Clinical trial NCT02643420
Conditions: Neutropenia Breast Cancer
Keywords: Neutropenia Breast Cancer Long-acting Myeloid Growth Factor Early Stage Breast Cancer Docetaxel + Cyclophosphamide (TC) chemotherapy
Sponsor: Spectrum Pharmaceuticals, Inc
Start date: 2016-01-19; Completion date: 2018-10-31
Enrollment: 406 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to compare the efficacy of a single dose of SPI-2012 versus pegfilgrastim in participants with early-stage breast cancer receiving docetaxel and cyclophosphamide (TC), as measured by the duration of severe neutropenia (DSN) in Cycle 1.

Detailed description:
This was a Phase 3, randomized, open-label, active-controlled, multicenter study to compare the efficacy and safety of SPI-2012 vs pegfilgrastim in participants with breast cancer treated with TC chemotherapy.

Each cycle was 21 days. Four cycles were evaluated in this study. On Day 1 of each cycle, participants received TC chemotherapy. On Day 2 of each cycle, participants received study drug (SPI-2012 or pegfilgrastim).

Arms: arm 1: Participants received SPI-2012 13.2 milligram (mg)/0.6 milliliter (mL) (3.6 mg Granulocyte Colony-Stimulating Factor \[G-CSF\]) fixed-dose subcutaneous (SC) injection once per cycle on Day 2 of each cycle up to Cycle 4 (each cycle was 21 days), approximately 24-26 hours after TC chemotherapy administration. TC chemotherapy was administered on Day 1 of each cycle and included Docetaxel 75 mg/m\^2 intravenous (IV) infusion and Cyclophosphamide 600 mg/m\^2 IV infusion per institute's standard of care. arm 2: Participants received pegfilgrastim 6 mg SC injection once per cycle on Day 2 of each cycle up to Cycle 4 (each cycle was 21 days), approximately 24-26 hours after TC chemotherapy administration. TC chemotherapy on Day 1 of each cycle included Docetaxel 75 mg/m\^2 IV infusion and Cyclophosphamide 600 mg/m\^2 IV infusion per institute's standard of care.
Interventions: intervention 1: SPI-2012 intervention 2: Pegfilgrastim intervention 3: Docetaxel intervention 4: Cyclophosphamide
Intervention descriptions: intervention 1: Single-use syringes for subcutaneous injection, administered on Day 2 of each cycle intervention 2: Single-dose subcutaneous injection administered on Day 2 of each cycle intervention 3: Standard therapy intervention 4: Standard therapy

Protocol documents:
Prot_000.pdf: 
Official Title: 
NCT Number: 
Document Date: 
RAnDomized Trial of SPI-2012 Versus Pegfilgrastim in the Management of 
Chemotherapy Induced Neutropenia in Breast CANCEr Patients Receiving 
Docetaxel and Cyclophosphamide (TC) (ADVANCE)
NCT02643420 
Amendment 1: 26 Jan 2017 












Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
SPI-2012 (HM10460A) 
Protocol Number: SPI-GCF-301 
Amendment 1/26 Jan 2017 
Confidential 
1 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
TITLE PAGE 
Study Title:  
RAnDomized Trial of SPI-2012 Versus Pegfilgrastim in the 
Management of Chemotherapy Induced Neutropenia in Breast 
CANCEr Patients Receiving Docetaxel and Cyclophosphamide 
(TC) (ADVANCE) 
Study Number: 
SPI-GCF-301 
Study Phase: 
Phase 3 
Study Drug: 
SPI-2012 (Rolontis™, eflapegrastim, HM10460A, LAPS-G-CSF) 
IND Number: 
103,461 
Sponsor: 
Spectrum Pharmaceuticals, Inc.  
157 Technology Drive 
Irvine, CA, USA 
 
Protocol Version/Date: 
Amendment 1/26 Jan 2017 
 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
Confidentiality Statement 
The information contained in this document, particularly unpublished data, is the property or 
under control of Spectrum Pharmaceuticals, Inc. and is provided to you in confidence as an 
Investigator, potential Investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Board/Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Spectrum Pharmaceuticals, Inc. except to the extent necessary to obtain Informed Consent from 
those persons to whom the drug may be administered. 
 
 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
SPI-2012 (HM10460A) 
Protocol Number: SPI-GCF-301 
Amendment 1/26 Jan 2017 
Confidential 
2 
INVESTIGATOR SIGNATURE  
 
Protocol Number: SPI-GCF-301 
RAnDomized Trial of SPI-2012 Versus Pegfilgrastim in the Management of Chemotherapy 
Induced Neutropenia in Breast CANCEr Patients Receiving Docetaxel and 
Cyclophosphamide (TC) (ADVANCE) 
I have read this protocol and agree that it contains all the necessary details for performing the 
study in accordance with the Declaration of Helsinki and the International Conference on 
Harmonization (ICH) for Good Clinical Practice (GCP). 
I will provide copies of the protocol and of the clinical and preclinical information on the 
investigational product, which was furnished to me by the Sponsor (Spectrum Pharmaceuticals, 
Inc.), to all members of the study team responsible to me who participate in the study. I will 
discuss this material with them to assure that they are fully informed regarding the study drug 
and the conduct of the study. 
I will perform the study according to specifications outlined in the protocol and agree to 
implement protocol requirements only after the protocol and patient information/Informed 
Consent form have been approved by the Institutional Review Board/Ethics Committee 
(IRB/EC). I will submit any protocol modifications (amendments) and/or any Informed Consent 
form modifications to the IRB/EC, and approval will be obtained before any modifications are 
implemented. 
I understand that the information presented in this study protocol is confidential, and I hereby 
assure that no information based on the conduct of the study will be released without prior 
consent from Spectrum Pharmaceuticals, Inc., unless this requirement is superseded by a 
regulatory authority (eg, FDA). 
 
__________________________________ 
Investigator Name (PLEASE PRINT):  
 
Signature: ________________________________ Date ______________  
 
 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
SPI-2012 (HM10460A) 
Protocol Number: SPI-GCF-301 
Amendment 1/26 Jan 2017 
Confidential 
3 
SYNOPSIS  
Title of Study: Randomized Trial of SPI-2012 Versus Pegfilgrastim in the Management of Chemotherapy 
Induced Neutropenia in Breast Cancer Patients Receiving Docetaxel and Cyclophosphamide (TC) (ADVANCE) 
Name of Sponsor: Spectrum Pharmaceuticals, Inc. 
Name of Investigational Product: SPI-2012 (Rolontis™, eflapegrastim, HM10460A, LAPS-G-CSF) 
Planned Number of Patients: Approximately 400 patients 
Study Centers: Approximately 150 study centers 
Duration of Study: Approximately 34 months with 22 months for 
enrollment and treatment and 12 months for safety follow-up.  
Clinical Phase: 3 
Objectives:  
Primary Objective: 
To compare the efficacy of a single dose of SPI-2012 with pegfilgrastim in patients with early-stage breast 
cancer receiving docetaxel and cyclophosphamide (TC), as measured by the Duration of Severe Neutropenia 
(DSN) in Cycle 1 
Key Secondary Objectives: 
 
To compare SPI-2012 with pegfilgrastim in: 
1. Time to Absolute Neutrophil Count (ANC) Recovery in Cycle 1 
2. Depth of ANC Nadir, defined as the patient’s lowest ANC in Cycle 1 
3. Incidence of Febrile Neutropenia (FN) in patients during Cycle 1 
Additional Secondary Objectives: 
 
To compare SPI-2012 with pegfilgrastim in: 
1. Duration of Severe Neutropenia in Cycles 2, 3, and 4 
2. Incidence of Neutropenic Complications, including anti-infective use and hospitalizations in 
patients during Cycle 1  
3. Incidence of FN in Cycles 2, 3, and 4 
4. Relative Dose Intensity (RDI) of TC in Cycles 1 to 4 
5. Safety 
Study Design and Treatment Plan: 
This is a Phase 3, randomized, open-label, active-controlled, multicenter study to compare the efficacy and 
safety of SPI-2012 with pegfilgrastim in breast cancer patients treated with TC chemotherapy.  
Approximately 400 patients will be enrolled and randomized in a 1:1 ratio to 2 treatment arms:  
 
Treatment Arm 1 (n= approximately200): SPI-2012 (13.2 mg/0.6 mL fixed dose SPI-2012 equivalent 
to 3.6 mg G-CSF) 
 
Treatment Arm 2 (n= approximately200): Pegfilgrastim (6 mg/0.6 mL)  
Prior to TC chemotherapy administration, patients may receive premedication according to institutional standard 
of care. Intravenous (IV) administration of TC on Day 1 of each cycle will be as follows:  
 
Docetaxel 75 mg/m2 IV infusion per institute’s standard of care 
 
Cyclophosphamide 600 mg/m2 IV infusion per Institute’s standard of care  


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
SPI-2012 (HM10460A) 
Protocol Number: SPI-GCF-301 
Amendment 1/26 Jan 2017 
Confidential 
4 
Each cycle will be 21 days. Only 4 cycles will be evaluated for this study. After Cycle 1, patients must have 
ANC ≥1.5×109/L and platelet count ≥100×109/L to begin each of the next cycles of chemotherapy.  
The study drug (SPI-2012 or pegfilgrastim) will be administered on Day 2 of each cycle, approximately 24 to 26 
hours after the last dose of TC chemotherapy is given. Study drug (SPI-2012 or pegfilgrastim) dose 
modifications are not allowed. 
On Day 1 of each cycle, patients will receive TC chemotherapy, and safety and efficacy assessments will be 
performed as outlined in the protocol. On Day 2 of each cycle, patients will receive study drug (SPI-2012 or 
pegfilgrastim), and the specified assessments will be performed.  
Absolute neutrophil count will be monitored on Day 1 and Days 4 to 15 in Cycle 1. In Cycles 2 to 4, all patients 
must have blood samples drawn on Day 1 (prior to chemotherapy administration), on Days 4, 7, 10, and 15 
(±1 day for each collection), and at the End-of-Treatment Visit. If the participating site is notified that the ANC 
is ≤1.0×109/L at any time during Cycles 2 to 4, then daily CBCs will be required until the ANC is ≥1.5×109/L, 
after reaching nadir, but blood samples must still be drawn on Days 4, 7, 10, and 15.  
After Cycle 1, as applicable, patients who have received at least one dose of study drug will be followed for 12 
months after the last dose of study treatment for safety follow-up.  
Duration of Study: Approximately 34 months with 22 months for enrollment and treatment and 12 months for 
safety follow-up. 
The duration of the study for each patient in SPI-GCF-301 will be approximately16 months including: 
 
Screening Period: 30 days 
 
Treatment Period: 4 cycles, 21 days per cycle 
 
End-of-Treatment Visit: 35 (±5) days after last dose of study treatment 
 
Safety Follow-up Period: 12 months after the last dose of study treatment 
 
End-of-Study Visit: At the 12 Month Visit or 35 (±5) days after the date of early discontinuation  
Patient Replacement Strategy: Patients who discontinue from the study prior to study treatment will be 
replaced. 
Inclusion & Exclusion Criteria:  
Inclusion Criteria: 
1. Patient must be willing and capable of giving written Informed Consent and must be able to adhere to 
dosing and visit schedules as well as meet all study requirements.  
2. Patient must have a new diagnosis of histologically confirmed early-stage breast cancer (ESBC), defined 
as operable Stage I to Stage IIIA breast cancer.  
3. Patient must be a candidate to receive adjuvant or neoadjuvant TC chemotherapy.  
4. Patient (male or female) must be at least 18 years of age.  
5. Patient must have adequate hematological, renal and hepatic function as defined by: 
 
ANC ≥1.5×109/L 
 
Platelet count ≥100×109/L 
 
Hemoglobin >9 g/dL 
 
Calculated creatinine clearance >50 mL/min  
 
Total bilirubin ≤1.5 mg/dL  
 
Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and alanine 
aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) ≤2.5×ULN, and alkaline 
phosphatase ≤2.0×ULN  
6. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
SPI-2012 (HM10460A) 
Protocol Number: SPI-GCF-301 
Amendment 1/26 Jan 2017 
Confidential 
5 
7. Patient must be willing to practice two forms of contraception, one of which must be a barrier method, 
from study entry through 30 days after the last dose of study drug administration or 30 days after date of 
patient early discontinuation. 
8. Females of childbearing potential must have a negative urine pregnancy test within 30 days prior to 
randomization. Females who are postmenopausal for at least 1 year (defined as more than 12 months 
since last menses) or are surgically sterilized do not require this test. 
Exclusion Criteria: 
1. Patient with an active concurrent malignancy (except non melanoma skin cancer or carcinoma in situ of 
the cervix) or life-threatening disease. If there is a history of prior malignancies or contralateral breast 
cancer, the patient must be disease free for at least 5 years. 
2. Patient with known sensitivity or previous reaction to Escherichia coli (E. coli) derived products (eg, 
filgrastim, recombinant insulin [Humulin®], L-asparaginase, somatropin [Humatrop®] growth hormone, 
recombinant interferon alfa-2b [Intron® A]), or any of the products to be administered during study 
participation.  
3. Patient with concurrent adjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, 
biologic therapy other than the trial-specified therapies).  
4. Patient has locally recurrent/metastatic breast cancer. 
5. Patient with previous exposure to filgrastim, pegfilgrastim, or other G-CSF products in clinical 
development within 12 months prior to the administration of study drug (SPI-2012 or pegfilgrastim).  
6. Patient with an active infection or receiving anti-infectives, an underlying medical condition, or another 
serious illness that would impair the ability of the patient to receive protocol-specified treatment. 
7. Patient has used any investigational drugs, biologics, or devices within 30 days prior to study treatment 
or plans to use any of these during the course of the study. 
8. Patient has had prior bone marrow or hematopoietic stem cell transplant. 
9. Patient has had prior radiation therapy within 30 days prior to enrollment. 
10. Patient has had major surgery within 30 days prior to enrollment. Patients who have breast surgery 
related to the breast cancer diagnosis or have had a port-a-cath placement may be enrolled prior to 30 
days once they have fully recovered from the procedure. 
11.  Patient is pregnant or breast-feeding. 
Investigational Product, Dose, and Route of Administration: 
SPI-2012 (0.6 mL) is supplied in a prefilled, single-use syringe for subcutaneous injection. Each prefilled 
syringe of SPI-2012 contains 13.2 mg SPI-2012, which is equivalent to a dose of 3.6 mg of G-CSF.  
The dose of SPI-2012 is to be administered subcutaneously on Day 2, approximately 24 to 26 hours after TC 
administration. 
Reference Therapy, Dose, and Route of Administration: 
Only pegfilgrastim (Neulasta), manufactured by Amgen in the United States (NDC 55513-190-01) will be used 
in this study; no other G-CSFs, including biosimilars, are to be used in this study. 
Pegfilgrastim will be supplied by Spectrum to all sites (US and ex-US) in 6 mg/0.6 mL prefilled single-use 
syringes for subcutaneous injection. Each syringe contains 6 mg G-CSF in a sterile solution. 
Pegfilgrastim should be administered subcutaneously once per chemotherapy cycle on Day 2, approximately 24 
to 26 hours after TC administration, according to the manufacturer’s prescribing information. 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
SPI-2012 (HM10460A) 
Protocol Number: SPI-GCF-301 
Amendment 1/26 Jan 2017 
Confidential 
6 
Efficacy Assessments: 
Primary Endpoint: 
 
Comparison of the Duration of Severe Neutropenia (DSN) in Cycle 1 between the SPI-2012 
Treatment Arm and the Pegfilgrastim Treatment Arm.  
DSN is defined as the number of days of severe neutropenia (ANC <0.5×109/L) from the first occurrence of an 
ANC below the threshold. The assessment of ANC will be performed on Day 1 and Days 4 to 15 in Cycle 1. The 
endpoint will be measured in all patients in an Intent-to-Treat Population (ITT Population). For patients who 
do not meet severe neutropenia criteria, the endpoint measurement will be defined as DSN=0. 
Key Secondary Endpoints: 
 
To compare SPI-2012 with pegfilgrastim in: 
1. Time to ANC Recovery in Cycle 1  
2. Depth of ANC Nadir, defined as the patient’s lowest ANC in Cycle 1 
3. Incidence of FN in patients during Cycle 1 
The analyses of the Key Secondary Endpoints will employ a hierarchical, closed testing procedure. 
Additional Secondary Endpoints: 
 
To compare SPI-2012 with pegfilgrastim in: 
1. Duration of Severe Neutropenia in Cycles 2, 3, and 4 
2. Incidence of Neutropenic Complications, including use of anti-infectives and hospitalizations, in 
patients during Cycle 1 
3. Incidences of FN in Cycles 2, 3, and 4 
4. RDI of TC in Cycles 1 to 4 
5. Safety 
Pharmacokinetic Assessments: 
All patients in the SPI-2012 treatment arm will have blood samples drawn for sparse PK sampling at 6 time 
points during the study period for PK analysis. The sampling time points will be: 
 
Cycle 1:  
 
Day 2 (1 to 4 hours after SPI-2012 administration) 
 
Day 4 (at the same time as CBC blood draw) 
 
Day 5 (at the same time as CBC blood draw) 
 
Cycle 3: 
 
Day 2 (1 to 4 hours post-dose) 
 
Day 4 (±1 day, at the same time as CBC blood draw) 
 
Day 7 (±1 day, at the same time as CBC blood draw)  
Safety Assessments: 
Safety (secondary endpoint) will be assessed by reported/elicited adverse events (AEs), laboratory assessments, 
and physical examinations. In addition, as applicable, patients who receive at least one dose of study drug will 
be followed for 12 months after the last dose of study treatment to assess long-term safety; patients who receive 
SPI-2012 will be tested for antibodies to SPI-2012, the Fc region of the SPI-2012 molecule, the PEG moiety, 
and G-CSF. Patients who receive pegfilgrastim will be tested for antibodies to SPI-2012, PEG and G-CSF. All 
sera samples positive for G-CSF-binding antibodies will be further tested for G-CSF neutralizing antibodies.  
Adverse Event and Serious Adverse Event Reporting: 
All AEs that occur from the first dose of study treatment through 35 (±5) days after the date of last study 
treatment or date of patient early discontinuation are to be recorded on the AE CRF. Additionally, as applicable, 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
SPI-2012 (HM10460A) 
Protocol Number: SPI-GCF-301 
Amendment 1/26 Jan 2017 
Confidential 
7 
patients who receive at least one dose of study drug (SPI-2012 or pegfilgrastim) will be followed for 12 months 
after the last dose of study treatment to evaluate the long-term safety and immunogenicity of SPI-2012. All AEs 
during this time period will be recorded. From the time the study Informed Consent is signed through the first 
dose of study drug administration, only SAEs that are related to study procedures are to be recorded. 
Statistical Methods: 
For the primary efficacy analysis, the mean DSN in Cycle 1 will be compared between the SPI-2012 and 
Pegfilgrastim Treatment Arms using a bootstrap resampling method with non-inferiority hypothesis. A 
2-sided 95% confidence interval (CI) of the difference between the mean DSN of the SPI-2012 Treatment Arm 
and the mean DSN of the Pegfilgrastim Treatment Arm will be calculated using bootstrap resampling with 
treatment as the only stratification factor. The study will use a non-inferiority margin of 0.62 day for the above 
comparison.  
The non-inferiority of SPI-2012 to pegfilgrastim will be declared if the upper bound of 95% CI of the difference 
in mean DSN between the treatment arms is <0.62 days. Primary analysis for the non-inferiority hypothesis will 
be based on the ITT Population. An analysis based on the Per Protocol Population will be performed as a 
sensitivity analysis.  
For the secondary efficacy analyses, the results will each be summarized by Treatment Arm and Cycle. The two-
sided 95% CI for the difference between the treatment arms will be calculated. 
For safety analysis, the number and percentage of patients with any treatment-emergent AEs (TEAEs), any 
serious AEs (SAEs), TEAEs related to study drugs, and TEAEs causing treatment discontinuation will be 
summarized. Adverse Events of Special Interest (AESI) (musculoskeletal pain, injection site reactions, and 
hypersensitivity reactions) will be assessed and summarized by Preferred Term. An exposure-response analysis 
will be performed based on sparse PK sampling. 
Sample size estimates are based on a non-inferiority design. The pooled standard deviation of the DSN is 
assumed to be 2.0 days, after referencing the assumptions used in the two Phase 3 registrational pegfilgrastim 
trials. The margin of non-inferiority is 0.62 days. The true difference between the means is assumed to be 0.0 
days. Sample sizes of 200 per treatment arm will provide 87% power to detect non-inferiority using a one-sided, 
two-sample t-test at 2.5% level of significance.  
The study will enroll and randomize approximately 200 patients per arm for a total of approximately 
400 patients. 
Amendment 1: 26 Jan 2017 
 
 








Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
SPI-2012 (HM10460A) 
Protocol Number: SPI-GCF-301 
Amendment 1/26 Jan 2017 
Confidential 
11 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................................1 
INVESTIGATOR SIGNATURE ..................................................................................................2 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ............................................................................................................11 
List of Tables ..........................................................................................................................14 
List of Figures .........................................................................................................................14 
LIST OF ABBREVIATIONS .....................................................................................................15 
1 
INTRODUCTION ................................................................................................................17 
1.1 
Background ................................................................................................................17 
1.1.1 
Breast Cancer and Role of Granulocyte Colony Stimulating Factor ...........17 
1.1.2 
SPI-2012 ..............................................................................................................19 
1.1.2.1 
Nonclinical Studies ........................................................................................19 
1.1.2.2 
Clinical Experience .......................................................................................20 
1.2 
Rationale for the Current Study ...............................................................................24 
2 
STUDY OBJECTIVES ........................................................................................................25 
2.1 
Primary Objective ......................................................................................................25 
2.2 
Key Secondary Objectives .........................................................................................25 
2.3 
Additional Secondary Objectives .............................................................................25 
3 
INVESTIGATIONAL PLAN ..............................................................................................26 
3.1 
Study Design and Treatment Plan............................................................................26 
3.2 
Study and Treatment Duration ................................................................................28 
4 
PATIENT POPULATION ...................................................................................................29 
4.1 
Inclusion Criteria .......................................................................................................29 
4.2 
Exclusion Criteria ......................................................................................................29 
4.3 
Patient Discontinuation/Withdrawal Criteria .........................................................30 
5 
STUDY PROCEDURES ......................................................................................................30 
5.1 
Screening .....................................................................................................................31 
5.2 
Patient Assignment ....................................................................................................31 
5.3 
Timing of Assessments and Procedures ...................................................................31 
5.3.1 
Screening (Days -30 to -1) .................................................................................31 
5.3.2 
Treatment Period – Cycle 1, Day 1 (Baseline) ................................................32 
5.3.3 
Treatment Period – Cycle 1, Day 2 ..................................................................32 
5.3.4 
Treatment Period – Cycle 1, Days 4 to 21 .......................................................32 
5.3.5 
Treatment Period – Cycles 2 to 4, Day 1 .........................................................33 
5.3.6 
Treatment Period – Cycles 2 to 4, Day 2 .........................................................33 
5.3.7 
Treatment Period – Cycles 2 to 4, Days 3 to 21 ..............................................33 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
SPI-2012 (HM10460A) 
Protocol Number: SPI-GCF-301 
Amendment 1/26 Jan 2017 
Confidential 
12 
5.3.8 
End-of-Treatment Visit (35 [±5] Days After the Last Dose of Study 
Treatment in Cycle 4 or 35 [±5] Days after the Date of Early 
Discontinuation) ..............................................................................................34 
5.3.9 
12 Month Safety Follow-up ...............................................................................34 
5.3.9.1 
Telephone Contact .........................................................................................34 
5.3.9.2 
Clinic Visit .....................................................................................................34 
5.3.10 
End of Study Visit (Month 12 Visit or 35 (±5) days after early 
discontinuation) ...............................................................................................35 
5.4 
Description of Study Assessments and Procedures.................................................35 
5.4.1 
Explanation of Study and Obtaining Written Informed Consent ................35 
5.4.2 
Medical History .................................................................................................35 
5.4.3 
Review Inclusion/Exclusion Criteria ...............................................................35 
5.4.4 
Randomization ...................................................................................................35 
5.4.5 
Physical Examination ........................................................................................35 
5.4.6 
ECOG Performance Status ..............................................................................35 
5.4.7 
Vital Sign Assessments ......................................................................................36 
5.4.8 
Body Temperature .............................................................................................36 
5.4.9 
Complete Blood Count ......................................................................................36 
5.4.10 
Chemistry ...........................................................................................................37 
5.4.11 
Pharmacokinetic Assessments ..........................................................................37 
5.4.12 
Anti-Infective Use ..............................................................................................37 
5.4.13 
Immunogenicity Testing ...................................................................................37 
5.4.14 
Adverse Event ....................................................................................................37 
5.4.15 
Concomitant Medications .................................................................................38 
6 
STUDY DRUG AND PHARMACEUTICAL INFORMATION .....................................38 
6.1 
SPI-2012 ......................................................................................................................38 
6.1.1 
SPI-2012 Composition .......................................................................................38 
6.1.2 
SPI-2012 Storage and Handling .......................................................................38 
6.1.3 
SPI-2012 Administration ..................................................................................38 
6.2 
Pegfilgrastim ...............................................................................................................38 
6.2.1 
Pegfilgrastim Composition ...............................................................................38 
6.2.2 
Pegfilgrastim Supply .........................................................................................39 
6.2.3 
Pegfilgrastim Storage and Handling ................................................................39 
6.2.4 
Pegfilgrastim Administration ...........................................................................39 
6.3 
Blinding of Study Treatments ...................................................................................39 
6.4 
Randomization of Study Treatments .......................................................................39 
6.5 
Non-study Treatments ...............................................................................................39 
6.5.1 
Prior and Concomitant Medications ...............................................................39 
6.5.2 
Prohibited Therapies or Medications ..............................................................40 
7 
SAFETY ASSESSMENT .....................................................................................................40 
7.1 
Safety Measures .........................................................................................................40 
7.2 
Adverse Events ...........................................................................................................40 
7.3 
Guidelines for Recording and Attribution Scoring of Adverse Events ................41 
7.3.1 
Recording of Adverse Events ...........................................................................41 
7.3.2 
Grading of Adverse Events ...............................................................................42 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
SPI-2012 (HM10460A) 
Protocol Number: SPI-GCF-301 
Amendment 1/26 Jan 2017 
Confidential 
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7.4 
Follow-up of Adverse Events ....................................................................................42 
7.5 
Relationship ................................................................................................................42 
7.6 
Expectedness ...............................................................................................................43 
7.7 
Serious Adverse Events .............................................................................................43 
7.7.1 
Serious Adverse Event Reporting ....................................................................44 
7.7.2 
Exclusions to Serious Adverse Event Reporting Requirements ....................44 
7.8 
Reproductive Risks ....................................................................................................45 
8 
STATISTICAL PLAN..........................................................................................................45 
8.1 
Sample Size .................................................................................................................45 
8.2 
Method of Treatment Assignment, Randomization, and/or Stratification ..........45 
8.3 
Analysis Populations ..................................................................................................46 
8.4 
General Statistical Methods ......................................................................................46 
8.5 
Efficacy Analyses .......................................................................................................46 
8.5.1 
Primary Endpoint ..............................................................................................46 
8.5.2 
Key Secondary Endpoints .................................................................................47 
8.5.3 
Additional Secondary Endpoints .....................................................................48 
8.6 
Analysis of Safety .......................................................................................................48 
8.7 
Clinical Laboratory and Vital Signs Evaluations ...................................................49 
9 
ADMINISTRATIVE PROCEDURES AND STUDY MANAGEMENT ........................49 
9.1 
Investigator Responsibilities .....................................................................................49 
9.1.1 
Good Clinical Practice ......................................................................................49 
9.1.2 
Institutional Review Board/Ethics Committee Approval ..............................49 
9.1.3 
Informed Consent ..............................................................................................49 
9.1.4 
Study Files and Retention of Records ..............................................................50 
9.2 
Recording and Collecting of Data ............................................................................50 
9.2.1 
Case Report Forms ............................................................................................50 
9.2.2 
Drug Accountability ..........................................................................................50 
9.3 
Protocol Compliance ..................................................................................................50 
9.4 
Sponsor Responsibilities ............................................................................................51 
9.4.1 
Study Monitoring ...............................................................................................51 
9.4.2 
Safety Monitoring ..............................................................................................51 
9.5 
Joint Investigator/Sponsor Responsibilities ............................................................51 
9.5.1 
Access to Information for Monitoring and Auditing .....................................51 
9.5.2 
Termination of the Study ..................................................................................51 
9.5.3 
Publication Policy ..............................................................................................51 
9.6 
Confidentiality ............................................................................................................52 
10 REFERENCES .....................................................................................................................53 
APPENDIX 1 
SCHEDULE OF ASSESSMENTS AND PROCEDURES - CYCLE 1 ......56 
APPENDIX 2 
SCHEDULE OF ASSESSMENTS AND PROCEDURES - CYCLES 2 TO 
4 
57 
 


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List of Tables 
Table 1 
Reported Incidence of Febrile Neutropenia Associated with TC as Adjuvant 
Therapy with and without G-CSF Prophylaxis in Patients with Early-Stage 
Breast Cancer ............................................................................................................18 
Table 2 
Summary of Treatment-Related Treatment-Emergent Adverse Events (≥5%) 
by Preferred Term-Phase 2 Study SPI-GCF-12-201 .............................................23 
Table 3 
Summary of Serious Treatment-Emergent Adverse Events by Preferred Term-
Phase 2 Study- SPI-GCF-12-201 .............................................................................24 
Table 4 
Eastern Cooperative Oncology Group Status ........................................................36 
Table 5 
Investigator Assessment of Adverse Event Causality ............................................42 
 
List of Figures 
Figure 1 
Study Design Diagram ................................................................................................8 
Figure 2 
Median Absolute Neutrophil Count Over Time - Cycle 1- SPI-GCF-12-201 .....22 
Figure 3 
Study Design Diagram ..............................................................................................27 
 
 
 






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1 INTRODUCTION 
1.1 Background 
1.1.1 Breast Cancer and Role of Granulocyte Colony Stimulating Factor 
According to the American Cancer Society (ACS), breast cancer is one of the most common 
forms of cancer and the second highest cause of cancer deaths in women [1]. In 2014 in the 
United States (US), an estimated 232,670 new cases of invasive breast cancer and 62,570 
additional cases of in situ breast cancer occurred, and approximately 40,430 US women were 
expected to die from breast cancer. In addition, breast cancer is also seen in males, with an 
estimated 2360 men being diagnosed with breast cancer and 410 dying from the disease in 2013. 
Data show that mortality rates from breast cancer increase with age, reaching a peak when 
patients are in their 70s [1].  
The National Comprehensive Cancer Network (NCCN) clinical guidelines recommend that most 
patients with early-stage breast cancer (ESBC) receive adjuvant chemotherapy after they have 
undergone complete surgical excision of the primary tumor by lumpectomy and axillary 
dissection or modified radical mastectomy [2]. Current NCCN guidelines for adjuvant 
chemotherapy regimens to treat ESBC include docetaxel, doxorubicin, and cyclophosphamide 
(TAC); dose dense doxorubicin plus cyclophosphamide (AC), with or without subsequent 
weekly or semiweekly paclitaxel; and docetaxel plus cyclophosphamide (TC).  
The use of adjuvant chemotherapy to improve survival in patients with ESBC has been widely 
adopted [3]. The TC regimen is an attractive therapeutic option because it has demonstrated 
efficacy [4] and reduced risk of cardiotoxicity compared with other therapies that contain 
anthracyclines [5]. USO 9735 was a pivotal Phase 3 trial that compared TC vs. AC among 
patients with operable ESBC [6]. Trial results showed that after 7 years of follow-up, 4 cycles of 
TC were associated with significantly improved Disease Free Survival (DFS) and Overall 
Survival (OS) compared with 4 cycles of AC. Specifically, the DFS was 81% and 75% for TC 
and AC, respectively, and the OS was 87% and 82%, respectively. Although the TC regimen has 
not been associated with cardiotoxicity [4, 6, 7], it has been associated with other adverse events, 
particularly hematologic toxicities [4, 6].  
In USO 9735, the reported rates of Febrile Neutropenia (FN) were 4% in women younger than 
65 years and 8% in those 65 years or older, although FN was not a pre-planned evaluable 
endpoint in the trial [4]. No dose reductions were permitted, and patients were taken off 
treatment if any study drug administration was delayed by more than 2 weeks because of drug-
related toxicities. Prophylactic use of quinolone antibiotics was recommended at the discretion of 
the treating physician. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not 
allowed, and reactive G-CSF support for chemotherapy-induced neutropenic complications was 
not specified [4]. 
Subsequent reports have suggested that TC is associated with higher rates of FN than those 
reported in USO 9735, ranging from 25% to 50% in the absence of G-CSF support and 
decreasing to 0% to 6.3% with primary G-CSF prophylaxis (Table 1) [8-12]. 




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Development of FN increases diagnostic and treatment costs, and often leads to prolonged 
hospitalizations. In addition, changes in neutrophil counts have been correlated with quality of 
life, as measured by physical functioning, vitality, and mental health [18].  
Filgrastim, tbo-filgrastim, and pegfilgrastim are G-CSFs currently approved by the US Food and 
Drug Administration (FDA) for the prevention of chemotherapy-induced neutropenia [15].While 
the European guidelines also include lenograstim as a recommended G-CSF in solid tumors and 
non-myeloid malignancies, it is not approved for use in the US. 
Studies have demonstrated that the use of G-CSF can reduce the risk, severity, and duration of 
FN [15]. Guidelines from the American Society of Clinical Oncology (ASCO), the European 
Organization for Research and Treatment of Cancer (EORTC) Guidelines, as well as NCCN 
recommend the use of G-CSF as primary prophylaxis when the anticipated risk of FN for a 
patient initiating chemotherapy is high [15, 19, 20].  
1.1.2 SPI-2012 
Spectrum Pharmaceuticals, Inc. (Spectrum) is developing a novel, long-acting form of G-CSF, 
SPI-2012 (also known as Rolontis™, eflapegrastim, HM10460A, Long Acting Protein/Peptide 
Discovery Platform Technology-G-CSF [LAPS-G-CSF]), a chemically conjugated form of a 
modified G-CSF, for the indication of the reduction in the Duration of Severe Neutropenia 
(DSN) and incidence of infection, as manifested by FN in patients with solid tumors and non-
myeloid malignancies receiving myelosuppressive anti-cancer therapy. SPI-2012 is a novel 
biologic and not a biosimilar to either filgrastim or pegfilgrastim. 
SPI-2012 is produced by conjugating a novel, modified recombinant human G-CSF (with no 
additional N-terminal Met, referred to as HM10411), and the human immunoglobulin G4 Fc 
fragment (referred to as HMC001) via a 3.4 kDa polyethylene glycol (PEG) linker to produce a 
new, long-acting G-CSF. 
HM10411 and HMC001 are each manufactured using recombinant-DNA technology in E. coli. 
Specifically, HM10411 is produced by fermentation of transformed E. coli in the periplasmic 
space followed by harvesting and purification. Whereas HMC001 is produced by fermentation of 
transformed E. coli as an inclusion body followed by harvesting, refolding, and purification. 
The human immunoglobulin G4 Fc fragment (HMC001) was specifically chosen as the 
conjugation partner for this novel G-CSF because it has a long in vivo half-life of several weeks. 
Details of the product’s characteristics can be found in the Investigator’s Brochure (IB).  
1.1.2.1 Nonclinical Studies 
The biological response to rh-G-CSF is not species specific, and therefore the biological 
response of rh-G-CSF has been examined in mice, rats, dogs, and monkeys in single- and repeat-
dose studies. Mouse bone marrow cells, chemotherapy-induced neutropenic mouse and rat 
models, normal and nephrectomized rats, and cynomolgus monkeys have all been used to 
study the effects of SPI-2012. All toxicology studies were performed under Good Laboratory 
Practice (GLP) conditions. 
The kinetics of neutrophil proliferation in neutropenic mice and rats stimulated with SPI-2012, 
pegfilgrastim, and filgrastim were also compared. SPI-2012 was shown to have an 
approximately 2-fold higher Area Under the Time-Concentration Curve (AUC) for Absolute 


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Neutrophil Count (ANC) when compared to pegfilgrastim at similar doses (ie, when comparing 
equivalent G-CSF concentrations of the compounds). Based on these results, SPI-2012 was 
estimated to have twice the in vivo potency as pegfilgrastim. The potential clinical benefit of the 
increased potency of SPI-2012 was analyzed by comparing the DSN in neutropenic rats to the 
DSN response to pegfilgrastim and filgrastim in this same model. SPI-2012 was found to be 
more potent in shortening the DSN with a lower G-CSF equivalent dose when compared to 
either pegfilgrastim or filgrastim. The DSN was 0.2 days when SPI-2012 was co-administered or 
sequentially administered as a single dose at 88 µg/kg (as G-CSF equivalent) with chemotherapy 
drugs in rats. In contrast, the DSN was 3.04 days with filgrastim administered at dose of 
20 µg/kg for 5 days and was 2.8 days with pegfilgrastim administered as a single dose of 
100 µg/kg. 
In cynomolgus monkeys, neutrophil counts increased as SPI-2012 dose levels increased (161.48 
to 322.96 μg/kg SPI-2012,) but were not dose-proportional. Maximum neutrophil levels peaked 
on Day 1 post-dose, decreased by Day 7 following IV administration, peaked on Day 3 post-
dose, and then decreased by Day 16 following SC administration of SPI-2012. SPI-2012 also 
showed an approximately 3-fold higher AUC for ANC compared to pegfilgrastim at the same 
G-CSF equivalent dosing level.  
1.1.2.2 Clinical Experience 
1.1.2.2.1 Phase 1 Studies 
Two Phase 1 studies of SPI-2012 (08-HM10460-101, N=60; 09-HM10460-101, N=30) were 
conducted in healthy volunteers to evaluate the safety and the pharmacokinetic (PK) and 
pharmacodynamic properties of SPI-2012. Most adverse events (AEs) reported in these studies 
were mild and comparable to those reported in other clinical trials with pegfilgrastim. Common 
treatment-related AEs included bone pain, back pain, and headache. No clinically significant 
changes were found in electrocardiogram (ECG), vital signs, or splenic evaluation. Isolated cases 
of tachycardia, palpitation, and transient elevations of liver enzymes were seen in some patients. 
Overall in the Phase 1 studies in healthy volunteers, doses of SPI-2012 between 1.1 µg/kg and 
350 µg/kg were generally well-tolerated and increased white blood cell (WBC) and neutrophil 
counts in a pronounced and dose-dependent manner.  
1.1.2.2.2 Phase 2 Study- SPI-GCF-12-201 
A Phase 2, open-label, dose-ranging, study (SPI-GCF-12-201, N=148) has also been completed. 
This study compared three weight-based doses of SPI-2012 (45, 135, and 270 µg/kg) versus 
pegfilgrastim (6 mg) for the management of neutropenia in breast cancer patients receiving TC 
chemotherapy, and provides safety and efficacy data supporting advancement to Phase 3 and the 
basis for the fixed dose recommendation. Brief results are presented below and additional results 
are presented in the Investigator’s Brochure (IB). 
1.1.2.2.2.1 Study Design 
SPI-GCF-12-201 was a Phase 2, open-label study to assess the effect of test doses of SPI-2012 
on the DSN during Cycle 1 in patients with breast cancer who were candidates for adjuvant or 
neoadjuvant chemotherapy with the docetaxel and cyclophosphamide (TC). 
The study included 4 single-dose treatment arms: 


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 Arm 1: SPI-2012 (45 μg/kg) 
 Arm 2: SPI-2012 (135 μg/kg) 
 Arm 3: SPI-2012 (270 μg/kg) 
 Arm 4: Pegfilgrastim (6 mg) 
Administration of TC on Day 1 of each cycle IV was:  
 Docetaxel at 75 mg/m2 IV infusion per Institute’s standard of care  
 Cyclophosphamide 600 mg/m2 IV infusion per Institute’s standard of care  
Each treatment cycle was 21 days with up to a maximum of 4 cycles of chemotherapy. To begin 
full-dose chemotherapy on Day 1 of the next cycle (Day 22 of the previous cycle), patients must 
have recovered to an ANC greater than 2.0×109/L and a platelet count ≥100×109/L. 
SPI-2012 was administered on Day 2 of each cycle, approximately 24 to 26 hours after TC 
chemotherapy. The dose of SPI-2012 administered depended on the treatment arm to which each 
patient was assigned. Pegfilgrastim was to be administered according to the manufacturer’s 
Prescribing Information (6 mg subcutaneously once per chemotherapy cycle).  
1.1.2.2.2.2 Disposition and Demographics 
In SPI-GCF-12-201, 148 patients were randomized into the 4 treatment arms. Most patients 
(147 patients [99%]) completed at least 1 cycle of treatment. Ten patients (7%) discontinued 
from the study. Three patients (2%) withdrew consent, two patients (1%) discontinued due to 
adverse events, and five patients discontinued for other reasons. Four patients (2 patients each in 
the 135 μg/kg SPI-2012 group [one patient withdrew consent and one patient initiated a non-
protocol therapy] and 270 μg/kg SPI-2012 dose group [both patients withdrew consent]) 
discontinued prior to beginning Cycle 2 and 138 patients (93%) were treated for all 4 cycles.  
The mean age of all patients in SPI-GCF-12-201 was 58.2 years and ranged from 32 years to 
77 years across all groups. Most patients were less than 65 years of age (n=100 [68%]), female 
(n=144 [98%]), and White (n=139 [95%]). There were 3 male patients in the study, two in the 
270 µg/kg SPI-2012 group and one in the 135 µg/kg SPI-2012 group. 
During Cycle 1 in SPI-GCF-12-201. During Cycle 1, most patients (≥64%) in all three SPI-
2012 dose groups and the pegfilgrastim group did not develop neutropenia; at SPI-2012 doses 
≥135 µg/kg, the proportion of patients not experiencing neutropenia was comparable or higher to 
the incidence with pegfilgrastim. 
1.1.2.2.2.3 Duration of Severe Neutropenia 
In the 270 µg/kg SPI-2012 group, neutropenia was reported in only one patient (3%), which 
lasted only 1 day. In the 135 µg/kg SPI-2012 group, seven patients (19%) experienced 
neutropenia, which lasted for 1 day in three patients (8%), 2 days in three patients (8%), and 
7 days in one patient (3%). Approximately one-third of patients in the 45 µg/kg SPI-2012 group 
experienced neutropenia that lasted between 1 to 5 days. In the pegfilgrastim group, five patients 
(14%) experienced neutropenia, which lasted for 1 day in one patient (3%), 2 days in two 
patients (6%), and 3 days in two patients (6%). The magnitude of DSN and the mean values in 
the various treatment arms may be much lower in this study as compared to that in the literature 








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clinical benefits of the prophylactic use of G-CSF for patient safety, to maximize treatment 
intensity and outcomes, and cost-efficiency. 
Pharmacological analysis of SPI-2012 in vivo revealed a 2- to 3-fold increase in the AUC of the 
ANC at G-CSF-equivalent doses similar to pegfilgrastim. Clinical experience from the Phase 2 
trial (SPI-GCF-12-201) in breast cancer patients has shown that SPI-2012 is non-inferior to 
pegfilgrastim and has a similar safety profile. All doses of SPI-2012 administered in 
SPI-GCF-12-201 were well tolerated. No significant dose-related toxicities were observed. The 
DSN in the 135 µg/kg SPI-2012 arm was non-inferior to pegfilgrastim in Cycle 1 and the DSN 
in the 270 µg/kg SPI-2012 Treatment Arm was superior to the Pegfilgrastim Treatment Arm. 
Non-inferiority in DSN was also observed in Cycles 2 to 4 in both the 135 µg/kg and 270 µg/kg 
treatment arms when compared to pegfilgrastim. 
The current Phase 3 study is designed to expand on the information obtained in the Phase 2 trial 
and evaluate the efficacy, and safety of SPI-2012, as compared with pegfilgrastim (Neulasta 
[NDC 55513-190-01] manufactured by Amgen in the United States), in breast cancer patients 
receiving TC.  
The dose of SPI-2012 to be studied in this trial is 13.2 mg SPI-2012 equivalent to 3.6 mg 
G-CSF, approximately half of the G-CSF equivalent dose in 6 mg pegfilgrastim. This dose was 
selected on the basis of the pharmacological and pharmacodynamic data from the Phase 2 trial 
(SPI-GCF-12-201).  
As applicable, patients who have received at least one dose of study drug (SPI-2012 or 
pegfilgrastim) will be followed for 12 months after the last dose of study treatment for safety 
follow-up. Patients will visit the clinic at approximately 6 months and 12 months for a blood 
draw for evaluation of immunogenicity and for evaluation of AEs, subsequent anti-cancer 
therapy, use of other myeloid growth factors, and participation in any other subsequent clinical 
trials. In addition, patients will also be contacted by telephone at approximately 3 months and 9 
months for evaluation of AEs, subsequent anti-cancer therapy, use of other myeloid growth 
factors, and participation in any other subsequent clinical trials.  
2 STUDY OBJECTIVES  
2.1 Primary Objective 
 To compare the efficacy of SPI-2012 with pegfilgrastim in patients with early-stage 
breast cancer receiving docetaxel and cyclophosphamide (TC), as measured by the DSN 
in Cycle 1 
2.2 Key Secondary Objectives 
 To compare SPI-2012 with pegfilgrastim in: 
 
Time to ANC Recovery in Cycle 1 
 
Depth of ANC Nadir, defined as the patient’s lowest ANC in Cycle 1 
 
Incidence of FN in patients during Cycle 1  
2.3 Additional Secondary Objectives 
 To compare SPI-2012 with pegfilgrastim in: 


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 
DSN in Cycles 2, 3, and 4 
 
Incidence of neutropenic complications, including anti-infective use and 
hospitalizations in patients during Cycle 1  
 
Incidence of FN in Cycles 2, 3, and 4 
 
Relative Dose Intensity (RDI) of TC in Cycles 1 to 4 
 
Safety 
3 INVESTIGATIONAL PLAN 
3.1 Study Design and Treatment Plan 
This is a Phase 3, randomized, open-label, active-controlled, multicenter study to compare the 
efficacy and safety of SPI-2012 with pegfilgrastim in breast cancer patients treated with TC 
chemotherapy.  
Approximately 400 patients will be enrolled and randomized in a 1:1 ratio to 2 treatment arms 
(Figure 3):  
 Treatment Arm 1 (n= approximately 200): SPI-2012 (13.2 mg/0.6 mL fixed dose SPI-
2012 equivalent to 3.6 mg G-CSF) 
 Treatment Arm 2 (n=approximately 200): Pegfilgrastim (6 mg G-CSF/0.6 mL)  




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Prior to TC chemotherapy administration, patients may receive pre-medications according to 
institutional standard of care. Intravenous (IV) administration of TC on Day 1 of each cycle will 
be as follows:  
 Docetaxel 75 mg/m2 IV infusion per institute’s standard of care 
 Cyclophosphamide 600 mg/m2 IV infusion per institute’s standard of care 
Each cycle will be 21 days. Only 4 cycles will be evaluated for this study. After Cycle 1, patients 
must have ANC ≥1.5 × 109/L and platelet count ≥100 × 109/L to begin the each of next cycles of 
chemotherapy.  
The study drug (SPI-2012 or pegfilgrastim) will be administered on Day 2 of each cycle, 
approximately 24 to 26 hours after the last dose of TC chemotherapy is given. Study drug (SPI-
2012 or pegfilgrastim) dose modifications are not allowed. 
On Day 1 of each cycle, patients will receive TC chemotherapy, and safety and efficacy 
assessments will be performed as outlined in Section 5.3. On Day 2 of each cycle, patients will 
receive study drug (SPI-2012 or pegfilgrastim), and the specified assessments will be performed. 
Patients will be monitored on Day 1 and Days 4 to 15 in Cycle 1. If the participating site is 
notified that the ANC is ≤1.0 × 109/L at any time during Cycle 1, then daily CBCs will be 
required until ANC is ≥1.5 × 109/L, after reaching nadir. In Cycles 2 to 4, all patients must have 
blood samples drawn on Day 1 (prior to chemotherapy administration), on Days 4, 7, 10, and 15 
(±1 day for each collection), and at the End-of-Treatment Visit. If the participating site is 
notified that the ANC is ≤1.0 × 109/L at any time during Cycles 2 to 4, then daily CBCs will be 
required until the ANC is ≥1.5 × 109/L, after reaching nadir, but blood samples must still be 
drawn on Days 4, 7, 10, and 15. As applicable, patients who have received at least one dose of 
study drug will be followed for approximately 12 months after the last dose of study treatment 
for safety follow-up.  
3.2 Study and Treatment Duration  
The duration of the SPI-GCF-301 study is approximately 34 months (22 months for enrollment 
and 12 months of treatment/follow-up). The total duration of the study for each patient in SPI-
GCF-301 will be for approximately 16 months including: 
 Screening Period: 30 days 
 Treatment Period: 4 cycles, 21 days per cycle 
 End-of-Treatment Visit: 35 (±5) days after last dose of study treatment 
 Safety Follow-up: 12 months after the last dose of study treatment 
 End-of-Study Visit: At the 12 Month Visit or 35 (±5) days after early discontinuation 
As applicable, patients who receive at least one dose of study drug will be followed for safety for 
12 months after the last dose of study treatment for safety follow-up. 


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4 PATIENT POPULATION  
4.1 Inclusion Criteria  
1. Patient must be willing and capable of giving written Informed Consent and must be able 
to adhere to dosing and visit schedules as well as meet all study requirements.  
2. Patient must have a new diagnosis of histologically confirmed early-stage breast cancer 
(ESBC), defined as operable Stage I to Stage IIIA breast cancer.  
3. Patient must be a candidate to receive adjuvant or neoadjuvant TC chemotherapy.  
4. Patient (male or female) must be at least 18 years of age.  
5. Patient must have adequate hematological, renal and hepatic function as defined by: 
 
ANC ≥1.5 × 109/L 
 
Platelet count ≥100 × 109/L 
 
Hemoglobin >9 g/dL 
 
Calculated creatinine clearance > 50 mL/min  
 
Total bilirubin ≤1.5 mg/dL  
 
Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) 
and alanine aminotransferase ALT/serum glutamic-pyruvic transaminase (SGPT) 
≤2.5 × ULN, and alkaline phosphatase ≤2.0 × ULN  
6. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance 
status ≤2. 
7. Patient must be willing to practice two forms of contraception, one of which must be a 
barrier method, from study entry through 30 days after the last dose of study drug 
administration or 30 days after date of patient early discontinuation. 
8. Females of childbearing potential must have a negative urine pregnancy test within 
30 days prior to randomization. Females who are postmenopausal for at least 1 year 
(defined as more than 12 months since last menses) or are surgically sterilized do not 
require this test.  
4.2 Exclusion Criteria  
1. Patient with an active concurrent malignancy (except non melanoma skin cancer or 
carcinoma in situ of the cervix) or life-threatening disease. If there is a history of prior 
malignancies or contralateral breast cancer, the patient must be disease free for at least 
5 years. 
2. Patient with known sensitivity or previous reaction to Escherichia coli (E. coli) derived 
products (eg, filgrastim, recombinant insulin [Humulin®], L-asparaginase, somatropin 
[Humatrop®] growth hormone, recombinant interferon alfa-2b [Intron® A]), or any of the 
products to be administered during study participation.  
3. Patient with concurrent adjuvant cancer therapy (chemotherapy, radiation therapy, 
immunotherapy, biologic therapy other than the trial specified therapies).  
4. Patient has locally recurrent/metastatic breast cancer. 
5. Patient with previous exposure to filgrastim, pegfilgrastim, or other G-CSF products in 
clinical development within 12 months prior to the administration of study drug (SPI-
2012 or pegfilgrastim).  


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6. Patient with an active infection or on anti-infectives, an underlying medical condition or 
another serious illness that would impair the ability of the patient to receive protocol-
specified treatment. 
7. Patient has used any investigational drugs, biologics, or devices within 30 days prior to 
study treatment or plans to use any of these during the course of the study. 
8. Patient has had prior bone marrow or hematopoietic stem cell transplant. 
9. Patient has had prior radiation therapy within 30 days prior to enrollment. 
10. Patient has had major surgery within 30 days prior to enrollment. Patients who have 
breast surgery related to the breast cancer diagnosis or have had a port-a-cath placement 
may be enrolled prior to 30 days once they have fully recovered from the procedure. 
11.  Patient is pregnant or breast-feeding. 
4.3 Patient Discontinuation/Withdrawal Criteria  
Patients can withdraw from participation in this study at any time, for any reason, specified or 
unspecified, and without prejudice.  
 Patients must be withdrawn from study drug treatment for any of the following reasons, 
but will continue in the 12-Month Safety Follow-up:  
 
Development of an adverse event (AE) that interferes with the patient’s participation 
 
Discontinuation of TC  
 
Discontinuation of SPI-2012 or pegfilgrastim 
 
Delay of TC administration for >42 days since last study drug administration 
 
Investigator decision 
 
Sponsor decision 
 
Pregnancy 
 Patients must be withdrawn from the study, treatment phase or 12-Month Safety 
Follow-up Period for any of the following reasons: 
 
Initiation of non-protocol systemic chemotherapy or biological therapy for the 
treatment of breast cancer 
 
Patient withdrawal of informed consent 
 
Treatment with additional myeloid growth factors during follow-up 
 
Lost to follow-up 
 
Death 
The reason for a patient’s discontinuation of study treatment or discontinuation from the study is 
to be recorded on the electronic case report form (CRF). As applicable patients who receive at 
least one dose of study drug (SPI-2012 or pegfilgrastim) will be followed for 12 months after the 
last dose of study treatment for safety. All AEs during this time period will be recorded.  
5 STUDY PROCEDURES  
The study design diagram is presented in Figure 3 and the Schedules of Study Assessments and 
Procedures is presented in Appendix 1 and Appendix 2. 


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5.1 Screening 
Informed consent is to be obtained prior to the start of any protocol-specified assessments or 
procedures. The procedures and evaluations required for enrollment into the study are 
summarized below. All potential study patients will be screened and eligibility determined prior 
to enrollment. Screening assessments performed prior to the signing of informed consent as part 
of the site’s routine standard of practice will be allowed at the discretion of Spectrum. This 
information should be discussed with the Medical Monitor.  
5.2 Patient Assignment 
Confirmation of eligibility is to be received by the investigational site from Spectrum prior to 
enrollment of a patient. After a patient has signed the ICF, the Investigator or site staff should 
log into IWRS and obtain a Patient ID. The Patient ID will include two parts: the site number 
comprised of 5 digits with a 2-digit alphabetic country code [Reference ISO 3166] followed by a 
3-digit site specific numeric code and a 3-digit patient sequential number, unique to a site, 
separated by a hyphen (ie, 
). Once the Investigator or site staff have completed the 
required CRFs, and approval for randomization has been received from Spectrum, the site will 
randomize the patient using a pre-specified randomization scheme. Please refer to the study 
binder for detailed instructions regarding enrollment.  
5.3 Timing of Assessments and Procedures 
5.3.1 Screening (Days -30 to -1) 
The following screening assessments and procedures are to be performed within 30 days of the 
first day of study drug administration. Screening assessments performed prior to the signing of 
the ICF as part of the site’s routine standard of practice (including, but not limited to imaging 
procedures, pathology biopsy results) will be allowed at the discretion of the Sponsor. This 
information should be discussed with the Medical Monitor. 
 Informed Consent 
 Complete medical history 
 Demographic data 
 Complete physical examination 
 Height and weight 
 Eastern Cooperative Oncology Group (ECOG) performance status 
 Vital signs 
 Complete blood count (CBC) with 5-part differential  
 Chemistry  
 Pregnancy test (urine beta human chorionic gonadotropin [β-hCG]) in women of 
childbearing potential)  
 Adverse events using NCI CTCAE Version 4.03, record Serious Adverse Events (SAEs) 
related to a study procedure only 
 Hormone receptor status, including estrogen receptor (ER), progesterone receptor (PR) 
and human epidermal growth factor 2 (HER2), number of nodes, and stage. 


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 Randomization (the patient can be randomized at any time between the time the patient is 
approved for study participation and Cycle 1, Day 1) 
5.3.2 Treatment Period – Cycle 1, Day 1 (Baseline) 
The following procedures and Baseline assessments are to be performed before the 
administration of TC chemotherapy: 
 Eligibility confirmation 
 Patient ID assignment 
 Physical examination  
 Weight  
 ECOG performance status 
 Vital signs (recorded before and after TC treatment)  
 Body temperature 
 Complete blood count (CBC) with 5-part differential (May be obtained up to 3 days prior 
to Cycle 1, Day 1 without repeating on Cycle 1, Day 1)  
 Chemistry (May be obtained up to 3 days prior to Cycle 1, Day 1 without repeating on 
Cycle 1, Day 1)  
 Blood draw for immunogenicity testing (all patients) 
 Concomitant medications  
 Adverse events using NCI CTCAE Version 4.03 
Docetaxel and cyclophosphamide are to be administered as described in Section 3.1. 
 Docetaxel 75 mg/m2 IV infusion per institute’s standard of care  
 Cyclophosphamide 600 mg/m2 IV infusion per institute’s standard of care  
5.3.3 Treatment Period – Cycle 1, Day 2  
 Vital signs (recorded prior to treatment, as well as approximately 30 and 60 minutes after 
drug (SPI-2012 or pegfilgrastim) administration 
 Body temperature 
 Concomitant medications  
 Adverse events  
 Study drug (SPI-2012 or pegfilgrastim) administration according to randomization 
assignment 
 Blood sample for PK analysis (SPI-2012 Treatment Arm only) 
5.3.4 Treatment Period – Cycle 1, Days 4 to 21  
 Twice daily body temperature  


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 Complete blood count with 5-part differential on Days 4 to 15 only. If the participating 
site is notified that the ANC is ≤1.0×109/L on Day 15, then daily CBCs will be required 
until their ANC is ≥1.5×109/L post-nadir. 
 Blood sample for PK analysis (SPI-2012 Treatment Arm only) (Days 4 and 5 only, at 
the same time as CBC blood draw)  
 Concomitant medications  
 Adverse events using NCI CTCAE Version 4.03 
5.3.5 Treatment Period – Cycles 2 to 4, Day 1  
The following procedures are to be performed before the administration of TC chemotherapy: 
 Physical examination  
 Weight  
 ECOG performance status 
 Vital signs (recorded before and after TC treatment) 
 Body temperature 
 Complete blood count with 5-part differential 
 Chemistry 
 Adverse events 
 Blood draw for immunogenicity testing (all patients) 
 Concomitant medications  
Docetaxel and cyclophosphamide are to be administered as described in Section 3.1. 
5.3.6 Treatment Period – Cycles 2 to 4, Day 2  
 Vital signs recorded prior to treatment, as well as approximately 30 and 60 minutes after 
study drug (SPI-2012 or pegfilgrastim) administration 
 Twice daily body temperature 
 Concomitant medications 
 Adverse events  
 Study drug (SPI-2012 or pegfilgrastim) administration  
 Blood sample for PK analysis (SPI-2012 Treatment Arm only) (Day 2 of Cycle 3 only) 
5.3.7 Treatment Period – Cycles 2 to 4, Days 3 to 21  
 Twice daily body temperature 
 Complete blood count with 5-part differential only on Days 4, 7, 10, and 15 (±1 day for 
each collection) or until patients’ ANC is ≥1.5×109/L post-nadir, whichever occurs first. 
If the participating site is notified that the ANC is ≤1.0×109/L at any time, then daily 
CBCs will be required until ANC is ≥1.5×109/L post-nadir. 
 Blood sample for PK analysis (SPI-2012 Treatment Arm only) (Days 4 and 7 of 
Cycle 3 only, ±1 day, at the same time as CBC blood draw) 


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 Concomitant medications  
 Adverse events using NCI CTCAE Version 4.03 
5.3.8 End-of-Treatment Visit (35 [±5] Days After the Last Dose of Study Treatment in 
Cycle 4 or 35 [±5] Days after the Date of Early Discontinuation) 
 Physical examination  
 Weight 
 ECOG performance status 
 Vital signs  
 Body temperature 
 CBC with 5-part differential  
 Chemistry  
 Blood draw for immunogenicity testing (all patients) 
 Concomitant medications  
 Adverse events using NCI CTCAE Version 4.03 
5.3.9 12 Month Safety Follow-up  
All randomized patients who have received at least one dose of study drug (SPI-2012 or 
pegfilgrastim) will continue to be followed for 12 months after the last dose of study treatment 
for evaluation of long-term safety, including immunogenicity.  
5.3.9.1 Telephone Contact  
At approximately 3 months (±2 weeks) and 9 months (±2 weeks) after the last dose of study drug 
(SPI-2012 or pegfilgrastim) in SPI-GCF-301 (through the end of Cycle 4 or early 
discontinuation), patients will be contacted by telephone for: 
 Myeloid growth factor use (including the type of G-CSF, the schedule of administration 
and reason for use) 
 Subsequent types of anti-cancer therapy, including doses and number of cycles received  
 Adverse events using NCI CTCAE Version 4.03 
 Participation in any other subsequent clinical trial, where investigational product is 
administered  
5.3.9.2 Clinic Visit  
At approximately 6 months (±2 weeks) and 12 months (±2 weeks) after the last dose of study 
drug (SPI-2012 or pegfilgrastim) in SPI-GCF-301 (through the end of Cycle 4 or early 
discontinuation), patients will visit the clinic for:  
 Blood draw for immunogenicity testing (patients who have used additional G-CSF 
products during the follow-up will be excluded) 
 Myeloid growth factor use (including the type of G-CSF, the schedule of administration 
and reason for use) 


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 Subsequent types of anti-cancer therapy, including doses and number of cycles received  
 Adverse events using NCI CTCAE Version 4.03 
 Participation in any other subsequent clinical trial, where investigational product is 
administered  
5.3.10 End of Study Visit (Month 12 Visit or 35 (±5) days after early discontinuation) 
 Blood draw for immunogenicity testing if discontinued prior to Month 12 
 Concomitant medications limited to G-CSF and other anti-cancer therapy 
 Adverse events using NCI CTCAE Version 4.03 
5.4 Description of Study Assessments and Procedures  
5.4.1 Explanation of Study and Obtaining Written Informed Consent 
Informed Consent is to be obtained prior to the start of any protocol-specified assessments or 
procedures (including required washout of any prohibited medications). The Principal 
Investigator or designee is to discuss the study fully with the patient and obtain written Informed 
Consent. The written ICF is to be signed by the patient and the Principal Investigator or 
designee. A copy of the signed ICF is to be given to the patient. 
5.4.2 Medical History 
Medical history includes the history of the neoplastic disease, its previous therapy and 
investigations as well as significant past and all co-existing diseases and current medications for 
the previous 5 years. 
5.4.3 Review Inclusion/Exclusion Criteria  
At Screening and prior to enrollment, the inclusion and exclusion criteria will be reviewed by 
the Principal Investigator or other qualified healthcare professional to ensure that the patient 
qualifies for the study.  
5.4.4 Randomization 
Once it has been confirmed that a patient is eligible for enrollment, as assessed by Spectrum, the 
patient will be randomized and receive a randomization number according to the information in 
Section 8.2. 
5.4.5 Physical Examination 
A complete physical examination, including a description of external signs of the neoplastic 
disease and co-morbidities is performed at the Screening Visit, Day 1 of each cycle, and at the 
End-of-Treatment Visit. Brief physical examinations are conducted at all other visits. Physical 
examinations are to be completed by a physician or other health professional licensed to perform 
such examinations. Findings will be documented in the patient’s medical record and on the 
appropriate CRF. Any abnormalities are to be recorded on the AE CRF.  
5.4.6 ECOG Performance Status 
Patient performance status will be evaluated using the ECOG criteria (Table 4).  




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agency will be made available for the convenience of patients who do not wish to make multiple 
trips to the study site. 
5.4.10 Chemistry 
Blood samples will be drawn for serum chemistry panel, including calcium, sodium, potassium, 
creatinine, total bilirubin, AST, ALT, alkaline phosphatase, will be drawn at Screening, Day 1 
of each treatment cycle and at the End-of-Treatment Visit. A urine beta-hCG pregnancy test 
needs to be performed at Screening for patients of childbearing potential.  
5.4.11 Pharmacokinetic Assessments 
All patients in the SPI-2012 Treatment Arm will have blood samples drawn for sparse PK 
sampling at 6 time points during the study period for population PK analysis. The sampling time 
points will be: 
 Cycle 1:  
 
Day 2 (1 to 4 hours after SPI-2012 administration) 
 
Day 4 (at the same time as CBC blood draw) 
 
Day 5 (at the same time as CBC blood draw) 
 Cycle 3: 
 
Day 2 (1 to 4 hours post-dose) 
 
Day 4 (±1 day, at the same time as CBC blood draw) 
 
Day 7 (±1 day, at the same time as CBC blood draw) 
5.4.12 Anti-Infective Use  
All anti-infectives prescribed by the Investigator or patients’ other health care providers during 
the study period will be recorded on the CRF.  
5.4.13 Immunogenicity Testing  
To assess immunogenicity, blood samples will be collected on Day 1 of Cycles 1 to 4, before the 
administration of corticosteroids, at the End-of-Treatment Visit, and also at approximately 
6 months and 12 months after Cycle 4, Day 2 or after the date of early discontinuation. Patients 
who received SPI-2012 will be tested for antibodies to SPI-2012, the Fc region of the SPI-2012 
molecule, the PEG moiety, and G-CSF, and those patients who received pegfilgrastim will be 
tested for antibodies to SPI-2012, PEG and G-CSF. All sera samples positive for G-CSF-binding 
antibodies will be further tested for G-CSF neutralizing antibodies.  
Details of blood sample collection, processing, and shipping instructions are described in the 
study binder/laboratory manual.  
5.4.14 Adverse Event  
At every visit, the Investigator or designee will inquire about adverse events and intercurrent 
illnesses since the last visit, which will be graded according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) Scale Version 4.03 for AE 
grading, and will record the pertinent information on the CRF. 


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At approximately 3 months and 9 months, the Investigator or designee will contact the patient by 
telephone and inquire about adverse events and intercurrent illnesses since the last visit, which 
will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Scale Version 4.03 for AE grading, and will record the pertinent 
information on the CRF. At approximately 6 months and 12 months AEs will be assessed at the 
study site. 
5.4.15 Concomitant Medications 
All medications administered from the time the ICF is signed through 35 (±5) days after the last 
dose of study drug administration will be recorded on the CRF. Start and stop dates and reasons 
for medication use will also be noted. Any hospitalizations will also be recorded on the CRF. 
After 35 (±5) days, and during the 12-Month Safety Follow-up Period, only additional 
treatment with myeloid growth factors, including filgrastim, pegfilgrastim or biosimilars, and 
additional anti-cancer therapy will be recorded.  
6 STUDY DRUG AND PHARMACEUTICAL INFORMATION  
6.1 SPI-2012 
SPI-2012 will be supplied by Spectrum.  
6.1.1 SPI-2012 Composition 
SPI-2012 (0.6 mL) is supplied in prefilled single-use syringes for subcutaneous injection. Each 
prefilled syringe of SPI-2012 contains 13.2 mg SPI-2012, equivalent to 3.6 mg G-CSF.  
6.1.2 SPI-2012 Storage and Handling 
SPI-2012 should be stored under refrigeration with temperature controlled between 2ºC and 8ºC 
(36ºF to 46ºF) and protected from light. Do not shake prefilled syringes. If SPI-2012 is 
accidentally frozen, do not use. SPI-2012 prefilled syringes can be left at room temperature for 
up to 12 hours.  
6.1.3 SPI-2012 Administration 
The dose of SPI-2012 to be administered is 13.2 mg/0.6 mL fixed dose SPI-2012 equivalent to 
3.6 mg G-CSF per cycle. SPI-2012 should be administered subcutaneously on Day 2, 
approximately 24 to 26 hours after TC administration. The entire content of the prefilled syringe 
should be administered. No dose modifications are allowed. 
6.2 Pegfilgrastim 
6.2.1 Pegfilgrastim Composition 
Pegfilgrastim will be supplied by Spectrum in 0.6 mL prefilled single-use syringes for 
subcutaneous injection. Each syringe contains 6 mg pegfilgrastim in a sterile solution. 


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6.2.2 Pegfilgrastim Supply  
Only pegfilgrastim (Neulasta [NDC 55513-190-01] manufactured by Amgen in the United 
States) and supplied by Spectrum will be used; no other G-CSFs, including biosimilars, are to 
be used in this study.  
6.2.3 Pegfilgrastim Storage and Handling 
Pegfilgrastim should be stored and handled in accordance with the Neulasta United States 
Package Insert (USPI).  
6.2.4 Pegfilgrastim Administration 
Pegfilgrastim 6 mg should be administered subcutaneously once per chemotherapy cycle on 
Day 2, approximately 24 to 26 hours after TC administration, according to the manufacturer’s 
prescribing information.  
The entire content of the prefilled syringe should be administered. No dose modifications are 
allowed. 
6.3 Blinding of Study Treatments 
This is an open-label study. No blinding will be applied.  
6.4 Randomization of Study Treatments 
Patients who meet all eligibility criteria will be considered for randomization. Eligibility of all 
patients will be reviewed and approved for randomization by the Sponsor’s Medical Monitor, or 
designee. Patients approved for randomization will be randomized 1:1 to receive either SPI-2012 
or pegfilgrastim. The detail of the randomization scheme is provided in Section 8.2. 
6.5 Non-study Treatments 
6.5.1 Prior and Concomitant Medications 
A concomitant medication is any medication a patient entering the trial is using from Day 1 of 
Cycle 1 to the End-of-Treatment Visit. The study drugs are not considered concomitant 
medications. 
All concomitant medications recorded at trial entry must have a related, ongoing concomitant 
illness listed under the medical history at the time of patient entry into the trial unless the 
medication is used for prophylaxis. Patients may continue to use any ongoing medications not 
prohibited by the protocol. 
All prescription and over-the-counter medications at trial entry as well as any new medications 
started during the trial must be documented on the CRF and in the source documents. The 
documentation should continue through the end of the 12-Month Safety Follow-up Period 
(approximately 12 months after the last dose of study treatment) or 35 (±5) days after the date of 
patient early discontinuation. During the study treatment period and the subsequent 12-Month 
Safety Follow-up Period, additional, concomitant treatment with myeloid growth factors, 
including filgrastim, pegfilgrastim or its biosimilars, and other anti-cancer therapy are prohibited 
with the exception of hormonal therapy and HER-2 targeted therapy for the patients who need 
such a targeted therapy.  


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Premedications (such as antiemetics) used for supportive care are allowed as per institutional 
standards or guidelines. 
Corticosteroids as premedication for docetaxel are allowed during study treatment. Other uses of 
systemic steroids must be approved by the Medical Monitor. 
6.5.2 Prohibited Therapies or Medications 
No other anti-cancer therapy including chemotherapy, radiation therapy, immunotherapy, or 
experimental medications are permitted during the study, except that radiation therapy is allowed 
during the 12-Month Safety Follow-up Period. Any disease progression that requires anti-
tumor therapy, other than TC, will be cause for discontinuation from the trial. 
No myeloid growth factors other than study drugs (SPI-2012 or pegfilgrastim) are to be 
administered to patients at any time during the treatment phase or follow-up. 
No white blood cell or whole blood transfusions are allowed. 
7 SAFETY ASSESSMENT 
7.1 Safety Measures 
It is the responsibility of the Principal Investigator to oversee the safety of the patients at their 
site and to report all AEs/SAEs that are observed or reported during the study, regardless of 
relationship to study drug or clinical significance.  
Safety data will also be reviewed on a regular basis by Spectrum’s study monitoring team, which 
includes a Clinical Research Associate (CRA), Medical Monitor, and other personnel from the 
company or its designee.  
Adverse events will be characterized by intensity (severity), causality, and seriousness by the 
Investigator based on the regulatory definitions included below. 
This study will utilize the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Scale Version 4.03 for AE grading. 
7.2 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
patient, temporally associated with the use of a medicinal product or study procedure, whether or 
not considered related to the medicinal product. Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a medicinal product. A treatment-emergent 
AE (TEAE) is any AE that occurs from the first dose of study treatment through 12 months after 
the last dose of study treatment or 35 (±5) days after the date of patient early discontinuation. 
Additionally, as applicable, patients who receive at least one dose of study drug (SPI-2012 or 
pegfilgrastim) will be followed for safety for 12 months after the last dose of study treatment or 
date of patient early discontinuation. All AEs during this time period will be recorded. 
The study will record all AEs according to the information in Section 7.3. 


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Examples of AEs include: 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after investigational product administration. 
 Signs, symptoms, or the clinical sequelae of a suspected drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concurrent medication. 
 AEs may include pre-treatment or post-treatment events that occur as a result of protocol-
mandated procedures, ie, invasive procedures. 
Abnormal laboratory results are to be recorded as AEs, if any of the following conditions are 
met: 
 The abnormal laboratory value leads to a therapeutic intervention. 
 The abnormal laboratory value is considered to be clinically significant by the 
Investigator. 
 The abnormal laboratory value is predefined as an AE in the protocol or in another 
document communicated to the Investigator by Spectrum or designee. 
 The abnormal laboratory value is ≥Grade 3 based on CTCAE Version 4.03. 
Examples of events that do not constitute AEs include: 
 Medical or surgical procedures (eg, endoscopy, appendectomy); the condition that leads 
to the procedure is an AE. 
 Situations where an untoward medical occurrence does not occur (eg, social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.  
 Planned and prescheduled hospitalizations and procedures.  
 Progressive disease. 
7.3 Guidelines for Recording and Attribution Scoring of Adverse Events 
Timely and complete reporting of all AEs is required for all patients. Monitoring and 
documentation of all AEs allows for identification of potential study-drug or dose-related AEs, 
and for adherence to regulatory requirements. Please refer to the CRF Completion Guidelines 
located in the study binder for detailed instructions for AE reporting. 
7.3.1 Recording of Adverse Events 
All AEs that occur from the first dose of study treatment through 35 (±5) days after last dose of 
study treatment (SPI-2012 or pegfilgrastim) or 35 (±5) days after the date of patient early 
discontinuation are to be recorded on the AE CRF. Additionally, all patients who receive at least 
one dose of study drug will have all AEs recorded through the end of the 12 Month Safety 
Follow-up Period. From the time the study ICF is signed through the first dose of study drug 
administration, only SAEs that are related to study procedures are to be recorded. 






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Adverse events that do not meet any of the above criteria for serious will be regarded as not 
serious. 
7.7.1 Serious Adverse Event Reporting 
All SAEs that occur from the time the study Informed Consent is obtained and through the end 
of the 12 Month Safety Follow-up Period are to be reported to Spectrum within 24 hours of 
knowledge of the event, with exception that from the time the study ICF is signed through the 
first dose of study drug administration, only SAEs that are related to study procedures are to be 
recorded.  
SAEs (regardless of their relationship to study treatment) are to be reported and the Serious 
Adverse Event Report (SAER) faxed or e-mailed within 24 hours of knowledge of the event to: 
Spectrum Pharmaceuticals, Inc. 
Primary Contact: Pharmacovigilance Department 
Fax: 
 
E-mail:
 
Spectrum may request additional information from the Investigator to ensure the timely 
completion of accurate safety reports. Safety data that are critical to the reportability of an SAE, 
such as causality assessment and seriousness criteria, should be included in the initial faxed or 
e-mailed SAER. If omitted, a timely response to drug safety data queries received from Spectrum 
or designee is expected. 
The Investigator is to take all appropriate therapeutic measures necessary for resolution of SAEs. 
Any medications necessary for treatment of the SAE are to be recorded in the concomitant 
medication section of the patient’s CRF. 
SAEs that are study treatment-related will be followed until resolution or until they have returned 
to Grade 1, whichever is longer, or until it is determined that the outcome will not change with 
further follow-up. 
Additionally, the SAE is to be entered in the AE CRF. Follow-up SAERs need to be submitted to 
Spectrum within 24 hours once additional information regarding the event becomes available 
(eg, final diagnosis is made, laboratory or test results, event course, outcome, etc).  
Spectrum or designee will be responsible for reporting SAEs to the regulatory authorities in 
accordance with applicable expedited reporting regulatory guidelines. The Investigator is 
responsible for submitting SAEs to his/her local Institutional Review Board (IRB)/Ethics 
Committee (EC). Copies of each SAER, and documentation of IRB/EC notification and 
acknowledgement of receipt, will be kept in the Site’s Regulatory Binder. 
7.7.2 Exclusions to Serious Adverse Event Reporting Requirements 
The following are not considered SAEs: 
 Situations where an untoward medical occurrence did not occur (eg, social and/or 
convenience admission to a hospital, hospitalization for diagnostic tests such as CT 
scans). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected prior to first study treatment administration that do not worsen. 


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 Planned and prescheduled hospitalizations and procedures.  
 Progressive disease. 
7.8 Reproductive Risks 
No adequate and well-controlled studies of SPI-2012 have been conducted in pregnant women. 
The effects of SPI-2012 on fertility and fetal development have not been studied in pregnant 
women. SPI-2012 is not recommended for use during pregnancy. 
Pregnancies involving a study patient or a patient’s partner, that occur from the first dose of 
study treatment through 35 (±5) days after last dose of study drug administration or 35 (±5) days 
after the date of patient early discontinuation, will be reported within 24 hours after the 
Investigator has gained knowledge of the event via fax or e-mail (see contact information in 
Section 7.7.1). Pregnancies should be followed up until outcome and follow-up information 
regarding the outcome of the pregnancy should be faxed or e-mailed to Spectrum’s 
Pharmacovigilance Department.  
All patients who become pregnant during participation in this study are to be withdrawn from the 
study. 
8 STATISTICAL PLAN  
This section contains a brief overview of the statistical analyses planned for this study. A formal 
statistical analysis plan (SAP) will be finalized prior to first patient enrolled.  
8.1 Sample Size  
Approximately 400 patients will be enrolled in this study. The primary endpoint analysis is based 
on the test of non-inferiority of SPI-2012 as compared to pegfilgrastim. The pooled standard 
deviation of DSN is assumed to be 2.0 days, after referencing the assumptions used in the two 
Phase 3 registrational pegfilgrastim trials [28]. The standard deviation used for sample size 
calculation in the two Phase 3 pegfilgrastim trials was 2.17 and 1.5 days, respectively.  
For the test of non-inferiority hypothesis, the margin of non-inferiority to be used in the study is 
0.62 day. The true difference between the means is assumed to be 0.0 days. Sample sizes of 
200patients per treatment arm will achieve 87% power to detect non-inferiority using a one-
sided, two-sample t-test at 2.5% level of significance. The study will enroll and randomize 200 
patients per arm for a total of approximately 400 patients.  
The non-inferiority of SPI-2012 to pegfilgrastim will be declared if the upper bound of 95% CI 
of the difference in mean DSN between the treatment arms is <0.62 days.  
8.2 Method of Treatment Assignment, Randomization, and/or Stratification 
The patients enrolled in this study will be randomized at a 1:1 ratio to the SPI-2012 and 
pegfilgrastim treatment arms and stratified by study site. A randomization scheme using a 
permuted block design will be developed. An interactive web response system will be used to 
assign a randomization identification (ID) once patients meet eligibility criteria and are ready to 
be randomized. The randomization ID will be different than the Patient ID, and a mapping of 
randomization ID to Patient ID will be kept in a secured database.  


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8.3 Analysis Populations 
 Intent-to-Treat Population (ITT): will consist of all patients who are randomized. 
Patients will be analyzed as randomized if the actual treatment assignments deviate from 
the randomization scheme.  
 Per Protocol (PP) Population: will include all patients in the ITT population with no 
major protocol deviation in Cycle 1. Patients will be analyzed as treated if the actual 
treatment assignments deviate from the randomization scheme.  
 Safety Analysis Population (SAF): will consist of all patients who receive at least one 
dose of any protocol-specified drug (TC or SPI-2012 or pegfilgrastim) 
Patients who discontinue from the study prior to randomization will be replaced as they are not 
considered to be the ITT patients.  
8.4 General Statistical Methods 
Spectrum’s Biostatistics and Data Management (BDM) group (or a contracted data management 
vendor) will be responsible for data management and statistical analysis of this study. All 
statistical analyses will be performed using SAS for Windows (version 9.3 or higher). Patient 
data listings and tabular presentations of results will be provided. Further details of the criteria 
and conduct of the statistical analyses will be included in the Statistical Analysis Plan for this 
study to be finalized prior to first patient enrolled. 
8.5 Efficacy Analyses 
8.5.1 Primary Endpoint 
The primary analysis of the comparison of the DSN in Cycle 1 between the SPI-2012 
Treatment Arm and the Pegfilgrastim Treatment Arm will be conducted using the ITT 
Population. 
DSN in Cycle 1 is defined as the number of days of severe neutropenia (ANC <0.5×109/L) from 
the first occurrence of an ANC below the threshold. The assessment of ANC will be performed 
on Day1 and Days 4-15 in Cycle 1. The endpoint will be measured in all patients in the ITT 
Population. For patients who do not meet severe neutropenia criteria, the endpoint measurement 
will be defined as DSN=0. 
For the primary efficacy analysis, the mean DSN in Cycle 1 will be compared between the 
SPI-2012 Treatment Arm and the Pegfilgrastim Treatment Arm using a bootstrap resampling 
method with non-inferiority hypothesis. A 2-sided 95% confidence interval (CI) of the difference 
between the mean DSN of the SPI-2012 Treatment Arm and the mean DSN of the 
Pegfilgrastim Treatment Arm will be calculated using bootstrap resampling with treatment as 
the only stratification factor. The study will use non inferiority margin of 0.62 days for the above 
comparison. The non-inferiority of SPI-2012 to pegfilgrastim will be declared if the upper bound 
of 95% CI of the difference in mean DSN between the treatment arms is <0.62 days.  
Primary analysis for the non-inferiority hypothesis will be based on the ITT population. An 
analysis based on the PP Population will be performed as a sensitivity analysis.  
In addition to bootstrap resampling method to calculate 95% CI of the difference in mean DSN 
between treatment arms, the test of the difference in mean DSN between treatment arms will be 


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conducted using Poisson distribution as another sensitivity analysis. If the data is overdispersed, 
a negative binomial distribution will be incorporated for the test. For the Poisson and negative 
binomial regression, the identical link will be used and treatment will be the only covariate in the 
model. The difference in mean DSN between SPI-2012 and pegfilgrastim will be calculated 
along with 2-sided 95% CI, based on Poisson or negative binomial regression. Based on the 
initial review of the efficiency of the estimates of bootstrap, Poisson and negative binomial 
distributions, 95% CI calculated using bootstrap resampling method appear to be robust and 
therefore is proposed to be the primary analysis method for the primary endpoint. Detailed 
simulation results will be provided along with SAP.  
Additional sensitivity analyses will also be used to examine the: 
 Treatment effect, adjusting for the various study sites. This analysis will be carried out 
using the same methodology as the primary analysis (bootstrap resampling method), and 
study site will be used as an additional stratification factor in the resampling.  
 Treatment effect, adjusting for disease status at randomization (adjuvant or neoadjuvant). 
This analysis will be the same as the primary analysis (bootstrap resampling method) and 
disease status will be used as additional stratification factor in the resampling. 
 Impact of missing data, using a worst case scenario. When ANC data are missing on or 
after Day 5, and before patients’ ANC increase to ≥1.5×109/L after the expected nadir in 
Cycle 1, missing ANC values will be imputed as <0.5×109/L for SPI-2012 and ≥0.5×
109/L for pegfilgrastim, for the purpose of DSN calculation. The method of analysis of 
imputed DSN data using worst case scenario will be the same as the primary analysis 
(bootstrap resampling method).  
In addition, the following subgroups will be examined for DSN in Cycle 1:  
 Age: <65 years, ≥65 years 
 Gender (Male, Female) 
 Race 
 Disease Status (Adjuvant, Neoadjuvant) at randomization 
 Geographic Region  
 Weight: <65 kg, 65 to 75 kg, or >75 kg 
8.5.2 Key Secondary Endpoints 
 To compare SPI-2012 with pegfilgrastim in:  
 Time to ANC Recovery in Cycle 1, defined as the time from chemotherapy 
administration until the patient’s ANC increases to ≥1.5×109/L after the expected 
nadir. For patients with ANC value ≥1.5×109/L at all times, Time to ANC Recovery 
will be assigned to a value of 0. 
 Depth of ANC Nadir, defined as the patient’s lowest ANC in Cycle 1 
 Incidence of FN in patients during Cycle 1, in which FN is defined as an oral 
temperature >38.3°C (101.0°F) or two consecutive readings of >38.0°C (100.4°F) for 
2 hours and ANC <1.0×109/L 


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8.5.3 Additional Secondary Endpoints 
 To compare SPI-2012 with pegfilgrastim in: 
 DSN in Cycles 2, 3, and 4 
 Incidence of neutropenic complications, including use of anti-infectives and 
hospitalizations, in patients during Cycle 1 
 Incidence of FN in Cycles 2, 3, and 4 
 RDI of TC in Cycles 1 to 4 
 Safety 
The analyses of Key Secondary Endpoints will employ a hierarchical closed testing procedure 
[29], where endpoints are ranked with the primary endpoint first and then the Key Secondary 
Endpoints in the order listed above. Specifically, the order of testing is: 
1. DSN in Cycle 1 
2. Time to ANC Recovery in Cycle 1 
3. Depth of ANC Nadir in Cycle 1 
4. Incidence of FN in Cycle 1 
For the secondary efficacy analyses, the results will each be summarized by Treatment Arm and 
Cycle and will use the ITT population. Two-sided 95% CI for the difference between the 
treatment arms will be calculated. 
No adjustment to alpha will be necessary once the preceding endpoint comparison is significant 
for the subsequent endpoints in the above order of endpoints, with each test at the same 
significance level of α=0.05. 
8.6 Analysis of Safety 
The overall incidence of treatment-emergent AEs (TEAE) (ie, AEs occurring from the time the 
first dose of the study drug through 12 months after the last dose of study drug administration or 
35 (±5) days after the date of patient early discontinuation) and the proportion of patients who 
discontinue because of a TEAE are the primary safety outcome measures.  
The number and percent of patients with new-onset TEAEs will be summarized by the MedDRA 
System-Organ-Class (SOC) level and Preferred Term (PT) for all treated patients. The summary 
of TEAEs will be presented in the following categories:  
 Number and percentage of patients with any TEAEs by SOC and PT. 
 Number and percentage of patients with any SAEs by SOC and PT. 
 Number and percentage of patients with related TEAEs by SOC and PT. 
 
Related to TC 
 
Related to SPI-2012 
 
Related to pegfilgrastim  
 Number and percentage of patients with TEAEs causing discontinuation of the study by 
SOC and PT. 


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 Number and percentage of patients with Adverse Events of Special Interest (AESIs) 
(musculoskeletal pain and injection site reactions) by PT. 
 Number and percentage of patients with AEs of Special Interest 
 
Musculoskeletal pain  
 
Injection site reactions 
 
Hypersensitivity reactions  
In addition, the number and percent of patients with TEAEs by grade will be summarized. 
Adverse events reported prior to treatment but after Informed Consent will be provided in a 
listing. An exposure-response analysis will be performed based on sparse PK sampling. 
8.7 Clinical Laboratory and Vital Signs Evaluations 
Key laboratory parameters and vital signs will be summarized using shift tables, which will 
display a cross-tabulation of the Baseline grade versus the highest on-study grade for each 
laboratory parameter.  
All abnormalities will be classified according to NCI CTCAE Version 4.03 and summarized by 
worst grade severity per patient by cycle and by treatment within cycle.  
9 ADMINISTRATIVE PROCEDURES AND STUDY MANAGEMENT  
9.1 Investigator Responsibilities  
9.1.1 Good Clinical Practice  
It is the responsibility of the Principal Investigator to oversee the safety of the patients at their 
site. The Investigator will ensure that this study is conducted in full compliance with the 
principles of the “Declaration of Helsinki” (as amended in Tokyo, Venice, Hong Kong, and 
South Africa), ICH guidelines, or with the laws and regulations of the country in which the 
research is conducted. By signing the US Form FDA 1572, “Statement of Investigator,” the 
Investigator commits to adhere to applicable sections of the US CFR parts 50 “Protection of 
Human Patients,” 54 “Financial Disclosure by Clinical Investigators,” 56 "Institutional Review 
Boards,” and 312 subpart D “Responsibilities of Sponsors and Investigators.” All Investigators 
will ensure adherence to ICH guidelines for GCP and Clinical Safety Data Management. 
9.1.2 Institutional Review Board/Ethics Committee Approval 
The Investigator shall assure that the IRB/EC will provide initial and continuing review of the 
study. Prior to screening and enrollment of study patients, documented IRB/EC approval of the 
protocol, ICF and any patient materials must be obtained and provided to Spectrum or its 
designee. 
9.1.3 Informed Consent  
The investigator will ensure that the method of obtaining and documenting the Informed Consent 
complies with ICH-GCP and all applicable regulatory requirement(s). Informed Consent must be 
obtained before study procedures are performed, unless performed as standard of care. The 
subject’s source documents shall document the informed consent process and that Informed 
Consent was obtained prior to study participation. A copy of each signed ICF must be provided 


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to the patient or the patient’s legally authorized representative. All signed ICFs must remain in 
each patient’s study file and must be available for verification at any time. 
9.1.4 Study Files and Retention of Records 
The Investigator will retain all study records until at least 2 years after the last approval of a 
marketing application or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer 
period, however, if required by the applicable regulatory requirements or by an agreement with 
Spectrum. If the Investigator relocates, or for any reason desires to dispose of the records, the 
study records may be transferred to another institution, another investigator, or to Spectrum upon 
written agreement between the Investigator and Spectrum.  
9.2 Recording and Collecting of Data 
In accordance with ICH and GCP guidelines, the Investigator will maintain complete, accurate, 
legible, and easily retrievable data, and will allow personnel authorized by Spectrum access to all 
study data at any time. Such data shall also be secured in order to prevent loss of data. 
9.2.1 Case Report Forms 
At scheduled monitoring visits, CRFs will be verified against source documentation and 
submitted as final data. Any subsequent changes to the CRFs are to be performed in accordance 
with Spectrum’s standard operating procedures for editing and clarifying CRFs. Data entry will 
be performed by the sites using an electronic data capture (EDC) system.  
9.2.2 Drug Accountability 
In accordance with all applicable regulatory requirements, the Investigator or designated site 
staff is to maintain study treatment accountability records throughout the course of the study. 
This person(s) will document the amount of the study drug (SPI-2012 or pegfilgrastim 
administered to patients. The CRA will review inventory and accountability documentation 
during monitoring visits. 
The Investigator will not supply investigational study drugs to other investigators not listed on 
the US Form FDA 1572 or equivalent. Investigational study drug use, other than as directed by 
this protocol, is not allowed. 
All unused syringes of SPI-2012 are to be accounted for at the site and maintained in a secured, 
locked storage area with access limited to authorized study personnel only. Used SPI-2012 
syringes will be destroyed per institution, local, and all applicable policies and procedures. After 
study conclusion, all unused syringes of SPI-2012 may be destroyed at the site, following 
verification of accountability by a Spectrum representative. 
9.3 Protocol Compliance 
The Principal Investigator is responsible for ensuring the study is conducted in accordance with 
the procedures and evaluations described in this protocol. 


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9.4 Sponsor Responsibilities 
9.4.1 Study Monitoring 
The study will be monitored by employees or representatives of Spectrum. CRAs will monitor 
each site on a periodic basis and perform verification of source documentation for each patient as 
well as other routine compliance reviews. Spectrum’s Medical Monitor and Pharmacovigilance 
Department will review safety data and be responsible for ensuring timely reporting of expedited 
SAERs to regulatory agencies and Investigators. 
9.4.2 Safety Monitoring 
The clinical drug safety of study treatment will be continuously evaluated by the study Medical 
Monitor or designee on an ongoing basis during the course of this clinical study. All SAEs 
related to study treatment in this study and all other ongoing clinical studies with study treatment 
will be processed in compliance with current regulatory guidelines by Spectrum’s 
Pharmacovigilance Department. This processing will include a formal assessment of each SAE 
by drug safety. In addition, a cumulative review of all SAEs from all sources will be assessed 
periodically  
9.5 Joint Investigator/Sponsor Responsibilities 
9.5.1 Access to Information for Monitoring and Auditing 
In accordance with ICH GCP guidelines and 21 CFR 312, the CRA/auditor is to have direct 
access to the patient’s source documentation in order to verify the data recorded in the CRFs. 
The CRA is responsible for routine review of the CRFs at regular intervals throughout the study 
and to verify adherence to the protocol, as well as the completeness, consistency, and accuracy of 
the data being recorded. The CRA/auditor is to have access to any patient records needed to 
verify the entries on the CRFs, as well as access to all other study-related documentation and 
materials. The Investigator agrees to provide the monitor with sufficient time and facilities to 
conduct monitoring. 
9.5.2 Termination of the Study 
For reasonable cause, either the Investigator or Spectrum may terminate the Investigator’s 
participation in this study. In addition, Spectrum Pharmaceuticals Inc. may terminate the study at 
any time upon immediate notice for any reason, including but not limited to, Spectrum’s belief 
that termination is necessary for the safety of patients. 
9.5.3 Publication Policy 
To coordinate the dissemination of data from this study, Spectrum encourages the formation of a 
publication committee consisting of the Principal Investigator and appropriate Spectrum staff. 
The committee is expected to solicit input and assistance from other Investigators and Sponsor 
staff as appropriate. Membership on the committee (both for Investigators and Staff) does not 
guarantee authorship- the criteria described below should be met for every publication. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirements for Manuscript Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors, 2005), which states: 


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Protocol Number: SPI-GCF-301 
Amendment 1/26 Jan 2017 
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 Authorship credit should be based on the following; authors should meet all three 
conditions:  
1. Substantial contributions to conception and design, acquisition of data, or analysis 
and interpretation of data;  
2. Drafting the article or revising it critically for important intellectual content; and  
3. Final approval of the version to be published.  
 When a large, multicenter group has conducted the work, the group should identify the 
individuals who accept direct responsibility for the manuscript. These individuals should 
fully meet the criteria for authorship defined above.  
 Acquisition of funding, collection of data, or general supervision of the research group 
alone does not constitute authorship. 
 All persons designated as authors should qualify for authorship, and all those who qualify 
should be listed. 
 Each author should have participated sufficiently in the work to take public responsibility 
for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, books chapters) based on 
this study must be submitted to Spectrum within 30 days (but no less than 10 days) prior to 
submission or publication for corporate review.  
9.6 Confidentiality 
All information provided to the Investigator by Spectrum, including nonclinical data, protocols, 
CRFs, and verbal and written information, will be kept strictly confidential and confined to the 
clinical personnel involved in conducting this study, and no disclosure shall be made except in 
accordance with any right of publication granted to the Investigator. All personnel will handle 
patient data in a confidential manner in accordance with applicable regulations governing clinical 
research. Upon request by a regulatory authority such as the US FDA and other regulatory 
authorities worldwide, the Investigator/institution is to make available for direct access all 
requested study-related records or reports generated as a result of a patient’s participation in this 
study. This information may be related in confidence to the IRB/EC or other committee 
functioning in a similar capacity. In addition, no reports or information about the study or its 
progress will be provided to anyone not involved in the study other than to Spectrum, or in 
confidence to the IRB/EC or similar committee, except if required by law. 


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Protocol Number: SPI-GCF-301 
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53 
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American Cancer Society - Cancer Facts and Figures 2014. 
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National Comprehensive Cancer Network. Breast Cancer (Version 3, 2014) [September 
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Harlan LC, Abrams J, Warren JL, Clegg L, Stevens J, Ballard-Barbash R. Adjuvant 
Therapy for Breast Cancer: Practice Patterns of Community Physicians. J Clin Oncol. 
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Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, et al. 
Docetaxel with Cyclophosphamide Is Associated with an Overall Survival Benefit 
Compared with Doxorubicin and Cyclophosphamide: 7-Year Follow-up of Us Oncology 
Research Trial 9735. J Clin Oncol. 2009;27(8):1177-83. 
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Cortes-Funes H, Coronado C. Role of Anthracyclines in the Era of Targeted Therapy. 
Cardiovasc Toxicol. 2007;7(2):56-60. 
6. 
Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S, et al. Phase 
Iii Trial Comparing Doxorubicin Plus Cyclophosphamide with Docetaxel Plus 
Cyclophosphamide as Adjuvant Therapy for Operable Breast Cancer. J Clin Oncol. 
2006;24(34):5381-7. 
7. 
Trent JC, Valero V, Booser DJ, Esparza-Guerra LT, Ibrahim N, Rahman Z, et al. A Phase 
I Study of Docetaxel Plus Cyclophosphamide in Solid Tumors Followed by a Phase Ii 
Study as First-Line Therapy in Metastatic Breast Cancer. Clin Cancer Res. 
2003;9(7):2426-34. 
8. 
Bordoni R, Haislip S, Gilmore J, Sharpe J, Abella E, Choi M. P5-20-07: Estimation of 
Febrile Neutropenia in Women Receiving Docetaxel Plus Cyclophosphamide as 
Adjuvant Therapy for Early Stage Breast Cancer: A Retrospective Analysis. Cancer 
Research. 2011;71(24 Supplement 3). 
9. 
Chan A, Fu WH, Shih V, Coyuco JC, Tan SH, Ng R. Impact of Colony-Stimulating 
Factors to Reduce Febrile Neutropenic Events in Breast Cancer Patients Receiving 
Docetaxel Plus Cyclophosphamide Chemotherapy. Support Care Cancer. 
2011;19(4):497-504. 
10. 
Myers R, Higgins B, Myers J, Leung M, Rajagopal S, Jones G, et al. Chemotherapy 
Induced Febrile Neutropenia of Docetaxel with Cyclophosphamide (Tc) for Adjuvant 
Therapy of Breast Cancer in the Community: Reality Check. Cancer Research. 
2009;69(24 Suppl):Abstract nr 2092. 
11. 
Soong D, Haj R, Leung MG, Myers R, Higgins B, Myers J, et al. High Rate of Febrile 
Neutropenia in Patients with Operable Breast Cancer Receiving Docetaxel and 
Cyclophosphamide. J Clin Oncol. 2009;27(26):e101-2. 
12. 
Vandenberg T, Younus J, Al-Khayyat S. Febrile Neutropenia Rates with Adjuvant 
Docetaxel and Cyclophosphamide Chemotherapy in Early Breast Cancer: Discrepancy 
between Published Reports and Community Practice-a Retrospective Analysis. Curr 
Oncol. 2010;17(2):2-3. 


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13. 
Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of Primary Prophylaxis with 
Granulocyte Colony-Stimulating Factor on Febrile Neutropenia and Mortality in Adult 
Cancer Patients Receiving Chemotherapy: A Systematic Review. J Clin Oncol. 
2007;25(21):3158-67. 
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Lyman GH, Michels SL, Reynolds MW, Barron R, Tomic KS, Yu J. Risk of Mortality in 
Patients with Cancer Who Experience Febrile Neutropenia. Cancer. 2010;116(23):5555-
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National Comprehensive Cancer Network. Myeloid Growth Factors (Version 2, 2014). 
Available from: www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf. 
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Dale DC, McCarter GC, Crawford J, Lyman GH. Myelotoxicity and Dose Intensity of 
Chemotherapy: Reporting Practices from Randomized Clinical Trials. J Natl Compr Canc 
Netw. 2003;1(3):440-54. 
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Lyman GH, Kuderer NM, Crawford J, Wolff DA, Culakova E, Poniewierski MS, et al. 
Predicting Individual Risk of Neutropenic Complications in Patients Receiving Cancer 
Chemotherapy. Cancer. 2011;117(9):1917-27. 
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Fortner BV, Schwartzberg L, Tauer K, Houts AC, Hackett J, Stolshek BS. Impact of 
Chemotherapy-Induced Neutropenia on Quality of Life: A Prospective Pilot 
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Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, et al. 2010 
Update of Eortc Guidelines for the Use of Granulocyte-Colony Stimulating Factor to 
Reduce the Incidence of Chemotherapy-Induced Febrile Neutropenia in Adult Patients 
with Lymphoproliferative Disorders and Solid Tumours. Eur J Cancer. 2011;47(1):8-32. 
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Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 2006 
Update of Recommendations for the Use of White Blood Cell Growth Factors: An 
Evidence-Based Clinical Practice Guideline. J Clin Oncol. 2006;24(19):3187-205. 
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Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tabbara I, et al. Reduction by 
Granulocyte Colony-Stimulating Factor of Fever and Neutropenia Induced by 
Chemotherapy in Patients with Small-Cell Lung Cancer. N Engl J Med. 
1991;325(3):164-70. 
22. 
Gabrilove JL, Jakubowski A, Scher H, Sternberg C, Wong G, Grous J, et al. Effect of 
Granulocyte Colony-Stimulating Factor on Neutropenia and Associated Morbidity Due to 
Chemotherapy for Transitional-Cell Carcinoma of the Urothelium. N Engl J Med. 
1988;318(22):1414-22. 
23. 
Morstyn G, Campbell L, Souza LM, Alton NK, Keech J, Green M, et al. Effect of 
Granulocyte Colony Stimulating Factor on Neutropenia Induced by Cytotoxic 
Chemotherapy. Lancet. 1988;1(8587):667-72. 
24. 
Trillet-Lenoir V, Green J, Manegold C, Von Pawel J, Gatzemeier U, Lebeau B, et al. 
Recombinant Granulocyte Colony Stimulating Factor Reduces the Infectious 
Complications of Cytotoxic Chemotherapy. Eur J Cancer. 1993;29a(3):319-24. 


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25. 
Meza LA, Green MD, Hackett JR, Neumann TA, Holmes FA. Filgrastim-Mediated 
Neutrophil Recovery in Patients with Breast Cancer Treated with Docetaxel and 
Doxorubicin. Pharmacotherapy. 2003;23(11):1424-31. 
26. 
Meza L, Baselga J, Holmes F, Liang B, Breddy J. Incidence of Febrile Neutropenia (FN) 
Is Directly Related to Duration of Severe Neutropenia (Dsn) after Myelosuppressive 
Chemotherapy Proc Am Soc Clin Oncol. 2002;21:2840. 
27. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-55. 
28. 
Gnecco C. Neulasta Statistical Review. In: Research Center for Drug Evaluation and 
Research and Center for Biologics Evaluation and Research. 2002. 
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Lubsen J, Kirwan B-A. Combined Endpoints: Can We Use Them? Statistics in Medicine. 
2002;21(19):2959-70. 
 
 
 
 





SAP_001.pdf: 
Official Title: 
NCT Number: 
Document Date: 
RAnDomized Trial of SPI-2012 Versus Pegfilgrastim in the Management of 
Chemotherapy Induced Neutropenia in Breast CANCEr Patients Receiving 
Docetaxel and Cyclophosphamide (TC) (ADVANCE)
NCT02643420 
SAP Version 1.3 : 31 Jul 2018 




SPI-2012 (Rolontis™, eflapegrastim, HM10460A, LAPS-G-CSF) 
Statistical Analysis Plan 
IND 103,461 – Version 1.3 – 31 Jul 2018 
1.1 SAP Amendment: Summary of Changes 
The purpose of Amendment Version 1.2 is to incorporate the following major changes to the 
current SAP: 
• Reorder the contents of SAP to reflect the updates of SOP of Spectrum Pharmaceuticals, 
Inc. 
• To revise section 7.1.2 for clarification of missing data handling. 
• To revise section 7.3.1.3 updating the method of sensitivity analysis using worst case 
scenario. 
See Appendix A - SAP Amendment: List of Changes, for an itemized list of all changes made to 
the SAP under this amendment. 
 
 




SPI-2012 (Rolontis™, eflapegrastim, HM10460A, LAPS-G-CSF) 
Statistical Analysis Plan 
IND 103,461 – Version 1.3 – 31 Jul 2018 
2.0 
TABLE OF CONTENTS 
 
1.0 
TITLE PAGE ................................................................................................. 1 
1.1 
SAP Amendment: Summary of Changes ............................................................................ 2 
2.0 
TABLE OF CONTENTS .............................................................................. 3 
2.1 
LIST OF TABLES .............................................................................................................. 5 
Table 1 
Summary of Baseline for Each Endpoint/Data 11 ..................... 5 
Table 2 
Simulation Results 19 ................................................................... 5 
2.2 
List of Appendices .............................................................................................................. 5 
3.0 
INTRODUCTION ......................................................................................... 6 
4.0 
OBJECTIVES ................................................................................................ 6 
4.1 
Primary Objective: .............................................................................................................. 6 
4.2 
Key Secondary Objectives: ................................................................................................. 6 
4.3 
Additional Secondary Objectives: ...................................................................................... 6 
5.0 
STUDY OVERVIEW .................................................................................... 6 
5.1 
Sample Size Considerations ................................................................................................ 8 
5.2 
Randomization .................................................................................................................... 8 
6.0 
ANALYSIS POPULATIONS ....................................................................... 9 
7.0 
STATISTICAL METHODS OF ANALYSIS ...........................................11 
7.1 
General Principles ............................................................................................................. 11 
7.1.1 Definition of Baseline Values ........................................................................................... 11 
7.1.2 Handling of Missing Data ................................................................................................. 12 
7.1.3 Pooling of Centers............................................................................................................. 14 
7.1.4 Interim Analysis ................................................................................................................ 14 
7.1.5 Testing/Validation Plan .................................................................................................... 14 
7.2 
Background Characteristics .............................................................................................. 14 
7.2.1 Patient Disposition ............................................................................................................ 14 
7.2.2 Demographic and Baseline Characteristics ...................................................................... 15 
7.2.3 Drug Exposure and Compliance ....................................................................................... 15 
7.2.4 Medical History ................................................................................................................ 16 
7.2.5 Concomitant Medication ................................................................................................... 16 
7.2.6 Protocol Deviations ........................................................................................................... 16 
7.3 
Efficacy Analyses ............................................................................................................. 17 
7.3.1 Primary Efficacy Endpoint ............................................................................................... 17 
7.3.1.1 
SAS Code for Primary Analysis ............................................................................. 18 


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IND 103,461 – Version 1.3 – 31 Jul 2018 
7.3.1.2 
Justification of Bootstrap Resampling Method as Primary Analysis ..................... 18 
7.3.1.3 
Additional Sensitivity Analysis .............................................................................. 20 
7.3.1.4 
Subgroup Analysis .................................................................................................. 21 
7.3.2 Key Secondary Efficacy Endpoints .................................................................................. 22 
7.3.2.1 
Time to ANC Recovery in Cycle 1 ......................................................................... 22 
7.3.2.2 
Depth of ANC Nadir in Cycle 1 ............................................................................. 22 
7.3.2.3 
Incidence of Febrile Neutropenia in Cycle 1 .......................................................... 22 
7.3.3 Testing Procedure for Primary and Key Secondary Efficacy Endpoints .......................... 23 
7.3.4 Additional Secondary Efficacy Endpoints ........................................................................ 23 
7.3.4.1 
DSN in Cycles 2, 3, and 4 ....................................................................................... 23 
7.3.4.2 
Incidence of Neutropenic Complications in Cycle 1 .............................................. 23 
7.3.4.3 
Incidence of Febrile Neutropenia in Cycles 2, 3, and 4 .......................................... 24 
7.3.4.4 
Relative Dose Intensity (RDI) ................................................................................ 24 
7.3.5 Other Efficacy Analyses ................................................................................................... 24 
7.3.5.1 
Time to ANC Recovery in Cycles 2, 3, and 4 ........................................................ 24 
7.3.5.2 
Depth of ANC Nadir in Cycles 2, 3, and 4 ............................................................. 24 
7.3.5.3 
Incidence of Neutropenic Complications in Cycles 2, 3, and 4 .............................. 25 
7.4 
Safety Analyses ................................................................................................................. 25 
7.4.1 Adverse Events ................................................................................................................. 25 
7.4.1.1 
General .................................................................................................................... 25 
7.4.1.2 
Incidence of Treatment Emergent Adverse Events ................................................ 25 
7.4.1.3 
Incidence of TEAEs of Special Interest .................................................................. 25 
7.4.1.4 
Incidence of Treatment Related Adverse Events .................................................... 26 
7.4.1.5 
TEAE Categorized by Severity ............................................................................... 26 
7.4.1.6 
Serious Adverse Events and Adverse Events Leading to Study Drug Modifications
 
26 
7.4.2 Laboratory Parameters ...................................................................................................... 27 
7.4.3 Vital Sign Data .................................................................................................................. 27 
7.4.4 ECOG Performance Status ............................................................................................... 27 
8.0 
REFERENCES ............................................................................................27 
Appendix - A. SAP Amendment: List of Changes ............................................29 
 
 
 


SPI-2012 (Rolontis™, eflapegrastim, HM10460A, LAPS-G-CSF) 
Statistical Analysis Plan 
IND 103,461 – Version 1.3 – 31 Jul 2018 
2.1 LIST OF TABLES 
Table 1 
Summary of Baseline for Each Endpoint/Data ........................................................... 11 
Table 2 
Simulation Results ...................................................................................................... 19 
 
2.2 List of Appendices 
Appendix - A. SAP Amendment: List of Changes ............................................29 
 
 
 


SPI-2012 (Rolontis™, eflapegrastim, HM10460A, LAPS-G-CSF) 
Statistical Analysis Plan 
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3.0 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical analyses 
that have been outlined within the original protocol for Study SPI-GCF-301, dated 04 Nov 2015. 
The scope of this plan includes all efficacy and safety analyses of SPI-2012 or pegfilgrastim in 
the management of chemotherapy induced neutropenia in breast cancer patients receiving 
docetaxel and cyclophosphamide (TC).  
4.0 
OBJECTIVES 
4.1 Primary Objective:  
• To compare the efficacy of a single dose of SPI-2012 with pegfilgrastim in patients with 
early-stage breast cancer receiving docetaxel and cyclophosphamide (TC), as measured 
by the Duration of Severe Neutropenia (DSN) in Cycle 1 
4.2 Key Secondary Objectives:  
• To compare SPI-2012 with pegfilgrastim in: 
1. Time to Absolute Neutrophil Count (ANC) Recovery in Cycle 1 
2. Depth of ANC Nadir, defined as the patient’s lowest ANC in Cycle 1 
3. Incidence of Febrile Neutropenia (FN) in patients during Cycle 1 
4.3 Additional Secondary Objectives:  
• To compare SPI-2012 with pegfilgrastim in: 
1. Duration of Severe Neutropenia in Cycles 2, 3, and 4 
2. Incidence of neutropenic complications, including anti-infective use and 
hospitalizations in patients during Cycle 1  
3. Incidence of FN in Cycles 2, 3, and 4 
4. Relative Dose Intensity (RDI) of TC in Cycles 1 to 4 
5. Safety 
5.0 
STUDY OVERVIEW 
This is a Phase 3, randomized, open-label, active-controlled, multicenter study to compare the 
efficacy and safety of SPI-2012 with pegfilgrastim in breast cancer patients treated with TC 
chemotherapy.  


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Approximately 400 patients will be enrolled and randomized in a 1:1 ratio to 2 treatment arms:  
• Treatment Arm 1 (n=200): SPI-2012 (13.2 mg/0.6 mL fixed dose SPI-2012 equivalent 
to 3.6 mg G-CSF) 
• Treatment Arm 2 (n=200): Pegfilgrastim (6 mg/0.6 mL) 
Prior to TC chemotherapy administration, patients may receive premedication according to 
institutional standard of care. Intravenous (IV) administration of TC on Day 1 of each cycle will 
be as follows:  
• Docetaxel 75 mg/m2 IV infusion over approximately 1 hour, or per institutes standard of 
care 
• Cyclophosphamide 600 mg/m2 IV infusion over approximately 30 to 60 minutes, or per 
institutes standard of care 
Each cycle will be 21 days. Only 4 cycles will be evaluated for this study. After Cycle 1, patients 
must have an ANC ≥1.5 × 109/L and platelet count ≥100 × 109/L to begin the next cycle of 
chemotherapy.  
The study drug (SPI-2012 or pegfilgrastim) will be administered on Day 2 of each cycle, 
approximately 24 to 26 hours after the last dose of TC chemotherapy is given. Study drug 
(SPI-2012 or pegfilgrastim) dose modifications are not allowed. 
On Day 1 of each cycle, patients will receive TC chemotherapy, and safety and efficacy 
assessments will be performed as outlined in the protocol. On Day 2 of each cycle, patients will 
receive study drug (SPI-2012 or pegfilgrastim), and the specified assessments will be performed.  
Absolute neutrophil count will be monitored on Day 1 and Days 4 to 15 in Cycle 1.  
In Cycles 2 to 4, all patients must have blood samples drawn on Day 1 (prior to chemotherapy 
administration), on Days 4, 7, 10, and 15 (±1 day for each timepoint), and at the End-of-
Treatment Visit. If the ANC is ≤ 1.0 × 109/L at any time during Cycles 2 to 4, then daily 
complete blood counts will be required until the ANC is ≥ 1.5 × 109/L, after reaching nadir, but 
blood samples must still be drawn on Days 4, 7, 10, and 15.  


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After Cycle 1, all patients who have received at least one dose of study drug will be followed for 
12 months after the last dose of study treatment for safety follow-up. 
5.1 Sample Size Considerations 
Approximately 400 patients will be enrolled in this study. The primary endpoint analysis is based 
on the test of non-inferiority of SPI-2012 as compared to pegfilgrastim. The pooled standard 
deviation of DSN is assumed to be 2.0 days, after referencing the assumptions used in the two 
Phase 3 registrational pegfilgrastim trials [1]. The standard deviation used for sample size 
calculation in the two Phase 3 pegfilgrastim trials was 2.17 and 1.5 days, respectively.  
For the test of non-inferiority hypothesis, the margin of non-inferiority to be used in the study is 
0.62 day. The true difference between the means is assumed to be 0.0 days. Sample sizes of 200 
per treatment arm will achieve 87% power to detect non-inferiority using a one-sided, two-
sample t-test at 2.5% level of significance. The study will enroll and randomize 200 patients per 
arm for a total of approximately 400 patients. 
The non-inferiority of SPI-2012 to pegfilgrastim will be declared if the upper bound of 95% 
confidence interval (CI) of the difference in mean DSN between the treatment arms is <0.62 
days.  
5.2 Randomization 
This is an open-label study. The randomization schedule will be generated and approved by 
Spectrum’s Biostatistics Department. The list will be sent to DSG - IWRS vendor for 
implementation. The randomization list will be securely located and only limited study team 
members will have access to it. These will include: 
• Lead Biostatistician, Spectrum Pharmaceuticals 
• Head of Biostatistics, Spectrum Pharmaceuticals 
• Overall Study Project Manager, DSG 
• IWRS Project Manager, DSG 
• Associate IWRS Project Manager, DSG 
The detailed randomization specification is as follows: 


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Total number of randomizations generated: 100 patients for each site with 200 sites. Total per 
study = 20,000 randomization numbers.  
Treatment Arm: A = SPI-2012; B = pegfilgrastim. 
Block size: 4 (A : B = 1 : 1) 
Stratification factor: Site (1 to 200) 
6.0 
ANALYSIS POPULATIONS 
Intent-to-Treat (ITT) Population 
The ITT Population will consist of all patients who are randomized. Patients will be analyzed in 
the treatment arm as randomized if the actual treatment assignments deviate from the 
randomization schema. This population will be used for the summary of demographics and 
baseline characteristics as well as efficacy analysis. The primary analysis will be based on the 
ITT Population.  
Per Protocol (PP) Population 
The PP Population will include all patients in the ITT Population with no important protocol 
deviations (IPDs) that affect the analysis of the primary efficacy endpoint. The following will be 
considered IPDs: 
• Failure to meet inclusion/exclusion criteria 
• Any dose modifications of the study drug (SPI-2012 or pegfilgrastim) in Cycle 1 
• RDI of TC chemotherapy <80% or >120% in Cycle 1 
• Any additional myeloid growth factors other than the protocol-specified study drug 
(SPI-2012 or pegfilgrastim) in Cycle 1 
• Study drug (SPI-2012 or pegfilgrastim) administered less than 12 hours or more than 48 
hours after the end of TC chemotherapy administration in Cycle 1 
Additional IPDs may be added after manual data review during the course of the study, if they 
will affect the primary efficacy analysis. These additional IPDs will be documented before 
database lock.  


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Patients will be analyzed as treated if the actual treatment assignments deviate from the 
randomization schema. This population will be used as sensitivity analysis for assessing non-
inferiority hypothesis for the primary efficacy endpoint (DSN in Cycle 1).  
Safety (SAF) Population 
The SAF Population will consist of all patients who receive at least one dose of any protocol-
specified drug (TC, SPI-2012 or pegfilgrastim). Patients will be analyzed in the treatment arm as 
treated. Patients who inadvertently receive both study drugs (SPI-2012 and pegfilgrastim) during 
the study will be discontinued from the trial. However, for the purposes of the safety analysis, 
these patients will be assigned to the treatment arm for which they received more doses (e.g., 
patients who received 3 doses of SPI-2012 and 1 dose of pegfilgrastim will be assigned to the 
SPI-2012 arm). This population will be used for safety analysis including dose exposure, adverse 
events, concomitant medications, vital signs, laboratory results and any other safety data. 
In order to properly assign patients to a treatment arm in the SAF population, the following 
criteria will be used: 
• Patients will be assigned as treated if the same drug is used for all 4 cycles 
• If a patient has switched allocation of study drug (either SPI-2012 or pegfilgrastim) 
among 4 cycles, the assignment of treatment in SAF population is as follows:  
o Patient will be assigned to a treatment arm in which more number of doses/cycles 
of that study drug was administered 
o If a patient has received equal number of doses of both study drugs (e.g. 2 cycles 
of SPI-2012 and 2 cycles of pegfilgrastim), the patient will be assigned to the 
treatment arm of the Cycle 1 
o If a patient has just received TC but not any dose of the study drug, the patient 
will be assigned to an arm as randomized and will still be included in the SAF 
population. 




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7.1.2 Handling of Missing Data 
Assessment of ANC will be performed daily from Days 4 to 15 in Cycle 1. During this time 
window, patients are expected to have severe neutropenia, and missing ANC values could affect 
the calculation of the primary efficacy endpoint. Missing ANC data are likely due to missing 
blood sampling in a daily blood sampling schedule from Days 4 to 15 in Cycle 1.  Spectrum’s 
Clinical Operations team will work closely with study sites to minimize missing data during the 
study conduct. Spectrum has engaged a home health care vendor, 
, to facilitate blood 
sampling at patients’ convenience at home or in the office. On a periodic basis during the study 
conduct, the Clinical Operations team tracks the blood sampling status of all enrolled patients to 
identify issues and implements mitigation plans wherever possible.   
It is expected that the extent of missing ANC data will be similar between treatment arms in this 
randomized study, as the reason for missing is mostly logistical and related to convenience rather 
than informed missing of the efficacy endpoint. The percentage of patients with missing ANC 
values from Days 4 to 15 in Cycle 1 will be presented by treatment arm.  
In general, missing data will not be imputed. However, it will be accounted for in a conservative 
manner to calculate the primary efficacy endpoint (DSN in Cycle 1) as follows.  
For all days in Cycle 1, if a patient has a missing ANC value(s) and the two adjacent ANC values 
(ie, the last available value before the missing value and the first available value after the missing 
value) are both ≥0.5×109/L, the missing ANC value(s) will be considered as ≥ 0.5 × 109/L and 
the day(s) with missing value(s) will not be counted to calculate DSN.  
If either of the two adjacent ANC values are <0.5×109/L, the missing ANC value(s) will be 
considered as <0.5×109/L and the day(s) with missing value(s) will be counted to calculate DSN.  
If an ANC value is missing in Cycle 1 but the corresponding WBC value is present and is 
≤0.5x109//L, the ANC value will be imputed as WBC value for that timepoint. 
In published studies of long-acting myeloid growth factors, when patients receive chemotherapy 
on Day 1 and a granulocyte colony-stimulating factor on Day 2 of each cycle, the ANC nadir 
tends to occur during a 3-day period between Days 6 to 8 in most patients and the mean DSN has 
been reported in the range of 0.3 to 2 days. According to the protocol, patients may discontinue 


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the study for a number of reasons as specified in the protocol. If a patient in either treatment arm 
has no blood draws (missing ANC values) because of discontinuation from Days 4 to 15 or for 
any part of this duration, the DSN will be imputed as 3 days for that patient.   
The missing ANC values in Cycles 2 to 4 will be handled differently from that in Cycle 1 as 
blood samples are only to be evaluated on nominal days 4, 7, 10, and 15 in Cycle 2 to 4. The 
missing data will be handled as below:  
• If there are multiple ANC values on a nominal visit day, use the latest one.  
• If a patient has a missing ANC value and the two adjacent ANC values (ie, the last 
available value before the missing value and the first available value after the missing 
value) are both ≥0.5×109/L, the missing ANC value(s) will be considered as ≥ 0.5 × 109/L 
and the day(s) with missing value(s) will not be counted to calculate DSN. 
• If the two adjacent ANC values are both <0.5×109/L, the missing ANC values will be 
considered as <0.5 to calculate DSN. 
• If either of the two adjacent ANC values is <0.5×109/L, only the timepoint with ANC 
values <0.5×109/L will be used for the calculate DSN 
• If a patient in either treatment arm has no blood draws (missing ANC values) because of 
the discontinuation from Days 4 to 15 or for any part of this duration, the DSN will be 
imputed as 3 days for that patient. 
A sensitivity analysis using worst case scenario will be performed to examine the impact of 
missing data in Cycle 1. As detailed in Section 5.3.1.3, when ANC data are missing on or after 
Day 5, and before patients’ ANC increase to ≥ 1.5×109/L after the expected nadir in Cycle 1, 
missing ANC values will be imputed as <0.5×109/L for SPI-2012 and ≥0.5×109/L for 
pegfilgrastim, for the purpose of DSN calculation in this sensitivity analysis.  
Patient discontinuation or missing blood sampling for the entire duration of Days 4 to 15 will 
also be handled differentially for DSN calculation between treatment arms in the worst-case 
scenario. If a patient has no blood draws (missing ANC values) because of discontinuation from 
Days 4 to 15 or for any part of this duration, the DSN will be imputed as 3 days for that patient 
for SPI-2012 and 0 for pegfilgrastim. The reason for imputing DSN=3 days for SPI-2012 is 
described above.  


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7.1.3 Pooling of Centers  
Data from different centers will be combined for the purpose of the analysis. The number of 
patients randomized will be presented by study site and country. A summary of the primary 
efficacy analysis will be provided by geographic region to determine if there is any regional 
difference. 
7.1.4 Interim Analysis 
There will be no formal interim analysis specified or conducted in this study. The data will be 
periodically reviewed for quality and completion. Since this is an open-label study, the data 
review will use a dry run of summary tables and listings using the actual treatment arms and the 
data knowledge will be restricted to the Study Team. No inferential statistics will be calculated 
and no decisions will be made. 
7.1.5 Testing/Validation Plan 
SAS® Version 9.3 on the Windows system will be used for creation of Tables, Listings, and 
Figures. All tables, listings, and figures will be validated and reviewed before being finalized. 
Independent programming will be conducted to verify tables and listings as appropriate. Tables 
will be reviewed for accuracy, consistency with this plan, consistency within tables, and 
consistency with corresponding outputs. 
7.2 Background Characteristics  
7.2.1 Patient Disposition 
Disposition of patients will be summarized by treatment arm and overall. The summary data will 
include number (%) of patients randomized and dosed, number (%) of patients that completed 4 
cycles of treatments and number (%) of patients who discontinued treatment. The reasons for 
treatment discontinuation will also be summarized. 
The analysis populations will be summarized by treatment arm and overall. The ITT Population 
will also be presented by country and study site.  
The percentage of patients with missing ANC values from Days 4 to 15 in Cycle 1 in the ITT 
Population will be presented by treatment arm. 


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7.2.2 Demographic and Baseline Characteristics 
Demographics (age, gender, ethnicity, race, age group <65, 65 to <75, and ≥75) and other 
baseline disease characteristics will be summarized using descriptive statistics. The summary 
will include, but will not be limited to, height, weight, body surface area, ECOG performance 
status, staging, hormone receptor status, and baseline ANC. These data will be summarized by 
treatment arm and overall. 
7.2.3 Drug Exposure and Compliance 
The extent of exposure to TC (docetaxel and cyclophosphamide) and study drug (SPI-2012 or 
pegfilgrastim) will be summarized by the following parameters: 
• Number of cycles administered 
• The number of cycles administered will be presented for both TC and study drug.  
• Total cumulative dose received 
• For each patient, the total dose received during the study will be calculated by adding the 
total doses received over all cycles. This parameter will be presented for TC. 
• Relative dose intensity (RDI) 
• Relative dose intensity is defined as the percentage of the planned dose that each patient 
actually received during the study, expressed as the total dose received, divided by total 
dose planned times 100.  
𝑅𝑅𝑅𝑅𝑅𝑅= 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑃𝑃𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙× 100 
The planned dose is defined as the dose that would be given if no doses were missed and/or no 
dose reductions were made for the number of cycles started. The total planned dose is the sum of 
planned doses over all cycles. RDI will be calculated for Cycles 1 to 4 and overall. This 
parameter will be presented for TC.  
• Dose Reduced, Discontinued, Delayed or Interrupted 
• The number and percentage of patients who experience dose compliance outside 80% to 
120%, or doses reduced, discontinued, delayed, or interrupted will be summarized by 
each cycle and overall. These will be presented for TC.  


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Study drug (SPI-2012 or pegfilgrastim) dose modifications are not allowed during the study. Any 
modification to the study drug will be reported.  
7.2.4 Medical History 
Medical history information will only be provided in patient data listings. 
7.2.5 Concomitant Medication 
A concomitant medication will be defined as any medication that was taken either on the day of 
or after the administration of the first dose of TC chemotherapy through the end of the study. 
This includes medications that started prior to the initiation of the first dose of TC chemotherapy 
if the patient continues using it.  
For all concomitant medications, counts and percentages of patients will be presented by 
medication class and preferred name coded by the World Health Organization Drug (WHO 
Drug) dictionary. Patients with more than one medication of the same medication class or 
preferred name will be counted only once. Patient data listings will be provided.  
7.2.6 Protocol Deviations 
Important protocol deviations (IPDs) will be defined as following: 
• Failure to meet inclusion/exclusion criteria 
• Any dose modifications of the study drug (SPI-2012 or pegfilgrastim) in Cycle 1 
• RDI of TC chemotherapy < 80% or > 120% in Cycle 1 
• Any additional myeloid growth factors other than the protocol specified study drug (SPI-
2012 or pegfilgrastim) in Cycle 1 
• Study drug (SPI-2012 or pegfilgrastim) administered less than 12 hours or more than 48 
hours after the end of TC chemotherapy administration in Cycle 1  
IPDs will be listed and summarized. Additional IPDs may be added after manual data review 
during the study, and will be documented before database lock. 
During monitoring of study sites, additional minor protocol deviations may be collected by the 
study monitors. These deviations will be captured in a Protocol Deviation Log and will be 


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categorized using a pre-defined deviation type. The broad minor deviation types are the 
following: 
• 01 – Informed Consent Procedures 
• 02 – Inclusion/Exclusion Criteria 
• 03 – Study Medication/Dosing 
• 04 – Laboratory/Procedures 
• 05 – Visit Schedules/Intervals 
 
• 06 – Safety 
 
• 07 – Randomization  
• 08 – Prohibited/Concomitant Medications 
• 09 – Others 
 
7.3 Efficacy Analyses 
7.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is DSN in Cycle 1, defined as the number of days in 
which the patient has an ANC < 0.5×109/L in Cycle 1, after administration of study drug (SPI 
2012 or pegfilgrastim). DSN will be calculated for all patients in the ITT Population. Patients 
who do not present with severe neutropenia will be given a DSN value of 0. If a patient has 
multiple ANC values within the same day, the last ANC value recorded will be used for that day.  
For the primary efficacy analysis, the mean DSN in Cycle 1 will be compared between the SPI 
2012 and Pegfilgrastim Treatment Arms using a bootstrap resampling method with non-
inferiority hypothesis. A 2-sided 95% confidence interval (CI) of the difference between the 
mean DSN of the SPI-2012 Treatment Arm and the mean DSN of the Pegfilgrastim Treatment 
Arm (i.e., SPI-2012 minus Pegfilgrastim) will be calculated based upon 10,000 bootstrap 
samples with treatment as the only stratification factor.  
For each sample, the difference between treatment arms will be calculated. The percentile 
confidence interval will be obtained from the resampling. The non-inferiority of SPI-2012 to 
pegfilgrastim will be declared if the upper bound of 95% CI of the difference in mean DSN 
between the treatment arms (i.e., SPI-2012 minus Pegfilgrastim) is < 0.62 day. The non-


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inferiority inferential statistics for primary endpoint inference will be based on the estimated 
95% CI as described above.  
Primary analysis for the non-inferiority hypothesis will be based on the ITT Population. Analysis 
based on the PP Population will be performed as sensitivity analysis. 
7.3.1.1 SAS Code for Primary Analysis 
The following are the SAS code used to generate 95% CI based on bootstrap resampling method.  
/*Beginning of program*/ 
/*Get DSN Data*/ 
proc sort data=adam.adef out=final;  
      where ITTFL='Y' and paramcd='DSN' and AVISIT='Cycle 1'; 
 
by trt01pn; 
run; 
 
/*Get 10000 Bootstrap Samples*/ 
proc surveyselect data=final method=urs samprate = 1 reps=10000 outhits 
seed=201502 out=SampleStrata; 
strata trt01pn; 
run; 
 
proc means noprint data=SampleStrata; where trt01pn=1; 
class Replicate; output out=t1 mean(aval)=dsn1; run; 
Data t1; set t1; if _TYPE_=1; keep Replicate dsn1; run; 
proc means noprint data=SampleStrata; where trt01pn=2; 
class Replicate; output out=t2 mean(aval)=dsn2; run; 
Data t2; set t2; if _TYPE_=1; keep Replicate dsn2; run; 
 
Data out; merge t1 t2; by Replicate; 
d1=dsn1-dsn2;        /*mean difference (SPI-2012 minus Neulasta) in each 
sample*/ 
run;  
 
/*Obtain 95% CI for Mean Difference*/ 
proc univariate data = out alpha = .05 noprint;  var d1;   
output out=c1 mean=mean pctlpts  = 2.5 97.5 pctlpre  = n pctlname = pct25 
pct975; run; 
Data CI95; set c1;  
mean=round(mean,.001);  npct25=round(npct25,.001);  
npct975=round(npct975,.001);  
run; 
/*End of program*/ 
 
7.3.1.2 Justification of Bootstrap Resampling Method as Primary Analysis 
The DSN takes the value of only non-negative integers (ie, 0, 1, 2, etc). Due to the skewness of 
the distribution, bootstrap resampling method [2] was used to construct confidence intervals for 
DSN data in two Phase 3 registrational Neulasta trials [3-4]. A simulation study was conducted 






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Additional sensitivity analysis will be used to examine treatment effect adjusting for study site. 
This analysis will be the same as the primary analysis (bootstrap resampling method) and study 
site will be used as additional stratification factor in the resampling. 
Additional sensitivity analysis will be used to examine treatment effect adjusting for disease 
status at randomization (adjuvant or neoadjuvant). This analysis will be the same as the primary 
analysis (bootstrap resampling method) and disease status will be used as additional stratification 
factor in the resampling. 
Summary statistics will be provided by treatment arm and subgroup along with nominal p-values 
at 5% level of significance for the difference between treatment arms for all subgroups included 
in Section 7.3.1.4.  
Additional sensitivity analysis using worst case scenario will be used to examine the impact of 
missing data and the details are included in Section 7.1.2. When ANC data are missing on or 
after Day 5, and before patients’ ANC increase to ≥ 1.5×109/L after the expected nadir in Cycle 
1, missing ANC values will be imputed as < 0.5×109/L for SPI-2012 and ≥ 0.5×109/L for 
pegfilgrastim, for the purpose of DSN calculation.  
The worst-case scenario analysis of DSN will use the same bootstrap resampling method as in 
the primary analysis.  
These additional sensitivity analyses will be performed based on the ITT Population. 
7.3.1.4 Subgroup Analysis  
The following subgroups will be examined for DSN in Cycle 1:  
• Age (<65 years, ≥65 years) 
• Age (<65 years, 65 to <75, ≥75 years) 
• Gender (Male, Female) 
• Race 
• Disease Status (Adjuvant, Neoadjuvant) at randomization 
• Geographic region  
• Weight (<65 kg, 65 to 75 kg, or >75 kg)  


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The subgroup analyses will be performed based on the ITT Population.  
7.3.2 Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints for the study are to compare SPI-2012 with pegfilgrastim 
in:  
1. Time to ANC Recovery in Cycle 1 
2. Depth of ANC Nadir in Cycle 1 
3. Incidence of FN in patients during Cycle 1 
7.3.2.1 Time to ANC Recovery in Cycle 1 
Time to ANC Recovery is defined as the time from chemotherapy administration until the 
patient’s ANC increases to ≥1.5×109/L after the expected nadir. For patients with ANC value 
≥1.5×109/L at all times, Time to ANC Recovery will be assigned a value of 0.  
The mean Time to ANC Recovery in Cycle 1 with two-sided 95% CI will be estimated for each 
treatment arm using negative binomial regression. Identical link will be used and treatment will 
be the only covariate in the model. The difference in the mean Time to ANC Recovery in Cycle 
1 between SPI-2012 and Pegfilgrastim will be calculated based on negative binomial regression, 
along with 2-sided 95% CI. The analysis will be performed based on the ITT Population. A 
sensitivity analysis will be performed based on the PP Population. 
7.3.2.2 Depth of ANC Nadir in Cycle 1 
Depth of ANC Nadir is defined as the lowest ANC value after administration of study drug (SPI-
2012 or pegfilgrastim) for each cycle. Mean and median Depth of ANC Nadir in Cycle 1 will be 
summarized by treatment arm. To assess treatment differences, log10 transformation will be used 
on the nadirs to satisfy the normality assumption, due to the skewness of the data. The ANC 
nadir ratio between the treatment arms, associated 2-sided 95% CI, assuming asymptotic 
normality on the log transformed data, will be provided. The analysis will be performed based on 
the ITT Population. A sensitivity analysis based on the PP Population will be performed. 
7.3.2.3 Incidence of Febrile Neutropenia in Cycle 1 
Febrile neutropenia is defined as an oral temperature >38.3°C (101.0°F) or two consecutive 
readings of >38.0°C (100.4°F) for 2 hours and ANC <1.0×109/L.  


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Incidence of FN after administration of study drug (SPI-2012 or pegfilgrastim) in Cycle 1 will be 
summarized by treatment arm. Patients who experience more than one event will be counted 
only once in each cycle. An exact 2-sided 95% CI will be provided. The analysis will be 
performed based on the ITT Population. A sensitivity analysis based on the PP Population will 
be performed. 
7.3.3 Testing Procedure for Primary and Key Secondary Efficacy Endpoints 
A hierarchical closed testing procedure [6] will be used to test primary and key secondary 
efficacy endpoints. The testing will be based on the following order:  
1. DSN in Cycle 1 
2. Time to ANC Recovery in Cycle 1 
3. Depth of ANC Nadir in Cycle 1 
4. Incidences of FN in Cycle 1 
No adjustment to alpha will be necessary once the preceding endpoint comparison is significant 
for the subsequent endpoints in the above order of endpoints, with each test at the same 
significance level of α=0.05. 
7.3.4 Additional Secondary Efficacy Endpoints 
The additional secondary efficacy endpoints are:  
1. DSN in Cycles 2, 3, and 4 
2. Incidence of neutropenic complications in Cycle 1 
3. Incidence of FN in Cycles 2, 3, and 4 
4. Relative Dose Intensity (RDI) of TC in Cycles 1 to 4 
7.3.4.1 DSN in Cycles 2, 3, and 4 
These endpoints will be defined and analyzed similarly to DSN in Cycle 1. Two-sided 95% CI 
comparing SPI-2012 to pegfilgrastim based on bootstrap resampling method will be provided. 
The analyses will be performed based on the ITT Population.  
7.3.4.2 Incidence of Neutropenic Complications in Cycle 1 
Neutropenic complications refer to hospitalizations due to neutropenic events and/or use of anti-
infectives due to neutropenia.  


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Incidence of neutropenic complications after administration of study drug (SPI-2012 or 
pegfilgrastim) in Cycle 1 will be summarized by treatment arm. Patients who experience more 
than one event will be counted only once for each cycle. An exact 2-sided 95% CI will be 
provided. The analysis will be performed based on the ITT Population.  
7.3.4.3 Incidence of Febrile Neutropenia in Cycles 2, 3, and 4 
These endpoints will be defined and analyzed similarly to incidence of FN in Cycle 1. An exact 
2-sided 95% CI comparing SPI-2012 to pegfilgrastim will be provided. The analyses will be 
performed based on the ITT Population.  
7.3.4.4 Relative Dose Intensity (RDI) 
The analyses of these endpoints are described in Section 7.2.3 (Drug Exposure and Compliance). 
7.3.5 Other Efficacy Analyses 
In addition to the endpoints specified in the protocol and described in the previous sections, this 
section presents some additional efficacy endpoints:  
1. Time to ANC Recovery in Cycles 2, 3, and 4 
2. Depth of ANC Nadir in Cycles 2, 3, and 4 
3. Incidence of neutropenic complications in Cycles 2, 3, and 4 
7.3.5.1 Time to ANC Recovery in Cycles 2, 3, and 4 
These endpoints will be defined and analyzed similarly to Time to ANC Recovery in Cycle 1. 
Two-sided 95% CI comparing SPI-2012 to pegfilgrastim based on negative binomial regression 
will be provided. Identical link will be used and treatment will be the only covariate in the 
model. The analyses will be performed based on the ITT Population.  
7.3.5.2 Depth of ANC Nadir in Cycles 2, 3, and 4 
These endpoints will be defined and analyzed similarly to Depth of ANC Nadir in Cycle 1. 
Log10 transformation will be used on the nadirs to satisfy the normality assumption. The ANC 
nadir ratio between the treatment arms, associated 2-sided 95% CI assuming asymptotic 
normality on the log transformed data, will be provided. The analyses will be performed based 
on the ITT Population.  


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7.3.5.3 Incidence of Neutropenic Complications in Cycles 2, 3, and 4 
These endpoints will be defined and analyzed similarly to incidence of neutropenic 
complications in Cycle 1. An exact 2-sided 95% CI comparing SPI-2012 to pegfilgrastim will be 
provided. The analyses will be performed based on the ITT Population.  
7.4 Safety Analyses 
7.4.1 Adverse Events 
7.4.1.1 General 
A treatment-emergent adverse event (TEAE) is any adverse event (AE) that occurs from the first 
dose of TC chemotherapy through 12 months after the last dose of study treatment or 30 days 
after the date of patient early discontinuation.  
AE severity will be graded by the Investigator according to the definitions set forth by the 
Common Terminology Criteria for Adverse Events (CTCAE version 4.03). AEs will be coded 
using the Medical Dictionary of Regulatory Activities (MedDRA) and will be classified by 
MedDRA system organ class (SOC) and preferred term (PT). Only treatment emergent adverse 
events (TEAEs) will be included in summary tables. If it cannot be determined whether an 
adverse event is treatment-emergent (based on start date or, if the start date is missing then based 
on the stop date), then the adverse event will be considered treatment-emergent. 
7.4.1.2 Incidence of Treatment Emergent Adverse Events 
Incidences of TEAEs will be summarized by MedDRA SOC and PT. Patients who experience 
more than one type of adverse event will be counted under each of the corresponding preferred 
terms. Patients who experience different episodes of the same adverse event will be counted only 
once under the corresponding preferred term. Similarly, for determination of MedDRA SOC 
incidences, patients who experience multiple adverse events under the same SOC will be counted 
only once for that SOC. 
7.4.1.3 Incidence of TEAEs of Special Interest 
Preferred Terms will be grouped together to assess the following three categories of AEs of 
special interest.  
• Musculoskeletal pain: includes SOC of musculoskeletal and connective tissue disorders. 


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• Injection site reactions: includes HLT of injection site reactions.  
• Hypersensitivity reactions: includes hypersensitivity SMQN and anaphylactic reaction 
SMQN. 
The incidence of AEs of special interest will be summarized by special interest category and 
preferred term within the special interest. Patients who experience multiple adverse events under 
the same special interest will be counted only once for that special interest. 
7.4.1.4 Incidence of Treatment Related Adverse Events 
Assessment of relatedness to TC or study drug (SPI-2012 or pegfilgrastim) for all adverse events 
will be classified by investigators and reported. The incidences of treatment related and unrelated 
AEs will be presented by MedDRA SOC and PT for each TC component and study drug. For 
this analysis, an adverse event will be assigned as treatment related if the relationship to study 
drug is missing. 
7.4.1.5 TEAE Categorized by Severity 
Incidences of TEAEs will also be summarized by MedDRA SOC, preferred term, and maximum 
CTCAE severity grade. Adverse events with a missing severity grade will not be included in 
these analyses. Patients who experience the same event at more than one severity level will be 
counted only once under the maximum severity level. The overall adverse event incidences will 
also be presented in these tables as a reference. 
The same analyses by maximum CTCAE severity grade will be presented for treatment related 
adverse events only. 
The incidence of TEAEs and treatment related AEs with severity Grade ≥3 will be summarized 
by MedDRA SOC and PT. 
7.4.1.6 Serious Adverse Events and Adverse Events Leading to Study Drug Modifications 
Incidences of serious adverse events and adverse events leading to dose reductions, dose delays, 
dose interruptions, and study drug discontinuation will be summarized overall and by 
relationship to study drug. Listings of patient deaths, discontinuations due to adverse events, and 
serious adverse events will also be presented. 


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7.4.2 Laboratory Parameters 
Clinical laboratory samples will be collected at screening and throughout the study. The clinical 
laboratory values will be classified according to the NCI CTCAE version 4.03. Tables of shifts 
in severity from baseline to worst post-baseline on study, for laboratory parameters, will be 
provided overall and by Cycle 1 and Cycles 2 to 4 separately.  
Laboratory values and change from baseline will be summarized using International System 
Units by panel, laboratory test, and time point. Separate summary tables and listings will be 
produced for laboratory abnormalities. 
Supporting laboratory data including normal ranges and abnormal laboratory flags will be 
provided in data listings. 
7.4.3 Vital Sign Data 
A summary of raw values and changes from baseline values will be provided by treatment arm at 
each scheduled time point for the following measurements: body temperature, systolic and 
diastolic blood pressure, and heart rate. A listing of all values will also be included. 
7.4.4 ECOG Performance Status 
Descriptive statistics will be presented for ECOG scores baseline. The number and percentage of 
patients with shifts from baseline ECOG score (0, 1, or 2) to the worst post-baseline ECOG score 
(0, 1, 2, 3, or 4) will be summarized overall and by Cycle 1 and Cycles 2 to 4 separately.  
8.0 
REFERENCES 
1. 
Gnecco C. Neulasta Statistical Review. In: Research Center for Drug Evaluation and 
Research and Center for Biologics Evaluation and Research. 2002.. 
2. 
Efron B, Tibshirani RJ. An Introduction to the Bootstrap. Chapman and Hall: London, 
1993. 
3. 
Green MD, Koelbl H, Baselga J, Galid A, Guillem V, Gascon P, et al. A Randomized 
Double-Blind Multicenter Phase III Study of Fixed-Dose Single-Administration 
Pegfilgrastim Versus Daily Filgrastim in Patients Receiving Myelosuppressive 
Chemotherapy. Ann Oncol. 2003;14(1):29-35. 


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4. 
Holmes FA, Jones SE, O'Shaughnessy J, Vukelja S, George T, Savin M, et al. 
Comparable Efficacy and Safety Profiles of Once-Per-Cycle Pegfilgrastim and Daily 
Injection Filgrastim in Chemotherapy-Induced Neutropenia: A Multicenter Dose-Finding 
Study in Women with Breast Cancer. Ann Oncol. 2002;13(6):903-9. 
5. 
Http://Support.Sas.Com/Documentation/Cdl/En/Imlug/59656/Html/ 
Default/Viewer.Htm#Langref_Sect215.Htm. 
6. 
Lubsen J, Kirwan BA. Combined Endpoints: Can We Use Them? Stat Med. 
2002;21(19):2959-70. 
 
 
 


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Appendix - A. SAP Amendment: List of Changes 
Changes from the SAP Version 1.2 to Version 1.3: 
The primary purpose of the SAP amendment is to provide more clarity and details of the 
handling of missing data for ANC and efficacy analysis.  No changes were made to the tests of 
comparison of efficacy endpoints and statistical methods of analysis.  
 
Section 7.1.2 Handling of Missing Data 
Paragraph deleted:  
ANC assessment will be collected daily from Days 4 to 15 in Cycle 1. During this time window, 
patients are expected to have severe neutropenia, and missing ANC values could affect the 
calculation of primary efficacy endpoint. Spectrum’s Clinical Operations team will work closely 
with study sites to minimize missing data during the study conduct. The percentage of patients 
with missing ANC values from Days 4 to 15 in Cycle 1 will be presented by treatment arm. 
 
Paragraphs added:  
Assessment of ANC will be performed daily from Days 4 to 15 in Cycle 1. During this time 
window, patients are expected to have severe neutropenia, and missing ANC values could affect 
the calculation of the primary efficacy endpoint. Missing ANC data are likely due to missing 
blood sampling in a daily blood sampling schedule from Days 4 to 15 in Cycle 1. Spectrum’s 
Clinical Operations team will work closely with study sites to minimize missing data during the 
study conduct. Spectrum has engaged a home health care vendor, 
, to facilitate blood 
sampling at patients’ convenience at home or in the office. On a periodic basis during the study 
conduct, the Clinical Operations team tracks the blood sampling status of all enrolled patients to 
identify issues and implements mitigation plans wherever possible.   
 
It is expected that the extent of missing ANC data will be similar between treatment arms in this 
randomized study, as the reason for missing is mostly logistical and related to convenience rather 
than informed missing of the efficacy endpoint. The percentage of patients with missing ANC 
values from Days 4 to 15 in Cycle 1 will be presented by treatment arm. 
 
Paragraph added:  
In published studies of long-acting myeloid growth factors, when patients receive chemotherapy 
on Day 1 and a granulocyte colony-stimulating factor on Day 2 of each cycle, the ANC nadir 
tends to occur during a 3-day period between Days 6 to 8 in most patients and the mean DSN has 
been reported in the range of 0.3 to 2 days. According to the protocol, patients may discontinue 
the study for a number of reasons as specified in the protocol. If a patient in either treatment arm 
has no blood draws (missing ANC values) because of discontinuation from Days 4 to 15 or for 
any part of this duration, the DSN will be imputed as 3 days for that patient.   
 
Paragraph deleted:  


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The missing ANC values will be handled the same way to calculate DSN in Cycles 2 to 4. 
Paragraphs added:  
The missing ANC values in Cycles 2 to 4 will be handled differently from that in Cycle 1 as 
blood samples are only to be evaluated on nominal days 4, 7, 10, and 15 in Cycle 2 to 4. The 
missing data will be handled as below:  
 
• If there are multiple ANC values on a nominal visit day, use the latest one.  
• If a patient has a missing ANC value and the two adjacent ANC values (ie, the last 
available value before the missing value and the first available value after the missing 
value) are both ≥0.5×109/L, the missing ANC value(s) will be considered as ≥ 0.5 × 109/L 
and the day(s) with missing value(s) will not be counted to calculate DSN. 
• If the two adjacent ANC values are both <0.5×109/L, the missing ANC values will be 
considered as <0.5 to calculate DSN. 
• If either of the two adjacent ANC values is <0.5×109/L, only the timepoint with ANC 
values <0.5×109/L will be used for the calculate DSN 
• If a patient in either treatment arm has no blood draws (missing ANC values) because of 
the discontinuation from Days 4 to 15 or for any part of this duration, the DSN will be 
imputed as 3 days for that patient. 
 
Paragraph added:  
Patient discontinuation or missing blood sampling for the entire duration of Days 4 to 15 will 
also be handled differentially for DSN calculation between treatment arms in the worst-case 
scenario. If a patient has no blood draws (missing ANC values) because of discontinuation from 
Days 4 to 15 or for any part of this duration, the DSN will be imputed as 3 days for that patient 
for SPI-2012 and 0 for pegfilgrastim. The reason for imputing DSN=3 days for SPI-2012 is 
described above. 
 
Section 7.3.1.3 Additional Sensitivity Analysis 
Paragraph added:  
Summary statistics will be provided by treatment arm and subgroup along with nominal p-values 
at 5% level of significance for the difference between treatment arms for all subgroups included 
in Section 7.3.1.4. 
 
Text deleted:  
When ANC data are missing on or after Day 5, and before patients’ ANC increase to ≥1.5×109/L 
after the expected nadir in Cycle 1, missing ANC values will be imputed as <0.5×109/L for SPI-
2012 and ≥ 0.5×109/L for pegfilgrastim, for the purpose of DSN calculation. 
Changes from the SAP Version 1.1 to Version 1.2:  


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The following specific changes have been incorporated in the SAP under this SAP amendment 
The primary change to this amendment is the change in the planned number of patients from 
approximately 580 patients to approximately 400 patients in study protocol, version Amendment 
1, dated 26Jan2017. Primary changes to this SAP are in the following sections: 
• Section 3.1: Sample size was changed, and the level of significance was updated since 
superiority was removed as a statistical test. This proposed update was accepted by the 
FDA in 12 Dec 2016 Type C Written Response. 
• Section 5.3.1.2: Simulation results are presented in Table 2 with revised sample size. 
 
Changes from the original SAP to Version 1.1:  
The following specific changes have been incorporated in the SAP under this SAP amendment 
The purpose of this amendment is to add or clarify the following analyses: 
• Analysis of the key secondary endpoint, “Time to ANC Recovery in Cycle 1”. The 
analysis will be performed based on the ITT Population. For patients with absolute 
neutrophil count (ANC) value ≥1.5×109/L at all times in Cycle 1, Time to ANC 
Recovery will be assigned to a value of 0. The analysis of this endpoint will be based 
on negative binomial regression with identical link and treatment as the only covariate. 
The affected changes are in Section 5.3.2.1 and Section 5.3.5.1 of the Statistical 
Analysis Plan (SAP). 
• Two sensitivity analyses for primary endpoint were added: sensitivity analysis 
adjusting for disease status at randomization (adjuvant or neoadjuvant) and sensitivity 
analyses using worst case scenario. The affected changes are in Section 5.1.2 and 
Section 5.3.1.3 of the SAP. 
• Subgroup analyses for primary endpoint were added: gender, race and disease status 
at randomization. The affected changes are in Section 5.3.1.4 of the SAP. 
• Analysis of Adverse Events of Special Interest was added: the search criteria was 
broadened for musculoskeletal pain and injection site reactions. Analysis of 
hypersensitivity reactions was added as an additional special interest category. 
The affected changes are in Section 5.4.1.3 of the SAP. 
• Superiority test for the primary endpoint was removed from the SAP, according to 
the protocol.