Clinical trial NCT02659514
Conditions: Breast Cancer
Keywords: Poziotinib Metastatic Breast Cancer HER2-positive Pan-HER inhibitor
Sponsor: Spectrum Pharmaceuticals, Inc
Start date: 2016-02-22; Completion date: 2020-03-11
Enrollment: 67 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to establish the dose regimen and evaluate the preliminary efficacy and the safety/tolerability of poziotinib in participants with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have received at least two prior HER2-directed treatment regimens.

Detailed description:
This is a phase 2, open-label, multicenter study to establish the dose regimen and evaluate the preliminary efficacy and the safety/tolerability of poziotinib in participants with HER2-positive metastatic breast cancer who have received at least two prior HER2-directed treatment regimens.

Each treatment cycle will be 21 days in duration. During each 21-day cycle, participants who are eligible for participation will receive poziotinib orally once daily.

All treated participants will be followed up until disease progression, death, intolerable adverse events or up to a maximum of 24 months whichever comes earlier.

Arms: arm 1: Participants received poziotinib 24 milligrams (mg), administered as three 8 mg tablets, orally, once daily (QD) on an intermittent dosing schedule of 14 days on treatment followed by 7 days off treatment, in a 21-day cycle until disease progression, death, intolerable adverse events (AEs) or for up to a maximum of 24 months, whichever occurs first. arm 2: Participants received poziotinib 16 mg, administered as two 8 mg tablets, orally, QD, on a continuous dosing schedule in a 21-day cycle until disease progression, death, intolerable AEs or for up to a maximum of 24 months, whichever occurs first.
Interventions: intervention 1: Poziotinib
Intervention descriptions: intervention 1: 8 mg oral tablets, administered QD.

Protocol documents:
Prot_000.pdf: 
Official Title: 
A Phase 2 Study of Poziotinib in Patients with HER2-Positive Metastatic 
Breast Cancer (MBC) Who Have Received Prior HER2 Regimens for MBC
NCT Number: 
NCT02659514 
Document Date: 
Clinical Study Protocol Version 2.0: 14 July 2017 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Report 
Poziotinib 
Protocol Number: SPI-POZ-201 Amendment 2 - List of Changes 
Confidential 
 
1 
Study Title:  
A Phase 2 Study of Poziotinib in Patients with HER2-
Positive Metastatic Breast Cancer (MBC) Who Have 
Received Prior HER2 Regimens for MBC 
Protocol Version/Date: 
Amendment 2/14 Jul 2017 
 
Deletions below are marked with red strikethrough text and 
additions are marked with red underlined text. 
Summary of Significant Changes to the Protocol 
Section 
Change 
Throughout Document 
Minor edits for grammar, spelling, and typos. 
Throughout Document: 
General Explanation 
Primary Reasons for Amendment: 
Inclusion criterion 4 stated that “at least 2, but no more than 4, prior HER2-
directed therapy regimens for breast cancer, including trastuzumab and 
trastuzumab emtansine (T-DM1, KADCYLA®)”. The majority of patients with 
advanced HER2 positive breast cancer have been treated with more than 4 
regimens of prior anti-cancer therapies. The restriction of patients having only 
up to 4 prior treatment regimens significantly limits a patient’s participation 
opportunity. In order to include more patients, the inclusion criterion was 
changed so that a patient must have had at least 2 prior treatments, but there is 
no upper limit.  
A change to the prior treatment washout requirement was based on the half-life 
of the treatments and to ensure provide enough time for recovery from side 
effects and minimization of influences from prior therapy. This change is 
intended to provide patients with study treatment earlier, as appropriate.  
Other changes in patient eligibility are based on the feedback from the 
investigators and study centers. These changes are expected to improve 
enrollment without an increased risk to patient safety.  
Throughout Document:  
Original Text: 
at least 2, but no more than 4, prior HER2-directed therapy regimens…  
New Text: 
at least 2, but no more than 4, prior HER2-directed therapy regimens 
Reason: 
To allow more patients to participate in the trial 
Title Page 
Footer 
Synopsis 
Original Text: 
Protocol Version/Date: Amendment 1/17 Feb 2017 
New Text: 
Protocol Version/Date: Amendment 2/14 Jul 2017 
Synopsis: Inclusion and 
Exclusion Criteria 
Section 4 
Original Text: 
Inclusion Criteria: 
1. At least 2, and no more than 4, prior HER2-directed therapy regimens 
for breast cancer, including trastuzumab and trastuzumab emtansine (T-
DM1, KADCYLA®). 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Report 
Poziotinib 
Protocol Number: SPI-POZ-201 Amendment 2 - List of Changes 
Confidential 
 
2 
Section 
Change 
2.  Patient has adequate hematologic, hepatic, and renal function, as 
defined by: 
• 
Absolute neutrophil count (ANC) ≥1.5×109/L 
3. Patient has an Eastern Cooperative Oncology Group (ECOG) 
performance status ≤2. 
Exclusion Criteria: 
4. Patient has brain metastases that are symptomatic or require therapy to 
control symptoms, as well as any history of radiation, surgery, or other 
therapy, including steroids, to control symptoms from brain metastases 
within 1 month (30 days) of enrollment.  
5. Patient has received anticancer chemotherapy, biologics, 
immunotherapy, cure-intent radiotherapy, or investigational treatment 
within 30 days, except for hormone therapy, palliative therapy, or 
supportive therapy  
New Text: 
Inclusion Criteria: 
4. At least 2 prior HER2-directed therapy regimens for breast cancer, 
including trastuzumab and trastuzumab emtansine (T-DM1, 
KADCYLA®). 
6.  Patient has adequate hematologic, hepatic, and renal function, as 
defined by: 
• 
Absolute neutrophil count (ANC) ≥1.0×109/L 
7. Patient has an Eastern Cooperative Oncology Group (ECOG) 
performance status ≤2. Life expectancy is more than 6 months.  
Exclusion Criteria: 
2. Patient has brain metastases that are symptomatic or require therapy to 
control symptoms, as well as any history of radiation, surgery, or other 
therapy, including steroids, to control symptoms from brain metastases 
within 15 days of enrollment.  
3. Patient has received anticancer chemotherapy, biologics, 
immunotherapy, cure-intent radiotherapy, or investigational treatment 
within 15 days, except for hormone therapy, palliative therapy, or 
supportive therapy  
Reasons: 
Inclusion: 
4. Reason discussed above.  
6. Investigators believe that ANC ≥1.0×109/L is acceptable for enrollment and 
patient safety will not be at risk. 
7. In order to measure the response properly, and since the limit of prior 
treatments has been removed, we have stipulated that patients must have a life 
expectancy of at least 6 months. 
Exclusion: 
2 and 3. Based on the half-life of the drugs, a 15-day washout was deemed 
adequate for enrollment into the study.  


Spectrum Pharmaceuticals, Inc. 
Clinical Study Report 
Poziotinib 
Protocol Number: SPI-POZ-201 Amendment 2 - List of Changes 
Confidential 
 
3 
Section 
Change 
Synopsis: 
Pharmacokinetic 
Assessments 
Schedule of Assessments 
and Procedures 
Section 5.3.2 
Section 5.4.6 
Original Text: 
The schedule for intensive PK sampling will be Day 1 of Cycle 1 pre-dose and 
30 minutes, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.  
New Text: 
The schedule for intensive PK sampling will be Day 1 of Cycle 1 pre-dose and 
30 minutes, 1, 1.5, 2, 3, 4, 6, and 24 hours post-dose.  
Reason: 
The change was made to improve enrollment. 
Section 5.4.5: Chemistry 
Panel 
Added: 
Added GGT (only at screening) and uric acid as part of the chemistry panel.  
Reason: 
These were already part of the chemistry panel but are now specified. 
 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
Confidential 
1 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
TITLE PAGE 
Study Title:  
A Phase 2 Study of Poziotinib in Patients with HER2-Positive 
Metastatic Breast Cancer (MBC) Who Have Received Prior 
HER2 Regimens for MBC 
Study Number:  
SPI-POZ-201  
Study Phase:  
Phase 2  
Study Drug:  
Poziotinib 
IND Number:  
127,487 
Sponsor:  
Spectrum Pharmaceuticals, Inc. 
157 Technology Drive 
Irvine, CA 92618 
USA 
Protocol Version/Date:  
Amendment 2/ 14 Jul 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 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
Confidential 
2 
INVESTIGATOR SIGNATURE  
Protocol Number: SPI-POZ-201 
A Phase 2 Study of Poziotinib in Patients with HER2-Positive Metastatic Breast Cancer 
(MBC) Who Have Received Prior HER2 Regimens for MBC  
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 (e.g., FDA). 
 
__________________________________ 
Investigator Name (PLEASE PRINT):  
 
Signature: ________________________________ Date ______________  
  
 
 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
Confidential 
3 
SYNOPSIS  
Title of Study: A Phase 2 Study of Poziotinib in Patients with HER2-Positive Metastatic Breast Cancer (MBC) 
Who Have Received Prior HER2 Regimens for MBC 
Name of Sponsor: Spectrum Pharmaceuticals, Inc. 
Name of Investigational Product: Poziotinib 
Study Centers: Approximately 35 study centers 
Planned Number of Patients: Approximately 75 patients 
Duration of Study: Approximately 3 years 
Clinical Phase: 2 
Objectives:  
Primary Objective 
• 
To establish the dosing schedule for poziotinib to be used in the clinical development program 
• 
To evaluate the Objective Response Rate (ORR) of poziotinib in patients with human epidermal 
growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC)  
Secondary Objectives 
• 
To assess the safety and tolerability of poziotinib in patients with HER2-positive MBC 
• 
To evaluate the pharmacokinetics of poziotinib in patients with HER2-positive MBC 
• 
To evaluate other efficacy variables of poziotinib in patients with HER2-positive MBC, including the 
following: 
• 
Progression Free Survival (PFS) 
• 
Disease Control Rate (DCR) 
• 
Time to Progression (TTP) 
Duration of Study: The total duration of the study will be approximately 3 years. The duration of study 
participation for each patient includes the following segments:  
• 
Screening Period: 30 days 
• 
Treatment Period: 21 days per cycle for up to 24 months  
• 
End-of-Treatment Visit: 35 (±5) days after the last dose of poziotinib  
Study Design and Treatment Plan: 
This is a Phase 2, open-label, multicenter study to establish the dose regimen and evaluate the preliminary 
efficacy and the safety/tolerability of poziotinib in approximately 75 patients with HER2-positive MBC who 
have received at least two prior HER2-directed treatment regimens including trastuzumab and T-DM1. The 
Screening period (Day -30 to Day -1) lasts up to approximately 30 days prior to Cycle 1, Day 1. Patients must 
meet all Inclusion/Exclusion Criteria to participate in the study. Eligible patients will provide written Informed 
Consent prior to undergoing any study procedures.  
Each treatment cycle is 21 calendar days in duration. Eligible patients will be enrolled into each dose cohort as 
described below. In Amendment 1, in addition to the original 24 mg cohort (Cohort 1), two additional treatment 
cohorts are being added:  
• 
Cohort 1: 24 mg (three 8-mg tablets once daily) for 2 weeks, rest 1 week (ENROLLMENT 
COMPLETE) 
• 
Cohort 2: 16 mg (two 8-mg tablets once daily) continuous dosing  
• 
Cohort 3: 12 mg (one 8-mg tablet and two 2-mg tablet once daily) continuous dosing 
Patient enrollment in Cohort 1 is complete. New patients will begin enrollment into Cohort 2. Rules for safety 
review and enrollment for Cohort 2 and Cohort 3 follow: 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
Confidential 
4 
Cohort 2: 
• 
Rate of Grade 3 or greater AEs of special interest (ie, diarrhea, skin rash, stomatitis) that are identified 
during Safety Data Review after the first 6 patients and again after 12 patients have completed Cycle 1: 
• 
>33%: Stop Cohort 2 (≥3 of 6 patients or ≥5 of 12 patients with Grade 3 or greater AEs of special 
interest) and begin Cohort 3  
• 
≤33%: Keep enrolling Cohort 2 until 30 patients are enrolled and treated and no additional patients 
will be enrolled. 
Cohort 3 - only if Cohort 2 is stopped due to toxicity: 
• 
Rate of Grade 3 or greater AEs of special interest (ie, diarrhea, skin rash, stomatitis) are identified during 
Safety Data Review after the first 6 patients and again after 12 patients have completed Cycle 1: 
• 
>33%: End enrollment in Cohort 3  
• 
≤33%: Keep enrolling Cohort 3 until 20 patients are enrolled and treated 
Toxicity will be assessed based on the grade of the Adverse events using CTCAE version 4.03.  
All treatments will be taken orally, once daily (QD) at approximately the same time each morning. On Day 1 of 
each cycle, the patient’s absolute neutrophil count (ANC) must be ≥1.0×109/L and platelet count must be 
≥100×109/L before administering poziotinib. Day 1 of a new cycle is equivalent to Day 22 of the previous cycle, 
with a window of ±3 days for the visit. If a visit is delayed during a cycle, then all subsequent cycles will be 
delayed sequentially. All patients will be treated until disease progression, death, intolerable adverse events, or 
up to a maximum of 24 months, whichever comes first.  
Patient Replacement Strategy: Patients who discontinue from the study will not be replaced.  
Inclusion & Exclusion Criteria:  
Inclusion Criteria: 
1. Patient, or patient’s authorized representative, 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 has histopathologically confirmed primary breast cancer with metastatic lesions. 
3. Patient has confirmed HER2 overexpression or gene-amplified tumor via immunohistochemistry (IHC) 
with IHC 3+ or IHC 2+ with confirmatory fluorescence in situ hybridization (FISH)+. 
4. At least two prior HER2-directed therapy regimens for breast cancer, including trastuzumab and 
trastuzumab emtansine (T-DM1, KADCYLA®). 
5. Patient is at least 18, and ≤90 years of age. 
6. Patient has adequate hematologic, hepatic, and renal function, as defined by: 
• 
Absolute neutrophil count (ANC) ≥1.0×109/L. 
• 
Platelet count ≥100×109/L 
• 
Hemoglobin ≥9 g/dL 
• 
Total bilirubin ≤1.5 mg/dL, if hepatic metastases are present, ≤2.5 mg/dL 
• 
Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT), alanine 
aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT), and gamma-
glutamyltransferase (GGT) ≤2.5×upper limit of normal (ULN); if hepatic metastases are present, 
≤5.0×ULN 
• 
Creatinine ≤2.2 mg/dL or calculated creatinine clearance ≥40 mL/min 
7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Life expectancy is 
more than 6 months.  
8. Patient has measurable disease, as per the Response Evaluation Criteria in Solid Tumors (RECIST, 
version 1.1) 
9. Patient is willing to practice 2 forms of contraception, one of which must be a barrier method, from 
study entry until at least 30 days after the last dose of poziotinib. 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
Confidential 
5 
10. Females of childbearing potential must have a negative pregnancy test within 30 days prior to 
enrollment. Females who are postmenopausal for at least 1 year (defined as more than 12 months since 
last menses) or who are surgically sterilized do not require this test.  
Exclusion Criteria: 
1. Patient has had previous treatment with poziotinib prior to study participation.  
2. Patient has brain metastases that are symptomatic or require therapy to control symptoms, as well as any 
history of radiation, surgery, or other therapy, including steroids, to control symptoms from brain 
metastases within 15 days of enrollment.  
3. Patient has received anticancer chemotherapy, biologics, immunotherapy, cure-intent radiotherapy, or 
investigational treatment within 15 days, except for hormone therapy, palliative therapy, or supportive 
therapy  
4. Patient has a history of congestive heart failure (CHF) Class III/IV according to the New York Heart 
Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring treatment. 
5. Patient has a cardiac ejection fraction <50% by either echocardiogram or multi-gated acquisition 
(MUGA) scan.  
6. Patient has a history of other malignancies within the last 5 years, except for non-melanoma skin cancer 
or carcinoma in situ of the cervix.  
7. Patient is confirmed to have clinically significant or recent acute gastrointestinal disease presenting as 
diarrhea and/or coloenteritis as a main symptom (ie, acute enteritis, malabsorption, or Common 
Terminology Criteria for Adverse Events (CTCAE, version 4.03) Grade 2 or above diarrhea due to other 
etiologies). 
8. Patient is unable to take drugs orally due to disorders or diseases that may affect gastrointestinal 
function, such as inflammatory bowel diseases (eg, Crohn’s disease, ulcerative colitis) or malabsorption 
syndrome, or procedures that may affect gastrointestinal function, such as gastrectomy, enterectomy, or 
colectomy.  
9. Patient has an active liver disease or biliary tract disease (except for Gilbert’s disease, asymptomatic 
biliary stones, liver metastasis, or stabilized chronic liver diseases).  
10. Patient has an active uncontrolled infection, underlying medical condition, or other serious illness that 
would impair the ability of the patient to receive protocol treatment. 
11. Patient has active bleeding disorders, uses warfarin or other coumadin-derived anticoagulants, has 
abnormal International Normalized Ratio (INR), or abnormal prothrombin time test within one month 
prior to the study.  
12. Patient is pregnant or breast-feeding. 
Investigational Product, Dose, and Route of Administration:  
Poziotinib is supplied as 8-mg and 2-mg tablets and will be administered orally once daily at approximately the 
same time each morning according to the schedule for each cohort, either for 14 days, followed by 7 treatment-
free rest days (Cohort 1 only) or continuous (Cohorts 2 and 3 only), during each 21-day cycle. If the morning 
dose is missed, this dose may be administered any time during the day, at least 8 hours prior to the next 
scheduled dose.   
Loperamide will be supplied by Sponsor and is to be taken by all patients on the following schedule: 
• 
Days 1 to 56: 4 mg two times a day (bid), or three times a day (tid) if needed 
• 
Days 56 until end of treatment: 4 mg taken as needed, but not to exceed 16 mg/24 hours 
The intra-patient dose modification following the first dose administration in Cohort 2 due to toxicity will be 
allowed as below: 
• 
After the first occurrence of an AE Grade ≥3, the dose of poziotinib will be temporarily withheld. Once 
the event has recovered to Grade ≤1, the treatment can resume at the same dose.  
• 
If the same AE occurs a second time (Grade ≥3), the dose of poziotinib will be reduced.  
• 
No dose reductions below 12 mg/day will be allowed.  


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
Confidential 
6 
No dose modification will be allowed in Cohort 3 if the toxicity as described above is observed. The patient will 
be discontinued.  
Reference Therapy, Dose, and Route of Administration: None  
Efficacy Assessments: 
Primary Endpoint: 
• 
The optimal dosing schedule for poziotinib to be used in the clinical development program 
• 
Objective Response Rate (ORR) 
Secondary Endpoints: 
• 
Safety 
• 
Pharmacokinetics (PK) 
• 
Progression-Free Survival (PFS)  
• 
Disease Control Rate (DCR) 
• 
Time to Progression (TTP)  
Pharmacokinetic Assessments: All patients will have blood samples drawn pre-dose and at 1 hour and 2 hours 
(±15 min) post-dose for sparse pharmacokinetic (PK) sampling on Day 1 of Cycle 1, Cycle 2, and Cycle 3 (all 
cohorts) and pre-dose on Day 14 (±3 days) of Cycle 1 (Cohort 1 only).  
Patients in Cohort 2 and Cohort 3, if consented, will undergo intensive PK sampling. Intensive PK 
sampling will replace sparse PK sampling in Cycle 1. The schedule for intensive PK sampling will be Day 1 of 
Cycle 1 pre-dose and 30 minutes, 1, 1.5, 2, 3, 4, 6, and 24 hours post-dose.  
In addition, if a patient presents with a potentially drug-related serious adverse event (SAE), PK samples may be 
collected during the visit for PK analysis. 
Safety Assessments: 
Safety will be assessed by reported/elicited adverse events (AEs), laboratory assessments including hematology 
and biochemistry, vital signs, physical examination, and neurological examination. The assessment of treatment-
emergent AEs (TEAEs) includes SAEs, AEs leading to study drug discontinuation, and AEs related to the study 
drug.  
Adverse Event and Serious Adverse Event Reporting: 
Adverse events will be recorded from the first dose of study drug administration until 35 (±5) days after the last 
dose of study drug is administered. From the time Informed Consent is signed to the first dose of study drug 
administration, only serious adverse events (SAEs) related to study procedures will be recorded and reported.  
Statistical Methods: 
A formal statistical analysis plan (SAP) providing full technical details of the planned analyses will be finalized 
prior to database lock.  
Sample Size Justification: 
Other important treatments for HER2-positive metastatic breast cancer include trastuzumab emtansine (T-DM1), 
lapatinib-capecitabine combination, and neratinib. Published ORRs reported for these regimens are 43.6%, 
30.8%, and 24%, respectively. The purpose of this study is to evaluate the safety and efficacy of poziotinib and 
identify the optimal dose for future clinical development. No statistical hypothesis testing will be performed.  
The enrollment into Cohort 1 is now complete. A total of 32 patients have received treatment of poziotinib in 
Cohort 1. A total of 30 patients are expected to be enrolled and treated in Cohort 2. If the enrollment in 
Cohort 2 is stopped due to toxicity, new patients will be enrolled into Cohort 3. A total of 20 patients will be 
enrolled in Cohort 3.  
Efficacy Analysis:  
The primary efficacy variable ORR will be analyzed descriptively along with the 95% CI for each cohort. The 
secondary efficacy variables, PFS, DCR, and TTP, will be analyzed descriptively for each cohort.  


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
Confidential 
7 
Analysis Populations: 
The following analysis populations will be defined. 
• 
The Evaluable Population (EP) consists of all patients who are enrolled, complete at least 1 cycle of 
poziotinib treatment, and have at least 1 post-Baseline tumor response evaluation using RECIST, 
Version 1.1 criteria. 
• 
The Safety Analysis Population (SAF) includes all patients who signed Informed Consent, enrolled, 
and received at least 1 dose of poziotinib. All demographics, Baseline characteristics, and safety data 
will be analyzed using the SAF population. 
Safety and Tolerability:  
The following variables will be summarized and analyzed descriptively for each cohort: number of completed 
cycles; number and percentages of patients with TEAEs, SAEs, TEAEs leading to study drug discontinuation, 
TEAEs related to the study drug; and the severity of TEAEs based on CTCAE, Version 4.03.  
Protocol Version/Date: Amendment 2/14 Jul 2017 
 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
Confidential 
8 
Study Design Diagram 
 
 
 
Day
Poziotinib
Cohort 1
24 mg PO
~30 Patients
Screening
Period
30 Days
7
8
9 10 11
1
2
3
4
5
6
12 13 14 15 16 17 18 19 20 21
Single Treatment Cycle
21 Day Cycles Until up to 24 Months
1
2
Next Cycle
Cohort 2
16mg PO
~30 Patients
Cohort 3
12 mg PO
~20 Patients
(if needed)


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
 
Confidential 
9 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
Assessment 
Screening 
Treatment Perioda 
(Each Cycle=21 [±3] Days) up to 24 Months 
End-of-Treatment 
Visit  
Cycle 1 
Cycle 2 
Cycle 3+ 
Day -30  
to Day-1 
Day 1 
Day 8±1 
Day 14±3 
Day 1 Day 8±1 
Day 1 
35 (±5) Days After 
Last Doseb 
Informed Consent 
x 
 
 
 
 
 
 
 
Relevant Medical History 
x 
 
 
 
 
 
 
 
Demographic Data 
x 
 
 
 
 
 
 
 
Height and Weight  
x 
x 
 
 
x 
 
x 
x 
Physical examination c 
x 
x 
 
 
x 
 
x 
x 
Vital signs  
x 
x 
 
 
x 
 
x 
x 
ECOG Performance Status 
x 
x 
 
 
x 
 
x 
x 
Pregnancy test (urine) d 
x 
 
 
 
 
 
 
 
Tumor Receptor Status (ER, PR, HER2) and Stage 
x 
 
 
 
 
 
 
 
Tumor Assessment e 
x 
 
 
 
 
 
x 
x 
CBC with 5-part differential and platelets f 
x 
x f 
x 
 
x 
x 
x 
x 
Serum Chemistry g 
x 
x g 
 
 
x 
 
x 
x 
Cardiac Ejection Fraction h 
x 
 
 
 
 
 
 
x 
PK Samples i 
 
x 
 
x i 
x 
 
x 
 
Dispense Poziotinib and Loperamidej 
 
x 
 
 
x 
 
x 
 
Adverse event assessment 
x k 
x 
x 
x 
x 
x 
x 
x 
Dispense and Collect Patient Diary  
 
x 
x 
 
x 
x 
x 
x 
Concomitant medications review 
x 
x 
x 
x 
x 
x 
x 
x 
a) 
Each cycle is comprised of 21 days. Day 1 of a new cycle is applicable to Day 22 of the previous cycle, with a window period of ± 3 days. If a visit is delayed during 1 cycle, the subsequent schedules 
will be delayed sequentially. 
b) 
An End-of-Treatment Visit will be performed 35 (±5) days after the last dose of poziotinib. An End of Study page will be recorded at that time.  
c) 
A complete physical examination is required at Screening, Day 1 of each Cycle, and at the End-of-Treatment Visit. Symptom-directed exams are required at other visits. 
d) 
Pregnancy test (urine β-HCG) in women of child-bearing potential. 
e) 
Tumor assessment will be performed at Screening and every 6 weeks (± 14 days) until disease progression, death, or intolerable adverse events, whichever comes earlier. Imaging studies performed 
prior to the signing of Informed Consent as part of the site’s routine standard of practice are allowed at the discretion of the Sponsor. 
f) 
Complete blood count (CBC), including white blood cells with 5-part differential, hemoglobin, and platelets, is to be obtained within 7 days prior to poziotinib administration on Day 1 of each cycle, 
at which time, the patient’s absolute neutrophil count must be ≥1.0×109/L and platelet count must be ≥100×109/L before administering the next dose of poziotinib. In addition, a CBC is to be 
performed on Day 8 of Cycles 1 and 2. 
g) 
Blood for chemistry is to be collected within 7 days prior to poziotinib administration on Day 1 of each Cycle. 
h) 
Cardiac ejection fraction will be evaluated using echocardiogram or multi-gated acquisition (MUGA) scan and will be monitored at Screening, 3 months after first treatment, then every 6 months 
thereafter, while the patient is treated, and at the End-of-Treatment Visit.  


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
 
Confidential 
10 
i) 
For all cohorts, patients will have blood samples drawn pre-dose and at 1 hour and 2 hours (±15 min) post-dose for sparse pharmacokinetic (PK) sampling on Day 1 of Cycles 1, 2, and 3 and pre-dose 
on Day 14 of Cycle 1 (Cohort 1 only). For patients in Cohort 2 and Cohort 3, if consented, intensive PK samples will be drawn pre-dose and 30 minutes, 1, 1.5, 2, 3, 4, 6, and 24 hours post-dose on 
Day 1 of Cycle 1. In addition, if a patient presents with a potentially drug-related serious adverse event (SAE), PK samples may be collected during the visit for PK analysis. 
j) 
Poziotinib and loperamide will be dispensed on Day 1 of each cycle. Patients will take poziotinib orally once daily at approximately the same time each morning according to the schedule for each 
cohort during each 21-day cycle.  
k) 
Adverse event assessment during Screening will utilize National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.03) and record only study-related SAEs. 
 
 
 


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Poziotinib Dosing Recommendations  
• After the first occurrence of an AE Grade ≥3, the dose of poziotinib will be temporarily 
withheld. Once the event has recovered to ≤Grade 1, the treatment can resume at the 
same dose.  
• If the same AE occurs a second time (Grade ≥3), the dose of poziotinib will be reduced.  
• No dose reductions below 12 mg/day will be allowed. 
Adverse 
Event 
Grade 
1st 
Occurrence 
2nd 
Occurrence 
3rd 
Occurrence 
Diarrhea 
Grade ≥3 (Despite 
adequate anti-diarrheal 
prophylaxis and/or 
treatment) 
Poziotinib Dose  
stays the same 
Poziotinib Dose  
Reduced: 
24 mg → 16 mg 
16 mg → 12 mg 
12 mg dose - 
discontinue treatment 
Poziotinib Dose 
Reduced: 
16 mg → 12 mg  
12 mg dose - 
discontinue treatment  
Grade ≥2 for ≥ 48 hours 
(Despite adequate anti-
diarrheal prophylaxis 
and/or treatment) 
Rash 
Grade ≥3 
Poziotinib Dose 
stays the same 
Poziotinib Dose  
Reduced: 
24 mg→ 16 mg 
16 mg → 12 mg  
12 mg dose - 
discontinue treatment 
Poziotinib Dose 
Reduced: 
16 mg → 12 mg  
12 mg dose - 
discontinue treatment  
Nausea 
and/or 
Vomiting 
Grade ≥3 (Despite 
adequate anti-emetics) 
Poziotinib Dose 
stays the same 
Poziotinib Dose  
Reduced: 
24 mg → 16 mg 
16 mg → 12 mg  
12 mg dose - 
discontinue treatment 
Poziotinib Dose 
Reduced: 
16 mg → 12 mg  
12 mg dose - 
discontinue treatment  
Grade ≥2 for ≥48 hours 
(Despite adequate anti-
emetics) 
LVEF 
Dysfunction 
Grade ≥3 
Discontinue Treatment 
 
 


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TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................................1 
INVESTIGATOR SIGNATURE ..................................................................................................2 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ............................................................................................................12 
List of Tables ..........................................................................................................................14 
List of Figures .........................................................................................................................14 
LIST OF ABBREVIATIONS .....................................................................................................15 
1 
INTRODUCTION ................................................................................................................18 
1.1 
Background ................................................................................................................18 
1.1.1 
Breast Cancer .....................................................................................................18 
1.1.2 
Human Epidermal Growth Factor Receptor Family- Role in Breast Cancer
 ...........................................................................................................................18 
1.1.3 
Poziotinib ............................................................................................................19 
1.1.4 
Poziotinib Nonclinical Studies ..........................................................................19 
1.1.5 
Poziotinib Clinical Studies ................................................................................22 
1.2 
Rationale for the Current Study ...............................................................................24 
2 
STUDY OBJECTIVES ........................................................................................................25 
2.1 
Primary Objective ......................................................................................................25 
2.2 
Secondary Objectives.................................................................................................25 
3 
INVESTIGATIONAL PLAN ..............................................................................................26 
3.1 
Study Design and Treatment Plan............................................................................26 
3.2 
Study and Treatment Duration ................................................................................27 
4 
PATIENT POPULATION ...................................................................................................28 
4.1 
Inclusion Criteria .......................................................................................................28 
4.2 
Exclusion Criteria ......................................................................................................28 
4.3 
Patient Discontinuation/Withdrawal Criteria .........................................................29 
5 
STUDY PROCEDURES ......................................................................................................30 
5.1 
Screening .....................................................................................................................30 
5.2 
Patient Assignment ....................................................................................................30 
5.3 
Timing of Assessments and Procedures ...................................................................30 
5.3.1 
Screening (Day -30 to Day -1) ...........................................................................30 
5.3.2 
Treatment Period – Cycle 1, Day 1 ..................................................................31 
5.3.3 
Treatment Period – Cycle 1, Day 8 (±1 Day) ..................................................32 
5.3.4 
Treatment Period – Cycle 1, Day 14 (±3 Days) (Cohort 1 only) ....................32 
5.3.5 
Treatment Period – Cycle 2, Day 1 ..................................................................32 
5.3.6 
Treatment Period – Cycle 2, Day 8 (±1 Day) ..................................................32 
5.3.7 
Treatment Period – Cycle 3+, Day 1 (up to 24 months) .................................32 
5.3.8 
End-of-Treatment Visit (35 [±5] Days Post-Study Treatment) .....................33 
5.4 
Description of Study Assessment Parameters .........................................................33 


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5.4.1 
Relevant Medical History .................................................................................33 
5.4.2 
Physical Examination ........................................................................................33 
5.4.3 
Vital Signs ...........................................................................................................34 
5.4.4 
ECOG Performance Status ..............................................................................34 
5.4.5 
Clinical Laboratory Tests .................................................................................34 
5.4.6 
Pharmacokinetics ..............................................................................................35 
5.4.7 
Cardiac Ejection Fraction ................................................................................35 
5.4.8 
Tumor Assessment .............................................................................................35 
5.4.9 
Confirmation of Diagnosis of HER2-Positive Breast Cancer ........................35 
5.4.10 
Concomitant Medications .................................................................................35 
6 
STUDY DRUG AND PHARMACEUTICAL INFORMATION .....................................37 
6.1 
Poziotinib ....................................................................................................................37 
6.1.1 
Poziotinib Composition .....................................................................................37 
6.1.2 
Poziotinib Supply and Labeling .......................................................................37 
6.1.3 
Poziotinib Administration .................................................................................37 
6.1.4 
Poziotinib Storage and Handling .....................................................................37 
6.1.5 
Poziotinib Dose Modifications ..........................................................................37 
6.2 
Comparator Treatment .............................................................................................38 
7 
SAFETY ASSESSMENT .....................................................................................................38 
7.1 
Safety Measures .........................................................................................................38 
7.2 
Adverse Events ...........................................................................................................39 
7.3 
Guidelines for Recording and Attribution Scoring of Adverse Events ................40 
7.3.1 
Recording of Adverse Events ...........................................................................40 
7.3.2 
Grading of Adverse Events ...............................................................................40 
7.4 
Follow-up of Adverse Events ....................................................................................40 
7.5 
Relationship ................................................................................................................40 
7.6 
Expectedness ...............................................................................................................41 
7.7 
Serious Adverse Events .............................................................................................42 
7.7.1 
Serious Adverse Event Reporting ....................................................................42 
7.7.2 
Exclusions to Serious Adverse Event Reporting Requirements ....................43 
7.8 
Reproductive Risks ....................................................................................................43 
8 
STATISTICAL PLAN..........................................................................................................43 
8.1 
Sample Size .................................................................................................................44 
8.2 
Method of Treatment Assignment ............................................................................44 
8.3 
Analysis Populations ..................................................................................................44 
8.4 
General Statistical Methods ......................................................................................44 
8.5 
Efficacy Analyses .......................................................................................................44 
8.5.1 
Primary Endpoint ..............................................................................................44 
8.5.2 
Secondary Endpoints .........................................................................................45 
8.6 
Safety Analysis ...........................................................................................................45 
8.7 
Clinical Laboratory Evaluations ..............................................................................46 
9 
ADMINISTRATIVE PROCEDURES AND STUDY MANAGEMENT ........................46 
9.1 
Investigator Responsibilities .....................................................................................46 


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9.1.1 
Good Clinical Practice ......................................................................................46 
9.1.2 
Institutional Review Board/Ethics Committee Approval ..............................46 
9.1.3 
Informed Consent ..............................................................................................46 
9.1.4 
Study Files and Retention of Records ..............................................................47 
9.2 
Recording and Collecting of Data ............................................................................47 
9.2.1 
Case Report Forms ............................................................................................47 
9.2.2 
Drug Accountability ..........................................................................................47 
9.3 
Protocol Compliance ..................................................................................................47 
9.4 
Sponsor Responsibilities ............................................................................................48 
9.4.1 
Safety Monitoring ..............................................................................................48 
9.5 
Joint Investigator/Sponsor Responsibilities ............................................................48 
9.5.1 
Access to Information for Monitoring and Auditing .....................................48 
9.5.2 
Termination of the Study ..................................................................................48 
9.5.3 
Publication Policy ..............................................................................................48 
9.6 
Confidentiality ............................................................................................................49 
10 REFERENCES .....................................................................................................................50 
APPENDIX 1 
SCHEDULE OF ASSESSMENTS AND PROCEDURES ..........................52 
APPENDIX 2 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS SCALE ..................................................................................................................53 
 
 
List of Tables 
Table 1 
Most Common Treatment-Emergent Adverse Events (≥30% in Group Total for 
each Study) in Descending Order by Preferred Term (Safety Population) - 
Phase 1 and Phase 2 Completed Studies with Poziotinib (Doses ≥12 mg/day)....23 
Table 2 
Poziotinib Dose Modifications .................................................................................38 
Table 3 
Investigator Assessment of Adverse Event Causality ............................................41 
 
List of Figures 
Figure 1 
In Vitro Growth Inhibitory Activity of Poziotinib (HM781-36B) Versus Other 
Epidermal Growth Factor Receptor Inhibitors in SK-BR-3 Cells ......................20 
Figure 2 
Study Design Diagram ..............................................................................................27 
 
 
  
 
 


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LIST OF ABBREVIATIONS  
Abbreviation/ 
Acronym 
Definition 
ACS 
American Cancer Society 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
β-hCG 
Beta human chorionic gonadotropin 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CR 
Complete Response 
CRA 
Clinical research associate 
CRF 
Case report form 
CT 
Computed tomography 
CTA 
Clinical Trial Agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP450 
Cytochrome P450 
DCF 
Data clarification form 
DCR 
Disease Control Rate 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EP 
Evaluable Population 
ER 
Estrogen receptor 
FDA 
Food and Drug Administration 
FISH 
Fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 


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Abbreviation/ 
Acronym 
Definition 
HER2 
Human epidermal growth factor receptor 2 
hERG 
Human ether-a-go-go 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MedDRA® 
Medical Dictionary for Regulatory Activities 
M1 
Metabolite 1 (of poziotinib) 
M2 
Metabolite 2 (of poziotinib) 
MRI 
Magnetic resonance imaging 
MTD 
Maximum Tolerated Dose 
MUGA 
Multi-gated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NOAEL 
No Observed Adverse Effect Limit 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
PD 
Progressive Disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
PR 
Progesterone receptor 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAER 
Serious adverse event report 
SAF 
Safety analysis population 
SAP 
Statistical analysis plan 
SD 
Stable Disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
T-DM1 
Trastuzumab emtansine 
TEAE 
Treatment-emergent adverse event 
TTP 
Time to Progression 
ULN 
Upper limit of normal 


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Abbreviation/ 
Acronym 
Definition 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 


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1 INTRODUCTION 
1.1 Background 
1.1.1 Breast Cancer  
Breast cancer is one of the most common forms of cancer and the second highest cause of cancer 
deaths in women [1]. About 1 in 8 (12%) women in the United States (US) will develop invasive 
breast cancer during their lifetime. In the US in 2015, an estimated 231,840 new cases of 
invasive breast cancer will occur. Breast cancer is the second leading cause of cancer death in 
women, exceeded only by lung cancer. The chance that breast cancer will be responsible for a 
woman’s death is about 1 in 36 (about 3%). Death rates from breast cancer have been declining 
since about 1989, with larger decreases in women younger than 50 years of age. These decreases 
are believed to be the result of earlier detection through screening and increased awareness, as 
well as improved treatment. However, even with these improvements, it is still estimated that 
approximately 40,290 women and 440 men are expected to die from breast cancer in 2015 [1].  
Important components of the treatment of breast cancer are not only the extent of the disease but 
its biologic features. Knowledge of these factors contributes to the determination of the disease 
stage, assist in the risk assessment of recurrence, and may predict response to therapy. Due to 
this, the National Comprehensive Cancer Network (NCCN) Guidelines for Breast Cancer 
recommend that estrogen receptors (ERs), progesterone receptors (PRs), and the human 
epidermal growth factor receptor (HER2) status be determined in all breast cancer samples [2]. 
1.1.2 Human Epidermal Growth Factor Receptor Family- Role in Breast Cancer 
The human epidermal growth factor receptor (EGFR) family consists of four members: 
epidermal growth factor receptor (EGFR/HER1 or erbB-1), HER2 (erbB-2), HER3 (erbB-3), and 
HER4 (erbB-4), and these proteins regulate cell growth, apoptosis, migration, adhesion, and 
differentiation.  Hyperactivation of these receptors triggers a complex, multilayered network of 
interrelated signaling pathways including downstream up-regulation of the mitogen activated 
protein kinase (MAPK), phosphoinositide-3-kinase/ AKT (PI3K/AKT), and Janus Kinase/Signal 
Transducer and Activator of Transcription (JAK/STAT) pathways promoting cancer growth [3]. 
HER2 is overexpressed in roughly 20% to 25% of breast cancers and is a prognostic marker [4-
5]. HER2-positive breast cancers are characterized as being more clinically aggressive and more 
invasive than HER2-negative subtypes, are associated with increased growth rates, early 
systemic metastasis, and worse outcome [5-6]. Treatments that specifically target HER2 have 
been shown to be particularly beneficial to patients with HER2-positive breast cancers, and 
several targeted drug therapies have been approved by the US Food and Drug Administration 
(FDA) to treat patients with HER2-positive breast cancer, including trastuzumab, lapatinib, 
pertuzumab, and trastuzumab emtansine (T-DM1). However, de novo and acquired resistance to 
HER2-directed approaches remains a clinical challenge and an unmet medical need. Thus, 
development of novel therapeutic agents aimed at preventing or circumventing resistance are still 
needed.  


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1.1.3 Poziotinib 
1.1.3.1 Pharmacology of Poziotinib 
Poziotinib (HM781-36B) is a novel, oral, quinazoline-based pan-HER inhibitor that irreversibly 
blocks signaling through the EGFR family of tyrosine-kinase receptors, including human 
epidermal growth factor receptor (HER1/ErbB1/EGFR), HER2 (ErbB2), and HER4 (ErbB4), as 
well as HER receptor mutations. This, in turn, leads to inhibition of the proliferation of tumor 
cells that overexpress these receptors. It is well established that several malignancies, including 
lung, breast, stomach, colorectal, head, and neck, and pancreatic carcinomas, are associated with 
a mutation in or overexpression of members of the EGFR receptor family [7].  
1.1.3.2 Drug Product Description 
Poziotinib (HM781-36B) is formulated as a hydrochloride salt of poziotinib. The chemical 
formula of poziotinib is (1-[4-[4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-
yloxy]-piperidin-1-yl]prop-2-en-1-one hydrochloride). For clinical trials conducted in the United 
States, the drug product will be supplied as tablets for oral administration, which contain 2.0 mg 
or 8.0 mg of poziotinib (as salt form), respectively.  
1.1.4 Poziotinib Nonclinical Studies 
Poziotinib demonstrated potent EGFR and HER2 inhibitory activity in vitro, irreversible HER-
family binding and inhibition of EGFR downstream signaling, inhibition of cell growth in 
various human cancer cell lines, and inhibition of tumor volume and growth rate in human 
cancer cell line xenograft animal models. The comparative dose-response effects of poziotinib 
(HM781-36B), and other EGFR family inhibitors including erlotinib (Tarceva®), lapatinib, and 
afatinib (BIBW 2992) on cell growth in a breast cancer cell line are presented in Figure 1.  The 
cells were treated with increasing doses of poziotinib (0.1-1000 nM) for 72 hours.  In all studies, 
poziotinib was the most potent inhibitor of cell growth compared with the other EGFR inhibitors 
tested in SK-BR-3 cells. 


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Figure 1 In Vitro Growth Inhibitory Activity of Poziotinib (HM781-36B) Versus Other 
Epidermal Growth Factor Receptor Inhibitors in SK-BR-3 Cells 
 
In enzyme-based, in vitro assays conducted in various human and mouse cancer cell lines, 
poziotinib effectively inhibited wild-type EGFR family kinases, including EGFR, HER2, and 
HER4 with 50% inhibitory doses (IC50) of 3.2 nM, 5.3 nM, and 23.5 nM, respectively, and 
mutated EGFRs, including EGFRT790M and EGFRL858R/T790M with IC50 values of 4.2 nM and 
2.2 nM, respectively. In in vivo cancer models, poziotinib monotherapy blocked the 
phosphorylation of EGFR and HER2 in HCC827, N-87, and NCI-H1975 cancer cell lines.  
Poziotinib was also shown to irreversibly bind to its target enzymes, which led to excellent in 
vivo anti-tumor effectiveness of poziotinib in xenograft models with various EGFR-dependent 
cancer cell lines harboring high expression levels of EGFRWT or HER2, EGFRDel E746_A750 and 
EGFRL858R/T790M. In vitro and in vivo studies have also been conducted to evaluate the effects of 
poziotinib when administered in combination with the well-established monoclonal antibody 
cancer drug trastuzumab. These studies were performed in HER2-driven cancer models, 
including breast cancer and gastric cancer, and indicate that poziotinib has synergistic 
antineoplastic effects when given in combination with trastuzumab. 
Safety pharmacology studies of poziotinib were conducted, including a rat Irwin study, a rat 
respiratory study, and a cardiovascular telemetry study in dogs. The inhibition of human ether-a-
go-go (hERG) tail current observed in vitro was not predictive of cardiovascular effects in 
telemetry-instrumented beagle dogs in vivo. The nonclinical efficacy and safety data support the 
continued development of poziotinib. 


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1.1.4.1 Poziotinib Absorption, Distribution and Metabolism  
Poziotinib is a compound with high plasma clearance, moderate oral bioavailability, high protein 
binding, slow metabolism in vitro, and extensive metabolism in vivo. Exposure to poziotinib 
increased with increase in dose, and pharmacokinetic profiles were similar between males and 
females in nonclinical species. Poziotinib was widely distributed in tissues, and was concentrated 
in the uveal tract and eye. Poziotinib was extensively metabolized in the rat following 
intravenous and oral administration of the drug; 10 metabolites were identified. Metabolites 
identified in vitro were similar to those identified in vivo, and in the clinic; M1 (dihydroxy-
poziotinib) and M2 (O-demethyl-poziotinib) were the major metabolites. Metabolite formation 
was NADPH-dependent, suggesting a role for cytochrome P450 (CYP450) enzymes. CYP3A4 
was the primary enzyme in the formation of M1, and CYP2D6 was the primary enzyme in the 
formation of M2. Both the M1 and M2 metabolites are pharmacologically active, but M2 is 
much more potent than M1 [8]. 
1.1.4.2 Poziotinib Toxicity Studies  
The toxicities of single or repeated daily doses of oral poziotinib were assessed in rats and dogs. 
In the 13-week toxicity study, rats tolerated poziotinib up to a daily dose of 0.45 mg/kg. Adverse 
toxicological effects included an increase in the incidence of skin lesions (degeneration/atrophy, 
erosion/ulcer, epidermal hyperplasia, exudates), stomach toxicity (histopathological epithelial 
hyperplasia, hyperkeratosis, inflammation and erosion/ulcer) and increased neutrophil counts 
secondary to inflammation. The NOAEL for the 13-week study was 0.15 mg/kg/day. The MTD 
for the study was 0.45 mg/kg/day, based on reductions in mean body weight in males (-18.7%) 
and females (-7.1%). 
In the 13-week toxicity study, dogs tolerated up to 0.15 mg/kg/day. The NOAEL following dose 
reduction was 0.075 mg/kg/day. The MTD following dose reduction was 0.15 mg/kg/day, based 
on reductions in body weight (13.2% and 13.9%) and food consumption (75.8% and 85.0%) in 
males and females, respectively. The major target organs were skin (hyperplasia, ulcer, and 
inflammation), gastrointestinal tract (inflammation, attenuation of luminal epithelium), eye 
(atrophy of the corneal epithelium), and lymphoid organ (lymphocyte depletion/necrosis). In 
regard to cardiovascular effects (electrocardiogram [ECG], blood pressure, heart rate, and QT), 
there were no changes up to 0.15 mg/kg/day of poziotinib in the 13-week dog toxicity study.  
Poziotinib and its M1 and M2 metabolites were not mutagenic in vitro in the bacterial reverse 
mutation assay (Ames test) or in the Chinese hamster ovary chromosome aberration assay; and, 
were not clastogenic in an in vivo rat bone marrow micronucleus test at doses of up to 
1000 mg/kg in males and 500 mg/kg in females. Poziotinib was evaluated in an embryo-fetal 
study in rats and rabbits. Effects of poziotinib on embryo-fetal development were limited and 
restricted to high doses. High-dose poziotinib exposure was associated with a reduction in the 
mean number of viable fetuses and this was correlated with increased post implantation loss and 
resorptions. Neither the rat nor the rabbit showed evidence of teratogenicity. Poziotinib did not 
show any evidence of skin irritation in male New Zealand White rabbits or any evidence of 
phototoxicity to BALB/c 3T3 clone A31 cells.  
The toxicological findings in animal studies have been entirely consistent with the adverse 
events reported in human clinical trials. The most frequent adverse events reported in human 
clinical trials conducted in South Korea to date include diarrhea, stomatitis, rash, decreased 


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appetite, and pruritus. These toxicological effects observed in rats, dogs and humans with 
poziotinib mirror those observed with other EGFR inhibitors [9-12], suggesting that poziotinib 
toxicity is a class effect of EGFR tyrosine kinase inhibition. Since the poziotinib metabolite M2 
exhibits in vitro EGFR inhibitory activity nearly identical to poziotinib (IC50 values = 5.6 nM 
and 5.4 nM, respectively), one cannot exclude the possibility that in vivo poziotinib EGFR 
inhibitory activity is due to systemic levels of both poziotinib and M2. As the formation of M2 is 
dependent on the variable activity of the human polymorphic CYP2D6 enzyme, accounting for 
poziotinib and M2 may be the most accurate estimate of TKI activity and hence toxicity. The 
mean safety margin at the NOAEL in dogs in the 13-week toxicity study, compared to humans at 
the MTD of 24 mg/day, was 0.8-fold using poziotinib exposure alone and 2.1-fold using 
poziotinib + M2 exposure.  
These values are in line with the Phase 1 studies completed in South Korea, in which patients 
were treated with poziotinib doses ranging from 0.5 mg to 32 mg (HM-PHI-101). The dose-
limiting toxicity (DLT) in these clinical trials was observed at 32 mg, and 24 mg was the MTD 
for the intermittent (14 days on treatment and 7 days off) dosing schedule. Taken together, these 
data support the planned and ongoing clinical trials utilizing doses of poziotinib up to 24 mg/day. 
1.1.5 Poziotinib Clinical Studies 
To date, the clinical development program for poziotinib has been conducted in Korea and 
comprises of 3 completed and 6 ongoing clinical studies in patients with advanced cancers. 
• Two completed Phase 1 studies conducted in patients with advanced cancers (solid 
tumors)  
• One completed Phase 1b/2 study conducted in patients with advanced gastric cancer 
• Six ongoing Phase 2 studies conducted in patients in various malignancies, including one 
Phase 2 study being performed in patients with breast cancer 
To date, more than 200 patients have received poziotinib monotherapy in open-label clinical 
trials at doses ranging from 0.5 mg to 32 mg on an intermittent dosing schedule and from 12 mg 
to 24 mg on a continuous dosing schedule, or as combination therapy with trastuzumab and 
paclitaxel. Clinical activity was observed in patients on poziotinib monotherapy and in 
combination with other anti-cancer agents, as defined by objective responses or prolonged 
stabilization of disease. Clinical benefit has been observed in patients with several solid tumors. 
Poziotinib monotherapy utilizing an oral dose of 16 mg/day on either an intermittent (2 weeks 
on, 1 week off) or continuous dosing regimen can induce partial response or disease stabilization 
in patients with several advanced solid tumor types (HM-PH1-102). For the cancer indications 
being investigated, the patients experienced adverse events (AEs) that were either expected for 
the underlying malignancies or commonly seen with other HER2-targeted therapies (e.g., 
diarrhea, rash, and stomatitis).  
Despite the fact that most patients treated in poziotinib clinical trials have had advanced and 
heavily pre-treated disease, the safety profile described for poziotinib in these trials and the anti-
tumor activity noted suggests a favorable benefit-risk ratio and provides justification for the 
continued development of poziotinib for the treatment of multiple EGFR- or HER2-driven solid 
tumor indications. 


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The most commonly reported (≥50%) treatment-emergent AEs in all three studies were diarrhea, 
rash, stomatitis, decreased appetite, paronychia and pruritus (Table 1). The most commonly 
reported treatment-related AEs (≥50% incidence in any 24-mg/day cohort) in HM-PHI-101 
(2 cohorts, 24 mg/day and 24 mg/day) and HM-PHI-102 (1 cohort) were as follows: 
• Diarrhea (100%, 100%, 100%) 
• Stomatitis (100%, 100%, 67%) 
• Rash (100%, 100%, 67%) 
• Pruritus (83%, 92%, 0%) 
• Palmar-plantar erythrodysesthesia syndrome (33%, 58%, 0%) 
• Decreased appetite (17%, 42%, 100%) 
• Rhinorrhea (33%, 75%, 33%) 
• Paronychia (67%, 25%, 33%) 
Many of these most commonly reported treatment-related AEs in the 24-mg/day cohorts were 
also reported at an incidence of ≥50% incidence in NOV120101-202 (16 mg/day continuous), ie, 
diarrhea (95%), stomatitis (59%), rash (77%), pruritus (64%), and paronychia (54%). 
The most commonly reported Grade 3 TEAEs (≥25% incidence in any 24-mg/day cohort) in 
HM-PHI-101 (2 cohorts, 24 mg/day and 24 mg/day) and HM-PHI-102 (1 cohort) were as 
follows: 
• Diarrhea (33%, 25%, 33%) 
• Nausea (0%, 8%, 33%) 
• Decreased appetite (0%, 8%, 33%) 
• Hemoglobin decreased (0%, 0%, 33%) 
Different from the most commonly reported Grade 3 TEAEs in the 24-mg/day cohorts, Grade 3 
TEAEs reported at an incidence of ≥25% in NOV120101-202 (16-mg/day continuous dosing) 
were rash (59%) and mucosal inflammation (26%). Refer to poziotinib IB for complete details. 
Table 1 
Most Common Treatment-Emergent Adverse Events (≥30% in Group Total for 
each Study) in Descending Order by Preferred Term (Safety Population) - Phase 
1 and Phase 2 Completed Studies with Poziotinib (Doses ≥12 mg/day) 
Preferred Term 
Number (%) Patients 
HM-PHI-101 a 
N=55 
HM-PHI-102 a 
N=20 
NOV120101-202  
N=39 
Any Adverse Event 
55 (100) 
20 (100) 
39 (100) 
Diarrhea 
48 (87) 
20 (100) 
36 (92) 
Rash 
47 (86) 
13 (65) 
30 (77) 
Stomatitis 
42 (76) 
16 (80) 
23 (59) 
Decreased Appetite 
34 (62) 
13 (65) 
21 (54) 


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Preferred Term 
Number (%) Patients 
HM-PHI-101 a 
N=55 
HM-PHI-102 a 
N=20 
NOV120101-202  
N=39 
Paronychia 
13 (24) 
13 (65) 
21 (54) 
Pruritus 
33 (60) 
11 (55) 
25 (64) 
Mucosal Inflammation 
13 (24) 
6 (30) 
18 (46) 
Rhinorrhea 
17 (31) 
8 (40) 
4 (10) 
Dry skin 
6 (11) 
6 (30) 
15 (38) 
Fatigue 
21 (38) 
3 (15) 
15 (38) 
PPE Syndrome 
18 (33) 
3 (15) 
3 (8) 
Acne 
18 (33) 
0 
0 
Vomiting 
16 (29) 
6 (30) 
4 (10) 
Dermatitis Acneiform 
2 (4) 
6 (30) 
5 (13) 
PPE = palmar-plantar erythrodysesthesia syndrome. 
(a) Includes all patients and all doses. 
Note: Adverse events are listed by decreasing order of highest percent in any study. 
MedDRA version: 14.0 was used for Studies HM-PHI-101 and HM-PH1-102; MedDRA version 17.0 was used for 
NOV120101-202. 
Source: Poziotinib IB Table 9. 
1.2 Rationale for the Current Study 
HER2-targeted approaches have revolutionized the treatment and outcomes associated with 
HER2-overexpressing breast cancer. However, de novo and acquired resistance to HER2- 
directed approaches remains a clinical challenge, and many metastatic breast cancer patients 
continue to progress or relapse, despite having initially responded to treatment. Several 
resistance mechanisms have been described, including mutations in other signaling pathways and 
expression of a truncated form of HER2 [13]. Therefore, there remains an unmet need to develop 
novel treatment approaches for HER2-positive breast cancer that can improve clinical outcomes, 
particularly in the context of strategies to overcome resistance to HER2-targeted therapy.  
Poziotinib is an orally administered, irreversible pan-HER inhibitor with activity against HER1, 
(ErbB1; EGFR), HER2 (ErbB2), and HER4 (ErbB4), as well as HER receptor mutations. The 
clinical results and safety profile of poziotinib to date in various studies involving patients with 
relapsed or refractory solid tumors as either a single agent or as combination therapy, have been 
very promising. These data support the expectation that poziotinib will be efficacious and well 
tolerated in HER2-positive metastatic breast cancer patients.  
In Phase 1 studies, the MTD of poziotinib was determined to be 18 mg for continuous daily 
dosing and 24 mg for intermittent dosing (14 days on treatment, 7 days off treatment). The most 
commonly occurring toxicities included diarrhea, rash, and stomatitis, which is consistent with 
the known toxicity profile of other EGFR inhibitors. For monoclonal antibody EGFR-targeted 
therapies, such as cetuximab or panitumumab, rates of Grade 2 diarrhea are up to 21% and for 
Grade 3 diarrhea (i.e., greater than 7 stools per day or requiring intravenous fluids) between 1% 
to 2% [14-17]. For small-molecule EGFR tyrosine kinase inhibitors like erlotinib, gefitinib, and 


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lapatinib, however, diarrhea is substantially more common, occurring in up to 60% for all grades 
and with Grade 3 diarrhea occurring in about 6% to 9% of patients [15].  
Although diarrhea is common with EGFR inhibitor treatment and can significantly impact 
patients’ quality of life, evidence suggests that diarrhea is also an indicator that EGFR TKIs are 
hitting their target [18]. In one study of gefitinib in NSCLC, the presence of diarrhea was 
identified as one of the independent predictors of a partial response, and the absence of diarrhea 
was one of the predictors of progressive disease [19]. In another study of gefitinib and erlotinib 
in patients with recurrent and metastatic squamous cell carcinoma of the head and neck, EGFR 
TKI–induced diarrhea was associated with clinical benefit and also an association with more 
favorable overall survival [20]. In afatinib lung cancer trials, a trend toward a higher rate of 
progression-free survival was observed in patients who had Grade 2 or greater diarrhea in the 
first 28 days of treatment with afatinib compared with patients who experienced no AEs [21]. 
Currently, prophylactic loperamide is often given to prevent diarrhea with other EGFR-directed 
therapies [22]. In addition, based on our experience from a recently completed Phase 2 breast 
cancer study, it is estimated that the average body size of US patients will be larger than that of 
the average Korean patient. Therefore, to address the expected issues with acute diarrhea in this 
study, prophylactic loperamide will be administered with the 24 mg starting dose of poziotinib 
(Section 5.4.10.1), which was not required in the Korean studies. In addition, intermittent dosing 
rather than continuous dosing will be used to also help address the more chronic toxicities of rash 
and stomatitis. Supportive care for mucositis/stomatitis will also be provided, aiming to control 
symptoms for all patients during the study. 
In Phase 1 studies, 18 mg/day was the maximum tolerated dose for continuous dosing, and 
16 mg/day was the recommended dose for continuous dosing. Based on the tolerability of 
poziotinib in patients in this study so far and the previous data, two additional cohorts with lower 
doses and continuous dosing are being added to this protocol amendment. No new patients will 
be enrolled into the original 24 mg per day with intermittent dosing cohort (Cohort 1) and new 
patients will be enrolled into Cohort 2 (16 mg/day, continuous dosing). If patients are unable to 
tolerate the dosing regimen in Cohort 2, new patients will be enrolled into Cohort 3 (12 mg/day, 
continuous dosing). These changes are being made in order to improve patient tolerability while 
maintaining consistent drug exposure.  
2 STUDY OBJECTIVES  
2.1 Primary Objective 
• To establish the dosing schedule for poziotinib to be used in the clinical development 
program 
• To evaluate the Objective Response Rate (ORR) of poziotinib in patients with HER2-
positive metastatic breast cancer (MBC) 
2.2 Secondary Objectives 
• To assess the safety and tolerability of poziotinib in patients with HER2-positive MBC  
• To evaluate the pharmacokinetics of poziotinib in patients with HER2-positive MBC  
• To evaluate other efficacy variables of poziotinib in patients with HER2-positive MBC, 
including the following:  


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• 
Progression-Free Survival (PFS)  
• 
Disease Control Rate (DCR)  
• 
Time to Progression (TTP)  
3 INVESTIGATIONAL PLAN 
3.1 Study Design and Treatment Plan 
This is a Phase 2, open-label, multicenter study to establish the dose regimen and evaluate the 
preliminary efficacy and the safety / tolerability of poziotinib in approximately 75 patients with 
HER2-positive MBC who have received at least two prior HER2-directed treatment regimens 
including trastuzumab and T-DM1. 
The Screening period (Day -30 to Day -1) lasts up to approximately 30 days prior to Cycle 1, 
Day 1. Patients must meet all Inclusion/Exclusion Criteria to participate in the study. Eligible 
patients will provide written Informed Consent prior to undergoing any study procedures.  
Each treatment cycle is 21 calendar days in duration. Eligible patients will be enrolled into each 
dose cohort as described below. In Amendment 1, in addition to the original 24 mg cohort 
(Cohort 1), two additional treatment cohorts were added.  
• Cohort 1: 24 mg (three 8-mg tablets once daily) for 2 weeks, rest 1 week 
(ENROLLMENT COMPLETE) 
• Cohort 2: 16 mg (two 8-mg tablets once daily) continuous dosing  
• Cohort 3: 12 mg (one 8-mg tablet and two 2-mg tablet once daily) continuous dosing  
Patient enrollment in Cohort 1 is complete. New patients will begin enrollment into Cohort 2. 
Rules for safety review and enrollment for Cohort 2 and Cohort 3 follow: 
Cohort 2:  
• Rate of Grade 3 or greater AEs of special interest (ie, diarrhea, skin rash, stomatitis) that 
are identified during Safety Data Review after the first 6 patients and again after 
12 patients have completed Cycle 1: 
• 
>33%: Stop Cohort 2 (≥3 of 6 or ≥5 of 12 patients with Grade 3 or above AE of 
special interest) and begin Cohort 3  
• 
≤33%: Keep enrolling Cohort 2 until 30 patients are enrolled and treated and no 
additional patients will be enrolled. 
Cohort 3 - only if Cohort 2 is stopped due to toxicity: 
• 
Rate of Grade 3 or greater AEs of special interest (ie, diarrhea, skin rash, stomatitis) 
are identified during Safety Data Review after the first 6 patients and again after 
12 patients have completed Cycle 1: 
• 
>33%: End enrollment in Cohort 3  
• 
≤33%: Keep enrolling Cohort 3 until 20 patients are enrolled and treated 
Toxicity will be assessed based on the grade of the adverse events using CTCAE version 4.03.  
All treatments will be taken orally, once daily (QD) at approximately the same time each 
morning. On Day 1 of each cycle, the patient’s absolute neutrophil count (ANC) must be 


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≥1.0×109/L and platelet count must be ≥100×109/L before administering poziotinib. For Cycle 1 
and Cycle 2 only, the ANC and platelet count should also be confirmed prior to the dose on 
Day 8. Day 1 of a new cycle is equivalent to Day 22 of the previous cycle, with a window of ±3 
days for the visit. If a visit is delayed during 1 cycle, then all subsequent cycles will be delayed 
sequentially. 
All patients will be treated until disease progression, death, intolerable adverse events, or up to a 
maximum of 24 months, whichever comes first. 
The study design diagram is presented in Figure 2, and the Schedule of Study Assessments and 
Procedures is presented Appendix 1. 
Figure 2 Study Design Diagram 
 
3.2 Study and Treatment Duration  
The total duration of the study will be approximately 3 years. The duration of study participation 
for each patient includes the following segments: 
• Screening Period: 30 days 
• Treatment Period: 21 days per cycle for up to 24 months  
• End-of-Treatment Visit: 35 (±5) days after the last dose of poziotinib 
Day
Poziotinib
Cohort 1
24 mg PO
~30 Patients
Screening
Period
30 Days
7
8
9 10 11
1
2
3
4
5
6
12 13 14 15 16 17 18 19 20 21
Single Treatment Cycle
21 Day Cycles Until up to 24 Months
1
2
Next Cycle
Cohort 2
16mg PO
~30 Patients
Cohort 3
12 mg PO
~20 Patients
(if needed)


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4 PATIENT POPULATION  
4.1 Inclusion Criteria  
1. Patient, or patient’s authorized representative, 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 has histopathologically confirmed primary breast cancer with metastatic lesions. 
3. Patient has confirmed HER2 overexpression or gene-amplified tumor via 
immunohistochemistry [IHC] with IHC 3+ or IHC 2+ with confirmatory fluorescence in 
situ hybridization [FISH]+. 
4. At least two prior HER2-directed therapy regimen(s) for breast cancer, including 
trastuzumab and trastuzumab emtansine (T-DM1, KADCYLA®). 
5. Patient is at least 18, and ≤90 years of age.  
6. Patient has adequate hematologic, hepatic, and renal function, as defined by: 
• 
Absolute neutrophil count (ANC) ≥1.0×109/L. 
• 
Platelet count ≥100×109/L 
• 
Hemoglobin ≥9 g/dL 
• 
Total bilirubin ≤1.5 mg/dL, if hepatic metastases are present, ≤2.5 mg/dL 
• 
Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT), 
alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT), and 
gamma-glutamyltransferase (GGT) ≤2.5×upper limit of normal (ULN); if hepatic 
metastases are present ≤5.0×ULN 
• 
Creatinine ≤2.2 mg/dL or calculated creatinine clearance ≥40 mL/min 
7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Life 
expectancy is more than 6 months.  
8. Patient has measurable disease, as per the Response Evaluation Criteria in Solid Tumors 
(RECIST, version 1.1). 
9. Patient is willing to practice 2 forms of contraception, one of which must be a barrier 
method, from study entry until at least 30 days after the last dose of poziotinib.  
10. Females of childbearing potential must have a negative pregnancy test within 30 days 
prior to enrollment. Females who are postmenopausal for at least 1 year (defined as more 
than 12 months since last menses) or who are surgically sterilized do not require this test. 
4.2 Exclusion Criteria 
1. Patient has had previous treatment with poziotinib prior to study participation.  
2. Patient has brain metastases that are symptomatic or require therapy to control symptoms, 
as well as any history of radiation, surgery, or other therapy, including steroids, to control 
symptoms from brain metastases within 15 days of enrollment. 
3. Patient has received anticancer chemotherapy, biologics, immunotherapy, cure-intent 
radiotherapy, or investigational treatment within 15 days, except for hormone therapy, 
palliative therapy, or supportive therapy.  


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4. Patient has a history of congestive heart failure (CHF) Class III/IV according to the New 
York Heart Association Functional Classification or serious cardiac arrhythmias 
requiring treatment. 
5. Patient has a cardiac ejection fraction <50% by either echocardiogram or multi-gated 
acquisition (MUGA) scan. 
6. Patient has a history of other malignancies within the last 5 years, except for non-
melanoma skin cancer or carcinoma in situ of the cervix. 
7. Patient is confirmed to have clinically significant or recent acute gastrointestinal disease 
presenting as diarrhea and/or coloenteritis as a main symptom (ie, acute enteritis, 
malabsorption, or Common Terminology Criteria for Adverse Events (CTCAE, version 
4.03) Grade 2 or above diarrhea due to other etiologies). 
8. Patient is unable to take drugs orally due to disorders or diseases that may affect 
gastrointestinal functions, such as inflammatory bowel diseases (eg, Crohn’s disease, 
ulcerative colitis) or malabsorption syndrome, or procedures that may affect 
gastrointestinal functions, such as gastrectomy, enterectomy, or colectomy.  
9. Patient has an active liver disease or biliary tract disease (except for Gilbert’s disease, 
asymptomatic biliary stones, liver metastasis, or stabilized chronic liver diseases).  
10. Patient has an active uncontrolled infection, underlying medical condition, or other 
serious illness that would impair the ability of the patient to receive protocol treatment. 
11. Patient has active bleeding disorders, uses warfarin or other coumadin-derived 
anticoagulants, has abnormal International Normalized Ratio (INR), or abnormal 
prothrombin time test within one month prior to the study.  
12. 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.  
All treated patients must be withdrawn from the study at 24 months or for the following reasons:  
• Development of an adverse event (AE) that interferes with the patient’s participation 
• Initiation of non-protocol therapy 
• Development of progressive disease (PD) 
• Patient withdrawal of informed consent 
• Delay of poziotinib administration for >42 days since last study drug administration 
• Investigator decision 
• Sponsor decision 
• Lost to follow-up 
• Pregnancy 
• Death 
The reason for the patient discontinuing study treatment or terminating from the study must be 
recorded on the case report form (CRF). Patients who discontinue treatment or who are 


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withdrawn from treatment will return for an End-of-Treatment Visit 35 (±5) days after the last 
dose of poziotinib or prior to beginning a new treatment, whichever is first.  
5 STUDY PROCEDURES  
The study design diagram is presented in Figure 2, and the Schedule of Study Assessments and 
Procedures is presented Appendix 1. 
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. The results of any procedures or laboratory assessments performed prior to the 
signing of Informed Consent as part of the site’s routine standard of practice will be allowed for 
use as a Screening Assessment at the discretion of the Sponsor. This information is to be 
discussed with the Medical Monitor before the patient is enrolled in the study. All procedures are 
to be performed as outlined in Appendix 1 prior to the start of study treatment, unless otherwise 
noted.  
5.2 Patient Assignment 
Each patient who signs an Informed Consent Form for participation in this study will be assigned 
a unique screening number according to the instructions in the study binder. 
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 
assign a Patient ID. The Patient ID will include two parts: the site number assigned by Spectrum 
will be 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, 
).  
A CRF will only be completed for patients who are enrolled and receive a Patient ID.  
5.3 Timing of Assessments and Procedures 
5.3.1 Screening (Day -30 to Day -1) 
The following screening assessments should be performed within 30 days of Cycle 1, Day 1. 
Obtain Informed Consent prior to any study procedures.  
• Informed Consent 
• Relevant medical history 
• Demographic data 
• Height and weight 
• Complete physical examination 
• Vital signs 
• Eastern Cooperative Oncology Group (ECOG) Performance Status assessment 


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• Complete blood count (CBC) with 5-part differential and platelets prior to poziotinib 
administration (may be obtained up to 7 days prior to Cycle 1, Day 1)  
• Prothrombin time/International Normalized Ratio (as needed, and only for those patients 
who may have bleeding disorders and are using warfarin or other coumadin-derived 
anticoagulants) 
• Serum biochemistry prior to poziotinib administration (may be obtained up to 7 days 
prior to Cycle 1, Day 1) 
• Pregnancy test (urine beta-human chorionic gonadotropin [β-HCG]) in women of 
childbearing potential 
• Echocardiogram or MUGA scan to evaluate cardiac ejection fraction 
• Tumor histopathology report (from local pathologist) 
• Tumor assessment (may be obtained prior to signing of IC and may be used for 
Screening purposes as long as it is performed prior to Cycle 1, Day 1; consultation with 
the Sponsor is required) 
• Hormone-receptor status, including ER, PR and HER2, number of nodes, and stage 
• Adverse event assessment using NCI CTCAE, version 4.03, record AEs related to study 
procedures only 
• Concomitant medications 
5.3.2 Treatment Period – Cycle 1, Day 1  
• Eligibility confirmation 
• Patient ID 
• Height and weight  
• Physical examination 
• Vital signs  
• ECOG Performance Status assessment 
• Pharmacokinetic blood sampling: 
• 
Sparse PK blood sampling taken pre-dose and at 1 hour and 2 hours (±15 min) post-
dose 
OR 
• 
Intensive PK blood sampling pre-dose and 30 minutes, 1, 1.5, 2, 3, 4, 6, and 24 hours 
post-dose (if consented) 
• Dispense poziotinib and loperamide  
• Adverse event assessment using NCI CTCAE, version 4.03, record AEs related to study 
procedures only 
• CBC with 5-part differential and platelets 
• Dispense Patient Diary  
• Concomitant medications review 


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5.3.3 Treatment Period – Cycle 1, Day 8 (±1 Day) 
• Complete blood count with 5-part differential and platelets 
• Adverse events using NCI CTCAE, Version 4.03, record AEs related to study procedures 
only 
• Patient Diary Collection 
• Concomitant medications 
5.3.4 Treatment Period – Cycle 1, Day 14 (±3 Days) (Cohort 1 only) 
• Sparse PK blood sampling collected pre-dose  
• Adverse event assessment using NCI CTCAE, Version 4.03, record AEs related to study 
procedures only (Cohorts 2 and 3 by telephone) 
• Concomitant medications (Cohorts 2 and 3 by telephone) 
5.3.5 Treatment Period – Cycle 2, Day 1  
• 
Weight  
• 
Physical examination 
• Vital Signs 
• 
ECOG Performance Status assessment 
• Complete blood count with 5-part differential  
• Serum biochemistry 
• Sparse pharmacokinetic blood sampling taken pre-dose and at 1 hour and 2 hours 
(±15 min) post-dose 
• Dispense poziotinib  
• Adverse event assessment using NCI CTCAE, Version 4.03, record AEs related to study 
procedures only 
• Patient Diary Collection 
• Concomitant medications 
5.3.6 Treatment Period – Cycle 2, Day 8 (±1 Day) 
• Complete blood count with 5-part differential and platelets 
• Adverse event assessment using NCI CTCAE, Version 4.03, record AEs related to study 
procedures only 
• Patient Diary Collection 
• Concomitant medications 
5.3.7 Treatment Period – Cycle 3+, Day 1 (up to 24 months) 
• Height and weight  
• Physical examination 
• Vital Signs 


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• ECOG Assessment 
• Tumor assessment (to be performed after Cycle 2, and approximately every 6 weeks 
thereafter) 
• Serum biochemistry 
• Echocardiogram or MUGA scan to evaluate cardiac ejection fraction (3 months after the 
first treatment and then every 6 months thereafter, during treatment) 
• Sparse pharmacokinetic blood sampling taken pre-dose and at 1 hour and 2 hours 
(±15 min) post-dose (Cycle 3 only)  
• Dispense poziotinib  
• Adverse event assessment using NCI CTCAE, Version 4.03, record AEs related to study 
procedures only 
• Patient Diary Collection 
• Concomitant medications 
5.3.8 End-of-Treatment Visit (35 [±5] Days Post-Study Treatment) 
The End-of-Treatment Visit is required 35 (±5) days after the last dose of poziotinib is 
administered. The following assessments are to be performed at this visit:  
• Physical examination 
• Vital signs  
• ECOG Performance Status assessment 
• Tumor assessment (unless the patient has documented disease progression or has 
undergone a tumor assessment within the previous 6 weeks)  
• CBC with 5-part differential and platelets  
• Serum biochemistry  
• Echocardiogram or MUGA scan to evaluate cardiac ejection fraction 
• Adverse event assessment  
• Patient Diary Collection 
• Concomitant medications 
5.4 Description of Study Assessment Parameters 
5.4.1 Relevant Medical History 
At Screening, the patient’s relevant medical history will be collected, to include the history of 
breast cancer, documentation of HER2 genetic confirmation, previous therapy, as well as 
significant and relevant past diseases and current medications.  
5.4.2 Physical Examination 
A complete physical examination, including a description of external signs of the neoplastic 
disease and co-morbidities, will be performed at Screening and Day 1 of each cycle, and at the 
End-of-Treatment Visit. Symptom-directed examinations are required at other visits. Physical 
examinations are to be completed by a physician or other health professional licensed to perform 


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such examinations. Findings will be documented in the patient’s medical record and on the 
appropriate CRF pages. Any abnormalities are to be recorded on the AE CRF.  
5.4.3 Vital Signs 
Vital signs, to include temperature, blood pressure, heart rate, and respiratory rate, are to be 
recorded at Screening and Day 1 of each cycle and at the End-of-Treatment Visit. Heart rate 
and blood pressure will be recorded before poziotinib administration. 
5.4.4 ECOG Performance Status 
Patients’ Performance Status will be evaluated using criteria as developed by the Eastern 
Cooperative Oncology Group (Appendix 2) at Screening and Day 1 of each cycle and at the 
End-of-Treatment Visit.  
5.4.5 Clinical Laboratory Tests 
A local laboratory will be used to process all clinical specimens. The following clinical 
laboratory parameters will be evaluated in this study: 
• Complete Blood Count (CBC): A CBC, including white blood cells (WBC), with 5-part 
differential, hemoglobin, and platelets will be performed at Screening, Day 1 and Day 8 
of Cycle 1 and Cycle 2, Day 1 of subsequent cycles, and at the End-of-Treatment Visit. 
The results of the laboratory assessments should be evaluated and medically accepted by 
the responsible physician before the start of each cycle.  
• Prothrombin Time (PT) and International Normalized Ratio (INR): Only for patients 
with active bleeding disorders or use warfarin or other coumadin-derived anticoagulants a 
PT/INR need to be evaluated at Screening.  
Use of warfarin or other coumadin-derived anticoagulants should be avoided during 
treatment with poziotinib. When it cannot be avoided, regular monitoring of INR is 
required and prior authorization from study medical monitor is required.  
• Chemistry Panel: A comprehensive chemistry and electrolytes, including blood urea 
nitrogen (BUN), AST/SGOT, ALT/SGPT, alkaline phosphatase (ALP), GGT (only at 
screening), total bilirubin,  albumin, calcium, lactate dehydrogenase, sodium, potassium, 
chloride, phosphate, magnesium, creatinine, uric acid, and glucose, will be performed at 
Screening, Day 1 of each cycle, and at the End-of-Treatment Visit.  
• 
Special note for the Day 1 sampling of each cycle: If possible, blood samples 
should be drawn on Day 1 of each cycle (prior to treatment); however, for logistical 
reasons, it is also acceptable to draw samples for assessment up to 7 days prior to the 
start of a cycle. The results of the laboratory assessments should be evaluated and 
medically accepted by the responsible physician before the start of each cycle. 
• Pregnancy Test: A urine β-hCG test will be performed at Screening for all women of 
childbearing potential. 


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5.4.6 Pharmacokinetics 
All patients will have blood samples drawn pre-dose and at 1 hour and 2 hours (±15 min) post-
dose for sparse PK sampling on Day 1 of Cycles 1, 2, and 3 and pre-dose on Day 14 (±3 days) of 
Cycle 1 (Cohort 1 only).  
If consented, intensive PK samples will be drawn pre-dose and 30 minutes, 1, 1.5, 2, 3, 4, 6, and 
24 hours post-dose on Day 1 of Cycle 1. In addition, if a patient presents with a potentially drug-
related SAE at any time during the study, PK samples may be collected during the clinic visit for 
PK analysis. 
5.4.7 Cardiac Ejection Fraction 
Cardiac ejection fraction will be assessed by either echocardiogram or multi-gated acquisition 
(MUGA) scan at Screening, 3 months after first treatment, then every 6 months thereafter, while 
the patient is being treated, and at the End-of-Treatment Visit.  
5.4.8 Tumor Assessment 
Tumor assessment must be performed by Investigators using computed tomography (CT) or 
magnetic resonance imaging (MRI) at Screening up to 30 days prior to Cycle 1, Day 1. Imaging 
studies performed prior to the signing of Informed Consent as part of the site’s routine standard 
of practice are allowed at the discretion of the Sponsor. This information is to be discussed with 
the Medical Monitor before the patient is enrolled in the study.  
Tumor assessments will be performed every 6 weeks (±14 days) until disease progression, death, 
intolerable adverse events, or for up to 24 months. 
Each subsequent tumor assessments must use the same Baseline radiologic technique, either CT 
or MRI. Tumor assessments will be made according to RECIST criteria, Version 1.1 [23] using 
appropriate radiologic imaging or other techniques. For radiographic assessment, CT or MRI 
must be performed at every assessment.  
Measurable and non-measurable lesions that will not be followed by radiological methods should 
be documented appropriately.  
5.4.9 Confirmation of Diagnosis of HER2-Positive Breast Cancer  
Confirmation of HER2 overexpression or gene-amplified tumor via immunohistochemistry 
(IHC) with IHC 3+ or IHC 2+ with confirmatory fluorescence in situ hybridization (FISH) is 
required. 
5.4.10 Concomitant Medications 
All medications administered from Screening to the End-of-Study Visit will be recorded on the 
CRF. A concomitant medication is any medication a patient is using from Day 1 of Cycle 1 to 
the End-of-Study Visit. The study drugs are not considered concomitant medications. 
All concomitant medications recorded at study 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. 


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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 until 35 (±5) days after the last dose of study drug. 
Premedications (such as antiemetics) used for supportive care are allowed as per institutional 
standards or guidelines. 
Endocrine or hormonal therapy for hormonal receptor positive breast cancer is allowed. 
Other supportive and palliative therapies may be allowed during the study upon prior 
authorization from study medical monitor.  
5.4.10.1 Premedication and Supportive Treatment 
All patients will receive prophylaxis with loperamide. Loperamide will be supplied by Sponsor 
and is to be taken by all patients on the following schedule: 
• Days 1 to 56: 4 mg two times a day (bid), or three times a day (tid) if needed 
• Days 56 until end of treatment: 4 mg taken as needed, but not to exceed 16 mg/24 hours 
Patients should also receive prophylactic mouth care to prevent possible mucositis and or 
stomatitis during poziotinib treatment.  
Mucositis/stomatitis should be treated in a supportive manner aiming to control symptoms. 
Prophylactic methods to reduce or prevent mucositis/stomatitis include: 
• Avoidance of spicy, acidic, or irritating foods and alcoholic drinks  
• Use of solutions such as saline (diluted solution with salt water and baking soda by 
dissolving ½ teaspoon of salt and 1 teaspoon of baking soda in approximately 1 liter of 
water) and using this solution every 4 hours 
• Use of Nystatin solution 
• Use of Magic Mouthwash (for instance, combination of viscous lidocaine 2% + 
Mylanta + diphenhydramine elixir + prednisolone solution)  
Pre-medications (including, but not limited to antiemetics), as per Institutional standard of care, 
should be administered before poziotinib on Day 1.  
5.4.10.2 Uses of Warfarin or Other Coumadin-Derived Anticoagulants  
Use of warfarin or other coumadin-derived anticoagulants should be avoided during treatment 
with poziotinib. When it cannot be avoided, regular monitoring of INR is required and prior 
authorization from study medical monitor is required.  
5.4.10.3 Other Anticancer Therapies 
No additional cytotoxic agents, biologic therapy, or immune response modifiers for cure-intent 
purpose are to be administered to patients until study treatment has been discontinued. 


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5.4.10.4 Prohibited Therapies or Medications 
No other anti-cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
experimental medications, are permitted during the trial. Any disease progression that requires 
anti-tumor therapy will be cause for discontinuation from the study. 
6 STUDY DRUG AND PHARMACEUTICAL INFORMATION  
Study treatment is to be handled and administered according to the study sites’ regulations for 
the handling and administration of cytotoxic anticancer agents. 
6.1 Poziotinib 
Poziotinib will be supplied by Spectrum.  
6.1.1 Poziotinib Composition 
The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet 
for oral administration. 
6.1.2 Poziotinib Supply and Labeling 
Poziotinib tablets are supplied in 2.0-mg and 8.0-mg dose strengths, and contain 2.0 mg and 
8.0 mg of poziotinib hydrochloride salt, respectively. 
6.1.3 Poziotinib Administration 
Poziotinib is supplied as 8-mg and 2-mg tablets and will be administered orally once daily at 
approximately the same time each morning according to the schedule for each cohort during each 
21-day cycle. If the morning dose is missed, this dose may be administered any time during the 
day, at least 8 hours prior to the next scheduled dose.  
• Cohort 1: 24 mg (three 8-mg tablets) for 14 days and then 7 treatment-free rest days  
• Cohort 2: 16 mg (two 8-mg tablets) once daily continuously  
• Cohort 3: 12 mg (one 8-mg tablet and two 2-mg tablets) once daily continuously  
6.1.4 Poziotinib Storage and Handling 
Poziotinib supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the drug supply label. 
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. 
6.1.5 Poziotinib Dose Modifications 
• After the first occurrence of an AE Grade ≥3, the dose of poziotinib will be temporarily 
withheld. Once the event has recovered to Grade ≤1, the treatment can resume at the 
same dose.  
• If the same AE occurs a second time (Grade ≥3), the dose of poziotinib will be reduced.  
• No dose reductions below 12 mg/day will be allowed. 
An algorithm for poziotinib dose modification is provided in Table 2.  


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Table 2 
Poziotinib Dose Modifications 
Adverse 
Event 
Grade 
1st 
Occurrence 
2nd 
Occurrence 
3rd 
Occurrence 
Diarrhea 
Grade ≥3 (Despite 
adequate anti-diarrheal 
prophylaxis and/or 
treatment) 
Poziotinib 
Dose  
stays the same 
Poziotinib Dose  
Reduced: 
24 mg → 16 mg 
16 mg → 12 mg 
12 mg dose - 
discontinue treatment 
Poziotinib Dose 
Reduced: 
16 mg → 12 mg  
12 mg dose - 
discontinue treatment  
Grade ≥2 for ≥48 hours 
(Despite adequate anti-
diarrheal prophylaxis 
and/or treatment) 
Rash 
Grade ≥3 
Poziotinib 
Dose stays the 
same 
Poziotinib Dose  
Reduced: 
24 mg→ 16 mg 
16 mg → 12 mg  
12 mg dose - 
discontinue treatment 
Poziotinib Dose 
Reduced: 
16 mg → 12 mg  
12 mg dose - 
discontinue treatment  
Nausea 
and/or 
Vomiting 
Grade ≥3 (Despite 
adequate anti-emetics) 
Grade ≥2 for ≥48 hours 
(Despite adequate anti-
emetics) 
Poziotinib 
Dose stays the 
same 
Poziotinib Dose  
Reduced: 
24 mg → 16 mg 
16 mg → 12 mg  
12 mg dose - 
discontinue treatment 
Poziotinib Dose 
Reduced: 
16 mg → 12 mg  
12 mg dose - 
discontinue treatment  
LVEF 
Dysfunction 
Grade ≥3 
Discontinue Treatment  
6.2 Comparator Treatment 
No comparator is used in this study.  
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. The decision to modify the dose of study 
treatment will be determined by the Investigator based on the decision rules shown in 
Section 6.1.5.  
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. 


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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, 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 until 35 (±5) days after the last dose of 
study treatment. 
The study will record all AEs according to the information in Section 7.3. 
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. 
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. 
The adverse events of special interest identified with poziotinib treatment in this study include 
diarrhea, skin rash, oral cavity mucositis/stomatitis, fatigue, and vomiting/nausea.  


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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 the last dose 
of study treatment is administered are to be recorded on the AE CRF. 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.  
The resolution of all AEs must be recorded at the end of the study. The following conventions 
will be followed when patient completes or discontinues from the study: 
• If a patient dies, the date of death should be the date of AE stop for all ongoing AEs at 
the time of death. 
• If a patient discontinues due to an AE(s), the outcome of the AE is to be followed for 
35 (±5) days from the date of discontinuation or until the AE has returned to Grade ≤1. 
The status of the AE and the date of last contact with the patient will be captured. If the 
AE has not returned to Grade ≤1 by the end of the study, the AE stop date should be left 
as ongoing. 
All AEs will be classified by intensity/severity (Section 7.3.2), relationship to study drug 
(Section 7.5), and as serious or nonserious (Section 7.7) by the Investigator. 
7.3.2 Grading of Adverse Events 
This study will utilize the NCI CTCAE Scale, Version 4.03 for AE grading. 
7.4 Follow-up of Adverse Events 
All AEs and significant abnormal laboratory values are to be followed up in accordance with the 
International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines, and 
other applicable regulatory requirements (eg, United States [US] Code of Federal Regulations 
[CFR]). 
7.5 Relationship 
The Investigator must make a causality assessment and document their opinion as to the 
relationship of all AEs and SAEs to study treatment (Table 3).  


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Table 3 
Investigator Assessment of Adverse Event Causality 
Relationship 
Description 
Not Related 
The event is clearly related to factors other than study treatment, such as the patient’s 
clinical state, therapeutic interventions, or concomitant medications administered to the 
patient. 
Unlikely Related 
The temporal association, patient history and/or circumstances are such that the study 
drug or treatment is not likely to have had an association with observed event.  
Possibly Related 
The event follows a reasonable temporal sequence from the time of study treatment 
administration, and/or follows a known response pattern to study treatment, but could 
have been produced by other factors, such as the patient’s clinical state, therapeutic 
interventions, or concomitant medications administered to the patient. 
Probably Related 
The event follows a reasonable temporal sequence from the time of study treatment 
administration, and follows a known response pattern to study treatment, and cannot be 
reasonably explained by other factors, such as the patient’s clinical state, therapeutic 
interventions, or concomitant medications administered to the patient. 
Definitely Related 
The event follows a reasonable temporal sequence from the time of study treatment 
administration, and follows a known response pattern to study treatment, and cannot be 
reasonably explained by other factors, such as the patient’s clinical state, therapeutic 
interventions, or concomitant medications administered to the patient.  
In addition, the event either occurs immediately following study treatment administration, 
improves on stopping study treatment, reappears on repeat exposure, or there is a positive 
reaction at the application site. 
7.6 Expectedness 
For investigational drugs, an AE is judged “expected” if its description agrees in nature and 
severity with the description of AEs previously noted with the study drug as detailed in the 
current Investigator’s Brochure. An “unexpected” AE is one for which the specificity or severity 
is neither consistent with the current Investigator’s Brochure nor the risk information described 
in the general investigational plan. The Sponsor will be responsible for assessing the 
expectedness of AEs. 
The most common AEs associated with poziotinib treatment include: 
• Diarrhea 
• Rash 
• Stomatitis 
• Fatigue 
• Vomiting 
• Decreased Appetite  
• Dry Skin 
• Nausea 


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7.7 Serious Adverse Events 
In the interest of patient care and to allow Spectrum to fulfill all regulatory requirements, any 
SAE, regardless of causal relationship to study treatment, is to be reported to the Sponsor within 
24 hours of knowledge of the event. SAEs are defined (21 CFR 312.32, ICH of Technical 
Requirements for Registration of Pharmaceuticals for Human Use E2A Guideline) as those AEs 
that meet any of the following criteria: 
• Results in death. 
• Is life-threatening: ie, any event that, in the opinion of the Investigator, poses an 
immediate risk of death from that event. 
• Requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospitalizations for study therapy, disease-related procedures, or placement of an 
indwelling catheter, unless associated with other SAEs). 
• Results in a persistent or significant disability/incapacity. 
• Results in a congenital anomaly/birth defect. 
• Includes important medical events that may not be immediately life threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the outcomes listed in this definition. 
Adverse events that do not meet any of the above criteria for serious should be regarded as non-
serious. 
7.7.1 Serious Adverse Event Reporting 
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. All SAEs that 
occur from the first dose of study drug administration through 35 (±5) days after the last dose of 
study treatment are to be reported to Spectrum within 24 hours of knowledge of the event.  
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 serious 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 the 
SAE. Any medications necessary for treatment of the SAE are to be recorded in the concomitant 
medication section of the patient’s CRF. 


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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 section of the 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).  
The Sponsor or its 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 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. 
• Planned and prescheduled hospitalizations and procedures.  
• Progressive disease. 
7.8 Reproductive Risks 
No adequate and well-controlled studies of poziotinib have been conducted in pregnant women. 
The effect of poziotinib on fertility and fetal development have not been studied in pregnant 
women. Poziotinib is not recommended for use during pregnancy. 
Any pregnancy involving a study patient or a patient’s partner that occur from the first dose of 
study treatment through 30 days after the last dose of study treatment is to be reported to the 
Sponsor 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), providing full technical details, will be finalized prior to database 
lock. 


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8.1 Sample Size  
Other important treatments for HER2-positive MBC include T-DM1, lapatinib-capecitabine 
combination, and neratinib. Published ORRs reported for these regimens are 43.6%, 30.8%, and 
24%, respectively [22, 24-25]. The purpose of this study is to evaluate the safety and efficacy of 
poziotinib and identify the optimal dose for future clinical development. No statistical hypothesis 
testing will be performed.  
The enrollment into Cohort 1 is now complete. A total of 32 patients have received treatment of 
poziotinib in Cohort 1. A total of 30 patients are expected to be enrolled and treated in 
Cohort 2. If the enrollment in Cohort 2 is stopped due to toxicity, new patients will be enrolled 
into Cohort 3. A total of 20 patients will be enrolled in Cohort 3.  
8.2 Method of Treatment Assignment 
This study is not randomized. Patients will be enrolled sequentially.  
8.3 Analysis Populations 
Two analysis populations have been defined as follows: 
• The Evaluable Population (EP) consists of all patients who are enrolled, complete at 
least one cycle of poziotinib treatment, and have at least one post-baseline tumor 
response evaluation using RECIST, Version 1.1.  
• The Safety Analysis Population (SAF) includes all patients who signed informed 
consent, enrolled, and received at least one dose of study treatment. All demographics, 
Baseline characteristics, and safety data will be analyzed using the SAF population.  
8.4 General Statistical Methods 
The Sponsor’s Biostatistics and Data Management (BDM) group 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 SAP for this study. 
8.5 Efficacy Analyses 
8.5.1 Primary Endpoint 
The primary efficacy variables, as described below, will be summarized and analyzed 
descriptively, along with 95% CI, for each cohort. 
• Objective Response Rate (ORR) will be assessed according to the Response Evaluation 
Criteria in Solid Tumors (RECIST) Guidelines, version 1.1 [23] and is defined as the best 
response [Complete Response (CR) + Partial Response (PR)] recorded from the start of 
the study until the end of study in patients who received at least 1 dose of poziotinib. The 
ORR will be based on the EP. 


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8.5.2 Secondary Endpoints 
• Safety, including adverse events and pharmacokinetics 
• 
Safety and adverse events: Safety will be assessed by reported/elicited AEs, 
laboratory assessments including hematology and biochemistry, vital signs, physical 
examination, and neurological examination. The assessment of treatment-emergent 
AEs (TEAEs) includes SAEs, AEs leading to study drug discontinuation, and AEs 
related to the study drug. 
• 
Pharmacokinetics: All patients will have blood samples drawn pre-dose and at 
1 hour and 2 hours (±15 min) post-dose for sparse PK sampling on Day 1 of 
Cycles 1, 2, and 3 and pre-dose on Day 14 (±3 days) of Cycle 1 (Cohort 1 only). If 
consented, intensive PK samples will be drawn pre-dose and 30 minutes, 1, 1.5, 2, 3, 
4, 6, and 24 hours post-dose on Day 1 of Cycle 1. In addition, if a patient presents 
with a potentially drug-related SAE, PK samples may be collected during the clinic 
visit for PK analysis. 
• PFS is defined as the number of days from the treatment start date to the date of 
documented disease progression or death due to any cause. Disease progression will be 
determined by RECIST Version 1.1.  
• DCR, including CR, PR, and Stable Disease (SD), will be assessed using RECIST, 
version 1.1 and defined as the proportion of subjects who achieve CR, PR, and SD by the 
best response from the first dose of poziotinib to the end of study. 
• TTP is defined as the period of time from the first dose of study drug to tumor 
progression, which excludes death without tumor progression, by the end of study. 
The secondary efficacy variables of PFS, DCR, and TTP will be analyzed descriptively, for 
each cohort. 
8.6 Safety Analysis 
The overall incidence of treatment-emergent AEs (TEAE) (ie, AEs occurring from the time the 
first dose of the study drug until 35 (±5) days after the last dose) 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 (version 17) 
system-organ-class (SOC) level and Preferred Term for all treated patients, for each cohort. The 
summary of TEAEs will be presented in the following categories:  
• Number and percentage of patients with any TEAEs by SOC and Preferred Term. 
• Number and percentage of patients with any SAEs by SOC and Preferred Term. 
• Number and percentage of patients with related TEAEs by SOC and Preferred Term. 
• Number and percentage of patients with TEAEs causing discontinuation of the study by 
Body System and Preferred Term. 
In addition, the number and percent of patients with TEAEs by grade will be summarized. 
Adverse events reported prior to treatment but after IC will be provided in a listing. 
Finally, the number of completed cycles will also be summarized and analyzed descriptively. 


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8.7 Clinical Laboratory Evaluations 
Key laboratory parameters will be summarized using shift tables, which display a cross-
tabulation of the Baseline grade versus the highest on-study grade for each laboratory parameter, 
for each cohort.  
All laboratory abnormalities will be classified according to NCI CTCAE, Version 4.03 and 
summarized by worst grade severity and by treatment.  
9 ADMINISTRATIVE PROCEDURES AND STUDY MANAGEMENT  
9.1 Investigator Responsibilities  
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. The Sponsor’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. 
9.1.1 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 is responsible for preparing the written Informed Consent document for this 
study. The Sponsor or its designee will provide the Investigator with an Informed Consent 
template. The Investigator may rearrange or reword the contents of the template, or may add 
other elements or language, provided the meaning and content are not changed or deleted. The 
Sponsor or designee is to review and approve the Informed Consent document that is used by the 
Investigator for this study prior to IRB/EC submission. 
Written Informed Consent will be obtained from all patients participating in this study before any 
procedures are conducted, in accordance with ICH GCP and current regulatory requirements. 
The case history for each patient is to document that the Informed Consent process was obtained 
prior to participation in the study. The original Informed Consent document will be kept in the 
patient’s record, and a copy will be provided to the patient. 


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9.1.4 Study Files and Retention of Records 
The Investigator is to retain all study records until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product as per 21 CFR 312.62 and ICH GCP E6 4.9.5 
and 5.5.12. These documents are to be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. It is the responsibility 
of the Sponsor to inform the Investigator when these documents no longer need to be retained. 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 the Sponsor upon written 
agreement between the Investigator and the Sponsor. 
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 the Sponsor 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 the Sponsor’s standard operating procedures for editing and clarifying CRFs. Data entry 
will be performed by the sites using an electronic data capture (EDC) system. Comment fields on 
the CRFs will be used as a means of clarification and communication between the Investigator 
and the Sponsor; however, comments entered in these fields will not be edited or clarified. 
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 poziotinib 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 vials of poziotinib 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 poziotinib 
vials/bottles will be destroyed per institution, local, and all applicable policies and procedures. 
After study conclusion, all unused vials of poziotinib 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. 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
Confidential 
48 
9.4 Sponsor Responsibilities 
9.4.1 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 the Sponsor’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, and to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring/auditing visits are resolved. 
9.5.2 Termination of the Study 
For reasonable cause, either the Investigator or the Spectrum may terminate the Investigator’s 
participation in this study, provided a written notice is submitted within the time period provided 
for in the Clinical Trial Agreement (CTA). In addition, the Sponsor 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, the Sponsor 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 Sponsor 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: 
• Authorship credit should be based on the following; authors should meet all three 
conditions:  
 Substantial contributions to conception and design, acquisition of data, or analysis 
and interpretation of data;  
 Drafting the article or revising it critically for important intellectual content  


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
Confidential 
49 
 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 the Sponsor for corporate review. 
9.6 Confidentiality 
All information provided to the Investigator by the Sponsor, 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 the 
Sponsor, or in confidence to the IRB/EC or similar committee, except if required by law. 
 
 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
Confidential 
50 
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American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer 
Society; 2015. Available from: 
http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-
044552.pdf. 
2. 
National Comprehensive Cancer Network. Breast Cancer (Version 3, 2015) [July 16, 
2015]. Available from: www.nccn.org/professionals/physician_gls/pdf/breast.pdf. 
3. 
Chong CR, Janne PA. The Quest to Overcome Resistance to EGFR-Targeted Therapies 
in Cancer. Nat Med. 2013;19(11):1389-400. 
4. 
Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH. Prognosis of Women 
with Metastatic Breast Cancer by Her2 Status and Trastuzumab Treatment: An 
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5. 
Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant 
Trastuzumab in Her2-Positive Breast Cancer. N Engl J Med. 2011;365(14):1273-83. 
6. 
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human Breast 
Cancer: Correlation of Relapse and Survival with Amplification of the HER-2/Neu 
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7. 
Roskoski R, Jr. Erbb/HER Protein-Tyrosine Kinases: Structures and Small Molecule 
Inhibitors. Pharmacol Res. 2014;87:42-59. 
8. 
Noh YH, Lim HS, Jung JA, Song TH, Bae KS. Population Pharmacokinetics of Hm781-
36 (Poziotinib), pan-Human Egf Receptor (HER) Inhibitor, and Its Two Metabolites in 
Patients with Advanced Solid Malignancies. Cancer Chemother Pharmacol. 
2015;75(1):97-109. 
9. 
Han SW, Hwang PG, Chung DH, Kim DW, Im SA, Kim YT, et al. Epidermal Growth 
Factor Receptor (EGFR) Downstream Molecules as Response Predictive Markers for 
Gefitinib (Iressa, ZD1839) in Chemotherapy-Resistant Non-Small Cell Lung Cancer. Int 
J Cancer. 2005;113(1):109-15. 
10. 
Kim DW, Lee DH, Kang JH, Park KM, Han JY, Lee J-S, et al. Clinical Activity and 
Safety of Hm61713, an EGFR-Mutant Selective Inhibitor, in Advanced Non-Small Cell 
Lung Cancer (NSCLC) Patients (Pts) with EGFR Mutations Who Had Received EGFR 
Tyrosine Kinase Inhibitors (Tkis). Journal of Clinical Oncology. 2014;32(15 Suppl. 1). 
11. 
Landi L, Cappuzzo F. Irreversible EGFR-Tkis: Dreaming Perfection. Transl Lung Cancer 
Res. 2013;2(1):40-9. 
12. 
Wang X, Batty KM, Crowe PJ, Goldstein D, Yang JL. The Potential of Panher Inhibition 
in Cancer. Front Oncol. 2015;5:2. 
13. 
Hurvitz SA, Hu Y, O'Brien N, Finn RS. Current Approaches and Future Directions in the 
Treatment of Her2-Positive Breast Cancer. Cancer Treat Rev. 2013;39(3):219-29. 
14. 
Davila M, Bresalier RS. Gastrointestinal Complications of Oncologic Therapy. Nat Clin 
Pract Gastroenterol Hepatol. 2008;5(12):682-96. 


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Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
Confidential 
51 
15. 
Stein A, Voigt W, Jordan K. Chemotherapy-Induced Diarrhea: Pathophysiology, 
Frequency and Guideline-Based Management. Ther Adv Med Oncol. 2010;2(1):51-63. 
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Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-Label 
Phase III Trial of Panitumumab Plus Best Supportive Care Compared with Best 
Supportive Care Alone in Patients with Chemotherapy-Refractory Metastatic Colorectal 
Cancer. J Clin Oncol. 2007;25(13):1658-64. 
17. 
Vincenzi B, Schiavon G, Pantano F, Santini D, Tonini G. Predictive Factors for 
Chemotherapy-Related Toxic Effects in Patients with Colorectal Cancer. Nat Clin Pract 
Oncol. 2008;5(8):455-65. 
18. 
Hirsh V, Blais N, Burkes R, Verma S, Croitoru K. Management of Diarrhea Induced by 
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors. Curr Oncol. 
2014;21(6):329-36. 
19. 
Thomas SK, Fossella FV, Liu D, Schaerer R, Tsao AS, Kies MS, et al. Asian Ethnicity as 
a Predictor of Response in Patients with Non-Small-Cell Lung Cancer Treated with 
Gefitinib on an Expanded Access Program. Clin Lung Cancer. 2006;7(5):326-31. 
20. 
Cohen EE, Halpern AB, Kasza K, Kocherginsky M, Williams R, Vokes EE. Factors 
Associated with Clinical Benefit from Epidermal Growth Factor Receptor Inhibitors in 
Recurrent and Metastatic Squamous Cell Carcinoma of the Head and Neck. Oral Oncol. 
2009;45(10):e155-60. 
21. 
Yang JC-H, Sequist L, O'Byrne K, Schuler M, Mok T, Geater S, et al. Epidermal Growth 
Factor Receptor (EGFR)-Mediated Adverse Events (Aes) in Patients (Pts) with EGFR 
Mutation Positive (EGFR M+) Non-Small Cell Lung Cancer Treated with Afatinib. 
European Journal of Cancer. 2013;49:S190. 
22. 
Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab 
Emtansine for Her2-Positive Advanced Breast Cancer. N Engl J Med. 
2012;367(19):1783-91. 
23. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
Response Evaluation Criteria in Solid Tumours: Revised Recist Guideline (Version 1.1). 
Eur J Cancer. 2009;45(2):228-47. 
24. 
Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, et al. Neratinib, an 
Irreversible Erbb Receptor Tyrosine Kinase Inhibitor, in Patients with Advanced Erbb2-
Positive Breast Cancer. J Clin Oncol. 2010;28(8):1301-7. 
25. 
Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, Geyer CE. Lapatinib Plus 
Capecitabine in Women with HER-2-Positive Advanced Breast Cancer: Final Survival 
Analysis of a Phase III Randomized Trial. Oncologist. 2010;15(9):924-34. 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
 
Confidential 
52 
APPENDIX 1 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
Assessment 
Screening 
Treatment Perioda 
(Each Cycle=21 [±3] Days) up to 24 Months 
End-of-Treatment 
Visit  
Cycle 1 
Cycle 2 
Cycle 3+ 
Day -30  
to Day-1 
Day 1 
Day 8±1 
Day 14±3 
Day 1 Day 8±1 
Day 1 
35 (±5) Days After 
Last Doseb 
Informed Consent 
x 
 
 
 
 
 
 
 
Relevant Medical History 
x 
 
 
 
 
 
 
 
Demographic Data 
x 
 
 
 
 
 
 
 
Height and Weight  
x 
x 
 
 
x 
 
x 
x 
Physical examination c 
x 
x 
 
 
x 
 
x 
x 
Vital signs  
x 
x 
 
 
x 
 
x 
x 
ECOG Performance Status 
x 
x 
 
 
x 
 
x 
x 
Pregnancy test (urine) d 
x 
 
 
 
 
 
 
 
Tumor Receptor Status (ER, PR, HER2) and Stage 
x 
 
 
 
 
 
 
 
Tumor Assessment e 
x 
 
 
 
 
 
x 
x 
CBC with 5-part differential and platelets f 
x 
x f 
x 
 
x 
x 
x 
x 
Serum Chemistry g 
x 
x g 
 
 
x 
 
x 
x 
Cardiac Ejection Fraction h 
x 
 
 
 
 
 
 
x 
PK Samples i 
 
x 
 
x i 
x 
 
x 
 
Dispense Poziotinib and Loperamidej 
 
x 
 
 
x 
 
x 
 
Adverse event assessment 
x k 
x 
x 
x 
x 
x 
x 
x 
Dispense and Collect Patient Diary  
 
x 
x 
 
x 
x 
x 
x 
Concomitant medications review 
x 
x 
x 
x 
x 
x 
x 
x 
a) 
Each cycle is comprised of 21 days. Day 1 of a new cycle is applicable to Day 22 of the previous cycle, with a window period of ± 3 days. If a visit is delayed during 1 cycle, the subsequent schedules 
will be delayed sequentially. 
b) 
An End-of-Treatment Visit will be performed 35 (±5) days after the last dose of poziotinib. An End of Study page will be recorded at that time.  
c) 
A complete physical examination is required at Screening, Day 1 of each Cycle, and at the End-of-Treatment Visit. Symptom-directed exams are required at other visits. 
d) 
Pregnancy test (urine β-HCG) in women of child-bearing potential. 
e) 
Tumor assessment will be performed at Screening and every 6 weeks (± 14 days) until disease progression, death, or intolerable adverse events, whichever comes earlier. Imaging studies performed 
prior to the signing of Informed Consent as part of the site’s routine standard of practice are allowed at the discretion of the Sponsor. 
f) 
Complete blood count (CBC), including white blood cells with 5-part differential, hemoglobin, and platelets, is to be obtained within 7 days prior to poziotinib administration on Day 1 of each cycle, 
at which time, the patient’s absolute neutrophil count must be ≥1.0×109/L and platelet count must be ≥100×109/L before administering the next dose of poziotinib. In addition, a CBC is to be 
performed on Day 8 of Cycles 1 and 2. 
g) 
Blood for chemistry is to be collected within 7 days prior to poziotinib administration on Day 1 of each Cycle. 
h) 
Cardiac ejection fraction will be evaluated using echocardiogram or multi-gated acquisition (MUGA) scan and will be monitored at Screening, 3 months after first treatment, then every 6 months 
thereafter, while the patient is treated, and at the End-of-Treatment Visit.  
i) 
For all cohorts, patients will have blood samples drawn pre-dose and at 1 hour and 2 hours (±15 min) post-dose for sparse pharmacokinetic (PK) sampling on Day 1 of Cycles 1, 2, and 3 and pre-dose 
on Day 14 of Cycle 1 (Cohort 1 only). For patients in Cohort 2 and Cohort 3, if consented, intensive PK samples will be drawn pre-dose and 30 minutes, 1, 1.5, 2, 3, 4, 6, and 24 hours post-dose on 
Day 1 of Cycle 1. In addition, if a patient presents with a potentially drug-related serious adverse event (SAE), PK samples may be collected during the visit for PK analysis. 
j) 
Poziotinib and loperamide will be dispensed on Day 1 of each cycle. Patients will take poziotinib orally once daily at approximately the same time each morning according to the schedule for each 
cohort during each 21-day cycle.  
k) 
Adverse event assessment during Screening will utilize National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.03) and record only study-related SAEs. 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-201 
Amendment 14 Jul 2017 
Confidential 
53 
APPENDIX 2 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS SCALE 
Grade 
ECOG Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction.  
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
 
 

SAP_001.pdf: 
Offici al Titl e:  
A P h as e 2 St u d y of P ozi oti ni b i n P ati e nts wit h H E R 2- P ositi v e M et ast atic 
Br e ast C a nc er ( M B C) W h o H a v e R ec ei v e d Pri or H E R 2 R e gi m e ns f or M B C
N C T N u m b er:  
N C T 0 2 6 5 9 5 1 4  
D oc u m e nt  D at e : 
S A P  V ersi o n  2 . 0: 0 4  Ja n u ar y 2 0 2 1  




S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
2  
S u m m ar y of C h a n g es f or V ersi o n 2  
T h e p ur p os e of V ersi o n 2 is t o  acc o m m o d at e c h a n g es i n P r ot oc ol A m e n d m e nt  1 a n d 
A m e n d m e nt 2 , a n d t o  p r o vi d e m or e d et ails. I m p ort a nt c h a n g es ar e s u m m ariz e d b el o w. 
O v er all:  
 T w o l o w er d os e c o h orts w er e a d d e d d u e t o t h e ori gi n al d os e l e v el w as n ot w ell 
t ol er at e d.  
 T h e st u d y c h a n g e d fr o m t est of h y p ot h es es st u d y t o pr o of -of -c o nc e pt st u dy. 
 N e w s ecti o ns ar e a d d e d t o pr o vi d e d et ails f or t u m or ass ess m e nts a n d r es p o ns e 
e v al u ati o n.  
S ecti o n 2: O bj ecti v es m o difi e d  t o m atc h pr ot oc ol c h a n g e. 
S ecti o n 3:  
 A d diti o n al c o h orts a d d e d t o m atc h pr ot oc ol c h a n g e.   
 M o difi c ati o ns m a d e f or s a m pl e siz e c o nsi d er ati o ns t o m atc h pr ot oc ol c h a n g e. 
 N e w s ecti o n a d d e d f or “T u m or Ass ess m e nts ” t o pr o vi d e d et ails. 
S ecti o n 4: M o difi e d  t o m atc h pr ot oc ol. 
S ecti o n 5 . 1: M o difi e d f or cl arific ati o n.  
S ecti o n 5. 2:  
 N e w s ec ti o n a d d e d f or “Pr ot oc ol D e vi ati o n ”. 
 “ Dr u g Ex p os ur e” m o v e d t o S ecti o n 5. 4.  
S ecti o n 5. 3 : 
 N e w s ecti o n a d d e d f or “ B est O v er all R es p o ns e” t o pr o vi d e d et ails.  
 W or di n g m o dific ati o ns t o acc o m m o d at e  n e w s ecti o ns.  
 R e m o v e “ O v er all S ur vi v al” t o m atc h pr ot oc ol c h a n g e.  
 A d d s u b gr o u p a n al ysis.  
S ecti o n 5. 4 : 
 “ Dr u g Ex p os ur e” m o v e d fr o m S ecti o n 5. 2 a n d m o difi e d.  
 W or di n g m o dific ati o n s f or cl arit y. 
 
 
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
3  
 
T A BL E O F C O N T E N T S  
T A B L E O F C O N T E N T S  ........................................................................................................................... 3  
1  
I N T R O D U C TI O N ............................................................................................................................... 5  
2  
O B J E C TI V E S  ..................................................................................................................................... 5  
2. 1  
Pri m ar y O bj ecti v e  ............................................................................................................ 5  
2. 2  
S ec o n d ar y O bj ecti v es  ....................................................................................................... 5  
3  
S T U D Y O V E R VI E W .......................................................................................................................... 5  
3. 1  
S a m pl e Siz e C o nsi d er ati o ns  .............................................................................................. 6  
3. 2  
R a n d o miz ati o n  ................................................................................................................ 7  
3. 3  
T u m or Ass ess m e nts  ......................................................................................................... 7  
3. 3. 1  
B as eli n e T u m or Ass ess m e nts  ................................................................................... 7  
3. 3. 2  
F oll o w -u p T u m or Ass ess m e nts  ................................................................................. 7  
3. 3. 3  
Ti m e P oi nt R es p o ns e at E ac h T u m or Ass ess m e nt  ...................................................... 8  
4  
A N A L Y SI S P O P U L A TI O N S  ............................................................................................................. 9  
5  
S T A TI S T IC A L M E T H O D S O F A N A L Y SI S  ................................................................................... 9  
5. 1  
G e n er al Pri nci pl es  ............................................................................................................ 9  
5. 1. 1  
D efi ni ti o n of B as eli n e V al u es ................................................................................... 9  
5. 1. 2  
H a n dli n g of Missi n g D at a  ......................................................................................... 9  
5. 1. 3  
P o oli n g of C e nt ers  ................................................................................................. 1 0  
5. 1. 4  
I nt eri m A n al ysis ..................................................................................................... 1 0  
5. 1. 5  
T esti n g/ V ali d ati o n Pl a n  ......................................................................................... 1 0  
5. 2  
B ac k gr o u n d C h ar act eristics  ............................................................................................ 1 0  
5. 2. 1  
P ati e nt Dis p ositi o n  ................................................................................................ 1 0  
5. 2. 2  
Pr ot oc ol D e vi ati o n  ................................................................................................. 1 0  
5. 2. 3  
D e m o gr a p hic a n d B as eli n e C h ar act eristics  ............................................................. 1 0  
5. 2. 4  
M e dic al Hist or y  ..................................................................................................... 1 1  
5. 2. 5  
C o nc o mit a nt M e dic ati o n  ....................................................................................... 1 1  
5. 3  
Effic ac y A n al ys es  ............................................................................................................ 1 1  
5. 3. 1  
B est O v er all R es p o ns e  ........................................................................................... 1 1  
5. 3. 2  
Pri m ar y Effic ac y E n d p oi nt  ...................................................................................... 1 2  
5. 3. 3  
S ec o n d ar y Effic ac y E n d p oi nts  ................................................................................. 1 2  
5. 4  
S af et y A n al ys es  .............................................................................................................. 1 3  
5. 4. 1  
Dr u g E x p os ur e  ....................................................................................................... 1 4  
5. 4. 2  
A d v ers e E v e nts  ...................................................................................................... 1 4  
5. 4. 2. 1  
O v er all S u m m ar y  .............................................................................................. 1 5  
5. 4. 2. 2  
Tr e at m e nt E m er g e nt A d v ers e E v e nts ................................................................. 1 5  
5. 4. 2. 3  
Tr e at m e nt -R el at e d A d v ers e E v e nts  ................................................................... 1 5  
5. 4. 2. 4  
S eri o us A d v ers e E v e nts  ..................................................................................... 1 5  
5. 4. 2. 5  
M a xi m u m S e v erit y of A d v ers e E v e nts  ................................................................ 1 6  
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
4  
5. 4. 2. 6  
Ot h er I m p ort a nt A d v ers e E v e nts  ....................................................................... 1 6  
5. 4. 2. 7  
A d v ers e E v e nts of S p eci al I nt er est  ..................................................................... 1 6  
5. 4. 3  
L a b or at or y P ar a m et ers .......................................................................................... 1 6  
5. 4. 4  
Vit al Si g n D at a  ....................................................................................................... 1 7  
5. 4. 5  
E C O G P erf or m a nc e St at us  ...................................................................................... 1 7  
5. 4. 6  
C ar di ac Ass ess m e nt  ............................................................................................... 1 7  
6  
R E F E R E N C E S  .................................................................................................................................. 1 8  
 
List of T a bl es 
 
T a bl e 1  
S u m m ar y of B as eli n e f or E ac h E n d p oi nt/ D at a  ............ Err or! B o o k m ar k n ot d efi n e d.  
 
 
 
 
 
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
5  
1  I N T R O D U C TI O N 
T h e p ur p os e of t his st atistic al a n al ysis pl a n  ( S A P) is t o pr o vi d e d et ails of t h e st atistic al a n al ys es 
t h at h a v e b e e n o utli n e d wit hi n P r ot oc ol A m e n d m e nt 2 f or S t u d y S PI -P O Z -2 0 1 , d at e d 1 4 J ul 
2 0 1 7 . T h e sc o p e of t his pl a n i ncl u d es all effic ac y  a n d s af et y a n al ys es of p ozi oti ni b  i n p ati e nts 
wit h H E R 2 -p ositi v e M et ast atic Br e ast C a nc er ( M B C) w h o h a v e rec ei v e d p ri or H E R 2 re gi m e ns f or 
M B C . T h e P K a n al ysis will b e c o v er e d i n a s e p ar at e a n al ysis pl a n.   
2  O BJ E C TI V E S  
2. 1  Pri m ar y O bj ecti v e   
 T o est a blis h t h e d osi n g sc h e d ul e f or p ozi oti ni b t o b e us e d i n t h e cli nic al  d e v el o p m e nt 
pr o gr a m  
 T o e v al u at e t h e O bj ecti v e R es p o ns e R at e ( O R R) of p ozi oti ni b i n p ati e nts wit h h u m a n 
e pi d er m al gr o wt h f act or r ec e pt or 2 ( H E R 2) -p ositi v e M B C  
2. 2  S ec o n d ar y O bj ecti v es   
 T o ass ess t h e s af et y a n d t ol er a bilit y of p ozi oti ni b i n p ati e nts wit h H E R 2 -p ositi v e M B C  
 T o e v al u at e t h e p h ar m ac o ki n etics of p ozi oti ni b i n p ati e nts wit h H E R 2 -p ositi v e M B C  
 T o e v al u at e ot h er effic acy v ari a bl es of p ozi oti ni b i n p ati e nts wit h H E R 2 -p ositi v e M B C, 
i ncl u di n g t h e f oll o wi n g: 
 Pr o gr essi o n Fr e e S ur vi v al ( P F S)  
 Dis e as e C o nt r ol R at e ( D C R) 
 Ti m e t o Pr o gr essi o n ( T T P)  
3  S T U D Y O V E R VI E W  
T his is a P h as e 2, o p e n -l a b el, m ultic e nt er st u d y t o est a blis h t h e d os e r e gi m e n a n d e v al u at e t h e 
pr eli mi n ar y effic ac y a n d t h e s af et y / t ol er a bilit y of p ozi oti ni b i n a p pr oxi m at el y 7 5 p ati e nts wit h 
H E R 2 -p ositi v e M B C w h o h a v e r ec ei v e d at l e ast 2 pri or H E R 2 -dir ect e d tr e at m e nt r e gi m e ns 
i ncl u di n g tr ast uz u m a b a n d T -D M 1 .  
T h e Scr e e ni n g p eri o d ( D ay -3 0 t o D a y -1) l asts u p t o 3 0 d a ys pri or t o Cycl e 1, D a y 1. P ati e nts 
m ust m e et all I ncl usi o n/ Exc l usi o n Crit eri a t o p artici p at e i n t h e st u d y. Eli gi bl e p ati e nts will 
pr o vi d e writt e n I nf or m e d C o ns e nt pri or t o u n d er g oi n g a n y st u d y pr oc e d ur es.  
E ac h tr e at m e nt cycl e will b e 2 1 d a ys i n d ur ati o n. T h e ori gi n al pr ot oc ol c o nt ai n e d o nl y C o h ort 1 . 
I n A m e n d m e nt 1, p ati e nt e nr oll m e nt i n C o h ort 1  w as c o m pl et e, a n d n e w p ati e nts b e g a n 
e nr oll m e nt i nt o C o h ort  2 .  C o h ort 2  w as c o nti n u e d aft er t w o S af et y D at a R e vi e ws a n d n o 
p ati e nt w as e nr oll e d i nt o a d diti o n al c o h orts.  
C o h ort 1:  2 4 m g (t hr e e 8 -m g t a bl ets o nc e d ail y) f or 2  w e e ks, r est 1 w e e k  
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
6  
 3 3 p ati e nts w er e e nr oll e d i nt o C o h ort 1  u n d er ori gi n al pr ot oc ol.  
C o h ort 2:  1 6 m g (t w o 8 -m g t a bl ets o nc e d ail y) c o nti n u o us d osi n g  
 S af et y D at a R e vi e w: R at e of Gr a d e 3 or gr e at er A Es of s p eci al i nt er est (i e, di arr h e a, 
s ki n r as h, st o m atitis) t h at ar e i d e ntifi e d aft er t h e first 6 p ati e nts a n d a g ai n aft er 
1 2  p ati e nts h a v e c o m pl et e d C ycl e 1 : 
 > 3 3 %:  St o p C o h ort 2  ( ≥3 of 6 p ati e nts or ≥5 of 1 2 p ati e nts wit h Gr a d e 3 or 
gr e at er A Es of s p eci al i nt er est) a n d b e gi n C o h ort 3 .  
 ≤3 3 %:  K e e p e nr olli n g C o h or t 2 u ntil 3 0 p ati e nts ar e e nr oll e d a n d tr e at e d a n d n o 
a d diti o n al p ati e nts will b e e nr oll e d.  
 3 4 p ati e nts w er e e nr oll e d i nt o C o h ort 2  u n d er A m e n d m e nt 1 or A m e n d m e nt 2.  
C o h ort 3: 1 2 m g ( o n e 8 -m g t a bl et a n d t w o 2 -m g t a bl et o nc e d ail y) c o nti n u o us d osi n g  
 O nl y if C o h ort 2  is st o p p e d d u e t o t oxicit y. 
 N o p ati e nt w as e nr oll e d i nt o C o h ort 3 . 
T oxicit y ar e ass ess e d b as e d o n t h e gr a d e of t h e a d v ers e e v e nts usi n g C T C A E V ersi o n  4. 0 3.  
All tr e at m e nts ar e t a k e n or all y, o nc e d ail y ( Q D) at a p pr oxi m at el y t h e s a m e ti m e e a c h m or ni n g. 
O n D a y 1 of e ac h cycl e, t h e p ati e nt’s a bs ol ut e n e utr o p hil c o u nt ( A N C) m ust b e ≥1. 5x 1 0 9/L a n d 
pl at el et c o u nt m ust b e ≥1 0 0x 1 0 9/L b ef or e a d mi nist eri n g t h e n ext d os e of p ozi oti ni b. F or Cycl e 1 
o nl y, t h e A N C a n d pl at el et l e v els s h o ul d als o b e c o nfir m e d pri or t o t h e d os e o n D a y 8. D a y 1 of a 
n e w c ycl e is e q ui v al e nt t o D a y 2 2 of t h e pr e vi o us cycl e, wit h a wi n d o w of ± 3 d a ys f or t h e visit. If 
a visit is d el a y e d d uri n g 1 cycl e, t h e n all s u bs e q u e nt cycl es will b e d el a y e d s e q u e nti all y.  
All tr e at e d p ati e nts will b e f oll o w e d u p u ntil dis e as e pr o gr essi o n, d e at h, i nt ol er a bl e a d v ers e 
e v e nts or u p t o a m axi m u m of 2 4 m o nt hs w hic h ev er c o m es e arli er.  
3. 1  S a m pl e Siz e C o nsi d er ati o ns  
Ot h er i m p ort a nt tr e at m e nts f or H E R 2 -p ositi v e M B C i ncl u d e T -D M 1, l a p ati ni b -c a p ecit a bi n e 
c o m bi n ati o n, a n d n er ati ni b. P u blis h e d O R Rs r e p ort e d f or t h es e r e gi m e ns ar e 4 3. 6 %, 3 0. 8 %, a n d 
2 4 %, r es p ecti v el y [1 -3 ]. T h e p ur p os e of t his st u dy is t o e v al u at e t h e s af et y a n d effic acy of 
p ozi oti ni b a n d i d e ntif y t h e o pti m al d os e f or f ut ur e cli nic al d e v el o p m e nt.  
T h e ori gi n al pr ot oc ol i ncl u d e d t est of h y p ot h eses wit h a s a m pl e siz e of 7 0  as d escri b e d b el o w . 
F or t h e pri m ar y e n d p oi nt of O R R i n a si n gl e-ar m st u d y, t o t est t h e n ull h y p ot h esis ( h y p ot h esis 
of n o i nt er est i n  t h e st u dy) of 2 4 % ( P 0 = 0. 2 4) vs. t h e alt er n ati v e h y p ot h esis ( h y p ot h esis of 
i nt er est i n t h e st u d y) of 4 2 % ( P 1 = 0. 4 2), a s a m pl e siz e of 7 0 p ati e nts ac hi e v es 8 8 % p o w er t o 
d et ect a diff er e nc e ( P 1 -P 0) of 0. 1 8 usi n g a t w o  si d e d bi n o mi al t est. T h e t ar g et si g nific a nc e l e v el 
is 0. 0 5. T h e act u al si g nific a nc e l e v el ac hi e v e d b y t his t est is 0. 0 3 4 5. T h es e r es ults ass u m e t h at 
t h e p o p ul ati o n pr o p orti o n u n d er t h e n ull h y p ot h esis is P 0 = 0. 2 4. 
I n A m e n d m e nt 1, t w o l o w er d os e c o h orts w er e a d d e d t o d et er mi n e t h e o pti m al d os e r e gi m e n. 
T h e t est of h y p ot h es es w as  r e m o v e d, a n d t h e st u d y b ec a m e  a pr o of -of -c o nc e pt st u d y. A 
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
7  
sa m pl e siz e of 3 0 w as pr o p os e d f or C o h ort 2 . If C o h ort 2  w as st o p p e d d u e t o t oxicit y , a s a m pl e 
siz e of 2 0 p ati e nts w as  pr o p os e d f or C o h ort 3 .  
3. 2  R a n d o miz ati o n  
T his st u d y is n ot r a n d o miz e d. P ati e nts will b e e nr oll e d s e q u e nti all y. T h e e nr oll m e nt of C o h ort 2 
st arts aft er e nr oll m e nt of C o h ort 1 is c o m pl et e.  
3. 3  T u m or Ass ess m e nts  
T u m or ass ess m e nt m ust b e p erf or m e d b y I n v esti g at ors usi n g c o m p ut e d t o m o gr a p h y ( C T) or 
m a g n etic r es o n a nc e i m a gi n g ( M RI) at Scr e e ni n g  u p t o 3 0  d a ys pri or t o C ycl e 1 , D a y 1. I m a gi n g 
st u di es p erf or m e d pri or t o t h e si g ni n g of I nf or m e d C o ns e nt as p art of t h e sit e’s r o uti n e 
st a n d ar d of pr actic e ar e all o w e d at t h e discr eti o n of t h e S p o ns or.  
T u m or ass ess m e nts will b e p erf or m e d e v er y 6 w e e ks ( ± 1 4 d a ys) u ntil dis e as e pr o gr e ssi o n, 
d e at h, i nt ol er a bl e a d v ers e e v e nts, or f or u p t o 2 4 m o nt hs.  
E ac h s u bs e q u e nt t u m or ass ess m e nts m ust us e t h e s a m e B as eli n e r a di ol o gic t ec h ni q u e, eit h er 
C T or M RI. R es p o ns e e v al u ati o n will b e p erf or m e d usi n g R E CI S T crit eri a, V ersi o n 1. 1 [4 ]. F or 
r a di o gr a p hic ass ess m e nt, C T or M RI m ust b e p erf or m e d at e v er y ass ess m e nt.  
M e as ur a bl e a n d n o n -m e as ur a bl e l esi o ns t h at will n ot b e f oll o w e d b y r a di ol o gic al m et h o ds 
s h o ul d b e d oc u m e nt e d a p pr o pri at el y.  
3. 3. 1  B as eli n e T u m or Ass ess m e nts  
T u m or ass ess m e nt a n d m e as ur e m e nt at b as eli n e as w ell as p ost -b as eli n e will f oll o w t h e R E CI S T 
v 1. 1 crit eri a a n d will b e ev al u at e d b y t h e l oc al Pri nci p al I n v esti g at ors. At B as eli n e t u m or 
ass ess m e nt, u p t o 5 m e as ur a bl e l esi o ns ( m axi m u m of 2 l esi o ns p er or g a n)  r e pr es e nt a bl e of all 
i n v ol v e d or g a ns will b e i d e ntifi e d as t ar g et l esi o ns. T ar g et n o n-n o d al t u m or l esi o ns ( TLs) s h o ul d 
h a v e l o n g est di a m et er ≥1 0 m m a n d c a n b e m e as ur e d r e pr o d uci bl y. T ar g et l y m p h n o d es (L Ns) 
s h o ul d h a v e s h ort axis ≥1 5 m m. T h e s u m of di a m et er s ( S O D), w hic h is t h e s u m of t h e l o n g est 
di a m et er of all t ar g et TLs a n d t h e s h ort axis of all t ar g et L Ns, will b e c alc ul at e d as t h e r ef er e nc e 
b as eli n e v al u e f or t u m or r es p o ns e e v al u ati o n l at er i n t h e st u d y.  
All t h e ot h er TLs, p at h ol o gic al L Ns (s h ort axis ≥1 0 m m), a n d l esi o ns n ot m e as ur a bl e b y C T or M RI 
will b e i d e ntifi e d as n o n -t ar g et l esi o ns a n d t h e siz e of t h es e l esi o ns ar e n ot r ec or d e d f or t h e 
p ur p os e of f oll o w -u p.  
3. 3. 2  F oll o w -u p T u m or Ass ess m e nts  
T ar g et l esi o ns  ar e f oll o w e d b y t u m or siz e, l o n g est di a m et er of TLs a n d s h ort axis of L Ns, a n d 
S O D ar e c alc ul at e d f or r es p o ns e e v al u ati o n. At e ac h t u m or ass ess m e nt, t h e t u m or r es p o ns e of 
t ar g et l esi o ns is d et er mi n e d as b el o w. 
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
8  
 C o m pl et e R es p o ns e ( C R) : dis a p p e ar a nc e of all t ar g et TLs a n d all t ar g et L Ns wit h s h ort 
axis < 1 0 m m  
 P arti al R es p o ns e ( P R) : ≥3 0 % d ecr e as e i n S O D fr o m B as eli n e , a n d n ot P D (s e e b el o w) 
 Pr o gr essi v e Dis e as e ( P D) : ≥2 0 % i ncr e as e i n S O D fr o m pr e vi o us s m all est S O D o n st u d y, 
a n d a n a bs ol ut e i ncr e as e of ≥5 m m  
 St a bl e Dis e as e ( S D) : S O D c h a n g e n eit h er s uffici e nt f or  P R n or s uffici e nt f or P D  
 N ot E v al u a bl e ( N E) : n ot all t ar g et l esi o ns e v al u at e d, a n d e v al u at e d l esi o ns n ot s uffici e nt 
f or P D 
N o n -t ar g et l esi o ns ar e ass ess e d q u alit ati v el y wit h pr es e nt, a bs e nt or u n e q ui v oc al pr o gr essi o n 
a n d t u m or r es p o ns e is d et er mi n e d as b e l o w. 
 C o m pl et e R es p o ns e ( C R) : dis a p p e ar a nc e of all n o n-t ar g et TLs, n or m aliz ati o n of t u m or 
m ar k er l e v el, a n d all n o n -t ar g et L Ns wit h s h ort axis < 1 0 m m 
 N o n -C R/ N o n -P D : p ersist e nc e of a n y n o n-t ar g et l esi o n a n d/ or m ai nt e n a nc e of a b n or m al 
t u m or m ar k er l e v el  
 Pr o gr essi v e Dis e as e ( P D) : u n e q ui v oc al pr o gr essi o n (s u bst a nti al w ors e ni n g) of existi n g 
n o n -t ar g et l esi o ns 
 N ot E v al u a bl e ( N E) : n ot all n o n -t ar g et l esi o ns e v al u at e d  
 N ot A p plic a bl e ( N A) : n o n o n-t ar g et l esi o ns i d e ntifi e d at B as eli n e  
N e w l esi o ns  ar e t u m or l esi o ns t h at w er e n ot pr es e nt at B as eli n e . T h e fi n di n g of a n e w l esi o n 
s h o ul d b e u n e q ui v oc al, a n d t h e a p p e ar a nc e of n e w m ali g n a nt l esi o ns d e n ot es dis e as e 
pr o gr essi o n.  
3. 3. 3  Ti m e P oi nt R es p o ns e at E ac h T u m or Ass ess m e nt  
As s u m m ariz e d b el o w, t h e ti m e p oi nt r es p o ns e at e ac h f oll o w -u p t u m or ass ess m e nt ar e 
d et er mi n e d acc or di n g t o t h e e v al u ati o n of t ar g et l esi o ns, n o n -t ar g et l esi o ns, a n d n e w l esi o ns.  
T a bl e 1. D et er mi n ati o n of Ti m e P oi nt R es p o ns e  
T ar g et L esi o ns  
N o n -T ar g et L esi o ns  
N e w L esi o ns  
Ti m e P oi nt 
R es p o ns e  
C R  
C R or N A  
N o  
C R  
C R  
N o n -C R/ N o n -P D or N E  
N o  
P R  
P R  
A n y b ut P D  
N o  
S D  
A n y b ut P D  
N o  
S D  
P D  
A n y  
Y es or N o  
P D  
A n y  
P D  
Y es or N o  
A n y  
A n y  
Y es 1 
N E  
A n y b ut P D  
N o  
N E  
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
9  
1 If t h e fi n di n g of n e w l esi o n is e q ui v oc al, it s h o ul d b e c o nfir m e d fr o m n ext sc a n. 
4  A N AL Y SI S P O P UL A TI O N S  
T w o  a n al ysis p o p ul ati o ns h a v e b e e n d efi n e d as f oll o ws:  
 T h e E v al u a bl e P o p ul ati o n ( E P) c o nsists of all p ati e nts w h o ar e e nr oll e d, c o m pl et e at 
l e ast o n e cycl e of p ozi oti ni b tr e at m e nt, a n d h a v e at l e ast o n e e v al u a bl e p ost -b as eli n e 
t u m or r es p o ns e e v al u ati o n usi n g R E CI S T  crit eri a, V ersi o n 1. 1.  
 T h e S af et y A n al ysis P o p ul ati o n ( S A F) i ncl u d es all p ati e nts w h o si g n e d i nf or m e d c o ns e nt, 
e nr oll e d, a n d r ec ei v e d at l e ast o n e d os e of st u d y tr e at m e nt. All d e m o gr a p hics, B as eli n e 
c h ar act eristics, a n d s af et y d at a will b e a n al yz e d  usi n g t h e S AF p o p ul ati o n.  
5  S T A TI S T IC AL M E T H O D S O F A N AL Y SI S  
5. 1  G e n er al Pri nci pl es  
T h e st atistic al a n al ys es will b e r e p ort e d usi n g s u m m ar y t a bl es, fi g ur es, a n d d at a listi n gs. All 
a n al ys es a n d t a b ul ati o ns will b e p erf or m e d usi n g S A S ® V ersi o n 9. 3 or hi g h er. All t a bl es, listi n gs, 
a n d fi g ur es will b e v ali d at e d a n d r e vi e w e d b ef or e b ei n g fi n aliz e d.  
I n s u m m ar y t a bl es of c o nti n u o us v ari a bl es, t h e mi ni m u m a n d m axi m u m will b e pr es e nt e d t o 
t h e s a m e n u m b er of d eci m al pl ac es as t h e ori gi n al d at a. T h e m e a n, m e di a n, a n d 9 5 % 
c o nfi d e nc e i nt er v al ( CI) will b e pr es e nt e d t o o n e m or e d eci m al pl ac e t h a n t h e ori gi n al d at a. T h e 
st a n d ar d d e vi ati o n ( S D) a n d st a n d ar d err or ( S E) will b e pr es e nt e d t o t w o m or e d eci m al pl ac e 
t h a n t h e ori gi n al d at a. 
I n s u m m ar y t a bles of c at e g oric al v ari a bl es, c o u nt  a n d p erc e nt a g e will b e pr o vi d e d. I n g e n er al, 
p erc e nt a g e v al u es ar e t o b e pr es e nt e d t o w h ol e n u m b er if s a m pl e siz e ≤1 0 0; t o o n e d eci m al 
pl ac e if s a m pl e siz e is b et w e e n 1 0 0 a n d 1 0 0 0; a n d t o t w o d eci m al pl ac es if s a m pl e siz e  is 
gr e at er t h a n 1 0 0 0. A n y t est of c o m p aris o n p erf or m e d will b e 2 -si d e d at 5 % l e v el of si g nific a nc e 
u nl ess ot h er wis e s p ecifi e d.  
5. 1. 1  D efi niti o n  of B as eli n e V al u es  
B as eli n e v al u e s will b e d efi n e d as t h e m ost r ec e nt n o n -missi n g m e as ur e m e nt s c oll ect e d pri or t o 
t h e first d os e of p ozi oti ni b . If t h er e is m or e t h a n o n e v al u e o n or b ef or e t h e d at e of t h e first 
d os e  of p ozi oti ni b , t h e v al u es cl os est t o a n d pri or t o (i ncl u di n g o n) t h e d at e of t h e first d os e will 
b e us e d as t h e b as eli n e v al u e. C h a n g e  fr o m b as eli n e will b e d efi n e d as p ost-b as eli n e v al u e 
mi n us b as eli n e v al u e.  
5. 1. 2  H a n dli n g of M issi n g D at a  
Missi n g d at a will b e n ot i m p ut e d.   
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
1 0  
5. 1. 3  P o oli n g of C e nt ers  
D at a fr o m diff er e nt c e nt ers will b e c o m bi n e d f or t h e p ur p os e of t h e a n al ysis. T h e n u m b er of 
p ati e nts e nr oll e d  will b e pr es e nt e d b y st u d y sit e.  
5. 1. 4  I nt eri m A n al ysis 
T h er e will b e n o f or m al i nt eri m a n al ysis s p ecifi e d or c o n d uct e d i n t his st u dy. T h e d at a will b e 
p eri o dic all y r e vi e w e d f or q u alit y a n d c o m pl eti o n.   
5. 1. 5  T esti n g/ V ali d ati o n Pl a n  
S A S ® V ersi o n 9. 3  or hi g h er o n t h e Wi n d o ws s yst e m will b e us e d f or  cr e ati o n of T a bl es, Listi n gs, 
a n d Fi g ur e s. All t a bl es, listi n gs, a n d fi g ur es will b e v ali d at e d a n d r e vi e w e d b ef or e b ei n g 
fi n aliz e d. I n d e p e n d e nt pr o gr a m mi n g will b e c o n d uct e d t o v erif y t a bl es a n d listi n gs as 
a p pr o pri at e. T a bl es will b e r e vi e w e d f or acc ur ac y, c o nsist e ncy wit h t his pl a n, c o nsist e ncy wit hi n 
t a bl es, a n d c o nsist e ncy wit h c orr es p o n di n g o ut p uts. 
5. 2  B ac k gr o u n d C h ar act eristics  
All b ac k gr o u n d c h ar act eristics will b e s u m m ariz e d b y c o h ort a n d f or all p ati e nts . C orr es p o n di n g 
p ati e nt d at a listi n gs will b e pr o vi d e d.  
5. 2. 1  P ati e nt  Dis p ositi o n  
Dis p ositi o n of p ati e nts will b e s u m m ariz e d f or all e nr oll e d p ati e nts. T h e s u m m ar y d at a will 
i ncl u d e n u m b er ( %) of p ati e nt s i n S A F, i n E P, a n d w h o c o m pl et e d t h e st u dy (i. e., tr e at m e nt f or 
2 4  m o nt h s). T h e r e as o ns f or tr e at m e nt disc o nti n u ati o n a n d st u d y disc o nti n u ati o n will als o b e 
s u m m ariz e d. 
5. 2. 2  Pr ot oc ol D e vi ati o n  
T h e f oll o wi n g i m p ort a nt pr ot oc ol d e vi ati o ns will b e s u m m ariz e d wit h c o u nt a n d p erc e nt a g e.  
 P ati e nts e nt er e d t h e st u d y e v e n t h o u g h t h e y di d n ot s atisf y t h e e ntr y crit eri a.  
 P ati e nts d e v el o p e d wit h dr a w al crit eri a d uri n g t h e st u d y b ut w er e n ot wit h dr a w n.  
 P ati e nts r ec ei v e d t h e wr o n g tr e at m e nt or i nc orr ect d os e.  
 P ati e nts r ec ei v e d a n excl u d e d c o nc o mi t a nt tr e at m e nt. 
All pr ot oc ol d e vi ati o ns will b e pr o vi d e d i n p ati e nt d at a listi n gs.  
5. 2. 3  D e m o gr a p hic a n d B as eli n e C h ar act eristics  
D e m o gr a p hics a n d ot h er b as eli n e dis e as e c h ar a ct eristics will b e s u m m ariz e d usi n g d es cript i v e 
st atistics. T h e s u m m ar y will i ncl u d e , b ut  will  n ot  b e  li mit e d t o, a g e  ( as c o nti n u o us a n d 
c at e g oric al [ <6 5, ≥6 5  a n d  < 7 5, ≥7 5 ]), g e n d er, et h nicit y, r ac e, h ei g ht, w ei g ht,  b o d y m ass i n d ex, 
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
1 1  
E C O G p erf or m a nc e st at us , st a gi n g, h or m o n e r ec e pt or st at us , pri or H E R 2 t h er a p y  a n d pri or 
c a nc er t h er a p y (s ur g er y, r a di ati o n a n d c h e m ot h er a p y) .  
5. 2. 4  M e dic al Hist or y  
M e dic al hist or y i nf or m ati o n will o nl y b e pr o vi d e d  i n p ati e nt d at a listi n gs. 
5. 2. 5  C o nc o mit a nt M e dic ati o n  
A c o nc o mit a nt m e dic ati o n will b e d efi n e d as a n y m e dic ati o n t h at w as t a k e n eit h er o n t h e d a y 
of or aft er t h e a d mi nistr ati o n of t h e first d ose of p ozi oti ni b t hr o u g h t h e e n d of t h e st u d y. T his 
i ncl u d es m e dic ati o ns t h at st art e d pri or t o t h e i niti ati o n of t h e first d ose of p ozi oti ni b if t h e 
p ati e nt c o nti n u es usi n g it.  
F or all c o nc o mit a nt m e dic ati o ns, c o u nts a n d p erc e nt a g es of p ati e nts will b e pr es e nt e d b y 
m e dic ati o n cl ass a n d pr ef err e d n a m e c o d e d b y t h e W orl d H e alt h Or g a niz ati o n Dr u g dicti o n ar y  
(W H O Dr u g  E n h a nc e d S E P -2 0 1 5  B 2 ). P ati e nts wit h m or e t h a n o n e m e dic ati o n of t h e s a m e 
m e dic ati o n cl ass or pr ef err e d n a m e will b e c o u nt e d o nl y o nc e. P ati e nt d at a listi n gs will b e 
pr o vi d e d.   
 
5. 3  Effic ac y A n al ys es  
All effic acy e n d p oi nts will b e a n al yz e d b as e d o n t h e E v al u a bl e P o p u l ati o n f or e ac h c o h ort.  
5. 3. 1  B est O v er all R es p o ns e  
Si nc e t h er e is n o st atistic al t est of h y p ot h es es i n t his pr o of-of -c o nc e pt st u d y, t h e o v er all 
r es p o ns es will b e pr o vi d e d usi n g v ari o us crit eri a or ass ess m e nt.  T h e d et er mi n ati o n of ti m e 
p oi nt o v er all r es p o ns e will b e m a d e b y t h e l oc al sit e i n v esti g at or usi n g R E CI S T crit eri a , V ersi o n 
1. 1 . T h e d et er mi n ati o n of b est o v er all r es p o ns e ( B O R)  will b e s u m m ariz e d as b el o w.  
1.  P er I n v esti g at or A ss ess m e nt: B O R will b e s u m m ariz e d as r e p ort e d b y t h e l oc al 
i n v esti g at or.  T his i ncl u d es C R, P R, S D, P D or N E. Pl e as e n ot e t he f oll o wi n g:  
 S p ectr u m will n ot cr oss-c h ec k or d eri v e t h e r es p o ns es b as e d o n t u m or m e as ur e m e nt 
or ti m e p oi nt r es p o ns es as all B O R will b e as r e p ort e d b y t h e i n v esti g at or.  
 L oc al I n v esti g at or m a y n ot r e p ort a C R  o r P R as c o nfir m e d or u nc o nfir m e d , or S D 
a dj u dic at e d b as e d o n t h e d ur ati o n of tr e at m e nt  a n d will b e r e p ort e d as is.  
2.  P er S p o ns or D eri v ati o n : S p ectr u m will us e t h e d et ail e d t u m or d at a as r e p ort e d o n c as e 
r e p ort f or m s uc h as t u m or m e as ur e m e nts, l esi o n ass ess m e nt, d ur ati o n of tr e at m e nt, 
a n d c o nfir m ati o n sc a n t o d eri v e  t h e ti m e p oi nt r es p o ns e a n d B O R  usi n g R E CI S T  crit eri a, 
V ersi o n 1. 1 .  
 Ti m e  p oi nt r es p o ns e will b e d et er mi n e d as d escri b e d i n S ecti o n 3. 3. 2 a n d 3. 3. 3 .  
 B O R  wit h c o nfir m ati o n will b e  d e t er mi n e d as d escri b e d i n T a bl e 2 b el o w . 
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
1 2  
 B O R wit h o ut c o nfir m ati o n will n ot r e q uir e a c o nfir m ati o n sc a n f or C R /P R  or  ≥6 
w e e ks  o n -tr e at m e nt.  
 If t h er e is a ti m e p oi nt wit h missi n g t u m or m e as ur e m e nt, b ut t h e ti m e p oi nt 
r es p o ns e is a v ail a bl e fr o m sit e, t his ti m e p oi nt r es p o nse  will b e us e d f or  
d et er mi n ati o n of B O R  r e g ar dl ess of missi n g t u m or m e as ur e m e nt. 
T a bl e 1 . D et er mi n ati o n of C o nfir m e d B est O v er all R es p o ns e  
I niti al B est R es p o ns e (c a n 
st art at a n y visit) 
R es p o ns e at S u bs e q u e nt Visi t 
B est O v er all 
R es p o ns e  
C R  
C R 1 
C R  
P R  
P R 2 or u nc o nfir m e d C R 2 
P R  
P R  
S D ( n ot f oll o w e d by C R/ P R)  
S D  
S D  
S D or u nc o nfir m e d C R/ P R  
S D  
C R or P R or S D  
P D  
S D 3 or P D 4 
C R or P R or S D  
N E ( n o a d diti o n al ev al u a bl e visit)  
S D 3 or N E 4 
P D  
A ny  
P D  
N E  
N E ( n o a d diti o n al ev al u a bl e visit)  
N E  
1 C o nfir m ati o n sc a n n e e ds t o b e ≥4 w e e ks fr o m pr e vi o us sc a n, 1 i nt erv e ni n g N E is all o w e d.  
2 C o nfir m ati o n sc a n n e e ds t o b e ≥4 w e e ks fr o m pr e vi o us sc a n, 1 i nt erv e ni n g N E/ S D is all o w e d.  
3 If i niti al C R/ P R/ S D is ≥6 w e e ks o n-tr e at m e nt.  
4 If i niti al C R/ P R/ S D is < 6 w e e ks o n-tr e at m e nt. 
 
5. 3. 2  Pri m ar y Effic ac y E n d p oi nt  
O bj ecti v e R es p o ns e R at e ( O R R)  
O R R  is t h e pr o p orti o n of p ati e nts w h os e B O R  is C R or P R. V ari o us O R Rs, b as e d o n  P er 
I n v esti g at or Ass ess m e nt B O R,  P er S p o ns or D eri v ati o n B O R wit h c o nfir m ati o n, a n d P er S p o ns or 
D eri v ati o n B O R wit h o ut c o nfir m ati o n  as d escri b e d i n S ecti o n 5. 3. 1, will b e esti m at e d usi n g  
c o u nt, p erc e nt a g e a n d ex act  ( Cl o p p er-P e ars o n)  9 5 % CI . 
5. 3. 3  S ec o n d ar y Effic ac y E n d p oi nts  
Pr o gr essi o n -Fr e e S ur vi v al ( P F S)  
P F S is d efi n e d as t h e n u m b er of m o nt hs fr o m t h e tr e at m e nt st art d at e t o t h e d at e of 
d oc u m e nt e d dis e as e pr o gr essi o n or d e at h d u e t o a n y c a us e. P F S of li vi n g p ati e nts wit h o ut  
d oc u m e nt e d P D will b e c e ns or e d at t h e ti m e of l ast t u m or ass ess m e nt  or t h e d at e of first 
tr e at m e nt if t h er e is n o p ost-b as eli n e t u m or  ass ess m e nt.  
Distri b uti o n of P F S will b e esti m at e d usi n g t h e K a pl a n -M ei er m et h o d  i n t h e E v al u a bl e 
P o p ul ati o n . T h e m e di a n a n d q u artil es of P F S  a n d t h e P F S  r at e at 3, 6, 9 a n d 1 2 m o nt hs will b e 
r e p ort e d wit h c orr es p o n di n g 9 5 % CI. 
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
1 3  
Dis e as e C o ntr ol R at e ( D C R)  
D C R is t h e pr o p orti o n of p ati e nts w h os e B O R is C R, P R, or S D . V ari o us D C Rs , b as e d o n P er 
I n v esti g at or Ass ess m e nt B O R, P er S p o ns or D eri v ati o n B O R wit h c o nfir m ati o n, a n d P er S p o ns or 
D eri v ati o n  B O R wit h o ut c o nfir m ati o n as d escri b e d i n S ecti o n 5. 3. 1,  will b e esti m at e d usi n g  
c o u nt, p erc e nt a g e a n d ex act  ( Cl o p p er-P e ars o n)  9 5 % CI.  
Ti m e t o Pr o gr essi o n ( T T P)  
T T P is d efi n e d as t h e n u m b er of m o nt hs  fr o m t h e first d os e of st u d y dr u g t o t u m or pr o gr essi o n, 
w hic h excl u d es d e at h wit h o ut t u m or pr o gr essi o n, b y t h e e n d of st u d y.  T T P of p ati e nts w h o di e 
wit h o ut  d oc u m e nt e d P D will b e c e ns or e d at d at e of d e at h . T T P of li vi n g p ati e nts wit h o ut  
d oc u m e nt e d P D is ce ns or e d at t h e s a m e ti m e as P F S , w hic h is t h e l ast t u m or ass ess m e nt  or t h e 
d at e of first tr e at m e nt if t h er e is n o p ost -b as eli n e t u m or  ass ess m e nt . 
Distri b uti o n of T T P will b e esti m at e d usi n g t h e K a pl a n -M ei er m et h o d  i n t h e E v al u a bl e 
P o p ul ati o n . T h e m e di a n a n d q u artil es of T T P  a n d t h e T T P  r at e at 3, 6, 9 a n d 1 2 m o nt hs will b e 
r e p ort e d wit h c orr es p o n di n g 9 5 % CI. 
D ur ati o n of R es p o ns e ( D o R)  
D o R will b e e v al u at e d o nl y f or p ati e nts w h o s e B O R is  C R or P R a n d is d efi n e d as t h e ti m e (i n 
m o nt hs) fr o m t h e d at e t h at r es p o ns e e v al u ati o n crit eri a ar e first m et f or C R or P R ( w hic h e v er 
st at us is r ec or d e d first) u ntil t h e first s u bs e q u e nt d at e t h at P D or d e at h is d oc u m e nt e d. D o R of 
p ati e nts wit h o ut d oc u m e nt e d P D or d e at h will b e c e ns or e d at t h e ti m e of l ast t u m or 
ass ess m e n t. 
Distri b uti o n of v ari o us D o R s will b e esti m at e d usi n g t h e K a pl a n -M ei er m et h o d . T h e m e di a n a n d 
q u artil es of D o R a n d t h e D o R r at e at 3, 6, 9 a n d 1 2 m o nt hs will b e r e p ort e d wit h c orr es p o n di n g 
9 5 % CI.  
5. 3. 4  S u b gr o u p A n al ysis  
A n al ysis of  t h e pri m ary a n d s el ect e d s ec o n dar y  effic acy e n d p oi nts will b e p erf or m e d f or t h e f oll o wi n g 
s u b gr o u ps: 
 
p ati e nts by t ot al li n es of pri or t h er a py ( 2 li n es, 3 li n es, > = 4  li n es);  
 
p ati e nts w h o r ec eiv e d pri or tr e at m e nt of p ert uz u m a b i n a d diti o n t o tr ast uz u m a b a n d T -D M 1 ; 
 
p ati e nts w h o r ec eiv e d at l e ast o n e pri or tr e at m e nt wit h  t yr osi n e ki n as e i n hi bit or ( T KI) f or H E R 2 
(l a p ati ni b a n d n er ati ni b). 
5. 4  S af et y A n al ys es  
All s af e a n al ys es will b e r e p ort e d b as e d o n t h e S af et y P o p ul ati o n f or e ac h c o h ort.  
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
1 4  
5. 4. 1  Dr u g E x p os ur e  
T h e ext e nt of ex p os ur e t o p ozi oti ni b  will b e s u m m ariz e d wit h d escri pti v e st atistics usi n g  t h e 
f oll o wi n g p ar a m et ers: 
 D ur ati o n of tr e at m e nt: n u m b er of d a ys b et w e e n first d os e a n d l ast d os e of p ozi oti ni b, 
i ncl usi v e (i. e. d a ys diff er e nc e b et w e e n first d os e a n d l ast d os e + 1). 
 N u m b er of cycl es tr e ate d  
 D a ys of tr e at m e nt a d mi nist er e d  
 R el ati v e d os e i nt e nsit y ( R DI) : t h e p erc e nt a g e of pl a n n e d d os e t h at e ac h p ati e nt act u all y 
r ec ei v e d d uri n g t h e st u dy. T h e pl a n n e d d os e is d efi n e d as t h e d os e t h at w o ul d b e gi v e n 
if n o d os es w er e miss e d a n d n o d os e r e d ucti o ns w er e m a d e f or t h e n u m b er of cycl es ( 2 8 
d a ys p er cycl e)  f or t h e d ur ati o n of tr e at m e nt r e g ar dl ess of t h e n u m b er of cycl es act u all y 
a d mi nist er e d. T h us,  
R DI = 1 0 0 ∗
t ot al d o s e  a d mi ni st e r e d
3 3 6 ∗[i nt e g e r of  ( d a y s  diff e r e n c e  b et w e e n  fi r st d o s e  a n d  l a st d o s e
2 1
) + 1 ]  
 Last d os e l e v el : t h e l ast d os e is ass u m e d t o b e t h e l o w est d os e l e v el pr escri b e d b y 
i n v esti g at or 
 N u m b er of d os e r e d ucti o n  
 N u m b er a n d p erc e nt a g e of p ati e nts wit h  n o r e d ucti o n , or wit h d os e r e d ucti o n t o 1 6 m g  
( C o h ort 1 o nl y), 1 2 m g, 1 0 m g a n d 8 m g.  
 St u d y d a y of first d os e r e d ucti o n 
 S t u d y d a y a n d d ur ati o n of first dr u g i nt err u pti o n 
5. 4. 2  A d v ers e E v e nts  
A n A E is d efi n e d as a n y u nt o w ar d m e dic al occ urr e nc e i n a p ati e nt or cli nic al i n v esti g ati o n 
p ati e nt, t e m p or all y ass oci at e d wit h t h e us e of a m e dici n al pr o d uct, w h et h er or n ot c o nsi d er e d 
r el at e d t o t h e m e dici n al pr o d uct. All A Es t h at occ ur fr o m t h e first d os e of st u d y tr e at m e nt 
t hr o u g h 3 5 ( ± 5) d a ys aft er t h e l ast d os e of st u d y tr e at m e nt is a d mi nist er e d will b e r ec or d e d o n 
t h e A E C R F. Fr o m t h e ti m e t h e st u d y I nf or m e d C o ns e nt is si g n e d t hr o u g h t h e first d os e of st u d y 
dr u g a d mi nistr ati o n, o nly s eri o us A Es ( S A Es) t h at ar e r el at e d t o st u d y pr oc e d ur es will b e 
r ec or d e d. 
A Es will b e c o d e d usi n g t h e M e dic al Dicti o n ar y of R e g ul at or y Acti viti es ( M e d D R A, V ersi o n 1 8 . 0) 
a n d will b e cl assif i e d b y M e d D R A s yst e m or g a n cl ass ( S O C) a n d pr ef err e d t er m ( P T). All A Es will 
b e cl assifi e d f or s e v erit y b y t h e I n v esti g at or acc or di n g t o t h e d efi niti o ns s et f ort h b y t h e 
C o m m o n T er mi n ol o g y Crit eri a f or A d v ers e E v e nts ( C T C A E V ersi o n 4. 0 3).  
All A E t a bl es wil l b e pr es e nt e d wit h n u m b er a n d p erc e nt a g e of p ati e nts. A E listi n gs will i ncl u d e 
p ati e nt I D, g e n d er, a g e, r ac e, A E v er b ati m t er m a n d pr ef err e d t er m, A E st art d at e a n d e n d d at e, 
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
1 5  
A E d ur ati o n, C T C A E gr a d e, if t h e A E is S A E or n ot, r el ati o n t o st u d y dr u g, st u d y  dr u g acti o n, 
o utc o m e, a n d if tr e at m e nt is gi v e n.  
O nl y tr e at m e nt -e m er g e nt A Es ( T E A E), as d efi n e d i n S ecti o n 5. 4. 2. 2, will b e s u m m ariz e d i n 
t a bl es. S A Es r e p ort e d pri or t o tr e at m e nt b ut aft er i nf or m e d c o ns e nt will o nl y b e pr o vi d e d i n A E 
listi n gs. 
5. 4. 2. 1  O v er all S u m m ar y  
A n o v er all s u m m ar y  t a bl e of T E A Es will  b e pr o vi d e d. T h e s u m m ar y will i ncl u d e a n y T E A E, T E A E 
b y s e v erit y , a n y tr e at m e nt-r el at e d A E, tr e at m e nt-r el at e d A E b y s e v erit y, S A Es, a n d A Es l e a di n g 
t o st u d y dr u g disc o nti n u ati o n. 
5. 4. 2. 2  Tr e at m e nt E m er g e nt A d v ers e E v e nts  
T E A Es ar e A Es t h at occ ur fr o m t h e first d os e of st u d y tr e at m e nt u ntil 3 5 ( ± 5) d a ys aft er t h e l ast 
d os e of st u d y tr e at m e nt. If it c a n n ot b e d et er mi n e d w h et h er a n A E is tr e at m e nt -e m er g e nt 
( b as e d o n st art d at e or, if t h e st art d at e is missi n g t h e n b as e d o n th e st o p d at e), t h e n t h e A E 
will b e c o nsi d er e d tr e at m e nt -e m er g e nt.  
S u m m ar y of T E A Es b y M e d D R A S O C a n d P T will b e pr es e nt e d i n a s e p ar at e t a bl e wit h a n y gr a d e 
a n d wit h Gr a d e 3 or 4. P ati e nts w h o ex p eri e nc e m or e t h a n o n e t y p e of A E will b e c o u nt e d 
u n d er e ac h  of t h e c orr es p o n di n g P Ts. P ati e nts w h o ex p eri e nc e diff er e nt e pis o d es of t h e s a m e 
A E will b e c o u nt e d o nl y o nc e u n d er t h e c orr es p o n di n g P T. Si mil arl y, f or d et er mi n ati o n of 
M e d D R A S O C i nci d e nc es, p ati e nts w h o ex p eri e nc e m ulti pl e A Es u n d er t h e s a m e S O C will b e 
c o u nt e d o nl y o nc e f or t h at S O C. Listi n g of all T E A Es will als o b e pr o vi d e d.  
5. 4. 2. 3  Tr e at m e nt -R el at e d A d v ers e E v e nts  
Ass ess m e nt of r el at e d n ess t o st u d y dr u g f or all A Es will b e cl assifi e d b y i nv esti g at ors a n d 
r e p ort e d. “ D efi nit el y r el at e d”, “ pr o b a bl y r el at e d” a nd “ p ossi bl y r el at e d” A Es will b e c o nsi d er e d 
as tr e at m e nt r el at e d. A n A E will b e assi g n e d as tr e at m e nt -r el at e d if t h e r el ati o ns hi p t o st u d y 
dr u g is missi n g.  
T h e i nci d e nc es of tr e at m e nt -r el at e d A Es will b e pr es e nt e d b y M e d D R A S O C a n d P T wit h a n y 
gr a d e a n d wi t h Gr a d e 3 or 4.  
5. 4. 2. 4  S eri o us A d v ers e E v e nts  
S A Es ar e d efi n e d ( 2 1 C F R 3 1 2. 3 2, I C H of T ec h nic al R e q uir e m e nts f or R e gistr ati o n of 
P h ar m ac e utic als f or H u m a n Us e E 2 A G ui d eli n e) as t h os e A Es t h at m e et a n y of t h e f oll o wi n g 
crit eri a:  
 R es ults i n d e at h.  
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
1 6  
 Is lif e-t hr e at e ni n g: i e, a ny e v e nt t h at, i n t h e o pi ni o n of t h e I n v esti g at or, p os es a n 
i m m e di at e ris k of d e at h fr o m t h at e v e nt.  
 R e q uir es i n p ati e nt h os pit aliz ati o n or pr ol o n g ati o n of existi n g h os pit aliz ati o n ( excl u di n g 
h os pit aliz ati o ns f or st u d y t h er a p y, dis e as e -r el at e d pr oc e d ur es, or pl ac e m e nt of a n 
i n d w elli n g c at h et er, u nl ess ass oci at e d wit h ot h er S A Es).  
 R es ults i n a p ersist e nt or si g nific a nt dis a bilit y/i nc a p acit y.  
 R es ults i n a c o n g e nit al a n o m al y/ birt h d ef ect.  
 I ncl u d es i m p ort a nt m e dic al e v e nts t h at m a y n ot b e i m m e diat el y lif e t hr e at e ni n g or 
r es ult i n d e at h or h os pit aliz ati o n b ut m a y j e o p ar diz e t h e p ati e nt or m a y r e q uir e 
i nt er v e nti o n t o pr e v e nt o n e of t h e o utc o m es list e d i n t his d efi niti o n.  
Listi n g of all S A Es will b e pr o vi d e d . T r e at m e nt-e m er g e nt S A Es a n d tr e at m e nt-r el at e d S A Es will 
b e s u m m ariz e d b y M e d D R A S O C a n d P T wit h a n y gr a d e a n d wit h Gr a d e 3 or 4 .  
5. 4. 2. 5  M a xi m u m S e v erit y of A d v ers e E v e nts  
T E A E s a n d tr e at m e nt -r el at e d A Es will b e s u m m ariz e d b y M e d D R A S O C, P T , a n d m axi m u m 
C T C A E s e v erit y gr a d e. A Es  wit h a miss i n g s e v erit y gr a d e will n ot b e i ncl u d e d i n t h es e a n al ys es. 
P ati e nts w h o ex p eri e nc e t h e s a m e e v e nt at m or e t h a n o n e s e v erit y l e v el will b e c o u nt e d o nl y 
o nc e u n d er t h e m axi m u m s e v erit y l e v el. T h e o v er all a d v ers e e v e nt i nci d e nc es will als o b e 
pr es e nt e d i n t h e s e t a bl es as a r ef er e nc e. 
5. 4. 2. 6  Ot h er I m p ort a nt A d v ers e E v e nts  
A Es l e a di n g t o d e at h a n d st u d y dr u g disc o nti n u ati o n will b e pr es e nt e d i n s e p ar at e listi n gs a n d 
t h e i nci d e nc e will b e s u m m ariz e d i n t h e o v er all s u m m ar y of T E A E t a bl e. 
5. 4. 2. 7  A d v ers e E v e nts of S p eci al I nt er e st 
S u m m ary of T E A Es, tr e at m e nt -r el at e d A Es, a n d S A Es f or di arr h e a, r as h, st o m atitis, a n d p n e u m o nitis by 
M e d D R A P T  will b e pr o vi d e d i n s e p ar at e t a bl es wit h a ny gr a d e a n d wit h Gr a d e 3 or 4. St u dy d ay of first 
i nci d e nc e f or di arr h e a, r as h, a n d st o m atitis will b e s u m m ariz e d usi n g m e di a n a n d r a n g e.  R as h of s p eci al 
i nt er est will b e r e p ort e d as c oll ectiv e of m ulti pl e P Ts  r el at e d t o r as h, i ncl u di n g r as h, d er m atitis 
ac n eif or m, r as h m ac ul o -p a p ul ar , etc. S i mil arly, st o m atitis of s p eci al i nt er est will b e r e p ort e d as c oll ecti v e 
of m ulti pl e P Ts r el at e d t o st o m atitis, i ncl u di n g st o m atitis a n d m uc os al i nfl a m m ati o n . 
5. 4. 3  L a b or at or y P ar a m et ers  
Cli nic al l a b or at or y s a m pl es will b e c oll ect e d at scr e e ni n g a n d t hr o u g h o ut t h e st u d y. T h e cli nic al 
l a b or at or y v al u es will b e cl assifi e d acc or di n g t o t h e N CI C T C A E V ersi o n 4. 0 3. T a bl es of s hifts i n 
s e v erit y a n d i n cli nic al a b n or m alit y fr o m b as eli n e t o w orst p ost-b as eli n e o n st u d y , f or k e y 
l a b or at or y p ar a m et ers, will b e pr o vi d e d.  
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
1 7  
5. 4. 4  Vit al Si g n D at a  
A s u m m ar y of r a w v al u es a n d c h a n g e s fr o m b as eli n e v al u es will b e pr o vi d e d at e ac h sc h e d ul e d 
ti m e p oi nt f or t h e f oll o wi n g m e as ur e m e nts : b o d y t e m p er at ur e, s yst olic a n d di ast olic bl o o d 
pr ess ur e, a n d h e art r at e.  A listi n g of all v al u es will als o b e i ncl u d e d.  
5. 4. 5  E C O G P erf or m a nc e St at us  
D escri pti v e st atistics will b e pr es e nt e d f or E C O G sc or es at b as eli n e. T h e n u m b er a n d p erc e nt a g e 
of p ati e nts wit h s hifts fr o m b as eli n e E C O G sc or e ( 0, 1, or 2) t o t h e  w orst  p ost -b as eli n e E C O G 
sc or e ( 0, 1, 2, 3, or 4) will b e s u m m ariz e d.  
5. 4. 6  C ar di ac Ass ess m e nt  
C ar di ac ass es s m e nt will b e pr o vi d e d i n t h e d at a listi n gs. 
 
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5


S pectr u m P h ar m ace utic als, I nc.  
St atistic al A n al ysis Pl a n  
P ozi oti ni b  
Pr ot oc ol N u m ber: S PI -P O Z -2 0 1  
C o nfi d e nti al  
1 8  
6  R E F E R E N C E S  
1.  
V er m a S, Mil es D, Gi a n ni L, Kr o p I E, W elsl a u M, B as el g a J, et al. Tr ast uz u m a b E mt a nsi n e 
f or H er 2-P ositi v e A d v a nc e d Br e ast C a nc er. N E n gl J M e d. 2 0 1 2; 3 6 7( 1 9): 1 7 8 3 -9 1.  
2.  
B urst ei n HJ, S u n Y, Dirix L Y, Ji a n g Z, P ari d a e ns R, T a n A R, et al. N er ati ni b, a n Irr e v ersi bl e 
Er b b R ec e pt or T yr osi n e Ki n as e I n hi bit or, i n P ati e nts wit h A d v a nc e d Er b b 2 -P ositi v e 
Br e ast C a nc er. J Cli n O nc ol. 2 0 1 0; 2 8( 8): 1 3 0 1 -7.  
3.  
C a m er o n D, C as e y M, Oliv a C, N e wst at B , I m w all e B, G e y er C E. L a p ati ni b Pl us 
C a p ecit a bi n e i n W o m e n wit h H E R -2 -P ositi v e A d v a nc e d Br e ast C a nc er: Fi n al S ur vi v al 
A n al ysis of a P h as e III R a n d o miz e d Tri al. O nc ol o gist. 2 0 1 0; 1 5( 9): 9 2 4 -3 4.  
4.  
Eis e n h a u er E A, T h er ass e P, B o g a erts J, Sc h w artz L H, S ar g e nt D , F or d R, et al. N e w 
R es p o ns e E v al u ati o n Crit eri a i n S oli d T u m o urs: R evis e d R ecist G ui d eli n e ( V ersi o n 1. 1). 
E ur J C a nc er. 2 0 0 9; 4 5( 2): 2 2 8 -4 7.  
 
 
D o c u Si g n E n v el o p e I D: 4 6 0 8 D 4 3 3- 8 B A 2- 4 B E 9- 9 8 8 9- 3 6 3 5 D B A A C 4 4 5