Clinical trial NCT01962103
Conditions: Neuroblastoma Rhabdomyosarcoma Ewing's Sarcoma Ewing's Tumor Sarcoma, Ewing's Sarcomas, Epitheliod Sarcoma, Soft Tissue Sarcoma, Spindle Cell Melanoma Malignant Melanoma Clinical Oncology Oncology, Medical Pediatrics, Osteosarcoma Osteogenic Sarcoma Osteosarcoma Tumor Sarcoma, Osteogenic Tumors Cancer Neoplasia Neoplasm Histiocytoma Fibrosarcoma Dermatofibrosarcoma
Keywords: Neuroblastoma Rhabdomyosarcoma Soft Tissue Pediatric Oncology Abraxane albumin-bound paclitaxel nab-paclitaxel ABI-007 taxane solid tumors
Sponsor: Celgene
Start date: 2013-12-04; Completion date: 2018-11-06
Enrollment: 107 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find the safe dose of nab-paclitaxel in children with solid tumors, and to see if it works to treat these solid tumors in children and young adults (in Phase 1 ≤ 18 years old and in Phase 2 ≤ 24 years old). After the final dose has been chosen, patients will be enrolled according to the specific solid tumor type, (neuroblastoma, rhabdomyosarcoma, or Ewing's sarcoma), to see how nab-paclitaxel works in treating these tumors.

Detailed description:
ABI-007-PST-001 is a Phase 1/2, multicenter, open-label, dose-finding study to assess the safety , tolerability, and preliminary efficacy of weekly nab-paclitaxel in pediatric patients with recurrent or refractory solid tumors (excluding brain tumors). The Phase 1 portion of the study, with a dose escalation design, ended and the recommended Phase 2 dose (RP2D) was determined as 240 mg/m\^2 intravenously (IV) in patients weighing \> 10 kg and 11.5 mg/kg in patients weighing ≤ 10 kg, on Days 1, 8 and 15 of a 28-day cycle. The Phase 2 portion of the study will enroll additional patients at the RP2D into 1 of 3 solid tumor groups \[neuroblastomas, rhabdomyosarcomas, Ewing's sarcomas\]. Both phases of the study are open-label and conducted at multiple centers.

The Phase 2 is using a Simon 2-stage design to monitor patient enrollment for each group separately. The rhabdomyosarcoma group, neuroblastoma or Ewing's sarcoma groups did not reach the expected number of 2 responders out of 14 efficacy eligible patients. Consequently, the groups were stopped.

Arms: arm 1: nab-paclitaxel 100-240 mg/m2 IV on Days 1, 8 and 15 of a 28-day cycle. arm 2: nab-paclitaxel 120 mg/m\^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. arm 3: nab-paclitaxel 150 mg/m\^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. arm 4: nab-paclitaxel 180 mg/m\^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. arm 5: nab-paclitaxel 210 mg/m\^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. arm 6: nab-paclitaxel 240 mg/m\^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. arm 7: nab-paclitaxel 270 mg/m\^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. arm 8: Participants with Ewing's sarcoma: nab-paclitaxel at the RP2D (240 mg/m\^2 in participants weighing \> 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity. arm 9: Participants with neuroblastoma: nab-paclitaxel at the RP2D (240 mg/m\^2 in participants weighing \> 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity. arm 10: Participants with rhabdomyosarcoma: nab-paclitaxel at the RP2D (240 mg/m\^2 in participants weighing \> 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Interventions: intervention 1: nab-paclitaxel intervention 2: nab-paclitaxel
Intervention descriptions: intervention 1: nab-paclitaxel 120-270 mg/m2 IV on Days 1, 8 and 15 of a 28-day cycle intervention 2: IV infusion

Protocol documents:
Prot_000.pdf: 
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
1
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
TITLE PAGE
A PHASE 1/2, MULTICENTER, OPEN-LABEL, DOSE-
FINDING STUDY TO ASSESS THE SAFETY, 
TOLERABILITY, AND PRELIMINARY EFFICACY OF 
WEEKLY nab®-PACLITAXEL IN PEDIATRIC 
PATIENTS WITH RECURRENT OR REFRACTORY 
SOLID TUMORS
INVESTIGATIONAL PRODUCT (IP):
nab-PACLITAXEL (ABRAXANE®)
PROTOCOL NUMBER:
ABI-007-PST-001
ORIGINAL DATE FINAL:
13 May 2013
AMENDMENT 1.0 DATE FINAL:
10 Sep 2013
AMENDMENT 2.0 DATE FINAL:
12 Mar 2014
AMENDMENT 3.0 DATE FINAL:
11 Jun 2014
AMENDMENT 4.0 DATE FINAL:
25 Mar 2015
AMENDMENT 5.0 DATE FINAL:
13 Jul 2016
EudraCT NUMBER:
2013-000144-26
IND NUMBER:
122810
SPONSOR NAME / ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901, USA
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
2
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title:
Address:
Phone:
E-mail:
Note: The back-up 24 hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24 Hour Global Emergency Contact Call Center: 
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
3
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
CELGENE® THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
4
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed 
consent/assent, Institutional Review Board (IRB)/Ethics Committee (EC) procedures, 
instructions from Celgene representatives, the Declaration of Helsinki, ICH Good 
Clinical Practices Guidelines, and local regulations governing the conduct of clinical 
studies.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
5
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
6
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
PROTOCOL SUMMARY
Study Title
A Phase 1/2, multicenter, open-label, dose-finding study to assess the safety, tolerability, and 
preliminary efficacy of weekly nab®-paclitaxel in pediatric patients with recurrent or refractory 
solid tumors. 
Indication 
Phase 1 Portion: Pediatric patients with recurrent or refractory solid tumors (excluding brain 
tumors). 
Phase 2 Portion: Pediatric patients with recurrent or refractory neuroblastoma, 
rhabdomyosarcoma, and Ewing’s sarcoma. 
Objectives
Primary Objective
!
Phase 1 portion: To determine the pediatric maximum tolerated dose (MTD)/ 
pediatric recommended Phase 2 dose (RP2D), safety and tolerability
!
Phase 2 portion: To characterize antitumor activity at RP2D assessed by overall 
response rate (ORR)
Secondary Objectives
!
Phase 1 portion: To evaluate pharmacokinetics (PK) and characterize ORR
!
Phase 2 portion: To characterize duration of response (DOR), disease control rate 
(DCR), progression-free survival (PFS), 1-year survival. To confirm safety and to 
evaluate PK
Study Design
The Phase 1 portion of the study will be a rolling-6 dose escalation design to determine the 
MTD/RP2D. A safety monitoring committee (SMC) will be formed to make dose escalation 
decisions. Approximately 64 patients are planned to be enrolled in this portion of the study; 
approximately 44 into the Dose Determining Sets (DDS), and about 20 additional patients at 
dose levels evaluated as safe by the SMC.
The Phase 2 portion of the study will enroll additional patients at the RP2D (240 mg/m2 in 
patients weighing > 10 kg, and 11.5 mg/kg in patients weighing ≤ 10 kg) into one of three solid 
tumor groups using a Simon two-stage minimax design for each group:
!
Neuroblastoma (≤ 23 patients)
!
Rhabdomyosarcoma (≤ 23 patients)
!
Ewing’s sarcoma (≤ 23 patients)
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
7
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Both phases of the study will be open-label and conducted at multiple centers. The study will be 
conducted in compliance with International Council for Harmonisation (ICH) Good Clinical 
Practices (GCPs).
Study Population
The Phase 1 portion of the study will be conducted in patients ≥ 6 months and < 18 years of age 
with recurrent or refractory solid tumors (excluding primary or metastatic brain tumors). 
The Phase 2 portion of the study will be conducted in patients ≥ 6 months and ≤ 24 years of age 
with radiologically documented measurable disease by RECIST 1.1 (for neuroblastoma,
evaluable disease by 123I-metaiodobenzylguanidine (MIBG)/Curie score is also acceptable) in 
several discrete recurrent or refractory solid tumor types (neuroblastoma, rhabdomyosarcoma, 
and Ewing’s sarcoma).
Length of Study
In both the Phase 1 and 2 portions of the study, patients will enter a 14 day screening period, and 
if eligible (and the cohort/group is open for recruitment) will proceed to the treatment phase.  
Patients may remain on treatment until disease progression, unacceptable toxicity, until they 
begin a new anticancer therapy, withdrawal of consent, parent/guardian/patient refusal, physician 
decision or death. 
All patients in both portions of the study will be followed for 28 days after the last study 
treatment for safety, monitoring of adverse events and for response until progression (if 
applicable). Patients will be followed for 1 year after the last dose of nab-paclitaxel for survival
and new anticancer therapies.  
The Phase 1 portion of the study is expected to last up to approximately 18 months.  The Phase 2 
portion of the study is expected to last for approximately 54 months.
The End of Trial is defined as either the date of the last visit of the last patient to complete the 
study, or the date of receipt of the last data point from the last patient that is required for primary, 
secondary and/or exploratory analysis, as pre-specified in the protocol and/or the Statistical 
Analysis Plan, whichever is the later date.
Study Treatments
In both the Phase 1 and 2 portions of the study, patients will receive the investigational product 
(IP) nab-paclitaxel, administered intravenously over approximately 30 minutes, on Days 1, 8,
and 15 of a 28-day cycle until disease progression or as described above. The starting dose for 
the Phase 1 portion will be 120 mg/m2. The dose will be escalated in subsequent cohorts until the 
MTD/RP2D has been identified. The Phase 2 portion will treat patients at the RP2D identified 
during the Phase 1 portion. In January 2016, the RP2D was identified as 240 mg/m2 in patients 
weighing > 10 kg and 11.5 mg/kg in patients weighing ≤ 10 kg.
Overview of Efficacy Assessments
All patients will be assessed by computed tomography (CT) or magnetic resonance imaging 
(MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at screening 
and every 8 weeks from Cycle 1 Day 1 until disease progression, the start of a new anticancer 
therapy or withdrawal of consent.  In patients with neuroblastoma, a MIBG scan will be 
performed according to the same schedule to assess MIBG response.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
8
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Response assessments include CT scan or MRI of the chest, abdomen, and pelvis, MIBG scan 
(for neuroblastoma), any other studies required for tumor imaging, and (for neuroblastoma) bone 
marrow biopsy for verification of confirmed complete response.
Overview of Safety Assessments
All patients will be monitored for adverse events, starting from the time the 
parent/guardian/patient signs the informed consent/assent form until 28 days after the last dose of 
IP and at the end of treatment (EOT) visit. A thorough evaluation of medical conditions will be 
conducted during screening for eligibility. Physical examination (source documented only), vital 
signs, laboratory assessments (eg, serum chemistry, hematology), 12-lead electrocardiogram 
(ECG), left ventricular shortening fraction (LVSF) assessment by echocardiogram/multi-gated 
acquisition (MUGA) scan/ other medically approved method, and Lansky/ Karnofsky 
performance status will be monitored regularly. The full schedule of assessments is described in 
Table 4 and Section 6. 
Overview of Statistical Methods
The Phase 1 portion uses a rolling-6 patient dose escalation design to establish the MTD/RP2D 
and the Phase 2 portion uses a Simon two-stage minimax design to monitor patient enrollment 
for each group separately.
Sample Size
During the Phase 1 portion of the study, up to approximately 64 patients will be enrolled, 
depending on the number of dose level cohorts evaluated and the number of additional patients 
enrolled at dose levels evaluated as safe by the SMC. In the Phase 2 portion, up to 69 efficacy 
evaluable patients (≤ 23 with neuroblastoma, ≤ 23 with rhabdomyosarcoma, and ≤ 23 with 
Ewing’s sarcoma) will be enrolled at the RP2D determined in the Phase 1 portion of the study, 
with at least 14 patients per group. A Simon two-stage minimax design will be used to monitor 
patient enrollment for each of the 3 groups separately. 
For each of the 3 groups, in the first stage, 14 efficacy evaluable patients will be enrolled. If < 2
of the 14 patients within a group has a response, the enrollment for this group will be stopped
upon determination of the number of responders. If ≥ 2 of the 14 patients have a response, the 
enrollment will continue until 23 efficacy evaluable patients are enrolled. At the final analysis, 
the regimen will be concluded with more than 5% true response rate if ≥ 5 of 23 patients have a 
response according to the maximum likelihood estimator. The sample size is based on an 80% 
power and 10% significance having fixed the lower and upper boundaries to 10% and 28%, 
respectively.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
9
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
LIST OF ABBREVIATIONS....................................................................................................16
1.
INTRODUCTION..................................................................................................19
1.1.
Pediatric Indication Background.............................................................................19
1.1.1.
Neuroblastoma........................................................................................................19
1.1.2.
Rhabdomyosarcoma ...............................................................................................19
1.1.3.
Other Pediatric Solid Tumors..................................................................................20
1.1.3.1.
Nonrhabdomyosarcoma Soft Tissue Sarcoma .........................................................20
1.1.3.2.
Ewing’s Sarcoma....................................................................................................20
1.1.3.3.
Melanoma...............................................................................................................21
1.1.4.
Conclusion .............................................................................................................21
1.2.
Taxanes ..................................................................................................................21
1.2.1.
nab-Paclitaxel.........................................................................................................22
1.2.2.
Taxanes in Pediatrics..............................................................................................24
1.2.3.
nab-Paclitaxel Preclinical Studies...........................................................................27
1.3.
Study Rationale ......................................................................................................28
1.3.1.
Role of nab-Paclitaxel in Fulfilling the Unmet Medical Need .................................28
1.3.2.
Rationale for Study Design.....................................................................................29
1.3.2.1.
Rationale for Patient Population..............................................................................30
1.3.2.2.
Rationale for Pharmacokinetics...............................................................................30
1.3.3.
Rationale for Dosing...............................................................................................31
2.
STUDY OBJECTIVES...........................................................................................32
2.1.
Primary Objective...................................................................................................32
2.2.
Secondary Objectives .............................................................................................32
2.3.
Exploratory Objectives ...........................................................................................32
3.
STUDY ENDPOINTS............................................................................................33
3.1.
Primary Endpoint(s) ...............................................................................................33
3.2.
Secondary Endpoint(s)............................................................................................33
3.3.
Exploratory Endpoints............................................................................................33
4.
OVERALL STUDY DESIGN ................................................................................34
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.1.
.1.
.2.
.2.


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4.1.
Study Design ..........................................................................................................34
4.2.
Study Duration .......................................................................................................36
4.3.
End of Trial ............................................................................................................36
5.
TABLE OF EVENTS.............................................................................................37
6.
PROCEDURES......................................................................................................41
6.1.
Treatment Period ....................................................................................................43
6.1.1.
End of Treatment....................................................................................................43
6.2.
Follow-up Period....................................................................................................44
6.2.1.
28-Day Follow-up ..................................................................................................44
6.2.1.1.
Special Monitoring .................................................................................................45
6.2.2.
Efficacy Follow-up.................................................................................................45
6.2.3.
Survival Follow-up.................................................................................................45
6.3.
Response Assessments............................................................................................45
6.3.1.
Assessment of Response According to RECIST 1.1................................................46
6.3.1.1.
Other Assessments..................................................................................................46
6.4.
Pharmacokinetics....................................................................................................46
6.5.
Biomarkers .............................................................................................................48
7.
STUDY POPULATION.........................................................................................49
7.1.
Number of Patients.................................................................................................49
7.2.
Inclusion Criteria....................................................................................................49
7.3.
Exclusion Criteria...................................................................................................50
8.
DESCRIPTION OF STUDY TREATMENTS........................................................52
8.1.
Description of Investigational Product(s)................................................................52
8.2.
Treatment Administration and Schedule .................................................................52
8.2.1.
Phase 1 Portion:  Dose Escalation...........................................................................52
8.2.1.1.
Definition of Dose-limiting Toxicity.......................................................................53
8.2.1.2.
Safety Monitoring Committee.................................................................................54
8.2.1.3.
Dose Escalation Procedures....................................................................................54
8.2.1.4.
Recommended Phase 2 Dose ..................................................................................55
8.2.2.
Phase 2:  Dose Expansion.......................................................................................55
8.2.3.
Treatment Modification ..........................................................................................55
8.2.3.1.
Body Surface Area or Weight Changes...................................................................55
8.2.3.2.
Treatment Delay.....................................................................................................55
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8.2.3.3.
Missed Treatment ...................................................................................................56
8.2.3.4.
Dose Adjustment ....................................................................................................56
8.2.3.5.
Intrapatient Dose Escalation ...................................................................................58
8.2.4.
Overdose ................................................................................................................58
8.3.
Method of Treatment Assignment...........................................................................58
8.4.
Packaging and Labeling..........................................................................................59
8.5.
Investigational Product Accountability and Disposal ..............................................59
8.6.
Investigational Product Compliance........................................................................59
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................60
9.1.
Permitted Concomitant Medications and Procedures...............................................60
9.2.
Prohibited Concomitant Medications and Procedures..............................................60
9.3.
Required Concomitant Medications and Procedures................................................61
10.
STATISTICAL ANALYSES..................................................................................62
10.1.
Overview................................................................................................................62
10.2.
Study Population Definitions ..................................................................................62
10.3.
Sample Size and Power Considerations...................................................................62
10.4.
Demographic and Baseline Characteristics..............................................................63
10.5.
Patient Disposition..................................................................................................63
10.6.
Efficacy Analysis....................................................................................................63
10.7.
Safety Analysis.......................................................................................................64
10.8.
Interim Analysis .....................................................................................................65
10.9.
Other Topics...........................................................................................................65
10.9.1.
Pharmacokinetic Analysis.......................................................................................65
11.
ADVERSE EVENTS..............................................................................................66
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................66
11.2.
Evaluation of Adverse Events.................................................................................66
11.2.1.
Seriousness.............................................................................................................66
11.2.2.
Severity / Intensity..................................................................................................68
11.2.3.
Causality ................................................................................................................68
11.2.4.
Duration .................................................................................................................69
11.2.5.
Action Taken..........................................................................................................69
11.2.6.
Outcome.................................................................................................................69
11.3.
Abnormal Laboratory Values..................................................................................69
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1.2.3.
1.2.3.
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11.4.
Pregnancy...............................................................................................................69
11.4.1.
Females of Childbearing Potential ..........................................................................69
11.4.2.
Male Patients..........................................................................................................70
11.5.
Reporting of Serious Adverse Events......................................................................70
11.5.1.
Safety Queries ........................................................................................................71
11.6.
Expedited Reporting of Adverse Events..................................................................71
12.
DISCONTINUATIONS .........................................................................................72
12.1.
Treatment Discontinuation......................................................................................72
12.2.
Study Discontinuation ............................................................................................72
13.
EMERGENCY PROCEDURES.............................................................................73
13.1.
Emergency Contact.................................................................................................73
13.2.
Emergency Identification of Investigational Products .............................................73
14.
REGULATORY CONSIDERATIONS...................................................................74
14.1.
Good Clinical Practice............................................................................................74
14.2.
Investigator Responsibilities ...................................................................................74
14.3.
Patient Information and Informed Consent / Assent ................................................74
14.4.
Confidentiality........................................................................................................75
14.5.
Protocol Amendments.............................................................................................75
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................75
14.7.
Ongoing Information for the Institutional Review Board / Ethics Committee..........76
14.8.
Closure of the Study ...............................................................................................76
15.
DATA HANDLING AND RECORDKEEPING.....................................................77
15.1.
Data / Documents ...................................................................................................77
15.2.
Data Management...................................................................................................77
15.3.
Record Retention....................................................................................................77
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................79
16.1.
Study Monitoring and Source Data Verification......................................................79
16.2.
Audits and Inspections............................................................................................79
17.
PUBLICATIONS ...................................................................................................80
18.
REFERENCES.......................................................................................................81
19.
APPENDICES........................................................................................................87
19.1.
Appendix A:  RECIST 1.1......................................................................................87
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A
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19.1.1.
Definitions..............................................................................................................87
19.1.1.1.
Measurable Disease ................................................................................................87
19.1.1.2.
Nonmeasurable Disease..........................................................................................87
19.1.1.3.
Special Considerations for Lesion Measurability ....................................................87
19.1.2.
Tumor Response Evaluation ...................................................................................87
19.1.2.1.
Target Lesions........................................................................................................87
19.1.2.2.
Nontarget Lesions...................................................................................................88
19.1.2.3.
Response Criteria....................................................................................................88
19.1.2.4.
Symptomatic Deterioration.....................................................................................90
19.2.
Appendix B: Curie Scale for MIBG Response ........................................................90
19.2.1.
MIBG Scan Assessable...........................................................................................91
19.2.2.
Tumor Response Evaluation ...................................................................................91
19.2.3.
Response Criteria....................................................................................................92
19.3.
Appendix C: Performance Status ............................................................................92
19.3.1.
Lansky Performance Status.....................................................................................92
19.3.2.
Karnofsky Performance Status................................................................................93
19.4.
Appendix D:  Pharmacokinetic Sample Handling Instructions ................................93
19.4.1.
Blood Sample Labeling ..........................................................................................93
19.4.2.
Blood Sample Collection: .......................................................................................94
19.4.3.
PK Sample Shipment..............................................................................................94
19.4.3.1.
Sample Collection Documents to Accompany Shipment(s).....................................94
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LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms........................................................................16
Table 2:
Phase 1 Trials of Taxanes in Children.....................................................................25
Table 3:
Phase 2 Trials of Taxanes in Children.....................................................................26
Table 4:
Table of Events.......................................................................................................37
Table 5:
Dense PK Sampling................................................................................................47
Table 6:
Sparse PK Sampling ...............................................................................................47
Table 7:
Phase 1 Portion Example Dose Levels ....................................................................53
Table 8:
Hematologic Toxicity:  Recommended Dose Reductions........................................57
Table 9:
Nonhematologic Toxicity:  Recommended Dose Reductions ..................................57
Table 10:
Time Point Response: Patients With Target (± Nontarget) Disease .........................90
Table 11:
Time Point Response: Patients With Nontarget Disease Only .................................90
Table 12:
Lansky Performance Scale......................................................................................92
Table 13:
Karnofsky Performance Status Scale.......................................................................93
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LIST OF FIGURES
Figure 1:
Phase 1 Study Design .............................................................................................35
Figure 2:
Phase 2 Study Design .............................................................................................35
Figure 3:
Curie Score Anatomical Regions ............................................................................91
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ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the curve
β-hCG
β-subunit of human chorionic gonadotropin
BSA
Body surface area
BUN
Blood urea nitrogen
CBC
Complete blood count
CL
Clearance
Cmax
Maximum plasma concentration of drug
CNS
Central nervous system
CR
Complete response
CRO
Contract research organization
CRF
Case report form
CRP
Clinical Research Physician
CRS
Clinical Research Scientist
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease control rate
DDS
Dose Determining Set
DEHP
di (2-ethylhexyl) phthalate
DLT
Dose-limiting toxicity
DMSO
Dimethyl sulfoxide
DOR
Duration of response
EC
Ethics committee
ECG
Electrocardiogram
EE
Efficacy evaluable
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EDMS Doc. Number:
nab-Paclitaxel
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ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Table 1:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
EEA
European Economic Area
EOT
End of treatment
ESMO
European Society for Medical Oncology
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIV
Human immunodeficiency virus
HSCT
Hematopoietic stem cell transplantation
HVA
Homovanillic acid
ICF
Informed consent form
ICH
International Council for Harmonisation
IND
Investigational New Drug
IP
Investigational Product
IRB
Institutional Review Board
IRT
Integrated Response Technology
IV
Intravenous
LDH
Lactate dehydrogenase
LVSF
Left ventricular shortening fraction
MCR
Maintained complete response
MedDRA
Medical Dictionary for Regulatory Activities
MIBG
123I-metaiodobenzylguanidine
MR
Minor response
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
MUGA
Multi-gated acquisition
NCI
National Cancer Institute
NE
Inevaluable
NRSTS
Nonrhabdomyosarcoma soft tissue sarcoma
NSCLC
Non-small cell lung cancer
ORR
Overall response rate
OS
Overall survival
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nab-Paclitaxel
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ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Table 1:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
PFS
Progression-free survival
PNET
Primitive neuroendocrine tumors
PK
Pharmacokinetics
PR
Partial response
PVC
Polyvinyl chloride
RBC
Red blood cell count
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 dose
SAE
Serious adverse event
SAP
Statistical analysis plan
SCLC
Small cell lung cancer
SD
Stable disease
SEER
Surveillance, Epidemiology, and End Results
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SIOPE
European Society of Pediatric Oncology
SMC
Safety monitoring committee
SOP
Standard operating procedure
SPARC
Secreted protein acidic and rich in cysteine
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Half-life
TEAE
Treatment-emergent adverse event
TTP
Time to tumor progression
ULN
Upper limit of normal
USA
United States of America
USP
United States Pharmacopeia
VMA
Vanillylmandelic acid
Vss
Volume of distribution
WBC
White blood cell count
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1.
INTRODUCTION
1.1.
Pediatric Indication Background
Sixty percent of all pediatric malignant neoplasms are solid tumors (Dome, 2008). Although 
brain tumors such as gliomas and medulloblastomas frequently occur in the pediatric population, 
patients with brain tumors will not be enrolled in this study as there are no data to-date that 
would indicate that Abraxane has any efficacy in primary or metastatic brain tumors. Therefore, 
brain tumors are not further discussed in this protocol. The most common non-central nervous 
system (CNS) solid tumors in the pediatric population (age 0 – 19 years, in the USA) are 
comprised of the following tumor types: neuroblastoma (7%), Wilms’ tumor (5%), 
rhabdomyosarcoma (3%), retinoblastoma (3%), osteosarcoma (3%), and Ewing’s sarcoma (1%) 
(ACS, Cancer Facts and Figures, 2012). 
Although childhood cancer is rare and the 5-year survival rate in non-CNS solid tumors is 
relatively high in the 0- to 19-years-old pediatric population (68% to 88%), childhood cancer is 
the leading cause of death by disease in the USA (ACS, Cancer Facts and Figures, 2012). The 
main reason for cancer death in the pediatric population is refractory and relapsed disease, and 
improved therapeutic options are needed in this population.
1.1.1.
Neuroblastoma
Neuroblastoma is a malignant embryonal tumor of the neural crest cells. In children < 1 year old
worldwide it is the most common tumor (Heck, 2009). The 5-year survival rates for children 
aged 0 to 19 years are in the range of 75% in the USA (SEER Table 29.6).  
The treatment options for neuroblastoma include surgery, particularly for low-risk tumors, 
multiagent chemotherapy, and radiation therapy (Ullrich, 2012). For high risk patients, standard 
treatment generally consists of induction chemotherapy to achieve remission, surgery, and 
radiotherapy for local control, high-dose chemotherapy with autologous hematopoietic stem-cell 
rescue and oral 13-cis-retinoic acid for consolidation and immunotherapy (Modak, 2010). The 
risk of local relapse has decreased with modern surgery and radiotherapy practices along with 
induction chemotherapy; however, in high-risk neuroblastoma refractory or recurrent disease in 
bone and bone marrow occurs in most patients (Modak, 2010).
Various combinations of cyclophosphamide, doxorubicin, cisplatin, carboplatin, etoposide, 
topotecan, vincristine, temozolomide, and irinotecan have been used with response rates of 50%
to 60%.  Preclinical and clinical pediatric studies showed potential utility of chemotherapy with 
paclitaxel and docetaxel in neuroblastomas (Izbicka, 2006; Table 2 and Table 3).
1.1.2.
Rhabdomyosarcoma
Rhabdomyosarcoma is a malignant childhood soft-tissue sarcoma of mesenchymal origin with a 
5-year survival rate of 70%.  The prognosis depends on the location and disease stage (Dasgupta, 
2012).
Treatment is also driven by the primary tumor location and disease stage, which defines the 
clinical group, and generally includes some combination of pre-operative chemotherapy, surgery, 
irradiation, and systemic chemotherapy. Standard chemotherapeutic agents include vincristine, 
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dactinomycin, and cyclophosphamide. In the most high-risk disease, more intensive use of 
multiagent chemotherapy with other agents is being evaluated in clinical trials (Arndt, 2011).
Although rhabdomyosarcoma is sensitive to first line therapy with a complete response (CR)
achieved in the majority of patients, local recurrences still occur in a substantial number of 
patients (Dantonello, 2008). The prognosis of patients who recur or progress after first line 
therapy is poor.  However, patients who remain disease free after 5 years have a good prognosis 
and relapses are uncommon, and at 10 years only 9% of patients have late events. However, 
patients who have gross residual disease following initial surgery in unfavorable sites and those 
who initially present with metastatic disease more commonly experience relapse (Sung, 2004). 
The prognosis has not improved significantly in the last 15 years for the more than 15% of 
children who present with metastatic rhabdomyosarcoma, and the overall cure rate remains 
below 30% despite the development of more intensive therapies (Oberlin, 2008).
Both docetaxel and paclitaxel have antitumor activity in pediatric rhabdomyosarcoma solid 
tumor models (Izbicka, 2006), as well as in Phase 1 and 2 clinical studies; however,
hypersensitivity and neurological reactions, among others, were dose-limiting with paclitaxel,
and clinical activity with taxanes was short-lived (Table 2 and Table 3). The central 
neurotoxicity of conventional solvent-based paclitaxel has been attributed to the large amount of 
alcohol and Cremophor contained in the formulation (see Section 1.2.2).
1.1.3.
Other Pediatric Solid Tumors
1.1.3.1.
Nonrhabdomyosarcoma Soft Tissue Sarcoma
Among pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTSs), the most common 
include dermatofibrosarcoma protuberans, malignant fibrous histiocytoma, synovial sarcoma, 
malignant peripheral nerve sheath tumor, and fibrosarcoma.  Other NRSTS that occur in children 
but not adults (except in rare cases) are infantile fibrosarcoma, infantile rhabdomyofibrosarcoma,
and infantile malignant rhabdoid tumor (Spunt, 2008). 
The likelihood of local invasion and distant metastases of NRSTSs is dependent on histological 
grade, dividing into low-grade and high-grade. The outcome of the initial surgical resection is the 
prognostic variable with the highest importance for nonmetastatic tumors.  Overall survival 
nearly reaches 90 % if tumors are completely resected (generally low-grade). However, 5 year 
survival is 55% and event free survival is 33% in unresected tumors (generally high grade and 
invasive). The poorest prognosis among NRSTS is in metastatic tumors, where 5-year survival 
is only 15% (Levy, 2011).
Accordingly, complete surgical resection is the standard treatment for NRSTS with or without 
adjuvant radiotherapy for prevention of local recurrence (Agarwala, 2006).  Combinations of 
ifosfamide, cyclophosphamide, vincristine, doxorubicin and etoposide seem to be the most active 
chemotherapy agents (Chui, 2007).  
1.1.3.2.
Ewing’s Sarcoma
After osteosarcoma, the second most common bone tumor in the pediatric population is Ewing’s 
sarcoma (Dome, 2008). Patients who develop recurrent disease within the initial 2 years have 5-
year survival rates of 7%, as compared to 30% if recurrent disease occurs after 2 years 
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1.1.3.2.
.1.3.2


EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
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ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
(Jain, 2010). The 5-year survival rate in patients with bone metastases (< 20%) is lower than 
those with lung/pleura metastases (20% to 40%) (Paulussen, 2009).
Treatment of Ewing’s sarcoma combines both neoadjuvant and adjuvant chemotherapy along
with local control measures such as surgery and/or radiation. In patients with localized disease, 
this approach has improved 5-year survival to ≥ 60% (Paulussen, 2009). Commonly used
therapeutic agents either as single-agent or primarily in combination include vincristine, 
dactinomycin, cyclophosphamide, doxorubicin, etoposide, topotecan, irinotecan and ifosfamide
(Paulussen, 2009), while clinical activity has also been observed with paclitaxel and docetaxel 
(Table 2 and Table 3).
1.1.3.3.
Melanoma
There has been a rise in the incidence of both adult and pediatric melanoma and it now occurs 7 
times more frequently in pediatric patients > 10 years old compared to those < 10 years old
(Mills, 2009; Morelli, 2011).The incidence of the disease in children and adolescents younger 
than 19 years is approximately 4.9 per 1,000,000 (SEER Table 29.1). Although in children with 
melanoma the overall mortality has declined steadily from 1968 to 2004 in the USA, the overall 
mortality rate in both children and adults remains at about 40% (Lewis, 2008; Morelli, 2011). 
The 5-year survival in pediatric patients with malignant melanoma is 96% (SEER Table 29.6), 
but is only 57% for patients with distant metastasis (Strouse, 2005).
Despite recent advances in treatment, the most effective approach for melanoma is prevention 
and early detection (Morelli, 2011). The treatment of melanoma in the pediatric populations is at 
present extrapolated from the adult population. Surgery is the primary course of treatment with 
adjuvant therapy mainly given only for advanced disease (Brenn, 2007) including chemotherapy, 
immunotherapy and to a limited extent radiation (Jen, 2009). Dacarbazine has been the standard 
chemotherapeutic treatment for metastatic melanoma for the past 3 decades. In 2011 two new 
agents, ipilimumab and vemurafenib, were approved for the treatment of metastatic melanoma.
Vemurafenib’s benefit is limited to patients with BRAF V600E mutations, which is 
approximately 40-45% of treatable patients. The efficacy of nab-paclitaxel in adult melanoma is 
described in Section 1.2.1.
1.1.4.
Conclusion
In the last decades, the prognosis of children with cancer has been improved and 70% of children 
can now be cured. However, some cancers display a 5-year survival rate of less than 50% and 
there is a clear unmet medical need in these patient populations. 
1.2.
Taxanes
Microtubule-stabilizing agents such as taxanes and epothilones are powerful antitumor agents
and commonly have been used in adults as anticancer agents. Taxanes specifically alone or in 
combination are approved in breast, prostate, non-small cell lung cancer (NSCLC), ovarian, 
gastric, and head and neck cancer. They have been investigated and have shown to be active in 
other refractory malignancies such as previously treated lymphomas, small cell lung cancer 
(SCLC), oesophageal, endometrial, and bladder cancer (André, 2006). 
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
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ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
1.2.1.
nab-Paclitaxel
nab-Paclitaxel (ABI-007, ABRAXANE® for Injectable Suspension [Celgene Corporation, 
Summit, New Jersey, United States, the Sponsor]) is a human serum albumin bound nanoparticle 
formulation of paclitaxel with a mean particle size of approximately 130 nanometers.  nab-
Paclitaxel has been developed to improve the therapeutic index of paclitaxel; the 
chemotherapeutic effect is enhanced by exploiting endogenous transport pathways to deliver 
higher doses of paclitaxel to the tumor (Desai, 2006), while at the same time the toxicities 
associated with conventional solvent-based paclitaxel formulations using a  Cremophor® EL 
 and ethanol vehicle are reduced.  
nab-Paclitaxel is bound to albumin in amorphous state and, unlike conventional solvent-based 
paclitaxel formulations where micellar entrapment is observed (Ibrahim, 2002; Sparreboom, 
1999; ten Tije, 2003), has linear pharmacokinetic (PK) characteristics.  Based on these 
pharmacokinetic properties, the dose and short infusion time, an increase of the maximum 
concentration (Cmax) of free paclitaxel up to 10-fold greater than with conventional solvent-based 
paclitaxel has been reported in the literature (Gardner, 2008).  The transport of paclitaxel across 
the endothelium is enhanced through albumin receptor mediated transcytosis, and the delivery of 
paclitaxel to tumors may be enhanced by binding of the albumin-bound paclitaxel to interstitial 
albumin binding proteins, such as secreted protein acidic and rich in cysteine (SPARC; also 
known as osteonectin) (Desai, 2006).  nab-Paclitaxel is not known to cross the blood-brain-
barrier. 
Although it has been hypothesized that SPARC expression may result in an increased 
concentration of nab-paclitaxel in tumors due to its albumin-binding ability, and may play a role 
in the enhanced antitumor activity, clinical studies remains conflicting (Alvarez-Gallego, 2012; 
Blackwell, 2010; Desai, 2009; Yardley, 2009) and therefore there is not sufficient data 
supporting the relationship of SPARC expression to clinical outcomes of nab-paclitaxel 
treatment.  
Type of solid tumors had no significant effect on paclitaxel pharmacokinetics in patients who 
received nab-paclitaxel.  Ethnic origin had no discernible effect upon PK parameters according 
to the studies conducted in Western countries, Japan and China.
The novel nab-paclitaxel nanoparticles conferred the ability to achieve a higher maximum 
tolerated dose (MTD) based on every 3-weeks dosing: 300 mg/m2 for nab-paclitaxel (DM97-
123) versus 175 mg/m2 for conventional solvent-based paclitaxel (Nyman, 2004).  The use of 
albumin also enables nab-paclitaxel to be given in a shorter, more convenient infusion time of 30 
minutes compared with 3 hours to 24 hours with conventional solvent-based paclitaxel.  nab-
Paclitaxel is given without steroid and antihistamine premedication, which is required for 
conventional solvent-based paclitaxel to prevent solvent-related hypersensitivity reactions (Taxol 
Label).  Cremophor EL has been shown to leach plasticizers, specifically di (2-ethylhexyl)
phthalate (DEHP), from polyvinyl chloride (PVC) bags and polyethylene-lined tubing (Allwood, 
1996; Gelderblom, 2001; Pfeifer, 1993; Song, 1996; Venkataramanan, 1986; Xu, 1998).  
Although no controlled epidemiologic toxicity studies have been conducted in humans exposed 
to DEHP, severe effects (eg, carcinogenicity, cardiopulmonary toxicity, hepatotoxicity, and 
nephrotoxicity) have been observed in experimental models.  The Taxol product information 
instructs users to prepare, store, and administer solutions in glass, polypropylene, or polyolefin 
containers; non-PVC-containing infusion sets (eg, those with polyethylene lining) should be used 
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
23
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
(Taxol Label).  By comparison, standard tubing and intravenous (IV) bags may be used for the 
IV administration of nab-paclitaxel (Ibrahim, 2002; Nyman, 2004).  
Clinical studies of nab-paclitaxel conducted in patients with breast cancer have demonstrated:
1. The ability to achieve a higher MTD of nab-paclitaxel at 300 mg/m2 vs 175 mg/m2 for 
conventional solvent-based paclitaxel. 
2. Elimination of the need for premedication, which is required with conventional solvent-
based paclitaxel to prevent solvent-related hypersensitivity reactions.  
3. Shortened infusion times (infusion time of 30 minutes with nab-paclitaxel vs 3 hours for 
conventional solvent-based paclitaxel).
4. Elimination of the need for specialized infusion set apparatus (standard infusion sets 
suffice whereas non-DEHP [diethylhexylphthalate] sets are required for conventional
solvent-based paclitaxel).
A Phase 3 comparison study (Study CA012-0) conducted in patients with metastatic breast 
cancer compared nab-paclitaxel (260 mg/m2) with conventional solvent-based paclitaxel (175 
mg/m2).  nab-Paclitaxel demonstrated greater efficacy (higher response rates, longer times to 
tumor progression [TTP], longer progression-free survival [PFS], and a 2.3 months overall 
survival advantage in patients previously treated for metastatic disease) with toxicity similar to 
that of conventional solvent-based paclitaxel, despite the higher dose of active agent achieved 
with nab-paclitaxel.  Grade 4 neutropenia occurred less frequently in the nab-paclitaxel group, 
and did not appear to be related to cumulative dose.  Instances of neutropenia were clinically 
asymptomatic and transient.  Grade 3 sensory neuropathies occurred more frequently in the nab-
paclitaxel group but improved in a median of 22 days.
A Phase 3 comparison study (Study CA031) conducted in patients with advanced NSCLC 
compared weekly nab-paclitaxel (100 mg/m2) and once every three weeks carboplatin (area 
under the curve [AUC] = 6) against once every three weeks conventional solvent-based 
paclitaxel (200 mg/m2) and carboplatin (AUC = 6) as first-line therapy. nab-Paclitaxel 
demonstrated significantly greater efficacy by overall response rate (ORR), with a trend toward 
greater response in PFS and overall survival (OS). There were significantly more ≥ Grade 3 
events of sensory neuropathy, neutropenia, arthralgia, and myalgia in the conventional solvent-
based paclitaxel arm, but more events of thrombocytopenia and anemia in the nab-paclitaxel arm 
(Socinski, 2012).  
A Phase 3 comparison study conducted in patients with metastatic malignant melanoma
compared nab-paclitaxel (150 mg/m2) on days 1, 8 and 15 with one week rest (28 day cycle) 
against once every three weeks dacarbazine (1000 mg/m2) as first line therapy.  nab-Paclitaxel 
demonstrated significantly greater efficacy by PFS (median PFS 4.8 vs 2.5 months) with a trend 
towards improvement in OS (interim OS 12.8 vs 10.7 months). Neuropathy and neutropenia 
occurred significantly more often in the nab-paclitaxel arm (Hersh, 2012).
A Phase 3 comparison study conducted in patients with metastatic adenocarcinoma of the 
pancreas compared nab-paclitaxel (125 mg/m2) with gemcitabine 1000 mg/m2 on Days 1, 8, and 
15 every 28 days against gemcitabine 1000 mg/m2 alone weekly for seven weeks with one week 
rest, then weekly for three weeks with one week rest as first line therapy.  nab-Paclitaxel with 
gemcitabine demonstrated statistically significant improvement in OS (8.5 versus 6.7 months 
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
24
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
respectively) and all efficacy endpoints overall and across subgroups when compared to 
gemcitabine alone.  The most common ≥ grade 3 adverse events reported in the nab-paclitaxel 
and gemcitabine combination arm included neutropenia, fatigue and neuropathy (Von Hoff, 
2013).
In Phase 1 studies conducted in the adult population with advanced solid tumors designed to 
determine the MTD of nab-paclitaxel, the following dose-limiting toxicities were observed:
keratitis, blurred vision, sensory neuropathy, stomatitis, and Grade 4 neutropenia. In general, 
hematologic toxicities were not important dose-limiting events; no life-threatening neutropenic 
infections and no Grade 4 anemia or thrombocytopenia were reported. The most frequently 
(> 50%) reported toxicities were all expected for this therapeutic drug class, namely fatigue, 
myalgia, nausea, alopecia, and stomatitis.
nab-Paclitaxel is approved globally for the treatment of metastatic breast cancer at a dosage of 
260 mg/m² administered IV over 30 minutes once every 3 weeks, in the USA for the treatment of 
locally advanced or metastatic NSCLC at a dosage of 100 mg/m2 on Days 1, 8, and 15 in 
combination with carboplatin (AUC = 6) on Day 1, every 21 days, and in the USA and EU for 
the treatment of first-line metastatic pancreatic adenocarcinoma at a dosage of 125 mg/m2
(followed immediately by gemcitabine) on Days 1, 8, and 15 of each 28-day cycle.
Please refer to the Investigator Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies and adverse event (AE) profile of 
the IP.
1.2.2.
Taxanes in Pediatrics
In children, taxanes have been studied in nine Phase 1 and five Phase 2 studies which are 
represented in Table 2 and Table 3, respectively. Although the efficacy and safety of nab-
paclitaxel have been evaluated in adult patients with various cancers, there have been no human 
studies thus far on the effects of nab-paclitaxel in the pediatric age group. 
In general, taxanes have demonstrated modest activity in children, mainly because of dose-
limiting toxicities that limit efficacious dose delivery (Table 2 and Table 3). Standard taxanes, 
conventional solvent-based paclitaxel and docetaxel, have shown antitumor activity, but have 
also produced dose-limiting toxicities such as severe hypersensitivity requiring prophylactic 
medication and/or neutropenia (Blaney, 1997; Geller, 2009). It is also notable that the alcohol in 
Cremophor EL (polyoxyethylated castor oil) produces central nervous system toxicity in 
pediatric patients receiving IV infusion of conventional solvent-based paclitaxel over 3 hours
(Doz, 2001).
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
25
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Table 2:
Phase 1 Trials of Taxanes in Children
Reference
Agent
N
Age 
(eligible/ 
enrolled)
Schedule
Maximum 
Tolerated 
Dose
Dose-Limiting 
Toxicity
Response
a
Hurwitz, 
1993
paclitaxel
31
≤ 22 
years / 
2-22 
years
24-h 
infusion/
21 days
350 mg/m2
Neurological
1 CR (papillary serous 
carcinoma)
2 PR 
(rhabdomyosarcoma, 
hepatocellular 
carcinoma)
9 SD (3 Ewing tumors, 2 
osteosarcomas, 2 
synovialosarcoma, 1 
glioma, 1 intrathoracic 
chordoma)
Doz, 2001
Paclitaxel
17
6 months 
to 
20years/ 
1.6 - 19 
years
3-h infusion/
21 days
No
Neurological, allergic
0 CR
1 PR
(rhabdomyosarcoma)
1 SD
(rhabdomyosarcoma)
Woo, 1999
Paclitaxel
7
≤ 21 
years / 
6 – 18 
years
24-h 
infusion/
21 days
Target AUC 
31 to < 45 
mM h
Mucositis
1 patient (leukaemia) 
responded sufficiently 
(response or SD) to 
receive a second cycle
Liu, 2001
Paclitaxel and 
radiotherapy
11
3-18 
years/ 
4 – 16 
years
24-h infusion 
times 7 days
4 mg/m2/day
Obstipation
2 PR: glioma
Hayashi, 
2003
Paclitaxel
16
≤ 21 
years / 
7 – 15 
years
3-h infusion 
twice weekly 
×6/28 days
50 mg/m2
/dose
Hematologic
0 CR
0 PR
3 SD (2 osteosarcomas, 1
ependymoma)
Horton, 
2008
Paclitaxel
63
≤ 21 
years at 
diagnosis
/ 
0.8 – 23 
years
24 h 
infusion/ 21 
days or 
weekly for 3 
weeks every 
28 days
430 mg/m2 
every 21 day, 
182 mg/m2 
weekly
Hypertension, 
coagulopathy, 
metabolic, hepatic, 
neurological, 
stomatitis, typhitis
1 CR (ALL)
3 PR (ALL)
4 SD 
Blaney, 
1997
Pocetaxel
44
1 – 21 
years/ 
1 – 22 
years
1-h infusion/
21 days
125 mg/m2
/dose
Hematologic, general
1 CR 
(rhabdomyosarcoma)
1 PR (PNET)
4 SD (3 PNET, 1 colon
carcinoma)
Seibel, 
1999
Docetaxel and 
filgrastim
17
1 – 21 
years/ 
2 – 20 
years
1-h infusion/
21 days
5μg/kg/
day
185 mg/m2
/dose
Dermatologic, 
myalgias
0 CR
1 MR
(colon carcinoma)
SD: not mentioned
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
26
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Table 2:
Phase 1 Trials of Taxanes in Children (Continued)
Reference
Agent
N
Age 
(eligible/ 
enrolled)
Schedule
Maximum 
Tolerated 
Dose
Dose-Limiting 
Toxicity
Response
Geller, 
2009
Paclitaxel and 
ifosfamide
15
≤ 21 
years/ 
2 – 18.8 
years
Pac 6-h 
infusion D1/  
ifos 2 g/m2
over 1 hour 
w/ mesna
D1-3, q3-4 
wk
425 mg/m2
Hypersensitivity, 
neurologic, 
3 MR
5 SD
Table adapted from André, 2006.
ALL = acute lymphocytic leukemia, AUC = area under the curve, CR = complete response, D = Day, DLT = dose-limiting 
toxicity, h = hour(s), ifos = ifosfamide, mesna = 2-mercaptoethane sulfonate sodium, MTD = maximum tolerated dose, MR = 
minor response, PNET = primitive neuroendocrine tumors, PR = partial response, SD = stable disease.
Table 3:
Phase 2 Trials of Taxanes in Children
Reference
Agent
N
Age
Dose/Schedule
Results
a
Hurwitz, 2001 Paclitaxel
73
≤ 21 years 
at 
diagnosis/ 
4 months –
19 years
350 mg/m2
24-h infusion/ 
21 days
Toxicities: mild nausea, central nervous 
system toxicity, myelosuppression, and 
febrile neutropenia, including one septic 
death. One Grade 2 and two Grade 3 
allergic reactions. No cardiac toxicities 
or arthralgias reported.
CR: 1 (meduloblastoma), PR: 3 
(astrocytoma, glioma, and primitive 
neuroectodermal)
SD (> 2 months): 20
Kretschmar, 
2004
Paclitaxel, topotecan, 
topotecan-
cyclophosphamide
100 total,
33 paclitaxel
1 – 21 
years/ 
13 months 
– 17 years 8 
months
33 patients: 
350 mg/m2 
intravenously 
for 24 h every
14–21 days
Grade 3/4 allergic reactions to paclitaxel 
in 4 patients. Grade 3/4 neutropenia in 
16 patients, Grade 3/4 thrombocytopenia 
in 6 patients.
CR= 1; PR = 5; MR=2, PD =  12, 
Objective responses (defined as 
complete responses + partial responses 
+ mixed responses) documented in 25% 
patients treated with paclitaxel. 
Zwerdling, 
2006
Docetaxel
160
≤ 21 years 
old at 
diagnosis/ 
1-27 years
125 mg/m2, 1-h 
infusion/
21 days
Hematologic toxicity most common 
during therapy. Dermatologic, 
neurologic, pulmonary, infectious side 
effects, and edema were significant. 
CR: 2 (1 patient with osteosarcoma and 
1 patient with rhabdomyosarcoma)
PR:  6 (3 patients with Ewing sarcoma, 
1 patient with osteosarcoma, 1 patient
with squamous cell carcinoma, 1 patient
with medulloblastoma) 
SD: 17 patients
The 1-year and 5-year overall survival 
rates for the 160 evaluable patients were 
24% (standard error = 4%) and 6% 
(standard error = 2%).
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
27
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Table 3:
Phase 2 Trials of Taxanes in Children (Continued)
Reference
Agent
N
Age
Dose/Schedule
Results
Taxotere®
prescribing 
information
Docetaxel, cisplatin, 
5-fluorouracil (5-FU)
75 (50 
docetaxel 
combination 
arm)
Not 
reported/ 1
– 22 years
Docetaxel 75 
mg/m2, 
cisplatin 75 
mg/m2, 5-FU 
750 mg/m2
Safety data not reported
CR: 1 (out of 50) in docetaxel/cisplatin/
5-FU arm
0 (out of 25) in cisplatin/5-FU arm
Harris, 1999
Paclitaxel
186
≤ 21 years\
not 
reported
350 mg/m2, 
24-h infusion 
every 3 weeks
(Safety presented by number of courses 
associated with event)
Neutropenia Grade 3/4: 297 courses
Neurotoxicity Grade 3/4: 2 courses
Hypersensitivity Grade 4: 1 courses
Cardiac toxicity Grade 3: 1 courses
CR+PR =11 (1 neuroblastoma, 1 
Ewing’s sarcoma, 3 rhabdomyosarcoma, 
2 nonrhabdo soft-tissue sarcoma, 2 
Wilms’ tumor, 1 Merkels tumor)
MR+SD = 56
PD= 99
a CR =  complete response, MR = minor response, PD = progressive disease, PR = partial response, SD = stable disease.
1.2.3.
nab-Paclitaxel Preclinical Studies 
In preclinical studies of neuroblastoma models, nab-paclitaxel inhibited cell proliferation in vitro 
and reduced tumor growth in xenograft models, and increased survival in metastatic 
neuroblastoma mouse models with intratumoral concentration of nab-paclitaxel 40 times higher 
compared to paclitaxel (data on file). In vitro, inhibition of cell proliferation was observed in all 
rhabdomyosarcoma cell lines studied (RH4, RH30, and RD) and a modest response was seen in 
the osteosarcoma cell line used in the study (KHOS). 
In Study S758, seven neuroblastoma cell lines (CHLA-20, CHLA-15, CHLA-90, LAN-5, SK-N-
BE(2), BE(2)C, and SH-SY5Y), three rhabdomyosarcoma (RH4, RH30, and RD), and one 
osteosarcoma cell line (KHOS) were exposed to increasing concentrations of nab-paclitaxel in 
vitro for 72 hours.
For the seven neuroblastoma cell lines, nab-paclitaxel exhibited dose-dependent cytotoxicity in 
vitro, as measured by cell viability with variable sensitivity. In addition, all three 
rhabdomyosarcoma cell lines were responsive to nab-paclitaxel treatment in a dose-dependent 
manner as measured by cell viability, while limited response was observed in the osteosarcoma 
cell line. nab-Paclitaxel was also more effective than an equivalent dose of paclitaxel dissolved 
in dimethyl sulfoxide (DMSO) after 72-hour treatment in all neuroblastoma cell lines tested. 
In a separate experiment, athymic nude mice bearing CHLA-20 human neuroblastoma 
xenografts were treated with nab-paclitaxel (10 mg/kg/day IV for 5 consecutive days, or 50 
mg/kg IV weekly), or DMSO-paclitaxel (20 mg/kg IV weekly). nab-Paclitaxel treatment resulted 
in significant tumor inhibition. nab-Paclitaxel at 50 mg/kg IV weekly also demonstrated 
significantly greater antitumor activity compared with DMSO-paclitaxel at 20 mg/kg IV weekly.
In athymic mice bearing RH4 rhabdomyosarcoma xenografts, nab-paclitaxel dosed at 50 mg/kg 
IV weekly for 3 weeks was better tolerated than DMSO-paclitaxel at 30 mg/kg IV weekly for 3 
weeks as shown by animal body weight.  Animals treated with DMSO-paclitaxel had earlier 
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
28
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
tumor relapses, which could be suppressed by rechallenging with nab-paclitaxel but not with 
DMSO-paclitaxel.
In athymic mice bearing RD rhabdomyosarcoma xenografts, nab-paclitaxel (50 mg/kg) and 
DMSO-paclitaxel (30 mg/kg) dosed IV weekly showed similar body weight change.  However, 
nab-paclitaxel was significantly more effective than DMSO-paclitaxel in suppressing RD tumor 
growth.  Further, nab-paclitaxel inhibited growth of tumors that continued to progress with 
DMSO-paclitaxel treatment.  
In a separate study with osteosarcoma xenograft nude mice models, nab-paclitaxel demonstrated 
a significantly greater tumor inhibitory rate when compared to adriamycin and conventional 
solvent-based paclitaxel (99 vs 46% and 41% respectively) (Yang, 2012).
The Pediatric Preclinical Testing Program at National Cancer Institute evaluated nab-paclitaxel
against a group of pediatric solid tumor xenografts. Results showed that nab-paclitaxel
administered IV at 50 mg/kg, every 4 days repeated 3 total times was well tolerated in non-
tumored and xenograft-bearing SCID mice. Two Ewing’s sarcoma xenografts tested (SK-NEP-1 
and EW8) and the rhabdomyosarcoma xenograft Rh65 showed maintained complete responses 
(MCR) following nab-paclitaxel treatment. Osteosarcoma xenografts OS-9 and OS-17, and 
neuroblastoma xenografts NB-1643 and NB-1691 did not show tumor regression to nab-
paclitaxel, and only showed minimal tumor growth delay. 
In summary, recent nonclinical study results have demonstrated that nab-paclitaxel displayed 
dose-dependent cytotoxicity and was also more effective than an equivalent dose of solvent-
based paclitaxel in the majority of pediatric solid tumor cell lines tested.  Higher doses of nab-
paclitaxel administered resulted in increased intratumor paclitaxel levels in vivo in mice bearing 
pediatric tumor xenografts. Further, nab-paclitaxel displayed antitumor activity in vivo against 
pediatric solid tumor models in a dose-dependent fashion and demonstrated increased efficacy 
compared to solvent-based paclitaxel. Taken together, these nonclinical results suggest that nab-
paclitaxel, delivered at higher dose than conventional paclitaxel, potentially may achieve clinical 
benefits in pediatric diseases where conventional paclitaxel is not effective (Zhang, 2013).
1.3.
Study Rationale
1.3.1.
Role of nab-Paclitaxel in Fulfilling the Unmet Medical Need
The prognosis of pediatric patients with metastatic disease continues to be poor. Survival rates 
for patients with localized disease are approximately 50% to 70% with the current treatment 
modalities for neuroblastoma, rhabdomyosarcoma, osteosarcoma, and Ewing’s sarcoma. Thus, a 
great unmet medical need remains for patients with metastatic disease or relapsed localized 
disease. In the light of therapies currently available for pediatric solid tumors, nab-paclitaxel 
may be a potentially superior alternative treatment option, due to its unique mechanism of action, 
safety profile (including absence of Cremophor EL), and pharmacodynamics/PK, which 
distinguish it from conventional solvent-based paclitaxel or docetaxel. 
nab-Paclitaxel may offer in children, similarly to the adult population, improved efficacy, with 
lower levels of toxicities as compared to conventional solvent-based paclitaxel due to:
!
Enhanced binding of paclitaxel to albumin, microtubules, and cells and increased 
tissue bioavailability of paclitaxel when compared to conventional solvent-based 
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
29
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
paclitaxel, since the paclitaxel is not trapped in the plasma compartment by 
Cremophor EL micelles
!
Increased transendothelial transport by albumin specifically binding to a 60-kDa 
glycoprotein receptor on the endothelial cell surface, which leads to the formation of 
caveolae and transcytosis across endothelial cells 
!
Increased accumulation of the drug at the tumor level
!
Linear pharmacokinetic profile
!
Absence of Cremophor EL and alcohol in the formulation of nab-paclitaxel, reducing 
the incidence of hypersensitivity reactions, sensory neuropathy, and central nervous 
system toxicity in children.
1.3.2.
Rationale for Study Design
This study will consist of two parts: a Phase 1 dose-escalation portion and a Phase 2 expansion 
portion.
In the Phase 1 portion of this pediatric study, the dose will be escalated using the rolling-6 
design, in which cohorts of up to 6 patients will be enrolled, starting with a dose of 120 mg/m² 
weekly, 80% of the maximum weekly dose investigated in adult patients (150 mg/m²). This 
strategy presumes that children may have a similar or higher threshold for toxicity in comparison 
to adults. The rolling-6 design allows a sufficient number of patients to be evaluated for safety 
and PK at each dose level, while limiting the duration of the study (Skolnik, 2008).
In the Phase 2 portion of this study, patients will be treated at the recommended Phase 2 dose 
(RP2D), determined during the Phase 1 portion of the study to be 240 mg/m2 in patients
weighing > 10 kg (11.5 mg/kg in patients weighing ≤ 10 kg), in order to assess antitumor activity 
in neuroblastoma, rhabdomyosarcoma, and Ewing’s sarcoma. Antitumor activity in the 
neuroblastoma group will be assessed by Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1 criteria or 123I-metaiodobenzylguanidine (MIBG)/Curie score, or both,
without crossover between assessment types over time. If both assessment types have been 
performed on a given subject across the assessment time points, to be considered as a partial 
response for the ORR analysis, both methodologies should show no worse than stable disease 
and at least one method should indicate complete response (CR) or partial response (PR). A 
response is only considered complete if both methodologies indicate CR. This analysis takes into 
account the fact that both methodologies are used in the assessment of response in neuroblastoma 
patients, and a partial response obtained by only one method is nevertheless clinically important 
for determining subsequent treatment options. Studies have shown that high-risk neuroblastoma 
patients with a Curie score > 2 following induction chemotherapy have extremely poor 
outcomes, leading to alternative therapies as subsequent options (Yanik, 2013). A Simon two-
stage minimax design (Simon, 1989) will be used to limit nab-paclitaxel exposure to 14 patients 
in each group without confirmation of some activity (≥ 2 patients) before moving forward with 9
additional patients in each group. The Simon two-stage design was chosen to minimize the 
number of patients exposed to nab-paclitaxel if the true ORR is less than 10% and yet to allow 
the trial to establish that an ORR greater than 10% is efficacious.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
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ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
1.3.2.1.
Rationale for Patient Population
In the Phase 1 dose escalation portion, the study will be conducted in patients ≥ 6 months and 
< 18 years old with recurrent and refractory solid tumors, except brain tumors, that have 
progressed on standard therapy or for which no standard anticancer therapy exists. The broad 
eligibility will allow the most rapid identification of the MTD/RP2D.  
In the Phase 2 portion, the study will focus on patients with recurrent/refractory neuroblastoma, 
rhabdomyosarcoma, and Ewing’s sarcoma. These types of tumors have been selected since they 
are most likely to be sensitive to nab-paclitaxel based on preclinical data. The age range is
extended to ≤ 24 years old (young adults) in the Phase 2 portion of the study to increase the 
likelihood of including patients with recurrent and refractory solid tumors. Patients 15 to 24 
years of age are now commonly referred to as “teenagers and young adults”; the European 
Society for Medical Oncology (ESMO) is collaborating with the European Society of Pediatric 
Oncology (SIOPE) to target the unmet medical needs of adolescents and young adults, due in 
part to the varied interfaces between adult and children’s services in different healthcare systems 
(Vassal, 2014).  Many patients diagnosed with neuroblastoma, rhabdomyosarcoma, and Ewing’s 
sarcoma are followed in pediatric clinics up to 24 years of age, particularly in the recurrent and 
relapsed setting. For example, an analysis of data from 1973 to 2007 from the United States
National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database shows 
that the median age at diagnosis of Ewing’s sarcoma is mid-to-late teens (Applebaum, 2011), so 
many patients with recurrent disease who have undergone several lines of treatment will be in 
their early twenties. In addition, it will be important to capture instances of confirmed PR as well 
as CR in order to have a proper chance to evaluate treatment effect and ORR (the primary Phase 
2 endpoint) using the Simon two-stage minimax design; therefore, the patients will be required to 
have radiologically documented measurable disease (for neuroblastoma, evaluable disease by 
MIBG/Curie score is also acceptable). Patients with these types of tumors may have 
compromised bone marrow function. In order to prevent their exclusion in the Phase 2 portion of 
this study, patients with known bone marrow involvement may be enrolled with a platelet level 
≥50 × 109 cells/L. 
Patients younger than 6 months old have been excluded from this study.  Spontaneous 
regressions of cancers have been reported, especially in neuroblastoma and renal cell carcinoma 
(Fritsch, 2004; Oluwole, 2009), and may occur in the proposed patient population. The current 
practice is to adopt a conservative observation (wait-and-see) strategy for patients identified at 6 
months of age with limited-stage disease. Furthermore, for more advanced pediatric tumors,
surgical treatment (in the case of resectable tumors), radiotherapy, or combination of 
chemotherapy provide good results as first-line treatment (Berg, 1991; Kim, 2006). Therefore, it 
would be highly unlikely that patients 0 to 6 months old could be enrolled in the study while a 
wait-and-see strategy is recommended for limited-stage diseases, and as effective treatment 
options are currently available for more advanced tumors; consequently, enrollment in a clinical 
study would not be the preferred treatment option.
1.3.2.2.
Rationale for Pharmacokinetics
The nab-paclitaxel PK in adult patients has not differed among different tumor types, and is not 
expected to differ among tumor types in pediatric patients. From this perspective, PK results 
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EDMS Doc. Number:
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Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
31
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
obtained from pediatric patients with various types of solid tumors can be extended to any 
particular type of tumor. 
1.3.3.
Rationale for Dosing
The starting dose in the Phase 1 portion of the study is 120mg/m² weekly on days 1, 8, and 15 of 
a 28-day cycle, which represents 80% of the maximum weekly dose investigated in adult patients 
(150 mg/m²) (see Section 1.2.1). Preliminary evaluation of the relationship between paclitaxel 
clearance and body surface area (BSA) or weight suggests that BSA or weight has minimal 
impact on paclitaxel clearance in adults patients treated with nab-paclitaxel. However, it is 
unknown if this observation can be extrapolated from adults to children. Since the BSA-based 
dosing is more conservative and is the approved dosing approach for adult patients, the nab-
paclitaxel dose will be based on BSA in the pediatric study.
As it is impractical to accurately calculate BSA in children weighing ≤ 10 kg, the BSA-based 
dose will be converted to mg per kg of weight in these children. The weight-based dose in each 
cohort is calculated by dividing the total dose at the median BSA (0.41 m²) with the median 
weight (8.7 kg) for children with weight ≤ 10 kg and aged ≥ 6 months. Additionally, in order to 
ensure safety in these small children, patients ≤10 kg will receive treatment at one dose level 
lower during the first cycle.  The dose-limiting toxicity (DLT) assessment period in these 
patients will last until the end of Cycle 2.
In three recent adult nab-paclitaxel Phase 3 Celgene sponsored studies (NSCLC, melanoma, 
pancreatic cancer), nab-paclitaxel was administered weekly alone (melanoma: 150 mg/m2 
weekly on days 1, 8, and 15 of a 28-day cycle) or in combination (NSCLC: 100 mg/m2 
continuous weekly dosing; pancreatic cancer: 125 mg/m2 weekly on days 1, 8, and 15 of a 28-
day cycle). As a single agent, the weekly dose of 150 mg/m2 used in the melanoma Phase 3 trial
and other Phase 1 and 2 studies, the proposed dose level 2 in this trial (See Table 7), was safe 
and well tolerated and with manageable toxicities.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
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2.
STUDY OBJECTIVES
2.1.
Primary Objective
The primary objective of the Phase 1 portion of the study is to determine the pediatric 
MTD/RP2D and characterize the safety and tolerability of nab-paclitaxel administered 
intravenously over approximately 30 minutes on Days 1, 8, and 15 of a 28-day cycle in patients 
≥ 6 months and < 18 years old with recurrent or refractory solid tumors.
The primary objective of the Phase 2 portion of the study is to determine the antitumor activity 
assessed by the overall response rate (ORR) of nab-paclitaxel given at the RP2D in patients ≥ 6 
months and ≤24 years old with several discrete recurrent or refractory solid tumor types 
including neuroblastoma, rhabdomyosarcoma, and Ewing’s sarcoma.
2.2.
Secondary Objectives
The secondary objectives of the Phase 1 portion are:
!
To evaluate pharmacokinetics (PK).
!
To characterize the ORR.
The secondary objectives of the Phase 2 portion are:
!
To characterize duration of response (DOR).
!
To characterize the disease control rate (DCR).
!
To characterize progression-free survival (PFS).
!
To characterize 1-year survival.
!
To confirm safety.
!
To evaluate PK.
2.3.
Exploratory Objectives
The exploratory objectives of the entire study are:
!
In the Phase 1 portion, to assess 123I-metaiodobenzylguanidine (MIBG) response in 
patients with neuroblastoma.
!
To explore the potential utility of biomarkers of response and resistance in this study 
population.  The most recent available tumor tissue sample will be optionally 
collected at the time of study entry.  Biomarkers will be prioritized for analysis in 
these samples after study completion, as informed by emerging data.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
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ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
3.
STUDY ENDPOINTS
3.1.
Primary Endpoint(s)
The primary endpoint of the Phase 1 portion of the study is the incidence of DLTs (defined in 
Section 8.2.1.1) and the incidence of treatment-emergent adverse events (TEAEs).
The primary endpoint of the Phase 2 portion of the study is the ORR, which is the combined 
incidence of CR and PR, confirmed no less than 4 weeks after the criteria for response are first 
met, based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. In 
the neuroblastoma group the ORR will be determined by RECIST and/or the Curie scale (MIBG 
response), as specified in Section 6.3.
3.2.
Secondary Endpoint(s)
The secondary endpoints for the Phase 1 portion of the study are:
!
Pharmacokinetic parameters including the maximum observed concentration in blood 
(Cmax), area under the blood concentration-time curve (AUC), clearance and volume 
of distribution (Vss).
!
ORR.
The secondary endpoints for the Phase 2 portion of the study are: 
!
DOR in patients with a confirmed objective complete response (CR) or partial 
response (PR).
!
DCR is the percentage of patients with a confirmed objective CR or PR, or stable 
disease for at least 16 weeks.
!
PFS based on investigator assessment of response using RECIST 1.1 guidelines. In 
the neuroblastoma group the PFS will be determined by RECIST and/or the Curie 
scale (MIBG response), as specified in Section 6.3.
!
Survival at 1 year.
!
The incidence of TEAEs.
!
Population PK parameters (eg, clearance and volume of distribution).  Data from the 
Phase 1 and 2 portions will be analyzed together for this endpoint.
3.3.
Exploratory Endpoints
The exploratory endpoints for the entire study are:
!
In the Phase 1 portion only, MIBG response using Curie score.
!
Biomarker analysis prioritized after study completion, as informed by emerging data.
!
In the Phase 2 portion only, bone marrow biopsy verification of confirmed complete 
response in patients with neuroblastoma.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
34
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
4.
OVERALL STUDY DESIGN
4.1.
Study Design
This is a Phase 1/2 multicenter, open-label, dose-finding study to assess the safety, tolerability, 
PK, and efficacy of nab-paclitaxel administered intravenously to patients ≥ 6 months and < 18
years old in the Phase 1 portion and patients ≥ 6 months and ≤24 years old in the Phase 2 
portion with recurrent and refractory solid tumors. 
The Phase 1 portion will be a dose-finding study (rolling-6 design, see section 8.2.1.3) to
determine the MTD/RP2D, safety, tolerability, and PK parameters of nab-paclitaxel in pediatric 
patients with recurrent and refractory solid tumors who have progressed on standard therapy or 
for whom no standard therapy exists. The decision to dose-escalate or to declare an MTD/RP2D 
will be determined by the safety monitoring committee (SMC) each time clinical and laboratory 
safety data for a given cohort are available for review. The SMC will also determine the dose(s)
appropriate for the Phase 2 portion of the study (or the RP2D). 
The Phase 2 portion of the study will be conducted at the RP2D, 240 mg/m2 in patients weighing 
> 10 kg and 11.5 mg/kg in patients weighing ≤ 10 kg, to determine: 
1. The antitumor activity of nab-paclitaxel in several solid tumor types (three groups: 
neuroblastoma, rhabdomyosarcoma, and Ewing’s sarcoma).
2. The safety profile and pharmacokinetics of nab-paclitaxel administered at the RP2D.  
During the Phase 2 portion, the SMC will continue to review safety data regularly and make 
recommendations about the study continuation, as appropriate (see Section 8.2.1.2).
The study will be conducted in compliance with the International Council for Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
35
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Figure 1:
Phase 1 Study Design
Screening
Patients ≥ 6 months and < 18 years old with recurrent/refractory solid tumors 
excluding patients with brain tumors/metastasis
N = Approximately 12 - 44 patients in DDS
Eligibility check
Treatment
Rolling-6 design
nab-Paclitaxel weekly on days 1, 8 and 15 of 28 day cycle starting with 120 mg/m2
Cohorts of up to 6 patients per dose level, until MTD/RP2D
Treatment until disease progression, death, withdrawal of consent, unacceptable toxicity
Post treatment follow-up
28 days post-treatment visit
Tumor evaluation according to protocol until progression or new cancer therapy
Survival follow-up for 1 year or until death
End of treatment
Refer to Table 7 for dose levels.
Figure 2:
Phase 2 Study Design
Screening
Patients ≥ 6 months and ≤ 24 years old 
recurrent/refractory solid tumors (radiologically documented measurable disease by RECIST 1.1; for neuroblastoma 
evaluable disease by MIBG / Curie is acceptable) fitting one of the three groups (excluding patients with brain 
tumors/metastasis) 
after failing up to three lines of treatment
Eligibility check
Treatment
nab-Paclitaxel weekly on days 1, 8 and 15 of 28 day cycle at RP2D from Ph1
Treatment until disease progression, death, withdrawal of consent, unacceptable toxicity
Post treatment follow-up
28 days post-treatment visit
Tumor evaluation according to protocol until progression or new cancer therapy
Survival follow-up for 1 year or until death
End of treatment
Group 1
Neuroblastoma
N = 14 to 23
Group 2
Rhabdomyosarcoma
N = 14 to 23
Group 3
Ewing’s Sarcoma
N = 14 to 23
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
36
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
4.2.
Study Duration 
In both the Phase 1 and 2 portions of the study, patients will enter a 14-day screening period, and 
if eligible (and the cohort/group is open for recruitment) will proceed to the treatment phase.  
Patients may remain on treatment at the discretion of the investigator until disease progression, 
unacceptable toxicity, until he/she begins a new anticancer therapy, withdrawal of 
parent/guardian/patient consent/assent, parent/guardian/patient refusal, physician decision, or 
death. At the discretion of the investigator, treatment may continue beyond radiologic 
progression if the patient is benefiting based on other response criteria.  
All patients in both portions of the study will be followed for 28 days after discontinuing 
treatment for safety and monitoring of adverse events, until progression (if applicable) for 
response, and for 1 year after the last dose of nab-paclitaxel for survival and new anticancer 
therapies.  
The Phase 2 portion of the study will begin when the RP2D has been declared in the Phase 1 
portion.  
4.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last patient to complete the 
study, or the date of receipt of the last data point from the last patient that is required for primary, 
secondary and/or exploratory analysis, as pre-specified in the protocol and/or the Statistical 
Analysis Plan, whichever is the later date.
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EDMS Doc. Number: 
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
37
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
5.
TABLE OF EVENTS
The Table of Events is applicable to both the Phase 1 and Phase 2 portions of the study.
Table 4:
Table of Events
Events
Screening 
Period
Treatment Period
Screening
Cycle 1
Subsequent Cycles
Follow-up Period
Day
a
-14 to -1
1
2
3
4
8
15
1
8
15
EOT
28 Day 
Safety 
Visit
b
Disease 
Progression/ 
Survival
STUDY ENTRY
Informed consent and if applicable assent
X
Prior cancer history
X
Prior cancer therapies
c
X
Complete medical history
X
Demographics
X
Prior/ concomitant medication evaluation
X (-28 from 
screening)
Continuous, until 28 days after treatment discontinuation
Prior/ concomitant procedures evaluation
X (-28 from 
screening)
Continuous, until 28 days after treatment discontinuation
Inclusion/exclusion criteria
X
IRT registration
X
Archival tumor tissue collection (optional)
X, after eligibility confirmation
SAFETY ASSESSMENTS
Adverse event evaluation
Continuous starting after informed consent/assent signature, until 28 days after treatment 
discontinuation (and as noted in Section 6.2.1.1)
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EDMS Doc. Number: 
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
38
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Table 4:
Table of Events (Continued)
Events
Screening 
Period
Treatment Period
Screening
Cycle 1
Subsequent Cycles
Follow-up Period
Day
a
-14 to -1
1
2
3
4
8
15
1
8
15
EOT
28 Day 
Safety 
Visit
b
Disease 
Progression/ 
Survival
Physical examination (source documented 
only)
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
Body surface area calculation
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
X
X
Hematology laboratory
X
X
X
X
X
X
X
X
X
Chemistry laboratorye
X
X
X
X
X
Urine homovanillic acid and 
vanillylmandelic acid (for neuroblastoma 
only)
X
Every other 
cycle, 
starting in 
Cycle 2
X
X
LVSF assessment by echocardiogram/ 
MUGA/ other medically appropriate 
method
X
Every other 
cycle 
starting in 
Cycle 3
X
12-lead electrocardiogram
X
Every other 
cycle 
starting in 
Cycle 3
X
Serum β-hCG (if indicated)f
X
As clinically indicated
Urine β-hCG (if indicated)f
X
As clinically indicated
X
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EDMS Doc. Number: 
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
39
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Table 4:
Table of Events (Continued)
Events
Screening 
Period
Treatment Period
Screening
Cycle 1
Subsequent Cycles
Follow-up Period
Day
a
-14 to -1
1
2
3
4
8
15
1
8
15
EOT
28 Day 
Safety 
Visit
b
Disease 
Progression/ 
Survival
Pharmacokinetic samplesg
X
X
X
X
EFFICACY ASSESSMENTS
Tumor evaluation (CT/MRI, see
Section 6.3)
X (-28 to -1)
Every 8 weeks (± 5 days) from Cycle 1 Day 1, until progression or new anticancer treatment
MIBG scan (in patients with 
neuroblastoma)
X (-28 to -1)
If assessable by MIBG scan at screening, every 8 weeks (± 5 days) from Cycle 1 Day 1, until 
disease progression or new anticancer treatment.  If not assessable by MIBG scan, at screening 
and suspected progression only.
Bone marrow biopsy (in patients with 
neuroblastoma)
Only at confirmation of complete response
Lansky performance status (in patients < 12 
years old)
X
X
X
X
X
Karnofsky performance status (in patients ≥ 
12 years old)
X
X
X
X
X
INVESTIGATIONAL PRODUCT (IP)
Administer nab-paclitaxel
X
X
X
X
X
X
FOLLOW-UP
Survival follow-up
Every 1 month 
for 1 year
Anticancer therapy since nab-paclitaxel 
discontinuation
X
At every 
survival follow-
up visit for 1 
year
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EDMS Doc. Number: 
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
40
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
β-hCG = β human chorionic gonadotropin, C#D# = Cycle number Day number, CR= complete response, CT = computed tomography scan, EOT = end of 
treatment visit, IRT = Integrated Response Technology, LVSF = left ventricular shortening fraction, MIBG = 123I- metaiodobenzylguanidine scan, MRI= 
magnetic resonance imaging, MUGA = multi-gated acquisition scan.
a An administrative window of ± 2 days is permitted for all visits except C1D1.
b If the EOT visit occurs within 7 days of the 28 day safety visit, laboratory evaluations only need to be repeated for abnormal parameters at the EOT visit.
c Prior cancer therapies includes surgery, radiation, stem cell transplant, systemic or any other therapy for the patient's cancer.
d Vital sign measurements must be recorded in the database at screening and EOT only, and kept in the source documents at all other visits.  However, if an 
abnormal (out of range) value is reported at a given visit, that parameter should be collected in the case report form (CRF) at every subsequent scheduled visit 
until it returns to normal.  
e In patients with neuroblastoma ferritin will be analyzed.
f For all female patients of childbearing potential (see Inclusion 8), a serum pregnancy test will be done at screening.  A urine pregnancy test will be repeated 
within 72 hours before first treatment if the serum pregnancy test occurred > 72 hours before dosing, and at EOT. Pregnancy tests conducted after screening 
will be recorded in the source documentation only.
g All patients will have pharmacokinetic samples taken on C1D1. A subset of patients will have samples taken on C1D2, C1D3, and C1D4 as described in 
Section 6.4.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
41
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
6.
PROCEDURES
Screening evaluations will be performed for all patients to determine study eligibility. These 
evaluations must be completed within 14 days of first dosing unless noted below. 
Any questions regarding patient eligibility should be directed to the Celgene medical monitor or 
designee. Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
Safety laboratory analyses and all assessments (with the exception of PK and biomarker 
analyses) will be performed locally. Laboratory normal ranges must be submitted to the Celgene 
or designated contract research organization (CRO) data manager. Screening laboratory values 
must demonstrate patient eligibility, but may be repeated within the screening window if 
necessary.
The following will be performed at screening as specified in the Table of Events, after informed 
consent/assent has been obtained:
!
Cancer history (including specific information regarding diagnosis, staging, and 
histology)
!
Demographics (initials, date of birth, sex, race, and ethnicity-if allowed by local 
regulations)
!
Prior cancer therapies:  includes surgery, radiation, stem cell transplant, systemic or 
any other therapy for the patient’s cancer 
!
Complete medical history (all relevant medical conditions occurring more than 28 
days before screening should also be included)
!
Prior and concomitant procedures (including all procedures occurring ≤ 28 days 
before screening)
!
Prior and concomitant medication evaluation (including those taken ≤ 28 days before 
screening, except for those taken for cancer)
!
Archival tumor sample collection (optional): If available and consented, the sample 
should be retrieved and sent after patient eligibility is confirmed.  It is recommended 
that this be sent before the end of Cycle 1
!
Physical examination (source documented only), height, weight
!
Vital signs (including blood pressure, temperature, and heart rate)
!
Performance status
∀
Lansky performance status recommended in patients < 12 years old at the time of 
informed consent/assent
∀
Karnofsky performance status recommended in patients ≥ 12 years old at the time 
of informed consent/assent
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
42
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
∀
An individual patient should be evaluated by the same performance status method
or scale for the duration of the study
!
Left ventricular shortening fraction (LVSF) assessment by echocardiogram, multi-
gated acquisition (MUGA) scan, or other medically appropriate method (eg, magnetic 
resonance imaging, MRI). Patients with a historical LVSF assessment performed      
≤ 14 days before the first dose need not repeat the assessment for the purposes of 
screening.
!
12-lead electrocardiogram (ECG). Patients with a historical ECG performed ≤ 14 
days before the first dose need not repeat the ECG for the purposes of screening.
!
Response assessment/ tumor evaluation (see Section 6.3). Patients with historical 
tumor scans evaluable per RECIST 1.1 (and MIBG scan for neuroblastoma) 
performed ≤ 28 days before the first dose need not repeat scans for the purposes of 
screening 
∀
Patients who are symptomatic for brain metastases must have a brain scan at 
screening to confirm eligibility
!
Complete blood count (CBC) with differential, including but not limited to red blood 
cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count, absolute 
neutrophil count (ANC), and platelet count. ANC should be measured with automated 
count where available
!
Chemistry panel including, but not limited to, sodium, potassium, chloride, 
bicarbonate, calcium, magnesium, phosphorus, blood urea nitrogen (BUN), 
creatinine, glucose, albumin, total protein, alkaline phosphatase, bilirubin (total and 
direct), aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
(AST/SGOT), alanine aminotransferase (ALT/SGPT), lactate dehydrogenase/serum 
glutamic pyruvic transaminase (LDH), and uric acid
!
For neuroblastoma the following will also be assessed: 
∀
Urine homovanillic acid (HVA) and vanillylmandelic acid (VMA)
∀
Blood ferritin
!
Pregnancy test is required for all female patients of childbearing potential defined as 
being ≥ 12 years of age or who have reached menarche, whichever occurs first. 
Serum β-hCG pregnancy test will be performed at screening. Urine pregnancy test 
will be performed to assess patient eligibility within 72 hours prior to the first 
administration of IP, if the serum pregnancy test did not already occur with 72 hours 
of dosing
!
Adverse event assessment begins when the parent/guardian/patient signs the informed 
consent/assent form
!
IRT registration: If the patient meets all eligibility criteria, registration in IRT should 
be performed as described in Section 8.3
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
43
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
6.1.
Treatment Period
The patient will begin treatment at the assigned dose upon confirmation of eligibility and 
authorization from the sponsor that there is a spot available in the current cohort/group(s) (see 
Section 8.3). The patient must start treatment within 14 days of signing the informed consent 
form (ICF).  For all subsequent visits, an administrative window of ± 2 days is permitted.
Treatment cycles are 28 days in duration. 
The following evaluations will be performed at the frequency specified in the Table of Events, 
Table 4. The evaluations should be performed prior to dosing on the visit day, unless otherwise 
specified:
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
Physical examination (source documented only)
!
Vital signs: In general, on-treatment vital sign measurements will be source 
documented only.  However, if an abnormal (out of range) value is reported at any 
given visit, that parameter should be collected in the case report form (CRF) at every 
subsequent scheduled visit until it returns to normal
!
Weight 
!
Height 
!
Complete blood count with differential
!
Chemistry panel (with ferritin for neuroblastoma)
!
Urine HVA and VMA for neuroblastoma: every other cycle starting in Cycle 2
!
Performance status 
!
LVSF assessment 
o
Every other cycle starting in Cycle 3
o
If the results are abnormal, the assessment should be repeated as clinically 
indicated
!
12- lead ECG: every other cycle starting in Cycle 3
!
Adverse event evaluation (continuously)
!
Response assessment/ tumor evaluation (see Section 6.3)
!
Pharmacokinetic sampling (see Section 6.4)
6.1.1.
End of Treatment
An end of treatment (EOT) evaluation should be performed for patients who are withdrawn from 
treatment for any reason as soon as possible after the decision to permanently discontinue 
treatment has been made. 
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6.1.1.
6.1
en


EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
44
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
The following evaluations will be performed as specified in the Table of Events:
!
Physical examination (source documented only), height, and weight
!
Vital signs 
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
Performance status
!
LVSF assessment 
!
12-lead ECG
!
Adverse event evaluation
!
Complete blood count with differential
!
Chemistry panel (with ferritin for neuroblastoma)
!
Urine HVA and VMA for neuroblastoma
!
Urine β-hCG (for females of childbearing potential)
!
Response assessment/ tumor evaluation will be continued at the schedule defined in 
the Table of Events, and does not need to be performed specifically for the EOT visit
except as specified in Section 6.3.1.1.1
6.2.
Follow-up Period
6.2.1.
28-Day Follow-up
All patients will be monitored for reporting of new or follow-up of existing AEs for 28 days after 
the last dose of IP, as well as SAEs made known to the investigator at any time thereafter that are 
suspected of being related to IP, as described in Section 11.1. If the 28-day Follow-up visit 
occurs within 7 days of the EOT visit and EOT laboratory values are not of clinical significance, 
laboratory collection is not required at the 28-day Follow-up visit.  The 28-day Follow-up 
assessments include:
!
Physical examination (source documented only), height, and weight
!
Vital signs 
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
Performance status
!
Adverse event evaluation
!
Complete blood count with differential 
!
Chemistry panel (with ferritin for neuroblastoma) 
!
Urine HVA and VMA for neuroblastoma
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Pere
!


EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
45
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
6.2.1.1.
Special Monitoring
Neuropathy (eg, motor neuropathy, sensory neuropathy, peripheral neuropathy) AEs present at 
the time of treatment discontinuation should be followed until 1 of the following are met, but no 
less than the minimum 28 days required in Section 6.2.1 and Section 11.1:
!
Improvement to ≤ Grade 1
!
At least 3 months have elapsed without improvement or worsening
!
The patient initiates any other anticancer therapy during the follow-up
6.2.2.
Efficacy Follow-up
All patients who discontinue treatment for reasons other than disease progression, start of a new 
anticancer therapy, or withdrawal of consent from the entire study will be followed for response
and new anticancer therapies as specified in Section 6.3.
6.2.3.
Survival Follow-up
After the EOT visit, all patients will be followed for survival until death, lost to follow-up, or one 
year after EOT, whichever occurs first. This evaluation should be conducted monthly for 1 year 
from the last dose of IP. New anticancer therapies should be collected at the same schedule for 1 
year from the last dose of IP.
Survival follow-up may be conducted by record review (including public records) and/or 
telephone contact with the patient, family, or the patient’s treating physician.
6.3.
Response Assessments
Response assessments (tumor evaluations) should be performed at screening (up to 28 days 
before the start of IP) and every 8 weeks (± 5 days) from Cycle 1 Day 1 until disease 
progression, start of a new anticancer therapy, or withdrawal of consent from the entire study. 
Evaluation of response should be performed using RECIST 1.1 guidelines. In the Phase 2
portion of the study, patients with neuroblastoma will also be assessed at screening for response 
using MIBG evaluation and the Curie score, as described in Section 6.3.1.1.1, and then (if 
evaluable by MIBG scan at screening) every 8 weeks (± 5 days) from Cycle 1 Day 1 until 
disease progression, start of a new anticancer therapy, or withdrawal of consent from the entire 
study.  Patients without MIBG evaluable lesions at screening should have a subsequent MIBG 
scan at suspected progression only.
New anticancer therapies will also be collected at the same schedule. New anticancer therapy 
includes (but is not limited to) any systemic or local-regional medication, surgery, radiation, or 
any other therapy intended to treat the patient’s cancer.  
If necessary, an independent (central) assessment of response may be conducted by the sponsor 
after study completion.  
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
46
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
6.3.1.
Assessment of Response According to RECIST 1.1
Response will be assessed using RECIST 1.1.  Response assessments include computed 
tomography (CT) scan or MRI.  The regions to be imaged are the chest and abdomen/pelvis, as 
well as any other studies required for tumor imaging. The same mode of imaging for lesion 
evaluation at screening must be used consistently throughout the study. 
The CT imaging should include contrast unless medically contraindicated. Conventional CT 
should be performed with contiguous cuts of 5 mm or less in slice thickness. Spiral CT should be 
performed by use of a 5 mm contiguous reconstruction algorithm.
All patients with evidence of objective tumor response (CR or PR) should have the response 
confirmed with repeat assessments at the next scheduled scan, but after no less than 4 weeks.  
Response assessments must have occurred ≥ 6 weeks from Cycle 1 Day 1 to be considered as
stable disease (SD) for a best response.
Additional details and definitions of response are found in Appendix A in Section 19.1.
6.3.1.1.
Other Assessments
Patients who are symptomatic for brain metastasis at screening must undergo a brain scan to 
confirm eligibility.
Additional scans, including further brain scans, MRI of the head, or nuclear medicine bone scan,
may be performed if clinically indicated (eg, symptoms of brain metastasis) at the discretion of
the investigator.
6.3.1.1.1. Other Assessments for Neuroblastoma
Patients with neuroblastoma should be assessed at screening for MIBG response using the Curie 
score.  The Curie score is a semi-quantitative scoring system for the comparison of sequential 
whole-body MIBG scans in children with neuroblastoma (Ady, 1995).
Patients with MIBG-evaluable lesions should be assessed for response using the Curie score 
(Section 19.2 Appendix B) at screening (up to 28 days before the start of IP) and every 8 weeks 
(± 5 days) from Cycle 1 Day 1 thereafter until disease progression, start of a new anticancer 
therapy, or withdrawal of consent from the entire study.  Patients without MIBG evaluable 
lesions at screening should have a subsequent MIBG scan at suspected progression only.
Patients with confirmed objective CR will be assessed for bone marrow disease through bone 
marrow biopsy. If the patient was assessed by both RECIST and MIBG/Curie score, both 
methodologies must show confirmed objective CR.  
6.4.
Pharmacokinetics
Pharmacokinetic blood samples will be collected for the first dose (Cycle 1 Day 1) from all 
patients in both the Phase 1 and 2 portions of the study to analyze paclitaxel concentrations in 
blood. 
Samples will be collected from all patients enrolled in the Phase 1 portion of the study according 
to a dense PK sampling strategy as specified in Table 5.
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lood. 


EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
47
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Samples will be collected from all remaining patients enrolled in the study according to a sparse 
PK sampling strategy as specified in Table 6, or if optionally consented according to a dense PK 
sampling strategy. 
Table 5:
Dense PK Sampling
Sample 
Number
Sample Time (hours)
Patients ≥ 6 
Years Old
Patients < 6 
Years Old
1
1-2 minutes prior to the end of infusion (no 
window, must be collected before end of infusion)
X
X
2
15 minutes after end of infusion (± 5 minutes)
X
X
3
1 hours after end of infusion (± 5 minutes)
X
4
3 hours after end of infusion (± 10 minutes)
X
X
5
5 hours after end of infusion (± 10 minutes)
X
X
6
8 hours after end of infusion (± 1 hour, 
recommended
a
)
X
7
24 hours after end of infusion
b
(± 3 hours)
X
X
8
48 hours after end of infusion
c
(± 3 hours)
X
9
72 hours after end of infusion
d
(± 3 hours, 
recommended
e
)
X
a Recommended sample at 8 hours after infusion should be performed in any center where the patient can remain to 
have the sample drawn.  Patients who are being treated as an out-patient may omit this sample.
b 24- hour sample may occur on study Day 2, depending on the timing.
c 48-hour sample may occur on study Day 3, depending on the timing.
d 72-hour sample may occur on study Day 4, depending on the timing.
e Recommended sample at 72 hours after infusion should be performed in patients who live close enough to the 
center to return on the third day.  Patients living far from the center may omit this sample.  
Table 6:
Sparse PK Sampling
Sample 
Number
Sample Time (hours)
Patients ≥ 6 Years 
Old
Patients < 6 Years 
Old
1
15 minutes after end of infusion (± 5 min)
X
X
2
3 hours after end of infusion (± 10 minutes)
X
X
3
24 hours after end of infusion (± 3 hours)
a
X
X
a 24-hour sample may occur on study Day 2 depending on the timing.
The following information must be captured in the CRFs for Cycle 1, Day 1 through Day 4: 
!
The dose level and total dose administered (Day 1 only)
!
The exact time of the start and end of infusion (Day 1 only)
!
The exact time of each PK sample collection in addition to the scheduled time point 
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
48
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
At each PK sampling time point, approximately 0.5 mL of blood will be drawn and distributed 
into tubes provided by Celgene or its representative as described in the laboratory manual. For 
PK samples collected at 1-2 minutes prior to, 15 minutes after, and 1 hour after the end of the 
infusion, the blood should be drawn from the arm contralateral to the arm used for drug infusion.
Instructions for sample collection, processing, storage, and shipping are included in Section 19.4,
Appendix D, and also in a laboratory manual.
6.5.
Biomarkers
The most recently available tumor tissue sample will be optionally collected at the time of study 
entry.  The study laboratory manual will include procedures for providing these samples, which 
will be used to study tumor characteristics and their correlation with patient outcomes and 
treatment response.  The specific use of these samples is not being pre-specified and will be 
determined based on emerging data and methodological advances.  A potential use of these 
samples is to assess in the pediatric patients in this study the value of markers of response to nab-
paclitaxel that may be identified in studies of adult patients.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
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ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
7.
STUDY POPULATION
7.1.
Number of Patients 
In the Phase 1 portion of the study, at least 12 to approximately 64 patients with various solid 
tumors will be enrolled, depending on the number of dose escalation cohorts and the number of 
additional patients enrolled at dose levels evaluated as safe by the SMC.
In the Phase 2 portion of the study, up to 69 efficacy evaluable patients will be enrolled, in 3 
different groups (≤23 with neuroblastoma, ≤ 23 with rhabdomyosarcoma, and ≤ 23 with 
Ewing’s sarcoma), with at least 14 patients per group.
7.2.
Inclusion Criteria
Patients must meet all of the following criteria to be enrolled in the study:
1. Patient is male or female, meeting the following age requirements at the time the 
informed consent document (and assent form, if applicable) is signed.
a.
Phase 1: patient is ≥6 months to < 18 years of age
b. Phase 2: patient is ≥6 months to ≤24 years of age
2. Patient has a confirmed solid tumor diagnosis according to the following:
a.
Phase 1: patient has a recurrent or refractory solid tumor that has progressed or 
did not respond to standard therapy, or for which no standard anticancer therapy 
exists
b. Phase 2: patient has radiologically documented measurable disease by RECIST 
1.1 (for neuroblastoma, evaluable disease by MIBG/Curie score is also 
acceptable) in one of the following tumor types and has failed up to three lines of 
treatment
i. Group 1: neuroblastoma (patients with bone marrow disease only are not 
permitted)
ii. Group 2: rhabdomyosarcoma
iii. Group 3: Ewing’s sarcoma
3. The patient has a Lansky/ Karnofsky performance status score of ≥ 70%
4. The patient has adequate serum chemistry levels, evidenced by the following laboratory 
values
a.
AST (SGOT), ALT (SGPT) ≤ 2.5 × upper limit of normal range (ULN) 
b. Total bilirubin ≤ 1.5 × ULN
c.
Creatinine ≤ 1.5 × ULN
5. The patient has adequate bone marrow function, evidenced by the following:
a.
Absolute neutrophil count ≥ 1.0 × 109 cells/L
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
50
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
b. Platelets ≥ 80 × 109 cells/L (transfusion independent, defined as not receiving 
platelet transfusions within 7 days prior to laboratory sample). In the Phase 2
portion, for patients with known bone marrow involvement, platelets ≥ 50 × 109
cells/L
c.
Hemoglobin ≥ 8 g/dL (transfusion is permitted to fulfill this criterion)
6. The patient (when applicable) or patient’s parent(s) or legal guardian(s) understand(s) 
and voluntarily signed an informed consent document prior to any study-related 
assessments/procedures being conducted. Where locally applicable, the patient also 
understands and voluntarily provides his/her assent prior to any study-related 
assessments/procedures being conducted.
7. Male patients of childbearing potential must use a condom during sexual intercourse and 
shall not father a child during the study and for 6 months after the last dose of study
medication.
8. Female patients of childbearing potential [defined as all female patients ≥ 12 years old or 
who have reached menarche, whichever occurs first] must have both of the following:
a.
Agree to the use of two physician-approved contraceptive methods 
simultaneously or practice complete abstinence while on study medication or for a 
longer period if required by local regulations
i. True abstinence: When this is in line with the preferred and usual lifestyle 
of the patient. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable 
methods of contraception. 
ii. Acceptable contraceptive methods include: oral, injectable, or implantable 
hormonal contraceptive; tubal ligation; intra-uterine device; barrier 
contraceptive with spermicide; or vasectomized partner) including at least 
one barrier method.
b. Have negative serum pregnancy test result at screening confirmed by negative 
urine pregnancy dipstick within 72 hours prior to first dose of IP (if serum test 
occurred > 72 hours from first dose); pregnancy test with sensitivity of at least 25 
mIU/mL
7.3.
Exclusion Criteria
The presence of any of the following will exclude a patient from enrollment:
1. The patient has a primary brain tumor(s) or brain metastasis (unless metastasis is treated 
and stable for > 28 days). In patients who are symptomatic, a brain scan is required to 
exclude metastasis.
2. The patient has ≥ Grade 2 peripheral neuropathy by National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) at screening.
3. The patient has received therapeutic dose chemotherapy or radiotherapy ≤ 21 days prior 
to start of IP.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
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ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
4. The patient has received maintenance dose chemotherapy (eg, low dose 
cyclophosphamide) ≤ 7 days from the first dose of IP.
5. The patient has received any investigational therapy ≤ 28 days prior to start of IP.  
Investigational therapy is defined as any medicinal product that is not approved in the 
country of treatment for any indication, adult or pediatric. 
6. The patient has received any biological therapy ≤ 7 days prior to the start of IP, or 
monoclonal antibody ≤ 3 half-lives or 28 days, whichever is shorter, prior to the first dose 
of IP.
7. The patient has received allogeneic hematopoietic stem cell transplantation (HSCT) ≤ 3 
months or autologous HSCT ≤ 21 days prior to start of IP.
8. The patient has had major surgery or significant trauma ≤ 14 days prior to start of IP.
9. The patient has not recovered from the acute toxic effects of prior chemotherapy, 
radiation, or major surgery/significant trauma.
10. The patient has had minor surgery ≤ 7 days from the start of study treatment (excluding 
the placement of central/peripheral lines, skin biopsy).
11. The patient has a known history of stroke, myocardial infarction, peripheral vascular 
disease, or recent (within 3 months) uncontrolled deep venous thrombosis.
12. The patient has a known history or current diagnosis of HIV infection, regardless of 
treatment status.
13. The patient has an uncontrolled intercurrent illness including but not limited to ongoing 
or active infection requiring antibiotic, antifungal, or antiviral therapy, symptomatic heart 
failure, cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements.
14. The patient has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the patient from participating in the study.
15. The patient has any condition, including the presence of laboratory abnormalities, that 
places the patient at unacceptable risk if he/she were to participate in the study.
16. The patient has any condition that confounds the ability to interpret data from the study.
17. The patient or parent(s)/guardian(s) is/are unable to comply with the study visit schedule 
and other protocol requirements, in the opinion of the investigator.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
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ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
Description of Investigational Product(s)
nab-Paclitaxel, the IP, will be supplied by the sponsor (Celgene) in single-use vials. Each single-
use 50 mL vial will contain paclitaxel (100 mg) and approximately 900 mg human albumin as a 
stabilizer. 
Unreconstituted nab-paclitaxel should be stored in accordance with the product label. 
Reconstituted nab-paclitaxel should be used immediately. Both forms should be stored in an area 
free of environmental extremes and must be accessible only to study personnel. Reconstitution 
and administration should follow local prescribing information and local practice.
Temperature records for nab-paclitaxel must be made available to Celgene or other Celgene 
representatives for verification of proper study drug storage.
To facilitate the administration of small volumes, nab-paclitaxel suspension may alternatively be 
administered using syringe based devices (eg, a syringe pump), provided that a silicone oil-free 
syringe is used to extract the reconstituted nab-paclitaxel suspension from the vial and the 
reconstituted nab-paclitaxel is stored in the syringe at room temperature for no longer than 8 
hours.
8.2.
Treatment Administration and Schedule
In both the Phase 1 and 2 portions of the study, the treatment will be given until disease 
progression, the patient begins a new anticancer treatment, withdrawal of parent/guardian/patient 
consent/assent, parent/guardian/patient refusal, physician decision, toxicity that cannot be 
managed by dose delay or dose reduction alone (reductions are prohibited in Cycle 1 [and Cycle 
2 for patients ≤ 10 kg] for the Phase 1 portion only), or the study ends for any reason. nab-
Paclitaxel will be administered intravenously over approximately 30 minutes, without 
corticosteroid or antihistamine premedication, weekly on Days 1, 8, and 15 of a 28-day cycle.
Following administration, the intravenous line should be flushed with sodium chloride 9 mg/ml 
(0.9%) solution for injection to ensure administration of the complete dose, according to local 
practice.
8.2.1.
Phase 1 Portion: Dose Escalation
In the Phase 1 portion of the study, up to 6 patients will be assessed at a starting dose of 120 
mg/m2 nab-paclitaxel (80% of the weekly investigated adult dosage). Dose escalation will occur
according to example dose levels described in Table 7, using the rolling-6 design (as described in 
Section 8.2.1.3). Doses not listed in Table 7, including intermediate doses or doses higher than 
210 mg/m2, may be tested based on study data and recommendations from the SMC. 
For patients who weigh ≤ 10 kg the dosage will be calculated per kg, and nab-paclitaxel will be 
administered according to the schedule in Table 7. In order to ensure their safety, patients
weighing ≤ 10 kg will receive a reduced dose (by one level) in Cycle 1, and if well tolerated (no 
DLTs) will receive the full dose starting in Cycle 2.  
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
53
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Table 7:
Phase 1 Portion Example Dose Levels
Dose
Dose (Patients ≤10 kg)
Dose Level
a
All Cycles
Cycle 1
Subsequent Cycles
-1
100 mg/m
2
4.0 mg/kg
b
4.5 mg/kg
1 (Starting dose)
120 mg/m
2
4.5 mg/kg
5.5 mg/kg
2
150 mg/m
2
5.5 mg/kg
7.0 mg/kg
3
180 mg/m
2
7.0 mg/kg
8.5 mg/kg
4
210 mg/m
2
8.5 mg/kg
10.0 mg/kg
a Dose levels are also used for dose reductions in both the Phase 1 and 2 portions, as described in Section 8.2.3.4.
Dose level -1 may reduce to 80 mg/m2 and 60 mg/m2, or 3.0/4.0 mg/kg and 2.0/3.0 mg/kg (Cycle 1/Subsequent 
Cycles).
b 4.0 mg/kg is the calculated equivalent of 80 mg/m2.
8.2.1.1.
Definition of Dose-limiting Toxicity
The DLT assessment period will be as follows:
!
For patients > 10 kg: the first cycle including Cycle 2 Day 1 predose evaluations
!
For patients ≤ 10 kg: the first two cycles including Cycle 3 Day 1 predose 
evaluations
A DLT is defined as IP-related AE(s) occurring during the DLT assessment period that lead to 
treatment discontinuation or meet one of the following criteria:
!
Grade 3 or 4 nonhematologic toxicity (excluding transient transaminitis)
!
Grade 3 or 4 nausea or vomiting that persists > 5 days despite maximal anti-emetic 
treatment
!
Grade 4 thrombocytopenia or anemia that persists > 7 days or requires transfusion > 7 
days
!
Grade 3 thrombocytopenia with bleeding
!
Grade 4 uncomplicated neutropenia lasting > 7 days
!
Febrile neutropenia with confirmed bacterial infection
!
Grade 3 hematologic toxicity requiring treatment delay > 21 days
Events that are considered DLTs based on their duration will be considered a DLT if they start 
during the DLT assessment period.  
Events due to disease progression or to current underlying disease cannot be considered DLTs. 
Events that are not considered related to IP cannot be considered DLTs.
If a patient experiences a DLT, the dose should be delayed until resolution of the AE to CTCAE 
Grade 1.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
54
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
8.2.1.2.
Safety Monitoring Committee
The SMC will decide whether to dose escalate, dose reduce, or declare an MTD, and will 
determine the dose(s) appropriate for the Phase 2 portion of the study (RP2D). During the Phase
2 portion, the SMC will continue to review safety data regularly and make recommendations 
about the study continuation, as appropriate.  
The members of the SMC will include the principal investigator, all investigators who recruited 
patients into the current cohort (or a subinvestigator designee), the Celgene Clinical Research 
Physician or designee, the Celgene Clinical Research Scientist or designee, and the Product 
Safety Physician or designee (if applicable). Additional details regarding the composition and 
responsibilities of the SMC are detailed in the SMC charter.
8.2.1.3.
Dose Escalation Procedures
Up to 6 patients will be treated at the first dose level, and subsequent dose escalation will 
proceed using the rolling-6 design. In each cohort a minimum of 2 patients treated and eligible 
for the Dose Determining Set (DDS, refer to Section 10.2) are required to make a dose decision.  
If zero DLTs are observed in the first 3 patients eligible for the DDS the SMC may decide to 
escalate the dose for the next cohort.  An additional 3 patients (up to a total of 6 per cohort) may 
be enrolled at the same dose while awaiting the DDS eligibility of 3 patients and SMC decision. 
If one DLT occurs prior to an SMC dose escalation decision, the cohort will be required to enroll 
6 patients total. If one or fewer patients experience a DLT in these 6 patients, the dose will be 
escalated in the next cohort, unless there are other safety considerations by the SMC. If more 
than one DLT occurs within the first dose level, a -1 dose level will be evaluated (100 mg/m2).
If two or more patients in a given cohort experience a DLT at any time during enrollment, the 
MTD will have been exceeded and the previous lower dose will be declared the MTD. 
Patients ineligible for the DDS may be replaced at the discretion of the sponsor.
For each cohort, the decision whether or not to dose-escalate in the next cohort or to declare the 
MTD/RP2D will be made by the SMC. The SMC will review all available clinical laboratory and 
safety data for a given cohort and, if applicable, data from previous cohorts.  
The SMC decision to escalate to the next dose level will be driven by the incidence of DLTs (as 
described in Section 8.2.1) and the totality of data. 
Additional factors for safety evaluation that may be considered by the SMC include (but are not 
limited to):
!
Incidence of TEAEs and SAEs
!
Physical examinations
!
Laboratory abnormalities (serum chemistry, hematology, and differentials)
!
Dose modifications (skipped doses, reduced doses, dose interruptions, and/or 
treatment discontinuation)
If other safety considerations are noted, the SMC may take other actions, including expansion of 
the current dose level or declaration of the RP2D despite not being at the MTD. 
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
55
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
8.2.1.4.
Recommended Phase 2 Dose
After the MTD has been established, the SMC will determine the dose to be used in the Phase 2 
portion of the study (RP2D). This dose may be the MTD determined in Phase 1 (or highest dose 
tested if no MTD is determined), but it may be a dose less than the MTD if this dose is 
determined to have a better risk-benefit profile. The RP2D cannot be greater than the MTD.
Once the RP2D has been formally established, recruiting for Phase 2 may begin immediately. In 
January 2016 the SMC determined that the RP2D is 240 mg/m2 in patients weighing > 10 kg,
and 11.5 mg/kg in patients weighing ≤ 10 kg.
8.2.2.
Phase 2: Dose Expansion
The Phase 2 portion of the study will be conducted at the established RP2D (as described in 
Section 8.2.1.4) at the same schedule as in the Phase 1 portion.  
8.2.3.
Treatment Modification
Treatment modifications are applicable during the Phase 1 and Phase 2 portions of the study, 
except that dose reductions during Phase 1 Cycle 1 are not permitted as noted below.
8.2.3.1.
Body Surface Area or Weight Changes
If the patient’s BSA (or weight for patients ≤10 kg) has changed by ≥ 10% from the last value 
used for dose calculations, then the patient’s dose should be recalculated with the new value. 
Otherwise, dose adjustments should be based on actual body weight/BSA and follow 
institutional guidelines.
8.2.3.2.
Treatment Delay
IP administration should occur within a ± 2 day administrative window of the scheduled day of 
dosing. IP may be delayed for other reasons based on the guideline below. If Day 8 or Day 15 
treatment is delayed ≤ 4 days, the treatment may be administered and the 28 days cycle continues 
per protocol. If the investigator suspects a drug related toxicity, an unscheduled visit with 
additional laboratory assessments may be performed. When treatment (either Day 1, 8, or 15) is 
consecutively delayed for two or more cycles, dose reduction should be considered.  Patients 
experiencing IP-related toxicities that require a delay in scheduled dosing of IP for > 21 days will 
be discontinued from further participation in this study (except if day 22 falls on a weekend or 
holiday, in which case IP may be administered the next business day).
Day 1 Treatment Delay
If the treatment to be given on Day 1 is delayed, the 28-day cycle will not be considered to start 
until the day IP is actually administered to the patient. 
Day 8 Treatment Delay
If the treatment to be given on Day 8 is held for ≤ 4 days, the treatment may be administered and 
the 28-day cycle continues per protocol. If Day 8 treatment is delayed > 4 days, the treatment 
will be considered as missed and will not be made up.
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28


EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
56
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Day 15 Treatment Delay
If the treatment to be given on Day 15 is held for ≤ 4 days, the treatment may be administered 
and the 28-day cycle continues per protocol. If Day 15 treatment is delayed > 4 days, that week 
becomes the week of rest.  The next dose (if counts and chemistries permit) becomes Day 1 of a 
new cycle, and the patient is considered to have had a 21-day cycle.  The subsequent cycle 
resumes the scheduled 28-day cycle.
8.2.3.3.
Missed Treatment
A missed Day 8 or Day 15 treatment is defined as IP not administered within ≤ 4 days of the 
expected dose day and should be entered in the CRF as a missed dose. If the investigator 
suspects drug-related toxicity, an unscheduled visit with additional laboratory tests may be 
performed.
Patients with a missed treatment during the DLT assessment period in the Phase 1 portion of the 
study are not eligible for the DDS (as defined in Section 10.2) and will be replaced at the 
discretion of the sponsor.
8.2.3.4.
Dose Adjustment
For the Phase 1 portion of the study, dose adjustments are not permitted during Cycle 1 (and 
during Cycle 2 for patients ≤ 10 kg). 
Starting with Cycle 2 in the Phase 1 portion of the study or anytime during the Phase 2 portion of 
the study, treatment dosing may be reduced for hematologic and other toxicities according to 
Table 8 and Table 9. Dose adjustments are to be made according to the AE showing the greatest 
degree of toxicity. Toxicities will be graded using the NCI CTCAE v4.0. 
If deemed necessary, a dose should be reduced by one dose level according to Table 7. A 
maximum of two dose reductions are permitted. If a toxicity requiring dose adjustment occurs 
after a second dose reduction, further treatment must be discontinued.  Once a dose has been 
reduced, it must not be increased to the previous level. If a patient experiences a severe 
hypersensitivity reaction, nab-paclitaxel should be permanently discontinued and the patient 
should not be rechallenged.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
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Table 8:
Hematologic Toxicity: Recommended Dose Reductions
Adverse Event/ Criteria
Occurrence
Action
a
Neutropenic fever (with 
confirmed bacterial infection)
OR
Neutropenia Grade 4
OR
Delay of next cycle due to 
persistent neutropenia Grade 3
1st occurrence
Dose reduction to the next lower level for 
subsequent cycles once ANC is ≥1000 cells/mm3.
2nd occurrence
Dose reduction to the next lower level for 
subsequent cycles once ANC is ≥1000 cells/mm3.
3rd occurrence
Discontinue treatment
Thrombocytopenia Grade 4 that 
persists > 7 days or requires 
transfusion > 7 days
1st occurrence
Dose reduction to next lower level; initiation of next 
cycle is delayed until platelet count is 80,000 
cells/mm3.
For Phase 2 patients with known bone marrow 
involvement, initiation of next cycle is delayed until 
platelet count is 50,000 cells/mm3.
2nd occurrence
Discontinue treatment
ANC =  absolute neutrophil count.
a For the Phase 1 portion of the study, dose adjustments are not permitted during Cycle 1. Patients with bone 
marrow disease should not be considered for dose reduction if the AE is related to the disease.
Table 9:
Nonhematologic Toxicity: Recommended Dose Reductions
Adverse Event
Occurrence
Action
a
Grade 3 or 4 peripheral 
neuropathy
b
1st occurrence
Interrupt treatment until toxicity improves to ≤ Grade 
1. When treatment is resumed, reduce by 1 dose level.
2nd occurrence
3rd occurrence
Discontinue treatment
Grade 2 or 3 cutaneous 
toxicity
c
1st occurrence
Interrupt treatment until toxicity improves to Grade 0 
or 1c. When treatment is resumed, reduce by 1 dose 
level.
2nd occurrence
Discontinue treatment
3rd occurrence
Discontinue treatment
Grade 4 cutaneous toxicity
1st occurrence
Discontinue treatment
Grade 3 mucositis or diarrhea
1st occurrence
Interrupt treatment until toxicity improves to Grade 0 
or 1. When treatment is resumed, reduce by 1 dose 
level.
2nd occurrence
3rd occurrence
Discontinue treatment
Grade 4 mucositis or diarrhea
1st occurrence
Discontinue treatment
Any other Grade 3 or 4 
nonhematologic toxicity,
excluding alopecia
1st occurrence
Interrupt treatment until toxicity improves to Grade 0, 
1, or 2
d
. When treatment is resumed, reduce by 1 dose 
level.
2nd occurrence
3rd occurrence
Discontinue treatment
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
58
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
a For the Phase 1 portion of the study, dose adjustments are not permitted during Cycle 1.
b Neuropathy should be followed as described in Section 6.2.1.1.
c Cutaneous toxicity should be considered for dose reductions only if clinically indicated, at the discretion of the 
investigator.
d The degree of adverse event resolution depends upon the type of nonhematologic toxicity seen and the course that 
is chosen to be medically most sound in the judgment of the physician investigator.
8.2.3.5.
Intrapatient Dose Escalation
Intrapatient dose escalation beyond the dose initially assigned to a patient is not permitted during 
Cycle 1 (or anytime in the Phase 2 portion). Once a patient’s dose has been reduced, it must not 
be increased to the previous level.
During the Phase 1 portion of the study, patients receiving treatment beyond Cycle 1 who have 
not had any dose reductions may, following approval by the SMC, have the dose level increased,
providing that the alternative dose level has been shown to be well tolerated by at least one 
cohort of other patients in this study. In these instances, additional PK evaluation at the higher 
dose level may be conducted.
8.2.4.
Overdose
On a per dose basis, an overdose of nab-paclitaxel is defined as 10% over the protocol-specified 
dose of IP assigned to a given patient, regardless of any associated adverse events or sequelae. 
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency. On an infusion rate basis, an overdose is defined as any 
rate faster than the protocol-specified rate. For nab-paclitaxel, an infusion completed in less than 
25 minutes may increase Cmax by approximately 20% which is the threshold for clinical 
relevancy.  For infusions completed between 25 and 30 minutes, there is no clinical significance.
A nab-paclitaxel infusion completed in less than 25 minutes will therefore meet the infusion rate 
criterion for an overdose.
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form.  See Section 
11.1 for the reporting of adverse events associated with overdose.
8.3.
Method of Treatment Assignment
In the Phase 1 portion of the study, patients will be assigned to a dose level using the Integrated 
Response Technology (IRT). The investigator or designee (eg, subinvestigator, study 
coordinator) will register the patient in the IRT system. Upon confirmation of eligibility, the 
patient will enrolled into the current dose level in the IRT system. If there is no availability 
within the current cohort, the CRP/CRS will permit enrollment via IRT at the last dose level 
evaluated as safe by the SMC. The date of the next SMC meeting, after which patients may be 
screened for the next cohort, will be provided to the investigator.
In the Phase 2 portion of the study, patients will be included in one of three indication-based 
groups as described in Inclusion criterion 2.b. Patients will be registered in IRT and upon 
confirmation of eligibility, enrolled to one of the three groups. Enrollment for each group will 
remain open according to a Simon two-stage design as described in Section 10.3. One or more 
groups may be closed while one or more groups remain open for enrollment.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
59
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
8.4.
Packaging and Labeling
The label(s) for IP will include sponsor name, address, and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations.
8.5.
Investigational Product Accountability and Disposal
Celgene (or designee) will review with the investigator and relevant site personnel the process 
for Investigational Product return, disposal, and/or destruction including responsibilities for the 
site vs Celgene (or designee).
Only completely unused IP vials should be retained by the site until a representative from 
Celgene or other Celgene-designated personnel have completed an inventory. Partially used and 
completely used vials should be destroyed according to local guidelines, and disposition should 
be recorded on the Investigational Drug Accountability Record Form.
The investigator, or designee, shall record the dispensing of IP to patients in the IP accountability 
record. The IP record will be made available to Celgene, or other authorized Celgene-designated 
monitoring personnel, for the purpose of accounting for the IP supply. Inspections of the IP 
supply for inventory purposes and assurance of proper storage will be conducted as necessary. 
Any significant discrepancy will be recorded and reported to Celgene or its designee and a plan 
for resolution will be documented.
Investigational product will not be loaned or dispensed by the investigator to another investigator 
or site.
8.6.
Investigational Product Compliance
Accurate recording of all IP administration will be made in the appropriate section of the 
patient’s CRF and source documents. The investigator or designee is responsible for accounting 
for all study-specific IP both administered or in their custody during the course of the study.
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uments. Th
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h adminis


EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
60
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
9.
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this trial, additional medications may be required to manage aspects of the 
disease state of the patients, including side effects from trial treatments or disease progression. 
Supportive care, including but not limited to anti-emetic medications, may be administered at the 
discretion of the investigator.
All concomitant treatments, including blood and blood products, must be reported on the CRF. 
For information regarding other drugs that may interact with nab-paclitaxel and affect its 
metabolism, pharmacokinetics, or excretion, please see the nab-paclitaxel (ABRAXANE) local 
package insert.
9.1.
Permitted Concomitant Medications and Procedures
Erythropoietin may be administered at the discretion of the investigator, consistent with 
institutional guidelines. Granulocyte colony-stimulating factors may not be given during the 
DLT assessment period, but subsequently may be given according to institutional guidelines for 
the treatment of neutropenic fever or infections associated with neutropenia and for the 
prevention of febrile neutropenia in patients with an ANC < 500 cells/μL.
9.2.
Prohibited Concomitant Medications and Procedures
Granulocyte colony-stimulating factors may not be given during the DLT assessment period.
Radiotherapy is not allowed during the study, except for palliative purposes for nontarget 
lesions. Surgical intervention as anticancer therapy during Cycle 1 will require the patient to 
discontinue from study treatment. Minor surgical intervention in subsequent cycles will be 
assessed on a case by case basis after discussion with the Celgene Clinical Research Physician. 
Although patients with neuroblastoma will be assessed for response using 123I-MIBG scans, 
administration of 131I-MIBG therapy (eg, for neuroblastoma treatment) is prohibited.  
Administration of other chemotherapy, immunotherapy, antitumor hormonal therapy, 
investigational therapy, or other anticancer therapy during the study is not allowed. 
Administration of Coumadin or coumarin derivatives is not allowed during this study; low-
molecular weight heparin should be used instead. 
The potential drug-drug interaction precautions contained in the nab-paclitaxel prescribing 
information will be applied to this study (refer to the local prescribing information). Specifically, 
the metabolism of paclitaxel is catalyzed by cytochrome P450 isozymes CYP2C8 and CYP3A4.
Strong inducers of CYP3A4 and CYP2C8 are prohibited for use from the first dose of IP until 
permanent discontinuation. Such medications include but are not limited to: 
!
Strong inducers of CYP3A4: avasimibe, carbamazepine, phenytoin, rifampin, and St. 
John’s wort.
Strong inhibitors of CYP3A4 and CYP2C8 should be avoided whenever possible from the first 
dose of IP until permanent discontinuation. If possible, patients should be switched to other 
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
61
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
medications for the comorbidity prior to starting IP. Such medications include but are not 
limited to:
!
Strong inhibitors of CYP2C8: gemfibrozil
!
Strong inhibitors of CYP3A4: boceprevir, clarithromycin, conivaptan, grapefruit 
juice, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, 
posaconazole, telaprevir, telithromycin, and voriconazole.
Caution is recommended when administering nab-paclitaxel concomitantly with any substrates 
or inhibitors of the cytochrome P450 isozymes CYP2C8 and CYP3A4. Similarly, drugs, herbal 
preparations, and/or dietary supplements known to influence the expression of CYP3A (eg, 
garlic supplements) and/or CYP2C8 should be used with caution (see www.drug 
interactions.com for a regularly updated list of drug interactions with cytochrome P450 
isozymes). 
Please check the prescribing information of the concomitant medication for full information on 
the CYP interaction potential.
Patients and parent(s)/guardian(s) must be made aware that the following medications are not 
allowed to be taken concomitantly with nab-paclitaxel: ritonavir, saquinavir, indinavir, 
nelfinavir, or investigational drug(s) other than described as a treatment regimen in this study.
9.3.
Required Concomitant Medications and Procedures
Not applicable.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
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62
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
10.
STATISTICAL ANALYSES
10.1.
Overview
The Phase 1 portion uses a rolling-6 patient dose escalation design to establish the MTD/RP2D,
and the Phase 2 portion uses a Simon two-stage minimax design to monitor patient enrollment 
for each group separately.
Statistical analyses will be performed by study phase, dose level, and tumor group as needed or 
applicable. 
10.2.
Study Population Definitions
The study population definitions are as follows:
!
Enrolled Population – All patients enrolled; ie, all patients who are marked as 
enrolled in the clinical database regardless of whether they have received IP.
!
Safety Population – All patients who take at least one dose of IP
!
Efficacy Evaluable (EE) Population – All treated patients who meet eligibility 
criteria, complete at least one dose of investigational product, and have baseline and 
at least one postbaseline efficacy assessment if having not discontinued the 
investigational product prior to postbaseline efficacy assessment due to disease 
progression or symptomatic deterioration. Here efficacy assessment means 
radiological assessment of the tumor or tumor assessment by other appropriate means.
Investigational product discontinuation due to disease progression or symptomatic 
deterioration must be documented as the primary reason for treatment discontinuation 
in the treatment discontinuation CRF.
!
Dose Determining Set (DDS) – The primary endpoint for the Phase 1 portion of the 
study, determination of the MTD/RP2D, will be performed on the DDS. In patients 
weighing > 10 kg, the DDS includes all patients who experienced a DLT, or received 
all 3 weekly doses of nab-paclitaxel at the cohort planned dose during Cycle 1 and 
had adequate safety assessments during the DLT assessment period (Cycle 1 
including predose assessments on Cycle 2 Day 1). In patients weighing ≤ 10 kg, the 
DDS includes all patients who experienced a DLT, or received all 6 weekly doses of 
nab-paclitaxel at the cohort planned doses during Cycles 1 and 2 and had adequate 
safety assessments during the DLT assessment period (Cycle 1 and 2 including 
predose assessments on Cycle 3 Day 1).
!
Pharmacokinetic Population – The pharmacokinetic population includes all patients 
who received at least 1 dose of nab-paclitaxel and had evaluable concentration data.
10.3.
Sample Size and Power Considerations
During the Phase 1 portion, a rolling-6 patient dose escalation design will be used to establish the 
MTD/RP2D, and up to approximately 24 patients will be enrolled into the DDSs, depending on 
the number of dose levels evaluated. Patients who are ineligible for the DDS in a given cohort 
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0.3.


EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
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ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
will be replaced at the discretion of the sponsor, and additional non-DDS patients may be 
enrolled at dose levels evaluated as safe by the SMC.  A minimum of 12 patients will be treated 
in the Phase 1 portion of the study, regardless of the number of dose levels tested.
In the Phase 2 portion, up to 69 additional efficacy evaluable patients (≤ 23 patients in each of 
the 3 groups) will be enrolled at the RP2D determined in the Phase 1 portion of the study. A 
Simon two-stage minimax design will be used to monitor patient enrollment for each of the 
groups separately.
The ORR is defined using the maximum likelihood estimator.
For each of the 3 groups in the first stage, 14 efficacy evaluable patients will be enrolled. If < 2
of the 14 patients has a response, the enrollment for this group will be stopped upon 
determination of the number of responders. If ≥ 2 of the 14 patients have a response, the 
enrollment will continue until 23 efficacy evaluable patients are enrolled. At the final analysis, 
the regimen will be concluded with more than a 5% true response rate if ≥ 5 of 23 patients have a 
response. The acceptance rate for the second stage will be 21.74% response rate, at 80% power 
and 10% significance having fixed the lower and upper boundaries to 10% and 28%, 
respectively. The response rate in the Phase 2 neuroblastoma group will be determined using 
both RECIST and the MIBG/Curie score.
A minimum of 14 patients will be treated in each tumor group.
10.4.
Demographic and Baseline Characteristics
In the Phase 1 portion of the study, the baseline characteristics of patients will be summarized by 
dose level for the Safety population and the EE population. In the Phase 2 portion of the study, 
the baseline characteristics of patients will be summarized by tumor group for the Safety 
population and the EE population. The age, weight, height, and other continuous demographic 
and baseline variables will be summarized using descriptive statistics (sample size, mean, 
standard deviation, median, minimum, and maximum). Lansky/Karnofsky performance status, 
gender, race, and other categorical variables will be summarized with frequency tabulations. 
Medical history data will be summarized using frequency tabulations by system organ class and 
preferred term.
10.5.
Patient Disposition
Patient disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percentage.  A listing of 
patients with protocol violations or protocol deviations will be provided.
10.6.
Efficacy Analysis
Efficacy endpoints will be analyzed for both the safety population and the efficacy evaluable 
population. Efficacy will be analyzed by dose cohort and tumor group once all patients have 
completed the study. The efficacy variable of primary interest is overall response rate (ORR). 
Tumor response will be based on RECIST 1.1 and will be assessed by the investigator. Patients 
with neuroblastoma additionally will be assessed for MIBG response using the Curie score 
(Phase 2 only). For patients in the neuroblastoma group, ORR will be based on either the 
RECIST criteria or the Curie score, or both, without crossover between assessment types over 
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m


EDMS Doc. Number:
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Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
64
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
time. If both assessment types have been performed on a given subject across the assessment 
time points, to be considered as a partial response for the ORR analysis, both methodologies 
should show no worse than stable disease and at least one method should indicate CR or PR. A 
response is only considered complete if both methodologies indicate CR. The efficacy variable 
of focus for the Phase 1 portion will be ORR. For the Phase 2 portion, efficacy variables to be 
analyzed include ORR, duration of response, disease control rate, PFS, and 1-year survival. 
Ninety-five percent confidence intervals of response rate will be provided. A case-by-case 
description of all patients who exhibited a confirmed CR or PR using RECIST, and additionally 
for neuroblastoma using MIBG/Curie score as applicable, will be provided. A descriptive 
analysis of other evidence of antitumor activity will be provided based on clinical, radiographic, 
and biologic assessments of efficacy. If there are sufficient data, Kaplan-Meier estimates will be 
provided for duration of response, PFS, and 1-year survival. 
Data listings will be provided for all relevant data collected during the study.
Full details of the efficacy analysis will be given in the statistical analysis plan (SAP).
10.7.
Safety Analysis
All patients in the Safety population will be included in the safety analyses. Adverse events, vital 
sign measurements, physical examination findings, clinical laboratory information, ECG, LVSF 
assessment, Lansky/Karnofsky performance status, and concomitant medications and procedures 
will be tabulated and summarized by study phase (Phase 1 or 2 portion), dose level, and tumor 
group, as appropriate.
During the Phase 1 DLT assessment period, DLTs and all available safety data will be reviewed 
on an ongoing basis by the investigators and sponsor and summarized at the conclusion of each 
dose level. 
Adverse events observed during both Phase 1 and Phase 2 will be coded using the MedDRA 
classification system. The severity of the AEs will be graded according to the NCI CTCAE
version 4.0 whenever possible. 
Adverse events will be analyzed in terms of treatment-emergent AEs. Treatment-emergent 
adverse events (TEAEs) are defined as any AEs that begin or worsen in grade after the start of IP 
through 28 days after the last dose of IP.
The frequency of AEs will be tabulated by MedDRA System Organ Class and Preferred Term. In 
the by-patient analysis, a patient reporting the same event more than once will be counted only 
once. Adverse events will also be summarized by NCI CTCAE grade. If a patient reports the 
same AE more than once, the event with the maximum grade will be tabulated in “by grade” 
tables. The incidence of serious adverse events (SAEs) and AEs that lead to dose reduction, drug 
interruption, or discontinuation of study drug will be summarized. Adverse events of special 
interest based on the Risk Management Plan will also be summarized. Listings of patients who 
discontinued study drug due to an AE, patients with SAEs, and deaths will be presented. 
Clinical laboratory data will be summarized. Laboratory data will be graded according to NCI 
CTCAE version 4.0 criteria wherever possible. The frequencies of the worst severity grade 
observed during treatment will be displayed in cross-tabulations by baseline status. 
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
65
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
Vital signs, ECG, and LVSF assessment will be summarized by cross-tabulations presenting 
normal and abnormal values by number of patients at pre- and post-IP initiation.
Performance status by cycle and change from baseline will be summarized using descriptive 
statistics. 
Graphical displays will be provided where useful in the interpretation of results.
Full details of the safety analysis will be given in the SAP.
10.8.
Interim Analysis
During the Phase 2 portion of the study, a Simon two-stage minimax design will be used to 
monitor patient enrollment and tumor response rate for each group separately, as described in 
Section 10.3.
10.9.
Other Topics
10.9.1.
Pharmacokinetic Analysis
Pharmacokinetic data from patients in the Phase 1 and 2 portion of the study will be analyzed 
together.
Noncompartmental PK analysis will be performed using the blood concentration versus time data 
obtained from patients participating in dense PK sampling to estimate Cmax, AUC, clearance 
(CL), volume of distribution at the steady state (Vss), and half-life (t1/2). If data allow, main PK 
parameters (CL and Vss) will be summarized by age group as appropriate (eg, < 2 years, 2 to < 6 
years, 6 to < 12 years, and 12 to ≤ 24 years).  
Population PK analysis will be performed using nonlinear mixed effect modeling. Concentration 
data obtained from both dense and sparse PK sampling will be combined to develop the 
population PK model. Effect of age and body size on nab-paclitaxel PK will be assessed. Other 
relevant covariates for the main PK parameters will also be identified. The between-patient
variability for PK parameters will be estimated, as appropriate. The relationship between 
systemic drug exposure and selected efficacy and toxicity endpoints may be explored.
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elected eff
elected eff


EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
66
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
11.
ADVERSE EVENTS
11.1.
Monitoring, Recording and Reporting of Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may 
appear or worsen in a patient during the course of a study. It may be a new intercurrent illness, a 
worsening concomitant illness, an injury, or any concomitant impairment of the patient’s health, 
including laboratory test values (as specified by the criteria below), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome, rather than the 
individual signs or symptoms of the diagnosis or syndrome, should be recorded on the AE page 
of the CRF. 
Clinically significant signs and symptoms associated with disease progression are expected to be 
reported as AEs; however, study indication progressive disease (PD) that is asymptomatic or 
solely documented radiographically per RECIST 1.1/MIBG does not require reporting as an AE.
An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to an investigational product should be reported as an AE.  If 
an overdose is associated with an AE, the overdose and adverse event should be reported as 
separate terms. See Section 8.2.4 for the definition of overdose. In the event of overdose, the 
patient should be monitored as appropriate and should receive supportive measures as necessary. 
There is no known specific antidote for nab-paclitaxel overdose. Actual treatment should depend 
on the severity of the clinical situation and the judgment and experience of the treating physician.
All patients will be monitored for AEs during the study.  Assessments may include monitoring of 
any or all of the following parameters:  the patient’s clinical symptoms, laboratory, pathological, 
radiological or surgical findings, physical examination findings, or other appropriate tests and 
procedures.
All AEs and serious adverse events (SAEs) will be recorded by the investigator from the time the 
parent/guardian/patient signs the informed consent/assent document (if applicable) to 28 days 
after the last dose of IP and during the EOT visit.  Serious adverse events made known to the 
investigator at any time thereafter that are suspected of being related to IP will also be recorded.  
AEs and SAEs will be recorded on the AE page of the CRF and in the patient’s source 
documents.  All SAEs must be reported to Celgene Drug Safety within 24 hours of the 
investigator’s knowledge of the event by facsimile, or other appropriate method, using the SAE 
Report Form, or approved equivalent form.
11.2.
Evaluation of Adverse Events
A qualified investigator will evaluate all adverse events as to: 
11.2.1.
Seriousness 
A SAE is any AE occurring at any dose that:
!
Results in death
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11.2.1.
1.2.1.


EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
67
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
!
Is life-threatening (ie, in the opinion of the investigator, the patient is at immediate 
risk of death from the AE)
!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay)
!
Results in persistent or significant disability/incapacity (a substantial disruption of the 
patient’s ability to conduct normal life functions)
!
Is a congenital anomaly/birth defect
!
Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the patient or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:
!
A standard procedure for protocol therapy administration.  However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 
!
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
!
The administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.
!
A procedure for protocol/disease-related investigations (eg, surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling).  However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE.
!
Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.
!
A procedure that is planned (ie, planned prior to starting of treatment on study); must 
be documented in the source document and the CRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
!
An elective treatment of a pre-existing condition unrelated to the studied indication. 
!
Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE form/screen of the CRF and the SAE Report Form 
must be completed.
For each SAE, the investigator will provide information on severity, start and stop dates, 
relationship to IP, action taken regarding IP, and outcome.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
68
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
11.2.2.
Severity / Intensity
For both AEs and SAEs, the investigator must assess the severity / intensity of the event. 
The severity / intensity of AEs will be graded based upon the patient’s symptoms according to 
the current active minor version of the NCI CTCAE, Version 4.0.
AEs that are not defined in the NCI CTCAE should be evaluated for severity / intensity
according to the following scale:
!
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
!
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required
!
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible
!
Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable
!
Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on patient/event outcome or action criteria associated with events that pose a threat to a 
patient’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
11.2.3.
Causality 
The investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
Means a causal relationship of the adverse event to IP 
administration is unlikely or remote, or other medications, 
therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event
Suspected:
Means there is a reasonable possibility that the administration 
of IP caused the adverse event.  ‘Reasonable possibility’ means 
there is evidence to suggest a causal relationship between the IP 
and the adverse event
If an event is assessed as suspected of being related to an ancillary treatment that has not been 
manufactured or provided by Celgene, please provide the name of the manufacturer when 
reporting the event.
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f an ev
f an ev


EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
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ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
11.2.4.
Duration
For both AEs and SAEs, the investigator will provide a record of the start and stop dates of the 
event.
11.2.5.
Action Taken
The investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation or reduction of IP, as appropriate) and report if concomitant and/or 
additional treatments were given for the event. 
11.2.6.
Outcome
The investigator will report the outcome for both AEs and SAEs. All SAEs that have not 
resolved upon discontinuation of the patient’s participation in the study must be followed until 
recovered, recovered with sequelae, not recovered, or death (due to the SAE). 
11.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:
!
results in discontinuation from the study;
!
requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or
!
is judged to be of significant clinical importance.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.  
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF.  If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
11.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female patient or partner of a male 
patient are immediately reportable events.
11.4.1.
Females of Childbearing Potential
For the purposes of this study, a female patient is considered of childbearing potential if she is ≥ 
12 years old or has reached menarche, whichever occurred first.
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female patient occurring while the patient is on IP, within 28 days of the 
patient’s last dose of IP, or at the EOT visit are considered immediately reportable events.  IP is 
to be discontinued immediately.  The pregnancy, suspected pregnancy, or positive pregnancy test 
must be reported to Celgene Drug Safety immediately by facsimile, or other appropriate method, 
using the Pregnancy Initial Report Form, or approved equivalent form.  
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Females of
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didisease s
sease
ien


EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
70
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
The female patient may be referred to an obstetrician-gynecologist (not necessarily one with 
reproductive toxicity experience) or another appropriate healthcare professional for further 
evaluation.
The investigator will follow the female patient until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous or therapeutic abortion), the 
investigator should report the abnormal outcome as an AE.  If the abnormal outcome meets any 
of the serious criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or 
other appropriate method, within 24 hours of the investigator’s knowledge of the event using the 
SAE Report Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
11.4.2.
Male Patients
If a female partner of a male patient taking investigational product becomes pregnant, the male 
patient taking IP should notify the investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately.
11.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE form/screen of the CRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the investigator’s knowledge of the event by facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form.  This 
instruction pertains to initial SAE reports as well as any follow-up reports.
The investigator is required to ensure that the data on these forms are accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the parent/guardian/patient signs informed consent/assent form (if applicable) to
28 days after the last dose of IP and at the EOT visit), and those made known to the investigator 
at anytime thereafter that are suspected of being related to IP.  SAEs occurring prior to IP 
administration (after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include summaries of 
hospital records and other relevant documents.  If a patient died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data will be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.  
Where required by local legislation, the investigator is responsible for informing the Institutional 
Review Board/ Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
71
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
11.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
11.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to nab-paclitaxel based on the Investigator Brochure.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
Committees concerned, suspected unexpected serious adverse reactions (SUSARs) in accordance 
with Directive 2001/20/EC and the Detailed Guidance on collection, verification and 
presentation of adverse reaction reports arising from clinical trials on investigational products for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.  
Celgene or its authorized representative shall notify the investigator of the following information 
!
Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human patients including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to patients.
The investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC.  (See Section 15.3 for record retention 
information).
Celgene Drug Safety Contact Information
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
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s or to th


EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
72
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
12.
DISCONTINUATIONS
12.1.
Treatment Discontinuation
Patients who are discontinued from IP for any reason are not discontinued from the study, and 
will continue to be followed as described in Section 6.2 until study discontinuation (Section 
12.2). 
The following events are considered sufficient reasons for discontinuing a patient from the IP:
!
Dose-limiting toxicity
!
Adverse event(s)
!
Disease progression
!
Symptomatic deterioration (global deterioration of health status without objective 
evidence of disease progression)
!
Physician decision
!
Withdrawal by patient
!
Withdrawal by parent/guardian
!
Death
!
Lost to follow up
!
Protocol violation
!
Pregnancy
!
Other (to be specified on CRF)
The reason for discontinuation should be recorded in the CRF and in the source documents.
The decision to discontinue a patient from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the sponsor.  However, prior to discontinuing 
a patient, the investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
12.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a patient from the study
follow-up periods:
!
Withdrawal by patient
!
Withdrawal by parent/guardian
!
Death
!
Lost to follow up
!
Protocol violation
!
Other
The reason for discontinuation should be recorded in the CRF and in the source documents.
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D
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EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
73
ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
13.
EMERGENCY PROCEDURES
13.1.
Emergency Contact
In emergency situations, the investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page).This global Emergency 
Call Center is available 24 hours a day and 7 days a week. The representatives are responsible 
for obtaining your call-back information and contacting the on-call Celgene/CRO Medical 
Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
13.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling.
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14.
REGULATORY CONSIDERATIONS
14.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and investigator abide by Good Clinical Practice (GCP), as described in ICH Guideline E6 and in 
accordance with the general ethical principles outlined in the Declaration of Helsinki. The study 
will receive approval from an IRB/EC prior to commencement. The investigator will conduct all 
aspects of this study in accordance with applicable national, state, and local laws of the pertinent 
regulatory authorities.
14.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
investigators, who in turn will select their staff.
The investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions,
including obligations of confidentiality of Celgene information. The investigator should maintain 
a list of subinvestigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The investigator is responsible for keeping a record of all patients/parents/guardians who sign an 
informed consent/assent document and are screened for entry into the study.  Patients who fail 
screening must have the reason(s) recorded in the patient’s source documents.
The investigator, or a designated member of the investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to patient records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The investigator must ensure timely and accurate completion of CRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example, on the investigator’s or their institution’s website) without express 
written approval from Celgene.  Information proposed for posting on the investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
14.3.
Patient Information and Informed Consent / Assent
The investigator must obtain informed consent of a patient or legal representative 
(parent/guardian) prior to any study-related procedures, and where applicable assent from the 
patient.  A patient considered adult by local regulations (eg, patients who are ≥ 18 years old, 
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4.3.


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emancipated minors, mature minors) must provide informed consent for him/herself.  In this 
section, it is implied that where applicable, the patient must also provide his/her assent for 
participation at the time of his/her parent/guardian consent.
Documentation that informed consent/assent occurred prior to the study patient’s entry into the 
study and of the informed consent/assent process should be recorded in the study patient’s source 
documents, including the date.  The original informed consent/assent document, signed and 
dated by the study patient’s parent/guardian or patient (when applicable) and by the person 
consenting the study patient prior to the study patient’s entry into the study, must be maintained 
in the investigator’s study files and a copy given to the study patient’s parent/guardian or to the 
patient (when applicable).  In addition, if a protocol is amended and it impacts on the content of 
the informed consent, the informed consent document must be revised.  Study patients 
participating in the study when the amended protocol is implemented must be re-consented with 
the revised version of the informed consent document.  The revised informed consent document,
signed and dated by the study patient’s parent/guardian/patient (when applicable) and by the 
person consenting the study patient, must be maintained in the investigator’s study files and a 
copy given to the study patient.  
14.4.
Confidentiality
Celgene affirms the patient's (parents’/guardians’) right to protection against invasion of privacy 
and to be in compliance with ICH and other local regulations (whichever is most stringent). 
Celgene requires the investigator to permit Celgene representatives, and when necessary, 
representatives from regulatory authorities, to review and/or copy any medical records relevant 
to the study in accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
patient’s parent/guardian signed informed consent document, it is the responsibility of the 
investigator to obtain such permission in writing from the appropriate individual.
14.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the investigator name, 
protocol number, study title, and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/EC approval but will be submitted to the IRB/EC for 
information purposes.
14.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, informed consent document (assent document if 
applicable), and any other appropriate documents will be submitted to the IRB/EC with a cover 
letter or a form listing the documents submitted, their dates of issue, and the site (or region or 
area of jurisdiction, as applicable) for which approval is sought. If applicable, the documents will 
also be submitted to the authorities in accordance with local legal requirements.
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IP can only be supplied to an investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first patient is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the informed consent/assent
document should also be revised.
The investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the investigator (or coordinating investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit patients for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
14.7.
Ongoing Information for the Institutional Review Board / Ethics 
Committee
If required by legislation or the IRB/EC, the investigator must submit to the IRB/EC:
!
Information on serious or unexpected adverse events as soon as possible 
!
Periodic reports on the progress of the study
!
Deviations from the protocol or anything that may involve added risk to patients.
14.8.
Closure of the Study
Celgene reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities).
In addition, the investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:
!
Unsatisfactory enrollment
!
GCP noncompliance
!
Inaccurate or incomplete data collection
!
Falsification of records
!
Failure to adhere to the study protocol.
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15.
DATA HANDLING AND RECORDKEEPING 
15.1.
Data / Documents
The investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed, and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; patient’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROMs.
15.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Celgene standard 
operating procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team.  Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary.  Resolutions 
to these issues will be reflected in the database.  An audit trail within the system will track all 
changes made to the data.
15.3.
Record Retention
Essential documents must be retained by the investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. The investigator must retain these 
documents for the time period described above or according to local laws or requirements, 
whichever is longer.  Essential documents include, but are not limited to, the following:
!
Signed informed consent documents for all patients (and assent documents where 
applicable)
!
Patient identification code list, screening log (if applicable), and enrollment log
!
Record of all communications between the investigator and the IRB/EC
!
Composition of the IRB/EC
!
Record of all communications between the investigator, Celgene, and their authorized 
representative(s)
!
List of subinvestigators and other appropriately qualified persons to whom the 
investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures
!
Copies of CRFs (if paper) and of documentation of corrections for all patients
!
IP accountability records
!
Record of any body fluids or tissue samples retained
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EDMS Doc. Number:
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!
All other source documents (patient records, hospital records, laboratory records, etc.)
!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial)
The investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location, or is unable to retain them for a specified period.  
The investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the investigator is unable to meet this obligation, the investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator/institution should take measures to prevent accidental or premature destruction of 
these documents.
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EDMS Doc. Number:
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16.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and standard 
operating procedures.
16.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during, and after 
the study.  All aspects of the study are reviewed with the investigator and the staff at a study 
initiation visit and/or at an investigator meeting.  Prior to enrolling patients into the study, a 
Celgene representative will review the protocol, CRFs, procedures for obtaining informed 
consent/assent, record keeping, and reporting of AEs/SAEs with the investigator.  Monitoring 
will include on-site visits with the investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, CRFs, patient’s source documents, and all other study
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the investigator and/or his/her 
staff. Monitoring procedures require that informed consents/assents, adherence to 
inclusion/exclusion criteria, and documentation of SAEs and their proper recording be verified.  
Additional monitoring activities may be outlined in a study-specific monitoring plan.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs, and applicable supporting records of study patient participation for 
audits and inspections by IRB/IECs, regulatory authorities (eg, FDA, European Medicines 
Agency, Health Canada) and company authorized representatives.  The investigator should make 
every effort to be available for the audits and/or inspections.  If the investigator is contacted by 
any regulatory authority regarding an inspection, he/she should contact Celgene immediately.
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Celgene Corporation
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17.
PUBLICATIONS
As described in Section 14.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications.  Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance.  This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.  
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable), and contribution to abstract, presentation, and/or publication development.
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18.
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atic cancer 
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wing sarcom
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man RM, 
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DeLaney TF
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19.
APPENDICES
19.1.
Appendix A:  RECIST 1.1
The following information is extracted/summarized from Eisenhauer, 2009, New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Please refer to the 
primary reference for further information.
19.1.1.
Definitions
At screening, tumor lesions/lymph nodes will be categorized as measurable or nonmeasurable.
19.1.1.1.
Measurable Disease
Tumor Lesions.  Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
!
10mm by CT scan (CT scan slice thickness no greater than 5 mm)
!
10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as nonmeasurable)
!
20mm by chest X-ray
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
19.1.1.2.
Nonmeasurable Disease
All other lesions are considered nonmeasurable, including small lesions (longest diameter 
<10mm or pathological lymph nodes with ≥ 10 to < 15mm short axis) as well as truly 
nonmeasurable lesions. Lesions considered truly nonmeasurable include: leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.
19.1.1.3.
Special Considerations for Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local (radiation) therapy should
be considered measurable or nonmeasurable according to Eisenhauer, 2009.
19.1.2.
Tumor Response Evaluation
19.1.2.1.
Target Lesions
When more than one measurable tumor lesion is present at baseline all lesions up to a maximum 
of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be 
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urable.
urable.
gest di
gest
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ame
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5 mm)
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easurable)
easurab
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gically enla
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by CT scan
by CT sca
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seline and
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measurab
odes with 
odes with ≥
s considere
s conside
al effusi
effusi
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on
on
masses/abd
masses/a
ucible imag
ucible im
ial
ial Consid
Consid
s, cysti
s, cystic les
c le
dered measu
ed measu
.2.
.2.
Tu
Tu
19.1.2.1.
9.1.2.1.
hen


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representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. Note that pathological nodes must meet the measurable 
criterion of a short axis of ≥ 15 mm by CT scan and only the short axis of these nodes will 
contribute to the baseline sum. All other pathological nodes (those with short axis ≥ 10 mm but < 
15 mm) should be considered nontarget lesions. Nodes that have a short axis < 10 mm are 
considered nonpathological and should not be recorded or followed. At baseline, the sum of the 
target lesions (longest diameter of tumor lesions plus short axis of lymph nodes: overall 
maximum of 5) is to be recorded.
After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately 
measured but are deemed to be present, a default value of 5 mm may be used. If lesions are too 
small to measure and indeed are believed to be absent, a default value of 0 mm may be used.
19.1.2.2.
Nontarget Lesions
All nonmeasurable lesions (or sites of disease) plus any measurable lesions over and above those 
listed as target lesions are considered nontarget lesions. Measurements are not required but these 
lesions should be noted at baseline and should be followed as “present,” “absent,” or 
“unequivocal progression.”
19.1.2.3.
Response Criteria
Target and nontarget lesions are evaluated for response separately, and then the tumor burden as 
a whole is evaluated as the Overall response.
19.1.2.3.1. Target Lesion Response
Target lesions will be assessed as follows:
!
Complete Response (CR). Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or nontarget) must have reduction in short axis to <10 
mm.
!
Partial Response (PR). At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.
!
Progressive Disease (PD). At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: 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 of diameters while on 
study.
19.1.2.3.2. Nontarget Lesion Response
Nontarget lesions will be assessed as follows:
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are too
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s over and
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separately
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as refe
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taking as 
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Stab
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1


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!
Complete Response (CR). Disappearance of all nontarget lesions and normalisation 
of tumor marker level. All lymph nodes must be nonpathological in size (<10mm 
short axis).
!
Non-CR/Non-PD. Persistence of one or more nontarget lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
!
Progressive Disease (PD). Unequivocal progression (see comments below) of 
existing nontarget lesions. (Note: the appearance of one or more new lesions is also 
considered progression).
When the patient also has measurable disease. In this setting, to achieve “unequivocal 
progression” on the basis of the nontarget disease, there must be an overall level of substantial 
worsening in nontarget disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of one or more nontarget lesions is usually not sufficient to quality for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in nontarget disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the patient has only nonmeasurable disease. This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above; however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in nonmeasurable disease burden. 
Because worsening in nontarget disease cannot be easily quantified (by definition: if all lesions 
are truly nonmeasurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in nonmeasurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: ie, an increase in tumor burden representing an 
additional 73% increase in “volume” (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from “trace” to “large,”
an increase in lymphangitic disease from localised to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.” If “unequivocal progression” is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to nonmeasurable disease, the very nature of that disease makes it 
impossible to do so: therefore, the increase must be substantial.
19.1.2.3.3. Overall Response
Overall response should be assessed according to Table 10 for patients with target lesions, and 
Table 11 for patients with only nontarget lesions.
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ality
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on the b
y
ll therefore
ll therefo
mstance ar
stance a
ble disease
ble diseas
nce there is
e there i
e in nonme
e in nonm
asily
sily quant
quan
y
i
applied wh
applied w
crease in o
rease in o
able in mag
able in mag
ease:
ease: ieie, a
(which is eq
(which is eq
ude an incre
e an incr
ase fro
ase from lo
m lo
quire a chan
uire a chan
ed to hav
d to have h
e
ly to nonm
ly to nonm
therefore
erefore t
rall
rall Respo
Res
pon
ponse shou
se shou
for pati
patien
en


EDMS Doc. Number:
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Table 10:
Time Point Response: Patients With Target (± Nontarget) Disease
Target Lesions Response
Nontarget Lesion Response
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/ non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
NO
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = inevaluable.
Table 11:
Time Point Response: Patients With Nontarget Disease Only
Nontarget Lesions Response
New Lesions
Overall Response
CR
No
CR
Non-CR/ non-PD
No
Non-CR/ non-PD
a
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
a “Non-CR/non-PD” is preferred over “stable disease” for nontarget disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised.
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = inevaluable.
19.1.2.4.
Symptomatic Deterioration
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and nontarget disease.
19.2.
Appendix B: Curie Scale for MIBG Response
The Curie score is a semiquantitative scoring system for the comparison of sequential whole-
body MIBG scans in children with neuroblastoma.  The following information is 
extracted/summarized from Ady, 1995, and Matthay, 2003.  Please refer to the primary
references for further information.
CCI
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Yes
Yes
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$7
$7
$7
$7
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0$
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PD
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PD
PD
25
)2
sease, NE = 
ease, NE = 
isease Only
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5<
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35
isease
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or
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response, SD
response, SD
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deteri
deteriorati
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dence of 
terioration
terioration
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ontinuat
inuatioio
esponse: it 
sponse: it 
tients is to b
tients is to 
9.2.
.2.
A
The Curi
The Curi
dy
d


EDMS Doc. Number:
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19.2.1.
MIBG Scan Assessable
Patients with neuroblastoma who have positive uptake of 123I-MIBG will be considered 
assessable by MIBG scan and will be assessed for response using the Curie score.  Patients with 
neuroblastoma whose disease is also measurable by CT and patients with all other tumor types
will be assessed by RECIST 1.1 (Matthay, 2010; Bagatell, 2011).
19.2.2.
Tumor Response Evaluation
The body is divided into nine anatomic sectors for osteomedullary lesions, with a tenth general 
sector allocated for any extra-osseous lesions. In each region, the absolute extension score of the 
lesions is graded as: 
!
0 = no site per segment 
!
1 = one site per segment 
!
2 = more than one site per segment 
!
3 = massive involvement (> 50% of the segment) 
The absolute score is obtained by adding the score of all the segments, as shown in Figure 3 and 
listed here: (1) head and face; (2) neck and back vertebral column; (3) ribs and sternum; (4) 
lumbar and sacral column; (5) pelvis; (6) arms; (7) forearms and hands; (8) thighs; (9) legs and 
feet; and (10) any soft tissue involvement.
Figure 3:
Curie Score Anatomical Regions
Source:  Ady, 1995.
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mn; (3) ribs 
and hands; 
and hands


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The relative score is calculated by dividing the absolute score at each time point by the 
corresponding pretreatment overall score. 
19.2.3.
Response Criteria
The relative score of each patient is calculated at each response assessment time point and 
classified as below:
!
Complete Response:  Postscreening absolute score = 0. All areas of uptake on MIBG 
scan completely resolved.
!
Partial Response:  Relative score ≥ 0.1 (lesions almost disappeared) to ≤ 0.5 (lesions 
strongly reduced).
!
Stable Disease (nonresponse):  Relative score > 0.5 (lesions weakly but significantly 
reduced) to < 1 (lesions not reduced).
!
Progressive Disease:  New lesions on MIBG scan, regardless of relative score.
19.3.
Appendix C: Performance Status
19.3.1.
Lansky Performance Status
The Lansky performance status is a play-performance scale designed for pediatric cancer patients 
(Lansky, 1987).  The Lansky performance status is recommended in this study for patients < 12
years of age.  The parent/caregiver should select the scale that is most representative (average) of
the child’s activity over the past week according to Table 12.
Table 12:
Lansky Performance Scale
Score
Description
100
Fully active, normal
90
Minor restrictions in physical strenuous activity
80
Active, but tires more quickly
70
Both greater restriction of, and less time spent in, active play
60
Up and around, but minimal active play; keeps busy with quieter activities
50
Gets dressed, but lies around much of the day; no active play; able to participate in all 
quiet play and activities
40
Mostly in bed; participates in quiet activities
30
In bed; needs assistance even for quiet activities
20
Often sleeping; play entirely limited to very passive activities
10
No play; does not get out of bed
0
Unresponsive 
CCI
&(/*(1(35235,(7$5<,1)250$7,21
(lesio
lesions
ns
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f rel
f re atative s
ive s
designed f
designed f
mmended 
mended in
cale
cale th
that i
at is
Table
Table 12
12
5,
35
physical str
physical 
23
more quick
more quic
52
r restriction
estriction
35
around, bu
around, b
( 3
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ts dressed, b
quiet play a
quiet play
1(
Mostly
Mostly
*(
*
0
In 
In
/*
/*
/*
/*
20
20
(/
10
10
&(
&


EDMS Doc. Number:
nab-Paclitaxel
Protocol ABI-007-PST-001
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19.3.2.
Karnofsky Performance Status
The Karnofsky performance status is an assessment of the patient’s ability to perform normal 
activity and care for himself/herself.  The Karnofsky performance status is recommended in this 
study for patients ≥12 years of age.  The research staff should interview the patient and 
determine the patient’s Karnofsky performance status according to Table 13.
Table 13:
Karnofsky Performance Status Scale
Condition
Performance 
Status %
Comments
A. Able to carry on normal 
activities and to work.  No 
special care is needed
100
Normal. No complaints. No evidence of disease
90
Able to carry on normal activity. Minor signs or 
symptoms of disease
80
Normal activity with effort. Some signs or 
symptoms of disease
B. Unable to work. Able to live 
at home, care for most 
personal needs. A varying 
degree of assistance is needed
70
Care of self. Unable to carry on normal activity or 
do active work
60
Requires occasional assistance, but is able to care 
for most of his/her needs
50
Requires considerable assistance, but is able to care 
for most of his/her needs.
C. Unable to care for self. 
Requires equivalent of 
institutional or hospital care. 
Disease may be progressing 
rapidly
40
Disabled. Requires special care or assistance
30
Severely disabled. Hospitalization is indicated 
although death is not imminent
20
Hospitalization necessary, very sick active 
supportive treatment necessary
10
Moribund. Fatal processes progressing rapidly.
0
Dead
Adopted from Karnofsky, 1949.
19.4.
Appendix D: Pharmacokinetic Sample Handling Instructions
19.4.1.
Blood Sample Labeling
Labels must contain the following information:
!
Protocol No.: ABI-007-PST-001
!
Patient ID number
!
Part: ie, Dense PK or Sparse PK
!
Nominal Time: eg, 1 h or 5 h after end of infusion
!
Sample Type: Primary or Back-up
CCI
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$7
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ase
$7
$7
$7
or signs or 
or signs or 
0$
me signs or
me signs or
25
carry on nor
arry on no
1)
onal assistan
onal assistan
s/her needs
s/her need
< ,
considerab
considerab
st of his/he
st of his/he
5<
isabled.
sabled. Req
Req
7$
Sever
Severely
ely
althou
althou
(7
5
0
H
35
10
10
2
52
35
3
9.
ndix D: 
dix D: P
ood Sampl
od Samp
ust contain 
t contain 
!
Proto
ro
!
P


EDMS Doc. Number:
nab-Paclitaxel
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ABI-007-PST-001 Amendment 5.0 Final: 13 Jul 2016
It is recommended that all blood collection tubes and storage vials should be labeled prior to
sample collection and processing.
19.4.2.
Blood Sample Collection:
Blood samples should be collected as follows:
!
Collect approximately 0.5 mL of whole blood into a K3 EDTA tube. For PK samples 
collected at 1-2 minutes prior to, and 15 minutes after and 1 hour after the end of 
infusion, the blood should be drawn from the arm contralateral to the arm used for 
drug infusion.
!
Accurately record the time of blood collection.
!
Gently invert the tube 3 to 5 times.
!
Transfer approximately 0.25 mL of blood into each of the two prelabeled, prechilled, 
polypropylene storage tubes (one primary and one back-up).  If the blood draw 
volume is less than 0.5 mL, the first aliquot (primary sample) should be filled with 
0.25 mL of blood, and the second aliquot (back-up) with the remaining volume.  
Keep storage tubes on ice until they are ready to be transferred into a freezer (-20ºC 
or colder) where they will remain stored until shipping.
19.4.3.
PK Sample Shipment
All PK sample label information on the storage tubes have to be checked against the requisition 
form and then the samples must be shipped frozen and on dry ice to the central lab.
19.4.3.1.
Sample Collection Documents to Accompany Shipment(s)
A copy of the completed specimen manifest must accompany the shipment, and must list the 
following information at minimum:
!
Sponsor name: Celgene Corp
!
Celgene Study Number: ABI-007-PST-001
!
Subject ID Numbers
!
Group: ie, Dense PK or Sparse PK
!
Nominal collection times: eg, 1 h or 5 h after end of infusion
!
Sample collection date: eg, 10 Jan 2013
!
Sample type: Primary or Backup
CCI
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abeled, pre
beled, pr
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the blood d
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should
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ainin
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sferred in
ng.
ng.
have to be 
have to be 
and on dry
and on dry
o Accompa
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est must ac
est must ac
e Corp
e Cor
mber
mber: ABI
ABI
mbers
mbers
Dense
Dense PK
P
nal co
nal collect
llecti
am
ample colle
ple colle
m
Sam
Sample 
ple
m


EDMS Doc. Number:
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
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EDMS Doc. Number:
nab-Paclitaxel
Summary of Changes ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
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ABI-007-PST-001 Amendment # 5.0 Final: 13 Jul 2016
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Updated Inclusion Criterion 1b for Phase 2 to Allow Enrollment of Patients ≥ 6 
Months to ≤ 24 Years of Age
In the Phase 2 portion of the study, the original protocol permitted enrollment of patients ≤ 
21 years of age. Limitation of the age to 21 years does not represent the entire population of 
patients seen by pediatric oncologists. Patients 15 to 24 years of age are now commonly 
referred to as “teenagers and young adults”; the European Society for Medical Oncology 
(ESMO) is collaborating with the European Society of Pediatric Oncology (SIOPE) to target 
the unmet medical needs of adolescents and young adults, due in part to the varied interfaces 
between adult and children’s services in different healthcare systems (Vassal, 2014).  Many 
patients diagnosed with neuroblastoma, rhabdomyosarcoma, and Ewing’s sarcoma are 
followed in pediatric clinics up to 24 years of age, particularly in the  recurrent and relapsed 
setting. For example, an analysis of data from 1973 to 2007 from the United States National 
Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database shows that 
the median age at diagnosis of extraskeletal Ewing’s sarcoma is 19.5 years and that of 
skeletal Ewing’s sarcoma is 16.3 years (Applebaum, 2011). By the time many of these 
adolescent patients have failed several lines of treatment they are 21 to 24 years old. 
(Protocol Summary and Sections 1.3.2.1, 2.1, 4.1, 7.2, and 10.9.1) 
!
Updated Inclusion Criterion 2b for Phase 2 to Allow Enrollment of Patients Who 
Have Failed up to Three Lines of Treatment
In the original protocol, patients were eligible to be enrolled in Phase 2 if they had failed first 
or second line treatment or if they had evidence of refractory disease. However, current 
pediatric clinical practice in North America and Europe already includes up to three standard 
lines of treatment. Limiting eligibility to patients who have failed only first or second line 
treatment thus prevents the participation of a majority of patients (who have failed three 
previous lines and for whom new treatment options are limited).
In addition, the phrase “or has evidence of refractory disease” is now removed in order to 
avoid ambiguity concerning the number of previous lines of treatment. (Figure 2 and Section 
7.2)
!
Modification of Exclusion Criterion 7 to Differentiate Between Autologous and 
Allogeneic Hematopoietic Stem Cell Transplant (HSCT)
The protocol required that patients should not have received any hematopoietic stem cell 
transplant (HSCT) ≤ 3 months prior to start of investigational product (IP).
Allogeneic HSCT carries a substantial risk of graft-versus-host disease. Therefore, it is sound 
clinical practice to delay the start of new chemotherapy for a period of at least 3 months after 
allogeneic HSCT. Autologous HSCT does not share this risk, and so it is clarified that the 
exclusion period prior to start of IP is ≤ 21 days for autologous HSCT. (Section 7.3)
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varied in
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2011). By tht
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1, 7.2, and 
and
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cl


EDMS Doc. Number:
nab-Paclitaxel
Summary of Changes ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
4
ABI-007-PST-001 Amendment # 5.0 Final: 13 Jul 2016
!
Updated Assessment of the Primary Endpoint (Overall Response Rate [ORR]) in 
the Phase 2 Neuroblastoma Group Using Both the Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1 Criteria and the Curie Score
In Protocol Amendment 4, the ORR for patients in the neuroblastoma group was based on
either the RECIST criteria or the Curie score without crossover between assessment types 
over time; should both assessment types have been performed on a given subject across the 
assessment time points, the less favorable assessment type (in terms of achievement of 
response) would be considered for the ORR analysis. 
However, response obtained by one of the methods is clinically meaningful even if the other 
method yields a measurement of stable disease; response in neuroblastoma patients is not 
adequately assessed by RECIST criteria alone. Studies have shown that high-risk 
neuroblastoma patients with a Curie score > 2 following induction chemotherapy have 
extremely poor outcomes, leading to alternative therapies as subsequent options (Yanik, 
2013). Even in patients who have received several previous lines of treatment, a response 
assessed by 123I-metaiodobenzylguanidine (MIBG)/Curie score is clinically important in 
determining subsequent treatment options.
With the implementation of Protocol Amendment 5, if both assessment types have been 
performed on a given subject across the assessment time points, to be considered as a partial 
response for the ORR analysis, both methodologies should show no worse than stable disease 
and at least one method should indicate complete response (CR) or partial response (PR). A 
response is only considered complete if both methodologies indicate CR. (Sections 1.3.2 and 
10.6)
!
Clarification of Definition of the Efficacy Evaluable Population
Per the Phase 2 Simon two-stage design in Section 10.3 (Sample Size and Power 
Considerations), for each of the 3 groups in the first stage, 14 efficacy evaluable patients will 
be enrolled. If < 2 of the 14 patients has a response, the enrollment for this group will be 
stopped upon determination of the number of responders. If ≥ 2 of the 14 patients have a 
response, the enrollment will continue until 23 efficacy evaluable patients are enrolled.
However, the Efficacy Evaluable Population was defined in Protocol Amendment 4 Section 
10.2 (Study Population Definitions) as “All treated patients who meet eligibility criteria, 
complete at least two doses of investigational product, and have baseline and at least one 
postbaseline efficacy assessment. Here efficacy assessment means radiological assessment of
the tumor or tumor assessment by other appropriate means.” Patients may experience 
symptomatic deterioration (a measure of clinical progression in the absence of objective 
radiological tumor assessment) prior to a post-baseline efficacy assessment, and may have 
had only one dose of investigational product. 
With the implementation of Protocol Amendment 5 the definition of the Efficacy Evaluable 
Population is updated as follows to accurately include patients with clinical progression in 
the analysis of ORR:  “All treated patients who meet eligibility criteria, complete at least one
dose of investigational product, and have baseline and at least one postbaseline efficacy 
assessment if having not discontinued the investigational product prior to postbaseline 
efficacy assessment due to disease progression or symptomatic deterioration. Here efficacy 
assessment means radiological assessment of the tumor or tumor assessment by other 
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the
d


EDMS Doc. Number: 
nab-Paclitaxel
Summary of Changes ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
5
ABI-007-PST-001 Amendment # 5.0 Final: 13 Jul 2016
appropriate means. Investigational product discontinuation due to disease progression or
symptomatic deterioration must be documented as the primary reason for treatment 
discontinuation in the treatment discontinuation CRF.”  In addition, the definition of 
symptomatic deterioration in Section 12.1 Treatment Discontinuation is updated from 
“Symptomatic deterioration (global deterioration of health status)” to “Symptomatic 
deterioration (global deterioration of health status without objective evidence of disease 
progression).” (Sections 10.2 and 12.1)
!
Addition of Definition of nab-Paclitaxel Overdose
Section 8.2.4 has been updated to align with current company standard protocol language 
concerning nab-paclitaxel overdose. (Section 8.2.4)
!
Identification of the Recommended Phase 2 Dose (RP2D)
During the Phase 1 portion of the study, the Safety Monitoring Committee (SMC) 
determined that the RP2D is 240 mg/m2 in patients weighing > 10 kg, and 11.5 mg/kg in 
patients weighing ≤ 10 kg. This information is added to the protocol. (Protocol Summary and 
Sections 1.3.2, 4.1, and 8.2.1.4) 
!
Updated Phase 1 Enrollment Numbers
During the Phase 1 portion of the study, 6 dose cohorts (a total of 44 patients in the Dose 
Determining Sets) were evaluated, and about 20 additional patients were enrolled at dose 
levels evaluated as safe by the SMC. This information is added to the protocol. (Protocol 
Summary, Figure 1 and Section 7.1)
!
Allowance for the Use of Historical Left Ventricular Shortening Fraction (LVSF) 
Assessments and Electrocardiograms (ECGs) at Screening
The protocol required that LVSF assessments and ECGs be performed at screening after 
informed consent/assent has been obtained. In order to avoid subjecting young patients to 
repeated stressful procedures during a short time period, with the implementation of Protocol 
Amendment 5 if a patient has a historic LVSF assessment or ECG that was performed prior 
to informed consent/assent for non-study reasons, the procedure does not need to be repeated 
for screening. The procedure must have been performed within 14 days of the first dose of 
nab-paclitaxel. (Section 6)
References: 
Applebaum MA, Worch J, Matthay KK, Goldsby R, Neuhaus J, West DC, et al. Clinical features 
and outcomes in patients with extraskeletal Ewing sarcoma. Cancer. 2011;117(13):3027-32.
Vassal G, Fitzgerald E, Schrappe M, Arnold F, Kowalczyk J, Walker D, et al. Challenges for the 
Children and Adolescents With Cancer in Europe: The SIOP-Europe Agenda. Pediatr Blood 
Cancer. 2014;61(9):1551-7.
Yanik GA, Parisi MT, Shulkin BL, Naranjo A, Kreissman SG, London WB, et al. 
Semiquantitative mIBG scoring as a prognostic indicator in patients with Stage 4 neuroblastoma: 
a report from the Children’s Oncology Group. J Nucl Med. 2013;54(4):541-548.
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Protocol 
total of 44 
total of 4
nal pat
nal patieientn
n is added
is adde
ft Ventricu
t Ventricu
ms (ECGs) 
ms (ECGs) 
ssments an
ssments an
obtained. In
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 a historic 
a historic
for non
for non-sts
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n 6)
MA, Worc
MA, Worc
omes in pat
es in p
al G, Fitzg
al G, Fitzg
hildren and
hildren and
Cancer
Cancer. 2
niki


EDMS Doc. Number: 
nab-Paclitaxel
Summary of Changes ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
3
ABI-007-PST-001 Amendment 4.0 Final: 25 Mar 2015
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Increased Scope of Dense Pharmacokinetic (PK) Sample Collection
This protocol amendment increases dense PK sampling from the first 18 to 24 patients 
(regardless of study phase) to all patients enrolled in Phase 1. The PK sampling scheme in 
the original protocol was based on the assumption that up to approximately 4 dose level 
cohorts would be enrolled, each with 6 patients. However, it was not taken into account that 
there were patients who had undergone PK sampling but did not meet all criteria for 
inclusion in the Dose Determining Sets (DDS); these patients were replaced and PK samples 
were collected, as per protocol and in agreement with the Safety Monitoring Committee 
(SMC). In addition, patients were also enrolled at a dose previously determined to be safe 
during the interim period between the closing of one cohort and an SMC dose escalation 
decision to open a new cohort; therefore, the number of patients who had PK samples 
collected is higher than anticipated. In order to permit full noncompartmental PK analysis of 
all Phase 1 dose levels, and in particular the dose determined to be the Recommended Phase 
2 Dose (RP2D), dense PK sampling will be obtained for all patients enrolled in Phase 1 (up 
to approximately 40 patients).
!
Change of the Third Solid Tumors Group in Phase 2 from Mixed Tumors to 
Ewing’s Sarcoma
For the Phase 2 portion of the study the original protocol was designed to determine the 
antitumor activity of nab-paclitaxel in patients with several discrete solid tumor types: 
neuroblastoma, rhabdomyosarcoma, and a mixed solid tumor group (eg, 
nonrhabdomyosarcoma soft tissue sarcomas, melanoma, or tumors in which the drug showed 
activity during the Phase 1 part of the study and/or in preclinical studies). Study investigators
strongly advised that the third group should be changed to include only one patient category, 
ie, patients with Ewing’s sarcoma. Analysis of a miscellaneous group of tumors would not 
lead to meaningful Phase 2 results since it may not be possible to accrue enough patients in 
any of the other indications to signal significant activity.  This recommendation by the 
pediatric investigators was based on consideration of the available preclinical data in Ewing’s 
sarcoma, and occurred following review of the patients enrolled to date in the Phase 1 portion 
of Study ABI-007-PST-001.
!
Harmonization of Sample Size and Simon Two-Stage Minimax Design for the Three 
Groups in Phase 2
Since the third Phase 2 group will include only Ewing’s sarcoma patients and not mixed 
tumor types, a Simon two-stage minimax design will now be used to evaluate treatment 
effect in this group as well.  In addition, based on feedback that in the Phase 2 portion of the 
study the neuroblastoma group is unnecessarily large and it would be appropriate to have the 
identical Simon 2-stage design for all 3 groups, the protocol design is now simplified, while 
maintaining its relevance. The 3 Phase 2 groups will now monitor enrollment using the same 
Simon 2-stage design already in place for the rhabdomyosarcoma group. For each of the 3
groups, in the first stage, 14 efficacy evaluable patients will be enrolled. If < 2 of the 14
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EDMS Doc. Number: 
nab-Paclitaxel
Summary of Changes ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
4
ABI-007-PST-001 Amendment 4.0 Final: 25 Mar 2015
patients within a group has a response, the enrollment for this group will be stopped upon 
determination of the number of responders. If ≥ 2 of the 14 patients have a response, the 
enrollment will continue until 23 efficacy evaluable patients are enrolled. At the final 
analysis, the regimen will be concluded with a greater than 5% true response rate if ≥ 5 of 23 
patients have a response according to the maximum likelihood estimator. The sample size is 
based on an 80% power and 10% significance, having fixed the lower and upper boundaries 
to 10% and 28%, respectively.
!
Updated Inclusion Criterion 2 for Phase 2 to Require Radiologically Documented 
Measurable Disease by Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 (for Neuroblastoma Evaluable Disease by MIBG/Curie Score is also 
Acceptable)
The primary endpoint of Phase 2 is Overall Response Rate (ORR); evaluation of instances of 
confirmed partial response (PR) in addition to complete response (CR) will be necessary in 
order to have a chance to properly evaluate treatment effect and ORR using the Simon two-
stage minimax design.  Patients will therefore be required to have radiologically documented 
measurable disease (for neuroblastoma, evaluable disease by MIBG/Curie score is also 
acceptable).
!
Updated Assessment of the Primary Endpoint (Overall Response Rate [ORR]) in 
the Phase 2 Neuroblastoma Group to Use Both the Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1 Criteria and the Curie Score 
In the original study protocol the response in all Phase 2 patients is assessed by computed 
tomography (CT) or magnetic resonance imaging (MRI) using RECIST criteria, with an 
exploratory endpoint of determination of response using 123I-metaiodobenzylguanidine (MIBG)
and Curie score in the neuroblastoma group. Based on investigator feedback that the lack of 
MIBG assessment would potentially weaken the significance of the study results, and could 
potentially make it difficult to enroll subjects in the neuroblastoma group, the assessment of 
ORR in the Phase 2 neuroblastoma group will now use both the RECIST criteria and the Curie 
score when possible.  The Curie score is a semiquantitative scoring system for the comparison of 
sequential whole-body MIBG scans in children with neuroblastoma (Ady, 1995), and MIBG 
scans are now considered the most sensitive and specific method of staging and response 
evaluation in neuroblastoma (Matthay, 2010). Using both methods will allow for a more 
comprehensive and relevant evaluation of response in neuroblastoma patients who do not have 
measurable disease by RECIST criteria. With this amendment, the ORR for patients in the 
neuroblastoma group will be based on either the RECIST criteria or the Curie score without 
crossover between assessment types over time. Should both assessment types have been 
performed on a given subject across the assessment time points, the less favorable assessment 
type (in terms of achievement of response) will be considered for the ORR analysis. In addition, 
consequently, this assessment of MIBG response in neuroblastoma patients is no longer 
considered an exploratory objective in Phase 2.
!
Confirmation of Complete Response in Phase 2 Neuroblastoma
Patients in the Phase 2 neuroblastoma group who exhibit confirmed complete response will have 
a bone marrow biopsy performed to ensure that disease not assessable by RECIST or by MIBG 
methodologies is not present. This has been added as an exploratory endpoint in Phase 2.
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EDMS Doc. Number: 
nab-Paclitaxel
Summary of Changes ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
5
ABI-007-PST-001 Amendment 4.0 Final: 25 Mar 2015
!
Decreased Minimum Platelet Level in Inclusion Criterion 5 for Phase 2 Patients 
with Known Bone Marrow Involvement
Patients with the solid tumor types being studied (particularly neuroblastoma) can have bone 
marrow involvement resulting in low platelet levels due to their disease and to previous 
treatment regimens. In order to allow their enrollment, Inclusion Criterion 5 is updated to allow 
platelets ≥ 50 × 109 cells/L for patients with known bone marrow involvement; these levels are 
considered acceptable for treatment in clinical practice and will not increase the risk to patients.
The amendment also includes several other minor clarifications and updates:
!
Addition of guidance on flushing of the intravenous line following administration of nab-
paclitaxel (Section 8.2)
!
Addition of statements regarding study conduct in compliance with International 
Conference on Harmonisation (ICH) Good Clinical Practices (GCPs) to align with 
updated company standard protocol language (Study Summary and Overall Study 
Design)
!
Clarification of Phase 1 sample size to include additional patients enrolled at dose levels 
evaluated as safe by the SMC (Protocol Summary)
!
Update to length of Phase 1 (from 12 months to up to 18 months) (Protocol Summary)
!
Clarification of SAE reporting during the 28-day follow-up period to align with updated 
company standard protocol language (Section 6.2.1)
!
Update to the description of response assessments to include that the sponsor may 
conduct an independent assessment of response after study completion (Section 6.3)
!
Update to Inclusion Criterion 8 to align with current Celgene Standard Risk Language  
(Section 7.2)
!
Clarification that the safety analysis will include summarization of adverse events of 
special interest (Section 10.7)
!
Update to treatment discontinuation information concerning the treating physician’s 
responsibilities (Section 12.1)
!
Update to Section 14.2 to align with current company standard protocol language 
concerning investigator responsibilities for handling of confidential information
!
Update to Section 17 to align with current company standard protocol language 
concerning publication
!
Addition of references (Section 18)
!
Clarification that the MIBG tumor response assessment includes a 10th segment for any 
soft tissue involvement (Section 19.2.2)
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EDMS Doc. Number: 
nab-Paclitaxel
Summary of Changes ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
3
ABI-007-PST-001 Amendment 3.0 Final: 11 Jun 2014
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Update to the new IND number for nab-paclitaxel for the pediatric solid tumors
indication.
 
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nab-Paclitaxel
Summary of Changes ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
3
ABI-007-PST-001 Amendment 2.0 Final: 12 Mar 2014
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
In the Phase 2 portion of the study, a change to the sample size for the Phase 2 
neuroblastoma arm, and modifications of the Simon two-stage minimax design to 
implement acceptance rates of approximately 20% response rates for the 
neuroblastoma and rhabdomyosarcoma arms.
!
The addition of ≥ Grade 2 peripheral neuropathy to the exclusion criteria.
!
The addition of information concerning the use of syringe-based devices for 
administration of small volumes of nab-paclitaxel suspension.
!
A change from cautionary use to prohibition of concomitant medications classified as 
strong inducers of cytochrome P450 isozymes CYP2C8 and CYP3A4, and additional 
guidance on the use of strong inhibitiors of the same isozymes.
Other minor changes included in this amendment are summarized below:
!
An administrative change to the Medical Monitor title and contact information.
!
An administrative change to include the approval of nab-paclitaxel in the USA and 
EU for the treatment of first-line metastatic pancreatic adenocarcinoma.
!
Clarification and updates to the description of the rolling-6 design for the Phase 1 
portion of the study.
!
The addition of the use of “other medically appropriate method” for left ventricular 
shortening fraction (LVSF) assessment.
!
The addition of company standard language for the description of investigational 
product.
!
Clarification of permitted dose reductions from dose level -1 in the Phase 1 portion of 
the study.
!
Clarification of recommendation concerning labeling of pharmacokinetic (PK) 
samples.
!
Administrative changes to clarify protocol language and provide one additional 
literature reference.
!
Administrative changes to correct minor formatting errors    
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nab-Paclitaxel
Summary of Changes ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
3
ABI-007-PST-001 Amendment 1.0 Final:  10 Sep 2013
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
A global administrative change of Sponsor name from‘Abraxis BioScience, LLC, a 
wholly-owned subsidiary of Celgene Corporation’ to ‘Celgene Corporation’ to reflect 
the retirement of the legacy entity ‘Abraxis BioScience, LLC, a wholly-owned 
subsidiary of Celgene Corporation’ as Sponsor Name. 
!
The addition of echocardiogram/multi-gated acquisition (MUGA) scans for increased 
cardiotoxicity monitoring.
!
Modification of the schedule of events to increase the frequency of 12-lead 
electrocardiogram (ECG) testing.
!
The addition of a 3-month washout period for hematopoietic stem cell transplantation 
(HSCT) to the exclusion criteria.
!
A decrease in the volume of blood drawn for pharmacokinetic (PK) sampling.
!
An administrative change to clarify the PK sampling requirements for samples 
collected up to 1 hour after the end of study drug infusion. 
!
Removal of Cycle 1 Day 1 urine homovanillic acid and vanillylmandelic acid testing.
!
Clarification and updates in the statistical analysis section (e.g. safety analysis).
!
An administrative change to include the use of Integrated Response Technology 
(IRT) for patient enrollment
!
Addition of company standard language for End of Trial, overdose, Adverse Events, 
Serious Adverse Events, pregnancy language, site responsibilities and monitoring, 
and administrative procedures.  
!
Administrative changes to correct minor errors and inconsistencies within the 
document and/or Case Report Forms. 
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 1/2, MULTICENTER, OPEN-LABEL, DOSE-FINDING STUDY TO ASSESS THE 
SAFETY, TOLERABILITY, AND PRELIMINARY EFFICACY OF WEEKLY nab®-
PACLITAXEL IN PEDIATRIC PATIENTS WITH RECURRENT OR REFRACTORY SOLID 
TUMORS
INVESTIGATIONAL PRODUCT (IP):
nab®1-paclitaxel (ABRAXANE®)
PROTOCOL NUMBER:
ABI-007-PST-001
DATE FINAL:
8 August 2017
DATE AMENDMENT #1 FINAL:
12 January 2018
Prepared by:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
1 nab® is a registered trademark of Celgene Corporation.
CONFIDENTIAL
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
2
SIGNATURE PAGE
33'
33'
33'
33'
33'
33'
33'
33'
$7,21
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
3
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................2
1.
LIST OF ABBREVIATIONS...................................................................................8
2.
INTRODUCTION..................................................................................................11
2.1.
Summary of Change ...............................................................................................11
3.
STUDY OBJECTIVES...........................................................................................12
3.1.
Primary Objectives .................................................................................................12
3.2.
Secondary Objectives .............................................................................................12
3.3.
Exploratory Objectives ...........................................................................................12
4.
INVESTIGATIONAL PLAN .................................................................................13
4.1.
Overall Study Design and Plan ...............................................................................13
4.2.
Study Endpoints .....................................................................................................16
4.2.1.
Primary Endpoints..................................................................................................16
4.2.2.
Secondary Endpoints ..............................................................................................16
4.2.3.
Exploratory Endpoints............................................................................................16
4.3.
Stratification, Randomization, and Blinding............................................................17
4.4.
Sample Size Determination.....................................................................................17
5.
ANALYSIS POPULATIONS.................................................................................18
5.1.
Informed Consent/Assent Population......................................................................18
5.2.
Enrolled Population ................................................................................................18
5.3.
Safety Population....................................................................................................18
5.4.
Efficacy Evaluable Population................................................................................18
5.5.
Dose-determining Set .............................................................................................18
5.6.
Pharmacokinetic Population....................................................................................19
6.
GENERAL STATISTICAL CONSIDERATIONS .................................................20
6.1.
Reporting Conventions ...........................................................................................20
6.2.
Calculation of Treatment Start Dates, Cycles, and Treatment End Dates.................21
7.
SUBJECT DISPOSITION......................................................................................23
8.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................25
9.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS AND 
MEDICAL AND TREATMENT HISTORIES .......................................................26
9.1.
Demographics.........................................................................................................26
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
4
9.2.
Baseline Characteristics..........................................................................................26
9.3.
Medical History......................................................................................................27
9.4.
Cancer History........................................................................................................27
9.5.
Prior and Concomitant Medications/Procedures......................................................27
9.5.1.
Prior Medications and Procedures...........................................................................27
9.5.2.
Concomitant Medications/Procedures.....................................................................28
10.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................29
10.1.
Treatment Duration.................................................................................................29
10.2.
Cumulative Dose ....................................................................................................29
10.3.
Dose Exposure........................................................................................................29
10.4.
Average Daily Dose................................................................................................30
10.5.
Average Dose Intensity...........................................................................................30
10.6.
Relative Dose Intensity...........................................................................................30
10.7.
Dose Reduction, Interruption and Escalation...........................................................30
11.
EFFICACY ANALYSIS ........................................................................................32
11.1.
Analysis of Primary Efficacy Endpoint...................................................................32
11.1.1.
Overall Response Rate............................................................................................32
11.2.
Analysis of Secondary Efficacy Endpoints..............................................................33
11.2.1.
Duration of Response .............................................................................................33
11.2.2.
Disease Control Rate ..............................................................................................34
11.2.3.
Progression Free Survival.......................................................................................34
11.2.4.
Survival at 1 Year...................................................................................................35
11.3.
Subgroup Analysis..................................................................................................35
11.4.
Analyses of Exploratory Efficacy Endpoints...........................................................35
11.4.1.
MIBG Response Using Curie Score........................................................................35
12.
SAFETY ANALYSIS ............................................................................................36
12.1.
Adverse Events.......................................................................................................36
12.2.
Adverse Events of Special Interest..........................................................................37
12.3.
Deaths ....................................................................................................................39
12.4.
Dose-limiting Toxicities .........................................................................................39
12.5.
Pregnancies ............................................................................................................39
12.6.
Clinical Laboratory Evaluations..............................................................................40
12.6.1.
Hematology............................................................................................................40
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5


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12.6.2.
Clinical Chemistry..................................................................................................40
12.6.3.
Urinalysis ...............................................................................................................41
12.7.
Vital Sign Measurements........................................................................................41
12.8.
Electrocardiograms.................................................................................................42
12.9.
Left Ventricular Shortening Fraction Assessment ...................................................42
12.10.
Survival..................................................................................................................43
12.11.
Lansky/ Karnofsky Performance status...................................................................43
12.12.
Other Safety Assessments.......................................................................................43
13.
PHARMACOKINETIC ANALYSIS......................................................................44
13.1.
Pharmacokinetic Sampling .....................................................................................44
13.2.
Handling of nab-paclitaxel Concentration Data.......................................................45
13.3.
Noncompartmental Pharmacokinetic Parameters ....................................................45
13.4.
Population Pharmacokinetic Analysis .....................................................................46
13.5.
Statistical Analysis .................................................................................................46
14.
QUALITY OF LIFE ANALYSIS...........................................................................47
15.
INTERIM ANALYSIS...........................................................................................48
16.
TOP-LINE AND CLOSE OF STUDY FINAL ANALYSIS ...................................49
17.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................50
REFERENCES .........................................................................................................................51
APPENDIX A1 – CONVENTIONS RELATED TO DATES....................................................52
1.
HANDLING OF DATES .......................................................................................53
2.
CALCULATION USING DATES..........................................................................54
3.
GUIDELINE OF MISSING DATE IMPUTATION................................................55
3.1
Impute Missing Adverse Events/ Prior or Concomitant Medications.......................55
3.2
Prior/Concomitant Procedures ................................................................................56
3.3
Medical History......................................................................................................56
3.4
Imputing Missing Disease Progression Date ...........................................................57
3.5
Imputing Missing Dates for Prior Therapies............................................................57
APPENDIX A2 – SCHEDULE OF ASSESSMENTS ...............................................................58
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APPEND
APPEND


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
6
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................8
Table 2:
Best Overall Response Per RECIST and the Curie Scale.........................................33
Table 3:
Normal Range of Vital Sign Measurements ............................................................42
Table 4:
Dense Pharmacokinetic Sampling...........................................................................44
Table 5:
Sparse Pharmacokinetic Sampling ..........................................................................44


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
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LIST OF FIGURES
Figure 1:
Phase 1 Study Design .............................................................................................15
Figure 2:
Phase 2 Study Design .............................................................................................15
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
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8
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
AE
Adverse event
ALT (SGPT)
Alanine aminotransferase
ANC
Absolute neutrophils count
AST (SGOT)
Aspartate amino transferase
ATC
Anatomical therapeutic chemical
AUC
Area under the curve
AUCt
Area under the plasma concentration-time curve
AUC24
Area under the plasma concentration-time curve from time zero to 
24 hours
AUC∞
Area under the plasma concentration-time curve from time zero 
extrapolated to infinity
BLQ
Below the limit of quantitation
BSA
Body surface area
CDC
Centers for Disease Control and Prevention
CI
Confidence interval
CL
Total clearance
Cmax
Maximum observed plasma concentration
CNS
Central nervous system
CR
Complete response
CRF
Case report form
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DBP
Diastolic blood pressure
DCR
Disease control rate
DDS
Dose-determining set
DLT
Dose-limiting toxicity
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
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9
Abbreviation or 
Specialist Term
Explanation
DoR
Duration of response
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
Electronic case report form
EE
Efficacy evaluable 
FCBP
Female of child bearing potential
GCP
Good Clinical Practice
IAF
Informed assent form
ICH
International Council for Harmonisation
ICF
Informed consent form
IV
Intravenously
IVRS
Interactive voice recognition system
LVSF
Left ventricular shortening fraction
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
MIBG
123I-metaiodobenzylguanidine
Min
Minimum
MRT
Maximum residence dose
MTD
Maximum tolerated dose
MUGA
Multi-gated acquisition
NCI
National Cancer Institute 
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PDI
Planned dose intensity
PFS
Progression-free survival
PK
Pharmacokinetic
PR
Partial response
PFS
PFS
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
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10
Abbreviation or 
Specialist Term
Explanation
PT
Preferred term
Q1
First quartile
Q3
Third quartile
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 dose 
Rsq
Regression coefficient for calculation of terminal phase rate constant
SAP
Statistical analysis plan
SAS
Statistical Analysis Systems
SBP
Systolic blood pressure
SD
Standard deviation
SJS
Stevens-Johnson syndrome
SMC
Safety monitoring committee 
SOC
System organ class
TEAE
Treatment-emergent adverse event
TEN
Toxic epidermal necrolysis
TLG
Tables, listings, and graphs
tmax
Time to maximum observed plasma concentration
t½
Terminal phase half-life
Vss
Volume of distribution at steady state
WBC
White blood cells
WHO
World Health Organization
WHODD
World Health Organization Drug Dictionary
λz
Terminal phase rate constant
Vz
Volume of distribution based on the terminal phase
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
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11
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol ABI-007-PST-001 “A Phase 1/2, Multicenter, Open-label, Dose-finding Study to
Assess the Safety, Tolerability, and Preliminary Efficacy of Weekly nab-paclitaxel in Pediatric 
Patients with Recurrent or Refractory Solid Tumors”, Amendment # 5, dated 13 July 2016. This 
study was set up with the objective of evaluating the safety profile of nab-paclitaxel as 
monotherapy in recurrent or refractory specific solid tumors in pediatric subjects, in addition to 
collecting pharmacokinetic (PK) data in this population and evaluating anticancer activity in the 
specific solid tumors in pediatric subjects. This SAP contains definitions of analysis populations, 
derived variables, and statistical methods for the analysis of all efficacy, safety, and PK 
endpoints. 
Furthermore, the purpose of this SAP is to specify, prior to database lock, the statistical 
approaches to the final analysis of study data. This SAP will be finalized and signed prior to the 
clinical database lock for the final analysis. All analyses detailed in this SAP will be conducted 
using Statistical Analysis Systems® (SAS®) version 9.2 or higher, except for the PK analysis 
which will be conducted using PK software (Phoenix WinNonlin 6.4 or higher, and other 
software as appropriate).
2.1.
Summary of Change
There are no major revisions from the 8th August 2017 version to the current version of this SAP. 
Minor revisions are refined to the addition of reporting of study disposition for scree-fail subjects 
and of cancer history. Other minor revision are clarifications of definitions and data reporting,
and correction of language used.
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
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3.
STUDY OBJECTIVES
3.1.
Primary Objectives
Phase 1
The primary objectives of Phase 1 of the study are to determine the pediatric maximum tolerated 
dose (MTD)/recommended Phase 2 dose (RP2D) and to characterize the safety and tolerability 
of nab-paclitaxel administered intravenously (IV) over approximately 30 minutes on Days 1, 8, 
and 15 of a 28-day cycle in subjects ≥ 6 months and < 18 years old with recurrent or refractory 
solid tumors.
Phase 2
The primary objective of Phase 2 of the study is to determine the antitumor activity assessed by 
the overall response rate (ORR) of nab-paclitaxel given at the RP2D in subjects ≥ 6 months and 
≤ 24 years old with several discrete recurrent or refractory solid tumor types, including 
neuroblastoma, rhabdomyosarcoma, and Ewing’s sarcoma.
3.2.
Secondary Objectives
Phase 1
To evaluate PK and to characterize the ORR.
Phase 2
To characterize duration of response (DoR), disease control rate (DCR), progression-free 
survival (PFS), and survival at 1 year. To confirm safety and to evaluate PK.
3.3.
Exploratory Objectives
Phase 1
To assess 123I-metaiodobenzylguanidine (MIBG) response in subjects with neuroblastoma.
Phase 1 and Phase 2
To explore the potential utility of biomarkers of response and resistance in this study population. 
The most recent available tumor tissue sample will be optionally collected at the time of study 
entry. Biomarkers will be prioritized for analysis in these samples after study completion, as 
informed by emerging data.
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
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4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a Phase 1/2 multicenter, open-label, dose-finding study to assess the safety, tolerability,
PK, and efficacy of nab-paclitaxel administered intravenously to patients ≥ 6 months and 
< 18 years old in the Phase 1 portion and patients ≥ 6 months and ≤ 24 years old in the Phase 2
portion with recurrent and refractory solid tumors.
Phase 1 is a dose-finding study to determine the MTD/RP2D (rolling-6 design), safety, 
tolerability, and PK parameters of nab-paclitaxel in pediatric subjects with recurrent and 
refractory solid tumors who have progressed on standard therapy or for whom no standard 
therapy exists. The decision to dose-escalate or to declare an MTD/RP2D will be determined by 
the Safety Monitoring Committee (SMC) each time clinical and laboratory safety data for a 
given dose-determining set (DDS) are available for review. The SMC will also determine the 
dose(s) appropriate for Phase 2 (or the RP2D) (Figure 1). In addition to DDS data, the SMC may 
take into consideration the totality of all data, including that of subjects enrolled in previous dose 
cohorts or enrolled at a dose previously assessed as safe.
Phase 2 will be conducted using the RP2D established in Phase 1 to determine:
!
The antitumor activity of nab-paclitaxel in several solid tumor types (3 groups: 
neuroblastoma, rhabdomyosarcoma, and Ewing’s sarcoma;
!
The safety profile and PK of nab-paclitaxel administered at the RP2D.
In Phase 2, three disease indications will be studied: neuroblastoma, rhabdomyosarcoma, and 
Ewing’s sarcoma, each forming an independent treatment arm. Each disease indication will be 
studied in the Simon’s Minimax Two-stage design, run in parallel to one another (Figure 2).
During Phase 2, the SMC will continue to review safety data regularly and to make 
recommendations about the study continuation, as appropriate.
The study will be conducted in compliance with the International Council for Harmonisation
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good
Clinical Practice (GCP) and applicable regulatory requirements.
The study will consist of 3 periods: Screening Period, Treatment Period, and Follow-up Period, 
outlined as follows:
Screening Period
The Screening Period will start from the time of signing the informed consent form 
(ICF)/informed assent form (IAF) and will last no more than 14 days, at which time the 
Treatment Period will begin (Cycle 1 Day 1). The subject's screening procedures are to occur 
during the Screening Period within 14 days prior to dosing on Cycle 1 Day 1; by exception 
historical tumor scans (and MIBG scans for neuroblastoma) performed ≤ 28 days before the first 
dose can be used for screening.
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Treatment Period
Subjects meeting all eligibility criteria will then enter the Treatment Period and start 
nab-paclitaxel treatment. Subjects must start treatment within 14 days of signing the ICF/IAF. 
For all subsequent visits, an administrative window of ± 2 days is permitted.
nab-paclitaxel will be administered as monotherapy, IV over approximately 30 minutes, without 
corticosteroid or antihistamine premedication, weekly on Days 1, 8, and 15 of a 28-day cycle. 
The treatment will be given until disease progression, the subject begins a new anticancer 
treatment, withdrawal of parent/guardian/subject consent/assent, parent/guardian/subject refusal, 
physician decision, toxicity that cannot be managed by dose delay or dose reduction alone, or the 
study ends for any reason.
If deemed necessary, a dose should be reduced by 1 dose level according to Table 7 in the 
protocol. A maximum of 2 dose reductions are permitted. If a toxicity requiring dose adjustment 
occurs after a second dose reduction, further treatment must be discontinued. Treatment 
modifications are applicable during Phase 1 and Phase 2 of the study, except that dose reductions 
during Phase 1 Cycle 1 (and during Cycle 2 for subject ≤ 10 kg) are not permitted.
Follow-up Period
Following treatment discontinuation, all subjects will be followed for 28 days from last 
nab-paclitaxel dose date for safety and monitoring of adverse events (AEs). This data will be 
collected at the 28-day Safety Visit.
Special Monitoring: Neuropathy (eg, motor neuropathy, sensory neuropathy, peripheral 
neuropathy) AEs present at the time of treatment discontinuation should be followed until 1 of 
the following are met, but no less than the minimum 28-day safety follow-up:
!
Improvement to ≤ Grade 1;
!
At least 3 months have elapsed without improvement or worsening;
!
The subject initiates any other anticancer therapy during the follow-up.
Follow-up will continue for 1 year after last dose of nab-paclitaxel with subjects being followed 
for survival status and start of any new anticancer therapies.
All subjects who discontinue treatment for reasons other than disease progression, start of a new
anticancer therapy, or withdrawal of consent from the entire study will be followed for response
and new anticancer therapies as specified in Section 6.3 of the protocol.
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
15
Figure 1:
Phase 1 Study Design
Figure 2:
Phase 2 Study Design
(7$5<,1)250$7,21


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Celgene Corporation
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4.2.
Study Endpoints
4.2.1.
Primary Endpoints
Phase 1
The incidence of dose-limiting toxicities (DLTs) (defined in Section 8.2.1.1 of the protocol and 
Section 12.4 of this SAP) and the incidence of treatment-emergent AEs (TEAEs).
Phase 2
The ORR, which is the combined incidence of complete response (CR) and partial response 
(PR), confirmed no less than 4 weeks after the criteria for response are first met, based on 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In the neuroblastoma 
group, the ORR will be determined by RECIST and/or the Curie score (MIBG response).
4.2.2.
Secondary Endpoints
Phase 1
!
Pharmacokinetic parameters including the maximum observed plasma concentration 
(Cmax), area under the blood concentration-time curve (AUC), clearance (CL) and 
volume of distribution at steady state (Vss);
!
Overall response rate.
Phase 2
!
Duration of response in subjects with a confirmed objective CR or PR;
!
Disease control rate: the percentage of subjects with a confirmed objective CR or PR, 
or stable disease for at least 16 weeks;
!
Progression-free survival based on investigator assessment of response using RECIST 
1.1 guidelines. In the neuroblastoma group the PFS will be determined by RECIST 
and/or the Curie score (MIBG response);
!
Survival at 1 year;
!
The incidence of TEAEs;
!
Population PK parameters (eg, clearance and volume of distribution). Data from 
Phase 1 and Phase 2 will be analyzed together for this endpoint.
4.2.3.
Exploratory Endpoints
Phase 1
!
MIBG response using the Curie Score in subjects with neuroblastoma.
Phase 2
!
Bone marrow biopsy verification of confirmed complete response in subjects with 
neuroblastoma.
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Celgene Corporation
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Phase 1 and Phase 2
!
Biomarker analysis prioritized after study completion, as informed by emerging data.
4.3.
Stratification, Randomization, and Blinding
This is an open-label, single therapy study. Treatment assignment does not require 
randomization, blinding, or stratification. 
4.4.
Sample Size Determination
Phase 1
During Phase 1, a rolling-6 subject dose escalation design will be used to establish the 
MTD/RP2D, with approximately 64 subjects anticipated to be enrolled depending on the number 
of dose levels required (approximately 44 considered evaluable for determination of the 
MTD/RP2D, and about 20 additional subjects at dose levels previously evaluated as safe by the 
SMC). Subjects who are ineligible for determination of the MTD/RP2D will be replaced at the 
discretion of the sponsor. Additional subjects may be enrolled at dose levels evaluated as safe by 
the SMC.
Phase 2
In Phase 2, Simon’s Minimax Two-stage design will be employed per disease indication with 
each incorporating the following parameters: 5% significance level, 80% power and an upper 
and lower boundary of interest of 10% and 28%, respectively, for the ORR. Each of the disease 
indications will therefore enroll up to 23 subjects across Phase 2 (14 subjects in stage one and an 
additional 9 subjects in stage two) meaning a maximum total of 69 subjects evaluable for the 
primary endpoint.
For purposes of the primary endpoint analysis, the ORR is defined using the maximum 
likelihood estimator.
For each of the 3 groups in stage one, if < 2 of the 14 evaluable subjects have a response, then 
enrollment into that disease indication group will be stopped; otherwise enrollment shall 
continue as planned in stage two. At the final analysis, the study treatment will be concluded 
with more than a 5% true response rate if ≥ 5 of 23 subjects have a response. The Phase 2 target 
response rate is therefore 21.74% with 80% power and a 10% significance level.
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1.74


nab®-paclitaxel 
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5.
ANALYSIS POPULATIONS
5.1.
Informed Consent/Assent Population
The informed consent population includes all subjects who signed informed consent and/or 
assent, ie, all subjects who entered the Screening Period regardless of later being a screen failure.
5.2.
Enrolled Population
The enrolled population includes all subjects enrolled, ie, all subjects who are marked as enrolled 
in the clinical database regardless of whether they received nab-paclitaxel.
5.3.
Safety Population
The safety population includes all subjects who received at least 1 dose of nab-paclitaxel. 
5.4.
Efficacy Evaluable Population
Phase 1 Regardless of Disease Indication 
All treated subjects who meet eligibility criteria, complete at least 1 dose of nab-paclitaxel, and 
have baseline and either at least 1 postbaseline efficacy assessment, or having discontinued nab-
paclitaxel due to disease progression or symptomatic deterioration before a postbaseline efficacy 
assessment could be conducted. Here efficacy assessment means radiological assessment of the 
tumor or tumor assessment by other appropriate means.
Phase 2 Rhabdomyosarcoma and Ewing’s Sarcoma Indications 
All treated subjects who meet eligibility criteria relevant to efficacy, complete at least 1 dose of 
nab-paclitaxel, and have baseline and either at least 1 postbaseline efficacy assessment assessed 
per RECIST 1.1, or having discontinued nab-paclitaxel due to disease progression or 
symptomatic deterioration before a postbaseline efficacy assessment could be conducted. Here
efficacy assessment means radiological assessment of the tumor or tumor assessment by any 
means appropriate.
Phase 2 Neuroblastoma Indication
All neuroblastoma subjects who meet eligibility criteria relevant to efficacy, complete at least 1 
dose of nab-paclitaxel, and have baseline and either at least 1 postbaseline efficacy assessment 
assessed per the RECIST 1.1 and/or the Curie score (MIBG response), or having discontinued 
nab-paclitaxel due to disease progression or symptomatic deterioration before a postbaseline
efficacy assessment could be conducted. Here efficacy assessment means radiological 
assessment of the tumor or tumor assessment by any appropriate means.
5.5.
Dose-determining Set
The primary endpoint for Phase 1, determination of the MTD/RP2D, will be performed on the 
DDS for each dose level tested. In subjects weighing > 10 kg, the DDS includes all subjects who 
experienced a DLT, or received all 3 weekly doses of nab-paclitaxel at the cohort planned dose 
during Cycle 1 and had adequate safety assessments during the DLT assessment period (Cycle 1 
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5.5.
5.5.
e p


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
19
including predose assessments on Cycle 2 Day 1). In subjects weighing ≤ 10 kg, the DDS 
includes all subjects who experienced a DLT, or received all 6 weekly doses of nab-paclitaxel at 
the cohort planned doses during Cycles 1 and 2 and had adequate safety assessments during the 
DLT assessment period (Cycle 1 and 2 including predose assessments on Cycle 3 Day 1).
5.6.
Pharmacokinetic Population
The PK population includes all subjects who received at least 1 dose of nab-paclitaxel and had 
evaluable concentration data.
&(/*(1(35235,(7$5<,1)250$7,21


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
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6.
GENERAL STATISTICAL CONSIDERATIONS
6.1.
Reporting Conventions
The summary tables, listings, and any supportive SAS output will include the explanatory 
“headers” that indicate, at a minimum:
!
protocol number;
!
data cutoff date;
!
company name (Celgene Corporation);
!
page number (Page x of x).
The summary tables, listings, and any supportive SAS output will include the explanatory 
“footers” that indicate, at a minimum:
!
program source (ie, SAS program name, including the path, run date);
!
data extraction date;
!
data source (ie, list of datasets used for the display).
The purpose of the data extraction date is to link the output to the database, either active or 
archived, that is write-protected for replication and future reference. The program run date is the 
output date which will appear on each output page and will indicate the date the output was 
generated by the analysis program. Individual source listings will display all the relative values 
supporting corresponding table(s) and figure(s).
In addition, the following reporting conventions will be implemented:
!
Data from all study sites will be combined for analysis;
!
Confidence intervals (CIs) will be presented as 2-sided 95% CIs unless otherwise 
specified;
!
Summary statistics will consist of the number and percentage of subjects in each 
category for discrete variables, and the sample size (n), mean, median, standard 
deviation (SD), minimum (Min), and maximum (Max) for continuous variables;
!
All mean and median values will be formatted to 1 more decimal place than the 
measured value. Standard deviation values will be formatted to 2 more decimal places 
than the measured value;
!
P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be 
presented as ‘<0.0001’ and p-values that round to 1.000 will be presented as ‘>0.9999’;
!
All percentages will be rounded to the nearest whole number. The number and 
percentage of responses will be presented in the form xx (xx), where the percentage is 
in the parentheses. In the case the numerator is equal to the denominator, the 
percentage should be presented as (100) instead of (100.0);
planatory
planatory
n date);
n date);
o the databa
o the datab
reference.
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will indicat
will indica
list
listings w
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ons
ons will be 
will be 
be combine
be combine
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) will be
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A


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
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!
All listings will be sorted for presentation in order of study phase, dose level (Phase 1 
only), study site, subject number, and date of procedure or event. Subjects who are 
not enrolled will be listed as a non-enrolled group after enrolled subjects;
!
All tables will be presented by study phase, and dose/disease indication;
!
All analysis and summary tables will have the analysis population sample size for each 
treatment group in the column heading (ie, number of subjects) where applicable;
!
Baseline is defined as the latest value collected on or before the date when the first 
dose of study treatment is administered. If multiple values are present for the same 
date, the mean of these values will be used as the baseline, except for laboratory data,
where the value with the worst Common Terminology Criteria for Adverse Events 
(CTCAE) grade will be set as baseline. For subjects who were not treated, the 
baseline value will be defined as the latest value collected on or prior Day 1 of the 
Cycle 1 visit, if available;
!
The day of first dose of study drug nab-paclitaxel will be defined as Day 1. For subjects
who are not treated, the Cycle 1 Day 1 visit will be defined as Day 1;
!
For tables and figures displaying results by visit, only scheduled visits will be 
considered beside clinical laboratory evaluations. Unscheduled visits will appear only 
in listings and could be considered in some derivations;
!
All the analyses will be performed separately for Phase 1 and Phase 2 unless specified 
otherwise.
6.2.
Calculation of Treatment Start Dates, Cycles, and Treatment End 
Dates
Treatment will commence on Day 1 and planned cycle lengths are 28 days. Day 1 of a cycle is 
defined as day 1 of study drug for the given cycle as recorded on the electronic case report form
(eCRF).
Cycle end dates are defined as the day before Day 1 of the following cycle, or if on the last cycle 
then the last day is the last treatment administration date plus 28 days, i.e. the treatment end date 
plus 28 days. The treatment end date, and the end date of the last cycle, will be calculated as 
follows:
!
For subjects who discontinue prior to the clinical cutoff date, treatment end date is the 
date of treatment discontinuation from the treatment disposition page in the eCRF;
!
For subjects who are still on treatment at the time of study closure or clinical cutoff, 
the last date of planned cycle (27 days after first dose of the last cycle) will be used as 
the treatment end date.
The cycle number for each date of interest, eg, AE start date, will be calculated based on the 
cycle window set by their start and end dates. 
The following rules will be implemented for cycle calculations for TEAEs:
!
TEAEs present on or after Day 1 Cycle i but before Day 1 of the subsequent cycle 
belong to Cycle i (where i stands for cycle number);
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
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!
All TEAEs that occur between Day 1 of the last cycle and 28 days after last dose 
administration date will be included only in the last cycle.
&(/*(1(35235,(7$5<,1)250$7,21


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
23
7.
SUBJECT DISPOSITION
Tables showing a summary of analysis population will present data by study phase, specifically 
by dose level and in aggregate (Phase 1) and by disease indication and in aggregate (Phase 2) for 
the following analysis populations:
!
Informed Consent/Assent Population;
!
Enrolled Population;
!
Safety Population;
!
Efficacy Evaluable Population;
!
Dose-determining Set;
!
Pharmacokinetic Population.
A summary of subjects enrolled by country, and site number/name will be provided.
A summary table showing subjects that did not enroll into the study, and reason for non-
enrollment, will be provided. The table will present data for Phase 1 and 2 individually but not by 
dose level nor disease indication.
Reasons for treatment discontinuation will be summarized overall and by cycle based on the 
safety population and presented by study phase, specifically by dose level and in aggregate 
(Phase 1) and by disease indication and in aggregate (Phase 2) and in aggregate across Phase 1 
and Phase 2 for the following categories:
!
Death;
!
Adverse event;
!
Pregnancy;
!
Progressive disease;
!
Withdrawal by subject;
!
Withdrawal by parent/guardian;
!
Lost to follow-up;
!
Study terminated by sponsor;
!
Physician decision;
!
Protocol violation;
!
Symptomatic deterioration;
!
Other.
Reasons for discontinuing the study follow-up/study will be collected on the case report form
(CRF) and will be summarized for the Informed Consent/Assent Population with the following 
categories:
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1 and 2 
overall an
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by do
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subject
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by parent/
by parent
follow
follow-up
-up
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dy termina
termin
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Physician
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!
Proto
oto
!
S


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
24
!
Screen failure;
!
Death;
!
Adverse event;
!
Withdrawal by subject;
!
Withdrawal by parent/guardian;
!
Lost to follow-up;
!
Study terminated by sponsor;
!
Other.
Included also is the number and proportion of subjects who completed the study, defined as those 
completing the 1-year survival follow-up. Summary tables for study discontinuation will present 
data by study phase, specifically by dose level and in aggregate (Phase 1) and by disease 
indication and in aggregate (Phase 2) and in aggregate across Phase 1 and Phase 2.
Listings will be provided for study discontinued subjects with reason for treatment 
discontinuation and for screen failure subjects.
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Phase 2
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or treatmen
or treatme


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Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
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8.
PROTOCOL DEVIATIONS/VIOLATIONS
Protocol deviations and protocol violations will be identified and assessed by the sponsor’s 
clinical monitor or designee following company standard operational procedure; these possible 
deviations and violations are entered into the clinical trial management system by the clinical 
monitor and are reviewed by the sponsor for confirmation/correction. This adjudicated protocol 
deviation/violation tracker maintained in an excel file will be used for analysis.
Protocol deviations and violations will be reviewed before database lock to partly determine the 
EE Population. 
It should be noted that not all protocol deviations or violations will result in the exclusion of 
subjects from the EE Population. Events that could trigger exclusion from the EE Population 
include certain inclusion/exclusion criteria violations, failure to take the study drug as assigned, 
and prohibited concomitant medications and procedures.
Protocol violations will be summarized for the Safety Population using frequency tabulations. 
Moreover, frequencies will be provided for number of subjects with 1, 2, or > 2 protocol 
violations.
A listing of subjects with protocol violations/deviations in the Enrolled Population will be 
provided. Summary tables will present data by study phase, specifically by dose level and in 
aggregate (Phase 1) and by disease indication (Phase 2) and in aggregate for Phase 1 and 
Phase 2, based upon subjects in the Safety Population.
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sion 
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ation
o
g as 
as assigne
assign
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ency tabula
r r > 2
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opu
cifically
cifica
by
b
y
n aggregate
n aggrega


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Statistical Analysis Plan. Protocol ABI-007-PST-001
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9.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS AND 
MEDICAL AND TREATMENT HISTORIES
Demographics and baseline characteristics, and medical and treatment histories will be 
summarized by study phase, specifically by dose level and in aggregate (Phase 1) and by disease 
indication (Phase 2) and in aggregate Phase 1 and Phase 2 for the Safety Population and EE 
Population unless specified otherwise. Baseline clinical characteristics are defined as the latest 
data collected on or before Cycle 1 Day 1, but before start of treatment. Individual subject
listings will be provided to support the summary tables.
9.1.
Demographics
Age (years), height (cm), and weight (kg) at baseline will be summarized using descriptive 
statistics (n, mean, SD, median, min and max). Age category (< 2 years, ≥ 2 years to < 12 years, 
≥ 12 years to < 18 years, and ≥ 18 years to ≤ 24 years [Phase 2 only]), weight category (≤10 kg, 
> 10 kg), gender, race, ethnicity, and other categorical variables will be summarized by 
frequency tabulations.
Age will be calculated as follows: age (year) = [(Date of informed consent/assent – Date of Birth 
+ 1) / 365.25]. In the table, age will be presented as an integer. In the listing, age < 2 years will 
be displayed in month(s), which will be calculated as age (month) = Integer ∀[(Date of informed 
consent/assent – Date of Birth + 1) / 30.4375]. Years reached are to be used for categorization.
Within listings, age will be displayed in years and months as computed following directions 
given in Appendix 1A, Section 2, while within tables summary statistics for age in years will be 
used. The World Health Organization (WHO) growth chart will be used for infants and children 
ages 0 to 2 years of age and the Centers for Disease Control and Prevention (CDC) growth chart
will be used for children age 2 years and older.
Body surface area (BSA) will not be recalculated for tables, listings, and graphs (TLG)
presentation but presented based on BSA as calculated and reported by the site per their 
institutional practice. 
9.2.
Baseline Characteristics
The number and percentage of subjects in each of the following categories will be presented:
!
Overall interpretation of electrocardiograms (ECG);
!
Lansky/Karnofsky performance status at baseline (the 2 performance assessments
will be presented separately);
!
Tumor type;
The time from initial diagnosis to the first recurrence/progression and time from first 
recurrence/progression to first dose date will be summarized descriptively.
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hed are to b
ntnths as co
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Disease Con
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be
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SA 
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fro
recurrenc
ecurrenc


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9.3.
Medical History
A summary of medical history will be presented by Medical Dictionary for Regulatory Activities
(MedDRA) Version 20.1 or later system organ class (SOC) and preferred term (PT) for the 
safety population. 
Medical and surgical history will be sorted in descending frequency for the SOC based on the 
overall column and within each SOC; the PTs will be displayed in alphabetical order.
9.4.
Cancer History
A summary of cancer history will be presented showing disease diagnosis and stage at initial 
diagnosis and at time of study screening, and time to and from specified cancer history 
timepoints including, but not limited to, prior disease progression/reoccurrence to first study 
treatment dose date.
Information pertaining to baseline lesion status will also be presented, including, but not limited 
to, lesion diameter, location and assessment method used.
9.5.
Prior and Concomitant Medications/Procedures
Medications initiated prior to the start of study treatment and continued after the start of study 
treatment will be counted as both prior and concomitant medications.
Tables and listings described in this section will use the Safety Population. 
9.5.1.
Prior Medications and Procedures
Prior medications and procedures, such as surgeries, are defined as medications or procedures 
that were started before the start of the study treatment and either ended before the start of the 
study treatment or continued after study treatment.
The number of prior therapies and procedure, such as surgeries, will be summarized for prior 
radiation therapies, prior cancer surgeries, prior systemic anticancer therapies, prior stem cell 
transplants and other prior anticancer therapies by frequency tabulations based on the Safety 
Population. Descriptive statistics may be provided also, if needed. The therapies/surgeries with 
the same sequence/regimen number are counted as 1 prior therapy/surgery. 
Prior anticancer therapies will be summarized, if applicable, based on the WHO Drug Dictionary 
(WHODD), version March 2015 or later, therapeutic drug class (Anatomical Therapeutic 
Chemical [ATC] level 1) and preferred name sorted by descending frequency of drug class in the 
overall column, and by alphabetical order of the preferred name within drug class.
Prior procedures will be summarized, if applicable, based on the MedDRA Version 20.1 or later 
system organ class (SOC) and preferred term (PT) for the safety population, sorted by 
descending frequency of SOC in the overall column, and by alphabetical order of the PT within 
SOC.
nitial
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urgeri
urgeries, ar
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udy treatm
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treat
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en
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surgeries
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OC
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9.5.2.
Concomitant Medications/Procedures
Concomitant medications and procedures are defined as medications and procedures, such as 
surgeries, that were either initiated before the first dose of study drug and continued during the 
study treatment, or initiated on/after the date of the first dose of study drug and on/before 28 days 
after the end of the study treatment. 
A summary showing the number and percentage of subjects who had concomitant medications 
and a separate summary showing the number and percentage of subjects who had concomitant 
procedures will be presented by WHO ATC level 1 drug name and preferred name, version 
WHODD March 2015 or later, sorted by descending frequency of ATC level 1drug name in the 
overall column, and by alphabetical order of the preferred name within drug class. Summaries
will be based on the safety population.
Concomitant procedures will be summarized, if applicable, based on the MedDRA Version 20.1 
or later system organ class (SOC) and preferred term (PT) for the safety population, sorted by 
descending frequency of SOC in the overall column, and by alphabetical order of the PT within 
SOC.
Individual listings of prior and concomitant medications will be provided to support the tables. 
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10.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
Study treatment and extent of exposure summaries will be provided based on the Safety 
Population. Descriptive statistics (n, mean, SD, median, min, and max) will be provided for the 
following nab-paclitaxel exposure parameters: treatment duration, cumulative dose, dose 
exposure, average weekly dose, dose intensity and relative dose intensity. Total number of, and 
frequency of, cycles administered, number and percentage of subjects dosed at each cycle, 
number and percentage for maximum number of cycles received per subject, total number of 
doses administered, and dose reduction/interruption will also be presented.
Tables will present data by study phase, specifically by dose level and in aggregate (Phase 1) and 
by disease indication (Phase 2) as well as an aggregate for all patients across Phases 1 and 2 
treated at the RP2D, and for all subjects included in the Safety Population across Phases1 and 2.
Individual subject listings of exposure to study drug will be provided. 
10.1.
Treatment Duration
The treatment duration (weeks) is defined as:
[(date of last study drug administration) – (date of first study drug administration) + 7] / 7.
Treatment duration will be presented separately for subjects with weight ≤ 10 kg versus > 10 kg; 
if no subjects are found within a given weight category then that weight category will not be 
displayed.
10.2.
Cumulative Dose
The cumulative dose (mg/m2 or mg/kg) is defined as the sum of all doses taken across the 
Treatment Period. Cumulative dose will be presented separately for subjects with weight ≤ 10 kg 
versus > 10 kg; if no subjects are found within a given weight category then that weight category 
will not be displayed.
10.3.
Dose Exposure
Dose exposure in days is defined as the total number of actual drug administration days during 
the Treatment Period. Dose exposure will be presented separately for subjects with weight ≤ 10 
kg versus > 10 kg; if no subjects are found within a given weight category then that weight 
category will not be displayed.
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1) and 
1) and 
nd 2
se
ses1 and 2
1 and 2
drug admin
ug admin
wi
with
th
i
wei
wei
h
ght
g
en that weig
en that wei
fined as th
fined as th
be presented
be presente
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within a 
defined as 
defined
Do
Dose 
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no subjec
be di
be display
splay


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10.4.
Average Daily Dose
Average daily dose will be calculated as:
Cumulative Dose / Dose Exposure.
Average weekly dose intensity will be presented separately for subjects with weight ≤ 10 kg 
versus > 10 kg; if no subjects are found within a given weight category then that weight category 
will not be displayed. Average daily dose shall be presented in mg/m2 and calculated as the 
actual administered dose divided by the reported BSA value.
10.5.
Average Dose Intensity
The weekly average dose intensity (mg/m2/week or mg/kg/week, depending on subject weight)
during treatment is calculated as:
Cumulative Dose / Treatment Duration.
Average dose intensity will be presented separately for subjects with weight ≤ 10 kg versus
> 10 kg; if no subjects are found within a given weight category then that weight category will 
not be displayed. Average dose intensity shall be presented in mg/m2 and calculated as the actual 
administered dose divided by the reported BSA value.
10.6.
Relative Dose Intensity
Relative Dose Intensity is calculated as:
Average Dose Intensity / Planned Dose Intensity.
For nab-paclitaxel administrated in Phase 2 to a subject of body weight > 10 kg, the planned 
dose intensity (PDI) is calculated as (RP2D*3)/7 mg/m2 per week. For subjects ∀10 kg body 
weight in Phase 2, the PDI is calculated as (RP2D*3)/7 mg/kg per week.
Relative dose intensity will be categorized into ≥90%, < 90% to 80%, < 80% to 70%, and 
< 70%.
10.7.
Dose Reduction, Interruption and Escalation
Dose reductions are identified as an actual scheduled dose as recorded on the study drug record 
CRF page, e.g. > 0 mg/m2 for subjects > 10 kg in weight / > 0 mg/kg for subjects ≤ 10 kg in 
weight at the time of administration, while being less than the scheduled dose directly prior to 
the current administration. Dose changes as a result in change of body weight will not be 
considered as a dose reduction. Dose reductions will be summarized as follows:
!
Number and percentage of subjects with at least 1 dose reduction, reasons for 
reduction, frequency of reductions;
!
Summary statistics (n, mean, median, SD, min, and max) for time to first reduction.
Drug interruption are identified as a non-administered planned dose, e.g. actual dose received = 0 
mg/m2 / 0 mg/kg, while being directly followed with an actual administered dose e.g. actual dose 
received > 0 mg/m2 / mg/kg, provided an actual dose had been administered previously. Drug 
interruption will be summarized as follows:
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entified
mg/m
mg/m2
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as a dose 
dose 
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red
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!
ug


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
31
!
Number and percentage of subjects with at least 1 drug interruption, reasons for each 
interruption, frequency of interruptions;
!
Summary statistics (n, mean, median, SD, min, and max) for time to first drug 
interruption.
During Phase 1, subjects receiving treatment beyond Cycle 1 who had not had any dose 
reductions may, following approval by the SMC, have their dose level increased, providing that 
the alternative dose level has been shown to be well tolerated by at least one cohort of other 
subjects in this study. Once a subjects’ dose has been reduced, it could not be increased to the 
previous level.
Dose escalations are identified as an actual scheduled dose as recorded on the study drug record 
CRF page, e.g. > 0 mg/m2 for subjects > 10 kg in weight / > 0 mg/kg for subjects ≤ 10 kg in 
weight at the time of administration, while being more than the scheduled dose (> 0 mg/m2 / 
mg/kg) administered directly prior to the current administration. Dose changes as a result in 
change of body weight will not be considered as a dose escalation. Dose escalations will be 
summarized as follows for Phase 1 subjects only:
!
Number and percentage of subjects with at least 1 dose escalation, reasons for each 
interruption, frequency of interruptions;
!
Summary statistics (n, mean, median, SD, min, and max) for time to first dose 
escalation.
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
32
11.
EFFICACY ANALYSIS
Tables will be provided to describe the efficacy endpoints for both the Safety Population and EE 
Population. Tables will present data by study phase, specifically by dose level and in aggregate 
(Phase 1) and by disease indication (Phase 2). A listing will display efficacy data for the Safety 
Population.
11.1.
Analysis of Primary Efficacy Endpoint
The primary efficacy endpoint, ORR, relates to Phase 2 only; in Phase 1 ORR is considered a 
secondary efficacy endpoint. In Phase 1, the primary endpoint is the incidents of DLTs and 
TEAEs. The ORR will be displayed by dose level and overall (Phase 1) and disease indication 
(Phase 2).
11.1.1.
Overall Response Rate
Overall response rate is defined as the percentage of subjects that achieve a CR or PR confirmed 
no less than 4 weeks after the criteria for response are first met, over the total number of subjects
available for the analysis within the given population, i.e. subjects contained within the EE 
Population as outlined within Section 5.2 of this SAP, as well as the Safety Population which is 
formed of all subjects receiving at least 1 dose of nab-paclitaxel as outlined within Section 5.3 of 
this SAP. The corresponding 2-sided, 95% Clopper-Pearson CI will also be provided.
Complete response is considered confirmed if another CR is observed at least 4 weeks (28 days) 
after the first CR is observed without another response type identified between assessments. 
Partial response is considered confirmed if another PR or a CR is observed at least 4 weeks 
(28 days) after the first PR is observed without another response type beside CR identified
between assessments. 
Disease assessments recorded on or after start of a new anticancer therapy will not be considered, 
nor will disease assessments reported after a progressive disease (PD) has been observed.
In addition, best overall response will be summarized by number and percentage of subject’s best 
response that meets one of the following categories: CR, PR, stable disease, symptomatic 
deterioration as recorded on the treatment discontinuation and/or the study discontinuation eCRF
(for subjects that discontinue treatment/study before a disease assessment can be taken), PD, or 
not evaluable. Stable disease will additionally show subcategories for SD lasting < 16 weeks or ≥ 
16 weeks.
In Phase 1, all subjects will be analyzed regardless of disease indication based on the RECIST 
postbaseline response assessments (as well as for neuroblastoma subjects only, based on the 
Curie score [MIBG response] postbaseline response assessments). 
In Phase 2, rhabdomyosarcoma and Ewing’s sarcoma subjects will be analyzed based on the 
RECIST postbaseline response assessments. Neuroblastoma subjects will be analyzed based on
the RECIST and/or the Curie score (MIBG response) postbaseline response assessments, without 
crossover between assessment types over time. If both the RECIST and the Curie score have 
been used and should both response assessments show a similar response (ie, either both are CR 
or both are PR) then that response shall be considered as the best response for calculation of the 
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CR
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her PR
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fter star o
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nse will be
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RECIST
RECIST
RE
RE


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
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best overall response; should both show a response but different, ie, CR and PR, the PR shall be 
considered the best overall response; should only one of the response assessments show a 
response (either a CR or PR) while the other shows a stable disease, then PR shall be considered 
the best overall response. For the best overall response to be considered a PD, a PD must have 
been recorded according to at least 1 of the response assessments, see Table 2 for further 
direction. If only RECIST or the Curie scale was used, a corresponding baseline assessment must 
have been conducted using the same assessment type method.
Table 2:
Best Overall Response Per RECIST and the Curie Scale
Response Assessment Method
Overall Best Response
RECIST
Curie Score
Complete Response
Complete Response
Complete Response
Partial Response
Complete Response
Partial Response
Complete Response
Partial Response
Partial Response
Complete Response
Stable Disease
Partial Response
Stable Disease
Complete Response
Partial Response
Partial Response
Stable Disease
Partial Response
Stable Disease
Partial Response
Partial Response
Stable Disease
Stable Disease
Stable Disease
Complete Response
Disease Progression
Disease Progression
Partial Response
Disease Progression
Disease Progression
Stable Disease
Disease Progression
Disease Progression
Disease Progression
Complete Response
Disease Progression
Disease Progression
Partial Response
Disease Progression
Disease Progression
Stable Disease
Disease Progression
Disease Progression
Disease Progression
Disease Progression
Waterfall plots of best percentage change from baseline in the sum of length (longest diameter)
of target lesions will be provided by dose/disease indication. Individual listings of tumor 
assessment will be provided.
11.2.
Analysis of Secondary Efficacy Endpoints
11.2.1.
Duration of Response
Duration of response will be presented in weeks and is defined as the time from the date of first 
observed response, either a confirmed CR or PR, until the date a PD is first observed. Subjects 
who do not have PD or have not died will be censored at the time of their last disease assessment 
or at the time of start of new anticancer therapy, whichever occurs first.
In Phase 1 subjects and Phase 2 Ewing’s sarcoma and rhabdomyosarcoma subjects, tumor 
assessments will be based on RECIST 1.1 while in Phase 2 neuroblastoma subjects it will be 
based on the Curie Score or RECIST 1.1; should a Phase 2 neuroblastoma subject have their 
response assessment conducted with both RECIST 1.1 and the Curie Score then an overall 
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Ph


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
34
response as shown in Table 2:
Best Overall Response Per RECIST and the Curie Scale will be 
used.
For identification of PD for this endpoint, PD is classed as either a PD as observed on the 
response assessments eCRF (both during the Treatment Period and the Follow-up Period if 
applicable), or as a PD or symptomatic deterioration as recorded on the treatment discontinuation 
and/or the study discontinuation eCRF; the first time this occurrence is observed is selected as 
the PD date.
Duration of response shall be summarized by descriptive statistics for non-censored subjects, and 
includes n, arithmetic mean, SD, median, min, and max, for each dose/disease indication.
11.2.2.
Disease Control Rate
Disease control rate is defined as the percentage of subjects that achieve either a stable disease
maintained for ≥ 16 weeks or confirmed CR (confirmed no less than 4 weeks after criteria for 
response are first met) or confirmed PR (confirmed no less than 4 weeks after criteria for 
response are first met) over the total number of subjects available for the analysis within the 
given population, i.e. subjects contained within the EE Population as outlined within Section 5.2
of this SAP, as well as the Safety Population which is formed of all subjects receiving at least 
1 dose of nab-paclitaxel as outlined within Section 5.3 of this SAP. The corresponding 2-sided, 
95% Clopper-Pearson CI will also be provided.
Complete response is considered confirmed if another CR is observed at least 4 weeks (28 days) 
after the first CR is observed without another response type identified between assessments. 
Partial response is considered confirmed if another PR or a CR is observed at least 4 weeks (28 
days) after the first PR is observed without another response type beside CR identified between
assessments. 
Calculation of stable disease duration starts at the time of first dose of nab-paclitaxel until the 
date first observation of PD is recorded, or until the date of the last disease assessment if no PD
is recorded; if the difference is ≥ 16 weeks (≥ 112 days) then the SD will be considered as being 
maintained for ≥ 16 weeks.
Disease assessments recorded on or after start of a new anticancer therapy will not be considered, 
nor will disease assessments reported after a PD has been observed.
In Phase 1 subjects and Phase 2 Ewing’s sarcoma and rhabdomyosarcoma subjects, tumor 
assessments will be based on RECIST 1.1 while in Phase 2 neuroblastoma subjects it will be 
based on the Curie Score or RECIST 1.1; should a Phase 2 neuroblastoma subject have their 
response assessment conducted with both RECIST 1.1 and the Curie Score then an overall 
response as shown in Table 2:
Best Overall Response Per RECIST and the Curie Scale will be 
used.
11.2.3.
Progression Free Survival
Progression-free survival will be presented in weeks and is defined as the time from the date of 
first nab-paclitaxel dose until the date a PD is first observed or date of death (any cause), 
and 
nd 
stabl
table disea
e dise
after criteri
fter criter
fter criteria 
ter criteria
e analysis w
analysi
outlined 
outlined w
ll subjects r
l subjects
AP
AP. The co
T
R is observ
is obse
se ty
e type iden
e iden
y
er 
er PR
PR or a
other respo
other respo
tarts at the 
arts at the
ded, or unti
ed, or un
16 weeks (
16 weeks 
ded on or a
ed on or a
ments repor
ments repo
and Phase
and Phase
l be based o
l be based 
Curie Scor
Curie Scor
assessment 
sessment 
se as shown
e as shown
2


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
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whichever occurs first. Subjects who do not have PD or have not died will be censored at the 
time of their last disease assessment or at the time of start of new anticancer therapy, whichever 
occurs first.
For the purpose of identification of PD for this endpoint, PD is classed as either a PD as 
observed on the response assessments eCRF (both during the Treatment Period and the Follow-
up Period if applicable), or as a PD or symptomatic deterioration as recorded on the treatment 
discontinuation and/or the study discontinuation eCRF; the first time this occurrence is observed 
is selected as the PD date.
In Phase 1 subjects and Phase 2 Ewing’s sarcoma and rhabdomyosarcoma subjects, tumor 
assessments will be based on RECIST 1.1 while in Phase 2 neuroblastoma subjects it will be 
based on the Curie Score or RECIST 1.1; should a Phase 2 neuroblastoma subject have their 
response assessment conducted with both RECIST 1.1 and the Curie Score then an overall 
response as shown in Table 2:
Best Overall Response Per RECIST and the Curie Scale will be 
used.
Progression-free survival will be summarized by median progression-free time along with the 
corresponding 95% CI, calculated using Kaplan-Meier methods (the estimate of variance will be 
calculated using Greenwood’s formula) (Kaplan and Meier, 1958). The Kaplan-Meier curves for 
progression-free survival will be presented graphically. The number and percentage of total 
disease progression/deaths, as well as cause of death, as identified for PFS event will be 
summarized.
11.2.4.
Survival at 1 Year
Overall survival (OS) will be presented in months and is defined as the duration in weeks from 
the date of first nab-paclitaxel dose to the date of death (any cause). Subjects who are alive at the 
time of analysis will be censored at the last known time that the subject was alive. Overall 
survival will be summarized by median survival time along with the corresponding 95% CI,
calculated using Kaplan-Meier methods (the estimate of variance will be calculated using 
Greenwood’s formula) (Kaplan and Meier, 1958). The Kaplan-Meier curve for survival will be 
presented graphically. The number and percentage of total deaths, as well as cause of death, will 
be summarized by dose/disease indication. The survival rate at 1 year, including the 
corresponding 95% CI, will be provided. 
11.3.
Subgroup Analysis
No subgroup analysis is planned for efficacy data.
11.4.
Analyses of Exploratory Efficacy Endpoints
11.4.1.
MIBG Response Using Curie Score
In Phase 1, overall response based on MIBG scan will be analyzed for neuroblastoma subjects 
only, analyzed in the same way as ORR was analyzed for all subjects in Phase 1 regardless of 
disease indication.
Individual listing of Curie score and overall response will be provided.
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be
ve their 
their 
overall
overall
urie Scale
urie Scale
e time
ime alon
stimate of 
stimate of 
The Kapla
The Kap
mber and pe
mber and pe
ified for PF
ified for P
ths and 
hs and isis d
te of death
te of death
st known ti
t known t
n survival t
survival 
hods (the es
ods (the 
and Meier, 
and Meier,
mber and p
mber and p
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indic
will
wil be pro
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analysis is
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An
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1.4.1.
1.4.1.
M
Pha
Pha


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12.
SAFETY ANALYSIS
The purpose of this section is to define the safety parameters for the study. All summaries of 
safety data will be conducted using the Safety Population and will be presented by study phase,
and dose/disease indication. Safety measurements will include AEs, clinical laboratory 
information, vital sign measurements, ECG, left ventricular shortening fraction (LVSF)
assessment, pregnancy status, and deaths. Individual subject listings will be provided to support 
the tables. 
Tables will present data by study phase, specifically by dose level and in aggregate (Phase 1) and 
by disease indication (Phase 2) as well as an aggregate for all subjects across Phases 1 and 2 
treated at the RP2D, and for all subjects included in the Safety Population across Phases 1 and 2.
12.1.
Adverse Events
Adverse events will be analyzed in terms of TEAEs which are defined as any AEs that begin or 
worsen on or after the start of study drug through 28 days after the last dose of study drug. 
Adverse events are documented on the eCRF together with their severity, according to the 
National Cancer Institute (NCI) CTCAE version 4.0, also referred to as NCI toxicity grading. 
For the categorization of the adverse events, the MedDRA Version 20.1 or later will be used and 
TEAEs will be summarized by SOC and PT.
Tables summarizing the incidence of TEAEs will be generated for each of the following:
!
All TEAEs;
!
Treatment-related TEAEs;
!
All TEAEs by cycle of onset;
!
Treatment-related TEAEs by cycle of onset;
!
All TEAEs by maximum NCI CTCAE grade;
!
All TEAEs by dose/disease indication, and maximum NCI CTCAE grade;
!
Treatment-related TEAEs by maximum NCI CTCAE grade;
!
Treatment-related TEAEs by dose/disease indication, and maximum NCI CTCAE 
grade;
!
All TEAEs with NCI CTCAE grade 3 or 4;
!
Treatment-related TEAEs with NCI CTCAE grade 3 or 4;
!
Serious TEAEs; 
!
Treatment-related serious TEAEs;
!
TEAEs leading to discontinuation of the study drug;
!
Treatment-related TEAEs leading to discontinuation of the study drug;
!
TEAEs leading to dose reduction of the study drug;
!
Treatment-related TEAEs leading to dose reduction of the study drug;
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Tre
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!


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
37
!
TEAEs leading to drug interruption of the study drug;
!
Treatment-related TEAEs leading to drug interruption of the study drug;
!
TEAEs leading to death;
!
Treatment-related TEAEs leading to death;
!
All death within 28 days of last dose with cause of death.
The following individual listings will be provided:
!
AE listings by subject;
!
Listing of serious TEAEs;
!
Listing of TEAEs leading to discontinuation of the study drug;
!
Listing of TEAEs with outcome of death.
Dose limiting toxicities will be summarized by dose cohort for Phase 1 only.
The incidence of TEAEs will be summarized by MedDRA SOC and PT. System organ classes will 
be sorted by descending order of frequency, and by alphabetical and then descending order of 
frequency of PT within SOC, according to the overall column.
Relationship of AEs to nab-paclitaxel treatment is documented on the eCRF as well. A 
treatment-related TEAE is defined as a TEAE which was suspected by the investigator to be 
related to the study drug. 
If a subject experiences the same TEAE more than once with different toxicity grade, then the 
event with the highest grade will be tabulated in “by grade” tables. If a subject experiences 
multiple TEAEs under the same PT (or SOC), then the subject will be counted only once for that 
PT (or SOC). In addition, TEAEs with a missing intensity will be presented in the summary table 
as an intensity category of “Missing”.
Treatment emergent adverse events, treatment-related TEAEs, TEAEs of Grade 3 or 4, 
treatment-related TEAEs of Grade 3 or 4, serious TEAEs and treatment-related serious TEAEs 
will also be analyzed within the following age subgroups:
!
Age category (< 2 years, ≥ 2 years to < 12 years, ≥ 12 years to < 18 years, and ≥ 18 years 
to ≤ 24 years [Phase 2 only].
12.2.
Adverse Events of Special Interest
The following AE of interest categories and PTs include, but are not limited to:
!
General myelosuppression;
!
Neutropenia;
!
Anemia;
!
Thrombocytopenia;
!
Peripheral neuropathy;
!
Cranial nerve palsies;
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n once with 
once with
n “by grade
“by grad
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), then the 
missing inte
missing int
s, treatm
treatmen
ade 3 or 4, 
de 3 or 4, 
the fo
the follo
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2 ye
y ars, 
s, ≥ 2
≥
[Phase 2
Phase 2 on
verse Eve
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!
Gener
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!
N
!


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Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
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!
Hypersensitivity reactions;
!
Pneumonitis;
!
Clinically severe infections, specifically sepsis;
!
Gastrointestinal events;
!
Myalgia and arthralgia;
!
Cardiotoxicity, including congestive heart failure/left ventricular dysfunction;
!
Cystoid macular edema;
!
Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN);
!
Infusion site reactions/extravasation;
!
Hepatic toxicity (drug-induced liver injury);
!
Acute renal failure and hemolytic-uremic syndrome;
!
Drug-induced lupus erythematosus;
!
Skin toxicity.
The following summaries will be provided for above-mentioned TEAEs of special interest: 
!
TEAEs;
!
Treatment-related TEAEs;
!
Grade 3 or 4 TEAEs; 
!
Treatment-related Grade 3 or 4 TEAEs;
!
Serious TEAEs; 
!
TEAEs leading to treatment discontinuation;
!
TEAEs leading to dose reduction;
!
TEAEs leading to drug interruption;
!
TEAEs leading to death. 
In addition, the following tables will be presented to further investigate the corresponding 
TEAEs of interest:
!
Time to first occurrence of NCI CTCAE Grade 2 or higher treatment-emergent
peripheral neuropathy;
!
Time to first occurrence of NCI CTCAE Grade 3 or higher treatment-emergent 
neutropenia;
!
Time to first occurrence of NCI CTCAE Grade 2 or higher, and Grade 3 or higher 
treatment-emergent skin toxicity;
!
Time to first occurrence of NCI CTCAE Grade 3 or higher treatment-emergent 
thrombocytopenia;
ed 
ed TE
TEAEs
AE
EAEs
EAEs;
ment discon
ent disco
ose reducti
ose reducti
to drug
o dru int
in
ding to deat
ding to dea
lowing tab
wing tab
est:
st:
Time
Time to fir
to fir
peri
peripher
phe
i
!
Tim
Tim


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Celgene Corporation
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!
Time to improvement of NCI CTCAE Grade 2 or higher treatment-emergent 
peripheral neuropathy to Grade 1 or better.
Listing of subjects with TEAEs of special interest will be provided.
12.3.
Deaths
Deaths will be coded according to MedDRA Version 20.1 or later. 
Tables summarizing the frequency and percentage of deaths by primary cause of death will be 
generated, sorted by descending frequency of primary cause in the overall column, by dose level 
(Phase 1) and disease indication (Phase 2) for each of the following:
!
All deaths;
!
All death during the Treatment Period (defined as deaths from first nab-paclitaxel 
dose date to 28 days after the last dose of nab-paclitaxel);
!
All death after 28 days after end of treatment.
12.4.
The incidence of deaths will be shown in subject listings showing
MedDRA SOC and PT. Dose-limiting Toxicities
The treatment-related DLTs as per NCI CTCAE version 4.0 will be summarized for subjects in 
Phase 1 in the DDS analysis population by dose level.
A subject listing of subjects with DLT in the DDS analysis population will also be provided.
The DLT assessment period will be as follows:
!
For subjects > 10 kg: the first cycle including Cycle 2 Day 1 predose evaluations;
!
For subjects ≤ 10 kg: the first 2cycles including Cycle 3 Day 1 predose evaluations.
A DLT is defined as a nab-paclitaxel-related AE occurring during the DLT assessment period 
that leads to treatment discontinuation or meets one of the following criteria:
!
Grade 3 or 4 nonhematologic toxicity (excluding transient transaminitis);
!
Grade 3 or 4 nausea or vomiting that persists > 5 days despite maximal anti-emetic 
treatment;
!
Grade 4 thrombocytopenia or anemia that persists > 7 days or requires transfusion 
> 7 days;
!
Grade 3 thrombocytopenia with bleeding;
!
Grade 4 uncomplicated neutropenia lasting > 7 days;
!
Febrile neutropenia with confirmed bacterial infection;
!
Grade 3 hematologic toxicity requiring treatment delay > 21 days.
12.5.
Pregnancies
Listings of subjects with data from the “Pregnancy Status Female Child Bearing Potential (FCBP)” 
and “Pregnancy Status Pregnancy Test” eCRF pages will be provided.
&(/*(1(35235,(7$5<,1)250$7,21
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cycles inc
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tion or me
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ematologic
ematologic
ausea or vo
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4 thromboc
4 thromboc
days
days;
Grade 3 th
Grade 3 th
!
Grade
Grade
!
Fe
Fe
!


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Celgene Corporation
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12.6.
Clinical Laboratory Evaluations
Clinical laboratory values from local laboratories will be graded per NCI CTCAE (version 4.0, 
May 2009) or later for applicable tests. Clinical laboratory values will be summarized by dose 
level (Phase 1) and disease indication (Phase 2).
Laboratory results by visit and change from baseline will be summarized using descriptive 
statistics. Maximum postbaseline values, minimum postbaseline values, and corresponding 
change from baseline will be summarized as well. Additionally, the worst result observed across 
all unscheduled visit samples taken while the subject is receiving nab-paclitaxel treatment up to 
28 days post last nab-paclitaxel dose, will be summarized and presented under the time visit 
‘Unscheduled’, after each planned cycle visit and end of treatment visit.
Baseline grade and worst grade during the Treatment Period for each gradable laboratory 
parameter will be summarized.
Frequency distributions for shift from baseline to the worst grade during the Treatment Period will 
be presented by dose level (Phase 1) and disease indication (Phase 2).
Normal ranges will be used to determine the categories of high, low, and normal for lab tests that 
have no severity grade. 
Listings of clinical laboratory data from local laboratories with abnormal flags will be provided by 
subject and tests.
12.6.1.
Hematology
The following parameters will be reported for this study:
!
Hemoglobin (g/L);
!
White blood cell (WBC) count (109/L);
!
Platelets count (109/L);
!
Neutrophils (109/L or %);
!
Lymphocytes (109/L or %).
In case of differential counts of white blood cells (ie, neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils) reported in percentage of WBC, a conversion rule will be applied to 
report these differential counts in absolute count (109/L).
To investigate the worst grade, the NCI-CTCAE grade for absolute neutrophil count (ANC), 
absolute lymphocyte count, WBC count, platelet count, and hemoglobin will be derived.
12.6.2.
Clinical Chemistry
The following parameters will be reported for this study:
!
Sodium (mmol/L);
!
Potassium (mmol/L);
!
Calcium (mmol/L);
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The follo
llow


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
41
!
Phosphorus (mmol/L);
!
Creatinine (μmol/L);
!
Uric acid (μmol/L);
!
Glucose (mmol/L);
!
Alkaline phosphatase (U/L);
!
Alanine aminotransferase (ALT; SGPT) (U/L) ;
!
Aspartate aminotransferase (AST; SGOT) (U/L);
!
Total bilirubin (μmol/L).
To investigate the worst grade, the NCI CTCAE grade for sodium (hypo/hypernatremia), 
potassium 
(hypo/hyperkalemia), 
calcium 
(hypo/ 
hypercalcemia), 
magnesium 
(hypo/ 
hypermagnesemia), phosphorus (hypophosphatemia), uric acid (hyperuricemia), glucose (hypo/ 
hyperglycemia), albumin (hypoalbuminemia), alkaline phosphatase, ALT (SGPT), AST (SGOT), 
total bilirubin, and creatinine will be derived. 
Nongradable hematology and clinical chemistry parameters will be compared with the relevant 
laboratory ranges in SI units (Gregory's Pediatric Anesthesia, 2012) and categorized as:
!
Low: Below the lower limit of the laboratory reference range;
!
Normal: Within the laboratory reference range (upper and lower limit included);
!
High: Above the upper limit of the laboratory reference range.
12.6.3.
Urinalysis
Neuroblastoma subject will have urinalysis laboratory samples taken and the parameters 
(homovanillic acid and vanillylmandelic acid) presented in listings.
12.7.
Vital Sign Measurements
Vital sign values by visit and change from baseline will be summarized using descriptive
statistics (n, mean, SD, median, min, and max). Maximum postbaseline values, minimum 
postbaseline values, and corresponding change from baseline will be summarized. Shift tables 
demonstrating the changes (low/normal/high) from baseline to worst postbaseline will be 
displayed in cross-tabulations.
Individual subject listings will be provided to support the summary tables.
Temperature in Fahrenheit will be converted to Celsius with the following formula:
!
Temperature in Celsius = (temperature in Fahrenheit – 32) * 5/9;
For each vital sign parameter, the baseline grade and the worst grade postbaseline will be 
determined for each subject classified in below, within, and above the normal ranges. Subjects 
may show both with normal and missing results for the vital sign, provided no abnormal (low or 
high) results will be reported. Low and high categories will be presented separately. Normal 
ranges are reported in Table 3.
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
42
Table 3:
Normal Range of Vital Sign Measurements
Test
Age Group (years) a
Normal Range (Unit)
Diastolic Blood Pressure
< 2
[34,66] (mmHg)
2-5
[34,74] (mmHg)
6-8
[35,80] (mmHg)
9-13
[37,87] (mmHg)
14-16
[40,91] (mmHg)
≥17
[40,89] (mmHg)
Systolic Blood Pressure
< 2
[58,112] (mmHg)
2-5
[60,125] (mmHg)
6-8
[65,131] (mmHg)
9-13
[68,141] (mmHg)
14-16
[76,153] (mmHg)
≥17
[70,139] (mmHg)
Pulse Rate
1-2
[95, 178] (bpm)
3-7
[62, 124] (bpm)
8-15
[48, 110] (bpm)
≥16
[60, 100] (bpm)
Temperature
All
[35, 38] (°C)
a Years reached at the time of the assessment.
12.8.
Electrocardiograms
Electrocardiogram observed values (local review) and change from baseline will be summarized 
by predetermined schedule of ECG evaluation using descriptive statistics. Postbaseline abnormal 
corrected QT (QTc) interval (both QTcF and QTcB) values by local review will be summarized 
using frequency tabulations for the following 5 categories separately: QTc > 450 msec; 
QTc > 480 msec; QTc > 500 msec; QTc increase from baseline > 30 msec; QTc increase from 
baseline > 60 msec. 
The overall ECG interpretation will be summarized using the number and percentage of subjects
with ‘Normal’, ‘Abnormal, not clinically significant’ and ‘Abnormal, clinically significant’ by 
predetermined schedule of ECG evaluation. Shift from baseline to the worst postbaseline in the 
overall ECG interpretation (‘Normal’, ‘Abnormal, not clinically significant’ and ‘Abnormal, 
clinically significant’) will be displayed in cross–tabulations, using investigator interpretation.
Listings of ECG data will be provided.
12.9.
Left Ventricular Shortening Fraction Assessment
Left ventricular shortening fraction (LVSF) (echocardiogram [ECHO] or multi-gated acquisition
[MUGA] scan) values by predetermined schedule of LVSF evaluation and change from baseline 
will be summarized using descriptive statistics. Shift from baseline to worst postbaseline in the 
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&
12.9.
12
t


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Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
43
overall LVSF interpretation (‘Normal’, ‘Abnormal, not clinically significant’ and ‘Abnormal, 
clinically significant’) will be displayed in cross–tabulations for each dose/disease indication.
Listings of LVSF data will be provided.
12.10.
Survival
Listings of subjects with data from “Survival” and "Survival Information" eCRF pages will be 
provided.
12.11.
Lansky/ Karnofsky Performance status
Performance status will be measured using the Karnofsky (Karnofsky, 1948) or Lansky (Lanksy, 
1987) performance status score, whichever is the most applicable for the subject. Performance 
status by cycle and change from baseline will be summarized using descriptive statistics.
Maximum postbaseline values, minimum postbaseline values, and corresponding change from
baseline during the treatment period will be summarized for the Safety Population. Lansky and 
Karnofsky performance status will be presented both separately and combined. A listing of 
performance status will be provided.
12.12.
Other Safety Assessments
Data collected for other safety assessments, including chest x-ray, will be listed.
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Celgene Corporation
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13.
PHARMACOKINETIC ANALYSIS
The PK population will be used for all PK analysis tables and figures. 
13.1.
Pharmacokinetic Sampling
Pharmacokinetic blood samples will be collected for the first dose (Cycle 1 Day 1) from all 
subjects in both Phase 1 and Phase 2 of the study to analyze paclitaxel concentrations in plasma. 
Samples will be collected from all subjects enrolled in Phase 1 of the study using a dense PK 
sampling strategy as specified in Table 4.
Samples will be collected from all remaining subjects enrolled in the study using a sparse PK 
sampling strategy as specified in Table 5, or if optionally consented using a dense PK sampling 
strategy. 
Table 4:
Dense Pharmacokinetic Sampling 
Sample 
Number
Sample Time (hours)
Subjects ≥ 6 
Years Old
Subjects < 6 
Years Old
1
1-2 minutes prior to the end of infusion (no window, must 
be collected before end of infusion)
X
X
2
15 minutes after end of infusion (± 5 minutes)
X
X
3
1 hour after end of infusion (± 5 minutes)
X
4
3 hours after end of infusion (± 10 minutes)
X
X
5
5 hours after end of infusion (± 10 minutes)
X
X
6
8 hours after end of infusion (± 1 hour, recommended
a)
X
7
24 hours after end of infusion
b (± 3 hours)
X
X
8
48 hours after end of infusion
c (± 3 hours)
X
9
72 hours after end of infusion
d (± 3 hours, recommended
e)
X
a Recommended sample at 8 hours after infusion should be performed in any site where the subject can remain to 
have the sample drawn. Subjects who are being treated as an out-patient may omit this sample.
b 24- hour sample may occur on study Day 2, depending on the timing.
c 48-hour sample may occur on study Day 3, depending on the timing.
d 72-hour sample may occur on study Day 4, depending on the timing.
e Recommended sample at 72 hours after infusion should be performed in subjects who live close enough to the 
center to return on the third day. Subjects living far from the center may omit this sample.
Table 5:
Sparse Pharmacokinetic Sampling
Sample Number
Sample Time (hours)
Subjects ≥ 6 
Years Old
Subjects < 6 
Years Old
1
15 minutes after end of infusion (± 5 min)
X
X
2
3 hours after end of infusion (± 10 minutes)
X
X
3
24 hours after end of infusion (± 3 hours)
a
X
X
a 24-hour sample may occur on study Day 2 depending on the timing.
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h


nab®-paclitaxel 
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Celgene Corporation
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13.2.
Handling of nab-paclitaxel Concentration Data
Predose concentrations that are below the limit of quantitation (BLQ) or missing will be assigned 
a numerical value of zero for PK analysis. Postdose concentrations that are BLQ and occur 
before the first quantifiable concentration will also be treated as zero for PK analysis. Postdose 
concentrations that are BLQ but occur after the first quantifiable concentration will be treated as 
missing for PK analysis.
Concentrations assigned a value of missing will be omitted from the calculation of descriptive 
statistics. A concentration value of zero will be excluded from the computation of geometric 
coefficient of variation mean (geometric CV%). Aberrant concentration data will be excluded 
from PK analysis and summary statistics but they will be included in the concentration listing. 
In tables and listings for the derived PK data, there should be 4 decimal places for numerical 
values below 1, 3 decimal places for numeric values below 10 but above 1, and 2 decimal places 
for numeric values above 10. However, the listings of raw data should not have more decimal 
places than the actual data.
13.3.
Noncompartmental Pharmacokinetic Parameters
Noncompartmental PK analysis will be performed using the plasma concentration versus time 
data obtained from subjects participating in dense PK sampling. Actual sampling times will be 
used in the calculations of nab-paclitaxel PK parameters.
The following noncompartmental PK parameters will be included, but not limited to:    
!
λz: terminal phase rate constant, determined by linear regression of the terminal 
portion of the log-concentration versus time curve in plasma. Visual assessment may 
be used to identify the terminal linear phase of the concentration versus time profile.  
A minimum of 3 data points will be used for calculation. #z will not be estimated if 
the terminal phase of the log-concentration versus time profile does not exhibit a 
linear decline phase or has a regression coefficient (Rsq) < 0.8;
!
AUCt: area under the plasma concentration-time curve from time zero to the last 
quantifiable time point, calculated by the linear trapezoidal rule;
!
AUC24: area under the plasma concentration-time curve from time zero to 24 hours, 
calculated by the linear trapezoidal rule;
!
AUC∞: area under the plasma concentration-time curve from time zero extrapolated 
to infinity, calculated as [AUCt + Ct/λz], where Ct is the last quantifiable 
concentration;
!
Cmax: maximum observed plasma concentration, obtained directly from the observed 
concentration versus time data;
!
tmax: time to Cmax, obtained directly from the observed concentration versus time data;
!
t½: terminal phase half-life, calculated as [0.693/λz];
!
CL: total clearance, calculated as [Dose/AUC∞];
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!
Vss: volume of distribution at the steady state, calculated as [MRT∞*CL], where 
MRT∞is the mean residence time extrapolated to infinity;
!
Vz: volume of distribution based on the terminal phase, calculated as [CL/λz].
The following PK parameters will be calculated for diagnostic purposes and listed, but they will 
not be summarized:
!
#z lower: Lower limit of time (h) included in the calculation of #z;
!
#z N: Number of data points used in the calculation of #z;
!
#z upper: Upper limit of time (h) included in the calculation of #z;
!
Rsq: Regression coefficient for calculation of #z;
!
AUC %Extrap: Percentage of AUC∞due to extrapolation from the last quantifiable 
time point to infinity.
Additional PK parameters may be determined when appropriate.
13.4.
Population Pharmacokinetic Analysis
Population PK analysis will be performed using nonlinear mixed effect modeling. Concentration 
data obtained from both dense and sparse PK sampling will be combined to develop the 
population PK model. Effect of age and body size on nab-paclitaxel PK will be assessed. Other 
relevant covariates for the main PK parameters will also be identified. The between-subject
variability for PK parameters will be estimated, as appropriate. The relationship between 
systemic drug exposure and selected efficacy and toxicity endpoints may be explored.
13.5.
Statistical Analysis
Plasma concentrations from nab-paclitaxel will be listed and summarized by nominal time and 
cohort using descriptive statistics (n, mean, SD, CV%, geometric mean, geometric CV%, median, 
min, and max).
Noncompartmental PK parameters from nab-paclitaxel will be listed and summarized by cohort
using descriptive statistics (n, mean, SD, CV%, geometric mean, geometric CV%, median, min, 
and max).
If data allow, select PK parameters (CL and Vss) will be summarized by age group as appropriate 
(eg, < 2 years, 2 to < 6 years, 6 to < 12 years, and 12 to ≤ 24 years). 
Mean and individual plots of plasma concentrations will be presented in both original and semi-
logarithmic scales.
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14.
QUALITY OF LIFE ANALYSIS
Not applicable for this study.
&(/*(1(35235,(7$5<,1)250$7,21


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15.
INTERIM ANALYSIS
In Phase 2, Simon’s Minimax Two-stage design will be employed per disease indication with 
each incorporating the following parameters: 5% significance level, 80% power and an upper 
and lower boundary of interest of 10% and 28%, respectively, for the ORR. Each of the disease 
indications will therefore enroll up to 23 efficacy evaluable subjects across Phase 2 (14 subjects
in stage one and an additional 9 subjects in stage two) meaning a maximum total of 69 subjects
evaluable for the primary endpoint.
For purposes of the primary endpoint analysis, the ORR is defined using the maximum 
likelihood estimator.
For each of the 3 groups in stage one, if < 2 of the 14 evaluable subjects have a response, then 
enrollment into that disease indication group will be stopped; otherwise enrollment shall
continue as planned in stage two.
No formal production of tables or listings is required for the interim analysis go/no-go decision 
regarding continuation into stage two for any of the 3 disease indications.
&(/*(1(35235,(7$5<,1)250$7,21
nse, then
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shall
s go/no
s go/no-go 
go


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16.
TOP-LINE AND CLOSE OF STUDY FINAL ANALYSIS
The top-line analysis will only be conducted once the last subject to discontinue treatment, 
regardless of disease indication, has completed their 28-day follow-up visit. The date the last 
subject’s 28-day follow-up visit occurs will become the earliest cut-off date upon which all 
TLGs will be produced and based, and used for production of the clinical study report (CSR).
The close of study analysis will be conducted once the last subject to discontinue from the study 
/complete the study has done so. At the maximum, the final analysis will take place 
approximately 1 year after the last subject to discontinue study treatment has done so, i.e. 1 year 
after the last subjects last dose date. All TLGs associated with data collected during the follow-
up period will be rerun at this time.
&(/*(1(35235,(7$5<,1)250$7,21
ear r
low-


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17.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
In the protocol, the EE Population is defined, partly, as “all treated subjects who meet eligibility 
criteria”. This has been modified to “all treated subjects who meet eligibility criteria relevant to 
efficacy”. Subjects found to have failed to meet eligibility likely to affect efficacy will be 
identified and logged in the protocol deviation/violation tracker.
&(/*(1(35235,(7$5<,1)250$7,21


nab®-paclitaxel 
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REFERENCES
Brookmeyer R and Crowley J. A confidence interval for the median survival time. Biometrics
1982;38:29-41.
Kaplan E L and Meier P. Nonparametric estimation from incomplete observations. Journal of the 
American Statistical Association 1958;53(282):457-481.
Karnofsky D, Abelman W, Craver L, Burchenal J. The use of nitrogen mustards in the palliative 
treatment of carcinoma. Cancer 1948;1:634-56.
Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR. The measurement of performance in 
childhood cancer patients. Cancer 1987;60(7):1651-6.
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mance in
ance in


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APPENDIX A1 – CONVENTIONS RELATED TO DATES
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1. Handling of Dates
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (ie, the Date9. date format in SAS). Dates in the clinical database are 
classified into the categories of procedure dates, log dates, milestone dates, outcome dates, and 
special dates.
!
Procedure Dates are the dates on which given protocol-specified procedures are 
performed. They include the dates of laboratory testing, physical examinations, tumor 
scans, etc. They should be present whenever data for a protocol-specified procedure 
are present and should only be missing when a procedure is marked as NOT DONE 
in the database. Procedure dates will not be imputed.
!
Log Dates are dates recorded in CRF data logs. Specifically, they are the start and 
end dates for adverse events and concomitant medications/procedures. They should 
not be missing unless an event or medication is marked as ongoing in the database. 
Otherwise, incomplete log dates will be imputed according to the rules in Appendix
A1, Section 3 (eg, for duration or cycle assignment, etc.). However, in listings, log 
dates will be shown as recorded without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study drug termination date, study closure date, etc.. They should not be 
missing if the milestone occurs for a subject. They will not be imputed.
!
Outcome Dates are dates corresponding to study endpoints such as survival, 
progression, etc. In most cases, they are derived either from a milestone (eg, the 
survival date is derived from the death date), or a procedure date (eg, the progression 
date is derived from the date of the tumor scan that was used to determine 
progression). They may be subject to endpoint-specific censoring rules if the outcome 
did not occur, but are not otherwise subject to imputation.
!
Special Dates cannot be classified in any of the above categories and they include the 
date of birth. They may be subject to variable-specific censoring and imputation rules. 
!
Last Contact Dates for the survival analysis is the maximum date collected in the 
database, if the imputed date used for response date or AE date, the last contact dates 
should be the latest date of those imputed date and maximum date in the database.
Dates recorded in comment fields will not be imputed or reported in any specific format. 
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n comment
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2. Calculation Using Dates
Calculations using dates (eg, subject’s age or relative day after the first dose of study drug) will 
adhere to the following conventions: 
!
Study days after the start day of study drug will be calculated as the difference 
between the date of interest and the first date of dosing of study drug plus 1 day. For 
subjects who are not treated, the Cycle 1 Day 1 will be defined as Day 1. The 
generalized calculation algorithm for relative day is the following: 
o
If TARGET DATE >= DSTART then STUDY DAY = (TARGET DATE –
DSTART) + 1; 
o
Else use STUDY DAY = TARGET DATE – DSTART.
Note that Study Day 1 is the first day of treatment of study drug or Cycle 1 Day 1 for 
subjects who are not treated. Negative study days are reflective of observations 
obtained during the baseline/screening period. Note: Partial dates for the first study 
drug are not imputed in general. All effort should be made to avoid incomplete study 
drug start dates. 
!
Age (expressed in days) is calculated: AGE = CONSENT/ASSENT DATE – DATE 
of BIRTH + 1. In practice, age will be transformed to years by dividing the difference 
by 365.25 days, then truncating.
∃
Preference is for using calculated age from clinical database. When not available, 
calculated age from CRF or interactive voice recognition system (IVRS) may be 
used
∃
Partial birth date: impute missing day as 15th of the month; impute missing month 
as July; set missing age for missing year
!
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS /7
!
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
MONTHS = DAYS /30.4375
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ONTHS = D
NTHS = 


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
55
3. Guideline of Missing Date Imputation
3.1 Impute Missing Adverse Events/ Prior or Concomitant Medications 
A. Incomplete Start Date:
If the stop date is not missing, and the imputed start date is after the stop date, the start date will 
be imputed by the stop date. 
Missing day and month
!
If the year is the same as the year of the first dosing date, then the day and month of 
the first dosing date will be assigned to the missing fields.
!
If the year is prior to the year of first dosing date, then December 31 will be assigned 
to the missing fields.
!
If the year is after the year of first dosing, then January 1 will be assigned to the 
missing fields.
Missing day only 
!
If the month and year are the same as the year and month of first dosing date, then the 
first doing date will be assigned to the missing day.
!
If either the year of the partial date is before the year of the first dosing date or the 
years of the partial date and the first dosing date are the same but the month of partial 
date is before the month of the first dosing date, then the last day of the month will be 
assigned to the missing day.
!
If either the year of the partial date is after the year of the first dosing date or the 
years of the partial date and the first dose date are the same but the month of partial 
date is after the month of the first dosing date, then the first day of the month will be 
assigned to the missing day.
!
If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date, i.e. set to the stop date. 
Missing day, month, and year
!
No imputation is needed; the corresponding AE will be included as TEAE provided 
the end date of the AE is after the first dose date or the end date is also missing. 
B. Incomplete End Date:
If the imputed stop date is before the start date, then the imputed stop date will be equal to the 
start date.
Missing day and month
!
If the year of the incomplete stop date is the same as the year of the last dosing date, 
then the day and month of the last dosing date will be assigned to the missing fields. 
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nth of 
will be assig
ill be assi
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e assigned
mo
montnth of fi
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date.
Missing da
Missing da


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
56
!
If the year of the incomplete stop date is prior to the year of the last dosing date or 
prior to the year of the first dosing date, then December 31 will be assigned to the 
missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dosing date but 
is the same as the year of the first dosing date, then the first dosing date will be 
assigned to the missing date. 
!
If the year of the incomplete stop date is after the year of the last dosing date, then 
January 1 will be assigned to the missing fields.
Missing day only 
!
If the month and year of the incomplete stop date are the same as the month and year 
of the last dosing date, then the day of the last dosing date will be assigned to the 
missing day. 
!
If either the year of the partial date is not equal to the year of the last dosing date or 
the years of the partial date and the last dosing date are the same but the month of 
partial date is not equal to the month of the last dosing date, then the last day of the 
month will be assigned to the missing day. 
3.2 Prior/Concomitant Procedures
Prior/concomitant procedures are defined as surgeries and transplants such as stem-cell 
transplants.
Partially missing start/stop dates for prior/concomitant procedures will be imputed in the analysis 
dataset for prior/concomitant procedures. If the stop date is complete with no missing year, 
month, or day, and the partially missing start date imputed by the rule below is after the stop 
date, then the start date will be imputed by the stop date.
Partially missing prior/concomitant procedure start dates will be imputed by the earliest possible 
date given the non-missing field(s) of the date.
Partially missing prior/concomitant procedure stop dates will be imputed by the latest possible 
date given the non-missing field(s) of the date.
3.3 Medical History
Partially missing medical history start dates will be imputed in the derived dataset for medical 
history. The 16th of the month will be used to impute a partially missing start date that has only 
the day missing, and July 1st will be used to impute a partially missing start date that has both the 
month and day missing. Should the imputed date equal or exceed the informed consent/assent 
date, the imputed medical history date will be set to 1 day prior to the informed consent/assent 
date.
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nth and y
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he
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same but th
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date, then th
te, then th
and transpl
and transpl
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tart date im
art date im
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procedure
d(s) of the d
d(s) of the d
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date.


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
57
3.4 Imputing Missing Disease Progression Date
If the day of the disease progression is missing, then the first day of the non-missing month will 
be assigned to the missing day; if the month or year of the missing date is missing, then the date 
will not be imputed and treated as missing. 
3.5 Imputing Missing Dates for Prior Therapies
Prior therapies are defined as prior radiation therapies, prior systemic anticancer therapies, and 
other prior anticancer therapies. Should the imputed date equal or exceed the informed 
consent/assent date, the imputed start date will be set to 2 days prior to the informed 
consent/assent date, while the imputed end date will be set to 1 day prior to the informed 
consent/assent date.
A. Incomplete Start Date:
If the start day of any prior therapy date is missing, then the first day of the non-missing month 
will be assigned to the missing day; if month or year of the missing date is missing, then the date 
will not be imputed and treated as missing.
B. Incomplete End Date:
Incomplete date of end of last therapy will be imputed using the following rule: If missing day, 
impute 15th day of the month; if missing month, impute missing month as middle month (or the 
earlier month of two month if two months tie) between therapy start month and month of cycle 1 
day 1. Should the imputed date be within 21 days of cycle 1 day 1, then the imputed date will be 
re-set to the 22nd day before cycle 1 day 1. 
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non
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missing mo
therapy
therapy sta
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f cycle 1 da
f cycle 1 d


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
58
APPENDIX A2 – SCHEDULE OF ASSESSMENTS
The Table of Events is applicable to both Phase 1 and Phase 2 of the study.
Events
Screening 
Period
Treatment Period
Screening
Cycle 1
Subsequent Cycles
Follow-up Period
Day
a
-14 to -1
1
2
3
4
8
15
1
8
15
EOT
28-day 
Safety 
Visit
b
Disease 
Progression/ 
Survival
STUDY ENTRY
Informed consent and if applicable assent
X
Prior cancer history
X
Prior cancer therapies
c
X
Complete medical history
X
Demographics
X
Prior/ concomitant medication evaluation
X (-28 from 
screening)
Continuous, until 28 days after treatment discontinuation
Prior/ concomitant procedures evaluation
X (-28 from 
screening)
Continuous, until 28 days after treatment discontinuation
Inclusion/exclusion criteria
X
IRT registration
X
Archival tumor tissue collection (optional)
X, after eligibility confirmation
SAFETY ASSESSMENTS
Adverse event evaluation
Continuous starting after informed consent/assent signature, until 28 days after treatment 
discontinuation (and as noted in protocol Section 6.2.1.1)
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23
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523
52
52
52
352
X, after eligib
X, after elig
35
35
35
3
Continuous
Continuo
( 3
1


nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
59
Events
Screening 
Period
Treatment Period
Screening
Cycle 1
Subsequent Cycles
Follow-up Period
Day
a
-14 to -1
1
2
3
4
8
15
1
8
15
EOT
28-day 
Safety 
Visit
b
Disease 
Progression/ 
Survival
Physical examination (source documented 
only)
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
Body surface area calculation
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
X
X
Hematology laboratory
X
X
X
X
X
X
X
X
X
Chemistry laboratorye
X
X
X
X
X
Urine homovanillic acid and 
vanillylmandelic acid (for neuroblastoma 
only)
X
Every other 
cycle, 
starting in 
Cycle 2
X
X
LVSF assessment by echocardiogram/ 
MUGA/ other medically appropriate 
method 
X
Every other 
cycle 
starting in 
Cycle 3
X
12-lead electrocardiogram
X
Every other 
cycle 
starting in 
Cycle 3
X
Serum β-hCG (if indicated)f
X
As clinically indicated
Urine β-hCG (if indicated)f
X
As clinically indicated
X
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
60
Events
Screening 
Period
Treatment Period
Screening
Cycle 1
Subsequent Cycles
Follow-up Period
Day
a
-14 to -1
1
2
3
4
8
15
1
8
15
EOT
28-day 
Safety 
Visit
b
Disease 
Progression/ 
Survival
Pharmacokinetic samplesg
X
X
X
X
EFFICACY ASSESSMENTS
Tumor evaluation (CT/MRI, see protocol
Section 6.3)
X (-28 to -1)
Every 8 weeks (± 5 days) from Cycle 1 Day 1, until progression or new anticancer treatment
MIBG scan (in subjects with 
neuroblastoma)
X (-28 to -1)
If assessable by MIBG scan at screening, every 8 weeks (± 5 days) from Cycle 1 Day 1, until 
disease progression or new anticancer treatment. If not assessable by MIBG scan, at screening 
and suspected progression only.
Bone marrow biopsy (in subjects with 
neuroblastoma)
Only at confirmation of complete response
Lansky performance status (in subjects
< 12 years old)
X
X
X
X
X
Karnofsky performance status (in subjects
≥ 12 years old)
X
X
X
X
X
INVESTIGATIONAL PRODUCT (IP)
Administer nab-paclitaxel
X
X
X
X
X
X
FOLLOW-UP
Survival follow-up
Every 1 month 
for 1 year
Anticancer therapy since nab-paclitaxel
discontinuation
X
At every 
survival follow-
up visit for 
1 year
β-hCG = β human chorionic gonadotropin, C#D# = Cycle number Day number, CR= complete response, CT = computed tomography scan, EOT = end of 
treatment visit, IRT = Integrated Response Technology, LVSF = left ventricular shortening fraction, MIBG = 123I-metaiodobenzylguanidine scan, MRI = 
magnetic resonance imaging, MUGA = multi-gated acquisition scan.
a An administrative window of ± 2 days is permitted for all visits except C1D1.
b If the EOT visit occurs within 7 days of the 28-day safety visit, laboratory evaluations only need to be repeated for abnormal parameters at the EOT visit.
c Prior cancer therapies includes surgery, radiation, stem cell transplant, systemic or any other therapy for the subject’s cancer.
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nab®-paclitaxel 
Statistical Analysis Plan. Protocol ABI-007-PST-001
Celgene Corporation
Confidential and Proprietary
61
d Vital sign measurements must be recorded in the database at screening and EOT only, and kept in the source documents at all other visits. However, if an 
abnormal (out of range) value is reported at a given visit, that parameter should be collected in the case report form (CRF) at every subsequent scheduled visit 
until it returns to normal.  
e In subjects with neuroblastoma ferritin will be analyzed.
f For all female subjects of childbearing potential (see protocol Inclusion 8), a serum pregnancy test will be done at screening. A urine pregnancy test will be 
repeated within 72 hours before first treatment if the serum pregnancy test occurred > 72 hours before dosing, and at EOT. Pregnancy tests conducted after 
screening will be recorded in the source documentation only.
g All subjects will have pharmacokinetic samples taken on C1D1. A subset of subjects will have samples taken on C1D2, C1D3, and C1D4 as described in 
protocol Section 6.4.
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C1D3, and