.
•
Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
patient and may require medical or surgical intervention to prevent one of the outcomes 
listed above.
9.2.2
Reporting Serious Adverse Events
All new SAEs occurring from the date the patient signs the study consent until 30 days after the 
last intervention or a new treatment is started, whichever comes first, will be reported. The RPCI 
SAE Source Form is to be completed with all available information, including a brief narrative 
describing the SAE and any other relevant information. 
SAEs occurring after the 30 day follow up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported.
SAEs identified as an Unanticipated Problem by the Investigator must be reported. Please refer 
to Section 9.5.2 for details on reporting Unanticipated Problems.
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9.3
Investigator Reporting: Notifying Nektar Therapeutics
Nektar is to be notified within 24 hours of first knowledge of the investigator 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 whether or not considered related to study treatment. To report such 
events, an FDA MEDWATCH form (whether initial or follow-up) must be completed by the 
investigator and transmitted to Nektar by fax. In addition, once each calendar quarter, the 
investigator must also provide a list of all adverse events observed during the study to Nektar. 
Network sites will notify Nektar directly (see Appendix A).
Nektar Drug Safety Department
Primary Fax: 1-85-482-7233
Backup Fax: 1-415-482-5410
In case of fax difficulties or questions regarding reporting SAEs please contact:
Email: Pharmacovigilance@nektar.com
General Telephone: 415-482-2300
Nektar Medical Contact
Mary Tagliaferri, M.D.
Nektar Therapeutics
455 Mission Bay Boulevard South
San Francisco, California 94158 USA
Office Phone: 415-482-5416
Cell Phone: 415-480-9100
9.3.1
E-Mail: mtaqliaferri@nektar.comFollow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study patient is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as 
stable or irreversible. New information will be reported when it is received.
9.4
Unanticipated Problems
9.4.1
Definition
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:
•
Unexpected (in terms of nature, severity, or frequency) given:
o
The research procedures that are described in the study-related documents, 
including study deviations, as well as issues related to compromise of subject 
privacy or confidentiality of data.
o
The characteristics of the patient population being studied.
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•
Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research).
•
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized 
and if in relation to an AE is also deemed Serious per Section 9.2.
9.4.2
Reporting Unanticipated Problems
Unanticipated problem reporting will begin at the time of participant consent. The Unanticipated 
Problem Form will be submitted to the CRS Compliance Office within 1 business day of 
becoming aware of the Unanticipated Problem.
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS Compliance with an updated Unanticipated Problem Form. The site 
Investigator or designated research personnel will report all unanticipated problems, whether 
related or unrelated to the investigational agent(s) to the IRB in accordance with their local 
institutional guidelines.
Network sites please see Appendix A for reporting instructions.
9.5
FDA Reporting
When RPCI is the IND holder the following describes the FDA reporting requirements by 
timeline for AEs and new safety findings that meet the criteria outlined below:
Within 7 Calendar Days
Any adverse event that meets ALL the following criteria:
•
Related or possibly related to the use of the study drug;
•
Unexpected; and
•
Fatal or life-threatening.
Within 15 Calendar Days
Any adverse event that meets ALL the following criteria:
•
Related or possibly related to the use of the study drug;
•
Unexpected; and
•
Serious but not fatal or life-threatening.


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Or, meets ANY of the following criteria:
•
A previous adverse event that is not initially deemed reportable but is later found to fit 
the criteria for reporting (report within 15 days from when event was deemed reportable).
•
Any findings from other studies, including epidemiological studies, pooled analysis of 
multiple studies, or other clinical studies conducted with the study drug that suggest a 
significant risk in humans exposed to the drug.
•
Any findings from animal or in vitro testing that suggest a significant risk for human 
patients including reports of mutagenicity, teratogenicity, or carcinogenicity or reports of 
significant organ toxicity at or near the expected human exposure.
•
Any clinically important increase in the rate of occurrence of a serious, related or 
possibly related adverse event over that listed in the protocol or investigator brochure.
Sponsors are also required to identify in IND safety reports, all previous reports concerning 
similar adverse events and to analyze the significance of the current event in the light of the 
previous reports.
Reporting Process
The principal investigator or designee will complete and submit a FDA Form 3500A Medwatch 
for any event that meets the above criteria. Forms will be submitted to the CRS Compliance 
Office email to: CRSCompliance@RoswellPark.org.
10 DATA AND SAFETY MONITORING
This study will be reviewed at the scheduled RPCI data and safety monitoring committee 
meetings and the minutes are forwarded to the IRB for review.
11
STATISTICAL METHODOLOGY
11.1 Sample Size Determination and Analysis
In a Phase II and Phase III study of single agent topotecan or single agent irinotecan as shown in 
Table 1 in recurrent SCLC, the median time to progression of the arms were 2.2 - 4 months.6,8-12 
Based on this, the primary endpoint of this trial will be the proportion of patients who are 
progression-free at 18 weeks. Progression-free survival was chosen as the primary endpoint, 
rather than response rate, as this is appropriate clinical endpoint for cytotoxic agents such as 
NKTR-102 and for SCLC.  A single-stage design will be used to assess the primary endpoint for 
each patient group. A treatment success was defined as a patient who was progression-free at 
18 weeks. To evaluate Group A, the largest success proportion where the proposed treatment 
regimen would be considered ineffective in this population is 5%, and the smallest that would 
warrant further subsequent studies is 25%. Twenty evaluable patients will be entered on this 
study. If 2 or fewer successes are observed, this regimen will be considered ineffective in this 
patient population. If 3 or more successes are observed, this will be considered evidence that this 
treatment may be recommended for further testing in subsequent studies. Assuming that the 
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number of successes is binomially distributed, this design controls the Type I Error to be < 10% 
and has 90% power to detect 25% 18-week PFS rate. To evaluate Group B, the largest success 
proportion where the proposed treatment regimen would be considered ineffective in this 
population is 10%, and the smallest that would warrant further subsequent studies is 35%. 
Eighteen evaluable patients will be entered on this study. If 3 or fewer successes are observed, 
this regimen will be considered ineffective in this patient population. If 4 or more successes are 
observed, this will be considered evidence that this treatment may be recommended for further 
testing in subsequent studies. Assuming that the number of successes is binomially distributed, 
this design controls the Type I Error to be < 10% and has 90% power to detect 25% 18-week 
PFS rate. Patients who come off study (e.g., due to toxicity) and start an off-protocol therapy 
prior to 18 weeks will be considered failures at that point.
The evaluable population is defined as patients who meet eligibility requirements and receive 
any protocol treatment. Unevaluable patients will be replaced.
Progression-free survival is defined as the time from registration to the date of first documented 
disease progression or death. Survival time is defined as the time from registration to death due 
to any cause. Patients who loss-to-follow-up or alive at time of analysis will be censored at the 
last contact of known alive. The distribution of time to disease progression and survival time will 
be estimated in each group using the method of Kaplan–Meier. Probability of PFS at 18 weeks 
and 24 week and probability of survival at 3, 6, and 9 months will be estimated. All eligible and 
treated patients will be included in the analysis of the primary endpoint.
All adverse events, regardless of attribution, will be summarized (overall and by group).34
11.2 Randomization
This is a nonrandomized study. No randomization scheme will be generated. Subjects will be 
assigned to each group based on their relapsed time.
11.3 Demographics and Baseline Characteristics
Descriptive statistics (as appropriate: n, percent, mean, median, min and max) will be used to 
summarize demographic and baseline characteristics.
11.4 Efficacy Analysis
Objective tumor response will be tabulated overall (and by dose level if appropriate). Best 
Response is defined to be the best objective status recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria. The RECIST 1.1 
criteria will be used for solid tumor evaluation and patients will be re-evaluated every other 
cycle. Responses will be summarized by simple descriptive summary statistics delineating 
complete and partial responses as well as stable and progressive disease in the cohorts (overall 
and by tumor group).
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11.5 Safety Analysis
As per NCI CTCAE v 4.0, the term toxicity is defined as adverse events that are classified as 
either possibly, probably, or definitely related to study treatment. Non-hematologic toxicities will 
be evaluated via the ordinal CTC standard toxicity grading. Hematologic toxicity measures of 
thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as 
the outcome measures (primarily nadir) as well as categorization via CTC standard toxicity 
grading. Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor 
site will be explored and summarized. Frequency distributions, graphical techniques and other 
descriptive measures will form the basis of these analyses.
11.6 Adverse Event
The number and severity of all adverse events (overall, by regimen, and by dose level if 
appropriate) will be tabulated and summarized. The Grade 3+ adverse events will also be 
described and summarized in a similar fashion. This will provide an indication of the level of 
tolerance for this treatment combination in this patient group.
12 CORRELATIVE DATA ANALYSIS
Correlation between correlative study (pharmacogenetic analysis) and other outcome measures 
like toxicity and response will be carried out in an exploratory manner as described below.
12.1 Pharmacogenetic Analysis
The genes that have been associated with irinotecan pharmacodynamic and pharmacokinetic 
pathways include those responsible for activation, inactivation and transport of the drug. These 
genes include ABCB1, ABCC2, ABCG2, BCHE, CES1, CES2, CYP3A4, CYP3A5, SLCO1B1, 
TOP1, UGT1A1, 1A3,1A4,1A6, 1A7,1A8, 1A9 and UGT1A10. As NKTR-102 is a conjugate of 
irinotecan, most of the irinotecan pathway genes may interact with it thus resulting in similar 
phenotypic effects. Hence, several genetic variants associated with the pathways may contribute 
to the clinical outcome of NKTR-102 therapy. Some of the well-known genetic variants that 
have been associated with irinotecan clinical outcomes include the polymorphic repeat in 
UGT1A1 promoter region (UGT1A1*28, rs8175347; UGT1A1*93) and the ABCB1 (1236C > T, 
2677G > T/A, 3435C > T), ABCC2 (-24C > T, 1249G > A, 3972C > T), and ABCG2 (34G > A, 
421C > A) polymorphisms. It is reported that nearly 50% of the variations in neutropenia among 
individuals could be explained by a combination of genetic polymorphisms and non-genetic 
covariates, with gene combinations attributing to 28% of the variations, suggesting a polygenenic 
basis for neutropenia.32 UGT1A1*28 and *93 genotypes have been associated with toxicity; 
ABCC2 3972C > T with severe diarrhea in both Korean and European patients while 
SLCO1B1*5 allele is reported to be associated with increased risk of severe neutropenia in 
Asians, and the SLCO1B1*1b allele is suggested to be protective of neutropenia.32-35
This Phase I study will initially focus, in an exploratory manner, on the primary genes which will 
activate (CES1, CES2, CYP3A4, CYP3A5) and inactivate (UGT1A1) NKTR-102. It is 
hypothesize that germline polymorphic variants in CES1, CES2, CYP3A4, CYP3A5 and UGT1A1 
may affect toxicity as well as response to NKTR-102 therapy.
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SNP Identification: We will generate tagSNPs from National Center for Biotechnology 
Information (NCBI), HapMap and/or the Genome Variation Server databases using the 
Caucasian SNP information for these 5 genes in addition to using SNPs previously reported in 
literature. These SNPs will be selected with sufficient frequency that its impact on the clinical 
outcome at a population level would be meaningful and have some degree of likelihood to alter 
the function of the gene in a biologically relevant manner. Fifty-three SNPs have been identified 
for genotyping.
Genotyping: The tagSNPs will be genotyped using the MassARRAY Compact system 
(Sequenom) at RPCI as previously described.36 Whenever possible, published methods and 
primers will be used for polymorphic variants such as UGT1A1*28.
13 ETHICAL AND REGULATORY STANDARDS
13.1 Ethical Principles
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC). Each subject (or legal guardian) shall read, understand, 
and sign an instrument of informed consent prior to performance of any study-specific 
procedure. It is the responsibility of the investigator to ensure that the subject is made aware of 
the investigational nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the subject log and subject records; although 
personal information may be reviewed by authorized persons, that information will be treated as 
strictly confidential and will not be made publicly available. The investigator is also responsible 
for obtaining subject authorization to access medical records and other applicable study specific 
information according to Health Insurance Portability and Accountability Act regulations (where 
applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the subject is treated, in accordance with the Declaration of 
Helsinki, Good Clinical Practice, and according to the guidelines in this protocol, including 
attached appendices.
13.2 Informed Consent
The Investigator is responsible for obtaining written consent from each subject or the subject's 
legally authorized representative in accordance with ICH-GCP guidelines using the approved 
informed consent form, before any study specific procedures (including screening procedures) 
are performed. The informed consent form acknowledges all information that must be given to 
the subject according to ICH-GCP, including the purpose and nature of the study, the expected 
efficacy and possible side effects of the treatment(s), and specifying that refusal to participate 
will not influence further options for therapy. Any additional information that is applicable to the 
study must also be included. Additional national or institutionally mandated requirements for 
informed consent must also be adhered to. The subject should also be made aware that by 
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signing the consent form, processing of sensitive clinical trial data and transfer to other countries 
for further processing is allowed.
The Investigator shall provide a copy of the information sheet and of the signed consent form to 
the subject and the signed original shall be maintained in the Investigator File. A copy of the 
signed consent form must be filed in the subject file. At any stage, the subject may withdraw 
from the study and such a decision will not affect any further treatment options.
14
STUDY RESPONSIBILITIES
14.1 Data Collection
Data entry into the database is to be completed in a timely fashion (approximately within 
28 days) after the subject’s clinic visit. If an AE is considered serious it is captured on both the 
Adverse Event page and the Serious Adverse Event Form, which is handled in an expedited 
fashion.
Data management activities will be performed using EXPeRT. EXPeRT is a suite of software 
tools that enables the collection, cleaning and viewing of clinical trial data. CRS data 
management will design the study-specific database and facilitate its development by the 
EXPeRT Information Technology team. Once the database design is approved by the 
Investigator, Statistician, and Clinical Research Coordinator, the database will be put into 
production and data entry can begin. Data can be entered and changed only by those with the 
rights to do so into the eCRFs. EXPeRT is compliant with all relevant technical aspects of 
relevant GCP guidelines.
•
The system can generate accurate copies of stored data and audit trail information in human 
readable form.
•
System access is limited to authorized individuals through the controlled assignment of 
unique ID and password combinations.
•
The system is designed to periodically force users to change their passwords and verifies that 
user ID and password combinations remain unique.
•
The system automatically generates a permanent time-stamped audit trail of all user 
interactions.
When data entry is complete, data management will review the data and will query any missing, 
incomplete, or invalid data points for resolution by the Clinical Research Coordinator and 
Investigator. Once all queries have been resolved, the data can be released to the statistician for 
analysis.
14.2 Maintenance of Study Documents
Essential documents should be retained per RPCI’s policy for 6 years from the study termination 
date. These documents could be retained for a longer period, however, if required by the 
applicable local regulatory requirements or by an agreement with RPCI. It is the responsibility of 
RPCI to inform the Investigator/ institution as to when these documents no longer need to be 
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retained. If, for any reason, the Investigator desires to no longer maintain the study records, they 
may be transferred to another institution, another investigator, or to RPCI upon written 
agreement between the Investigator and RPCI.
15 ADMINISTRATIVE RULES
15.1 Revisions to the Protocol
RPCI may make such changes to the protocol as it deems necessary for safety reasons or as may 
be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to the 
IRB/ERC for written approval before implementation.
15.2 Termination of the Study
It is agreed that, for reasonable cause, either the Investigators or the Sponsor, RPCI may 
terminate this study, provided a written notice is submitted within the time period provided for in 
the Research Support Agreement. In addition, RPCI may terminate the study at any time upon 
immediate notice if it believes termination is necessary for the safety of subjects enrolled in the 
study.
15.3 Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will 
be identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
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16 APPENDICES
Appendix A. Instructions for Network Sites
1. CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Cancer Institute
CRS Network Office
ASB K 102B
Buffalo, New York 14263
Telephone:
Monday - Friday; 7:30 AM to 4:00 PM EST
716-845-3870
After hours, weekends, and holidays request the RPCI Investigator
716-845-2300
Fax: 716-845-8743
2. INFORMED CONSENT
•
Informed consent must be obtained by the site Investigator from any subjects wishing to 
participate, prior to any procedures or change in treatment.
•
An informed consent template is provided by RPCI and can be amended to reflect 
institutional requirements.
•
All consent changes must be reviewed by RPCI Network Office prior to submission to 
the site IRB.
•
The informed consent must be IRB approved.
•
Always check that the most up to date version of the IRB approved consent is being used.
3. SUBJECT REGISTRATION
The subject completes the Gender, Race, and Ethnicity Form and this is placed in the study 
binder.
RPCI does not grant exceptions to eligibility criteria.
Phase 2 Protocol Registration Instructions
The Subject Screening and Enrollment Log must be faxed or emailed to the RPCI Network 
Office within 24 hours of the date the subject is consented. Once the Investigator has reviewed   
eligibility, complete the Eligibility Verification Form and fax to the RPCI Network Monitor at 
716-845-8743 or email to CRSNetworkMonitors@RoswellPark.org.
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4. STUDY DEVIATIONS
•
If a deviation has occurred to eliminate hazard, this must be reported to the RPCI 
Network, site IRB and any other regulatory authority involved in the trial.
•
ANY study deviation will be recorded on the Study Deviation Log.
•
Subjects inadvertently enrolled with significant deviation(s) from the study-specified 
criteria will be removed from the study.
•
Notify the RPCI Network Office of any early subject withdrawal and appropriately 
document the discontinuation and the reason why.
5. STUDY DOCUMENTATION
•
Study documents must be filled out completely and correctly. Ditto marks are not 
allowed.
•
If an entry has been documented in error put a single line through the entry and initial and 
date the change. The RPCI Network Monitor must be able to read what has been deleted.
o
Do NOT use white-out, magic marker, scratch-outs.
o
Do NOT erase entries.
•
Use only black ink for documentation on the accountability form and any other study 
forms.
6. DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.
•
Responsibility rests solely with the Investigator but can be delegated as appropriate 
(e.g., to pharmacy personnel).
•
A drug accountability record form (DARF) will record quantities of study drug received, 
dispensed to subjects and wasted, lot number, date dispensed, subject ID number and 
initials, quantity returned, balance remaining, manufacturer, expiration date, and the 
initials of the person dispensing the medication.
•
Study drug supply will only be used in accordance with the IRB approved study.
•
Drug accountability forms are protocol and agent specific, they are study source 
documents and will be used to verify compliance with the study.
•
An inventory count must be performed with each transaction. Any discrepancies shall be 
documented and explained.
•
Drug accountability forms must be stored with study related documents.
•
Each medication provided for this study and each dosage form and strength must have its 
own DARF.
•
Dispensing the wrong study supply is considered a medication error.
o
NEVER replace investigational agents with commercial product.
o
Do NOT “transfer”, “borrow” or “replace” supplies between studies.
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7. SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the RPCI Network Monitor within 1 business day of being made 
aware of the SAE. A preliminary written report must follow within 24 hours (1 business day) of 
the first notification using the following forms:
•
RPCI SAE report form
•
MedWatch 3500A
•
Notify Nektar Therapeutics. A complete follow-up report must be sent to the RPCI 
Network Monitor within 10 working days.
8. UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the 
criteria in Section 9.4.
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff 
from each site will notify their local IRB in accordance with their local institutional 
guidelines. The site must also notify the RPCI Network Monitor within 24 hours of being made 
aware of the Unanticipated Problem by completing the IRB Unanticipated Problem Report 
Form and faxing or emailing it to the RPCI Network Monitor.
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Appendix B. ECOG Performance Status Scores
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
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Appendix C. Cockcroft-Gault Calculation for Creatinine Clearance
 
	
    
   !"#!$%
If the patient is female, multiply the above by 0.85.
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17
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Masuda N, Fukuoka M, Kusunoki Y, et al: CPT-11: a new derivative of 
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